NO155345B - PROCEDURE FOR PREPARING 2- (2-THIENYL) -ETHYLAMINES AND 2- (3-THIENYL) -ETHYLAMINES. - Google Patents

Description

The present invention relates to a new process for the production of 2-(2-thienyl)-ethylamines and 2-(3-thienyl)-ethylamines, a large number of which are known and used as intermediates in both the chemical and pharmaceutical industries.

The compounds produced according to the present invention have the formula:

where:

is in the 2-, 3-, 4- or 5-position, and and R2, which may be the same or different, is hydrogen, straight-chain or branched alkyl or a thienyl, furyl, pyridyl, phenyl or naphthyl group which optionally is mono- or poly-substituted with halogen, nitro, cyano, amino, carboxy, alkyl, alkoxy or phenyl.

The derivatives of formula (I) have already been prepared by a number of methods: reduction of 0-2- or -3-nitrovinyl-thiophenes with lithium aluminum hydride [R. T. Gilsdorf & F. F. Nord, J. Org. Chem., 15, 807 (1950); E. Campaigne & W. C. McCarthy,

J. Am. Chem. Soc, 76, 4466 (1954) or by an electrochemical method [FR 78.01 992];

reduction of 2-(2-thienyl)- and -(3-thienyl-acetonitrile with lithium aluminum hydride [B. F. Crowe & F. F. Nord, J. Org. Chem., 15, 81 (1950); E. Campaigne & W. C. Mc Carthy,

ref indicated] or with sodium amalgam [F. F. Blicke &

J.H. Burckhalter, J. Am. Chem. Soc, 6_4 , 477 (1942)];

Curtius decomposition of 3-(2-thienyl)- and -(3-thienyl)-propionic acids [G. Barger & A.P.T. Eassou, J. Chem. Soc, 2100

(1938); E. Campaigne & W. C. Mc Carthy ref indicated];

from 2-(2-thienyl)- and -(3-thienyl)-ethanol derivatives (halogenides or arylsulfonates) by direct amination [F. F. Blicke & J. H. Burckhalter, ref indicated;

FR 75 03 142] or over a phthalimide (FR 75 03 142 ).

However, such difficult-to-use methods have not yielded satisfactory results from an industrial point of view.

It is also already known to prepare compounds of the arylethylamino type according to the following scheme:

ie by catalytic hydrogenation of γ-nitrovinyl aryl compounds. However, this reaction has never been used in cases where the aromatic group is the thiophene group. Even so, some hydrogenation of 2-(£-nitrovinyl)-thiophene has already been described, however limited to the preparation of 2-(2-thienyl)-acetaldehyde oxime in the presence of palladium £1. Kh. Freidlin, E.F. Litvin & V.M. Chursina, Khimiya G. et Soed. 3, 22 (1967), Chem. Abstract 67_, 73 465 y] , but the amounts of catalyst used (0.200 g of palladium metal per 0.775 g of compound to be hydrogenated) preclude a reasonable industrial application: the amount of palladium constitutes more than 25% of the amount of the compound to be hydrogenated.

In contrast, the present invention allows the production of 2-(2-thienyl)- or -(3-thienyl)-ethylamines under very acceptable and economically reasonable conditions, i.a. because small amounts of catalyst are used.

The invention thus provides a simple and inexpensive method for producing compounds with the above formula (I). In the process, a compound of the general formula: where and R_ is as indicated above, hydrogenated catalytically to a compound of the general formula:

which is isolated, after which the compound of formula (V) which is characteristically new in the method is catalytically hydrogenated under a hydrogen pressure of 1-100 atm, preferably 5-25 atm,

and at a temperature of 20-100°C, preferably 40-80°C..

In the first step of the method according to the invention, the compound of formula (IV) is hydrogenated in a non-alkaline medium, in a solvent which can be an alcohol, such as e.g. methanol, ethanol or isopropanol, or an organic acid such as formic acid, acetic acid, propionic acid, or preferably in a mixture of two solvents, each selected from one of the aforementioned groups, e.g. in a mixture of methanol or ethanol and acetic acid, in the presence of a metal catalyst which may be selected from palladium, platinum, ruthenium, rhodium and iridium.

The metal is advantageously diluted 10-100 times

its weight by a carrier such as e.g. charcoal, aluminum oxide or barium sulphate, and in general the amount of such a combination used is 1-10% of the compound to be hydrogenated, which corresponds to a quantity ratio of from 1/10,000 to 1/100 between the catalyst component and the compound to be hydrogenated. The hydrogenation is carried out under a hydrogen pressure which is generally between 1 and 100 atmospheres, and which is preferably between 5 and 25 atmospheres, at a temperature which is generally between 20° and 100°C, preferably between 30° and 60°C. The hydrogenation generally starts from

30 minutes to a few hours.

Prior to the second step, the derivative is given by formula

(V) isolated from the reaction medium in a suitable manner. It will be

then hydrogenated in a solvent which may be an alcohol, such as e.g. methanol, ethanol or isopropanol, as with advantage

- to prevent the formation of secondary amines - will contain dissolved ammonia. The hydrogenation is carried out in the presence of a metal catalyst, preferably a nickel catalyst, either so-called Raney nickel or nickel placed on a support such as silicon

cium oxide or aluminum oxide, the amount of metal used being 1-10% with respect to the compound to be hydrogenated. The hydrogenation is carried out under a hydrogen pressure between 1 and 100 atmospheres, preferably between 5 and 25 atmospheres, at a temperature between 20° and 100°C, preferably between 40°

and 80°C, and it generally takes from 30 minutes to a few hours.

The prepared compounds of formula (I) can then be isolated and purified by conventional methods. For this purpose, it may be advantageous to transfer the free compounds of formula (I) to their salts, e.g. their acid addition salts by reaction with inorganic or organic acids. The compounds of formula (i) can then be freed from their salts by known methods.

The compounds of formula (IV), which are used as starting materials, can be prepared by a number of methods which are well known in the art, such as e.g. by condensation of a compound with the formula:

with a carbonyl derivative of the formula: where is as indicated above, under well-known conditions, whereby a derivative of the formula is obtained:

The following examples illustrate the invention.

Example 1

Preparation of 2-(2-thienyl)-ethylamine hydrochloride

a) 2-thienyl-acetaldehyde-oxime

100 g (0.645 mol) 2-(2-thienyl)-nitroethylene dissolved in

2 liters of acetic acid:ethanol (75:25) are hydrogenated in a pressure vessel at 35°C under a pressure of 20 bar in the presence of 5 g of 5% palladium-on-charcoal until absorption ceases (time: approx. 2 hours). The catalyst is then filtered off and cleaned with ethanol, after which the resulting solution is evaporated in a vacuum at 50°C. The oily residue is taken up in 500 ml of methylene chloride, and the solution is washed successively with an approx. IN aqueous sodium hydroxide solution and with water and then evaporated, whereby 97 g of 2-thienyl-acetaldehyde-oxime (syn + anti mixture) is obtained as an orange-yellow oil which is used as such in the following step,

b) The oxime mixture obtained above, dissolved in 2 liters of methanol saturated with ammonia, is hydrogenated in a pressure vessel at

60°C under a pressure of 20 bar in the presence of 10 g of Raney nickel until absorption ceases (time: approx. 20 hours). The catalyst is filtered off and cleaned with methanol, and the resulting solution is evaporated. Toluene (500 ml) is added to the oily residue. This organic phase is extracted with an aqueous hydrochloric acid solution (approx. 1N). The obtained acidic aqueous phase is made alkaline with about 1N aqueous sodium hydroxide and then extracted with toluene. Addition to the isolated organic phase of a solution of hydrogen chloride gas in isopropyl ether leads to . to the formation of a precipitate which is filtered off and dried, thereby obtaining 68 g (yield: 65% with respect to 2-(2-thienyl)-nitroethylene) of 2-(2-thienyl)-ethylamine hydrochloride, as white crystals.

Temp. = 202°C

Analysis: CgHgNS . HCl = 163.67

Calculated %: C 44.03; H 6.15; N 8.55

Found %: 43.98 6.16 8.54

Example 2

2-(3-thienyl)ethylamine hydrochloride

When the method is carried out as stated in example 1, but the 5% Pd/C is replaced by 5% Rh/C, the hydrochloride of the compound is obtained in a yield of 66%.

Temp. = 216°C

Analysis: CgHgNS . HCl = 163.67

Calculated %: 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

Under the conditions described in Example

1, with the 5% Pd/C being replaced by 5% Pt/C, the hydrochloride of the compound is produced in a yield of 81%.

Temp. = 138°C

Analysis: C^-^NS . HCl = 177.69

Calculated %: C 47.31; H 6.80; N 7.88

Found %: 47.55 6.85 7.92

Claims (3)

1. Procedure for the production of 2-(2-thienyl)- and 2-(3-thienyl)-ethylamines with the general formula: where: R^ stands in 2-, 3-, 4- or 5-st Ulingen, and R^ and R2 , which can be the same or different, is hydrogen, straight chain or branched alkyl or a thienyl, furyl, pyridyl, phenyl or naphthyl group which is optionally mono- or polysubstitu- tuated with halogen, nitro, cyano, amino, carboxy, alkyl, alkoxy or phenyl, whereby a compound with the general formula: where R1 and R2 are as indicated above, is catalytically hydrogenated to a compound of the general formula: which is isolated, characterized in that the compound of formula (V) is catalytically hydrogenated under a hydrogen pressure of 1-100 atm, preferably 5-25 atm, and at a temperature of 20-100°C, preferably 40-80°C. 2. Method according to claim 1, characterized in that the two catalytic hydrogenation steps are carried out under different sets of conditions. 3. Method according to claim 1 or 2, in which the first hydrogenation step, where the compound of formula (IV) is hydrogenated, is carried out in a non-alkaline medium under a hydrogen pressure of 5-25 atm and at a temperature of 30-60 °C, using a catalyst containing a metal component selected from palladium, platinum and rhodium deposited on an inert support, and which is used in an amount corresponding to a weight ratio of from 1/10,000 to 1/100 between the metal component and the compound which is to be hydrogenated, characterized in that the second hydrogenation step, where the compound of formula (V) is hydrogenated, is carried out in an alkaline medium, using a Raney nickel catalyst in an amount corresponding to a weight ratio of from 1/100 to 1/ 10 between the metal component of the catalyst and the compound to be hydrogenated.