NZ205514A

NZ205514A - Preparation of alpha-hydroxy-2-thiophene acetic acid derivatives

Info

Publication number: NZ205514A
Application number: NZ205514A
Authority: NZ
Inventors: J Prost-Marechal; G Tomasik
Original assignee: Roussel Uclaf
Priority date: 1983-04-28
Filing date: 1983-09-07
Publication date: 1987-03-31
Also published as: DE3325456A1; SE8303887L; PT77010A; JPS59204185A; LU84931A1; JPH0439469B2; GB8323492D0; IT8348823A0; HU194206B; IE55905B1; DK307583D0; CH655316A5; SE451018B; SE8303887D0; AU559749B2; DE3325456C2; KR900006558B1; DK307583A; DK157493C; AU1730983A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £05514 205514 Priority D8te(s): 3. Complete Specification Filed: ;.*?A Class: .£r'P.l.lX Publication Date: . !W. !??7. P.O. Journal, No: f."?. ..... ho drawings Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "PRODUCTION OF THIOPHENE ACETIC ACID COMPOUNDS" -I-WE ROUSSEL-UCLAF, a French Body Corporate of 35 Boulevard des Invalides, Paris 7 erne, France, hereby declare the invention, for which -P/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement 1 (followed by page FA.) 2055 14 This invention relates to the production of thiophene compounds of formula (I): in which R represents an alkyl radical of 1 - 4 carbon atoms and R^, Rg and R^ are the same or different and each represents a hydrogen atom or an alkyl radical of 1- 4 carbon atoms. These compounds are intermediates useful for the preparation of pharmaceuticals, in particular anti-inflammatory products. Starting with the compounds of formula (I), acids of formula (A): 2 may be prepared according to the process described in the publication by F. Clemence et al, Eur. J. Med. Chem. 1974 (9) 390, or French Patent 2167334 (available on request). This process is characterised by using a mild metallic reducing agent such as stannous chloride in a hydrochloric medium. The acids of formula (A) can then be converted into end compounds possessing pharmacological properties. Such a conversion is described, for example, in United Kingdom Patent 1331505 and in French Patent 2167334 mentioned above. In the Eur. J. Med. Chem. 1974 (9) 39 0 article mentioned above, a process for the preparation of a compound of formula (I) is described. This process is as follows: A new process for the preparation of the compounds of formula (I) has now been discovered. Accordingly, the invention provides a process for c-co2h OH NEW ZEALAND 12FEB1987 patepjt office. 205514 the preparation of an G6-hydroxy-2-thiophene acetic acid of formula (I): R in which R represents an alkyl radical of 1 - 4 carbon atoms and R^, Rg and R3 are the same or different and each represents a hydrogen atom or an alkyl radical of 1 - 4 carbon atoms, which process comprises reacting a magnesium halide of formula (II): in which X represents a halogen atom, with a ketone of formula (III): 205514 R-C-CO2A (III) in which R is as defined above and A represents a hydrogen atom, an alkali metal atom or an equivalent of magnesium or of an alkaline earth metal, to produce a product which is then reacted to hydrolyse its magnesium 5 group and produce the desired 06-hydroxy-2-thiophene acetic acid of formula (I). The starting material of formula (II) can readily be prepared from the corresponding 2-halothiophene. The starting material of formula (III) either is or can 10 readily be prepared from an acid of formula: R-C-C02H The 2-halothiophene and the acid are both readily accesssible. In addition, the present process can be carried out without isolation of the intermediate magnesium compound. Thus, the present process is 15 extremely simple. R represents, and R^, Rg and R^ may represent, a lower alkyl radical, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl♦ X may represent a chlorine, iodine or bromine atom; 2055 14 bromine is preferred. A may represent a hydrogen, sodium, potassium or lithium atom. The hydrogen or lithium values are preferred, especially lithium. A may also represent an equivalent of magnesium or of an alkaline earth metal such as calcium or barium. The magnesium halide of formula (II) which reacts with the ketone of formula (III) is preferably prepared immediately when required in an organic solvent such as tetrahydrofuran or ethyl ether. When an alkali metal salt, preferably a lithium salt, is used as the ketone of formula (III), this salt can also be prepared immediately when required in an organic solvent such as toluene or tetrahydrofuran. Benzene or an ether such as ethyl ether can also be used. The reaction of the magnesium halide of formula (II) with the ketone of formula (III) is advantageously carried out in the solvent in which the magnesium halide has been prepared (for example a solvent specified above for this purpose) or in a mixture of this solvent with the solvent in which the ketone has been prepared (for example a solvent specified above for this purpose) where these solvents are different. The hydrolysis of the magnesium intermediate is generally carried out in an aqueous acid medium, the acid utilized preferably being hydrochloric acid, sulphuric acid or acetic acid. The operation can also \ - 6 - 2055 1 4 be carried out in the presence of ammonium chloride. Preferably, R^, Rg and each represent a hydrogen atom; hence an oC-hydroxy-2-thiophene acetic acid of formula (11): 5 in which R is as defined above, is prepared from 2-thienylmagnesium halide. Preferably R in formula (I') represents a methyl or ethyl radical; hence a ketone of formula (III) in which R represents a methyl or ethyl radical is employed. 10 Most preferred is the production of (X-methyl-#- -hydroxy-2-thiophene acetic acid; hence a magnesium halide of formula (II) in which R^, R^ and R3 each represent a hydrogen atom is reacted with a ketone of formula (III) in which R represents a methyl radical. 15 The preferred starting material of formula (II) is one in which X represents a bromine atom. The preferred starting material of formula (III) is one in which A represents a hydrogen or lithium atom. 20 present process is conveniently carried out in an aqueous acid medium. Preferably, the magnesium halide of formula (II) is reacted with the ketone of formula (III) and the obtained product is then reacted with an aqueous acid medium to R Hydrolysis of the magnesium group obtained in the 205514 - 7 - hydrolyse the magnesium group and produce thecC-hydroxy--2-thiophene acetic acid of formula (I). Especially preferred is the production of c£-methyl-o£-hydroxy-2--thiophene acetic acid by a process comprising reacting 5 2-thienylmagnesium bromide with lithium pyruvate and reacting the obtained product with an aqueous solution of hydrochloric acid. The a-hydroxy-2- thiophene acetic acid of formula (I) prepared in the present way can be employed as an intermediate in the preparation of a pharmaceutical. The invention is illustrated by the following Examples. Examples. 15 EXAMPLE 1 : 0i-methyl-0C-hydroxy-2-thiophene acetic acid a) Preparation_of lithium_pyruvate A suspension of 7.96 kg of lithium carbonate in 210 1. of toluene is heated to boiling and over a period of 2 - 3 hours under agitation, while maintaining the 20 interior temperature at between 105 and 108°C and condensing off the water formed, 24.6 kg of pyruvic acid .is introduced. The mixture formed is kept at reflux for « one and a half hours while 1 1. of a mixture of water formed and pyruvic acid is condensed off. 25 The mixture is then distilled at normal pressure over about 30 minutes so as to eliminate the last traces of water and acid. 35 1. of a toluene-acid-water mixture is thus collected. 205514 - 8 - b) P£eparatlon_of_thien^lmagnesium_bromide Under argon, 5.74 kg of magnesium turnings is introduced into 81.5 1. of tetrahydrofuran, followed by about 2.5 g of sublimed iodine. This is agitated for 10 minutes at between +20 and +25°C, and then about 5 1. of a solution of 35 kg of 2-bromothiophene in 60 1. of tetrahydrofuran is introduced. After starting, the temperature is allowed to rise to 35°C; when it stabilizes, the remainder of the solution of 2-bromothiophene solution prepared above is introduced gradually over 1 hour 30 minutes while maintaining the same temperature. When the introduction is complete, the mixture is agitated for 2 hours under argon, keeping the temperature at between 30 and 35°C. c) Condensation The suspension of lithium pyruvate obtained in a) above is cooled with agitation to -15°C and the magnesium solution prepared in b) above is introduced gradually over about 5 minutes by transferring it by nitrogen pressure, at the same time cooling the suspension by means of an external circulation of brine at a temperature of -15 to -20°C. The temperature rises to about 45°C. In the course of introduction, the magnesium solution is dispersed by rapid agitation. The suspension is rinsed with 35 1. of tetrahydrofuran, then over about 30 minutes the interior temperature is gradually lowered to 20 - 25°C and the mixture is agitated for about 16 hours under 2055 14 - 9 - nitrogen at this temperature. Over a period of about 15 minutes the suspension is poured into a mixture of 140 kg of crushed ice and 47 1. of hydrochloric acid. The interior temperature 5 is kept at 25°C by addiiton of ice as necessary. The equipment is rinsed with 50 1. of water, and the pH is adjusted to 1 by hydrochloric acid. After agitating at between 20 and 25°C until solution is complete, the organic phase is separated, the aqueous 10 phase being extracted three times, each time with 20 1. of toluene; the organic phases are put together, then 12 1 of water is added and about 1.5 1. of ammonia is introduced slowly up to pH 4; by decanting, washing again with 12 1. of demineralized water then adding a little 15 ammonia up to pH 4, separating the organic phase and concentrating it under reduced pressure to a volume of 122 1., while maintaining the interior temperature below 40°C, about 175 1. of toluene containing tetrahydrofuran and water is collected. Three successive distillations 20 are carried out under the same conditions, each time with 70 1. of toluene. After cooling to 0°C and agitating for two hours at this temperature, the product obtained is separated, washed twice with 35 1. of toluene at 0°C and dried in an oven; 27.35 kg of the 25 product sought is obtained. MP = 115°C. Use to Prepare fl6-methyl-2-thlophene acetic acid A mixture of 75 1. of 22°Be hydrochloric acid and 75 kg of tin protochloride is heated to 40°C under v.. 205514 - 10 - nitrogen, and then, in one lot, 125 1. of glacial acetic acid is added. When solution is complete, 50 kg of oc— -methyl-0d-hydroxy-2-thiophene acetic acid is gradually introduced with agitation and with sweeping by nitrogen. 5 The temperature is kept at 40°C for 1 hour 30 minutes while agitating and with sweeping by nitrogen. After cooling to between 20 and 25°C, pouring over 15 minutes into a mixture of 150 1. of demineralized water and 100 kg of crushed ice, and agitating again for 15 minutes, the 10 aqueous phase is extracted 6 times with 50 1. of dichloroethane at 20°C + 2°C. The dichloroethane extracts are washed 4 times with 8.5 1. of 22°Be hydrochloric acid in 42.5 1. of water and then 3 times with 50 1. of water. 15 The dichloroethane solution is concentrated under reduced pressure without exceeding 40°C. About 225 1. of dichloroethane is collected and 45.3 kg of the expected crude acid is obtained. This product is distilled under a pressure of 0.7 20 torr without exceeding 120°C. 39.45 kg of the expected product is obtained. EXAMPLE 2 : oc-methyl-QC-- hydroxy-2-thiophene acetic acid 50 cm3 of a solution of 375 g of 2-bromothiophene in 500 cm3 of tetrahydrofuran is introduced into a mixture 25 of 59.3 g of magnesium turnings in 750 cm3 of tetrahydrofuran. An iodine crystal is added. After commencement of the reaction, the remainder of the </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 11 - 205514 bromothiophene solution is introduced under agitation at 35°C over one hour. Agitation is continued for two hours after the end of the introduction while allowing the temperature to fall to 25°C. A solution of 102 g of pyruvic acid in 500 cm3 of tetrahydrofuran is then added at 25aC over 45 minutes. The mixture is agitated for 18 hours at 25°C, and then poured into 2.6 1. of a water-ice mixture containing 130 cm3 of 66°Be sulphuric acid, and agitated for 10 minutes. The organic phase is decanted and re-extracted 4 times with 260 cm3 of ethyl acetate. The organic phases are washed twice with 260 cm3 of demineralized water and then re-extracted first with 520 cm3 and then 3 times with 260 cm3 of 2N aqueous, iced, sodium hydroxide. The sodium liquors are washed 4 times with 260 cm3 of ethyl acetate and acidified to pH 1 by the addition, in the presence of ice and with agitation, of 120 cm3 of 22°Be hydrochloric acid. Extraction is carried out first with 520 cm3 and then 4 times with 260 cm3 of ethyl acetate, and the resulting organic phases are washed twice with 260 cm3 of demineralized water, dried on sodium sulphate and about 10 g of active carbon is added to them; after separating, the solvents are evaporated to dryness under reduced pressure and 145.5 g of the expected product is obtained. 12 - 205514 WHAT WE CLAIM IS

1. Process for the preparation of an Qi-hydroxy-2--thiophene acetic acid of formula (I): R 1 CD R in which R represents an alkyl radical of 1 - 4 carbon atoms and R^, Rg and R^ are the same or different and each represents a hydrogen atom or an alkyl radical of 1-4 carbon atoms, which process comprises reacting a magnesium halide of formula (II): in which X represents a halogen atom, with a ketone of formula (III): R^ R-C-CO-A r 2 (in) o 205514 in which P is as defined above and A represents a hydrogen atom, an alkali metal atom or an equivalent of magnesium or of an alkaline earth metal, to produce a product which is then reacted to hydrolyse its 5 magnesium group and produce the desired oC-hydroxy-2--thiophene acetic acid of formula (I).

2. Process according to claim 1 wherein R^, R2 and R3 each represent a hydrogen atom.

3. Process according to claim 2 wherein R represents 10 a methyl or ethyl radical.

4. Process according to claim 3 wherein R represents a methyl radical.

5. Process according to any one of the preceding claims wherein X represents a bromine atom and A 15 represents a hydrogen or lithium atom.

6. Process according to any one of the preceding claims wherein the magnesium halide of formula (II) is reacted with the ketone of formula (III) and the obtained product is then reacted with an aqueous acid medium to 20 hydrolyse the magnesium group and produce the od-hydroxy--2-thiophene acetic acid of formula (I).

7. Process for preparing o6-methyl-d£-hydroxy-2-thiophene acetic acid, which process comprises reacting 2-thienylmagnesium bromide with lithium pyruvate and 25 reacting the obtained product with an aqueous solution of hydrochloric acid.

8. Process according to claim 1 performed substantially as described herein.

9. Process for the preparation of an o£-hydroxy-2- - 14 - -thiophene acetic acid of formula (I) as defined in claim 1, which process is performed substantially as described herein in Example 1 or Example 2.

10. An ^-hydroxy-2-thiophene acetic acid of formula (I) as defined in claim 1, prepared by a process claimed in any one of the preceding claims. </div>