FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION (Sec Section 10)
MHTHOD OF PRODUCING 2, 2-DISUBSTITUATED I, 3- PROPANEDIOL
DICARBAMATE
HARMAN FINOCHEM LIMITED, 107, Vinay Bhavya Complex, 1st Floor, 159-A, C.S.T. Road, Kalina, Mumbai 400098, Maharashtra, India, Indian National
Thc following spccification particularly describes the invention and the manner
in which it is to be performed.

This invention relates to a method of producing 2, 2-disubstituatcd 1,3- propanediol dicaramatc. Particularly the invention relates to an improved method for producing 2-Methyl-2-propyl 1,3-propanediol dicaramate , known as Meprobamate. More particularly the invention relates to an improved high yielding method. Further, the method is cost effective and capable of yielding highly pure title compound.
BACKGROUND OF INVENTION:
Meprobamate is a tranquilizing drug that act as a depressant of the central nervous system and is commonly used in the treatment of anxiety and sometimes Schizophrenia.
Although Meprobamate is chemically unlike barbiturates and has lower toxicity, it has similar pharmacological effects, especially the ability to introduce sleep and alleviate anxiety. The drugs possess to suppress some forms of epilepsy.
A muscle relaxant, Meprobamate is also used to treat abnormal motor activity.
Meprobamate was first synthesized by Bernie Ludwig at carter products in 1950, Wallace Laboratories brought the License and named it Miltown.in 1955 which rapidly became a best seller and famous in the popular media as 'Happy Pills'. Later it was listed as a controlled substance after it was discovered to cause physical and psychological dependence.
It is already known in the prior art to convert dihydric alcohol to the corresponding dicaramate. The literature teaches various methods by which one can synthesizes these dicarbamate from their respective diol. These are by phosgene and ammonia, by Urea/ metal acetate catalyst, by Ethyl urethane/ Al Alkoxide & by Sodium cyan ate/ MCI gas.
The relevant prior art known to the applicant includes publication titled "Some Anticonvulsant Agents Derived from 1, 3-Propanediols" by Ludwig et al, vol. 73, 5779-5780, December 1951. According to the disclosure in the said article, method described by Cook in the opinion of the Author is most suitable for conversion of dihedric alcohols to corresponding dicarbamate derivatives. The method as described

by Cook comprises low temperature phosgenation of diol in inert solvent in presence of tertiary amine followed by conversion of bis (chlorocarbonate) thus produced to desired diamide by direct ammoniation. Since the alkyl groups remain in solution, dicarbamates of diols substituted with higher alkali poses problems in the isolation of final product. The Author opines that employing antipyrine is advantageous over amine in getting consistently overall higher yields of pure product. Generally, the inert solvent used is toluene.
US 2,724,720 related to dicarbamates per-se, reported the synthesis of Meprobamate by reaction of diol with phosgene in presence of acid combining compound selected from sodium hydroxide, antipyrine, dialkylaniline to produce chlorocarbonates followed by ammoniation to get dicarbamates. The solvents illustrated are toluene, acetone, and antipyrine. The yield is 60 to 70%. The process gives relatively low yields of impure product
US 2,806,053 reported the synthesis of meprobamate wherein the improvement resides in low temperature phosgenation in THF and reaction with ammonia containing sodium sulphite. This helps in improving yield and ensuring a white product.
Chim. Ind. 40, 13-15 (1958) reported the synthesis of meprobamate from diol by reaction with Urea in the presence of acetates salts of Pb & Zn. The drawback associated with the process is that the process is cost extensive and yields are unsatisfactory.
US 2,837,560 reported the synthesis of meprobamate from diol by reaction with Urea. The patent claims to produce dicarbamate with increased yield and greater ease of purification by employing reactive solvents such as alkanols having boiling points between 64°C to 150°C, preferably butanol and aluminum alkoxide, cupric acetate particularly Al. isopropoxide as a catalyst. The products are crystallized from volatile liquids and then isolated by filtration, centrifugation and drying. However the products obtained have rather low bulk density that in turn results in poor flowability and poor compressibility and thus proving to be unsuitable for preparing tablets in addition to increase in cost due to incorporation of costly expedients.
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Brit. 797,474 reported the synthesis of diol from its diesters by reduction with LiAIH4 and then its reaction with phosgene and Ammonia in toluene
Dan. 86,257 reported the synthesis of meprobamate by reaction of diol with urethane in the presence of Al alkoxide
US 2,857,680 & US 2, 857,681 teach about the polymorphism of meprobamate to increase the bulk density by performing drying in a specific manner.
US 2,917,535 describes the exchange of methyl carbamate with diol in the presence of inert solvent capable of forming binary azetrope withwith alkyl calbamate. The process also advocate using Al isopropoxide by azeotropically distillation of alcohol.
Formaco (Pavia) Ed. Sci. 11, 1014-17 (1956) teaches about the transesterification of diol with ethyl urethane in the presence of Al propylate
Indian Patent 67,983 describes the synthesis by reaction of diol with urea in the presence of Cu acetate
Fr. 1,443,093 describes the synthesis with urea in the presence of Zinc Acetate
J. Med. Chem. 1969, 12(3), 462-472 describes the various routes for the synthesis of 2-substitutcd-1, 3-propanediol dicarbamate
Arch Pharma (Weinheim Ger) 1981, 314 (5), 398-408 describes the different polymorph of meprobamate by re-crystallisation in water
J. Am. Chem. Soc. 73, 5779 (1951) describes the disubstited derivatives of 1, 3-propandiols
J.Org. Chem., 28, 3421 (1963) describes the improved synthesis of carbamate by cynic-acid route
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C11 359126(1956)
This patent describes the synthesis of meprobamate by reaction of diol with sodium cyan ate and HCI gas.
All these methods have their advantages and disadvantages. The synthesis of dicarbamatc by phosgene route is difficult to commercialize due to difficult handling of phosgene at bulk scale.
The synthesis of dicarbamate by urea / metal acetate method as well as Ethyl urethane / Aluminum alkoxide method needs very high temperature and reaction times arc very long leading to the formation of impurities.
The best method on the basis of yield and quality of the product seems to be the formation of dicarbamate from their diols by sodium cyan ale and HCI gas. The cyanic-acid rout isdisclosed in Patent CH 359126 (1956), J.Med.Chem.1969,12(3),462 472 & J.Org. Chem., 28, 3421 (1963).
All these prior art disclosed that diol was reacted with sodium cyan ate and Dry MCI gas in the Chloroform at low temperature. Chloroform is used as reaction medium in all these prior arts. As chloroform is a carcinogenic and its ICH limit as an organic volatile impurity in any drug is very less i.e. PDH (mg/day) is 0.6 and concentration limit is 60 ppm whereas for Dichloromethane PDK (mg/day) is 6 and concentration limit is 600 ppm and for 1,2-Dichloroethane PDE (mg/day) is 18.7 and concentration limit is 1870 ppm.
SUMMARY OF THE INVENTION:
It is therefore a principal object of this invention to provide a method of producing 2, 2-disubstituated 1,3- propanediol dicarbamate generally referred to as and herein after designated as "Meprobamate" obviating the drawbacks associated with the existing processes, if not eliminating the same.
The other object is to provide a simple method for producing hitherto difficultly prepared carbamates of alcohol particularly tertiary alcohols.
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Another object is to provide an improved high yielding method.
Yet other object is to provide a simple method for producing highly pure Meprobamate having residual impurities well within ICH guidelines.
Yet another object is to provide a simple method capable of industrial application for producing Meprobamate having good bulk density and flowability. Thus the title product can be converted to the desired shape that can be comfortably administered.
The method described in this invention for producing Meprobamate comprising reacting 2-Methy1-2-propyl 1,3-propanediol using Sodium Cyanate & HCI gas in chlorocarbon selected from Dichloromethane or1,2-dichoroethane atemperature in higher yields and at lower costs with very high level of purity of product.
STATEMENT OF INVENTION:
Accordingly the present invention provides a method of producing 2, 2-disubstituated
1,3- propanediol dicarbamate (Meprobamate) comprising
reacting 2-methyI-2-propyI 1,3-propanediol in chlorosolvent selected from
Dichloromethane or dichloroethane, with alkali metal cyanate preferably sodium or
potassium cyanate and HO at low temperature till completion of reaction, quenching
the reaction with water, isolating the product by conventional methods such as herein
described to get a crude product followed by optionally purifying by hot water to get
the title product.
The process comprises of following steps:
v dissolving -methyl-2-propyl 1,3-propanediol in Dichloromethane or dichloroethane at room temperature,
v cooling the reaction mass to a subzero temperature preferably ranging from -20 to +20°C,
v adding sodium cyanate and purging HCI gas while maintaining the temperature,
v after complete conversion, the reaction is quenched by adding water to the reaction mass, isolating the product by distilling out dichloromethane and filtering as a slurry by addition of water,

v optionally drying the crude product and purifying from hot water. One of the embodiments of the present invention is to provide a method wherein the the reaction temperature is -20 to +20°C preferably 0 to 10 °C and most preferably 0-5 °C.
According to other embodiment of the invention, the volume of Dichloromethane or 1,2-Dichloroethane used may be 2-100 times of diol preferably 5-25 times and most preferably 10-15 times.
According to another embodiment of the invention sodium cyan ate or potassium cyan ate used may be in the range of 1-10 mole of diol preferably 4-5 mole of diol.
According to yet other embodiment of the invention, the isolation of the product may be carried out by distilling out chlorosolvent (dichioromethane or dichloroethane) and filtering as a slurry by addition of water.
The following examples are presented to illustrate working of the invention in detail Howevcr the invention is not intended to be limited in any way by these examples. Thus, the following examples are included solely to aid in a more complete understanding of the invention described and claimed herein. The examples do not limit the scope of the claimed invention in any fashion. However, one of the ordinary skilled in the art appreciates the modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below.
EXAMPLE-1
Charged 2-Methyl-2-propyl 1,3-propanediol (175 gms, 1.33 mole) in dichioromethane ( 2188 ml) at room temperature. The reaction mass was cooled to 0-5 °C. Sodium Cyanate (345.8 gms, 5.0 mole) was added to the reaction mass. Dry HCI gas was purged into reaction mass at the same temperature till the completion of reaction. On completion of reaction, the reaction mass was quenched by adding water. The organic layer containing product was separated. The solvent was distilled out to get a residue. Crude product was isolated by adding water into this residue which was further purified by hot water to give Pure Meprobamatc ( 262.5 gms, 91.0% of Theo.) ; Melting range:
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104-1060 C , Assay : 99.08%, Chromatographic purity : Single spot with any other spot less than 0.10%.
EXAMPLE-2 Charged 2-Methyl-2-propy 1,3-propanedi(17.5gms,0.133 mole) in 1,2-dichloroethanc ( 200 ml) at room temperature. The reaction mass was cooled to 0-50C. Sodium Cyanate (34.58 gms, 0.5 mole) was added to the reaction mass. The rest of the process was same as in Example-1. Pure Meprobamate ( 25.50 gms, 88.0% of Theo.) ; Melting range: 104-106 °C , Assay : 98.48%, Chromatographic purity : Single spot with any other spot less than 0.10%.
EXAMPLE-3 Charged 2-Methyl-2-propyl 1,3-propanediol (175 gms, 1.33 mole) in dichloromethane ( 2188 ml) at room temperature. The reaction mass was cooled to 8-12 °C. Sodium Cyanate (345.8 gms, 5.0 mole) was added to the reaction mass. The rest of the process was same as in Example-1. Pure Meprobamate ( 227.50 gms, 79.0% of Thco.) ; Melting range: 103-106 °C
EXAMPLE-4 Charged 2-Methyl-2-propyl 1,3-propanediol (1.7 gms, 0.0 mole) in dichloromethane (22 ml) at room temperature. The reaction mass was cooled to 0-5 °C.Potassium Cyanate (4.05 gms, 0.05 mole) was added to the reaction mass. The rest of the process was same as in Example-1 Pur Meprobamate ( 2.2 gms, 76.0% of Thco.) ; Melting range: 103-105 °C

WE CLAIM:
1) A method of producing 2, 2-disubstituat 1,3- propanediol dicarbamate
(Meprobamate) comprising:
(i) reacting 2-methyl-2-propyl 1,3-propanediol in chlorosolvent selected from
Dichloromethanc or dichloroethane, with alkali metal cyanate preferably sodium or
potassium cyanate and HCI at low temperature till completion of reaction,
(ii) quenching the reaction with water, isolating the product by conventional
methods such as herein described to get a crude product followed by
(iii) optionally purifying by hot water to get the title product.
2) The process as claimed in claim I wherein the volume of Dichloromethane or 1,2-Dichloroethane used may be 2-100 times of diol preferably 5-25 times and most preferably 10-15 times.
3) The process as claimed in claim 1 wherein the reaction temperature is -20 to +120°C preferably 0 to l0 0C and most preferably 0-50 C
4) The process as claimed in claim 1 wherein sodium cyanate potassium cyan ate used ranges from 1-10 mole of diol preferably 4-5 mole of diol.
5) The process as claimed in claim 1 wherein, the isolation of the product is carried out by distilling out chlorosolvent (dichloromethane or dichloroethane) and filtering as a slurry by addition of water.
6) A method of producing 2, 2-disubstituated 1,3- propanediol dicarbamate
(Meprobamate) substantially as herein described with reference to examples.

Dated this 29lh day of September 2006

ABSTRACT
A METHOD OF PRODUCING 2, 2-DISUBSTITUATED 1,3- PROPANEDIOL DICARBAMATE
The Method involves (i) reacting 2-methyl-2-propyl 1,3-propanediol in chlorosolvcnt selected from Dichloromethane or dichloroethane, with alkali metal cyanate preferably sodium or potassium cyanate and HCI at low temperature till completion of reaction, (ii) quenching the reaction with water, isolating the product by conventional methods such as herein described to get a crude product followed by (iii) optionally purifying by hot water to get the title product.