JPS59204185A - Novel manufacture of alpha-hydroxy-2-thiophene acetic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Here, R represents an alkyl group having 1 to 4 carbon atoms, each of R1, R2, and R3 may be the same or different, and each of R1, R2, and R3 may be the same or different, and The subject matter is a method for producing an α-hydroxy-2-thio-7-acetic acid salt conductor (representing an alkyl group having a carbon atom).

These compounds are useful intermediate compounds in the production of pharmaceutical compounds, especially anti-inflammatory compounds.

Starting from a compound of formula (I) and F. Clemen
Eur. ce et al. J, Med-Chem,
The compound of the following formula (A) can be prepared by the method described in FR 2,167,354 or in French Patent No. 2,167,354. This method is characterized by the use of a mild residual reducing agent, for example stannous chloride in hydrochloric acid.

These compounds of formula (A) can be modified into target compounds with pharmacological properties. Such a conversion is described, for example, in the already indicated French Patent No. 2, 0 6 8, 4
25 and 2, 167, and 334.

FJur. J, Med, Chem
, 1974(9), T), 390 describes a method for preparing compounds of formula (I). This method is as follows.

A new process for the preparation of derivatives of formula (I) has now been developed starting from 2-halokeophene and an acid of formula (I).

These two compounds are readily available and the reaction can be carried out without isolating the intermediate compound.

This process, which forms the object of the present invention, comprises converting a compound of the following formula (II), in which X represents a halogen atom, into a compound of the following formula (III), in which R has the meaning already indicated and A is hydrogen. (representing an atom, an alkali metal atom, or an equivalent amount of a magnesium or alkaline earth metal atom) to hydrolyze the magnesium group, thereby obtaining the desired compound of formula (I).

Substituent 1' (, R4, R2 and R3 may have lower alkyl groups, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5e
Examples include c-butyl and t-butyl. X can represent a chlorine, iodine or bromine atom. A bromine atom is preferred.

In addition to hydrogen, A can represent a sodium, potassium or lithium atom. Hydrogen or lithium is preferred, particularly lithium. A can also represent an equivalent amount of an alkaline earth metal atom such as magnesium or calcium or thurium.

The magnesium compound of formula (II) acting on the compound of formula (m) is preferably prepared extemporaneously on demand in an organic solvent such as tetrahydrofuran or ethyl ether.

An alkali metal salt, preferably a lithium salt, of formula (III)
When used as a compound, the salt can also be prepared extemporaneously in an organic solvent such as toluene or tetrahydrofuran. Ethers such as benzene or ethyl ether can also be used.

The reaction is carried out in a solvent or solvent mixture such as those mentioned above in which the magnesium preparation was carried out.

Hydrolysis of the magnesium compound is carried out in an aqueous acid medium and the acids used are hydrochloric acid, sulfuric acid or acetic acid.

The operation can also be carried out in the presence of ammonium chloride.

In particular, the invention is characterized in that the process is carried out as described above starting from halogenated 2-chenylmagnesium of the following formula (T'), where R has the meaning given above: The subject is methods for producing compounds.

More specifically, the present invention is characterized in that a compound of formula (1) in which R represents a methyl or ethyl group is used in the above method.
The subject matter is a method for producing compounds of

Furthermore, the method that is the subject of the invention further comprises the addition of R to the aforementioned method.
1. Compounds of formula (JT) in which each of R2 and R3 is a hydrogen atom and formula (liI) in which R represents a methyl group
The present invention relates to the production of α-methyl-α-hydroxy-2-thiophene acetic acid characterized by using the compound of

Preferably, compounds of the formula (H) in which X represents a bromine atom and compounds of the formula (III,) in which A represents a hydrogen or lithium atom are used as starting materials for the process that is the subject of the invention.

Hydrolysis of the obtained magnesium compound is carried out in an aqueous acid medium.

Finally, the subject of the invention provides, in particular, for the treatment of alpha-methyl-alpha-hydroxy -Relates to a method for producing 2-thiophene acetic acid.

The examples below are illustrative of the invention and do not limit it in any way.

Example 1: α-Methyl-α-hydroxy-2-thiophene acetic acid 7. A 1'1'δ suspension obtained by adding 96 kg of rehydrated lithium to 2101 parts of toluene was heated to boiling, and the internal temperature was reduced to 1.
24.6 kg in 2 hours under stirring while maintaining the temperature between 05 and 108°C and decanting the water produced.
of pyruvate is introduced. The mixture was refluxed for 1.5 hours and the mixture of 4 volumes of produced water and pyruvic acid was decanted.

This mixture is then distilled at normal pressure for about 30 minutes to remove trace amounts of water and acid. This collected 351 toluene-acid-water mixtures.

1)) Preparation of Chenyl Magnesium Bromide 5.74 kg of magnesium pieces are introduced into 815 kg of tetrahydrofuran under an argon atmosphere, followed by about 25 g of sublimed iodine. This was stirred for 10 minutes between 2D and 25°C, then 55 kp of 2-bromothiophene was added to 6
About 51% of a solution dissolved in 0% tetrahydrofuran
will be introduced. After starting, the temperature rises to 65°C. Once stabilized, the remainder of the 2-bromothiophene solution prepared above in 14 is gradually introduced over 1 hour and 30 minutes while maintaining the same temperature. Once the introduction is complete, reduce the temperature to 60~5°.
The mixture is stirred under an argon atmosphere for 2 hours while maintaining the temperature at 100°C.

C) Condensation 4e + 7) The suspension of lithium pyruvate obtained in a) was cooled to -15°C while stirring, and the magnesium solution prepared in i)) was transferred in about 5 minutes by nitrogen pressure. Gradually introduce the suspension at the same time as −1
Cooling is achieved by external circulation of brine at a temperature of 5 to -20°C.

The temperature rises to about 45°C. During introduction, the magnesium solution is dispersed by vigorous stirring. The suspension is washed with 35° C. of tetrahydrofuran, the internal temperature is then gradually lowered to 20-25° C. over about 30 minutes, and the mixture is stirred at this temperature under nitrogen for about 16 hours.

This suspension is poured over a period of about 15 minutes onto a mixture of 140 kg of crushed ice and 47 g of hydrochloric acid. Keep the internal temperature at 25°C by adding ice if necessary. 50I equipment! of water and adjust the pH to 1 with hydrochloric acid. After stirring at 20-25 °C until complete dissolution, the organic phase is separated and the aqueous phase is extracted 6 times (
200 toluene each). Combine the organic phases and then 121! of water and slowly add ammonia of about 1.51 to pH 4. Decant and again
Wash with distilled water at pH 21, then add a small amount of ammonia to pH 4.
The organic phase is separated and concentrated under reduced pressure to a volume of 122° C., keeping the internal temperature below 40° C., to collect about 1751° C. of toluene containing tetrahydrochloride and water. Three consecutive distillations are carried out under the same conditions, each using 701 g of toluene. After cooling to 0°C and stirring at this temperature for 2 hours, the product obtained was separated and heated to 55100°C.
Wash twice with toluene and dry in the open. 2765
kg of expected product was obtained. M P = 115°C.

A mixture of 751 of 220 hydrochloric acid and 751 (g of stannous chloride) is heated to 40°C under chlorine and 1251 of glacial acetic acid is added all at once. Once dissolved, 501 (g of
of .alpha.-methyl-.alpha.-hydroxy-2-thiopheneacetic acid is gradually introduced while purging with nitrogen and stirring. Maintain temperature at 40° C. with nitrogen purge and stirring. Then, cool to 20-25°C and add 150% demineralized water and 100%
After pouring into the mixture with crushed ice for 15 minutes and stirring again for 15 minutes, the aqueous phase is extracted 6 times with dichloroethane at 20° C. ± 2° C. in SOZ. Wash the dichloroethane extract four times with 8.51 parts of 22013e hydrochloric acid in 42.57 parts of water, then three times with 50A of water.

The dichloroethane solution is concentrated under reduced pressure without exceeding 4D°C. Approximately 2251 of dichloroethane was collected and 45.3 kg of the desired crude acid was obtained.

This product is distilled under a pressure of 0.7 torr and not above 120°C. 39.45 kg of expected product was obtained.

593 g of 50 cc of a solution prepared by dissolving 675 g of 2-bromothiophene in 500 g of tetrahydrofuran
of magnesium pieces and 750 ee of tetrahydrofuran. Add iodine crystals. After the reaction has started, the remainder of the bromothiophene solution is introduced at 65° C. with stirring for 1 hour. Stirring is continued for 2 hours after introduction and the temperature is lowered to 25°C.

A solution of 102,9 pyruvic acid dissolved in 500 cc of tetrahydrone is then added at 25° C. for 45 minutes. The mixture was stirred for 18 hours at 251°C, then 2 containing 66°Ba hydrochloric acid at 130eC.
61 into the ice-water mixture and stir for 10 minutes. The organic phase was decanted and diluted with 260 cc of ethyl acetate.
Re-extract twice. The organic phase was washed twice with 260 CQ of demineralized water, then first with 520 ω and then with 260 cc (3 times) of 2
Re-extract with N cold sodium hydroxide. 2 drops of sodium solution
Wash 4 times with 60cc of vinegar (2) ethyl and add 120cc of 22°Be hydrochloric acid with stirring in the presence of ice to p.
Acidify to H1. First 520eC, then 260C
By extracting with C (3 times) of ethyl acetate, the resulting organic phase is washed twice with 26 DCC of demineralized water, dried over sodium sulphate and about ioy of activated carbon is added. After separation, the solvent is evaporated under wave pressure and 145.5. The expected product of F was obtained.

Agent's name: Motohiro Kurauchi Same storehouse bridge

Claims (7)

[Claims] (1) The following formula (I) (Here, R represents an alkyl group having 1 to 4 carbon atoms, each of R1, R2 and R3 may be the same or different, and a hydrogen atom or 1 to 4 carbon atoms may be used. In producing an α-hydroxy-2-thiophene acetic acid derivative (representing an alkyl group having 4 carbon atoms), the following formula <m> is added to a compound of the following formula (n) (where X represents a halogen atom). A compound of R-C-CO2A (UI) (where R has the meaning already indicated and A represents a hydrogen atom, an alkali metal atom, or an equivalent magnesium or alkaline earth metal atom) is reacted to form a magnesium group. α- characterized in that after hydrolysis, the desired compound of formula (I) is obtained.
A method for producing a hydroxy-2-thiophene acetic acid derivative. (2) Starting from halogenated 2-chenylmagnesium and carrying out the method described in claim 1, the following formula ((I) (where R is the same as already shown in claim 1) 2. A method according to claim 1, characterized in that a compound having the meaning ) is obtained. (3) A compound of formula (m) in which R represents a methyl or ethyl group is used in the method described in claim 1, and the compound of the formula (m) in which R represents a methyl or ethyl group is 3. A method according to claim 1 or 2, characterized in that the compound of I') is obtained. (4) A compound of formula (IF) in which R1, R2 and R3 each represent a hydrogen atom, and a compound of formula (II) in which R represents a methyl group.
According to any one of claims 1 to 3, wherein the compound I) is used in the method described in claim 1 to obtain α-methyl-α-hydroxy-2-thiophene acetic acid. Method described. (5) The method according to claim 1 is carried out starting from a compound of formula (II) in which X represents a bromine atom and a compound of formula (III) in which A represents a hydrogen or lithium atom. A method according to any one of claims 1 to 4. (6) The method according to any one of claims 1 to 5, characterized in that the hydrolysis of the magnesium group is carried out in an aqueous acid medium. (7) A method characterized by reacting lithium pyruvate with 2-chenylmagnesium bromide and hydrolyzing the resulting product with an aqueous hydrochloric acid solution to obtain α-methyl-α-hydroxy-2-thiopheneacetic acid. Claim 1
6. The method according to any one of items 6 to 6.