FI92054B - Process for the preparation of 3- (o-methoxyphenoxy) -1,2-propanediol-1-carbamate - Google Patents

Description

92054

The invention relates to a process for the preparation of 3- (o-methoxyphenoxy) -1,2-propanediol-1-carbamate - for the preparation of 3- (o-methoxyphenoxy) -1,2-propanediol-1-carbamate Process for the preparation of 3- (o-methoxyphenoxy) -1,2-propanediol-1-carbamate by formation of a propyl group from a 2,3-substituted propyl (o-methoxyphenyl) ether in an inert solvent 4-t (o-methoxyphenoxy) methyl] -2- oxo-dioxolane, which is cleaved with ammonia.

Methocarbamol is known to be prepared by reacting guaiacol with 3-chloro-1,2-propanediol, converting the OH groups of the terminal product to chlorine by the action of phosgene, and reacting the chlorine derivative with ammonia (A. Kleemann, Pharmz. Wirkstoffe, 2nd ed. 81982), pp. 578; US-PS 2,770,649).

The yield is not entirely satisfactory. f 20

It has now been found that the synthesis of methocarbamol can advantageously be carried out according to the following reaction scheme: 1-h 25 ° ch3 Ϊ: 0- ° »* —V» · - Οτ ° Ηιν "(I) (ID (III) 30 OCH, 2. ϊ

c/o. / V

('s' OCHj-HC - CH,

'111 -► I A A

Dabco \ /

s C

‘II

o 35 (IV) 92054 2 OCH, “» X.

> -OCH, - CH- CH, - O · CONH, 3- IV - * 'm (methocarbamol)

The reaction of Step 1 is accomplished in good yield when the compounds I and II are reacted in aqueous alkali hydroxide-10 solution (molar ratio of alkali hydroxide to guaiacol about 1: 1, excess epichlorohydrin) by adding a small amount of benzyltriethylammonium chloride. The resulting 2,3-epoxypropyl-2-methoxyphenyl ether, m.p. 31-33 ° C, can be obtained in good yield by fractional distillation under reduced pressure.

It has now been found that reacting the resulting compound with carbon dioxide under elevated pressure and elevated temperature in the presence of a catalytic amount of 1,4-diazabicyclo [2.2.2] -20 octane (Dabco) in a small amount of an inert solvent, e.g. toluene, gives 4 - [(o- methoxy-phenoxy) -methyl] -2-oxodioxolone in good yield when a CO2 pressure of 400 to 1000 kPa and a temperature of 110 to 160 ° C are used. preferably 120-140 ° C. The reaction proceeds relatively slowly. After almost a theoretical amount of carbon dioxide has reacted, the reaction is stopped.

The cleavage of 4- [o-methoxyphenoxy] methyl] -2-oxodioxolane is carried out without intermediate separation at 26 ° C, preferably using gaseous or liquid ammonia.

Example.

(a) 2,3-epoxypropyl-2-methoxyphenyl ether: 35

A solution of 200 g (5 moles) of sodium hydroxide in 200 ml of water is cooled to 10 ° C. After 10 minutes, a mixture of 1300 g (14 moles) of epichlorohydrin, 620.7 g (5 moles) of guaiacol and 6.3 g (0.028 moles) of benzyltriethylammonium chloride is added. The temperature rises to 80 ° C and is then maintained at 65 ° C for one hour. After cooling to room temperature, 100 ml of dichloromethane are added and the precipitated sodium chloride is filtered off with suction. Wash twice with 100 ml of dichloromethane and evaporate the organic phase under reduced pressure (2.5 kPa) and at a bath temperature of 70 ° C. The residual orange oil is fractionated at 3 kPa and 110 ° C to give 633.6 g (70.3%) of the title compound, m.p. 31-33 ° C.

b) 3- (o-Methoxyphenoxy) -1,2-propanediol-1-carbamate 54040 g (3 moles) of the compound obtained in a) and 3.4 g (0.03 moles) of Dabco are dissolved in 125 ml of xylene. The solution is stirred for 4 hours at 130 ° C under a pressure of 650 kPa CO 2 and then cooled to 24 ° C. 2012 ml of toluene are added, followed by the addition of liquid ammonia, whereupon the title compound begins to crystallize. After 1 hour, 200 ml of isopropyl alcohol are added, the crystalline porridge is dissolved at 70 ° C and then cooled. The title compound is filtered off with suction, washed with 300 ml of toluene and dried.

• Yield 674.8 (93% of theory).

f

Claims (1)

Process for the preparation of 3- (o-methoxyphenoxy) -1,2-propanediol-1-carbamate by formation of a propyl group 5 from a propyl (o-methoxyphenyl) ether substituted in the 2,3-position in an inert solvent 4 - [(o-methoxyphenoxy) -methyl] -2-oxo-dioxolane cleaved with ammonia, characterized in that the dioxolane is formed by reacting 2,3-epoxypropyl (o-methoxyphenyl) ether 10 with carbon dioxide in the presence of a catalytic amount of 1,4-diazabicyclo (2.2.2) octane At a CO 2 pressure of 400 to 1000 kPa at a temperature of 110 to 160 ° C and the cleavage of 4 - [(o-methoxy-phenoxy) methyl] -2-oxo-dioxolone is carried out without intermediate separation at a temperature below 30 ° C with gaseous or liquid ammonia. For example, 3- (o-methoxyphenoxy) -1,2-20 propanediol-1-carbamate genomes are substituted in the propyl group with 2,3-substituted substituents propyl (o-methoxyphenyl) ethers and inert solvents 4- [ (o-methoxyphenoxy) -methyl] -2-oxo-dioxolane, with the addition of ammonia, on the other hand, with the aid of dioxolane in the genome of 2,3-epoxypropyl (o-methoxyphenyl) ethers with nuclear dioxide. from the catalytic game 1,4-diazabicyclo (2.2.2) octane and CO 2 tric at 400 to 1000 kPa at 110 to 160 ° C and 4 - [(o-methoxyphenoxy) methyl] -2-oxo -dioxo-lonens are obtained after the addition of 30 ° C below 30 ° C with ammonia and gas or steam. i