FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR TRIMETHOBENZAMIDE"
Emcure Pharmaceuticals Limited.
an Indian Company, registered under the Indian Company's Act
1957 and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of trirnethobenzamide hydrochloride conforming to regulatory specifications. Specifically, the invention relates to a process for preparation of trirnethobenzamide hydrochloride, which is free from the associated impurities that are normally encountered during coupling of 4-(2-dimethylaminoethoxy) benzyl amine with 3,4,5-trimethoxy benzoic acid.
BACKGROUND OF THE INVENTION
Trirnethobenzamide of formula (I), chemically known as N-[(2-dimethylaminoethoxy) benzyl]-3,4,5-trimethoxybenzamide is administered as its hydrochloride salt (Ia) and is used as an antiemetic agent for nausea associated with gastrointestinal disturbances, motion sickness or induced by the administration of other therapeutics agents.

Trirnethobenzamide hydrochloride for administration as an injection (100 mg/ml) was approved by USFDA on January 1, 1982 under the brand name 'TIGAN' Later, on December 13, 2001, it was approved for administration as an oral capsule (300 mg).
Various researchers have attempted to synthesize trirnethobenzamide hydrochloride of formula (la).

US 2,879,293 disclose a method for preparing trimethobenzamide hydrochloride comprising reaction of 4-(dirnethylaminoethoxy)benzylamine with 3,4,5-trimethoxybenzoyl chloride in presence of organic solvent such as benzene or acetonitrile. 4-(Dimethylaminoethoxy)benzylamine in turn, was prepared by refluxing 4-hydroxybenzaldehyde with 2-dimethylaminoethylchloride in chlorobenzene as solvent to obtain 4-(dimethylaminoethoxy)benzaldehyde, which on reductive animation gave 4-(dimethylaminoethoxy)-benzylamine.
However, it should be noted that the use chlorobenzene for reaction between 4-hydroxy benzaldehyde with 2-dimethylaminoethylchloride at high temperature generated an impurity of the formula (II) which was extremely difficult to remove in the subsequent stages of trimethobenzamide synthesis.
Further, the use of thionyl chloride as an acid activating agent for 3,4,5-trimethoxybenzoic acid, during coupling reaction with 4-(dimethylaminoethoxy)-benzylamine at high temperatures, is likely to give an associated impurity of compound of formula (VI).

US 4,983,633 disclose a method for preparing trimethobenzamide hydrochloride comprising reaction of acid halides, acid anhydrides or mixed anhydrides of 3,4,5-

trimethoxybenzoic acid with 4-(dimethylaminoethoxy)-benzylamine in presence of organic solvents and a base. However, the specification does not disclose any purity of the final product and further duplication of these experiments at our laboratory resulted in formation of desmethyltrimethobenzamide of formula (III) due to the elimination of one of N-methyl group during reductive ammonation reaction, which is very difficult to eliminate from the final product with out affecting the yield.

Therefore, it was necessary to significantly minimize or eliminate formation of desmethyl trimethobenzamide impurity during the preparation of trimethobenzamide.
US 4,507,499 relates to a method for producing trimethobenzamide hydrochloride wherein, a chloromethylation reaction is carried out on anisole in presence of hexamethylenetetramine followed by acidic hydrolysis to provide 4-hydroxybenzylamine hydrochloride, which on further reaction with 3,4,5-trimethoxybenzoic acid chloride gave N-(4-hydroxybenzyl)-3,4,5-trimethoxybenzamide. Further the reaction with sodium hydride and N,N-dimethylaminoethylchloride in toluene provided trimethobenzamide hydrochloride. The utilization of sodium hydride requires anhydrous conditions as contact with moisture results in inflammable condition, which would be difficult to control on an industrial scale.
US 7,256,312 disclose a method for preparing 4-[2-(dimethylamino)-ethoxy] benzylamine by treating 4-chlorobenzonitrile with an alkali metal salt of 2-dimethylaminoethanol to give 4-[2-(dimethylamino)ethoxy]benzonitrile, which on catalytic hydrogenation gave 4-(dimethylaminoethoxy)benzyl amine. A major disadvantage of the method was the generation of desmethyl-4-

(dimethylaminoethoxy)-benzylamine impurity of formula (IV) which was difficult to remove in the subsequent steps of synthesis.

Chem. Pharm. Bull. 40(1) 202-211 (1992) discloses a method by reaction of 3,4,5-trimethoxybenzoic acid, thionyl chloride and 4-(dimethylaminoethoxy)-benzylamine in presence of chloroform and triethylamine with a yield of 83% but without any mention about the level of impurities that are likely to be formed in the subsequent steps. Further, it requires several crystallizations for minimizing the associated impurities below the regulatory limits. Hence, there is need to develop an efficient process for trimethobenzamide.
Journal of Labelled Compounds (January-March) vol VI, No.l, 1970 discloses a method to prepare trimethobenzamide from 4-bromophenol and 2-dimethylaminoethyl chloride. The 4-(2-dimethylaminoethoxy)-l-bromobenzene thus obtained was converted to 4-(2-diinethylaminoethoxy)-l-benzoic acid through Grignard reaction. Further, amidation and reduction with lithium aluminum hydride (LAH) gave 4-(2-dimethylaminoethoxy)-l-benzyl amine, which on subsequent treatment with 3,4,5-trimethoxybenzoyl chloride gave N-[4-(2-dimethylaminoethoxy)-benzyl]-3,4,5-trirnethoxybenzamide hydrochloride in an overall yield of 29%. Due to the generation of associated impurities, the obtained product required several crystallizations or chromatographic purification to get pure trimethobenzamide. Several purifications coupled with low yield rendered the method unfeasible for industrial scale.

WO 2006051079 application disclose a method to prepare 4-(dimethylamino ethoxy)-benzaldehyde from toluene solution of 2-dimethylaminoethylchloride, 4-hydroxy benzaldehyde, potassium carbonate and phase transfer catalyst (PTC) catalyst (tetrabutylammonium bromide) in ethyl acetate as solvent. However, the use of biphasic condition results in an emulsion during work-up, which subsequently reduces the yield. Therefore, there is need to develop an industrially applicable process for prepare of 4-(dimethylaminoethoxy)-benzaldehyde and trimethobenzamide.
Thus, there is a need to develop a process for the preparation of trimethobenzamide hydrochloride (la), which reduces the formation of impurities below regulatory limits and does not require column chromatography or repeated crystallization for getting the desired purity.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for preparation of trimethobenzamide hydrochloride, which is free from associated impurities and does not utilize column chromatography or other purification methods.
Another object of the present invention is to provide a process for preparation of trimethobenzamide free from associated impurities of formula (II), (III) and (IV) by condensation of N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) with 4-(dimethylaminoethoxy)benzyl amine.


Another object of the present invention is to provide a process for preparation of 4-(dimethylaminoethoxy)benzaldehyde free from impurity of formula (II) which finally gives trimethobenzamide conforming to regulatory specifications.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to an improved process for preparation of trimethobenzamide hydrochloride free from desmethyl trimethobenzamide impurity of formula (III), comprising reaction of N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) with 4-(dimethylaniinoethoxy)benzyl amine in an organic solvent and further treating the resulting trimethobenzamide with paraformaldehyde and formic acid in a second organic solvent and isolating trimethobenzamide of desired purity by extracting the reaction mixture with ethyl acetate and adding an anti-solvent.
Another aspect of the present invention relates to a process for the preparation of 4-(dimethylaminoethoxy) benzaldehyde free from impurity of formula (II) by reaction of 4-hydroxybenzaldehyde with 2-(dimethylamino)ethyl chloride in an organic solvent and in presence of an inorganic base, isolating the product by quenching with aqueous inorganic acid, extracting with ethyl acetate, adjusting the pH of the separated aqueous layer between 8.5 and 9.5, extracting with ethyl acetate and concentrating the mixture,
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have found that the coupling reaction of 4-(dimethylamino ethoxy)benzyl amine with 3,4,5-trimethoxybenzoyl chloride in presence of organic solvent resulted in formation of associated impurities, such as desmethyltrimethobenzamide of formula (III) and dimer impurity of formula (VI).
The present inventors have unexpectedly found after several experiments that associated impurities like unreacted starting material and intermediates could be

eliminated by utilizing N,N-carbonyldiimidazole (CDI) as the activating group for the
condensation.
The present inventors found that the reaction between 4-(dimethylamino
ethoxy)benzyl amine and 3,4,5-trimethoxybenzoic acid activated with carbonyl
diimidazole was quite facile and resulted in minimal formation of the dimer impurity
of formula (VI).
Further, any formation of the desmethyl trimethobenzamide impurity of formula (III) formed during the preceding steps could be eliminated by treating the impure trimethobenzamide of formula (I) with a combination of paraformaldehyde and formic acid to provide trimethobenzamide of the desired purity. The resulting trimethobenzamide base thus formed was found to be conforming to regulatory specification. In this manner, an impurity which normally ought to be removed for getting the desired purity was converted to the desired product without compromising on yield and purity. It should be noted that an additional step of purification for removing the impurity of formula (III) would have resulted in a lower yield, which however is not the case in this method. Thus, an additional step of purification, which could considerably lower the yield, was avoided.
In an embodiment, the present invention relates to a process for preparation of trimethobenzamide by reaction of 4-(dimethylaminoethoxy)benzyl amine with N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) in an organic solvent in presence of base. The synthetic sequence for trimethobenzamide is represented in Scheme L


Scheme-I: Route of synthesis for preparation of Trimethobenzamide
In another embodiment, the present invention relates to a process for preparation of N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) is obtained by reaction of 3,4,5-timethoxy benzoic acid with N,N-carbonyldiimidazole (CDI) in an organic solvent to give N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) (Scheme II).


Scheme-II: Synthesis of N-(3,4,5-Trimethoxybenzoyl)imidazoIe (Formula V)
In a further embodiment, the inventors also found that when a relatively low boiling ethers were employed for carrying out the reaction between 4-hydroxy benzaldehyde and 2-(dimethylamino)ethyl chloride, the formation of an associate impurity with formula (IV) was found to be lower than prior art methods.
The detailed reaction process for trimethobenzamide is described in the following steps:
1. reaction of 4-hydroxy benzaldehyde with 2-(dimethylamino)ethylchloride and inorganic base in an organic solvent,
2. reductive amination of 4-(dimethylamino ethoxy)benzaldehyde to give 4-(dimethylaminoethoxy)benzylamine,
3. coupling of 4-(dimethylaminoethoxy)benzylamine with N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) in presence of an inorganic base and in an organic solvent followed by treatment with paraformaldehyde and formic acid to give trimethobenzamide free base of desired purity, which is then converted to its hydrochloride salt conforming to regulatory specifications.

The coupling of 4-hydroxy benzaldehyde with 2-(dimethylamino)ethyl chloride in an organic solvent was carried out at about 90°C in presence of an inorganic base selected from carbonates preferably sodium carbonate.
The solvent for the coupling reaction is selected from the group comprising of ethers like tetrahydrofuran, 1,4-dioxane etc.
Prior art methods utilizing chlorobenzene or high boiling aromatic hydrocarbon solvents for reaction between 4-hydroxy benzaldehyde with 2-dimethylamino ethyl chloride generate impurity of the formula (II) and is very difficult to remove in the subsequent stages. Therefore, the present inventors have developed a method wherein the formation of impurity of formula (II) is eliminated or reduced below regulatory limits.
After completion of reaction, 4-(dimethylamino ethoxy)benzaldehyde was obtained from aqueous work up of reaction mixture. The reaction mixture was quenched with aqueous inorganic acid and ethyl acetate and the pH of the aqueous layer was adjusted between pH 8.5 and 9.5 and extracted with ethyl acetate, which was then concentrated and concentrated to provide a viscous liquid, which had impurity levels below the prescribed limits. The control of impurities in this reaction was possible due to the low temperature of the reaction at 90°C as well as the isolation of 4-(dimethylaminoethoxy)-benzaldehyde at a pH between 8.5 and 9.5 due to which the impurities got partitioned into the aqueous phase during extraction with ethyl acetate.
4-(Dimethylaminoethoxy)benzaldehyde thus obtained was reduced with Raney- nickel in presence of ammonia and methanol as solvent to give 4-(dimethylaminoethoxy)benzyl amine.
4-(Dimethylaminoethoxy)benzyl amine reacts with N-(3,4,5-trimethoxybenzoyl) imidazole of formula (V) in presence of an inorganic base and an organic solvent;

further the reaction is treated with paraformaldehyde/formic acid in presence of ester as solvent.
Since, prior art references reveals that the reductive ammoniation reaction in presence of Raney-nickel results in formation of impurity of compound of formula (IV) and the presence o'f this impurity in the final stage coupling with N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) results in formation of impurity of formula (III) i.e. desmethyltrimethobenzamide, which is very difficult to eliminate by simple crystallization method. Additionally, the presence of desmethyltrimethobenzamide of formula (III) in the final step, reacts with N-(3,4,5-trimethoxybenzoyl)imidazole to another impurity of the formula (VI).
Thus, the present inventors after carrying out several experiments unexpectedly discover a method to convert the desmethyltrimethobenzamide impurity by methylation at the nitrogen atom to trimethobenzamide; the resulting product shows all the associated impurities below the regulatory limits.
The elimination of impurity by converting desmethyltrimethobenzamide by methylation in presence of paraformaldehyde/formic acid is an essential part of the invention involving isolation of trimethobenzamide hydrochloride.
Therefore, the present inventors have established a process wherein trimethobenzamide is isolated after treatment with paraformaldehyde/formic acid.
Another embodiment of the present invention provides a method to preparation of N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) comprising reaction of 3,4,5-timethoxy benzoic acid with N,N-carbonyldiimidazole (CDI) in presence of organic solvent.

The organic solvent was selected from the group comprising of ketone, esters, ethers etc. but preferably ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK).
The reaction was carried out at a temperature between 50 and 60°C utilizing a solvent such as ethyl acetate.
After completion of reaction, the reaction mixture was quenched with water and the organic layer after separation was concentrated and the residue thus obtained was dissolved in a ketone solvent such as acetone and treated with a mixture of formaldehyde and formic acid. The mixture was heated gently to 50-55°C and after filtration to remove un-dissolved impurities was concentrated to provide a residue. The residue thus obtained was isolated from a mixture of ethyl acetate and aliphatic hydrocarbon like cyclohexane as anti-solvent to give trimethobenzamide base of desired purity and conforming to regulatory specifications.
In a further embodiment, trimethobenzamide was isolated and then treated with a mixture of formaldehyde and formic acid as mentioned earlier.
Trimethobenzamide free base (I) was then converted to its hydrochloride salt by treating with alcoholic hydrochloric acid to give trimethobenzamide hydrochloride of desired purity and yield.
A further advantage of the invention is that the present invention did not utilize multiple crystallization or column chromatography for purification trimethobenzamide free base as reported in prior art methods, which reduces burden on environment and in turn has a salutory effect on production cost.

Furthermore, the invention provides a process for preparation of trimethobenzamide hydrochloride, which eliminates the presence of desmethyltrimethobenzamide or impurity of formula (VI) and other associated impurities in the final product as compared to prior art methods.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
EXAMPLE:
Example 1: Preparation of 4-(dimethylamino ethoxy)-benzaIdehyde:
4-Hydroxy benzaldehyde (500 gms; 4.09 moles), sodium carbonate (1519 gms; 14.33 moles) and 2-(dimethylamino)ethylchloride (1003.0 gms; 6.96 moles) were added to 1,4-dioxane at 25°C to 30°C with stirring. The reaction mixture was heated to 97-105°C till completion of reaction as monitored by HPLC. The mixture was cooled to 25°C to 30°C and filtered. Water (1000 ml) was added to the filtrate and partially concentrated the mixture under reduced pressure. Aqueous hydrochloric acid (300 ml) was added to the concentrated solution at 10-20°C. The aqueous layer was separated and the pH of the aqueous layer was adjusted to 8,5 to 9.5 with sodium hydroxide solution. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. Methanol (500ml) was added to the concentrated residue and concentrated to give the pure viscous product. Yield: 380 gms Purity > 99.5%
Example 2: Preparation of 4-(dimethylamino ethoxy)-benzylamine:

4-(Dimethylaminoethoxy)-benzaIdehyde (500 gms), Raney-nickel (75 gms; 15 %) and methanolic ammonia (3000 ml; 20% solution) were taken in a pressure reactor and heat to 50-55°C for 8 hours at hydrogen pressure 8-10 kg / cm2. After reaction completion as monitored by HPLC, the mixture was cooled to 25°C to 30°C and filtered. The filtrate was concentrated under reduced pressure to provide a pure viscous oily material. Yield: 400 gms Purity > 99.4%
Example 3: Preparation of N-(3,4,5-trimethoxybenzoyl) imidazole of formula (V):
3,4,5-Trimethoxy benzoic acid (100 gms; 0.47 moles), N,N-carbonyldiimidazole (CDI 95.6 gms; 0.589 moles) and ethyl acetate (600 ml) were added to a flask and heated to a temperature of 50-55°C for 2 hours. After reaction completion as monitored by HPLC, the mixture was cooled to 30°C to 35°C and carried forward to the next stage.
Example 4: Preparation of trimethobenzamide:
4-(Dimethylaminoethoxy)benzyl amine (101 gm; 0.52 moles), potassium carbonate (65.14 gms; 0.47 moles) were added to ethyl acetate (600 ml) at 25°C to 30°C under nitrogen atmosphere. A mixture of N-(3,4,5-rrimethoxybenzoyl) imidazole (prepared in example 3) was added to the above reaction mixture at 5-30°C and stirrer for 2.5 hours. Additional water (100ml) was added to the reaction mixture and heated to 55-60°C for 30 minutes. After completion of reaction, the reaction mixture was filtered and the organic layer separated and concentrated under reduced pressure. The residue was dissolved in acetone (150 ml) and treated with paraformaldehyde (1.74 gm) and formic acid (2.66 gm) at 50-55°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Trimethobenzamide of desired purity was isolated from a mixture of ethyl acetate and cyclohexane. Finally trimethobenzamide was converted to its hydrochloride salt by utilizing acetone and aqueous hydrochloric acid solution.

Yield: 100 gms, Purity > 99.5%.
Example 5: Preparation of N-(3,4,5-trimethoxybenzoyl) imidazole of formula (V): 3,4,5-Trimethoxy benzoic acid (100 gms; 0.47 moles), N,N-carbonyldiimidazole (CDI 95.6 gms; 0.589 moles) and ethyl acetate (600 ml) were added to a flask and heated to a temperature of 50-55°C for 2 hours. After reaction completion as monitored by HPLC, the mixture was cooled to 30°C to 35°C and the pure N-(3,4,5-trimethoxybenzoyl) imidazole isolated from the reaction mixture by concentration of organic solvent under reduced pressure. Yield: 110 gms Purity > 99.5%

We Claim,
1. A process for preparation of trimethobenzamide hydrochloride comprising,

a) reaction of 4-hydroxybenzaldehyde with 2-(dimethylamino)ethyl chloride in an organic solvent and in presence of an inorganic base and quenching reaction mixture with aqueous inorganic acid, extracting with ethyl acetate, at pH between 8 & 9 and isolating 4-(dimethylaminoethoxy) benzaldehyde,
b) treating 4-(dimethylaminoethoxy)-benzaldehyde with raney nickel in methanolic ammonia,
c) coupling 4-(dimethylaminoethoxy)-benzylamine with N-(3,4,5-trimethoxybenzoyl)imidazole of formula (V) in presence of inorganic base in an organic solvent, quenching with water, concentrating the organic layer and
d) treating with paraformaldehyde and formic acid in an organic solvent and isolating trimethobenzamide hydrochloride.

2. The process as claimed in claim 1(a) wherein the organic solvent is a cyclic ether and is selected from tetrahydrofuran and 1,4-dioxane.
3. The process as claimed in claim 1(d) wherein the organic solvent is a ketone and is selected from the group comprising of acetone, methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK).

4. The process as claimed in claim 1(c) wherein the process for preparing N-(3,4,5-trimethoxyberizoyl)irnidazole (formula V) comprises,

reaction of 3,4,5-trimethoxy benzoic acid with N,N-carbonyldiimidazole (CDI) in presence of an organic solvent.
5. The process as claimed in claim 4 wherein the organic solvent is selected from the group comprising of ester, alcohol, and ether,
6. The process as claimed in claim 4 & 5, wherein the organic solvent is an ester is selected from the group comprising of ethyl acetate and isobutyl acetate.
7. A process for preparation of trimethobenzamide hydrochloride free from desmethyl trimethobenzamide (Formula III) impurity comprising reaction of N-(3,4,5-trimethoxyben2oyl)imidazole of formula (V) with 4-(dimethylaminoethoxy)benzyl amine in an organic solvent and further treating the resulting trimethobenzamide with paraformaldehyde and formic acid in a second organic solvent and isolating trimethobenzamide hydrochloride.

8. The process as claimed in claim 1 and 7, wherein the trimethobenzamide hydrochloride obtained is free from impurities of formula (II), (III), (IV) and (VI)