IE53278B1

IE53278B1 - Process for preparing 2-(2-thienyl)-ethylamines and 2-(3-thienyl)-ethylamines

Info

Publication number: IE53278B1
Application number: IE1314/82A
Authority: IE
Original assignee: Sanofi Sa
Priority date: 1981-06-30
Filing date: 1982-06-01
Publication date: 1988-09-28
Also published as: AU8475282A; DD202711A5; ES514220A0; IL65984A0; ATE15369T1; AU556916B2; IL65984A; JPH039914B2; SU1148562A3; CS236482B2; NO155345B; FR2508456A1; FI822318L; ZA824618B; DK153793C; ES8305348A1; NO155345C; DK291782A; AR231444A1; KR840000539A

Abstract

1. Process for the preparation of 2-(2-thienyl)- and -(3-thienyl-ethylamines of the formula I : see diagramm : EP0069002,P5,F2 in which R1 and R2 , which may be the same or different, represent each a hydrogen atom, a straight- or branched-chain alkyl radical, a heterocyclic or non-heterocyclic aromatic radical, optionally mono- or poly-substituted, comprising catalytically hydrogenating in non alcaline medium in an alcohol or an organic acid or their mixture under a hydrogen pressure of 1 to 100 atmospheres at a temperature of 20 to 100 degrees C, and in the presence of a metal catalyst associated with an inert carrier, a compound of the formula IV : see diagramm : EP0069002,P5,F3 in which R1 and R2 are as defined above, to give a compound of the formula V : see diagramm : EP0069002,P5,F4 in which R1 and R2 are as defined above, isolating compound (V) and then catalytically hydrogenating same in alcaline medium under a hydrogen pressure of 1 to 100 atmospheres, at a temperature of 20 to 100 degrees C, and in the presence of a metal catalyst on a carrier to give a compound of the formula (I).

Description

The present invention is concerned with a process for preparing a 2-(2-thienyl)-ethylamine and a 2-(3-thienyl)-ethylamine, a considerable number of which are known and used as intermediates for obtain5 ing derivatives used in the chemical industry as pharmaceuticals.

The compounds prepared by the process according to the present invention have the general formula:4 3 in which and Rj, which may be the same or different, each represent a hydrogen atcm or a straight-chain or branched alkyl radical or a heterocyclic or non-heterocyclic aromatic radical such as thienyl, furyl, pyridyl, phenyl or naphthyl, each of which is optionally monoor polysubstituted.

The aminoethyl radical and the substituent R^ may be in any desired position of the thiophene nucleus.

The compounds of general formula (I) have already 20 been prepared by various methods: reduction of 2- or 3-p-nitrovinylthiophenes with the use of lithium aluminium hydride (see R.T. Gilsdorf and F.F. Nord, L. Org. Chem., 15. 807/1950; E. Campaxgne and W.C. McCarthy, J.A.C.S., 76, 4466/1954) or electro53278 -3chemically (see French Patent Specification No. 01 992); reduction of 2-(2-thienyl)- and 2-(3-thienyl)-acetonitriles 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-(2-thienyl)~ and 3(3-thienyl)-propionic acids (see G. Barger and A.P.T. Eassou, J. Chem. Soc., 2100/1938; E. Campaigne and W.C. McCarthy, loc. cit.); starting from halide or arylsulphonate derivatives of 2-(2-thienyl)- or 2-(3-thienyl)-ethanol by direct amination (see F.F. Blicke and J.H. Burckhalter, loc.cit; French Patent Specification No. 75 03 142) or via a phthalimide intermediate (see French Patent Specification No. 75 03 142).

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 (I) 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;53278 ch=c(r2)-no2 (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-no2 (II) in which R2 has the same meaning as in general formula (I), with a carbonyl derivative of the general formula:- (III) in which R^ has the same meaning as in general (I), operating under known conditions, to give of the general formula:formula a compound *1----CH=C(R2^NO2 (IV) in which and R2 have the same meanings as in general 15 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 -5catalytic hydrogenation reaction under known conditions to give a compound of the general formula:1^/- CH2-C=N-OH (V) in which and R2 have the same meanings as above; and 5 b) the compound of general formula (V) is, in turn, also converted by catalytic hydrogenation into a compound of general formula (I) but under conditions different from those used in the previous step.

Generally speaking, obtaining confounds of the 10 arylethylamino type according to the following equation: Ar-CH=C-N0, I 2 R -> Ar-CH.-CH-NHcatalyst 1 R i.e. by the catalytic hydrogenation of β-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-p-nitrovinylthiophene but limited to obtaining the oxime of 2-(2-thienyl)-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., 67, 73465 y) but the quantities of catalyst employed (0.200 g. of metallic palladium per 0.775 g. of substrate to be hydrogenated) -6exclude 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-(2-thienyl)- and 2-(3-thienyl)-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.

In the first stage, a compound of general formula (IV) is hydrogenated in a non-alkaline medium in a solvent medium, which may be an alcohol, such as methanol, ethanol or isopropanol, or an organic acid, such as 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 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 associated with an inert carrier.

The metal catalyst is advantageously diluted with 10 to 100 times its weight of the inert carrier, 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. -7which 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 100°C. 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 a solvent medium, which may be an alcohol, for example methanol, ethanol or isopropanol, which, in order to avoid the formation of secondary amines, advantageously contains ammonia in a dissolved state. The hydrogenation is carried out in an alkaline medium in the presence of a metal catalyst and particularly of nickel, which may be Raney nickel or nickel deposited on a carrier, 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 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 following Examples are given for the purpose of illustrating the present invention:10 Example 1.

Preparation of 2-(2-thienyl)-ethylamine hydrochloride a) 2-Thienylacetaldehyde oximes.

A solution of 100 g. (0.645 mole) 2-(2-thienyl)53378 -9nitroethylene 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-thienylacetaldehyde 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 -1010 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-(2-thienvl)nitroethylene used), of the hydrochloride of 2-(2-thienyl) ethylamine in the form of white crystals; m.p. 2O2°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-(3-Thienvl)-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; CgHgNS.HCl (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-(3-thienyl)-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. -11Analyalsi C7H11NS.HC1 (M.W. 177.69) calc. : C 47.31%; H 6.80%· found : 47.55%; 6.85% N 7.88% 7.92%

Claims

1. CLAIMS;

1. A process for the preparation of a 2-(2-thienyl)general formula:or a 2-(3-thienyl)-ethylamrne of the f J-CH 2 -CH-NH 2 5 in which R^ and R2, which different, each represent can be the a hydrogen (I) same or atom, a straightchain or branched alkyl radical or a heterocyclic or nonheterocyclic aromatic radical, each of which is optionally mono- or polysubstituted, which comprises 10 subjecting a compound of the general formula:- in which and R2 have the same meanings as above, to catalytic hydrogenation in a non-alkaline medium in an alcohol or an organic acid or a mixture thereof under a 15 hydrogen pressure of from 1 to 100 atmospheres, at a temperature of from 20 to 100°C, and in the presence of a metal catalyst associated with an inert carrier to give a compound of the general formula:- (V) 53878 - 13 in which Rj and R2 have the same meanings as above, and after isolation thereof, converting the compound of formula (V) into a compound of general formula (I) by catalytic hydrogenation in an alkaline medium under a hydrogen pressure of from 1 to 100 atmospheres, at a temperature of from 20 to 100°C and in the presence of a metal catalyst on a carrier.

2. A process as claimed in Claim 1, wherein the first hydrogenation step carried out on the compound of general formula (IV) is effected in a mixture of an alcohol and an acid.

3. A process as claimed in Claim 1 or 2, wherein the metal catalyst of the first hydrogenation step is selected from palladium, platinum, ruthenium, rhodium and iridium, associated with an inert carrier.

4. A process as claimed in claim 3, wherein the inert carrier is charcoal, alumina or barium sulfate.

5. A process as claimed in any preceding claim, wherein the first hydrogenation step is carried out under a hydrogen pressure of from 5 to 25 atmospheres.

6. A process as claimed in any preceding claim, wherein the first hydrogenation step is carried out at a temperature of from 30 to 60°C.

7. A process as claimed in Claim 4, wherein the metal component of the catalyst is used in a ratio of from 1/10,000 to l/lOO with respect to the substrate.

8. A process as claimed in any preceding claim, wherein the catalyst of the second hydrogenation step 53378 - 14 -- . . carried out on the compound of formula (V) is a Raney nickel catalyst or a catalyst comprising nickel deposited on an inert carrier.

9. A process as claimed in Claim 8, wherein the metal 5 component of the catalyst is used in an amount of 1 to 10. % with respect to the substrate.

10. A process as claimed in any preceding claim, wherein the second hydrogenation step is carried out under a hydrogen pressure of from 5 to 25 atmospheres. 10

11. A process as claimed in any preceding claim, wherein the second hydrogenation step is carried out at a temperature of from 40 to 80°C.

12. A process as claimed in Claim 8, wherein the reaction is carried out in an alcohol, in combination 15 with dissolved ammonia.

13. A process according to Claim 12, wherein the alcohol is methanol, ethanol or isopropanol.

14. A process as claimed in any preceding claim, wherein the aromatic radical is selected from thienyl, 20 furyl, pyridyl, phenyl and naphthyl.

15. A process according to Claim 1 for the preparation of a 2-(2-thienyl)- or 2-(3-thienyl)-ethylamine, substantially as hereinbefore described and exemplified.

16. A 2-(2-thienyl)- or 2-(3-thienyl)-ethylamine, 25 whenever prepared by the process according to any one of claims 1 to 15.