EA007988B1 - ζ-ZETA FORM OF PERINDOPRYL ERBUMINE - Google Patents

Abstract

The invention relates to novel crystalline form of perindopryl-erbumine, in particular to ζ-zeta form and to a process for preparation thereof. The inventive method provides enhanced properties of the targeted product, which ensures quick filtration and drying thereof.

Description

FIELD OF THE INVENTION

The invention relates to a new crystalline form of perindopril erbumin, and in particular to a ξ-zeta form and to a method for its preparation.

State of the art

Perindopril erbumin is the tert-butylamine salt of perindopril: {(28, Za8,7a8) -1- [2- (1-ethoxycarbonyl- (8) -butylamino) - (8) propionyl] octahydroindole-2carboxylic acid}.

Perindopril is used as an ACE inhibitor (angiotensin converting enzyme) II generation. It reduces blood pressure, helps to restore the elasticity of large arterial vessels, normalizes heart function (Vidal Handbook. Medications in Russia. M.: Astrafarm Service, 2004).

Perindopril Erbumin has the following structural formula (I)

sn ₃ sn, —s --- ΝΗ,

I

CH ₃ (I)

A known method of producing perindopril erbumin (I8 2004/0248814 A1) by the reaction of Ν- [1- (8) ethoxycarbonyl-3-butyl] - (8) -alanine (II) with compound X ₂ C = O (III), preferably phosgene, obtaining Ν-carboxyanhydride of Ν- [1- (8) -ethoxycarbonyl-3-butyl] - (8) -alanine (IV) followed by reaction of compound (IV) with (28.3a8.7a8) octahydroindod-2-carboxylic acid (Wa ) or its ether (V), giving perindopril. Subsequent interaction of perindopril with tert-butylamine in acetonitrile or ethyl acetate gives perindopril erbumin.

The starting compounds for the synthesis of I- [1- (8) -ethoxycarbonyl-3-butyl] - (8) -alanine (II) and (28, 3αδ, 7a8) octahydroindole-2-carboxylic acid (Wa) are known: Ν- [ 1- (8) -ethoxycarbonyl-3-butyl] - (8) -alanine (II) I8 4914214, I8 2003/0045744 A1, I8 20030109743 A1, EP 1403278, EP 0309324 B1, UO 2005/100317 and (28, 3αδ, 7a8) octahydroindole-2-carboxylic acid (Ya) 8I 1153827, I8 5258525, EP 0037231, EP 0173199, I8 4508729, EP 0115345.

The synthesis of perindopril erbumin according to the application US 2004/0248814 A1 can be represented by the following scheme.

IV

N

= Ν ^ν juice H N

V (a K = H)

1-ΒιιΝΗ ₂

- 1 007988 *

CH ₃ sn ₃ s --- νη ₂ sn ₃

Perindopril

1 (K = H)

In the case when K is a protective group, a stage of its removal is necessary.

The main disadvantage of this method is the use of toxic phosgene or its compounds, which leads to certain difficulties in the process of industrial implementation of the present invention.

A known method of producing perindopril erbumin (λ ¥ Ο 2005/068425 A1), consisting of the following stages:

1) protecting the secondary amino group of 14- [1- (8) ethoxycarbonyl-3-butyl] - (8) -alanine (II) with a trimethylsilyl group, to give the silylated compound (VI)

(CH ₃ ) ₃ 81C1

II

O81 (CH ₃ ) ₃

VI

2) activation of compound (VI) with an activating agent, thionyl chloride or a complex of thionyl chloride with 1H-benzotriazole, to obtain the acyl chloride of formula (VII)

5KSN ₃ ) s O

OZSTsN ₃ ) s

5OS1 _g _____ ►

CH _:

CH ₃

A, h / ^{s | Ν} II 3 | (CH ₃ ) s O (VII)

3) the interaction of the acyl chloride of formula (VII) with (28, Zoc8, 7oc8) octahydroindole-2-carboxylic acid (V) having a protected carboxyl group K, where K-trimethylsilyl, 1-tert-butyl or benzyl group; obtaining a protected perindopril derivative of the formula (VIII)

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COOC.

(V)

COOC.

81 (CH ₃ ) ₃

4) the conversion of the derivative of formula (VIII) into perindopril by the removal of all protective groups.

5) the interaction of perindopril with tert-butylamine in methylcyclohexane, or 2-pentanone, or ethyl acetate to obtain perindopril erbumin.

A significant disadvantage of the above method is the multi-stage process, the need for additional cleaning operations of the product from organosilicon compounds.

B \ ¥ O 01/87835; G) 01/87836 and G) 01/87839 the crystallization of perindopril erbumin from ethyl acetate (G) 01/87835) is described; from dichloromethane or ethyl acetate (G) 01/87836); from chloroform (G) 01/87839) and the resulting crystalline forms of perindopril erbumin are described: a (G) 01/87835), β (G) 01/87836) γ (G) 01/87839).

There is also known a method for producing perindopril erbumin, described in patent I8 4914214 and consisting in the reaction (28, Zoc8.7oc8) of octahydroindole-2-carboxylic acid, wherein the carboxyl group is protected by a benzyl group or esterified with a linear or branched alkyl group; with the (8.8) diastereoisomer And - [(8) -1-carbethoxybutyl] - (8) -alanine in an alkaline medium in the presence of a dicyclohexylcarbo diimide type catalyst and in the presence of 1-hydroxybenzotriazole, giving a perindopril benzyl or alkyl ester. Subsequent removal of the protective group gives perindopril, which is dissolved in a solvent selected from lower aliphatic alcohol, acetonitrile, ethyl acetate, dioxane or mixtures thereof and reacted with tert-butylamine, the resulting perindopril erbumin is recrystallized by heating the reaction mass, filtering the hot solution, cooling and final filtering the resulting perindopril erbumin.

The patent provides a detailed description of the synthesis of key components of the process: (28, Zoc8.7oc8) octahydroindole-2-carboxylic acid; M- [1- (8) -ethoxycarbonyl-3-butyl] - (8) -alanine; and the reaction of these compounds to produce perindopril and perindoprilerbumin.

The synthesis of perindopril erbumin according to this patent can be represented by the following scheme.

Stage I. Synthesis of (28, Zoc8.7oc8) octahydroindole-2-carboxylic acid ester

COOH *

СООЕ1

EYUN, HC1, tin ||

γ СООЕ1

N

YUN

Yaon

(A) K-lower branched or linear alkyl;

Stage II. Synthesis of b1- [1- (8) -ethoxycarbonyl-3-butyl] - (8) -alanine (B)

CH ₃ CH ₃

CH --- C --- OE1 ( ^§ ) II

Crystallization from acetonitrile

ΕΐΟΙ ^ 01Ή ₃ Ν8ОС1 ₂ g + >>

CH ₃

BUT - C - CH - ΝΗII (§)

CH ₃

-CH (8)

OE1 (B)

Stage III. Obtaining perindopril erbumin

N

H alkaline environment

DTsGK, 1-NOVT ether of perindopril removal ΐΛ-ΒϋΝΗίΒίΟΑο, MESA, di oxane, lower sirt

2- Crystallization of any solvent

CH ₃

Perindopril erbumin

Significant disadvantages of the method are technological difficulties encountered in the stages of filtration and drying of the product. The separation of the product from the mother liquor due to the consistency of the solution and the nature of the precipitate is a complex and lengthy process.

This technical solution, according to the authors, is the closest to the claimed method in terms of technical nature and the achieved result.

Disclosure of invention

The inventive method is aimed at improving the properties of the target product, which together allow for quick filtering and drying.

Ultrasonic irradiation is known to be an extremely effective method of precipitating solids from oversaturated liquids. It leads to the formation of finely divided and homogeneous particles, since the crystallization nuclei, as they form and grow, are crushed themselves with the formation of new nuclei in the system.

It was unexpectedly found that the use of ultrasonic irradiation during crystallization of perindopril erbumin allows to obtain the product in crystalline form, which especially facilitates the processes of filtration, drying and ease of processing.

Moreover, it was found that the use of ultrasonic irradiation during the crystallization of perindopril erbumin from dioxane leads to a new crystalline form of the compound of formula I, characterized by the following X-ray powder diffraction pattern, measured on a DRON-4 powder diffractometer and expressed in values of interplanar distances b (A); Bragg angles 2Θ (°) and relative intensities, expressed as% of the most intense beam.

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Table I

Ts 2TNETS I (KE)% 14.466147 6.1047 33.75 12.621563 6.9979 09/15 8.598448 10.2796 01/25 7.890395 11.2048 67.66 7.270175 12.1642 8.17 5.360552 16.5237 32.05 5.122267 17.2982 100.00 4.984985 17.7784 64.45 4.797616 18.4787 46.10 4.591134 19.3175 14.64 4.417972 08.2023 25.73 4.203392 11/21/90 16.51 3.972590 22.3613 89.18 3.872588 22.9465 70.14 3.802164 23.3775 46.26 3.534014 25.1793 15.73 3.445755 25.8353 21.22 3.214857 27.7266 22.51 3.114560 28.6382 18.33 2.938768 30.3913 11.74 2.783047 32.1365 8.16 2.728237 32.8002 11.09 2.631692 34.0395 12.96 2.494068 35.9802 7.95 2.417166 37.1661 9.97 2.331594 38.5830 7.73 2.266611 39.7350 5.80

The invention also relates to a method for producing crystalline zeta of compound (I), the inventive method characterized in that the solution of perindopril erbumin in dioxane is heated to boiling and then cooled under ultrasound irradiation until crystallization is complete.

In the crystallization process according to the proposed method, you can use the compound of formula (I) obtained by any method. Advantageously, the compound of formula (I) is prepared according to the patent and § 4914214.

It was found that upon crystallization of other crystalline forms (for example, α-, β-, γ-) of perindopril erbumin in dioxane under the action of ultrasonic irradiation, it is possible to obtain a crystalline form ξ.

The perindopril erbumin salt under such conditions is obtained in the form of individual needles ~ 0.2 mm long. This is essential for particularly fast and efficient filtration and drying.

The implementation of the invention

The inventive method is illustrated by the following examples:

Example 1. 10 g of perindopril erbumin obtained according to the process described in US patent No. 4914214, dissolved in 100 ml of 1,4-dioxane when heated in an ultrasonic bath PSB-1341-2, include ultrasound and when the bath is turned off, the crystallization process is carried out to ambient temperature. The resulting solid is filtered off.

X-ray diffraction pattern of the product (measured on a DRON-4 powder diffractometer, CuKa radiation) expressed in terms of the E (A) interplanar distances. Bragg angles 2Θ (°) and relative intensities 1L _max (%) are given in table. I.

Example 2. 1) Obtaining the α-crystalline form of perindopril erbumin according to the application 1182003/186896.

g of perindopril erbumin obtained according to the method described in patent 118 4914214, dissolved in 125 ml of ethyl acetate, heated to boiling and gradually cooled over the course of 2.5 hours to a temperature of 56 ° C and then to room temperature. The resulting solid is filtered off. The X-ray diffraction pattern of the product (measured on a DRON powder diffractometer, CuKa radiation) showed that the α-crystalline form of perindopril erbumin was obtained.

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2) Obtaining the ξ crystalline form of perindopril erbumin from the α-crystalline form.

g “-crystalline form of perindopril erbumin is dissolved in 75 ml of 1,4-diocane when heated in an ultrasonic bath PSB-1341-2, ultrasound is turned on, and when the heating is turned off, crystallization of the product is carried out under ultrasound irradiation to room temperature. The resulting solid was filtered.

The X-ray diffraction pattern of the product (measured on a DRON-4 powder diffractometer, CuKa radiation) showed that the characteristics of the obtained substance coincide with the characteristics of the ξ crystalline form of perindopril erbumin.

Comparative example 3. The effect of ultrasonic treatment on the time of receipt of the target product (perindopril erbumin).

1) 10 g of perindopril erbumin, obtained according to the method described in patent I8 4914214, dissolved in 125 ml of ethyl acetate, heated to boiling and cooled to room temperature. The solid precipitates as a dense glassy mass. The precipitate obtained is filtered off. Grind, dry at 40 ° C under vacuum for 6 hours

2) 10 g of perindopril erbumin obtained according to the method described in patent I8 4914214, dissolved in 125 ml of ethyl acetate, heated to boiling in an ultrasonic wave PSB-1341-2, include ultrasound and when the bath is turned off, the crystallization process is carried out to ambient temperature. A solid is obtained in the form of a crystalline powder. Dry at 40 ° C under vacuum for 3 hours.

Claims (3)

CLAIM 1. The crystalline form of ξ-zeta perindopril erbumine, characterized by the powder diffractogram shown in the table below: ϋ 2TNET I (KE)% 14.466147 6.1047 33.75 12.621563 6.9979 September 15 8.598448 10.2796 25.01 7.890395 11.2048 67.66 7.270175 12.1642 8.17 5.360552 16.5237 32.05 5.122267 17.2982 100.00 4.984985 17.7784 64.45 4.797616 18.4787 46.10 4.591134 19.3175 14.64 4.417972 20.0823 25.73 4.203392 21.1190 16.51 3.972590 22.3613 89.18 3.872588 22.9465 70.14 3.802164 23.3775 46.26 3.534014 25.1793 15.73 3.445755 25.8353 21.22 3.214857 27.7266 22.51 3.114560 28.6382 18.33 2.938768 30.3913 11.74 2.783047 32.1365 8.16 2.728237 32.8002 11.09 2.631692 34.0395 12.96 2.494068 35.9802 7.95 2.417166 37.1661 9.97 2.331594 38.5830 7.73 2.266611 39.7350 5.80 where in columns ϋ - interplanar distance, A, 2Т11с1а - Bragg angles, °; I (K.е1) - relative intensity, I (Ke1) = 1/1 _max ,%; CuC radiation; shooting interval of 2Θ 5-42 °, shooting step of 0.1 °. -6007988 2. A method of obtaining the crystalline form of ξ-zeta perindopril erbumine, characterized in claim 1, characterized in that the solution of perindopril α-butylamine salt in 1,4-dioxane is heated to boiling and then cooled under ultrasound to room temperature, the solid is filtered. 3. The method of obtaining the crystalline form of ξ-zeta perindopril erbumine, characterized in claim 1, characterized in that the suspension of perindopril ΐ-butylamine salt in 1,4-dioxane is subjected to the action of ultrasonic radiation.