HU199448B - Process for producing n-thienyl-chloro-acetamides - Google Patents

Abstract

N-Thienyl chloro-acetamide cpds. of formula (I), in which R is 1-4C alkoxy, or 2-4C alkyl, whose 1-4C alkoxy gp. is sepd. by at least 2C atoms from the N atom to which R is linked, R2 and R4 are methyl or ethyl, and R5 is H or methyl, are made by reacting a tetrahydro-thiophen-3-one of formula (IV) with an amine R-NH2.

Description

The present invention relates to a novel process for the preparation of N-thienyl chloroacetamide derivatives.

More particularly, the present invention relates to the preparation of N-thienyl chloroacetamide derivatives of formula (III). In formula (III)

R is (1-4C) alkoxy (2-4C) alkyl, wherein the (1-4C) alkoxy is separated by at least two carbon atoms from the nitrogen to which the R group is attached; and

R ₂ and R ₄ are email.

It has now been found that compounds of formula (III) are novel and advantageously prepared by dehydrogenation of a compound of formula (I) and N-chloroacetylation of the resulting compound of formula (II). In the formulas I and II, the substituents have the meanings given above.

The compounds of formula (111) are known herbicides.

The compounds of formula (II) and (III) are disclosed in British Patent Publication No. 2,114,566A. This publication discloses several processes for the preparation of compounds of formula (III), however, neither these methods nor other methods disclosed in the literature allow the preparation of compounds of formula (III) from readily available starting materials.

The invention makes it possible to prepare the compounds of formula (III) in a very convenient (convenient) way.

According to the invention, the compounds of the formula II are prepared by dehydrogenation of the new compounds of the formula I.

This dehydrogenation may be carried out catalytically or with oxygen or oxidizing agents such as sulfur, sulfuryl chloride or thionyl chloride; preferably, the dehydrogenation is carried out catalytically or thionyl chloride is used as the oxidizing agent. Surprisingly, it has been found that thionyl chloride is very useful for the dehydrogenation of compounds of formula (I).

The catalytic dehydrogenation of the compounds of formula (I) may be carried out in the presence of any dehydrogenation catalyst. Examples of dehydrogenation catalysts are precious metals such as platinum or palladium or other metals such as chromium (III) trioxide or mixtures thereof with other metals such as copper (II) oxide. Such catalytic dehydrogenation may be carried out under known conditions for such reactions. For example, when platinum is used as the catalyst, it is desirable to precipitate this metal in a finely divided state on a carrier such as charcoal (for example, a 5% platinum on charcoal can be obtained). The dehydrogenation reaction is conveniently carried out by heating, preferably at a temperature above 180 ° C, for example at 220 ° C or higher, under an inert gas atmosphere, such as nitrogen.

The compounds of formula (I) are already reactive with oxygen at temperatures below room temperature to form intermediates which, upon heating, usually to about 100 ° C or higher, are converted to compounds of formula (II) by decomposition. This conversion is suitably carried out in a single step such that the oxidation is carried out at a temperature above the decomposition point, i.e. under reflux, of a suitable solvent such as an aromatic solvent such as toluene.

If an oxidizing agent is used, the oxidation step is conveniently carried out in a solvent which is inert to the reaction conditions. Suitable solvents for this purpose include chlorinated hydrocarbons such as dichloromethane and hydrocarbons such as toluene or cyclohexane. If sulfur is used as the oxidizing agent, the oxidation reaction is conveniently carried out under heating; when sulfuryl chloride or thionyl chloride is used as the oxidizing agent, the reaction is conveniently carried out at a temperature in the range of -30 ° C to 80 ° C, for example at room temperature (i.e. about 20 ° C to 30 ° C).

Surprisingly, thionyl chloride may also be used as the oxidizing agent in this reaction, which may be carried out under mild conditions and without the occurrence of unwanted side reactions such as chlorination, overoxidation.

The compounds of formula (II) obtained above are converted to the compounds of formula (III) by chloroacetylation on nitrogen. This chloroacetylation can be carried out by known methods which are used to convert the corresponding amines to chloroacetamides; this reaction may be carried out under mild conditions, for example, as disclosed in British Patent Specification No. 2,114,566A.

When the compounds of formula (I) are oxidized with sulfuryl chloride or thionyl chloride, the compounds of formula (II) are obtained after the reaction in the form of the hydrochlorides. These hydrochlorides can be reacted with chloroacetyl chloride without isolation from the reaction mixture in the absence of a base to give the compounds of formula (III) in substantially quantitative yield.

The compounds of formula (I) are readily prepared by reacting a tetrahydrothiophen-3-one derivative of formula (IV) wherein R ₂ and R ₄ are the same as in formula (I) with a compound of formula (V).

-2HU 199448 Β where R is the same as in formula (I).

This condensation reaction is conveniently carried out in a solvent inert to the reaction conditions, such as cyclohexane or toluene. The reaction product is conveniently dried, for example, by means of a device for precipitating water or by using a suitable molecular sieve, for example 5 X. This operation can be carried out continuously using a condenser, such as a water cooler, by passing the condensed solvent through a molecular sieve column protected by a nitrogen atmosphere to exclude atmospheric oxygen.

The above described process of the compounds of formula (III) from the compounds of formula (IV) can be carried out in one reaction vessel via the compounds of formula (I) and (II), since the compounds of formula (I) and (II) it is obtained in good yield and does not need to be isolated from the reaction vessel to carry out the next reaction step.

The compounds of formula (IV) are novel. These compounds can be prepared by cyclizing the compounds of formula (VI) wherein R ₂ and R ₄ are the same as in formula (1).

This ring-closure reaction is carried out using the Ruziöka cyclization method or modified versions of this method.

This cyclization is conveniently carried out by heating. The ring sealing reaction is facilitated by a condensing agent such as barium hydr. a combination of oxide, manganese (II) carbonate, iron powder, iron (II) or iron (III) acetate, cobalt (II) or nickel (II) acetate, acetic anhydride and lithium chloride, or a tertiary amine such as a trialkylamine. It is particularly advantageous to use iron powder or iron, cobalt (II) or nickel (II) acetates as a condensing agent.

In this context, iron acetates are understood to mean ferric (II) and ferric (III) acetates, such as ferric (II) acetate and ferric (III) dihydroxyacetate.

The compounds of formula VI are also novel. These compounds can be prepared from readily available starting materials by reacting a compound of Formula VII, wherein R ₂ is the same as in Formula I, with a compound of Formula VIII, wherein R ₄ is the same as in Formula I ) is carried out in an addition reaction.

The addition of the compounds of formula (VII) to the compounds of formula (Vili) is conveniently carried out under the conditions of the Michael addition or modified versions of this reaction. The addition process is conveniently carried out by heating. The compounds of formula (VII) are preferably carboxylate salts thereof, such as alkali metal 4

salt thereof, i.e., carboxylate sodium. In contrast, the compounds of formula (VII) may also be used in the free acid form, in which case the addition is conveniently a tertiary amine such as a trialkylamine such as tri (n-butyl) amine or iron, cobalt (II) or nickel (II) acetate.

The latter process is carried out in the absence of solvent: the reaction proceeds rapidly, yields a good yield, and the unreacted starting material can be recovered; the resulting compounds of formula (VI) can be cyclized without isolation to compounds of formula (IV).

In the above formulas, R _{2 is} preferably methyl, R ₄ is methyl, R is preferably -CH (CH ₃ ) -CH ₂ -OCH ₃ , -CH ₂ -CH ₂ -OnC ₃ H ₇ or -CH ₂ -CH ₂ -OiC ₃ H ₇ , more preferably -CH (CH ₃ ) -CH ₂ -OCH ₃ .

The following examples illustrate the process of the invention. In these examples, temperatures are given in degrees Celsius.

Example 1

Preparation of N- (1-methoxy-2-propyl) -2,4-dimethyl-tetrahydro-thien-3-ylideneimine This reaction was carried out with a thermometer, water cooler and 21 g.

It is carried out in a reaction vessel with a column filled with a molecular sieve of size X. A mixture of 0.2 mol of 2,4-dimethyltetrahydrothiophen-3-one, 0.225 mol of 1-methoxy-2-aminopropane and 50 ml of cyclohexane was placed in the reaction vessel, then a thermometer and a water cooler were added to the reaction vessel and An X-sized molecular sieve is placed so that the condensate formed by the vapors of the boiling reaction mixture continuously passes through the molecular sieve. To prevent atmospheric oxygen, the device is protected by a nitrogen atmosphere.

The reaction mixture was refluxed for 9 hours, and then the title compound was distilled under vacuum. Boiling point 65-80 ° C / 67 Pa.

Example 2

Preparation of Ν- (1-methoxy-2-propyl) -3-amino-2,4-dimethylthiophene

A solution of 0.1 molar thionyl chloride in toluene (20 ml) was stirred and cooled to 10-20 ° C with 0.1 mol of N- (1-methoxy-2-propyl) -2,4-dimethyltetrahydrothien-3 of ilidene imine in 80 ml of toluene was added dropwise, and the reaction mixture was stirred for one hour and then made basic by addition of concentrated sodium hydroxide solution. The aqueous layer was separated, the organic layer washed with water, dried and the toluene evaporated in vacuo. The residue was distilled in vacuo. The title compound has a boiling point of 70-72 ° C / 27 Pa.

-3MU iyy-i-io d

Example 3

Preparation of N- (1-methoxy-2-propyl) -3-amino-2,4-dimethylthiophene

To a solution of 0.013 mol of sulfur powder in 2 ml of hot toluene was added dropwise 0.01 mol of N- (1-methoxy-2-propyl) -2,4-dimethyl-tetrahydro-thien-3-ylideneimine in 5 minutes under reflux. The mixture was then refluxed for 5 minutes with stirring and the crude product was distilled in a balloon at 150-170 ° C under pressure. The title compound is obtained as a clear liquid.

Example 4

Preparation of N- (1-methoxy-2-propyl) -3-amino-2,4-dimethylthiophene

0.1 mol (N- (1-methoxy-2-propyl) -2,4-dimethyl-tetrahydro-thien-3-ylideneimine) in the presence of 2 g of 5% platinum on carbon in nitrogen at 200 ° C for 11 hours After heating, the catalyst is filtered off and the filtrate is distilled off at 13 Pa. The title compound boils at 68-71 ° C / 13 Pa.

Example 5

Preparation of N- (2,4-dimethyl-3-thienyl) -N- (1-methoxy-2-propyl) chloroacetamide

Method a) Use of the amine of formula II in salt form

A solution of 0.02 mol of thionyl chloride in 5 ml of toluene over 40 minutes at 20 ° C was treated with 0.02 mol of N- (1-methoxy-2-propyl) -2,4-dimethyl-tetrahydro-thien-3-ylidenimine 10 ml. dropwise to a solution of toluene. The reaction mixture was then stirred for 2 hours to give N- (1-methoxy-2-propyl) -3-amino-2,4-dimethylthiophene hydrochloride. Chloroacetyl chloride (0.02 mol) in toluene (5 ml) was added to the reaction mixture and the mixture was refluxed for one hour. Meanwhile, hydrogen chloride gas is released. The title compound is obtained by chromatography on a column of silica gel, eluting with a 8: 2 by weight mixture of cyclohexane and ethyl acetate. The title compound boils at 148-150 ° C / 4 Pa.

Method b): Use of the amine of formula II in base form

315 g (1.58 moles) of N- (1-methyl-2-methoxyethyl) -3-amino-2,4-dimethylthiophene, 1500 ml of dichloromethane, 240 g (1.75 moles) of potassium To a mixture of carbonate and 250 mL of water was added dropwise 200 g (1.77 mole) of chloroacetyl chloride at room temperature with vigorous stirring. The reaction was continued at room temperature for half an hour, then the organic layer was separated, washed with water (2 x 200 mL), dried over anhydrous sodium sulfate and evaporated. The title compound was obtained by chromatography on a silica gel column (eluent: hexane: diethyl ether 85:15). The title compound has an Rf of 0.3 silica gel, developed with diethyl 4

ether and hexane (2: 1 by weight), boiling at 148-150 ° C / 4 Pa.

Example 6

Preparation of 2.4-Dimethyl-tetrahydrothiophen-3-one by cyclization of 2,5-dimethyl-3-thia-adipic acid

Method a: with iron powder

100 parts of 2,5-dimethyl-3-thiaadipic acid, together with 7.5 parts of iron powder, are heated to 180-220 ° C and the distillate thus obtained is dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium. dried over sulfate and then the title compound is distilled off in vacuo. Boiling point 39-40 ° C / 267 Pa.

Method (b): using barium hydroxide

A mixture of 0.94 mol of 2,5-dimethyl-3-thiaadipic acid and 10 g of barium hydroxide was heated in a distillation flask at 230-250 ° C for 24 hours. The distillate was extracted with diethyl ether, the ether solution was dried over anhydrous magnesium sulfate and distilled under vacuum. Boiling point 39-40 ° C / 267 Pa.

Method c) using acetic anhydride

A mixture of 0.5 mol of 2,5-dimethyl-3-thiaadipic acid, 300 ml of acetic anhydride and 4 g of lithium chloride was heated at 120 ° C for 6 hours with stirring. The crude reaction mixture was poured onto ice and 10 mL of concentrated sulfuric acid was added. The mixture was stirred overnight, then basified with concentrated sodium hydroxide solution under ice-cooling and extracted several times with diethyl ether. The ethereal phases were combined, washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue is distilled using a Vigreux flask. The title compound has a boiling point of 81-88 ° C / 2667 Pa.

Example 7

Preparation of 2.5-Dimethyl-3-thia-adipic acid

To a solution of 320 g (8 mol) of sodium hydroxide in 1300 ml of water was added 424 g (4 mol) of thio-lactic acid over 15 minutes. After completion of the exotherm (35 ° C), methacrylic acid (344 g, 4 mol) was added and the mixture heated at 80 ° C for 18 hours. The mixture was cooled to 50 ° C, poured into a mixture of 3 kg of ice and 750 ml of concentrated hydrochloric acid, and extracted four times with 1000 ml of dichloromethane each. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo on a rotary evaporator. The title compound is obtained in the form of colorless crystals, m.p. 78-80 ° C.

Example 8

Preparation of 2.5-Dimethyl-tetrahydrothiophen-3-one

-4HU 199448 Β

Method a) Using a tertiary amine

To a mixture of 0.2 mol of thiotic acid and 0.2 mol of methacrylic acid was added 0.2 mol of tributylamine. Meanwhile, the reaction temperature was increased to 60 C ^e. The reaction mixture is then heated at 150-160 ° C for one hour, then at 210-220 ° C. Under these conditions, a mixture of the title compound, water and tributylamine is distilled at 150-170 ° C, which is dissolved in ethyl acetate, diluted with water and neutralized with 10% hydrochloric acid. The organic layer was extracted with 2N sodium hydroxide solution, washed to neutral pH, dried and evaporated. The residue was distilled in vacuo. The title compound boils at 70-73 ° C / 2 RPa.

Method (b): using ferric acetate,

A mixture of 85.9 g of thiotic acid, 70.9 g of methacrylic acid and 0.8 g of ferric acetate was heated at 150-160 ° C for one hour with stirring, and then 0.8 g of ferric acetate was added again. and maintaining the temperature at 200-210 ° C for 2 hours. This gives 103.9 g of a distillate which is dissolved in 200 ml of cyclohexane, made basic by the addition of sodium hydroxide and separated in a shaking funnel. The aqueous phase is extracted with 100 ml of cyclohexane, the organic phases are combined, washed with water, dried over anhydrous sodium sulfate and distilled under 2 kPa. This affords the title compound.

The aqueous phase was acidified with hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate and distilled under 2 kPa. 10.6 g of a distillate are obtained, which is a 2: 1 by weight mixture of methacrylic acid and thiolactic acid.

Example 9

Preparation of N- (1-methoxy-2-propyl) -3-amino-2,4-dimethylthiophene g (0.01 mol) of N- (1-methoxy-2-propyl) -2,4-dimethyltetrahydrothiene A mixture of -3-ylideneimine and 3 g of carbon tetrachloride was stirred at room temperature under an oxygen atmosphere for 1 hour. The reaction mixture consumes 200 ml of oxygen. The NMR spectrum of the solution does not contain signals for aromatic protons. At this time, the product was distilled in a balloon at 150-180 ° C under a pressure of 27 Pa to give the title compound.

Claims (8)

A process for the preparation of a compound of formula III wherein: 5 R is (C 1-4 alkoxy) - ( C 2 -C 4 alkyl) wherein the C 1 -C 4 alkoxy is separated by at least two carbon atoms from the nitrogen to which the R group is substituted; and R ₂ and R ₄ are methyl, characterized in that a compound of formula (I) wherein R, R ₂ and R ₄ are as defined herein is dehydrogenated and the resulting compound of formula (II) or hydrochloric acid is obtained. of its salt, wherein R, R ₂ and R ₄ are as defined in the foregoing nitrogen atom, by chloroacetylation in a known manner. 2. A process according to claim 1 wherein the compound of formula I wherein R, R ₂ and R ₄ are as defined above is catalytically dehydrogenated with molecular oxygen or an oxidizing agent. The process according to claim 2, wherein the dehydrogenation is carried out catalytically. 30 The process of claim 2, wherein the dehydrogenation is carried out with an oxidizing agent. 5. A process according to claim 4, wherein the oxidizing agent is selected from the group consisting of sulfur, thiouroyl chloride and sulfuryl chloride. 6. The process according to claim 5, wherein the oxidizing agent is thionylchloride. 7. A process according to any one of claims 1 to 3, characterized in that the hydrochloride of a compound of formula II, wherein R, R ₂ and R ₄ are as defined above, is chloroacetylated. 8. Figures 1-7. A process for the preparation of N- (2,4-dimethyl-3-thienyl) -N- (1-methoxy-2-propyl) chloroacetamide according to any one of claims 1 to 4, Characterized in that N- (1-methoxy-2-propyl) -2,4-dimethyl-tetrahydro-thien-3-ylideneimine is dehydrogenated and the resulting N- (1-methyl-2-methoxy-ethyl) -3- -amino-2,4-dimethylthiophene is reacted with chloroacetyl chloride.