FR2564834A1 - PROCESS FOR THE PREPARATION OF ALKYL 3-CHLOROSULFONYLTHIOPHENE-2-CARBOXYLATE - Google Patents

Abstract

THE INVENTION RELATES TO ORGANIC CHEMISTRY. IT CONCERNS A PROCESS FOR THE PREPARATION OF ALKYL 3-CHLOROSULFONYLTHIOPHENE-2-CARBOXYLATE BY CONTACT OF A THIOPHENAMINE WITH SODIUM NITRITE OR POTASSIUM TO PRODUCE A DIAZONIUM SALT, THEN BY CONTACT WITH DIAZONIUM SULPHUROUS ANHYDRIDE AND COPPER OR COPPER CHLORIDE OR BROMIDE. ADDING GASEOUS HCL, HSO CONCENTRATE OR OLEUM TO THE DIAZOTATION MIXTURE IMPROVES PERFORMANCE. ITS OBTAINED PRODUCTS ARE USED AS AN INTERMEDIATE FOR THE PRODUCTION OF MEDICINES AND HERBICIDES.

Description

3-Chlorosulfonylthiophene-2-carboxylates

  of alkyl are of considerable interest in the preparation of

  pharmaceutical products and herbicides. The U.S. Patent No. 4,224,445, issued September 23, 1980 to Hromatka et al., Describes the utility of such intermediates in the preparation of compounds having

  antinflammatory, analgesic and antirheumatic activity

  tismale. European Patent Application No. 30,142 describes

  herbicidal sulfonyl ureas derived from 3-chlorosulfonyl-

  substituted thiophene-2-carboxylates of alkyl.

  It is therefore of great importance to find

  economically attractive processes of preparing 3-ch] o-

  substituted alkylsulfonylthiophene-2-carboxylates which

  involve a small number of chemical steps, with

  easy to carry out, and use

  start and low cost reagents.

  The U.S. Patent No. 4,230,873 issued October 28, 1980 to Hromatka et al.

  multi-step process leading to 3-chlorosulphonate

  substituted alkylthiophene-2-carboxylates which comprises the conversion of the 2-hydroxythiophene-2-carboxylic acid methyl ester. This process, in addition to its many steps, is encumbered by the use of large amounts of reagents such as PC15 and SOC12 which

  pose serious problems for the disposal of waste.

  The present invention relates to a process for the preparation of compounds of formula I

X S02C1

C R

  C2R I o R is a C1-C3 alkyl radical; and

X is H, Cl, Br or CH 3.

  The method comprises: (a) contacting a thiophenamine of

  Formula II suspended in an excess of hydrochloric acid

  aqueous and a cosolvent selected from acetic, formic or propionic acid with sodium or potassium nitrite, optionally in the presence of a promoter

  5. mineral acid selected from gaseous hydrochloric acid ,.

  concentrated sulfuric acid or oleum, to produce a diazonium salt of formula III:

X NE2 X N2C

C02R C02R

II III

  and (b) contacting a solution of the diazonium salt of formula III with sulfur dioxide in the presence of cupric or cuprous chloride or bromide to produce the compound of formula I. When hydrochloric acid is used of low concentration and a tbophenamine of formula II containing water, it has been found that high yields of sulfonyl chloride I can be obtained and the formation of by-products can be minimized by the addition of a promoter mineral acid,

  chosen from gaseous hydrochloric acid, sulphuric acid

  concentrate or oleum, to the diazotisation mixture.

  It is preferred for reasons of greater ease

  process and / or higher yield and / or higher purity of the products: 1) the above process o the cosolvent is

  acetic acid and the concentration of hydrochloric acid

  aqueous drique is at least 35% by weight; 2) the preferred method of 1) o R is CH3; 3) the preferred method of 2) X is CH3; 4) the preferred method of 2) o X is H; 5) the preferred method of 1) a mineral acid promoter is present; 6) the preferred method of 5) o the promoter

  mineral acid is present in the amount of 0.1 to 3.5 moles of

  concentrated sulfuric acid per mole of diazonium salt; 7) the preferred method of 5) o the mineral acid promoter is present in a proportion of 0.2 to 2.5 moles of concentrated sulfuric acid per mole of diazonium salt, R is CH3 and X is H. It is It is well known in the art that various substituted anilines can be converted to the corresponding sulfonyl chlorides by a two-step process of diazotisation and decomposition with SO 2 -CuCl 2: 1. HCl / NaNO 2 (2) Ar-NH 2 ArSO 2 Cl 2 SO 2 CuO 2 O Ar is a phenyl or substituted phenyl moiety. A

  detailed description of such a process by H. Meerwein, Go

  Dittmar, G. Gollner, K. Hafner, F. Mensch and O. Steinfort can be found in Chemische Berichte, Vol. 90, 1957,

pages 841-852.

  However, it is not known in the art that a thiophenamine or a substituted thiophenamine can be converted to the corresponding thiophene sulfonyl chloride (Equation 3): (3) 2 2. 2SO 2 -CuaOl 2

  It has been found that such a transformation is

  is good when a thiophenamine of the general formula II is suspended in a mixture of an excess of acid

  concentrated hydrochloric acid (also referred to herein as chlo-

  aqueous hydride) and a cosolvent selected from the group consisting of

  formic, acetic or propionic, possibly in pre-

  a mineral acid promoter agent selected from hydrogen chloride, concentrated sulfuric acid or oleum, and the suspension is (a) contacted with an aqueous solution of sodium or potassium nitrite which produces a diazonium salt of the general formula III; and (b) the diazonium salt thus produced is contacted with cupric or cuprous bromide or bromide, in the presence of excess sulfur dioxide, to give

  the desired thiophenesulfonyl chloride of general formula

  However, the procedure described above requires that the concentrated hydrochloric acid be at least% by weight to obtain very high yields and low levels of byproducts. When

  hydrochloric acid of low concentration is used

  (28-32% by weight), inexpensive, and / or thio-

  phenamine containing readily available water, yields of thiophenesulfonyl chlorides decrease sharply. In addition, sulfonyl chlorides have

  poor purities, being contaminated by many

  secondary products, of which the type represented by the general formula IV is predominant:

X NHNHS02 X

S: CO2R R02C

  This type of impurity is very difficult to eliminate

  corresponding thiophenesulfonyl chloride I.

  In these cases, high yields of sulfonyl chloride I can be maintained and the formation of by-products can be minimized by the addition of hydrogen chloride, concentrated sulfuric acid or oleum to the diazotization mixture. It is particularly preferred to obtain a higher yield

  and / or greater purity of products, the addition of

  concentrated sulfuric acid 0.2 to 2.5 moles

per mole of diazonium salt III.

  The reactions of Equation 1 constituting the present improved process can be carried out preferably according to the following procedure: To concentrated hydrochloric acid (35-38% by weight), glacial acetic acid is added as co-solvent. The amount of the first is selected to provide about 5.0 molar equivalents of HCl per mole of the starting thiophenamine. The amount of cosolvent acetic acid is chosen so as to give a slurry

  stirrable starting thiophenamine.

  If a concentrated hydrochloric acid is used

  (28-32% by weight), inexpensive, and / or thiophenamine containing water, concentrated sulfuric acid is added at this stage because of the convenience

  of sulfuric acid with the hydrochloric acids

drique and acetic.

  The amount of hydrochloric acid

  The weaker setting is chosen to give from 2 to 4

  molar equivalents of HCl per mole of thiophenamine.

  The amount of concentrated sulfuric acid varies from 0.2 to 2.5 moles per mole of thiophenamine, depending on the amount of water in a wet cake of thiophenamine and

  the concentration of concentrated hydrochloric acid.

  To the acid mixture, the thiophenamine is added gradually while cooling a little. If a reaction body containing water is used, the water content of the wet cake can vary within wide limits,

for example from 0 to 65% by weight.

  The resulting slurry is cooled to 0-7 ° C and diazotized with 1 molar equivalent of sodium nitrite dissolved in water. During the diazotation, the material

starting point goes into solution.

  To the solution of the diazonium salt, add

  sulfur dioxide. The quantity of the latter can vary

  from 1.2 to 5 molar equivalents for each equivalent

  molar diazonium salt. Preferably,

  Viron 3 molar equivalents of sulfur dioxide. it

  followed by the addition of cuprous chloride, the quanti-

  can vary from 3 to 6 moles per cent.

  The mixture is heated to room temperature

  and let the decomposition of the diazonium salt

follow until the end.

  Alternatively, sulfur dioxide is dissolved in acetic acid containing cuprous chloride and then the solution of the diazonium salt is gradually added. The amount of acetic acid is chosen so as to dissolve the required amount of anhydride

  sulfur. The reaction mixture is then left

  dial completely at room temperature.

  The resulting suspension of thiophene chloride

  Sulfonyl is cooled and diluted with water. The product

  is collected by filtration, washing with water and drying.

  The following table is a guide for examples

that follow.

  Preparation of methyl 3-chlorosulphonylthiophene-2-carboxylate HCl% Thiophen-Concenminal acid% by weight of amine yield,% by weight of IV EX product. * mental 1 dry 36 nil 85.6 <0.5 2 aqueous 37 HCl 79.0 (1.0 3 aqueous 31.5 nil 56.1 16.0 4 aqueous 31.5 H2S04 82.3 0.12 dry 31 , Nil 65.1 10.8 6 dry 31.5 H2SO4 82.7 0.26 a) dry hydrogen chloride, concentrated H2SO4 or oleum b)% by weight of the secondary product IV in the

raw product.

  Preparation of methyl 3-chlorosulfonylthiophene-2-carboxylate

Example 1

  To a mixture of 385 g of hydrochloric acid

  36% by weight) and 120 ml of glacial acetic acid, 133 g of 3-aminothiophene-2-carboxylate were added.

  methyl with a purity of 92.4% while maintaining the temperature

  internal gap between 0 and 70C. To the resulting slurry was slowly added 58 g of sodium nitrite dissolved in 77 ml of water between 0 and 7 ° C. A solution of the diazonium salt thus obtained in a vessel was gradually transferred to a second vessel containing 310 ml. of glacial acetic acid, 30 g of concentrated hydrochloric acid

  (36% by weight), 4.8 g of cuprous chloride and 90 g of anhy-

  sulfur dioxide and maintained at 15-17 C. During the trans-

  diazonium salt, 60 g

  of sulfur dioxide under the surface in the second vessel. The temperature of the reaction mixture was then allowed to rise to 21 ° C. The mixture was stirred at room temperature until the evolution of nitrogen was complete. The title sulfonyl chloride was precipitated by the addition of 660 ml of water. It was then separated by filtration, washed with water and dried under

  vacuum at 40 C. The crude product weighed 179.28 g and was

  by high pressure liquid chromatography it contained 164.94 g of pure sulfonyl chloride for a yield of 85.67% of the theoretical amount. The raw product contained less than 0.5% by weight of the secondary product

of formula IV.

Example 2

  To 49 ml of concentrated hydrochloric acid (36-38%) and 20 ml of acetic acid, a solution of 45.5 g of a methyl aminothiophene-2-carboxylate wet cake (purity of 69%) was added. 2% and water content of 26.2%) in 40 ml of glacial acetic acid at 0-50C and then a solution of 15.0 g of sodium nitrite in 21.6 ml of water also at 050C. To this mixture, maintained at 0-5 °, 15 g of dry hydrogen chloride were slowly added. After stirring the reaction mixture at 0-5 C for 30 minutes,

  20 g of sulfur dioxide were added; 10 ml of acetic acid

  tick and 1.0 g of cupric chloride dihydrate. The re

  Decomposition action was conducted at room temperature until completion. The product was precipitated

  by the addition of 200 ml of cold water at 0-5 C, the crystals

  The rates were separated by filtration, washed with water and separated

  vacuum under nitrogen at 40 C. The crude product weighed

  , 41 g and found by free-phase chromatography.

  high pressure medium which contained 38 g of the sulfonyl chloride of the title, which corresponded to a yield of 79% of the theoretical amount. The raw product contained

  also less than 1% by weight of the secondary product of

the IV.

Example 3

  To 150.5 g of 31.5% aqueous hydrochloric acid

  and 180 ml of glacial acetic acid, was added progressively

  under cooling, 0.40 moles of 3-aminothiophene-2-

  methyl carboxylate in the form of a moist cake

  containing 30.5% water. The resulting slurry was slowly

  0-7 ° C with 30 g of sodium nitrite dis-

  under in 43 ml of water. After completion of the addition of sodium nitrite, the mixture was stirred at 0-5 ° C. for a further 20-30 minutes. To the diazonium salt solution was added 80 g sulfur dioxide gas, 20 ml acid

  glacial acetic acid and 4 g of cupric chloride dihydrate.

  The mixture was stirred at 20.degree.-250.degree.

  nitrogen is complete. The reaction mixture was cooled to 0-5 ° C, 330 ml of water was added gradually and the precipitate was stirred at 05 ° C for 30 minutes. The solid product was filtered off, washed with water and dried under vacuum at 40 ° C. The crude material weighed 71.7 g and found by high pressure liquid chromatography to contain 53.9 g. of sulfonyl chloride for a yield of 56.1 of the theoretical amount. The raw material also contained 16.0% by weight of the product

secondary having the formula IV.

Example 4

  In the procedure of Example 3,

  drip-36 ml concentrated sulfuric acid-before

  the starting material at room temperature. The decompo-

  In the presence of sulfur dioxide was then carried out as described in Example 3. There was thus obtained 5 g of a crude product which by analysis contained 79.2 g of the title sulfonyl chloride for a yield of 82%. , 3% of the theoretical probability. The raw material contained

  also 0.12% by weight of the by-product of formula IV.

Example 5

  In the procedure of Example 3, it was used

  instead of the wet cake, 67 g of 3-aminothiophene-

  Substantially dry methyl 2-carboxylate (94.7% pure and containing 0.1% water). The experiment yielded 79.0 g of a crude product; by high pressure liquid chromatography, it was found to contain 62.7 g of the title sulfonyl chloride. This corresponds to a yield of 1% of the theoretical amount. The raw material also contained 10.8% by weight of the by-product of Formula IV.

Example 6

  In the procedure of Example 3, we have

  used, instead of the wet cake, 67 g of 3-aminothio-

  methyl phene-2-carboxylate substantially (94.7% pure containing 0.15% water). In addition, 26 ml of concentrated sulfuric acid was used as described in Example 4. The experiment yielded 85.7 g of a crude product which, according to high-level liquid chromatography, pressure, 79.6% of the title sulfonyl chloride. This corresponded to a return of 82.7% of the theoretical amount. The raw material also contained

  0.26% by weight of the by-product of formula IV.

Claims (9)

  1. A process for the preparation of thio derivatives   phene of formula I ## STR2 ## wherein R is a C 1 -C 3 alkyl radical; and X is H, Cl, Br or CH; this process comprising: (a) contacting a thiophenamine of   Formula II suspended in an excess of hydrochloric acid   than aqueous and a cosolvent selected from acetic acid,   formic or propionic with sodium nitrite or   tassium, optionally in the presence of a mineral acid promoter agent chosen from gaseous hydrochloric acid, concentrated sulfuric acid or oleum, to produce a diazonium salt of formula III N + Cl X NH2 X2N S \ Co 002R 02R II III   and (b) contacting a solution of the diazonium salt of formula III with sulfur dioxide in the presence of cupric or cuprous chloride or bromide, to produce the compound of formula I.   2. The process according to claim 1, in which   cosolvent is acetic acid and the concentration   aqueous hydrochloric acid is at least 35% in weight.   3. The process according to claim 2, in which which R is CH3.   4. The process according to claim 3, in which which X is CH3.   5. The process according to claim 3, in which which X is H.   6. The process according to claim 1, in which   which a mineral acid promoter agent is present.   7. The process according to claim 2, in which   which a mineral acid promoter agent is present.   8. The process according to claim 7, in which   the mineral acid promoter is present at 0.1 to 3.5 moles of concentrated sulfuric acid per mole of diazonium salt.   9. The process according to claim 7, in which   wherein the mineral acid promoter is present at 0.2 to 2.5 moles of concentrated sulfuric acid per mole of diazonium salt, R is CH3 and X is H.