NZ200856A

NZ200856A - Preparation of 2-(thien-(2 or 3)-yl)ethylamines

Info

Publication number: NZ200856A
Application number: NZ200856A
Authority: NZ
Inventors: A Heymes; G Valette; G Anne-Archard
Original assignee: Sanofi Sa
Priority date: 1981-06-30
Filing date: 1982-06-04
Publication date: 1985-11-08
Also published as: NO155345B; KR840000539A; FR2508456B1; DE3266028D1; EP0069002A1; PT75156B; FI822318A0; JPS5810575A; IL65984A0; PT75156A; ZA824618B; DK153793B; ES514220A0; CS236482B2; ATE15369T1; AU8475282A; AU556916B2; IL65984A; JPH039914B2; NO155345C

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £00856 NO DRAWIfSP Priority Date(s)*. k.*?? Complete Specification Filed: Class: ...££I?-k?v?.3 Publication Data (' P.O. Journal, No: ...... J.Q-i7.~7. Patents Form No. 5 Number PATENTS ACT 1953 Dated COMPLETE SPECIFICATION Process for preparing 2-(thienyl-2)-ethylamines and 2-(thienyl-3)-ethylamines MWe SANOFI a French company of 40, Avenue George V, 75008 Paris, France do hereby declare the invention for which yiwe pray that a Patent may be granted to ros/us, and the method by which it is to be performed, to be particularly described in and by the following statement: 2008 56 -2- The present invention is concerned with a new process for preparing 2-(thienyl-2)-ethylamines and 2-(thienyl-3)-ethylamines, a considerable number of which are known and used as intermediates for obtaining derivatives used in the chemical industry as pharmaceuticals. The compounds prepared by the process according to the present invention have the general formula in which and 1*2, which may be the same or different, are hydrogen atoms or straight-chained or branched alkyl radicals or heterocyclic or non-heterocyclic aromatic radicals, such as thienyl, furyl, pyridyl, phenyl or naphthyl, which are optionally mono- or poly-substituted. The aminoethyl radical and the substituent may be in any desired position of the thiophene nucleus. The compounds of general formula (I) have already been prepared by various methods: reduction of 2- or 3-0-nitrovinylthiophenes with the use of lithium aluminium hydride (see R.T. Gilsdorf and F.F. Nord, L. Org. Chem., ljj, 807/1950; E. Campaigne and W.C. McCarthy, J.A.C.S., 7_6# 4466/1954) or electro- 4 3 (I) 200856 -3- chemically (see British Patent Specification No. 2013196): reduction of 2-(thienyl-2)- and 2-(thienyl-3)-aceto-nitriles with lithium aluminium hydride (see B.F. Crowe and F.F. Nord, J. Org. Chem., 15, 81/1950: E. Campaigne and W.C. McCarthy, loc. cit. ) or with sodium amalgam (see F.F. Blicke and J.H. Burckhalter, J.A.C.S., 64, 477/1942); by the Curtius degradation of 3-(thienyl-2)- and 3-(thienyl-3)-propionic acids (see G. Barger and A.P.T. Eassou, J. Chem. Soc., 2100/1938; E. Canpaigne and W.C. McCarthy, loc. cit.); starting from halide or arylsulphonate derivatives of 2-(thienyl-2)- or 2-(thienyl-3)-ethanol by direct amination (see F.F. Blicke and J.H. Burckhalter, loc.cit; British Patent Specification No. 1469226 ) or via a phthalimide intermediate (see BritishPatent Specification No. 1469226 ). However, these various processes, which are difficult to carry out, do not give good yields which are of interest for use on a large scale. It is an object of the present invention to provide a process for obtaining compounds of general formula (X) which is simple and not very laborious. In order to achieve this object, in practice, as starting material there is used a compound of the general formula:- F ; !— 200856 ri -4- ch=c(r2)-n02 (iv) in which and R2 have the same meanings as in general formula (I), which may be prepared by various known methods, for example by condensing a compound of the general formula R2~CH2~N02 (I3:) in which R2 has the same meaning as in general formula (I), with a carbonyl derivative of the general formula:- R1 cho (iii) in which R^ has the same meaning as in general formula (i), operating under known conditions, to give a compound of the general formula rich=c(r2)no2 (iv) in which R^ and R2 have the same meanings as in general formula (I). Thus, according to the present invention, there is provided a process for preparing compounds of general formula (I), wherein a) a compound of general formula (IV) is subjected to a 200 -5- catalytic hydrogenation Reaction in a non-alkaline solvent, under a hydrogen pressure of from 1 to 100 atomospheres and at a temperature of from 20 to 100°C, to give a compound of the general formula :- *1 \ f.—3^-^ ch2-c=n-°h (v) *2 " s in which Ri and R2 have the same meanings as above; and b) the compound of general formula (V) is, in turn, also converted by catalytic hydrogenation in an alcoholic solvent medium which contains ammonia in a dissolved state, under a hydrogen pressure of from 1 to 100 atmospheres and at a temperature of from 20 to 100°C, into a compound of general formula (I). Generally speaking, obtaining the compounds of the arylethylamino type according to the following equation: R2 Ar-CH=C—NO- > Ar-CH2-CH-NB2 I catalyst ' R * i.e. by the catalytic hydrogenation of ^-nitrovinylaryl compounds, is already known. However, it has never been used in cases in which the aromatic radical is thiophene. Nevertheless, there has previously been described the hydrogenation of 2-^-nitrovinylthiophene but limited to obtaining the oxime of 2-(thienyl-2 )-acetaldehyde and carried out in the; presence of- palladium (see L. Kh. Freidlin, E.F.Litvin and V.M. Chursina, ! — :•> Khimiya G. et Soed., 3 22/1967; Chem. Abs., 62 73465 y) but the quantities of catalyst employed (0.200 g. of metallic -6- 200856 palladium per 0.775 g. of substrate to be hydrogenated) exclude all reasonable industrial application of the process: the proportion of palladium used is, in effect, more than 25%, referred to the substrate. In contradistinction thereto, by the process according to the present invention, 2-(thienyl-2)- and 2-(thienyl-3)-ethylamines are obtained under conditions which are simple to carry out and which are not expensive because of the small amounts of catalyst employed. The process according to the present invention is, in particular, characterised by carrying out the reduction in two stages using different conditions. In the first stage, a compound of general formula (IV) is hydrogenated in a non-alkaline solvent, which may be an alcohol, such as methanol, above, for example a mixture of methanol or ethanol and acetic acid. The hydrogenation is carried out in the presence of a metal catalyst, for example palladium, platinum, ruthenium, rhodium or iridium. The metal catalyst is advantageously diluted with 10 to 100 times its weight of a support material, for example charcoal, alumina or barium sulphate, and, generally speaking, use is made of a quantity which is from 1 to 10% of the amount of substrate to be hydrogenated. formic acid, acetic acid or propionic acid, or, still more advantageously, in a mixture of two solvents each selected from one of the groups of solvents mentioned ethanol or isopropanol, or an organic acid, such as 200856 -7- which corresponds to amounts of 1/10,000 to 1/100 of palladium. The hydrogenation is carried out under a hydrogen pressure which is generally from 1 to 100 atmospheres and preferably from 5 to 25 atmospheres at a temperature Which is generally from 20 to l00°cl and preferably from 30 to 60°C. The duration of the operation is generally from 30 minutes to several hours. In the second stage, the derivative of general formula (V), isolated in appropriate manner from the reaction mixture, is, after removal of the catalyst, hydrogenated in an alcoholic solvent medium, for I example methanol, ethanol or isopropanol, which, in order to avoid the formation of secondary amines, contains ammonia in a dissolved state. The hydrogenation is carried out in the presence of a metal catalyst and particularly of nickel, which may be Raney nickel or nickel deposited on a support, such as silica or alumina, the quantity of metal catalyst used being from 1 to 10% of the substrate to be hydrogenated. The hydrogenation is carried out under a hydrogen pressure of generally from 1 to 100 atmospheres and preferably of from 5 to 25 atmospheres at a temperature which is generally from 20 to 100°C. and preferably from 40 to 80°C. The duration of the operation is generally from 30 minutes to several hours. The compounds thus obtained of general formula (I) may subsequently be isolated and purified according to 20085 6 -8- conventional methods. In order to carry out these operations, it may be advantageous to convert the free bases of general formula (I) into their salts, for example their acid addition salts, by reaction with mineral or organic acids. Starting from the salts, the free bases of general formula (I) may be liberated by known methods. The present invention is also concerned with the intermediates obtained at different stages of the synthesis, i.e. the compounds of general formula:- in which and R£ have the same meanings as above. The following Examples are given for the purpose of illustrating the present invention Example 1. Preparation of 2-(thienyl-2)-ethylamine hydrochloride, a) 2-Thienylacetaldehyde oximes. A solution of 100 g. (0.645 mole) 2-(thienyl-2)- (V) in which R^ and R2 have the same meanings as above; and the compounds of the general formula:- (I) 2008 56 -9- nitroethylene in 2 litres of a mixture of acetic acid and ethanol (75/25 v/v) is hydrogenated in an autoclave at 35°C. under a pressure of 20 bars in the presence of 5 g. of palladium-charcoal (5%) until absorption of hydrogen ceases (duration: about 2 hours). After filtering off the catalyst and washing it with ethanol, the solution obtained is evaporated in a vacuum at 50°C. The oily residue obtained is taken up in 500 ml. methylene chloride and the solution is successively washed with an approximately IN aqueous solution of sodium carbonate and then with water and finally evaporated to give 97 g. of the oximes (mixture of syn and anti) of 2-thienyl-acetaldehyde in the form of an orange-yellow oil which is used as such in the following step. b) The mixture of oximes obtained above, in solution in 2 litres of methanol saturated with ammonia, is hydrogenated in an autoclave at 60°C. at a pressure of 20 bars in the presence of 10 g. of Raney nickel until absorption ceases (duration about 20 hours). After filtering off the catalyst and washing it with methanol, the solution is evaporated. The oily residue obtained is added to 500 ml. toluene. The organic phase is extracted with approximately IN aqueous hydrochloric acid. The aqueous acid phase is isolated and rendered alkaline with an approximately IN aqueous solution of sodium carbonate and then extracted with toluene. The addition to the isolated organic phase of a solution 100856 -10- of gaseous hydrogen chloride in diisopropyl ether brings about the formation of a precipitate which is filtered off and dried. There are thus obtained 68 g. (yield 65% of theory, referred to the 2-(thienyl-2)-nitroethylene used), of the hydrochloride of 2-(thienyl-2)-ethylamine in the form of white crystals; m.p. 202°C. Analysis: C6HgNS.HCl (m.w. 163.67) calc. : C 44.03%: H 6.15%; N 8.55% found : 43.98%; 6.16%; 8.54% Example 2. 2-(Thienyl-3)-ethylamine hydrochloride. Operating under the reaction conditions described in Example 1 but using 5% rhodium/charcoal instead of 5% palladium/charcoal, there is obtained the desired hydrochloride in a yield of 66% of theory; m.p. 216°C. Analysis: C6H9NS.HC1 (m.w. 163.67) calc. : C 44.03%; H 6.15%; N 8.55% found : 43.92%; 6.18%; 8.50% Example 3. 1-Methyl-2-(thienyl-3)-ethylamine hydrochloride. Operating under the reaction conditions used in Example 1 but using 5% platinum/charcoal instead of 5% palladium/charcoal, there is obtained the desired hydrochloride in a yield of 81% of theory; m.p. 138°C. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2 008 5 6 -li- Analy3is; C7H11NS,HC1 (m*W* 177-69) calc. : C 47.31%; H 6.80%; N 7.88% found : 47.55%; 6.85% 7.92% 200356 -12- what we claim is:

1. A process for the preparation of 2-(thienyl-2)- and 2-(thienyl-3)-ethylamines of the general formula:- f 4 ^ s ^ CH--CH-HH-I ^ R„ (I) in which R^ and R2/ which can be the same or different, are hydrogen atoms, straight-chained or branched alkyl radicals or heterocyclic or non-heterocyclic aromatic radicals, which are optionally mono- or polysubstituted, wherein a compound of the general formula:- F' O* > cz CD <0 O 35 J i CH=C-NO. (IV) oo ! |? • in which Ri and R2 have the same meanings as above, is subjected to catalytic hydrogenation in a non-alkaline solvent under a hydrogen pressure of from 1 to 100 atmospheres and at a temperature of from 20 to 100°C. to give a compound of the general formula:- s CH2-C=N-OH (V) in which R^ and R2 have the same meanings as above, and after 2C0E56 isolation thereof, this is converted into a compound of general formula (I) by catalytic hydrogenation in an alcoholic solvent which contains ammonia in a dissolved state, under a hydrogen pressure of from 1 to 100 atmospheres and at a temperature of from 20 to 100°C.

2. A process according to claim 1, wherein the first catalytic hydrogenation phase is carried out in an organic solvent or in an organic acid or in a mixture thereof.

3. A process according to claim 2, wherein the organic solvent is methanol, ethanol or isopropanol and the organic acid is formic acid, acetic acid or propionic acid.

4. A process according to any one of the preceding claims, wherein the catalyst used for the first hydrogenation stage is used on a substrate and in an amount of from 1:10,000 to 1:100 by weight.

5. A process according to any one of the preceding claims, wherein the alcoholic solvent in which the second catalytic hydrogenation phase is carried out is methanol, ethanol or isopropanol.

6. A process according to any one of the preceding claims, wherein one or both of the hydrogenation phases is carried out 200856 -14- under a hydrogen pressure of from 5 to 25 atmospheres.

7. A process according to any one of the preceding claims, wherein the first hydrogenation phase is carried out at a temperature of from 30 to 60°C.

8. A process according to any one of the preceding claims, wherein the second hydrogenation phase is carried out at a temperature of from 40 to 80°C.

9. A process according to claim 1 for the preparation of 2-(thienyl-2)- and 2-(thienyl-3)-ethylamines substantially as hereinbefore described and exemplified.

10. 2-(thienyl-2)- and 2-(thienyl-3)-ethylamines of general formula (I) given in claim,1, whenever prepared by the process according to any one of claims 1 to 9. WEST-WALKER, McCABE pen ATTO </div>