CA1060030A - Process for producing 5-carboxy-2-acetylthiophene - Google Patents

Abstract

Abstract of the Disclosure 5-Carboxy-2-acetylthiophene, which is useful as a intermediate for the production of a therapeutic agent, can be prepared in a high yield by the selective oxidation of 5-acetyl-2-thienylacetic acid or its derivative with particularly selected oxidizing agent, i.e. chromic anhyd-ride complex, dichromate and hypohalite.

Description

106003~

The present invention relates to a process ~or producing 5-carboxy-2-acetylthiophene.
5-Carboxy-2-acetylthiophene has been known to be a useful intermediate ior the production of the thienyl-thiazole derivative of the formula:

H2NCO - ~ N CH3 S JJ- s CH2 - a~ - CH2 - ~H - c - C1~3 OH CH~

which is useful as a potent therapeutic agent for the treat-ment of heart diseases such as arrhythmia and coronary heart diseases(U.S. Patent No. 3,932,400).
With respect to the preparation of 5-carboxy-2-acetylthiophe~e, there have been proposed the following processes:
(1) Xydrolysis of 5-cyano-2-acetylthiophene, ~instead7 Noble and Wright; J. Chem. Soc., 1937, 911. Dann; Ber., B76, 419 (1943)~

(2) Cxidation of 2,5-diacetylthiophene, ~Hartough and Kosak; J. Am. Chem. ~oc., 69, 1012 (1947)~

(3) Acylation of thenoic acid ester, ~K. Schoe~el and H. Pelonsek; Ann., 1 (1962)3

(4) Carboxylation of 2-methyl-2'-thienJl-1,3-dioxolane (acetylthiophene ketal). ~'~hames and McClesky; J. Hetero-cyclic Chem., 3, (1), 104 (1966)~ -These knoum processes areS however, unsatisfactory for the commercial production of said compound.
As the result of study, it has now been found that

5-carboxy-2-acetylthiophene can advantageously be prepared _ 2 -...

~O~iO030 in a high yield by the selective oxidation of 5-acetyl-2-thienylacetic acid or its derivative with a chromic acid derivative or a hypohalite.
So far, it has been quite difficult, or rather impossible to expect whether oxidation occurs at the acetyl methyl group or at the methylene group linked to the thio-phene ring when 5-acetyl-2-thienylacetic acid or its deriva-tive is subjected to the oxidation;re~action~
According to the present invention, however, 5-carboxy-2-acetylthiophene can advantageously be prepared by the selective oxidation of the methylene group linked to the thiophene ring of 5-acetyl-2-thienylacetic acid or its derivative. Specifically, 5-carboxy-2-acetylthiophene can be prepared by the oxidation of 5-acetyl-2-thienylacetic acid, which has the following ~ormula (II):

~3C - C _ ~ - CH2~00H (II) with a chromic anhydride-solvent complex or a dichromate, or by the oxidation of a compound of the formula (III):

H3C C - ~ - CH2COOR (I~I) X S

wherein X is a conventional carbonyl protecting group, and R is a conventionalester residue, with a hypohalite.
~ he term 1'conventional carbonyl protecting group"
as used herein means any carbo~yl protecting group which does not disturb the progress of the oxidation reaction and which is removable. ~xamples of such carbonyl protecting group are ketal, hemithioketal, dithioketal, thiazolidine, imidazoli-dine and oxazolidine. ~'he term "conventional ester residue"
means any ester residue which does not disturb the progress of the oxidation reaction. Examples of such ester residue are lower alkyl (e.g. methyl, ethyl, etc.) and phenyl groups.
With respect to the oxidation of 5-acetyl-2-thienyl-acetic acid with said chromic acid derivatives, it can gene-rally be conducted in a solvent at a temperature from 0C.
to a boiling point of the solvent employed, preferably 0 to 100C.
Examples of preferred chromic anhydride-solvent complex are chromic anhydride-acetic acid complex, chromic anhydride-pyridine complex, chromic anhydride-dimethylform~
amide complex and the like. ~xample~ of preferred dichromate are potassium dichromate, sodium dichromate, etc.
In carrying out the process using said chromic anhydride-solvent complex, the use of the solvent which, together with chromic anhydride, forms the chromic anhydride-solvent oomplex is particularly preferable, but the process can also be carried out in other inert solvent such as dichloro-methane, carbontetrachloride and hydrocarbons such as light petroleum and petroleum benzine.
While, when a dichromate i~ used, the process can be carried out in organic acid solvents, water or a mixture thereof. Examples of preferred organic acid solvent are ali-phatic acids or anhydrides thereof such as acetic acid, propionic acid, butyric acid, or acetic anhydride.
The chromic anhydride-solvent complex and the di-chromate may be used in an amount of 2 to 3 moles per 1 mole of 5-acetyl-2-thienylacetic acid.

16~60030 It i~ particularly advantageous to conduct the proces~ in the following manner:
(1) by adding chromic anhydride to acetic acid, acetic anhydride or a mi~ture thereof to give chromic anhydride-acetic acid complex, (2) adding thereto 5-acetyl-2-thienylacetic acid, and then (3) reacting them at a xoom temperature for several hours.
In thi~ case, the oxidation reaction proceeds completely to give only 5-carboxy-2-acetylthiophene as the product.
With respect to the oxidation o~ a compound of the formula (III) with a hypohalite, the process can be conducted in a mixture of water and an alcohol (e.g. methanol, ethanol, etc.) at a temperature from O to 60C. and then removing the carbonyl protecting group.
Examples o~ pre~erred hypohalite are sodium hypo-chlorite, sodium hypobromite~ potassium hypoohlorite and potassium hypobromite.
In carrying out the process, it is preferable to use at least 3 moles of a hypohalite per 1 mole of the compound of the formula (III).
After the reaction is finished, the carbonyl protecting group can be removed by a conventional method as disclosed in McOMIE; "Protective Groups in Organic Chemistry", Plenum Press London and New York, (1973~. For example, ketal, hemithioketal, oxazolidine and imidazolidine can be removed by treating them with a dilute acid such as dil. hydrochloric acid, dil. sulfuric acid, aqueous acetic acid, etc. LC. Djerassi, F. Batres, J. Romo and ~. Rosenkranz; J. ~m. Chem. Soc., 74, 3634 (1952). ~. P. Goldberg and H.R. Nace; J. Am. Chem. Soc., 779 359 ~1955). H. W. Wanzlict and W. Loechell; Chem. Ber., 86, 1463 (1953)~ Thioketal can be removed with a mercury salt. ~H. Zinner, K. H. Rohde and A. ~Iattheus; Ann , 677, 160 (1964). ~. J. Corey and R. ~. Mitra; J. Am. Chem. Cos., 84, 2g38 (1962)~
The isolation of the product can be carried out in a conventional manner. For e~ample, well-refined 5-carboxy-2-acetylthiophene, which sometimes precipitates when the reaction system is diluted with, for example, water and, if necessary, acidified with a ~uitable acid such as hydro-chloric acid, can be isolated by filtration and washing with water, or it may be isolated by extracting with an inert solvent such as ether or by evaporating the solvent and washing the product with water.
5-acetyl-2-thienylacetic acid and the compound of the formula (III) can be prepared from 2-thienylacetic acid as follows:

AC20 ~D
S 3 4 2 3 " ~ -CH2COOH
(A)CH2C00~ S

¦ esterification . . ~ ~ 1 I H P0 or ZnCl ' l S~ ~-CH2COOR 3 4 2 H3C-C- S -CH2COOR
(~) / (C) H~jC-C-1 ~ 1-CH2COOR
(III)

- 6 -~060~30 ~he compound (II) can be prepared by acylating 2-thienyl-acetic acid (A) with acetic anhydride in the presence of phosphoric acid or zinc chloride. The compound (C) can be obtained in the same manner as above from the compound (~), which can be prepared by the esterification of the compound (A).
The compound (III) can be prepared by introducing the carbonyl protecting group by a conventional method as disclosed in the ~'Protective Groups in Organic Chemi~try".
As mentioned previously, 5-carboxy-2-acetylthio-phene can be used as an intermediate for the production of a therapeutic agent, which can be prepared from 5-carboxy-2-acetylthiophene as follows:

~ amidation ~
H3C-,C, S COOH H3C-,C, S CONH2 O O

brominatisn ~ H2NCSNH4 BrH C-C S CONH2 2 "
OH CH
al-CH2-CH-CH2-~X - C - CH3 ~2~C0 ~ ~

H2~CO ~ ~ ~ OH CH3 CH~

The following examples are given to illustrate the present invention more concretely, but it is not intended to limit the present invention thereto.

Example To an aqueous solution (5.3 g.) of sodium hypochlorite containing excess sodium hydroxide (prepared from a part of chlorine and 2.5 parts of sodium hydroxide) was added a solu-tion of 0.204 g. of 5-acetyl-2-thienylacetic acid methyl ester ketal in 5 ml of ethanol dropwise at such a rate that the temperature could be maintained below 40C. by means of cooling bath. After the addition was completed, stirring was continued until the temperature fell to 25 - 30C. without aid of cooling bath (0.5 - 4 hrs.). ~odium bisulfite was added to destroy an excess o~ sodium hypochlorite. ~he resulting solu-tion was made acidic with conc. hydrochloric acid (pH 1), diluted with 30 ml of water and extracted with ether. ~ther layer was washed with water~ dried and stripped to provide the residue, which was recrystallized from water to afford 0.12 g.
(78.2 %) of 5-carboxy-2-acetyl thiophene. This product was identified with an authentic sample prepared according to the known procedure. (IR, ~MR and mixed m.p.) ~xample 2 In a mixture of acetic acid (8 ml) and acetic anhyd-ride (2 ml) was dissolved 0.3 g. (0.003 mol) of CrO3 and 0.186 g.
(0.001 mol) of 5-acetyl-2-thienylacetic acid was added portion-wise with stirring mechanically and cooling at 10C. The resulting mixture was stirred at room temperature for 3.5 hrs.
and diluted ~ith 20 ml of water followed by e~traction with ether. ~ther layer was washed with water, dried and evaporated.

-- ~3 --lQ60030 The crude product was recrystallized from water to provide 0.13 g. (76 ~0) of 5~carboxy-2-acetyl thiophene, identical to an authentic sample. (IR, NMR and mixed m.p.) ~xample 3 Chromic anhydride, 0.~42 g. (0.00342 mol) was added portionwise to a cooled (0 - 5~.) pyridine (10 ml). After few minutes, orange complex began to precipitate. 5-Acetyl-2-thienylacetic acid, 0.202 g. (0.0011 mol) was added and stirred at roo~ temperature overnight. The reaction mixture was made acidic with conc. hydrochloric acid and extracted with ether. Ether layer was washed with water, dried and evaporated. Crude product was purified by recrystallization ~rom water. Yield; 0.14 g. (75.1 ~). This material was iden-tified with an authentic sample. (IR, NMR and mixed m.p.) Example 4 To a solution of 5-acetyl-2-thienylacetic acid, 9.985 g. (0.0543 mol) in 90 ml of acetic acid was added potas-sium dichromate portionwise at 60C. with stirring. After the addition was compIete, the mixture was warmed up to 80C.
and 30 ml of acetic anhydride was dropped slowly while the temperature of the reaction mixture rose gradually to its reflux. The resulting solution was heated moreover under reflux for 4 hrs. and cooled to 15~. The green precipitate was remo~ed by filtration and the filtrate was diluted with large volume o~ water. Precipitate was collected,washed with water and dried. Yield; 3.81 g. (41.3 %). The material was identical to an authentic sample. (IR, NMR and mixed m.p.) ~060030 Preparation of 5-acetyl-2-thienylacetic acid methyl ester:
A mixture of 2-thienylacetic acid methyl ester, 1.41 g. (0.01 mol) and acetic anhydride, 4.2 g. (0.04 mol) was heated at 70 - 80C. and 0.2 g. of 85% H3P04 was added dropwise with stirring mechanically. The reaction was some-what exothermic but cooling was not necessary. ~he mixture was maintained between 70 - 80C. for 3 hrs., and then, poured onto ice-water followed by extraction with ether. Organic layer was washed with water several times 9 dried over anhyd.
MgS04 and evaporated. ~he re~idue was distilled at 2 mmHg and a fraction between 160~. and 172C. was collected. This material was gradually crystallized and could be recrystalli~ed from the mixture of light-petroleum and benzene. m.p. 43 - 44C.
Yield; 1.39 g. (76~5 %) ~etallization of 5-acetyl-2-thienylacetic acid methyl ester:
A solution of ethyleneglycol, 0.997 g. (15.7 mmol) ethyl orthoformate, 1.~07 g. ~9.47 mmol), 5-acetyl-2-thienyl-acetic acid methyl ester, 0.572 g. (~.14 mmol) and a trace of p-toluenesulfonic acid was allowed to stand at room temperature for 3 hrs. ~he mixture was poured into water and organic layer wa~ separated. An aqueous layer was extracted with benzene (50 ml x 2). Both organic layer~ were combined, washed with water, dried over anhyd. MgSG4 and evaporated in vacuo to provide 0.286 g. ~91 %) of its ketal as an yellow oil. This product can be characterized as the ethylene ketal of 5-acetyl-~-thienylacetic acid methyl ester on the basis of disappearance of carbonyl absorbtion at 1670 cm 1 (IR) and appearance of singlet of dioxolane methylene at 4.00 (o) (NMR).

'~ , ' : '

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing 5-carboxy-2-acetylthiophene which comprises oxidizing 5-acetyl-2-thienylacetic acid with a chromic anhydride-solvent complex or a dichromate in a sol-vent at a temperature from 0°C. to a boiling point of the solvent employed, or oxidizing a compound of the formula, wherein X is a conventional carbonyl protecting group and R
is a conventional ester residue, with a hypohalite in a mix-ture of water and alcohol at a temperature from 0° to 60°C.
and then removing the carbonyl protecting group.

2. A process for producing 5-carboxy-2-acetylthiophene which comprises oxidizing 5-acetyl-2-thienylacetic acid with a chromic anhydride-solvent complex or a dichromate in a sol-vent at a temperature from 0° to 100°C.

3. The process according to Claim 2, wherein said chromic anhydride-solvent complex is chromic anhydride-acetic acid complex or chromic anhydride-pyridine complex and the reaction is conducted in acetic acid, acetic anhydride, acetic acid- acetic anhydride mixed solvent, or pyridine.

4. The process according to Claim 2, wherein the said dichromate is employed in acetic acid, acetic anhydride or a mixture thereof.

5. A process for producing 5-carboxy-2-acetylthio-phene which comprises oxidizing a compound of the formula, wherein X is a carbonyl group protected with a ketal, hemi-thioketal, dithioketal, thiazolidine, imidazolidine or oxazolidine and R is a lower alkyl or phenyl, with a hypochlo-rite in a mixture of water and alcohols at a temperature from 0° to 60°C., and then removing the protecting group.