DE1047770B - 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-propanediol dicarbamate. 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 compound is made by transesterification of a low molecular weight urethane with 2-phenyl-1,3-propanediol obtained namely heated a mixture of about 1 mole of 2-phenyl-l, 3-propanediol and 2 moles of a low molecular weight Urethane with possible addition of a transesterification catalyst. That in the production of the new compound used 2-phenyl-l, 3-propanediol can be prepared by known methods, for. B. by reducing 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 amount of ethyl acetate. The reaction mixture was worked up in the usual way with water and dilute sulfuric acid, the organic compounds being extracted with ether. 16 g (about 50 ° / ₀ of the theoretical yield) of purified product with F. 49 to 52 ° C were obtained.

Analysis:

Calculated C 71.03, H 7.95;

found C 71.04, H 7.88.

Then 20 g of 2-phenyl-1,3-propanediol and 25 g of ethyl urethane were dissolved in 320 cm ^{3 of} anhydrous toluene, 3 g of aluminum isopropoxide were added and the mixture was distilled to remove the ethanol formed. The alcohol distills in the form of an azeotrope with Touol, which boils at around 77 ° C. The distillation is continued until essentially the theoretical amount of ethanol has been removed. The toluene is distilled off from the mixture under reduced pressure, and the solid material obtained is extracted with hot aqueous isopropanol solution. On cooling, this solution gives 16.5 g of purified product, which corresponds to a yield of approximately 52% of theory. The purified 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 January 13, 1956

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

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

Product has a melting point of 151 to 152 ° C and is only slightly soluble in water at room temperature.

Analysis for C ₁₁ H ₁₄ N ₂ O ₄ :

Calculated N 11.8;

found N 11.7.

The compound according to the invention was made according to the method described by JEP Toman, EA Swinyard and LS Goodman in "J. Neurophysiol. «, 9, 231 [1946], tested the method described on male white mice of the CF-I strain for their ability to prevent 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 carbamate was used, which was administered in the same way. Groups of two mice each were treated with doses which increased in geometric progression by a factor of approximately 1.5; the electroshock treatments were applied 30, 90, 150, 210 and 270 minutes after administration of the two substances. The tonic extensor muscle contraction phase, as described by Toman and co-workers, was viewed as convulsion.

809 727/478

Claims (1)

3 4 The results were evaluated graphically (L. C binding is noteworthy because of its very low toxicity beMiller and ML Tainter, Proc. Soc. Exper. Biol. And. The mean lethal dose in mice according to Med In terms of dose (ED ₆₀ ), intraperitoneal administration is approximately 50% of animals against the tonic extensor phase 4000 mg / kg, and the mean lethal dose in mice protected from electroshock spasms.5 after oral administration is approximately 8000 mg / kg. The value of ED ₅₀ determined in this way for The new compound is primarily for oral 2-phenyl-1,3-propanediol dicarbamate is 52 φ 6.9, determined turning and becomes pills, tablets or while the ED ₅₀ value for the known 2-ethyl capsules is formed in the usual technique. It can be in one 2-phenyl-1,3-propanediol dicarbate is 360 ± 32. suitable solvent, e.g. B. a mixture of Accordingly, it should be noted that the compound after the io water and polyethylene glycol are dissolved and the present invention is more effective than the known, solution for injections or used as an enema, since a much smaller amount of the former is required, to achieve the same result patent claim: However, it turned out to be relatively ineffective to protect animals against convulsion caused by 15 processes for the production of 2-phenyl-l, 3-propane Pentylenetetrazole was caused. The new diol dicarbamate, characterized in that one bond has no effective sleep-inducing a mixture of about 1 mole of 2-phenyl-1,3-propanediol Effect and does not cause paralysis of arbitrary and 2 moles of a low molecular weight urethane Muscles stand out if they are not used in very large doses, possibly with the addition of a transesterification catalyst is given. Doses heating sleep or paralysis at 20. Eliciting mice are greater than 2000 mg / kg, while ~ Cans that protect against electric shock attacks, in the publications considered: Of the order of 60 to 80 mg / kg. The Ver Journ. amer. former soc, 1951, 5780. 809-727 / 47B 12.58