HK1095840B

HK1095840B - Method for the synthesis of derivatives of (2s,3as,7as)-1[(s)-alanyl]-octahydro-1h-indole-2-carboxylic acid and use thereof for the synthesis of perindopril

Info

Publication number: HK1095840B
Application number: HK07102977.6A
Authority: HK
Inventors: Thierry Dubuffet; Jean-Pierre Lecouve
Original assignee: Les Laboratoires Servier
Priority date: 2003-12-10
Filing date: 2004-12-09
Publication date: 2009-07-24

Description

Process for the synthesis of (2S, 3AS, 7AS) -1- [ (S) -1-alanyl ] -octahydro-1H-indole-2-carboxylic acid derivatives and their use for the synthesis of perindopril

The present invention relates to a process for the synthesis of a compound of formula (I),

wherein R represents a hydrogen atom or an amino-functional protecting group,

and their use in the synthesis of perindopril of formula (II) and pharmaceutically acceptable salts thereof,

perindopril and its pharmaceutically acceptable salts, more particularly its tert-butylamine salt, have valuable pharmacological properties.

Their main property is to inhibit angiotensin I converting enzyme (or kininase II), which on the one hand prevents the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and on the other hand prevents the degradation of bradykinin (a vasodilator) to an inactive peptide.

Both effects contribute to the beneficial effects of perindopril in cardiovascular diseases, more particularly in hypertension and heart failure.

Perindopril, its preparation and its use in therapeutics have been described in european patent specification EP 0049658.

In view of the pharmaceutical value of this compound, it has become very important to be able to obtain it by an efficient synthesis process which is easy to convert to industrial scale, which gives perindopril in good yield and excellent purity.

Patent specification EP 0308341 describes the industrial synthesis of perindopril by coupling benzyl (2S, 3aS, 7aS) -octahydroindole-2-carboxylate and ethyl N- [ (S) -1-carboxybutyl ] - (S) -alanine by coupling in the presence of dicyclohexylcarbodiimide and then deprotecting the carboxylic acid groups of the heterocycle by catalytic hydrogenation.

This method has disadvantages associated with the use of dicyclohexylcarbodiimide.

The applicant has developed a process for the synthesis of perindopril using other coupling reagents.

More specifically, the present invention relates to a process for the synthesis of perindopril, which process is characterized in that: addition salts of benzyl esters of the formula (IIIa) or (IIIb) or esters of the formula (IIIa) or (IIIb) with inorganic or organic acids

With alanine compounds of the formula (IV)

Wherein R' represents an amino-functional protecting group,

in the presence of a coupling agent selected from the group consisting of the following agents and agent pairs, optionally in the presence of a base,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxy-7-azabenzotriazole,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazine,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/N-hydroxyphthalimide, dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole,

dicyclohexylcarbodiimide N-hydroxysuccinimide,

dicyclohexylcarbodiimide/3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazine,

dicyclohexylcarbodiimide N-hydroxyphthalimide,

o- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate,

o- (7-aza-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate,

o- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

benzotriazol-1-yl-oxytriazolidinylphosphonium hexafluorophosphate,

benzotriazol-1-yl-oxytis (dimethylamino) phosphonium hexafluorophosphate,

o- (benzotriazol-1-yl) -1, 1, 3, 3-bis (tetramethylene) uronium hexafluorophosphate,

o- (benzotriazol-1-yl) -1, 1, 3, 3-di (pentamethylene) uronium hexafluorophosphate,

chloro-trispyrrolidinophosphonium 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,

o- [ (ethoxycarbonyl) -cyanomethyleneamino ] -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (3, 4-dihydro-4-oxo-1, 2, 3-benzotriazin-3-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (3, 4-dihydro-4-oxo-1, 2, 3-benzotriazin-3-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole,

o- (3, 4-dihydro-4-oxo-1, 2, 3-benzotriazin-3-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate/N-methylmorpholine,

o- (3, 4-dihydro-4-oxo-1, 2, 3-benzotriazin-3-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate/collidine,

o- (1, 2-dihydro-2-oxo-1-pyridyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (1, 2-dihydro-2-oxo-1-pyridinyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole,

o- (1, 2-dihydro-2-oxo-1-pyridyl) -1, 1, 3, 3-di (tetramethylene) uronium hexafluorophosphate,

o- (1, 2-dihydro-2-oxo-1-pyridinyl) -1, 1, 3, 3-di (tetramethylene) uronium hexafluorophosphate/1-hydroxybenzotriazole,

o- (N-succinimidyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate,

o- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate/1-hydroxybenzotriazole,

o- (5-norbornene-2, 3-dicarboximido (dicarboximide)) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, propanephosphonic anhydride,

n-hydroxy-5-norbornene-2, 3-dicarboximide, and

n-hydroxy-1, 2-dihydro-2-oxo-pyridine,

depending on whether a compound of formula (IIIa) or formula (IIIb) is used as starting material, a compound of formula (Va) or formula (Vb) is produced, respectively,

wherein R' is as defined above,

which is subjected to a catalytic hydrogenation reaction in the presence of palladium to produce the product of formula (I).

Among the amino-functional protecting groups which can be used in the present invention, t-butyloxycarbonyl, benzyl and benzyloxycarbonyl can be mentioned without implying any limitation.

The catalytic hydrogenation of the compound of formula (Va) is preferably carried out under a hydrogen pressure of less than 10 bar.

The catalytic hydrogenation of the compound of formula (Vb) is preferably carried out under a hydrogen pressure of from 10 to 35 bar.

If desired, the compound of formula (I) thus prepared is then subjected to a deprotection reaction of the amino function and then to a coupling reaction with ethyl 2-oxo-valerate under reductive amination conditions, or to a coupling reaction with a compound of formula (VI),

wherein X represents a leaving group selected from: halogen, -O-SO₂CH₃Andoptically pure perindopril is formed and, if desired, converted into a pharmaceutically acceptable salt such as the tert-butylamine salt.

The following examples illustrate the invention.

Example 1: (2S, 3aS, 7aS) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino]-propionyl } -octahydro-1H-indole-2-carboxylic acid/method 1:

step A: (2S, 3aS, 7aS) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino]-propionyl } -octahydro-1H-indole-2-carboxylic acid benzyl ester

200g of benzyl (2S, 3aS, 7aS) -octahydroindole-2-carboxylate p-toluenesulfonate, 65ml of triethylamine and 1 l of ethyl acetate are introduced into a stirred reactor and, after stirring for 10 minutes at ambient temperature, 87g N- [ tert-butoxycarbonyl ] - (S) -alanine and 175g O- (benzotriazol-1-yl) -1, 1, 3, 3-bis (tetramethylene) uronium hexafluorophosphate are added. The heterogeneous mixture was then heated at 30 ℃ for 3 hours while stirring thoroughly, then cooled to 0 ℃ and filtered.

The filtrate is then washed and subsequently evaporated to dryness to give the desired product.

Step B: (2S, 3aS, 7aS) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino]-propionyl } -octahydro-1H-indole-2-carboxylic acid

The residue obtained in the preceding step (200g) was dissolved in 200ml of methylcyclohexyl and transferred to a hydrogenator; 26g of 5% palladium on carbon suspended in 80ml of methylcyclohexane are then added, followed by 640ml of water. The mixture is then hydrogenated at a pressure of 0.5 bar at a temperature of 15-30 ℃ until the theoretical amount of hydrogen has been absorbed.

After filtering off the catalyst, the aqueous phase of the filtrate was washed with methylcyclohexane and then lyophilized to give the desired product in 94% yield.

Example 2: (2S, 3aS, 7aS) -1- { (2S) -2- [ (tert-Butoxycarbonyl) -amino [ ] -]-propionyl } -octahydro-1H-indole-2-carboxylic acid/method 2:

step A: (2S) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino]-propionyl } -2, 3-dihydro-1H-indole-2-carboxylic acid benzyl ester

200g of 2, 3-dihydro-1H-indole-2-carboxylic acid benzyl ester p-toluenesulfonate, 66ml of triethylamine and 1 l of ethyl acetate are introduced into a stirred reactor and, after stirring for 10 minutes at ambient temperature, 89g N- [ tert-butoxycarbonyl ] - (S) -alanine and 151g O- (benzotriazol-1-yl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate are added. The heterogeneous mixture was then heated at 30 ℃ for 3 hours while stirring thoroughly, then cooled to 0 ℃ and filtered.

Step B: (2S, 3aS, 7aS) -1- { (2S) -2- [ (tert-Butoxycarbonyl) -amino [ ] -]-propionyl } -octahydro-1H-indole-2-carboxylic acid

The residue obtained in the preceding step (200g) was dissolved in 200ml of methylcyclohexane and transferred to a hydrogenator; 26g of 5% palladium on carbon suspended in 80ml of methylcyclohexane are then added, followed by 640ml of water. The mixture is then hydrogenated at a pressure of 0.5 bar at a temperature of 15-30 ℃ until the theoretical amount of hydrogen required for debenzylation has been absorbed; the mixture is then heated to a temperature of from 50 to 100 ℃ and hydrogenated at a pressure of 30 bar until the theoretical amount of hydrogen required for ring hydrogenation has been absorbed.

After filtering off the catalyst, the aqueous phase of the filtrate is washed with methylcyclohexane and then lyophilized to give the desired product.

Claims

1. A process for the synthesis of a compound of formula (I),

wherein R represents a hydrogen atom or a functional protecting group for amino groups, characterized in that:

addition salts of benzyl esters of the formula (IIIa) or (IIIb) or esters of the formula (IIIa) or (IIIb) with inorganic or organic acids

With alanine compounds of the formula (IV)

Wherein R' represents an amino-functional protecting group,

o- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate,

o- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (N-succinimidyl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

o- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate,

o- (N-succinimidyl) -1, 1, 3, 3-bis (tetramethylene) uronium tetrafluoroborate/1-hydroxybenzotriazole, and

o- (5-norbornene-2, 3-dicarboximido) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate,

wherein R' is as defined above,

2. The process according to claim 1, characterized in that a compound of the formula (IIIa) is used as starting material.

3. The process according to claim 1, characterized in that a compound of the formula (IIIb) is used as starting material.

4. Process according to claim 2, characterized in that the hydrogenation of the compound of formula (Va) is carried out under a hydrogen pressure of less than 10 bar.

5. A process according to claim 3, characterized in that the hydrogenation of the compound of formula (Vb) is carried out under a hydrogen pressure of 10 to 35 bar.

6. Process for the synthesis of perindopril or its pharmaceutically acceptable salts, characterized in that the compound of formula (I) is obtained by the synthesis process according to any one of claims 1 to 5 and is used as starting material.