GB2132607A

GB2132607A - Preparation of thiophene compounds

Info

Publication number: GB2132607A
Application number: GB08312701A
Authority: GB
Inventors: Roger Nabet; Serge Andres
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1982-12-03
Filing date: 1983-05-09
Publication date: 1984-07-11
Also published as: AU1357483A; FI831115A0; DK138490A; CH655722A5; KR900005681B1; AU556803B2; BE896439A; FI831115L; NL8301692A; JPS59106482A; FI83646B; CH659817A5; DK139983A; DK164550B; FR2537137A1; ATA286683A; ES521230A0; LU84748A1; NZ204509A; AT392784B

Abstract

A 2-thiophene acetic acid compound of formula (I): <IMAGE> in which: R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; is prepared by decarbalkoxylating an alkylmalonate of formula (IV): <IMAGE> in which R, R1, R2 and R3 are as defined above and Alk1 and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms. The 2-thiophene acetic acid compound is an intermediate in the production of pharmaceuticals. The alkylmalonate used is itself claimed per se.

Description

SPECIFICATION Preparation of thiophene compounds This invention relates to the preparation of 2-thiophene acetic acid compounds of formula (I):

in which R represents an alkyl radical of 1 to 4 carbon atoms and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom.

These compounds are intermediates which can be used in the preparation of pharmaceutical products, in particular anti-inflammatory products. End products which can be prepared from the compounds are described in particular in French Patent 2 068 425.

Several processes for the preparation of the compounds are already known.

The following process is described in M. Bercot-Vatteroni et al., Bull. Soc. Chim. France 1961 p 1 820:

R= alkyl The following process is described in F. Clemence et al., Eur J. Med. Chem. 1 974 (9) 390:

The following process is described in French Patent Application 2 398 068 in the name of the Sagami company:

R't=H or a lower alkyl Hal=halogen R'2=H, hydrocarbon radical or halogen These processes involve at least 4 stages starting from thiophene or in the case of the last mentioned process an optionally substituted thiophene of formula

A new process for the preparation of the compounds has now been discovered.Accordingly, the invention provides a process for the preparation of a 2-thiophene acetic acid compound of formula (I):

in which R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises decarbalkoxylating an alkylmalonate of formula (IV?:

in which R, R1, R2 and R3 are as defined above and Alk, and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms.

The new process is better because it produces the compounds more readily. If one starts from chemicals which are available in large quantities at economical prices, the present process produces the compounds in fewer stages.

The alkylmalonate of formula (IV) is preferably prepared by alkylating in the presence of a strong base a malonate of formula (Ill):

in which P1, R2, R3, Alk, and Alk2 are as defined above.

The malonate of formula (Ill) is preferably prepared by reacting an alkyl carbonate of formula (Alk,)2CO3 in which Alkr is as defined above, in the presence of a strong base with an ester of formula (ill):

in which P1, R2, R3 and Alk2 are as defined above.

The ester for formula (II) is an ester of thienyl-2-acetic acid optionaily substituted on the thienyl ring. Such thienyl-2-acetic acids are used particularly in the synthesis of antibiotics, especially cephalosporins. The esters of formula (II) are thus available in large quantities at economical prices.

The esters can readily be prepared from the corresponding acids by the usual esterification methods.

Thus, the present compounds can be prepared in 3 stages from a readily accessible starting material, the ester of formula (II).

R represents a lower alkyl radical, i.e. an alkyl radical of 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl. Rr, R2 and R3 can independently represent one of these alkyl radicals or equally a halogen atom, namely fluorine, chlorine, bromine or iodine.

Alk, and Alk2 likewise can take any of the lower alkyl values listed above for R.

The esters of formula (II) can be prepared by the usual methods from the corresponding acids which are described for example in French Patent 2 377 398.

The reaction of the alkyl carbonate with the ester of formula (II) can be carried out in the presence of a strong base such as an alkali metal alcoholate, preferably sodium ethylate prepared in situ by the addition of sodium to anhydrous ethanol. Sodium or potassium tert-butylate can be used. It is also possible to use a different strong base such as sodium hydride or another alkali metal hydride. This reaction can equally be carried out as a phase transfer reaction under the usual conditions.

The reaction of the alkyl carbonate with the ester of formula (II) can be conducted in a reaction medium constituted by the alcohol when using an alkali metal alcoholate as the strong base. It is equally possible to proceed in the presence of another solvent, for example toluene which can be used also to expel excess alcohol present in the medium.

The proportions of the different materials can be varied according to the methods known to those skilled in the art. For example the quantity of sodium can vary between 1 and 1.5 equivalents in relation to the ester of formula (II) when using sodium alcoholate as the base. The temperature and reaction time can likewise be varied. The length of reaction can vary for example from about 2 to 8 hours. The temperature can vary for example from 90 to 1350 approximately (reflux of toluene or xylene). Finally, the carbonate of formula (Alk,)2C03 can be used in variable proportions.

The malonate of formula (III) in which R,, R2 and R3 each represent a hydrogen atom and Alk, and Alk2 each represent an ethyl radical is described with its process for preparation in J.A.C.S. 68, 1 934 (1946).

The conversion of the malonate of formula (III) into the alkylmalonate of formula (IV) is carried out in the presence of a strong base which can be as described above. The procedure is preferably the same as described above concerning sodium ethylate prepared in situ. The process is preferably carried out in the presence of another solvent such as toluene. It is equally possible to proceed using a phase transfer reaction.

The alkylating agent used to alkylate the malonate of formula (Ill) to the alkylmalonate of formula (IV) can be considered as being of formula RX where R is as defined above and X is a group which functions so as to permit the alkylation. Aikylating agents are well known. The alkylating agent RX can be for example an alkyl halide such as the chloride, bromide, or iodide. The alkylating agent can equally be an alkyl sulphate of formula (R)2SO4 (X then represents half an SO4).

As previously, one can use varied conditions of temperature, reaction time and quantities of reagents. For example, one can use 1 to 1.5 moles of the alkylating agent RX per mole of the malonate of formula (Ill). The reaction time can vary for example from 30 minutes to 3 hours. The temperature is preferably between 50 and 1 000C, especially between 50 and 80"C.

In a preferred embodiment, the alkylation is carried out in the presence of sodium ethylate after eliminating the ethanol by means of a solvent such as toluene in which the alkylation is to be carried out.

The conversion of the alkylmalonate of formula (IV) into the 2-thiophene acetic acid compound of formula (I) can be carried out by treatment with an alkaline base to obtain a salt of the desired acid compound, and then with an acid to produce the desired acid compound. The first phase can be carried out either in water or in a mixture of water and water-miscible solvent. The solvent used is preferably a lower alcohol such as methanol, ethanol or isopropanol. Sodium or potassium hydroxide is preferably used as the alkaline base.

The temperature is preferably between 200C and the reflux temperature, especially between 500C and the reflux temperature. The reaction time is preferably between 2 hours and 1 5 hours.

The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is preferably carried out with the addition of an organic solvent such as toluene; the process is usually carried out at a temperature between the ambient temperature and the reflux temperature of the solvent.

Preferably, Rr, R2 and R3 each represents a hydrogen atom, so that the compound is of formula (1'):

In that event, the corresponding ester of formula (II) is a thienyl acetic acid ester of formula (ill'):

in which Alk2 is as defined above.

Preferably, R represents a methyl or ethyl radical, especially a methyl radical.

Preferably, the present 2-thiophene acetic acid compound of formula (1) is produced in the 3 stages described, starting with the ester of formula (II), converting this into the malonate of formula (Ill), alkylating this to the alkylmalonate of formula (IV), and converting this to the compound of formula (I). The sequence of the final 2 stages, however, the alkylation of the malonate of formula (111) to the alkylmalonate of formula (IV) and the conversion of this alkylmalonate to the compound of formula (I), is particularly significant. Especially preferred is this sequence of the last 2 stages wherein R,, R2 and R3 each represents a hydrogen atom.

A preferred embodiment is the 3 stage process described above starting from ethyl carbonate and an ester of formula (II) in which Alk2 represents an ethyl radical.

In the process of the invention, the strong base is preferably sodium ethylate. The alkylating agent is preferably an alkyl sulphate, especially methyl sulphate.

Especially preferred is carrying out the present process in the following way to produce a-methyl 2-thiophene acetic acid: The process comprises reacting ethyl carbonate in the presence of sodium ethylate with ethyl thienyl-2-acetate to produce ethyl thienyl-2-malonate, which is reacted with methyl sulphate to produce ethyl thienyl-2-methyl malonate, which is reacted with sodium hydroxide and then hydrochloric acid to produce the a-methyl 2-thiophene acetic acid.

The alkylmalonate of formula (IV) is a new compound and the invention provides it per se and its production by alkylating in the presence of a strong base the malonate of formula (Ill). It is preferred that in the alkylmalonate of formula (IV) Rr, R2 and R3 each represent a hydrogen atom. The most preferred alkylmalonate is ethyl thienyl-2-methyl malonate, and this is preferably used to produce amethyl 2-thiophene acetic acid.

The invention also provides a process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined above, in which process the compound is prepared in the present way.

The invention is illustrated by the following Examples.

Example 1: a-methyl 2-thiophene acetic acid Stage A: ethyl thienyl-2-malonate 225 cc of absolute ethanol and 1 6.5 g of sodium were mixed under nitrogen. Ethanol reflux was maintained until the sodium had dissolved, and the solution was then concentrated to dryness under reduced pressure in order to eliminate the excess ethanol. 1 50 cc of ethyl carbonate were introduced onto the sodium ethylate at 1000C while the temperature was maintained between 90 and 950C and then, in 10 minutes, 100 g of ethyl thienyl-2-acetate and 100 cc of toluene were added. The temperature was brought to 1 050C and in about 2 hours 1 20 cc of the toluene-ethanol-ethyl carbonate mixture were distilled off.The temperature was maintained at 1 050C for a further 2 hours and then cooled down to 200 C, whereupon the resultant mixture was poured into 600 cc of iced water containing 80 cc of pure 220Be hydrochloric acid. After decanting, the aqueous phase was reextracted with toluene and the combined toluene extracts were washed with water. The toluene solution was concentrated under reduced pressure. The expected crude product was obtained and this was distilled under a pressure of 2 mm of mercury. 134.4 g of the expected product was obtained.

Boiling point under 2 mm of mercury=l 18--1200C.

Stage B: ethyl thienyl-2-methyl malonate 10.45 g of sodium were introduced under nitrogen into 1 60 cc of absolute ethanol. Reflux was maintained for 45 minutes and 60 cc of ethanol were distilled off. 300 cc of toluene were added. The mixture was heated to reflux with continuous stirring and the ethanol was distilled off at constant volume by the addition of toluene. 250 cc of toluene were added and about 250 cc of the ethanoltoluene mixture were recovered.

The mixture was cooled down to 200 C, and 100 g of ethyl thienyl-2-malonate and 200 cc of toluene were added. Stirring was continued for 20 minutes. 1 50 cc of the toluene-ethanol mixture were distilled off under reduced pressure, and then 100 cc of toluene were introduced under nitrogen.

The mixture was heated to 700 C, and 60.9 g of dimethyl sulphate were added in 30 minutes. The temperature was maintained at 800C for 45 minutes and then reduced to 20--250C, when 200 cc of demineralised water were added. After 1 5 minutes stirring, the mixture was decanted, and the toluene phase washed with 100 cc of water containing 5% 220Be hydrochloric acid and then 4 times with 100 cc of demineralised water. 450 cc of toluene were distilled off under reduced pressure and the concentrate was left at 700C under a pressure of 1 5-20 mm of mercury for one hour, yielding 105 g of the expected product.

Stage C: a-methyl 2-thiophene acetic acid.

100 g of ethyl thienyl-2-methyl malonate and 200 cc of ethanol were added to a solution of 62.6 g of sodium hydroxide in 400 cc of dimineralised water. The resultant mixture was brought to 500C over 4 hours, and then 300 cc of an ethanol-water mixture were distilled off under reduced pressure whilst maintaining the temperature below 500 C. The mixture was placed under nitrogen and 200 cc of toluene and 140 cc of 220Be hydrochloric acid were added in succession. The mixture was brought to reflux over 1 hour 30 minutes and then cooled to 200 C. After decanting, the toluene phase was washed several times with 50 cc of water and concentrated under reduced pressure by distilling off 1 80 cc of toluene.The solvent was removed from the concentrate at 700C for one hour under a pressure of 1 5-20 mm of mercury. 58.8 g of the expected product was obtained.

Example 2: thienyl-2-butyric acid Stage A: ethyl thienyl-2-ethyl malonate 12.54 g of sodium were introduced into 1 92 cc of absolute ethanol. Reflux was maintained for 45 minutes, and then 72 cc of ethanol were distilled off. 360 cc of toluene were added. The mixture was heated to reflux to distill off the ethanol at constant volume by the addition of toluene. 300 cc of toluene were thus added and the same volume of toluene-ethanol mixture were recovered. The reaction mixture was cooled to 200C and 120 g of ethyl thienyl-2-malonate and 240 cc of toluene were added. After stirring for 20 minutes, 1 80 cc of toluene-ethanol mixture were distilled off under reduced pressure and 120 cc toluene were introduced under nitrogen. The mixture was heated to 750C, and 99.3 g of diethyl sulphate were then added over 30 minutes.The mixture was brought to reflux over one hour and then cooled to 20-250C, and 240 cc of demineralised water were added.

After stirring for 1 5 minutes and decanting, the toluene phase was washed with 120 cc of demineralised water containing 5% 220Be hydrochloric acid and then 4 times with 1 20 cc of water.

The toluene phase was concentrated under reduced pressure after drying over sodium sulphate. The solvent was removed from the concentrate under a pressure of 1 5-20 mm of mercury at 700C for one hour. 1 45.6 g of the expected product was obtained.

This product was purified by distillation under a pressure of 0.5 mm of mercury. 11 3 g of the distilling product was recovered at a temperature of 95-1 200 C.

Stage B: thienyl-2-butyric acid A mixture of 62.6 g of sodium hydroxide in 400 cc of demineralised water were stirred under nitrogen until totally dissolved, after which 1 05.4 g of ethyl thienyl-2-ethyl malonate and then 200 cc of ethanol were added. The resultant mixture was brought to 500C over 4 hours and then 300 cc of ethanol-water mixture were distilled off under a pressure of 20 mm mercury at a temperature of about 500C. 200 cc of toluene followed by 140 cc of 220Be hydrochloric acid were then introduced under nitrogen. The mixture was brought to reflux over 1 hour 30 minutes, cooled to 200C and decanted. The aqeueous phase was extracted with 50 cc of toluene and the toluene phase was washed several times with 50 cc of water. The toluene phase was dried over sodium sulphate and concentrated to dryness under a pressure of 1 5 to 20 mm mercury at 700 C. After a further hour of these conditions, 66.3 g of the expected product were obtained.

Claims

1. Process for the preparation of a 2-thiophene acetic acid compound of formula (I):

in which R represents an alkyl radical of 1 to 4 carbon atoms; and P1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises decarbalkoxylating an alkylmalonate of formula (IV):

in which R, R,, R2 and R3 are as defined above and Alk, and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms.

2. Process according to claim 1 wherein the alkylmalonate of formula (IV) is prepared by alkylating in the presence of a strong base a malonate of formula (III):

in which R,, R2, R3, Alkr and Alk2 are as defined in claim 1.

3. Process according to claim 2 wherein the malonate of formula (III) is prepared by reacting an alkyl carbonate of formula (Alk,)2CO3 in which Alk, is as defined in claim 2, in the presence of a strong base with an ester of formula (ill):

in which Ra, R2, R3 and Alk2 are as defined in claim 2.

4. Process according to claim 2 or 3 wherein the strong base is sodium ethylate.

5. Process according to any one of claims 2-4 wherein the malonate of formula (III) is aikylated with an alkyl sulphate of formula

in which R is as defined in claim 1.

6. Process according to any one of the preceding claims wherein R, R2 and R3 each represents a hydrogen atom.

7. Process according to claim 6 wherein R represents a methyl radical.

8. Process according to claim 6 wherein R represents an ethyl radical.

9. Process according to any one of the preceding claims wherein Alk, and Alk2 each represents an ethyl radical.

10. Process for the preparation of a-methyl 2-thiophene acetic acid, which process comprises reacting ethyl carbonate in the presence of sodium ethylate with ethyl thienyl-2-acetate to produce ethyl thienyl-2-malonate, which is reacted with methyl sulphate to produce ethyl thienyl-2-methyl malonate, which is reacted with sodium hydroxide and then hydrochloric acid to produce the a-methyl 2-thiophene acetic acid.

11. Process according to any one of the preceding claims performed substantially as described herein.

12. Process according to any one of claims 1-10 performed substantially as described herein in Example 1 or in Example 2.

1 3. A 2-thiophene acetic acid compound as defined in claim 1 when prepared by a process claimed in any one of the preceding claims.

14. An alkylmalonate as defined in claim 1.

1 5. An alkylmalonate according to claim 14 wherein RX, R2 and R3 each represents a hydrogen atom.

1 6. Ethyl thienyl-2-methylmalonate.

17. A process for preparing an alkylmalonate claimed in any one of claims 14-1 6, which process comprises alkylating in the presence of a strong base a malonate of formula (III) as defined in claim 2.

18. A process according to claim 1 7 performed substantially as described herein.

1 9. A process according to claim 1 7 performed substantially as described herein in Example 1 or in Example 2.

20. An alkylmalonate claimed in any one of claims 14-1 6 when prepared by a process claimed in any one of claims 1 7-19.

21. A process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined in claim 1, in which process the 2-thiophene acetic acid compound is as claimed in claim 13.