IE832074L - Production of thiophene acetic acid compounds - Google Patents
Production of thiophene acetic acid compoundsInfo
- Publication number
- IE832074L IE832074L IE832074A IE207483A IE832074L IE 832074 L IE832074 L IE 832074L IE 832074 A IE832074 A IE 832074A IE 207483 A IE207483 A IE 207483A IE 832074 L IE832074 L IE 832074L
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- acetic acid
- hydroxy
- thiophene acetic
- magnesium
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The alpha -hydroxy-2-thiophene acetic acid of formula (I): <IMAGE> in which R represents an alkyl radical of 1-4 carbon atoms and R1, R2 and R3 are the same or different and each represents a hydrogen atom or an alkyl radical of 1-4 carbon atoms, is prepared by reacting a magnesium halide of formula (II): <IMAGE> in which X represents a halogen atom, with a ketone of formula (III): <IMAGE> 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 group and produce the desired alpha -hydroxy-2-thiophene acetic acid. The alpha - hydroxy-2-thiophene acetic acid is useful as an intermediate for producing pharmaceuticals, such as anti-inflammatory products.
[GB2139215A]
Description
- J0 - This invention relates to the production of thiophene compound:--, ol" formula (I): ft2 F.
KJH ^>S-^C-COnH (I) l 2 R in which R represents an alkyl radical of 1-4 carbon atom.:, and Hj, R0 and R are the same or different arid each -i represents a hydrogen atom or an alkyl radical of 1- a carbon atom;;.
Ther.e compounds arc' Lntenne '.ir.cl'ul for the preparation of pharmaceutical!;, in particular anti-inflammatory products. 10 Starting with the compounds of formula (I), acids of formula (A): R? R3 R 'Xk^v I 2 R M - 2 - may be prepared according to the process described in the publication by F. Clemerice et al, Eur. J. Med. Chem. 1974 (9) 390, or French patent 2167334. This process is characterized by using a mild metallic reducing 5 agent such as stannous chloride in a hydrochloric medium.
The acids of formula (A) can then be converted into end compoundspossessing pharmacological properties. Such a conversion Is described, lor example, in French patent 10 206842b and in French patent. 2167334 mentioned above. in the Fur. J. Med. Chem. 1974 (9) 3'.to article mentioned above, a process for the preparation of a compound of formuLa (1) is described. This process is as follows: Q CICCCO^ I CK-Mgl , CH, OH ]5 A new process for the preparation of the compounds of formula (I) has now been discovered.
Accordingly, the invention provides a process for 3 I.Ik? proparaf. i un nl" an G£.-hydroxy-2-th i opheno acetic ,'njici o!" !"■ ■ r-nii i l.i ( I ) : in which H represents an alkyl radical ol" I - 4 carbon atoir.K and , R,, and R,( arc the same or different and each 5 represents a hydrogen atom or an alkyl radical ol" l - 4 carbon atoms, which process comprise:? reacting a in,■.))',ra.'s ium halide of formula (II): (I) R (ID in which X represents a halogen atom, with a ketone of formula (III): - It - 0 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 0L-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-CO-H II 2 0 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^, and R^ may represent, an alkyl radical of 1-4 carbon atoms, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-buty1.
X may represent a chlorine, iodine or bromine atom; - 5 - br-omi rit- is pre('• ■ rred .
A may represent, a hydrogen, sodium, potassium or lithium atom. The hydrogen or lithium values are preferred, osper.ially lithium. A may also represent 5 an equivalent of magnesium or of an alkaline earth metal such as calcium or barium.
The magnesium halide of formula (IL) which reacts with the ketone of formula (III)^ is preferably prepared immediately when required Ln an organic solvent 1() such as tetrahydrofuran or ethyl ether.
When an alkali metal salt, preferably a lithium salt, in used as the ketone of formula (III), this salt can also be prepared immediately when required in an organic solvent such as toluene or tetrahydrofurnn. 15 Benzene or an ether such as ethyl ether can also be used.
The reaction of the magnesium halide of formula (11) with the ketone of formula (111) is advantageously carried out in the solvent in which the magnesium halide has been prepared (for example a solvent specified above 20 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 2b generally carried out in an aqueous acid medium, the acid utilized preferably being hydrochloric acid, sulphuric acid or acetic acid. The operation can also be carried out in the presence of ammonium chloride.
Preferably, R^, Rg and R^ each represent a hydrogen atom; hence an e£-hydroxy-2-thiophene acetic acid of formula (11): in which R is as defined above, is prepared from 2-thieriy Imagnesium 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.
Most preferred is the production of cx-methy 1- 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.
Hydrolysis of the magnesium group obtained in the 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 hydrolyse the magnesium group and produce the cC-hydroxy--2-thiophene acetic acid of formula (I). Especially preferred is the production of fl6-methyl- The invention also provides a process for preparing a pharmaceutical using as an intermediate anc£rhydroxy-2-10 -thiophene acetic acid of formula (I) as defined above, in which process the acid of formula (I) is prepared in the present way.
The invention is illustrated by the following Examples. 15 EXAMPLE 1 : QL-methy l-Oi.-hydroxy-2-thi ophene acetic acid a) Preparation of lithium pyruvate A suspension of 7.96 leg 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 4 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. - 8 - b) Pregaration_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 5 between +20 and +25°C, and then about b 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 10 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. lb c) Condensation The suspension of lithium pyruvate obtained in a) above is cooled with agitation to -lb°C and the magnesium solution prepared in b) above is introduced gradually over about 5 minutes by transferring it by nitrogen 20 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 oy rapid agitation. The suspension is rinsed 25 with 35 I. 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 nitrogen ac this temperature;.
Over a period of about; IS minutes the suspension is poured into a mixture of 140 kg of crushed ice and 47 1. of hydrochloric acid. The interior temperature is kept at 2b"C by addiitjon of ice as necessary. The equipment is rinsed with 50 1. of water, and the pll 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 phase b^inu extracted three times, each time with 20 I. of toluene; the organic phases are put together, then 12 1. of water is added and about 1.5 I. of ammonia is introduced slowly up to pH 4; by decanting, washing again with 12 1. of demineraiized water then adding a little ammonia up to pH 4, separating the organic phase and concentrating i !: under reduced pressure to a volume of 122 I., while maintaining the interior- temperature below 40°C , about 175 i. of toluene containing tetrahydrofuran and water is collected. Three successive distillations are carried out under the same conditions, each time with 70 I. of toluene. After cooling to 0°0 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 product sought is obtained. MP = 115°C.
Use to Prepare 56-methy"1 -2-thiophene acetic acid A mixture of 7b 1. of 22°Be hydrochloric acid and 75 kg of tin protochioride is heated to 40°C under - .10 - [] i trogon, and then, in one lot;, 12b t. of glacial acetic acid la added. When so Lut ion is complete, 50 kg of oc — -iii<:! thy l-iX-hydroxy-2-th i ophene acetic acid is gradually 1 introduced with agitation and with sweeping by nitrogen. 5 The temperature is kept at 40°C for 1 hour 30 minutes n 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 demineraiized water and 100 kg of crushed ice, and agitating again for lb minutes, the 10 aqueous phase is extracted 6 time.-; wll.li 50 1. uf dichloroethane at 20°C + 2°C. The dichloroethane extracts are washed 4 times with 8.5 1. of 22°Be hydrochloric acid in 42.b I. of water and then 3 times with 50 1. of wa te r. 15 The dichloroethane solution is concentrated under reduced pressure without exceeding 40°C. About. 22b 1. of dichloroethane is collected and 4b.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 : QC-methyl-iL—hydroxy-2-thLophene acetic acid 50 cmJ of a solution of 375 g of --Jromothiophene in 500 cm3 of tetrahydrofuran is introduced into a mixture 2b of 59.3 g of magnesium turnings in 750 cmJ of tetrahydrofuran. An iodine crystal is added. After commencement of the reaction, the remainder of the -II- lic inn i l.h i o | il m mi ' solution iL ti I rodi n'"i I under agitation at 3'o"C over one hour. Agitation is continued for two hour:-; after the end of the introduction whilo allowing the temperature to fail to 2S°C. 6 A solution of 102 g of pyruvic acid in 500 cm'1 of tet rahydrof'urari ithen added at 25°C over- 45 minutes. The mixture is agitated for L8 hours at 2'j"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 10 organic phase is decanted and re-extracted 4 times with 260 cm' of ethyl acetate. The organic phases are washed twice with 260 em' of demineraiized water and then re-ex t. r-ae ted first, with L)20 cm' and then 3 times wlt.h 260 cm' of ;.'N aqueous, iced, sodium hydroxide. The 15 sod i tun 1 Lquor-s are washed 4 times with 260 cm' of ethyl acetate and acidified to pH J by the addition, in the presence of ice and with agitation, of 120 cm'1 of 22°Be hydrochloric acid. Extraction is carried out first with 520 cm3 and then 4 times with 260 cm1 of ethyl acetate, 20 and the resulting organic phases are washed twice with 260 cm' of ditnineralized 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 25 obtained.
Claims (3)
1. WHAT HE CLAIM Hi 1. Process for the preparation of an 04-hydroxy-2-- thiopherie acetic acid of formula (I): in which K represents an alkyl radical of 1-4 carbon atonic and H^, R0 and 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-S-CO A (m) 0 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 n product which is then reacted to hydrolyse its 5 magnesium group and produce the desiredcC-hydroxy-2--thiophene acetic acid of formula (I).
2. Process according to claim 1 wherein , R^ and R^ each represent a hydrogen atom. 3. Process according to claim 2 wherein R represents 10 a methyl or ethyl radical. A. Process according to claim 3 wherein R represents ;i methyl radical. '.
3. Process according to any one of the preceding claims wherein X represents a bromine atom anc! A IS 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 ot-hydroxy--2-thiophene acetic acid of formula (I). 7. Process for preparing Ot-rnethyl-Al-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 0(.-hydrox>-2- L 4 - - t.hioptuiiie acr I. i <: ue Id of formula (I) as defined in claim I, which proces:-; is performed substantially as described herein in Example 1 or Example 2. 10. An cji-hydroxy-2-thiophene acetic acid of formula (I) b as defined in claim 1, prepared by a process claimed in any one of the preceding claims. 11. Process for preparing a pharmaceutical using as an intermediate an <*--hydroxy-2-thiophene acetic acid of formula (I) as defined in claim 1, in which process the 10 oC-hydroxy-2-thiophene acetic acid is as claimed in claim 10. Dated this 2nd day of September 1983 5, Dartmouth Road Dublin 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8307021A FR2545085B1 (en) | 1983-04-28 | 1983-04-28 | NOVEL PROCESS FOR THE PREPARATION OF A-HYDROXY 2-THIOPHENE ACETIC ACID DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE832074L true IE832074L (en) | 1984-10-28 |
| IE55905B1 IE55905B1 (en) | 1991-02-14 |
Family
ID=9288331
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2074/83A IE55905B1 (en) | 1983-04-28 | 1983-09-02 | Production of thiophene acetic acid compounds |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59204185A (en) |
| KR (1) | KR900006558B1 (en) |
| AT (1) | AT392786B (en) |
| AU (1) | AU559749B2 (en) |
| BE (1) | BE897362A (en) |
| CA (1) | CA1201443A (en) |
| CH (1) | CH655316A5 (en) |
| DE (1) | DE3325456A1 (en) |
| DK (1) | DK157493C (en) |
| ES (1) | ES524648A0 (en) |
| FI (1) | FI832473L (en) |
| FR (1) | FR2545085B1 (en) |
| GB (1) | GB2139215B (en) |
| HU (1) | HU194206B (en) |
| IE (1) | IE55905B1 (en) |
| IT (1) | IT1171855B (en) |
| LU (1) | LU84931A1 (en) |
| NL (1) | NL8302564A (en) |
| NZ (1) | NZ205514A (en) |
| PT (1) | PT77010B (en) |
| SE (1) | SE451018B (en) |
| ZA (1) | ZA835613B (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1067828A (en) * | 1951-01-19 | 1954-06-18 | Sterling Drug Inc | Improvements relating to a process for preparing organic chemicals |
| GB806710A (en) * | 1955-07-05 | 1958-12-31 | Metal & Thermit Corp | Reactions of organomagnesium chloride complexes |
| GB820083A (en) * | 1955-07-05 | 1959-09-16 | Metal & Thermit Corp | Reactions of organomagnesium chloride reagents |
| FR2068425B1 (en) * | 1969-11-12 | 1973-01-12 | Roussel Uclaf | |
| FR2167334A1 (en) * | 1972-01-13 | 1973-08-24 | Roussel Uclaf | 4-aroyl-5-alkylthiophene-2-acetic acids - with analgesic and antiinflammatory activity |
| GB1584120A (en) * | 1977-07-21 | 1981-02-04 | Sagami Chem Res | Process for the preparation of thiophene derivatives and thiophene derivatives obtained therethrough |
| GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
| JPS5835145A (en) * | 1981-08-26 | 1983-03-01 | Taisho Pharmaceut Co Ltd | Preparation of alpha-arylalkanoic acid ester |
-
1983
- 1983-04-28 FR FR8307021A patent/FR2545085B1/en not_active Expired
- 1983-07-04 DK DK307583A patent/DK157493C/en not_active IP Right Cessation
- 1983-07-05 FI FI832473A patent/FI832473L/en not_active Application Discontinuation
- 1983-07-06 HU HU832431A patent/HU194206B/en unknown
- 1983-07-07 SE SE8303887A patent/SE451018B/en not_active IP Right Cessation
- 1983-07-11 PT PT77010A patent/PT77010B/en not_active IP Right Cessation
- 1983-07-14 DE DE19833325456 patent/DE3325456A1/en active Granted
- 1983-07-18 NL NL8302564A patent/NL8302564A/en active Search and Examination
- 1983-07-22 CH CH4036/83A patent/CH655316A5/en not_active IP Right Cessation
- 1983-07-25 BE BE0/211226A patent/BE897362A/en unknown
- 1983-07-26 AU AU17309/83A patent/AU559749B2/en not_active Ceased
- 1983-07-27 LU LU84931A patent/LU84931A1/en unknown
- 1983-07-27 KR KR1019830003476A patent/KR900006558B1/en not_active IP Right Cessation
- 1983-07-28 JP JP58136930A patent/JPS59204185A/en active Granted
- 1983-08-01 ES ES524648A patent/ES524648A0/en active Granted
- 1983-08-01 ZA ZA835613A patent/ZA835613B/en unknown
- 1983-08-08 IT IT48823/83A patent/IT1171855B/en active
- 1983-08-08 AT AT2868/83A patent/AT392786B/en not_active IP Right Cessation
- 1983-08-22 CA CA000435081A patent/CA1201443A/en not_active Expired
- 1983-09-01 GB GB08323492A patent/GB2139215B/en not_active Expired
- 1983-09-02 IE IE2074/83A patent/IE55905B1/en not_active IP Right Cessation
- 1983-09-07 NZ NZ205514A patent/NZ205514A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |