WO1993013095A1 - A reduction method for substituted 5-methylene-thiazolidinediones - Google Patents

A reduction method for substituted 5-methylene-thiazolidinediones Download PDF

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WO1993013095A1
WO1993013095A1 PCT/US1992/010329 US9210329W WO9313095A1 WO 1993013095 A1 WO1993013095 A1 WO 1993013095A1 US 9210329 W US9210329 W US 9210329W WO 9313095 A1 WO9313095 A1 WO 9313095A1
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formula
alkyl
compound
borohydride
moiety
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PCT/US1992/010329
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French (fr)
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Joel Edward Huber
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The Upjohn Company
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Priority to CA002122712A priority Critical patent/CA2122712C/en
Priority to EP93900732A priority patent/EP0618915A1/en
Priority to JP5511663A priority patent/JP2766730B2/en
Priority to US08/397,130 priority patent/US5585495A/en
Publication of WO1993013095A1 publication Critical patent/WO1993013095A1/en
Priority to KR1019940702123A priority patent/KR100214908B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms

Definitions

  • the present invention provides a new method of making organic compounds.
  • the present invention provides a new reduction method for making certain pharmaceutically active compounds, such as thiazolidinedione derivatives, including pioglitazone, ciglitazone, englitazone and CS-045. These compounds are known for the treatment of diabetes and as insulin sensitizing agents.
  • Pioglitazone hydrochloride ((+)-5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4- thiazolidinedione monohydrochloride), a thiazolidinedione derivative, is currently under clinical evaluation and is expected to effectively ameliorate the abnormal glucose and lipid metabolism associated with NIDDM or obesity (cf. Y. Momose et al., Chem. Pharai. Bull., 39:1440 (1991)).
  • Another thiazolidine derivative under-going clinical studies as a hypoglycemic agent is englitazone sodium, 5-([3,4-dihydro-2-(phenylmethyl)-2H-l-benzopyran-6-yl]methyI]-2,4- thiazolidinedione sodium salt) (cf. D.A. Clark et al., J. Med. Chem., 34:319-325 (1991)).
  • Ciglitazone ((+)-5-[4-[(l-methylcyclohexyl)methoxy]benzyl]-2,4-thiazolidinedione) is characteristic of a new class of thiazolidine antidiabetic agents which lower blood glucose in animal models of noninsulin diabetes mellitus (NIDDM), while actually reducing circulating concentrations of insulin. This is believed to be accomplished by improving the responsiveness of the peripheral tissues to insulin. See, e.g., Chang, et al, Diabetes 32:830-838 (September 1983).
  • NIDDM noninsulin diabetes mellitus
  • CS-045 is an antidiabetic, thiazolidinedione derivative. Its activity and preparation are described in Drugs Fut. 1991, 16(9).
  • thiazolidine derivatives useful for the treatment of diabetes are described in U.S. patents 4,287,200; 4,687,777; and 4,572,912. Their effect on insulin resistance are described, e.g. in, Chang, et al, Diabetes 32: 839-845 (1983) and Chang, et al, Diabetes 32:830-838 (1983).
  • the preparation of these thiazolidinedione derivatives, especially pioglitazone hydrochloride includes the reduction of an intermediate previously performed by a troublesome high pressure hydrogenation on a palladium on carbon catalyst. What is needed in the art is an easier, more efficient method for performing this reduction.
  • D.A- Clark et al-, J- Med. Chem., 34:319-325 (1991) discloses the process for making substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones, including englitazone, using hydrogen on a palladium on carbon catalyst.
  • Drugs Fut 1991, 16(9) discloses the multistep process, via carbon alkylation, for the preparation of the thiazolidinedione CS-045.
  • X j is the residue of an antidiabetic compound; This process wherein X j is a) aryl, or b) HeU wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
  • organic residue is meant the residue of an organic compound that would be compatible with the reaction conditions of the process of the present invention.
  • a residue will be one that does not react with the reactants of the process of the present invention so that only the double bond at the 5-position of the thiazolidinedione ring will be reduced.
  • the reactants of the present invention include a cobalt ion, a ligand and a reducing agent.
  • Such an organic residue would be readily determined by one of ordinary skill in the chemical arts.
  • antidiabetic compound By “residue of an antidiabetic compound” is meant the organic moiety that is attached to the 5-position of a thiazolidinedione derivative, which derivative has antidiabetic activity, such as those described in Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 (1988); Chem. Abst ⁇ , 109:6504h (1988); D.A. Clark et al., J. Med. Chem., 34: 319-325 (1991); U.S. patents 4,287,200; 4,687,777; and 4,572,912; Drugs Fut 1991, 16(9); and J. Med.
  • aryl is meant phenyl or naphthyl substituted by zero to three of the following: C j -C 3 alkyl, hydroxy, C j -C 3 alkoxy, halo, amino, mono- or di-C j -C ⁇ alkylamino, nitro, mercapto, CJ-CJ alkylthio, C j -C*-* alkylsulfinyl, C j -C 3 alkylsulfonyl, -NH-C- [ -C 3 alkylsulfonyl, - NC r C 3 alkyl-C r C 3 alkylsulfonyl, SO 3 H, SO 2 NH 2 , -CH 2 NH 2 , -A r (CH 2 ) n -Het, -A r (CH 2 ) n - (CJ-C 6 alkyl substituted cyclohexyl), or -A 1 -
  • the reaction temperature range for the process of the present invention is -20°C to +45°C.
  • the preferred range is +5° to +20°C. +15°C is most preferred.
  • Solvents that will wor in the process of the present invention include methanol, ethanoL i-propanol, acetone, dimethylfo ⁇ namide (DMF) and tetrahydrofuran (THF); with the proviso that if acetone, DMF or THF are used then a proton source, such as an alcohol, like the ones mentioned above, or water must also be present The amount of such proton source required would typically be ⁇ leq., but would be readily apparent to one of ordinary skill in the art. Water and tetrahydrofuran are a preferred solvent combination.
  • Cobalt is the preferred metal ion (Co or Co +3 ).
  • Sources of cobalt include CoCl 2 (cobaltous chloride) and Co(OAc) 2 (cobaltous diacetate) or CoCl 3 (cobaltic chloride).
  • ligand is meant a complexing agent for a metal ion.
  • dimethylglyoxime which is the preferred ligand
  • other ligands that may be used are 2, 2'- bipyridyl and 1,10-phenanthroline, which should be used in at least a 1:1 mole ratio with the cobalt ion- Most preferred is the ligand to cobalt ratio of 50:1.
  • Sodium borohydride (NaBH ⁇ is the preferred reducing agent, but other borohydrides, such as lithium borohydride, potassium borohydride, tetraalkylammonium borohydride or zinc borohydride may be used.
  • halo is meant the halogens: fluorine, chlorine and boimine-
  • the compound of formula A-l is prepared as described in Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 (1988); and Chem. Abstr., 109:6504h (1988); which are expressly incorporated by reference herein.
  • the compound of formula A-l is reduced to the compound of formula A-2 using a cobaltous chloride/bidentate ligand/sodium borohydride catalyst system. These reactants may be varied, as described above, by one of ordinary skill in the art.
  • the compound of formula A-2 is converted to the hydrochloride salt of formula A-3 by procedures readily known and available to one of ordinary skill in the art, including the use of concentrated hydrochloric acid.
  • Example 3 Below are detailed examples illustrating this new reduction method. The procedures of Example 3 are most preferred.
  • the silica gel is removed by filtration and the flask and solids are rinsed with a little water.
  • the combined filtrate and rinse are treated with a solution of 1.90 ml acetic acid in 14ml of water in order to precipitate the product.
  • the solids are collected by filtration, rinsed with three- 14 ml portions of water and vacuum dried at 60°C overnight to provide 3.20 g of crude product of formula A-2.
  • Part B This product is slurried with 3.2 g of magnesol in 70 ml of ethyl acetate for 2 hours at 70°C.
  • This slurry is transferred to a soxlet extraction thimble and the solids are extracted with hot ethyl acetate (100 ml) for 5 days.
  • the volume of the product slurry is adjusted to 70 ml by distillation and then the temperature is lowered to 50°C and 2.2 ml of concentrated hydrochloric acid is added.
  • the resulting slurry of the hydrochloric acid (HC1) salt is stirred at 50°C for 1 hour and then cooled to 0°C.
  • the solids are collected, rinsed with three-8 ml portions of room temperature ethyl acetate and dried at 60°C overnight to give 3.025 g of the title product.
  • catalyst solution prepared by dissolving 0.232 g of dimethylglyoxime and 0.012 g of cobaltous chloride-6 H 2 O in 5.0 ml of dimethylformamide, and then a solution of 0.378 g of sodium borohydride and 0.5 ml of 1.0N sodium hydroxide diluted with 3.5 ml of water is added at a rate of 0.1 ml/min. The reaction is stirred at 15°C for 3 hours and then 2.6 ml of acetone is added to quench any remaining sodium borohydride.
  • the solution is extracted with three 15 ml portions of ethyl acetate, and then it is acidified by the dropwise addition of 2.3 ml of glacial acetic acid diluted with 5.0 ml of water. Upon acidification, the product precipitates as white solids. The slurry is cooled to 0°C and stirred for 0.5 hours prior to filtration. The collected product is washed with three 15 ml portions of water and dried at 45°C under vacuum. The yield of crude product of formula A-2 is 1.583 g.
  • the reaction mixture is quenched with 5.3 ml of acetone and then extracted with ethyl acetate as described in Example 2.
  • the aqueous layer containing crude product of formula A-2 is acidified to pH 6.5 using 9 ml of 20% aqueous acetic acid.
  • the resulting slurry is treated with 25 ml of ethyl acetate and is stirred at 70°C for 2 hours. After cooling the slurry to 15°C, the solids are collected, washed first with water and then with methanol followed by drying at 65°C.
  • the yield of the product of formula A-2 is 4.75 g.
  • Part B A 5.00 g sample of the above solids is slurried at room temperature in

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

The present invention provides a method for making known pharmaceutical compounds. More particularly the present invention provides a new reduction method for making thiazolidinedione derivatives, particularly ciglitazone, pioglitazone, and englitazone. This reduction method comprises reacting a compound of formula (II) with a cobalt ion, a ligand and a reducing agent to achieve a compound of formula (I).

Description

A REDUCTION METHOD FOR SUBSTITUTED 5-METHYLENE-THIAZOLIDINEDIONES
FIELD OF INVENTION The present invention provides a new method of making organic compounds. In particular, the present invention provides a new reduction method for making certain pharmaceutically active compounds, such as thiazolidinedione derivatives, including pioglitazone, ciglitazone, englitazone and CS-045. These compounds are known for the treatment of diabetes and as insulin sensitizing agents.
BACKGROUND Pioglitazone hydrochloride ((+)-5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4- thiazolidinedione monohydrochloride), a thiazolidinedione derivative, is currently under clinical evaluation and is expected to effectively ameliorate the abnormal glucose and lipid metabolism associated with NIDDM or obesity (cf. Y. Momose et al., Chem. Pharai. Bull., 39:1440 (1991)).
T. Sohda, et al., J. Med. Chem. 35:2617-2626 (1992), discloses additional thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents, including 5-[4- [2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione, which had the most potent activity, more than 100 times that of pioglitazone.
Another thiazolidine derivative under-going clinical studies as a hypoglycemic agent is englitazone sodium, 5-([3,4-dihydro-2-(phenylmethyl)-2H-l-benzopyran-6-yl]methyI]-2,4- thiazolidinedione sodium salt) (cf. D.A. Clark et al., J. Med. Chem., 34:319-325 (1991)). Ciglitazone ((+)-5-[4-[(l-methylcyclohexyl)methoxy]benzyl]-2,4-thiazolidinedione) is characteristic of a new class of thiazolidine antidiabetic agents which lower blood glucose in animal models of noninsulin diabetes mellitus (NIDDM), while actually reducing circulating concentrations of insulin. This is believed to be accomplished by improving the responsiveness of the peripheral tissues to insulin. See, e.g., Chang, et al, Diabetes 32:830-838 (September 1983).
CS-045 is an antidiabetic, thiazolidinedione derivative. Its activity and preparation are described in Drugs Fut. 1991, 16(9).
Also, thiazolidine derivatives useful for the treatment of diabetes are described in U.S. patents 4,287,200; 4,687,777; and 4,572,912. Their effect on insulin resistance are described, e.g. in, Chang, et al, Diabetes 32: 839-845 (1983) and Chang, et al, Diabetes 32:830-838 (1983). The preparation of these thiazolidinedione derivatives, especially pioglitazone hydrochloride, includes the reduction of an intermediate previously performed by a troublesome high pressure hydrogenation on a palladium on carbon catalyst. What is needed in the art is an easier, more efficient method for performing this reduction. INFORMATION DISCLOSURE
Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 (1988); Chem- Abstr., 109:6504h (1988); disclose the process for making thiazolidinedione derivatives, including pioglitazone, using hydrogen on a palladium on carbon catalyst-
D.A- Clark et al-, J- Med. Chem., 34:319-325 (1991) discloses the process for making substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones, including englitazone, using hydrogen on a palladium on carbon catalyst.
Drugs Fut 1991, 16(9) discloses the multistep process, via carbon alkylation, for the preparation of the thiazolidinedione CS-045.
The following references disclose cobalt catalyzed reductions: U. Leutenegger et al., Angew. Chem. InL Ed., 28:60 (1989) discloses the enantioselective reduction of α,β-unsaturated carboxylates with sodium borohydride and catalytic amounts of chiral cobalt semicorrin complexes; and M.N. Ricroch and A. Gaudemer, J- Organometal. Chem., 67:119 (1974) discloses (pyridinato) cobaloxime, chloro (pyridinato) cobaloxime and vitamin B12 catalyzing the hydrogenation of α, β-unsaturated esters by hydrogen or sodium borohydride. J. O. Oshy, et al., J.A.C.S. 108:67-72 (1986), discloses cobalt (Et)-mediated sodium borohydride and lithium aluminum hydride reductions, which do not involve the use of ligands.
SUMMARY OF THE INVENTION The present invention particularly provides:
A process for preparing a compound of the formula I (refer to Formula Chart below) wherein Xj is an organic residue; which comprises:
(a) reacting a compound of the formula π with a cobalt ion, a ligand and a reducing agent;
This process wherein the temperature is -20° to 45°C and wherein a suitable solvent is used;
This process wherein Xj is the residue of an antidiabetic compound; This process wherein Xj is a) aryl, or b) HeU wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
(a) Cj-Cj alkyl,
(b) hydroxy,
(c) CJ-CJ alkoxy,
(d) halo, (e) amino,
(f) mono- or di-Cj-Cj alkylamino, (g) nitro,
(h) mercapto,
(i) CrC3 alkylthio,
(j) CrC3 alkylsulflnyl, (k) CrC3 alkylsulfonyl,
(1) -NH-CrC3 alkylsulfonyl,
(m) -NCΓC3 alkyl-Cj-C, alkylsulfonyl,
(n) S03H,
(0) S02NH2, (p) -CH2NH2,
(q) -Ar(CH2)n-Het,
(r) -Aj-(CH2)n-(C1-C6 alkyl substituted cyclohexyl), or
(s) -A1-(CH2)π- cyclohexyl; wherein Aj is (a) O, or
(b) S; wherein Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and including any bicyclic group in which any of the above heterocyclic rings is fused to a phenyl ring; which heterocycle ring is substituted by zero to three of the following:
(a) CrC6 alkyl,
(b) hydroxy,
(c) hydroxy (CrC5 alkyl),
(d) halogen, (e) amino,
(f) amino (CrC5 alkyl),
(g) nitro,
(h) mercapto,
(i) mercapto (Cj-C^ alkyl), (j) -S03H,
(k) -S02NH2,
(1) -0-CrC5 alkyl, (m) -(CH2)n- aryl, or (n) -(CH2)n- cyclohexyl; wherein n is zero to five, inclusive; This process wherein Xj is the moiety of formula HI (refer to Formula Chart below) wherein Rj is hydrogen; wherein R2 is
(a) -0-(CH2)-(5-ethyl-2-pyridyl), (b) -0-CH2-(l-methylcyclohexyI),
(c) the moiety of formula IN (refer to Formula Chart below); or wherein Rj and R2 taken together are the moiety of formula V (refer to Formula Chart below);
This process wherein Xj is the moiety of formula VI (refer to Formula Chart below); This process wherein the cobalt ion is in the form of
(a) cobaltous chloride,
(b) cobaltous diacetate, or
(c) cobaltic chloride; wherein the ligand is (a) dimethylglyoxime,
(b) 2,2'-bipyridyl, or
(c) 1,10-phenanthroline; wherein the reducing agent is
(a) sodium borohydride, (b) lithium borohydride,
(c) potassium borohydride,
(d) tetraalkylammonium borohydride, or
(e) zinc borohydride;
This process wherein the cobalt ion is in the foπn of cobaltous chloride, the ligand is dimethylglyoxime and the reducing agent is sodium borohydride; This process wherein the solvent is
(a) methanol,
(b) ethanol,
(c) i-propanol, (d) acetone,
(e) dimethylformamide, or
(f) tetrahydrofuran; provided, however, that if (d), (e) or (f) is the solvent, (a), (b), (c) or water must also be present; This process wherein the temperature is 5° to 20°C and the solvent is water and tetrahydrofuran;
This process wherein Xχ is the moiety of formula VI (refer to Formula Chart below); This process which further comprises:
(b) reacting the compound of the formula I (refer to Formula Chart below) with hydrochloric acid to obtain a compound of the formula VII (refer to Formula Chart below). Previously, the preparation of thiazolidinedione derivatives included the reduction of an intermediate done as a troublesome high pressure hydrogenation on a palladium on carbon catalyst. Surprisingly and unexpectedly, the present invention provides a new, more efficient method for performing this reduction which uses a cobaltous chloride/bidentate ligand/sodium borohydride catalyst system and the variations thereof as described below. This new reduction method is faster and easier and results in improved yield of the desired product. It is also more convenient to scale into production equipment since no high pressure apparatus is required. By "organic residue" is meant the residue of an organic compound that would be compatible with the reaction conditions of the process of the present invention. Preferably, such a residue will be one that does not react with the reactants of the process of the present invention so that only the double bond at the 5-position of the thiazolidinedione ring will be reduced. The reactants of the present invention include a cobalt ion, a ligand and a reducing agent. Such an organic residue would be readily determined by one of ordinary skill in the chemical arts.
By "residue of an antidiabetic compound" is meant the organic moiety that is attached to the 5-position of a thiazolidinedione derivative, which derivative has antidiabetic activity, such as those described in Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 (1988); Chem. Abstπ, 109:6504h (1988); D.A. Clark et al., J. Med. Chem., 34: 319-325 (1991); U.S. patents 4,287,200; 4,687,777; and 4,572,912; Drugs Fut 1991, 16(9); and J. Med. Chem. 35:2617-2626 (1992). The description of the preparation of the intermediates of these compounds of formula II is expressly incorporated by reference herein. The process of the present invention is preferably applicable to the commercially important thiazolidinediones, pioglitazone hydrochloride (the compound of formula VII in the Formula Chart,) ciglitazone (the compound of formula X in the Formula Chart), englitazone (the compound of formula XX in the Formula Chart), CS-045 (the compound of formula XXX in the Formula Chart) and the recently disclosed thiazolidinedione of formula XL. All of the intermediates of formula II may readily be prepared by procedures analogous to those described above by one of ordinary skill in the art.
By "aryl" is meant phenyl or naphthyl substituted by zero to three of the following: Cj-C3 alkyl, hydroxy, Cj-C3 alkoxy, halo, amino, mono- or di-Cj-C^ alkylamino, nitro, mercapto, CJ-CJ alkylthio, Cj-C*-* alkylsulfinyl, Cj-C3 alkylsulfonyl, -NH-C-[-C3 alkylsulfonyl, - NCrC3 alkyl-CrC3 alkylsulfonyl, SO3H, SO2NH2, -CH2NH2, -Ar(CH2)n-Het, -Ar(CH2)n- (CJ-C6 alkyl substituted cyclohexyl), or -A1-(CH2)n- cyclohexyl; wherein Aj is O, or S; By "Het" is meant a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a phenyl ring; which heterocycle ring is substituted by zero to three of the following: Cj-Cg alkyl, hydroxy, hydroxy (Cj-C5 alkyl), halogen, amino, amino (Cj-Cg alkyl), nitro, mercapto, mercapto (CrC5 alkyl), -S03H, -S02NH2, -0-CrC5 alkyl, -(CH2)n- aryl, or -(CH2)n- cyclohexyl; wherein n is zero to five, inclusive.
The reaction temperature range for the process of the present invention is -20°C to +45°C. The preferred range is +5° to +20°C. +15°C is most preferred. Solvents that will wor in the process of the present invention include methanol, ethanoL i-propanol, acetone, dimethylfoπnamide (DMF) and tetrahydrofuran (THF); with the proviso that if acetone, DMF or THF are used then a proton source, such as an alcohol, like the ones mentioned above, or water must also be present The amount of such proton source required would typically be ≥leq., but would be readily apparent to one of ordinary skill in the art. Water and tetrahydrofuran are a preferred solvent combination.
Cobalt is the preferred metal ion (Co or Co+3). Sources of cobalt include CoCl2 (cobaltous chloride) and Co(OAc)2 (cobaltous diacetate) or CoCl3 (cobaltic chloride).
By "ligand" is meant a complexing agent for a metal ion. In addition to dimethylglyoxime, which is the preferred ligand, other ligands that may be used are 2, 2'- bipyridyl and 1,10-phenanthroline, which should be used in at least a 1:1 mole ratio with the cobalt ion- Most preferred is the ligand to cobalt ratio of 50:1.
Sodium borohydride (NaBH^ is the preferred reducing agent, but other borohydrides, such as lithium borohydride, potassium borohydride, tetraalkylammonium borohydride or zinc borohydride may be used. By "halo" is meant the halogens: fluorine, chlorine and boimine-
CHART A Chart A illustrates the preparation of pioglitazone hydrochloride using the new reduction step of the present invention.
The compound of formula A-l is prepared as described in Y. Momose et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 (1988); and Chem. Abstr., 109:6504h (1988); which are expressly incorporated by reference herein.
The compound of formula A-l is reduced to the compound of formula A-2 using a cobaltous chloride/bidentate ligand/sodium borohydride catalyst system. These reactants may be varied, as described above, by one of ordinary skill in the art. The compound of formula A-2 is converted to the hydrochloride salt of formula A-3 by procedures readily known and available to one of ordinary skill in the art, including the use of concentrated hydrochloric acid.
Below are detailed examples illustrating this new reduction method. The procedures of Example 3 are most preferred.
DETAILED DESCRIPTION OF THE INVENTION The present invention is seen more fully by the examples below.
EXAMPLE 1 Reduction Step in the Preparation of Pioglitazone Hydrochloride
(Formula A-3) Refer to Chart A. Part A A slurry of 3.544 g of the compound of formula A-l in 45 ml of water is cooled to 3°C and 0.51 ml of 50% sodium hydroxide is added. The resulting solution is then treated with 22 mg of dimethylglyoxime, and then 1.0 g of powdered blue indicating silica gel (containing about 0.7 wt% CoCl2), 432 mg of sodium borohydride and 5.0 ml of dimethylformamide (DMF) are added in that order. A thin black slurry results. The reaction mixture is stirred at about 17°C for 25 hours at which time high pressure liquid chromatography (LC) indicates no remaining starting material. The silica gel is removed by filtration and the flask and solids are rinsed with a little water. The combined filtrate and rinse are treated with a solution of 1.90 ml acetic acid in 14ml of water in order to precipitate the product. After stirring for 2 hours at room temperature, the solids are collected by filtration, rinsed with three- 14 ml portions of water and vacuum dried at 60°C overnight to provide 3.20 g of crude product of formula A-2. Part B This product is slurried with 3.2 g of magnesol in 70 ml of ethyl acetate for 2 hours at 70°C. This slurry is transferred to a soxlet extraction thimble and the solids are extracted with hot ethyl acetate (100 ml) for 5 days. The volume of the product slurry is adjusted to 70 ml by distillation and then the temperature is lowered to 50°C and 2.2 ml of concentrated hydrochloric acid is added. The resulting slurry of the hydrochloric acid (HC1) salt is stirred at 50°C for 1 hour and then cooled to 0°C. The solids are collected, rinsed with three-8 ml portions of room temperature ethyl acetate and dried at 60°C overnight to give 3.025 g of the title product.
EXAMPLE 2 Reduction Step in the Preparation of Pioglitazone Hydrochloride
(Formula A-3) Refer to Chart A. Part A To a 100 ml 3-necked round bottomed flask, equipped with mechanical stirrer, is charged 1.772 g of the compound of formula A-l, 25 ml of water, 6.0 ml of tetrahydrofuran, and 2.0 ml of 1.0N sodium hydroxide. The mixture is stirred at 25°C for 10 min. and cooled to 15°C. To the cooled mixture is added 0.05 - 0.50 ml of catalyst solution, prepared by dissolving 0.232 g of dimethylglyoxime and 0.012 g of cobaltous chloride-6 H2O in 5.0 ml of dimethylformamide, and then a solution of 0.378 g of sodium borohydride and 0.5 ml of 1.0N sodium hydroxide diluted with 3.5 ml of water is added at a rate of 0.1 ml/min. The reaction is stirred at 15°C for 3 hours and then 2.6 ml of acetone is added to quench any remaining sodium borohydride. After stirring for 0.5 hours , the solution is extracted with three 15 ml portions of ethyl acetate, and then it is acidified by the dropwise addition of 2.3 ml of glacial acetic acid diluted with 5.0 ml of water. Upon acidification, the product precipitates as white solids. The slurry is cooled to 0°C and stirred for 0.5 hours prior to filtration. The collected product is washed with three 15 ml portions of water and dried at 45°C under vacuum. The yield of crude product of formula A-2 is 1.583 g.
Part B The crude product of formula A-2 is converted to the hydrochloride salt title product by the method described in Example 1, Part B. EXAMPLE 3 Reduction Step in the Preparation of Pioglitazone Hydrochloride
(Formula A-3) Refer to Chart A. Part A A slurry of 5.0 g of the compound of formula A-l in 15 ml of water, 9 ml of tetrahydrofuran and 9.5 ml of IN sodium hydroxide is treated with a solution of 42 mg of cobalt (JΣ) chloride »H20 in 4 ml of 1:1 aqueous tetrahydrofuran. The temperature is adjusted to 15°C and a solution of 667 mg of sodium borohydride in 15 ml of water containing 1.8 ml of IN sodium hydroxide is added dropwise while mamtaining the temperature at 15°C to 18°C. The reaction mixture is quenched with 5.3 ml of acetone and then extracted with ethyl acetate as described in Example 2. The aqueous layer containing crude product of formula A-2 is acidified to pH 6.5 using 9 ml of 20% aqueous acetic acid. The resulting slurry is treated with 25 ml of ethyl acetate and is stirred at 70°C for 2 hours. After cooling the slurry to 15°C, the solids are collected, washed first with water and then with methanol followed by drying at 65°C. The yield of the product of formula A-2 is 4.75 g.
Part B A 5.00 g sample of the above solids is slurried at room temperature in
30 ml of methanol and then treated with 1.0 equivalent of cone, hydrochloric acid in 13 ml of methanol. The slurry is stirred at 24°C until all of the solids dissolved (2 hours). The solution is concentrated by vacuum distillation to 20 ml. The solvent changes over to ethyl acetate by displacement vacuum distillation. The desired hydrochloride salt precipitates during this solvent exchange. The slurry is cooled to 2°C and the solids are collected by vacuum filtration, washed with cold ethyl acetate and dried in the vacuum oven at 60°C. The pioglitazone hydrochloride salt weighed 5.06 g and showed 97.7% quality by LC analysis. FORMULA CHART
Figure imgf000011_0001
Figure imgf000011_0002
15
Figure imgf000011_0003
20
Figure imgf000011_0004
30
Phenyl ■ *<Pv V
35 FORMULA CHART (continued)
Figure imgf000012_0001
10
Figure imgf000012_0002
Figure imgf000012_0003
25
Figure imgf000012_0004
35 FORMULA CHART (continued)
Figure imgf000013_0001
10
Figure imgf000013_0002
CHART A
Figure imgf000014_0001
A-3

Claims

CLAIMS 1. A process for preparing a compound of the formula I
0
Figure imgf000015_0001
wherein Xj is an organic residue; which comprises: (a) reacting a compound of the formula II
H 0
Figure imgf000015_0002
with a cobalt ion, a ligand and a reducing agent.
2. The process of claim 1 wherein the temperature is -20° to 45°C and wherein a suitable solvent is used.
3. The process of claim 1 wherein Xj is the residue of an antidiabetic compound.
4. The process of claim 3 wherein Xj is a) aryl, or b) Het; wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
(a) CrC3 alkyl,
(b) hydroxy, (c) CrC3 alkoxy,
(d) halo,
(e) amino,
(f) mono- or di-Cj-C^ alkylamino,
(g) nitro, (h) mercapto,
(i) CrC3 alkylthio, (j) CrC3 alkylsulfinyl,
(k) Cj-Cj alkylsulfonyl,
(1) -NH- -Cg alkylsulfonyl,
(m) -NCj-Cg alkyl-Cj-Cg alkylsulfonyl, (n) S03H,
(o) S02NH2,
(p) -CH2NH2,
(q) -A^CH-^-Het,
(r) -A1-(CH2)n-(C1-C6 alkyl substituted cyclohexyl), or (s) -Ar(CH2)n- cyclohexyl; wherein Aj is
(a) O, or
(b) S; wherein Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and including any bicyclic group in which any of the above heterocyclic rings is fused to a phenyl ring; which heterocycle ring is substituted by zero to three of the following:
(a) CrC6 alkyl,
(b) hydroxy, (c) hydroxy (CrC5 alkyl),
(d) halogen,
(e) amino,
(f) amino (CrC5 alkyl),
(g) nitro, (h) mercapto,
(i) mercapto (C-*-C5 alkyl),
(j) -S03H,
(k) -S02NH2,
(1) -0-CrC5 alkyl, (m) -(CH2)n- aryl, or
(n) -(CH2)n- cyclohexyl; wherein n is zero to five, inclusive.
5. The process of claim 4 wherein X1 is the moiety of formula HJ
Figure imgf000017_0001
wherein Rj is hydrogen; wherein R2 is
(a) -0-(CH2)-(5-ethyl-2-pyridyl),
(b) -0-CH2-(l-methylcyclohexyl),
(c) the moiety of formula IV; or
Figure imgf000017_0002
wherein Rj and R2 taken together are the moiety of formula V
Figure imgf000017_0003
6. A process of claim 5 wherein Xj is the moiety of formula VI
Figure imgf000017_0004
The process of Claim 1 wherein the cobalt ion is in the form of
(a) cobaltous chloride,
(b) cobaltous diacetate, or
(c) cobaltic chloride; wherein the ligand is (a) dimethylglyoxime,
(b) 2,2'-bϊpyridyl, or
(c) 1,10-phenanthroline; wherein the reducing agent is (a) sodium borohydride,
(b) lithium borohydride,
(c) potassium borohydride,
(d) tetraalkylammonium borohydride, or
(e) zinc borohydride-
8. The process of claim 7 wherein the cobalt ion is in the form of cobaltous chloride, the ligand is dimethylglyoxime and the reducing agent is sodium borohydride.
9. The process of claim 2 wherein the solvent is
(a) methanol,
(b) ethanol,
(c) i-propanol-
(d) acetone, (e) dimethylformamide, or
(f) tetrahydrofuran; provided, however, that if (d), (e) or (f) is the solvent, (a), (b), (c) or water must also be present
10. The process of claim 9 wherein the temperature is 5° to 20°C and the solvent is water and tetrahydrofuran.
11. The process of claim 8 wherein Xj is
Figure imgf000018_0001
12. The process of claim 11 which further comprises: (b) reacting the compound of the formula I with hydrochloric acid to obtain a compound of the formula VII
Figure imgf000019_0001
PCT/US1992/010329 1991-12-20 1992-12-04 A reduction method for substituted 5-methylene-thiazolidinediones WO1993013095A1 (en)

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WO1998042704A1 (en) * 1997-03-20 1998-10-01 Roche Diagnostics Gmbh Improved method for producing thiazolidinediones, and new thiazolidinediones
WO2001096321A1 (en) * 2000-06-14 2001-12-20 Kyorin Pharmaceutical Co., Ltd. Process for the preparation of thiazolidinedione derivatives
US6632947B2 (en) 1997-02-18 2003-10-14 Smithkline Beecham Plc Process for the preparation of substituted thiazolidinedione
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WO2006026934A1 (en) * 2004-09-10 2006-03-16 Zentiva, A.S. Method for the preparation of rosiglitazone
US7015320B2 (en) 2002-03-19 2006-03-21 Bristol-Myers Squibb Company Process for the manufacture of optically active 3-substituted lactams by asymmetric hydrogenation of 3-alkylidenelactams
US7091359B2 (en) 1997-11-04 2006-08-15 Smithkline Beecham Plc Process for the preparation of thiazolidinedione derivatives
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US7351832B2 (en) 1997-11-04 2008-04-01 Smithkline Beecham P.L.C. Process for the preparation of thiazolidinedione derivatives
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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191169B1 (en) * 1992-08-28 2001-02-20 City Of Hope Human leukocyte 12-lipoxygenase and its role in the pathogenesis of disease states
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AU2002337749A1 (en) * 2001-09-28 2003-04-07 Teva Pharmaceutical Industries Ltd. Pioglitazone hydrochloride
US20050187258A1 (en) * 2001-12-20 2005-08-25 Ben-Zion Dolitzky Hydrogenation of precursors to thiazolidinedione antihyperglycemics
WO2004024059A2 (en) * 2002-09-12 2004-03-25 Themis Laboratories Private Limited, Improved process for preparation of thiazolidinedione derivatives
US20060089387A1 (en) * 2004-10-26 2006-04-27 Le Huang Stabilized pharmaceutical composition comprising antidiabetic agent
US20090118514A1 (en) * 2007-11-06 2009-05-07 Raghupathi Reddy Anumula Processes for preparing pioglitazone and its pharmaceutically acceptable salts
AR081268A1 (en) * 2010-06-02 2012-07-18 Cardiolynx Ag PIOGLITAZONA NITRATE DERIVATIVES
WO2012153312A1 (en) 2011-05-11 2012-11-15 Ranbaxy Laboratories Limited Process for the purification of pioglitazone

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257781A1 (en) * 1986-07-24 1988-03-02 Takeda Chemical Industries, Ltd. A method for producing thiazolidinedione derivatives
EP0332331A2 (en) * 1988-03-08 1989-09-13 Pfizer Inc. Thiazolidinedione hypoglycemic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0257781A1 (en) * 1986-07-24 1988-03-02 Takeda Chemical Industries, Ltd. A method for producing thiazolidinedione derivatives
EP0332331A2 (en) * 1988-03-08 1989-09-13 Pfizer Inc. Thiazolidinedione hypoglycemic agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 115, no. 17, 28 October 1991, Columbus, Ohio, US; abstract no. 183284f, page 926 ; *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. vol. 108, no. 1, 8 January 1986, GASTON, PA US pages 67 - 72 JOHN O. OSBY ET AL 'Studies on the mechanism of transition-metal-assisted sodium borohydride and lithium aluminium hydride reductions' cited in the application *

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