IE55905B1 - Production of thiophene acetic acid compounds - Google Patents
Production of thiophene acetic acid compoundsInfo
- Publication number
- IE55905B1 IE55905B1 IE2074/83A IE207483A IE55905B1 IE 55905 B1 IE55905 B1 IE 55905B1 IE 2074/83 A IE2074/83 A IE 2074/83A IE 207483 A IE207483 A IE 207483A IE 55905 B1 IE55905 B1 IE 55905B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- acetic acid
- hydroxy
- thiophene acetic
- magnesium
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- WBMKDDSMYHLQTN-UHFFFAOYSA-N acetic acid;thiophene Chemical class CC(O)=O.C=1C=CSC=1 WBMKDDSMYHLQTN-UHFFFAOYSA-N 0.000 title 1
- -1 magnesium halide Chemical class 0.000 claims abstract description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 15
- 239000011777 magnesium Substances 0.000 claims abstract description 15
- 150000002576 ketones Chemical class 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 3
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000011260 aqueous acid Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical group C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002641 lithium Chemical group 0.000 claims description 3
- OFJHGWPRBMPXCX-UHFFFAOYSA-M lithium;2-oxopropanoate Chemical compound [Li+].CC(=O)C([O-])=O OFJHGWPRBMPXCX-UHFFFAOYSA-M 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims 1
- HTJPDOPKPWUNBX-UHFFFAOYSA-M magnesium;2h-thiophen-2-ide;bromide Chemical compound [Mg+2].[Br-].C=1C=[C-]SC=1 HTJPDOPKPWUNBX-UHFFFAOYSA-M 0.000 claims 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229940107700 pyruvic acid Drugs 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000010408 sweeping Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The alpha -hydroxy-2-thiophene acetic acid of formula (I): 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): in which X represents a halogen atom, with a ketone of formula (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 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.
Description
This invention relates to the production of thiophene compounds of formula (I): R m winch R represents ar. alkyl radical of 1-4 carbon atoms and Kj, Ro 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 produc ts.
Starting with the compounds of formula (I), acids of formula (A): 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. This process is characterized 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 French patent 206842b and in French patent 2167334 mentioned above. in the Eur. J. Med. Chem. 1974 (9) 39U article mentioned above, a process for the preparation of a compound of formula (I) is described. This process is as follows.* 4/ cK-Mgi OH A new process for the preparation of the compounds of formula (I) has now been discovered.
Accordingly, the invention provides a process for - 3 Lhe preparut i nn ai* an Ct-hydrox.y-2- th ί nphene acetic ,'ieid o',' i'«»rani ι la ( I ) : In which H represents an alkyl radical of I - 4 carbon atoms and R , R9 and arc the same or different and each represents a hydrogen atom or an alkyl radical of · - 4 carbon atoms, which process comprises, reacting a magnesium halide of formula (II): ( TT\ \ J. / fgX in which X represents a halogen atom, with a ketone of formula (ITT): R-C-CV (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 group and produce the desired Ot-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 readily be prepared from an acid of formula: r-c-co2h The 2-halothiophene and the acid are both readily aecesssible. 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^ , R2 and Rg may represent, an alkyl radical of 1-4 carbon atoms, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl.
X may represent a chlorine, iodine or bromine atom; 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 N) such as tetrahydrofuran or ethyl other.
When an alkal. i metal salt, preferably a lithium salt, ir. 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 bi? used.
The reaction of the magnesium halide of formula (II) 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 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 be carried out in the presence of ammonium chloride.
Preferably, R^t Rg and Rg each represent a hydrogen atom; hence an c£-hydroxy-2-thiophene acetic acid of formula (I'): C-CO h ί 2 R 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.
Most preferred is the production of Qt-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 - 7 hydrolyse the magnesium group and produce the oC-hydroxy-2-thiophene acetic acid of formula (I). Especially preferred is the production of 06-methyl- The invention also provides a process for preparing a pharmaceutical using as an intermediate arK£rhydroxy-2-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.
EXAMPLE 1 : <3t-methyI-Ji-hydroxy-2-th j ophene 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 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.
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. b) Freparat i.on_of _thien^^magnesium bromide Under argon, 5.74 kg of magnesium turnings is introduced into 81.5 I. 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 minutes while maintaining the same temperature.
When the introduction is complete, the mixture is agitated ('or 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 coo Led 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 oy 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 nitrogen ac this temperature.
Over a period of about 15 minutes the suspension .is poured i.nto a mixture of 140 kg of crushed ice and 47 1. of hydrochloric acid. The interior temperature is kept at 25°C by addiition of ice as necessary.
The equipment is rinsed witli 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 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 I. of ammonia is introduced slowly up to pH 4; by decanting, washing again with 12 L. 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 I., while maintaining the interior temperature below 40uC, about 175 1. 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°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 product sought is obtained. MP - 115°C.
Use to Prepare Qt-methyl-2-thiophene acel·.ic acid A mixture of 75 1. of 22°Be hydrochloric acid and 75 kg of tin protochloride is heated to 40°C under - JO nitrogen, and then, in one lot, 125 I. of glacial acetic acid is added. When soLution is complete, 50 kg of PC — -me thy l-»X-hydroxy-2-th i ophene acetic ae id is gradual ly 1 introduced with agitation and with sweeping by nitrogen.
The temperature is kept at 40°C for 1 hour 30 minutes » whi Le 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 aqueous phase is extracted 6 times with 50 i. of iliehloroethane at 20°C + 2°C. The dichLoroethane extracts are washed 4 times with 8.5 1. of 22°Be hydrochloric acid in 42.5 L. of water and then 3 times with 50 I. of water.
The dichloroethane solution is concentrated under reduced pressure without exceeding 40°C. About 225 1. of di chloroethane 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 : of-methyl-jt— hydroxy-2-thiophene acetic acid 50 cmJ of a solution of 375 g of --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 I I br· »mot.h i o |»h< ·ιι«· solution i g ί 111 r*o< l< i« ' < *< 1 under ag i tab Lou 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 cm:i of tetrahydrofuran is then added at 25°C over 45 minutes. The mixture is agitated for 18 hour's 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 cm’ of ethyl acetate. The organic phases are washed twice with 260 cm’ of demineralized water and then re-extracted first, with 620 emJ and then 3 times with 260 cm3 of 3N aqueous, iced, sodium hydroxide. The sodium Iiquors 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 cm3 of 22°Bo hydrochloric acid. Extraction is carried out first with 520 cm3 and then 4 times with 260 cmJ 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 pres,sure and 145.5 g of the expected product is obtained.
Claims (10)
1. Process for Lhe preparation of an Oi-hydroxy-2* -thiophene acetic acid of formula (I): R ln which H represents an alkyl radical of 1-4 carbon atoms and Rp R o and are the same or different and
2. Process according to claim 1 wherein R^, and R 3 each represent a hydrogen atom.
3. Process according to claim 2 wherein R represents 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 represents a hydrogen or lithium atom. 5 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-C-CO„A (XII)
6. Process according to any one of the preceding claims wherein the magnesium halide of formula (11) is reacted with the ketone of formula (III) and the obtained product is then reacted with an aqueous acid medium to hydrolyse the magnesium group and produce the oi-hydroxy-2-thiophene acetic acid of formula (I).
7. Process for preparing 06-rnethyl-d6-hydroxy-2-thiophene «acetic acid, which process comprises reacting 2-thienylmagnesium bromide with lithium pyruvate and reacting the obtained product with an aqueous solution of hydrochloric acid.
8. Process according to claim 1 performed substantially as described herein. Process for the preparation of an ot-hydroxy-2L4 -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 iZ-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 tY—hydroxy-2-thiophene acetic acid of formula (I) as defined in claim 1, in which process the
9. in which R in 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 deni redct-hydroxy-2-thiophene acetic acid of formula (I).
10. O(.-hydroxy-2-thiophene acetic acid is as claimed in claim 10.
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 IE832074L (en) | 1984-10-28 |
| IE55905B1 true 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 |
| GB820083A (en) * | 1955-07-05 | 1959-09-16 | Metal & Thermit Corp | Reactions of organomagnesium chloride reagents |
| GB806710A (en) * | 1955-07-05 | 1958-12-31 | Metal & Thermit Corp | Reactions of organomagnesium chloride complexes |
| 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 KR KR1019830003476A patent/KR900006558B1/en not_active IP Right Cessation
- 1983-07-27 LU LU84931A patent/LU84931A1/en unknown
- 1983-07-28 JP JP58136930A patent/JPS59204185A/en active Granted
- 1983-08-01 ZA ZA835613A patent/ZA835613B/en unknown
- 1983-08-01 ES ES524648A patent/ES524648A0/en active Granted
- 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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| MK9A | Patent expired |