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:
AN IMPROVED PROCESS FOR THE PREPARATION OF BETHANECHOL
CHLORIDE
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 an improved process for the preparation of bethanechol chloride.
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 an improved process for the preparation 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.

##STR(

H9N

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 found an improved process for the preparation of bethanechol chloride by reacting 2-hydroxy propyl trialkyl ammonium halide in halogenated solvent with triphosgene. This involves simple workup to isolate the bethanechol chloride thereof in high yield with high purity. The Bethanechol chloride obtained by this invention is highly crystalline and free flowing in nature.
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 trialkyl ammonium halide with triphosgene solution,
b) isolating the bethanechol chloride from reaction mass using organic solvent.
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The process involves treating propylene oxide with trimethylamine aqueous solution under cooling. The 2-hydroxy propyl trimethyl ammonium chloride obtained thereof was reacted with triphosgene solution in halogenated solvent. After completion of reaction the ammonia gas was passed to adjust the pH of reaction mixture to 8.0 to 10.0. The reaction mixture was cooled and filtered. The solid mass was suspended in mixture of water and alcohol (about 6-7%, water and 92-93% alcohol) such as methanol, ethanol, n-propanol, isopropanol and the like. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The reaction mass obtained thereof was then added with organic solvent such as ketone solvent, which includes acetone, butanone, methyl isobutyl ketone and the like. The bethanechol chloride thereof was then isolated from the reaction mass and purified. The pure bethanechol chloride thus obtained has purity of 99.9% or more when measured by HPLC, free flowing and crystalline in nature.
The non-limiting examples of halogenated solvent such as carbon tetrachloride, chloroform, ethylene dichloride, methylene chloride, monochlorobenzene, trichloroethane, monochlorotoluene 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.
EXAMPLE Stage:-I Bethanechol chloride
Trimethyl amine aqueous solution (30%, 17.7 kg) cooled to 5-10°C and added propylene oxide (3.5 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
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attaining the pH the water was removed under reduced pressure to dryness. The free solid mass obtained was treated with chloroform (85.0 L). Chloroform (~15 L) was partially removed at atmospheric pressure. The reaction mixture cooled to 0-5°C and then charged triethyl amine solution (6.6 kg) under stirring. Added Triphosgene solution (6.2 kg, 9.2 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 centrifuged the reaction mass. The wet solid was suspended in water (3.9 L) isopropyl alcohol (54 L). The reaction mixture was heated at 50-60°C for 30 minutes and cooled to room temperature. The reaction mixture was filtered. The filtrate was then distilled out. The reaction mass was then cooled and acetone (21 L) was added with stirring. The precipitate obtained was then suspended in chloroform (13 L). The product was then isolated and dried. Dry weight: 8.5 kg Purity by HPLC: 95%
Stage:-ll Bethanechol chloride crystallization
Bethanechol Chloride (8.5 Kg) was dissolved in methanol (21 L) under reflux.
The clear solution was charcolized and filtered. To the filtrate isopropyl alcohol
(85 L) 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: 7.9 kg
Purity: 99.9% by HPLC
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WE CLAIM
1. A process for the preparation of Bethanechol chloride, wherein the said
process comprises of
a) reacting 2-hydroxy propyl trialkyl ammonium halide with triphosgene solution,
b) isolating the bethanechol chloride from reaction mass using organic solvent.
2. A process of claim 1 wherein the 2-hydroxy propyl trialkyl ammonium halide
is 2-hydroxy propyl trimethyl ammonium chloride.
3. A process of claim 1 wherein the triphosgene solution is in halogenated
solvent.
4. A process of claim 3 wherein the halogenated solvent includes carbon
tetrachloride, chloroform, ethylene dichloride, methylene chloride and the like.
5. A process of claim 1, wherein the organic solvent used for isolating the
bethanechol chloride from reaction mass is ketone solvent.
6. A process of claim 5, wherein the ketone solvent includes such as acetone,
butanone, methyl isobutyl ketone and the like.
7. Crystalline bethanechol chloride having purity 99.9% or more when measured
by HPLC.
Dated this 1st day of December, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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