HK1086281B - Novel method for synthesising perindopril and the pharmaceutically acceptable salt thereof - Google Patents

Description

Process for the synthesis of perindopril and its pharmaceutically acceptable salts

The present invention relates to a process for the synthesis of perindopril of formula (I) and pharmaceutically acceptable salts thereof:

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

Their main properties are an inhibitory effect on the angiotensin I converting enzyme (or kininase II), which on the one hand prevents the conversion of the decapeptide angiotensin I into the octapeptide angiotensin II (a vasoconstrictor) and on the other hand prevents the degradation of bradykinin (a vasodilator) into inactive peptides.

These two effects make perindopril have a beneficial effect in cardiovascular diseases, especially in hypertension and heart failure.

Perindopril, its preparation and use in therapy are described in european patent specification EP 0049658.

In view of the pharmacological value of this compound, it is of utmost importance to be able to obtain this compound by an efficient synthetic process, which is easy to convert to an industrial scale, which enables perindopril to be obtained in good yield and excellent purity, and which is reasonably priced as starting material.

EP 0308341 describes a process for the industrial synthesis of perindopril which comprises reacting benzyl (2S, 3aS, 7aS) -octahydroindole-2-carboxylate with ethyl N- [ (S) -1-carboxybutyl ] - (S) -alanine and deprotecting the carboxylic acid groups of the heterocycle by catalytic hydrogenation.

However, (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid ester is not commercially available and the preparation process requires a multi-step synthesis step (including a resolution step) using indole-2-carboxylic acid aS a starting material.

The applicant has now developed a new process for the synthesis of perindopril from readily available starting materials.

More specifically, the present invention relates to a process for the industrial synthesis of perindopril and its pharmaceutically acceptable salts, characterized in that 1- (1-cyclohexen-1-yl) -pyrrolidine of formula (II):

with a compound of formula (III):

wherein R is₁Indicating acid functionalityProtecting group, R₂A protecting group representing an amine function, to give a compound of formula (IV):

wherein R is₁And R₂As defined above, the above-mentioned,

deprotection of the amine functionality prior to cyclization followed by dehydration affords compounds of formula (V):

wherein R is₁As defined above, the above-mentioned,

or an addition salt thereof with an inorganic or organic acid,

reacting it with a compound of formula (VI) in ethyl acetate at a temperature of 20 to 77 ℃:

the reaction is carried out in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, the amount of 1-hydroxybenzotriazole being from 0.4 to 0.6 mol and the amount of dicyclohexylcarbodiimide being from 1 to 1.2 mol per mol of compound of the formula (V) employed,

the reaction is carried out in the presence of triethylamine in an amount of 0.25 to 1.2 mol per mol of compound of formula (V) employed,

after isolation, a compound of formula (VII):

wherein R is₁As defined above, the above-mentioned,

hydrogenation thereof in the presence of a catalyst such as palladium, platinum, rhodium or nickel under a hydrogen pressure of 1 to 30 bar, preferably 1 to 10 bar, gives, after deprotection of the acid functions, perindopril of formula (I) which, if desired, can be converted into a pharmaceutically acceptable salt such as the tert-butylamine salt.

The following examples are intended to illustrate the invention, but not to limit it.

Example (b): (2S, 3aS, 7aS) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -octahydro-1H-indole-2-carboxylic acid tert-butylamine salt

Step A: (2S) -2- [ (tert-Butoxycarbonyl) -amino ] -3- (2-oxocyclohexyl) -propionic acid benzyl ester

In a reactor equipped with a reflux column, 200g of 1- (1-cyclohexen-1-yl) -pyrrolidine, 535g of benzyl (2S) -2- [ (tert-butoxycarbonyl) -amino ] -3-iodopropionate and 1.5L of acetonitrile were charged.

Reflux for 1 hour, then return the mixture to room temperature. After the solvent was distilled off, 2L of water was added, and acetic acid was further added. Extracted with ethyl acetate and evaporated to dryness.

Benzyl (2S) -2- [ (tert-butoxycarbonyl) -amino ] -3- (2-oxocyclohexyl) -propionate was obtained in 80% yield in this way.

And B: (2S) -2-amino-3- (2-oxocyclohexyl) -propionic acid benzyl ester

In a reactor, 200g of the compound obtained in the previous step, 1, 5L of dichloromethane and 60g of trifluoroacetic acid were charged. After stirring at room temperature for 1 hour 30 minutes, 2L of saturated sodium bicarbonate solution was added. Extracted with dichloromethane and evaporated to dryness.

Benzyl (2S) -2-amino-3- (2-oxocyclohexyl) -propionate was obtained in 90% yield in this way. And C: (2S) -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylic acid benzyl ester p-toluenesulfonate salt

In the reactor, 200g of the compound obtained in the previous step, 151.9g of p-toluenesulfonic acid and 1L of toluene were refluxed, and the water formed was removed by azeotropic distillation. When no more water is separated off, toluene is distilled off.

Benzyl (2S) -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate p-toluenesulfonate was obtained in this way in a crude yield of 97%.

Step D: (2S) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylic acid benzyl ester

In a reactor, 200g of the compound obtained in the previous step, 46g of triethylamine and 1L of ethyl acetate were charged, and after stirring at room temperature for 10 minutes, 104g N- [ (S) -ethoxycarbonyl-1-butyl ] - (S) -alanine, 30g of 1-hydroxybenzotriazole and 100g of dicyclohexylcarbodiimide were further added. The heterogeneous mixture was then heated at 30 ℃ for 3 hours with good stirring, then cooled to 0 ℃ and filtered. The filtrate was washed again and evaporated to dryness to give the desired product in 95% yield.

Step E: (2S, 3aS, 7aS) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl-octahydro-1H-indole-2-carboxylic acid

200g of the compound obtained in the preceding step, dissolved in acetic acid, were added to the hydrogenation reactor, followed by 5g of 10% Pt/C. The hydrogenation was carried out at a pressure of 5 bar and room temperature until the theoretical amount of hydrogen had been absorbed. The catalyst was removed by filtration and then cooled to 0-5 ℃ and the solid formed was collected by filtration. The filter cake is washed and dried to constant weight. (2S, 3aS, 7aS) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -octahydro-1H-indole-2-carboxylic acid was obtained in this way in 85% yield and in 99% enantiomeric purity.

Step F: (2S, 3aS, 7aS) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -octahydro-1H-indole-2-carboxylic acid tert-butylamine salt

The compound (200g) obtained in the previous step was dissolved in 2.8L of ethyl acetate, followed by addition of 40g of t-butylamine and 0.4L of ethyl acetate. The suspension obtained is then refluxed until complete dissolution, and the solution obtained is filtered while hot and cooled to 15-20 ℃ with stirring. Then, the obtained precipitate was filtered off, again made into a paste with ethyl acetate, dried and then pulverized to obtain the objective product with a yield of 95%.

Claims (4)

1. A process for the synthesis of perindopril of formula (I) or a pharmaceutically acceptable salt thereof,

characterized in that 1- (1-cyclohexen-1-yl) -pyrrolidine of formula (II):

with a compound of formula (III):

wherein R is₁Represents an acid functional protecting group, R₂A protecting group representing an amine function, to give a compound of formula (IV):

wherein R is₁And R₂As defined above, the above-mentioned,

deprotection of the amine functionality prior to cyclization followed by dehydration affords compounds of formula (V):

wherein R is₁As defined above, the above-mentioned,

or an addition salt thereof with an inorganic or organic acid,

reacting it with a compound of formula (VI) in ethyl acetate at a temperature of 20 to 77 ℃:

the reaction is carried out in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, the amount of 1-hydroxybenzotriazole being from 0.4 to 0.6 mol and the amount of dicyclohexylcarbodiimide being from 1 to 1.2 mol per mol of compound of the formula (V) employed,

the reaction is carried out in the presence of triethylamine in an amount of 0.25 to 1.2 mol per mol of compound of formula (V) employed,

after isolation, a compound of formula (VII):

wherein R is₁As defined above, the above-mentioned,

which is hydrogenated in the presence of a catalyst under a hydrogen pressure of 1-30 bar, to give, after deprotection of the acid function, perindopril of formula (I), which is converted into a pharmaceutically acceptable salt in the case of synthesis of a pharmaceutically acceptable salt thereof.

2. The synthesis process according to claim 1, characterized in that the hydrogen pressure in the hydrogenation is from 1 to 10 bar.

3. The synthesis process according to claim 1, wherein the catalyst is selected from the group consisting of palladium, platinum, rhodium and nickel.

4. The method according to claim 1, wherein said pharmaceutically acceptable salt is a tert-butylamine salt.