DE1088484B - Process for the production of bicyclically substituted carbinamines or their non-toxic salts with an effect on blood pressure - Google Patents

Description

GERMAN

It has been found that carbinamines of the formula
CH ₂

.R '

CH _a

¹ R "

are characterized by interesting pharmacological properties, in particular by their partly antihypertensive, partly antihypertensive effect. In the formula, R denotes an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl radical optionally substituted in the aryl nucleus, R 'and R "denotes hydrogen, a saturated or unsaturated alkyl, cycloalkyl, cycloalkylalkyl or aralkyl radical optionally substituted in the aryl nucleus, and η = 0 or 1.

These compounds are obtained by using tertiary alcohols of the formula

CH ₃

in which R and η have the meanings given above, or reacts corresponding compounds obtainable from these alcohols by elimination of water and unsaturated in the side chain with hydrocyanic acid or with alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted aryl or aralkyl cyanides in the aryl nucleus. Strong inorganic or organic acids, in particular sulfuric acid or sulfonic acids, such as p-toluenesulfonic acid, are used as condensing agents. Glacial acetic acid is preferably used as the solvent, but other inert organic solvents such as methylene chloride or chloroform can also be added. The condensation takes place with evolution of heat, wherein the temperature of the reaction mixture rises to about 50 to 6O ⁰ C. If necessary, it can also be cooled. Acylamides of the formula are isolated from the reaction mixture by decomposition with ice and neutralization with suitable alkaline agents, such as sodium hydroxide solution or potassium carbonate

(CH ₂ ) "-C-NH - CO - R '"

CH ₃

in which R '"is a hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted in the aryl nucleus

Method of manufacture
blood pressure effective bicyclic

substituted carbinamines
or their non-toxic salts

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Hartmund Wollweber, Dr. Rudolf Hiltmann

and Dr. Wolfgang Wirth, Wuppertal-Elberfeld,

have been named as inventors

Aryl or aralkyl radical and is chosen so that the group CO - R '"can be converted into one of the two radicals R' or R" by conventional procedures can. As far as the radicals R and R '"are small, these amides represent distillable oils, some of which crystallize, and are according to known working methods, for. B. with the help of complex metal hydrides, catalytically or electrolytically reduced to the corresponding secondary amines, which according to known procedures in tertiary amines can be converted. As far as these are unsaturated, they can be according to known methods reduce to saturated amines. The acylamides mentioned can generally only be achieved by very energetic Saponify agent. The only exception are formamides, which are well hydrolyzed with alkalis can, while the treatment with acids leads to a destruction of the molecule, whereby under EHminierung the nitrogen unsaturated compounds are formed. It is advisable to heat the formamides with strong Alkalis, such as sodium or potassium hydroxide, in the presence of water and / or with water-miscible substances Alcohols or polyalcohols such as methanol or ethylene glycol. The addition of alcohol or glycol is appropriate chosen so that the hydrolysis takes place in a homogeneous medium. The resulting primary amines can optionally converted into secondary or tertiary bases by working methods known per se and the latter, as far as they are unsaturated, are reduced to saturated amines.

The free bases obtained in this way can be converted into their salts with inorganic or organic acids will.

009 590/423

3 4

The carbinols used as the starting material are. N-Benzyl ^ -bicyclo-P ^ .lJ-heptyldimethylcarbin-

obtainable by reaction of 2-bicyclo [2,2, l] -heptyl amine, Kp. ₄ 15O ⁰ C, hydrochloride-F. 225 to 23O ⁰ C

methyl ketone or 2-bicyclo- [2.2, l] -heptylacetone with (sublimed),

Grignard compounds, such as alkyl magnesium bromides, N-ß-phenethyl-2-bicydo- [2.2, l] -heptyldimethyl-

Benzylmagnesium bromide or phenethylmagnesium-5 carbinamine, b.p. ₇ 168 ° C, hydrochloride-F. 197 to

bromide. - 198 "C,

-r, · · _T η N-jS-Hydroxyäthyl ^ -bicydo-PÄll-heptyldimethyl-

r> eispiei carbinamin, b.p., 144 ° C, hydrochloride-F. 170 to

To 150 g; Glacial acetic acid, 169.7 g of 2-bicyclo- [2.2.1] -heptyldi-172 ° C.

methylcarbinol and 66 g of sodium cyanide are added in Example 4
A mixture of 300 g of H ₂ SO _{4 took place over one hour}

and 150 ecm of glacial acetic acid, the temperature being 50 to 61 g of 2-bicyclo- [2.2, l] -heptyldimethylcarbinamine

60 ° C should be kept. The mixture is stirred with 51 g of dimethyl sulfate and stirred overnight,

short time, it decomposes by pouring into dilute man then adds a to the reaction product

Sodium hydroxide solution, ethers out the reaction product, distilled a solution of 12 g of NaOH in 250 ecm of water, heated the

it in a vacuum and receives 85gN- (2-bicyclo- [2.2, l] -heptyl mixture briefly at 100 ⁰ C, ethers out the bases and receives

dimethylcarbinyl) formamide, Kp. _4140-144 ° C. after distillation in vacuo 13.7 g of N, N-dimethyl

The hydrolysis of 100 g of N- (2-bicyclo [2,2, l] -heptyl 2-bicyclo [2,2, l] -heptyldimethylcarbinamin, bp. _10, 102 ° C,

dimethylcarbinyl) formamide is obtained by 12 hours of Er hydrochloride-F. 152 ° C, iodine methylate-F. 223 to 225 ° C.

heat with 100 g of KOH, 150 g of water and 150 g of methanol ao. In addition, 20.9 g of N-methyl-2-bicyclo- [2.2, l] -heptyl-

carried out. The reaction mixture is poured in. ■ - Dimethylcarbinamine obtained, boiling point ₁₀ 91 ° C, hydro-

Completed reaction in water, ether out and distilled chloride-F. 152 ° C.

the essential solution in a vacuum. 80 g of 2-bis Example 5 are obtained
cyclo-P ^ .H-heptyldimethylcarbinamine of bp ₁₅ 80 ^o C,

Hydrochloride-F. 245 ° C. 35 To a mixture of 275g 2- (2-bicyclo- [2.2, l] -heptyl) ~

In an analogous procedure, 2-bicyclo- _:. 1,1-dimethylethanol, 110 g of sodium cyanide and 250 g

[2.2, l] -heptyldimethylcarbinol, acetonitrile, glacial acetic acid and glacial acetic acid are added dropwise over the course of one hour

H ₂ SO ₄ N- (2-bicyclo- [2,2,1] -heptyldimethylcarbinyl) - mixture of 400 g sulfuric acid and 200 ecm glacial acetic acid

acetamide, b.p. ₅ 148 to 150 ° C, with alcoholic potash in such a way that the temperature remains at 50 to 60 ° C. Man

Caustic solution to 2-bicyclo- [2,2,1] -heptyldimethylcarbinamine decomposes the reaction product with sodium hydroxide solution, separates

is soaping. the oil from, and obtained after its distillation in vacuo

Used as starting material 2-bicyclo [2,2, l] The - 262 g N-formyl-2- (2-bicyclo [2 _J 2, l] heptyl) -l, l-dimethyl-

heptyldimethylcarbinol, Kp. ₄ 62 to 64 ° C, bp. "72 to ethylamine, bp. 152 ° C _4, F.40 ° C.

76 ° C, by reaction of 2-bicyclo- [2.2, l] -heptyl- The saponification of 225 g of this compound leads to

obtained methyl ketone and methyl magnesium bromide. As 35 of the method given in Example 1 to 170 g of 2- (2-Bi-

By-product in this reaction some cyclo- [2,2, l] heptyl-l, l-dimethyläthylamin, Kp. _N 90 ⁰ C,

1- (2-Bicyclo- [2,2,1] -heptyl) -l-methylethylene, boiling point ₄ 45bis hydrochloride-F. 201 to 202 ° C.

47 ° C. The 2- (2-bicyclo-

Example 2 [2,2, l] -heptyl) -l, l-dimethylethanol, _{b.p. 12} 100 to 10 ⁰ C,

^P 40 is made by reacting 2-bicyclo- [2.2, l] -heptylessig-

To a mixture of 25 ecm of glacial acetic acid, 28 g of 1- (2-biacid ester with methylmagnesium bromide are obtained.
cyclo- [2,2,1] -heptyl) -l-methylethylene and 22 g NaCN

.will a mixture of 50 g of H ₂ SO ₄ and 25 ecm of glacial acetic acid Example 6
added dropwise. The mixture is stirred for a further 12 hours

obtained by the procedure described in Example 1 45 A solution of 40 g of N-formyl-2- (2-bi-

30 g of N- (2-bicyclo- [2.2, l] -heptyldimethylcarbinyl) -form-cyclo- [2.2, l] -heptyl) -l, l-dimethylethylamine in 100 ecm

amide, b.p. ₄ 140 to 144 ° C, which by saponification in the ether to a suspension of 30 g of lithium aluminum

2-Bicyclo- [2.2, l] -heptyldimethylcarbinamine, b.p. _ls 80 ° C, hydride in 200 ecm of ether, the mixture is heated for 12 hours

Hydrochloride-F. 245 ° C. under reflux, it decomposes with 50 ecm of ethyl acetate

50 ester, 10 cc water and 20 cc of 20 ° / ₀ sodium hydroxide solution.

Example 3 After inorganic constituents have been filtered off

the filter residue is boiled three times at 200 ecm

To 61.2 g of 2-bicyclo- [2.2, l] -heptyldimethylcarbinamine, benzene from, the benzene filtrates and the combined

dissolved in 50 ecm of benzene, 25 g of allyl ethereal filtrate are added dropwise and distilled in vacuo. Included

bromide joined. The mixture is boiled for a further 12 hours, 32.5 g of N-methyl-2- (2-bicyclo- [2.2, l] -heptyl) -

after suctioning off the excreted amine-1,1-dimethylethylamine, boiling point _u 98 ^° C., hydrochloride-F.

hydrobromide, the filtrate is alkaline, it ethers down- 160 ° C.

separated oil and fractionated it in a vacuum. In addition to example 7
llg of the starting amine from bp ₄ 57.5 to 58 ° C is kept

25 g of N-allyl-2-bicyclo- [2.2, l] -heptyldimethylcarbinamine _J 60 For 28 g of 2- (2-bicycto- [2.2, l] -heptyl) -l, l-dimethyl-

Bp ₄ 91 ° C, hydrochloride-F. 181 to 183 ⁰ C. ethanol, 35 ecm glacial acetic acid and 35 g diethylaminoacetonitrile

In an analogous procedure, a mixture of 55 g of sulfuric acid and is obtained from 2-bicyclo

[2,2, l] -heptyldimethylcarbinamin and the corresponding 25 cc glacial acetic acid at 55 to 6O ⁰ C a. One stirs that

the following compounds to the alkyl halides: Mixture still 12 hours and after the

N-n-Propyl ^ -bicyclo-p ^ .lj-heptyldimethylcarbin- 65 game 1 described procedure 24gN- / 5-diethylamino-

amine, b.p. ₅ 90 ° C, hydrochloride-F. 222 ° C, acetyl-2- (2-bicyclo- [2.2, l] -heptyl) -l, l-dimethylethylamine,

N-Isopropyl ^ -bicyclo-p ^ .lJ-heptyldimethylcarbin- Kp., 160 to 170 ° C.

amine, _{b.p. 5} 75 ⁰ C _/ hydrochloride-MP 291 ° C (sublimed), 24 g of the above amide are after the im

N-secondary-butyl ^ -bicyclo-P ^ lj-heptyldimethyl- Example 6 described procedure with 10 g of lithium

carbinamine, b.p. _lo 117 ° C, hydrochloride-F. 210 ⁰ C ₁ 70 aluminum hydride reduced, with 18 g of N-ß-diethyl

aminoethyl-2- (2-bicyclo - [2.2.1] heptyl) -1,1 -dimethyläthylamin, bp ₇₁₅₈ to 160 ⁰ C are obtained..

Example 8

33.5 g of 2- (2-bicyclo _[2,2, l] heptyl) _-l) l-dimethyläthylamin one adds 16 g / 3 Phenäthylchlorid and heated 25 hours at 130 to 140 ⁰ C; the reaction product is taken up in alkali, etherified and, after distillation in vacuo, 28 g of N - /? - phenethyl-2- (bicyclo- [2.2, l] -heptyl) -l, l-dimethylethylamine, bp ₆ 170 ⁰ C, hydrochloride mp 216 ° C.

In an analogous procedure, 2- (2-bicyclo- [2.2, l] -heptyl) -1,1 -dimethylethylamine and corresponding alkyl halides, the following compounds:

N-secondary butyl-2- (2-bicyclo- [2.2, l] -heptyl) -1,1-dimethylethylamine, b.p. ₆ 117 ° C, hydrochloride-F. 194 ° C,

N-Allyl-2- (2-bicyclo- [2.2, l] -heptyl) -l, l-dimethylethylamine, b.p. ₅ 108 ° C, hydrochloride-F. 163 ° C.

Example 9

16 g of dimethyl sulfate are added dropwise to 24.4 g of N-methyl-2- (2-bicyclo- [2.2, l] -heptyl) -l, l-dimethylethylamine over the course of one hour, and the mixture is stirred for 12 hours and heated reflux it with a solution of 5 g of sodium hydroxide in 50 ecm of water for 2 hours, extract the oily base with ether and distill it under reduced pressure, with 5 g of N, N-dimethyl-2- (2-bicyclo- [2, 2, l] heptyl) C, are obtained -1,1 -dimethyläthylamin, bp ₅₁₀₃ ^0th; Hydrochloride-F. 124 ⁰ C.

The compounds prepared according to the invention are with regard to intravenous and subcutaneous administration with regard to its effect on the blood pressure of the compound of the formula known from German patent specification 945 391

CH,

! - CH, - CH- NH- CH ₉ -HCl

and the compound of the formula known from German Patent 963 424

CH ₂ I.
J> - ^CH

.N.

HCl

and that known from the German Auslegeschrift 1 001 257 Compound of formula

CH ₂ -NH ₂

roughly equivalent. In the case of enteral administration, however, the compounds prepared according to the invention are far superior to the known compounds mentioned, since their use does not lead to blood irregularities, as they are observed to a large extent when using the compounds mentioned.

Claims (3)

Claims ·. 1. Process for the preparation of bicyclically substituted carbinamines of the formula which have an effect on blood pressure (CH ₈ ) ,, - -c -n; CH, R " in which R is an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl radical optionally substituted in the aryl nucleus, R 'and R "are hydrogen, a saturated or unsaturated alkyl, cycloalkyl, cycloalkylalkyl or aralkyl radical optionally substituted in the aryl nucleus and η = 0 or 1 mean, or their non-toxic salts, characterized in that tertiary alcohols of the formula - (CHJ _n -C-OH CH, in which R and η have the meanings given above, or corresponding compounds obtainable from these alcohols by elimination of water and unsaturated in the side chain with hydrocyanic acid or with alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted aryl or aralkyl cyanides in the presence of strong inorganic compounds or organic acids converts the acyl amides obtained of the formula - (CH ₂ ), - C - NH - CO - R '" CH, in which R '"denotes hydrogen, an alkyl, cycloalkyl, cycloalkylalkyl or aryl or aralkyl radical which is optionally substituted in the aryl nucleus and is selected so that the group CO - R'" can be converted into one of the radicals R 'according to conventional procedures or R "can be converted, and in which R and η are the same radicals as above, reduced by known methods, for example catalytically, electrolytically, or with suitable metal hydride complex compounds, if necessary the secondary amines obtained by known processes to tertiary ones Bases converted and these, if they are unsaturated, optionally reduced to corresponding saturated bases by known processes or that, if the acylamides mentioned are formamides, these are hydrolyzed to the free primary amines in the customary manner, the free amines afterwards if necessary known processes converted into secondary or tertiary bases and these, insofar as they are unsaturated, optionally all reduced to corresponding saturated bases by known processes and the carbinamines obtained are, if desired, converted into non-toxic salts with inorganic or organic acids. 2. The method according to claim 1, characterized in that the implementation of the tertiary Alcohols or the side chain unsaturated compound obtainable therefrom by elimination of water with hydrocyanic acid or nitriles in the presence 7 8 of sulfuric acid or p-toluenesulfonic acid. and glacial acetic acid used as a solvent. _. ,,. ,, ... ^ ₁ . . __. _o __ 3. The method according to claim 1 and 2, characterized in German Auslegeschrift No. 1 001 257; characterized in that the saponification of the form German Patent Nos. 945 391, 963 424; amides with strong alkalis, especially with potassium 5 Houben-Weyl, methods d. organ. Chem., Vol. 8, or sodium hydroxide in the presence of water 4th edition, 1952, p. 664, Vol. 11/1, 4th edition, p. 574 bis and / or with water mixers lower aliphatic 897; Alcohols or polyalcohols, such as methanol or P. Karrer, Lehrb. d. organ. Chem., 12th edition, 1954, Ethylene glycol. P. 131, last paragraph. © 009 590/423 8.60