CS236482B2 - Method of 2-(2-or 3-thienyl)ethylamines production - Google Patents

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 relates to a process for the preparation of 2- (2-thiityl) ethylamines and 2- (3-thlenyl) ethylamines. These compounds are known and are valuable intermediates for the production of compounds for chemical and pharmaceutical applications.

These substances can be represented by the lunch formula I

- CH - NH ₂ (I) by straight or branched chain of 1 to 4 atoms up to now prepared in different ways:

<1 ^L _S -2 ^C 2 where

R is hydrogen and

R 8 represents a hydrogen atom or an alkyl of carbon.

Compounds of formula (I) tulles

- reduction of 2-beta-nierovinyl or -3-lienosulfonothiophenes by treatment with lithium aluminum hydride as described in R. T. Gilsoorf and F. P. Nord, J. Org. Chem., £ 5,

807 (1950), E. Camppagni and W. C. tic. Cartty, J. Am. Chem. Soc. £ 6. 4,466 (1954) or electrochemically (French Patent No. 78 01 9912),

reduction of 2- (2-chloro-1-) - and 2- (3-ethyl) -cyclonitriles with lithium fluorine hydrides according to B. F. Crowe and F. F. Nord, J. Org. Chem. JJ 81 (1950), E. Campalgne et al

W. C. Mc. Cartty, according to the above citation, or by the action of sodium, according to F. F. Blicke and J. H. Wigkowski, J. Am. Chem. Soc., 64 477 (1942),

By the curative degradation of 3- (2-ethynyl) - or 3- (3-thienyl) iso -ionic acids according to G. Barger and A. Ρ. T-Bssou, J. Chem. Soc., 2,100 (193β) »E. Cernmpigne and W. C. l. · Certhy according to the above quotation,

- from halogenated or isosylonated derivatives of 1-Gl-thienyl) - or 2- (3-thienyl) ethano by direct coinage according to FF Blicke and JH BirckhaHer, cited above or French Patent No. 75 03 142 or via ft. ^ aimid according to French Patent No. 75 · 03 142.

All of these processes are difficult to obtain and do not yield the good yields required to carry out the process on an industrial scale.

The object of the invention is a simple and economical process for the production of the compounds of the general formula (I).

The compounds of formula IV are used as starting materials

CH = c (r ₂ ) = no ₂ (IV) where

And R are as defined in general formula I, these compounds can be prepared by various known methods, for example by condensation of compounds of general formula II R ₂ - CH ₂ - _N0? where

R _o is as defined above, with a carbonyl derivative of formula III

Rff-NH ¹ with ^x (II) (III.) Wherein X has the meaning given in formula X, the procedure is carried out in a known manner to give compounds of formula IV

-F r _r JJ-CH = C (fi ₂₎ NOG (IV) ^'V S''wherein

R, and R _? are as defined above.

According to the process of the invention, the compounds of the formula I can be obtained by subjecting them to catalytic hydrogenation at a hydrogen pressure of 0.1 to 10 MPa, preferably 0.5 to 2.5 MPe at a temperature of 20 to 100 ° C, preferably 30 to 60 MPa. ° C, a compound of formula IV

(IV) where and R? are as defined above to form a compound of formula (V)

(V) where

Xij ε Rg is not mentioned above. after isolation, this material is converted by second catalytic tydrogenation in an organic alkaline medium at a hydrogen pressure of 1 to 10 bar. preferably 0.5 to 2.5 MPa at a temperature of 20 to 100 ° C, preferably 40 to 80 ° C per compound of formula I.

In general, the recovery of arylethylamino derivative compounds can be illustrated by the following reaction scheme:

Ar = CH = C-NO.

catalyst where

Ar is aryl.

It is a catalytic tydrogenation of beta-nitrovinylaryl compounds, which is fundamentally known, but has never been used again when thiophene has been used as the aromatic residue. Only the hydrogenation of 2-nitrile-vinylthiophene has been described, but the tulle is always limited to obtaining 2- (2-thienyl) aieteldiphyde oxime in the presence of palladium, as described in L. Kh. Freidlin, E.F. Lltvin and V.M, Chursina, Khimiya'G. and Sced. 22, 1967, Chem. Abbt. & £ 73,465 y. In this case, it was necessary to use 0.200 g of palladium metal per 0.775 g of hydrogenated sulphate, which precludes any use of this process on an industrial scale, since the palladium content is even higher than 25%, based on not the bihydrate.

In contrast, in the process according to the invention for obtaining 2- (2-thietylethyrines or 2- (3-thienyl) ethylamines, the amount of catalyst used with respect to the substrate is much smaller and the process according to the invention can therefore be used as an economical process on an industrial scale.

The method is characterized in that the reduction is carried out in two steps.

In the first step, the compound of formula (I) is hydrogenated in a non-alcoholic medium

in a solvent environment, which may be an alcohol, for example methanol, ethanol, isopropanol; or an orgenic acid such as formic acid, acetic acid, acetic acid, or preferably in a two-solvent environment selected from the foregoing may, for example, be composed of methanol or ethanol and acetic acid,

- in the presence of a metal catalyst, namely palladium, platinum, ruthenium, rhodium or iridium.

The metal is preferably diluted with 10 to 100 times the amount of carrier, for example carbon, aluminum or barium sulfate, and is used in an amount of 1 to 10%, based on hydrogenated substrate, corresponding to 1/10 000 and 1/100 · pure palladium.

- a hydrogen pressure of 0.1 to 10 MPa, preferably 0.5 to 2.5 MPa, is usually used,

The temperature is moving. in the range of ^{20 to 100} ° C, preferably 3 to ⁶⁰ ° C

- the procedure usually takes 30 minutes to several hours.

In the second step, the compound of formula (V) isolated from the reaction medium is hydrogenated appropriately after separation of the catalyst

- in a solvent such as Plcrole as methanol, ethanol or isopropanol, the alcohol preferably containing dissolved ammonia to avoid secondary amines being formed,

- from the presence of a metal catalyst, in particular nickel such as Raney nickel or supported nickel, for example on silica or alumina, the amount of metal used is more than 10%, based on the hydrogenated substrate,

- at a hydrogen pressure in the range from 0.1 to 10 MPa, preferably 0.5 to 2.5 tPa,

- the process s is carried out at a temperature of 20 to 100 ° C, preferably 40 to 80 ° C,

- hydrogenation lasts from 30 minutes to several hours.

The compounds of formula (I) thus obtained can be isolated and purified in conventional manner. For carrying out these processes, it may be advantageous to convert the free compound of formula I into a salt, for example an acid addition salt by reaction with inorganic or organic acids. Compounds of formula (I) may be liberated from these salts in a conventional manner.

Between the product is a compound of formula V £ _R 4 -CH ₂ - _E

N - OH where

R | and Rp are as defined above.

The invention will be illustrated by the following examples.

Example 1

Process for preparing 2- (2-thienyl) ethylamine hydrochloride

a) Oximes of 2-thienylaceteldehyde

100 g (0.645 mol) of 2- (2-thienyl) nitroethylene in solution in 2 liters of acetic acid / ethanol (75:25) are hydrogenated in an autoclave at 35 ° C and 2 MPa in the presence of 5 g of palladium on active coal until absorption is complete, which takes about 2 hours. The concentration of palladium on activated carbon is 5%. After filtering off the catalyst and washing it with ethanol, the solution obtained is evaporated under vacuum at 50 ° C. The oily residue is dissolved in 500 ml of methylene chloride and the solution is washed successively with aqueous 1N sodium hydroxide solution and water and then evaporated to dryness to give 97 g of oxime (syn 4 anti) 2-thienylacetaldehyde as a yellow-orange oil. the liquid which is used as such in the next step.

b) A mixture of the oximes obtained above in solution in 2 liters of methanol saturated with ammonia is hydrogenated in an autoclave at 60 ° C at 2 KPa. from the presence of 10 g of Raney nickel until the end of the absorption, which lasts approximately 20 hours. The catalyst is filtered off and washed with methanol, the solution is evaporated and the oily residue is treated with 500 ml of toluene. The organic phase was extracted with aqueous rozookem hydrochloric acid at ₀ with 1N aqueous acid phase was alkaiizuje aqueous solution of sodium hydroxide 1N and then extracted with toluene. The organic phase was separated and treated with a solution of hydrogen chloride gas in isopropyl ether to give a precipitate which was filtered off and dried. 68 g of 2- (2-thienyl) elytamine are obtained in the form of white crystals, m.p. ²⁰² DEG. Yield ^{65% |} related to

Analysis for C ^ HH ^N. · HCl (molecular weight: 163.67):

calculated: H, 6.15; N, 8.55. found: H, 6.16; N, 8.54.

Example 1

Hyldoohlorid

The procedure is as described in Example 1, but using 5% rubidium on activated carbon instead of 5% palladium on charcoal, yielding the title hydrochloride in 66% yield, m.p. 216 ° C.

Analysis for CjHHgNS.HCl? (moocular hmoonnot: 163.67):

calculated: H, 6.15; N, 8.55. found: % C, 43.92;% H, 6.18;

Example 3

Hy1doohlorif 1 -mey

Using the procedure described in Example 1 A, but the bridge 5% palladium on charcoal is used% platinum on charcoal, in a yield of 81% ^{hydrochloride} The title compound of ^melting point e ^p ture. ¹³⁸ ° ^C

Analysis for γH-JNS.HCl (mc> 1: 1: 177.69):

H, 6.80; N, 7.08. Found:% C, 47.55;% H, 6.85;

Severography, n. P., MOST

Price 2,40 Kčs

Claims (9)

A process for the preparation of 2- (2- or 3-thienyl) ethyl8mines of the general formula I (I), wherein it represents a hydrogen atom and R ₂ represents hydrogen or alkyl with straight or branched 6 1-4 carbon atoms, characterized in that it is subjected to catalytic hydrogenation at a hydrogen pressure of 0.1 to 10 MPa, preferably 0> to 2.5 MPa at a temperature 20 to 100 ° C, preferably 30 to 60 ° C, a compound of formula IV (IV) wherein and R ₂ are as defined above to form a compound of formula V Rf-jf i] - CH ₂ - C = N - ОН (V) K ₂ wherein a Rg is as defined above, and after isolation, this is converted by a second catalytic hydrogenation in an organic alkaline medium under a hydrogen pressure of 0.1 to 10 MPa, preferably 0.5 to 2.5 MPa at 20 to 100 ° C C, preferably 40 to 80 ° C per compound of formula I. Process according to Claim 1, characterized in that the first hydrogenation is carried out in an alcohol, in particular methanol, ethanol or isopropanol or in an organic acid, in particular formic, acetic or propionic, or expediently in a mixture of an alcohol and an acid. 3. The process according to claim 1, wherein the catalyst in the first hydrogenation step consists of a metal, namely palladium, platinum, ruthenium, rhodium or iridium on an inert support. ! 3ο4 <32 4. The process according to claim 3, wherein the inert carrier is activated carbon, alumina or swamp sulphate. 5. A process according to claim 3, wherein the metal component of the catalyst is used in an amount of 1:10,000 to 1: 100, based on the substrate. 6. The process of claim 1, wherein the catalyst in the second hydrogenation step is Raney nickel or a catalyst containing nickel on an inert support. 7. The method of claim 6, wherein the inert carrier is alumina or silica. 8. A process according to claim 7, wherein the metal component of the catalyst is used in an amount of 1 to 10%, based on the substrate. 9. The process according to claim 8, wherein the second hydrogenation is carried out in an organic solvent such as an alcohol, in particular methanol, ethanol or isopropenol, in the presence of dissolved ammonia.