DD202711A5 - PROCESS FOR THE PREPARATION OF (THIENYL-2) - AND (THIENYL-3) -2-ETHYLAMINES - Google Patents

Abstract

The present invention relates to a novel process for the preparation of (thienyl-2) - and (thienyl-3) -2-ethylamines of the formula I in which R is 1 and R 2 is a hydrogen atom, a linear or branched alkyl radical, an aromatic radical , heterocyclic or non-heterocyclic radical such as thienyl, furyl, pyridyl, phenyl or naphthyl, optionally mono- or polysubstituted, characterized in that one carries out a catalytic hydrogenation with a compound of formula II, in which R deep 1 and R deep 2 are as defined above.

Description

241258 4 -'- ^to91111

15/11/82

AP C07D / 241 258/4

Process for the preparation of (thienyl-2) - and (thienyl-3) -2 · ethylamines

Field of application of the invention

The Torliegende invention relates to a novel process for the preparation of (thienyl-2) - and (2hienyl-3) -2-ethylamine compounds, of which a significant number are known and used as intermediates for the preparation of useful compounds in the chemical and used in the pharmaceutical industry ·

The compounds according to the invention correspond to the general formula X.

R ₂ U_ 4J CH ₂ -CH-HH ₂ (I)

"\ _s / R ₂

in which R ₁ and R _{2 represent} a hydrogen atom, a linear or branched alkyl radical, an aromatic, heterocyclic or non-heterocyclic radical such as thienyl, furyl, pyridyl, phenyl or naphthyl, optionally mono- or polysubstituted,

The aminoethyl chain and the group R ₁ can occupy any position of the thiophene nucleus ·

Characteristic of the known technical solutions

The derivatives of the formula I have hitherto been prepared by the following different methods:

Reduction of β-fibrominyl-2 or 3-thiophenes with the aid of lithium aluminum hydride (E.T. GILSDORF and F. F NORD, J. Org. Chem., J, 807 (1950); E, CAMPAIGHE and WC Mc. CAROLY, J. Am. Chem. Soc. 76, 4466 (1954) or on electrochemical

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chemical route (I ¹ R-PS 7 801 992);

Reduction of (thienyl-2) · and (! Qiienyl-3) -2-acetonitriles with the aid of Idthiunaluminiunhydrid (B.F.CROWE and PF UORD, J. OPg. Chem., ^, 81 (1950); CAMPAIGME and W · C. Mc · CABTHY, supra) or a sodium amalgam (FF BLICKE and J. H * BRÜCKHALTER, J. Am. Chem. Soc., 477 (1942))?

by Curtius degradation via the (thienyl-2) - and (oleicyl-3) -3-propionic acids (G. BAEGSR and APT SASSOU, J. Chem. Soc., 2100 (1938); E. CAMPAIGI] E and WC Mc. CARXHY, supra);

- Starting from the derivatives (halides or arylsulfonates of (Ihienyl-2) - and (lhienyl-3) -2-ethanol by direct amination (F ₉ F. BLICKE and JH BRUCKHALTER, supra, FR-PS 7 503 142) or above the intermediate of a phthalimide (FR-PS 7 503 142).

However, these various processes are difficult to carry out and do not lead to satisfactory yields in order to be of interest from an industrial point of view.

Object of the invention

The aim of the invention is to provide a simple and economical process by which compounds of the formula I can be prepared in good yield and high purity.

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Explanation of the essence of the invention

The invention has for its object to find readily available Auagangererbindungen for the preparation of (Tb.ienyl-2) - and (Hiieny1-3) -2-ethyl-araines

According to the invention, a derivative of the formula »

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₁ φ- - | p0H = C-II0 ₂ (IV)

in which B ₁ and E ₂ are defined as in formula I which can be prepared by a number of methods known to the person skilled in the art, for example by condensation of a compound of the formula II

E ₂ - CH ₂ - NO ₂ (II)

with a carbonyl derivative of formula III

in which R-j is also defined as in formula I, by working under the general conditions known to the person skilled in the art, to obtain a derivative of the formula IV

R ₁ H- -If- CH = C - NO ₂ (IV)

to get ^

In accordance with the process of the invention for the preparation of the compounds of formula I

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a) subjecting a compound of formula IV under the conditions known for this Realitat the catalytic hydrogenation, resulting in a compound of the formula V

-u

CH ₂ - C a IT - OH (V)

stirred "

b) This compound is in turn also converted by catalytic hydrogenation, but under different process conditions, into the derivative of formula I as defined above. «

In general, the preparation of arylethylamino type compounds is according to the following scheme

H₀ Ar - CH = C - HO₂ Ar - CH₂ - CH -

Although the catalytic hydrogenation of β-uterovinylaryl is a well-known fact, it has so far been used as in the Pail, where the aromatic radical is thiophene. Nevertheless, the hydrogenation of β-nitrovinyl-2-thiophene In Presence of palladium, restricted to the preparation of the oxime of (thienyl-2) -2-acetaldehyde (L. Kh. "PSEIDLIIT," J ¹ "LITVDT, and VM CHURSIHA, Khimiyd'G Se et", 22 (1967 Chem. Abstr. §Z, 73 465 2)> ^{but the amounts of} catalyst required for ^ ³ processes (0.200 g palladium metal on 0.775 g hydrogenation substrate) exclude any acceptable industrial application: the ratio of palladium used

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is greater than 25% with respect to the substrate

In contrast, obtained by the process according to the invention (thienyl ^ 2) - or (I! Hienyl-3) -2- ethylamines under einfach'durchzuführenden conditions, with small amounts of catalyst to be used and in little expensive way and V / iron.

The invention is characterized in particular by carrying out this reduction in two stages of operation.

In a first step, the derivative of formula IV is hydrogenated in non-alkaline medium, namely

in a solvent, which may be an alcohol, eg methanol, ethanol or isopropanol, or an organic acid, eg formic acid, acetic acid or propionic acid, or advantageously in a mixture of two solvents, each from the family is selected mentioned, z ^ B "is a mixture of methanol or ethanol with acetic acid;

in the presence of a metallic catalyst, which may be palladium, platinum, ruthenium, rhodium or iridium

The metal is advantageously diluted with a carrier, the amount amounts to 10 to 100 times the amount of catalyst · There is z. Carbon, alumina or barium sulfate and the catalyst is generally used in an amount between 1 % and 10% with respect to the substrate to be hydrogenated, which corresponds to a palladium amount of 1/10000 to 1/100

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under a hydrogen pressure of generally between 1 and 100 atmospheres, in particular between 5 and 25 atmospheres;

- At a generally between 20 ⁰ C and 100 ⁰ C, in particular between 30 ⁰ C and 60 ⁰ C lying temperature;

at a duration of the operation, which is generally between 30 minutes and a few hours

In a second step, the derivative of the formula V isolated from the reaction mixture is hydrogenated after separation of the catalyst by means of suitable methods, namely

in a solvent which may be an alcohol, e.g. B, methanol, ethanol or isopropanol, and which advantageously contains dissolved ammonia to prevent the formation of secondary amines;

in the presence of a metallic catalyst and in particular Raney-Uickel or ITickel on a support such as silica or alumina, the amount of metal employed being between 1 % and 10% with respect to the substrate to be hydrogenated;

under a hydrogen pressure of generally between 1 and 100 atmospheres, in particular between 5 and 25 atmospheres;

- At a generally between 20 ⁰ C and 100 ⁰ C, in particular between 40 ⁰ C and 80 ⁰ C lying temperature;

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- At a duration of the operation, which is generally between 30 minutes and a few hours.

The compounds of formula I obtained in this way can then be isolated and purified by ordinary methods. In order to carry out these methods, it may be advantageous to convert "the free compounds of the formula I into their salts", for example into their acid addition salts, by reaction with mineral or organic acids. Starting from these salts, the compounds of the formula I can be released by customary methods.

The invention also includes the intermediates obtained in the various stages of the synthesis;

the compounds of the formula V

CH ₂ - O * N - OH (V)

^B 2

the compounds of the formula I

ki - Yf- -nw " _O - <" »** - xmj _o CI)

embodiment

The invention is explained in more detail below with reference to some examples. The following examples illustrate the invention without restricting it.

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Example 1 - Preparation of (thienyl-2) -2-ethylamine

hydrochloride

a) Qxim of (thienyl-2) -acetaldehyde

100 g (0.645 mol) of (2-thienyl) -2-nitroethylene in solution of 2 l of a mixture of acetic acid and ethanol (75/25) are in an autoclave at 35 ⁰ C under a pressure of 20 bar in the presence of 5 g of palladium hydrogenated on charcoal (5%) until the absorption is complete (duration: approx. 2 hours). After filtering off the catalyst and its rinsing with Sthanol The obtained solution is evaporated under vacuum at 50 ⁰ C. The oily residue is taken up in methylene chloride (500 ml) and the solution is washed successively with an aqueous solution of N-soda and with water, after which it is finally evaporated to obtain 97 g of the oxime (syn + anti mixture) (Thienyl-2) -acetaldehyde in the form of an orange-yellow oil, which is used unchanged in the following stage.

b) The above-obtained oxime mixture, in solution of 2 saturated with ammonia methanol is hydrogenated in an autoclave at 60 ⁰ G under a pressure of 20 bar and in the presence of 10 g of Raney-JNTickel until the absorption is complete (duration: about 20 hours). After filtering off the catalyst and rinsing it with methanol, the resulting solution is evaporated. Then, 500 ml of toluene are added to the oily residue. This organic phase is extracted with an aqueous, about H hydrochloric acid solution. The aqueous, acid phase is made basic with about H-soda solution and then extracted with toluene. To the isolated organic phase is added a solution of gaseous hydrogen chloride in isopropyl ether, which

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formation of a precipitate, which is subsequently filtered off and then dried. 68 g (yield 65 % with respect to (thienyl-2) -2-nitroethylene) (thienyl-2) -2-ethylamine are obtained in this way. Hydrochloride in the form of white crystals «

1 = 202 ⁰ C.

Analysis CgH ₉ IiS, HCl * 163.67 Calculated: C % 44.03 H % 6.15 H % 8.55 Found j 43.98 6.16 8.54

Example 2 - (ghienyl "3) ~ 2-ethylamine hydrochloride

The procedure is as in the conditions described in Example 1, but replacing the 5 # Pd / C by 5% Rd / C, and obtained in a yield of 66 %, the hydrochloride of the above compound «

F * 216 ⁰ C

Analysis CgH ₉ NS, HCl «163.67

Calculated: C % 44.03 H % 6.15 IT % 8.55 Bills: 43.92 6.18 8.50

Example 3 - 1 methyl (Thieny 1-3) -2-etJby laminar

hydrochloride

The procedure is as under the conditions described in Example 1, but with the 5% Pd / C replaced by 5 # Ptiges / C, and obtained in a yield of 81 %

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Hydrochloride of the above compound »

P = 138 ^° C.

Analysis G ₇ H ₁₁ IiS, HCl = 177.69 Calculated: G% 47.31 H% 6.80. H % 7.88 Found: 4?, 55 6.85 7.92

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Claims (11)

invention claim 1. A process for the preparation of (thienyl-2) - and (thienyl-3) -2-ethylamines of the general formula I. (D in which R ₁ and R _{2 represent} a hydrogen atom, a linear or branched alkyl radical, an aromatic, heterocyclic or non-heterocyclic radical, optionally mono- or polysubstituted, characterized in that a catalytic hydrogenation under a hydrogen pressure between 1 and 100 Atmospheres and in particular between 5 and 25 atmospheres, at a temperature between 20 ° and 100 ° G and in particular between 30 ° and 60 ° C with a compound of formula IV is carried out, in which R ₁ and R _{2 are} as defined above, a compound of formula V 1-ΙΕ, (τ) ¹ N p to obtain, after isolation in turn by catalytic hydrogenation under a hydrogen pressure between 1 and 100 atmospheres and in particular between 5 and 25 atmospheres at a temperature between 20 ° and 100 ° C and in particular between 40 ° and 80 ° C, in a compound of Formula I is converted · 241258 k 60 911 11 "12 - 2. The method according to item 1, characterized in that the two phases of the catalytic hydrogenation are different and are carried out under different conditions * 3. The method according to any one of items 1 and 2, characterized in that the first phase of the catalytic hydrogenation, which relates to the derivative of formula IV, is carried out in a non-alkaline medium. 4 · Method according to item 3, characterized in that the reaction is carried out in an organic solvent, in particular methanol, ethanol or isopropanol, or an organic acid, in particular formic acid, acetic acid, propionic acid or preferably a mixture of alcohol and acid. 5. The method of item 3, characterized in that the catalyst of the first hydrogenation step comprises a metal selected from palladium, platinum, ruthenium, rhodium and iridium, in conjunction with an inert carrier. 6. The method according to item 5, characterized in that the inert carrier is carbon, alumina or barium sulfate. 7. The method according to item 5, characterized in that the metallic component of the catalyst is applied in various ratios of 1/10000 to V100 with respect to the substrate. 8. The method according to item 1 or 2, characterized in that the second phase of the catalytic hydrogenation, which relates to the derivative of formula V, is carried out in an alkaline medium. 241258 A 9. The method of item 8, characterized in that the catalyst of the second hydrogenation stage Raney nickel or is a catalyst containing nickel in an inert carrier st off. 10, process according to item 9, characterized in that the inert carrier is silica or alumina. 11. The method according to item 10 _9, characterized in that the metallic component of the catalyst in the ratio of 1 "to 10 #, with respect to the substrate applied. Method according to item 8, characterized in that the reaction is carried out in an organic solvent such as an alcohol, in particular methanol, ethanol or isopropanol in combination with ammonia in the dissolved state. 13. The method according to item 1, characterized in that the aromatic radical is selected from the groups thienyl, furyl, pyridyl, phenyl or saphthyl. 17.HOl 1982 * 0482 * 1