Claims
- 1. A process for obtaining an .alpha.-amino nitrile of the formula ##STR24## wherein R is a substituted or unsubstituted mono-or bicyclic hetero aryl of 4 to 7 links in each ring optionally interrupted with 1 or 2 heteroatoms selected from the group consisting of --O--, --S-- and --NH-- and optionally substituted with at least one member of the group consisting of lower alkyl, hydroxy (lower) alkyl, pyridyl, phenyl and pyrimidinyl and R' is hydrogen or an organo selected from the group consisting of unsubstituted or substituted alkyl of 1 to 3 carbon atoms and a mono or bicyclic aromatic comprising reacting a nitrile selected from the group consisting of an alkyl nitrile having 1 to 30 carbon atoms, an alkenyl nitrile of 2 to 30 carbon atoms and an aryl nitrile selected from the group consisting of mon-cyclic aryl nitrile and bicyclic aryl nitrile, an arylalkyl nitrile in which the alkyl moiety has from 1 to 15 carbon atoms, an aryloxy lower alkyl nitrile unsubstituted or substituted by one to three substituents on the aryl moiety or a cycloalkyl nitrile of 4 to 7 carbon atoms comprising reacting a compound of formula
- R--C.ident.N II
- wherein R has the above-given meaning with a metallic reducing agent selected from the group consisting of an aluminum hydride, an organo magnesium salt of the formula R' Mg X wherein R' is an unsubstituted or substituted alkyl or 1 to 30 carbon atoms or a mono-or bicyclic aryl, an organozinc salt of the formula
- Hal--Zn--R'
- wherein R' is defined as previously given and Hal and X are a halogen atom other than fluorine, organo cadmium salt and organo copper salt to form a metallic imine of the formula ##STR25## in which R and R' have the previously given definitions, Me is a metal atom selected from the group consisting of aluminum, magnesium, zinc, cadmium and copper, Z is lower alkyl or halogen and n is an integer equal to the valence of the metal less one, reacting the latter with a cyaniding agent selected from the group consisting of methylsilyl cyanide, diethylaluminum cyanide, tributylstannicyanide and alkali- or alkaline-earth metal cyanoborohydride, an alkali metal cyanide in the presence of a Crown Ether and hydrocyanic acid in solution in an oxygen-bearing solvent and recovering the corresponding .alpha.-amino nitrile of formula I.
- 2. A process according to claim 1 in which the metallic reducing agent is an aluminum hydride having at least one free hydrogen atom.
- 3. A process according to claim 1 and 2 in which the metallic reducing agent is diisobutylaluminum hydride, diterbutoxy-aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride.
- 4. A process according to claim 1 in which the metallic reducing agent is an alkylating or arylating agent selected from the group consisting of organomagnesium salts, organocadmium salts, organozinc salts and organocopper salts.
- 5. A process according to claim 1 in which the cyaniding agent is selected from the group consisting of diethylaluminum cyanide, trimethylsilyl cyanide, tributylstannic cyanide, an alkaline metal cyanide or hydrocyanic acid.
- 6. A process according to claim 1 in which the two reactions are carried out successively, in the same reaction mixture.
- 7. A process according to any one of claims 1 and 2 to 5, in which the two reactions are carried out at low temperature and under an inert gas atmosphere.
- 8. A process of claim 1 for preparing amino-3-(5-methoxy-3-indolyl)-propionitrile.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 85-17214 |
Nov 1985 |
FRX |
|
PRIOR APPLICATION
This application is a division of U.S. Pat. application Ser. No. 086,731 filed Aug. 4, 1987, now U.S. Pat. No. 4,942,221.
The present invention relates to the synthesis of nitriles an amine function on the adjacent carbon.
It relates more especially to a process for preparing .alpha.-aminonitrile which consists in transforming a nitrile into its upper homologue bearing an amine function in .alpha.-position, by a one-stage process.
Thus, the present invention provides a process for obtaining .alpha.-aminonitriles of the general formula I: ##STR3## wherein R represents an aliphatic, aromatic or cycanic radical, R' represents a hydrogen atom, an unsubstituted or substituted alkyl radical, or an aryl radical, in which an aliphatic, aromatic or cyclanic nitrile of the general formula II
In a preferred way, the metallic reducing agent is a metal hydride as an aluminohydride having at least one free hydrogen atom. It may also be an alkylating or arylating reducing agent such as an organomagnesian salt of the formula
The cyaniding agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, and tributylstannicyanide (Bu).sub.3 Sn-CN. This list is not limiting and other cyaniding agents able to give up a CN group may also be used such, for example, as an alkaline or alkaline-earth metal cyanoborohydride, an alkaline metal cyanide in the presence of a brown Ether, or hydrocyanic acid in solution in an oxygen-bearing solvent, as for example THF.
The following table gives a comparison between the different reducing agent and the different cyaniding agents.
Without limiting the invention, the process of the present invention may be illustrated by the two following reaction schemes ##STR17##
In these two schemes, R is a substituted or unsubstituted alkyl radical having from 1 to 30 carbon atoms, a mono- or bi-cyclic aryl radical, an akenyl radical having from 2 to 30 carbon atoms, a mono- or bi-cyclic hetero-aryl radical; an aryl-alkyl radical in which the alkyl moiety has from 1 to 15 carbon atoms and the aryl moiety may carry from 1 to 3 substituents, an aryloxy-(lower)alkyl radical optionally substituted by one to three substituents on the aryl moiety, or a cycloalkenyl radical having from 4 to 7 carbon atoms lower alkyl.
As much as the invention is concerned, the term lower alkyl means a hydrocarbonic radical having from 1 to 6 carbon atoms, in a straight or branched chain. There may be mentioned as example: butyl, terbutyl, neopentyl, n-hexyl, methyl or ethyl radicals.
When the alkyl radical is substituted, it may carry a group functional towards organometal compound as a halogen atom, or an amino radical as a chain of the formula ##STR18## in which R.sub.1 and R.sub.2 each represent a hydrogen atom, an alkyl radical, an aryl radical or an alkylene chain and n is an integer from 1 to 30. It may also carry a hydroxy, alkoxy or aryloxy substituent in order to form a chain of the formula:
The term lower alkenyl radical means a hydrocarbonic radical having a double bond and containing from 2 to 6 carbon atoms. As alkenyl radical, there may be mentioned for example, allyl, methallyl, but-2-enyl, isopropenyl and 3-methyl-butylenyl radicals.
When R represents a substituted aryl radical, the substituents may be from 1 to 3 halogen atoms, a trifluoromethyl or trifluoromethoxy radical or 1 to 3 lower alkyl or lower alkoxy radicals.
The term aryl (lower) alkyl radical means a monocyclic aryl radical carrying a hydrocarbonic chain having from 1 to 6 carbon atoms in a straight or branched chain. Some examples of such radicals may be benzyl, phenyl-ethyl, .alpha.-methylphenyl,ethyl 2,6-dichlorobenzyl and 2,3,5-trimethoxy-benzyl radicals. The term heteroaryl(lower)alkyl radical means a heterocyclic aromatic radical carrying a hydrocarbonic chain having from 1 to 6 carbon atoms. As example of such radicals, there may be mentioned (2-pyridyl)methyl, furyl-ethyl, pyranyl-ethyl, (2-thienyl)methyl and indololymethyl radicals.
A heteroaryl radical means a cyclic structure having from 4 to 7 links as azetidine, pyrrolidine, piperidine or hexamethyleneimine when this chain is interrupted by one or two hetero-atoms such as a sulfur, or an oxygen atom or an imino group, the resulting cycle may be, for example, tetrahydropyrimidine, tetrahydrooxazine, morpholine, thiazine, pyrazolidine or piperazine. These cycles may carry substituents as, for example, lower alkyl, hydroxy(lower)alkyl pyridyl, unsubstituted or substituted phenyl or pyrimidinyl radicals.
The invention may, furthermore, be performed by the following operating methods which are at the present time, the preferred embodiments.
The process of the present invention may be used for preparing starting materials of the general formula IV: ##STR20## as described in European Patent Application No. 85401360, 4 of July 4, 1985.
Such amino-acids or amino-esters are obtained starting from .alpha.-cyano-amines of the general formula 1, either by an acid hydrolysis in a diluted mineral acid, or by an enzymatic hydrolysis, or again by a Pinner reaction giving first an imidolate giving then an .alpha.-amino-ester: ##STR21## It is also possible to obtain, according to the process of the invention, .alpha.-substituted .alpha.-cyano-amines which constitute some precious precursors for the synthesis of .alpha.-substituted .alpha.-amino acids such for example as .alpha.-methyl DOPA or .alpha.-fluoroamino acids named suicidal enzymes.
The synthesis scheme is the following: ##STR22## An other interest of the process of the invention consists in the possibility of obtaining a large range of intermediates of synthesis by attack of the nitrile group:
All these compounds are precious intermediates to form after cyclization some hetero-cyclic compounds such as oxazolines, imidazolines, oxadiazoles or triazoles.
An other interest of the process of the present invention consists in the fact that .alpha.-cyano-amines of the general formula I may be submitted to an enzymatic hydrolysis to form, preferably an optically active amino-acid. Thus it is possible to access, with a good yield, either to an amino-acid having an antipodal configuration such for example as D-alanine which finds many uses in the synthesis of Enkephaline antibacterial products or enzymatic inhibitors, or to an aminoacid having a natural configuration.
It is possible to access, by the process of the invention, to some amino acids or to some aromatic or heterocyclic aminonitriles, which may be substituted or unsubstituted, the isolation of which, in nature, is difficult or uneconomic. Thus, starting from 2-cyanopyridine, there may be obtained 2-(2-pyridyl)-2-cyano aminomethane, which is hydrolyzed in 2-(2-pyridyl)-2-amino-acetic acid.
There may also be obtained, according to the process of the invention, phenylglycine or p-hydroxyphenylgycine which are precious starting materials for making semi-synthetic penicillins.
The following examples describe and illustrate the invention without limiting it.
US Referenced Citations (4)
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 2174186 |
Oct 1973 |
FRX |
| 2380256 |
Sep 1978 |
FRX |
Divisions (1)
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Number |
Date |
Country |
| Parent |
86731 |
Aug 1987 |
|
Patent Grant
5103019
