DE1046020B - Process for the preparation of 2-methyl-2-phenyl-1,3-propanediol dicarbamate - Google Patents

Description

The invention relates to a process for the preparation of a new compound, the anticonvulsant activity of unusually high intensity, namely 2-methyl-2-phenyl-1,3-propanediol dicarbamate. This compound is a white crystalline solid that is present in most organic solvents is soluble, but is only slightly soluble in water. He makes stable solutions in Water and organic solvents. When heated or boiled with acid or alkali, this hydrolyzes Compound with formation of 2-methyl-2-phenyl-1,3-propanediol, ammonia and carbonic acid.

The new compound is made by adding 2-methyl-2-phenyl-1,3-propanediol with phosgene to form of the corresponding dichlorocarbonate derivative. Here is the addition of acid-binding agents, such as Sodium hydroxide, antipyrine or dialkylaniline are advantageous. The dichlorocarbonate derivative is then acted upon converted into the dicarbamate by anhydrous or aqueous ammonia.

The 2-methyl-2-phenyl-l, 3-propanediol used to prepare the new compound can be used in a known manner Way, e.g. B. by reduction of the corresponding disubstituted malonic acid ester or by condensation of formaldehyde and hydratropinaldehyde.

example

a) Preparation of 2-methyl-2-phenyl-1,3-propanediol: 53.6 g of hydratropinaldehyde and 87 g of 37% formaldehyde solution are dissolved in 150 cm ^{3 of} alcohol. This solution is added to a solution of 30 g of potassium hydroxide in 150 cm ^{3 of} alcohol over a period of 20 minutes. The resulting mixture is refluxed for 2 hours and the alcohol is removed by distillation. The residue is extracted with ether and the crude product is obtained by removing the solvent. The product is recrystallized from benzene and petroleum ether. 45 g of 2-methyl-2-phenyl-1,3-propanediol with a melting point of 81 to 82 ° C. are obtained.

b) 33 g of phosgene (0.3 mol + 10%) are placed in a 500 cm ³ flask with 150 cm ^{3 of dry toluene cooled to -10 ° C.} To this end, 25.2 g of 2-methyl-2-phenyl-1,3-propanediol, dissolved in 100 cm ^{3 of} toluene, are added with 31 g (0.3 mol) of Ν, Ν-dimethylaniline. The internal temperature is kept at -5 to + 5 ^° C .; the addition takes about 20 minutes. The cold reaction mixture is washed with 5% hydrochloric acid. The toluene layer is _{dried over Na 2} SO ₄ and saturated with ammonia gas, the temperature rising. The mixture is heated to reflux and filtered. The solid product, 2-methyl-2-phenyl-1,3-propanediol dicarbamate, is recrystallized from a 1: 1 benzene-petroleum ether solution, m.p. = 110 to 111.5 ° C.

Process for the production of

2-methyl-2-phenyl-1,3-propanediol

dicarbamate

Applicant:

Carter Products, Inc., New York,
NY (V. St. A.)

Representative: Dr. H.-H. Willrath, patent attorney,
Wiesbaden, Hildastr. 32

ng Claimed priority:

V. St. v. America January 13, 1956

Frank Milan Berger, Princeton, NJ,
and Bernard John Ludwig, North Brunswick,

NJ (V. St. A.),
have been named as inventors

The compound prepared according to the invention was tested on male white mice of the CF-I strain for their ability to prevent by the method described by JEP Toman, EA Swinyard and LS Goodman in J.NeurophysioL., 9, p. 231 (1946) checked for the occurrence of electric shock attacks. A current of 50 mAmp. (four times the convulsive threshold dose) was applied by skin electrodes for 0.2 seconds each time. The substance according to the invention was administered as a suspension in a 10 ° / ₀ solution of gum acacia; for comparison, the known 2-ethyl-2-phenyl-1,3-propanediol dicarbamate was used, which was administered in the same way.

Groups of 10 mice each were treated with doses increasing in geometric progression by a factor of increased approximately 1.5 and the electroshock treatments were 30, 90, 150, 210 and 270 minutes after administration of the two substances applied. The tonic extensor muscle contraction phase became the convulsion viewed as described by Tom and coworkers.

The results were evaluated graphically (L. C. Miller and M. L. Tainter, Proc. Soc. Exper. Biol.

, the 50 ° / ₀ of the animals protected and Med. 57, p 261 [1944]) and expressed as the dose (ED ₅₀₎ against the tonic extensor phase of Elektroschockkonvulsion.

The value of ED ₅₀ determined in this way for 2-methyl-2-phenyl-1,3-propanediol dicarbamate is

809 698/528

102 Jr 6.0, while the ED _B0 value for the known 2-ethyl-2-phenyl-1,3-propanediol dicarbamate is 360 ± 32. Accordingly, it is found that the compound of the present invention is more effective than the known one, since a much smaller amount of the former is required to achieve the same result.

However, the compound has not only excellent anti-convulsion activity, but also muscle loosening Effect.

It is primarily intended for oral use and is incorporated into appropriate pills, tablets, or capsules shaped in a known manner. But you can also in a suitable solvent, for. B. a mixture of Water and polyethylene glycol, dissolved and the solution used for injections or as an enema.

Claims (2)

Claims. 1. Process for the preparation of 2-methyl-2-phenyl-1,3-propanediol dicarbamate, characterized in that 2-methyl-2-phenyl-1,3-propanediol is mixed with phosgene to form the corresponding dichlorocarbonate converts and this by the action of anhydrous or aqueous ammonia in the dicarbamate convicted. 2. The method according to claim 1, characterized in that an acid-binding one in the first process stage Means is added. Considered publications:
Journ. amer. former Soc, 1951, p. 5779.