WO2008104847A2

WO2008104847A2 - Processes for the preparation of pramipexole and salts thereof

Info

Publication number: WO2008104847A2
Application number: PCT/IB2008/000406
Authority: WO
Inventors: Aziz Imam Quadri Syed; Mohammad Rafeeq; Mohammed Jaweed Mukarram Siddiqui
Original assignee: Wockhardt Research Centre
Priority date: 2007-02-26
Filing date: 2008-02-25
Publication date: 2008-09-04
Also published as: WO2008104847A3

Abstract

The invention relates to processes for the preparation of pramipexole or pharmaceutically acceptable salts thereof. More particularly, it relates to a process for the preparation of pramipexole dihydrochloride monohydrate. The invention also relates to a novel compound, 2-bromo-4-aminocyclohexanone and processes for its preparation. The 2- bromo-4-aminocyclohexanone is a useful intermediate in the preparation of pramipexole or salts thereof. The invention further relates to a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole, an intermediate useful in the preparation of pramipexole or salts thereof.

Description

PROCESSES FOR THE PREPARATION OF PRAMIPEXOLE AND SALTS

THEREOF

Field of the Invention

The field of the invention relates to processes for the preparation of pramipexole or pharmaceutically acceptable salts thereof. More particularly, it relates to a process for the preparation of pramipexole dihydrochloride monohydrate. The invention also relates to a novel compound, 2-bromo-4-aminocyclohexanone and processes for its preparation. The 2-bromo-4-aminocyclohexanone is a useful intermediate in the preparation of pramipexole or salts thereof. The invention further relates to a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole, an intermediate useful in the preparation of pramipexole or salts thereof.

Background of the Invention

Pramipexole dihydrochloride, chemically known as (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino) benzothiazole dihydrochloride monohydrate, is represented by Formula I. Pramipexole dihydrochloride is indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease. Pramipexole is commercially available in the form of dihydrochloride salt as monohydrate.

Formula I

U.S. Patent No. 4,886,812 discloses pramipexole or salts thereof and processes for their preparation. Several processes have been reported for the preparation of pramipexole and its intermediates for example, in U.S. Patent No. 6,727,367, U.S. Patent No. 6,770,761 ; U.S. Patent application No. 2006/0100256 and International (PCT) Publication No. WO 06/097014.

International (PCT) Publication No. WO 06/1 17614 discloses polymorphic Forms A and B of anhydrous pramipexole dihydrochloride.

Journal of Medical Chemistry, 30, 494-498, (1987), discloses a process for the preparation of optically pure pramipexole and a process for the resolution of an intermediate used in the preparation of pramipexole.

Summary of the Invention

The inventors have found a novel compound, 2-bromo-4-aminocyclohexanone of Formula III as a useful intermediate for the preparation of pramipexole or salts thereof.

Formula III

In one general aspect there is provided a process for the preparation of 2-bromo-4- aminocyclohexanone compound of Formula III and its use in the synthesis of pramipexole.

The inventors also have developed a single step cost-effective process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole, a useful intermediate in the preparation of pramipexole or salts thereof. The process is simple and avoids multiple isolation steps.

In another aspect there is provided a process for the preparation of pramipexole dihydrochloride monohydrate. The inventors found that when anhydrous pramipexole dihydrochloride is dissolved in water and alcohol, followed by the addition of an anti- solvent, it is precipitated as a monohydrate in high purity.

In another aspect there is provided a process for preparing pramipexole or salts thereof having purity more than 99.7% by HPLC.

The details of one or more embodiments of the inventions are se forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

In one aspect of the invention there is provided 2-bromo-4-aminocyclohexanone compound of Formula III.

Formula III

In a second aspect of the invention there is provided a process for the preparation of 2- bromo-4-aminocyclohexanone of Formula III. The process includes: a) brominating a compound of Formula II in glacial acetic acid; and

Formula II

b) isolating the 2-bromo-4-aminocyclohexanone of Formula III from reaction mixture thereof.

Formula III

In general, a solution of 4-aminocyclohexanone in glacial acetic acid may be stirred with bromine. After completion of the reaction, the reaction mass may be mixed with water and one or more solvents. The aqueous layer may be separated and organic layer may be concentrated under reduced pressure to get the 2-bromo-4-aminocyclohexanone of Formula III.

Examples of suitable solvents include ester solvents such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, and isopropyl acetate.

In a third aspect of the invention there is provided a process for the preparation of tetrahydrobenzothiazole of Formula IV. The process includes: a) cyclizing a compound of Formula III with thiourea

Formula III

to obtain tetrahydrobenzothiazole of Formula IV; and

Formula IV b) isolating the compound of Formula IV from reaction mass thereof. In a fourth aspect of the invention there is provided a process for the preparation of pramipexole or salts thereof. The process includes: a) cyclizing a compound of Formula III with thiourea

Formula III

to obtain tetrahydrobenzothiazole of Formula IV;

Formula IV b) resolving the compound of Formula IV with a chiral auxiliary to get isomer of Foπnula V;

Formula V c) reacting the compound of Formula V with a propylating agent in alcohol; and d) isolating the pramipexole or a salt thereof from reaction mass thereof.

In a fifth aspect of the invention there is provided a process for the preparation of pramipexole or salts thereof. The process includes: a) cyclizing a compound of Formula III with thiourea

Formula III to obtain tetrahydrobenzothiazole of Formula IV;

b) reacting the compound of Formula IV with a propylating agent in alcohol to get a compound of Formula VI;

Formula VI c) resolving the compound of Formula VI with a chiral auxiliary; and d) isolating the pramipexole or salts thereof from reaction mixture thereof.

In general, a mixture of 2-bromo-4-aminocycIohexanone in glacial acetic acid may be stirred with thiourea at about 60-80 ⁰C. The resulting mixture may be further heated for the completion of reaction. The reaction mixture may be cooled and the compound of Formula IV may be isolated.

The compound of Formula IV may be converted to pramipexole or salts thereof by any of the following methods.

The racemic product of Formula IV may be resolved first by dissolving in a suitable aqueous organic solvent in the presence of a chiral auxiliary. The compound of Formula

IV (S-isomer) may be then propylated using different propylating agents to get pramipexole or salts thereof. The resolution may be carried out by methods known in the art including methods described in U.S. Patent No. 6,727,367, which are incorporated herein by reference.

Examples of chiral auxiliary which may be used include (L)-tartaric acid, ditoluoyl-D- tartaric acid, dibenzoyl-D-tartaric acid, O,O-dibenzoyl tartaric acid, camphor acid, camphorsulphonic acid and α-methoxyphenylacetic acid.

Alternatively, the propylation may be done prior to resolving the racemic product of Formula IV to get pramipexole or salts thereof.

The propylating agent can be selected from a compound of Formula CH₃-CH₂-CH₂-X, wherein X is a leaving group such as a tosylate, a mesylate or a halide.

The propylation reaction may be carried out in the presence of an aqueous organic solvent. The reaction may be carried out a temperature from about 25°C to a reflux temperature of the solvent selected. Examples of solvents which may be used include Q.₄ alcohols such as methanol, ethanol, propanol or mixtures thereof. The desired compound may be obtained by removing the solvent under vacuum.

In this disclosure, the term "salt" refers to a compound of Formula I or its monobasic or dibasic acid addition salt. The acid addition salt can be selected from inorganic or organic acid addition salt. The dibasic acid addition salt can be a mixed acid addition salt of two different acids. The term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salts thereof.

In a sixth aspect of the invention there is provided a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole of Formula IV. The process includes:

a) reacting 4-/røAzs-aminocyclohexanoI with an acetylating agent to produce N-(4- hydroxycyclohexyl) acetamide; b) adding an oxidizing agent to produce N-(4-oxocyclohexyl) acetamide; c) adding bromine to produce 2-bromo-N-(4-oxocyclohexyl) acetamide; d) adding thiourea to produce 6-acetylamino-2-amino-4,5,6,7-tetrahydro- benzthiazole; e) adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7- tetrahydro-benzthiazole; and f) isolating the compound of Formula IV from reaction mass thereof.

The intermediate compounds may not be isolated which may result in a higher yield and may reduce the processing time. The process may result in the product with a higher purity.

The 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole may be converted to pramipexole or salts thereof by method known in the literature. In particular, it may be converted to pramipexole or salts thereof by methods described in U.S. Patent No. 4,886,812.

The preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole of Formula IV may be carried out in a single step without isolating any intermediates thereof. 4-trans- aminocyclohexanol may be reacted with an acetylating reagent like acetic anhydride or acetyl chloride in a solvent like dimethylformide, dimethylsulfoxide, tetrahydrofuran, N- methyltetrahydrofuran, dioxane, dimethylacetamide, hexamethyl phosphorictriamide, N- methylpyrrolidone, formamide or a mixture thereof. After completion of the reaction, the reaction mixture may be concentrated. A ketone solvent such as acetone, methyl ethyl ketone, methyl iso-butyl ketone or a mixture thereof may be added to the residue so obtained and it may be cooled from about 5⁰C to about 20 ⁰C. An oxidizing agent such as Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate may be added to the reaction mixture at about 5⁰C to about 20⁰C. The resulting mixture may be further stirred for 2-6 hours. The reaction mixture may be quenched by adding isopropyl alcohol and it may be concentrated. An ester solvent such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate or a mixture thereof may be added to the residue so obtained and it may be stirred for 10-30 minutes. The organic layer may be separated and concentrated. Water may be added to the residue followed by the drop wise addition of bromine in 45-60 minutes at room temperature. The temperature may be raised to 45 ⁰C and further stirred for the completion of reaction. Thiourea may be added to the reaction mixture and it may be heated from about 70⁰C to about 90⁰C for 3-6 hours. Aqueous hydrobromic acid may be added after completion of reaction and the reaction mixture may be further refluxed for 5-10 hours. The reaction mass may be cooled to about 5⁰C -20 ⁰C and basified with addition of a base like sodium hydroxide and resultant solid may be isolated from the reaction mass thereof.

In a seventh aspect of the invention there is provided a process for the preparation of pramipexole dihydrochloride monohydrate. The process includes the steps of:

a) dissolving anhydrous pramipexole dihydrochloride in one or more solvents; b) adding an anti-solvent; and c) isolating the pramipexole dihydrochloride monohydrate from reaction mass thereof.

In general, a solution of anhydrous pramipexole dihydrochloride may be obtained in one or more solvents. Alternatively, such a solution may be obtained directly from a reaction in which pramipexole dihydrochloride is formed.

The term "solvents" includes any solvent or solvent mixture in which pramipexole dihydrochloride can be solubilized, including, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol and mixtures thereof.

The solution of pramipexole dihydrochloride can be obtained by dissolving, slurrying, stirring, or a combination thereof.

In this disclosure, an antisolvent is characterized by the fact that pramipexole dihydrochloride monohydrate is insoluble, slightly soluble or practically insoluble but is miscible with a solvent or solvent mixture in which pramipexole dihydrochloride solution is obtained.

Examples of anti-solvents that may be added to precipitate out pramipexole dihydrochloride include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec- butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate and mixtures thereof.

The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

Isolation of the pramipexole dihydrochloride monohydrate from the reaction mass may include, for example, one or more isolating techniques such as filtration, distillation, evaporation, decantation and centrifugation.

The process may produce the pramipexole dihydrochloride monohydrate having purity 99.7% or more when measured by HPLC.

The invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example- 1 : Preparation of 2-bromo-4-aminocvclohexanone

To a stirred mixture of 4-aminocyclohexanone (1.0 gm) in glacial acetic acid (20ml), bromine (1.48 gm) was added and the mixture was further diluted with 1 ml of glacial acetic acid. The mixture was stirred at 15°C for 4 hrs. After completion of the reaction, water and ethyl acetate were added and stirred for 15 minutes. Aqueous layer was separated and concentrated under reduced pressure to get the title compound.

Yield: 1.5 gm.

Example-2: Preparation of 2,6 -diamino-4,5.6,7- tetrahydrobenzothiazole

To a stirred mixture of 2-bromo-4-aminocyclohexanone (2.0 gm) in glacial acetic acid (40 ml), thiourea was added at about 80 ⁰C. The solution was further heated for 3 hrs. The product precipitated out on cooling of the reaction mixture to room temperature.

Yield: 2.3 gm.

Example-3: Preparation of 2,6-diamino-4,5.6.7-tetrahydrobenzathiazole

4-£ra/«-aminocyc!ohexanol (50.0 gm) was taken in dimethylformamide (500 ml) and cooled to 10°- 15⁰C. To this, acetic anhydride (44.34 gm) was added. After completion of the reaction, the reaction mixture was concentrated. To the residue obtained thereof, acetone (630 ml) was added and cooled to 10°- 15⁰C. To the reaction mixture, Jone's reagent was added at 10°- 15⁰C. The mixture was stirred for three hours. The reaction mixture was quenched by adding isopropyl alcohol (252 ml) and concentrated. To the residue, ethyl acetate (630 ml) was added and stirred for 15-20 minutes. The organic layer was separated and washed with ethyl acetate (630 ml). The organic layer was concentrated. To the residue, water (250 ml) was added followed by drop wise addition of bromine (56 gm) in 45-60 minutes at room temperature. The temperature was raised to 45⁰C and stirred till the reaction was complete. To this reaction mixture, thiourea (62.5gm) was added and heated to 80°-85°C for 4-5 hours. To this reaction mass, aqueous hydrobromic acid (50 ml) was added and further the reaction mixture was refluxed for 6- 8 hours. The reaction mass was then cooled to 10-15⁰C and basified with addition of sodium hydroxide. The resultant solid was isolated from the reaction mass thereof. Yield: 24-25 gm.

Example-4: Preparation of pramipexole dihvdrochloride monohydrate

To a solution of anhydrous pramipexole dihydrochloride (10.0 g) in water (10.0 ml), ethanol (70.0 mj) was added drop wise at 0-5°C temperature. To the resulting mixture, ethyl acetate (200 ml) was added. The product pramipexole dihydrochloride monohydrate was isolated from the reaction mass thereof.

Yield: 9.5 g.

Purity: 99.8 % (by HPLC).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. For example, the pramipexole dihydrochloride monohydrate described herein can be formulated into ndosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial. Specifically, the pramipexole dihydrochloride monohydrate can be formulated with one or more pharmaceutically acceptable excipients into a dosage form and administered to treat signs and symptoms of idiopathic Parkinson's disease.

Claims

We Claim:

1. 2-bromo-4-aminocyclohexanone of Formula III.

Formula III

2. A process for the preparation of 2-bromo-4-aminocyclohexanone, the process comprising: a) brominating acompound of Formula II in glacial acetic acid; and

Formula II b) isolating the 2-bromo-4-aminocyclohexanone of Formula HI from reaction mixture thereof.

Formula III

3. The process of claim 2, wherein the isolation comprises one or both of extraction with one or more solvents and concentration of solvent.

4. The process of claim 3, wherein the solvent comprises one or more of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, and isopropyl acetate.

5. A process for the preparation of pramipexole or salts thereof, the process comprising: a) cyclizing a compound of Formula HI with thiourea

Formula III to obtain tetrahydrobenzothiazole of Formula IV;

Formula IV b) converting the compound of Formula IV to pramipexole or salts thereof; and c) isolating the pramipexole or salts thereof from reaction mass thereof.

6. The process of claim 5, wherein converting the compound of Formula IV to pramipexole or salts thereof further comprising: a) resolving the compound of Formula IV with a chiral auxiliary to get isomer of Formula V;

Formula V b) reacting the compound of Formula V with a propylating agent in alcohol; and c) isolating the pramipexole or a salt thereof from reaction mass thereof.

7. The process of claim 5, wherein converting the compound of Formula IV to pramipexole or salts thereof further comprising: a) reacting the compound of Formula IV with a propylating agent in alcohol to get a compound of Formula VI;

Formula VI b) resolving the compound of Formula VI with a chiral auxiliary; and c) isolating the pramipexole or salts thereof from reaction mixture thereof.

8. The process of claim 5, wherein the cyclization is carried out in the presence of glacial acetic acid.

9. The process of claims 6 or 7, wherein the alcohol comprises one or more of methanol, ethanol, and isopropanol.

10. The process of claims 6 or 7, wherein the chiral auxiliary comprises one or more of (L)-tartaric acid, ditoluoyl-D-tartaric acid, dibenzoyl-D-tartaric acid, O,O-dibenzoyl tartaric acid, camphor acid, camphorsulphonic acid and α-methoxyphenylacetic acid.

1 1. A process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole of Formula IV,

Formula IV the process comprising: a) reacting 4-frøHs-aminocyclohexanol with an acetylating agent to produce N-(4- hydroxycyclohexyl) acetamide; b) adding an oxidizing agent to produce N-(4-oxocyclohexyl) acetamide; c) adding bromine to produce 2-bromo-N-(4-oxocyclohexyl) acetamide; d) adding thiourea to produce 6-acetylamino-2-amino-4,5,6,7-tetrahydro- benzthiazole; e) adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7- tetrahydro-benzthiazole; and f) isolating the 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole of Formula IV from reaction mass thereof.

12. The process of claim 1 1, wherein the reaction of 4-/rø>«-aminocyclohexanol with an acetylating agent is carried out in the presence of one or more organic solvents.

13. The process of claim 12, wherein the organic solvent comprises one or more of dimethylformide, dimethylsulfoxide, tetrahydrofuran, N-methyltetrahydrofuran, dioxane, dimethylacetamide, hexamethyl phosphorictriamide, N-methylpyrrolidone, and formamide.

14. The process of claim 1 1, wherein the acetylating agent comprises one or both of acetic anhydride and acetyl chloride.

15. The process of claim 1 1, wherein the oxidizing agent comprises one or more of Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate, and potassium permanganate.

16. A process for the preparation of pramipexole dihydrochloride monohydrate, the process comprising: a) dissolving anhydrous pramipexole dihydrochloride in one or more solvents; b) adding an anti-solvent; and c) isolating the pramipexole dihydrochloride monohydrate from reaction mass thereof.

17. The process of claim 16, wherein the solvent comprises one or more of water, methanol, ethanol, propanol, isopropyl alcohol and butanol.

18. The process of claim 16, wherein the anti-solvent comprises one or more of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, and isopropyl acetate.

19. The process of claim 16, wherein the isolation comprises one or more of filtration, distillation, evaporation, decantation and centrifugation.

20. The process of claim 16, wherein the pramipexole dihydrochloride monohydrate is having purity of 99.7% or more by HPLC.