WO2013014486A1 - Improved synthesis of 2-(4-(4-chlorophenyl) cyclohex-1-enyl) -3, 4-dihydronaphthalen-1 (2h)-one; an intermediate for atovaquone - Google Patents

Improved synthesis of 2-(4-(4-chlorophenyl) cyclohex-1-enyl) -3, 4-dihydronaphthalen-1 (2h)-one; an intermediate for atovaquone Download PDF

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WO2013014486A1
WO2013014486A1 PCT/IB2011/002134 IB2011002134W WO2013014486A1 WO 2013014486 A1 WO2013014486 A1 WO 2013014486A1 IB 2011002134 W IB2011002134 W IB 2011002134W WO 2013014486 A1 WO2013014486 A1 WO 2013014486A1
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chlorophenyl
compound
cyclohexyl
dihydronaphthalen
reaction
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French (fr)
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Bhairab Nath Roy
Girij Pal Singh
Piyush Suresh Lathi
Manoj Kunjabihari Agrawal
Rangan Mitra
Aunrag TRIVEDI
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Lupin Limited
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
    • C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C46/00—Preparation of quinones
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    • C07C46/00—Preparation of quinones
    • C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
    • C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/14—The ring being saturated
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C2602/00—Systems containing two condensed rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • DIHYDRONAPHTHALEN-H2HVONE AN INTERMEDIATE FOR ATOVAQUONE
  • the invention relates to a novel process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one, key intermediate for synthesis of Atovaquone [I].
  • Atovaquone 2-[7>a «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, as disclosed in US patent number US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria, toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US patent number US 5206268, US 5856362 and US 5567738, respectively.
  • the mechanism of action for Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome bci complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron Lett, 1998, 39 7629).
  • This invention describes a) Genesis of poor yield of compound (V) from compound (VI) and, b) An alternative chemistry which is efficient, easily operable, high yielding process for synthesis of compound (V) from compound (VI).
  • an object of this invention is to provide a novel cost effective and efficient process for the synthesis of an intermediate of Atovaquone i.e. 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V).
  • Another object of the present invention is synthesis of the novel compound 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through esterifcation of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (IV) with trifluro acetic anhydride.
  • Yet another object of the present invention is synthesis of the compound 2-(4-(4- chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V) from 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through E2 elimination (elimination, bimolecular) of trifluro acetyl functionality.
  • An aspect of the present invention is to provide compound 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V), a key intermediate for synthesis of Atovaquone through a novel, cost effective, green, and eco-friendly process.
  • Fig 1 Scheme showing rate of protonation of compound (IV) for formation of compound (A) & (B) via path [A] and [B]
  • Fig 3 Scheme showing that in path B; oxygen of carbonyl functionality was protonated, which through “retro-aldoV reaction gives a-tetralone (XII) & 4-(4- chlorophenyl)cyclohexanone (III) DETAILED DESCRIPTION OF THE INVENTION
  • selection of a base for carrying out esterification reaction was limited to only organic amine, which only polarizes hydroxyl function such as pyridine, N,N- di/sopropylethylamine, etc.
  • the synthesis of compound (V) from compound (IV) comprised of the following two steps 1) synthesis of compound (XIa) from compound (IV) in 90% isolated yield (example 1) and 2) synthesis of compound (V) from compound (XIa) in 90% isolated yield (example 7).
  • overall isolated yield for compound (V) from compound (IV) comes to 81 %, which is 31% more than that obtained by the process reported in our co-pending PCT application PCT/IB2011/001507(Example 10; yield 50%).
  • reaction mass was cooled to 0 °C and trifluoroacetic anhydride (22.2 g, 0.1 1 mol) in dichloromethane (50 mL) was added into it in a dropwise manner over a period of 30 min.
  • the resultant mixture was stirred at room temperature for 3 h after which DM water (300 mL) was added to it, followed by organic layer separation.
  • the organic layer was washed with 1M HC1 soln. (10 mL) and after separation and drying with anh. Na 2 S0 4 solvent was evaporated to afford the desired product as an off-white solid (18.3 g, 96 % yield).
  • FTIR (neat): 3027, 2946, 2934, 2874, 1768, 1688, 1600, 1491, 1443, 1372, 1218, 1165, 1 154, 1090 cm '1 .
  • FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251 , 1 188, 1140, 1093, 919, 860, 845, 737 cm 4 .
  • Example 8 Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one (V) in presence of DABCO
  • Example 16 Synthesis of cis/trans-2-(4-(4-ch!orophenyl)cyclohexyl)naphthalen-l-ol (VIII) and method for separation of cis and trans isomers
  • reaction mass was cooled to RT and solvent was evaporated under reduced pressure and 10% aqueous solution of hydrochloric acid (180 mL) was added to the residue.
  • the resultant mixture was extracted with DCM (150 mL) and evaporated to give crude product (47.0 g). Generally average yield of the product ranges from 70 to 80 %.
  • Example 17 Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthaIene-l,4-dione (IX) in presence of sodium nitrite/ 50% aqueous sulphuric acid.
  • FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451, 1306, 1287, 1157, 1089, 944, 886, 801, 725 cm -1 .
  • FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm -1 .

Abstract

A process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- 1(2H)-one (V), key intermediate for synthesis of Atovaquone [I]. The process for preparation of compound(V) comprising of the steps of; i) Reaction of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of base in organic solvent to yield compound of formula (XIa) ii) Elimination of trifluoroacetyl functionality of compound (XIa) in organic solvent and in presence of organic base to give compound of formula (V). The invention also provides a Process for preparation of compound(XIa) comprising of the steps of; i) reaction of 2-(4-(4-chlorophenyl)-l-hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of organic base in organic solvent. A further process is provided for preparation of compound(V) from compound (XIa) comprising elimination reaction of trifluoroacetyl functionality compound (XIa) in organic solvent and in presence of organic base.

Description

IMPROVED SYNTHESIS OF 2-(4-(4-CHLOROPHENYL) CYCLOHEX-l-ENYD-3.4-
DIHYDRONAPHTHALEN-H2HVONE; AN INTERMEDIATE FOR ATOVAQUONE
FIELD OF THE INVENTION
The invention relates to a novel process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one, key intermediate for synthesis of Atovaquone [I].
BACKGROUND OF THE INVENTION
2-[7>a«5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, as disclosed in US patent number US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria, toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US patent number US 5206268, US 5856362 and US 5567738, respectively. The mechanism of action for Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome bci complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron Lett, 1998, 39 7629).
Figure imgf000003_0001
There are only few reports available for the synthesis of Atovaquone employing various synthetic alternatives essentially based on Hunsdiecker decarboxylative condensation, which proceeds through a radical mechanism. However, the overall yield of the desired product in almost all the reported processes is exceedingly poor i.e. economically far from being attractive. Our previous co-pending PCT application numbered PCT/IB201 1/001507 dated 28 June 201 1 entitled "Novel method for synthesis of Atovaquone", describes a novel, cost effective, eco-friendly, industrial process for synthesis of Atovaquone without using any toxic, hazardous chemicals, disclosers of which, including prior art are incorporated herein by reference.
Stepwise schematic representation of chemistry employed in co-pending PCT application number PCT/IB201 1/001507 entitled "Novel method for synthesis of Atovaquone" for synthesis of Atovaquone is shown below in Scheme I.
Scheme I
STEP-1
Figure imgf000004_0001
STEP-2
Figure imgf000004_0002
IV [trans] V[Mixture of diastereomers] STEP-3
Figure imgf000005_0001
STEP-4
Figure imgf000005_0002
VII [cis/trans]
Figure imgf000006_0001
VIII (cis/trans) IX(cis trans)
STEP-7
Figure imgf000006_0002
\X[cis/trans] X[cis/tram]
STEP-8
Figure imgf000006_0003
X[cis trans]
I [trans]
In the above scheme I, hydroxyl compound IV is dehydrated with a Br0nsted acid to yield compound V in around 50% isolated yield, schematically represented in Step 2, rendering process for the synthesis of Atovaquone poor in terms of atom economy and thus increasing the raw material cost for manufacture of Atovaquone. Hence there is a need for invention of an efficient and more economic process for dehydration of compound (IV) to compound (V).
Figure imgf000007_0001
IV [trans] VfMixture of diastereomers]
This invention describes a) Genesis of poor yield of compound (V) from compound (VI) and, b) An alternative chemistry which is efficient, easily operable, high yielding process for synthesis of compound (V) from compound (VI).
OBJECTS OF THE INVENTION
Thus an object of this invention is to provide a novel cost effective and efficient process for the synthesis of an intermediate of Atovaquone i.e. 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V).
Another object of the present invention is synthesis of the novel compound 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through esterifcation of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (IV) with trifluro acetic anhydride.
Yet another object of the present invention is synthesis of the compound 2-(4-(4- chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V) from 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through E2 elimination (elimination, bimolecular) of trifluro acetyl functionality. SUMMARY OF INVENTION
An aspect of the present invention is to provide compound 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V), a key intermediate for synthesis of Atovaquone through a novel, cost effective, green, and eco-friendly process.
A process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4- dihydronaphthalen-l(2H)-one (V) comprising the steps of-
1) Esterification of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (IV) with trifluro acetic anhydride in presence of base such as pyridine and catalytic amount of N-N-dimethyl amino pyridine (DMAP) in organic solvent such as dichloromethane to obtain 4-(4-chlorophenyl)-l-(l-oxo-l ,2,3,4- tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) in quantitative yield.
2) Elimination of trifluoroacetyl functionality of 4-(4-chlorophenyl)-l-(l-oxo- l,2,3,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) in organic solvent such as toluene or xylene and in presence of organic base such as 1,4- diazabicyclo[2.2.2]octane (DABCO) or Ν,Ν-Diisopropylethylamine to obtain diastereomeric mixtures of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one [V] in excellent yields.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig 1 : Scheme showing rate of protonation of compound (IV) for formation of compound (A) & (B) via path [A] and [B]
Fig 2: Scheme showing that in path A the A-I intermediate on a pericyclic "e«e" reaction
th
((March's Advanced Organic Chemistry, 6 edition, Wiley Interscience, Chapter 17, page 1 103-1105) gives diastereomeric mixture of compound (V)
Fig 3: Scheme showing that in path B; oxygen of carbonyl functionality was protonated, which through "retro-aldoV reaction gives a-tetralone (XII) & 4-(4- chlorophenyl)cyclohexanone (III) DETAILED DESCRIPTION OF THE INVENTION
On reaction of compound (IV) with catalytic amount of a Br0nsted acid to give compound (V), it has been observed that along with diastereiomeric mixture of compound (V) having the following structures [a] and [b],
Figure imgf000009_0001
two other product namely a-tetralone (XII) and 4-(4-chlorophenyl)cyclohexanone (III) are produced and the ratio of (V) and a-tetralone (XII) & 4-(4-chlorophenyl)cyclohexanone (III) taken together is found to be approximately 1 :1.
Surprisingly, on reaction of compound (IV) with Lewis acid hardly any amount of compound (V) is formed, but it is observed that compound (IV) practically completely degraded to α-tetralone (XII) and 4-(4-chlorophenyl)cyclohexanone (III).
Hence, one could rationalized the rate of protonation of compound (IV) for formation of compound (A) & (B) via path [A] and [B] was comparable (figure 1) and subsequent reactions through path A and B are even faster which result in equal proportion of compound (V) and α-tetralone (XII) & 4-(4-chlorophenyl)cyclohexanone (III) taken together.
Once could further rationalized that in case of path A, where "OH" functionality was protonated and resulted into better leaving group which was readily eliminated via El elimination to yield tetra-substituted intermediate (A-I). This (A-I) intermediate on a pericyclic "e«e" reaction ((March's Advanced Organic Chemistry, 6th edition, Wiley Interscience, Chapter 17, page 1 103-1105) gives diastereomeric mixture of compound (V) (figure 2) as both the adjacent hydrogen are chemically equivalent. In case of path B; oxygen of carbonyl functionality was protonated, which through "retro-aldol" reaction gives a-tetralone (XII) & 4-(4-chlorophenyl)cyclohexanone (III) as shown in figure 3.
In case of Lewis acid such as TiCl4 or ZrCl4 the reaction proceeds through only path B, hence only α-tetralone (XII) and 4-(4-chlorophenyl)cyclohexanone (III) are formed and no compound (V) is obtained.
Since, olefin formation through El elimination mechanism did not give compound (V) in desirable yield from compound (IV), hence synthesis of compound (V) has been attempted through E2 elimination mechanism.
Surprisingly, it was also observed that compound (IV) is sensitive to bases giving rise to corresponding retro aldol products very fast in practically qutitative yields.
When "OH" functionality of compound (IV) was attempted to derivatise to its corresponding acetoxy derivative in presence of strong base such as sodium hydride, instead of obtaining the corresponding acetoxy product, complete reto-aldol reaction was observed to give α-tetralone (XII) and 4-(4-chlorophenyl)cyclohexanone (III).
Hence, selection of a base for carrying out esterification reaction was limited to only organic amine, which only polarizes hydroxyl function such as pyridine, N,N- di/sopropylethylamine, etc.
Thus, "OH" functionality of compound (IV) was attempted to derivatise to its corresponding acetoxy or sulfonate derivative through reaction of compound (IV) with acetic anhydride/ pyridine, trifluroacetic anhydride/ pyridine, methane sulfonyl chloride/pyridine, trifilic anhydride/pyridine or toluene sulfonyl chloride/pyridine in presence of catalytic amount of Ν,Ν-dimethylamino pyridine (DMAP).
Figure imgf000011_0001
IV [trans] [XIa-d]
Surprisingly, only trifluroroacetate was obtained as a crystalline solid in excellent yield and in other cases no ester was formed.
The E2 elimination (March's Advanced Organic Chemistry, 6th edition, Wiley Interscience, Chapter 17, page 1477-1501) of compound (XI) on refluxing with DABCO in toluene for 5 h gave pure compound (V) in more than 90% isolated yield in 1 : 1 ratio of two diastereomers as theory demands, since two β-hydrogens are kinetically identical and proton abstraction is the rate determining step.
As per the present invention, the synthesis of compound (V) from compound (IV) comprised of the following two steps 1) synthesis of compound (XIa) from compound (IV) in 90% isolated yield (example 1) and 2) synthesis of compound (V) from compound (XIa) in 90% isolated yield (example 7). Hence overall isolated yield for compound (V) from compound (IV) comes to 81 %, which is 31% more than that obtained by the process reported in our co-pending PCT application PCT/IB2011/001507(Example 10; yield 50%).
It is worthwhile to mention that change in elimination mechanism from El elimination of compound (IV), to E2 elimination as mentioned hereinbefore resulted in significant improvement in atom economy of the process as no impurities were formed. This makes process efficient with respect to cost and operation friendliness.
Indeed, improvement in the process for synthesis of compound (V) resulted in making the process for synthesis of Atovaquone described in our co-pending PCT application PCT/IB201 1/001507, more competitive compared to all the reported literature processes. Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra 12.
Analytical Methods:
The purity was determined by HPLC using a Shimadzu LC 2010 system equipped with a column (Purosphere star RP-18e (4.6 x 150mm), 5μηι), column oven temperature 25 °C and UV visible detector (UV at 340nm). Mobile phase was buffer: acetonitrile (55:45) with flow rate 3.0 mL"1, injection volume 20 μΐ. Gas-Liquid chromatography analysis was carried out on Shimadzu GC 2010 using Column: DB-5 (30m x 0.53mm x 0.5mm) and having FID detector (Detector-300 °C, Injector- 280°C; Nitrogen -4psi, injection volume 20 μΐ). NMR spectra were obtained at 200 and 400 MHz Bruker instruments, with CDC13 as solvent unless otherwise stated. Chemical shifts (δ) are given in ppm relative to tetramethylsilane (δ = 0 ppm). IR spectra were recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm"1. DSC was recorded on Perkin Elmer model Diamond DSC at the rate of 10 °C/min, and endothermic peak was recorded in 0 C.
Example 1: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3,4-tetrahydronaphthalen-2- yl)cyclohexyl 2,2,2-trifluoroacetate (XIa)
Figure imgf000012_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3,4-dihydronaphthalen- 1 - (2H)-one (15.0 g, 0.04 mol) and dissolved in dichloromethane (150 mL) at room temperature. To the above solution were added pyridine (8.4 g, 0.11 mol) and DMAP (0.3 g, 2.0 mmol). The reaction mass was cooled to 0 °C and trifluoroacetic anhydride (22.2 g, 0.1 1 mol) in dichloromethane (50 mL) was added into it in a dropwise manner over a period of 30 min. The resultant mixture was stirred at room temperature for 3 h after which DM water (300 mL) was added to it, followed by organic layer separation. The organic layer was washed with 1M HC1 soln. (10 mL) and after separation and drying with anh. Na2S04 solvent was evaporated to afford the desired product as an off-white solid (18.3 g, 96 % yield).
FTIR (neat): 3027, 2946, 2934, 2874, 1768, 1688, 1600, 1491, 1443, 1372, 1218, 1165, 1 154, 1090 cm'1.
l NMR (CDCI3, 200 MHz): δ 1.59-1.67 (m, 3H), 3.89-3.94 (m, 2H), 2.06-2.18 (m, 3H), 2.69- 2.78 (m, 3H), 3.04-3.09 (m, 2H), 3.79-3.83 (m, 1H), 7.15 (d, 2H), 7.26-7.36 (m, 4H), 7.49-7.53 (m, 1H), 8.00 (d, 1H).
13C NMR (CDCI3, 50 MHz): 24.4, 28.4, 29.0, 29.3, 29.9, 31.4, 42.2, 52.4, 91.7, 126.8, 127.5, 128.0, 128.6, 131.8, 133.3, 133.6, 143.2, 144.7, 155.9, 156.3, 196.4.
MS (EI): C24H22C1F303 : 450.12; [M-(-OCOCF3)]+: 337.10;
DSC peak at 148.56. °C (10°C/min)
Example 2: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3,4-tetrahydronaphthalen-2- yl)cyclohexyl acetate (Xlb)
Figure imgf000013_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l-(2H)-one (10.0 g, 0.03 mol) and dissolved in dichloromethane (100 mL) at room temperature. To the above solution were added pyridine (3.4 g, 0.04 mol) and DMAP (0.2 g, 2.0 mmol). The reaction mass was cooled to 0 °C and acetic anhydride (4.5 g, 0.05 mol) in dichloromethane (20 mL) was added into it in a dropwise manner over a period of 20 min. The resultant mixture was stirred at room temperature for 24 h after which minor amount of the corresponding olefin product was identified by TLC analysis. However, majority of the starting material remained unchanged even after this time. The olefin product was not isolated due to very low yield.
Example 3: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3»4-tetrahydronaphthalen-2- yl)cyclohexyI acetate (Xlb) in acetic anhydride as the medium
Figure imgf000014_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 -(2H)-one (10.0 g, 0.03 mol) and dissolved in acetic anhydride (50 mL). To the above solution, cooled to 0 °C, were added pyridine (3.4 g, 0.04 mol) and DMAP (0.2 g, 2.0 mmol). The resultant mixture was stirred at room temperature for 2 h followed by stirring under reflux for 24 h after which time the reaction mass turned black for which TLC analysis showed undesired spots concluding that reaction underwent undesired path.
Example 4: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3,4-tetrahydronaphthalen-2- yl)cyclohexyl trifluoromethanesulfonate (XIc)
Figure imgf000015_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l-(2H)-one (5.0 g, 0.014 mol) and dissolved in dichloromethane (50 mL) at room temperature. To the above solution were added pyridine (2.8 g, 0.035 mol) and DMAP (0.2 g, 2.0 mmol). The reaction mass was cooled to 0 °C and triflic anhydride (10.0 g, 0.035 mol) in dichloromethane (30 mL) was added into it in a dropwise manner over a period of 20 min. The resultant mixture was stirred at room temperature for 24 h even after which time no conversion of the starting material could be observed due to which the reaction mass was disposed off carefully.
Example 5: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3?4-tetrahydronaphthalen-2- yl)cyclohexyl methanesulfonate (XIc)
Figure imgf000016_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l-(2H)-one (5.0 g, 0.014 mol) and dissolved in pyridine (50 mL) at room temperature. To the above solution was added DMAP (0.2 g, 2.0 mmol). The reaction mass was cooled to 0 °C and methanesulfonyl chloride (2.5 g, 0.035 mol) in dichloromethane (30 mL) was added into it in a dropwise manner over a period of 20 min. The resultant mixture was stirred at room temperature for 24 h even after which time no conversion of the starting material could be observed due to which the reaction mass was disposed off carefully.
Example 6: Synthesis of 4-(4-chlorophenyl)-l-(l-oxo-l,2,3i4-tetrahydronaphthalen-2- yl)cyclohexyl 4-methylbenzenesulfonate (Xld)
Figure imgf000017_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 -(2H)-one (5.0 g, 0.014 mol) and dissolved in pyridine (50 mL) at room temperature. To the above solution was added DMAP (0.2 g, 2.0 mmol). The reaction mass was cooled to 0 °C and p- toluenesulfonyl chloride (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added into it in a dropwise manner over a period of 20 min. The resultant mixture was stirred at room temperature for 24 h even after which time no conversion of the starting material could be observed due to which the reaction mass was disposed off carefully.
Example 7: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one (V) in presence of DABCO
Figure imgf000017_0002
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, were charged 4-(4-chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (5.0 g, 0.01 mol) and DABCO (3.1 g, 0.027 mol) and dissolved in toluene (50 mL) at room temperature. The reaction mass was refluxed for 5 h after which it was cooled and toluene removed under reduced pressure. To the resultant residue was added 1 M HC1 (20 mL) and extracted with dichloromethane (2x 50 mL). The organic layer was dried over anh. Na2S04 and evaporated to obtain desired product which was recrystallized from methanol to give product as white solid (3.3 g, 90 % yield).
FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251 , 1 188, 1140, 1093, 919, 860, 845, 737 cm4.
1H NMR (CDC13, 200 MHz): δ 1.78-1.88 (m, 2H), 2.12-2.32 (m, 6H), 2.83-2.86 (m, IH), 3.06 (s, 2H), 3.18-3.24 (m, IH), 5.56 (d, IH), 7.17-7.19 (m, 2H), 7.27-7.35 (m, 4H), 7.49 (t, IH), 8.07 (d, lH).
,3C NMR (CDCb, 50 MHz): 27.0, 27.2, 28.3, 28.4, 28.7, 29.8, 33.4, 39.4, 55.6, 56.0, 124.1 , 124.2, 126.6, 127.4, 128.2, 128.4, 128.7, 131.8, 132.8, 136.0, 144.0, 145.4, 145.4, 198.8, 198.9. MS (EI): C22H2]C10 : 336.12; [M+H]+: 337.10
DSC peak at 136.02. °C (10°C/min)
Example 8: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one (V) in presence of DABCO
Figure imgf000018_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, were charged 4-(4-chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (5.0 g, 0.01 mol) and DABCO (3.1 g, 0.027 mol) and dissolved in xylene (50 mL) at room temperature. The reaction mass was refluxed for 2 h after which it was cooled and xylene removed under reduced pressure. To the resultant residue was added 1 M HCl (20 mL) and extracted with dichloromethane (2x 50 mL). The organic layer was dried over anh. Na2S04 and evaporated to obtain desired product which was recrystallized from methanol to give product as white solid (3.31 g, 90 % yield).
Example 9: Synthesis of 2-(4-(4-chlorophenyl) cycIohex-l-enyI)-3,4-dihydronaphthalen- l(2H)-one (V) in presence of Ν,Ν-Diisopropylethylamine
Figure imgf000019_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, were charged 4-(4-chlorophenyl)- 1 -(1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (5.0 g, 0.01 mol) and N,N-Diisopropylethylamine (3.6 g, 0.025 mol) and dissolved in toluene (50 mL) at room temperature. The reaction mass was refluxed for 5 h after which it was cooled and toluene removed under reduced pressure. To the resultant residue was added 1 M HCl (20 mL) and extracted with dichloromethane (2x 50 mL). The organic layer was dried over anh. Na2S04 and evaporated to obtain desired product which was recrystallized from methanol to give product as white solid (3.0 g, 85 % yield). Example 10: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4- dihydronaphthalen-l(2H)-one (V) (Co-pending PCT application
Figure imgf000020_0001
IV
2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one
(122.0 g, 0.0.345mol) was charged in a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (2 L) was added to suspend the material and p- toluene sulfonic acid (3.05 g, 2.5 mol %) was added to the reaction mass which was then heated to 60 °C and stirred for 2h. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under pressure to obtain residue. To the residue, was added ethyl acetate (1500 mL) and washed with sat. NaHC03 soln. and brine followed by evaporation of solvent to give crude product which was further re-crystallised from methanol to obtain white solid compound (V) (55.2 g, 50%).
FTIR (neat): 3020, 3045, 2920, 2894, 2863, 2839, 1683, 1597, 1491, 1218, 1088, 818, 747 cm"
1
1H NMR (CDCI3, 400 MHz): δ 1.79-1.96 (m, 2H), 2.16-2.34 (m, 6H), 2.83-2.87 (m, 1H), 3.18 (s, 2H), 3.19-3.24 (m, 1H), 5.58 (d, 1H), 7.17-7.35 (m, 6H), 7.49 (t, 1H), 8.08 (d,lH); 13C NMR (CDCI3, 100 MHz): S 27.0 (27.2), 28.3 (28.5), 28.8, 29.8 (29.9), 33.4 (33.5), 39.3(39.4), 55.7(56.0), 124.1 (124.2), 126.7, 127.4 (127.5), 128. 3 (128.31), 128.4 (128.5), 128.7, 131.5, 132.8 (132.9), 133.4, 136.0 (136.1), 144.0 (144.1), 145.4 (145.5), 198.8 (198.9); MS (EI): C22H2iC10: 336.12; [M+H]+: 337.10 DSC peak at 136.02. °C (10°C/min)
Example 11: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4- dihydronaphthalen-l(2H)-one in presence of TSA
Figure imgf000021_0001
2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one (12.0 g, 0.0.034 mol) was charged in a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (200 mL) was added to suspend the material and /?-toluene sulfonic acid (0.3 g, 2.5 mol %) was added to the reaction mass which was then heated to 60 °C and stirred for 6 h. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under pressure to obtain residue. To the residue, was added ethyl acetate (150 mL) and washed with sat. NaHC03 soln. and brine followed by evaporation of solvent to give crude product which was further recrystallised from methanol to afford white solid compound (5.3 g, 50 % yield). The mother liquor obtained after re-crystallisation was subjected to GC analysis wherein both a-tetralone and 4-(4-chlorophenyl) cyclohexanone were identified to be present in approx. 1 : 1 ratio (by respective retention times and AUCs in the mother liquor) and in 50 % yield.
GC retention time:
a-tetralone (XII): 17.21 min (Area % : 46)
4-(4-chlorophenyl) cyclohexanone (III): 24.31 min (Area % : 54) Spectral data for 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)- one:
FTIR (neat): 3020, 3045, 2920, 2894, 2863, 2839, 1683, 1597, 1491, 1218, 1088, 818, 747 crn 1.1!! NMR (CDC13, 400 MHz): δ 1.79-1.96 (m, 2H), 2.16-2.34 (m, 6H), 2.83-2.87 (m, 1H), 3.18 (s, 2H), 3.19-3.24 (m, 1H), 5.58 (d, 1H), 7.17-7.35 (m, 6H), 7.49 (t, 1H), 8.08 (d,lH); 13C NMR (CDC13, 100 MHz): δ 27.0 (27.2), 28.3 (28.5), 28.8, 29.8 (29.9), 33.4 (33.5), 39.3(39.4), 55.7(56.0), 124.1 (124.2), 126.7, 127.4 (127.5), 128. 3 (128.31), 128.4 (128.5), 128.7, 131.5, 132.8 (132.9), 133.4, 136.0 (136.1), 144.0 (144.1), 145.4 (145.5), 198.8 (198.9); MS (EI): C22H21C10: 336.12; [M+H]+: 337.10
Example 12: Retro -Aldol reaction catalyzed by zirconium tetrachloride
Figure imgf000022_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)- 1 -hydroxy cyclohexyl)-3 ,4-dihydronaphthalen- 1 -(2H)-one (5.0 g, 0.04 mol) and dissolved in toluene (50 mL) at room temperature. To the above solution was added ZrCl4 (0.33 g, 1.4 mmol) and the reaction mass was stirred at 50 °C for 2 h. The reaction mass showed complete conversion of starting material to a-tetralone and 4-(4- chlorophenyl) cyclohexanone in 1 :1 ratio and no olefin product could be identified and isolated. Example 13: Retro -Aldol reaction catalyzed by sodium hydride
Figure imgf000023_0001
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged with sodium hydride (0.36 g) and tetrahydrofurane (10 mL). To above reaction mixture solution of ((2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l - (2H)-one (1.0 g) and in tetrahydrofurane (10 mL) was added slowly at room temperature. The reaction mass was stirred at 25 °C for 0.5 h. Then acetic anhydride (0.31 g) was added and stirred further for 3 h at RT. The reaction mass showed complete conversion of starting material to a-tetralone and 4-(4-chlorophenyl) cyclohexanone in 1 : 1 ratio and no corresponding acylated product could be identified and isolated.
Example 14: Synthesis of c«/ira«s-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (VI)
Figure imgf000024_0001
2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3, 4-dihydronaphthalen-l(2H)-one (51.0g, 0.151 mol) was dissolved in acetone (1.1 L) at RT and transferred to a Parr autoclave reactor. Platinum oxide (0.097 g, 3 mol %) was added to the reaction mass and flushed twice with nitrogen and once with hydrogen. Subsequently, a hydrogen pressure of 5 kg/cm2 was maintained for 4-5h at RT after which the platinum black was filtered off through a Celite bed. The mother liquor was evaporated under reduced pressure to give crude product which was re-crystallized from methanol to give product as white solid (43.29g, 90% yield). Generally yield of the product ranges from 85to 95 %.
C/Vtra«5,-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one ( 10 g) was suspended in cyclohexane (100 mL) and stirred for 1 h. c ,s-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was soluble in cyclohexane and tr<ms-2-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one remained insoluble (4.8 g).
FTIR (neat): 2917, 2887, 2850, 1681, 1491, 1294, 1089, 1012, 749, 530 cm"1.
1H NMR (CDCb, 400 MHz): δ 1.24-1.28 (m, 1H), 1.44-1.59 (m, 3H), 1.74-1.85 (m, 3H), 1.90- 196 (m, 3H), 2.02-2.09 (m, 2H), 2.19-2.27 (m, 1H), 2.99-3.09 (m, 2H), 7.14-7.24 (m, 2H), 7.25- 7.35 (m, 5H), 7.47-7.5 (t,lH), 8.05-8.07 (d,lH) ; MS (EI): C22H23C10 : 338.15 [M+H]+: 339.00; DSC peak at 82.95 °C (10°C/min) Example 15: Synthesis of cis/trans-2-bromo-2-(4-(4-chlorophenyl)cyc!ohexyl)-3,4- dihydronaphthalen-l(2H)-one (VII) and method for separation of cis and trans isomers
Figure imgf000025_0001
C5/tra«5'-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one (43.2 g, 0.127 mol) was charged into a reactor equipped with thermo-pocket and dropping funnel. Acetic acid (86.4 g) and diethyl ether (1.5 L) were added and the reaction mass was cooled to 0 °C. Bromine (24.5 g, 0.153 mol) was dissolved in diethyl ether (100 mL) and added drop wise to the reaction mass at 0 °C. The resultant orange solution was stirred at 0 °C for lh and gradually the temperature was allowed to increase to 15-20 °C when the reaction mass started decolourizing, after which reaction temperature was allowed to increase upto 25 °C. After completion of reaction, dichloromethane (300 mL) was added to dissolve solid, if any, precipitated during the reaction. Organic layer was washed with water (2 x 500 mL) and then with aqueous solution of 5% sodium thiosulphate (500 mL). Solvent was removed from the reaction mass under reduced pressure to obtain product as white solid (53.1 g, 99 %). Generally yield of the product ranges from 95 to 99 %.
C/Vtra«5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)- one (39 g) was suspended in methanol (100 mL) and stirred for 1 h. c s-2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was soluble in methanol and trara-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one remained insoluble. Pure /ra«s-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one was obtained through filtration as white solid (19 g) and major cw-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was obtained after evaporation of solvent under reduced pressure as sticky semi-solid material (21 g).
7>fl«s-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one
FTIR (neat): 2929, 2850, 1687, 1599, 1490, 1454, 1292, 1234, 1090, 1013, 916, 810, 747, 631 cm"1. l NMR (CDCb, 400 MHz): δ 1.29-1.33 (m, IH), 1.44-1.48 (m, IH), 1.58-1.65 (m, 2H), 1.83- 1.91 (m, 2H), 2.06-2.09 (d, IH), 2.25-2.31 (m, IH), 2.38-2.54 (m, 3H), 2.70-2.76 (t, IH), 2.93- 2.97 (d, IH), 3.27-3.31 (m, IH), 7.15-7.17 (d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, IH) 7.52- 7.56 (t,lH), 8.18-8.20 (d,lH) ; 13C NMR (CDCI3, 100 MHz): δ 27.0, 28.3, 29.1, 31.5, 33.9, 34.2, 43.9, 44.2, 74.7, 127.1, 128.1, 128.3, 128.4, 128.6, 128.9, 129.1, 130.3, 131.6, 133.8, 142.5, 145.2, 190.3
DSC: peak at 182.95 °C
Example 16: Synthesis of cis/trans-2-(4-(4-ch!orophenyl)cyclohexyl)naphthalen-l-ol (VIII) and method for separation of cis and trans isomers
Figure imgf000026_0001
Vtl
Potassium rt-butoxide (31.2 g, 0.278 mol) was charged into a reactor containing dimethoxyethane (500 mL) at room temperature. Temperature of the reaction mass was increased to 40 °C and to this was added a solution of cis/trans-2- xomo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (53.0 g, 0.126 mol) in dimethoxyethane (500 mL). Temperature of the reaction mass was further increased to 80°C and was allowed to stir for 1.5 h at this temperature. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under reduced pressure and 10% aqueous solution of hydrochloric acid (180 mL) was added to the residue. The resultant mixture was extracted with DCM (150 mL) and evaporated to give crude product (47.0 g). Generally average yield of the product ranges from 70 to 80 %.
Mixture of c/Vtra/i5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (25 g) was suspended in cyclohexane and stirred for 1 h. cw-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol was soluble in cyclohexane and trans-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol remained insoluble. Pure tra«,y-2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was obtained through filtration as light orange solid (7.5 g) and major czs-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one was obtained after evaporation of solvent under reduced pressure as sticky semi-solid material (1 1 g). Obtained major cw-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol was further purified by column chromatography to obtain pure c/s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol as sticky semi-solid brown colored material (7 g).
7> «5'-2-(4-(4-chIorophenyl)cycIohexyl)naphthalen-l-oI
FTIR (neat): 3563, 3016, 2928, 2853, 2400,, 1492, 1263,1216, 1094, 807, 768,755 cm"1. lH NMR (CDCb, 400 MHz): δ 1.63-1.85 (m, 4H), 2.06-2.09 (m, 4H), 2.68-2.70 (t, IH), 3.03- 3.08 (t, IH), 7.15-7.17(d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, IH) 7.82-7.84 (d,lH), 8.12-8.14 (d,lH) ; ,3C NMR (CDCI3, 100 MHz): δ 33.18, 34.58, 37.01, 43.51, 76.73, 127.1 , 128.3, 129.0, 129.1 , 130.3, 131.6, 133.8, 145.71, 147.24 MS (EI): C22H2iC10: 336.12; [M-H]': 335.20
DSC: peak at 195.14°C PXRD [20] (Cu K«i = 1.54060 A, = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV):
10.76, 12.38, 13.00, 13.33, 13.76, 14.37, 15.51, 16.10, 17.41, 17.73, 18.71, 19.67, 20.05, 21.36, 22.39, 23.04, 23.40, 24.02, 24.56, 26.1 1, 27.72, 28.97, 30.01 , 31.78 c/s-2-(4-(4-chlorophenyl)cyclohexyI)naphthalen-l-ol
FTIR (neat): 3563, 3434, 2928, 2853, 1724, 1488, 1265, 1088, 806 cm-1.
Ή NMR (CDCb, 400 MHz): δ 1.29-1.33 (m, IH), 1.44-1.48 (m, IH), 1.55-1.67 (m, 3H), 1.82- 1.88 (m, 2H), 2.06-2.09 (d, IH), 2.24-2.31 (m, IH), 2.37-2.54 (m, 2H), 2.70-2.76 (t, IH), 2.93- 2.97 (d, IH), 3.26-3.34 (m, IH), 7.15-7.17(d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, IH) 7.52-7.56 (t,lH), 8.17-8.19 (d,lH) ; 13C NMR (CDC13, 100 MHz): S 27.0, 28.3, 29.1, 31.5, 33.9, 34.1 , 43.9, 44.2, 74.7, 127.1, 128.3, 129.0, 129.1, 130.3, 131.6, 133.8, 142.5, 145.2, 190.3 MS (EI): C22H21C10: 336.12; [M-H]": 335.20
Example 17: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthaIene-l,4-dione (IX) in presence of sodium nitrite/ 50% aqueous sulphuric acid.
Figure imgf000028_0001
To a stirred solution of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (42.3 g, 125.9 mmol) in 1,4-dioxane (850 mL) were added 50 % aqueous sulphuric acid (170 mL) and sodium nitrite (17.4 g, 251.7mmol) at 5 °C and temperature of the resultants reaction mixture was increased to 80 °C and stirred for another 2 h. After cooling to RT, water (50 mL) was added to the reaction mass and extracted with ethyl acetate (3x 500 mL), dried over anhydrous Na2S04 and solvent was evaporated to crude product, which was further purified by column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid. (30.3 g, 70%) Example 18: Synthesis of c/s//rans-ia-(4-(4-chlorophenyl)cyclohexyI)naphtho[2,3- b]oxirene-2,7(laH,7aH)-dione (X)
Figure imgf000029_0001
4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (13.5 g, 38.5 mmol) was charged into a reactor along with 1,4-dioxane (135 mL) at RT. To this were added sodium carbonate (4.5 g, 42.4 mmol) and a 30% soln. of H202 (5.23 g, 154.0 mmol) and the reaction mass was refluxed for 30 min. After cooling the reaction mass to RT, water (50 mL) was added and extracted with ethyl acetate (3*300 mL). Solvent was removed under reduced pressure to give product as off-white solid (13.7 g, 96% yield).
FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451, 1306, 1287, 1157, 1089, 944, 886, 801, 725 cm-1.
1H NMR (CDCb, 400 MHz): δ 1.28-1.41 (m, 2H), 1.56-1.62 (t, 2H), 1.9 (s, 4H), 3.96 (s, 1H) 7.16-7.18(d, 2H), 7.28-7.29 (d, 2H), 7.76-7.78 (t, 2H) 7.97-7.98 (d,2H), 8.03-8.05 (d,2H) ;13C NMR (CDCI3, 100 MHz): δ 26.6, 29.3, 33.3, 33.4, 34.3, 37.7, 43.3, 57.7, 58.2, 66.3, 66.9, 126.5, 126.6, 127.6, 128.4, 128.5, 131.5, 131.6, 132.8, 134.3, 134.6, 143.2, 145.2, 191.5, 192.1
Example 19: Synthesis of Atovaquone [I]
Figure imgf000030_0001
x
To la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (13.5g, 1.6 mmol) taken in a reactor was added cone. H2S04 (135 mL) and stirred for 5 h at RT. Water (2 L) was added to the reaction mass and extracted with DCM (3*200 mL). Solvent was evaporated under reduced pressure to give crude product which was further re-crystallized from acetonitrile to obtain pure compound as a yellow solid (10 g, 74% yield).
FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm-1.
Ή NMR (CDCb, 400 MHz): δ 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m, 2H), 2.63 (t, 1H), 3.16 (t, 1H), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, 1H), 7.68 (t, 1H), 7.76 (t,lH), 8.07 (d, 1H), 8.13 (d, 1H); 13C NMR (CDC13, 100 MHz): δ 29.18, 34.34, 34.46, 34.64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02, 146.05, 152.98, 181.80, 184.56; MS (EI): C22H19C103: 366.1023; [M+Na]+: 388.95, [M-H]': 365.30; DSC peak at 220.44 °C (10°C/min)
DSC: peak at 221.2 °C
PXRD [20] (Cu K„i = 1.54060 A, Ka2 = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV): 7.30, 9.70, 10.79, 1 1.1 1, 1 1.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68, 25.35, 26.18, 26.84, 28.52, 28.70, 29.52, 30.68, 34.23, 36.84.

Claims

1) A process for preparation of compound(V)
Figure imgf000031_0001
comprising of the steps of; i) Reaction of 2-(4-(4-chlorophenyl)-l -hydroxy eye lohexyl)-3, 4-dihydronaphthalen- 1 (2H)-one (IV) with trifluro acetic anhydride in presence of base in organic solvent to yield compound of formula (XIa) ii) Elimination of trifluoroacetyl functionality of compound (XIa) in organic solvent and in presence of organic base to give compound of formula (V)
2) The process according to Claim 1 step i) wherein base used is is pyridine/dimethyl amino pyridine (DMAP).
3) The process according to Claim 1 step i) wherein organic solvent used is dichlormethane.
4) The process according to Claim 1 step i) wherein reaction is carried out at 25-30°C
5) The process according to Claim 1 step ii) wherein organic base used is 1,4- diazabicyclo[2.2.2]octane (DABCO) or N,N-Diisopropylethylamine. 6) The process according to Claim 1 step ii) wherein organic solvent used is toluene or xylene
7) The process according to Claim 1 step i) wherein reaction is carried out in tempreautre range 100-140°C
8) A Process for preparation of compound(XIa) comprising of the steps of; i) reaction of 2-(4-(4-chlorophenyl)-l -hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one (IV) with trifluro acetic anhydride in presence of organic base in organic solvent.
9) The process according to Claim 8 step i) wherein base used is pyridine/dimethyl amino pyridine (DMAP).
10) The process according to Claim 8 step i) wherein organic solvent used is dichlormethane.
11) The process according to Claim 8 step i) wherein reaction is carried out at 25-30°C
12) A Process for preparation of compound(V) from compound (XIa) comprising of the steps of; i) Elimination reaction of trifluoroacetyl functionality compound (XIa) in organic solvent and in presence of organic base
13) The process according to Claim 12 step i) wherein organic base used is 1 ,4- diazabicyclo[2.2.2]octane (DABCO) or N,N-Diisopropylethylamine.
14) The process according to Claim 12 step i) wherein organic solvent used is toluene or xylene 15) The process according to Claim 12 step i) wherein reaction is carried out in tempreautre range 100-140°C
16) A Process of conversion of compound (V) into Atovaquone (I) comprising the steps of; i) hydrogenation of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one[V] with Pt02 to obtain cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VI] ii) ketone bromination of cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VI] to obtain cis/trans mixture of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [VII] iii) elimination of cis/trans mixture of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)- 3,4-dihydronaphthalen-l(2H)-one [VII] with a strong base to give cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol [VIII] iv) oxidizing cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to obtain cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene- 1,4-dione [IX] v) base catalyzed epoxidation of cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX] to cis/trans mixture of la-(4-(4- chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) in presence of hydrogen peroxide vi) acid catalyzed hydrolysis of cis/trans mixture of la-(4-(4- chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) to obtain 2- [tra«5,-4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I] 17) Compound of formula (XIa)
Figure imgf000034_0001
PCT/IB2011/002134 2011-07-28 2011-09-14 Improved synthesis of 2-(4-(4-chlorophenyl) cyclohex-1-enyl) -3, 4-dihydronaphthalen-1 (2h)-one; an intermediate for atovaquone WO2013014486A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981874A (en) 1988-08-16 1991-01-01 Latter Victoria S Medicaments
US5206268A (en) 1988-08-16 1993-04-27 Burroughs Wellcome Co. Medicaments
US5567738A (en) 1992-08-07 1996-10-22 Glaxo Wellcome Inc. Use of 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-Naphthoquinone for the treatment of cancer
US5856362A (en) 1994-09-02 1999-01-05 Glaxo Wellcome Inc. Medicaments for the treatment of toxoplasmosis
WO2008122988A1 (en) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Process for preparation of atovaquone and the conversion of cis-isomer to trans- isomer

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* Cited by examiner, † Cited by third party
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US4981874A (en) 1988-08-16 1991-01-01 Latter Victoria S Medicaments
US5206268A (en) 1988-08-16 1993-04-27 Burroughs Wellcome Co. Medicaments
US5567738A (en) 1992-08-07 1996-10-22 Glaxo Wellcome Inc. Use of 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-Naphthoquinone for the treatment of cancer
US5856362A (en) 1994-09-02 1999-01-05 Glaxo Wellcome Inc. Medicaments for the treatment of toxoplasmosis
WO2008122988A1 (en) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Process for preparation of atovaquone and the conversion of cis-isomer to trans- isomer

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Title
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TETRAHEDRON LETT, vol. 39, 1998, pages 7629
WILLIAMS D R ET AL: "Synthesis of Atovaquone", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 39, no. 42, 15 October 1998 (1998-10-15), pages 7629 - 7632, XP004134267, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(98)01691-8 *

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