JPH0439468B2 - - Google Patents
Info
- Publication number
- JPH0439468B2 JPH0439468B2 JP58087836A JP8783683A JPH0439468B2 JP H0439468 B2 JPH0439468 B2 JP H0439468B2 JP 58087836 A JP58087836 A JP 58087836A JP 8783683 A JP8783683 A JP 8783683A JP H0439468 B2 JPH0439468 B2 JP H0439468B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- thiophene
- acid
- phase transfer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- 229930192474 thiophene Natural products 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 150000001299 aldehydes Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000006276 transfer reaction Methods 0.000 claims description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- GEDJSTBRFXDCAM-UHFFFAOYSA-N 2-(1-chloroethyl)thiophene Chemical compound CC(Cl)C1=CC=CS1 GEDJSTBRFXDCAM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- QTOABKRIUPTTPQ-UHFFFAOYSA-N 2-thiophen-2-ylpropanenitrile Chemical compound N#CC(C)C1=CC=CS1 QTOABKRIUPTTPQ-UHFFFAOYSA-N 0.000 claims description 3
- KTKWUKAYWFMQSO-UHFFFAOYSA-N 2-thiophen-2-ylpropanoic acid Chemical compound OC(=O)C(C)C1=CC=CS1 KTKWUKAYWFMQSO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 claims description 3
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical compound [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 3
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 claims description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000005394 2-thiopheneacetic acids Chemical class 0.000 claims 2
- 238000000034 method Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- 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 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- -1 alkaline earth metal cyanides Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 3
- 229960003868 paraldehyde Drugs 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003577 thiophenes Chemical class 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- FMOIXKQKOWLYEK-UHFFFAOYSA-N 2-(2-chloroethyl)thiophene Chemical compound ClCCC1=CC=CS1 FMOIXKQKOWLYEK-UHFFFAOYSA-N 0.000 description 1
- 150000005395 2-thiopheneacetic acid derivatives Chemical class 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 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
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910000611 Zinc aluminium Inorganic materials 0.000 description 1
- CWVZGJORVTZXFW-UHFFFAOYSA-N [benzyl(dimethyl)silyl]methyl carbamate Chemical compound NC(=O)OC[Si](C)(C)CC1=CC=CC=C1 CWVZGJORVTZXFW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- VUEDNLCYHKSELL-UHFFFAOYSA-N arsonium Chemical class [AsH4+] VUEDNLCYHKSELL-UHFFFAOYSA-N 0.000 description 1
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000003459 chloroalkylation reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 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
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004094 surface-active agent 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
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 1
- TVVPMLFGPYQGTG-UHFFFAOYSA-M tetramethylphosphanium;iodide Chemical compound [I-].C[P+](C)(C)C TVVPMLFGPYQGTG-UHFFFAOYSA-M 0.000 description 1
- CHXZRHMQQRUVHF-UHFFFAOYSA-N thiophene A Natural products CC#CC1=CC=C(C#CC#CC=C)S1 CHXZRHMQQRUVHF-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 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
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
-
- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明の主題は、次式（）
（ここで、Ｒは１〜４個の炭素原子を有するア
ルキル基を表わし、R1、R2及びR3は同一又は異
なつていてよく、それぞれ水素原子、１〜４個の
炭素原子を有するアルキル基又はハロゲン原子を
表わす）
の２−チオフエン酢酸の誘導体の製造法にある。DETAILED DESCRIPTION OF THE INVENTION The subject of the present invention is the following formula () (Here, R represents an alkyl group having 1 to 4 carbon atoms, R 1 , R 2 and R 3 may be the same or different, and each has a hydrogen atom and 1 to 4 carbon atoms. (representing an alkyl group or a halogen atom) is a method for producing a 2-thiopheneacetic acid derivative.
これらの化合物は、製薬用化合物、特に抗炎症
性化合物の製造に用いることができる中間体化合
物である。 These compounds are intermediate compounds that can be used in the preparation of pharmaceutical compounds, especially anti-inflammatory compounds.
本発明の方法により得られた化合物から出発し
て製造することができる最終生成物は、特にフラ
ンス国特許第2068425号に記載されている。 The final products that can be prepared starting from the compounds obtained by the process of the invention are described in particular in French Patent No. 2,068,425.
式（）の化合物のいくつかの製造法は既に知
られている。 Several methods for producing compounds of formula () are already known.
例えば、下記の方法がM.Bercot−Vatteroni他
によりBull.Soc.Chim.France1961、p.1820に記載
されている。 For example, the following method is described by M. Bercot-Vatteroni et al. in Bull. Soc. Chim. France 1961, p. 1820.
また、下記の方法が、F.Clemence他により
Eur.J.Med.Chem.1974(9)、p.390に記載されてい
る。 Additionally, the following method was proposed by F. Clemence et al.
Described in Eur.J.Med.Chem.1974(9), p.390.
また、下記の方法がフランス国特許第2398068
号に記載されている。 In addition, the following method is covered by French Patent No. 2398068.
listed in the number.
R1＝Ｈ又は低級アルキル
Hal＝ハロゲン
R2＝Ｈ、炭化水素基又はハロゲン
これらの方法は、チオフエン又は置換チオフエ
ンから出発して少なくとも４段階を含む。 R 1 =H or lower alkyl Hal = halogen R 2 =H, hydrocarbon group or halogen These processes involve at least four steps starting from thiophene or substituted thiophene.
ここに、置換チオフエン又はチオフエンから出
発して３段階での式（）の誘導体の新製造法が
完成された。さらに、この方法は工業的規模での
実施に対して多くの利点を提供する。 A new method for producing derivatives of formula () in three steps starting from substituted thiophenes or thiophenes has now been completed. Furthermore, this method offers many advantages for implementation on an industrial scale.
この方法は、次式（）
（ここでR1、R2及びR3は前記の意味を有する）
の化合物に式Ｈ−Halのハロゲン化水素酸の存在
下に式Ｒ−CHOのアルデヒドか又は式Ｒ−CHO
のアルデヒドの誘導体を反応させて次式（）
（ここでHalはハロゲン原子を表わす）
の化合物を得、式（）の化合物を次式
Ａ−CN
（ここでＡはアルカリ金属原子、当量のアルカ
リ土金属又は水素原子を表わす）
の化合物と反応させて次式（）
の化合物を得、式（）の化合物に加水分解剤を
作用させて式（）の所期化合物を得ることを特
徴とする。 This method uses the following formula () (wherein R 1 , R 2 and R 3 have the abovementioned meanings) in the presence of a hydrohalic acid of formula H-Hal to form an aldehyde of formula R-CHO or an aldehyde of formula R-CHO
The following formula () is obtained by reacting the aldehyde derivative of (where Hal represents a halogen atom) is obtained, and the compound of formula () is reacted with a compound of the following formula A-CN (where A represents an alkali metal atom, an equivalent alkaline earth metal or a hydrogen atom). Let the following formula () The method is characterized in that a compound of formula () is obtained, and a hydrolyzing agent is allowed to act on the compound of formula () to obtain a desired compound of formula ().
置換基Ｒ、R1、R2及びR3を表わすことができ
る意味としては、低級アルキル基、即ちメチル、
エチル、プロピル、イソプロピル、ブチル、イソ
ブチル、sec−ブチル又はｔ−ブチルがあげられ
る。また、置換基R1、R2及びR3はハロゲン原子、
即ちふつ素、塩素、臭素及びよう素を表わすこと
ができる。 Substituents R, R 1 , R 2 and R 3 can be represented by lower alkyl groups, i.e. methyl,
Mention may be made of ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl. In addition, substituents R 1 , R 2 and R 3 are halogen atoms,
That is, it can represent fluorine, chlorine, bromine and iodine.
式Ｒ−CHOで表わされるアルデヒドは、所望
のＲの意味に相当するアルデヒドである。 An aldehyde of the formula R-CHO is an aldehyde corresponding to the desired meaning of R.
Ｒがメチル基を表わすときは、アセトアルデヒ
ド三量体であるパラアルデヒドが好ましくは用い
られる。他のアルデヒドのうちではプロパナール
及びブタナールがあげられる。 When R represents a methyl group, paraaldehyde, which is an acetaldehyde trimer, is preferably used. Among other aldehydes, mention may be made of propanal and butanal.
用いられるハロゲン化水素酸は、好ましくは塩
酸又は臭化水素酸である。塩酸がもつぱら用いら
れる。 The hydrohalic acid used is preferably hydrochloric acid or hydrobromic acid. Hydrochloric acid is also commonly used.
式（）の化合物を式（）の化合物に変換せ
しめる反応はハロアルキル化、好ましくはクロル
アルキル化、特にクロルエチル化であり、そして
有機溶媒を添加し又は添加しないで行うことがで
きる。用いることできる溶媒としては、好ましく
は塩化メチレンのような塩素化溶媒があげられる
が、四塩化炭素又はクロロホルム、イソプロピル
エーテルのようなエーテル、シクロヘキサン、エ
タノール又はメタノールも用いることができる。
好ましくは合成順序は、溶液状の式（）の化合
物から出発して行われる。しかして、その溶液
は、反応溶媒と同一又は異なつている抽出溶媒で
あつてよい。反応溶媒が好ましくは用いられる。
好ましい溶媒は、抽出にも同じように使用できる
塩化メチレンである。 The reaction converting a compound of formula () into a compound of formula () is a haloalkylation, preferably a chloroalkylation, especially a chloroethylation, and can be carried out with or without the addition of an organic solvent. Solvents that can be used include preferably chlorinated solvents such as methylene chloride, but carbon tetrachloride or chloroform, ethers such as isopropyl ether, cyclohexane, ethanol or methanol can also be used.
Preferably, the synthetic sequence is carried out starting from a compound of formula () in solution. The solution may thus be an extraction solvent that is the same or different from the reaction solvent. A reaction solvent is preferably used.
A preferred solvent is methylene chloride, which can also be used for extraction.
反応に直接係るハロゲン化水素酸の他に、媒体
の酸性度は、りん酸又は酢酸のような他の酸を添
加することにより変えることができる。さらに、
塩化亜鉛又はアルミニウムのようなルイス酸を用
いることができる。 Besides the hydrohalic acid directly involved in the reaction, the acidity of the medium can be varied by adding other acids such as phosphoric acid or acetic acid. moreover,
Lewis acids such as zinc chloride or aluminum can be used.
明らかであるが、各種の反応剤、即ちチオフエ
ン、アルデヒド及び酸は、用いた操作条件に従つ
ていろいろな順序で導入することができる。 Obviously, the various reactants, namely thiophene, aldehyde and acid, can be introduced in various orders depending on the operating conditions used.
反応温度も広範に及ぶ。好ましい操作温度は−
10℃から周囲温度の間であつてよい。特に−５℃
附近の温度が用いられる。このような反応の特別
の例がOrg.Synth.Vol.38、p.86に記載されてい
る。 Reaction temperatures also range over a wide range. The preferred operating temperature is -
It may be between 10°C and ambient temperature. Especially -5℃
The nearby temperature is used. A particular example of such a reaction is described in Org.Synth.Vol.38, p.86.
式Ｒ−CHOのアルデヒドの反応性誘導体が用
いられるときは、この反応性誘導体は好ましくは
次式
（ここでHalはハロゲン原子を表わし、Alkは
好ましくは１〜３個の炭素原子を有するアルキル
基を表わす）
の化合物である。式
の上記化合物は、式Alk−OHのアルコール溶媒
中で式Ｒ−CHOのアルデヒドと式Ｈ−Halのハ
ロゲン化水素酸を反応させることによつて製造さ
れる。明らかなように、この場合に好んで用いら
れる反応性誘導体は、式Alk−OHのアルコール、
好ましくはメタノール又はエタノール中でアセト
アルデヒドCH3−CHOと塩酸を作用させること
により得られる次式
の化合物である。 When a reactive derivative of an aldehyde of the formula R-CHO is used, this reactive derivative preferably has the formula (Here Hal represents a halogen atom and Alk represents an alkyl group preferably having 1 to 3 carbon atoms). formula The above compound is prepared by reacting an aldehyde of formula R-CHO with a hydrohalic acid of formula H-Hal in an alcoholic solvent of formula Alk-OH. As is clear, the preferred reactive derivatives in this case are alcohols of the formula Alk-OH,
The following formula obtained by reacting acetaldehyde CH 3 -CHO with hydrochloric acid, preferably in methanol or ethanol It is a compound of
式（）の化合物から式（）の化合物への変
換は、好ましくはシアン化アルカリ金属又はアル
カリ土金属、例えばシアン化ナトリウム、カリウ
ム、リチウム又はカルシウムにより行われる。同
様にシアン化水素酸も使用できよう。シアン化ナ
トリウムが好ましい。操作は、塩基の存在に行な
われ、又はそれなしで行われる。塩基の存在下で
実施されるときは、水酸化ナトリウム又はカリウ
ム、特に水酸化ナトリウムが好ましい。しかしな
がら塩基なしで行うのが好ましい。好ましくは式
（）の化合物から式（）の化合物への反応は、
いわゆる相移動反応によつて行われる。そして操
作は特定の触媒の存在下に行われる。この触媒
は、例えば、テトラアルキル又はアラールキルア
ンモニウム、ホスホニウム又はアルソニウム塩、
又はスルホニウム塩であつてよい。この種の触媒
としては、例えば塩化トリエチルベンジルアンモ
ニウム、臭化テトラプロピルアンモニウム、臭化
テトラブチルアンモニウム、硫酸テトラブチルア
ンモニウム、水酸化テトラブチルアンモニウム、
塩化テトラ−ｎ−ブチルアンモニウム、よう化テ
トラメチルホスホニウム、臭化テトラ−ｎ−ブチ
ルホスホニウムがあげられる。これらの塩はイオ
ン交換樹脂に固定されていてよい。また、一般に
エーテル環と呼ばれる巨大環状ポリエーテルを用
いることもできる。このような化合物は、例えば
Tetrahedron LettersNo.18（1972）、p.1793に記載
されている。用いることができる化合物として
は、１，４，７，10，13，16−ヘキサオキサシク
ロオクタデカンがあげられる。要するに、高級ア
ルコール又は脂肪酸を例えばエチレンオキシドと
反応させることによつて形成される界面活性剤を
用いることができる。用いられる触媒は、好まし
くはハロゲン化アンモニウム、好ましくは臭化又
は塩化トリアルキルベンジル又はテトラアルキル
アンモニウムである。好ましい化合物は、塩化ト
リエチルベンジルアンモニウムである。 The conversion of compounds of formula () to compounds of formula () is preferably carried out with alkali metal or alkaline earth metal cyanides, such as sodium, potassium, lithium or calcium cyanide. Hydrocyanic acid could also be used. Sodium cyanide is preferred. The operation may be carried out in the presence of a base or without it. When carried out in the presence of a base, sodium or potassium hydroxide, especially sodium hydroxide, is preferred. However, it is preferred to work without a base. Preferably the reaction of a compound of formula () to a compound of formula () is
This is carried out by a so-called phase transfer reaction. The operation is then carried out in the presence of specific catalysts. The catalyst can be, for example, a tetraalkyl or aralkyl ammonium, phosphonium or arsonium salt,
Or it may be a sulfonium salt. Examples of this type of catalyst include triethylbenzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate, tetrabutylammonium hydroxide,
Examples include tetra-n-butylammonium chloride, tetramethylphosphonium iodide, and tetra-n-butylphosphonium bromide. These salts may be immobilized on an ion exchange resin. Furthermore, a giant cyclic polyether generally called an ether ring can also be used. Such compounds include, for example
Described in Tetrahedron Letters No. 18 (1972), p. 1793. Compounds that can be used include 1,4,7,10,13,16-hexaoxacyclooctadecane. In short, surfactants formed by reacting higher alcohols or fatty acids with, for example, ethylene oxide can be used. The catalyst used is preferably an ammonium halide, preferably trialkylbenzyl bromide or chloride or tetraalkylammonium. A preferred compound is triethylbenzylammonium chloride.
上述のように、好ましい実施方法においては、
式（）の化合物は有機溶液状、好ましくは塩化
メチレン又はジクロルエタン溶液で用いられる。
また、ジメチルホルムアミド又はジメチルスルホ
キシドのような極性溶媒を用いることもできる。
好ましくは塩化メチレンが用いられる。相移動触
媒の量は、用いる反応に応じて変えることができ
る。例えば、それは式（）の化合物に対して
0.2〜0.5部であろう。 As mentioned above, in a preferred method of implementation:
The compounds of formula () are used in organic solution, preferably in methylene chloride or dichloroethane.
It is also possible to use polar solvents such as dimethylformamide or dimethylsulfoxide.
Preferably methylene chloride is used. The amount of phase transfer catalyst can vary depending on the reaction used. For example, it is for a compound of formula ()
It would be 0.2 to 0.5 parts.
温度は、０℃から溶媒の還流温度までである。
０〜＋５℃程度の低温度で実施するのが好まし
い。 The temperature is from 0° C. to the reflux temperature of the solvent.
It is preferable to carry out at a low temperature of about 0 to +5°C.
式（）の化合物から式（）の化合物への加
水分解は、まず、ニトリルを所期の酸の塩、好ま
しくはナトリウム又はカリウム塩に変換するもの
である。この段階では水性相は、有機溶媒により
精製することができる。最後に水性相は酸性化さ
れ、そして所期生成物が抽出される。 The hydrolysis of a compound of formula () to a compound of formula () first converts the nitrile into the salt of the desired acid, preferably the sodium or potassium salt. At this stage the aqueous phase can be purified with organic solvents. Finally the aqueous phase is acidified and the desired product is extracted.
第一段階は水中で又は水と水混和性溶媒との混
合物中で行われる。用いられる溶媒は、好ましく
はエタノール又はイソプロパノールのような低級
アルコールである。アルカリ剤、好ましくは水酸
化ナトリウム又はカリウムが好ましくは50℃から
還流温度までの間の温度で反応せしめられる。操
作は、好ましくは純水中で還流状態で行われる。
反応時間は２時間〜15時間であつてよい。 The first step is carried out in water or in a mixture of water and a water-miscible solvent. The solvent used is preferably a lower alcohol such as ethanol or isopropanol. An alkaline agent, preferably sodium or potassium hydroxide, is reacted preferably at a temperature between 50°C and reflux temperature. The operation is preferably carried out in pure water at reflux.
The reaction time may be between 2 hours and 15 hours.
得られた塩の水溶液を精製するのに用いる有機
溶媒は、トルエン、ジクロルエタン又は塩化メチ
レンよりなる群から選ばれ、好ましくは塩化メチ
レンである。 The organic solvent used to purify the aqueous solution of the salt obtained is selected from the group consisting of toluene, dichloroethane or methylene chloride, preferably methylene chloride.
最後の酸性化は、好ましくは濃塩酸により行わ
れる。反応は、好ましくは、上記の群から選ばれ
る溶媒を添加した後に実施される。操作は、周囲
温度から溶媒の還流温度までの間であつてよい温
度で行われる。 The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is preferably carried out after adding a solvent selected from the above group. The operation is carried out at a temperature which may be between ambient temperature and the reflux temperature of the solvent.
式（）の化合物から式（）の化合物への加
水分解は、また、酸性媒体中で、好ましくは塩
酸、硫酸又はりん酸のような無機酸の存在下に行
うことができる。 Hydrolysis of compounds of formula () to compounds of formula () can also be carried out in an acidic medium, preferably in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid.
特に、本発明は、チオンフエンから上記のよう
実施して次式（′）
（ここでＲは前記の意味を有する）
の化合物を得ることを特徴とする製造法に係る。 In particular, the present invention can be carried out as described above from thionephen to form the formula (') (Here, R has the above-mentioned meaning) It relates to a production method characterized by obtaining the compound.
式（′）の化合物は、R1、R2及びR3がそれぞ
れ水素原子を表わす式（）の化合物に相当す
る。 The compound of formula (') corresponds to the compound of formula () in which R 1 , R 2 and R 3 each represent a hydrogen atom.
さらに詳しくは、本発明は、チオフエンとアセ
トアルデヒドから出発して上記のように実施する
ことを特徴とするα−メチル−２−チオフエン酢
酸の製造法に係る。 More particularly, the invention relates to a process for the production of α-methyl-2-thiophenoacetic acid, characterized in that it is carried out as described above starting from thiophene and acetaldehyde.
本発明の主題である方法の好ましい実施態様と
しては、式（）の化合物に対する式Ａ−CNの
化合物の作用が相移動反応により行われることを
特徴とする方法が用いられる。この方法は、好ま
しくは、塩化トリエチルベンジルアンモニウム、
臭化テトラプロピルアンモニウム、臭化テトラブ
チルアンモニウム、硫酸テトラブチルアンモニウ
ム及び水酸テトラブチルアンモニウムよりなる群
から選ばれる触媒の存在下に行われる。 A preferred embodiment of the process that is the subject of the invention is a process characterized in that the action of the compound of formula A-CN on the compound of formula () is carried out by a phase transfer reaction. The method preferably comprises triethylbenzylammonium chloride,
It is carried out in the presence of a catalyst selected from the group consisting of tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate and tetrabutylammonium hydroxide.
本法の特に好ましい実施方法においては、式
（）の化合物の塩化メチレン溶液がシアン化ナ
トリウムと相移動触媒との水溶液に注入される。
相移動触媒は、上述のように好ましくは塩化トリ
エチルベンジルアンモニウムである。 In a particularly preferred method of carrying out the process, a methylene chloride solution of the compound of formula () is injected into an aqueous solution of sodium cyanide and a phase transfer catalyst.
The phase transfer catalyst is preferably triethylbenzylammonium chloride as described above.
最後に、本発明の主題であるα−メチル−２−
チオフエン酢酸の製造法は次の好ましい条件で行
われる。 Finally, α-methyl-2-
The method for producing thiopheneacetic acid is carried out under the following preferred conditions.
塩酸とパラアルデヒドをチオフエンに反応させ
て２−（１−クロルエチル）チオフエンを得、こ
れに相移動反応により塩化トリエチルベンジルア
ンモニウムの存在下にシアン化ナトリウムを作用
させてα−メチル−２−チオフエンアセトニトリ
ルを得、これにまず水酸化ナトリウム、次いで塩
酸を作用させて所望の化合物を得る。 Hydrochloric acid and paraldehyde are reacted with thiophene to obtain 2-(1-chloroethyl)thiophene, which is then reacted with sodium cyanide in the presence of triethylbenzylammonium chloride through a phase transfer reaction to obtain α-methyl-2-thiophene. Acetonitrile is obtained and treated with sodium hydroxide and then with hydrochloric acid to obtain the desired compound.
下記の例は本発明を例示するもので、これを何
ら制限しない。 The examples below are illustrative of the invention and do not limit it in any way.
例１
α−メチル−２−チオフエン酢酸
工程Ａ：２−（１−クロルエチル）チオフエン
336c.c.の塩化メチレンと75c.c.の塩酸水溶液との
混合物をかきまぜながら−５℃に冷却し、次いで
一方で84ｇのチオフエンと44ｇのパラアルデヒド
との混合物を、他方で36.5ｇの塩酸水溶液を上記
温度で５時間にわたり導入した。この混合物をか
きまぜ、3.5ｇの塩酸を30分間で加えた。−５℃で
３時間かきまぜた後、混合物を０℃になし、50ｇ
の氷を入れた。全体を０〜＋５℃で15分間かきま
ぜ、有機相をデカンテーシヨンし、水性相を０〜
＋５℃で42c.c.の塩化メチレンにより抽出し、二つ
の有機相を一緒にした。Example 1 α-Methyl-2-thiopheneacetic acid Step A: 2-(1-chloroethyl)thiophene A mixture of 336 c.c. of methylene chloride and 75 c.c. of hydrochloric acid aqueous solution was cooled to -5°C with stirring, and then A mixture of 84 g of thiophene and 44 g of paraaldehyde was introduced on the one hand and 36.5 g of an aqueous hydrochloric acid solution on the other hand at the above temperature for 5 hours. The mixture was stirred and 3.5 g of hydrochloric acid was added over 30 minutes. After stirring at -5℃ for 3 hours, the mixture was brought to 0℃ and 50g
of ice was added. Stir the whole for 15 minutes at 0-5°C, decant the organic phase and remove the aqueous phase from 0-5°C.
Extracted with 42 c.c. of methylene chloride at +5°C and the two organic phases were combined.
工程Ｂ：α−メチル−２−チオフエンアセトニト
リル
88.5ｇのシアン化ナトリウムを168c.c.の脱塩水
に溶解して０〜＋５℃に冷却した溶液に8.4ｇの
塩化トリエチルベンジルアンモニウムを加えた。
間断なくかきまぜたこの媒体に上で得た２−（ク
ロルエチル）チオフエンの塩化メチレン溶液を１
分間で注いだ。０〜５℃で18時間激しくかきまぜ
続け、次いで252c.c.の脱塩水を加えた。10分間か
きまぜた後、有機相をデカンテーシヨンし、水性
相を84c.c.の塩化メチレンで抽出し、次いで42c.c.づ
つの同一溶媒で２回抽出した。有機相を一緒に
し、次いで脱塩水で洗い、さらに１％の純塩酸を
含む水、次いで脱塩水で洗つた。有機相を減圧下
に２時間濃縮し、105ｇの所期生成物を得た。Step B: α-Methyl-2-thiopheneacetonitrile 8.4 g of triethylbenzylammonium chloride was added to a solution of 88.5 g of sodium cyanide dissolved in 168 c.c. of demineralized water and cooled to 0 to +5°C.
To this constantly stirred medium was added 1 portion of the methylene chloride solution of 2-(chloroethyl)thiophene obtained above.
Poured in minutes. Vigorous stirring was continued for 18 hours at 0-5°C, then 252 c.c. of demineralized water was added. After stirring for 10 minutes, the organic phase was decanted and the aqueous phase was extracted with 84 c.c. of methylene chloride and then twice with 42 c.c. of the same solvent. The organic phases were combined and then washed with demineralized water, then with water containing 1% pure hydrochloric acid, and then with demineralized water. The organic phase was concentrated under reduced pressure for 2 hours to obtain 105 g of the expected product.
工程Ｃ：α−メチル−２−チオフエン酢酸
105ｇの上で得た生成物、500c.c.の脱塩水及び
63.2ｇの水酸化ナトリウムの混合物を２時間30分
還流させた。これを20℃に冷却し、168c.c.の塩化
メチレンを加えた。10分間かきまぜた後、塩化メ
チレン相をデカンテーシヨンした。同じ操作を２
回反復した。168c.c.のトルエン、次いで168゜Be´塩
酸を水性相に加えた。これを１時間還流させ、20
℃に冷却し、15分間かきまぜ、次いで水性相をデ
カンテーシヨンし、42c.c.づつの脱塩水で４回洗つ
た。有機相を減圧下に濃縮した。71〜74ｇの所期
化合物を得た。Step C: α-Methyl-2-thiopheneacetic acid 105 g of the product obtained above, 500 c.c. of demineralized water and
A mixture of 63.2 g of sodium hydroxide was refluxed for 2 hours and 30 minutes. This was cooled to 20°C and 168 c.c. of methylene chloride was added. After stirring for 10 minutes, the methylene chloride phase was decanted. Same operation 2
Repeated times. 168 c.c. of toluene was added to the aqueous phase followed by 168° Be' hydrochloric acid. Reflux this for 1 hour, and
C. and stirred for 15 minutes, then the aqueous phase was decanted and washed four times with 42 c.c. of demineralized water. The organic phase was concentrated under reduced pressure. 71-74 g of the expected compound were obtained.
例 ２ 例１の工程Ａ〜Ｃを下記の方法で変えた。Example 2 Steps A to C of Example 1 were modified in the following manner.
工程A1：２−（１−クロルエチル）チオフエン
84ｇのチオフエン、44ｇのパラアルデヒド及び
75c.c.の22゜Be´塩酸の混合物に、温度を10〜13℃に
保ちながら、ガス状塩酸を飽和するまで25分間吹
き込んだ。Step A 1 : 2-(1-chloroethyl)thiophene 84g thiophene, 44g paraaldehyde and
Gaseous hydrochloric acid was bubbled into a mixture of 75 c.c. of 22° Be´ hydrochloric acid for 25 minutes until saturation, maintaining the temperature between 10 and 13°C.
全体を75c.c.の氷冷水に注ぎ、デカンテーシヨン
した後、有機相を168c.c.の塩化メチレンで抽出し、
有機相を50c.c.の冷水で３回洗つた。 After pouring the whole into 75 c.c. of ice-cold water and decanting, the organic phase was extracted with 168 c.c. of methylene chloride and
The organic phase was washed three times with 50 c.c. of cold water.
工程A2
46ｇのエタノールと44ｇのパラアルデヒドとの
混合物にガス状塩酸を＋10℃で飽和するまで導入
した。この反応剤を84ｇのチオフエンに＋10℃で
かきまぜながら10分間で加えた。次いで操作を
A1に示したようにして行つた。 Step A 2 Gaseous hydrochloric acid was introduced into a mixture of 46 g of ethanol and 44 g of paraldehyde at +10° C. until saturation. This reactant was added to 84 g of thiophene at +10° C. over 10 minutes with stirring. Then operate
This was done as shown in A1 .
工程A3
84ｇのチオフエン、44ｇのパラアルデヒド、
168c.c.の塩化メチレン及び75c.c.の22゜Be´塩酸の混
合物を10〜13℃でかきまぜた。これに40ｇのガス
状塩酸を飽和させ、次いで０℃に冷却した。50ｇ
の氷を加え、デカンテーシヨンした後、水性相を
42c.c.の塩化メチレンで抽出し、全有機相を63c.c.の
冷水で２回洗つた。Step A 3 84g thiophene, 44g paraaldehyde,
A mixture of 168 c.c. of methylene chloride and 75 c.c. of 22° Be' hydrochloric acid was stirred at 10-13°C. This was saturated with 40 g of gaseous hydrochloric acid and then cooled to 0°C. 50g
After adding ice and decanting, remove the aqueous phase.
Extracted with 42 c.c. of methylene chloride and washed all organic phases twice with 63 c.c. of cold water.
工程B1
塩化トリエチルベンジルアンモニウムに代えて
下記の反応剤を用いた。Step B The following reactant was used in place of triethylbenzylammonium 1 chloride.
臭化テトラプロピルアンモニウム
臭化テトラブチルアンモニウム
硫酸テトラブチルアンモニウム
水酸化テトラブチルアンモニウム
工程C1
抽出溶媒として塩化メチレンに代えてジクロル
エタンを用いた。 Tetrapropylammonium bromide Tetrabutylammonium bromide Tetrabutylammonium sulfate Tetrabutylammonium hydroxide Step C1 Dichloroethane was used in place of methylene chloride as the extraction solvent.
Claims (1)
ルキル基を表わし、R1、R2及びR3は同一又は異
なつていてよく、それぞれ水素原子、１〜４個の
炭素原子を有するアルキル基又はハロゲン原子を
表わす）の２−チオフエン酢酸の誘導体を製造す
るにあたり、次式（） （ここでR1、R2及びR3は前記の意味を有する） の化合物に式Ｈ−Halのハロゲン化水素酸の存在
下に式Ｒ−CHOのアルデヒドか又は式Ｒ−CHO
のアルデヒドの誘導体を反応させて次式（） （ここでHalはハロゲン原子を表わす） の化合物を得、式（）の化合物を次式 Ａ−CN （ここでＡはアルカリ金属原子、当量のアルカ
リ土金属又は水素原子を表わす） の化合物と反応させて次式（） の化合物を得、式（）の化合物に加水分解剤を
作用させて式（）の所期化合物を得ることを特
徴とする２−チオフエン酢酸の誘導体の製造法。 ２ チオフエンから出発して次式（′） （ここでＲは特許請求の範囲第１項記載の意味
を有する） の化合物を製造することを特徴とする特許請求の
範囲第１項記載の製造法。 ３ チオフエンとアセトアルデヒドから出発して
α−メチル−２−チオフエン酢酸を製造すること
を特徴とする特許請求の範囲第２項記載の製造
法。 ４ 式（）の化合物に対する式Ａ−CNの化合
物の作用が相移動反応により行われることを特徴
とする特許請求の範囲第１〜３項のいずれかに記
載の製造法。 ５ 式（）の化合物に対するＡ−CNの化合物
の作用が、塩化トリエチルベンジルアンモニウ
ム、臭化テトラプロピルアンモニウム、臭化テト
ラブチルアンモニウム、硫酸テトラブチルアンモ
ニウム及び水酸化テトラブチルアンモニウムより
なる群から選ばれる触媒の存在下に相移動反応に
より行われることを特徴とする特許請求の範囲第
１〜４項のいずれかに記載の製造法。 ６ 相移動反応の間に式（）の化合物の塩化メ
チレン溶液がシアン化ナトリウムと相移動触媒と
の水溶液中に注入されることを特徴とする特許請
求の範囲第１〜５項のいずれかに記載の製造法。 ７ 塩酸とパラアルデヒドをチオフエンに反応さ
せて２−（１−クロルエチル）チオフエンを得、
これに相移動反応により塩化トリエチルベンジル
アンモニウムの存在下にシアン化ナトリウムを作
用させてα−メチル−２−チオフエンアセトニト
リルを得、これにまず水酸化ナトリウム、次いで
塩酸を作用させてα−メチル−２−チオフエン酢
酸を製造することを特徴とする特許請求の範囲第
１〜６項のいずれかに記載の製造法。[Claims] Linear formula () (Here, R represents an alkyl group having 1 to 4 carbon atoms, R 1 , R 2 and R 3 may be the same or different, and each has a hydrogen atom and 1 to 4 carbon atoms. In producing a derivative of 2-thiopheneacetic acid (representing an alkyl group or a halogen atom), the following formula () (wherein R 1 , R 2 and R 3 have the abovementioned meanings) in the presence of a hydrohalic acid of formula H-Hal to form an aldehyde of formula R-CHO or an aldehyde of formula R-CHO
The following formula () is obtained by reacting the aldehyde derivative of (where Hal represents a halogen atom) is obtained, and the compound of formula () is reacted with a compound of the following formula A-CN (where A represents an alkali metal atom, an equivalent alkaline earth metal or a hydrogen atom). Let the following formula () 1. A method for producing a derivative of 2-thiopheneacetic acid, which comprises obtaining a compound of formula () and reacting the compound of formula () with a hydrolyzing agent to obtain a desired compound of formula (). 2 Starting from thiophene, the following formula (') (Here, R has the meaning as defined in claim 1.) A manufacturing method according to claim 1, characterized in that the compound is manufactured as follows. 3. The production method according to claim 2, characterized in that α-methyl-2-thiopheneacetic acid is produced starting from thiophene and acetaldehyde. 4. The production method according to any one of claims 1 to 3, wherein the action of the compound of formula A-CN on the compound of formula () is carried out by a phase transfer reaction. 5 The action of the compound of A-CN on the compound of formula () is a catalyst selected from the group consisting of triethylbenzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate, and tetrabutylammonium hydroxide. The manufacturing method according to any one of claims 1 to 4, characterized in that the manufacturing method is carried out by a phase transfer reaction in the presence of. 6. Any one of claims 1 to 5, characterized in that during the phase transfer reaction a methylene chloride solution of the compound of formula () is injected into an aqueous solution of sodium cyanide and a phase transfer catalyst. Manufacturing method described. 7. React hydrochloric acid and paraaldehyde with thiophene to obtain 2-(1-chloroethyl)thiophene,
This was reacted with sodium cyanide in the presence of triethylbenzylammonium chloride through a phase transfer reaction to obtain α-methyl-2-thiopheneacetonitrile, which was first reacted with sodium hydroxide and then with hydrochloric acid to obtain α-methyl-2-thiopheneacetonitrile. 7. The manufacturing method according to any one of claims 1 to 6, characterized in that 2-thiopheneacetic acid is manufactured.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220272A FR2537138A1 (en) | 1982-12-03 | 1982-12-03 | PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES |
| FR8220272 | 1982-12-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59106483A JPS59106483A (en) | 1984-06-20 |
| JPH0439468B2 true JPH0439468B2 (en) | 1992-06-29 |
Family
ID=9279758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58087836A Granted JPS59106483A (en) | 1982-12-03 | 1983-05-20 | Manufacture of 2-thiopheneacetic acid derivative |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59106483A (en) |
| KR (1) | KR900003281B1 (en) |
| AT (1) | AT392785B (en) |
| AU (1) | AU557065B2 (en) |
| BE (1) | BE896440A (en) |
| CA (1) | CA1201442A (en) |
| CH (1) | CH653681A5 (en) |
| DE (1) | DE3314028C2 (en) |
| DK (1) | DK157492C (en) |
| ES (1) | ES8401958A1 (en) |
| FI (1) | FI80882C (en) |
| FR (1) | FR2537138A1 (en) |
| GB (1) | GB2132608B (en) |
| HU (1) | HU191831B (en) |
| IE (1) | IE55097B1 (en) |
| IT (1) | IT1174758B (en) |
| LU (1) | LU84749A1 (en) |
| NL (1) | NL8301693A (en) |
| NZ (1) | NZ204510A (en) |
| PT (1) | PT76535B (en) |
| SE (1) | SE453918B (en) |
| ZA (1) | ZA832697B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1276738B1 (en) * | 1995-06-16 | 1997-11-03 | Erregierre Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF -METHYL-2- THIOPHENEACETIC ACID |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE33054B1 (en) * | 1968-04-16 | 1974-03-06 | Ici Ltd | Heterocyclic compounds |
| GB2003570B (en) * | 1977-06-08 | 1982-01-20 | Imi Opella Ltd | Stop valve |
-
1982
- 1982-12-03 FR FR8220272A patent/FR2537138A1/en active Granted
-
1983
- 1983-03-28 DK DK140083A patent/DK157492C/en not_active IP Right Cessation
- 1983-03-30 SE SE8301786A patent/SE453918B/en not_active IP Right Cessation
- 1983-03-31 FI FI831116A patent/FI80882C/en not_active IP Right Cessation
- 1983-04-05 ES ES521231A patent/ES8401958A1/en not_active Expired
- 1983-04-11 PT PT76535A patent/PT76535B/en not_active IP Right Cessation
- 1983-04-12 BE BE0/210537A patent/BE896440A/en unknown
- 1983-04-12 CH CH1966/83A patent/CH653681A5/en not_active IP Right Cessation
- 1983-04-14 LU LU84749A patent/LU84749A1/en unknown
- 1983-04-14 HU HU831307A patent/HU191831B/en unknown
- 1983-04-15 AU AU13573/83A patent/AU557065B2/en not_active Ceased
- 1983-04-18 DE DE3314028A patent/DE3314028C2/en not_active Expired - Lifetime
- 1983-04-18 ZA ZA832697A patent/ZA832697B/en unknown
- 1983-04-23 KR KR1019830001730A patent/KR900003281B1/en not_active IP Right Cessation
- 1983-05-04 IT IT48216/83A patent/IT1174758B/en active Protection Beyond IP Right Term
- 1983-05-09 GB GB08312702A patent/GB2132608B/en not_active Expired
- 1983-05-10 IE IE1074/83A patent/IE55097B1/en not_active IP Right Cessation
- 1983-05-11 NL NL8301693A patent/NL8301693A/en active Search and Examination
- 1983-05-20 JP JP58087836A patent/JPS59106483A/en active Granted
- 1983-06-09 NZ NZ204510A patent/NZ204510A/en unknown
- 1983-07-28 CA CA000433422A patent/CA1201442A/en not_active Expired
- 1983-08-08 AT AT2867/83A patent/AT392785B/en not_active IP Right Cessation
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