Novel processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof

Abstract: The present invention relates to novel processes for preparing intermediates of the formula I and to novel intermediates thereof which are useful in the preparation of inhibitors of enkephalinase and angiotensin converting enzyme.

Description: The present invention relates to novel processes for preparing compounds of the formula I, which are useful intermediates for preparing inhibitors of enkephalinase and angiotensin converting enzyme, including [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid and [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid and pharmaceutically acceptable salts thereof (European Patent Application No. 0 481 522 A1, published 22 April 1992, 209th ACS National Meeting, Division of Medicinal Chemistry, Abst. No. 161 (1995), and European Patent Application No. 657 453 A1, published 14 June 1995) and to novel intermediates thereof. EP-A-0 534 396 discloses 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE as well as a process for preparing said derivatives. The present invention provides a novel process for preparing a compound of formula I wherein G completes an aromatic ring selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy; comprising: (a) reacting a phthalimido aryl amino acid derivative of the formula wherein A is selected from the group consisting of -OH, - Cl, -Br, anhydride, mixed anhydride, and activated ester; Ar is a radical selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of phenyl and C 1 -C 4 alkoxy; with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a 2-cyano-1,2,3,4-tetrahydro-pyridine derivative of the formula wherein Ar is as defined above; (b) reacting the 2-cyano-1,2,3,4-tetrahydro-pyridine derivative with an appropriate cyclizing acid to give a 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine of the formula wherein G is as defined above; (c) hydrolyzihg the 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine. In addition, the present invention provides a novel compound of the formula: wherein Ar is a radical selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy. In addition, the present invention provides a novel compound of the formula: wherein G completes an aromatic ring selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy. As used in this application: a) the designation refers to a bond that protrudes forward out of the plane of the page; b) the designation refers to a bond that protrudes backward out of the plane of the page; c) the designation refers to a bond for which the stereochemistry is not designated; d) the term "C 1 -C 4 alkoxy" refers to a straight or branched alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc; e) the term "phenyl" refers to a radial of the formula f) the designation refers to a thienyl or pyrrolyl group and it is understood that the radical may be attached at either the 2-position or the 3-position; g) the designation refers to an indolyl, benzthienyl, or benzfuryl group and it is understood that the radical may be attached at either the 2-position or the 3-position; h) the designation refers to a naphthyl group and it is understood that the radical can be attached at either the 1-position or the 2-position; i) it is understood that when G completes an aromatic ring the compound of formula I is of the formula j) it is understood that when G completes an aromatic ring the compound of formula I is of the formula k) it is understood that when G completes an aromatic ring the compound of formula I is of the formula l) it is understood that when G completes an aromatic ring the compound of formula I is of the formula m) it is understood that when G completes an aromatic ring the compound of formula I is of the formula n) it is understood that when G completes an aromatic ring the compound of formula I is of the formula o) it is understood that when G completes an aromatic ring the compound of formula I is of the formula p) the term "pharmaceutically acceptable salts" refers to either acid addition salts or to base addition salts. The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of inhibitors of enkephalinase and angiotensin converting enzyme, including [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4α, 7α(R*), 12bβ)]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid or any intermediates thereof. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salt of inhibitors of enkephalinase and angiotensin converting enzyme, including [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid or [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid or any intermediates thereof. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, cyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, isopropyldiethylamine, pyridine and picoline. As is appreciated by one of ordinary skill in the art, the methodology disclosed herein can be used to prepare all isomers at the 4-position and 7-postition of instant intermediates, including 7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-5-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid and thereby the isomers of the inhibitors of enkephalinase and angiotensin converting enzyme produced therefrom. The stereochemistry at the 7-position of the intermediates is determined by the stereochemistry of the phthalimido aryl amino acid amide or the activated phthalimido aryl amino acid derivative selected. The specific 4-position stereoisomers can be resolved and recovered by techniques known in the art, such as chromatography on silica gel or on a chiral stationary phase, or fractional recrystallization of the 4-position carboxylic acids or derivatives thereof as described herein; in European Patent Application No. 0 481 522 A1, published 22 April 1992; Stereochemistry of Organic Compounds , E. L. Eliel and S. H. Wilen, Wiley (1994); and in Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981). A general synthetic procedure is set forth in.Scheme A. In Scheme A, all substituents unless otherwise indicated, are as previously defined. Starting materials, reagents, techniques and procedures used in Scheme A are well known and appreciated by one of ordinary skill in the art. In Scheme A, step a, an appropriate phthalimido aryl amino acid derivative of structure (1) is contacted with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a 2-cyano-1,2,3,4-tetrahydro-pyridine derivative of structure (6). An appropriate phthalimido aryl amino acid derivative are readily available or are readily derived from aromatic amino acids which are well known in the art. Examples of aromatic amino acids which are useful in this instant process include: phenylalanine, tryptophan, tyrosine and its ether derivatives, thien-2-ylalanine, 3-thienylalanine, fur-2-ylalanine, fur-3-ylalanine, benzthien-2-ylalanine, indol-2-ylalanine, etc., The Peptides, vol. 5, E. Gross and J. Meienhoffer ed. (Academic Press, 1983). In addition, aromatic amino acids can be obtained by methods known in the art or analogously known in the art, such as D. A. Evans et al. , J. Am. Chem. Soc., 112 , 4011-4030 (1990); S. Ikegami et al. , Tetrahedron 44 , 5333-5342 (1988); W. Oppolzer et al. , Tet. Lets. 30 , 6009-6010 (1989); Synthesis of Optically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis , Tetrahedron Symposia in print, No. 33, Tetrahedron 44 , No. 17. (1988); U. Schollkopf, Pure Appl. Chem. 55 , 1799 (1983); U. Hengartner et al. , J. Org. Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. , Tet. Lets. , 2641-2644 (1978); M. J. O'Donnell et al. , Tet. Lets. 23 , 4255-4258 (1982); M. J. O'Donnell et al. , J. Am. Chem. Soc. 110 , 8520-8525 (1988). An appropriate phthalimido aryl amino acid derivative is one in which the stereochemistry is as desired in the final product, Ar is as required to give G as desired in the final product, and the group A is an activating group which can be displaced by 2-cyano-1,2,3,4-tetrahydropyridine in an amidation reaction. An amidation reaction may proceed through an acid, A is -OH; or an acid halide, such as an acid chloride, A is -Cl; or acid bromide, A is -Br; or an activated intermediate; such as an anhydride; or a mixed anhydride of substituted phosphoric acid, such as dialkylphosphoric acid, diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroacetic acid, trifluoroacetic acid, and the like; of aromatic carboxylic acids, such as benzoic acid and the like; of an activated ester, such as phenol ester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenol ester, pentachlorophenol ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester, and the like; activated amide, such as imidazole, dimethylpyrazole, triazole, or tetrazole; or an intermediate formed in the presence of coupling agents, such as dicyclohexylcarbodiimide or 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide. Acid halides and activated intermediates may be prepared and used without isolation. Alternately, acid halides and activated intermediates may be prepared and isolated but not purified before use. The use and formation of acid halides and activated intermediates is well known and appreciated in the art. For example, an appropriate phthalimido aryl amino acid derivative of structure (1) in which A is -Cl is contacted with a molar excess of 2-cyano-1,2,3,4-tetrahydro-pyridine which can be generated in situ by reacting 2,6-dicyano-piperidine with a suitable base such as potassium t-butoxide. The reaction is carried out in a suitable solvent, such as, tetrahydrofuran. The amide formation reaction is carried out using a suitable base, such as N-methylmorpholine. The reaction is carried out at temperatures of from -50°C to 40°C and generally requires from 1 hour to 5 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, chromatography, and recrystallization. In Scheme A, step b, an appropriate 2-cyano-1,2,3,4-tetrahydro-pyridine derivative of structure (6) is contacted with an appropriate cyclizing acid to give a 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazegine of structure (7). An appropriate cyclizing acid is one which allows.for the formation of product without leading to significant degradation of either the starting material or the product. Examples of appropriate cyclizing acids include, sulfuric acid, trifluoromethanesulfonic acid, sulfuric acid/trifluoroacetic anhydride mixtures, and trifluoromethanesulfonic acid/trifluoroacetic anhydride mixtures. For example, an appropriate 2-cyano-1,2,3,4-tetrahydro-pyridine derivative of structure (6) is contacted with an appropriate cyclizing acid. The reaction is carried out neat in the appropriate cyclizing acid selected or in a suitable aprotic solvent, such as dichloromethane. The reaction is carried out at temperatures of from 10°C-40°C and generally requires from 1 to 18 hours. It is preferred that the product of this step, obtained in solution, be used without isolation, however, the product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization. In Scheme A, step c, an appropriate 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine of structure (7) is hydrolyzed to give a compound of the formula I. For example, an appropriate 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine of structure (7) is contacted with water. The reaction is carried out in the presence of a suitable acid catalyst. A suitable acid catalyst is one which allows for the hydrolysis of a cyano group, under the reaction conditions, to a carboxylic acid without removing the phthalimide group or hydrolyzing the cyclic amide bond. Suitable acid catalysts are well known in the art and include, sulfuric acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic acid/ trifluoroacetic acid mixtures and sulfuric acid/trifluoroacetic anhydride mixtures. When the product of the previous step is used without isolation the appropriate cyclizing acid selected may be used as the suitable acid catalyst for the hydrolysis. The reaction is carried out at temperatures of from about 10°C to about 40°C. Generally the reaction requires from 10 minutes to 2 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization. The following examples present typical syntheses as described in Scheme A. These examples and preparations are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples and preparations, the following terms have the meanings indicated: "mg" refers to milligrams, "g" refers to grams, "kg" refers to kilograms, "mmol" refers to millimoles, "mol" refers to moles, "µL" refers to microliters, "mL" refers to milliliters, "L" refers to liters, "°C" refers to degrees Celsius, "mp" refers to melting point, "dec" refers to decomposition, "[α] 20 D " refers to specific rotation of the D line of sodium at 20° C obtained in a 1 decimeter cell, "c" refers to concentration in g/100mL, "M" refers to molar, "L" refers to liter, "2-PrOH" refers to isopropanol, "MeOH" refers to methanol, "R f " refers to retention factor, "TLC" refers to thin layer chromatography, "psi" refers to pounds per square inch. PREPARATION 1 Synthesis of N-Phthaloyl-(S)-phenylalanine, acid chloride Combine phthalic anhydride (1.82 kg, 12.3 mol), (S)-phenylalanine (1.84 kg, 11.1 mol) and anhydrous dimethylformamide (2.26 L). Stir at 115-120°C for 2 hours under a nitrogen atmosphere. Pour into rapidly stirred water (32.6 L) and cool overnight at 0°C. Filter, wash with cold water (2 X 2L), and air dry. Dissolve in a mixture of 9A ethanol (8.05 L) and water (8.05 L) and heat at reflux temperature. Gravity filter, cool to ambient temperature and refrigerate overnight at about 0°C. Filter the crystallized product, wash with cold 50:50 9A ethanol/water (2 X 2L) and air dry to yield 2.96 kg (90.3%) of N-phthaloyl-(S)-phenylalanine; mp 177-179°C. Combine N-phthaloyl-(S)-phenylalanine (50.2 g, 0.17 mol), methylene chloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogen atmosphere. Add oxalyl chloride (17.7 mL, 0.2 mol) over about 5 minutes. Stir at ambient temperature for 3 hours and evaporate the solvent in vacuo to give the title compound. EXAMPLE 1 Synthesis of N-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydropyridine Generate 2-cyano-1,2,3,4-tetrahydro-pyridine in situ , combine 2,6-dicyano-piperidine (1.0 g, 7.4 mmol) tetrahydrofuran (20 mL). Cool to about -23°C using a dry ice/carbon tetrachloride bath. Slowly, add potassium t-butoxide (0.913 g, 95%, 8.14 mmol). Slow addition of the potassium t-butoxide is required to minimize the formation of by-products. After the addition of potassium t-butoxide is complete, the reaction mixture is stirred for 20-30 minutes to give a solution of 2-cyano-1,2,3,4-tetrahydro-pyridine. Warm the solution to ambient temperature. Add N-phthaloyl-(S)-phenylalanine, acid chloride (2.55 g, 8.14 mmol) and N-methylmorpholine (0.8 mL, 7.4 mmol). After 2 hours, partition the reaction mixture between chloroform and and aqueous 1M sodium bicarbonate solution. Separate the organic layer, dry over MgSO 4 , filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% ethyl acetate/hexane to give the title compound. EXAMPLE 2 Synthesis of 4-cyano-(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine Combine N-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydro-pyridine (100 mg, 0.26 mmol), sulfuric acid (3 mL, 99.999%), and trifluoroacetic anhydride. (0.03 mL). After 24 hours, the title compound is obtained as a solution. EXAMPLE 3 (S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-(S)-4-carboxylic acid Combine a solution of 4-cyano-(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine as obtained in Example 2 and water (30 mL). After 3 hours, extract the reaction mixture with chloroform. Separate the organic layer, dry over Na 2 SO 4 , filter, and evaporate in vacuo to give a residue (10:1 mixture of S:R isomers at the 4-position carboxylic acid as determined by NMR analysis). Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then ethyl acetate/acetic acid 99/1 to give the title compound. [α] 20 D = -60.74° (c=0.915, MeOH). PREPARATION 2 Preparation of [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Synthesis of [4S-[4α, 7α(R*), 12bβ]]-7-(Amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid Combine [4S-[4α, 7α(R*), 12bβ]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid (1.63 kg, 4.03 mol), triethylamine (429 g, 4.24 mol), and methanol (5.59 kg). Add hydrazine monohydrate (241 g, 4.82 mol). Heat at reflux. After 3 hours, cool to 60°C and pour the reaction mixture into a mixture of water (7.326 kg) and aqueous 37% hydrochloric acid solution (821 g). Evaporate in vacuo at 50°C until the reaction mixture is reduced to about 7.8 kg. Dilute the reaction mixture with water (8.078 kg) and adjust the pH to about 2.82 using aqueous 37% hydrochloric acid solution. Heat to 50°C. After 1 hour, filter to remove the solids and rinse with water (pH adjusted to 2.5 with hydrochloric acid, 1.502 kg). Combine the filtrate and the rinse. Adjust the pH to 7.22 using triethylamine. Evaporate in vacuo at 60°C until the reaction mixture is reduced to about 4.65 kg to obtain a slurry. Dilute the slurry with isopropanol (3.53 kg) and stir for 30 minutes. Cool to 5°C to obtain a solid. Collect the solid by filtration, rinse with isopropanol, and dry to give the title compound (933 g, 84.4%). Synthesis of [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-1,2,3,5,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Mix 3-phenyl-2(R)-bromopropionic acid (967 g, 4.22 mol), tetrahydrofuran (7.74 kg) and N-hydroxysuccinimide (607 g, 5.27 mol) and cool to 5°C. Add, by slow addition over 2.5 hours, a solution of 1,3-dicyclohexylcarbodiimide (828 g, 4.01 mol) in tetrahydrofuran (1.936 kg), maintaining the temperature between -3 and 3°C. Stir for 19 hours, remove 2,3-dicyclohexylurea by vacuum filtration and wash the filter cake with tetrahydrofuran (1.927 kg). Place the filtrate and wash in a 50 L bottom-drain round-bottom flask, add [4S-[4α, 7α(R*), 12bβ]]-7-(amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (869 g, 3.17 mol) and stir at 22°C for 5.5 hours. Add triethylamine (77 g, 0.76 mol) and stir for an additional 17 hours at 22°C. Dilute with ethyl acetate (10.427 kg), wash with water (9.94 kg) with 37% hydrochloric acid (214.2 g) and sodium chloride (418 g), then with 12.328 kg water with sodium chloride (418 g). Dry (MgSO 4 ), filter and wash the filter cake with ethyl acetate (2.193 kg). Evaporate the solvent in vacuo , add isopropanol (4.210 kg), stir at 12-16°C for 17 hours, chill and isolate the product by vacuum filtration. Wash with isopropanol (621 g) and dry to give the title compound (940 g, 61%). Synthesis of [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Mix [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (1.052 kg, 2.17 mol), acetone (13.256 kg) and thioacetic acid (207.1 g, 2.72 mol). Cool to -2°C and add, over approximately 10 minutes, a solution of potassium hydroxide (279.5 g) in water (270 g). Stir at -4°C for 23 hours, add 1.054 kg water containing 37% hydrochloric acid (210 g) and evaporate the solvent in vacuo . Dissolve the solid residue in toluene (11.517 kg) at 43°C, transfer to a 22 L bottom-drain round bottom flask and wash with water (4.067 kg). Wash at 41°C with 4.099 kg water containing sodium chloride (213 g). Evaporate the solvent in vacuo , dissolve the solid residue in toluene (10.239 kg), filter and cool. After cooling to -2°C, collect the solid by vacuum filtration, wash with toluene (1.103 kg) and dry under vacuum at up to 80°C to give the title compound (859 g, 82.5%). Preparation of [4S-[4α, 7α(R*), 12bβ]]-7-[(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Dissolve [4S-[4α, 7α(R*), 12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzaiepine-4-carboxylic acid (57 mg, 0.12 mmol) in deoxygenated methanol (3 mL) containing lithium hydroxide (0.25 mL, 1M in water, 0.25 mmol). Stir for 30 minutes under argon atmosphere at ambient temperature. Reduce in volume to 1.5 mL in vacuo , then add, by dropwise addition, to a rapidly stirring solution of 2M hydrochloric acid (2 mL). Collect the resulting precipitate, wash with water and dry in a vacuum dessicator for 1 hour. Dry at 35°C overnight to give the title compound as a white electrostatic powder.

Claims: A process for preparing a compound of the formula wherein G completes an aromatic ring selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy; comprising: (a) reacting a phthalimido aryl amino acid derivative of the formula wherein A is selected from the group consisting of -OH, -Cl, -Br, anhydride, mixed anhydride, and activated ester; Ar is a radical selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl and C 1 -C 4 alkoxy; with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a 2-cyano-1,2,3,4-tetrahydro-pyridine derivative of the formula wherein Ar is as defined above; (b) reacting the 2-cyano-1,2,3,4-tetrahydro-pyridine derivative with an appropriate cyclizing acid to give a 4-cyano-1,2,3,4,6,7,8.12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine of the formula wherein G is as defined above; (c) hydrolyzing the 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrida[2,1-a][2]benzazepine. A process according to Claim 1 wherein the appropriate cyclizing acid is a trifluoromethanesulfonic acid/trifluoroacetic anhydride mixture. A process according to Claim 1 wherein the appropriate cyclizing acid is sulfuric acid/trifluoroacetic anhydride mixture. A process according to Claim 1 wherein the 2-cyano-1,2,3,4-tetrahydro-pyridine is generated in situ from 2,6-dicyano-piperidine. A compound of the formula wherein Ar is a radical selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy. The compound according to Claim 5 wherein the compound is N-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydro-pyridine. A compound of the formula wherein G completes an aromatic ring selected from the group consisting of wherein X 1 is selected from the group consisting of S and NH; X 2 is selected from the group consisting of S, O, and NH; and R is selected from the group consisting of hydrogen, hydroxy, phenyl, and C 1 -C 4 alkoxy. The compound according to Claim 7 wherein the compound is 4-cyano-(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine.

Inventors: BEIGHT DOUGLAS WADE, FLYNN GARY ALAN, GENIN MICHAEL JAMES, BEIGHT, DOUGLAS WADE, FLYNN, GARY ALAN, GENIN, MICHAEL JAMES
Applicants: AVENTIS PHARMA INC, AVENTIS PHARMACEUTICALS INC.
Application year: 1995
Main classification: C07K5
IPC codes: C07D491, C07D405, C07D409, C07D471, C07D401, C07D495, C07K5, A61K38