IE55075B1 - Preparation of thiophene compounds - Google Patents
Preparation of thiophene compoundsInfo
- Publication number
- IE55075B1 IE55075B1 IE1075/83A IE107583A IE55075B1 IE 55075 B1 IE55075 B1 IE 55075B1 IE 1075/83 A IE1075/83 A IE 1075/83A IE 107583 A IE107583 A IE 107583A IE 55075 B1 IE55075 B1 IE 55075B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- process according
- malonate
- alkylmalonate
- acetic acid
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000003577 thiophenes Chemical class 0.000 title description 2
- -1 2-thiophene acetic acid compound Chemical class 0.000 claims abstract description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 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 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 230000002152 alkylating effect Effects 0.000 claims description 6
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000005910 alkyl carbonate group Chemical group 0.000 claims description 4
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 claims description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 8
- 229910052753 mercury Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 description 1
- 150000005394 2-thiopheneacetic acids Chemical class 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 244000309464 bull Species 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 239000008096 xylene Substances 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
- C07D333/06—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
A 2-thiophene acetic acid compound of formula (I): <IMAGE> in which: R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; is prepared by decarbalkoxylating an alkylmalonate of formula (IV): <IMAGE> in which R, R1, R2 and R3 are as defined above and Alk1 and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms. The 2-thiophene acetic acid compound is an intermediate in the production of pharmaceuticals. The alkylmalonate used is itself claimed per se.
[GB2132607A]
Description
5507B This invention relates to the preparation c-f 2-thiophene acetic acid compounds of formula (I): in which R represents an alkyl radical of 1 to 4 carbon atoms and R, , R-, and R~ are the same or different and i e. O each represents a hydrogen atom, an alkyl radical of 1 tc 4 carbon atoms or a halogen atom.
These compounds are intermediates which can be us in the preparation of pharmaceutical products, in particular anti-inflammatory products. End products 10 which can be prepared from the compounds .are described in particular in French Patent 2 058 425.
Several processes for the preparation of the compounds are already known.
The following process is described in M. BERCOT-15 VATTERONI et al., Bull. Soc. Chim. France 1961 p 1820: 2 NaCN KCKO, ch2cn jCOyitj il The following process is described in F. CLEMENCE et al., Eur J. Med. Chem. 1974 (9) 390: ch3 oh The following process is described in French Patent Application 2 398 068 in the name of the SAGAM1 5 company: 3 alkali metal hydroxide / = S or a lower alkyl Hal= halogen Eg = H , hydrocarbon radical or halogen These processes involve at least 4 stages starting from thiophene or in the case of the last mentioned process an optionally substituted thiophene of formula A new process for the preparation of the compounds 5 has now been discovered. Accordingly, the invention provides a process for the preparation of a 2-thiophene acetic acid compound of formula (I): in which R represents an alkyl radical of 1 to 4 carbon 4 - 4 - atoms; and R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; 5 which process comprises decarbalkoxylating an alkylmalonate of formula (IV); (IV) in which R, R2 and R3 are as defined above and Al^ and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms.
The new process is better because it produces the compounds more readily. If one starts from chemicals which are available in large quantities at economical prices, the present process produces the compounds in fewer stages.
The alkylmalonate of formula (IV) is preferably prepared by alkylating in the presence of a strong base a malonate of formula (III): 5 (in) in which R^, R2, Rg, Alk^ and Aik,, are as defined above The malonate of formula (III) is preferably prepared by reacting an alkyl carbonate of formula (Alk^gCOg 5 in which Alk^ is as defined above, in the presence of a strong base with an ester of formula (II): )2Alk2 (ID in which R^, Rg, Rg and Alk2 are as defined above.
The ester for formula (II) is an ester of 6 thienyl-2-acetic acid optionally substituted on the thienyl ring. Such thienyl-2-acetic acids are used particularly in the synthesis of antibiotics, especially cephalosporins. The esters of formula (II) are thus available in large quantities at economical prices.
The esters can readily be prepared from the corresponding acids by the usual esterification methods.
Thus, the present compounds can be prepared in 3 stages from a readily accessible starting material, the ester of formula (II).
R represents a lower alkyl radical,i.e. an alkyl radical of 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl. Rg and Rg can independently represent one of these alkyl radicals or equally a halogen atom, namely fluorine, chlorine, bromine or iodine.
Alkx and likewise can take any of the lower alkyl values listed above for R.
The esters of formula (II) can be prepared by the usual methods from the corresponding acids which are described for example in French Patent 2 377 398.
The reaction of the alkyl carbonate with the ester of formula (II) can be carried out in the presence of a strong base such as an alkali metal alcoholate, preferably sodium ethoxicLe prepared in situ by the addition of sodium to anhydrous ethanol. Sodium or potassium tert-butoxide can be used. It is also possible 7 to use a cUfl'erent strong base such as sodium hydride or another alkali metal hydride. This reaction can equally be carried out as a phase transfer reaction under the usual conditions.
The reaction of the alkyl carbonate with the ester of formula (II) can be conducted in a reaction medium constituted by the alcohol when using an alkali metal alcoholate as the strong base. It is equally possible to proceed in the presence of another solvent, 10 for example toluene which can be used also to expel excess alcohol present in the medium.
The proportions of the different materials can be varied according to the methods known to those skilled in the art. For example the quantity of sodium can vary 15 between 1 and 1,5 equivalents in relation to the ester of formula (II) when using sodium alcoholate as the base.
The temperature and reaction time can likewise be varied. The length of reaction can vary for example from about 2 to 8 hours. The temperature can vary for example from 20 90 to 135° approximately (reflux of toluene or xylene). Finally, the carbonate of formula (Alk^JgCOg can be used in variable proportions.
The malonate of formula (III) in which R^, R2 and R3 each represent a hydrogen atom and Alk·^ and Alkg 25 each represent an ethyl radical is described with its process for preparation in J.A.C.S. 68, 1934 (1946).
The conversion of the malonate of formula (III) 8 into the alkylmalonate of formula (IV) is carried out in the presence of a strong base which can be as described above. The procedure is preferably the same as described above concerning sodium ethoxitle prepared in situ. The 5 process is preferably carried out in the presence of another solvent such as toluene. It is equally possible to proceed using a phase transfer reaction.
The alkylating agent used to alkylate the malonate of formula (III) to the alkylmalonate of formula (IV) can 10 be considered as being of formula RX where R is as defined above and X is a group which functions so as to permit the alkylation. Alkylating agents are well known. The alkylating agent RX can be for example an alkyl halide such as the chloride, bromide, or iodide. The alkylating agent 15 can equally be an alkyl sulphate of formula (R)2S0^ (X then respresents half an S04).
As previously, one can use varied conditions of temperature, reaction time and quantities of reagents. For example, one can use 1 to 1.5 moles of the alkylating 20 agent RX per mole of the malonate of formula (III). The reaction time can vary for example from 30 minutes to 3 hours. The temperature is preferably between 50 and 100°C, especially between 50 and 80°C.
In a preferred embodiment, the alkylation is carried 25 out in the presence of sodium eth'OxicLe after eliminating the ethanol by means of a solvent such as toluene in which the alkylation is to be carried out. 9 The conversion of the alkylmalonate of formula (IV) into the 2-thiophene acetic acid compound of formula (I) can be carried out by treatment with an alkaline base to obtain a salt of the desired acid compound, and 5 then with an acid to produce the desired acid compound.
The first phase can be carried out either in water or in a mixture of water and water-miscible solvent. The solvent used is preferably a lower alcohol such as methanol, ethanol or isopropanol. Sodium or potassium hydroxide 1° is preferably used as the alkaline base.
The temperature is preferably between 20"C and the reflux temperature, especially between 50°C and the reflux temperature. The reaction time is preferably between 2 hours and 15 hours.
The final acidification is preferably carried out with concentrated hydrochloric acid. The .reaction is preferably carried out with the addition of an organic solvent such as toluene; the process is usually carried out at a temperature between the ambient temperature and 20 the reflux temperature of the solvent.
Preferably, R^,.Rg and each represents a hydrogen atom, so that the compound is of formula (X1); R In that event, the corresponding ester of formula (II) is a thienyl acetic acid ester of formula (II1): (II*) CK2-C02Alk2 in which Alk2 is as defined above.
Preferably, R represents a methyl or ethyl radical, 5 especially a methyl radical.
Preferably, the present 2-thiophene acetic acid compound of formula (I) is produced in the 3 stages described, starting with the ester of formula (II), converting this into the malonate of formula (III), 10 alkylating this to the alkylmalonate of formula (IV), and converting this to the compound of formula (I). The sequence of the final 2 stages, however, the alkylation of the malonate of formula (III) to the alkylmalonate of formula (IV) and the conversion of this alkylmalonate to 15 the compound of formula (I), is particularly significant. Especially preferred is this sequence of the last 2 stages wherein Rj, R2 and R^ each represents a hydrogen atom.
A preferred embodiment is the 3 stage process described above starting from ethyl carbonate and an ester 11 of formula (IX) in which Aik,, represents an ethyl radical.
In the process of the invention, the strong base is preferably sodium ethoxiAe. The alkylating agent is preferably an alkyl sulphate, especially methyl sulphate.
Especially preferred is carrying out the present process in the following way to produce Λ-methyl 2-thiophene acetic acid: The process comprises reacting ethyl carbonate in the presence of sodium ethoxiie with ethyl thienyl-2--acetate to produce ethyl thienyl-2-malonate, which is 1° reacted with methyl sulphate to produce ethyl thienyl-2--methyl malonate, which is reacted with sodium hydroxide and then hydrochloric acid to produce the ot-methyl 2-thiophene acetic acid.
The alkylmalonate of formula (IV) is a new compound I5 and the invention provides it per se and its production by alkylating in the presence of a strong base the malonate of formula (III). It is preferred that in the alkylmalonate of formula (IV) R1, R2 and Rg each represent a hydrogen atom. The most preferred alkylmalonate is 20 ethyl thienyl-2-methyl malonate, and this is preferably used to produce Λ-methyl 2-thiophene acetic acid.
The invention also provides a process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined above, in which process 25 the compound is prepared in the present way.
The invention is illustrated by the following Examples. 12 EXAMPLE 1: OCr-methyl 2-thiophene acetic acid Stage A: ethyl thienyl-2-malonate 225 cc of absolute ethanol and 16.5 g of sodium were mixed under nitrogen. Ethanol reflux was maintained until the sodium had dissolved, and the solution was then concentrated to dryness under reduced pressure in order to eliminate the excess ethanol. 150 cc of ethyl carbonate were introduced onto the sodium ethoxide at 100°C while the temperature was maintained between 90 and 95°C and then, in 10 minutes, 100 g of ethyl thienyl-2-acetate and 100 cc of toluene were added. The temperature was brought to 105°C and in about 2 hours 120 cc of the toluene-ethanol--ethyl carbonate mixture were distilled off. The temperature was maintained at 105°C for a further 2 hours and then cooled down to 20°C, whereupon the resultant mixture was poured into 600 cc of iced water containing 80 cc of pure 22°Be hydrochloric acid. After decanting, the aqueous phase was re-extracted with toluene and the combined toluene extracts were washed with water.
The toluene solution was concentrated under reduced pressure. The expected crude product was obtained and this was distilled under a pressure of 2 mm of mercury. 134.4 g of the expected product was obtained.
Boiling point under 2 mm of mercury = 118-120°C. Stage B: ethyl thienyl-2-methyl malonate 10.45 g of sodium were introduced under nitrogen into 160 cc of absolute ethanol. Reflux was maintained 13 for 45 minutes and 60 cc of ethanol were distilled off 300 cc of toluene were added. The mixture was heated to reflux with continuous stirring and the ethanol was distilled off at constant volume by the addition of 5 toluene. 250 cc of toluene were added and about 250 cc of the ethanol-toluene mixture were recovered.
The mixture was cooled down to 20°C, and 100 g of ethyl thienyl-2-malonate and 200 cc of toluene were added. Stirring was continued for 20 minutes. 150 cc 10 of the toluene-ethanol mixture were distilled off under reduced pressure, and then 100 cc of toluene were introduced under nitrogen. The mixture was heated to 70°C, and 60.9 g of dimethyl sulphate were added in 30 minutes. The temperature was maintained at 80°C for 15 45 minutes and then reduced to 20-25°C, when 200 cc of demineralised water were added. After 15 minutes stirring, the mixture was decanted, and the toluene phase washed with 100 cc of water containing 5% 22°Be hydrochloric acid and then 4 times with 100 cc of demineralised water. 450 cc of toluene were distilled off under reduced pressure and the concentrate was left at 70°c under a presssure of 15-20 mm of mercury for one hour, yielding 105 g of the expected product.
Stage C: ot-methyl 2-thiophene acetic acid. 100 g of ethyl thienyl-2-methyl malonate and 200 cc of ethanol were added to a solution of 62.6 g of sodium hydroxide in 400 cc of demineralised water. The resultant H mixture was brought to 50°C over 4 hours, ana then 300 cc of an ethanol-water mixture were distilled off under reduced pressure whilst maintaining the temperature below 50°C. The mixture was placed under nitrogen and 200 cc of 5 toluene and 140 cc of 22"Be hydrochloric acid were added in succession. The mixture was brought to reflux over 1 hour 30 minutes and then cooled to 20°C. After decanting, the toluene phase was washed several times with 50 cc of water and concentrated under reduced 10 pressure by distilling off 180ccof toluene. The solvent was removed from the concentrate at 70°C for one hour under a pressure of 15-20 mm of mercury. 58.8 g of the expected product was obtained.
EXAMPLE 2: thienyl-2-butyric acid 15 Stage A: ethyl thienyl-2-ethyl malonate 12.54 g of sodium were introduced into 192 cc of absolute ethanol. Reflux was maintained for 45 minutes, and then 72 cc of ethanol were distilled off. 360 cc of toluene were added. The mixture was heated to reflux 20 to distill off the ethanol at constant volume by the addition of toluene. 300 cc of toluene were thus added and the same volume of toluene-ethanol mixture were recovered. The reaction mixture was cooled to 20°C and 120 g of ethyl thienyl-2-malonate and 240 cc of toluene 25 were added. After stirring for 20 minutes, 180 cc of toluene-ethanol mixture were distilled off under reduced presssure and 120 cc toluene were introduced under nitrogen.
The mixture was heated to 75°C, and 99.3 g of diethyl sulphate were then added over 30 minutes. The mixture was brought to reflux over one hour and then cooled to 20-25°C, and 240 cc of demineralised water were added. After 5 stirring for 15 minutes and decanting, the toluene phase was washed with 120 cc of demineralised water containing 5% 22°Be hydrochloric acid and then 4 times with 120 cc of water. The toluene phase was concentrated under reduced pressure after drying over sodium sulphate. The 10 solvent was removed from the concentrate under a pressure of 15-20 mm of mercury at 70°C for one hour. 145.6 g of the expected product was obtained.
This product was purified by. distillation under a pressure of 0.5 mm of mercury. 113 g of the distilling 15 product was recovered at a temperature of 95-120°C.
Stage B: thienyl-2-butyric acid A mixture of 62.6 g of sodium hyroxide in 400 cc of demineralised water were stirred under nitrogen until totally dissolved, after which 105.4 g of ethyl thienyl-2-20 -ethyl malonate and then 200 cc of ethanol were added. The resultant mixture was brought to 50°C over 4 hours and then 300 cc of ethanol-water mixture were distilled off under a pressure of 20 mm mercury at a temperature of about 50°C. 200 cc of toluene followed by 140 cc of 22"Be hydrochloric 25 acid were then introduced under nitrogen. The mixture was brought to reflux over 1 hour 30 minutes, cooled to 20°C and decanted. The aqueous phase was extracted with 50 cc of toluene and the toluene phase was washed several times 16 with 50 cc of water. The toluene phase was dried over sodium sulphate and concentrated to dryness under a pressure of 15 to 20 mm mercury at 70°C. After a further hour of these conditions, 66,3 g of the expected product 5 were obtained. 17
Claims (5)
1. Process for the preparation of a 2-thiophene acetic acid compound of formula (I): (I) R. R in which R represents an alkyl radical of 1 to 4 carbon atoms; and R.j, Rg and R^ are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises decarbalkoxylating an alkylmalonate of formula (IV) (IV) in which R, R-j, R2 and Rg are as defined above and Aik^ and Alk2 are the same or different and each represents an alkyl radical of 1 to 4 carbon atoms.
2. Process according to claim 1 wherein the alkylmalonate of formula (IV) is prepared by alkylating in the presence of a strong base a malonate of formula (III): 18. In which R^, Rg, Rg, Alk^ and Alkg are as defined in claim 1.
3. Process according to claim 2 wherein the malonate of formula (III) is prepared by reacting an alkyl carbonate of formula in which Alk^ is as defined in claim 2, in the presence of a strong base with an ester of formula (II): (II) in which R^, Rg, R3 and Aik,, are as defined in claim 2.
4. Process according to claim 2 or 3 wherein the strong base is sodium ethoxid e. 5. Process according to any one of claims 2 to 4 wherein the malonate of formula (III) is alkylated with an alkyl sulphate of formula in which R is as defined in claim 1. 6. Process according to any one of the preceding claims wherein R^, R2 and R3 each represents a hydrogen atom. 7. Process according to claim 6 wherein R represents a methyl radical. 8. Process according to claim 6 wherein R represents an ethyl radical. 9. Process according to any one of the preceding claims wherein Alk^ and Aik,, each represents an ethyl radical. 10. Process for the preparation of o-methyl 2-thiophene acetic acid, which process comprises reacting ethyl carbonate in the presence of sodium 10 ethoxiie with ethyl thienyl-2-acetate to produce ethyl thienyl-2-malonate, which is reacted with methyl sulphate to produce ethyl thienyl-2-methyl malonate, which is reacted with sodium hydroxide and then hydrochloric acid to produce the α-methyl 2-thiophene acetic acid. Π. Process according to any one of the preceding claims performed 15 substantially as described herein. 12. Process according to any one of claims 1 to 10 performed substantially as described herein in Example 1 or in Example 2. 13. A 2-thiophene acetic acid compound as defined in claim 1 when prepared by a process claimed in any one of the preceding claims. 14. An alkylmalonate as defined in claim 1. 15. An alkylmalonate according to claim 14 wherein R , R? and R3 each represents a hydrogen atom. 16. Ethyl thienyl-2-methylmalonate. 17. A process for preparing an alkylmalonate as claimed in any one of 25 claims 14 to 16, which process comprises alkylating in the presence of a 20. 5 strong base a malonate of formula (III) as defined in claim 2. 18. A process according to claim 17 performed substantially as described herein. 19. A process according to claim 17 performed substantially as described herein in Example 1 or in Example 2. 20. An alkylmalonate as claimed in any one of claims 14 to 16 when prepared by a process as claimed in any one of claims 17 to 19. 21. A process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined in claim 1, in which process the 2-thiophene acetic acid compound is as defined in claim 13. Dated this 10th day of May 1983, TOMKINS & CO.,
5. Dartmouth Road DUBLIN 6 (signed) 21.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220271A FR2537137B1 (en) | 1982-12-03 | 1982-12-03 | PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES AND INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE831075L IE831075L (en) | 1984-06-03 |
| IE55075B1 true IE55075B1 (en) | 1990-05-23 |
Family
ID=9279757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1075/83A IE55075B1 (en) | 1982-12-03 | 1983-05-10 | Preparation of thiophene compounds |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59106482A (en) |
| KR (1) | KR900005681B1 (en) |
| AT (1) | AT392784B (en) |
| AU (1) | AU556803B2 (en) |
| BE (1) | BE896439A (en) |
| CA (1) | CA1201441A (en) |
| CH (2) | CH659817A5 (en) |
| DE (1) | DE3314029A1 (en) |
| DK (2) | DK160427C (en) |
| ES (1) | ES521230A0 (en) |
| FI (1) | FI83646C (en) |
| FR (1) | FR2537137B1 (en) |
| GB (1) | GB2132607B (en) |
| HU (1) | HU192136B (en) |
| IE (1) | IE55075B1 (en) |
| IT (1) | IT1174757B (en) |
| LU (1) | LU84748A1 (en) |
| NL (1) | NL8301692A (en) |
| NZ (1) | NZ204509A (en) |
| PT (1) | PT76534B (en) |
| SE (2) | SE453992B (en) |
| ZA (1) | ZA832698B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE132865T1 (en) * | 1988-04-22 | 1996-01-15 | Byk Gulden Lomberg Chem Fab | 3-ANILINO-2-HYDROXYCARBONYL-4-THIOPHENACETIC ACID N |
| IT1276738B1 (en) * | 1995-06-16 | 1997-11-03 | Erregierre Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF -METHYL-2- THIOPHENEACETIC ACID |
| DE102004008807A1 (en) | 2004-02-20 | 2005-09-08 | Bayer Cropscience Ag | pyrazolopyrimidine |
| CN113896709B (en) * | 2021-11-22 | 2023-02-28 | 南京一苇医药科技有限公司 | Synthetic method of benzothiophene-3-acetic acid |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB683337A (en) * | 1949-10-01 | 1952-11-26 | Warner Hudnut Inc | Improvements in or relating to the preparation of antispasmodic compounds |
| IE33054B1 (en) * | 1968-04-16 | 1974-03-06 | Ici Ltd | Heterocyclic compounds |
| FR2260575A1 (en) * | 1974-02-11 | 1975-09-05 | Innothera Lab Sa | Cyclohexyl 3-thienyl acetic acid prodn - from methyl 3-thienylacetate through diethyl cyclohexyl 3-thienyl malonate as starting material for basic esters as drugs |
| GB2003570B (en) * | 1977-06-08 | 1982-01-20 | Imi Opella Ltd | Stop valve |
| FR2421897A1 (en) * | 1978-04-04 | 1979-11-02 | Labaz | Alpha substd. 3-thienyl:acetamide derivs. - useful as hypnotic, anticonvulsant and tranquillising agents |
-
1982
- 1982-12-03 FR FR8220271A patent/FR2537137B1/en not_active Expired
-
1983
- 1983-03-28 DK DK139983A patent/DK160427C/en not_active IP Right Cessation
- 1983-03-30 SE SE8301785A patent/SE453992B/en not_active IP Right Cessation
- 1983-03-31 FI FI831115A patent/FI83646C/en not_active IP Right Cessation
- 1983-04-05 ES ES521230A patent/ES521230A0/en active Granted
- 1983-04-11 PT PT76534A patent/PT76534B/en not_active IP Right Cessation
- 1983-04-12 BE BE0/210536A patent/BE896439A/en unknown
- 1983-04-12 CH CH4155/85A patent/CH659817A5/en not_active IP Right Cessation
- 1983-04-12 CH CH1967/83A patent/CH655722A5/en not_active IP Right Cessation
- 1983-04-14 LU LU84748A patent/LU84748A1/en unknown
- 1983-04-14 HU HU831308A patent/HU192136B/en not_active IP Right Cessation
- 1983-04-15 AU AU13574/83A patent/AU556803B2/en not_active Ceased
- 1983-04-18 DE DE19833314029 patent/DE3314029A1/en active Granted
- 1983-04-18 ZA ZA832698A patent/ZA832698B/en unknown
- 1983-04-23 KR KR1019830001729A patent/KR900005681B1/en not_active IP Right Cessation
- 1983-05-04 IT IT48215/83A patent/IT1174757B/en active
- 1983-05-09 GB GB08312701A patent/GB2132607B/en not_active Expired
- 1983-05-10 IE IE1075/83A patent/IE55075B1/en not_active IP Right Cessation
- 1983-05-11 NL NL8301692A patent/NL8301692A/en active Search and Examination
- 1983-05-20 JP JP58087835A patent/JPS59106482A/en active Granted
- 1983-06-09 NZ NZ204509A patent/NZ204509A/en unknown
- 1983-07-28 CA CA000433421A patent/CA1201441A/en not_active Expired
- 1983-08-08 AT AT2866/83A patent/AT392784B/en not_active IP Right Cessation
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1987
- 1987-09-09 SE SE8703494A patent/SE457724B/en not_active IP Right Cessation
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1990
- 1990-06-06 DK DK138490A patent/DK164550C/en not_active IP Right Cessation
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