EP0506687A1

EP0506687A1 - Process for the production of 3-thienyl malonic acid dialkyl esters

Info

Publication number: EP0506687A1
Application number: EP19910900019
Authority: EP
Inventors: Knut Riedel; Heinz Litterer
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1989-12-23
Filing date: 1990-12-11
Publication date: 1992-10-07
Also published as: CA2072019A1; JPH05501414A; WO1991009854A1

Abstract

Procédé de fabrication de dialkylesters de l'acide 3-thiénylmalonique ayant la formule générale (I), où les résidus R1 et R2 représentent, ou bien deux hydrogènes, ou bien l'un de ces résidus, un méthyle ou un éthyle, et l'autre résidu, un hydrogène, R3 est un hydrogène ou un alkyle en C1-C4, et R4 et R5 sont des alkyles en C1-C4, à partir des 3-bromo-thiophènes correspondants et des esters dialkyliques déprotonisés de l'acide malonique, en présence de composés de cuivre, caractérisé en ce que la réaction est effectuée dans un solvant aprotique polaire, inerte dans les conditions réactionnelles, en présence de: a) de sels de cuivre(II) d'acides monocarboxyliques aliphatiques ou de composés C-H-acides, ou de, b) d'environ 0,1 à environ 8 moles%, par rapport au 3-bromothiophène, de bromure ou de iodure de cuivre(I).Process for the production of 3-thienylmalonic acid dialkylesters having the general formula (I), in which the residues R1 and R2 represent either two hydrogens or one of these residues, methyl or ethyl, and l other residue, hydrogen, R3 is hydrogen or C1-C4 alkyl, and R4 and R5 are C1-C4 alkyls, from the corresponding 3-bromo-thiophenes and deprotonized dialkyl esters of malonic acid , in the presence of copper compounds, characterized in that the reaction is carried out in a polar aprotic solvent, inert under the reaction conditions, in the presence of: a) copper (II) salts of aliphatic monocarboxylic acids or of CH compounds -acids, or of, b) from about 0.1 to about 8 mole%, relative to the 3-bromothiophene, of bromide or iodide of copper (I).

Description

description

Process for the preparation of 3-thienylmalonic acid dial yl esters

The invention relates to an improved process for the preparation of 3-thienylmalonic acid dialkyl esters, which are optionally further substituted on the thiophene ring, from the corresponding 3-bromo-thiophenes and ^• 5 malonic acid dialkyl esters.

3-Thienylmalonic acid dialkyl esters are used in particular in the production of partially synthetic penicillins and cephalosporins (see, for example, DE-PS 16 70 222 = 10 GB 1 125 557 = US 3 502 656; JP Clayton, Chem. And Ind. 1989 129-134 ).

For the production of 3-thienylmalonic acid (often referred to in the literature as 3-TMA) and the product thereof

A number of methods are known from 15 derived diesters. JP Clayton et al. (JCS Chem. Commun. 1979 500) assumed acyclic precursors. They put l, 4-dichlorobut-3-en-2-one with diethyl malonate in pyridine in the presence of around and got out of it

20 (3-chloro-1-chloromethyl-allylidene) malonic acid diethyl ester, which they then reacted with ^ S and KOH to the desired 3-thienylmalonic acid diethyl ester. In other processes (DE-OS 21 57 540 = GB 1 359 991; DE-OS 21 63 523 = GB 1 359 992) 3-thienylacetonitrile was used

25 represents an important intermediate. The 3-thienylacetonitrile was converted into 3-thienyl-acetic acid ethyl ester with ethanol and HC1 and subsequently with 3-thienylmalonic acid-diethyl ester with diethyl carbonate and Na-ethanolate.

30 According to EP-OS 0 002 846 (= US Pat. No. 4,262,129 = GB 2,009,158), 3-thienylmalonic acid diethyl ester could be reacted with 3-iodo-thiophene Prepare deprotonated malonic acid diethyl ester in a polar solvent in the presence of CuBr. With quinoline as the polar solvent and at a reaction temperature of 95 ° C, the highest yield, 69%, based on the 3-iodothiophene used, was achieved. In an analogous reaction at 150 to 170 ° C, 3-bromo-thiophene could only be converted into the desired product in 11% yield. In addition to quinoline, hexamethylphosphoric triamide (HMPA) and dimethylformamide (DMF) were also used as polar solvents. The

Using CuCl or Cul instead of CuBr turned out to be less favorable. In all examples, the CuBr, CuCl or Cul was used in at least an equimolar amount, based on 3-iodo or 3-bromothiophene. In the description (p. 4 / 20-26) a ratio of 0.1 to 2.0 moles of Cu (I) halide per mole of 3-bromo or 3-iodothiophene was designated as suitable. The molar ratio of deprotonated dialkyl malonate to 3-bromo- or 3-iodothiophene was 1: 1 or greater.

Using 3-iodo-thiophene instead of 3-bromo-thiophene gave higher yields, but the preparation of 3-iodo-thiophene is considerably more complex than that of 3-bromo-thiophene. By using the specified large amounts of Cu (I) halide, mine also gets poorly stirrable suspensions in which the heat exchange is hindered during the reaction and from which the products are difficult to separate during workup.

The use of quinoline as a solvent is disadvantageous because it has to be separated off with an equivalent amount of aqueous hydrochloric acid. If the quinoline is then freed from the hydrochloric acid aqueous solution by adding NaOH, a large amount of salt is formed. In the best case, example la of EP-OS 0 002 846, there are 421 kg of NaCl per 100 kg of 3-thienylmalonic acid diethyl ester. Hexamethylphosphoric triamide should be avoided due to its carcinogenicity. However, it has now been found that all the disadvantages mentioned can be avoided and, moreover, better yields can be achieved if the reaction of the optionally substituted 3-bromo-thiophene with the deprotonated malonic dialkyl ester in the presence of a) copper (II) salts is more aliphatic Monocarboxylic acid or CH-acidic compounds or b) a relatively small amount of copper (I) bromide or iodide in a polar aprotic solvent which is inert under the reaction conditions, preferably in a polar ether.

It has surprisingly been found that the desired dialkyl 3-thienylmalonate is obtained with higher selectivity, the less copper (I) halide is used. However, if the proportion of copper (I) halide in the reaction mixture is too small, very little is added

Starting material implemented. The best results between these two undesirable extremes - low selectivity with too high a proportion of copper (I) halide on the one hand, low conversion with too low a proportion on the other hand - are obtained when using about 0.1 to about 8 mol% copper (I) bromide and / or iodide, based on 3-bromo-thiophene.

The invention accordingly relates to a process for the preparation of 3-thienylmalonic acid dialkyl esters of the general formula (see claim 1), where the radicals R ¹ and R ^ are either both hydrogen or one of the two is methyl or ethyl and the other is hydrogen, R ^{3 is} hydrogen or C - ^ - C ^ alkyl and R ⁴ and R ^{5 are} C- _j -C ^ alkyl, from the corresponding 3-bromo-thiophenes of the formula II

and deprotonated malonic dialkyl esters of the formula R "* OOC-C ^" H-COOR ⁵ (III) in the presence of copper compounds, characterized in that the reaction in a polar aprotic solvent which is inert under the reaction conditions in the presence of a) copper (II) salts of aliphatic monocarboxylic acids or CH azide compounds or b) about 0.1 to about 8 mol% of copper (I) bromide or iodide, based on 3-bromothiophene, is carried out. In process variant b), the reaction is preferably carried out in the presence of 0.5 to 3 mol% of copper (I) bromide or iodide, based on 3-bromothiophene.

The deprotonated malonic acid dialkyl esters can be prepared by conventional methods, usually from malonic dialkyl esters, by treatment with alkali metal hydrides in an aprotic solvent which is preferably identical to that used for the subsequent reaction.

Examples of Cu (II) salts of aliphatic monocarboxylic acids are those of hexanoic acid,

2-ethyl-hexanoic acid and resin acid, and as Cu (II) salts C-H-azide compounds, for example Cu (II) acetylacetonate. The Cu (II) salts are generally used in a ratio of 0.1 to 10 mol%, preferably 0.5 to 3 mol%, per mol of 3-bromo-thiophene.

In a particular embodiment, in addition to the copper (II) salt, Cu powder, preferably 0.1 to 10 gram atom% of Cu powder per mole of 3-bromothiophene, is added to the reaction mixture. The amounts of Cu powder and Cu (II) salt are preferably equivalent.

Particularly suitable polar aprotic solvents are polar ethers, preferably tetrahydrofuran or an ether of the general formula R ⁶ - (0-CHR ⁸ -CH ₂ ) _n -OR ⁷ , in which R ⁶ and -R ^{7 are} methyl, ethyl or propyl, R ^{8 is} hydrogen or methyl and n = 1, 2, 3 or 4, especially di or triethyl glycol dimethyl ether or di or triethylene glycol diethyl ether, or any mixture of these ethers.

The reaction temperature in the process according to the invention is advantageously in the range from about 60 to 100 ° C., preferably from 75 to 85 ° C.

The molar ratio of deprotonated malonic acid dialkyl ester to 3-bromo-thiophene is generally between 1: 1 and 1:10, preferably between 1: 2 and 1: 4. 3-bromo-thiophene, which has not yet reacted after the reaction has ended, can be easily recovered and used again.

The following examples serve to explain the invention.

Examples

1. In an apparatus consisting of a round bottom flask, stirrer, reflux condenser and dropping funnel, 400 ml of tetrahydrofuran and 12 g (0.50 ol) of NaH were placed in the form of an 80% suspension in paraffin oil. Then 80 g (0.50 mol) of malonic acid diethyl ester were added dropwise at 60 to 80 ° C. After the evolution of hydrogen had subsided, 488 g (3.0 mol) of 3-bromo-thiophene and 2.1 g (0.015 mol) of CuBr were added, and the reaction mixture was stirred for a further 1 hour _. 85 ° C stirred. The mixture was then cooled to 30 ° C; 31 g of glacial acetic acid were added and the suspension obtained was then filtered. Distillation of the filtrate gave .21.3 g

3-thienylmalonic acid diethyl ester in addition to unreacted starting material. Based on converted 3-bromo-thiophene, this corresponded to a yield of 85.7%.

2. Example 1 was repeated with the difference that 66 g (0.5 mol) of dimethyl malonate instead of Malonic acid diathylester, 732 g (4.5 mol) 3-bromo-thiophene and 17.2 g (0.09 mol) CuJ were used. After working up, 58.9 g of 3-thienylmalonic acid dimethyl ester, corresponding to 79.2%, based on converted 3-bromo-thiophene.

3. Example 1 was repeated, increasing the amount of CuBr to 12.9 g (0.09 mol). After 3 h at 85 ° C the reaction was stopped. The yield of 3-thienylmalonic acid diethyl ester was 63.4 g, corresponding to 81.4% based on converted 3-bromothiophene.

4. 400 ml of diethylene glycol dimethyl ether and 12 g (0.50 mol) of NaH in the form of an 80% suspension in paraffin oil were introduced into the apparatus described in Example 1.

Then 80 g (0.50 mol) of malonic acid diethyl ester were added dropwise at 60 to 80 ° C. After the hydrogen evolution had ceased, 534 g (3.0 mol) of 3-bromo-4-methyl-thiophene and 34.3 g (0.24 mol) of CuBr were added. The reaction mixture was then stirred at 85 ° C. for a further 3 h. The mixture was then cooled and the reaction mixture was worked up as described in Example 1. This gave 37.5 g of diethyl 4-methyl-thiophene-3-yl-malonate, corresponding to a yield of 43.8%, based on the 3-bromo-thiophene reacted.

5. When repeating Example 2 with 573 g (3.0 mol) of 3-bromo-2,5-dimethyl-thiophene instead of

3-bromo-thiophene gave 19.8 g (2,5-dimethyl-thiophene-3-yl) -malonic acid dimethyl ester, correspondingly, 57.1%, based on converted 3-bromo-2,5-dimethyl-thiophene .

6. The procedure was as in Example 1, but with 80 g (0.605 mol) of dimethyl malonate and 5.6 g (0.021 mol)

Cu (II) acetylacetonate instead of CuBr. Distillation of the filtrate gave 19.8 g of 3-thienylmalonic acid dimethyl ester in addition to unreacted starting material. Based on converted 3-bromo-thiophene, this corresponded to a yield of 70.9%.

7. Example 6 was repeated with the difference that 94 g (0.58 mol) of malonic acid diathylester instead of malonic acid dimethyl ester, 732 g (4.5 mol) of 3-bromo-thiophene and 16.8 g (0.064 mol) of Cu (II ) acetylacetonate were used. After working up, 54.6 g were obtained

3-thienylmalonic acid diethyl ester, corresponding to 77.9%, based on converted 3-bromo-thiophene.

8. Example 6 was repeated, with 1.4 g (0.022 gram atom) in addition to the Cu (II) acetylacetonate.

Cu powder were added. After 3 h at 85 ° C the reaction was stopped. The yield of 3-thienylmalonic acid dimethyl ester was 36.4 g, corresponding to 69.3%, based on converted 3-bromo-thiophene.

9. Example 6 was repeated, with 1.4 g (0.22 gram atom) of Cu powder being added to the Cu (II) acetylacetonate. This time the reaction was stopped after 9 h at 75 ° C. 49.2 g of 3-thienylmalonic acid dimethyl ester, corresponding to 85.4%, based on converted 3-bromo-thiophene were obtained.

10. 400 ml of diethylene glycol dimethyl ether and 12 g (0.50 mol) of NaH in the form of an 80% suspension in paraffin oil were placed in the apparatus described in Example 1.

Then 80 g (0.605 mol) of malonic acid dimethyl ester were added dropwise at 60 to 80 ° C. After the evolution of hydrogen had subsided, 488 g (3.0 mol) of 3-bromo-thiophene and 29 g of Cu (II) salt of 2-ethyl-hexanoic acid were added. The reaction mixture was then stirred at 85 ° C. for a further 3 h:

The mixture was then cooled and the reaction mixture was worked up as described in Example 1. 13.3 g were obtained 3-thienylmalonic acid dimethyl ester, corresponding to 48.4%, based on converted 3-bromo-thiophene.

11. When repeating Example 8 with 573 g (3. 0 mol) of 3-bromo-2,5-dimethyl-thiophene instead of

3-Bromo-thiophene gave 38.2 g (2,5-dimethyl-thiophene-3-yl) -malonic acid dimethyl ester, corresponding to 57.1%, based on the converted 3-bromo-2,5-dimethyl-thiophene.

12. Repeating Example 8 with 534 g (3.0 mol) of 3-bromo-4-methyl-thiophene instead of 3-bromo-thiophene gave 35.7 g (4-methyl-thiophene-3-yl) -malonic acid- dimethyl ester. This corresponded to a yield of 59.8%, based on the converted 3-bromo-4-methyl-thiophene.

Claims

Claims:

1. Process for the preparation of 3-thienylmalonic acid dialkyl esters of the general formula I

wherein the radicals R ^x and R are either both hydrogen or one of the two methyl or ethyl and the other

Represent hydrogen, R is hydrogen or C ^ -C ^ alkyl and R and R ⁵ are, from the corresponding 3-bromo-thiophenes and deprotonated malonic dialkyl esters in the presence of copper compounds, characterized in that the reaction in a polar aprotic solvent which is inert under the reaction conditions in the presence of a) copper (II) salts of aliphatic monocarboxylic acids or CH-acidic compounds or b) about 0.1 to about 8 mol% of copper (I) bromide or iodide, based on 3-bromothiophene, is carried out.

2. The method according to claim 1, characterized in that the reaction is carried out in the presence of 0.1 to 10 mol%, preferably 0.5 to 3 Mbl% copper (II) salt per mole of 3-bromo-thiophene.

3. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of copper (II) salts and copper powder.

4. The method according to claim 3, characterized in that the reaction in the presence of 0.1 to 10 mol%, preferably 0.5 to 3 mol%, copper (IΙ) salt and 0.1 to 10 gram atom% copper powder, preferably equivalent amounts of copper (II) salt and copper ulver are used.

5. The method according to one or more of claims 1 to 4, characterized in that copper (II) acetylacetonate is used.

6. The method according to claim 1, characterized in that about 0.5 to about 3 mol% of copper (I) bromide or iodide, based on 3-bromo-thiophene, are present.

7. .Verfahren according to one or more of claims 1 to 6, characterized in that a polar ether, preferably as a polar aprotic solvent

Tetrahydrofur n or an ether of the general formula R ⁶ - (0-CHR ⁸ -CH ₂ ) _n -OR ⁷ , in which R ⁶ and R ^{7 are} methyl, ethyl or propyl, R ^{8 is} hydrogen or methyl and n = 1, 2, 3 or 4, in particular di- or triethylene glycol dimethyl ether or di- or

Triäthylenglykoldiäthyläther, or any mixture of these ethers is used.

8. The method according to one or more of claims 1 to 7, characterized in that the molar ratio of deprotonated malonic acid dialkyl ester to 3-bromo-thiophene between 1: 1 and 1:10, ^" preferably between 1: 2 and 1: 4 lies.

9. The method according to one or more of claims 1 to 8, characterized in that the reaction is carried out at temperatures from 60 to 100 ° C, preferably 75 to 85 ° C.