DE1237571B - Process for the preparation of the new 5- (3'-dimethylamino-2'-methylpropyl) -3-chloriminodibenzyl - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY Int. CL:

C07d

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ρ - 5

Number: 1237571

File number: G 33665IV d / 12 ρ

Filing date: November 24, 1961

Open date: March 30, 1967

The invention relates to a process for the preparation of the new 5- (3'-dimethylamine-2'-methylpropyl) -3-chloriminodibenzyl of formula I and its salts.

Method of making the new

5- (3'-dimethylamino-2'-methylpropyl) -

3-chloriminodibenzyls

¹ - Cl

CH ₂ - CH - CH ₂ - N <
CH ₃

'CH ₃
^V CH ₃

These compounds have valuable pharmacological properties Properties, especially serotonin antagonistic, antiemetic and anti-inflammatory properties, also antiallergic effects. The new connection has no disruptive influence on cardiovascular functions, and their vegetative side effects are minor. The connection is of interest and can mainly because of its depressant effect on the central nervous system Used as a tranquilizer with an antidepressant component in various forms of mental disorders Find.

The process product (I) shows, with significantly lower toxicity, a significantly more pronounced central damping effect in a standard test than the 5 - (β - dimethylaminopropyl) - 3,7 - dichloroiminodibenzyl (II) known from German patent specification 1,038,047.

Applicant:

J. R. Geigy A.-G., Basel (Switzerland)

Representative:

Dr. F. Zumstein, Dr. E. Assmann

and Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Named as inventor:

Dr. Walter Schindler, Riehen;

Dr. Henri Dietrich, Birsfelden (Switzerland)

Claimed priority:

Switzerland of 25 November 1960 (13 253)

b) Results

a) method

Group toxicity of d, l-amphetamine sulfate
at the mouse

In this experiment, that dose of the test substance is determined, the groups of mice protects against the lethal effects of amphetamine sulfate (mice in groups are more sensitive against amphetamine sulfate as single animals). The experiment is carried out as follows:

In beakers with a diameter of 7 cm each five mice are placed, which were previously 50 mg / kg i. p. d, l-amphetamine sulfate in aqueous solution. At this dose amphetamine sulfate At a room temperature of 24 ° C, all animals perish within 24 hours. The test substances be s. c. Injected 30 minutes before the amphetamine sulfate. The mean dose is determined in which 50% of the animals survive the experiment.

Effective dose in mg / kg,

with the help of which 50%

of the mice survive

Compound I 50

Compound II> 100

c) toxicity

To determine the lethal dose DL50, the compounds to be tested are placed in white mice various single doses in aqueous solution i. v.

administered and the results evaluated as usual.

DL50

Compound I 42 mg / kg

Compound II 28 mg / kg

The compound of the formula I is prepared in a manner known per se according to one of the following two Procedure.

1. One puts 3-chloroiminodibenzyl in the presence of an acid-binding agent with a reactive ester of 3-dimethylamino-2-methylpropanol (Formula II)

/ CH ₃

HO-CH ₂ -CH-CH ₂ -N ^ II

^X CH ₃
around. CH ₃

709 547/405

Sodium amide, lithium amide, potassium amide and sodium are particularly suitable as condensing agents or potassium, butyllithium, phenyllithium, sodium hydride or lithium hydride. The implementation can be done in Presence or absence of an inert organic solvent, examples of which are benzene, toluene and xylene may be mentioned.

As reactive esters of the basic alcohol of the formula II, there are in particular the halides, Arylsulfonic acid esters and methanesulfonic acid esters in question. For example, the y-dimethylamino - /? - methyl-n-propyl chloride, called the corresponding bromide and the p-toluenesulfonic acid ester.

The starting compound y-dimethylamino - ^ - methyl-n-propyl chloride is z. B. by addition of hydrogen bromide to methallyl chloride and implementation of the γ-bromo-α-methylpropyl chloride thus obtained made with dimethylamine.

2. The compound of formula III is heated

/ CH ₃

CO - O - CH ₂ - CH - CH ₂ - N <
CH ₃

^ CH ₃

the ether phase washed with water, dried and evaporated, 58 parts of amorphous crude base being obtained. This base is distilled in a high vacuum, 47 parts of 5- (3'-dimethylamino-2'-methylpropyl) -3-chloroiminodibenzyl being obtained. Bp 134-137 ° C / 0.005 torr, n ' _D ⁵ = 1.5855.

The hydrochloride prepared from this base with alcoholic hydrochloric acid melts after recrystallization from acetone at 204 to 205 ° C.

Example 2

60 parts of 5- (3'-dimethylamino-2'-methyl-r-propyloxycarbonyl) -3-chloriminodibenzyl, prepared from 5-chlorocarbonyliminodibenzyl of melting point 140 to 142 ° C and S-dimethylamino ^ -methyl-1-propanol, are in water-jet vacuum heated to 16O ⁰ C. ^{The temperature is gradually increased to 210 °} C. until the elimination of carbon dioxide has ended. The residue is distilled further in a high vacuum, the fraction having a boiling point of 129 to 139 ° C. at 0.01 torr being separated off. The hydrochloride of 5- (3'-dimethylamino-2'-methylpropyl) -3-chloriminodibenzyl, prepared analogously to Example 1 from the Cd thus obtained, melts at 204-205.degree. Yield: 28 parts of hydrochloride.

until 1 mol of carbon dioxide is split off. This reaction occurs under reduced pressure at about 160 to 180 ° C and the temperature is completed at 200 to 240 ⁰ C by gradually increasing. The starting compound III is z. B. by allowing phosgene to act on 3-chloroiminodibenzyl and reacting the resulting 5 - chlorocarbonyliminodibenzyl with γ - dimethylamino - /? - methyl-n-propanol.

Compound.I is made according to the above procedures 1 and 2 obtained in racemic form. With the help of optically active acids, z. B. tartaric acid or its O-benzoyl or op-toluyl ester, are split into antipodes in a manner known per se.

With inorganic or organic acids, such as hydrochloric, hydrogen bromide, sulfur, phosphorus, methanesulphone, Ethandisulphone, vinegar, lemon, apple, amber, maleic, fumaric, wine, benzoin and Phthalic acid forms the compound I salts, some of which are water-soluble.

The following examples are intended to illustrate the invention Explain the creation of the new connection in more detail. Parts therein mean parts by weight; these relate to parts of volume as grams to cubic centimeters.

example 1 Example3

1.65 parts of the racemic base with a refractive index of U ² S = 1.5855 and 2 parts of d (-) - di-p-toluyltartaric acid are dissolved in 10 parts by volume of hot acetone, cooled to room temperature, and ether is added to the point of cloudiness and left to crystallize.

The crystallizate is made four more times from acetone. Ether recrystallized, after which 1.2 parts of d (-) - dip-toluyl tartrate des (+) - 5- (3'-dimethylamino-2'-methylpropyl) -3-chloroiminodibenzyl can be obtained.

M.p. 146-147 ° C, [a] f = -61.4 °, c = 1.11 in ethanol. From this, usually 0.5 parts of (+) - base and its hydrochloride can be obtained, mp 192 to 193 ° C.

Claims (1)

Claim: Process for the preparation of the new 5- (3'-dimethylamino - 2 '- methylpropyl) - 3 - chloriminodibenzyl of the formula I.
50 46 parts of 3-chloroiminodibenzyl are reacted with 7.8 parts of sodium amide in 400 parts by volume of boiling benzene in a nitrogen atmosphere with stirring. After completion of ammonia evolution (about 1 hour) y-dimethylamino-zi-methyl-n-propyl chloride was added dropwise at about 70 ⁰ C a solution of 30 parts in 150 parts by volume of benzene, and after completion of dropwise addition, stirring is continued for 14 hours under reflux. It is then cooled, mixed with about 250 parts by volume of water and the benzene phase is extracted with 2η hydrochloric acid. The acidic extracts are made alkaline, etherified, and its salts with inorganic or organic acids, characterized in that one is known per se Way either a) 3-Chloriminodibenzyl in the presence of an acid-binding agent with a reactive one Ester of JS-dimethylamino ^ -methylpropanol implements or b) the compound of formula III ΑΑΛΛ CO-O-CH ₂ - CH - CH ₂
CH ₃ ^ CH ₃ ^ CH ₃ heated until 1 mol of carbon dioxide is split off and, if appropriate, the base of the formula I thus obtained is split into its optical antipodes by means of optically active acids and optionally converted into a salt with an inorganic or organic acid. Considered publications:
German patent specification No. 1 038 047.