SI21801A - New procedure for preparation of perindopril in new crystal form - Google Patents

Abstract

The submitted invention deals with a synthesis of ACE inhibitor perindopril, starting from a stereospecific aminoacid N-((S)-carbethoxy-1-butyl)-(S)-alanine, which is protected with a trimethylsilyl group and then transformed into a reactive acidic bromide or fluoride which in the final phase reacts with (2S, 3aS, 7aS)-octahydroindol-2-carboxylic acid with the trimethylsilyl protection on the carboxylic group to obtain perindopril after removal of protection groups.

Description

A new process for the preparation of perindopril in a new crystalline form

The invention is in the field of organic chemical synthesis and relates to a new process for the synthesis of perindopril in a new crystalline form and its salts. The invention is a continuation of our previous patent application for the synthesis of perindopril no. P-20040012.

There was a need for a simple, effective and industrially suitable process for the preparation of perindopril in a novel crystalline form, which is a known compound with ACE inhibitory action.

Perindopril erbumine with the formula:

is a salt of 2-methylpropan-2-amine with (2S, 3aS, 7aS) -1 [(2S) -2 - [[(1S) -1-ethoxycarbonyl) butyl] amino] propanoyl] octahydro-1H-indol-2- carboxylate.

Perindopril acts as a transport form (prodrug) of the diacid perindoprilate, which is its active form. Following oral administration, perindopril is rapidly absorbed and metabolized, predominantly in the liver, to perindoprilat and inactive metabolites. It is used for the treatment of hypertension and for heart problems.

ACE inhibitors (Angiotensin Converting Enzyme) prevent the conversion of angiotensin I. to angiotensin II., And are antihypertensive compounds that also act as vasodilators.

The state of the art

Perindopril was first synthesized in 1981 and described in EP 0049658B1 and US Pat. 4,508,729. The synthesis is complicated and a mixture of stereoisomers is formed which must be separated. The condensation reagent is N, N'-dicyclohexylcarbodiimide.

EP 0308341 B1 (1987) protects a process for the production of perindopril-t-butyl-amine salt by reaction of N - [(S) -carbethoxy-1-butyl] - (S) -alanine with benzyl ester (2S, 3aS, 7aS) - octahydroindole-2-carboxylic acids. The condensing reagent is N, N -cyclohexylcarbodiimide. The benzyl group is eventually removed by catalytic hydrogenation.

The synthesis of (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acids is described by US Pat. No. 4,914,214 (1988) by hydrogenation of (S) -2-carboxy indoline. Following this process, another key intermediate, N - [(S) -carbethoxy-1-butyl] - (S) -alanine, is activated by N, N'-dicyclohexylcarbodiimide in the presence of 1-hydroxy-benzotriazole or N, N'- carbonyldiimidazole.

EP 1279 665 A2 (2001) protects the process of synthesis of perindopril erbumine via the oxazolidine intermediate formed by the reaction of N - [(S) -carbethoxy-1-butyl] - (S) alanine with phosgene or triphosgene. This intermediate then reacts with (2S, 3aS,

7aS) -octahydroindole-2-carboxylic acid to perindopril. It is converted into perindopril erbumine by the addition of butylamine in an organic solvent.

The downside of synthesis is the use of highly toxic phosgene.

Slovenian patent no. 9500140 (1995) deals with the synthesis of perindopril from N - [(S) carbt toxi-1-butyl] - (S) -alanine by the intermediate formation of an N-sulfoxy derivative which is then reacted with a silylated form of (2S, 3aS, 7aS) -octahydroindole -2-carboxylic acids in perindopril according to the scheme:

The formation of chlorothylimidazole is already problematic because not only one compound is produced. The further course of the reaction is also problematic due to the sensitivity of this reagent to moisture and the possibility of reaction via imidazolide.

Patent PCT / IB03 / 00691, WO 03/064388 (2003) describes the synthesis of perindopril by the intermediate formation of the acid chloride of N - [(S) -carbethoxy-1-butyl] - (S) -alanine with a protected NH group and further reaction with ( 2S, 3aS, 7aS) -octahydroindole-2carboxylic acid. Acid chloride is formed using thionyl chloride at room or room temperature. slightly elevated temperature. The NH group is protected by an N-alkoxy carbonyl group such as: the .:-ethoxycarbonyl-, N-methoxycarbonyl- and N-benzyloxycarbonyl groups. The deficiency of the synthesis, on the one hand, is the poor persistence of the Naloxycarbonyl groups under the strongly acidic chlorination conditions (these groups decompose here) or. over-persistence of the N-benzyloxycarbonyl group requiring catalytic hydrogenation for removal. However, this is not stated anywhere in the synthesis, so the actual course of the synthesis is unlikely. For this reason, the yields are very low: from 38 to 82% for the introduction of the protecting group and from 35 to 55% for the acylation. Final yield is the product of partial yields.

Our prior patent application P-20040012 addresses the synthesis of perindopril by the intermediate formation of the acid chloride of N - [(S) -carbethoxy-1-butyl] - (S) -alanine previously protected by a trimethylsilyl group reacting with (2S, 3aS, 7aS) octahydroindole-2-carboxylic acid, wherein the carboxyl group is also protected by a trimethylsilyl group, tert. a butyl or benzyl group. The condensation of the two intermediates proceeds best at reduced temperature. Removal of the trimethylsilyl group after condensation is straightforward; it already occurs upon contact with aqueous solutions in the insulation phase, whereas tert. remove the butyl and benzyl groups with other reagents.

This patent application also addresses a novel crystalline form of perindopril determined by spectral analysis.

In the continuation of our research, we have found that it is also possible and reasonable to prepare perindopril by the intermediate formation of other acid chlorides such as bromide and fluoride. This is a novelty and, as we know, has not yet been used in this synthesis.

According to the present invention, perindopril of the formula I is prepared:

such that the secondary amino group of the stereospecific amino acid N - [(S) carboxy-1-butyl] - (S) -alanine of formula II:

is protected with a trimethylsilyl group to give the compound of formula lil:

which, by reaction with a bromination or fluorination reagent, is converted to the acid halide of formula IV:

wherein X is bromine or fluorine which is then reacted with (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid with a protected carboxylic group of formula V:

—COOR

H V.

wherein R represents a trimethylsilyl, tert-butyl or benzyl group to give the perindopril derivative of formula VI:

which is converted to perindopril of formula I by removal of both protecting groups.

According to the present invention, the novel crystalline form of perindopril mentioned in our previous patent application may also be prepared.

Acid bromides are prepared by reacting the corresponding acid protected trimethylsilyl group with thionyl bromide or the thionyl bromide complex with 1-Hbenzotriazole (1: 1).

Acid fluorides are otherwise known from peptide chemistry as an option for the activation of amino acids in peptide synthesis (GA Grant, Synthetic Peptides, VVH.Freeman and Co., New York, 1992, p. 125). the reaction is accompanied by a very low degree of racemization (Carpino et al, J. Am. Chem. Soc., 1990, 112, 9651).

The acid fluoride of N - [(S) -carbethoxy-1-butyl] - (S) -alanine is prepared by reaction first with a trimethylsilyl group of protected acid with an appropriate fluorination reagent, such as: thionylfluoride, diethyl (2-chloro-1, 1,2-trifluoroethyl) amine, selenium tetrafluoride, N, N-difluoro-2,2-bipyridinium salts or preferably cyanuric trifluoride.

A specific fluorination reaction of N - [(S) -carbethoxy-1-butyl] - (S) -alanine is carried out by adding to the cyanuric trifluoride solution in acetonitrile while stirring at room temperature a solution with the trimethylsilyl group of the protected acid dissolved in acetonitrile and of triethylamine. The reaction was stopped for about 2 hours. The yields of the fluorination reaction are very high, from 85 to 95%.

The synthesis of perindopril is further conducted by adding octahydroindole-2-carboxylic acid trimethylsilyl ester (2S, 3aS, 7aS) to the resulting acylfluoride or bromide solution and allowing it to react for a certain time.

The product is isolated by extraction and flow over a chromatographic column, if necessary for high purity of the final product.

The trimethylsilyl protecting groups after the reaction are eliminated by themselves already in the insulation phase in contact with water, while any tert-butyl and benzyl groups must be removed separately, e.g. with strong acids or catalytic hydrogenation. It is important, however, to remove traces of sulfur from the crude product before catalytic hydrogenation, otherwise the catalyst will be inactivated. For this purpose, filtration through a suitable layer of active basic alumina is sufficient.

After synthesis, the crude product is dissolved in methylene chloride and simply passed through a suitable layer of silica gel, where most polar and non-polar impurities are removed to give very pure perindopril in the form of a colorless or slightly yellowish solid resin. Also, by this process, the perindopril obtained crystallizes from diethyl ether as the new crystalline form described in our prior patent application P-200400012.

The solid amorphous perindopril, however, can be converted to a salt with tert.butylamine by crystallization from a suitable solvent, e.g. methylene chloride, ether, tert-butyl methyl ether, ethyl acetate, butyl acetate, 2-pentanone, cyclohexane, methylcyclohexane or similar solvents.

The advantage of our present process is the use of fully protected reactants and the use of highly reactive activation reagents, but the reaction can nevertheless be controlled in such a way that the formation of by-products is very small. Therefore, the efficiency is even better than before. All raw materials and reagents are commercially available and industrial production is possible. The procedure is illustrated but not limited by the following examples:

Example 1.

The silylated (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid derivative is prepared separately as follows: 1.5 g (0.0058 mol) (2S, 3aS, 7aS) octahydroindole-2-carboxylic acid suspension in 18 ml of methylene chloride 0.74 ml of trimethylchlorosilane (0.0058 mol) and 0.81 ml (0.0058 mol) of triethylamine are added at room temperature while stirring. Stirred for 75 minutes at room temperature.

A solution of 1.26 g (0.0058 mol) of N - [(S) -carbethoxy-1-butyl] - (S) alanine in 20 ml of methylene chloride is specially prepared, cooled to -15 ° C and 1.47 added with stirring. ml (0.0116 moles) of trimethylchlorosilane and 1.61 ml (0.00116 moles) of triethylamine. The solution was allowed to stand at -15 ° C for 2.5 hours, respectively. stir it occasionally.

Then, a thionyl bromide complex with 1-Hbenzotriazole (1: 1) prepared from 0.69 g of 1-H-benzotriazole (0.0058 mol _z and 0.60 ml of thionyl bromide (97% content) was added to this solution while stirring. 0.0058 mol) diluted with 4 ml of methylene chloride and stirred for 30 minutes at -10 ° C. The precipitate was filtered off with argon overpressure and washed with 5 ml of methylene chloride.

A solution of the silylated (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid derivative, previously prepared, is added while stirring at -20 ° C to the above acyl bromide solution. The mixture is first stirred at -20 ° C for 1 hour, then allowed to warm to + 20 ° C while stirring, then continued stirring for a further 24 hours.

When the reaction is complete, 22 ml of water are added, the pH of the suspension is adjusted to 4.38 +/- 0.1 with 6 mol. hydroxides (2.0 ml), 6.5 g of salt was added and stirred well. We separate the layers. The methylene chloride phase is washed again with 10% brine. The combined brines at pH 4.4 were extracted twice more with 10 ml of methylene chloride. The combined methylene chloride extracts were dried with MgSO4 and evaporated in vacuo at 40-50 ° C. 3.9 g of a yellow drying material containing perindopril are obtained.

This material was dissolved in methylene chloride (10 ml) and applied to a column filled with 38 g of silica gel (Merck 60, 0.2-0.0063 mm granularity) moistened with methylene chloride / ethanol 94/6 (vol / vol). This solvent was washed first with 1-Hbenzotriazole and then separately with perindopril.

The separation was followed by thin layer chromatography on silica gel plates using mobile phase methylene chloride / ethanol 90/10, detection with Draggendorf reagent. 1.90 g (89.4%) of an amorphous solid identical to perindopril are obtained.

It can be crystallized from diethyl ether (2 days state) at room temperature to give perindopril in a new crystalline form with a melting point at 110 -115 ° C.

Example 2.

2.10 g (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid (0.00812 mol,) was suspended in 26 ml of methylene chloride and 1.03 ml (0.00812 mol) of trimethyl chlorosilane and 2.25 ml (0 were added) , 01624 moles) of triethylamine. Stirred at 20 ° C for 2 hours.

Meanwhile, 1.76 g (0.00812 mol) of N - [(S) -carbethoxy-1-butyl] (S) -alanine are suspended separately in 26 ml of methylene chloride, cooled to -15 ° C and 2.05 ml added while stirring. (0.01624 mol) of trimethylchlorosilane and 2.25 ml (0.01624 mol) of triethylamine. Stirred at -15 ° C for 105 min.

The solution was purged with argon and cooled to -25 ° C. 0.83 ml of thionyl bromide (containing 97%, 0.00812 mol) dissolved in 5 ml of methylene chloride are added by syringe. The mixture was stirred at this temperature for 1 hour, then at -15 ° C for another 30 minutes. A pre-prepared solution of silylated (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid is then added while stirring. Stirred at -15 ° C for 15 hours, added 2 ml of triethylamine and stirred at room temperature for another 24 hours.

25 ml of water were added to the reaction mixture, the pH was adjusted to 4.1 +/- 0.1 by the addition of 6 molar NaOH solution, dissolved in the aqueous phase, 3 g of salt and stirred well. Separate the phases, extract the methylene chloride phase twice more with 25 ml of 9% aqueous NaCl solution each. The combined brines were adjusted to pH 4.4 +/- 0.1 and re-extracted 3 times with 20 ml of methylene chloride each. These methylene chloride extracts were briefly washed with 30 ml of 9% brine and then combined with the major methylene chloride fraction, dried with MgSO ₄ and evaporated in vacuo at 50 ° C to dryness.

The dry, crude perindopril was crystallized from diethyl ether as described above. 3.34 g of perindopril (89.9%) are obtained.

Example 3.

To a solution of 0.44 g of cyanur trifluoride (0.00326 mol) in acetonitrile (10 ml) in an argon atmosphere was added while stirring a solution containing 1.76 g (0.00812 mol) previously with the trimethylsilyl group protected N - [(S ) -carbethoxy-butyl] - (S) -alanine in 26 ml of methylene chloride and 1.13 ml (0.00812 mol) of triethylamine. The trimethylsilyl group was introduced as described in Example 1.

The mixture was stirred for 1 hour at room temperature for 1 hour. The precipitate was filtered with argon pressure and washed with 8 ml of methylene chloride.

To the pooled methylene chloride solution, a stirred pre-prepared solution of 1.76 g of (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid protected with a trimethylsilyl group is added.

Stirred for 24 hours at room temperature.

Perindopril was then isolated from the reaction mixture according to the procedure described in Example 1. It was crystallized from diethyl ether. The product is identical to the perindopril obtained in cases 1 and 2.

Example 4.

Composition of a mixture for the preparation of 1000 tablets containing 4 mg of active substance in 1 tablet:

perindopril from Example 2. 3.34 g tertiary butylamine 0.66 g hydroxypropylcellulose 2 g starch 10 g lactose 100 g magnesium stearate 3 g talc 3 g

Terc. dissolve the butylamine in the granulate preparation solvent, add perindopril and mix to dissolve and then mix with the other components by trituration and prepare the tablet granulate.

Claims (8)

Patent claims A method for the synthesis of an ACE inhibitor of perindopril of formula I: starting from the stereospecific amino acid of N - [(S) -carbethoxy-1-butyl] - (S) -alanine of formula II: which is protected by a trimethylsilyl group to give the compound of formula III: and characterized in that the compound of formula III. with the halogenating agent, is converted into an acid halide of the formula IV: wherein X is bromine or fluorine which is further reacted with (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid with a protected carboxylic group of formula V. —COOR H V. where R is trimethylsilyl, tert. a butyl or benzyl group, to give the perindopril derivative of formula VI: Si (CH ₃ ) 3 VI. wherein R has the same meaning as for a compound of formula V. which is converted to perindopril of formula I by removal of both protecting groups. 2. New Formula IV Compounds: where X is bromine or fluorine. Process according to claim 1, characterized in that for the preparation of a compound of formula IV, X = F,. thionylfluoride, diethyl- (2-chloro-1,1,2-trifluoroethyl) -amine, selenium tetrafluoride, N, N'-difluoro-2,2-bipyridinium salts or preferably cyanur trifluoride are used. Process according to claim 1, characterized in that thionyl bromide or its complex (1: 1) with 1-H-benzotriazole is used to prepare the compound of formula IV, X = Br. A process according to claim 1, characterized in that the trimethylsilyl protecting group is removed by hydrolysis with water. 6. A process according to claim 1, characterized in that the benzyl protecting group is removed by catalytic hydrogenation or strong acid. A process according to claim 1, characterized in that the tert. the butyl protecting group is removed with strong acid. Pharmaceutical preparations containing a therapeutically effective amount of a compound prepared according to the method of claims 1 to 4, in combination with one or more pharmaceutically acceptable, inert and non-toxic carriers.