Field of the invention:

The present invention relates to a process for preparing highly pure Meprobamate of formula (I).

Background of the invention:

The chemical name of Meprobamate is 2-Methyl-2-propyl-1,3-propanediol dicarbamate. The current pharmaceutical product containing this drug is being sold by WATSON LABS and Alembic using the tradename Meprobamate, in the form of tablets oral. The drug is also sold using tradename Miltown, Petranquil, Equanil and Cabaxin in the form of tablets.

Meprobamate is a compound of tranquillising action with indication in anxiety neurosis, over work, mental strain, sleeplessness etc. Meprobamate is used as Anxiolytic and Anticonvulsant. It is used as antidepressant.

US patent 2724720 describes a process for the preparation of Meprobamate. The synthetic reaction is as shown in below Scheme-I

Scheme-I
The known process for preparing this substance are based upon the phosgenation of 2-methyl-2-n-propyl-1,3-propandiol to form corresponding dichlorocarbonate derivative, followed by ammoniation of the dichlorocarbonate derivative to form the desired dicarbamate, using anhydrous ammonia or aqueous ammonium hydroxide as suitable sources of ammonia for the purpose. This is purified by recrystallisation to give pure Meprobamate. The above process is not much suitable at industrial scale as it requires multiple purification steps in final compound which lowers the overall yield.

The intermediate for Meprobamate is generally prepared by following synthetic route which is well known in the art.

Scheme-II
In this process, two molecule of n-propanaldehyde (IV) reacts in presence of sodium hydroxide to give 2-methylpent-2-enal (V). The double bond is reduced to form 2-methylpentanal(VI). Which on reaction with formaldehyde and sodium hydroxide gives intermediate 2-methyl-2-n-propyl-1,3-propandiol (II). This intermediate is used for preparation of Meprobamate (I).

The above process generally imparts impure intermediate (II) and in turn impure Mepromate (I) having impurity which may be formed due to unhydrogenated compound present and which is carry forwarded to the next steps of process. The possible impurities generated are 2-methyl-2-propene-1,3-propanediol (Impurity-I) and 2-methyl-2-propene-1,3-propanediol dicarbamate (Impurity-II). However, Impurity-I is being converted to Impurtiy II over number of steps of subsequent reactions.

After hydrogenation of 2-methylpent-2-enal, any unreacted starting material remained is proceeded to condensation with formaldehyde which generates 2-methyl-2-propene-1,3-propanediol (Impurity-I). This impurity further reacted in next steps to give 2-methyl-2-propene-1,3-propanediol dicarbamate (Impurity-II). The generated impurities are difficult to remove by multiple crystallization process. For a pharmaceutical drug it is very important to get highly pure compound. It is therefore, a need to develop a smooth and industrially feasible process for preparing Meprobamate wherein highly pure product is obtained. Further, this process should ensure the formation of impurity to a minimum desirable level. The present invention addresses these needs.

Present inventors have directed their research work towards developing a process for the preparation of Meprobamate which is devoid of the above disadvantages. The present inventors developed a process to produce highly pure intermediate which in turn increased the purity of Meprobamate without affecting the yield.

Summary of the invention:
Accordingly, it is an object of the present invention to provide a process for preparing highly pure Meprobamate (I).

Another object of the present invention is to provide highly pure intermediate which is used for the synthesis of Meprobamate (I).

Another object of the present invention is to provide a process for preparation of highly pure 2-methyl-2-n-propyl-1,3-propandiol (II) which the process is operationally simple and cost effective.

Accordingly, present invention provides a process for preparation of highly pure Meprobamate (I)

comprising a step of purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process and optionally crystallizing it.

Accordingly, present invention provides a process for preparation of Meprobamate (I)

comprising
(i) purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process

and optionally crystallizing it;
(ii) converting pure 2-methyl-2-n-propyl-1,3-propandiol (II) to Meprobamate (I) by phosgenation and amination.

Accordingly, present invention provides a process for preparation of Meprobamate (I) having impurities not more than 0.01%

comprising a step of purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process and optionally crystallizing it.

Detailed description of the invention:
The present invention provides a process for preparation of highly pure Meprobamate (I)

comprising a step of purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process and optionally crystallizing it.

The synthetic reaction scheme of the present invention is shown in the scheme-III.

Scheme-III
The process of present invention relates to preparation of highly pure Meprobamate. The present invention also relates to preparation of pure 2-methyl-2-n-propyl-1,3-propandiol (II) which is used as an intermediate for the preparation of Meprobamate.

The process for purification of impure 2-methyl-2-n-propyl-1,3-propandiol (II) involves reduction process wherein the impurity containing unsaturation at carbon double bond is being reduced to give saturated desired compound.

The term “impure” refers to a compound having impurity equal or greater than 0.1%.
The reduction process refers to all the commonly known processes wherein reduction of double bond is taking place using reducing agents. The reduction includes hydrogenation using nobel metal catalyst such as raney Ni, Pd. Pt, Ru, Rh optionally supported on carbon or charcoal. The metal can be neutral or having varying valency. For example Pd(0) or Pd(II). The reduction also includes use of reducing agents such as sodium borohydride, Lithium aluminum hydride, diborane, 9-BBN and the like.

The reduction step is performed in the presence of suitable solvent and reducing agents. The preferred reduction step involves hydrogenation using metal catalyst such as raney nickel in suitable solvent.

The examples of solvent are selected from a group comprising polar protic solvent such as alcohols, water, or polar aprotic solvent such as nitriles, ketones, DMF, DMSO. The solvent can be used alone or mixture of two polar solvent or in combination with other aprotic nonpolar solvent such as hydrocarbons. Alcohols used herein above are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol etc. Nitriles used herein above are selected from acetonitrile, benzonitrile. Ketones used are acetone, methylethyl ketone. Hydrocarbons used herein above are selected from THF, diethyl ether, toluene, xylene etc. The preferred solvent is methanol or ethanol.

The hydrogenation can be performed at ambient temperature of at elevated temperature applying hydrogen gas pressure about 4-5 kg. Generally the reaction completes within 3 to 4 hours. The progress of the reaction is monitored on thin layer chromatography (TLC). After completion of reaction, the reaction mixture is filtered through hyflo bed. The filtrate is distilled out under vaccum. The pure residue is used as such in next reaction step.

Pure 2-methyl-2-n-propyl-1, 3-propandiol (II) is phosgeneated in suitable solvent and in presence of base. A mixture of pure 2-methyl-2-n-propyl-1, 3-propandiol (II), solvent and base is cooled to a temperature of about -5°C to 0°C and liquid phosgene is added. The reaction mixture is stirred at 0-15°C for 2 to 2.5 hours to give 2-methyl-2-n-propyl-1, 3-propandiol dichloro carbonate intermediate.

Base is selected from the organic base or inorganic base. Organic bases are selected from triethyl amine, methylamine, diethyl amine and the like or mixtures thereof. Inorganic bases are selected from NaOH, KOH, LiOH, NaHCO3, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, Mg(OH)2, Ca(OH)2, CaCO3 and the like or mixtures thereof..

The solvent is selected from the group comprising aromatic hydrocarbon, chlorinated solvents such as toluene, xylene, dichloromethane, dichloroethane and the like or mixtures thereof.

2-methyl-2-n-propyl-1, 3-propandiol dichloro carbonate obtained above is reacted with ammonia solution to give Meprobamate.
Meprobamate is optionally recrystallised from methanol/water to give highly pure meprobamate.
Highly pure meprobamate is having impurity not more than 0.01%, preferably not more than 0.002%.

The advantage of this process is that the impurity which is difficult to remove by repeated crystallization is removed by this reduction process. Especially the impurities containing double bond gets reduced and is absent in final Meprobamate prepared by the process of the present invention. The advantage of the present invention can be understand from the following data depicted in Table-1

Table-1

Meprobamate
Prior art process
Present invention
% of impurity present 0.1% 0.002%
Yield ~80% ~90%

The process of the present invention has following advantages:

(i) Avoid multiple purification in final step to remove impurities.
(ii) Increase overall yield and purity of final compound.
(iii) Cost effective.
(iv) Easy isolation process.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example-1
Purification of 2-methyl-2-propyl-1,3-propane diol (II)
2-methyl-2-propyl-1,3-propane diol (100.0 g) was dissolved in methanol (300 ml) and was charged in hydrogenator. Catalyst Raney nickel (6.0g) was charged with methanol (50 ml) to hydrogenator. The hydrogenator was flushed with nitrogen gas and then flushed with hydrogen gas. The hydrogen gas was purged at 5.0 Kg pressure and 25-35°C temperature. Pressure and temperature in hydrogenator was maintained for 3-4 hrs. After completion of reaction was on GC, the reaction mixture was filtered through hyflobed. The hyflobed was washed with methanol. The filtrate and washings were combined and distilled under vaccum to give residue. This residue was used as such for the next step.

Example-2
Preparation of 2-methyl-2-n-propyl-1, 3-propanediol dichlorocarbonate (III)
The residue of previous step was dissolved in toluene (500.0ml) and triethylamine (153.33g) was charged at ambient temperature and stirred till clear solution was obtained. Phosgene gas (150.0 g) was purged at -5°C. The gas was passed till approximately 150.0 g weight of the reaction mixture was increased. The reaction mixture was stirred at -15°C for 2 hours. After completion of the reaction mixture, the solvent was evaporated to give Liquid title product (155.0 g)

Example-3
Preparation of 2-methyl-2-n-propyl-1, 3-propanediol dicarbamate (Meprobamate final) (I)
2-methyl-2-n-propyl-1,3-propanediol dichlorocarbonate (120.0 g) was charged in ammonia solution (340 ml) at ambient temperature and was stirred for half an hour to one hour. The reaction mixture was chilled to 5-10°C. The reaction mass was stirred at this temperature for one hour. The solid material was filtered and washed with water. The wet cake was crystallized in methanol /water (60.0ml/140.0ml) mixture. The material was dried at 60°C under vacuum to give the title product Meprobamate (94.0 g).
Purity by HPLC: 99.9%

We claim:
1. A process for preparation of highly pure Meprobamate (I)

comprising a step of purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process and optionally crystallizing it.

2. A process for preparation of Meprobamate (I)

comprising
(i) purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process

and optionally crystallizing it;
(ii) converting pure 2-methyl-2-n-propyl-1,3-propandiol (II) to Meprobamate (I) by phosgenation and amination.

3. A process for preparation of Meprobamate (I) having impurities not more than 0.01%

comprising a step of purifying impure 2-methyl-2-n-propyl-1,3-propandiol (II) by reduction process and optionally crystallizing it.

4. A process according to any preceding claims, wherein reduction process includes hydrogenation using nobel metal catalyst or by reacting with reducing agents.

5. A process according to claim 4, wherein nobel metal catalyst are selected from raney Ni, Pd. Pt, Ru, Rh or mixtures thereof.

6. A process according to claim 5, wherein reduction is done by hydrogenation using raney nickel and hydrogen gas.

7. A process according to claim 2, wherein phosgenation is done using phosgene and amination is done using ammonia.

8. A process according to any preceding claims, wherein crystallization of Meprobamate is done from methanol /water.