MXPA06006562A - Method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof - Google Patents

Abstract

The invention relates to a method for the industrial synthesis of perindopril having formula (I) and the pharmaceutically-acceptable salts thereof.

Description

METHOD FOR THE SYNTHESIS OF PERINDOPRIL AND PHARMACEUTICALLY ACCEPTABLE SALTS OF THE SAME FIELD OF THE INVENTION The present invention relates to a process for the synthesis of perindopril of formula (I): and pharmaceutically acceptable salts thereof.

ANTECEDENTS OF THE. INVENTION 5 Perindopril and its pharmaceutically acceptable salts, and more especially its terbutylamine salt, have valuable pharmacological properties. Its main property is that the inhibition of the converted enzyme angiotensin I (or kinase II), which allows, on the one hand, the prevention of the conversion of decapétide angiotensin I to octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, the prevention of the degradation of bradykinin (a dilator vessel) to an active peptide. These two actions contribute to the beneficial effects of perindopril in cadiovascular diseases, especially in hypertension and heart failure. Perindopril, its preparation and its use in therapeutic agents have been described in the specification of the European patent EP 0 049 658. In view of the pharmaceutical value of this compound, it has been important to be able to obtain this by an effective synthesis process, easily transplantable on an industrial scale, which leads to the perindorpil in a good yield and with an excellent purity. The specification of the patent EP 0 308 341 describes the industrial synthesis of perindopril by the coupling of benzyl ester of. (2S, 3a, 7aS-octahydroindol-2-carboxylic acid with N - [(S) -1-carboxybutyl] - (S) -alanine ethyl ester in the presence of dicyclohexylcarbodiimide, followed by deprotection of the carboxyl group of the heterocycle by. Catalytic hydrogenation This process has disadvantages related to the use of dicyclohexylcarbodiimide.

THE INVENTION The Applicant has developed a process for the synthesis of perindopril that uses other coupling agents. More specifically, the present invention relates to a process. for the synthesis of perindopril, which process. characterized in that the benzyl ester of formula (lia) or (Ilb): (Ha) • (Ilb) or an addition salt of the ester of formula (Ha) or (Hb) with a mineral acid or an organic acid is reacted with the alanine compound. Formula (III): in the presence of a coupling agent selected from the following reagents and pairs of reagents: (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / 1 -hydroxybenzotriazole, (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / l-hydroxy-7-azabenzo-triazole, (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / N-hydroxysuccinimide, hydrochloride (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide / 3-hydroxy-3,4-dihydro-4-oxo-l, 2,3-benzotriazine, (1,3-dimethylaminopropyl) -3-ethyl hydrochloride -carbodiimide / N-hydroxyphthalimide, dicyclohexylcarbodiimide / l-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide / N-hydroxysuccinimide, dicyclohexylcarbodiimide / 3-hydroxy-3, -dihydro-4-oxo-l, 2,3-benzotriazine, dicyclohexylcarbodiimide / N- hydroxyphthalimide, O- (benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyl hexafluorophosphate ronio, 0- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) hexafluorophosphate phosphonium, O- (benzotriazol-1-yl) -1, 1, 3, 3-bis (tetramethylene) uronium hexafluorophosphate, 0- (benzotriazol-1-yl) -1, 1, 3, 3-bis f .pentamethylene) uronium, chloro-tripyrrolidinephosphonium hexafluorophosphate, chloro-1, 1,3,3-bis (tetramethylene) formamidinium hexafluorophosphate, chloro-1,1,3,3-bis (pentamethylene) formamidinium hexafluorophosphate, N-ethoxycarbonyl -2-ethoxy-l, 2-dihydroquinoline, tetrafluoroborate 0- [(ethoxycarbonyl) -cyanomethyleneamino] -1,1,3,3-tetramethyl-uronium, tetrafluoroborate of O- (3,4-dihydro-4-oxo-l, 2,3-benzotriazin-3-yl) ) -1, 1, 3, 3-tetramethyluronium, tetrafluoroborate of 0- (3, 4-dihydro-4-oxo-l, 2,3-benzotriazin-3-yl) -1,1,3, 3-tetramethyluronium / l-hydroxybenzotriazole, 0- (3, 4-dihydro-4-oxo-l, 2, 3-benzotriacin-3-yl) -1,1,3, 3-tetramethyluronium / N-methylmorpholine tetrafluoroborate, tetrafluoroborate of 0 - (3, 4-dihydro-4-oxo-l, 2, 3-benzotriacin-3-yl) -1, 1,3,3-tetramethyluronium / collidine, 0- (1,2-dihydro-2-tetrafluoroborate oxo-l-pyridyl) -1,3,3-tetramethyluronium, 0- (1, 2-dihydro-2-oxo-l-pyridyl) -1, 1,3,3-tetramethyluronium / l-hydroxybenztriazole tetrafluoroborate , 0- (1, 2-dihydro-2-oxo-l-pyridyl) -1,3,3-bis (tetramethylene) uronium hexafluorophosphate, • 0- (1, 2-dihydro-2- hexafluorophosphate oxo-l-pyridyl) - 1,1,3, 3-bis (tetramethylene) uronium / 1-hydroxy-benzotriazole, 0- (N-succinimidyl) -1 tetrafluoroborate, 1, 3, 3-tramethyluronium, Q- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate, 0- (N-succinimidyl) -1, 1,3, 3- tetrafluoroborate bis (tetramethylene) uronium / 1-hydroxybenzotriazole, 0- (5-norbornene-2,3-dicarboximido) -1,1,3, 3-tetramethyluronium tetrafluoroborate, propane phosphonic anhydride, N-hydroxy-5-norbornene 2, 3-dicarboxylyl, and N-hydroxy-1,2-dihydro-2-oxo-pyridine, optionally in the presence of a base, to produce, after catalytic hydrogenation in the presence of palladium, perindopril of formula (I), which is converted, if desired, into a pharmaceutically acceptable salt such as the tert-butylamine salt. When the compound of. Formula (Ha) is used as starting material, the catalytic hydrogenation is preferably carried out under a hydrogen pressure of less than 10 bar. When the compound of formula (Hb) is used as starting material, the catalytic hydrogenation is preferably carried out under a hydrogen pressure of 10 to 35 bar. The examples below illustrate the invention.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES OF THE INVENTION The following Examples illustrate the invention. . . Example 1: acid (2S, 3aS, 7a.S) -l-. { (2S) -2- [(ter-but ± lox ± carbon ± l) -amino] -propionyl} -octahldro-lH- ± ndol-2-carhoxylcoate: 200 g of toluene sulphonate of benzyl ester of (2S, 3aS, 7aS) -octahydroindol-2-carboxylic acid, 65 ml of triethylamine and 1 liter of acetate are introduced of ethyl in a stirred reactor, followed, after stirring for 10 minutes at room temperature, by 100 g of N- [tert-butoxycarbonyl] - (S) -alanine and 175 g of 0- (benzotriazole-1-hexafluorophosphate il) -1, 1, 3, 3-bis (tetra-methylene) uronium. The heterogeneous mixture is then heated at 30 ° C for 3 hours while stirring well and then cooled to 0 ° C and filtered. The filtrate is then washed and subsequently evaporated to dryness. produce the expected product.

Example 2: Acid (2S, 3aS, 7aS) -l-. { (2S) -2- [(tert-Butyl? -carbonyl) -amino] -propionyl} -octahi'dro-lH-indole-2-carboxylic acid: The residue obtained in the previous step (200 g) is dissolved in 200 ml of methyl cyclohexane and transferred to a hydrogenator; then 26 g of 5% palladium on carbon suspended in 80 ml of methylcyclohexane are added, followed by 640 ml of water. The mixture is then hydrogenated under a pressure of 0.5 bar at a temperature of 15 to 30 ° C, until the theoretical amount of hydrogen has been absorbed. After filtering the catalyst, the aqueous phase of the filtrate is washed with methyl cyclohexane and then lyophilized to yield the expected product in 94% yield.

Example 3: Tert-butylamine salt of (2S, 3aS, 7aS) -l- acid. { (2S) -2- [(1S) -1- (ethoxycarbonyl) -butylamino] -propionyl} -octahydro-lH-indole-2-carboxylic acid The lyophilizate obtained in the previous step (200 g) is dissolved in 2.8 liters of ethyl acetate, and then 44 g of tert-butylamine and 400 ml of ethyl acetate are added.

The suspension obtained is then subjected to reflux until its complete dissolution; then the solution obtained is filtered while it is hot and cooled to a temperature of 15-20 ° C, with stirring. The precipitate obtained is then filtered, converted into a paste again using ethyl acetate, and dried, and then ground to produce the expected product in 95% yield

Claims (6)

1. CLAIMS 1. Process for the synthesis of perindopril of formula (I): and pharmaceutically acceptable salts thereof characterized in that the benzyl ester. of formula (Ha) or (Hlb): '. '' '
2. [Ha) (I-Ib) or an addition salt of the ester of formula (Ha) or (Hb) with a mineral acid or. Organic acid is reacted with the allan compound of formula (III): in the presence of a coupling agent selected from the following reagents and pairs of reagents: (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, (1,3-dimethylamidoopropyl) -3-ethyl-carbodiimide hydrochloride / 1-hydroxybenzotriazole, (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / l-hydroxy-7-azabenzo-triazole, (1,3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / N-hydroxysuccinimide , (1,3-dimethylaminopro-yl) -3-ethyl-carbodiimide hydrochloride / 3-hydroxy-3,4-dihydro-4-oxo-l, 2,3-benzotriazine, (1,3-dimethylamino) inopropyl hydrochloride ) -3-ethyl-carbodiimide / N-hydroxyphthalimide, dicyclohexylcarbodiimide / l-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide / N-hydroxysuccinimide, dicyclohexylcarbodiimide / 3-hydroxy-3,4-dihydro-4-oxo-l, 2, 3-benzotriazine, dicyclohexylcarbodiimide / N-hydroxyphthalimide, O- (benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -1, 1 hexafluorophosphate, 3, 3-tetramethylidene nio, O- (benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, 0- (benzotriazol-1-yl) -1, 1, 3, 3-bis (tetramethylene) uronium hexafluorophosphate, O- (benzotriazol-1-yl) -1,1,3, 3-bis (pentamethylene) hexafluorophosphate uronium, chloro-tripyrrolidinphosphonium hexafluorophosphate, chloro-1, 1,3, 3-bis (tetramethylene) formamidinium hexafluorophosphate, chloro-1, 1,3,3-bis (pentamethylene) formamidinium hexafluorophosphate, N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline, tetrafluoroborate 0- [(ethoxycarbonyl) -cyanomethyleneamino] -1,3,3-tetramethyl-uronium, tetrafluoroborate of 0- (3,4-dihydro-4-oxo-l, 2, 3-benzotriazin-3-yl) -1, 1,3, 3-tetramethyluronium, 0- (3,4-dihydro-4-oxo-l, 2,3-benzotriazin-3-yl) tetrafluoroborate -1.1 , 3, 3-tetramethyluronium / l-hydroxybenzotriazole, 0- (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) tetrafluoroborate) -1, 1, 3, .3-tetramethyluronium / N-methylmorpholine, 0- (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) tetrafluoroborate -1,1,3, 3-tetramethyluronium / collidine, 0- (1, 2-dihydro-2-oxo-l-pyridyl) -1, 1,3,3-tetramethyluronium tetrafluoroborate, 0- (1,2-dihydro-2-oxo) tetrafluoroborate ~ l-pyridyl) -1, 1, .3, 3-tetramethyluronium / l-hydroxybenzotriazole, O- (1,2-dihydro-2-oxo-1-pyridyl) -1,1,3, 3-bis hexafluorophosphate (tetramethylene) uronis-, 0- (1, 2-dihydro-2-oxo-l-pyridyl) -1,1,3, 3-bis (tetramethylene) uronium / 1-hydroxy-benzotriazole hexafluorophosphate, 0-9 etrafluoroborate (N-succinimidyl) -1, 1, 3, 3-tetramethururonium, O- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate, 0- (N-succinimidyl) -tetrafluoroborate - 1, 1, 3, 3-bis (tetrame ilen) uronium / 1-hydroxybenzotriazole, 0- (5-norbornen-2, 3-dicarboximido) -1,1,3, 3-tetramethyluronium tetrafluoroborate, propane phosphonic anhydride, N-hydroxy-5-norbornene-2, 3-dicarboxylic acid, and N-hydroxy-1 acid imide , 2-dihydro-2-oxo-pyridine, optionally in the presence of a base, to produce, after catalytic hydrogenation in the presence of palladium, perindopril of formula (I), which is converted, if desired, into a pharmaceutically acceptable salt. Process according to claim 1, characterized in that the synthesis of perindopril in the form of its tert-butylamine salt.
3. 3. Process according to claim 1, characterized in that the compound of formula (Ha) is used as initial material.
4. 4. Process according to. Claim 1, characterized in that the compound of formula (Hb) is used as starting material. Process according to claim 3, characterized in that the hydrogenation reaction is carried out under a hydrogen pressure of less than 10 bar. Process according to claim 4, characterized in that the hydrogenation reaction is carried out under a hydrogen pressure of less than 10 to 35 bar.