DE1047769B - Process for the preparation of 2-phenyl-1,3-propanediol dicarbamate - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of a new organic compound, the anticonvulsant activity of unusually high intensity to prevent electric shock attacks from occurring has, namely 2-phenyl-1,3-propanediodicarbamate. This compound is a white crystalline solid that is found in most organic Solvent soluble, but only to a small extent dissolves in water. He makes steadfast Solutions in water and organic solvents. When heating or cooking with acid or alkali hydrolyzes this compound to form the corresponding 2,2-disubstituted 1,3-propanediol as well of ammonia and carbon dioxide.

The new compound is produced by reacting 2-phenyl-1,3-propanediol with phosgene to form the corresponding dichlorocarbonate derivatives. This reaction is promoted by adding acid-binding agents, such as sodium hydroxide, antipyrine, or dialkylaniline, to the reacting compounds. The dichlorocarbonate derivative is then converted into the dicarbamate by treatment with anhydrous or aqueous ammonia.

The 2-phenyl-1,3-propanediol used for the preparation of the new compound can be according to any known one Method, e.g. B. by reduction of the corresponding 2-substituted malonic acid ester.

example

To prepare 2-phenyl-1,3-propanediol, 50 g of diethylphenylmalonate were reduced in the usual way with 12 g of lithium aluminum hydride, the reduction being ^{carried out in 500 cm 3 of} anhydrous ether. The excess reducing agent was removed by adding a small volume of ethyl acetate. The reaction mixture was worked up in the usual way with water and dilute sulfuric acid, the organic constituents being extracted with ether. 16 g (approximately 50% of the theoretical yield) of the purified product with a melting point of 49 to 52 ° C. were obtained.

Analysis:

Calculated C 71.03, H 7.95;

found C 71.04, H 7.88.

33 g of phosgene (0.3 mol + 10%) were then placed in a 500 cm ³ flask containing 150 cm ^{3 of dry toluene cooled to -10 ° C .;} 23 g of 2-phenyl-1,3-propanediol, dissolved in 100 cm ^{3 of} toluene, which contained 31 g (0.3 mol) of N, N-dimethylaniline, were added to this. The internal temperature was kept at -5 to 5 ° C; the addition took place within about 20 minutes. The cold reaction mixture was washed with 5% hydrochloric acid. The toluene layer was _{dried over Na 2} SO ₄ and saturated with ammonia gas, Method of Manufacture
of 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

Claimed priority:
V. St. v. America from. January 13, 1956

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

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

the temperature rising. The mixture was heated to reflux and filtered. After the Filtrates, the solid product, 2-phenyl-1,3-propanediol dicarbamate, was filtered and extracted from a 1: 1 benzene-petroleum ether solution recrystallized; F. 151 to 152 ° C.

The compound of the invention was prepared according to the method described by J. E. P. Toman, E. A. Swinyard and L. S. Goodman in "J. Neurophysiol.Ä, 9, 231 [1946], described method on male white mice of the CF-I strain Tested for their ability to prevent an electric shock from occurring. 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 made as a suspension in a 10% solution of acacia gum administered, and for comparison the known 2-ethyl-2-phenyl-1,3-propanediol dicarbamate was used, administered in the same way. Groups of ten mice each were treated with doses, which increased in geometric progression by a factor of approximately 1.5, and the electroshock treatments were used 30, 90, 150, 210 and 270 minutes after administration of the two substances. The tonic extensor muscle contraction phase, as described by Toman and Employees is described.

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

809 727/477

Med., 57, 261 [1944]) and expressed as the dose (ED ₅₀ ) that protected 50% of the animals against the tonic extensor muscle phase of electroshock spasms.

_{The ED 50} value determined in this way for 2-phenyl-1,3-propanediol dicarbamate is 52 ± 6.9, while the ED ₅₀ value for the known 2-ethyl-2-phenyl-1,3-propanediol dicarbamate is 360 ± 32 is. 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.

The 2-phenyl-1,3-propanediol dicarbamate was found however, considered relatively ineffective in protecting animals against convulsion caused by pentylenetetrazole was caused. The new compound has no effective sleep inducing effect and does not induce any Paralysis of voluntary muscles emerges when not given in very large doses. Cans, which Sleep or paralysis in mice are greater than 2000 mg / kg, while doses counteracting electroshock attacks protect, are of the order of 60 to 80 mg / kg. The connection is great because of her low toxicity is noteworthy. The mean lethal dose in mice after intraperitoneal administration Approximately 4000 mg / kg, and the median lethal dose in mice after oral administration about 8000 mg / kg.

The compound of the invention is primarily intended for oral use and is made into pills, Tablets or capsules formed using conventional technology. It can be in a suitable solvent, e.g. B. a Mixture of water and polyethylene glycol, dissolved and the solution used for injections or as a KH bull will.

Claims (2)

Patent claims: 1. Process for the preparation of 2-phenyl-1,3-propanediol dicarbamate, characterized in that 2-phenyl-l, 3-propanediol with phosgene to form of the corresponding dichlorocarbonate derivative and this by treatment with anhydrous or aqueous ammonia converted into the dicarbamate. 2. The method according to claim 1, characterized in that the reacting compounds of an acid-binding agent is added to the first stage. Considered publications:
Journ. Amer. Chem. Soc, 1951, p. 779. © 809 727/477 12.58