WO2007096724A1

WO2007096724A1 - An improved process for the preparation of amlodipine besylate

Info

Publication number: WO2007096724A1
Application number: PCT/IB2007/000293
Authority: WO
Inventors: Mahender Rao Siripragada; Unni Santhosh; Thirumurugan Kunchithapatham; Chinnam Naidu Kundrappu
Original assignee: Orchid Chemicals and Pharmaceuticals Ltd
Current assignee: Orchid Pharma Ltd
Priority date: 2006-02-21
Filing date: 2007-02-08
Publication date: 2007-08-30
Anticipated expiration: 2008-08-21

Abstract

The present invention provides a process for the preparation of amlodipine, which comprises purging of methylamine gas under stirring in phthaloyl amlodipine in presence of an organic solvent selected from the group consisting of toluene and isopropyl alcohol.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE

BESYLATE

Field of the invention:

The present invention relates to an improved process for the preparation of anti- ischemic and anti-hypertensive compound amlodipine.

Background of the invention :

Amlodipine, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl- 5-methoxycarbonyl-6-methyl-l,4-dihydropyridine having formula (I), is a long-term calcium-channel blocker useful for treating cardiovascular diseases such as angina, hypertension etc.

(D

Amlodipine and its salt were first reported in EP 89167, which also describes its preparation from the precursor phthalimido derivative. Phthaloyl amlodipine of formula II is stirred in 33% ethanoHc methylamine solution at room temperature. After evaporation of solvent the residue is slurried in industrial methylated spirits and filtered. The filtrate is washed and crystallized with industrial methylated spirits to obtain amlodipine base.

US patent 6,784,297 describes a process for the preparation of amlodipine from phthaloyl amlodipine of formula II. Phthaloyl amlodipine purified in acetone and water is hydrolyzed with monomethylamine in the presence of protic solvent such as ethanol, denatured spirit, methanol, isopropyl alcohol, chloroform or dioxane preferably denatured spirit at room temperature for 8 hours. This process involves an additional step of purification, which increases the manufacturing cost.

WO 2005/023769 describes a one pot process for the preparation of Amlodipine salts from the phthaloyl amlodipine of formula II by a process involving deprotection of the phthalimido group and converting the free base thus obtained to the desired salt without isolating the Amlodipine free base. Phthaloyl amlodipine is treated with aqueous solution of methylamine in a water immiscible solvent such as methylene dichloride, ethylene dichloride, chloroform, ethyl acetate, toluene, or is treated with alcoholic solution of methylamine at room temperature.

DE 20201878 describes the process of preparation of Amlodipine by hydrolyzing Phthaloyl amlodipine of formula II using 40% aq. methylamine. This process uses toluene for the extraction of Amlodipine base.

None of the prior art references claimed or disclosed the use of monomethylamine gas in toluene for the hydrolysis of phthaloyl amlodipine.

We focused our research on the hydrolysis of phthaloyl amlodipine using monomethylamine gas in toluene, which avoids the preparation of methylamine solution and thus makes the process more easy, time saving, economical and industrially viable.

Object of the invention:

The object of the present invention is to provide an improved process for the preparation of Amlodipine free base of formula (I), which is easy to handle at industrial scale.

Another objective of the present invention is to provide a process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts in good yield and high purity. Summary of the invention:

The present invention provides a process for the preparation of Amlodipine, which comprises hydrolyzing phthaloyl amlodipine using monomethylamine gas in an organic solvent. The process can be represented schematically as below.

(H) (I)

Detailed description of the invention:

Accordingly, the present invention provides a process by which amlodipine is prepared from phthaloyl amlodipine using monomethylamine gas and an organic solvent.

In an embodiment of the invention the organic solvent is selected from the group consisting of aromatic hydrocarbon and alcoholic solvent. The aromatic hydrocarbon solvent may be selected from the group consisting of toluene, xylene, benzene and the like. The alcoholic solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA) and the like.

In another embodiment of the invention, the hydrolysis of the phthaloyl amlodipine with monomethylamine gas is carried out in presence of toluene or isopropyl alcohol preferably toluene.

In yet another embodiment of the invention, the hydrolysis is carried out at a temperature in the range of room temperature to reflux temperature preferably in the range of 40 to 70° C. Phthaloyl amlodipine, which is the starting material for this invention is prepared according to the known processes in the prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example (1)

100 g (0.185 mol) of phthaloyl amlodipine and toluene (1-1.5 L) were charged to 2 L autoclave. Methylamine gas was purged to the above reaction mass at room temperature. The reaction mass was stirred at 40-70 ⁰C for 8-10 hrs. and then at room temperature (25 ⁰C) for 8-12 hrs to complete the reaction. The completion of the reaction was monitored by TLC. After completion of the reaction, IPA (400 mL) was added to the reaction mixture and further stirred for 10-20 min. The reaction mixture was washed with 2 x 400 mL of water. The organic layer was separated and the volume was reduced to 100-150 mL by evaporation under vacuum. Hexane (1-1.5 L) was added slowly (20-30 min) to the above concentrated mass at 40-50⁰C. The solid obtained was filtered and dried at 45-50⁰C for 10-15 hrs. to obtain 55-70 g of amlodipine free base as the product.

Example (D

100 g (0.185 mol) of phthaloyl amlodipine and isopropyl alcohol (IL) were charged to a 2 L autoclave. Methylamine gas was purged to the above reaction mass at room temperature. The reaction mass was stirred at 50 ⁰C for 4-8 hrs. and then at room temperature for 8-12 hrs for the reaction to complete. The completion of the reaction was monitored by TLC. The reaction mass was filtered and the filtrate was concentrated to syrupy mass at reduced pressure and at bath temperature of about 40- 50 ⁰C. To the above residue toluene (600 mL) was added and was stirred for 20-40 min. The reaction mixture was washed with 3 x 300 mL of water. The organic layer was separated, dried over sodium sulfate and was evaporated under vacuum to near completion by maintaining the bath temperature at 50-60 ⁰C. Hexane (1-1.5 L) was added slowly (20-30 min) to the above concentrated mass at 40-50⁰C. The solid obtained was filtered and dried at 45-50 ⁰C for 10-15 hours to obtain 55-70 g of amlodipine free base as the product.

Example (3)

Preparation of amlodipine besylate

Amlodipine free base (100 g) was dissolved in IPA (600 mL) upon heating at 55-60 ⁰C. The temperature was slowly reduced to 45 ⁰C. Activated charcoal (5 g) was added and was stirred for 30 minutes at 55-60 ⁰C. The hot solution obtained was filtered through hyflo bed. Benzene sulfonic acid (40.6 g) in IPA (200 mL) was added slowly (30-45 min) to the above solution at 45-50 ⁰C. and was stirred for 2 hrs. The reaction mixture was cooled to 25 ⁰C and stirred for 1 h. The solid obtained was filtered and the residue was washed using IPA (400 mL). The product obtained was further purified by recrystallisation from IPA: methanol (1 :7) to get 85-95 g of amlodipine besylate.

Claims

We claim:

1. A process for the preparation of Amlodipine base, which comprises hydrolyzing phthaloyl Amlodipine with monomethylamine gas in presence of an organic solvent.

2. A process according to the claim 1, wherein the organic solvent is selected from the group consisting of aromatic hydrocarbon and alcohol.

3. A process according to the claim 2, wherein the aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene, benzene and the like.

4. A process according to the claim 2, wherein the aromatic hydrocarbon solvent is toluene.

5. A process according to the claim 2, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol and the like.

6. A process according to the claim 2, wherein the alcoholic solvent is isopropyl alcohol.

7. A process according to the claim 1, wherein the hydrolysis is carried out at a temperature in the range of room temperature to reflux temperature.

8. A process according to the claim 1, wherein the hydrolysis is carried out at a temperature in the range of 40 to 70⁰C.

9. A process according to the claim 1, wherein Amlodipine base is further reacted with benzenesulphonic acid to form Amlodipine besylate.