DE1046021B - Process for the preparation of 2-methyl-2-phenyl-1,3-propanediol dicarbamate - Google Patents

Description

GERMAN

The invention relates to the preparation of a new compound which has anticonvulsant activity of uncommon has high intensity, namely 2-methyl-2-phenyl-1,3-propanediol dicarba'mat. 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 constant solutions in Water and organic solvents. Hydrolyzed when heated or boiled with acid or alkali this compound with the formation of 2-methyl-2-phenyl-1,3-propanediol, Ammonia and carbonic acid.

The compound is made from the diol by transesterification of a low molecular weight urethane manufactured. In this reaction, a mixture of about 1 mole of 2-methyl-2-phenyl-1,3-propanediol and 2 mol of a low molecular weight methane, possibly with the addition of a transesterification catalyst, heated.

The 2-methyl-2-phenyl-l, 3-propanediol used to prepare the new compound can, for. B. by Reduction of the corresponding disubstituted malonic acid ester or by condensation of formaldehyde and hydratropaaldehyde can be obtained.

example

a) 53.6 g of hydratopaaldehyde and 87 g of a 37% formaldehyde solution are dissolved in 150 cm ^{3 of} alcohol. This solution is added in the course of 20 minutes to a solution of 30 g of potassium hydroxide in 150 cm ^{3 of} alcohol. 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 is obtained
2-Methyl-2-phenyl-1,3-propanediol with a melting point of 81 to 82 ° C.

_t> b) 16.6 g of 2-methyl-2-phenyl-1,3-propanediol and 19 g of ethyl urethane are dissolved in 200 cm ^{3 of} anhydrous toluene. 1 g of aluminum isopropoxide is added and the mixture is distilled to remove the ethanol formed in the condensation of ethyl urethane with the diol. The ethanol distills in the form of azeotrope with toluene from a boiling point of about d

Method of manufacture

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

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

₁₂ H ₁₆ N ₂ O ₄ : N 11.1%;

G

77 ° C. Distillation is continued until essentially the theoretical amount of ethanol is removed has been. The toluene is distilled off from the mixture under reduced pressure, and the residue is extracted with hot aqueous isopropanol solution. The hot solution is allowed to cool, whereupon approximately 6 g of purified dicarbamate can be obtained as a white crystalline solid which can be dissolved in water is sparingly soluble at ordinary room temperature and has a melting point of 110 to 112 ° C.

Analysis:

Calculated for C
found: N 10.6%.
Sp. 110 to 115 ° 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. ", 9, p. 231 (1946), described method on male white Mice of the CF-1 strain m for their ability to prevent the occurrence of electroshock attacks checked. A current of 50 mAmp. (four times the convulsive threshold dose) was each Applied by skin electrodes for 0.2 seconds. The substance according to the invention was made as a suspension administered in a 10% solution of acacia gum, and became known for comparison 2-ethyl-2-phenyl-1,3-propanediol dicarbamate 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 30, 90, 150, 210 and 270 minutes after administration of the two substances applied. The convulsion became tonic

"" - - 809 698,529

Extensor contracting phase viewed as viewed from To man and employees is described.

The results were evaluated graphically (LC Miller and ML Tainter, Proc. Soc. Exper. Biol. And Med. 57, p. 261 [1944]) and expressed as the dose (ED ₅₀ ) which 50% of the animals against the tonic extensor muscle phase from electroshock spasms.

_{The ED 50} determined in this way for 2-methyl-2-phenyl-1,3-propanediol dicarbamate is 102 ± 6.0, while the ED ₅₀ value for the known 2-ethyl-2-phenyl-1,3 -propanediol carbamate is 360 + 32. Accordingly, it is found that the compound of the present invention is more effective than the known in that a much smaller amount of the former is required to achieve the same result.

The compound has not only excellent anticonvulsant activity but also one muscle loosening effect.

The new dicarbamate is primarily for oral use Use is determined and is formed into suitable pills, tablets or capsules in a known manner. It can also be in a suitable solvent, e.g. B. a mixture of water and polyethylene glycol, dissolved and die'Lösung can be used for injection purposes or as an enema.

Claims (1)

Claim: Process for the preparation of 2-methyl-2-phenyl-1,3-propanediol dicarbamate, characterized in that a mixture of about 1 mole of 2-methyl-2-phenyl-l, 3-propanediol and 2 moles of one low molecular weight urethanes heated with the possible addition of a transesterification catalyst. Considered publications:
Journ. amer. formerly soc, 1951, p. 780. © 809 698/529 12.58