FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR THE PREPARATION AND PURIFICATION OF
BETHANECHOL OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation and purification of Bethanechol or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation and purification of Bethanechol chloride.
Bethanechol chloride of formula I is chemically known as 2-[(amino carbonyl) oxy]-N, N, N-trimethyl-1-propanaminium chloride. It is an active cholinergic agent.

H,N

O

CH3 H3C

CI"

Formula I
US patent No. 2, 322, 375 describes the process of preparation of Bethanechol chloride by reacting choline halide or an alkyl substituted choline halide with phosgene in chloroform. Thereafter reacting with ammonia in chloroform.
The inventors have surprisingly found that reacting 2-hydroxy propyl trimethyl ammonium halide in halogenated hydrocarbon with triphosgene instead of phosgene affords safe and high yielding process. The present invention also provides purification process, which can be easily scaled-up and give high purity bethanechol chloride.
In one of the aspect of present invention there is provided a process for the preparation of bethanechol chloride, wherein the said process comprises of
a) reacting 2-hydroxy propyl trimethyl ammonium halide with triphosgene
solution,
b) isolating the bethanechol chloride from reaction mass thereof.
In another aspect of the present invention there is provided a process for the purification of bethanechol chloride, wherein the said process comprises of
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a) crude bethanechol chloride was dissolved in alcoholic solvent,
b) isolation of crystalline bethanechol chloride from the reaction mixture by addition of anti-solvent.
The process involves treating propylene oxide with trimethylamine aqueous solution under cooling. The 2-hydroxy propyl trimethyl ammonium halide obtained thereof was reacted in halogenated hydrocarbon with triphosgene solution in halogenated hydrocarbon. After completion of reaction the ammonia gas was passed to adjust the pH of reaction mixture became 8.0 to 10.0. The bethanechol chloride thereof was then isolated from the reaction mass thereof. The purification of bethanechol or salt involves making the solution of bethanechol chloride in alcoholic solvent and heated to get clear solution. The reaction mixture was then filtered and product is precipitated by addition of anti solvent such as isoprapanol and n-propanol. The precipitated product was cooled and filtered.
The non-limiting examples of halogenated hydrocarbon such as carbon tetrachloride, chloroform, ethylene dichloride, methylene chloride, monochlorobenzene, trichloroethane, monochlorotoluene and the like.
The non-limiting examples of alcohol include (C1-C4) straight and branched chain alcohols, such as methanol, ethanol, n-propanol and isopropanol and the like.
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.
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Example
Stage-1: Bethanechol chloride (Crude)
Trimethyl amine aqueous solution (30%, 21.80 kg) cooled to 5-10°C and added propylene oxide (4.4 kg) at same temperature in period of 3-4 hrs. Reaction mixture was brought to room temperature and stirred for 8 hrs. After completion of reaction removed water under reduced pressure. Residue was cooled and treated with concentrated hydrochloric acid to adjust the pH between 1-1.5. After attaining the pH the water was removed under reduced pressure to dryness. The free solid mass obtained was treated with chloroform (60.0 Litre). Chloroform (~15 Litre) was partially removed at atmospheric pressure. The reaction mixture cooled to 0-5°C and then charged triethyl amine solution (8.34 kg) under stirring. Added Triphosgene solution (7.75 kg ,20.0 L chloroform) in 2-3 hrs at temperature 0-20°C.
After addition mass temperature raised to room temperature and stirred for 2 hours. Cooled the mass to 0-5°C and adjusted the pH to 8.5 to 9.0 by purging ammonia gas. Stirred the mass for 3.0 hrs and added water (2.15 Litre) and separated chloroform layer.
Aqueous layer was treated with isopropyl alcohol (25.0 Litre) and removed the isopropyl alcohol and water under reduced pressure to dryness. Methanol (35 Litre) was added to mass and filtered to remove inorganic solid. Filtrate was concentrated to dryness, in dry solid methanol and isopropyl alcohol mixture (2:4, 105 Litre) was added. Reflux the reaction mixture to get clear solution. Reaction mixture was then cooled to 40°C and filtered to remove undissolved solid. Finally obtained filtrate was cooled to room temperature 0-5°C, stirred for 1.0 hr and solid was isolated and dried.
Dry weight = 9.88 kg
Purity = 90% by HPLC
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Stage- II: Bethanechol chloride
Bethanechol Chloride crude (9.8 kg) was dissolved in methanol (24 Litre) under reflux. The clear solution was charcolized and filtered. To the filtrate isopropyl alcohol (98 Litre) was added at room temperature and then cooled the reaction mixture to 0-5°C and stirred for 1 hour for complete precipitation. The precipitated solid was filtered and dried to get bethanechol chloride.
Yield = 7.20 kg
Assay = 99.29% by HPLC
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WE CLAIM
1. A process for the preparation of bethanechol or salt thereof, wherein the said
process comprises of
a) reacting 2-hydroxy propyl trimethyl ammonium halide with triphosgene solution,
b) isolating the bethanechol chloride from reaction mass thereof.

2. A process of claim 1 wherein the 2-hydroxy propyl trimethyl ammonium halide is a chloride salt.
3. A process of claim 1 wherein the triphosgene solution is in halogenated hydrocarbon.
4. A process of claim 1 and 3 wherein the halogenated hydrocarbon includes carbon tetrachloride, chloroform, ethylene dichloride, methylene chloride and the like.
5. A process for the purification of bethanechol or salt thereof, wherein the said process comprises of

a) crude bethanechol chloride was dissolved in alcoholic solvent,
b) isolation of crystalline bethanechol chloride from the reaction mixture by addition of anti-solvent.

6. A process of claim 5 wherein the alcohol solvent includes (C1-C4) straight and branched chain alcohols, such as methanol, ethanol, n-propanol and isopropanol and the like.
7. A process of claim 5 wherein the anti-solvent is isoprapanol or n-propanol.
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8. A process of claim 1 and 5 wherein the alcoholic solvent and anti-solvent are methanol and isoprapanol respectively.

Dated this 30th day of October 2006

For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory