US2186976A

US2186976A - Tkialkylacetamides having satu

Info

Publication number: US2186976A
Authority: US
Publication date: 1940-01-16
Anticipated expiration: 1957-01-16

Description

Patented Jan. 16, 1940 UNITEDSTATES PATENT OFFlCE TRIALKYLACE TAIHIDES HAVING SATU- RATED ALKYL GROUPS AND A METHOD OF MAKING THE SAME Karl Junkmanm Berlin, and Hans-Georg Allardt, Philippsthal, Kreis Teltow, Germany, assignors to Schering Aktiengesellschaft, a corporation of Germany No Drawing. Application January 8,

Serial No. 119,658. In Germany August 16,

10Claims. (01.260 66!) This invention relates to trialkylacetamides having saturated alkyl groups and a method of making the same.

By the researches of Fromherz, Arch. -f. exp. Pathologie und Pharmakologie, vol. 1'73, page 78, it has become known that the substituted acetamides possess peripheral paralysing (spasmolytic) properties. This assertion is accompanied on page 83 by three examples, which are, however, only very weakly active acetamides.

The present invention is based on the discovery that the tertiary saturated alkyl substitutedacetic acid amides with from 12 to 17 C-atoms,

' manufactured according to known processes from tertiary nitriles of the general formula:

R" g in which R, R and R" indicate the same or different saturated alkyl groups such that in the case of the saturated trialkylaceta'mides with 12 carbon atoms R, R and R" constitute alkyls with at least 3 carbon atoms, compared with those described by Fromherz exhibit an unexpectedly good spasmolytic action. I

By comparing the different trialkylacetamides on a superior rabbit intestine maintained permanently in Tyrode solution containing barium, the individual preparations being standardised against novocaine hydrochloride as comparative preparation, the following results are obtained:

Activity number papaverino HO]- solution=l00 Acetamide examined C-number I. Saturated triallcylacetamides containing up to ZZJ-C-atams M ethyl-diethyl-ace tamide iiiiiiiii Triethyl-acetamide Diethyl-n-propyl-acetamide i Methyl-dipropyl-acotamide Ethyl-clipropyl-acetamide Diethyl-butyl-acetamide. Tripropyl-acetamide. i Ethyl-dibutylacetamides i H; Unsaturated trialkylacetamidas containing up to IZ-C-utoms Diethyl-allyl-acetamidc M othyl-diallyl-acetamide i. Ethyl-diallyl-acetamide. i n-Propyl-diallyl'acetainide i Isopropyl-diallyl-acetamide i n-Butyl-dia]lyl-aoetamide 'Iriallyl-acetamide Activitynumber papaverine H01- solution=l00 Acetamide examined O-number III. Saturated trialkylacetamides contaming 12-17- C-atoms (according to the invention) Dipropyl-butyl-acetamide -l2 100. Propyl-dibutyl-acetamide 13 110 Tributyl-acetamide i. 14 130 Ethyl-di-isoamyl-acetamide. 14 187. 5 Ethyl-dihexyl-acetamide 16 125. O Tri-isoamyl-acetamide 17 125. 0 Propyl-diamyl-acetamide. 15 125. 0 Butyl-diainyl-acetamide 8 Dibutyl-amyl-acetamide In these experiments novocaine' hydrochloride was equal to 1/75 papaverine hydrochloride. It

- was thereforepossible by a simple calculation to bring the numbers'obtained into relation with those given by Fromherz'; who uses papaverine as standard and makes this equal to 100.

From this table .it ,is clearly "seen that the strong effects obtained with the tertiary saturated amides of this invention were not to be foreseen. v

In addition it should be remarked that the hitherto known acetamides with small C-number examined by Fromherz are fairly strong scporifics, while the new substances according to the present invention even in large doses have practically 'no soporific effect which is extremely separating extracted with a solvent immiscible with water, for example, benzene, the extract washed with sodium carbonate solution and the amide produced therefrom in the customary manner. It is separated from small quantities of starting material by vacuum distillation. The amide has the B. P. 176 C. under 16 mm. pressure, the M. P. 69 to 70 C. and constitutes a white crystal powder which easily dissolves in ether, alcohol, petrol-ether and benzene.

o H N Found 73. 47 12.8 6.9 Calculated 13.2 12. 6. 5s

The hydrolysis can be carried out instead of with sulphuric acid by heating with water to 180 to 200 C., if desired with the addition of an emulsifying agent such as the sodium salt of di-isopropylnaphthalene-B-su1phonic acid.

(b) 19.5 parts of di-n-butyl-n-pr0pyl-acetonitrile are dissolved in 200 parts of alcohol and 48 parts of 10% hydrogen peroxide and 0.8 part of caustic soda in a little Water added. The whole is heated with stirring gradually to 40 to 60 C., neutralised after completion of the hydrolysis with acid and the alcohol evaporated. The residue recrystallised from dilute alcohol yields white needles of M. P. 69-'70 C., the pure dibutyl-propyl-acetamide.

Example 2 50 parts of tri-n-butyl-acetonitrile B. P. 142 to 146 C. under 17 mm. pressure, 300 parts of butyl or amyl alcohol and 60 parts of potassium hydroxide in 10 parts of water are boiled with stirring under a reflux condenser for hours, the alcohol is thereupon removed by steam distillation and the residue extracted with benzene. From the benzene solution is obtained in the customary manner the amide, which passes over in a vacuum of 12 mm. at 183 C. It solidifies to white needles which have the M. P. 60 to 61 C. It is easily soluble in ether, petrol-ether benzene, alcohol, and chloroform, insoluble in water.

For acceleration of the saponification it can be carried out suitably in autoclaves at a temperature of 150 to C. Otherwise the process is conducted as set forth above.

Example 3 Triisoamyl acetonitrile, obtained according to U. S. Patent 1,958,653 from acetonitrile, sodium amide and isoamyl bromide, yields on saponification triisoamyl acetamide of the boiling point 198 C. at a vacuum of 14 mm. and the melting point 67 to 685 C. It crystallizes from petrol ether in White platelets.

Of course, in a similar manner other saturated trialkylacetamides having at least 12 and at most 17 carbon atoms in the molecule may be obtained from the corresponding trialkylacetonitriles.

What we claim is:

1. A process for the manufacture of a trialkylacetamide with saturated alkyl groups and of strong spasmolytic action, comprising saponifying tri-n-butyl acetonitrile to the corresponding acetamide.

2. Tri-n-butyl acetamide of the general formula CmHzcON and the melting point 60-61 C.

3. A process for the manufacture of substances having a high spasmolytic action, comprising hydrolyzing tertiary nitriles with at least 12 and at most 17 carbon atoms in the molecule, of the general formula:

atoms in the molecule, of the general formula:

RI! in which R, R and R" indicate saturated alkyl groups all higher than methyl, at least two of such groups having at least four carbon atoms.

5. A trialkylacetamide of strong spasmolytic action having at least 12 and at most 1'7 carbon atoms in the molecule, and of the general formula:

a ccoum R in which R, R and R" indicate saturated alkyl groups, at least two of such groups having at least four carbon atoms.

6. As a spasmolytic agent, and trialkylacetamide of strong spasmolytic action having more than 12 but no more than 17 carbon atoms in the molecule, and of the general formula:

w-coozvm in which R, R and R" indicate saturated alkyl groups all higher than methyl.

'7. A trialkylacetamide of strong spasmolytic action of the general formula:

in which R, R and R indicate saturated alkyl groups, at least two of such groups having each at least 4 carbon atoms and the third at least 3 carbon atoms, the total number of carbon atoms in the compound not exceeding 1'7.

8. A trialkylacetamide of strong spasmolytic action of the general formula:

rv-ccoxm in which R, R and R" indicate saturated alkyl groups of 3 to 5 carbon atoms, at least two of such groups having more than 3 but no more than 5 carbon atoms.

9. As a spasmolytic agent, n-propyl-di-n-butyl acetamide of the general formula C13H2'1ON and the melting point 69-70 C. from dilute alcohol.

10. As a spasmolytic agent, tri-isoamyl acetamide of the general formula C1'1H35ON and the melting point 67-68.5 C.

KARL JUNKMANN. HANS-GEORG ALLARDT.