DE1177139B - Process for the production of carbamic acid esters - Google Patents

Description

Process for the preparation of carbamic acid esters The present invention relates to a process for the preparation of carbamic acid esters of the general formula RO-CO-NH2 where R is a tertiary pentyl group substituted by a lower alkyl radical represents.

The compounds according to the invention are valuable medicaments with muscle relaxing and calming properties, their administration does not dull the psychological or physical capacity.

The compounds of the invention are obtained by either a) an alcohol of the general formula ROH with a carbamic acid halide, if appropriate in a basic medium, or with ethyl carbamate in the presence of a transesterification catalyst or with a cyanate in an acidic medium or b) a carbonic acid ester of general formula ROCOOR1 in which Ri represents an aryl group, treated with ammonia or c) a carbamic acid ester of the general formula R'OCONHs wherein R'eine through is a lower alkyl radical substituted tertiary pentenyl or pentynyl group, catalytically hydrogenated.

Particularly valuable compounds of the invention are the carbamic acid {3-methyl-pentyl- (3)] - ester, the carbamic acid [3-ethyl-pentyl- (3)] - ester and the carbamic acid [2-methyl-pentyl- (2)] - ester. The esters of the invention are heavy in water as well as in a physiological environment soluble. In order to be able to use them therapeutically, they are made in an advantageous manner with the help of absorption-promoting, inherently ineffective solubilizers converted into applicable preparation. The appropriate clinical dosage is in usually 50 to 800 mg, advantageously more adhesive way at 100 to 400 mg, two to four times a day.

It has been found that the compounds of the invention correspond to the known, carbamic esters used as tranquilizers, e.g. B. the carbamic acid [3-methyl-butyl- 3-ester and 2-methyl-2n-propyl-1,3-propanediol dicarbamate, in many layers are superior.

While z. B. in mice the therapeutic index, the LDso-I) osis and the AD50 dose (active or effective dose) of carbamic acid [3-methyl-pentyl- (3)] - ester approximately correspond to the values of the known dicarbamate, on the other hand, will the spontaneous mobility of mice is much more reduced by the pentyl ester than by the dicarbamate, as shown in Table I below. By means of a photocell counter were the movements of the caged mice within 5 minutes determined before and after administration of the compounds at a dose of 50 mg / kg.

Table I. Reduction of Movements of the experimental animals Movements after the Administer connection Administration on percent before after normal movements Administration administration 49 30 74 40 114 98 2-methyl-2n-propyl-1,3-propanediol dicarbamate ...... # 74 32 380 | 259 l 73 39 133 65 103 59 Carbamic acid [3-methyl-pentyl- (3)] ester ........ # 37 171 31 619 1,229 The increased anti-spasmodic effect is shown in Table II below. In the device described by de J ongh (Acta Physiol. Pharmacol. Neerlandica, 6 [1957], 511), mice were exposed to such an electric shock treatment that all test animals were exposed to a tranquilizer without administration Convulsions were generated.

The electroshock treatment was carried out 60 minutes after the administration the test compound, only a portion of the test animals were attacked by convulsions.

In the table, the numbers indicate the number of convulsions Animals per test group (ten animals) again.

Table II Electrical shock- Dose in cramps Compound administered mg / kg prao group group Control group ................ - 10/10 Carbamic acid [3-methyl- butyl (3)] ester 100 10/10 150 5/10 2-methyl-2n-propyl-1,3-propane dioldicarbamate 100 8/10 150 5/10 Carbamic acid [3-methyl- pentyl (3)] ester ............ 100 8/10 150 0/10 The clinical studies on test persons showed that the carbamic acid [3-methy! -Pentyte- (3)] ester is twice as active as 2-methyl-2n-propyl-1,3-propanediol dicarbamate in terms of its muscle-relaxing and antispasmodic properties both against susceptibility to convulsions from certain chemical substances that attack the central nervous system and from electric shock. The carbamic acid ester also has a good tranquilizing effect at low doses, which does not induce relaxation of the skeletal muscles. The carbamic acid [3-methyl-pentyl- (3)] - ester blocks impulses, transmits via reflex arcs with several nerve switching points (synapses) and, like the dicarbamate, causes a reduction in spontaneous activity in electroencephalographic examinations without changes being observed in the sensory lines can be.

The following examples illustrate the process of the invention.

Example 1 40 g of (1-methyl-1-ethyl-propyl) -phenyl-carbonate become Dissolved in 100 cm3 of ether and mixed with 100 cm3 of liquid ammonia. The reaction mixture is stirred in an autoclave for 2 hours. The temperature rises to -20 ° C a pressure of 7 kg / cm3.

After removing the ammonia, the solution is made with 4% sodium hydroxide solution (twice with 150 cm3 each) and washed with 100 cm3 of water and with magnesium sulfate dried. The ether solution is driven off and the residue is recrystallized from petroleum ether. The formed carbamic acid [3-methyl-pentyl- (3)] - ester has a melting point from 54 to 55'C. The yield is 50%.

Example 2 Following the procedure described in Example I is from (I, l-diethyl-propyl) -phenyl-carbonate and ammonia carbamic acid- [3-ethyl-pentyl- (3)] esters with a melting point of 81 to 82 ° C.

The yield is 45%.

Example 3 Following the procedure described in Example I is from (I, I-dimethyl-butyl) -phenyl-carbonate and ammonia carbamic acid- [2-methyl-pentyl- (2)] esters with a melting point of 58 to 59 ° C.

The yield is 46%.

Example 4 8 g of carbamyl chloride are added to a cooled solution of 10.2g of 3-methyl-3-pentanol and 50cm3 of benzene were added so slowly that the temperature does not rise above 0 ° C. Then 12.1 g of dimethylaniline are added dropwise, and the reaction mixture is then left for 2 hours at room temperature touched. The benzene solution is mixed with 25 cm3 of distilled water, with 10 cm3 of 5% hydrochloric acid, then washed with a saturated sodium carbonate solution and finally with water. The benzene solution is dried over magnesium sulfate, filtered and dried to dryness evaporated to give carbamic acid [3-methyl-pentyl- (3)] - ester. To Recrystallization from petroleum ether has a melting point of 54 to 55 ° C. The yield is 51 ° / 0.

Example 5 The procedure described in Example 4 is followed from 3-ethyl-3-pentanol and carbamyl chloride carbamic acid [3-ethyl-pentyl- (3)] - ester obtained with a melting point of 81 to 82 ° C. The yield is 47%.

Example 6 The procedure described in Example 4 is followed from 2-methyl-2-pentanol and carbamyl chloride carbamic acid [2-methyl-pentyl- (2)] ester obtained with a melting point of 58 to 59 ° C. The yield is 60 "/.

Example 7 To a cooled solution of 10.2 g of 3-methyl-3-pentanol 8 g of carbamyl chloride are added to 50 cm3 of toluene. Then another 12, 4 g of 3-methyl-3-pentanol were added so slowly that the temperature does not rise above 0.degree. After washing the toluene solution with distilled water, subsequent drying and evaporating the toluene solution to dryness, carbamic acid [3-methyl-pentyl- (3)] - ester obtained which, after recrystallization from petroleum ether, has a melting point bon has 54 to 55 ° C. The yield is 80%.

Example 8 According to Example 7, sodium 3-ethyl-3-pentanol and carbamyl chloride are converted into carbamic acid [3-ethylpentyl (3)] ester with a melting point of 81 to 82 ° C. was obtained. the The yield is 79%.

Example 9 The procedure described in Example 7 is followed from 2-methyl-2-pentanol-sodium and carbamyl chloride carbamic acid [2-methyl-pentyl- (3)] esters having a melting point of 58 to 59 ° C. The yield is 77 ° / 0.

Example 10 10.2 g of 3-methyl-3-pentanol in 50 cm3 of dry ethyl ether are added dropwise with stirring to 8 g of carbamyl chloride in 25 cm3 of dry ethyl ether added at 0 ° C. The reaction mixture is left to stand overnight; on this will washed with distilled water, dried and evaporated to dryness. Of the The residue is recrystallized from petroleum ether, whereupon carbamic acid [3-methylpentyl- (3)] ester having a melting point of 54 to 55 ° C is obtained. The yield is 20 ° / o.

Example 11 8 g of carbamyl chloride are converted into 10.2 g of 3-methyl-3-pentanol with cooling given in 50 cm3 of chloroform. This solution is then added slowly in portions 5 g of dried calcium carbonate so that the temperature does not rise above 0 ° C. To 2 hour Stirring at room temperature, the precipitate formed is filtered off. The chloroform solution is washed with distilled water and dried over magnesium sulfate. That Solvent is removed and the residue is recrystallized from petroleum ether, whereupon carbamic acid [3-methyl-pentyl- (3)] - ester with a melting point of 54 to 55 ° C is obtained. The yield is 83%.

Example 12 According to Example 11, 3-ethyl-3-pentanol and carbamyl chloride are used Carbamic acid [3-ethyl-pentyl- (3)] - ester with a melting point of 81 to 82 ° C obtain. The yield is 81%. Example 13 The example is similar 11 from 2-methyl-2-pentanol and carbamyl chloride [2-methyl-pentyl- (2)] carbamic acid ester obtained with a melting point of 58 to 59 ° C and a yield of 80%.

Example 14 A suspension of 20 g of 3-methyl-3-pentanol, 40 g of urethane and 1, 5g of aluminum isopropoxide is slowly heated until that occurs during the reaction formed ethanol is distilled off. After 4 hours the reaction mixture is cooled and mixed with 53 cm3 of water. The formed carbamic acid [3-methyl-pentyl- (3)] - ester is extracted with petroleum ether. The ester with a melting point of 54 to 55 ° C is obtained in a yield of 15%.

Example 15 According to Example 14, 3-ethyl-3-pentanol is converted accordingly and urethane carbamic acid [3-ethylpentyl- (3)] - ester with a melting point of 81 to 82 ° C and a yield of 12% obtained.

Example 16 From 2-methyl-2-pentanol and urethane, according to the example 14 Carbamic acid [2-methyl-pentyl- (2)] - ester with a melting point of 58 to 59 ° C and a yield of 10% obtained.

Example 17 30, 5 g of 3-methyl-3-pentanol, 8, 1 g of potassium cyanate and 16.3 g of trichloroacetic acid are heated with stirring to 45 to 50 ° C and 24 hours stirred at this temperature and then by the gradual addition of dry Sodium carbonate neutralized.

The precipitate is removed, unreacted 3-methyl-3-pentanol distilled off and the residue mixed with a small amount of water. After precipitation and filtration is dried and the carbamic acid [3-methyl-pentyl- (3)] - ester recrystallized from petroleum ether. The ester with a melting point of 54 to 55 ° C is obtained in a yield of 61%.

Example 18 Following the procedure described in Example 17 is from 3-ethyl-3-pentanol and potassium cyanate carbamic acid [3-ethyl-pentyl- (3)] ester obtained with a melting point of 81 to 82 ° C and a yield of 57 ° / 0.

Example 19 Correspondingly, according to Example 17, 2-methyl-2-pentanol is used and potassium cyanate [2-methyl-pentyl- (2)] carbamic acid ester having a melting point from 58 to 59 ° C and a yield of 55 ° yes.

Example 20 10 g of 3-methyl-1-pentyn-3-ol-carbamate are poured into 100 cm3 Dissolved methanol and in the presence of 0, 2 g of platinum oxide at a temperature of Hydrogenated at 20 to 40 ° C and a hydrogen pressure of 1 kg / cm2.

After the hydrogenation has ended, the solution is filtered and the methanol aborted. The residue is recrystallized from petroleum ether. The educated Carbamic acid [3-methyl-pentyl- (3)] - ester has a melting point of 54 to 55 ° C. The yield is 91%. Example 21 Example 20 is converted from 3-methyl-1-pentene-3-olcarbamate and hydrogen carbamic acid [3-methylpentyl- (3)] - ester having a melting point obtained from 54 to 55 ° C and a yield of 90%.

Claims (1)

Claim: Process for the production of carbamic acid esters of the general formula ROCONH2 wherein R substituted one by a lower alkyl radical represents tertiary pentyl group, characterized by the fact that either a) one Alcohol of the general formula ROH with a carbamic acid halide, if appropriate in a basic medium, or with ethyl carbamate in the presence of a transesterification catalyst or with a cyanate in an acidic medium or b) a carbonic acid ester of general formula R - O - CO - OR1 in which Ri represents an aryl group, with ammonia treated or c) a carbamic acid ester of the general formula R'O - CO - NH2 wherein R 'is a tertiary pentenyl or tertiary alkyl radical substituted Pentynyl group means catalytically hydrogenated. Publications considered: German Patent No. 953 875.