HK1096409B - Novel method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof - Google Patents

Description

Novel method 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) below and pharmaceutically acceptable salts thereof:

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

Their main property is to inhibit angiotensin I converting enzyme (or kininase II), so that they are capable of preventing, on the one hand, the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, their degradation of bradykinin (a vasodilator) to inactive peptides.

Both effects contribute to the beneficial effects of perindopril in cardiovascular diseases, especially arterial hypertension and insufficient blood supply to the heart.

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

In view of the pharmaceutical value of said compounds, it is important to be able to obtain perindopril in high yield and excellent purity using reasonably priced raw materials with a competitive synthesis process that is easy to convert to industrial scale.

Patent EP 0308341 describes the industrial synthesis of perindopril by coupling of benzyl (2S, 3aS, 7aS) -octahydroindole-2-carboxylate with ethyl N- [ (S) -1-carboxybutyl ] - (S) -alanine followed by deprotection of the carboxyl group of the heterocycle using catalytic hydrogenation.

The applicant has now developed a new process for the synthesis of perindopril.

More specifically, the present invention relates to a process for the synthesis of perindopril and its pharmaceutically acceptable salts, characterized in that a compound of formula (II):

in the formula R₁Represents a hydrogen atom or a benzyl group or a linear or branched chain (C)₁-C₆) An alkyl group, with a compound of formula (III) having S configuration:

wherein X represents a halogen atom and R₂Represents a protecting group for the amino function, which, after deprotection of the amino function, gives the compound of formula (IV):

in the formula R₁As defined above, the compound of formula (IV) is then reacted with a compound of formula (V) below in the presence of a base:

wherein G represents a chlorine, bromine or iodine atom or a p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy group, to give a compound of the following formula (VI):

in the formula R₁As is defined above, the first and second parts,

hydrogenation of the compounds of the formula (VI) in the presence of catalysts, for example palladium, platinum, rhodium or nickel, if necessary after deprotection gives the compounds of the formula (I).

In the process of the invention, mention may be made, as non-limiting examples, of tert-butoxycarbonyl and benzyl groups of amino-functional protecting groups which may be used.

Preferably R₁Represents a benzyl group. In this case, the amino-functional group-protecting group is preferably a tert-butoxycarbonyl group.

In the reaction of the compounds of formulae (II) and (III) or of formulae (IV) and (V), as non-limiting examples, the bases which can be used are organic amines, such as triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine, and inorganic bases, such as NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃Or KHCO₃。

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

Step A: (2S) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino]-propionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylic acid benzyl ester

A reactor was charged with 200g of benzyl (2S) -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate, 1.5 l of dichloromethane, the temperature of the reaction mixture was then adjusted to 0 ℃ and 107ml of triethylamine were added, followed by 162g of (2S) -2- [ (tert-butoxycarbonyl) -amino ] -propionyl chloride. The mixture was then brought to room temperature. After stirring at this temperature for 1h, the mixture was washed with water and then with a dilute acetic acid solution. The benzyl (2S) -1- { (2S) -2- [ (tert-butoxycarbonyl) -amino ] -propionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate solution thus obtained may be used as it is in the subsequent step.

Step B: (2S) -1- { (2S) -2-aminopropionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylic acid benzyl ester

A reactor was charged with the solution obtained in the previous step, and then 133g of trifluoroacetic acid was added. After stirring at room temperature for 1 hour 30 minutes, the mixture was washed with water and then with a saturated sodium bicarbonate solution, and then the solvent was distilled off to give benzyl (2S) -1- { (2S) -2-aminopropionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate.

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

A reactor was charged with 200g of the compound obtained in the previous step, 106ml of diisopropylethylamine and 1.5L of tetrahydrofuran, and then 183g of (2R) -2-p-toluenesulfonyloxy-pentanoic acid ethyl ester was added, followed by heating at 70 ℃ for 2 h. After cooling back to room temperature, the medium is washed with water and then dried. The residue was dissolved in dichloromethane. Hydrochloric acid solution (2M) was added until the pH was about 7.5. After decantation, the solvent is evaporated to give benzyl (2S) -1- (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate.

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

A hydrogenator was charged with 200g of the compound obtained in the previous step in acetic acid, followed by the addition of 5g of 10% Pt/C. Hydrogenation at a pressure of 5 bar and a temperature of 15-30 ℃ until the theoretical amount of hydrogen is absorbed.

The catalyst was removed by filtration and then cooled to 0-5 ℃ and the resulting solid was collected by filtration. The filter cake was washed and dried until constant weight.

This gave (2S, 3aS, 7aS) -1- (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -octahydro-1H-indole-2-carboxylic acid in a yield of 85% and an enantiomeric purity of 98%.

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

The precipitate (200g) from the previous step was dissolved in 2.8 liters of acetonitrile, then 40g of tert-butylamine and 0.4 liters of ethyl acetate were added.

The suspension obtained is then heated to reflux until complete dissolution, and the solution obtained is then filtered while hot and cooled with stirring until the temperature reaches 15-20 ℃. The precipitate was filtered, reslurried in acetonitrile, dried, and recrystallized from ethyl acetate to give the desired product in 95% yield and 99% enantiomeric purity.

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

Steps A and B: same as in steps A and B of example 1

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

A reactor was charged with 200g of the compound obtained in the previous step, 106ml of diisopropylethylamine and 1.5 l of ethyl acetate, followed by addition of 165g of ethyl (2R) -2-chloro-pentanoate and heating at 50 ℃ for 3 h. After cooling to room temperature, the medium is washed with water and dried. The residue was dissolved in dichloromethane. Hydrochloric acid solution (2M) was added to adjust the pH to about 7.5. After decantation, the solvent was evaporated to give benzyl (2S) -1- { (2S) -2- [ (1S) -1- (ethoxycarbonyl) -butylamino ] -propionyl } -2, 3, 4, 5, 6, 7-hexahydro-1H-indole-2-carboxylate.

Steps D and E: same as in steps D and E of example 1.

Claims (9)

1. A process for synthesizing a compound of the formula (I):

characterized in that a compound of formula (II):

in the formula R₁Represents a hydrogen atom or a benzyl group or a linear or branched C_1-6An alkyl group, with a compound of formula (III) having S configuration:

wherein X represents a halogen atom and R₂A protecting group representing an amino function which, after deprotection of the amino function, gives a compound of formula (IV):

in the formula R₁As defined above, the compound of formula (IV) is then reacted with a compound of formula (V) below in the presence of a base:

wherein G represents a chlorine, bromine or iodine atom or a p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy group, to give a compound of the following formula (VI):

in the formula R₁As is defined above, the first and second parts,

hydrogenating the compound of formula (VI) in the presence of a catalyst to obtain the compound of formula (I) after deprotection when a protecting group is present, and optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.

2. The synthesis method according to claim 1, characterized in that the catalyst is a palladium, platinum, rhodium or nickel catalyst.

3. The method of claim 1, wherein the amino-functional protecting group is tert-butoxycarbonyl or benzyl.

4. The method of synthesis of claim 3, wherein R is₁Represents a benzyl group and the amino functional group protecting group is tert-butoxycarbonyl.

5. Synthesis process according to any one of claims 1 to 4, characterized in that the base used for the reaction of the compounds of formula (II) with (III) is an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or an inorganic base.

6. The synthesis method according to claim 5, characterized in that the inorganic base is NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃Or KHCO₃。

7. Synthesis process according to any one of claims 1 to 4, characterized in that the base used for the reaction of the compound of formula (IV) with (V) is an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or an inorganic base.

8. The synthesis method according to claim 7, characterized in that the inorganic base is NaOH, KOH, Na₂CO₃、K₂CO₃、NaHCO₃Or KHCO₃。

9. A synthesis process according to any one of claims 1-4, wherein perindopril is in the form of the tert-butylamine salt.