CA1330441C - Process for trans-6-[2-(substituted-pyrrol-1-yl) alkyl] pyran-2-one inhibitors of cholesterol synthesis - Google Patents

Abstract

ABSTRACT
An improved process for the preparation of trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where 1,6-heptadien-4-ol is converted in eight operations to the desired products, as well as an improved process for the preparation of (2R-trans) and trans-(?)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide by a novel synthesis where 4-methyl-3-oxo-N-phenylpentanamide is converted in eight operations to the desired product or alternatively 4-fluoro-.alpha.-[2-methyl-1-oxopropyl]-?-oxo-N,.beta.-diphenylbenzenebutaneamide is converted in one step to the desired product, and additionally, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide from (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, as well as other valuable intermediates used in the processes.

Description

13~47 ,. , BACKGROUND OF THE INVENTION

United States Patent 4,647,576 discloses certain trans-6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2-ones.
,o United states Patent 4,681,893 discloses certain trans-6-[2-~3- or 4-carboxamido-substituted pyrrol-l-yl)alkyl]-4-hydroxy-pyran-2-ones.
The compounds disclosed in the above Ullited States patents are useful as inhibitors of the e~zyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents. Particularly valuable as hypolipidemic and hypocholesterolemic agents are trans(~) 5-(4-fluorophenyl)-2-(1-methylethyl)-N,4~
diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2E~-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide and (2R-trans)-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-di~ ellyl-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl~- ~
25 lH-pyrxole-3-carboxamide. The aforementioned -compounds have been prepared by a linear synt~letic - route which employed two reactions conducted at low temperatures (-78C) under carefully controlled conditions. The two reactions included the addition of the dianion of ethyl acetoacetate to an aldehyde and thè reduction of the hydroxy ketone produced in ~ this reaction with sodium borohydride and a i ~ trialkylborane. Although these reactions provide the !'.' ': target compounds in high diastereomeric excess, they ,.
: '~

~; 1' ~'' ~ `
~ X

1 3 3 ~

are difficult to conduct on large-scale and use expen-~, sive reagents which are difficult to handle. They also do not produce enantiomerically pure products. The !,, materials produced by the earlier methods can be i 5 separated into enantiomerically pure products but the process is very expensive, time-consuming, and results in the loss of more than 50% of the starting material.
The object of the present invention is an improved process for preparing the compounds described above by using a novel synthesis.
Further, we have unexpectedly found that the particularly valuable hypolipidemic and hypocholestero-lemic agents trans(~)5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide and (2R-_rans)-5-(4-fluorophenyl)-2-(1-methylethyl) N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- :
-~ yl)ethyl]-lH-pyrrole-3-carboxamide can be prepared from a novel intermediate in fewer steps and higher yields than the previous methods. Moreover, the present method proceeds from inexpensive starting materials and is amenable to large-scale synthesis.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of Formula I
OH

-CH2CH2 ~

, .,~A 2'f~

1 3 3 ~

and a dihydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of a compound of Formula I
' wherein R1 is l-naphthyl, 2-naphthyl, cyclohexyl.
~1 cyclohexylmethyl, 31 norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, j~ bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, ; alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide;
R2 or R3 is independently : 25 hydroyen, ~-~: alkyl of from one to six carbon atoms, . cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ~; phenyl, ..
~: phenyl substituted with fluorine, ~:

:~

1330~1 - 4 ;:

chlorine, bromine, hydroxyl, .
trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or -CONR5R6 where Rs and R~ are independently hydrogen, , alkyl of from one to 6iX carbon atoms, , phenyl, `
phenyl substituted with ~ fluorine, j` ~ 15 chlorine, bromlne, cyano, or trifluoromethyl;
R4 is : 20 alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, ;~ cyclohexyl, or trifluoromethyl;
which comprises:
(a) reacting 1,6-heptadien-4-ol with an (l). alkyl .lithium (2) followed by iodine and carbon dioxide `~ 30 and ~: ~ (3) treating the resulting iodocarbonate .~ intermediate in situ with a base in an ~
'~ aqueou~ alcohol at about 0C to about 40C -``::~ to afford a compound of Formula IX;
,.~
,' ~

, ~
., ` ` ~330~

OH
CH2C--CH2 CH = C H2 H H

IX

(b) treating the compound of Formula IX with (1) an alkali cyanide at about O~C to about 40C and (2) reacting the resulting diol intermediate in situ with a ketal-forming reagent in the presence of an acid to afford ~: . a compound of Formula VIII

R~XR8 NC -H2C~ CH2CH = CH2 ` ' H H

VIII

~ 10 wherein R7 and R8 are independently hydrogen, i';~ alkyl of from one to three carbon atoms, phenyl :-~ or R7 and R8 taken together as - (CH2)n~, wherein : n is 4 or 5; ~- -(c) treating the compound of Formula VIII with ~ 15 (1) ozone in an inert solvent and :
.; (2) reacting the resulting intermediate in ,;~ situ with oxygen and triphenylphosphine at bout -20C to about -78C to afford a compound of Formula VII
.~
,,'~;
,i~

~-1330~

; r , .' 7VR~ . .
0~0 0 NC--H2C ~ CH2--CH
H H
~, VII

wherein R7 and R8 are as defined above;
.~ (d) treating the compound of Formula VII with an :i oxidizing reagent at about 0c to afford a compound of Formula VI
, ~:~ R7 R8 ~ oXo :
^. ~ NC--H2C ~ CH2C02H
H H
.
~i: VI
: ::
.:; ;; ~ wherein R7 and R8 are as defined above;
(e) treating the compound of Formula VI with a :
compound of Formula '~ ' 10 Hal-Rga ;; wherein Hàl is halogen and Rga is alkyl of from one to eight carbon atoms or a three- to six-membered cycloalkyl group, in the presence of a base to afford a compound of Formula Va i~

~ ,. ~ ~

~330~
.

.

.
s X
' o O
C-H2C ~ cH2cO2R9a H H
f ~ .
J Va wherein R7, R8, and Rga are as defined above;
. or treating the compound of Formula VI with a compound '~f of Formula ::
HO-Rgb wherein Rgb is tertiary butyl, tertiary amyl, or a, a- -~
dimethylbenzyl in the presence of an activating agent, a catalytic amount of a base and an inert solvent to afford a compound of Formula V
:~ b R7 Rs '~ 0~0 ', ~ ' NC-H2C~CH2CO2Rgb H H
,~
Vb :
wherein R7, R8, and Rgb are as defined above;
2 '~ ~ (f) treating the compound of Formula Va with hydrogen if ;,~.' in the presence of a catalyst and an acid at about 0C
h ~ to about 70C to afford a compound of Formula IVa '~
. ,~, a~

1330~

R7x Q O
H2NcH2cH2 ~ cH2co2Rga H H
IVa s wherein R~, R8, and Rga are as defined above, or treating the compound of Formula Vb with hydrogen in the presence of a catalyst and an acid or a catalyst and a base at about 0C to about 70C to afford a compound of Formula IVb R7 R~
~ o~<o ':
I
H2NCH2CH2~CH2Co2R9b H H -~i`'., . ~, b ::
~- wherein R7, R8, and Rgb are as defined above;
(g) treating the compound of Formula IVa with a ~ compound of Formula III
j:'~.' 10 .. 3 ~ ~ ll ll Rl-C-CH-CH-C-R4 ~-' wherein Rl, R2, R3, and R4 are as defined above in an inert solvent to afford a compound of Formula IIa ,:, ~

1, .' ~ ~ , .

1330~

.. :.

R2 ~( Ro7XRo8 ~ N-CH2CH2 ~ CH2C02Rsa ~ .
~1 . IIa wherein Rl, R2, R3, R4, R7, R8, and Rga are as defined , above, or treating the compound of Formula IVb with a compound of Formula III in an inert solvent to afford ~: 5 a compound of Formula IIb ~: R R7XR8 R2 ~( O O : :
)~ ~N--CH2CH2~CH2CO2Rgb , ~ R4 ~` IIb "~
.. wherein Rl, R2, R3, R4, R~, R8, and Rgb are as defined . above;
~h) and finally treating a compound of Formula IIa with ~ (.1) an acid in the presence of an inert solvent ;r ~ (2) followed by hydrolysis with a base ~ -~
! 'i;~ ~ (3) followed by neutralization with an acid and :.
(4) dissolution and/or heating in an inert solvent with concomitant removal of water to give ~. a compound of Formula I, ,~;~ or treating a compound of Formula IIb with l ,, ~ - -~ ,~

'~ :.

133~

(1) an acid in the presence of an inert solvent (2) followed by addition of a base (3) followed by neutralization with an acid and (4) dissolution and/or heating in an inert solvent with concomitant removal of water to give a compound of Formula I;
(i) and if desired converting the resulting compound of Formula I to a dihydroxy acid corresponding to the opened lactone ring of structural Formula I by conventional hydrolysis and further, if desired converting the dihydroxy acid to a correspondiing pharmaceutically acceptable salt by conventional 1. means, and if so desired converting the corresponding pharmaceutically acceptable salt to a dihydroxy acid ,~ 15 by conventional means, and if so desired converting ¦ the dihydroxy acid to a compound of Formula I by heating in an inert solvent.
A second aspect of the present invention is an ~; improved process for the preparation of the compound 3~ 20 of Formula I
a OH

~: N CH(CH3)2 ; ~C--O

~ a ., ~
and the hydroxy acid and pharmaceutically acceptable ~ ;
; salts thereof, corresponding to the opened lactone ring of the compound of Formula Ia which comprises:

~;~
:
. ~ .
,;`~

1 3 ~

--11-- . .

~ (a) reacting the compound of Formula XVII

"~ ~ o o i~ F ~ C-CH - lH-c-CH(cH3)2 ~ ~3 1=
NH

XVII
. ::
with a compound of Formula ' ~

~ , o o H2NCH2CH2 ~ CH2C02Rl3 ' ~
~ H H
;,~
: :
, i wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n~ wherein n is 4 or 5 and ~ : CH3 ~ `~Rl3 is hydrogen or -C -CH3 in an inert solvent and r /~ CH3 10 treating the resulting intermediate with an acid to ::
afford the compound of Formula Ia ~.
(b) and if desired, converting the resulting ~compound of Formula Ia to a hydroxy acid corresponding ht ~to the opened lactone ring of structural Formula Ia by , ~15 conventional hydrolysis and further, if desired, converting the hydroxy acid to a corresponding ~pharmaceutically acceptable salt by conventional ,i~ ! ~ :means, and if so desired, converting the hydroxy acid ~ ``~to a compound of Formula Ia by dissolution and/or 1330~

heating in an inert solvent with concomitant removal of water.
A third aspect of the present invention is an improved process for the preparation of t.he compound of Formula Ia OH

and the hydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of the compound of Formula Ia which comprises (a) reacting 4-methyl-3-oxo-N-phenylpentanamide with benzaldehyde in the presence of a catalyst and an inert solvent to afford the compounds of Formula XVIII

~ ~ o ~

;~
~ XVIII

.~

E

1330~

(b) reacting the compounds of Formula XVIII with 4-fluorobenzaldehyde in the presence of a catalyst, a base, and an inert solvent to afford the compound of Formula XVII

,~ o o F~C--CH--CH-C--CH (CH3) 2 XVII ~:~

(c) reacting the compound of Formula XVII with a compound of Formula !~
~
;: f OR1o ~ NH2CH2CH2-CH
j: 10 OR
:
wherein R1o and R11 are alkyl of one to eight carbon atoms or R1o and R11 together are -CH2-CH-, -CEI2-CH2-:~: CH3 or -CH2-CH2--CH2- in the presence of a catalyst and an inext solvent to afford a compound of Formula XVI
:~

CH2CH2-c~o . ~ ~ CH~CH3)2 ~ ~f=o NH

:~

. ~ . ". ~

., ~ ", :~.,; " ; .~ j ,, . . :, .: , .: ~ . -.. : ~ ~ :
,~j ~,,,,.,,",. : " ~, ~',',-; ~,, ,',.. ,`.' ' ' ' ~

~ 3 3 0 ~ ~ ~

. wherein Rlo and Rll are alkyl of one to eight carbon atoms or Rlo and Rll together are -CH2-CH-, -CH~CH2-or -CH.2-CH2-CH2-, (d) and finally converting a compound of Formula XVI in a conventional manner to afford a !, compound of Formula I
(e) and if desired, converting the resulting compound of Formula Ia to a hydroxy acid corresponding to the opened lactone ring of structural Formula Ia by conventional hydrolysis and further, if desired, converting the hydroxy acid to a corresponding pharmaceutically acceptable salt by conventional ~: means, and if so desired, converting the hydroxy acid 15 to a compound of Formula Ia by dissolution and/or ..
heating in an inert solvent with concomitant removal of water.
A fourth aspect of the present invention is a !' . novel intermediate of Formula II
, :
:

N CHzCH2 ~ CHzCo2R9 ~ H H

.- 20 II
, ~ .
:~:
`~ wherein Rg is alkyl of from one to eight carbon atoms, ~: a three to six-membered cycloalkyl group or a,a-dimethylbenzyl and Rl, R2, R3, R4, R7, and R8 are ~; as defined above, which iD useful in the preparation of inhibitors of cholesterol biosynthesis of Formula I.
"~
, ~ ~

l ~ ,, ,' ,., ,.'." ' `

~' - i33a~

A fifth aspect of the present invention is a novel intermediate of Formula XVI
.

F ~ CH2CH2--CH
~ ~--CH ~CH3 ) 2 ~f=
, NH

XVI

wherein Rlo and Rl1 are alkyl of one to eight carbon atoms or R1o and R1l together are -CH2-CH-, or -CH2CH2CH2- which is useful in the preparation of the inhibitor of cholesterol biosynthesis of Formula Ia.
A sixth aspect of the present invention is a novel intermediate of Formula IV
j:~

: R7 X R8 ": O O
~ H2NcH2cH2~cH2co2 l :~ H H
~ ,. .. .. . ..
~ IV
, ~
wherein R7, R8, and Rg are as defined above, which is useful in the preparation of a compound of Formula II, which in turn is useful in the preparation of ~; 15 inhibitors of cholesterol biosynthesis of Formula I. ~.

:
-~

1330~1 A seventh aspect of the present invention is a novel intermediate of Formula XXI

o o NH2-CH2CH2~CH2C02H
H H
I XXI

:~ wherein R7 and R~ are independently hydrogen, alkyl of i, 5 from one to three carbon atoms, phenyl or R7 and R8 .~ are taken together as -(C~2)n~, wherein n is 4 or 5, .~ which is useful in the preparation of the inhibitor of cholesterol biosynthesis of Formula Ia.
An eighth aspect of the present invention is a ~.
novel intermediate of Formula V
:~

, X

NC--H2C~CH2CO2Rg ~:
;~ H H

~ V
f ~wherein R7, R8, and Rg are as defined above, which is useful in the preparation of a compound of Formula IV, which in turn is useful in the preparation of a .~:~15 compound of Formula II, which in turn is useful in the preparation of inhibitors of cholesterol biosynthesis -~ of Formula I.
~:
;
' ,~ .

r~ .~:,'3'~ "" ,~," r,~

~ . ' ' . ~i . ~ ~ . ~ . ' , ~ ; ' i "

133~4~
.

A ninth aspect of the present invention is a novel intermediate of Formula VI
., R~Ra o o '' NC~2C~CH2CO2H
H H
VI
.~ .
whereln R7 and R8 are as defined above; which is , 5 useful in the preparation of a compound of Formula V, I which in turn is useful in the preparation of a ~:~ compound of Formula IV, which in turn is useful in the :
preparation of a compound of Formula II, which in turn is useful in the preparation of inhibitors of ~.
lO cholesterol biosynthesis of Formula I.
A tenth aspect of the present invention is a novel intermediate of Formula VII
~ ~: R~<R8 ' O O
. NC-H2C ~ CH2-CH
.~ ~ ~
VII
.
. ' wherein R7 and R8 are as defined above, which is : 15 useful in the preparation of a compound qf Formula V!I, which in turn is useful in the preparation of a ; compound of Formula V, which in turn is useful in the preparation of a compound of Formula IV, which in turn is useful in the preparation of a compound of Formula II, wh~ich in turn is useful in the preparation . ~ of inhibitors of cholesterol biosynthesis of Formula I.

1 ~ :
~ .~

133~

1%-- ....

An eleventh aspect of the present invention is a I novel intermediate of Formula VIII

R7 Rs . 0~0 NC-H2C~CH2CH=CH2 i H H
VIII

, wherein R7 and R8 are as defined above, which is useful in the preparation of a compound of Formula VII, which in turn is useful in the preparation of a compound of Formula VI, which in turn is useful in the preparation of a compound of Formula V, which in turn is useful in the preparation of a compound of Formula IV, which in turn is useful , in the preparation of a compound of Formula II, which in turn is useful in the preparation of inhibitors of cholesterol biosynthesis of Formula I.
A twelfth aspect of the present invention is the novel intermediate of Formula XVII
.,.,' ,~ O -:.
F~=~ C--CH--CH-C--CH (CH3) 2 1~1 I H ~
".:~ :
~ XVII
~ .
which is useful in the preparation of a compowld of Formula XVI, which in turn is useful in the ;"' .~ ~
~y ~,, i'~ ~ ' ' ' ~ ,- "~,"

~`- 133~
.

--19-- , ., .
; preparation of the inhibitor of cholesterol biosynthesis of Formula Ia~
- A thirteenth aspect of the present invention is ; the novel intermediates of Formula XVIII

:, ` H~
C=C-C-CH(CH3)2 i, ~f=
i . ~ NH

XVIII
,`,~j which are useful in the preparation of the compound of Formula XVII, which, in turn, is useful in the preparation of a compound of Formula XVI, which, in turn, is useful in the preparation of the inhibitor of ; 10 cholesterol biosynthesis of Formula Ia. ~:

DETAILED DESCRIPTION OF THE INVENTION
, In this invention, the term "alkyl" means a straight or branched hydrocarbon group having from one ;`
~: to eight carbon atoms and includes, for example, ~:
: 15 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ; tertiary-butyl, n-pentyl, tertiary-amyl, n-hexyl, _-heptyl, n-octyl, and the like. -` "Cycloalkyl" refers to a three- to six-membered l} saturated hydrocarbon ring and includes, for example, :
J` m~' 20 cyclobutyl, cyclopentyl, cyclohexyl, and the like.
. ~ "Alkoxy" is O-alkyl in which alkyl is as defined above.
. ~:
,:
~:~
,~

,' ~

133~

"Alkanoyloxy" is an alkyl group, as defined above, attached to a carbonyl group and thence, through an oxygen atom, to the parent molecular } residue.
"Carboalkoxy" is an alkyl group, as defined above, attached to an oxygen atom and thence, through a carbonyl group, to the parent molecular residue.
"Norbornenyl" is a group derived by the removal of a hydrogen atom (other than at a bridgehead carbon atom) from bicyclo[2.2.1]hept-2-ene.
"Halogen" is iodine, bromine, and chlorine.
"Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
;'Alkaline-earth metal" is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, and the like.
"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like.
~ 20 A preferred compound of Formula I prepared by the -~ improved process of the present invention is one wherein R1 is 1-naphthyl, norbornenyl, phenyl, or phenyl substituted with i fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms.
- Also preferred is a compound of Formula I
prepared by the improved process of the present invention wherein R4 is alkyl of from one to `~j ~ six carbon atoms, cyclopropyl, or trifluoromethyl.
.
~ .

1330~

Particularly preferred compounds of Formula I
prepared by the improved process of the presellt invention are the following:
trans-6-[2-[2-(4-fluorophenyl)-S-(trifluoromethyl)-lH-pyrrol-l-yl]ethyl]tetrahydro-4-hydroxy-2EI-pyran-2-one;
trans-6[2-[2-(4-fluorophenyl)-5-methyl-lEI-pyrrol-l-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-lH-pyrrol-l-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-lH-pyrrol-l-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluoro- `
phenyl)-lH-pyrrol-l-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-:: phenyl)-5-methyl-lH-pyrrol-l-yl]ethyl]-2H-2-one; ~ - trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-phenyl)-5-(1-methylethyl)-lH-pyrrol-l-yl]ethyl]-2H-pyran-2-one;
~: 20 trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1- ~`naphthalenyl)-lH-pyrrol-l-yl]ethyl]-2H-pyran-2-one; .-~ trans-6-[2-(2-bicyclo[2.2.1]hept-5-en-2-yl-5-:~ methyl-lH-pyrrol-l-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans(i)-5-(4-fluorophenyl~-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-` pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide;
~ (2R)-trans)-5-(4-fluorophenyl)-2-(lrmethylethyl)-: N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide;
trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetra-hydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-trifluoro-methyl-lH-pyrrole-3-carboxamide;
trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetra-hydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-trifluoro-. ~ methyl-lH-pyrrole-3-carboxamide; and .
,~

~330~
.

-22~

a dihydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of compounds of structural Formula I.
,1 As previously described, the compounds of Formula I are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG
CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents.
The process of the present invention in its first 10 aspect is a new, improved, economical, and commercially : .
feasible method for preparing HMG CoA reductase ~ inhibitors of Formula I. The process of the present ';~ invention in its first aspect is outlined in Scheme I:

; :' ~ .
~ .
: :
~: ;
," ~ .
,, "~

-.:
';

":
:;, `/ ~

., ~ -:
'r ~
.,!: ~,~
.~
.
, . ~
~

,i~ . ~

-- ~3~0~1 , SCHEME I

OH _ _ : ~:
I O O
H2C=CHCH2-CH--CH2cH=cH2 I--CH2 ~ CH2CH=CH2 ~

XI X

: I ~

¦ R7XR8 O OH
,~ NC--H2c~cH2cH=cH2 ~CH2C--CH2CH=CH2 :~ H H H H
VIII IX
: :
1, 1 :

; NC-HzC~CH~--C8 ' NC-HzC~CH~C02H

.~ j ~ VI I VI
., i, ~

., ;.

'~ R7 R8 R~XR8 ;

H2NCH2CH2~CH2Co2R9a (Rsb) ~ - NC~H2C~CH2C02Rga (Rsb) H H H H ~`
~ Iva (Rga) Va (R9a) 4 ~ ~ IVb (Rgb) Vb (R9b) . 1330~1 SCHEME I ( continued ) . R7 R8 oXo NC-CH2 ~ CH2C02H
H H
V~
~, ' / \ ' NCCH2~ 2 2 , 3 H2NCH2CH2~CHzCO2H

H H
XXV XXI
~ I

~3~ ' R, X R8 O 1) CH3 H2NcH2cH2~cH2co2--~C--CH3 : H H CH3 ~:
~ XXIII
,, . , .
, ~
;

~: :
'1' ~
,. '' :::
''':
.
":~
~:

~ 330'~1 -25- :

A compound of Formula IX is prepared from the known 1,6-heptadien-4-ol (XI) using the methodology described by Bongini, A., et al, Jouxnal of Organic : Chemistry, 47, pp 4626-4633 (1982) and Majewski, M., et al, Tetrahedron Letters, 25, pp 2101-2104 (1984).
~ Thus, the homoallylic alcohol (XI) is reacted with an !' alkyl lithium such as, for example, _-butyllithium followed by iodine and carbon dioxide to give the iodocarbonate (X) at -35C to -20C which is not isolated but treated in situ with a base such as an alkali or alkaline-earth metal hydroxide or carbonate, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, and the like, in an aqueous alcohol of from one to three carbon atoms such as, for example, methanol, ethanol, isopropanol, and the like, at about 0C to about 40C, to afford the epoxide of Formula IX. Preferably the reaction is ~; carried out with potassium carbonate in aqueous methanol at about 0C to about 40C, preferably 0C.
The epoxide ring of Formula IX is opened with either potassium or sodium cyanide in an aqueous alcohol such ~:~ as, for example, methanol, ethanol, tertiary butanol, ~ ~:
isopropanol, and the like, at about 0C to about 40C.
25 Preferably the reaction is carried out with potassium :-cyanide in aqueous isopropanol at about 25C. The resulting diol intermediate is not isolated but treated in situ with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxy-~i ,~ 30 propene, benzaldehyde, cyclopentane, cyclohexanone, dimethoxycyclopentane, l,l-dimethoxycyclohexane, r~ ~ I and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic .~ acid, and the like, in the presence of excess reagent ~: 35 or in an inert solvent such as, for example, dichloromethane, and the like, at about 0C to the .~ , jy ~r ~

- ~L330~

-~6-reflux temperature of the reagent or solvent to afford a compound of Formula VIII, wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n~, wherein n is 4 or 5. A compourld of Formula VIII is treated with ozone in an inert solvent such as, for example, dichloromethane and the like, and the resulting intermediate ozonide which is not isolated is flushed in situ with oxygen to remove the ozone and then treated with triphenylphosphine or dimethyl sulfide at about -20C to about -78C, preferably about -78C, to afford a compound of Formula VII, wherein R7 and R8 are as defined above.
A compound of Formula VII is treated with an oxidizing 15 reagent such as, for example, chromium trioxide- ~ -~ sulfuric acid~water, and the like, at about 0C to ¦~ afford a compound of Formula VI, wherein R7 and R8 are as defined above. A compound of Formula VI is treated with a compound of Formula 9a wherein Hal is halogen such as, for example, iodine, . chlorine, bromine, and Rga is alkyl of from one to `~ 25 eight carbon atoms, or a three- to six-membered cycloalkyl group, preferably isopropyl, isobutyl, and the like in the presence of a base such as, for example, 1,8-diazabicyclo[5.4.0~undec-7-ene (DBU), and the l~ke to afford a compound of Formula Va, wherein R7, R8, and Rga are as defined above. Additionally, treating the compound of Formula VI with a compound of Formula 3SH0-Rgb wherein R9b is tertiary butyl, tertiary amyl, or a,~-dimethylbenzyl in the presence of an activating agent such as, for example, dicyclohexylcarbodiimide, . ~

.,'.",..`,'.',...'' ''`' ' '',' - , , ., ...,Ø., ~ ~330~ ~

carbonyldiimidazole and the like in the presence of a base such as, for example, 4-dimethylaminopyridine and the like in an inert solvent such as, for example, dichloromethane, tetrahydrofuran, and the like to afford a compound of Formula Vb, wherein R~, R8, and Rgb are as defined above. A compound of Formula Va is j treated with hydrogen in the presence of a catalyst ., such as a noble metal, for example, platinum, palladium, rhodium, ruthenium, derivatives thereof, and the like, or Raney nickel, preferably platinum dioxide, and an acid, such as, for example, acetic acid, propanoic acid and the like, preferably acetic acid, at about 0C to about 70C and about 14 to about 100 pounds per square inch pressure to afford a compound of Formula IVa, wherein R7, R8, and Rga are as defined above. Additionally, a compound of Formula Vb is treated with hydrogen in the presence of a catalyst such as a noble metal, for example, platinum, palladium, rhodium, ruthenium, derivatives thereof, and the like, and an acid such as, for example, acetic acid, propanoic acid and the like, or a catalyst such as, for example, Raney nickel, Raney cobalt and the like, in an inert solvent such as, for ~`~ example, methanol, ethanol, isopropanol, tetrahydro- -~
y j~ 25 furan and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide or aqueous sodium hydroxide, preferably the reaction is carried out with Raney!nickel in methanol saturated with anhydrous ammonia at about 0C to about 70C and 30 about 14 to about 100 pounds per square inch pressure to afford a compound of Formula IVb, wherein R7, R8, and Rgb are as defined above. Raney nickel and Raney cobalt as described above are finely divided forms of nickel and cobalt.
~ .
~ '~
j~s ~

~ ~ "

1 3 ~

.- -28-A compound of Formula XXI is prepared by treating a compound of Formula VI
., R7 ~R~ v 0~0 NCCH2 ~ CH2CO2H
H H

wherein R7 and R8 are as defined above with hydrogen ;! 5 in the presence of a catalyst such as, for example, Raney nickel, Raney cobalt and the like in finely .~ divided form, in an inert solvent such as, for example, methanol, ethanol, isopropanol, tetrahydrofuran and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide solution or a catalyst such as, for example, platinum, ~:
: palladium and the like, in an inert solvent such as, ~ :
for example, methanol, ethanol, isopropanol, tetrahydrofuran and the like in the presence of an ~;
~`: 15 acid such as, for example, acetic acid, propanoic acid and the like, at about 0C to about 70C and about 14 to about 100 pounds per s~uare inch pressure to afford ::
. a compound of Formula XXI. ~ ::
A compound of Formula XXIII is prepared from a ::
20 compound of Formula XXV ~
~ .
:
'~ O o :
, ~ NCCH2 ~ CH2C02- C~CH3 . H H CH8 s ~
!.: :, ''~ XXV "
.i `~ wherein R7 and R8 are as defined above using the methodology previously described for preparing a h ~ compound of Formula XXI from a compound of Formula VI.
;~, y ~ ~ ~

` ~330~ -29-A compound of Formula XXV i5 prepared by treating a compound of Formula VI

R7~< 8 O O
NCCH2~ CH2C02H
H H
VI

wherein R7 and R8 are as defined above and tertiary butyl alcohol with a coupling reagent such as, for example, dicyclohexylcarbodiimide and the like in the presence of a base such as, for example, 4-dimethyl-aminopyridine and the like in an inert solvent such as, for example dichloromethane and the like to afford a compound of Formula XXV.
An optically active (R) compound of Formula XXIIIa is prepared as outlined in Scheme II. The starting material (R)-4-cyano-3-[[(l,l-dimethylethyl)dimethyl-silyl]oxy]butanoic acid of Formula XXIX is synthesized starting from isoascorbic acid using syntheses well ' known to pxactitioners of the art. This chemistry is identical to that disclosed in United States Patent 4,611,067 (Merck & Co. Inc.) using ascorbic acid which produces (S)-4-cyano-3-[[(1,1-dimethylethyl)dimethyl-silyl]oxy]butanoic acid.
., ''6"~, U.S. Patent 4,611,067 apparently incorrectly assigned the configuration R to the product of this sequence of reactions starting with ascorbic acld.

, ~,~
, ~

~330~

SCHEME I I
s ICH3 ICH3 CH3-Si - CH3 CH3-~-CH3 o CH3-Si - CH3 Nac-cH2cHcH2co2H ,CH3 XXIX CH
~ XXVIII

s H
CH H H
N--CCH2CHCH2COCH2CO2--C--CH3 - ~ N3CCH2CHCH2CHCH2C02--C--CH3 ~- XXVII CH3 XXVI CH3 ' ~':
, -- N = CCH3C~_,f-CH3C03- C-CH3 _ N7 X H, ; XxVa XXIIIa l ~

'i~

. ~~ ~ :-.
.."~
!~

',~ ~

~ '? ~
r,. ,,~
:b l33a44~

.
Thus, the optically active compounds are prepared tt from the known isoascorbic acid using the methodology described by Volante R. P. et al, in United States Patent 4,611,067 but in that case starting with 5 ascorbic acid. This establishes the optically active j centers desired in Formula XXVa and Formula XXIIIa as : R. Thus, the (R)-4-cyano-3-~[(1,1-dimethylethyl)-dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0C to -40C, preferably -20C, warmed to 25C and the , activated acid derivative is not isolated but the solution is added to a suspension of a salt of j 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid ~ 15 (half ester, half salt) anhydrous magnesium chloride, :
j: and an amine such as, for example, diisopropylethylamine in acetonitrile at -10C to 20C preferably at 5C.
. The mixture is poured into a mixture of lN hydrochloric .:~ acid and ethyl acetate to afford the (R)-1,1-dimethyl-;~ 20 ethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-:~: 3-oxohexanoate of Formula XXVIII. The ketone of : Formula XXVIII i8 treated wit.h fluoride ion at 0C to ~ 65C, preferably 25C to afford the (R)-l,1-dimethyl-,~ ethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of ~;: 25 Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and : methanol in tetrahydrofuran at -78C to -110C, preferably -100C to afford [R-(R*,R*)]-1,1-dimethyl-ethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI.
The diol of Formula XXVI is treated with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, ~, ~t ~ cyclopentanone, cyclohexanone, 1,1-dimethoxycyclo-~,'t`~ , 35 pentane, 1,1-dimethoxycyclohexane and the like, in the ;::~ presence of an acid such as, for example, camphorsulfonic b ." ~ ~ .
~"'; ' 1 3 3 ~
. -32-acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at oC
to the reflux temperature of the reagent or solvent to 5 afford a compound of Formula XXVa wherein R~ and R8 î are independently hydrogen, alkyl of from one to s'. three carbon atoms, phenyl or R~ and R8 are taken together as -(CH2)n~, wherein n is 4 or 5.
A compound of Formula XXVa is treated with 10 hydrogen gas in an alcohol such as methanol saturated with anhydrous ammonia or aqueous ammonium hydroxide ~ in the presence of a catalyst such as Raney nickel or :;~ Raney cobalt or with a nobel metal catalyst such as J~ platinum oxide in the presence of an alkanoic acid 15 such as acetic acid to afford a compound of Formula XXIIIa, wherein R7 and R8 as defined above.
Additionally, an optically active compound of ~: Formula IVa or Formula IVb may be prepared starting from the optically active epoxide of Formula IX. The :~: 20 preparation of the optically active epoxide of`
Formula IX is described by Kocienski, P. J., et al, Journal of the Chemical SocietY Perkin Transaction I, . pp 2183-2187 (1987).
The process of preparing a compound of Formula I
2J is outlined in Scheme III:
,~
~ ~ .
~ . '; ' ' : :
~'~
`~
;. .~
, ~
;, ~ , :, ~ .~
i~ ,s~.~

3 ~

SCHEME I I I

R7~<R~
o o g O
H2NCH2CH2~CH2Co2Rsa (Rgb) + Rl--C--CH--CH--C R4 IVa~Rga) III
IVb (Rgb) ¦

.~ ' , æ

~(N~CH2CH2~CH2C2Rga (Rgb) R3/~( H H
R4 :.
:,,.,~ ` ~' IIa (Rsa) I I b ( Rsb ) N CH2CH2 ~

'!~ ~

, .
~ 3 3 ~

A compound of Formula IVa or Formula IVb i5 reacted with a compound of Foxmula III, -~. wherein R~ is 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, ; 10 phenyl substituted with ~-~
~ fluorine, j chlorine, ¦ bromine, hydroxyl, : 15 trifluoromethyl, -alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or . : alkanoyloxy of from two to eight carbon ~: atoms, ~:~ 20 benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide;
~: R2 or R3 is independently hydrogen . , . ~: 25 alkyl of from one to six carbon atoms, '. ~ cyclopropyl, cyclobutyl, cyclopentyl, :~ cyclohexyl, phenyl, phenyl substituted with fluoxine, ; ~ chlorine, ~: bromine, ; 35 hydroxyl, ~' ~330~
-35~

trifluoromethyl, r alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or -CONR5R6 where R5 and R6 are independently ~ hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with , fluorine, i, chlorine, bromine, cyano, or trifluoromethyl;
R4 is :~ alkyl of from one to six carbon atoms, ~: cyclopropyl, - cyclobutyl, cyclopentyl, cyclohexyl, or trifluoromethyl;
in an inert solvent such as, for example, toluene, and ~:
the like, at the reflux temperature of the solvent to give a compound of Formula IIa, or Formula IIb, wherein R1, R2, R3, R4, R~, R8, Rga and Rgb are as defined above. Finally, a compound of Formula IIa is treated with an acid such as, for example, aqueous : hydrochloric acid, and the like, in an inert solvent ~;30 such as, for example, tetrahydrofuran, followed by hydrolysis with a base such as, for example sodium "~hydroxide. The reaction is neutralized with an acid such as, for example, agueous hydrochloric acid and dissol~ed and/or heated in an inert solvent such as, ~^~35 for example, toluene, and the like, with concomitant ,~

~ i :: ;; :: '': : ~ : ::::'': : ':' ~ : : ' ~; ' :, '`"` 1330~

removal of water to give a compound of Formula I
wherein R1, R2, R3, and R4 are as defined above.
Additionally, a compound of Formula IIb i8 treated with an acid such as, for example, aqueous hydrochloric acid, and the like, in an inert solvent such as, for example, tetrahydrofuran and the like for about 15 hours, followed by the addition of a base such as, for example, sodium hydroxide and the like and stirred for about 30 hours. The reaction is reacidified with an acid such as, for example, aqùeous hydrochloric acid and dissolved and/or heated in an inert solvent such as, for example, toluene and the like, with concomitant removal of water to give a compound of Formula I, wherein R1, R2, R3, and R~ are as defined above.
The process of the present invention in its ~;~ second aspect is a new, improved, economical, and commercially feasible method for preparing the HMG CoA
reductase inhibitor of Formula Ia. The process of the present invention in its second aspect is outlined in - Scheme IV:
. ..
:~
~:~
~ :

: , ., , l ~
l ~

,.~:

.. ,",",,,.,".. ",,,,,,,,,,,,,,,~

133~fl~

SCHEME IV

R7 R8 R7 Ra 0~0 0~<0 NH2-CH2CH2~CH2CO2HNH2-CH2CH2~CH2Co2--$--CH3 X~YI XXI I I

F~3C--CH--CH-C--CH (CH3) 2F~3C--CH--~CH-C--CH (CH3) 2 b c o b NH ~
¦ ~ XVII XVII ~ ~

~ 0~O ~ r ~ CN2C02--C--C; ~
f=o f=o , ~ ~ NH ~3 ~ NH

LYIV

` ~ ~C=O

Ia ~3 ,'` ' ~.
~::

133B~

The compound of Formula XVII is reacted with a compound of Formula XXI

',~ , 0~<0 NH2-CH2CH2~ CH2Co2H

XXI

, wherein R7 and R8 are independently hydrogen, alkyl of ,3~ 5 from one to three carbon atoms, phenyl or R~ alld R8 are taken together as -(CH2)n~ wherein n is 4 or S in the presence of an inert solvent such as, for example, dimethyl sulfoxide and the like for about 15 hours at about 105C with the removal of water to afford the intermediate derivative ~XXII). Preferably the reaction is carried out in dimethyl sulfoxide for about 15 hours at about 105C. The intermediate derivative XXII, which is not isolated, is treated with an acid such as, for example, concentrated 15 hydrochloric acid and the like in an inert solvent : .
: such as, for example, ethyl acetate and the like to ~ afford the compound of Formula Ia. Preferably, the :~ reaction is carried out with concentrated hydrochloric acid in ethyl acetate.

: ~:

`~:

.. ~
,~ ~
`~1 `.'~
.`i 13~0~

? Additionally, the compound of Formula XVII is reacted with a compound of Formula XXIII

~, , `i O O
H2NCH2CH2~cH2c02--C--CH3 .?
~? XXIII
wherein R7 and R8 are independently hydrogen, alkyl or 5 from one to three carbon atoms, phenyl or R7 and R8 -~ are taken together as -(CH2)n-, wherein n is 4 or 5 in the presence of an inert solvent or solvents such as, ~- for example, hexane, toluene and the like for about 24 hours at about the reflux temperature of the -~
~: 10 solvent or solvents. The intermediate derivative XXIV, which is not isolated, is treated with an acid such as, for example, a 10% aqueous solution of hydrochloric acid for about 15 hours, followed by the ~: addition of a base such as, for example, sodium .~ 15 hydroxide and the like and reacidification with an ~ ~ acid for about 30 hours to afford the compound of ;~ Formula Ia.
The process of the present invention in its third aspect is a ne~, improv~ed, economical, and .
20 commercially feasible method for preparing the ?~MG CoA
.~: reductase inhibitor of ~ormula Ia. The process of the `~ present invention in its third aspect is outlined in ~.` '~ Scheme V:
,.. ~
i `.,~
,~
.~, ~

,- ~ 3", ~ " ;, j-, ; , ,,, ,~, 'ii ''' '' ;''~ ' ::~?: i:

~33~

¦ N
O=1Olp,, ~ ~ :

9' o ~ z ~ ~~ ` ~

~( N ~ ~
OaOOr ~ ~ b ~ ~

. , .

~ ` .......

4-Methyl-3-oxo-N-phenylpentanamide (XIX) is obtained by heating a mixture of methyl 4-methyl-3-oxopentanoate (Xx), aniline and ethylene diamine in toluene. 4-Methyl-3-oxo-N-phenylpentanamide (XIX) is subsequently reacted with benzaldehyde in the presence `j of a catalyst such as, for example, piperidine and glacial acetic acid, ethylene diamine and glacial -; acetic acid, ~-alanine and glacial acetic acid, and the like in an inert solvent such as, for example, toluene, heptane, hexane, and the like for about 24 to about 36 hours at about 60 to about 120C with the removal of water to afford 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (XVIII). Preferably the reaction is carried out with ~-alanine and glacial acetic acid at reflux for about 24 hours in hexane.
The 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)-~-~ pentanamide (XVIII) is reacted with 4-fluorobenz-aldehyde in the presence of a catalyst such as, for example, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium ~; ~ iodide, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride, and the like, and a base such as, for example, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diaza-bicyclo[2.2.2]octane (DABC0), 4-dimethylaminopyridine (DMAP), N,N,N',N'-tetramethylethylenediamine (TMEDA) and the like, either neat or in the presence of a solvent such as, for example, tetrahydrofuran, tertiary-butyl methyl ether, ethanol, dimethyl-i~ formamide, dimethylsulfoxide, N-methylpyrrolidone, '~i~ acetonitrile, methylisobutyl ketone, ethyl acetate, isopropanol, pyridine and the like for about 20 to ~ about 30 hours under anhydrous conditions at about `~35 room temperature to about the reflux temperature of ~ the solvent to afford the compound of Formula XVII.
,' ~

133~

Preferably the reaction is carried out in the presence of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and triethylamine in ethanol at about 75-80C
for about 24 hours. The compound of Formula XVII is reacted with a compound of Formula , ORl o OR

wherein R1o and R1l are alkyl of one to eight carbon atoms or R1o and R11 together are -CH2-CH-, -CE~2CH2-'" CH3 ~, or -CH2CH2CH2- in the presence of a catalyst of `~ Formula wherein Rl2 is CH3, CF3, ClCH2-, C6HscH2cH2-~ C6HsCH2~, ;. H02CCH2-, H02CCH2CH2-, C6H5-, ~ Cl-C6H5-, ClCH2CH2-, : meta-H3C-C6H5-, para-H3C-C6H5-, tertiary-C4H9- or .~, triet,hylamine hydrochloride and a solvent or mixtures , ,~: thereof such as, for example, tetrahydrofuran, hexane, toluene, ethanol, tertiary-butyl acetate, ethyl acetate, 1,2-dichloroethane, isopropanol, dimethyl , sulfoxide and the like for about 24 to about 48 hours at about 5C to about the reflux temperature of the solven~ with the removal of water to aff~rd a compound of Formula XVI. Preferably, the reaction is carried ` ~: out in the presence of pivalic acid and a mixture of , ,'~ toluene and heptane at reflux for about 48 hours with . ~ the removal of water. A compound of Formula XVI is converted in a conventional manner using the methodology disclosed in United States Patent 4,681,893 to the compound of Formula Ia.
.::
,,,, ,-~

;` ;~

~33~

Certain of the compounds of Formula III are either known or capable of being prepared by methods known in the art. The ring-opened dihydroxy acids of formula "
,, .

R2 ~ ~ C2H
)~N--CH2CH2 t~ OH

:~ R3 \ 4 H ~ .
.~ .

wherein R~, R2, R3, and R4 are as defined above may be prepared from the lactone compounds of Formula I by conventional hydrolysis such as, for example, sodium hydroxide in methanol, sodium hydroxide in tetrahydro-furan-water, and the like, of the lactone compounds of Formula I.
The ring-opened dihydroxy acid of Formula XII may be produced from the lactone compound of Formula Ia by conventional hydrolysis of the lactone compound of Formula Ia.
In the ring-opened dihydroxy acid form, compounds of the present invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases. The term "pharmaceutically acceptable metal salt" contemplates ; 20 salts formed with the sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. The term "pharmaceutically acceptable amine salt" contemplates salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids.
` 25 Bases useful for the formation of pharmaceutically acceptable nontoxic base addition salts of the compound of the present invention form a class whose .
:~

',---` 133~4~1 I limits are readily understood by those skilled in the j art.
The dihydroxy free acid form of the compounds of the invention may be regenerated from the salt form, 3 5 if desired, by contacting the salt with a dilute j aqueous solution of an acid such as hydrochloric acid.
The ring closed lactone form of the compounds of the invention may be regenerated by dissolution of the dihydroxy acid form of the compounds of the invention l 10 in an inert solvent such as, for example, toluene, !, benzene, ethyl acetate, and the like, at about 0C to about the boiling point of the solvent usually but not 1 necessarily with concomitant removal of the resulting i water and usually but not necessarily with strong acid 15 catalysis such as, for example, concentrated hydrochloric acid and the like.
The base addition salts may differ from the free acid forms of the compounds of this invention in such physical characteristics as solubility and melting 20 point, but are otherwise considered equivalent to the free acid form for the purposes of this invention.
The compounds of the present invention may exist in solvated or unsolvated form and such forms are equivalent to the unsolvated form for the purposes of 25 this invention.
The compounds of structural Formulas I, Ial and XII above possesses two asymmetric carbon centers, one at the 4-hydroxy position of the pyran-2-one ring, and the other at~the 6-position of the pyran-2-one ring 30 where the alkylpyrrole group is attached. This asymmetry gives rise to four possible isomers, two of -~ which are the 4R,6S and 4S,6R-isomers and the other ;-~ two of which are the 4R,6R and 4S,6S-isomers. The preferred isomer in this invention is the 4R,6R-isomer r~ 35 of the compounds of Formulas I, Ia and XII above.
~: ~
,`, ,;, : ~
.,, r ~

-133~

The following nonlimiting examples illustrates the inventors' preferred method for preparing the compounds of the invention.

Trans-6-[2-[2-ethyl-5-(4-fluorophenyl)-l~-pyrrol-l-yl]
ethyl]~tetrahydro-4-hxdrox;y--2~-pyran-2-one.
,:
step A: _Preparation of ~*,~*)-a-2-propenxloxirane-ethanol.
_-Butyllithium, 129 mL (200 mmol), is added dropwise to a 0c solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mol~, in 200 mL of anhydrous tetrahydro-1~ furan until the triphenylmethane indicator turned red.
I~ Carbon dioxide is then bubbled in for 30 minutes (lecture bottle carbon dioxide passed through drierite) and the light yellow solution is stirred for30 minutes under a balloon of carbon dioxide. To this solution is added iodine, 101.4 g (0.4 mol), dissolved in ~200 mL of anhydrous tetrahydrofuran over 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl ace~ate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine, and dried (magnesium sulfate). The crude product is dissolved in 200 mL of methanol and 20 mL of water, cooled to 0C and 0.5 g of solid potassium carbonate is added.
The mixture is vigorously stirred for six hours, filtered, concentrated, and partitioned between ethyl acetate and brine. After extracting the aqueous layer 2x with ethyl acetate, the combined organics are washed with brine and dried (magnesium sulfate).
Flash chromatography (4:1 hexane-ethyl acetate) ~ provides, after concentration in vacuo, 18 g of ;-~ (R*,R*)-a-2-propenyloxiraneethanol.
,~
.
, ,.

1 3 3 0 ,~

i 200 M~z NMR (CDCl3) ~ 1.5-1.65 (m, lH), 1.90 (dt, lH, J = 15, 4 Hz), 2.2 (m, 3H), 2.53 (m, lH), 2.79 (m, lH), 3.12 (m, lH), 3.94 (m, lH), 5.19 tm, 2H), 5.80 ' (m, lH).
' .
IR (film) 3400, 3077, 2980, 2925, 1643, 1412, 1260, 918, 827 cm~l.
:
Step B: Preparation of (~)-çis-2~2-dimethYl-6-(2 propenyl)-1,3-dioxane-4-acetonitrile.
Potassium cyanide, 1.3 g (20 mmol), is added to a ~ 10 room temperature solution of (R*,R*)-a-2-propenylo i oxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 isopropanol-water. The solution is stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2x with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of 2,2-dimethoxypropane, camphorsulfonic acid is added and the solution stirred for 18 hours at room temperature. Concentration and flash chromatography provides 1.30 g of (i)-cls-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.
. ~ ~ .
200 MHz NMR (CDCl3) ~ 1.35 (m, lH), 1.40 (s, 3~), 1.45 (s, 3H), 1.67 (m, lH), 2.20 (m, lH), 2.33 (m, lH), 2.50 (m, 2H), 3.89 (m, lH), 4.10 (m, lH), 5.10 (m, '?''i,! ~ 2H), 5.7-5.9 (m, lH).
,, ~" ~ ~ :
IR (film) 2995, 2944, 2255, 1644, 1334 cm~l.
,,~
~, ,, ~
,; ~ Step C: Preparatlon of (i~ çis-6-(2-oxoethYl)-2,2-';~ ~ dimethyl-1,3-dioxane-4-acetonitrile.
~,j 30 A solution of (~)-cls-2,2-dimet~yl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 3 g (15.36 mmol), in 0~ ~

~^ l 1 3 ~

~ -47-s 100 mL of dichloromethane is cooled to -78C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged.
Triphenylphosphine, 4.2 g (16 mmol~, is added and the colorless solution allowed to warm to room temperature. Flash chromatography provides, after concentration in vacuo, 2.5 g of pure (t)-cis-6-(2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.

200 MHz NMR (CDCl3) ~ 1.30 (m, lH), 1.39 (s, 3H), 1.48 ~; (s, 3H), 1.78 (m, lH~, 2.46-2.75 (m, 4H), 4.2 (m, lH), 4.40 (m, lH), 9.79 (t, lH, J = 1.6 Hz).
: - .
IR (film) 2250, 1720 cm~1.
: :' .
~ Step D: Preparation of (i)-çl -6-(cyanomethyl)-2,2-; dimethvl-1,3-dioxane-4-acetic acid.
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (7.6 mmol), is added dropwise to a 0C
solution of (~)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-`~ dioxane-4-acetonitrile, 1.50 g (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are ~ ` colorless. The diethyl ether layer is dried `3~ (magnesium sulfate), filtered, and concentrated to ;;~ provide 1.2 g of the acid which solidifies on standing. Trituration with isopropyl ether provides 30 (~)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid as a colorless solid; mp 92-95C. A
second trituration/recrystallization from isopropyl . ~ ether provides material of mp 98-103C.

~, ,.~

i ~ ~ ~

- 1330~

200 MHz NMR (CDC13) ~ 1.35 (m, lH), 1.42 (s, 3H), 1.49 (s, 3H), 1.82 (m, lH), 2.4-2.7 (m, 4H), 4.18 (m, lH), 4.35 (m, lH).

13C-NMR(d6-acetone, 50 MHz) ~ 19.95, 24.91, 30.17, 35.88, 41.34, 65.79, 66.35, 99.70, 117.77, 171.83.

IR (KBr) broad OH 3500-2400, 2254, 1711, 940 cm~l.

, Step E: Preparation of (~)-=c~ methylethyl 6-(cyano-¢ methyl~-2,2-dimethyl-1,3-dioxane-4-acetate.To a solution of (~)-cls-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 mL, is added 1,8-diazabicyclo[5.4.0]-i~ undec-7-ene (DBU), 0.45 mL (3 mmol), and 2 iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight ~' at room temperature, diluted with diethyl ether, washed with brine, and dried (magnesium sulfate).
Flash chromatography provides 0.55 g of (~)-cls-l-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
.
~ 90 MHz NMR (CDCl3) 8 1.22 (d, 6H, J = 7 Hz), 1.3 (m, .
~` 20 lH)I 1.35 (s, 3H), 1.40 (s, 3H), 1.75 (m, lH), 2.2-2.7~ (m, 4H~, 3.9-4.4 (m, 2H), 4.95 (septet, lH, J = 7 Hz).:.
Step F: Preparation of (i)-çi_-1-methyIethY1 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
A mixture of (~)-cls-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.55 g, in glacial ; acetic acid is hydrogenated with platinum dioxide at 3 ~`.` 50 pounds per square inch (PSI). Concentration, dilution with ethyl acetate an~ bicarbonate wash, followed by washing with brine and drying provides 250 mg of (i)-cls-l~methylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate. MS 260.1, 244.1 ,;,,~
~ ;.;~

!~ ~,'.',.. : ' . ~ ~ i ~

1330~

- _49_ .
200 MHz NMR tCDCl3) ~ 1.25 (d, 6H, J = 7 Hz), 1.32 (m, lH), 1.36 (s, 3H), 1.45 (s, 3H), 1.60 (m, lH), 2.33 (dd, lH, J = 15, 6 Hz), 2.49 (dd, lH, J = 15, 6 Hz), 2.85 (br t, 2H, J = 6 Hz), 3.40 (br s, 2H), 4.00 (m, lH), 4.29 (m, lH), 12.03 tseptet, lH, J = 7 Hz).
,-- .
l IR (film) 1734, 1387 cm~l.

Ste~ G: Preparation of (~)-cis-1-methylethyl 6-[2-[2-eth~-5-(4-fluorophenyl)-1~-pyrrol-1-Yl]
ethyll-2,2-dimethy~ 3-dioxane-4-acetate.
A solution of (i)-cls-l-methylethyl 6-(2-amino ethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.15 g (0.58 mmol), and 1-(4-fluorophenyl)~1,4-hexanedione (Example A), 0.125 g (0.6 mmol), in 5 mL of toluene is stirred and heated at reflux overnight. The cooled solution is concentrated and the highly W active pyrrole is separated from startinq material by preparative thin layer chromatography, eluting 2x with 4:1 hexane-ethyl acetate. This provides 130 mg of pure (~)-cls-1-methylethyl 6-[2-[2-ethyl-5-(4-fluoro-phenyl)-lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate.
;~ ~
~.. ; :,., ~ .
200 MHz NMR (CDCl3) ~ 1.51 (m, lH), 1.23 (d, 6~, J
= 6 Hz), 1.33 (m, 9H), 1.5-1.6 (m, 3H), 2.27 (dd, lH, J = 15.3, 6 Hz), 2.44 (dd, lH, J = 15.3, 6 Hz), 2.66 (q, 2H~, J = 7.5 Hz), 3.62 (m, lH), 3.8-4.2 (m, 3H), `
5.03 (septet, lH, J = 6 Hz), 5.97 (d, lH, J = 3.5 Hz), 6.11 (d, lH, J = 3.5 Hz), 7.0-7.4 (m, 4H).
... , ,~ ~
A solution of (i)-cis-l-methylethyl 6-[2-2-ethyl-5-(4-fluorophenyl)-lH-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 0.13 g (0.3 mmol), in 12 mL of 2 2M hydrochloric acid-tetrahydrofuran is stirred ~; overnight at room temperature. To this is added .~ .
,~
G,' ~5'. .' .

. ~'' ''`, `,' ," ;," `" ''',` ' "'' ', ''" "'"' ` " `' :'"'"" ;' ` ' '' ''' '`' `"''' `' ' '`''' '''',' " `' ;"`" ;, '''' ' "

133~

sufficient 2M sodium hydroxide to bring the pH to 10.
Stirring is continued for 30 minutes, water, 30 mL, is added and the mixture is extracted with diethyl ether.
The aqueous layer is acidified with ice cold 6N
hydrochloric acid and extracted with ethyl acetate (2x). The organic layer is washed with brine and dried (magnesium sulfate). The residue which remains on filtration and concentration is dissolved in ! toluene (50 mL) and heated at reflux with azeotropic , 10 removal of water (6 hours). The cooled solution is concentrated and flash chromatographed to provide 60 mg of trans-6-[2-[2-ethyl-5-(4-fluorophenyl~-lH-pyrrol-l-yl]ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one (elution with 2:l hexane-ethyl acetate).

90 MHz NMR (CDCL3) ~ 1.25 (d, 6H, J = 7 Hz) 1.3-1.8 (m, 4H), 2.3 (br s, lH, -OH), 2.55 (m, 2H), 2.65 (q, 2H, J = 7Hz), 3.9-4.5 (m, 4H), 5.90 (d, lH, J =
3.5 Hz), 6.05 (d, lH, J = 3.5 Hz), 6.9-7.4 (m, 4H).
,~

.:
~r3n~ )-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-, ~ diPhenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2~-pyran-'~,~ 2-yl~ethyl]-l~-pYrro-l-e-3-carboxamide.

` METHOD A
` - , .
Step A: Preparatlon of 4-Methyl-3-oxo-N-Phenyl-2-~ 25 (phenylmethylene)pentanamide.
`~ A suspension of 100 kg of 4-methyl-3-oxo-N-phenyl-pentanamide (Example B) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of ~-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to ;-~ reflux with removal of water for 20 hours. An ''~

' 1 3 3 .
j -51-,.~
additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for one hour. The reaction mixture is cooled 3 to 20-25C and the product is isolated by filtration.
The product is purified by slurrying in hexanes at 3 50-60C, cooling, and filtration. The product is lurried twice with water at 20-25C, filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7-154.4C.

Vapor Phase Chromatography (VPC): 30 meter DB 5 capillary column 50-270C at 15C/min. 19.33 min, 99.7% (area).

Gas Chromatography/Mass Spectrometry (GC/MC): M/Z 293 [M]+-,,.
=~ Nuclear Magnetic Resonance (NMR): (CDC13) ~ 1.16 (6H, d), 3.30 (lH, quin.), 7.09 (lH, m), 7.28 (5H, m), 7.49 (5H, m), 8.01 (lH, brs).

Step B-._ Preparation of (~)4-Fluoro-a-~2-methyl-1-oxopropy-L~y-oxo-N~-diphenylbenzenebutane amide mixture of [R-(R*,R*)], [R-(R*,S*~], [S-(R*,R*)l and ~S-(R*,S*)] isomers.
A solution of 17.5 kg of 3-ethyl-5-(2-hydroxy-ethyl)-4-methylth'iazolium bromide in 300 L of anhydrous ethanol is concentrated by distillation of 275 L of the ethanol. Under an argon atmosphere, 100 kg (340 mol) of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, 47.5 L (340 mol) of triethylamine, and 40 L (375 mol) of 4-fluorobenz- -~i;; 30 aldehyde are added. The resulting solution is stirred and heated at 75-80C for 23 hours. The product `~-~ begins to form as a solid after approximately ~, ~
~ ...
... .. ..

133~

1.5 hours but approximately 24 hours is required for ~ essentially complete conversion. The slurry is ;13, dissolved in 600 L of isopropanol at 80c. The '~ resulting solution is slowly cooled and the (~)4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-di-phenylbenzenebutaneamide mixture of [R-(R*,R*)], [~-(-J, R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers isolated ' by filtration. Washing the precipitate with isopropanol and drying in vacuo yielded 99 kg of (~)4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-diphenyl-benzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-( R*,S*)] isomers;
mp 206.8-207.6C.
. , NMR: (CDCl3) ~ 1.03 (3H, d), 1.22 (3H, d), 2.98 (lH, quin.), 4.91 (lH, d, J - 11 Hz), 5.51 (lH, d, J = 11 Hz), 6.98-7.43 (12H, m), 8.17 (2H, dd), 9.41 ' (lH, brs).
.
High Pressure Liquid Chromatography (HPLC):
(Acetonitrile:tetrahydrofuran:water) (40:25:55) Econosil Cl85~ 25 cm 1.0 mL/min. 254 nm 16.77 min.
~ 99.2% (area).
~,., Step C: Preparation of 1-(3,3-DiethoxYpropyl)-' ~ 5-(4-fluorophenyl)-2-(1-meth~lethYl)-N,4 diphenyl-lH-pyrroie-3-carboxamide.
To a nitrogen purged flask'equipped~with a mechanical stirrer is added 130 kg (311 mol) of (i)4-fluoro-~-[2-methyl-1-oxopropyl]-y-oxo-N,~-di-phenylbenzenebutaneamide mixture of [R-(R*,R*)], ,~ [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomer~, ;~ 39 54Q L of heptanes and 60 L of toluene, 59 kg (400 mol) of 3-amino-1,1-diethoxypropane, and 22.3 kg (218 mol) of pivalic acid. The mixture is stirred and heated to reflux, removing water with a Dean Stark trap. The .~
. j .

1330~1 mixture is refluxed 32 hours and slowly cooled to 60-65C, diluted wi~h 500 L of 2-propanol-water (3:2), I seeded, and cooled to 20-25C. The product is ¦ isolated by filtration, washed with 300 L of 2-propanol, and dried in vacuo to yield 133.5 kg of 1-(3,3-diethoxypropyl~-5 (4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-lH-pyrrole-3-carboxamide;
mp 125.1-127.7C after recrystallization from ethanol.

HPLC: (acetonitrile:tetrahydrofuran:water) (40:25:55) 1.5 mL/min 25~ nm Econosil C18 5~ 25 cm R.T. =
37.70 min 99.4% (area) NMR: ((CD3)2CO) ~ 1.04 (6H, m, t), 1.47 (6H, d), 1.82 (2H, m), 3.40 (5H, m), 3.99 (2H, m), 4.43 (lH, brt), 6.90-7.50 (14H, m), 8.26 (lH, brs) , -~
In a process analogous to Step C using appropriate starting materials, the following ~-~
~ compounds of Formula XVI are prepared:
'~
1-(3,3-Dimethoxypropyl)-5-(4-fluorophenyl)-2-(1-methyl~
ethyl)-N,4-diPhenyl-lH-pyrrole-3-carboxamide;
~ 20 mp 167-168.2C.

,'~ 5-(4-Fluorophenyl?-1-[2-(4-methyl-1,3-dioxolan-2-yl)-- eth ~ -N,4-diphenyl-lH-pyrrole-3- ~ -carboxamide; bp 141.5-145.9~C.

; Step D: Preparation of 5-(4-FluorophenYlL-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diPhenyl--pyrrole-3-carboxamide.
To a nitrogen purged flask fitted with an overhead stirrer, a thermometer, and a condenser is ;~ added 20 kg (37.8 mol) of 1-(3,3-diethoxypropyl)-~ 30 5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-)~

330~
..

~ lH-pyrrole-3-carboxamide along with 200 L of acetone.
`l The solution is stirred and 100 L of 2N hydrochloric acid solution is added. The mixture is heated to reflux for four hours then cooled to 50C ~ 5c, seeded, and cooled to oC ~ 5C. The product is ~; collected by filtration, washed with 100 L 2-propanol-water (1:1) and dried in vacuo at 50C for 64 hours to yield 16.2 kg of 5-(4-fluorophenyl)-2-(1-methylethyl)-~3; 1-(3-oxopropyl)-N,4-diphenyl-lH-pyrrole-3-carboxamide as an off-white solid.

SteP E: Preparation of 2-(4-Fluoro~henyl)-~-hydroxy-5-~1-methylethyl)-~-oxo-3-phenyl-4-[(phenyl-~;~ amino)carbonYl]-lH-pyrrole-1-heptanoic acid, methyl ester. s A 22-L three-necked flask fitted with an overhead stirrer, a low temperature thermometer, and a 2-L
calibrated addition funnel is dried with a nitrogen ` -~ purge and 78 g (1.95 mol) 60% sodium hydride in mineral oil is added, followed by 248 mL (1.76 mol) diisopropylamine and 8 L tetrahydrofuran. The reaction is cooled to -10 to 0C, a significant nitrogen purge was introduced through the flask, and ~`
212 mL (1.92 mol) methyl acetoacetate is added in a slow stream over a 10 to 30-minute period. Stirring is continued at -10 to 10C for an additional 10 to 30 minutes. After cooling to -15 to -5C, 2.2 L of 1.6 M n-butyllithium in hexanes is added over a 30 to ~ 60-minute period while maintaining the temperature !'i` ~ ' below 0C. Stirring is continued for an additional 1 -~ 30 to 1.5 hours at -15 to 0C and the mixture cooled to -35 to -15C.
In a separate 5-L flask, 0.7 kg (1.54 mol) ` 5-(4-fluorophenyl)-2-(l-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-lH-pyrrole-3-carboxamide is dissolved with 2.0 L of dry tetrahydrofuran, cooled to 0 to ..

.

,~",,, .,,:,.",, .;,,' , ' ", ~ " .'.';

13~Q~

-5C, and added to the anion solution over a 30 to 45 minute period. The reaction is stirred at -20 to ~ -15C for 30 to 45 minutes, then quenched by the J ~ addition of 4 L aqueous 2 N hydrochloric acid solution ~ 5 over 5 to 15 seconds while stirring rapidly. After 3 stopping the agitation, the lower layer is separated and the remaining organic layer washed with 4 L
saturated aqueous sodium chloride.

Step F PreParation of ci_-(4-FluorophenYl)-~
dihydroxy-5-(l-methylethYl)-3-phenyl-4- -~
[(phenylamino)carbonyl]-l~-pyrrole-1-he~tanoic acid, methyl ester.
The reaction solution obtained from Step E
contained in a 50-L jacketed glass still is ; 15 concentrated by vacuum distillation to a thick oil, then dissolved with 19 L tetrahydrofuran and cooled to 0C under an air atmospherè. Triethylborane, a ~; 1 molar solution in hexanes, (3.20 L, 1.4 equivalents based on Step E) is added over a 10 minute period, the atmosphere on the flask is switched to nitrogen, and the flask cooled to -105C over 3.5 hours. During this period two liters of methanol are added when the temperature reaches -67C. Powdered sodium borohydride (184 g, 4.8 mol) is added in 20 to 50-g portions over 1.5 hours, and the reaction maintained between -95 and -106C for 13 hours, then between -60 and -100C for 10 hours. Unreacted sodium borohydride is quenched by the addition of 750 mL
(12.7 mol) acetic acid in 50-mL portions over a 45 minute period with a substantial amount of gas evolution and with a temperature rise from -60 to -40C. Further quenching is accomplished by the addition of a solution of 1.0 L 30% hydrogen peroxide (9.7 mol), 3.0 L water, and 100 g dihydrogen sodium phosphate over a 15 minute period and is accompanied `.~ 133~

~ .
by a temperature rise from -40 to 0C. The reaction is allowed to warm to room temperature overnight, then the lower layer separated off and the upper layer washed with 4.0 L of saturated aqueous sodium chloride solution.

varlation of step F__ Preparation of cls-2-(4 Fluoro-phenylL-~,~-dihy~ y ~ ll-methy~thyl)-3-phenyl-4-(~henylamino)carbonyl-l~-pyrrole hePtanoic acid, methyl ester.
The reaction solution obtained from Step E is concentrated under vacuum to a volume of 5 to 8 L, then dissolved in 20 L tetrahydrofuran and 4 L
methanol under a nitrogen atmosphere. This solution is cooled to -85C and 2.1 L of a 15% solution of -~
methoxydiethylborane in tetrahydrofuran (2.1 mol, ~ 1.0 equivalent based on Step E) is added. The `~ reaction is cooled to -97C over one hour and 144 g 'i:!' (3.78 mol) of sodium borohydride added in 20 to 50-g portions over 1.5 hours. The reaction is maintained between -93 and -97C for 13 hours and allowed to ~ warm to room temperature and stand for 60 hours under m a nitrogen atmosphere.
The reaction is quenched by the addition of 460 mL (7.g mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 8 L methanol, concentrated by vacuum distillation, redissolved with 8 L methanol, and reconcentrated by vacuum distillation to a volume of 6 L. The solution is diluted with 8 L tetrahydro-furan, 4 L hexanes, and carried into the next step.

'~
,~: ,~

. ~?

:~ ~33~

~57-Step G: Preparation of ~ s~ 5-~4-FluorophenYl)-2-(l-met~ylethyl~-N,4-diphen~l-1-[2-5tetra-hvdro-4-hYdroxy-6-oxo-2H-pyr-an-2-yl)eth lH-pyrrole-3-carboxamide.
The crude reaction mixture of Step F is cooled to 8C, 8.0 L of 2.0 N aqueous sodium hydroxide is added, and the reaction stirred for 2 hours at 15 to 18C.
The reaction is diluted with 12 L water and the upper layer removed. The remaining aqueous layer is washed I 10 with 8 L hexanes then 8 L ethyl acetate is added I followed by 1 L concentrated aqueous hydrochloric acid solution. The wPll-stirred mixture is allowed to separate, the lower layer discarded, and the upper layer washed four times with 4 L each of 2 N aqueous hydrochloric acid solution.
The ethyl acetate layer is concentrated to a foamy syrup by vacuum distillation, and the residue dissolved in 8 L toluene. The toluene is concentrated by vacuum distillation to a volume of 6 L, then allowed to stand at room temperature for 16 hours.
The resulting thick slurry is filtered on a Buchner funnel, washed with 1 L of cool toluene, washed with 2 L of hexanes, and dried in a vacuum oven for 24 hours at room temperature, resulting in 686 g of trans~ 5-(4-fluorophenyl)-2~ methylethyl)-N,4-'~; diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- -yl)ethyl)-lH-pyrrole-3-carboxamide. The filtrates are washed with 2 N aqueous hydrochloric acid solution and , concentrated in vacuo to a volume of 2 L, then allowed to stand at room temperature for three days. The resulting solid is filtered, washed, and dried as before, resulting in 157 g of trans-(~)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetra-hydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-lH-pyrrole-3-carboxamide. HPLC of the solids indicates 95% trans I ~ with 1.3% cis lactone for the first crop and 95% trans c~ ,~
io ~
~, , ~ :

.

.--.
~33a~

¦ with 2.3% cis lactone for the second crop. The two crops of solid are dissolved in 8 L ethyl acetate by heating to 50 to 60C, then filtered through a ~ Buchner funnel along with 8 L of hexanes which has ¦ 5 been warmed to 50C. The solution is allowed to cool to room temperature over 16 hours, the resulting slurry filtered through a Buchner funnel, and the solid washed with 2 L hexanes. The resulting solid is dried in a vacuum oven for 24 hours at room temperature, resulting in 720 g of trans~ 5-(4-fluorophenyl)-2-(1-methyl~thyl)-N,4-diphenyl-1-[2-(tetrahydro~4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-lH-pyrrole-3-carboxamide with a ~8%:0.9% trans:cis HPLC
assay. The second crop obtained by concentration as before is approximately 100 g.

METHOD B
.~.
1:.
~ Step A: Preparatlon of (~-çi_-6-(2-aminoethyl)-2,2-`~ dimethyl-1~3-dioxane-4-acetic acid.
A solution of 1.04 g (4.88 mmol) of (+)-cls-6--~ 20 (cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45C and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue i6 dissolved in ., methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and ~ evaporated to give 0.56 g of (~)-cls-6-(2-amino-; ethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, mp 165 ~- with decompo~ition at 169C.
. ~
`;~

3 , i: ~"~''.`.'"","''"'"""",'."',"'.''.'' il ~

: 1330~

Fourier Transform Infrared (FTIR) (KBr): 1201.1, 1399.2, 1561.2, 2924.4, 3569.9 cm~l.

1 1H-NMR (D2O, 200 MHz) ~ 0.84 (m, lH), 0.96 (s, 3H), --, l.11 (s, 3H), 1.2-1.5 (m, 3H), 1.84 (dd, lH, J =
14.0 Hz, J = 6.6 Hz), 1.99 (dd, lH, J = 14.0 Hz, 3 J = 6.8 Hz), 2.68 (t, 2H, J = 7.2 Hz), 3.6-3.85 (m, lH), 3.85-4.15 (m, lH).
"
13C-NMR (D20, 50 MHz) ~ 19.64, 29.32, 32.94, 35.86, - 36.95, 44.73, 68.16, 68.25, 100.18, 178.56.
i.~
3 10 Mass Spectrum (GC/MS), m/z 202, 198, 173, 142, 138, 120, 97, 82, 59, 43.
:~
Step B: Preparation of ~ra~ 5-(4-fluorophenYl)-2-(1-methylethyll-N,4-di~henyl-1-[2-(tetra-hydro-4-hydroxy-6~oxo-2H-~yran-2-~l~ethyl]-1~-pyrrole-3-carboxamide. --A solution of 0.26 g (1.21 mmol3 of (~)-cls-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (~)4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-diphenylbenzene~utaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)~ isomers in 5 mL of dimethyl sulfoxide is .~ ~ heated at 105C for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and theiorganic layer washed with water - (2 x 50 mL) and 5% sodium hydroxide solution , ~` (2 x 100 mL - to extract the intermediate from unreacted diketone). The aqueous layer is acidified ; ;~ with dilute hydrochloric acid solution and extracted , ~ 30 with 30 mL of ethyl acetate. A drop of concentrated ~ hydrochloric acid is added to the ethyl acetate ',,!,, ~ solution and allowed to stand 18 hours. The solution ;~:
~ '-~

.. ~ :

~ 3 3 ~

is concentrated in vacuo and the concentrate is j redissolved in 30 mL of ethyl acetate and treated with ¦ one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans~ 5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(+)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.

METHOD C

Step A: Pre~aration of either (i)-(2~,4~,6~) or ~; 15 (~)-(2a,4,6~)-2-phenyl-6-(2-propenYl~-1,3-dioxane-4-acetonitrile.
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-a-2-propenyl-~ oxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 ;~ 20 isopropanol:water. The solution iB stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The agueous layer is extracted 2x with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dxied (magnesium sulfate). The crudeproduct is dissolyed in 20 mL of benzaldehyde dimethyl acetal, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature.
Concentration and flash chromatography after concentration in vacuo provides 1.30 g of either (2,4~,6~) or (i)-(2!4,6~)-2-phenyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile `~
. ,.
; ,.

.~.~

;L~! ''1 . ~ . . . ' .. ' ' . ' . ~ ~ ~ ', , ` , . ., . ... ~ . .

133~

200 MHz NMR (CDCl3) ~ 1.48 (m, lH), 1.71 (m, lH), 2.41 (m, 2H), 2.58 (m, 2H), 3.87 (m, lH), 4.03 (m, lH), 5.1 - 5.2 (m, 2H), 5.53 (s, lH), 5.87 (m, lH), 7.3 - 7.6 (m, 5H) 13C-NMR (CDCl3, 50 MHz) ~ 24.23, 35.07, 39.79, 71.57, 75.48, 100.44, 116.37, 117.53, 125.89, 127.91, 128.61, 133.05, 137.71.

GC/MS m/e 243 (M ), 242, 203, 202, 120, 107, 105, 79, 75, 41.

FTIR (neat) 699.6, 758.7, 920.8, 1028.8, 1051.9, 1121.4, 1345.2, 1383.7, 1401.7, 2253.1, 2916.6 cm-1.
1: . ~
Ste~ B Pre~aration of ei5b~l2 ~ gl~or (2a,4~,6~)-6-(2-oxoethyl)-2-phenyl-1 3-dioxane-4-acetonitrile.
l ., ~ , ~
A solution of either (t) (2a,4~,6~) or (2a,4~,6a)-2-phenyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 4.11 g (16.89 mmol), in 100 mL of dichloromethane is cooled to -78C under nitrogen.
Ozone (Welsbach generator, flow rate 0.1, voltage =
90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen ` bubbled through until the blue color is discharged.
Triphenylphosphine, 4.87 g (18.58`mmol),lis added and -the colorless solution is allowed to warm to room temper~ture. Flash chromatography provides after concentration in vacuo 3.75 g of pure either (2a,4a,6a) or (i)-(2a,4~,6~)-6-(2-oxoethyl)-2-phenyl-1,3-dioxane-4-acetonitrile.

GC/MS m/e 245 (~ ), 244, 123, l05, 95, 94, 77, 51, 41.

~ 1~30~

Step C: Pre~aration of either (i~ a,4a,6a) or (i)-(2a,4~,6~)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid.
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (g7.6 mmol), is added dropwise to a 0C solution of either (~)-(2a,4a,6a) or (~)-(2a,4~,6~)-6-(2-oxoethyl~-2-phenyl-1,3-dio~ane-4-acetonitrile, 1.86 g (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged.
After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.84 g of either (i)-(2a,4a,6a) or (i)-(2a-(2~,4~,6~)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid as a yellow gum.
: :
200 MHz NMR (CDCl3) ~ 1.61 (m, lH), 2.04 (m, lH), 2.6 - 2.8 (m, 3H) 2.82 (dd, lH, J = 15.9 Hz, J = 7.1 Hz), 4.20 (m, lH), 4.40 (m, lH), 5.60 (s, lH), 7.2 - 7.5 (m, 5H).
.
Step D: PreParation of either (~)-(2a,4a,6a) or (i)-(2a,4~,6~)-6-(2-aminoethyl)-2-Phenyl-1,3-dioxane-4-acetic acid.
A solution of 0.16 g (0.61 mmol) of either (~)-(2a-4a,6a) or (i)-(2a,4~,6~)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid in 50 mL of methanol saturated with anhydrous ammonia is added to a Parr ;~ shaker bottle containing 0.2 g of water wet Raney ;~;~ nickel #30. The solution is heated at 40C and ~30 50 pounds per square inch gage (psig) hydrogen pressure for 6 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The . ~

~ ~ .

t~

_'`
~3~04~

residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.11 g of either (t)-(2~,4a,6a) or ($)-(2a,4~,6~)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid;
mp 215.9 - 217.9C with decomposition.

200 MHz NMR (D20) ~ 1.4 - l.9 (m, 4H), 2.39 (dd, lH, J
= 14.8 Hz, J = 6.7 Hz), 2.S5 (dd, lH, J = 14.8 Hz, J =

7.4 Hz), 2.73 (t, 2H, J = 7.2 Hz) 4.11 (m, lH), 4.33 (m, lH), 5.70 (s, lH), 7.4 - 7.6 (m, 5H).

l3C-NMR (D20, 50 MHz) ~ 39.20, 39.78, 40.83, 47.11, 78.34, 78.73, 104.06, 129.15, 131.56, 132.3~, 140.51, 181.89.

Step E: Preparation of ~a~s-(~)-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-diphen~l-l-[2-(tetra hydro-4-hYdroxy-6-oxo-2~-~yran-2-yl)ethyll--pyrrole-3-carboxamide.
A solution of 0.31 g (1.21 mmol) of either (i)-(2~,4a,6a) or (i)-(2a,4~,6~)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid and 0.504 g .A
, (1.20 mmol) of (i)-4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)]
isomers in 5 mL of dimethyl sulfoxide is heated at 105C for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers ara separated and the organic layer washed with water (2 x 50 mL) and 5% sodium hydroxide solution (2 x 100 mL - to extract the intermediate from unreacted diketone).
The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate. A drop of concentrated ,~, .~
,~ :' ~ 33~4~

hydrochloric acid is added to the ethyl acetate I solution, the solution is stirred and allowed to stand ¦ 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(+)-5-(4-fluorophenyl)-2-(1-methyl-I ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide ¦ crystallizes and is isolated by filtration. A total I of 0.16 g of trans-(~)-5-(4-fluorophenyl)-2-(1 methyl-I ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-1 2H-pyran-2-yl3ethyl]-lH-pyrrole-3-carboxamide is ~ 15 isolated in two crops.
, ~ METHOD D
"
Step A: Preparation of (i)-çi_-9-(2-Dro~enyl)-6,10-dioxasPiro[4.5]decane-7-acetonitrile.
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-a-2-propenyl-oxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated, and ;~ partitioned between ethyl acetate and brine. The ; 25 aqueous layer is extracted 2x with ethyl acetate and the combined ethyl açetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of l,l-dimethoxycyclo-pentane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature.
Concentration and flash chromatography after concen-tration in vacuo provides 1.40 g of (~)-cls-9-(2-propenyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.
' ':
.- ~ .

~3304~1 ste~ B: _Preparation of (t)-çis-9-(2-oxoethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.
A solution of (~)-cls-9-(2-propenyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), S in 100 m1 of dichloromethane is cooled to -78c under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) i5 then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged.
Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room ~emperature. Flash chromatography provides after concentration in vacuo 2.5 g of pure (t)-cls-9-(2-oxo-ethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile. ~;s Step C: Preparation of (_)-çis-9-lcYanomethYl)-6!10-dioxaspiro[4.5ldecane-7-acetic acid.
Jone6 reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (97.6 mmol), is added dropwise to a 0C solution of (i)-cls-9-(2-oxoethyl)-6-10-dioxa-spiro[4.5]decane-2-acetonitrile 1.70 (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.20 g of (~)-cls-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid as a colorless solid.

~; Step D ~e~5~9~L5~ L5i~t~L! 2-aminoethyl)-6 ! 10-dloxaspiro[4.5]decane-7-acetic acid.
A solution of 1.17 g (4.88 mmol) of (~)-cls-9-~cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid :
., ., .

133Q~l in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45C and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol.
The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (i)-cls-9-(2-aminoethyl)-6,10-dioxaspiro-[4.5]decane-7-acetic acid. -~

Step E: Preparation of ~r~_-(iL-5-(4-fluoropllenyl)-2-(1-methylethyl)-N,4-diphen~l-1-t2-(tetra-hydro-4-hydroxy-6-oxo-2~-pyran-2-yl ? ethyl]-lH-pyrrole-3-carboxamide.
A solution of 0.2g5 g (1.21 mmol) of (~)-c1s-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid and 0.504 g (1.20 mmol) of (t)-4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N,~-diphenylbenzenebutane-~ amide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*~]
!~ and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105C for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separàted and the organic layer waslled with water (2 x 50 mL) and 5% sodium hydroxide solution (2 x 100 mL - to extract the intermediate protected acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ~ ethyl acetate. A drop of concentrated hydrochloric ;;~ acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is 1 3 3 ~

concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(~)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(i)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl~ 2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.

METHOD E

Step ~ _-4-l2-propenyl)-1,5-dioxaspiro L5.5]undecane-2-acetonitrile.
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-a-2-propenyl-oxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 isopropanol:water. The solution is stirred for 20 hour~ at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2~ with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of 2,2-dimethoxycyclo-hexanel camphor~sulfonic acid is added, and the solution is stirred for 18 hours at room temperature.
Concentration and flash chromatography after `~ concentration in vacuo provides 1.50 g of (i)-cls-4-(2-propenyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile :~
200 MHz NMR (CDCl3) ~ 1.26 (m, lH), 1.4 - 1.7 (m, 8H), 1.87 (m, 2H), 2.1 - 2.3 (m, 2H), 2.51 (d, 2H, J = 6.05 ''`

~:
, t . i i . ~ ' ' .... , ! . ~ .

~33~

Hz), 3.95 (m, lH), 4.15 (m, lH), 5~0 - 5.2 (m, 2H3, 5.83 (m, lH).

t3C-NMR ~CDCl3, 50 MHz) ~ 22.16, 24,71, 25.42, 28.20, 35.47, 38.33, 40.30, 64.08, 66.87, g8.84, 116.~3, 116.83, 113.46.

GC/MS m/e 235 (m+), 206, 192, 120, 99, 93, 79, 69, 55, 41.

FTIR (film) 964.5, 1121.4, 1160.0, 2253.1, 2937.2 cm~1.

step B: Preparation of (~ ~ thyl)-1,5-dioxaspiro[5.51undecane-2-acetoni-trile.
A solution of (+)-cis-4-(2-propenyl~-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), ~ in 100 mL of dichloromethane is cooled to -78c under ; 15 nitrogen. Ozone (Welsbach generator, flow rate 0.1, ~- voltage - 90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen ;~ bubbled through until the blue color is discharged.
; 20 Triphenylphosphine, 5.6 g (21.36 mmol), is added and the colorles~ solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 4.04 g of pure (~)-cls-4-(2-oxo-ethyl~-1,5-dioxaæpiro[5.5]undecane-2-acetonitrile.
:
200 MHz NMR (CDCl3) ~ 1.3 - 2.0 (m, 12H), 2.5 - 2.7 (m, 4H), 4.20 (m, lH), 4.36 (m, lH), 9.81 (t, lH, J =
1.74 Hz).
,..... : .
3C-NMR (CDCl3, 50 MHz) ~ 22.39, 22.44, 24.97, 25.59, `~
28.44, 35.82, 38.48, 49.54, 63.25, 64.17, 99.66, 116.57, 199.82.
~.
.::, , ::

. ~33a4~

GC/MS m/e 237 (m+), 208, 194, 122, 94, 81, 55, 42, 41.

FTIR (film) 969.6, 1069.9, 1126.5, 1160.0, 1368.3, 1386.3, 1728.4, 2934.6 cm~

Step C: Preparation of (~)-cl_-4-(cyanomethyl)-1,5-dioxaspiro[5.5~undecane-2-acetic acid.
Jones reagent (chromium trioxide-sulfuric acid-water), 4.4 mL (8.85 mmol), is added dropwise to a 0C solution of (~)-cls-4-(2-oxoethyl)-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile, 3.62 g (12.6 mmol), dissolved in 30 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of `
diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 3.65 g of (i)-cls-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid as a yellow solid.

200 MHz NMR (Pyridine) ~ 1.2 - 2.0 (m, 12H), 2.5 - 2.9 (m, 4H), 4.19 (m, lH), 4.50 (m, lH).
" .
Step D: Preparation of (i)-çi_-4-(2-aminoethYl)-1,5-dioxaspiro[5.51undecane-2-acetic acid.
A solution of 0.13 g of (i)-cls-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 mL of methanol saturated with anhydrous ammonia is added to ~`~ a Parr shaker bottle containing 0.2 g of water wet Raney nickel #30. The solution is heated at 40C and 50 pounds per sguare inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The i33~

, I residue is dissolved in methanol saturated with I anhydrous ammonia, treated with decolorizing charcoal, ! filtered through filter aid and evaporated to give 0.13 g of (~)-cls-4-(2-aminoethyl)-1,5-dioxaspiro-[5.5]undecane-2-acetic acid.

¦ 200 MHz NMR (D20) ~ 1.1 - 1.7 (m, lOH), 1.75 - 2.1 (m, ¦ 4H), 2,19 (dd, lH, J = 14.6 Hz, J = 6.7 Hz), 2.31 (dd, ¦ lH, J = 14.6 Hz, J = 7.3 Hz), 2.69 (t, 2H, J =
7.1 Hz), 4.09 (m, lH), 4.34 (m, lH).

l3C-NMR (D20, 50 MHz) ~ 24.50, 24.73, 27.55, 30.80, 38.91, 39.39, 39.63, 40.48, 47.03, 69.37, 69.5~, 102.74, 181.33.

Ste~L~33~L _ _~on of ~3~ )-5-~fluoropllenyl)-2-~1-methYlethyl)-N,4-diphenyl-1-[2-~tetra-hydro-4-hydroxy-6-ox--o-2H-pyran-2-yl)eth "
lH-~yrrole-3-carboxam de.
A solution of 0.31 g (1.21 mmol) of (~)-cls-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid and 0.504 g (1.20 mmol) of (i)-4-fluoro-~-[2-methyl-l-oxopropyl]-y-oxo-N,~-diphenylbenzenebutane-amide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,~*)]
and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide `~ is heated at 105C for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2 x 50 mL) and 5% sodium hydroxide solution ~ (2 x 100 mL - to extract the intermediate acid from i unreacted diketone~. The aqueous layer is aci~ified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate to remove the protecting group before lactonization.
The extract is concentrated and dissolved in 30 mL of :
, .
..~.
~::

133~

:
ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. T~le solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(~)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl~-lH-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.155 g of trans-(~)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.
:
METHOD F
; -Step A: Preparation of_(~)-çis~6-(2-~roPenyl)-1,3-dioxane-4-acetonitrile Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-~-2-propenyl-oxiraneethanol, 2.56 g (20 mmol), in 25 mL of 4:1 i.
isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2x with ethyl acetate and the combined~ethyl acebate extracts are washed with brine and dried (magnesium sulfate). The crude ; product is dissolved in 20 mL of dimethoxymethane, ~ camphorsulfonic acid is added, and the solution is ,~; 30 stirred for 18 hours at room temperature.
Concentration and flash chromatography after , .~
concentration in vacuo provides 1.20 g of ~ cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

,,~

133~

Step B: Preparation of (~)-cls-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile.
A solution of (t)-cls-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78c under nitrogen.
Ozone (Welsbach generator, flow rate 0.1, voltage =
90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged.
Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.3 g of pure (i)-cls-6-(2-oxo-ethyl)-1,3-dioxane-4-acetonitrile.
~ .
Step C:_ Preparation of (~)-ci$-6~(cyanomethyl)-1,3- ~;
dioxane-4-acetic acid.
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (97.6 mmol), is added dropwise to a 0C solution of (i)-cls-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile, 1.29 g (7.6 mmol), dissolved in 50 mL
of acetone until the orange color is not discharged.
After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.2 g of (~)-cls-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.
I ~ ~ ~
! ~:30 Step D: Prepara ~ aminoethyl)-1,3-dioxane-4-acetic acid.
A solution of 1.04 g (4.88 mmol) of (~)-cls-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 mL of ~;methanol saturated with anhydrous ammonia is added to ,~

. ` . 13~4~ .

a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45c and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrou.s ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (~)-cls-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid.

SteP_E: P~ f T~a~ 5-(4-fluorophenyl)-2-( ~ iphenyl-1-[2-(tetra-hydro-4-h ~ 2~-pyran-2-yl?eth 1~-pyrrole-3-carboxamide.
A solution of 0.26 g (1.21 mmol) of (t)-cis-6-(2-~ aminoethyl)-1,3~dioxane-4-acetic acid and 0.504 g ,~ (1.20 mmol) of (i)-4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-diphenylbenzenebutaneamide in 5 mL of dimethyl sulfoxide is heated at 105C for 15 hours.
The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2 x 50 mL) and 5% sodium hydroxide solution (2 x 100 mL - to e~tract the intermediate~acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to s- stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl ~; acetate and treated with one drop of concentrated -~ 35 hydrochloric acid. The solution is stirred two hours, ::s~ ~;

~, ~

~"! ~ , " '," . ~ , ~

1~3~

.
concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(i)-5-(4-fluorophenyl)-2~ methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.15 g of trans-(i)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.

METHOD G

Step A: PreParation of either (i)-(2~,4~,6~) or ( i ) - ( 2a, 4a, 6a ) -2-methYl-6- ( 2-Propenyl ) -1, 3-dioxane-4-acetonitrile.
_ .
Potassium cyanide, 1.3 g (20 mmol), is added to a room temperature solution of (R*,R*)-a-2-propenyl-oxiraneethanol, 2 . 56 g (20 mmol~, in 25 mL of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated, and partitioned between ethyl acetate and brine. The aqueous layer is extracted 2x with ethyl acetate and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 mL of 1,1-dimethoxyethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentra-tion and flash chromatography ater concentration in vacuo provides 1.30 g of either (i)-(2a,4~,6~) or (i)-(2a,4~,6a)-2-methyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

}~
~, ~L 3 ~
~ -75-Step B: Preparation of either (~)-(2a,4~,6a) or (~)-(2a,4~,6~)-2-methyl-6-(2-oxoethYl)-1,3-dioxane-4-acetonitrile.
A solution of either (i)-(2a,4~,6~) or (~)~(2a,4a,6a)-2-methyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.78 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78C under nitr~gen.
Ozone (Welsbach generator, flow rate 0.1, voltage =
90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged.
Triphenylphosphine, 4.2 g (16 mmol), is added and the ¦ colorless solution is allowed to warm to room l15 temperature. Flash chromatography provides after ¦concentration in vacuo 2.5 g of pure either 5~)-(2a,4a,6a) or (~)-(2a,4~,6~)-2-methyl-6-(2-oxo-ethyl)-1,3-dioxane-4-acetonitrile.

Step C: Preparation of either (i)-~2~,4a,6aL or (i)-(2a,4~,6~)-6-(cyanomethyl)-2-methyl-~,3-dioxane-4-acetic acid.
Jones reagent (chromium trioxide-sulfuric acid-water~, 3.8 mL (7.6 mmol), is added dropwise to a 0C solution of either (~)-(2a,4a,6a) or (~)-(2a,4~,6~)-2-methyl-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile, 1.40 g (7.6 mmol), dissolved in 50 mL
of acçtone until the orange color is not discharged.
After stirring a further 15 minutes, the mixture is poured into 300 mL sf diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.01 g of either ;~ (~)-(2a,4a,6a) or ~)-(2a,4~,6~)-6-(cyanomethyl)-2-methyl-1,3-dioxane-4-acetic acid as a colorless solid.

:
,~
~ ::

., 1 3 3 ~

-76- ~ -Step D: Preparation of either (~)-(2~,4~,6~3 Gr (i)-(2a,4~,6~)-6-(2-aminoet~y~-2-methyl-1,3-dioxane-4-acetic acid.
A solution of 0.97 g (4.88 mmol) of either (~)-(2a,4a,6a) or (+)-(2a,4~,6~)-6-(cyanomethyl)-2-methyl-1,3-dioxane-4-acetic acid in 100 mL of ~-methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45C and 50 pounds per square inch gage ~psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.50 g of either (i)-(2a,4a,6a) or (i)-(2a,4~,6 6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid.

Step E: Pre~aration of ~L~s-(+)-5-(4-fluorophenYl)-2-(1-methylethyl)-N~4-diphenyl-1-[2-(tetra-hYdro-4-hYdroxy-6-oxo-2E~-pYran-2-yl)ethYl]--pYrrole-3-carboxamide.
A solution of 0.31 g of either (i)-(2a,4a,6a) or (~)-(2a,4~,6~)-6-(2-aminoethyl)-2-methyl-1,3-dioxane-~ 4-acetic acid and 0.504 g (1.20 mmol) of (~)-4-fluoro-;~ a-~2-methyl-l oxopropyi]-y-oxo-N,~-diphenylbenzene-butaneamide in 5 mL of dimethyl sulfoxide is heated at ~--105C for 15 hours. The solution is cooled and poured ; 30 into 100 mL of diethyl ether and 50 mL of saturated ~;
ammonium chloride in water. The layers are separated and the organic layer washed with water (2 x 50 mL) and 5% sodium hydroxide solution (2 x 100 mL - to ~ -extract the intermediate acid from unreacted diketone).
The aqueous layer is acidified with dilute hydrochloric ~ .
.-,r~

?~

13304~1 _ acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(i)-5-~4-10 fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.14 g of trans-(i)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.

-~ METHOD H
. !
Step A: Preparation of (~)-cis-l,l-dimethYletllyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
cls-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-; 4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 mL of dichloromethane, cooled to 0C and 0.2 g of 4-dimethylaminopyridine (DMAP) is added, followed by t-butyl alcohol and followed by 4.32 g of dicyclo-hexylcarbodiimide (DCC). This solution is allowed to ~ slowly warm to room temperature over a 76.5-hour -~ period. Thin layer chromotography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloro-methane is added and stirring continues five hours.
An additional 100 mL of diethyl ether is added and the mixture filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an `:

~ 330~1 oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to yield (~)-cis-1,1-dimethyl-ethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

200 MHz NMR (CDCl3) ~ 1.36 (m, lH), 1.42 (s, 3H), 1.49 (s, 9H), 1.50 (s, 3H), 1.79 (dt, lH, J = 2.5 H~, J =
12.1 Hz), 2.40 (dd, lH, J = 6.2 Hz, J = 15.4 Hz), 2.5 - 2.7 (m, lH), 2.55 (d, 2H~ J = 6.1 Hz) 4.18 (m, lH), 4.32 (m, lH).

l3C-NMR (CDCl3, 50 MHz) ~ 19.80, 25.16, 28.30, 29.94, 35.66, 42.56, 65.27, 65.87, 80.96, 99.57, 116.72, 169.83.

GCMS m/e 254, 199, 198, 154, 138, 59, 57, 43, 41.

FTIR (neat) 954.2, 987.6, 1152.3, 1201.1, 1257.7, 1316.9, 1368.3, 1383.7, 1728.4, 2253.1, 2942.4, 2983.5 cm~l.

~; Step B: Preparation of (+)-cis~ dimethvlethyl 6-(2-aminoethyl ? -2~2-dimethyl-1,3-dioxane-4-i'` ~:
acetate.
A solution of 6.75 g of (i)-cis-1,1-dimethyl ethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4- -acetate in 80 mL of methanol saturated with gaseous ammonia is treated with 0.7 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch gage (psig) and 40C. After 10 hours, thin layer chromatography indicates no starting nitrile present. - -The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 3Q:20:1 (ethyl acetate:methanol-ammonium hydroxide) as eluent to give 5.48 g of (~)-cis-l,l-dimethylethyl ~ :
'~

~ ~L3~0~L~

- -7g--6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil which hardens after time.

200 MHz NMR (CDCl3) ~ 1.0 - 1.2 (m, lH), 1.22 (9, 3H), 1.31 (s, 12H), 1.35 - 1.45 (m, lH), 1.77 (brS, 2H), 2.15 (dd, lH, J = 15.1 Hz, J = 6.2 Hz), 2.29 (dd, lH, J = 15.1 Hz, J = 7.0 Hz), 2.66 (t, 2H, J = 6.6 Hz), 3.82 (m, lH), 4.12 (m, lH).

l3C-NMR (CDCl3, 50 MHz) ~ 19.56, 27.92, 29.96, 36.43, 38.18, 39.65, 42.55, 66.03, 67.16, 80.'19, 98.32, 169.80.

GC/MS m/e 258, 216, 215, 202, 200, 142, 113, 100, 99, 72, 57, 43.

FTIR ~neat) 951.6, 1157.4, 1201.1, 1260.3, 1314.3, 1368.3, 13~1.2, 1728.4, 2361.1, 2939.8, 2980.9 cm~1.

St ~ -(4-fluorophenyl)-; 2- ~ tetra-hYdro-4-hYdroxy-6-oxo-2~-Dyran-2-Yl)eth l~-pyrrole-3-carboxamide.
A solution of 0.79 g (2.89 mmol) of (i)-cls-l,l-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate and 1.00 g (2.41 mmol) of (~)-4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N,~3-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], ~ -[R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 15 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled and poured iTltO
100 mL of tetrahydrofuran and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with brine. To the ~; 30 organic layer is added 5 mL of 10% hydrochloric acid solution and the solution is stirred for 15 hours. To 1330~

this solution is added 1.2 g of sodium hydroxide and the mixture is stirred for 30 hours. The reaction is stopped by adding 50 mL of water, 30 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 50 mL of ethyl acetate.
A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 10 mL of toluene. Trans-(i)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-~H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide is isolated in two crops.

METHOD I

Step A: PreParation of either (+)-(2a,4a,6a) or (_ ~ hyl 6-(2-cyano-methyl)-2-pheny~ -dioxane-4-acetate.
;~ Either (i)-(2a,4a,6a) or (+)-(2a,4~,6~)-6-(cyano-methyl)-2-phenyl-1,3-dioxane-4-acetic acid (3.07 g, 11.75 mmol) is dissolved in 15 mL of dichloromethane, cooled to 0C and 0.1 g of 4-dimethylaminopyridine ¦ (DMAP) added, followed by t-butyl alcohol, followed by ; 2.91 ~ of dicyclohexylcarbodiimide (DCC). This ;~ solution is allowed to slowly warm to room temperature -~ and stirred over a 16.5-hour period. Thin layer chromatography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloromethane is added, and stirring is continued for five hours. An additional 100 mL of diethyl ether is added and then filtered.

.
.~

133~

The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate ls concentrated to yield either (~)-(2~,4~,6~) or (i)-(2a,4~,6~)-1,1-dimethylethyl 6-(2-cyanomethyl)-2-phenyl-1,3-dioxane-4-acetate.

GC/MS m/e 260, 244, 202, 138, 107, 105, 77, 57, 41.

SteP B. Preparation of either (i)-(2a,4a,6a) or (i)-(2a, 4~, 6~) l,l-dimethYlethYl 6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate.
A solution of 1.72 g of either (i)-(2~,4a,6a) or (i)-(2a, 4~, 6~)-1,1-dimethylethyl 6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch gage (psig) and 40C. After 10 hours, thin layer chromatography indicates no starting nitrile present. The suspension iB cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chroma-tography on silica gel with 30:20:1 (ethyl acetate:methanol: ammonium hydroxide) as eluent to give 1.56 g of either (i)-(2a,4a,6a) or (i)-(2~,4~,6~)-1,1-dimethylethyl 6-(2-aminoethyl)-2-phenyl_1,3-dioxane-4-acetate (98.2 area %) as a clear oil which hardens after time.

200 MHz NMR (CDCl3) ~ 1.2 - 1.9 (m, 4H) 1.44 (s, 9H), 2.03, (br.s, 2H), 2.42 (dd, lH, J = 15.3 Hz, J = 6.3 Hz), 2.63 (dd, lH, J = 15.3 Hz, J = 7.0 Hz), 2.89 (t, 2H, J = 6.8 Hz), 3.97 (m, lH), 4.26 (m, lH), 5.56 (s, lH), 7.3 - 7.4 (m, 3H), 7.4 - 7.5 (m, 2H).

'~
; .

~33~

13C NMR (CDCl3, 50 MHz) ~ 28.07, 36.57, 38.23, 39.25, 42.17, 73.47, 74O87~ 80.60, 100.36, 125.82, 127.88, 128.34, 138.45, 169.73.

GC/MS, m/e 321, 320, 248, 215, 174, 142, 105, 57.

FTIR (film) 699.6, 756.2, 1026.2, 1116.2, 1149.7, 1368.3, 1394.0, 1718.1, 1733.5, 2872.9, 2932.1 cm~1.

Step C: PreParation of ~=a~s-(~?-5-(4-fluorophenYl)-2~ methYlethyl)-N,4-diphenyl-1-[2-(tetra-hydro-4-hydroxy-6-oxo-2~-Pyran-2-yl)ethyl]-lH-Pyrrole-3-carboxamide.
In a process analogous to Method H by substituting (~)-(2a,4a,6a~ or (~)-(2a,4~,6~) l,l-dimethylethyl-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate for (~)-cis~ dimethylethyl 6-(2-amino-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetate one obtains the title compound.
i METHOD J
:
; Step A: PreParation of (i)-cis-1!1-dimethylethYl 4-(cyanocc~ L5-dioxaspiro[5.5]undecane-2-acetate.
(t)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]-undecane-2-acetic acid 3.32 g (13.12 mmol), is dissolved in 15 mL o$ dichloromethane, cooled to 0C
and 0.1 g of 4-dimethylaminopyridine (DMAP) added, followed by t-butyl alcohol, and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature ~ over a 16.5-hour period. TLC shows mainly product, -~ and some slightly lower Rf by-product. The mixture is ~` 30 stirred one hour and 50 mL of dichloromethane is added and stirring continued four hours. One hundred mL of ., , 133~

diethyl ether is added and then filtered. The filtrate is concentrated at reduced pressure. This crude concentrate is chromatographed on silica gel and eluted with 4:1 hexane:ethyl acetate to yield (~)-cls-l,1-dimethylethyl 4-(cyanomethyl)-1~5-dioxa-spiro[5.5]undecane-2-acetate.

200 MHz NMR (CDCl3) ~ 1.1 - 2.0 (m, 12H) 1.43 (s, 9H), 2.36 (m, 2H), 2.48 (m, 2H), 4.1 - 4.4 (ml 2H).

13C-NMR (CDCl3, 50 MHz) 22.37, 22.45, 25.08, 28.15, 10 28.55, 35.80, 38.57, 42.59, 64.31, 64.92, 80.76, 99.56, 116.65, 169.82.

GC/MS m/e 309 (m ), 266, 224, 210, 138, 120, 99, 57, 55.

FTIR (KBr) 964.5, 1149.7, 1157.4, 1332.3, 1368.3, 15 1712.9, 2939.8 cm~l.
. .
¦; steP B: Preparation of (i~-cis-l,1-dimethyletllyl 4-~2-aminoethyl)-1,5-dioxas~iro[5.5]--~ undecane-2-acetate.
A solution of 1.19 g of (i)-cis-1,1-dimethyl-20 ethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel ~30 and hydrogen gas in a shakqr at 50 pounds per square inch gage (psig) and 40C. After 22 hours, thin layer ;~ 25 chromatography indicates no starting nitrile present.
The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1;
ethyl acetate:methanol:ammonium hydroxide) to give `~ 30 1.18 g of (~)-cis-1,1-dimethylethyl 4-(2-aminoethyl)-1 3 3 0 L~ ~ ~

1,5-dioxaspiro[5.5]undecane-2-acetate as a clear oil which solidifies upon standing.

200 MHz NMR (CDCl~) ~ 1.2 - 2.0 (m, 12H), 1.43 (s, 9H), 2.34, (m, 2H), 2.50 (br.s, 2H), 2.84 (t, 2H, J =
6.7 Hz), 3.99 (m, lH), 4.28 (m, lH).

GC/MS, m/e 313, 270, 214, 185, 144, 142, 99.

FTIR (film) 961.9, 1098.2, 1154.8, 1368.3, 1725.8, 2934.6 cm~1.

Step C: Preparation of ~a~s-(~)-5-(4-fluorophenYl)-2-(1-methylethY~ 4-diphenyl-1-[2-(tetra-hYdro-4 hydroxv-6-oxo-2~-pyran-2-yl)ethyl]-yrrole-3-carboxamide.
~ In a process analogous to Method H by -~ substituting (i)-cls-1,1-dimethylethyl 4-(2-amino-ethyl)-1,5-dioxaspiro[5.5]undecane~2-acetate for (i)-cis-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate one obtains the title colnpound.

~ EXAMPLE 3 ,, (2R-~ -5-(4-fluorophenyl?-2-(1-methylethyl)-N~4-diDhenyl-1-[2-(tetrahYdro-4-hydroxy-6-oxo-2H-~Yran-2-vl)ethyl]-1~-pyrrole-3-carboxamide.

METHOD A

Step A: Pre~aration of ~R)-l,1-dimethylethyl 6-cYano-5-[[(1,1-dimethvlethyl)dimethvlsilyl]oxy]-3-oxohexanoate.
(R)-4-cyano-3-[[(l,l.dimethylethyl)dimethylsilyl]-oxy]butanoic acid, 32 g (0.132 mol), is dissolved in 300 mL of tetrahydrofuran. The solution is cooled to 133~

-20C and carbonyldiimidazole, 27 g (0.165 mol), is added. The solution is stirred and allowed to warm to 25C over two hours. The solution is added to a slurry of potassium l,1-dimethylethyl malonate (half ester, half salt), 60 g (0.3 mol), anhydrous magnesium chloride, 27.2 g (0.246 mol), diisopropylethylamine, 53 mL (0.3 mol) in 700 mL of dry acetonitrile. The mixture is stirred at 5C for 18 hours and at 15C for 108 hours. The mixture is poured into a mixture of 1 L of lN hydrochloric acid and l L of ethyl acetate and the resulting two-phase system is stirred for 15 minutes. The layers are separated. The organic layer is washed with 500 mL of saturated salt solution and concentrated to yield an oil. The oil consists of (R)~ dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-3-oxohexanoate and some 1,1-dimethylethyl malonate thalf ester, half acid) that is used directly in Step B. The oil has acceptable NMR spectra after subtracting the recovered malonate spectra.
. .
of (R)-1,1-dimethylethyl 6-cyano-5-hydroxy~3-oxo-hex-anoate.
A solution of crude (R)-l,1-dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 mL of tetrahydro-furan is treated with 213 mL of tetrabutylammonium fluoride solution (l. O M in hexane). The resulting mixture is stirred for five hours, at 25C. The mixture is treated with 500 mL of water, 300 mL of diethyl ether is added, and the layers separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel with the aid of anhydrous diethyl ether. The solvent is removed under ~,;
,~:
. ~

~ . ,' .~ '. "' ~ ;

~`
~ 3 ~

-~6-a vacuum to obtain 21 g of crude (R)-l,l-dimethyl-ethyl 6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra.

200 MHz NMR (CDCl3) ~ 1.48 (s, 9H), 2.62 (m, 2H), 2.89 (d, 2H, J = 6.1), 3.43 (s, 2H), 4.41 (pentet, 2H, J =
6.1 Hz) l3C-NMR (CDCl3, 50 mHz) ~ 25.05, 27.86, 48.03, 50.81, 63.39, 82.43, 117.03, 165.84, 202.03.

MS (Chemical ionization) m/e 228, 200, 172, 154.

FTIR (KBr) 1144.5, 1327.2, 1370.9, 1715.5, 1733.5, 2253.1, 2934.6, 2980.9, 3459.3 cm~l.

Step C: Preparation of [R-(R*,R*)]-1,1-dlmethvlethyl -; 6-cyano-3,5-dihYdroxyhexanoate.
Crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-i 15 oxohexanoate, 21 g (0.0924 mol), is dissolved in940 mL of tetrahydrofuran and 190 mL of methanol under a nitrogen atmosphere. This solution is cooled to -85CC and 95 mL of a 15% solution of methoxydiethyl-borane in tetrahydrofuran is added. The reaction is ; 20 cooled to -97C and 6.5 g (0.172 mol) of sodium borohydride is added in 0.5 g portions over 1.5 hours.
The reaction is maintained between -93C and -97C for 13 hours and allowed to warm to room temperature and stand for 60 hours under a nitrogen atmosphere. The 2S reaction is guenched by the addition of 25 mL
(0.395 mol) acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 mL methanol, concentrated by vacuum distillation, - redissolved with 500 mL methanol and reconcentrated by vacuum distillation to give a dark brown oil. This oil is taken up in 500 mL of ethyl acetate and `
- 133la ~

filtered through a plug of silica gel with the aid of 250 mL of ethyl acetate. The solution is evaporated to give 15 g of crude [R-(R*,R*~]-l,l-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate which is used without further purification.

Step D: PreParation of (4R-cis~ -dimethylethyl 6-cYanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.
Crude [R-(R*,R*)]-l,l-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, 15 g (61 mol), is dissolved in 150 mL of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo provides ll.8 g of (4R-cls)-l,l-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate as an off-white solid, mp 64.7-68C with acceptable IR, NMR, C-NMR and ~ analysis.
''=~ ' ~;~ 200 MHz NMR (CDCl3) ~ 1.36 (m, lH), 1.42 (s, 3H), 1.49 ~s, 9H), 1.50 (s, 3H), 1.79 (dt, lH, J = 2.5 Hz, J =
12.1 Hz), 2.40 (dd, lH, J = 6.2 Hz, J = 15.4 Hz), 2.5 - 2.7 (m, lH), 2.55 (d, 2H, J = 6.1 Hz), 4.18 (m, lH), 4.32 (m, lH).
, 3C-NMR (CDCl3, 50 MHz) ~ 19.74, 25.09, 28.24, 29.88, 35.58, 42.50, 65.20, 65.81, 80-87, 99.48, 116.68, 169.75.

`~ GC~MS m/e 254, 198, 154, 138, 120, 59, 57, 43, 41.
~ .
:~
FTIR (KBr) 941.4, 1116.2, 1154.8, 1188.3, 1257.7, 1293.7, 1309.1, 1368.3, 1725.8, 2361.1, 2983.5, 2996.4 cm~l.
.~

5~

~t'li.'.'",~;?-.f. '' ~- ~ 3 3 ~

Step E: Preparation of (4R-cis)-l,l-dimethylethyl 6-(2-aminoet~yl)-2,2-dlmethyl-1,3-dioxane-4-acetate.
A solution of (4R-c1s)-l,1-dimethylethyl 6-cyano-methyl-2,2-dimethyl-1,3-dioxane-4-acetate, 5.63 g (0.048 mol), in 100 mL of methanol saturated with gaseous ammonia is treated with 0.5 g of Raney nickel #30 and hydrogen gas in a shaker at 50 psi and 40C.
After 16 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide~ as eluent to give 4.93 g of of (4R-cls)-l,l-15 dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil with acceptable IR, MMR, C-NMR and MS spectra.
,~, 200 MHz NMR (CDCl~) 1.0 - 1.2 (m, lH), 1.22 (s, 3H), 1.31 (s, 12 H), 1.35 - 1.45 (m, 3H), 2.15 (dd, lH, J =
20 15.1 Hz, J = 6.2 Hz), 2.29 (dd, lH, J = 15.1 Hz, J =
7.0 Hz), 2.66 (t, 2H, J - 6.6 Hz), 3.82 (m, lH), 4.12 (m, lH).
, ~
3C-NMR ~CDCl3, 50 MHz) ~ 19.60, 27.95, 30.00, 36.50, 38.25, 39.79, 42.61, 66.08, 67.18, 80~21, 98.35, 25 169.82.
: , , , ~ , ! ' ~ , GC/MS m/e 202, 200, 173, 158, 142, 140, 114, 113, 100, 99, 97, 72, 57.

FTIR (neat) 951.6, 1159.9, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1731.0, 2870.3, 2939.8, 2980.9, 30 3382.2 cm~1.

, ~

,; , ~.

: ; ~

;.~
t33~4~

SteP F: PreParation of (4R-cis)-l,l-dimethylethvl 6-[2[2-(4-fluoroPhenyl)-5-(l-me-~ ylethyl)--3-phenyl-4-[(DhenYlamino)carbonyl]-1~-pYrrol-l-yl]ethyl]-2,2-dimethYl-1,3-di_xane-4-acetate.
,-A solution of (4R-cls)-l,l-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4 acetate, 1.36 g (4.97 mol), and (i)-4-fluoro-a-[2-methyl-1-oxopropyl]-y-oxo-N,~-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-R*,S*)]
isomers, 1.60 g (3.83 mol), in 50 mL of ~;
heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled slightly and 15 mL
of 2-propanol added. The mixture is allowed to cool to 25C and filtered to give 1.86 g of (4R-cis)-l,l-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol~
yl]ethyl]-2,2-dimethyl-1,3-dioxane-4~acetate as a yellow ~olid with acceptable PNMR & C-NMR spectra.

~ lH-NMR (CDCl3, 200 MHz) ~ 1 - 1.7 (m, 5H), 1.30 (s, ; 20 3H), 1.36 (s, 3H), 1.43 (8, 9H), 1.53 (d, 6H, J = 7.1 ~;~ Hz), 2.23 (dd, lH, J = 15.3 Hz, J = 6.3 Hz), 2.39 (dd, lH, J = 15.3 Hz, J = 6.3 Hz), 3.5 - 3.9 (m, 3H), 4.0 - 4.2 ~m, 2H), 6.8 - 7.3 (m, 14H).

3C-NMR (CDCl3, 50 MHz) ~ 19.69, 21.60, 21.74, 26.12, 27.04!~ 28.12j 29t95, 36.05, 38.10, 40.89', 42.54, 65.92, 66.46, 80.59, 98.61, 115.00, 115.34, 115.42, 119.52, 121.78, 123.36, 126.44, 128.21, 128.31, 128.52, 128.75, 130.~3, 133.01, 133.17, 134.69, 138.38, 141.47, 159.72, 164.64, 169.96.
. ~
"~
~, ii , ~;

5, ~'? ,` ;., ; ' ; ., 1330~1 -so-Step G: Preparation of (2R-~ra~s)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetra-hydro-4-hydroxy-6-oxo-2~-~yran-2-yl)ethyl]-lH-pvrrole-3-carboxamlde.
(4R-cls)-l,1-dimethylethyl 6-[2[2-(4-fluoro-phenyl)-5-(1-methylethyl)-3-phenyl-4-l(phenylamino)-carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 mL of tetrahydrofuran and 15 mL of 10%
hydrochloric acid solution is added, and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(l-methyl-` ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide (3.01 g) is isolated in two crops.
., METHOD B
A solution of (4R-cls)-1,1-dimethylethyl ; 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 2.56 g (9.36 mol), and (i)-4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N,~-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*j] isomers, 3.00 g (7.20 mol), in 60 mL of 133~
` .
...
, . -91-heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled and poured into 300 mL of tetrahydrofuran and 150 mL of saturated ammonium chloride in water. The layers are separated and the organic layer is added to 15 mL of 10%
hydrochloric acid solution and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers.
The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl ; :
acetate and treated with one drop of concentrated ; hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-tra~s)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-lH-pyrrole-3-carboxamide (2.92 g) is isolated in two crops.

PREPARATION OF STARTING MATERIALS
: :~
~ ; EXAMPLE A
,7 : ' ' 1-(4-Fluoropheny1)1,4-hexanedione.
A mixture of 36.61 g (295 mmol) of 4-fluorobenz-',,~ A~ aldehyde, 25 g (297.2 mmol) of ethyl vinyl ketone, 29 mL (206.9 mmol) of triethylamine and 11.94 g ~, ~ (44.25 mmol) of 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride is stirred and heated at 70C for six hours. The cooled solution is diluted with ~ is~ . ~

..`' I
` ` ~33 2 liters of diethylether and washed with 2 x 300 mL of water, 2 x 100 mL of 2M hydrochloric acid, 100 mL of water, 200 mL of a saturated solution of sodium bicarbonate and brine. The organic layer is separated, dried (magnesium sulfate), filtered, and concentrated to provide 55 g of 1-(4-fluorophenyl)-1,4-hexanedione after recrystallization from methanol;
mp 56-57C.

EXAMPLE B

4-Methyl-3-oxo-N-phenYlPentanamide A three-necked, 12-L round-bottom flask e~uipped with a mechanical stirrer, a thermometer and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylene diamine. The mixture is heated to 30C and charged with 0.49 kg of aniline.
The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 4Q minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further ; one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours and a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to 40C and a further 1.0 L of water is charged. Seven hundred milliliters of ~; 30 toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration ` ~ and washed with three portions of hexane. Drying in ~u~ " ,,,,, ~ "~ ", ,, , , ~", ", ~ " , ,~ ,, " ~

' l3ao~l . -93-vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentan-amide as a hydrate; mp 46.5-58.8C.

HPLC: 98 . 8% - retention time 3.56 min. 65/35 acetonitrile/water on a dry basis.

5 VPC: 87.6% - retention time 12.43 min. also 10. 8%
aniline (decomposition).
. .~ ', '~' . .

, .
' ~.

': , '~
`' ~ .

~ ` ' ' !

:~ " ~ .

Claims (49)

1. A process for the preparation of a compound of Formula I

I
and a dihydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of a compound of Formula I
wherein R1 is 1-naphthyl,

2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide;
R2 or R3 is independently hydrogen, alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or -CONR5R6 where R5 and R6 are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl;

R4 is alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or trifluoromethyl;
which comprises:
(a) reacting 1,6-heptadien-4-ol with an (1) alkyl lithium (2) followed by iodine and carbon dioxide and (3) treating the resulting iodocarbonate intermediate in situ with a base in an aqueous alcohol at about 0°C to about 40°C to afford a compound of Formula IX;
IX

(b) treating the compound of Formula IX with (1) an alkali cyanide at about 0°C to about 40°C and (2) reacting the resulting diol intermediate in situ with a ketal-forming reagent in the presence of an acid to afford a compound of Formula VIII

VIII
wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 taken together as - (CH2)n-, wherein n is 4 or 5;
(c) treating the compound of Formula VIII
with (1) ozone in an inert solvent and (2) reacting the resulting intermediate in situ with oxygen and triphenylphos-phine at about -20°C to about -78°C to afford a compound of Formula VII

VII
wherein R7 and R8 are as defined above;
(d) treating the compound of Formula VII
with an oxidizing reagent at about 0°C to afford a compound of Formula VI

VI
wherein R7 and R8 are as defined above;
(e) treating the compound of Formula VI
with a compound of Formula Hal-R9a wherein Hal is halogen and R9a is alkyl of from one to eight carbon atoms or a three-to six-membered cycloalkyl group, in the presence of a base to afford a compound of Formula Va Va wherein R7, R8, and R9a are as defined above;
or treating the compound of Formula VI with a compound of Formula HO-R9b wherein R9b is tertiary butyl, tertiary amyl, or .alpha., .alpha.-dimethylbenzyl in the presence of an activating agent, a catalytic amount of a base and an inert solvent to afford a compound of Formula Vb Vb wherein R7, R8, and R9b are as defined above;
(f) treating the compound of Formula Va with hydrogen in the presence of a catalyst and an acid at about 0°C to about 70°C to afford a compound of Formula IVa IVa wherein R7, R8, and R9a are as defined above, or treating the compound of Formula Vb with hydrogen in the presence of a catalyst and an acid or a catalyst and a base at about 0°C to about 70°C to afford a compound of Formula IVb IVb wherein R7, R8, and R9b are as defined above;
(g) treating the compound of Formula IVa with a compound of Formula III
III
wherein R1, R2, R3, and R4 are as defined above in an inert solvent to afford a compound of Formula IIa IIa wherein R1, R2, R3, R4, R7, R8, and R9a are as defined above, or treating the compound of Formula IVb with a compound of Formula III in an inert solvent to afford a compound of Formula IIb IIb wherein R1, R2, R3, R4, R7, R8, and R9b are as defined above;
(h) and finally treating a compound of Formula IIa with (1) an acid in the presence of an inert solvent (2) followed by hydrolysis with a base (3) followed by neutralization with an acid and (4) dissolution and/or heating in an inert solvent with concomitant removal of water to give a compound of Formula I, or treating a compound of Formula IIb with (1) an acid in the presence of an inert solvent (2) followed by addition of a base (3) followed by neutralization with an acid and (4) dissolution and/or heating in an inert solvent with concomitant removal of water to give a compound of Formula I;
(i) and if desired converting the resulting compound of Formula I to a dihydroxy acid corresponding to the opened lactone ring of structural Formula I by conventional hydrolysis and further, if desired converting the dihydroxy acid to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired converting the corresponding pharmaceutically acceptable salt to a dihydroxy acid by conventional means, and if so desired converting the dihydroxy acid to a compound of Formula I by heating in an inert solvent.

2. A process according to Claim 1 wherein the alkyl lithium in step (a) is n-butyllithium.

3. A process according to Claim 1 wherein the alkali cyanide in step (b) is potassium cyanide.

4. A process according to Claim 1 wherein the oxidizing reagent in step (d) is chromium trioxide-sulfuric acid-water.

5. A process according to Claim 1 wherein the catalyst in step (f) for preparing a compound of Formula IVa is platinum dioxide.

6. A process according to Claim 1 wherein the catalyst and base in Step (f) for preparing a compound of Formula IVb are Raney nickel and anhydrous ammonia, respectively.

7. A process according to Claim 1 wherein the acid in step (h) is hydrochloric acid.

8. A process according to Claim 1 wherein the base in step (h) is sodium hydroxide.

9. A process according to Claim 1 wherein R1 is 1-naphthyl, norbornenyl, phenyl, or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms.

10. A process according to Claim 9 wherein R4 is alkyl of from one to six carbon atoms, cyclopropyl, or trifluoromethyl.

11. A process according to Claim 1 and for the preparation of a compound selected from the group consisting of:
trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoro-methyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-(4-fluorophenyl)-5-(1-methyl-ethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-phenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one;
trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-phenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one;

trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one;
trans-6-[2-(2-bicyclo[2.2.1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
trans(?)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide;
(2R-trans)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide;
trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-trifluoromethyl-lH-pyrrole-3-carboxamide; and trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-trifluoromethyl-1H pyrrole-3-carboxamide.

12. A process for the preparation of the compound of Formula Ia Ia and the hydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of the compound of Formula Ia which comprises:
(a) reacting the compound of Formula XVII

XVII

with a compound of Formula wherein R7 and R8 are independently hydrogen alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-wherein n is 4 or 5, and R13 is hydrogen or in an inert solvent and treating the resulting intermediate with an acid to afford the compound of Formula Ia;
(b) and if desired, converting the resulting compound of Formula Ia to a hydroxy acid corresponding to the opened lactone ring of structural Formula Ia by conventional hydrolysis and further, if desired, converting the hydroxy acid to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the hydroxy acid to a compound of Formula Ia by heating in an inert solvent.

13. A process according to Claim 12 wherein the acid in Step (a) is hydrochloric acid.

14. A process according to Claim 12 and for the preparation of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

15. A process for the preparation of the compound of Formula Ia Ia and the hydroxy acid and pharmaceutically acceptable salts thereof, corresponding to the opened lactone ring of the compound of Formula Ia which comprises (a) reacting 4-methyl-3-oxo-N-phenyl-pentanamide with benzaldehyde in the presence of a catalyst and an inert solvent to afford the compound of Formula XVIII
XVIII

(b) reacting the compound of Formula XVIII
with 4-fluorobenzaldehyde in the presence of a catalyst, a base, and an inert solvent to afford the compound of Formula XVII
XVII

(c) reacting the compound of Formula XVII
with a compound of Formula wherein R10 and R11 are alkyl of one to eight carbon atoms or R10 and R11 together are , -CH2-CH2- or -CH2CH2CH2- in the presence of a catalyst and an inert solvent to afford a compound of Formula XVI.
XVI

wherein R10 and R11 are alkyl of one to eight carbon atoms or R10 and R11 together are , -CH2-CH2- or -CH2-CH2-CH2-(d) and finally converting a compound of Formula XVI in a conventional manner to afford the compound of Formula Ia, (e) and if desired, converting the resulting compound of Formula Ia to a hydroxy acid corresponding to the opened lactone ring of structural Formula Ia by conventional hydrolysis and further, if desired, converting the hydroxy acid to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the hydroxy acid to a compound of Formula Ia by heating in an inert solvent.

16. A process according to Claim 15 wherein the catalyst in step (a) is selected from the group consisting of piperidine and glacial acetic acid, ethylene diamine and glacial acetic acid, and .beta.-alanine and glacial acetic acid.

17. A process according to Claim 16 wherein the catalyst is .beta.-alanine and glacial acetic acid.

18. A process according to Claim 15 wherein the catalyst in step (b) is selected from the group consisting of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-thiazolium bromide and thiamine hydrochloride.

19. A process according to Claim 18 wherein the catalyst is 3-ethyl-5-(2-hydroxyethyl)-4-methyl-thiazolium bromide.

20. A process according to Claim 15 wherein the catalyst in step (c) is selected from the group consisting of R4CO2H wherein R4 is CH3, CF3, ClCH2-, C6H5CH2CH2-, C6H5CH2-, HO2CCH2-, HO2CCH2CH2-, C6H5-, para-C1-C6H5-, ClCH2CH2-, meta-H3C-C6H5-, para-H3C-C6H5-, or tertiary-C4H9-and triethylamine hydrochloride.

21. A process according to Claim 20 wherein the catalyst is tertiary-C4H9CO2H.

22. A process according to Claim 15 wherein the base in step (b) is selected from the group consisting of N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, triethylamine, 1,8-diaza-bicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo-[2.2.2]octane, 4-dimethylaminopyridine, and N,N,N',N'-tetramethylethylenediamine.

23. A process according to Claim 22 wherein the base is triethylamine.

24. A process according to Claim 15 and for the preparation of (2R-trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

25. A compound of Formula II
II
wherein R1 is 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide;
R2 or R3 is independently hydrogen, alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or -CONR5R6 where R5 and R6 are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl;
R4 is alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or trifluoromethyl;
R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5; and R9 is alkyl of from one to eight carbon atoms, a three- to six-membered cycloalkyl group, or .alpha.,.alpha.-dimethylbenzyl.

26. A compound according to Claim 25 wherein R7 and R8 are methyl, R9 is tertiary butyl, and the two optically active centers are R.

27. A compound according to Claim 25 wherein R7 is 4-fluorophenyl, R2 and R3 are hydrogen, R4 is ethyl, R7 and R8 are methyl, and R9 is isopropyl.

28. A compound according to Claim 25 wherein R1 is 4-fluorophenyl, R2 is phenyl, R3 is C6H5NHCO-, R4 is isopropyl, R7 and R8 are methyl, and R9 is tertiary butyl.

29. A compound according to Claim 28 wherein the two optically active centers are R.

30. A compound of Formula XVI

XVI

wherein R10 and R11 are alkyl of one to eight carbon atoms or R10 and R11 together are .

31. A compound according to Claim 30 wherein R10 and R11 are methyl or ethyl or R10 and R11 together are .

32. A compound of Formula IV

IV

wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5, and R9 is alkyl of from one to eight carbon atoms, a three- to six-membered cycloalkyl group, or .alpha.,.alpha.-dimethylbenzyl.

33. A compound according to Claim 32 wherein R9 is .

34. A compound according to Claim 32 wherein R7 and R8 are methyl, and R9 is isopropyl.

35. A compound according to Claim 32 wherein R7 and R8 are methyl, and R9 is tertiary butyl.

36. A compound according to Claim 32 selected from the group consisting of (4R-cis)-1,1-dimethyl-ethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; [2R-(2.alpha.,4.alpha.,6.alpha.)]-1,1-dimethylethyl 6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate;
[2S-(2.alpha.,4.beta.,6.beta.)]-1,1-dimethylethyl 6-(2-amino-ethyl)-2-phenyl-1,3-dioxane-4-acetate; (7R-cis)-1,1-dimethylethyl 9-(2-aminoethyl)-6,10-dioxa-spiro[4.5]decane-7-acetate; (2R-cis)-1,1-dimethyl-ethyl 4-(2-aminoethyl)-1,5-dioxaspiro[5.5]-undecane-2-acetate; (4R-cis)-1,1-dimethylethyl 4-(2-aminoethyl)-1,3-dioxane-4-acetate;
[2R-(2a,4a,6a)]-1,1-dimethylethyl 6-(2-amino-ethyl)-2-methyl-1,3-dioxane-4-acetate; and [2S-(2.alpha.,4.beta.,6.beta.)]-1,1-dimethylethyl 6-(2-amino-ethyl)-2-methyl-1,3-dioxane-4-acetate.

37. A compound of Formula XXI
XXI

wherein R7 and R8 are independently hydrogen alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5.

38. A compound according to Claim 37 selected from the group consisting of (4R-cis)-6-(2-amino-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid;
[2R-(2.alpha., 4.alpha., 6.alpha.)]-6-(2-aminoethyl)-2-phenyl-1, 3-dioxane-4-acetic acid; [2S-(2.alpha.,4.beta.,6.beta.)]-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid; (7R-cis)-9-(2-aminoethyl)-6,10-dioxaspiro [4.5]decane-7-acetic acid; (2R-cis)-4-(2-amino-ethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid;
(4R-ciLs)-4-(2-aminoethyl) 1,3-dioxane-4-acetic acid; [2R-(2.alpha.,4.alpha.,6.alpha.)]-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid; and [2S-(2.alpha.,4.beta.,6.beta.)]-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid.

39. A compound of Formula V
V
wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5, and R9 is alkyl of from one to eight carbon atoms, a three- to six-membered cycloalkyl group, or .alpha.,.alpha.-dimethylbenzyl.

40. A compound according to Claim 39 wherein R7 and R8 are methyl, and R9 is isopropyl.

41. A compound according to Claim 39 wherein R7 and R8 are methyl, R9 is tertiary butyl, and the two optically active centers are R.

42. A compound of Formula VI
VI

wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5.

43. A compound according to Claim 42 wherein R7 and R8 are methyl and the two optically active centers are R.

44. A compound of Formula VII

VII

wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5.

45. A compound according to Claim 44 wherein R7 and R8 are methyl and the two optically active centers are R.

46. A compound of Formula VIII
VIII

wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as -(CH2)n-, wherein n is 4 or 5.

47. A compound according to Claim 46 wherein R7 and R8 are methyl and the two optically active centers are R.

48. A compound of Formula XVII

XVII

49. A mixture of compounds of Formula XVIII
XVIII