DE1119286B - Process for the preparation of blood pressure-effective tertiary amines - Google Patents

Description

GERMAN

PATENT OFFICE

F28065IVb / 12q

REGISTRATION DATE: MARCH 28, 1959

NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL: DECEMBER 14, 1961

It has been found that tertiary amines of the general formula

CH ₃

R-CH ₂ -C-N '

CH,

R '

CH ₃

due to their strong antihypertensive and, in some cases, ganglia-blocking effects distinguish. In the formula, R denotes hydrogen or an alkyl group with 1-3 carbon atoms, R 'is a straight, branched, saturated or unsaturated alkyl radical with at least 2 carbon atoms, which can be substituted by a hydroxyl and / or a phenyl group.

For the preparation of the amines obtainable according to the invention you can, for. B. reactive hydrohalic acid, Alkyl or aryl sulfonic acid esters of alcohols of the formula ROH with amines of formula

R _ CH ₂ -C (CHs) ₂ -NH-CH ₃

implement in a manner known per se.

Or you can use reactive derivatives of methanol, such as its hydrogen halide, alkyl or Arylsulfonic acid ester, with an amine of the formula

R _ CH ₂ - C (CHg) ₂ - NH - R '

realize.
You can also use amines of the formula

R - CH ₂ - C (CHs) ₂ - NH - R '

alkylate either catalytically with formaldehyde or reductively with sodium amalgam or with zinc-hydrochloric acid or with formic acid.
You can also use amines of the formula

R-CH ₂ -C (CHs) ₂ -NH-CH ₃

convert by methods known per se into a corresponding acylamide or thioacylamide, the acyl or thioacyl group of which contains at least 2 carbon atoms, and reduce this in a manner known per se electrolytically or with sodium amalgam or with complex metal hydrides.
Finally, you can also get amines of the formula

R - CH ₂ - C (CHs) ₂ - NHR '

Convert into the corresponding formyl compound and reduce this.

Method of manufacture
blood pressure acting tertiary amines

Applicant:

Paint factories Bayer Aktiengesellschaft,
Leverkusen-Bayerwerk

Dr. Rudolf Hiltmann, Dr. Hartmund Wollweber,

Dr. Wolfgang Wirth, Wuppertal-Elberfeld,

and Dr. Rudolf Gösswald, Wuppertal-Vohwinkel,

have been named as inventors

The tertiary amines obtained according to the invention are colorless liquids, which are in a vacuum without Allow decomposition to distill and which are soluble in organic solvents. They form with inorganic ones or organic acids, stable salts which crystallize well and which dissolve in water.

example 1

To 34.5 g of N-tert-butyl-isopropylamine are added dropwise with cooling 34.5 g of formic acid and then 33 g of 30% formaldehyde solution added strength to ^e. The mixture is heated to 100 ° C. in a reflux condenser for 12 hours and then, after adding 15 ml of hydrochloric acid, evaporated in vacuo. The residue is taken up with a little water, the amine separated with concentrated sodium hydroxide solution and distilled with steam. Sodium hydroxide solution is added to the distillate, the separated oil is separated off, dried with solid potassium hydroxide and distilled. The N-tert-butyl-N-methyl-isopropylamine with a boiling point of 130 ° C. is obtained as a shapeless liquid; Hydrochloride F. 205 to 206 ° C.

The N-tert-butyl-isopropylamine used as the starting material is obtained by heating tert-butylamine with isopropyl iodide in an autoclave 150 to 200 ° C and separation of the base with sodium hydroxide solution. Bp. 98 to 99 ° C.

Example 2

26.3 g of N-tert-butyl-ethylamine are added Cooling with 30.5 g formic acid. After adding 30 g of formaldehyde, the mixture is heated to 100 ° C., with Dissolution of the precipitated salt takes place. Man

109 749/533

holds 12 hours at 100.degree. C. and works according to the procedure given in Example 1. N-tert-butyl-N-methyl-ethylamine boils at 106 to 108 ° C. The hydrochloride melts at 206 to 207 ° C.

The N-tert-butyl-ethylamine used as starting material is obtained from tert-butylamine and ethyl iodide by heating in an autoclave to about 200 ° C. and separating the base with sodium hydroxide solution. Bp. 84 ° C. In the same way, N-tert-butyl-N-methyl-benzylamine with a b.p. ₁₃ 104 to 105 ° C. is obtained from N-tert-butyl-benzylamine. Hydrochloride, mp 208 to 209 ° C.

Example 3

15 g of N-tert-butylamino-2-pentane are refluxed with 60 g of formic acid and 75 g of formaldehyde solution (30%) for 12 hours. By the procedure described in Example 1, the mixture is worked up and obtains 9.5 g of N-tert-butyl-N-methyl-2-pentylamine, bp. _75o 168-170 ° C. F. hydrochloride 114 ° C.

The N-tert-butylamino-2-pentane used as starting material is obtained by reacting 73 g of sec-amyl bromide with 73 g of tert-butylamine in 50 g of glycerol on heating under reflux in an amount of 34%, _{b.p. 750} 138 up to 140 ° C. Hydrochloride F. 185 to 186 ° C.

Example 4

219 g of tert-butylamine, 271.5 g of ethyl α-bromopropionate and 200 ml of trichlorethylene are heated to 120 ° C. in an autoclave for 24 hours. After cooling, the precipitated tert-butylamine hydrobromide is filtered off with suction. The filtrate is dried with sodium carbonate solution and then extracted with dilute hydrochloric acid. The base is precipitated from the hydrochloric acid solution while cooling with ice, taken up in ether and dried with solid potassium hydroxide. After the solvent has been driven off, the mixture is distilled in vacuo and 184 g of ethyl (N-tert-butylamino) propionate of KP. ₁₆ 66.5 ° C.

52 g of ethyl a- (N-tert-butylamino) propionate in 300 ml of dry ether are added dropwise to a stirred suspension of 18 g of lithium aluminum hydride in 800 ml of dry ether. After boiling for 1 hour, it is decomposed with 90 ml of ethyl acetate and 30 ml of 20% sodium hydroxide solution, filtered off with suction and the filter residue is boiled three times with 300 ml of benzene each time. Evaporate the ether and the benzene solution a, combine the residue and distilled in a vacuum at a column, 29.6 g of N-tert-butyl-2-aminopropanol, bp. ₁₈ 78.5 pass to 80 ° C.

14.9 g of N-tert-butyl-2-aminopropanol, 14.3 g Formic acid and 12.5 g of 30% formaldehyde solution are heated to 100 ° C. for 24 hours Addition of 12 ml of pure hydrochloric acid is evaporated in vacuo and the solid residue is dissolved Isopropyl alcohol. 13.9 g of N-tert-butyl-N-methyl-2-aminopropanol hydrochloride are obtained from m.p. to 168.5 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of blood pressure-effective tertiary amines of the general formula CH _S R —CH ₂ -C - CH ₃ -R ' CH ₃ where R is hydrogen or an alkyl group having 1 to 3 carbon atoms and R 'is a straight, branched, saturated or unsaturated alkyl radical having at least two carbon atoms which can be substituted by a hydroxyl and / or phenyl group, characterized in that either a) reactive hydrohalic acid, alkyl or aryl sulfonic acid esters of alcohols of the formula ROH with amines of the formula R - CH ₂ - C (CH ₃ ) ₂ - NHCH ₃ implement or that one b) reactive derivatives of methanol with an amine of the formula R - CH ₂ - C (CHs) ₂ NHR ' implement or that one c) wet nurse of the formula R _ CH ₂ - C (CHs) ₂ - NH - R ' reductively alkylated or that one d) amines of the formula R-CH ₂ -C (CHs) ₂ -NHCH ₃ converted into corresponding acylamides or thioacylamides, the acyl or thioacyl group of which at least Contains 2 carbon atoms, and these are reduced or that one e) amines of the formula R _ CH ₂ - C (CHg) ₂ - NHR ' converted into a corresponding formyl compound and this reduced and the bases obtained in this way are optionally converted into salts. Considered publications:
Beilstein, Handbook of Organic Chemistry, Edition, Ergw. nj Vol. 4, p. 644. © 109 749/539 12.61