DE1100031B - Process for the preparation of basic substituted diphenylmethane derivatives - Google Patents

Description

GERMAN

Diphenylmethane derivatives having an aminoalkyl group or a heterocyclic group are for example known from German patent specification 766 207 as spasmolytics.

It has now been found that basic substituted diphenylmethane derivatives of the general formula can be obtained

Method of manufacture
of basic substituted
Diphenylmethane derivatives

x:

CH,

H. 'XN · ~ "" "~ ™ ν / XJL ν / XXo" * "

wherein X is a straight-chain or branched alkylene group with 2 or 3 carbon atoms, R is a hydrogen atom ^J 5 or a low molecular weight, aliphatic acyl group, R _{2 is} a hydrogen atom or a low molecular weight alkyl group and R ₃ and R _{4 are} hydrogen atoms, hydroxyl groups or low molecular weight alkoxy groups, their salts and Quaternary ammonium salts are obtained when diphenylacetonitrile or diphenylmethane is used with compounds of the general formula

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Gustav Ehrhart, Bad Soden (Taunus),

Heinrich Ott, Eppstein (Taunus),

And Dr. Ernst Lindner, Frankfurt / M.-Höchst,

have been named as inventors

CH ₃

Hal-XN-CH-CH ₂ -.

_R ₆

= x

R ₇

where Hai is a halogen atom, R _{5 is} a low molecular weight alkyl radical or the benzyl group and R ₆ and R _{7 are} hydrogen atoms or low molecular weight alkoxy radicals, in the presence of agents which split off hydrogen halide and then a nitrile group which may be present in the reaction products either by the action of alkyl magnesium halides and saponification of the The resulting imino group is converted into a low molecular weight acyl group or is replaced by a hydrogen atom by heating with sodium amide in the presence of benzene or toluene or by saponification with strong acids and heating of the carboxyl compound that is formed and / or a benzyl group optionally bonded to the nitrogen atom by catalytic hydrogenation in the presence of a noble metal catalyst split off and any compounds obtained in this way which carry a hydrogen atom on the nitrogen atom, methylated in a manner known per se on the nitrogen atom and / or any alkoxy group present en is optionally converted into hydroxyl groups in a manner known per se and / or the bases obtained are converted into their salts with acids or into their quaternary ammonium salts with alkyl halides.

The reaction of diphenylacetonitrile with halogen-substituted bases of the above formula can in accordance with the specification given in Liebigs Annalen, 561, p. 52 ff. (1948). As such Bases come into question in the process according to the invention, for example: 1-phenyl-2- (N-chloroethyl-N - methyl) - amino - propane, 1 - phenyl -2 - (N - chloroethyl-N-benzyl) -amino-propane, 1- (3 ', 4'-dimethoxyphenyl) -2- (N-chloroethyl-N-methyl) -amino-propane, 1- (3', 4'-dimethoxyphenyl) -2- (N-chloroethyl -N-benzyl) -amino-propane, 1- (4'-Methoxyphenyl) -2- (N-chloroethyl-N-benzyl) aminopropane.

The reaction is preferably carried out in inert organic solvents, for example benzene or toluene or xylene. Agents that split off hydrogen halide include, for example: sodium amide, Phenyl sodium, phenyllithium and metallic sodium, two of the three required will be advantageous

\ o Reaction components (diphenylacetonitrile, agents splitting off hydrogen halide and halogen base) dissolved or slurried in an inert solvent and the third component added in portions. When the addition is complete, it is expediently refluxed for some time and, after adding water, the reaction mixture is worked up in the customary manner, for example by extracting the basic constituents from the organic solvent with dilute acids.

The reaction of diphenylmethane with the halogen-substituted bases mentioned is carried out in an analogous manner and a hydrogen halide releasing agent carried out; the latter is in this case with special

. the advantage of which is phenyl sodium.

109 527/555

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The transfer of a product in the process. After 1 hour of refluxing, the if diphenylacetonitrile is used as the reaction mixture, water is added and the benzene starting material is added any nitrile group present separated from the layer. Add to the benzene layer In a hydrogen atom, dilute hydrochloric acid and ether can be added in a manner known per se, whereupon the hydro (cf. Liebigs Annalen, 561, p. 52ff. [1948]) by prolonged 5 chloride des 2- [N- (I ', l'-diphenyl-l'-cyano-propyl-3') - N-me heating with sodium amide in benzene or toluene-ethyl] -amino-3-phenyl-propane in an amount of 70 g follow. The nitrile group can also be crystallized out with strong acids.

for example, 70 ° / ₀ sulfuric acid, to carboxyl 36.8 g of this nitrile dissolved in 100 cc of xylene are

group are saponified, whereupon by heating from the to a Grignard solution of 3.6 g of magnesium and 18 g

Carboxyl compound carbon dioxide is split off. io bromoethane given in ether. After 4 hours of cooking

The conversion of the nitrile group into a keto group in an oil bath of 145 ° C is the cooled solution with

takes place through the action of alkyl magnesium halide 100 ecm hydrochloric acid (1: 1) added and 5 hours

niden and subsequent saponification of the imino group heated in the steam bath. Three layers are formed

in a manner known per se (cf. Liebigs Annalen, 561, the middle, dark brown layer is separated and

P. 58 [1948]). 15 made alkaline with ammonia. After leaving

The splitting off of any ether present, drying and distilling off the ether is preserved

Benzyl group on the nitrogen atom is also added to 30 g of 4,4-diphenyl-6- [N-methyl-N- (3'-phenyl-propyl-

carried out in a known manner, namely by 2 ')] - amino-hexanone- (3); Kp _0j4 . 213 to 215 ° C.
catalytic hydrogenation in the presence of a noble metal

catalyst. The methyl, if necessary, to be carried out
lation at the nitrogen atom of the —NH-

Group is also according to a known method, 33g2- [N- (l ', l'-diphenyl-l'-cyano-propyl-3') - N-methyl] -

for example by catalytic hydrogenation in counter-amino-3-phenyl-propane are dissolved in 150 ecm of benzene

wart of formaldehyde or by heating with form and the solution with 33 g of sodium amide for 2 hours

aldehyde and concentrated formic acid, feasible. 25 refluxed. After suctioning off the excess

The elimination of methoxy groups in the aromatic sodium amide is reduced by the benzene

The core of the process products can be distilled off in a known manner, pressure. The residue (28 g) is distilled,

for example by boiling with hydrobromic acid, one obtains 20g2- [N- (l ', l'-diphenyl-propyl-3') - N-methyl] -

be made. amino-3-phenyl-propane in the form of a colorless oil;

The process products can be used as basic 30 Kp _{0> 08} . 170 to 175 ° C.

bonds with the help of inorganic or organic. .

Acids are converted into the corresponding salts. .Example ο

Inorganic acids include, for example, In a mixture of 38.6 g of diphenylacetonitrile and

Consideration: hydrohalic acids such as hydrochloric acid 58 g of l-phenyl-2- [N-benzyl-N-chloroethyl] -amino-propane

chemical acid and hydrobromic acid, as well as sulfuric acid (prepared according to the US Pat. No. 2,597,247,

acid, phosphoric acid and sulfamic acid. As orga- Example 1, specified regulation) in. 200 ecm benzene

Examples of niche acids are: Ants, 10 g of sodium amide are added. After an hour

acid, acetic acid, propionic acid, lactic acid, maleic acid, like refluxing the reaction mixture

Succinic acid, tartaric acid, benzoic acid, salicylic acid, mixed with water and the benzene layer separated.

Citric acid, aceturic acid, oxyethanesulfonic acid and 4 °. Dilute hydrochloric acid and ether are added and obtained

Ethylenediaminetetraacetic acid. One can process the 2- [N- (I ', l'-diphenyl-l'-cyano-propyl-3') - N-benzyl] -

including products with the aid of alkyl halides in entamino-3-phenyl-propane hydrochloride in the form of an oil;

Transferring speaking quaternary salts, provided the yield: 32 g.

basic radical contains a tertiary nitrogen atom. 30g 2- [N- (I ', l'-diphenyl-l'-cyano-propyl-3') - N-benzyl] -

The process products have a relatively low 45 amino-3-phenyl-propane are dissolved in 150 ecm benzene;

Toxicity an extremely favorable heart and the solution is mixed with 30 g of sodium amide and

Circulatory effect on. So z. B. the administration refluxed for 2 hours. After suction

of 4,4-diphenyl-6- [N-methyl-N- (3'-phenyl-propyl-2 ')] - from the excess sodium amide, the benzene is under

Amino-hexanone- (3) distilled off at rabbit heart after Langen- reduced pressure. The residue (23 g)

village f with a flow rate of 6 to 15 y 50 is cleaned via the hydrochloride. The corresponding

per minute to a strong coronary vasodilation. Maleat of the compound melts at 138 to 140 ° C.

The heart rate and the length of the beat remain un- 16 g 2- [N- (I ', l'-Diphenylpropyl-3') - N-benzyl] -amino-

changes. 3-phenyl-propane are dissolved in 100 ecm isopropanol in

The products of the process are hydrogenated even in such a small presence of palladium black. After on cans Coronary and peripheral vasodilators that the 55 would take the calculated amount of hydrogen is from Toxicity - the lethal dose of 4,4-diphenyl-6- [N-me catalyst filtered off and the filtrate under reduced ethyl-N- (3'-phenyl-propyl-2 ')] -amino-hexanone- (3) is concentrated under pressure. The colorless oil obtained is with z. B. 30 mg / kg in the experiment on the mouse - practically the calculated amount of glycolic acid in the 2- [N- (I ', 1'-Dinot | ns weight falls. phenyl-propyl-3 ')] - amino-3-phenyl-propane-glycolate over-

The coronary caused by the process products; M.p. 140 to 141 ° C. The yield is 11.5 g.

flow through is about eight to ten times stronger than

after administration of the known compound 1-p-Hy- l-phenyl-2- [N-benzyl-N- (2'-chloro-propyl-l ')] - amiao-pro-

droxyphenyl-1-hydroxy-2-methylamino-propane, which pan (produced analogously to that in the USA secondary increased coronary blood flow (2,597,247 specified prescription) and sodium amide

evokes. 65 the 2- [N- (l ', l'-diphenyl-l'-cyano-2'-methyl-propyl-3') -

For example 1 N-benzyl] -amino-3-phenyl-propane was obtained. The Abspal-

treatment of the nitrile group and the benzyl group takes place

. ' Into a mixture of 38.4 g of diphenylacetonitrile and 42 g according to the instructions given above. To l-Phenyl-2- (N-methyl-N-chloroethyl) -amino-propane in addition of hydrochloric acid gives the hydrochloride of

50 ecm of benzene, 9 g of sodium amide are added. 70 2- [N- (l ', l'-diphenyl-2'-methyl-propyl-3')] - amino-3-phe-

nyl propane; F. 218 to 220 ° C. The yield is about 50% of theory.

In an analogous manner, diphenylacetonitrile and l-phenyl-2- [N-benzyl-N- (l'-chloro-propyl- (2 ')] aminopropane are obtained (prepared analogously to the specification given in US Pat. No. 2,597,247) and sodium amide das 2- [N- (I ', 1' -Diphenyl-1 '-cyano-S'-methyl-propyl-S'J-N -benzyl] -amino-3-phenyl-propane. After splitting off the nitrile group and the benzyl radical and adding aminosulfonic acid the aminosulfonic acid salt of 2- [N- (I ', l'-diphenyl-3'-methyl-propyl-3')] -amino-3-phenyl-propane is obtained; F. 147 to 148 ° C. The yield is about 50% of theory.

Example 4 ¹ p

In a mixture of 38.6 g of diphenylacetonitrile and 62 g of 1-p-methoxyphenyl-2- (N-benzyl-N-chloroethyl) aminopropane (prepared according to the specification given in Example 4 of US Pat. No. 2,597,247) in 250 ecm 10 g of sodium amide are added to benzene. After refluxing for 90 minutes, water is added to the reaction mixture and the benzene layer is separated off. After adding dilute hydrochloric acid and ether, the 2- [N- (I ', 1'-diphenyl-1'-cyano-propyl-3') - N-benzyl] -amino-3- (p-methoxyphenyl) crystallizes -propane in the form of the hydrochloride; Yield: 43 g.

35 g of the base of the above hydrochloride are dissolved in 200 ecm of benzene; the solution is 35 g Added sodium amide and reboiled for 2 to 3 hours. After suctioning off the excess Sodium amide, the benzene is distilled off from the filtrate under reduced pressure. The residue (26 g) is purified via the hydrochloride. 19 g of 2- [N- (I ', l'-diphenyl-propyl-3') -N-benzyl] -amino-3- (p-methoxyphenyl) -propane obtained in this way are hydrogenated in 130 ecm isopropanol in the presence of palladium black. After admission the calculated amount of hydrogen is filtered and the filtrate is concentrated under reduced pressure. The oily residue is converted into 2- [N- (I ', l'-diphenylpropyl-3')] amino-3- (p-methoxyphenyl) propane hydrochloride with the calculated amount of hydrochloric acid convicted. The yield is 12 g.

50 ecm of 48% strength aqueous hydrobromic acid are added to 12 g of the hydrochloride and the mixture is 2 hours refluxed. The red oil that has settled out solidifies when it cools down. After adding diluted Caustic soda and ether are separated from the ether layer. So long carbonic acid becomes in the aqueous alkaline solution initiated until a pa value of 8 is reached. The deposited, oily base solidifies after a short time. After recrystallization from ethyl acetate, 7g2- [l ', l'-diphenyl-propyl-3')] -amino-3- (p-hydroxyphenyl) propane is obtained; F. 144 to 145 ° C.

Claims (1)

Claim: Process for the preparation of basic substituted diphenylmethane derivatives of the general formula C ₈ H ₅ C _fi H _s CH ₃ "XN-CH-CH ₂ -.
R, v ^Rs 'R ₁ where X is a straight-chain or branched alkylene group with 2 or 3 carbon atoms, R is a hydrogen atom or a low molecular weight, aliphatic acyl group, R _{2 is} a hydrogen atom or a low molecular weight alkyl group and R ₃ and R _{4 are} hydrogen atoms, hydroxyl groups or low molecular weight alkoxy groups, their salts and quaternary ammonium salts , characterized in that one diphenylacetonitrile or diphenylmethane with compounds of the general formula CH, Hai - X - N - CH _{- CH 2 - χ} \> . , R ₆ R ₇ where Hai is a halogen atom, R _{5 is} a low molecular weight alkyl radical or the benzyl group and R ₆ and R _{7 are} hydrogen atoms or low molecular weight alkoxy radicals, in the presence of agents which split off hydrogen halide, and then a nitrile group which may be present in the reaction products either by the action of alkyl magnesium halides and saponification the resulting imino group converted into a low molecular weight acyl group or replaced by heating with sodium amide in the presence of benzene or toluene or by saponification with strong acids and heating of the carboxyl compound formed by a hydrogen atom and / or a benzyl group optionally bonded to the nitrogen atom by catalytic hydrogenation in the presence of a Noble metal catalyst is split off and, if appropriate, compounds obtained in this way which carry a hydrogen atom on the nitrogen atom, methylated in a manner known per se on the nitrogen atom and / or any alkoxy group present pen is optionally converted into hydroxyl groups in a manner known per se and / or the bases obtained are converted into their salts with acids or into their quaternary ammonium salts with alkyl halides. © 109 527/555 2.61