JPH0269473A - Production of thiopheneacetic acid derivative - Google Patents
Production of thiopheneacetic acid derivativeInfo
- Publication number
- JPH0269473A JPH0269473A JP22214788A JP22214788A JPH0269473A JP H0269473 A JPH0269473 A JP H0269473A JP 22214788 A JP22214788 A JP 22214788A JP 22214788 A JP22214788 A JP 22214788A JP H0269473 A JPH0269473 A JP H0269473A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- thiophene
- methyl
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical class OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 239000011630 iodine Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract 3
- WBMKDDSMYHLQTN-UHFFFAOYSA-N acetic acid;thiophene Chemical class CC(O)=O.C=1C=CSC=1 WBMKDDSMYHLQTN-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical class OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 33
- 239000002253 acid Substances 0.000 abstract description 15
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 9
- 150000004820 halides Chemical class 0.000 abstract description 5
- 239000002841 Lewis acid Substances 0.000 abstract description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 4
- 150000007517 lewis acids Chemical class 0.000 abstract description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 229930192474 thiophene Natural products 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- FUOHKPSBGLXIRL-UHFFFAOYSA-N 2-(chloromethyl)thiophene Chemical compound ClCC1=CC=CS1 FUOHKPSBGLXIRL-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- -1 ethyl α-cyano(2-thienyl)acetate Chemical compound 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- MFPZQZZWAMAHOY-UHFFFAOYSA-N 2-Propanoylthiophene Chemical compound CCC(=O)C1=CC=CS1 MFPZQZZWAMAHOY-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 229910015900 BF3 Inorganic materials 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- CLSHQIDDCJTHAJ-UHFFFAOYSA-N 2-thienylacetonitrile Chemical compound N#CCC1=CC=CS1 CLSHQIDDCJTHAJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 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 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- KETQAJRQOHHATG-UHFFFAOYSA-N 1,2-naphthoquinone Chemical compound C1=CC=C2C(=O)C(=O)C=CC2=C1 KETQAJRQOHHATG-UHFFFAOYSA-N 0.000 description 1
- FEIFPQVJDGUDDG-UHFFFAOYSA-N 2-(3-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C=CC(C(=O)C=2C=CC=CC=2)=C1C(C(O)=O)C FEIFPQVJDGUDDG-UHFFFAOYSA-N 0.000 description 1
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 1
- QTOABKRIUPTTPQ-UHFFFAOYSA-N 2-thiophen-2-ylpropanenitrile Chemical compound N#CC(C)C1=CC=CS1 QTOABKRIUPTTPQ-UHFFFAOYSA-N 0.000 description 1
- KTKWUKAYWFMQSO-UHFFFAOYSA-N 2-thiophen-2-ylpropanoic acid Chemical compound OC(=O)C(C)C1=CC=CS1 KTKWUKAYWFMQSO-UHFFFAOYSA-N 0.000 description 1
- RUJYJCANMOTJMO-UHFFFAOYSA-N 3-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC(C(Cl)=O)=C1 RUJYJCANMOTJMO-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical class CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- KNKIXYMOHMYZJR-UHFFFAOYSA-N methyl 2-thiophen-2-ylacetate Chemical compound COC(=O)CC1=CC=CS1 KNKIXYMOHMYZJR-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 竜朶よ五皿里丘! 本発明は、チオフェン酢酸誘導体の製造法に関する。[Detailed description of the invention] Ryūto, Gosara-Satooka! The present invention relates to a method for producing thiophene acetic acid derivatives.
一般式
(式中、R及びR1は前記に同じ。)
〔式中R,R’及びR2は、同−又は異なって水素原子
又はアルキル基を示す。〕
で表わされるチオフェン酢酸誘導体は、非ステロイド系
鎮痛、抗炎症作用に著しい効力を発揮する一方において
、胃粘膜刺激作用が繁用の消炎鎮痛剤に比し比較的弱い
という特徴を有する、−最大〔式中R,R’−及びR2
は前記に同じ。Arは)工二ル基、シクロヘキシル基又
はチエニル、フリル、テトラヒドロフリル、ピリジル等
の複素環残基を示す。上記フェニル環及びシクロヘキシ
ル環上には、ハロゲン原子、アルキル基、トリハロゲノ
メチル基及びアルコキシ基が置換されていてもよい。〕
で表わされるチオフェン酢酸誘導体を合成するための中
間体として重要な化合物である。General formula (in the formula, R and R1 are the same as above) [In the formula, R, R' and R2 are the same or different and represent a hydrogen atom or an alkyl group. ] The thiophene acetic acid derivative represented by is characterized by its remarkable non-steroidal analgesic and anti-inflammatory effects, but its gastric mucosal stimulating effect is relatively weak compared to commonly used anti-inflammatory analgesics. [In the formula, R, R'- and R2
is the same as above. Ar) represents a cyclohexyl group, a cyclohexyl group, or a heterocyclic residue such as thienyl, furyl, tetrahydrofuryl, and pyridyl. The phenyl ring and cyclohexyl ring may be substituted with a halogen atom, an alkyl group, a trihalogenomethyl group, or an alkoxy group. ] It is an important compound as an intermediate for synthesizing the thiophene acetic acid derivative represented by
従来、上記−最大(1)で表わされるチオフェン酢酸誘
導体は、例えば下記に示す方法で製造されている。Conventionally, the thiophene acetic acid derivative represented by -maximum (1) above has been produced, for example, by the method shown below.
即ち、まず2−(クロロメチル)チオフェンとシアン化
ナトリウムとの反応で得られた(2−チエニル)アセト
ニトリルを金属ナトリウムの存在下、炭酸ジエチルと反
応させてα−シアノ(2−チエニル)酢酸エチルを製造
しく K、 pettersson。That is, first, (2-thienyl)acetonitrile obtained by the reaction of 2-(chloromethyl)thiophene and sodium cyanide is reacted with diethyl carbonate in the presence of metallic sodium to form ethyl α-cyano(2-thienyl)acetate. K. Pettersson.
Acta、Chem、5cand、、 7.1311
(1953)参照)、次いでこれをナトリウムエトキシ
ドの存在下沃化メチルでメチル化した後、エタノール−
水酸化カリウムにより加水分解し、更に生成したα−メ
チル−(2−チエニル)シアノ酢酸を脱炭酸してα−メ
チル−(2−チエニル)アセトニトリルとし、最後にこ
れを加水分解してα−メチル−2−チオフェン酢酸が製
造すれている()1. BerCOt−Vattero
ni、Bull、Soc、Chim、Fr、、 182
0(1961)参照)。Acta, Chem, 5cand,, 7.1311
(1953)), which was then methylated with methyl iodide in the presence of sodium ethoxide, followed by ethanol-
Hydrolyzed with potassium hydroxide, the resulting α-methyl-(2-thienyl)cyanoacetic acid is further decarboxylated to α-methyl-(2-thienyl)acetonitrile, and finally this is hydrolyzed to form α-methyl -2-thiopheneacetic acid is produced ()1. BerCOt-Vattero
ni, Bull, Soc, Chim, Fr,, 182
0 (1961)).
上記の方法において、出発原料として用いられる2−(
クロロメチル)チオフェンは、チオフェンのクロロメチ
ル化により製造される( F、 F。In the above method, 2-(
chloromethyl)thiophene is produced by chloromethylation of thiophene (F, F).
B!1cke、J、Amer、Chem、Soc、、6
旦、1934(1946)参照〕が、この際に副生物と
して発ガン性のビス(クロロメチル)エーテルが生成す
るを避は得ず、しかも2−(クロロメチル)チオフェン
の収率は約47%と低く、加えてこの2−(クロロメチ
ル)チオフェンは爆発性であるため、その取扱いに細心
の注意を要する等の致命的欠点があり、従って2−(ク
ロロメチル)チオフェンは入手容易な化合物とは言い得
ないものである。B! 1cke, J., Amer, Chem, Soc,, 6
1934 (1946)], but in this process, carcinogenic bis(chloromethyl)ether is unavoidably produced as a by-product, and the yield of 2-(chloromethyl)thiophene is approximately 47%. In addition, this 2-(chloromethyl)thiophene is explosive, so it has fatal drawbacks such as requiring extreme care when handling it. Therefore, 2-(chloromethyl)thiophene is not an easily available compound. cannot be said.
更にこの2−(クロロメチル)チオフェンを(2−チエ
ニル)アセトニトリル変換する際には、猛毒なシアン化
ナトリウムの使用が不可欠とされている。Furthermore, when converting this 2-(chloromethyl)thiophene into (2-thienyl)acetonitrile, it is essential to use highly toxic sodium cyanide.
このように従来の方法は、上記−最大(1)のチオフェ
ン酢酸誘導体の工業的製造法として不適当なものである
。As described above, the conventional method is unsuitable as an industrial method for producing the thiophene acetic acid derivative (1) above.
C1戸をr決するための手段
本発明の目的は、上記−最大(1)のチオフェン酢酸誘
導体の工業的に有利な製造法を提供することにある。Means for Determining C1 The object of the present invention is to provide an industrially advantageous method for producing the above-mentioned thiophene acetic acid derivative (1).
即ち、本発明は、−最大
〔式中Rは前記に同じ。〕
で表わされる化合物と一般式
%式%(4)
C式中Xはハロゲン原子を示す。R1は前記に同じ。)
で表わされる化合物とを反応させ、次いで得られる一般
式
〔式中、R及びR1は前記に同じ。〕
で表わされる化合物にヨード活性種の存在下、オルト蟻
酸エステル類を反応させて一最大〔式中R,R1及びR
2は前記に同じ。〕で表わされるチオフェン酢酸誘導体
を得ることを特徴とするチオフェン酢酸誘導体の製造法
に係る。That is, the present invention provides - maximum [wherein R is the same as above. ] A compound represented by the general formula %Formula % (4)C In the formula, X represents a halogen atom. R1 is the same as above. ) is then reacted with a compound represented by the following general formula [wherein R and R1 are the same as above]. [In the formula, R, R1 and R
2 is the same as above. The present invention relates to a method for producing a thiophene acetic acid derivative, which is characterized by obtaining a thiophene acetic acid derivative represented by the following.
上記−最大(5)の化合物は、−最大(3)の化合物に
一般式(4)の酸ハロゲン化物を適当な触媒の存在下に
、フリーデル・クラフッ反応させることにより製造され
る。出発原料として用いられる一般式(3)の化合物及
び−最大(4)の酸ハロゲン化物は、いずれも入手容易
な公知の化合物である。−最大(4)の酸ハロゲン化物
には、例えば塩化プロピオニル、臭化プロピオニル等が
包含される。−最大(4)の酸ハロゲン化物の使用量は
、−最大(3)の化合物に対して通常0.7〜1.2倍
モル量程度、好ましくは0.8〜1.1倍モル量程度と
するのがよい。該反応に用いられる触媒としては、慣用
の触媒を広く使用でき、例えば塩化アルミニウム、塩化
第二鉄、五塩化アンチモン、三弗化硼素、塩化亜鉛、四
塩化錫、塩化チタン、弗化硼素、四塩化チタン等を挙げ
ることができる。斯かる触媒の使用量は、−最大(3)
の化合物に対して通常0.5〜2倍モル最程度、好まし
くは0.7〜1.5倍モル量程度とするのがよい。上記
反応は、無溶媒下又は適当な溶媒中で行なわれる。用い
られる溶媒としては、例えば二硫化炭素、ニトロベンゼ
ン、ベンゼン、トルエン、キシレン、クロロホルム、四
塩化炭素、塩化メチレン、ジクロロエタン等を挙げるこ
とができる。斯かる溶媒は、−最大(3)の化合物に対
し、通常1〜30倍重量程度、好ましくは1.5〜25
倍重量程度使用するのがよい。該反応は、通常−10〜
30℃程度、好ましくは一5〜20℃程度で好適に進行
し、一般に該反応は2〜5時間程度で終了する。斯くし
て一般式(5)で表わされる化合物が製造される。The above compound (5) is produced by subjecting the compound (3) to a Friedel-Krach reaction with an acid halide of general formula (4) in the presence of a suitable catalyst. The compound of general formula (3) and the acid halide of -maximum (4) used as starting materials are both easily available and known compounds. - Maximum (4) acid halides include, for example, propionyl chloride, propionyl bromide, and the like. - The maximum amount of acid halide (4) to be used is usually about 0.7 to 1.2 times the molar amount, preferably about 0.8 to 1.1 times the molar amount of the maximum (3) compound. It is better to As the catalyst used in this reaction, a wide variety of conventional catalysts can be used, such as aluminum chloride, ferric chloride, antimony pentachloride, boron trifluoride, zinc chloride, tin tetrachloride, titanium chloride, boron fluoride, tetrafluoride, etc. Examples include titanium chloride. The amount of such catalyst used is -maximum (3)
The amount is usually about 0.5 to 2 times the molar amount, preferably about 0.7 to 1.5 times the molar amount of the compound. The above reaction is carried out without a solvent or in a suitable solvent. Examples of the solvent used include carbon disulfide, nitrobenzene, benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, and dichloroethane. Such a solvent is usually about 1 to 30 times the weight of the compound (3) at most, preferably 1.5 to 25 times the weight of the compound (3).
It is best to use about twice the weight. The reaction is usually −10 to
The reaction proceeds suitably at about 30°C, preferably about -5 to 20°C, and generally completes in about 2 to 5 hours. In this way, a compound represented by general formula (5) is produced.
本発明では、斯くして得られる一般式く5)の化合物を
単離した後、次の反応に供してもよいし、反応混合物の
まま次の反応に供してもよい。In the present invention, the compound of general formula (5) thus obtained may be isolated and then subjected to the next reaction, or the reaction mixture may be subjected to the next reaction.
本発明においては、次いで一般式(5)の化合物にヨー
ド活性種の存在下、オルト@酸エステル類を反応させる
。ヨード活性種としては、例えば沃素、沃化メチル、沃
化亜鉛、沃化銅、沃化銀等が挙げられる。斯かるヨード
活性種は、−最大(5)の化合物に対して、通常0.1
〜1.5倍モル量程度、好ましくは0.2〜1.4倍モ
ル量程度使用するのがよい。またオルト1!酸エステル
類としては、従来公知のものを広く使用でき、例えばオ
ルト蟻酸メチル、オルト蟻酸エチル等を挙げることがで
きる。オルト1!酸エステル類は、−最大(5)の化合
物に対して、通常0.8〜15倍重量程度、好ましくは
1〜14倍重量程度使用するのがよい。上記反応は、無
溶媒下及び適当な溶媒中のいずれでも行なわれるが、溶
媒中で反応を行なう場合には、上記オルト蟻酸エステル
類の使用量を大幅に減じることができる。溶媒としては
、ハロゲン化メタン、ハロゲン化エタン等を例示できる
。また上記反応系内には、プロトン酸やルイス酸を添加
して、該反応の反応速度を増大させることができる。こ
こでプロトン酸としては、例えば硫酸、p−トルエンス
ルホン酸、メタンスルホン酸、トリクロロ酢酸、トリク
ロロスルホン酸等を、またルイス酸としては、例えば塩
化アルミニウム、塩化第二鉄、五塩化アンチモン、三弗
化硼素、塩化亜鉛、塩化チタン、弗化硼素、四塩化錫、
四塩化チタン等が挙げられる。これらプロトン酸やルイ
ス酸の使用量としては、−最大(5)の化合物に対して
、通常0.1〜1.5倍モル量程度、好ましくは0.2
〜1.4倍モル量程度とするのがよい。該反応は、通常
O〜40’C程度、好ましくは10〜30’C程度で好
適に進行し、−般に10〜30時間程度で該反応は完結
する。斯くして本発明の目的化合物である一般式(1)
のチオフェン酢酸誘導体が製造される。In the present invention, the compound of general formula (5) is then reacted with an ortho-acid ester in the presence of an iodine active species. Examples of the iodine active species include iodine, methyl iodide, zinc iodide, copper iodide, and silver iodide. Such iodine active species are usually 0.1 for -maximum (5) compounds.
It is preferable to use about 1.5 to 1.5 times the molar amount, preferably about 0.2 to 1.4 times the molar amount. Alto 1 again! As the acid ester, a wide variety of conventionally known ones can be used, such as methyl orthoformate, ethyl orthoformate, and the like. Alt 1! The acid esters are usually used in an amount of about 0.8 to 15 times, preferably about 1 to 14 times, the weight of the -maximum (5) compound. The above reaction can be carried out either in the absence of a solvent or in a suitable solvent; however, when the reaction is carried out in a solvent, the amount of the orthoformates used can be significantly reduced. Examples of the solvent include halogenated methane and halogenated ethane. Furthermore, the reaction rate of the reaction can be increased by adding a protonic acid or a Lewis acid to the reaction system. Examples of the protonic acid include sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, trichlorosulfonic acid, etc., and examples of the Lewis acid include aluminum chloride, ferric chloride, antimony pentachloride, trifluorochloride, etc. Boron chloride, zinc chloride, titanium chloride, boron fluoride, tin tetrachloride,
Examples include titanium tetrachloride. The amount of these protonic acids and Lewis acids to be used is usually about 0.1 to 1.5 times the molar amount of the compound (5), preferably 0.2
It is preferable to set the amount to about 1.4 times the molar amount. The reaction normally proceeds suitably at about 0 to 40'C, preferably about 10 to 30'C, and is generally completed in about 10 to 30 hours. Thus, the object compound of the present invention, general formula (1)
A thiophene acetic acid derivative is produced.
上記で得られる一般式(1)のチオフェン酢酸誘導体は
、下記に示す方法に従い、−最大(2)のチオフェン酢
酸誘導体に誘導される。The thiophene acetic acid derivative of general formula (1) obtained above is induced into the thiophene acetic acid derivative of -maximum (2) according to the method shown below.
即ち、−最大(2)のチオフェン酢酸誘導体は、−最大
(1)のチオフェン酢酸誘導体と酸塩化物とを適当な触
媒の存在下にフリーデル・クラフッ反応させることによ
り製造される。酸塩化物としては、従来公知のものを広
く使用でき、例えばベンゾイルクロリド、p−り咀しベ
ンゾイルクロリド、ヘキサヒドロベンゾイルクロリド、
α−テノイルクロリド、m−トリフルオルメチルベンゾ
イルクロリド等が挙げられる。斯かる酸塩化物は、−最
大(1)の化合物に対し、通常0.8〜1.3倍モル量
程度、好ましくは0.9〜1.1倍モル量程度とするの
がよい。該反応に用いられる触媒としては、上記−最大
(3)の化合物と一般式(4)の化合物との反応で用い
られる触媒をいずれも使用できる。斯かる触媒の使用量
は、−最大(1)の化合物に対し、通常0.5〜1.5
倍モル量程度、好ましくは0.7〜1.2倍モル量程度
とするのがよい。上記反応は、無溶媒下又は適当な溶媒
中で行なわれる。溶媒としても、上記−最大(3)の化
合物と一般式(4)の化合物との反応で用いられる溶媒
をいずれも使用できる。That is, - the maximum (2) thiophene acetic acid derivative is produced by - subjecting the maximum (1) thiophene acetic acid derivative and an acid chloride to a Friedel-Krach reaction in the presence of a suitable catalyst. As the acid chloride, a wide variety of conventionally known ones can be used, such as benzoyl chloride, p-triated benzoyl chloride, hexahydrobenzoyl chloride,
Examples include α-thenoyl chloride, m-trifluoromethylbenzoyl chloride, and the like. The amount of such acid chloride is usually about 0.8 to 1.3 times, preferably about 0.9 to 1.1 times, the amount of the compound (1). As the catalyst used in the reaction, any catalyst used in the reaction between the compound of (3) above and the compound of general formula (4) can be used. The amount of such catalyst used is usually 0.5 to 1.5 per compound (1).
The amount should be about double the molar amount, preferably about 0.7 to 1.2 times the molar amount. The above reaction is carried out without a solvent or in a suitable solvent. As the solvent, any of the solvents used in the reaction between the compound of maximum (3) above and the compound of general formula (4) can be used.
溶媒は、−最大(1)の化合物に対し、通常1〜30倍
重量程度、好ましくは1.5〜25倍重量程度使用する
のがよい。該反応は、通常O〜20℃程度、好ましくは
5〜10’C程度で好適に進行し、一般に該反応は2〜
5時間程度で終了する。The solvent is usually used in an amount of about 1 to 30 times, preferably about 1.5 to 25 times, the weight of the compound (1). The reaction normally proceeds suitably at a temperature of about 0 to 20°C, preferably about 5 to 10°C, and generally the reaction proceeds at a temperature of about 2 to 20°C.
It will be completed in about 5 hours.
斯くして一般式(2)で表わされるチオフェン酢酸誘導
体が!!!造される。Thus, the thiophene acetic acid derivative represented by the general formula (2) is obtained! ! ! will be built.
発明の効果 本発明の方法の利点は以下の通りである。Effect of the invention The advantages of the method of the invention are as follows.
(1) 本発明の方法で使用される原料化合物は、い
ずれも極めて安価であり、しかも市場において豊富に供
給され得る化合物である。(1) The raw material compounds used in the method of the present invention are all extremely inexpensive and can be abundantly supplied on the market.
(2) 本発明の各工程の反応は、いずれも容易に進
行するものであり、しかも副反応物の生成が極めて少な
く、従って目的物を高収率且つ高純度で製造し得る。(2) The reactions in each step of the present invention proceed easily, and produce very few by-products, so that the desired product can be produced in high yield and purity.
(3) 本発明の方法で使用されるヨード活性種やオ
ルト蟻酸エステル類は、反応終了後、特に精密装置を必
要とすることなく高収率で回収され、次回の反応に再使
用することができる。(3) After the reaction, the iodine active species and orthoformates used in the method of the present invention can be recovered in high yield without requiring any precision equipment, and can be reused in the next reaction. can.
従ってヨード活性種やオルト蟻酸エステル類の補充を殆
んど行なうことなく、容易に本発明の目的化合物を製造
することができる。Therefore, the target compound of the present invention can be easily produced without almost any replenishment of active iodine species or orthoformates.
(4) 本発明の方法は、高温、高圧を必要とせず、
室温でしかも常圧下で極めて安全に行なうことができ、
また複雑且つ高価な設備を必要としないので、操作が簡
便でおる上に、経済性も優れている。(4) The method of the present invention does not require high temperature or high pressure;
It can be carried out extremely safely at room temperature and under normal pressure.
Furthermore, since no complicated and expensive equipment is required, the operation is simple and economical.
実 施 例 以下に実施例を掲げて本発明をより一層明らかにする。Example Examples are given below to further clarify the present invention.
実施例1
プロピオニルチオフェンの合成
チオフェン’1OOCI及びプロピオニルクロリド11
0(]を反応装置に仕込み、撹拌しなから四塩化錫30
0gを反応温度−5〜20℃に保持しながら、数時間要
して滴下した。更に同温度で4時間撹拌を続けた後、こ
れを加水分解してクロロホルムで抽出した。クロロホル
ムを留去後、真空蒸留して73°C/7mmHg留分を
採取すると、プロピオニルチオフェン159.5qが得
られた。これは理論量の95.9%に相当する。Example 1 Synthesis of propionylthiophene Thiophene '1OOCI and propionyl chloride 11
0 () into the reactor, and without stirring tin tetrachloride 30
0 g was added dropwise over several hours while maintaining the reaction temperature at -5 to 20°C. After further stirring at the same temperature for 4 hours, the mixture was hydrolyzed and extracted with chloroform. After chloroform was distilled off, a 73°C/7mmHg fraction was collected by vacuum distillation to obtain 159.5q of propionylthiophene. This corresponds to 95.9% of the theoretical amount.
IRスペクトルに−ト):
1670.1420,800,712cm−1M5スペ
クトル(m/e):140.248NMRスペクトル
δppmニ
ア、1〜7.7 (m、3H)、
2.8 (Q、2H) 、1.3 (t、3H)実施例
2
α−メチル−2−チオフェン 酸メチルの合成プロピオ
ニルチオフェン21(7、沃素46q1オルト蟻酸メチ
ル64 mf2及びジクロルエタン200m12を反応
装置に仕込み、反応温度20〜30’Cに保持しながら
20時間撹拌を続けた。その後ジクロルエタン、沃素及
びオルト1!メチルを回収し、残渣を真空蒸留して85
°C/ 7 mmHg留分を採取すると、α−メチル−
2−チオフェン酢酸メチル24.1CIが得られた。こ
れは理論量の94.5%に相当する。IR spectrum): 1670.1420,800,712cm-1M5 spectrum (m/e): 140.248NMR spectrum
δppm near, 1-7.7 (m, 3H), 2.8 (Q, 2H), 1.3 (t, 3H) Example 2 Synthesis of methyl α-methyl-2-thiophene acid Propionylthiophene 21 (7 , 46q1 iodine, 64 mf2 ortho-methyl formate, and 200 m12 dichloroethane were charged into a reactor, and stirring was continued for 20 hours while maintaining the reaction temperature at 20-30'C.Then, dichloroethane, iodine, and ortho-1!methyl were collected, and the residue was Vacuum distilled to 85
When the °C/7 mmHg fraction is collected, α-methyl-
24.1 CI of methyl 2-thiophene acetate was obtained. This corresponds to 94.5% of the theoretical amount.
IRスペクトルに−ト):
1740.1435.700cm’
MSスペクトル(m/e): 170.038NMRス
ペクトル δppm:
6.9〜7.2 (m、3H)、
4、 0 (q 、 1 H) 、 3.
7 (s、 3H) 、1.6 (d、3H
)
実施例3
α−メチル−2−チオフェン 酸メチルのAプロピオニ
ルチオフェン21g、沃素46Q、オルト蟻酸メチル2
10mf2. p −トルエンスルホンM3c+及び塩
化アルミニウム2qを反応装置に仕込み、反応温度20
〜30℃に保持しながら15時間撹拌を続けた。その後
実施例2と同様に処理して、α−メチル−2−チオフェ
ン酢酸メチル23.50を得た。これは理論量の92.
2%に相当する。IR spectrum: 1740.1435.700 cm' MS spectrum (m/e): 170.038 NMR spectrum δppm: 6.9-7.2 (m, 3H), 4, 0 (q, 1H), 3.
7 (s, 3H), 1.6 (d, 3H
) Example 3 A of methyl α-methyl-2-thiophene acid 21 g of propionylthiophene, 46Q of iodine, 2 of methyl orthoformate
10mf2. p-Toluenesulfone M3c+ and aluminum chloride 2q were charged into a reaction apparatus, and the reaction temperature was set at 20
Stirring was continued for 15 hours while maintaining the temperature at ~30°C. Thereafter, treatment was carried out in the same manner as in Example 2 to obtain 23.50 methyl α-methyl-2-thiophene acetate. This is the theoretical quantity of 92.
This corresponds to 2%.
実施例3
α−メチル−2−チオフェン酢酸メチルの合プロピオニ
ルチオフェン21C]、沃素46C1及びオルト蟻酸メ
チル210mf2を反応装置に仕込み、反応温度20〜
30℃に保持しながら23時間撹拌を続けた。その後実
施例2と同様に処理して、α−メチル−2−チオフェン
酢酸メチル24.90を得た。これは理論量の97.6
%に相当する。Example 3 Synthesis of α-methyl-2-thiophene methyl acetate Propionylthiophene 21C], iodine 46C1 and methyl orthoformate 210mf2 were charged into a reactor, and the reaction temperature was 20~
Stirring was continued for 23 hours while maintaining the temperature at 30°C. Thereafter, it was treated in the same manner as in Example 2 to obtain 24.90 methyl α-methyl-2-thiophene acetate. This is the theoretical quantity of 97.6
Corresponds to %.
参考例
5−ベンゾイル−α−メチル−2−チオフェン酢酸の合
成
α−メチル−2−チオフェン酢酸メチル20.5g及び
ベンゾイルクロリド25.0CIを反応装置に仕込み、
クロロホルム150m12に溶解後、無水塩化アルミニ
ウム17.2Gを反応温度10〜30℃に保持しながら
1時間要して投入した。更に同温度で45分間撹拌を続
けた後、これを加水分解し、エーテルで抽出、濃縮した
。これをアルカリ性水溶液に投入し、50〜60℃で数
時間撹拌後、1N−塩酸を用いて酸性化し、結晶を析出
させた。その析出した結晶を四塩化炭素で再結晶すると
、5−ベンゾイル−α−メチル−2−チオフェン酢!2
9.9Clが得られた。これは理論量の95.6%に相
当する。Reference Example 5 - Synthesis of benzoyl-α-methyl-2-thiopheneacetic acid 20.5 g of methyl α-methyl-2-thiophene acetate and 25.0 CI of benzoyl chloride were charged into a reaction apparatus.
After dissolving in 150 ml of chloroform, 17.2 G of anhydrous aluminum chloride was added over a period of 1 hour while maintaining the reaction temperature at 10 to 30°C. After further stirring at the same temperature for 45 minutes, the mixture was hydrolyzed, extracted with ether, and concentrated. This was poured into an alkaline aqueous solution, stirred at 50 to 60°C for several hours, and then acidified using 1N hydrochloric acid to precipitate crystals. When the precipitated crystals are recrystallized with carbon tetrachloride, 5-benzoyl-α-methyl-2-thiophene vinegar is obtained! 2
9.9Cl was obtained. This corresponds to 95.6% of the theoretical amount.
融点:94.2〜95.8℃ (以 上)Melting point: 94.2-95.8℃ (that's all)
Claims (1)
れる化合物と一般式 R^1CH_2COX 〔式中R^1は水素原子又はアルキル基を示す。 Xはハロゲン原子を示す。〕 で表わされる化合物とを反応させ、次いで得られる一般
式 ▲数式、化学式、表等があります▼ 〔式中、R及びR^1は前記に同じ。〕 で表わされる化合物にヨード活性種の存在下、オルト蟻
酸エステル類を反応させて一般式 ▲数式、化学式、表等があります▼ 〔式中R^2は水素原子又はアルキル基を示す。 R及びR^1は前記に同じ。〕 で表わされるチオフェン酢酸誘導体を得ることを特徴と
するチオフェン酢酸誘導体の製造法。(1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, R represents a hydrogen atom or an alkyl group. ] and the general formula R^1CH_2COX [wherein R^1 represents a hydrogen atom or an alkyl group]. X represents a halogen atom. [In the formula, R and R^1 are the same as above. ] The compound represented by is reacted with orthoformic acid esters in the presence of an iodine active species to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^2 represents a hydrogen atom or an alkyl group. R and R^1 are the same as above. ] A method for producing a thiophene acetic acid derivative, the method comprising obtaining a thiophene acetic acid derivative represented by:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22214788A JPH0269473A (en) | 1988-09-05 | 1988-09-05 | Production of thiopheneacetic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22214788A JPH0269473A (en) | 1988-09-05 | 1988-09-05 | Production of thiopheneacetic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0269473A true JPH0269473A (en) | 1990-03-08 |
Family
ID=16777917
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP22214788A Pending JPH0269473A (en) | 1988-09-05 | 1988-09-05 | Production of thiopheneacetic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0269473A (en) |
-
1988
- 1988-09-05 JP JP22214788A patent/JPH0269473A/en active Pending
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