CA2041620C - An ortho-lithiation process for the synthesis of 2-substituted-1-(tetrazol-5-yl) benzenes - Google Patents
An ortho-lithiation process for the synthesis of 2-substituted-1-(tetrazol-5-yl) benzenes Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
A process utilizes the tetrazole functional group to direct lithiation at the ortho position of a phenyltetrazole and generate a nucleophilic aryllithium species which then undergoes reaction with an electrophile to generate a 2-substituted 1-(tetrazol-5-yl)benzene. The process is useful in the production of intermediates in the synthesis of angiotensin II antagonists. This novel process is a more cost effective and versatile route for the large-scale preparation of these key intermediates.
Description
TITLE OF THE INVENTION
AN ORTHO-LITHIATION PROCESS FOR THE SYNTHESIS OF
AN ORTHO-LITHIATION PROCESS FOR THE SYNTHESIS OF
2-SUBSTITUTED 1-(TETRAZOL-5-YL)BENZENES
BACKGROUND OF THE INVENTION
The renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hYPertension development and maintenance as well as in congestive heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
x~~~~
33/VJC8 - l - 18056 One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of angiotensin II (A II) are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist g activity and lack of oral absorption [M. Antonaccio.
Clin. Exp. Hy~ertens. A4, 27-46 (1982); D. H. P.
Streeten and G. H. Anderson, Jr., Handbook of hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp.
246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents ~5 4,207,324; 4,340,598; 4,576,958; and 4,582,847; and 4,880,804 in European Patent Applications 028,834;
245,637; 253,310; 323,841; and 291,969; and in articles by A.T. Chiu, e~t al. [Eur. J. Pharm. Exp.
Therap, 157, 13-21 (1988)] and by P.C. Wong, ~ ~l.
20 [J. Pharm. Ex~i Therav, 247, 1-7(1988)]. All of the cited references disclose compounds containing substituted imidazole and triazole compounds, which are generally bonded through a lower alkyl bridge to a substituted phenyl and preferably a biphenyl moiety 25 containing a carboxylic acid or an acid equivalent.
European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2H-imidazo-[4,5-~]pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.
33 /V,TC8 - 3 - 180564 ~~ ~- '~
The process previously used in the synthesis of 1-(tetrazol-5-yl)-2-(4-tolyl)benzene entailed the cross-coupling of p-tolylzinc chloride and 1-cyano-2-bromobenzene, the biphenyl adduct is then converted to the tetrazole with ammonium azide (Finnegan, et al., ~-Am. Chem. ~~, 80, 3908-11, 1958.) or trimethyltin azide (Aldrich, et al., US
Patent 4,870,186) to give the product 1-(tetrazol-5-yl)-2-(4-tolyl)benzene. The ammonium azide procedure requires long reaction times and produces low yields of the desired material. Prior to this invention, the preferred procedure required the use of trimethylstannyl chloride to generate the trimethylstannyl azide followed by reaction with the biphenyl adduct to give the desired tetrazole and the corresponding tin by-products. The disposal of these bY-Products is costly and coupled with the toxicity of tin make this route commercially unattractive.
These problems can be circumvented by the present invention which employs the reverse sequence of steps. The ortho-lithiation procedure is performed on (tetrazol-5-yl)benzene which is readily available from benzonitrile and ammonium azide (Finnegan, et. al.), or its N-trityl protected derivative, in high yields. The novel ortho-lithiation procedure allows for the preparation of the desired 1-<tetrazol-5-yl)-2-(4-tolyl)benzene through a more versatile and cost effective method.
~ ~ -a '~'~ L1.3.~~~' DETAILED DES RIPTIO_N OF THE INV:ENTI N
The novel process of this invention comprises as a first step the treatment of a (tetrazol-5-y1)benzene or an N-trityl protected derivative with a straight or branched (C1-C6)-alkyllithium in an aprotic solvent at a temperature of between -40 and 10 °C and for a reaction time ranging between 30 minutes and 5 hours. The lithiation of the (tetrazol-5-yl)benzene is directed by the tetrazole substituent to lithiate the benzene ring at the ortho position, Scheme 1.
The alkyllithium reagents preferably are n-butyllithium, sec-butyllithium and t-buytllithium;
the preferred aprotic solvents are tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether; the preferred reaction time is between 30 minutes and 2 hours; and the preferred reaction temperature is between -20 to 0 °C.
The second step of the process comprises reacting the ortho-lithiated intermediate either directly, or after transmetallation with an electrophile, Scheme 2. The reaction mixture containing the ortho-lithiated intermediate is cooled to -78 to -60 °C and the electrophile, E1, is added slowly. The reaction time ranges between 10 minutes and 5 hours and the reaction temperature ranges between -78 to 25° C. Alternatively, the ortho-lithiated intermediate reacts with a metal halide, where the metal is selected from the group consisting of Zn, Mg, Cu, B, A1, and Cd, to give the transmetallated intermediate which then reacts with an electrophile, E2, either in the presence or 33/VJC8 - 5 - 18056 ~~ t5 ~~ ~ ~~ ii absence of a phosphinated nickel or palladium catalyst activated, when necessary, by a Grignard or an aluminum hydride reagent at a reaction temperature of between -40 and 79°C for a reaction time of 30 minutes to 16 hours to give the desired ortho-substituted product. This two-step process decreases the processing time and improves the yield of the product, such as 1-(2-trityltetrazol-5-yl)-2-<4-tolyl)benzene.
The more preferred process is the generation of an aryllithium by treating the protected or unprotected form of the tetrazole with n-butyllithium at -20 to -10°C for between 30 minutes to 2 hours in tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether. The aryllithium intermediate is then reacted with zinc chloride in tetrahydrofuran while maintaining the temperature between -10 and 0°C. The nickel catalyst, (PPh3)2NiC12, and the electrophile, p-iodotoluene, in tetrahydrofuran at 0°C is activated with methylmagnesium chloride. The activated catalyst solution is added to the transmetallated product, arylzinc chloride, and maintaining the reaction temperature between 20 and 25°C for a reaction time of between 30 minutes and 16 hours.
Scheme 1 illustrates the ortho-lithiation of the protected and unprotected aryltetrazole species to give the ortho-lithiated products B and A, respectively. Scheme 2 illustrates the versatility of the aryllithium species, showing the addition of the electrophile directly to the aryllithium, ac well as the ability to transmetallate and then alkylate or arylate with the appropriate electrophile in the presence or absence of a catalyst.
td ~ ~~ ,~. :~ ~ ~
33/V,1C8 - 6 - 18056 Scheme 1 N'N H N'N Li N ~ N
n- BuLi /THF
-1 0°C Li R~ R' A
CPh3 CPh3 N'N ~ N'N /
NON ~ v NON
n- BuLi /THF' -1 0°C Li R' R' H
~h~m~2 CPh3 N-N/
N O N
Li R' B
Fn 11( L) n ~CPh3 N-N /CPh3 t NON
N O N N U N
R ~ ~L)n_t R' R' IEa 'w/ or w/o catalyst j ,CPh3 N-_N
NN
Ra R' R1 is: hydrogen, t-butyl, phenoxy , phenyl, 3o di(Cl-C6)alkylamino, or trimethylsilyl;
'. ~ "~y .. C- (r.1 f~n~ ~~.j: a ~,~ 4~r R2 is:
hydrogen, or trityl;
E1 is:
benzaldehyde, trimethylsilyl chloride, phenyl disulfide, methyl disulfide, carbon dioxide, ethylene oxide, tosyl azide, trimethylstannyl chloride, (Cl-C6)-alkyl iodide, iodine, or bromine;
R3 is:
a-hydroxybenzyl, trimethylsilyl, 2o thiophenyl, thiomethyl, carboxyl, 2-hydroxyethyl, azide, trimethylstannyl, (Cl-C6)-alkyl, iodide, or bromide, respectively;
E2 is benzaldehyde, (C1-C6) -alkanal, (C1-C6)-alkyl halide, wherein the halide is Br, Cl, I, aryl halide, wherein aryl is defined as phenyl or phenyl substituted with o-, m-, or p- (C1-C6) -alky, o,p-di (C1-C6) -alkyl, o-, m- or p-(C1-C6)-alkoxy,o-, m- or p-phenyl, o-, m- or p-cyano, m- or p- [carboxy- (cl-C6) -alkyl] , m- or p-nitro, o-, m- or p-chlorophenyl, and the halide is Br or I, bromine, iodine, or 3-bromopropene;
R4 i s a-hydroxybanzyl, a-hydroxy-(C1-C6)-alkyl, (C1-C6)-alkyl, phenyl , o-, m- or p-(C1-C6)-alkylphenyl, o,p-di(C1-C6)-alkylphenyl, o-, m- or p-(C1-C6)-alkoxyphenyl, 3- or 4-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6)-alkyl]phenyl, p- or m-nitrophenyl, o-, m- or p-chlorophenyl, bromide, iodide, or n,, (n na '~ ~:~ ~. ~~
2-propen-1-yl, respectively;
M is:
Zn, Mg, Cu, A1, or Cd;
L is:
Cl, Br, or I;
n is:
l~
2, or 3; and the catalyst is: phosphinated Ni and Pd complexes such as NiL2(PPh3)2, PdL2(PPh3)2, or Pd(PPh3)4, wherein L is as deffined above.
The preferred route used in the preparation of 1-(2-trityltetrazol-5-yl)-2-(4-tolyl)benzene is illustrated in Scheme 3 and which employs the ortho-lithiation of (2-trityltetrazol-5-yl)benzene.
followed by transmetallation of the lithiated species and cross'-coupling with 4-iodotoluene in the presence of a phosphinated nickel catalyst activated by CH3MgCl.
~W tit .~ ~' l i chem.
CPh3 CPh~
N'N N'N
NON NON
ZnCl2/THF
Li -10°C nCl n N~N
I ' ( Ph3P~2NiC12 TI
CH3MgCl ~
The process of this invention is illustrated by the following Examples which are not intended to and should not constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in degrees Celsius and percentages are by weight, unless otherwise indicated.
° r~
n3'~~_~~c.~~
EXAMPLE 1.
1-C2Tr~ltetrazo7.-5w~ ~4-tolyl nzene C Ph3 CPh3 N-N 1 ) n-BuLi, -1 0°C, THF N-N
N ~ ' 2) ZnCl2, THF, 0°C N O N
3 ) CH3--« ) rI
(PPh3)ZNiClz, CH3NY~C1 (2-Trityltetrazol-5-yl)benzene (25.0 g) was dissolved in dry THF (250 mL) and the solution of the tetrazole was cooled to -20°C and n_-butyllithium (28.3 mL, 2.5 M in hexanes) was added. The mixture was gradually warmed to -10°C over 1 hour and then aged at this temperature for an additional 30 minutes. A 1.4M THF solution of zinc chloride (51.3mL) was then added to the aryllithium reagent 2o prepared above while maintaining the lithium reagent solution at s0°C. In another flask an activated nickel catalyst solution was prepared as follows. To a solution of (PPh3)2NiCl2 (2.5g) in THF (35mL) at 0°C was added methylmagnesium chloride (2.5 mL, 3M in THF) followed by ~-iodotoluene (17.5 g). The catalyst solution was warmed to 20°C and the solution of the zinc reagent was added at a rate that maintained the reaction temperature between 2U to 25°C. Ten hours after the :,,';p. '~o~~~
!.'y ,,. C~ ~ ~_7 Gv i addition of the zinc reagent to the reaction was complete, the reaction mixture was cooled to 0°G, 8.0 g of SuperCel (filter aid) was added, followed by the addition of concentrated ammonium hydroxide (lSmL) over 30 minutes. The heterogeneous solution was aged at 0°C for 1 hour and filtered. The filter cake was washed with THF (50 mL). The filtrate was washed with a mixture of saturated NaCl (80mL) and saturated NaHC03 (30 mL) and the layers separated. The THF
layer was dried with anhydrous Na2C03 (30g) and filtered. The volume of the filtrate was reduced to 150mL and cyclohexane (300 mL) was added. The THF
was further distilled in vacuo while the temperature of the mixture was maintained at 40 to 45°C.
Cyclohexane was added periodically to maintain the volume at 200mL. When the amount of THF dropped to s3 percent, the distillation was stopped and the mixture was cooled to room temperature. Hexanes (150 mL) was then added and the mixture further aged at 0°C for 1 hour. The product was collected and washed with hexanes (100 mL). The yield was 28.8 g (94%).
Employing the procedures substantially as described in Example 1, but substituting an equivalent amount of reagent E2 depicted in Table I
for 4-iodotoluene to prepare 2-substituted 1-(tetrazol-5-yl)benzenes, also depicted in Table I.
TABLE I
CPh~ ~CPh~
N-N 1 ) n-HuLi, -1 0°C, THF
N O N 2) ZnClz, THF, 0°C N N
O 3 ) Ez , (PPh3)zNiClz, CH3M3C1 R' R' EX E2 R~ R4 2 phenyl iodide t-butyl phenyl 3 o-iodotoluene hydrogeno-tolyl 4 m-iodotoluene hydrogenm-tolyl 5 p-iodotoluene phenoxy p-tolyl 6 p-iodoanisole hydrogenp-anisyl 7 3-cyano-1-iodobenzene hydrogenm-cyanophenyl g 4-cyano-1-iodobenzene hydrogenp-cyanophenyl 9 1-iodo-2,4-diethylbenzenet-butyl 2,4-diethylphenyl 10 3-ethoxy-1-iodobenzenehydrogenm-ethoxyphenyl 11 methyl 4-iodobenzoate phenyl 4-methoxycarbonylphenyl 12 methyl 3-iodobenzoate phenyl 3-methoxycarbonylphenyl :.
EXAMPLE 1_ 2-Bromo-~- t~trazol-5-vl)benzene N-NH N'NH
NON NON
1 J n-BuLi, THF Hr -30 to -10°C O
1 '~a hr.
2) BrZ/ -60 to -50°C
3) f~Cl To (tetrazol-5-yl)benzene (0.298) in THF
(lOml) at -25°C was slowly added n_-butyllithium (2 mL, 2.5M in hexanes) while maintaining the reaction temperature below -15°C. When the addition was over in 10 to 15 minutes, the mixture was aged at -10°C
for 30 minutes. The reaction mixture was cooled to -60°C and bromine (0.2 mL) was added dropwise. To the reaction mixture was added aqueous 10% sodium sulfite (5mL). An HPLC assay showed a starting material/products ratio of 3.5/96.5. The product was Precipitated by the addition of water (20 mL) and acidification with 2N HC1 to pH 2. The mixture was aged at 0°C for 1 hour and filtered. The yield was 0.4278 (95%).
Employing the procedures substantially as described in Example 13, but substituting for the bromine used therein an equivalent amount of reagent E2 depicted in Table II there are prepared the ortho-substituted (tetrazol-5-yl)benzenes also depicted in Table II.
_T_ABLE II
CPh3 CPh3 N-N N-N
NON NON
1 ) n- BuLi, THF
-30 to -10°C O
1 % hr.
R' 2) E" -78 to 25°C R~
3~ FiC1 EX ~1 R~ R~.
14 benzaldehyde t-butyl a-hydroxybenzyl 15 benzaldehyde hydrogen a-hydroxybenzyl 16 phenyl disulfide phenyl phenylthio 17 phenyl disulfide t-butyl phenylthio 18 ethylene oxide hydrogen 2-hydroxyethyl 19 ethylene oxide phenyl 2-hydroxyethyl 20 carbon dioxide phenoxy carboxyl 21 carbon dioxide phenyl earl>ox~l 22 ethyl iodide phenoxy ethyl 3p 23 butyl iodide phenyl butyl 24 tosyl azide phenoxy azide
BACKGROUND OF THE INVENTION
The renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hYPertension development and maintenance as well as in congestive heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
x~~~~
33/VJC8 - l - 18056 One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of angiotensin II (A II) are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist g activity and lack of oral absorption [M. Antonaccio.
Clin. Exp. Hy~ertens. A4, 27-46 (1982); D. H. P.
Streeten and G. H. Anderson, Jr., Handbook of hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp.
246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents ~5 4,207,324; 4,340,598; 4,576,958; and 4,582,847; and 4,880,804 in European Patent Applications 028,834;
245,637; 253,310; 323,841; and 291,969; and in articles by A.T. Chiu, e~t al. [Eur. J. Pharm. Exp.
Therap, 157, 13-21 (1988)] and by P.C. Wong, ~ ~l.
20 [J. Pharm. Ex~i Therav, 247, 1-7(1988)]. All of the cited references disclose compounds containing substituted imidazole and triazole compounds, which are generally bonded through a lower alkyl bridge to a substituted phenyl and preferably a biphenyl moiety 25 containing a carboxylic acid or an acid equivalent.
European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2H-imidazo-[4,5-~]pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.
33 /V,TC8 - 3 - 180564 ~~ ~- '~
The process previously used in the synthesis of 1-(tetrazol-5-yl)-2-(4-tolyl)benzene entailed the cross-coupling of p-tolylzinc chloride and 1-cyano-2-bromobenzene, the biphenyl adduct is then converted to the tetrazole with ammonium azide (Finnegan, et al., ~-Am. Chem. ~~, 80, 3908-11, 1958.) or trimethyltin azide (Aldrich, et al., US
Patent 4,870,186) to give the product 1-(tetrazol-5-yl)-2-(4-tolyl)benzene. The ammonium azide procedure requires long reaction times and produces low yields of the desired material. Prior to this invention, the preferred procedure required the use of trimethylstannyl chloride to generate the trimethylstannyl azide followed by reaction with the biphenyl adduct to give the desired tetrazole and the corresponding tin by-products. The disposal of these bY-Products is costly and coupled with the toxicity of tin make this route commercially unattractive.
These problems can be circumvented by the present invention which employs the reverse sequence of steps. The ortho-lithiation procedure is performed on (tetrazol-5-yl)benzene which is readily available from benzonitrile and ammonium azide (Finnegan, et. al.), or its N-trityl protected derivative, in high yields. The novel ortho-lithiation procedure allows for the preparation of the desired 1-<tetrazol-5-yl)-2-(4-tolyl)benzene through a more versatile and cost effective method.
~ ~ -a '~'~ L1.3.~~~' DETAILED DES RIPTIO_N OF THE INV:ENTI N
The novel process of this invention comprises as a first step the treatment of a (tetrazol-5-y1)benzene or an N-trityl protected derivative with a straight or branched (C1-C6)-alkyllithium in an aprotic solvent at a temperature of between -40 and 10 °C and for a reaction time ranging between 30 minutes and 5 hours. The lithiation of the (tetrazol-5-yl)benzene is directed by the tetrazole substituent to lithiate the benzene ring at the ortho position, Scheme 1.
The alkyllithium reagents preferably are n-butyllithium, sec-butyllithium and t-buytllithium;
the preferred aprotic solvents are tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether; the preferred reaction time is between 30 minutes and 2 hours; and the preferred reaction temperature is between -20 to 0 °C.
The second step of the process comprises reacting the ortho-lithiated intermediate either directly, or after transmetallation with an electrophile, Scheme 2. The reaction mixture containing the ortho-lithiated intermediate is cooled to -78 to -60 °C and the electrophile, E1, is added slowly. The reaction time ranges between 10 minutes and 5 hours and the reaction temperature ranges between -78 to 25° C. Alternatively, the ortho-lithiated intermediate reacts with a metal halide, where the metal is selected from the group consisting of Zn, Mg, Cu, B, A1, and Cd, to give the transmetallated intermediate which then reacts with an electrophile, E2, either in the presence or 33/VJC8 - 5 - 18056 ~~ t5 ~~ ~ ~~ ii absence of a phosphinated nickel or palladium catalyst activated, when necessary, by a Grignard or an aluminum hydride reagent at a reaction temperature of between -40 and 79°C for a reaction time of 30 minutes to 16 hours to give the desired ortho-substituted product. This two-step process decreases the processing time and improves the yield of the product, such as 1-(2-trityltetrazol-5-yl)-2-<4-tolyl)benzene.
The more preferred process is the generation of an aryllithium by treating the protected or unprotected form of the tetrazole with n-butyllithium at -20 to -10°C for between 30 minutes to 2 hours in tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether. The aryllithium intermediate is then reacted with zinc chloride in tetrahydrofuran while maintaining the temperature between -10 and 0°C. The nickel catalyst, (PPh3)2NiC12, and the electrophile, p-iodotoluene, in tetrahydrofuran at 0°C is activated with methylmagnesium chloride. The activated catalyst solution is added to the transmetallated product, arylzinc chloride, and maintaining the reaction temperature between 20 and 25°C for a reaction time of between 30 minutes and 16 hours.
Scheme 1 illustrates the ortho-lithiation of the protected and unprotected aryltetrazole species to give the ortho-lithiated products B and A, respectively. Scheme 2 illustrates the versatility of the aryllithium species, showing the addition of the electrophile directly to the aryllithium, ac well as the ability to transmetallate and then alkylate or arylate with the appropriate electrophile in the presence or absence of a catalyst.
td ~ ~~ ,~. :~ ~ ~
33/V,1C8 - 6 - 18056 Scheme 1 N'N H N'N Li N ~ N
n- BuLi /THF
-1 0°C Li R~ R' A
CPh3 CPh3 N'N ~ N'N /
NON ~ v NON
n- BuLi /THF' -1 0°C Li R' R' H
~h~m~2 CPh3 N-N/
N O N
Li R' B
Fn 11( L) n ~CPh3 N-N /CPh3 t NON
N O N N U N
R ~ ~L)n_t R' R' IEa 'w/ or w/o catalyst j ,CPh3 N-_N
NN
Ra R' R1 is: hydrogen, t-butyl, phenoxy , phenyl, 3o di(Cl-C6)alkylamino, or trimethylsilyl;
'. ~ "~y .. C- (r.1 f~n~ ~~.j: a ~,~ 4~r R2 is:
hydrogen, or trityl;
E1 is:
benzaldehyde, trimethylsilyl chloride, phenyl disulfide, methyl disulfide, carbon dioxide, ethylene oxide, tosyl azide, trimethylstannyl chloride, (Cl-C6)-alkyl iodide, iodine, or bromine;
R3 is:
a-hydroxybenzyl, trimethylsilyl, 2o thiophenyl, thiomethyl, carboxyl, 2-hydroxyethyl, azide, trimethylstannyl, (Cl-C6)-alkyl, iodide, or bromide, respectively;
E2 is benzaldehyde, (C1-C6) -alkanal, (C1-C6)-alkyl halide, wherein the halide is Br, Cl, I, aryl halide, wherein aryl is defined as phenyl or phenyl substituted with o-, m-, or p- (C1-C6) -alky, o,p-di (C1-C6) -alkyl, o-, m- or p-(C1-C6)-alkoxy,o-, m- or p-phenyl, o-, m- or p-cyano, m- or p- [carboxy- (cl-C6) -alkyl] , m- or p-nitro, o-, m- or p-chlorophenyl, and the halide is Br or I, bromine, iodine, or 3-bromopropene;
R4 i s a-hydroxybanzyl, a-hydroxy-(C1-C6)-alkyl, (C1-C6)-alkyl, phenyl , o-, m- or p-(C1-C6)-alkylphenyl, o,p-di(C1-C6)-alkylphenyl, o-, m- or p-(C1-C6)-alkoxyphenyl, 3- or 4-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6)-alkyl]phenyl, p- or m-nitrophenyl, o-, m- or p-chlorophenyl, bromide, iodide, or n,, (n na '~ ~:~ ~. ~~
2-propen-1-yl, respectively;
M is:
Zn, Mg, Cu, A1, or Cd;
L is:
Cl, Br, or I;
n is:
l~
2, or 3; and the catalyst is: phosphinated Ni and Pd complexes such as NiL2(PPh3)2, PdL2(PPh3)2, or Pd(PPh3)4, wherein L is as deffined above.
The preferred route used in the preparation of 1-(2-trityltetrazol-5-yl)-2-(4-tolyl)benzene is illustrated in Scheme 3 and which employs the ortho-lithiation of (2-trityltetrazol-5-yl)benzene.
followed by transmetallation of the lithiated species and cross'-coupling with 4-iodotoluene in the presence of a phosphinated nickel catalyst activated by CH3MgCl.
~W tit .~ ~' l i chem.
CPh3 CPh~
N'N N'N
NON NON
ZnCl2/THF
Li -10°C nCl n N~N
I ' ( Ph3P~2NiC12 TI
CH3MgCl ~
The process of this invention is illustrated by the following Examples which are not intended to and should not constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in degrees Celsius and percentages are by weight, unless otherwise indicated.
° r~
n3'~~_~~c.~~
EXAMPLE 1.
1-C2Tr~ltetrazo7.-5w~ ~4-tolyl nzene C Ph3 CPh3 N-N 1 ) n-BuLi, -1 0°C, THF N-N
N ~ ' 2) ZnCl2, THF, 0°C N O N
3 ) CH3--« ) rI
(PPh3)ZNiClz, CH3NY~C1 (2-Trityltetrazol-5-yl)benzene (25.0 g) was dissolved in dry THF (250 mL) and the solution of the tetrazole was cooled to -20°C and n_-butyllithium (28.3 mL, 2.5 M in hexanes) was added. The mixture was gradually warmed to -10°C over 1 hour and then aged at this temperature for an additional 30 minutes. A 1.4M THF solution of zinc chloride (51.3mL) was then added to the aryllithium reagent 2o prepared above while maintaining the lithium reagent solution at s0°C. In another flask an activated nickel catalyst solution was prepared as follows. To a solution of (PPh3)2NiCl2 (2.5g) in THF (35mL) at 0°C was added methylmagnesium chloride (2.5 mL, 3M in THF) followed by ~-iodotoluene (17.5 g). The catalyst solution was warmed to 20°C and the solution of the zinc reagent was added at a rate that maintained the reaction temperature between 2U to 25°C. Ten hours after the :,,';p. '~o~~~
!.'y ,,. C~ ~ ~_7 Gv i addition of the zinc reagent to the reaction was complete, the reaction mixture was cooled to 0°G, 8.0 g of SuperCel (filter aid) was added, followed by the addition of concentrated ammonium hydroxide (lSmL) over 30 minutes. The heterogeneous solution was aged at 0°C for 1 hour and filtered. The filter cake was washed with THF (50 mL). The filtrate was washed with a mixture of saturated NaCl (80mL) and saturated NaHC03 (30 mL) and the layers separated. The THF
layer was dried with anhydrous Na2C03 (30g) and filtered. The volume of the filtrate was reduced to 150mL and cyclohexane (300 mL) was added. The THF
was further distilled in vacuo while the temperature of the mixture was maintained at 40 to 45°C.
Cyclohexane was added periodically to maintain the volume at 200mL. When the amount of THF dropped to s3 percent, the distillation was stopped and the mixture was cooled to room temperature. Hexanes (150 mL) was then added and the mixture further aged at 0°C for 1 hour. The product was collected and washed with hexanes (100 mL). The yield was 28.8 g (94%).
Employing the procedures substantially as described in Example 1, but substituting an equivalent amount of reagent E2 depicted in Table I
for 4-iodotoluene to prepare 2-substituted 1-(tetrazol-5-yl)benzenes, also depicted in Table I.
TABLE I
CPh~ ~CPh~
N-N 1 ) n-HuLi, -1 0°C, THF
N O N 2) ZnClz, THF, 0°C N N
O 3 ) Ez , (PPh3)zNiClz, CH3M3C1 R' R' EX E2 R~ R4 2 phenyl iodide t-butyl phenyl 3 o-iodotoluene hydrogeno-tolyl 4 m-iodotoluene hydrogenm-tolyl 5 p-iodotoluene phenoxy p-tolyl 6 p-iodoanisole hydrogenp-anisyl 7 3-cyano-1-iodobenzene hydrogenm-cyanophenyl g 4-cyano-1-iodobenzene hydrogenp-cyanophenyl 9 1-iodo-2,4-diethylbenzenet-butyl 2,4-diethylphenyl 10 3-ethoxy-1-iodobenzenehydrogenm-ethoxyphenyl 11 methyl 4-iodobenzoate phenyl 4-methoxycarbonylphenyl 12 methyl 3-iodobenzoate phenyl 3-methoxycarbonylphenyl :.
EXAMPLE 1_ 2-Bromo-~- t~trazol-5-vl)benzene N-NH N'NH
NON NON
1 J n-BuLi, THF Hr -30 to -10°C O
1 '~a hr.
2) BrZ/ -60 to -50°C
3) f~Cl To (tetrazol-5-yl)benzene (0.298) in THF
(lOml) at -25°C was slowly added n_-butyllithium (2 mL, 2.5M in hexanes) while maintaining the reaction temperature below -15°C. When the addition was over in 10 to 15 minutes, the mixture was aged at -10°C
for 30 minutes. The reaction mixture was cooled to -60°C and bromine (0.2 mL) was added dropwise. To the reaction mixture was added aqueous 10% sodium sulfite (5mL). An HPLC assay showed a starting material/products ratio of 3.5/96.5. The product was Precipitated by the addition of water (20 mL) and acidification with 2N HC1 to pH 2. The mixture was aged at 0°C for 1 hour and filtered. The yield was 0.4278 (95%).
Employing the procedures substantially as described in Example 13, but substituting for the bromine used therein an equivalent amount of reagent E2 depicted in Table II there are prepared the ortho-substituted (tetrazol-5-yl)benzenes also depicted in Table II.
_T_ABLE II
CPh3 CPh3 N-N N-N
NON NON
1 ) n- BuLi, THF
-30 to -10°C O
1 % hr.
R' 2) E" -78 to 25°C R~
3~ FiC1 EX ~1 R~ R~.
14 benzaldehyde t-butyl a-hydroxybenzyl 15 benzaldehyde hydrogen a-hydroxybenzyl 16 phenyl disulfide phenyl phenylthio 17 phenyl disulfide t-butyl phenylthio 18 ethylene oxide hydrogen 2-hydroxyethyl 19 ethylene oxide phenyl 2-hydroxyethyl 20 carbon dioxide phenoxy carboxyl 21 carbon dioxide phenyl earl>ox~l 22 ethyl iodide phenoxy ethyl 3p 23 butyl iodide phenyl butyl 24 tosyl azide phenoxy azide
Claims (28)
1. A process for the synthesis of a compound of structural formula:
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R2 is hydrogen or trityl; and R3 i s .alpha.-hydroxybenzyl, trimethylsilyl, thiophenyl, thiomethyl, carboxyl,
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R2 is hydrogen or trityl; and R3 i s .alpha.-hydroxybenzyl, trimethylsilyl, thiophenyl, thiomethyl, carboxyl,
2-hydroxyethyl, azido, trimethylstannyl, (C1-C6) alkyl, bromo, or iodo, respectively, and which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium in an aprotic solvent at a temperature range of between -40 to 10°C, for 0.5 to 5 hours, to give an ortho-lithiated intermediate, and reacting in situ with an appropriate electrophile, E1, wherein:
E1 is benzaldehyde, trimethylsilyl chloride, phenyldisulfide, methyldisulfide, carbon dioxide, ethylene oxide, p-toluenesulfonyl azide, trimethylstannyl chloride, (C1-C6)-alkyl iodide, bromine, or iodine, respectively.
2. The process of Claim 1, wherein R1 is hydrogen, alkyllithium is straight or branched chain (C1-C6)alkyllithium, E1 is benzaldehyde, phenyldisulfide, carbon dioxide, (C1-C6)-alkyl iodide, bromine, or iodine and R3 is .alpha.-hydroxybenzyl, phenylthio, carboxyl, (C1-C6)-alkyl, bromo, or iodo, respectively.
with a straight chain or branched (C1-C6) alkyllithium in an aprotic solvent at a temperature range of between -40 to 10°C, for 0.5 to 5 hours, to give an ortho-lithiated intermediate, and reacting in situ with an appropriate electrophile, E1, wherein:
E1 is benzaldehyde, trimethylsilyl chloride, phenyldisulfide, methyldisulfide, carbon dioxide, ethylene oxide, p-toluenesulfonyl azide, trimethylstannyl chloride, (C1-C6)-alkyl iodide, bromine, or iodine, respectively.
2. The process of Claim 1, wherein R1 is hydrogen, alkyllithium is straight or branched chain (C1-C6)alkyllithium, E1 is benzaldehyde, phenyldisulfide, carbon dioxide, (C1-C6)-alkyl iodide, bromine, or iodine and R3 is .alpha.-hydroxybenzyl, phenylthio, carboxyl, (C1-C6)-alkyl, bromo, or iodo, respectively.
3. The process of Claim 2, wherein the alkyllithium is n-, s-, or t-butyllithium and the aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether.
4. The process of Claim 3, wherein the alkyllithium is n-butyllithium, the aprotic solvent is tetrahydrofuran or 2-methyltetrahydrofuran, the electrophile, E1, is bromine, and R3 is bromo.
5. A process for the preparation of a compound of structural formula:
wherein:
R1 is hydrogen, t-butyl, phenoxy , phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R2 is hydrogen, or trityl; and R4 is .alpha.-hydroxybenzyl, .alpha.-hydroxy-(C1-C6)-alkyl, (C1-C6)-alkyl, phenyl, o-, m-, or p- (C1-C6)-alkylphenyl, o,p-di (C1-C6)-alkylphenyl, o-, m- or p- (C1-C6)-alkoxyphenyl, m- or p-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6)-alkyl]phenyl, m- or p-nitrophenyl, o-, m-, or p-chlorophenyl, bromide, iodide, or 2-propen-1-yl which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium, in an aprotic solvent at a temperature range between -40 to 10°C for 30 minutes to 5 hours, to give an ortho-lithiated intermediate followed by reaction with a metal halide, M(L)n, in tetrahydrofuran or diethyl ether at -30° to 0°C, to give the transmetallated compound, wherein the metal (M) is selected from the group consisting of: Zn, Mg, Cu, B, Al, or Cd, and the ligand (L) is selected from the group consisting of: Cl, Br, or I and the number of ligands (n) corresponds to the valence on the metal, followed by reaction with an electrophile, E2, wherein:
E2 is benzaldehyde, (C1-C6) -alkanal, (C1-C6)-alkyl halide, wherein the halide is Br, Cl, I, phenyl halide, o-, m-, or p-(C1-C6)-alkylphenyl halide, o,p-di(C1-C6)-alkylphenyl halide, o-, m- or p-(C1-C6)-alkoxyphenyl halide, o-, m- or p-halobiphenyl, o-, m- or p-cyanophenyl halide, m- or p- [carboxy-(c1-C6)-alkyl] phenyl halide, m- or p-nitrophenyl halide, o-, m- or p-chlorophenyl halide, wherein the halide in the above aryl halide is Br or I, bromine, iodine, or 3-bromopropene, respectively, either in the presence or absence of a phosphinated nickel or palladium catalyst which is activated, if necessary, by a Grignard reagent in an aprotic solvent selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether at a reaction temperature of between -40 and 79°C
for a reaction time of between 0.5 and 16 hours to give the desired product.
wherein:
R1 is hydrogen, t-butyl, phenoxy , phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R2 is hydrogen, or trityl; and R4 is .alpha.-hydroxybenzyl, .alpha.-hydroxy-(C1-C6)-alkyl, (C1-C6)-alkyl, phenyl, o-, m-, or p- (C1-C6)-alkylphenyl, o,p-di (C1-C6)-alkylphenyl, o-, m- or p- (C1-C6)-alkoxyphenyl, m- or p-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6)-alkyl]phenyl, m- or p-nitrophenyl, o-, m-, or p-chlorophenyl, bromide, iodide, or 2-propen-1-yl which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium, in an aprotic solvent at a temperature range between -40 to 10°C for 30 minutes to 5 hours, to give an ortho-lithiated intermediate followed by reaction with a metal halide, M(L)n, in tetrahydrofuran or diethyl ether at -30° to 0°C, to give the transmetallated compound, wherein the metal (M) is selected from the group consisting of: Zn, Mg, Cu, B, Al, or Cd, and the ligand (L) is selected from the group consisting of: Cl, Br, or I and the number of ligands (n) corresponds to the valence on the metal, followed by reaction with an electrophile, E2, wherein:
E2 is benzaldehyde, (C1-C6) -alkanal, (C1-C6)-alkyl halide, wherein the halide is Br, Cl, I, phenyl halide, o-, m-, or p-(C1-C6)-alkylphenyl halide, o,p-di(C1-C6)-alkylphenyl halide, o-, m- or p-(C1-C6)-alkoxyphenyl halide, o-, m- or p-halobiphenyl, o-, m- or p-cyanophenyl halide, m- or p- [carboxy-(c1-C6)-alkyl] phenyl halide, m- or p-nitrophenyl halide, o-, m- or p-chlorophenyl halide, wherein the halide in the above aryl halide is Br or I, bromine, iodine, or 3-bromopropene, respectively, either in the presence or absence of a phosphinated nickel or palladium catalyst which is activated, if necessary, by a Grignard reagent in an aprotic solvent selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether at a reaction temperature of between -40 and 79°C
for a reaction time of between 0.5 and 16 hours to give the desired product.
6. The process of Claim 5, wherein the aprotic solvent is tetrahydrofuran or diethyl ether, the alkyl-lithium is straight or branched chain (C1-C6) alkyllithium, E2 is phenyl halide, o-, p- or m-(C1-C6)-alkylphenyl halide, o,p-di(C1-C6)-alkylphenyl halide, o-, m- or p-(C1-C6)-alkoxy-phenyl halide, 3- or 4-halobiphenyl, o-, m- or p-cyano-phenyl halide, m- or p-carboxy-(C1-C6)-alkylphenyl halide, wherein halide is defined as bromide or iodide, the metal halide is Z n Cl2, MgC1 2, or CuC1 2 and the phosphinated nickel or palladium catalyst is NiCl2(PPh3)2, PdC1 2(PPh3)2, or Pd(PPh3)4, and R4 is phenyl, o-, p- or m-(C1-C6)-alkylphenyl, o,p-di(C1-C6)-alkylphenyl, o-, m- or p-(C1-C6)-alkoxyphenyl, 3- or 4-biphenyl, o-, m- or p-cyanophenyl, m- or p[carboxy-(C1-C6)-alkyl]phenyl, respectively.
7. A process for the preparation of a compound of structural formula:
which comprises treating (2-trityltetrazol-5-yl)-benzene with n-butyllithium in tetrahydrofuran at -20 to -10°C, for 1 1/2 hours, followed by a transmetallation of the lithiated species with zinc chloride in tetrahydrofuran at 0°C and cross-coupling of the transmetallated species with 4-iodotoluene, in the presence of an activated phosphinated nickel catalyst which is derived from bis(triphenylphosphine)nickel(II) chloride and CH3MgC1 in tetrahydrofuran at 20°C.
which comprises treating (2-trityltetrazol-5-yl)-benzene with n-butyllithium in tetrahydrofuran at -20 to -10°C, for 1 1/2 hours, followed by a transmetallation of the lithiated species with zinc chloride in tetrahydrofuran at 0°C and cross-coupling of the transmetallated species with 4-iodotoluene, in the presence of an activated phosphinated nickel catalyst which is derived from bis(triphenylphosphine)nickel(II) chloride and CH3MgC1 in tetrahydrofuran at 20°C.
8. A process for the synthesis of the ortho-lithiated intermediate of formula:
wherein:
R1 is:
hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkyl amino, or trimethylsilyl, and R5 is trityl or Li, which comprises treatment of an aryltetrazole, of structure:
wherein R1 is as defined above and R6 is trityl or H
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to -10°C, for 0.5 to 5 hours.
wherein:
R1 is:
hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkyl amino, or trimethylsilyl, and R5 is trityl or Li, which comprises treatment of an aryltetrazole, of structure:
wherein R1 is as defined above and R6 is trityl or H
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to -10°C, for 0.5 to 5 hours.
9. A compound of structural formula:
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R4 is lithium or trityl.
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and R4 is lithium or trityl.
10. The process of claim 1, wherein R2 is trityl.
11. The process of claim 1, wherein R1 is hydrogen.
12. The process of claim 10, wherein R1 is hydrogen, E1 is benzaldehyde, phenyldisulfide, carbon dioxide, (C1-C6)-alkyl iodide, bromine or iodine and R3 is .alpha.-hydroxybenzyl, phenylthio, carboxyl, (C1-C6)-alkyl, bromo or iodo, respectively.
13. The process of claim 11, wherein E1 is benzaldehyde, phenyldisulfide, (C1-C6)-alkyl iodide, carbon dioxide, bromine or iodine; and R3 is .alpha.-hydroxy-benzyl, phenylthio, (C1-C6)-alkyl, carboxyl, bromo or iodo, respectively.
14. The process of claim 1, 10, 11, 12 or 13, wherein the aprotic solvent is tetrahydrofuran or diethyl ether.
15. The process of claim 1, 10 or 11, wherein the alkyllithium is n-, s- or t-butyllithium and the aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether.
16. The process of claim 15, wherein the alkyllithium is n-butyllithium and the aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether.
17. The process of claim 16, wherein the aprotic solvent is tetrahydrofuran or 2-methyltetrahydrofuran, the electrophile, E1, is bromine and R3 is bromo.
18. The process of claim 5, wherein R2 is trityl.
19. The process of claim 5 or 18, wherein R1 is hydrogen.
20. The process of claim 5, 18 or 19, wherein the aprotic solvent is tetrahydrofuran or diethyl ether.
21. The process of claim 20, wherein the metal halide is ZnCl2, MgCl2, CuCl, CuCl2 and the phosphinated nickel or palladium catalyst is NiL2(PPh3)2, PdL2(PPh3)2 or Pd(PPh3)4, wherein L is Cl, Br, I.
22. The process of claim 5, 18, 19, 20 or 21, wherein E2 is phenyl halide, o-, p- or m-(C1-C6)-alkyl-phenyl halide, o-,p-di(C1-C6)-alkylphenyl halide, o-, m- or p-(C1-C6)-alkoxyphenyl halide, m- or p-halobiphenyl, o-, m- or p-cyanophenyl halide, m- or p-carboxy (C1-C6)-alkylphenyl halide, m- or p-nitrophenyl halide, o-, m- or p-chlorophenyl halide, halide is defined as bromide or iodide and R4 is phenyl, o-, p- or m-(C1-.C6)-alkylphenyl, o-, p-di (C1-C6)-alkylphenyl, o-, m- or p-(C1-C6)-alkoxy-phenyl, m- or p-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6)-alkyl]phenyl, m- or p-nitrophenyl, or o-, m- or p-chlorophenyl, respectively.
23. The process of claim 22, wherein the metal halide is ZnCl2, MgCl2 or CuCl2 and the phosphinated nickel or palladium catalyst is NiCl2(PPh3)2, PdCl2(PPh3)2 or Pd(PPh3)4 and R4 is phenyl, o-, p- or m-(C1-C6)-alkyl-phenyl, o-, p-di (C1-C6) -alkylphenyl, o-, m- or p- (C1-C6) -alkoxyphenyl, 3-or 4-biphenyl, o-, m- or p-cyanophenyl, m- or p-[carboxy-(C1-C6) -alkyl] phenyl, respectively.
24. The process of claim 22 or 23, wherein the alkyllithium is n-, s- or t-butyllithium.
25. The process of claim 5, wherein said Grignard reagent is CH3MgCl, PhMgCl or diisobutylaluminum hydride.
26. A process for the synthesis of an ortho-lithiated intermediate of formula:
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl, and which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to 10°C for 0.5 to 5 hours.
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl, and which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to 10°C for 0.5 to 5 hours.
27. A process for the synthesis of an ortho-lithiated intermediate of formula:
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkyl amino, or trimethylsilyl, and which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to 10°C for 0.5 to 5 hours.
wherein:
R1 is hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkyl amino, or trimethylsilyl, and which comprises treatment of an aryltetrazole, of structure:
with a straight chain or branched (C1-C6) alkyllithium reagent in an aprotic solvent at a temperature range of between -40° to 10°C for 0.5 to 5 hours.
28. A compound of structural formula:
wherein:
R1 is:
hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and' R4 is lithium or trityl;
for use in the synthesis of 2-substituted 1-(tetrazol-5-yl)benzene.
wherein:
R1 is:
hydrogen, t-butyl, phenoxy, phenyl, di(C1-C6)-alkylamino, or trimethylsilyl; and' R4 is lithium or trityl;
for use in the synthesis of 2-substituted 1-(tetrazol-5-yl)benzene.
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EP0550313A1 (en) * | 1991-12-30 | 1993-07-07 | Synthelabo | 2-(Tetranol-5-yl)-(1,1'-biphenyl)derivatives, their preparation and use as intermediates |
FR2696746B1 (en) * | 1992-10-12 | 1994-11-18 | Synthelabo | Benzeneborinic acid derivatives, their preparation and their use as synthesis intermediates. |
FR2696745B1 (en) * | 1992-10-12 | 1995-05-12 | Synthelabo | Process for the preparation of phenyltetrazole derivatives. |
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US5567815A (en) * | 1994-07-18 | 1996-10-22 | Bridgestone Corporation | Teritary amine containing antonic initiators used in preparing polymers and process for the preparation thereof |
ES2129850T3 (en) * | 1994-09-20 | 1999-06-16 | Wakunaga Seiyaku Kk | PRODUCTION PROCEDURE OF A DERIVATIVE OF N-BIPHENYL METHYLTIADIAZOLINE OR A SALT OF IT AND ITS INTERMEDIATE PRODUCTION OF PRODUCTION. |
KR100354802B1 (en) * | 1994-10-20 | 2002-12-26 | 한국화학연구원 | Process for preparing tetrazole derivatives |
ATE240325T1 (en) * | 1995-06-07 | 2003-05-15 | Wyeth Corp | METHOD FOR PRODUCING BIPHENYL DERIVATIVES |
US5760220A (en) * | 1995-06-07 | 1998-06-02 | American Home Products Corporation | Process for preparation of biphenyl derivatives |
IT1292437B1 (en) | 1997-06-30 | 1999-02-08 | Zambon Spa | ORTHO-METALLATION PROCESS USEFUL FOR THE SYNTHESIS OF 1 - TETRAZOL- 5-IL) 2-SUBSTITUTED BENZENES |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3534113A (en) * | 1968-02-08 | 1970-10-13 | Lithium Corp | Preparation of aryllithium compounds by metalation |
CH531511A (en) * | 1969-03-05 | 1972-12-15 | Sandoz Ag | Process for the preparation of the N, o-dilithium derivative of 2-phenyl-2-imidazoline |
US4620025A (en) * | 1984-08-01 | 1986-10-28 | Merck & Co., Inc. | Process for the preparation of biphenyl intermediates |
US4870186A (en) * | 1987-05-22 | 1989-09-26 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
US4820843A (en) * | 1987-05-22 | 1989-04-11 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
CA1338238C (en) * | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
-
1990
- 1990-05-02 US US07/517,889 patent/US5039814A/en not_active Expired - Lifetime
-
1991
- 1991-04-25 DK DK91303757.8T patent/DK0455423T3/en active
- 1991-04-25 ES ES91303757T patent/ES2095907T3/en not_active Expired - Lifetime
- 1991-04-25 DE DE69123632T patent/DE69123632T2/en not_active Expired - Lifetime
- 1991-04-25 AT AT91303757T patent/ATE146461T1/en not_active IP Right Cessation
- 1991-04-25 EP EP91303757A patent/EP0455423B1/en not_active Expired - Lifetime
- 1991-04-30 PT PT97528A patent/PT97528B/en not_active IP Right Cessation
- 1991-04-30 IE IE145591A patent/IE911455A1/en unknown
- 1991-05-01 CA CA002041620A patent/CA2041620C/en not_active Expired - Lifetime
- 1991-05-02 JP JP3100245A patent/JPH0717619B2/en not_active Expired - Lifetime
-
1992
- 1992-10-27 RO RO92-01355A patent/RO110339B1/en unknown
-
1996
- 1996-12-19 GR GR960403182T patent/GR3022107T3/en unknown
-
1997
- 1997-05-08 HK HK59497A patent/HK59497A/en not_active IP Right Cessation
- 1997-09-05 LV LVP-97-162A patent/LV11893B/en unknown
- 1997-12-05 CY CY199897A patent/CY1998A/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP0455423B1 (en) | 1996-12-18 |
DE69123632D1 (en) | 1997-01-30 |
EP0455423A2 (en) | 1991-11-06 |
CA2041620A1 (en) | 1991-11-03 |
GR3022107T3 (en) | 1997-03-31 |
PT97528A (en) | 1992-01-31 |
ATE146461T1 (en) | 1997-01-15 |
JPH0717619B2 (en) | 1995-03-01 |
RO110339B1 (en) | 1995-12-29 |
US5039814A (en) | 1991-08-13 |
LV11893A (en) | 1997-12-20 |
LV11893B (en) | 1998-03-20 |
DK0455423T3 (en) | 1997-06-09 |
HK59497A (en) | 1997-05-16 |
IE911455A1 (en) | 1991-11-06 |
PT97528B (en) | 1998-08-31 |
ES2095907T3 (en) | 1997-03-01 |
DE69123632T2 (en) | 1997-05-15 |
CY1998A (en) | 1997-12-05 |
EP0455423A3 (en) | 1992-12-09 |
JPH04225966A (en) | 1992-08-14 |
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