CA2072019A1

CA2072019A1 - Process for the preparation of dialkyl 3-thienylmalonates

Info

Publication number: CA2072019A1
Application number: CA 2072019
Authority: CA
Inventors: Knut Riedel; Heinz Litterer
Original assignee: Individual
Current assignee: Hoechst AG
Priority date: 1989-12-23
Filing date: 1990-12-11
Publication date: 1991-06-24
Also published as: WO1991009854A1; EP0506687A1; JPH05501414A

Abstract

Process for the preparation of dialkyl 3-thienylmalonates Abstract Process for the preparation of dialkyl 3-thienylmalonates of the formula (I), where the radicals R1 and R2 are either both hydrogen or one of the two is methyl or ethyl and the other is hydrogen, R3 is hydrogen or C1-C4-alkyl and R4 and R5 are C1-C4-alkyl, from the corresponding 3-bromothiophenes and deprotonated dialkyl malonates in the presence of copper compounds, characterized in that the reaction is carried out 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 C-H-acidic compounds or b) about 0.1 to about 8 mol %
of copper (I) bromide or copper (I) iodide, relative to 3-bromothiophene.

Description

2~720~9 Description Process fox the preparation of dialkyl 3-thienylmalonates The invention relates to an improved process for the preparation of dialkyl 3-thienylmalonates, which may be further substituted on the thiophene ring, from the corresponding 3-bromothiophenes and dialkyl malonates.

Dialkyl 3-thienylmalonates are used in particular in the preparation of partially synthetic penicillins and cephalosporins tsee, for example, DE Patent 16 70 22~ =
GB 1 125 557 = US 3 502 656; J. P. Clayton, Chem. and Ind. 1989 129-134).

A number of processes are known for the preparation of 3-thienylmalonic acid (frequently termed 3-TMA in the literature) and also of the die~ters derived therefrom.
J. P. Clayton et al. (J.C.S. Chem. Commun. 1979 500) started from acyclic precur~ors for this purpose. They reacted 1,4-dichlorobut-3-en-2-one with diethyl malonate in pyridine in the pre6ence of TiCl~ and obtained there from diethyl (3-chloro-1-chlor~methylallylidene)malonate, which they then reacted with H2S and ~OH to give the desired diethyl 3-thienylmalonate~ In o~her processes (German Offenlegungsschrift 21 57 540 = GB 1 359 991;
German Offenlegungsschrift 21 63 523 = GB 1 359 992) 3-thienylacetonitrile was an important in~ermediate. The 3-thienylacetonitrile was converted to ethyl 3~thienyl-acetate by means of ethanol and ~Cl and subsequently to diethyl 3-thienylmalonate by mean~ of die~hyl carbonate and Na-ethanolate.

According to ~P-A 0 002 846 (= US Patent 4 262 129 =
GB 2 009 158), diethyl 3-thienylmalonate can be prepared by reaction of 3-iodothiophone with deprotenated diethyl malonate in a polar solvent in the presence of CuBr. The highest yield, 69%, relative to the 3-iodothiophene u~ed, was achieved using quinoline as polar Rolvent and at a , .. . . .

2~7201~
wo 91~09854 - 2 - PCT/EP90/02152 reaction temperature of 95C. 3-Bromothiophene, in an analogous reaction at 150 to 170C, could only be con-verted to the desired product in an 11% yield. The polar solvents used were, apart from quinoline, hexamethyl phosphoric triamide (HMPA) and dimethylformamide (DMF).
The use of CuCl or CuI instead of CuBr proved to be less favorable. In all the examples CuBr, CuC1 or CuI was used in at least an equimolar amount, relative to 3-iodothio-phene or 3-bromothiophene. In the text of the description (p. 4/20-26) a ratio of 0.1 to 2.0 mol of Cu(I) halide per mole of 3-bromothiophene or 3 iodothiophene was described as suitable. The molar ratio of deprotena~ed dialkyl malonate to 3-bromothiophene or 3-iodothiophene was 1:1 or greater.

Although the use of 3-iodothiophene instead of 3-bromo-thiophene did lead to higher yields, the preparation of 3-iodothiophene is substantially more laborious than that of 3-bromothiophene. The use of the large amounts stated of Cu~I) halide additionally results in suspensions which are difficult to stir, in which the heat exchange during the reac~ion is hi.ndered and from which the products can only be separated with difficulty during work-up.

The use of quinoline as a solvent is disadvantageous, since it must be separated off during work-up with an equivalent amount of aqueous hydrochloric acid. If the quinoline is again liberated from the aqueous hydro-chloric acid solution by addition of NaOH a large ~mount of salt results. In the most favorable case, the example la of EP-A 0 002 846, 421 kg of ~aCl are produced per 100 kg of diethyl 3-thienylmalonate. Hexamethylpho~phoric triamide, on the other hand, should be avoided because of its cancerogenicity.

However, it has now been found that all of the disadvan-tages mentioned may be avoided and, furthermore, bekter yields may be achieved, if the reactiorl of the unsub~tituted or substituted 3-bromothiophene with the deprotonated ~: ' ~72~1~
Wo 91/09854 3 - PCT/EP90/02152 dialkyl malonate is carried out in the presence of a) copper(II) salts of aliphatic monocarboxyliC acids or of C-H-acidic compounds or b) a relatively small amount of copper(I) bromide or copp~r(I) iodide in a polar aprotic solvent which i5 iner~ under the reaction conditions, preferably in a polar ether.

It has surprisingly been shown ~ha~ the desired dialkyl 3-thienylmalona~es are obtained with higher ~electivity the lower the amount of copper(I) halide is u~ed. How-ever, if the proportion of copper(I) halide in thereaction mixture is too low~ only a very little of the starting material i~ reacted. The best results between these two undesirable extremes - low ~electi~ity a~ too high a proportion of copper(I) halide on the one hand, 15 low conver9ion at too low a proportion on the other hand - are obtained with the u~e of about Ool to about 8 mol % of copper(I) bromide and~or copper(I) iodide, rela~ive to 3-bromothiophene.

The invention accordingly relates ~o a process for the preparation of dialkyl 3-thienylmalonates of the fonmula (see claim 1), where the radical R1 and R2 are either both hydrogen or one of the two is methyl or ethyl and the other is hydrogen, R3 is hydrogen or Cl C4-alkyl and R~ and Rs are Cl-C~-alkyl, from the corresponding 3-bromo-thiophenes of the formula II
~2 (II) and deprotonated dialkyl malonates of the formulaR4OoC-C-H-CooRs (III) in the pre~ence of copper compounds, characterized in that the reaction i~ carried out in a polar aprotic solvent, inert under the reaction condi-tions, in the presence of a~ copper(II) ~alts of ali-phatic monocarboxylic acids or of C-H-acidic compound~ or b) about 0.1 to about 8 mol % of copper(I) bromide or copper(I) iodide, relative to 3-bromothiophene. In the .., ",~ .

.

20720~

process variant- b), the reaction is preferably carried out in the pxesence of 0.5 to 3 mol % of copper(I) bromide or copper~I) iodide, relative to 3-bromothiophene.

The deprotonated dialkyl malona~es may be prepared ~y conventional processes, usually from dialkyl malon~tes by treatment with alkali metal hydride~ in an aprotic solvent, which is preferably identical to that used for the following reaction.

Examples of Cu(II) salts of aliphatic monocarboxylic acids which may be mentioned are those of hexanoic acid, 2-ethylhexanoic acid and oleoresin acid, and an example of Cu(II) salts of C-H-acidic compounds which may be mentioned is Cu (II) acetylacetonate. The Cu(II) salts are generally used in a ratio o 0.1 ~o 10 mol %, prefer-ably 0.5 to 3 mol ~ per mole of 3-bromothiophene.

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

Polar apro~ic solvênts which are particularly suitable are polar ethers, preferably tetrahydrofuran or ~n ether of the formula R6-(o-CHR8~CX2)n-oR7, in which R5 and R7 are methyl, ethyl or propyl, R~ is hydrogen or me~hyl and n =
1, 2, 3 or 4, in particular di- or triethylene ~lycol dimethyl ether or di- o~ triethylen~ glycol diethyl ether, or any mixtures of these ethers.

The reaction temperature in the pxocess according to the invention is advantageou~ly in the range rom about 60 to 100C, preferably from 75 to 85C.

The molar ratio of deprotonated dialkyl malonate to 3-bromothiophene i5 generally between 1:1 and 1:10, - :; , . ~
- . .
- . ~ . , .

2~720~9 preferably between 1:2 and 1:~. 3-Bromo~hiophene which i~
still unreacted after completion of the reaction can be recovered without problems and reused.

The following examples serve to illustra~e the invention.

Examples 1. 400 ml of tetrahydrofuran and 12 g ~0.50 mol) of NaH
in the form of an 80% strength suspension in parafin oil were introduced in~o an apparatus comprising a round-bottomed flask, stirrer, reflux condenser and dropping funnel. 80 g (0.50 mol) of diethyl malonate were then added dropwise at 60 to 80C. Af~er the evolution of hydrogen had subsided, 488 g (3.0 mol) of 3-bromothio-phene and 2.1 g (0.015 mol~ of CuBr were added, and the reaction mixture was stirred for a further hour at 85C.
The reaction mixture was then cooled to 30C; 31 g of glacial ace~ic acid were added and the re~ulting suspen-sion was then filtered. On distillation of the filtrate, 21.3 g of diethyl 3-thienylmalonate were obtained a~ well as unreacted starting ma~erial. Relative to reacted 3-bromothiophene, 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 were used instead of diethyl malonate and 732 g (4.5 mol) of 3-bromothiophene and 17.2 g (0.09 mol) of CuI were used. After wor~-up, 58.9 g of dLmethyl 3-thienylmalonate were obtained, cor.responding to 79.2~, rel~tive to reacted 3-bromo thiophene.

3. Example 1 was repeated, the amount of CuBr being increased to 12.9 g (0.09 mol). After 3 h at 85C the reaction was terminated. The yield of diethyl 3-thienyl~
malonate was 63.4 g, corresponding to 81.4% relative to reacted 3-bromothiophene.

4. 400 ml of diethylene glycol dimethyl ether and 12 g .:
, ' 2~2019 (O.50 mol) of NaH in the form of an 80% strength suspen-sion in paraffin oil were introduced into the apparatus described in Example 1. 80 g (0.50 mol) of diethyl malonate were then added dropwise at 60 to 80C. After the evolution of hydrogen had subsided, 534 g (3.0 mol) of 3-bromo-4-methylthiophene and 34.3 g (0.24 mol) of CuBr were added. The reaction mixture was then stirred for a further 3 h at 85C. The reaction mixture was then cooled and worked up as described in Example 1. 37.5 g of diethyl (4-methylthiophen-3-yl)malonate were obtained, corresponding to a yield of 43.8~, rela~ive to reacted 3-bromothiophene.

5. On repetition of Example 2 usin~ 573 g (3.0 mol) of 3-bromo-2,5-dime hylthiophene instead of 3-bromothio-phene, 19.8 g of dimethyl (2,5-dimethylthiophen-3-yl)-malonate were obtained, corresponding to 57.1%, relative to reacted 3-bromo-2,5-d~methylthiophene.

6. The procedure of Example 1 was followed, but using g (0.605 mol) of dimethyl malonate and S.6 g (0.021 mol) of Cu(II) acetylacetonate instead of CuBr.

On distillation of the filtrate 19.8 g of dimethyl 3-thienylmalonate were obtained as well as unreacted starting material. Relative to reacted 3-bromothiophene, this corresponded to a yield of 70.9%.

7. Example 6 was repeated wi~h the difference that 94 g (0.58 mol) of diethyl malonate were used instead of dimethyl malonate, and that 732 g t4.5 mol) of 3-bromo-thiophene and 16.8 g (0.064 mol) of Cu(II) acetylac0-tonate were used. After the work-up, 54.6 g of diethyl 3-thienyl malonate were obtained, corre~ponding to 77.9%, relative to reacted 3-bromothiophene.

8. Example 6 was repeated, a further 1~4 g (0.022 gramatom) of Cu powder being added additionally to the Cu(II) acetylacetonate. The reaction was terminated after 3 h at , : . ; ~ , ' ~. , :, .

20720~9 85C. The yield of dimethyl 3-thienylmalonate was 36.4 g, corresponding to 69.3%, relative ~o reacted 3-bromothio-phene.

9. Example 6 was repeated, a further 1.4 g (0.22[sic]
gramatom) of Cu powder being added additionally to Cu(II) acetylacetonate. This time, the reaction was terminated after 9 h at 75C. 49.2 g of dLmethyl 3-thienylmalonate were obtained, corresponding to 85.4%, relative to reacted 3-bromothiophene.

10. 400 ml of diethylene glycol dLmethyl ether and 12 g (O.50 mol) of NaH in the fonm of an 80% strength suzpen-sion in paraffin oil were introduced into the apparatus described in Example 1. 80 g (0.605 mol) of dLmethyl malonate were then added dropwise at 60 to 80C. After the evolution of hydrogen had subsided, 488 g (3.0 mol) of 3-bromothiophene and 29 g of Cu(II) salt of 2-ethyl-hexanoic acid were added. The reaction mixture was then s~irred for a further 3 h at 85C. The reac~ion mixture was then cooled and worked up as described in Example 1.
13.3 g of dimethyl 3-thienylmalonate were obtained, corresponding to 48.4%, relative to reacted 3-bromothio-phene.

11. In the repetition of Example 8, using 573 g (3.0 mol) of 3-bromo-2,5-dLmethylthiophene instead of 3-bromothiophene, 38.2 g of dimethyl (2,5-dimethylthio-phene3-yl)malonate ware obtained, corresponding to 57.1%, rel~tive to reacted 3-bromo-2,5-dimethylthiophene.

12. On repetition of Example 8, using S34 g t3.0 mol) of 3-bromo-4-methylthiophene instead of 3-bromothiophene, 35.7 g of dimethyl (4-methylthiophen-3-yl)malona~e were obtained. This corresponded ~o a yield of 59.8%, relative to reacted 3-bromo-4~methylthiophone.

.

; ', : ' , . .
:

Claims

amended claims Patent Claims:

1. Process for the preparation of dialkyl 3-thienyl-malonates of the formula I, (I) where the radicals R1 and R2 are either both hydrogen or one of the two is methyl or ethyl and the other is hydrogen, R3 is hydrogen or C1-C4-alkyl and R4 and R5 are C1-C4-alkyl, from the corresponding 3-bromo-thiophenes and deprotonated dialkyl malonates in the presence of copper compounds, characterized in that the reaction is carried out in a polar aprotic solvent which is inert under the reaction condi-tions, in the presence of a) copper(II) salts of aliphatic monocarboxylic acids or of C-H-acidic com-pounds or b) 0.1 to 8 mol % of copper(I) bromide or copper(I) iodide, relative to 3-bromothiophene.

2. Process 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 mol % of copper(II) salt per mole of 3-bromothiophene.

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