HK1187060B - Process for the preparation of the l-arginine salt of perindopril - Google Patents

Description

Process for the preparation of L-arginine salt of perindopril

Technical Field

The present invention relates to a process for the preparation of perindopril L-arginine salt of formula (I):

background

Perindopril and its pharmaceutically acceptable salts, more particularly its L-arginine salt, have valuable pharmacological properties.

Its main characteristic is the inhibition of 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.

Those two effects contribute to the beneficial effects of perindopril in cardiovascular diseases, more specifically in arterial hypertension, heart failure and stable coronary heart disease.

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

The L-arginine salt of perindopril is described for the first time in European patent specification EP 1354873.

The alpha and beta crystalline forms of the L-arginine salt of perindopril are described in european patent specifications EP 1989182 and EP 2016051.

The gamma crystalline form of the L-arginine salt of perindopril is described in patent application WO 2009/157018.

In view of the pharmaceutical value of perindopril L-arginine it is of great importance to obtain this drug in good yield and excellent purity.

More specifically, the problem consists of finding the conditions for correctly converting perindopril into salts with L-arginine and of easily isolating the L-arginine salt of perindopril from the reaction mixture.

In fact, the majority of tests carried out by the applicant starting from perindopril and L-arginine to obtain the L-arginine salt of perindopril, produced products of gel-like appearance which were extremely difficult to carry out for subsequent processing.

A process for obtaining perindopril salts, more particularly the tert-butylamine salt, is described in patent specification EP 1279665. The process describes the coupling of an N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine moiety with a (2S,3aS,7aS) -2-carboxy perhydroindole moiety while avoiding the cyclization impurities typically resulting from peptide coupling. Thus, good yields (80%) and excellent purity (99%) of perindopril tert-butylamine salt were obtained in example 3 of EP 1279665.

Disclosure of Invention

The applicant prepared the L-arginine salt of perindopril using the process described in example 3 of EP 1279665. However, replacing tert-butylamine with (L) -arginine and additionally following the process of EP 1279665 does not give good yields of the L-arginine salt of perindopril (see comparative example A).

Surprisingly, when converting to a salt with a solvent system selected from the group consisting of acetonitrile/dimethylsulfoxide, ethyl acetate/dimethylsulfoxide and acetonitrile/dimethylsulfoxide/toluene, the L-arginine salt of perindopril is obtained in good yield and excellent purity and is very advantageous to isolate.

More specifically, the present invention relates to a process for the preparation of the L-arginine salt of perindopril by reaction between perindopril and L-arginine, the reaction being carried out in a solvent system selected from the group consisting of:

a binary mixture of acetonitrile and dimethylsulfoxide;

a binary mixture of ethyl acetate and dimethyl sulfoxide;

a ternary mixture of acetonitrile, dimethyl sulfoxide and toluene;

the reaction temperature is between 10 and 100 ℃, preferably between 40 and 80 ℃,

then, the L-arginine salt thus obtained was isolated by filtration.

According to an embodiment of the present invention, perindopril (free acid) used in the reaction is obtained by the following reaction: reacting N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine of formula (II):

with an activating agent, preferably N, N '-carbonyldiimidazole, phosgene, triphosgene, (1, 1' -carbonylbis (1,2, 4-triazole)) or bis (N-succinimidyl) carbonate

In an organic solvent or organic solvent system, preferably acetonitrile, ethyl acetate or dichloromethane,

the reaction temperature is-20-80 ℃, preferably-10-40 ℃,

the intermediate compound of formula (III) thus obtained is then reacted:

and (2S,3aS,7aS) -2-carboxyperhydroindole

At a temperature of 0 ℃ to 80 ℃, preferably 5 ℃ to 40 ℃.

"activators" are understood to mean the formula X₂A compound of formula wherein X represents a leaving group such as a halogen atom or tosylate, mesylate, imidazolyl, 1,2, 4-triazolyl, succinimidyl or optionally substituted alkoxy.

When the activator is N, N '-carbonyldiimidazole, the preferred amount of N, N' -carbonyldiimidazole is 0.8-1.2 moles, including 0.8 and 1.2 moles, per mole of N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine.

Preferred amounts of (2S,3aS,7aS) -2-carboxyperhydroindole are 0.8-1.2 moles, including 0.8 and 1.2 moles, per mole of N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine.

According to another embodiment of the invention perindopril (free acid) used in the reaction is obtained by desalting perindopril tert-butylamine by the action of an acid.

"desalination of perindopril tert-butylamine" is understood to be the return of perindopril to the free acid form.

Drawings

Figure 1 is a diffractogram of a crystalline form of perindopril L-arginine.

Detailed Description

The following examples illustrate the invention.

Not all of these examples gave pure forms.

Abbreviations：

CDT (1, 1' -carbonylbis (1,2, 4-triazole))

DMSO dimethyl sulfoxide

DSC (bis (N-succinimidyl) carbonate)

HPLC high performance liquid chromatography

Filtering is expressed according to standard means: in kg of filtered liquid per hour and m²Filter area is expressed.

Example 1: l-arginine salt of perindopril-starting from perindopril (free acid), in a binary mixture of acetonitrile/DMSO 25/75, without seeding

Perindopril (12.5g, 1eq.) and L-arginine (5.32g-0.9eq) were suspended in a mixture of acetonitrile (20g, d ═ 0.787) and DMSO (61g, d ═ 1.100). The reaction mixture was heated at 50 ℃ overnight. The product was then isolated by filtration with frit. The filter cake is washed and dried.

Arginine perindopril (14.5g) was obtained in a yield of 79% relative to perindopril. The separated crystalline phase is the phase. The HPLC mass of the isolated product was greater than 99.0%.

The filtration rate of the mother liquor is about 6000kg/h/m²。

The L-arginine salt of perindopril thus obtained is in crystalline form. The crystal form has the following X-ray powder diffraction pattern: it was determined using a diffractometer with copper anticathode and expressed as interplanar spacing d, 2 θ bragg angle and relative intensity (expressed as a percentage of the strongest line):

each line is considered to have an accuracy of ± 0.2 ° at 2-theta.

FIG. 1: diffractogram of crystalline form of L-arginine perindopril.

Example 2: l-arginine salt of perindopril-starting from perindopril (free acid), in a binary mixture of acetonitrile/DMSO 25/75, seeded with

Perindopril (100g, 1eq.) and L-arginine (42.6g, 0.9eq.) were suspended in a mixture of acetonitrile (220g, d 0.787) and dimethylsulfoxide (630g, d 1.100). The reaction mixture was heated at 70 ℃ for 3 hours, seeded with 2% phase and then cooled to 40 ℃ over 1 hour. The mixture was kept at 40 ℃ for 18 hours while stirring, and then cooled to 20 ℃ over 1 hour. The product was then isolated by filtration. The filter cake is washed and dried.

(L) -arginine perindopril (119g) was obtained in a yield of 79% with respect to perindopril. The HPLC mass of the isolated product was greater than 99.0%.

The filtration rate of the mother liquor is about 6000kg/h/m²。

Example 3: from (2S,3aS,7aS) -2-carboxy-perhydroindole and N- [1- (S) -Ethoxy-carbonyl-butyl]General Process for the production of Perindopril (free acid) starting from- (S) -alanine by activation with N, N' -carbonyl-diimidazole

N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine (65g, 1eq.) and N, N' -carbonyldiimidazole (48g, 1eq.) were introduced, followed by addition of acetonitrile (500 g). The reaction mixture was then stirred at a temperature below +10 ℃ for 3 hours.

The reaction mixture was poured into (2S,3aS,7aS) -2-carboxy perhydroindole (50g, 1 eq.); an amount of fresh acetonitrile (80g) was used to rinse the instrument.

The reaction mixture was then stirred for 5 hours at a temperature below +10 ℃ and then purged with a filter to give a clear solution.

Example 4: l-arginine salt of perindopril starting from (2S,3aS,7aS) -2-carboxy-perhydroindole in a binary mixture of acetonitrile/DMSO 50/50 seeded with

Perindopril L-arginine (110g) was obtained by pouring a solution of perindopril (100g of product) synthesized according to the general procedure of example 3 in acetonitrile into a suspension of L-arginine (44.3g, 0.85eq.) in DMSO (540g, d 1.100) at 50 ℃, and the reaction mixture was seeded with 2% of the crystalline form (compound of example 1). The mixture was maintained at 50 ℃ for 15 hours with stirring and then cooled to 20 ℃ at a rate of 0.5 ℃/min. The suspension was filtered using a filtration cell. The yield relative to perindopril used was 75%. The mass of the isolated product was greater than 99.0% according to HPLC.

The filtration rate of the mother liquor was about 5000kg/h/m²。

Example 5: l-arginine salt of perindopril starting from (2S,3aS,7aS) -2-carboxy-perhydroindole in a binary mixture of acetonitrile/DMSO 75/25 seeded with

L-arginine perindopril (42g) was obtained after seeding with 4% by weight of perindopril L-arginine (compound of example 1) in the form of seeds by pouring a solution of perindopril (38g of product) synthesized according to the general method of example 3 in acetonitrile (17g, 0.85eq.) at a temperature of 40 ℃ in dimethyl sulfoxide (78 g). Filtration was carried out at 40 ℃ using a filtration tank.

The yield relative to perindopril used was 73%. The mass of the isolated product was greater than 99.0% according to HPLC.

The filtration rate of the mother liquor was about 5700kg/h/m²。

Example 6: l-arginine salt of perindopril starting from (2S,3aS,7aS) -2-carboxy-perhydroindole and triphosgene

Reacting N- [1- (S) -ethoxycarbonyl-butyl]- (S) -alanine (20g, 1eq.) and Na₂HPO₄.12H₂O (43g, 1.3eq.) was suspended in dichloromethane (212 g). The reaction mixture was heated to reflux and then a solution of triphosgene (9.55g, 0.35eq.) in dichloromethane (64g) was poured. After washing the organic phase with aqueous liquid/liquid, the dichloromethane is evaporated to give the activated N- [1- (S) -ethoxycarbonyl-butyl ] of the formula III]- (S) -alanine (22 g). The latter was then dissolved in acetonitrile (180 g). The solution was poured into (2S,3aS,7aS) -2-carboxy perhydroindole (15g, 1eq.) and the reaction mixture was stirred in the presence of triethylamine (9.15g, 1eq.) at a temperature below 10 ℃ for about 5 hours and then purged through a filter to give a clear solution. The L-arginine salt of perindopril was obtained by addition of L-arginine (14.5g, 0.90eq.) suspended in DMSO (180g) at a temperature of 50 ℃. After about 5 hours of contact time, the mixture was seeded with 2% crystal form and then stirred at 50 ℃ overnight and filtered using a filter cell.

L-arginine perindopril (43g) was obtained in 89% yield (seed-excluded) relative to (2S,3aS,7aS) -2-carboxyperhydroindole. The HPLC mass of the isolated product was greater than 99%.

The filtration rate of the mother liquor was about 2000kg/h/m²。

Example 7: l-arginine salt of perindopril-starting from perindopril tert-butylamine, in a ternary mixture of acetonitrile/dimethyl sulfoxide/toluene 30/40/30, seeded with

Perindopril tert-butylamine (103g, 1.00eq.) and sodium chloride (5.84g) were suspended in toluene (268g, d 0.867). Stirring was carried out at ambient temperature.

Hydrochloric acid solution (57.8mL, #4N, 1eq.) was added. Stir at ambient temperature for 40 minutes. The toluene phase was separated from the aqueous phase.

The aqueous phase was washed with toluene (2x90g, d ═ 0.867).

At this stage perindopril is in the form of a solution with a concentration of 16% w/w in toluene.

L-arginine (36.6g, 0.90eq.) and dimethylsulfoxide (566g, d ═ 1.100) were added and the reaction mixture was heated at 50 ℃ for 5 hours. Acetonitrile (405g, d 0.787) was added and the reaction mixture was seeded with 2% by weight of crystalline L-arginine perindopril (the compound of example 1).

The suspension was stirred for 17 hours; the temperature was then brought to 30 ℃ in 30 minutes. After stirring for 2 hours, the product was isolated by filtration. The filter cake is washed and dried.

L-arginine perindopril (95g) was obtained in a yield of 75% relative to perindopril tert-butylamine. The HPLC mass of the isolated product was greater than 99.8%.

The filtration rate of the mother liquor is about 4000kg/h/m²。

Example 8: l-arginine salt of perindopril-starting from perindopril (free acid), in a ternary mixture of acetonitrile/DMSO/toluene 30/40/30, crystals were placedSeed of a plant

Lyophilized perindopril (8.3g, 1eq.) was dissolved in a mixture of toluene (43g) and DMSO (55 g). L-arginine (3.9g, 1eq.) was introduced as a suspension in acetonitrile (40g) and the batch was heated at 50 ℃.

The reaction mixture was seeded with 3% of crystalline form of arginine perindopril and the suspension was stirred at 50 ℃ for 22 hours.

The product was isolated by filtration.

L-arginine perindopril (9g) was obtained in a yield of 73% with respect to perindopril. The HPLC mass of the isolated product was greater than 99%.

Example 9: l-arginine salt of perindopril-starting from perindopril tert-butylamine, in a binary mixture of ethyl acetate/DMSO 55/45, seeded with

Perindopril erbumine (200g, 1eq.) methyl tetrahydrofuran (700g) and methanesulfonic acid (43.5g, 1eq.) were added to the reactor.

Insoluble matter was filtered off, and L-arginine (78.8g, 1eq.) and DMSO (500g) were added to the solution.

The methyltetrahydrofuran was distilled off and heated at 70 ℃ for 1 hour.

Ethyl acetate (600g) was added and 2% of crystalline form of arginine perindopril was seeded.

Cooled to 25 ℃ over 4 hours, filtered and the product washed with ethyl acetate/DMSO mixture.

L-arginine perindopril (217g, seed-excluded) was obtained in 88% yield relative to perindopril. The HPLC mass of the isolated product was greater than 99%.

The filtration rate of the mother liquor is more than 1500kg/h/m²。

Example 10: l-arginine salt of perindopril-starting from perindopril (free acid), in a ternary mixture of acetonitrile/DMSO/toluene 45/50/5, seeded with

Lyophilized perindopril (30g, 1eq.) and DMSO (100g) and L-arginine (13.8g, 1eq.) were added to the reactor. The mixture was heated at 70 ℃ for 2 hours.

A mixture of acetonitrile (90g) and toluene (10g) was added, seeded with 2% of arginine perindopril in crystalline form. The suspension was heated at 70 ℃ for 2 hours.

Cool to 25 ℃ over 4 hours, filter, and wash the product with acetonitrile and DMSO.

L-arginine perindopril (41g, seed-removed) was obtained in a yield of 92% relative to perindopril. The HPLC mass of the isolated product was greater than 99%.

The filtration rate of the mother liquor is more than 1500kg/h/m²。

Comparative example A: EP 1279665 an improvement of the process to obtain the L-arginine salt of perindopril of example 3

The reactor was cooled to 0 ℃ beforehand. N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine (80g to 1eq.) and dichloromethane (1325g, d ═ 1.325) were introduced. N, N' -carbonyldiimidazole (71.5g-1.2eq.) and 0.336L of methylene chloride were added to the mixture. The temperature of the mixture was brought to-5 ℃ and then (2S,3aS,7aS) -2-carboxy perhydroindole (81g-1.3eq.) was added. After 2 hours and 30 minutes of contact time, the mixture was dried and then dissolved in water (1200g, d ═ 1.00). After acidification of the aqueous phase (with 185ml of 4N HCl solution), the solution was extracted with dichloromethane (2517.5g, d ═ 1.325) and the aqueous phase was saturated with NaCl. The organic phase was dried and the residue from the drying was dissolved in ethyl acetate (1176.6g, d ═ 0.902). L-arginine (68g-1.06eq.) was then added and the mixture was kept at 50 ℃ overnight with stirring.

It was found that the mixture could not be filtered because the solid had a viscous consistency. The solids were removed from the reactor via a disengagement tank.

Yield (determined by titration): 1.6 percent.

Comparative example B: example 6 according to patent application WO 2009/157018

Perindopril (30g) and L-arginine (13.8g) were suspended in toluene (130g, d ═ 0.867) at ambient temperature. The mixture was refluxed for 1 hour. Acetonitrile (1180.5g, d 0.787) was then added at 80 ℃. After maintaining stirring at this temperature for 1 hour, the suspension was filtered using a cell under a nitrogen atmosphere of 0.3 bar.

The average filtration rate of the mother liquor was determined to be 100kg/h/m². The isolated product had a viscous consistency and a pink color. The weight yield was 46.5%. The HPLC mass of the isolated product was about 83%.

Claims (6)

1. Process for the preparation of perindopril L-arginine salt of formula (I):

by reaction between perindopril and L-arginine in a solvent system selected from the group consisting of:

a binary mixture of acetonitrile and dimethylsulfoxide;

a binary mixture of ethyl acetate and dimethyl sulfoxide;

a ternary mixture of acetonitrile, dimethyl sulfoxide and toluene;

the reaction temperature is 10-100 ℃,

then isolating the L-arginine salt thus obtained by filtration,

wherein the ratio of acetonitrile/dimethylsulfoxide in a binary mixture of acetonitrile and dimethylsulfoxide is 25/75, 50/50 or 75/25 w/w;

the ratio of ethyl acetate/dimethyl sulfoxide in the binary mixture of ethyl acetate and dimethyl sulfoxide is 55/45 w/w;

the ratio of acetonitrile/dimethylsulfoxide/toluene in the ternary mixture of acetonitrile, dimethylsulfoxide and toluene was 30/40/30 or 45/50/5 w/w.

2. A process for the preparation of perindopril L-arginine salt according to claim 1, wherein perindopril is obtained by the following reaction: reacting N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine of formula (II):

with an activator of the formula X₂C ═ O reaction, where X represents a leaving group,

the reaction is carried out in an organic solvent or organic solvent system,

the reaction temperature is between 20 ℃ below zero and 80 ℃,

the intermediate compound of formula (III) thus obtained is then reacted:

reacting with (2S,3aS,7aS) -2-carboxyl perhydroindole at the temperature of 0-80 ℃,

perindopril thus obtained is then reacted with L-arginine according to the process of claim 1.

3. A process for the preparation of perindopril L-arginine salt according to claim 2, wherein the activator is N, N '-carbonyldiimidazole, phosgene, triphosgene, 1' -carbonylbis (1,2, 4-triazole) or bis (N-succinimidyl) carbonate.

4. A process for the preparation of perindopril L-arginine salt according to claim 3, wherein the activator is N, N '-carbonyldiimidazole and the amount of N, N' -carbonyldiimidazole is 0.8-1.2 moles, including 0.8 and 1.2 moles, per mole of N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine.

5. A process for the preparation of perindopril L-arginine salt according to any one of claims 2 to 4, wherein the amount of (2S,3aS,7aS) -2-carboxyperhydroindole used is 0.8 to 1.2 moles, including 0.8 and 1.2 moles, per mole of N- [1- (S) -ethoxycarbonyl-butyl ] - (S) -alanine.

6. A process for the preparation of perindopril L-arginine salt according to claim 1, wherein perindopril is obtained by desalting perindopril tert-butylamine by the action of an acid and then reacting the perindopril thus obtained with L-arginine according to the process of claim 1.