DE1144735B - Process for the production of basic substituted propanols and alkenylamines obtainable therefrom by splitting off water - Google Patents

Description

GERMAN

PATENT OFFICE

F30188IVb / 12q

REGISTRATION DATE: DECEMBER 28, 1959

NOTICE ABOUT REGISTRATION AND ISSUE OF EDITORIAL:

MARCH 7, 1963

It is known from German patents 925 468 and 875 660 that basic substitution is used Diphenylpropylamine is obtained when either basic substituted propionphenones or /3-tert.- aminopropionic acid esters are used Reacts with organometallic compounds; by splitting off water from the corresponding hydroxy compounds obtained and subsequent hydrogenation of the basic ones formed Basically substituted diarylpropane derivatives are obtained from alkenylamines.

It has now been found that basic substituted propanols that are on the same carbon atom Carry hydroxyl group and at least one phenyl radical, of the general formula

OH

CH ₃

RC ^ ³

/ \
R ₁ CH ₂ CH ₂ N-CH-CH ₂ -C ₆ H ₅

R ₂

in which R is hydrogen or a low molecular weight alkoxy group, R _{1 is} a phenyl radical optionally substituted by a low molecular weight alkoxy group and R _{2 is} hydrogen, which is methyl or the benzyl group, the corresponding alkenylamines obtainable therefrom by dehydration and the corresponding acid addition salts are valuable cardiovascular agents.

The present invention relates to the preparation of these compounds by in usual way

a) / 3- [l-phenyl-propyl- (2) -amino] -propionic acid ester or ß- [1-phenyl-propyl- (2) -amino] -ethylaryl ketone with organometallic compounds or

b) Basically substituted phenylpropanols reduced in the presence of phenylacetone or with 1-phenyl-2-halogenpropanes implements or

c) jö-Hydroxy-jS-phenyl-carboxylic acid-N- [1-phenylpropyl- (2)] - amides reduced to the corresponding amines

and optionally splitting off water from the compounds obtained.

Method of manufacture

of basic substituted propanols

and from it by splitting off water

available alkenylamines

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M.

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

and Heinrich Ott, Eppstein (Taunus),

have been named as inventors

As starting materials for the reaction of basic substituted propionic acid _{esters with organometallic compounds, for example: j} ö- [1-phenyl-propyl- (2) -amino] -propionic acid ethyl ester, / S- [1-phenyl-propyl- (2 ) -N-methylamino] -propionic acid-

ethyl ester, /? - [l-Phenyl-propyl- (2) -N-benzylamino] -propionic acid ethyl ester and the corresponding methyl, propyl, butyl, amyl or isoamyl esters. Preferred organometallic compounds are phenylmagnesium bromide, phenylmagnesium iodide, -o, m- or p-Methoxyphenylmagnesiumhalogenide used. Implementation will be more common Way in the presence of an inert solvent such as ether, benzene or toluene, by action both reaction components carried out on top of one another, with at least 2 moles of the organometallic Compound can be used on 1 mole of the ester. After longer or shorter boiling, the reaction mixture becomes decomposed in the usual way by water, acidified and removed from the ogganic solvent layer the corresponding hydroxy compound isolated in the usual way. When exposed to organometallic Compounds based on propionic acid esters

309 538/406

are according to the reaction scheme

CH ₃

2C ₆ H ₅ -MgBr, H ₆ C ₂ OC-CH ₀ -CH ₂ -N-CH

O CH ₂

2 H ₉ O

CH ₂ -CH ₂ -N-CH

+ 2MgBr (OH) + C ₂ H ₅ OH

always introduced two identical aromatic radicals, goes Li-N- (aralkyl) -acetamide can in the J. Am. Chem.

one carried out, however, of basic substituted Propiophe-Soc, 75, 2415, described manner

nones, i.e. keto compounds that are already becoming one. You can also use a modified one

containing aromatic radical, it is possible to carry out a Reformatsky reaction analogous to that in J. Am. Chem.

from the already existing various aromatic 20 Soc, 70, 677, specified procedure. the

or aliphatic radical on the carbon atom of the keto group Reduction of the amides thus obtained by means of lithium

to introduce. aluminum hydride is in the usual manner in the presence

As such propiophenones, for example, inert solvents such as ether, dioxane or

β- [I -phenyl-propyl- (2) -amino] -ethyl-phenyl ketone, tetrahydrofuran, made. Appropriately there

jS- [l-phenyl-propyI- (2) -N-methylamino] -ethyl-phenyl- 25 you add the amide to the lithium aluminum hydride

ketone, jS- [l-phenyl-propyl- (2) -N-benzylamino] ethyl suspension in one of the solvents mentioned,

phenyl ketone, /? - [l-phenyl-propyl- (2) -N-benzylamino] - then leaves the reaction mixture for some time

ethyl- (p-, m- or o-methoxyphenyl) ketone. Boiling under reflux as metal, then carefully decomposes with

Organic compounds are those already water above and works in the usual way by separating

mentioned Grignard-Verbin fertilize, furthermore also 30 of the organic of the inorganic constituents

aliphatic Grignard compounds, such as on. The reduction of the carbonamides described

wise ethylmagnesium halides, isopropyl, methyl, to the amines can also be carried out electrolytically.

Butyl or isobutyl magnesium halides. It is still possible to use the products of the process

The setting for the carboxylic acid esters is carried out by reducing amines of the formula
wrote way. 35

The products of the process can also be found under R

Use of Li-organic compounds her- <Χ - / ^^

place. For example, you can use the mentioned '^ = / - /

basic substituted propiophenones with phenyl-Li um- / ν

set. The reaction conditions correspond to those, 40 r> ου ητι χτυ

,. . ,, ».. .. _ _T. . . JK-I ^ JtI ₂ vjtl ₂ INJdL ₂

which have been explained above iur the reaction with organomagnesium compounds. The basic substituted propanols which are desired to be prepared in the presence of phenylacetone can be obtained from the lithium compounds obtained in R and R _{1 as defined above by the preparation of the decomposition with water which can be considered as starting materials.} 45 coming amines can be carried out, for example, by Hy-This reaction can also be carried out with aliphatic lithium hydration of the corresponding nitriles of the formula compounds, such as n-butyllithium.

According to a further embodiment of the process according to the invention, amides can also be used general formula

OH Ri CH ₂ -CN

CH ₃ in which R and R _{1 have} the above meaning;

I 55 the latter are e.g. B. by condensation of phenyl

CH ₂ - CO N - CH CH ₂ C ₈ H ₅ ketones can be obtained with acetonitrile using sodium amide

(cf. Annalen der Chemie, 603, p. 189 [1957]). As £ amines, for example: 1,1-Diphenyl-

² l-hydroxy-3-aminopropane, lo-, m- or p-methoxy-

reduce in the usual way, with particular 60 phenyl-1-phenyl-1-hydroxy-3-aminopropane, 3-phenyl advantage the reduction using lithium aluminum 3 - hydroxy - 1 - aminopentane, 3 - phenyl - 3 - hydroxyhydride is used. The production of the 1 - aminobutane, 3 - phenyl - 3 - isopropyl - 3 - hydroxy starting materials The amides used succeed, for example, in 1-aminopropane, 3-phenyl-3-iso- (or sec.) - butyl Implementation of diaryl or aryl alkyl ketones 3-hydroxy-1-aminopropane.

by means of araliphatic - in the sense of the above formula - 65 This reduction of the amines in the presence of substituted acetamides, in which a hydrogen phenylacetone is preferably catalytic atom of the methylene group in «position for carbonyl hydrogenation, z. B. with metals of the VIII. Group des group is replaced by Li. The production of this periodic table, preferably with nickel catalysts

5 6

Sators, in the presence of the usual solution Kraskow-Pissemski in small doses a mean, z. B. aqueous alcohols, alcohols or marked vasodilatory effect. 5 γ lead to

Water. Precious metals of a weak, 15Oy to a strong vascular-

or Raney catalysts can be used. Likewise extension. The process products are already in this way

can also be used with nascent hydrogen, e.g. B. 5 low dose coronary and peripheral vasodilators,

with aluminum amalgam and alcohol, sodium- that toxicity (for the above compounds

amalgam, lithium aluminum hydride or sodium - for example Dos. let. min. 15 to 20 mg / kg) practical

borohydride, reduce. The reduction is also negligible. The dehydration

can be carried out electrolytically. ization from the basic substituted propanols

Finally, it is also possible to have the corresponding alkenylamines obtainable in the process

products from the above-mentioned amines due to good cardiovascular effects.

with l-phenyl-2-halo-propanes. 2- [Γ ₅ Γ-diphenyl-Γ-hydroxy-propyl- (3 ') - amino] -

Halogen means chlorine, bromine or iodine to ver 3-phenylpropane and 2- [r, l'-diphenyl-propyl- (l ') - en-

stand. The reaction takes place in the usual way, am (3 ') ~ amino] -3-phenylpropane were in the form of their

best in the presence of a basic compound 15 hydrochloric acid salts further on the rabbit heart

for binding the released hydrogen halide ^, according to Langendorff in comparison with that as a vasodilator

where advantageous also a second mole of the unknown compound l- (p-hydroxyphenyl) -2- (l'-me-

. Settling amine can be used. You can use thyl-3'-phenyl-propyl-amino) -propanol- (I) -hydro-

but also tested with tertiary organic bases, such as chloride. All three substances showed one

Pyridine, quinoline, trimethylamine or triethylamine, 20 equally strong coronary vasodilator effects. Of the

as well as inorganic compounds, for example benefit of the products of the present process

Sodium, potassium or calcium carbonate or -bi lies in the fact that they are not like the reference substance

carbonate, work. The implementation can cause an increase in the frequency of the heartbeat

Essence or presence of an organic solvent and that its effect is specific to the coronary

solvent take place. Especially when using 25 vessels is turned off while the reference substance

inorganic, hydrogen halide binding agents strongly dilate peripheral vessels in the whole organism

one works preferably in suspension in one acts and thus an undesirable drop in blood pressure

organic solvents. As such a solvent evokes.

Indifferent organic products are suitable, for example. The process products can be used as basic Solvents such as benzene, toluene, ether or chloro-30 compounds with the help of inorganic or form. When the organic acids mentioned are used, they are converted into corresponding salts Bases such as pyridine or quinoline can become these. As inorganic acids, for example, come at the same time as solvents such as as water halide wise into consideration: hydrohalic acids, such as act as substance releasers. Hydrochloric acid and hydrobromic acid, so-

In those cases where R ₂ in the general formula 35 such as sulfuric acid, phosphoric acid and amidosulfone

the significance of acid for process products. Examples of organic acids are

Benzyl, it is possible either to be named after: formic acid, acetic acid, propionic acid,

the manufacture of process products of general lactic acid, glycolic acid, gluconic acid, maleic acid,

mean formula or succinic acid, tartaric acid, benzoic acid, salicylic acid,

Split off benzyl radical. This cleavage takes place 40 citric acid, aceturic acid, oxyethane sulfonic acid and

advantageously by catalytic hydrogenation using ethylenediaminetetraacetic acid.

Noble metal catalysts such as palladium black. The process products can be used as such or Cases where a hydrogenation in the presence of noble salts in the form of corresponding salts, possibly also in metal catalysts for the production of the amines applied to mixtures with conventional pharmaceutical carriers This splitting off of benzyl takes place in the 45 substances administered parenterally or orally. in the same operation. Oral application comes as a dosage

The basic substituted propanols obtained form preferably tablets or dragees in Fi age,

can optionally by splitting off water in which the process products are used as active ingredients

corresponding alkenylamines are converted. with the usual carrier substances, such as lactose,

This conversion takes place with the help of the usual dehydrated starch, tragacanth and magnesia tearate, processed

sizing agent, for example phosphoric acid, p-toluene can be,

sulfonic acid, phosphorus pentoxide, acetic anhydride example 1
etc. (cf., for example, those in the annals of the

Chemie, 603, p. 189 [specification given in 1571). a) 75 g ^ -hydroxy- ^ jS-diphenyl-propionitrile (her-

The products of the process are valuable drugs. 55 According to Annalen der Chemie, 603, p. 194), they are medium-sized and, above all, have an extraordinarily beneficial cardiovascular effect in 500 ecm of methanol in the presence of Raney nickel. Thus resulting hydrogenated at 80 to 85 ⁰ C. After filtration, the z. B. the administration of the 2- [r, l'-diphenyl-l'-hy solution is concentrated, the residue dissolved in dilute SaIzdroxypropyl- (3 ') - amino] -3-phenyIpiopan-hydrochloride acid and filtered with charcoal. After adding 2N sodium hydroxide solution to rabbit mink according to Langendorff at a duration of 60%, the 1,1-diphenyl-1-hydroxy infusion of 1.2 y / minute to form a significant propylamine (3) crystalline is obtained. The melting point is the increase in the coronary flow, which is 143 to 144 ° C during infusion.

of 2 y / minute becomes a maximum. Even after switching off b) 11.4 g 1,1-diphenyl-l-hydroxypropylamine- (3)

the infusion keeps the flow rate increasing as starting material with 6.7 g phenylacetone in

for a long time. In addition, there is a decrease in isopropanol in the presence of palladium black in the

the heart rate, which is also hydrated in the entire animal shaker. After recording the calculated

makes noticeable. The same compound also has neten amount of hydrogen and separation of the catalyst

on the isolated, perfused rabbit heart after Sators by filtration, the solution is

Claims (1)

reduced! Pressure restricted. 17 g of an oily residue are obtained which, after work-up, is customary Way the hydrochloride of 2- [r, r-diphenyl-l'-hydroxy - propyl - (3 ') - amino] - 3 - phenylpropane with a melting point of 213 to 214 ° C gives. Example 2 According to the instructions given in Example 1, a), hydrogenation from the β- (m-methoxyphenyl ) - /? - phenyl- / S-hydroxy-propionitrile, obtained according to Annalen der Chemie, 603, p. 194, from m-methoxybenzophenone and acetonitrile, the ß- (m-methoxyphenyl) - β - phenyl - β - hydroxypropylamine is produced as the starting material, the melting point of which is 61 to 62 ° C. The hydrogenation in the presence of phenylacetone is carried out in the manner described in Example 1, b). After work-up, a.us 12.5 g of (/ Sm-methoxyphenylJ-jS-phenyl - ^ - hydioxy-propylamine 16 g of hydrochloride of 2- [l'-m-methoxyphenyl-l'-phenyl-1 '-hydroxy- propyl- (3 ') - amino] -3-phenylpropane obtained of melting point 175-176 ⁰ C. Example 3 According to the instructions given in Example 1, a), hydrogenation from the jff-phenyljS-hydroxy-valeronitrile with a melting point of 59 to 60 ° C, obtained according to Annalen der Chemie, 603, p. 194, from propiophenone and acetonitrile, the 3- phenyl-3-hydroxy-5-aminopentane as a starting material whose melting point is 99 to 100 ⁰ C. The hydrogenation in the presence of phenylacetone follows as described in Example 1, b). From 17.9 g S-phenyl-S-hydroxy-1-aminopentane and 13.4 phenylacetone 16.9 g of 2- [3'-phenyl-3'-hydroxypentyl- (5 ') -amino] -3-phenylpropane are obtained obtained from melting point 93 to 95 ° C. The hydrochloride of this base melts at 161 to 163 ° C. Example 4 a) 32.5 g | 5- [N-Benzyl-N-l-phenyl-propyl- (2) -amino] -propionic acid ethyl ester, made from / 3-chloro-propionic acid ethyl ester and N-benzyl-N-1-phenyl-propyl- (2) -amine, become a phenylmagnesium bromide solution made from 10 g of magnesium and 60 g Bromobenzene in 150 ecm of ether, dripped. Then the reaction mixture is under for a few hours Refluxed. After pouring onto ice and acidifying with dilute hydrochloric acid, the hydrochloride precipitates of 2- [N-benzyl-N-r, r-diphenyl-1'-hydroxypropyl- (3 ') -amino] -3-phenylpropane the end. b) By catalytic hydrogenation in the shaking duck in the presence of palladium black in isopropanol the benzyl radical is split off as a solvent. After filtration and concentration, the residue is obtained the hydrochloride of 2- [r, l'-diphenyl-l'-hydroxypropyl - (3 ') - amino] - 3 - phenylpropane from Melting point 213-214 ° C obtained. Example 5 According to the procedure given in Example 4, 35.7 g of ^ - [N-benzyl-N-1-phenyl-propyl- (2) -amino] -propiophenone, prepared from jS-chloropropiophenone and N-benzyl-Nl-phenyl- propyl- (2) -amine, with a Grignard solution, prepared from 8 g of magnesium and 60 g of m-methoxy-bromobenzene, converted into ether and, as described there, worked up and debenzylated. This gives the hydrochloride of 2- [rm-methoxy-phenyl-l-phenyl-l-hydroxy propyl - (3 ') - amino] - 3 - phenyl propane, melting point 175-176 ⁰ C. Example 6 35.7 g of jS- [N-Benzyl-N-1-phenyl-propyl- (2) -amino] -propiophenone are in accordance with the instructions given in Example 5 with a lithium phenyl solution, made from 4 g lithium and 40 g bromobenzene. The work-up is carried out as in Example 5 described. After debenzylation according to the procedure of Example 4, the Hydrochloride of 2 - [1 ', Γ - diphenyl -Γ - hydroxy propyl- (3') - amino] -3-phenylpropane obtained from melting point 213 to 214 ° C. Example 7 Analogous to that in J. Am. Soc. 75, p. 2415 ao way is made from propiophenone and Li- [N-benzyl-N-1 -phenyl-propyl- (2)] - acetamide jS-phenyl - ^ - hydroxy-N-1 -Phenyl-propyl- (2) -N-benzyl-propionamide. 10 g / S-phenyl- / 3-hydroxy-Nl-phenyl-propyl- (2) -N-benzyl-propionamide as starting material are added to a suspension of 20 g of lithium aluminum hydride in 500 ecm of anhydrous ether and the mixture is refluxed for 6 hours cooked. After decomposition with water, 3-phenyl-3-hydroxy-5-[N-Γ-phenyl-propyl-(2 ') -N-benzylamino] pentane is obtained from the ethereal layer after drying and distilling off the solvent. After debenzylation as in Example 4 and the addition of dilute hydrochloric acid, the hydrochloride of 2- [3'-phenyl-3'-hydroxypentyl- (5 ') -amino] -3-phenylpropane with a melting point of 93 to 95 ° C. is obtained. The hydrochloride of this base melts at 161 to 163 ^° C. Example 8 ll, 1 g!, l-diphenyl-l-hydroxy-3-aminopropane and 3.9 g l-phenyl-2-cb.lorpropan be 3 hours in an oil bath at an internal temperature of 160 ⁰ C heated. After cooling, the reaction mixture is treated with dilute hydrochloric acid. The crystalline hydrochloride des2- [l ', 1' -diphenyl-1 '-hydroxy-propyl- (3') -amino] -3-phenylpropane melts after recrystallization from alcohol-ether at 211 to 212 ° C. Examples 4.4 g of 2- [r, r-diphenyl-1'-hydroxypropyl- (3 ') -ammo] -3-phenylpropane are heated for about 15 minutes in 30 ecm of toluene and 2 g of p-toluenesulfonic acid, until no more water is separated. After cooling, the reaction mixture is washed with 2N sodium hydroxide solution made alkaline and etherified. After the ether has dried and distilled off, the The residue converted into the hydrochloride with dilute hydrochloric acid. After recrystallizing from a The alcohol-ether mixture is the hydrochloride of 2- [r, r-diphenyl-propyl- (1 ') - en- (3') - amino] -3-phenylpropane obtained from melting point 202 to 203 ° C. ⁶ S PATENT CLAIM: Process for the preparation of basic substituted propanols of the general formula OH CH, - GH »- N - CH - CH in which R is hydrogen or a low molecular weight alkoxy group, R _{1 is} a phenyl radical optionally substituted by a low molecular weight alkoxy group and R _{2 is} hydrogen, which is methyl or benzyl group, and alkenylamines obtainable therefrom by dehydration and their acid addition salts, characterized in that one in usual way a) /? - [l-Phenyl-propyl- (2) -amino] -propionic acid ester or / 3- [l-phenyl-propyl- (2) -amino] -ethyl- _ao- aryl-ketones with corresponding organometallic compounds or b) corresponding basic substituted phenylpropanols in the presence of phenylacetone reduced or with l-phenyl-2-halopropane implements or c) jS-Hydroxy-β-phenyl-carboxylic acid-N- [1-phenylpropyl- (2)] - amides reduced to the corresponding amines and optionally splitting off water from the compounds obtained. Considered publications:
HP Kaufmann, "Drugs Synthesis" (1953), p. 198; W. Hü ekel, "Pharmaceutical Chemistry and Drug Syntheses", Volume II (1954), p. 333. © 309 538/406 2.63