Patent EA-004984-B1 (EA)
Title: Method for stereoselective synthesis of cyclic amino acids
Inventor: BRYANS JUSTIN STEPHEN
IPC: C07C227/34
Filed: 2000-11-30
Abstract: 1. A process for the preparation of a compound of Formula I wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises: a) adding a cyanoacetate of formula (A) NC(CO2R1, wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (1) a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of formula (2) b) adding the product of step a) above to a mixture of benzylmagnesium chloride, benzylmagnesium bromide, or benzylmagnesium iodide, in a solvent to produce the addition products of formulae (3a) and (3b) c) adding the products of step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent and stirring, and then acidifying to produce the carboxylic acids of formulae (4a) and (4b) adding the products of step b) above to an acid mixture and stirring to produce the carboxylic acids of formulae (4a) and (4b) d) contacting the products of step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the amine salt; e) converting the product of step d) to a carboxylic acid of formula (6) f) adding the product of step e) to a mixture of iodomethane, a solvent, and a base, and stirring to produce the ester of formula (7) or adding the product of step e) to methanol and an acid to produce the ester of formula (7) or adding the product of step e) above to trimethylsilyldiazo-methane and methanol in a solvent to produce the ester of formula (7) or adding the product of step e) to a solution of diazomethane or trimethylsilyl-diazomethane in a solvent to produce ester of formula (7) g) adding the product of step f) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium (III) chloride, and stirring to produce the carboxylic acid of formula (8) h) adding the product of step g) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA), and stirring to produce the isocyanate of formula (9) or adding the product of step g) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from-40 degree C to 78 degree C, followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce the isocyanate of formula (9) i) adding the product of step h) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (10) j) adding the product of step i) to a mixture of a solvent and aqueous hydrochloric acid, and stirring to produce a compound of formula (Ia) k) converting the product of step j) to a compound of formula (I) and further converting, if desired, to a pharmaceutically acceptable salt by known means. 2. A process according to Claim 1 which comprises: a) adding a cyanoacetate of formula (A) NC(CO2R1, wherein R1 ethyl to a mixture of a chiral cyclopentanone of formula (1) toluene, acetic acid, and a Knoevenagel reaction catalyst which is ammonium acetate, and heating the mixture at reflux over a Dean-Stark trap to produce the alkene of formula (2) b) adding the product of step a) above to a mixture of benzylmagnesium chloride and dry tetrahydrofuran at a temperature from -100 degree C to 25 degree C to produce the addition products of formulae (3a) and (3b) c) adding the products of step b) above to a mixture of potassium hydroxide and ethylene glycol and heating the mixture at a temperature from 100 degree C to 200 degree C, and then acidifying to produce the hydrolysis products of formulae (4a) and (4b) d) contacting the products of step c) above with an amine selected from (S)-alpha-methyl-benzylamine in ethyl and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the (S)-alpha-methyl-benzylamine salt; e) adding the product of step d) to aqueous sulfuric acid and stirring to produce the carboxylic acid of formula (6) f) adding the product of step e) above to a mixture of iodomethane, dichloromethane and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and stirring to produce the ester of formula (7) or adding the product of step e) above to a mixture of methanol and concentrated sulphuric acid produce the ester of formula (7) or adding the product of step e) above to a mixture of diazomethane or trimethylsilyldiazomethane in dichloromethane to give a compound of formula (7) g) adding the product of step f) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium (III) chloride, and stirring to produce the carboxylic acid of formula (8) h) adding the product of step g) above to a mixture of triethylamine, toluene and diphenylphosphoryl azide (DPPA), and refluxing to produce the isocyanate of formula (9) or adding the product of step g) above to ethyl chloroformate or isobutyl chloroformate and triethylamine in tetrahydrofuran at a temperature of from -40 degree C to 78 degree C, followed by adding a solution of sodium azide in water and tetrahydrofuran, followed by adding toluene or benzene, and refluxing to produce the isocyanate of formula (9) i) adding the product of step h) to a mixture of toluene and to produce the carbamate of formula (10) j) adding the product of step i) to a mixture of 1,4-dioxane, and aqueous hydrochloric acid at a 6M concentration and stirring to produce a compound of formula la k) converting the product of step j) to a compound of Formula I and further converting, if desired, to a pharmaceutically acceptable salt by known means. 3. A process for the preparation of a compound of Formula II wherein R is C1-C10 alkyl or C3-C10 cycloalkyl, and pharmaceutically acceptable salts thereof, which comprises: a) adding a cyanoacetate of formula (A) NC(CO2R1, wherein R1 is alkyl or benzyl, to a mixture of a chiral cyclopentanone of formula (1) a solvent, a carboxylic acid, and a Knoevenagel reaction catalyst, and stirring the mixture in the presence of a means of removing water to produce the alkene of formula (2) b) adding the product of step a) above to a mixture of benzylmagnesium chloride, benzylmagnesium bromide, or benzylmagnesium iodide, in a solvent to produce the addition products of formulae (3a) and (3b) c) adding the products of step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent and stirring, and then acidifying to produce the carboxylic acids of formulae (4a) and (4b) adding the products of step b) above to an acid mixture and stirring to produce the carboxylic acids of formulae (4a) and (4b) d) contacting the products of step c) above with an amine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the amine salt; e) converting the product of step d) to a carboxylic acid of formula (6) f) adding the product of step e) to a mixture of a tertiary amine base, a solvent, and diphenylphosphoryl azide (DPPA), and stirring to produce the isocyanate of formula (11) or adding the product of step g) above to ethyl chloroformate or isobutyl chloroformate and a base in a solvent at a temperature of from -40 degree C to 78 degree C, followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce the isocyanate of formula (11) g) adding the product of step f) to a mixture of a solvent and methanol, and stirring to produce the carbamate of formula (12) h) adding the product of step g) to a mixture of carbon tetrachloride or ethyl acetate, and acetonitrile, water, sodium periodate, and ruthenium (III) chloride, and stirring to produce the carboxylic acid of formula (13) i) adding the product of step h) to a mixture of a solvent and aqueous hydrochloric acid solution and stirring to produce a compound of formula (IIa) j) converting the product of step i) to a compound of Formula (II) and further converting, if desired, to a pharmaceutically acceptable salt by known means. 4. A process according to Claim 1 which comprises: a) adding a cyanoacetate of formula (A) NC(CO2R1, wherein R1 ethyl to a mixture of a chiral cyclopentanone of formula (1) toluene, acetic acid, and a Knoevenagel reaction catalyst which is ammonium acetate, and heating the mixture at reflux over a Dean-Stark trap to produce the alkene of formula (2) b) adding the product of step a) above to a mixture of benzylmagnesium chloride and dry tetrahydrofuran at a temperature from -100 degree C to 25 degree C to produce the addition products of formulae (3a) and (3b) c) adding the products of step b) above to a mixture of potassium hydroxide in ethylene glycol and heating the mixture at a temperature from 100 degree C to 200 degree C, and then acidifying to produce the hydrolysis products of formulae (4a) and (4b) d) contacting the products of step c) above with an amine selected from (S)-alpha-methyl-benzylamine in ethyl acetate and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the (S)-alpha-methyl-benzylamine salt; e) adding the product of step d) to aqueous sulfuric acid and stirring to produce the carboxylic acid of formula (6) f) adding the product of step e) to a mixture of a tertiary amine, toluene and diphenylphosphoryl azide (DPPA), and refluxing to produce the isocyanate of formula (11) or adding the product of step e) above to ethyl chloroformate or isobutyl chloroformate and triethylamine in tetrahydrofuran at a temperature of from-40 degree C to 78 degree C, followed by adding a solution of sodium azide in water and tetrahydrofuran or acetone, followed by adding toluene or benzene, and refluxing to produce the isocyanate of for