NZ201412A

NZ201412A - Preparation of 4-aminobutyramide

Info

Publication number: NZ201412A
Application number: NZ201412A
Authority: NZ
Inventors: J Gosteli
Original assignee: Synthelabo
Priority date: 1981-07-29
Filing date: 1982-07-28
Publication date: 1984-11-09
Also published as: NO822264L; IL66419A0; FI822647A0; EP0071500A1; JPS5826846A; ES8305686A1; AU8652282A; GR77232B; PT75340A; FR2510560B1; EP0071500B1; DE3263745D1; FI822647A7; ATE13421T1; AR230045A1; ZA825432B; DK337182A; PT75340B; FI822647L; ES514464A0

Description

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P, > r^*' /T» **"• T V;, 1*0" • ■ • * is NEW ZEALAND 17/ 3 53>0 THE PATENTS ACT 1953 PATENTS FORM NO. 5 COMPLETE SPECIFICATION "PROCESS FOR THE PREPARATION OF 4-AMINOBUTYRAMIDE" WE, SYNTHELABO, a French Body Corporate of 58, rue de la Glaciere, 7 5013 Paris, France, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: i- 7; -> .u.,. j.A 2 014 12 - DESCRIPTION "PROCESS FOR THE The present invention relates to a process for the preparation of 4-aminobutyramide of the formula: h2nch2ch2ch2conh2 (i) and acid addition salts thereof. This 4-aminobutyric acid 5 derivative is of great value because of its psychotropic properties (cf. V.M. Kopelevich* Usp. Khim. 48» 1273 [1979]).

The known synthesis of 4-aminobutyramide« according to which succinic acid dinitrile is used as the starting 10 material* is not suited to the requirements of manufacture, because of the poor yields (C. Berther# Chem. Ber. 92, 2616 [l959]). The recently published method for the preparation of 4-aminobutyramide involves the use of free hydrocyanic acid* which is highly toxic# and hydrogenation 15 under pressure# that is to say a series of reactions requiring safety measures and particular apparatuses (A. Kleeman et al_. , Angew. Chem. 9^« 640 [1980]).

According to the present invention, in an advantageous manner, 4-aminobutyramide is prepared by the 20 reduction of 4-azidobutyramide of the formula: n3ch2ch2ch2conh2 (ii) 201412 The reduction can be effected by means of hydrogen in the presence of a hydrogenation catalyst (e.g. palladium), and when that method is used it can be carried out without the application of pressure and at ambient temperature optionally in the presence of an acid (e.g. hydrogen chloride), resulting in the formation of an acid addition salt of 4-aminobutyramide. However, it is also possible to use other reducing agents. Thus, for example, it is possible first to react 4-azidobutyramide with a phosphine, such as a'trialkylphosphine or triphenyl-phosphine, and then to hydrolyse the intermediate imino-phosphine which has formed and which corresponds to the formula: r3p=n-ch2ch2ch2conh2 (hi) wherein R represents an alkyl radical, preferably containing at most 4 carbon atoms, or the phenyl radical. 4-Azidobutyramide, which is not described in the literature, can be prepared in a simple manner starting from the 4-azidobutyronitrile/ which is a known compound, by partial hydrolysis in an acid or basic medium. A particularly advantageous method of hydrolysis consists in carrying out the reaction in a basic medium with the addition of hydrogen peroxide. 2014 12 The following Examples illustrate the invention.

EXAMPLE 1 A solution of 1.53 g (12 millimols) of 4-azidobutyramide in 20 ml of absolute ethanol and 3.32 ml 5 of ethyl acetate, containing 12 milliinols of hydrogen chloride, is hydrogenated for 4 hours at ambient pressure and temperature in the presence of 1.53 g of palladium (5 %) on a barium sulphate support.

After filtration and evaporation of the filtrate 10 in vacuo, 1.13 g of a crystalline residue are collected; by extraction of the catalyst with hot methanol and evaporation in vacuo, a second fraction of 0.45 g of the crude crystalline hydrochloride of 4-aminobutyramide is obtained. Yield of crude product: 95 %. 15 At the expense of a loss of product, the crude product can be recrystallised from absolute alcohol. The pure product melts at 136-137°C.

EXAMPLE 2 3.62 g (10 millimols) of 4-triphenylphosphinimino-20 butyramide (formula III, R representing the phenyl radical) are dissolved in 17 ml of hot 95% alcohol.

After cooling to ambient temperature, 17 ml of concentrated ammonia solution (2 5%) are added and the clear solution is stirred for 24 hours. The major part of the alcohol is 25 evaporated off in vacuo, which causes triphenylphosphine oxide to precipitate. The residue is dissociated with a ? 0 1 4 1 2 mixture of water and methylene chloride# and the aqueous phase is cautiously concentrated in a rotary evaporator* which gives 1.20 g of a clear colourless oil: this crystallises in the cold. The crude product is triturated with diethyl ether* filtered off# washed with diethyl ether and dried. This gives 1.00 g of 4-aminobutyramide» which melts at 56-58°C. Yield 98 %.

EXAMPLE 3 22.8 g of triphenylphosphine are added to a solution of 11.1 g (87 millimols) of 4-azidobutyramide in 100 ml of toluene# at 60°C« the triphenylphosphine being added in small doses so as not to cause the temperature to rise above 70°C. Cooling of the mixture causes the 4-triphenylphosphiniminobutyramide (formula III# R representing the phenyl radical) to crystallise. By filtration# washing with cold toluene and drying in vacuo# 27.0 g of colourless crystals are collected# which corresponds to a yield 86% of theory. The melting point of the crystals is 124-128°C. After recrystallisation from ethyl acetate# the product#viz. triphenylphosphinimo-butyramide# melts at 128-132°C.

C22H23N2OP (362*4) % C calculated: 72.91 found: 72.66 % H 6.40 6.41 % N 7.73 7.83 014 12 - 5 -EXAMPLE 4 9.0 g (82 millimols) of 4-azidobutyronitrile and 20 ml of concentrated hydrochloric acid are stirred at ambient temperature; after a certain time, a single phase 5 is formed. After seven hours, the mixture is concentrated in vacuo and the 19 g of residual oil are diluted with 30 ml of water. The pH is adjusted to 8 by cautiously adding solid sodium carbonate, the solution is extracted four times with methylene chloride and the extracts are 10 dried over sodium sulphate. By evaporation in vacuo, 7.0 g of crude 4-azidobutyramide are obtained.

Yield: 66 %. After recrystallisation from diethyl ether, the 4-azidobutyramide melts at 73-73.5°C.

C4H8N4° % C calculated: 37.49 found: 37.66 % H 6.29 6.33 % N 43.73 43.62 EXAMPLE 5 46 ml of a 30 % solution of hydrogen peroxide 20 are added to a solution of 23.3 g of 4-azidobutyronitrile in 70 ml of alcohol. 17 ml of normal sodium hydroxide solution are introduced, with stirring, care being taken not to exceed a temperature of 37°C. After this addition, the mixture is stirred for a further two hours, 25 the alcohol is driven off by distillation in a vacuum evaporator, the residue is diluted with a small amount of 2014 12 water and extraction is carried out twice with pentane. The extract is discarded and the aqueous phase is saturated with sodium chloride and shaken six times with ethyl acetate. The extracts are combined, washed with a solution of sodium chloride, dried over sodium sulphate and concentrated in a rotary evaporator. The crystalline residue is suspended in diethyl ether, the suspension is brought briefly to the boil and, after cooling, the product is filtered off. After drying in vacuo, 17.7 g of crystals of 4-azidobutyramide, melting at 73-73. 5°C, are collected. By concentration of the mother liquor, a second fraction of 5.3 g of crystals of 4-azidobutyramide, melting at 70.5-71.5°Ct is obtained. Yield: 85 %. 9> 0 J £ -i o

Claims

WHAT WE CLAIM IS:

1. Process for the preparation of 4-aminobutyramide and acid addition salts thereof characterised in that 4-azidobutyramide is reduced.

2. Process according to claim 1 characterised 5 in that the reduction of 4-azidobutyramide is effected by means of hydrogen in the presence of a hydrogenation catalyst.

3. Process according to claim 1 or 2 characterised in that the reduction of 4-azidobutyramide 10 is carried out' at ambient temperature and under normal pressure.

4. Process according to claim 1 characterised in that 4-azidobutyramide is first reacted with a trialkyl-phosphine or a triphenylphosphine* and the iminophosphine 15 thus obtained is then hydrolysed.

5. Process according to claim 1 characterised in that the 4-azidobutyramide is prepared by the partial hydrolysis of 4-azidobutyronitrile.

6. Process according to claim 5 characterised 20 in that the hydrolysis is effected by means of an aqueous acid.

7. Process according to claim 5 characterised in that the hydrolysis is effected in an aqueous medium by adding hydrogen peroxide. ByiWsr/Their Authorised Agents. A. J. PARK & snw ! A. J. PARK & SON