LU84748A1 - PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES AND INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION - Google Patents

Description

INVENTION PATENT.

* '”. k “* *" ^. “1 · \ Ί i. i” * “ί *

So-called Anonymous Company; ROUSSEL-UCLAF.

Process for the preparation of 2-thiophene acetic acid derivatives and intermediate products necessary for their preparation.

(Inventors: Roger NABET and Serge ANDRES)

International Convention - Priority of a patent application filed in France on December 3, 1982 under No. 82-20271.

The subject of the present invention is a process for the preparation of 2-thiophene acetic acid derivatives of formula (I) i

x CH-COoH

1 i 2.

R

5 in which R represents an alkyl radical having from 1 to 4 carbon atoms and, R £ and R ^ which are identical or different, each represents a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms or an atom halogen.

These products are intermediate products which can be used for the preparation of pharmaceutical products, in particular anti-inflammatory products.

Final products which can be prepared from the products obtained by the present process are in particular described in French patent 2,068,425.

Several processes for the preparation of the products of formula (I) have already been known.

In the reference M. BERÇOT-VATTERONI et al. Bull. Soc. Chim. France 1961 p 1820 is described the following process: 2 “O ECHO, HCl ίΓ ~ \ NaCN IJ ~ \ -> L> H2C1-> ^ / - CH2CN - C0 ^ Et2

\ J

not-. KOH π — n KOH n ft 9 ° 2And RI n — λ [I ^ jch-go2h <_11 ^ y zh-cn <- <- v JMF-cn * * R = alkyl C02Et

In the reference F. CLEMENCE et al. Eur. j. Med. Chem.

1974 (9) 390, the following process is described:

Q

o o

v CH3 Mgl ACOH CH

<(^ uraco2H

ch3 oh 5 In the French patent application 2,398,068 from the firm SAGAMI, the following process is described: R CH,

R1> J7 — ï * halogenation η — n \ J1 | D

JT. \ _C-CH, RST Vc-CH Hal2 -> A, f_CH Hal2 R ^ s / ^ Il 3 yVl 2η, Λ3 ia 0 K2 0 2 un R ^ = H or lower alkyl Hal =. halogen hydroxide of R2 = H, hydrocarbon radical of alkali metal or halogen ψ

* H

These methods include at least 4 steps from thiophene or a substituted thiophene.

3> * t

A new process for the preparation of the derivatives of formula (I) has now been developed in three stages starting from an ester of thienyl-2-acetic acid optionally substituted on the thienyl nucleus. Thienyl acetic acid is used. especially for the synthesis of antibiotic products, in particular of cephalosporins. ”The esters of acids derived from 2-thienyl-acetic acid are therefore accessible in large quantities and at attractive prices.

These starting materials can be easily prepared from the corresponding acids by the usual esterification methods.

The process which is the subject of the present application is characterized in that an alkyl carbonate of the formula: 15 (Alk1) 2CO3 in which Alk ^ represents an alkyl radical having from 1 to 4 is made to act in the presence of a strong base carbon atoms, with an ester of formula (II): & 2 ^ 3

XX

/ CEp-CCL Alk- R1 22 2 in which Alk2 represents an alkyl radical having from 1 20 to 4 carbon atoms, to obtain a product of formula (III): K --.....

| ^ C02 Alk2 ........------------- - _______________ _ H; which is reacted in the presence of a strong base with a product of formula RX in which R has the above meaning and X represents a functional derivative or an equivalent of functional derivative of the radical R to obtain a product of formula ( 17):> • t 4 R2 R3 /% ^^ c02 U *, <") R1 | ^ C02 Alk2 ·· -— product of formula (IV) which is subjected to a decarbalkoxylation reaction to obtain the product of formula ( I) expected.

Among the values which the substituents R 1, R 2 and R 1 may represent, mention may be made of lower alkyl radicals, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl. The substituents R ^, R2 and R ^ may also represent a halo-10 .gene atom, namely fluorine, chlorine, bromine, iodine.

The values Alk ^ and Alk2 can take one of the values indicated above for the radicals R to R ^,

The starting materials of formula (II) can be prepared according to the usual methods from the corresponding acids which are described in particular in French patent 2,377,398.

The reaction of the alkyl carbonate on the product of formula (II) can be carried out in the presence of a strong base such as an alkali metal alcoholate, preferably the sodium ethyl-late prepared in situ by addition of sodium in anhydrous ethanol. However, you can operate using it. sodium or potassium tert-butoxide. Another strong base can also be used, such as sodium hydride or another alkali metal hydride. This reaction can also be carried out by phase transfer under the usual conditions.

We can operate in the medium consisting of alcohol when using an alkali metal alcoholate. It is also possible to operate in the presence of another solvent, for example toluene, which can also be used to drive off the excess alcohol present in the medium.

The proportions of the various constituents can be varied according to methods known to those skilled in the art. Thus, for example, the amount of sodium can vary between 1 and 1.5 equivalent with respect to the ester of formula 5 (II) when a sodium alcoholate is used as a base.

The temperature and the reaction time can also be variable. The reaction time can vary from 2 to 8 hours approximately. The temperature can vary from 90 to 135 ° in approximately 5 (reflux of toluene or xylene).

Finally the carbonate of formula (Alk ^^ CO ^ can be used in variable proportion.

The product of formula (III) in which R> |, R2 and R ^ each represent a hydrogen atom and Alk ^ and Alk2 each represent an ethyl radical, is described with its preparation process in the reference JACS 68, 1934 (1946).

The transformation of the product of formula (III) into the product of formula (iv) is carried out in the presence of a strong base which can be chosen from the same group as that mentioned above. The operation is carried out as above preferably in the presence of sodium ethoxide prepared in situ. It is preferably carried out in the presence of another solvent such as toluene.

One can also operate using a phase transfer reaction.

The derivative RX can represent, for example, an alkyl halide such as chloride, bromide or iodide. RX can also represent an alkyl sulphate of formula (X then represents a half molecule of SO ^).

The derivative RX can also represent another derivative, of alkylation, the radical X representing a functional derivative or an equivalent of functional derivative known in organic chemistry.

As before, it is also possible to operate under various conditions of temperature, reaction time or respective amounts of reagents.

Thus, per mole of product of formula (III), it is possible to use from 1 to 1.5 moles of product RX.

The reaction time can vary from 30 minutes to 3 hours, for example, the temperature preferably being between 50 and 100 ° C, more preferably between 50 and 80 ° C.

In a preferred embodiment of the process, the operation is carried out in the presence of sodium ethylate after elimination of the ethanol using a solvent such as toluene in which the alkylation reaction is carried out.

6

The transformation of the product of formula (IY) into the product of formula (I) is carried out first by treatment with an alkaline base to obtain a salt of the expected acid, acid which is then isolated by addition of an acid. The first 5 phase is carried out either in water or in a water-solvent-miscible water mixture. As solvent, use is preferably made of a lower alcohol such as inethanol, 1 ’ethanol or 1’ i so-propanol. Soda or potash is preferably used as the alkaline base. The operation is preferably carried out at a temperature between 20 ° C. and the reflux temperature more preferably between 50 ° C. and the reflux temperature. The reaction time can be between two hours and 15 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; one operates at a temperature which can vary between room temperature and the reflux of the solvent.

The present invention particularly relates to a process for the preparation of a product of formula (I ’) :. Oy- ,,

R

in which R has the meaning indicated above, characterized in that the process as described above is carried out starting from an ester of thienyl acetic acid (II ’):. ..... fl CH2-C02 Alk2

More particularly, a product of formula RX in which R represents a methyl or ethyl radical is used, and in particular a product of formula RX in which R represents a methyl radical.

30 It should be noted that if, as indicated above, the subject of this patent application is a three-step process * 7

steps leading from the products of formula (II) to the products of formula (III) then to the products of formula (IV) and finally to the products of formula (I), the two-step process, characterized in that one reacts by presence of a strong base 5 a product of formula (III): R? R

H ™ r ^ C02Alki ___ 1 ^ 0 ° 2 Alkz with a. product of formula R-X in which R has the above meaning and X represents a functional derivative or an equivalent of functional derivative of the radical R to obtain a product of formula (IV):

AC- ut, W

R1 \ ^ coz Alk2

R

a product of formula (IV) which is subjected to a decarbalkoxylation reaction in order to obtain the expected product of formula (I), constitutes a particularly advantageous invention.

It is of course the same for the process characterized in that one starts from the products of formula (III *): (Jk C02 Ut, (m ·) \ C02 Alk2 to obtain, according to the process indicated above, the pro- 20 duits of formula (IV *): (IV,) | Alk9 R d * then the products of formula (Γ) indicated above.

* 8

A more particular subject of the present invention is the three-step process as described in the paragraphs preceding the two above-mentioned paragraphs, characterized in that this process is carried out starting from ethyl 5-carbonate and a product of formula (II) in which Alkp represents an ethyl radical.

In the process which is the subject of the present application, the strong base that is used is preferably sodium ethylate. Likewise, an alkyl sulphate is preferably used as product of formula RX, in particular methyl sulphate.

Finally, the process which is the subject of the present application is implemented under the following preferential conditions for preparing the α-methyl 2-thiophene acetic acid: The process is characterized in that it is made to act, in the presence of ethyl -15 sodium late, ethyl carbonate on ethyl thienyl-2- acetate to obtain ethyl thienyl-2-malonate on which methyl sulfate is made to obtain thienyl-2-methyl malonate ethyl on which the sodium hydroxide and then the hydrochloric acid are made to act to obtain the expected product.

The present application also relates, as new industrial products necessary for the preparation of the products of formula (I) as described above, the products of formula (IY): R2 R3 / ^ C02 Μ *, (IV) R1 I ^ COp Alkp

R

in which R, R ^, Rp, R ^> Alk ^ and Alkp have the meaning indicated above.

More specifically, the subject of the invention is, as new industrial products and in particular as industrial products necessary for the preparation of the products of formula (I ') as described above, the products of formula (IV' ): f 9 / C02 Alk1 UT,) | ^ CCU Alk9 R ά ά in which R, Alk ^ and Alk2 have the meaning indicated above.

Finally, the subject of the invention is, as a new industrial product and in particular as a new industrial product necessary for the preparation of α-methyl 2-thiophene acetic acid, thienyl-2-methyl malonate d 'ethyl.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1: α-methyl 2-thionhene acetic acid.

Stage A: ethyl 2-thienyl-malonate.

225 cm3 of absolute ethanol and 16.5 g of sodium are mixed under nitrogen. The reflux of ethanol is maintained until dissolution and then concentrated to dryness under reduced pressure to remove the ethanol. 150 cm 3 of ethyl carbonate are introduced over sodium ethylate at 100 ° C. and maintaining the temperature between 90 and 95 ° C., then, in 10 minutes, 100 g of ethyl thienyl-2-acetate and 100 cm% of toluene. It is brought to 105 ° C. and distilled over 2 hours about 120 cm 3 of toluene-ethanol-ethyl carbonate mixture. Maintained at 105 ° C for an additional 2 hours then cooled to 20 ° C and poured into 600 cm 3 of ice water containing 80 cm 3 of pure hydrochloric acid 22 ° Be.

Decanted, re-extracts the aqueous phase with toluene and the combined toluene phases are washed with water. The toluene solution is concentrated under reduced pressure. The expected crude product is obtained which is distilled under a pressure of 2 mm of mercury. 134.4 g of expected product are obtained.

Eb2 = 118-120 ° C.

Stage B: ethyl thienyl-2-methyl malonate.

10.45 g of sodium are introduced under nitrogen into 160 cm 3 'of absolute ethanol. The reflux is maintained for 45 minutes and 60 cm 3 of ethanol are distilled. 300 cm3 of toluene are added. The mixture is heated to reflux while stirring and the ethanol is distilled at constant volume by the addition of toluene. 250 cm 3 of toluene i 10 are thus added and approximately 250 cm 3 of ethanol-toluene mixture are recovered.

Cool to 20 ° C and add 100 g of ethyl thienyl-2-malonate and 200 cm3 of toluene. The mixture is stirred for 20 minutes. 150 cm3 of toluene-ethanol mixture are distilled under reduced pressure and then 100 cm3 of toluene are introduced under nitrogen. The mixture is heated to 70 ° C. and approximately 60.9 g of dimethyl sulphate are added over 30 minutes. Maintained at 80 ° C for 45 minutes, cooled to 20-25 ° C and added 200 cm3 of demineralized water.

The mixture is stirred for 15 minutes, decanted, the toluene phase washed with 10 100 cm3 of water at 5% hydrochloric acid 22 ° Be and then 4 times 100 cm3 of demineralized water. 450 cm3 of toluene are distilled under reduced pressure and the concentrate is left at 70 ° C. under a pressure of 15-20 mm of mercury for one hour and 105 g of expected product are obtained.

15 Stage C: α-methyl 2-thiophene acetic acid.

100 g of ethyl 2-thienyl-methylalonate and 200 cm 3 of ethanol are added to a solution of 62.6 g of sodium hydroxide in 400 cm 3 of demineralized water. The mixture is brought to 50 ° C. for 4 hours and then distilled under reduced pressure while maintaining the temperature below 50 ° C., 300 cm3 of an ethanol-water mixture. Place under nitrogen and successively add 200 cm3 of toluene and then 140 cm3 of 22 ° Be hydrochloric acid. The mixture is brought to reflux for one hour and then cooled to 20 ° C. Decanted, washed the toluene phase several times with 50 cm3 of water and concentrated at reduced pressure by distilling 180 cm3 of toluene. The concentrate is desolvated at 70 ° C for one hour under a pressure of 15-20 mm of mercury. 58.8 g of expected product are obtained.

EXAMPLE 2: thienvl-2-butyric acid.

Stage A: ethyl thienyl-2-ethyl malonate.

12.54 g of sodium are introduced under nitrogen into 192 cm3 of absolute ethanol. The reflux is maintained for 45 minutes then distilled 72 cm3 of ethanol. 360 cm3 of toluene are added. The mixture is heated to reflux to distill the ethanol at a constant volume by the addition of toluene. 300 cm3 of toluene are thus added and the same volume of toluene-ethanol mixture is recovered. Cool to 20 ° C and add 120 g of ethyl thienyl-2-malonate and 240 cm3 of toluene. The mixture is stirred for 20 minutes then distilled under reduced pressure 180 cm3 of to-40 luene-ethanol mixture, then introduced under nitrogen 120 cm3 of toluene.

* t 11

The mixture is heated to 75 ° C. and then 99.3 g of diethyl sulphate are added in 30 minutes "The mixture is refluxed for one hour, cooled to 20-25 ° C. and 240 cm3 of demineralized water are added" The mixture is stirred for 15 minutes, decanted and wash the toluene phase with 5 120 cm3 of demineralized water at 5% 22 ° hydrochloric acid

Be then with 4 times 120 cm 3 of water. The toluene phase is concentrated under reduced pressure after drying over sodium sulfate. The concentrate is desolvated under a pressure of 15-20 mm of mercury at 70 ° C for one hour. 145.6 g 10 of expected product are obtained.

This product is purified by distillation under pressure of 0.5 mm of mercury. 113 g of distillation product are collected at a temperature of 95-120 ° C.

Stage B: thienyl-2-butyric acid.

15 A mixture of 62.6 g of sodium hydroxide in 400 cm3 of demineralized water is stirred under nitrogen until complete dissolution, then 105.4 g of ethyl thienyl-2-ethyl malonate and then 200 cm3 of ethanol are added. brought to 50 ° C for 4 hours then distilled under a pressure of 20 mm of mercury at a temperature of 50 ° C, about 300 cm3 of ethanol-water mixture · 200 cm3 of toluene are then introduced under nitrogen and then 140 cm3 of 22 ° Be hydrochloric acid. The medium is refluxed for 1 hour 30 minutes, cooled to 20 ° C., decanted, the aqueous phase is extracted with 50 cm3 of toluene and the toluene phase is washed several times with 50 cm3 of water. The toluene phase is dried over sodium sulfate and concentrated to dryness under pressure from 15 to 20 mm of mercury at 70 ° C. Maintained under these conditions an additional hour and 66.3 g of expected product is obtained.

Claims (11)

1. Alkp H ^ which is reacted in the presence of a strong base with a product of formula RX in which R has the above meaning and X represents a functional derivative or an equivalent of functional derivative of the radical R to obtain a product of formula (IV): ο * P - —- R2 R3 / A ^ \ c ^ C02 ωΐ £ 1 (I7) R1 I ^ COp Alk "R product of formula (IV) which is subjected to a reaction decarbalkoxylation to obtain the expected product of formula (I). 5 2) Process according to claim 1 for the preparation of one. product of formula (I ′): I 2 R in which R has the meaning indicated in the claim characterized in that the process as described above is carried out starting from an ester of thienyl acetic acid (II1): r \ CH2-C02 Alk2 1. Process for the preparation of 2-thiophene acetic acid derivatives of formula (I): Ro R · * E R-, CH-CO-H I 2 R i * in which R represents an alkyl radical having from 1 to 4 5 carbon atoms and R ^, R2 and identical or different each represent a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms or a halogen atom, characterized in that one acts, in the presence of a strong base, an alkyl carbonate of formula: 10 (Alk> |) 2C0 ^ in which Alk ^ represents an alkyl radical having from 1 to 4 carbon atoms, with an ester of formula (II): R? R * / CH2-C02 Alk2 R1 in which Alk2 represents an alkyl radical having from 1 15 to 4 carbon atoms, to obtain a product of formula (III): ^ „Λ <m 3. Method according to one of claims 1 or 2 for the preparation of a product of formula (I ') as described in claim 2 in which R represents a methyl or ethyl radical ^ characterized in that one uses , in the process described in claim 1, a product of formula RX in which R represents a methyl or ethyl radical. 4. Method according to one of claims 1 to 3 for the preparation of a product of formula (I ') as described in claim 2 in which R represents a methyl radical characterized in that one uses, in the process described in claim 1, a product of formula RX in which R represents a methyl radical. 25 5) Process according to one of Claims 1 to 4, characterized in that the process described in Claim 1 is used, starting with ethyl carbonate and a product of formula (II) in which Alk "Represents an ethyl * radical. 6. Method according to one of claims 1 to 5 characterized in that the strong base that is used is sodium ethylate. 5 7) Method according to one of claims 1 to 5 charac terized in that the product of formula RX is alkyl sulfate. 8. Method according to one of claims 1 to 7 for the preparation of α-methyl 2-thiophene acetic acid, characterized in that one acts, in the presence of sodium ethylate, “the carbonate d on ethyl thienyl-2-acetate to obtain ethyl 2-thienyl malonate on which methyl sulphate is made to obtain ethyl thienyl-2-methyl malonate on which sodium hydroxide is made to act then hydrochloric acid to obtain the expected product. 9. As new industrial products, the products of formula (IV): R2 r3 / X ^^ C02 Ufc, A | A ™ Alk2 R in which R, R ^, R2, R3, Aük ^ and Alk2 have the meaning indicated in claim 1. 10. As new industrial products according to claim 9, the products of formula (IV): X A / C02 Alki (IV) | Alkp R. A wherein R, Alk ^ and Alk2 have the meaning given in claim 1. 11. As a new industrial product according to claim 10, ethyl thienyl-2-methyl malonate.