IE42786B1 - Improvements in and relating to a process for the preparation of 2-(2-thienyl)-ethylamine and deivatives thereof - Google Patents

Description

This invention' relates to a new process for the preparation of 2-(2- thienyl) - ethylamine and derivatives thereof, which are known compounds used as intermediates in the synthesis of a large number of derivatives used in both the chemical and pharmaceutical industries.

The compounds prepared according to the process of this invention have the following general formula: S ./ I! i| 2 in which R und R each represent hydrogen or a C^_4 alkyl or an optionally substituted phenyl radical. They have already been pre pared according to a variety of methods. Thus, their synthesis was effected by reduction of 2 - 0 - nitrovinyl - thiophene with lithium aluminium hydride (S. Gronovitz & F, Sandberg, Arkiv. ffir Kemi, 1970, 32, 217; M. L. Dressier, M. Soullii, J. Het. Chem., CO 1970, 7, 1257).

They have also been prepared from 2-(2- thienyl) - propylamide, by means of a Hoffman degradation reaction (G. Barger, A. Easson, J. Chem. Soc., 1938, 2100).

Other authors have also operated by reduction of 2-cyanomethyl thiophene with lithium aluminium hydride (B. F. Crowe, F. F. Nord. J. Org. Chem., 1950, 15, 81; J. ty. MacFarland, H. L. Howes, J. Med. Chem., 1969, 12, 1079), However, such prior methods are, all three, difficulty applicable industrially and do not provide compounds of the formula (I) in good yields.

Consequently, the object of the present invention is to provide an inexpensive industrial synthesis process which will produce 2-(2- thienyl) - ethylamine and derivatives thereof of the aforementioned formula (I) in good yields.

The process according to this invention comprises aminating a derivative of the formula: in which R^ and R2 are as defined for formula (Τ), and in which r3 is an optionally substituted alkyl, aryl or aralkyl group, such as CH3, CC13, CF3, and p. CH3—CgHj.

According to an embodiment of the process of this invention, the amination is carried out directly by reacting the derivative of the formula (II) with ammonia.

The reaction is generally conducted at elevated temperatures, in an autoclave, during a period of time of 10—20 hours.

According to another embodiment of the process of this invention, the derivative of the formula (XI) is reacted with phthalimide, to give a compound having the formula; which is subsequently transaminated with an amine or hydrazine 5 hydrate.

As amine, use is made of a markedly basic mono- or polyfunctional amine of high boiling point. Typically useful amines have the formula RNH2 in which R may be a Cg—Cg,. straight or branched chain alkyl radical, an aralkyl radical, (typically benzyl10 amine and its substituted derivatives), an aryl radical such as an optionally substituted phenyl or naphthyl radical, particularly the halogenoanilines, the alkyloxyanilines and benzidine. The radical R itself may carry other NH or NH2 functions, as in bis(2 - aminoethyl) amine (diethylenetriamine), ethylenediamine, triethylene15 tetramine, or even other functional groups such as hydroxy, ester, and alkoxy. Thus, the amine may be 4 - hydroxy - butylamine, 2pentoxy - propylamine, or ethanolamine.

The reaction is preferably effected at elevated temperature, and diethylene triamine, benzylamine or ethanolamine are advan20 tageously used.

The reaction of the derivative of the formula (II) with phthalimide is usually carried out in the presence of an inorganic or organic base, such as an alkali metal (Na, K) or alkaline-earth metal (.Ca) carbonate or hydroxide, an alkali metal tNa, K) amide, an alkali metal (Jia) hydride, or an alkali metal alkoxide.

The starting compounds of general formula II, some of which are novel, can all be prepared by known chemical methods.

The following non limiting examples are given to illustrate the invention.

EXAMPLE 1 Preparation of 2 - amino - 1 - (2 - thienyl) propane, via direct amination Into a 1000 ml autoclave, are added 1-(2- thienyl) - 2propanol p-toluenesulfonate (75 g) and ammonia (600 ml). The whole is heated to 80°C during 15 hours. After cooling, the autoclave is opened and the ammonia is allowed to evaporate. After adding water (100 ml) and a IN sodium hydroxide solution (175 ml), the resulting material is extracted with ether. The ether phase is separated and then mixed with IN hydrochloric acid (75 ml). The aqueous phase is made alkaline and is then extracted with ether.

The ether extract is washed with a 5% sodium bicarbonate solution, and then with a saturated sodium chloride solution, after which it is dried over sodium sulfate. After evaporation, the residue is distilled in vacuo, to give 19 g 2 - amino - 1 - (2 - thienyl)propane (Yield: 53%) boiling at 84—86°C under 12 mm Hg.

EXAMPLE 2 Preparation of 2 - (2 - thienyl) - ethylamine, via indirect amination a) Preparation of N - 2 - (2 - thienyl) - ethyl phthalimide To a solution maintained at 80°C and comprising 294 g (2 moles) phthalimide dissolved in 800 ml dimethylformamide, are added 120 g anhydrous sodium carbonate followed, within 1.25 hour, by a solution of 564 g (2 moles) 2-(2- thienyl) - ethyl paratoluenesulfonate in 20 ml dimethylformamide. The reaction medium is maintained at 80°C during 2 hours and 20 minutes and is then cooled and poured over 1 litre water.

The resulting precipitate is collected by filtration; it is then washed, dried and recrystallized from ethanol, to give 396 g - 5 42786 N-2 - (.2 - thienyl} - ethylphthalimide (Yield; 44%) which has a melting point (Koefler Block} of 129—130°C. b) Preparation of 2 - (2 - thienyl) - ethylamine 51.4 g CO.2 mole ) of the N-2 - C2 - thienyl) - ethyl 5 phthalimide are mixed with 10.3 g. diethylenetriamine (0.1 mole) and heated at 120°C during 4 hours. The pressure is then gradually decreased to 19 Torr, and distillation gives 19.7 g 2 - (2 thienyl) - ethylamine (Yield; 77%) which has a boiling point of 98°C/19 Torr.

Claims (11)

1. Process for the preparation of compounds having the formula; CH—CH—NH n R 2 R 1 (I) in which and R 2 each represent hydrogen or a C^_ 4 alkyl or an optionally substituted phenyl radical, comprising aminating a derivative having the formula; R 2 R 1 \ I 1 x __CH PH S —CH—CH—SO 3 R 3 (II) in which radicals R p and R 2 have the above-mentioned meanings and 10 R 3 is an optionally substituted alkyl, aryl or aralkyl group.

2. Process as claimed in claim 1, wherein the amination is carried out by reacting the derivative of the formula (II) with ammonia.

3. Process as claimed in claim 2, wherein the reaction is 15 carried out at elevated temperature in an autoclave.

4. Process as claimed in claim 1, wherein the derivative of the formula (II) is reacted with phthalimide, to give a compound (III) - 7 43786 which, is subsequently transaminated with, an amine or with hydrazine hydrate.

5. Process as claimed in claim 4, wherein the reaction of the derivative of the formula Cll) with phthalimide is effected 5 in the presence of a base.

6. A process as claimed in claim 5 wherein the base comprises an alkali metal or alkaline-earth metal carbonate or hydroxide or an alkali metal amide, hydride or alkoxide.

7. Process as claimed in claim 4, wherein the amine is 10 diethylenetriamine, benzylamine or ethanolamine.

8. A process as claimed in any one of claims 4 to 7 wherein the reaction is effected at elevated temperature.

9. A process as claimed in claim 1 substantially as herein disclosed. 15

10. A process as claimed in claim 1 substantially as herein disclosed in either of Examples 1 or 2.

11. Compounds of general formula I whenever prepared by a process as claimed in any of claims 1 to 8.