FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: PREPARATION OF DENATONIUM HYDROXIDE
AND USE THEREOF FOR QUATERNARY
AMMONIUM SALTS
2. Applicant(s)
(a) NAME : Dishman Pharmaceuticals & Chemicals Ltd.,
(b) NATIONALITY An Indian Company
(c) ADDRESS : Bhadr-Raj Chambers, Swastik Cross Roads,
Narvangpura, Ahmedabad 380 009
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which
it is to be performed:

unstable denatonium hydroxide intermediate. It is mentioned in GB 955,309 that the quaternary hydroxide is best used in the organic solvent in which it is prepared to produce the final quaternary ammonium compound of interest.
Because denatonium halides are known to be extremely bitter and highly contaminating compounds, every working step involving these compounds requires costly precautions to avoid contact while handling. This is especially the case where such a compound is isolated from its solvent environment. It is therefore an object of the present invention to provide a process for the preparation of quaternary ammonium salt, in particular denatonium benzoate or related salt, wherein the pure quaternary ammonium salt thus prepared meets the international standards set thereto, wherein the process lacks any superfluous isolation steps, wherein the solvent conditions throughout the process do not change significantly and where possible contact with the bitter compounds used in the process is minimized.
DESCRIPTION OF THE INVENTION
Accordingly the present invention relates to a process for the preparation of a quaternary ammonium hydroxide R+OH-, in which R+ has the formula:

(I)

in which Ri and R2 each independently represent an alkyl group containing from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl or n-butyl groups, and R3 represents a benzyl group or a substituted benzyl group, such as o- or p-chlorobenzyl, said process comprising forming an aqueous solution containing a quaternary ammonium halide having said cation R+ and said halide preferably being a CT ion, contacting said aqueous solution with

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hydroxide ions, to obtain a quaternary ammonium hydroxide and isolating said quaternary ammonium hydroxide.
In the process of the invention the quaternary ammonium hydroxide rather than the corresponding ammonium halide starting material is isolated. It is found that the purity of the hydroxide form has a direct effect on the quality of the final product to be prepared from this compound, but that the quaternary ammonium hydroxide is isolated much more straightforwardly than the halide form, despite the warnings for instability of the hydroxide given in GB 955,309. The invention takes advantage of the water insolubility of the quaternary ammonium hydroxide by exchanging the halide ions with hydroxide ions in an aqueous environment rather than in the organic, mostly alcoholic environment applied in the prior art.
It is considered unnecessary and even unwanted to subject the quaternary ammonium halide after formation to any purification and isolation steps other than extraction. The extraction step allows for the. removal of any starting materials or other impurities originating from the formation of the halide salt. It is considered economically favourable to provide the quaternary ammonium halide in the solvent in which it is prepared over a complete isolation of this compound using vacuum distillation and crystallization as taught in GB 955,309. Conveniently, the quaternary ammonium halide is provided in an aqueous environment which is preferably washed at least once with an organic solvent, preferably toluene. Preferably the aqueous solution provided to the reaction comprises quaternary ammonium halide in an amount between 30 wt% and 90 wt%, more preferably between 50 wt% and 75 wt%, based on the weight of the aqueous solution.
The source of hydroxide ions in the above-mentioned reaction can be caustic alkali or an ion-exchange resin in the hydroxide form. It is preferred that the hydroxide ions are provided by an aqueous caustic alkali solution, preferably a sodium hydroxide solution having a concentration of at least 40 wt% and up to 60 wt%, more preferably 45-55 wt%, most preferably 48-52 wt%, based on the
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weight of the solution. The reaction is preferably performed at atmospheric conditions and at temperatures between 10-50°C, more preferably between 20 and 40 °C, most preferably between 25 and 30 °C.
The quaternary ammonium halide and the hydroxide ions are provided in such relative amounts that there is an excess hydroxide ions over quaternary ammonium halide, "excess" meaning a molar ratio of hydroxide ions to quaternary ammonium halide higher than 1:1, preferably between 1.1:1 and 2:1, more preferably between 1.1:1 and 1.3:1.
Where it is mentioned that the reaction is performed in an aqueous environment, it is preferred that the solvent comprises at least 80 wt% of water, preferably at least 90 wt%, more preferably at least 95 wt% of water, based on the total weight of the solvent, and most preferably the solvent does not contain a detectable amount of organic solvent at all. With the "solvent" it is meant both the water provided by the aqueous solution containing the quaternary ammonium halide and the solvent containing the hydroxide ions.
Purification of the quaternary ammonium hydroxide involves washing with excess water to remove salts such as sodium or potassium hydroxide present in solution. Due to its aforementioned water-insolubility, the quaternary ammonium hydroxide precipitates as it forms, and the solid can be isolated in crystalline form by centrifugation and/or filtering techniques known to those skilled in the art.
The invention also relates to a denatonium hydroxide in its crystalline form, having a melting point between 150 and 160 °C, more preferably 150-157 °C, preferably having an off-white appearance, which can be obtained by the above described process.
The quaternary ammonium halide is preferably formed from the reaction of a tertiary amine of the formula:
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with a halide having the general formula R3halide, wherein R1, R2 and R3 each have the aforementioned meaning, and the halide being a F, CI, Br, I group, preferably a CI group, wherein the reaction is performed in aqueous conditions. It is preferred that the tertiary amine according to formula (II) is a lignocaine (co-diethylamino-2,6-dimethylacetanilide or lidocaine) compound, or a derivative thereof. The lignocaine is understood to comprise both its acidic and its free base form. When the R3-halide is highly reactive, the quaternising reaction may take place at room temperature. In most cases, however, it is necessary to employ heating, preferably involving a temperature between 50 and 100 °C, more preferably 70 - 90 °C. These conditions can readily be determined by those skilled in the art. As mentioned above, recovery of the contaminating quaternary ammonium halide is to be avoided. The halide salt thus obtained is washed at least once with an organic solvent, preferably toluene, to remove excess R3-halide and organic impurities.
In a preferred embodiment of the present invention the lignocaine compound or derivate thereof is brought into contact with a benzyl halide, preferably a benzyl chloride, which upon reacting yields denatonium chloride (Ri, R2 = ethyl: R3 = benzyl in formula (I)). Lignocaine, having the formula (II) in which Ri and R2 are ethyl groups, can for instance be prepared by reacting N-chloroacetyl-2,6-dimethylaniline with diethylamine in the presence of aqueous sodium carbonate. The preferred quaternary ammonium hydroxide of the present invention is a N-{2-[2,6-dimethylphenyl)-amino]-2-oxoethyl}-N,N-diethyl-benzenemethanaminium hydroxide or denatonium hydroxide, meaning that Ri and R2 are ethyl groups and R3 is a benzyl group in formula (I).
The process of the present invention allows for the production of an extremely bitter quaternary ammonium salt from a lignocaine compound in a one-pot synthesis involving mostly water, without the necessity to intervene in between
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through isolation of an intermediate compound, up to the point where quaternary ammonium hydroxide is obtained as a stable solid. Extensive contact with contaminating intermediate states and distillations at reduced pressure and high temperatures can thus be avoided.
The invention also relates to a process for the preparation of a quaternary ammonium salt having a benzoate, a hydrogen phthalate, a hydrogen tartrate, a hydrogen oxalate or a capsaicinate anion, or their substituted analogues, by reacting the corresponding isolated quaternary ammonium hydroxide of the invention with the conjugated acid of the anion, i.e. benzoic acid, pthalic acid, tartaric acid, oxalic acid or capsaicin, respectively, in the presence of an organic solvent such as methanol or acetone, preferably acetone. With the process of the present invention it is now possible to produce such quaternary ammonium salts with up to 50 % production time reduction.
The quaternary ammonium salt is preferably a denatonium benzoate, prepared from the reaction of a denatonium hydroxide according to the invention with benzoic acid, preferably using acetone as the solvent.
EXAMPLE 1 - Preparation of N-(2-[2,6-dimethylphenyl)-amino]-2-oxoethyl)-N,N-diethyl-benzenemethanaminium hydroxide (denatonium hydroxide)
250 gram (1.07 mol) of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (Lignocaine) was added to 600 ml of water at 30-35 °C. It was then slowly heated to 70-90 °C, followed by the addition of 175.4 gram (1.39 mol) benzyl chloride at 70-90 °C. The temperature was maintained at 70-90 °C for 20-24 hours while monitoring the reaction by thin layer chromatography for every 4 hours, until the remaining unreacted Lignocaine was less than 10%. The reaction mass was then cooled to 35-40 °C. The aqueous reaction solution was extracted with 100 ml of toluene (twice) at 35-40 °C. Approximately 920 gram of aqueous denatonium chloride solution was obtained. The assay was 50.7 % as measured by titrimetry.
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50% sodium hydroxide solution (129.3 gram sodium hydroxide in 129.3 ml water) was added hereto, i.e. 1.25 mol sodium hydroxide against 1 mol denatonium chloride, at 25-30 °C over a period of 3.0 hrs. The solid denatonium hydroxide was filtered and washed with 400 ml demineralized water and finally with 50 ml acetone.
After drying the residual product weighed 255 gram (Assay 98.75% by titrimetry, melting range 151 - 155°C, off-white crystals; LOD