CH655316A5 - Derivatives for the preparation of alpha-hydroxy acid 2-acetic thiophene. - Google Patents

Description

655,316

2

CLAIMS 1) Process for the preparation of a-hydroxy 2-thiophene acetic acid derivatives of formula (I):

2 T

i i ^

(I)

in which R represents an alkyl radical having from 1 to 4 carbon atoms and Ri, R2 and R3, which are identical or different, each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, characterized in that a product of formula (II) is made to act:

R-C-COoA Il 2 0

in which R has the abovementioned meaning and A represents a hydrogen atom, an alkali metal atom or an equivalent of magnesium or of an alkaline earth metal, to obtain after hydrolysis of the magnesium group, the product of formula (I) sought.

2) Process according to claim 1 for the preparation of a product of formula (I):

Q4

OK

': -C02H R

d;)

in which R has the meaning indicated in claim 1, characterized in that the method as described in claim 1 is carried out, starting from a 2-thienyl magnesium halide.

3) Method according to one of claims 1 or 2 for preparing a product of formula (I ') as described in claim 2, wherein R represents a methyl or ethyl radical, characterized in that one uses in the process described in claim 1, a product of formula (III) in which R represents a methyl or ethyl radical.

4) Process according to one of claims 1 to 3 for the preparation of a-methyl a-hydroxy 2-thiophene acetic acid, characterized in that a product of formula is used in the process described in claim 1 (II) in which R 1, R 2 and R 3 each represent a hydrogen atom and a product of formula (III) in which R represents a methyl radical.

o

ClCOCO-, St

5) Method according to one of claims 1 to 4, characterized in that the method described in claim 1 is implemented using a product of formula (II) in which X represents a bromine atom and of a product of

5 formula (III) in which A represents a hydrogen or lithium atom.

6) Method according to one of claims 1 to 5, characterized in that the hydrolysis of the magnesium group is carried out in an acidic aqueous medium.

7) Process according to one of claims 1 to 6 for the preparation of a-methyl a-hydroxy 2-thiophene acetic acid, characterized in that the 2-thienyl magnesium bromide is made to act on the pyruvate of lithium and hydrolyzes the product obtained with the acid of an aqueous solution of hydrochloric acid

15 that.

(II)

in which X represents a halogen atom, on a product of formula (III):

(III)

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

25

R.

/ ^ S> N: -co? K

(i)

wherein R represents an alkyl radical having from 1 to 4 carbon atoms and R 1, R2 and R 3, which are identical or different, each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms.

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

From the products of formula (I) can be prepared according to the method described in the publication F. Clemence et al. Eur. J. Med. Chem. 1974 (9) 390 or the French patent 2167334 of formual products (A):

40

R.

00

R

K- € 02K

This process is characterized in that a soft metallic reducing agent is used such as stannous chloride in hydrochloric medium.

These products of formula (A) can then be transformed into final products having pharmacological properties. Such a transformation is described for example in 50 the French patents 2068425 and 2167334 cited above.

In the aforementioned reference Eur. J. Med. Chem. 1974 (9) 390 a method of preparing the formuale products has been described (I). This process is as follows:

O-î-

C02E1

OH®

O-t co2h

^ CH_ Mg I

ÇHj

U-CO ^ H (I)

Ah

A new process for pre- 65 has now been developed. These two products are easily accessible and the reaction reaction of the derivatives of formula (I) from a 2-halo thio- can be carried out without isolation of intermediate products, phene and an acid of formula RC-CO H. The object method of the present invention is characterized

It 2 "* in that we make a product of formula (II):

3

655,316

in which X represents a halogen atom, on a product of formula (III):

R-C-C02A (III)

0

wherein R has the above meaning and A represents a hydrogen atom, an alkali metal atom or a magnesium equivalent of an alkaline earth metal, to obtain after hydrolysis of the magnesium group, the product of formula

(I) searched.

Among the values which the substituents R, 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.

X can represent a chlorine, iodine or bromine atom; we prefer the bromine value.

Apart from the hydrogen value, A can represent a sodium, potassium or lithium atom. The hydrogen or lithium values, more particularly lithium, are preferred. A can also represent an equivalent of magnesium or of an alkaline earth metal such as calcium or barium.

The magnesium of formula (II) which is made to act on the product of formula (III) is preferably prepared extempora-ment in an organic solvent such as tetrahydro-furan or ethyl ether.

When using an alkali metal salt, preferably the lithium salt as product of formula (III), this salt can also be prepared extemporaneously in an organic solvent such as toluene or tetrahydrofuran. Benzene or an ether such as ethyl ether can also be used.

The reaction is carried out in the magnesium preparation solvent or the mixture of the solvents indicated below.

The hydrolysis of magnesium is carried out in an acidic aqueous medium, the acid used being hydrochloric, sulfuric or acetic acid. One can also operate in the presence of ammonium chloride.

The present invention particularly relates to a process for the preparation of a product of formula (II): in

O4ÜC02K »•>

R

which R has the meaning indicated below, characterized in that the process as described above is carried out, starting from a 2-thienyl magnesium halide.

The process of the present invention more particularly relates to the preparation of a product of formula (I ′) in which R represents a methyl or ethyl radical, characterized in that one uses in the process described above, a product of formula (III) in which R represents a methyl or ethyl radical.

More particularly still, the process which is the subject of the present invention relates to the preparation of a-methyl a-hydroxy 2-thiophene acetic acid, characterized in that a product of formula is used in the process described above

(II) in which R 1, R 2 and R 3 each represent a hydrogen atom and a product of formula (III) in which R represents a methyl radical.

As starting material for the process of the present invention, a product of formula (II) is preferably used.

in which X represents a bromine atom and a product of formula (III) in which A represents a hydrogen or lithium atom.

The hydrolysis of the magnesium group obtained is carried out in an acidic medium.

Finally, the subject of the present invention relates particularly to a mode of preparation of a-methyl a-hydroxy 2-thiophene acetic acid, characterized in that the 2-thienyl magnesium bromide is made to act on litio pyruvate hium and hydrolyzes the product obtained using an aqueous hydrochloric acid solution.

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

Example 1: Acid a-methyl a-hydroxy 2-thiophene acéti-15.

Example 1: α-methyl α-hydroxy 2-thiophene acetic acid.

a) Preparation of lithium pyruvate

A suspension of 7.96 kg of lithium carbonate in 210 l of toluene is heated to boiling point and introduced over 2 to 3 hours with stirring, maintaining the internal temperature between 105 and 108 ° C. and decanting the water formed, 24.6 kg of pyruvic acid. Is maintained at reflux for 1 h 30 by decanting 41 of a mixture of water formed and pyruvic acid.

25 Distilled at normal pressure in about 30 minutes to remove the last traces of water and acid. 35 l of a toluene-acid-water mixture are thus collected.

b) Preparation of thienyl magnesium bromide

5.74 kg of magnesium are introduced under argon in turnings into 81.5 1 of tetrahydrofuran and then approximately 2.5 g of sublimed iodine. Stirred for 10 minutes between +20 and + 25 ° C and introduced about 5 1 of a solution of 35 kg of 2-bromothiophene in 60 I of tetrahydrofuran. After priming, the temperature is allowed to rise to 35 ° C., when it stabilizes, the rest of the 2-bromothiophene solution prepared above is introduced regularly over 1 hour 30 minutes and while maintaining the temperature. . When the introduction is complete, the mixture is stirred for 2 hours under argon while maintaining the temperature between 30 and "35 ° C.

c) Condensation

The lithium pyruvate suspension obtained in a) above is cooled with stirring to -15 ° C. and introduced regularly over about 5 minutes, transferring it by nitrogen pressure, the magnesium solution prepared in b) above, while cooling the suspension using external circulation of brine to a temperature of - 15 to - 20 ° C. The temperature rises to around 45 ° C. During the introduction, the magnesian solution is dispersed by rapid stirring. Ringed with 35 l of tetrahydrofuran and then regularly lowered, in about 30 minutes, the internal temperature to 20-25 ° C and stirred for about 16 hours under nitrogen at this temperature.

53 The suspension is poured in about 15 minutes into a mixture of 140 kg of crushed ice and 47 l of hydrochloric acid. The interior temperature is maintained at 25 ° C by adding ice if necessary. The apparatus is rinsed with 501 of water and the pH is adjusted to 1 with hydrochloric acid. It is stirred at 20 to 25 ° C until complete dissolution, the organic phase is separated and the aqueous phase is extracted three times with 20 l of toluene each time. The organic phases are joined and 12 l of water are added. Then introduced slowly to pH 4 about 1.5 1 of ammonia. Decanted and t> 5 performs a second wash with 12 l of demineralized water and then adds a little ammonia until pH 4. The organic phase is separated and concentrated under reduced pressure to a volume of 122 1 while maintaining indoor temperature in

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below 40 ° C. About 175 l of toluene are thus collected, containing tetrahydrofuran and water. Three successive entrainments are carried out while distilling under the same conditions, with 70 l of toluene each time. Cool to 0 ° C and stir for 2 hours at this temperature. The product obtained is filtered off and washed twice with 35 l of toluene at 0 ° C, dried in an oven and 27.35 kg of expected product are obtained, F = 115 ° C.

Application: α-methyl 2-thiophene acetic acid.

A mixture of 75 l of 22 ° Be hydrochloric acid and 75 kg of tin protochloride is heated to 40 ° C. under nitrogen, to which 125 l of glacial acetic acid have been added at once. After dissolution, 50 kg of a-methyl a-hydroxy 2-thiophene acetic acid are regularly introduced with stirring and flushing with nitrogen over 30 minutes. The temperature is maintained at 40 ° C while stirring for 1 h 30 with a nitrogen sweep. It is then cooled to between 20 and 25 ° C and poured in 15 minutes into a mixture of 1501 of demineralized water and 100 kg of crushed ice. The mixture is stirred again for 15 minutes after addition and the aqueous phase is extracted 6 times with 501 of dichloroethane at 20 ° C. ± 2 ° C. The dichloroethane extracts are washed 4 times with 8.5 I of 22 'Be hydrochloric acid in 42.5 1 of water and then 3 times with 50 1 of water.

The dichloroethane solution is concentrated under reduced pressure without exceeding 40 "C. About 225 l of dichloroethane are collected and 45.3 kg of expected crude acid are obtained.

This product is distilled under a pressure of 0.7 torr without exceeding 120 ° C. 39.45 kg of expected product are obtained.

Example 2: α-methyl α-hydroxy 2-thiophene acetic acid.

50 cm3 of a solution of 375 g of 2-bromo thiophene in 500 cm3 of tetrahydrofuran are introduced into a mixture of 59.3 g of magnesium in turn in 750 cm3 of 5 tetrahydrofuran. Add an iodine crystal. After initiating the reaction, the sale of the bromothiophene solution is introduced with stirring at 351C in one hour. Stirring is continued two hours after the end of the introduction, allowing the temperature to drop to 25 ° C.

io A solution of 102 g of pyruvic acid in 500 cm3 of tetrahydrofuran is then added at 25 ° C. and over 45 minutes. The mixture is stirred for 18 hours at 25 ° C. and then poured into 2.61 of a water-ice mixture containing 130 cm3 of 66 "Be sulfuric acid. Stirred 10 minutes, decanting the organic phase and reextracting 4 times 260 cm3 d ethyl acetate. The organic phases are washed with twice 260 cm3 of demineralized water and then reextracted with 520 cm3 then 3 times 260 cm3 of 2N ice-cold soda. The soda liquors are washed with 4 times 260 cm3 of acetate d ethyl and acidified to pH 1 by addition, in the presence of ice and with stirring, of 120 cm 3 of 22 "Be hydrochloric acid. Extracted with 520 cm3 and 4 times 260 cm3 of ethyl acetate. The organic phases are washed with twice 260 cm3 of demineralized water, dried over sodium sulphate and added with approximately 10 g of activated carbon. After spinning, the solvents are evaporated to dryness under reduced pressure. 145.5 g of expected product are obtained.

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