JP3564791B2 - Method for producing α-aminoketones - Google Patents
Method for producing α-aminoketones Download PDFInfo
- Publication number
- JP3564791B2 JP3564791B2 JP09666295A JP9666295A JP3564791B2 JP 3564791 B2 JP3564791 B2 JP 3564791B2 JP 09666295 A JP09666295 A JP 09666295A JP 9666295 A JP9666295 A JP 9666295A JP 3564791 B2 JP3564791 B2 JP 3564791B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- phenyl
- alkyl group
- substituted
- 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
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- 238000004519 manufacturing process Methods 0.000 title claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 130
- -1 2- (t-butyldimethylsilyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine Chemical compound 0.000 claims description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 150000003335 secondary amines Chemical class 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000004593 Epoxy Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 11
- 229940125670 thienopyridine Drugs 0.000 description 11
- 239000002175 thienopyridine Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 150000003457 sulfones Chemical class 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 239000003495 polar organic solvent Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- PCYLOCRJSMJPLW-UHFFFAOYSA-N 1-chlorobut-3-enylsulfonylbenzene Chemical compound C=CCC(Cl)S(=O)(=O)C1=CC=CC=C1 PCYLOCRJSMJPLW-UHFFFAOYSA-N 0.000 description 4
- CHAXRDWQGMRTIK-UHFFFAOYSA-N 2-(benzenesulfonyl)-2-cyclopropyl-3-(2-fluorophenyl)oxirane Chemical compound FC1=CC=CC=C1C1C(S(=O)(=O)C=2C=CC=CC=2)(C2CC2)O1 CHAXRDWQGMRTIK-UHFFFAOYSA-N 0.000 description 4
- QLLKWDNSSAEGJE-UHFFFAOYSA-N 2-(benzenesulfonyl)-3-(2-fluorophenyl)-2-prop-2-enyloxirane Chemical compound FC1=CC=CC=C1C1C(S(=O)(=O)C=2C=CC=CC=2)(CC=C)O1 QLLKWDNSSAEGJE-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- VNSSCDAIYIQLHG-UHFFFAOYSA-N [chloro(cyclopropyl)methyl]sulfonylbenzene Chemical compound C=1C=CC=CC=1S(=O)(=O)C(Cl)C1CC1 VNSSCDAIYIQLHG-UHFFFAOYSA-N 0.000 description 4
- NXAIQSVCXQZNRY-UHFFFAOYSA-N chloromethylsulfonylbenzene Chemical compound ClCS(=O)(=O)C1=CC=CC=C1 NXAIQSVCXQZNRY-UHFFFAOYSA-N 0.000 description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- CJHONDZWLQBAMB-UHFFFAOYSA-N 1-chloroethylsulfonylbenzene Chemical compound CC(Cl)S(=O)(=O)C1=CC=CC=C1 CJHONDZWLQBAMB-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-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
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 3
- 235000019645 odor Nutrition 0.000 description 3
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 3
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical group CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- GIEKCUCBZADVJL-UHFFFAOYSA-N C1=CC=C(C=C1)CC2(C(O2)C3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4 Chemical compound C1=CC=C(C=C1)CC2(C(O2)C3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4 GIEKCUCBZADVJL-UHFFFAOYSA-N 0.000 description 2
- BEMVHKLRVGLYAD-UHFFFAOYSA-N C1CC1C(S(=O)C2=CC=CC=C2)Cl Chemical compound C1CC1C(S(=O)C2=CC=CC=C2)Cl BEMVHKLRVGLYAD-UHFFFAOYSA-N 0.000 description 2
- NEQUWVMVCWPBGA-UHFFFAOYSA-N C1CC1C2(C(O2)C3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4 Chemical compound C1CC1C2(C(O2)C3=CC=CC=C3)S(=O)(=O)C4=CC=CC=C4 NEQUWVMVCWPBGA-UHFFFAOYSA-N 0.000 description 2
- XOAFILOPMQAICZ-UHFFFAOYSA-N C=CCC1(C(O1)C2=CC=CC=C2)S(=O)(=O)C3=CC=CC=C3 Chemical compound C=CCC1(C(O1)C2=CC=CC=C2)S(=O)(=O)C3=CC=CC=C3 XOAFILOPMQAICZ-UHFFFAOYSA-N 0.000 description 2
- OERNXNVGOQHFIQ-UHFFFAOYSA-N CC1(C(O1)C2=CC=CC=C2F)S(=O)(=O)C3=CC=CC=C3 Chemical compound CC1(C(O1)C2=CC=CC=C2F)S(=O)(=O)C3=CC=CC=C3 OERNXNVGOQHFIQ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- QCOGKXLOEWLIDC-UHFFFAOYSA-N N-methylbutylamine Chemical compound CCCCNC QCOGKXLOEWLIDC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- ORTADKWRLALGSC-UHFFFAOYSA-N cyclopropylmethylsulfanylbenzene Chemical compound C1CC1CSC1=CC=CC=C1 ORTADKWRLALGSC-UHFFFAOYSA-N 0.000 description 2
- SEYPDLZKHODFFO-UHFFFAOYSA-N cyclopropylmethylsulfinylbenzene Chemical compound C=1C=CC=CC=1S(=O)CC1CC1 SEYPDLZKHODFFO-UHFFFAOYSA-N 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 description 2
- GVWISOJSERXQBM-UHFFFAOYSA-N n-methylpropan-1-amine Chemical compound CCCNC GVWISOJSERXQBM-UHFFFAOYSA-N 0.000 description 2
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 description 2
- 125000004344 phenylpropyl group Chemical group 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RVEZZJVBDQCTEF-UHFFFAOYSA-N sulfenic acid Chemical compound SO RVEZZJVBDQCTEF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 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
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 1
- TVIJTKGKFZDXRQ-UHFFFAOYSA-N thiophene-2-sulfinamide Chemical compound NS(=O)C1=CC=CS1 TVIJTKGKFZDXRQ-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Epoxy Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
【０００１】
【産業上の利用分野】
本発明の製法は、例えば２−（ｔ−ブチルジメチルシリルオキシ）−５−〔１−（２−フルオロフェニル）−２−オキソプロピル〕−４，５，６，７−テトラヒドロチエノ〔３，２−ｃ〕ピリジンなどのα−アミノケトン類の製法に関する。
前記のα−アミノケトン類は、血小板凝集抑制作用をもつ抗血栓剤を合成する際の中間体として有用である。
【０００２】
本発明の製法によって得られる目的化合物において、例えば２−（ｔ−ブチルジメチルシリルオキシ）−５−［１−（２−フルオロフェニル）−２−オキソプロピル］−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンは、例えば特開平０８−８１１２０３（ＷＯ ９６／１１２０３）号公報に記載された方法に準じて、酸無水物と、塩基とアシル化触媒の存在下に反応させて、血小板凝集抑制作用を持つ２−アシルオキシ−５−［１−（２−フルオロフェニル）−２−オキソプロピル］−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンに誘導される。
【０００３】
【従来技術】
従来の２−アミノケトン類の製法としては、以下に示すような方法がある。
▲１▼．ジャ−ナル オブ オルガニック ケミストリ−（Ｊｏｕｒｎａｒ ｏｆＯｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ、第２４巻、４７８頁、１９５６年）には、２級アミンとα−ハロケトン類とを用いて反応させる方法が記載されている。しかし、この方法は、位置選択的にハロゲン化されたカルボニル化合物が、容易に入手可能で、また熱的にも安定である化合物に限定され、さらに副反応により収率が低いという点で問題があった。
▲２▼．ケミカル レビュ−ス（Ｃｈｅｍｉｃａｌ Ｒｅｖｉｅｗｓ、第６４巻、８１頁、１９６４年）には、ケトキシムとｐ−トルエンスルホニルクロライドから得られるオキシムトシレ−ト類（例えばベンジルメチルケトンオキシムトシレ−ト）とナトリウムエチラ−トを使用した、アジリンあるいはナイトレン中間体を経由する分子内求核置換反応によってα−アミノケトン（例えば１−アミノ−１−フェニル−２−プロパノン）が得られるＮｅｂｅｒ転位反応が記載されている。
しかし、この方法は無置換アミノ基のみの導入に限られ、また収率が低いという点で問題があった。
▲３▼．テトラヘドロン レタ−ズ（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ、第２５巻、２９７７頁、１９８４年）には、アシルクロライドのシアン化銅を用いた処理によって得られるアシルシアニド類（例えば１−シアノ−２−フェニル−１−エタノン）を、過剰の無水酢酸の存在下、亜鉛／酢酸を用いた選択的還元反応させ、次いで酸加水分解によるα−アミノケトン（例えば１−アミノ−３−フェニル−２−プロパノン）が得られる反応が記載されている。
しかし、この方法はα−アシルメチルアミン類の合成には有用であるが、適応範囲が狭く、本願には適用できないという点で問題があった。
【０００４】
▲４▼．ジャ−ナル オブ オルガニック ケミストリ−（Ｊｏｕｒｎａｒ ｏｆＯｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ、第２７巻、４３９２頁、１９６２年）には、エポキシエ−テル類（例えば１，２−エポキシ−１−メトキシ−２−メチル−１−フェニルプロパン）とアミン類（例えばピペリジン）とを反応させ、α−アミノケトン類（例えば１−フェニル−２−メチル−２−（１−ピペリジノ）−１−プロパノン）を得る方法が記載されている。
しかし、この方法はフェニルα−アミノケトン類の合成には有用であるが、適応範囲が狭く、本願には適用できないという点で問題があった。
▲５▼．ケミストリ− レタ−ズ（Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ、第巻、５８５頁、１９８２年）には、エポキシ化合物として、脱離基であるスルフィニル基を導入したα、β−エポキシスルホキシド類のアミノリシス反応が記載されている。
しかし、この反応は、穏和な条件で目的物が得られるという利点はあるが、この反応においてスルホキシドの脱離によって生じるスルフェン酸は、一般に不安定であり、スルフェン酸二分子の脱水によりチオ−ルスルフィナ−トが発生、さらに不均化して、極めて悪臭を持つジスルフイドおよびチオ−ルスルホナ−トを発生させる欠点があり、さらに収率よくアミノケトン類を得るためにはアミンを大過剰に加える必要があるなどの点で問題があった。
【０００５】
従って、公知の▲１▼〜▲５▼のいずれもが、α−アミノケトン類を製造する場合の工業的製法としては、不満があった。
【０００６】
【発明が解決しようとする課題】
【０００７】
本発明者らは、前記公知の製法における問題点を解決すべく、α−アミノケトン類の製造方法を鋭意検討した結果、エポキシ化合物として、脱離基であるスルホニル基を導入したα、β−エポキシスルホン類と、２級アミン類を用いたアミノリシス反応を用いれば、穏和な条件下、収率、選択率よくα−アミノケトン類を製造することを見出して本発明を完成するに至った。
【０００８】
本発明は、α、β−エポキシスルホン類と２級アミン類とを、塩基の存在下、反応させるα−アミノケトン類の製造方法を提供することを目的とする。
【０００９】
本発明は、
一般式（１）
【００１０】
【化４】
［式中、Ｒ１、Ｒ２は、同一または異なって、水素原子、炭素原子数１〜１０個のアルキル基、炭素原子数３〜１０個のシクロアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示し、Ｒ３は、炭素原子数１〜１０個のアルキル基、炭素原子数３〜１０個のシクロアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示し、Ｒ４は、炭素原子数１〜１０個のアルキル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示す。］で表されるα，β−エポキシスルホン酸類と、
【００１２】
一般式（２）
【００１３】
【化５】
［式中、Ｒ５、Ｒ６は、同一または異なって、炭素原子数１〜１０個のアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基を示すか、Ｒ５、Ｒ６が結合して置換されていてもよい複素環を示していてもよい。］で表される２級アミンまたはその塩とを、塩基存在下に、有機溶媒中で、反応させることを特徴とする、
【００１５】
【化６】
〔式中、Ｒ１ 、Ｒ２ 、Ｒ３ 、Ｒ５ 、Ｒ６ は前記と同じ意味を示す。〕で表されるα−アミノケトン類の製造方法に関する。
【００１７】
本発明の好ましい態様は、以下の通りである。
【００１８】
１）Ｒ１、Ｒ２が、同一または異なって、水素原子、炭素原子数１〜１０個のアルキル基、炭素原子数３〜１０個のシクロアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示し、Ｒ３が、炭素原子数１〜１０個のアルキル基、炭素原子数３〜１０個のシクロアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数２〜１０個のアルケニル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示し、Ｒ４が、炭素原子数１〜１０個のアルキル基、炭素原子数７〜１２個のアラルキル基；炭素原子数１〜１０個のアルキル基、炭素原子数１〜１０個のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基を示す一般式（１）で表されるα，β−エポキシスルホン酸類であり、
【００１９】
Ｒ５ 、Ｒ６ が、同一または異なって、炭素原子数１〜１０個のアルキル基、
炭素原子数２〜１０個のアルケニル基、炭素原子数７〜１２個のアラルキル基を示すか、
Ｒ５ 、Ｒ６ が結合して置換されていてもよい複素環を示す一般式（２）で表される２級アミンまたはその塩である特許請求の範囲第１項に記載の製造方法。
【００２０】
２）Ｒ１ 、Ｒ２ が、同一または異なって、水素原子、炭素原子数１〜８個のアルキル基、炭素原子数２〜８個のアルケニル基、炭素原子数３〜８個のシクロアルキル基、炭素原子数７〜１０個のアラルキル基、ハロゲン原子で置換されていてもよいフェニル基を示し、
Ｒ３ が炭素原子数１〜８個のアルキル基、炭素原子数２〜８個のアルケニル基、炭素原子数３〜８個のシクロアルキル基、炭素原子数７〜１０個のアラルキル基、ハロゲン原子で置換されていてもよいフェニル基を示し、
Ｒ４ がフェニル基を示す化合物である一般式（１）で表されるα，β−エポキシスルホン類を示し、
Ｒ５ 、Ｒ６ が、炭素原子数１〜８個のアルキル基、炭素原子数２〜８個のアルケニル基、炭素原子数７〜１０個のアラルキル基であるか、又は結合して、置換されていてもよいピペリジン、置換されていてもよい４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、モルホリン、１，２，３，４−テトラヒドロイソキノリンを示す一般式（２）で表される２級アミン類またはその塩である請求項１に記載の製造方法。
【００２１】
３）Ｒ１ 、Ｒ２ が、同一または異なって、水素原子、炭素原子数１〜４個のアルキル基、炭素原子数３〜５個のアルケニル基、炭素原子数３〜６個のシクロアルキル基、炭素原子数７〜８個のアラルキル基、フッ素原子で置換されていてもよいフェニル基を示し、
Ｒ３ が、炭素原子数１〜４個のアルキル基、炭素原子数３〜５個のアルケニル基、炭素原子数３〜６個のシクロアルキル基、炭素原子数７〜８個のアラルキル基、フッ素原子で置換されていてもよいフェニル基を示す、
Ｒ４ がフェニル基を示す化合物である一般式（１）で表されるα，β−エポキシスルホン類であり、
Ｒ５ 、Ｒ６ が結合して、ピペリジン、２−（ｔ−ブチルジメチルシリル）−４，５，６，７−テトラヒドロチエノ〔３，２−ｃ〕ピリジンを示す一般式（２）で表される２級アミン類またはその塩である請求項１に記載の製造方法。
【００２２】
本発明の製法における主反応は、例えば次に示すような反応式（１）
【００２３】
【化７】
で示すことができる。
【００２５】
本発明の製法において使用する一般式（１）で表されるα、β−エポキシスルホン類において、Ｒ１、Ｒ２、Ｒ３は、同一または異なって、
炭素原子数１〜１０個である直鎖状または分枝状のアルキル基、
炭素原子数３〜１０個である直鎖状または分枝状のシクロアルキル基、
炭素原子数２〜１０個である直鎖状または分枝状のアルケニル基、
炭素原子数１〜６個の直鎖状または分枝状のアルキル基部分を持つ炭素原子数７〜１２個のアラルキル基、
置換基を有していてもよいフェニル基、
であればよい。
【００２６】
前記の炭素原子数１〜１０個のアルキル基としては、炭素原子数１〜８個（特に炭素原子数１〜４個）である直鎖状または分枝状のアルキル基が好ましく、例えば、メチル基、エチル基、プロピル基（異性体を含む）、ブチル基（異性体を含む）、ペンチル基（異性体を含む）、ヘキシル基（異性体を含む）、ヘプチル基（異性体を含む）、オクチル基（異性体を含む）、ノニル基（異性体を含む）、デシル基（異性体を含む）などを挙げることができ、好ましくはメチル基、エチル基、プロピル基（異性体を含む）、ブチル基（異性体を含む）、ペンチル基（異性体を含む）、ヘキシル基（異性体を含む）、ヘプチル基（異性体を含む）、オクチル基（異性体を含む）であり、特に好ましくはメチル基、エチル基、プロピル基（異性体を含む）、ブチル基（異性体を含む）である。
【００２７】
前記の炭素原子数３〜１０個のシクロアルキル基としては、炭素原子数３〜８個（とくにい炭素原子数３〜６個）である直鎖状または分枝状のシクロアルキル基が好ましく、例えばシクロプロピル基、シクロブチル基（異性体を含む）、シクロペンチル基（異性体を含む）、シクロヘキシル基（異性体を含む）、シクロヘプチル基（異性体を含む）、シクロオクチル基（異性体を含む）、シクロノニル基（異性体を含む）、シクロデシル基（異性体を含む）などを挙げることができ、好ましくはシクロプロピル基、シクロブチル基（異性体を含む）、シクロペンチル基（異性体を含む）、シクロヘキシル基（異性体を含む）、シクロヘプチル基（異性体を含む）、シクロオクチル基（異性体を含む）であり、特に好ましくはシクロプロピル基、シクロブチル基（異性体を含む）、シクロペンチル基（異性体を含む）、シクロヘキシル基（異性体を含む）である。
【００２８】
前記の炭素原子数２〜１０個のアルケニル基としては、炭素原子数２〜８個（特に炭素原子数３〜５個）である直鎖状または分枝状のアルケニル基が好ましく、例えばエチレン基、プロピレン基（異性体を含む）、ブテン基（異性体を含む）、ペンテン基（異性体を含む）、ヘキセン基（異性体を含む）、ヘプテン基（異性体を含む）、オクテン基（異性体を含む）、ノネン基（異性体を含む）、デセン基（異性体を含む）などを挙げることができ、好ましくはプロピレン基（異性体を含む）、ブテン基（異性体を含む）、ペンテン基（異性体を含む）、ヘキセン基（異性体を含む）、ヘプテン基（異性体を含む）であり、特に好ましくはプロピレン基（異性体を含む）、ブテン基（異性体を含む）、ペンテン基（異性体を含む）、ヘキセン基（異性体を含む）であり、さらに好ましくはプロピレン基（異性体を含む）、ブテン基（異性体を含む）、ペンテン基（異性体を含む）である。
【００２９】
前記の炭素原子数１〜６個の直鎖状または分枝状のアルキル基部分を持つ炭素原子数７〜１２個のアラルキル基としては、炭素原子数７〜１０個（特に炭素原子数７〜８個）である直鎖状または分枝状のアルキル基部分を持つ炭素原子数７〜１２個のアラルキル基が好ましく、例えばフェニルメチル基、フェニルエチル基（異性体を含む）、フェニルプロピル基（異性体を含む）、フェニルブチル基（異性体を含む）、フェニルペンチル基（異性体を含む）、フェニルヘキシル基（異性体を含む）などを挙げることができ、好ましくはフェニルメチル基、フェニルエチル基（異性体を含む）、フェニルプロピル基（異性体を含む）、フェニルブチル基（異性体を含む）であり、特に好ましくは、フェニルメチル基、フェニルエチル基（異性体を含む）である。
【００３０】
前記の、置換されていてもよいフェニル基は、置換基を有していないフェニル基、置換基を有しているフェニル基であればよい。
【００３１】
前記の『置換基を有するフェニル基の置換基』は、フェニル基の環上の置換位置が任意であり、前記のアルキル基、後記のハロゲン原子、アルコキシ基であればよい。
【００３２】
前記の『置換基を有するフェニル基の置換基』のハロゲン原子としては、例えばフッ素原子、塩素原子、臭素原子、ヨ−ド原子を挙げることができ、好ましくはフッ素原子、塩素原子であり、特にフッ素原子が好ましい。
【００３３】
一般式（１）で表されるα，β−エポキシスルホン類において、『置換基を有するフェニル基の置換基』のアルコキシ基は、炭素原子数１〜１０個の直鎖状または分枝状のアルキル基部分を持つアルコキシ基であればよい。
【００３４】
前記の炭素原子数１〜１０個のアルコキシ基としては、炭素原子数１〜８個（特に炭素原子数１〜６個）である直鎖状または分枝状のアルキル基部分を持つアルコキシ基が好ましく、例えば、メトキシ基、エトキシ基、プロポキシ基（異性体を含む）、ブトキシ基（異性体を含む）、ペンチルオキシ基（異性体を含む）、ヘキシルオキシ基（異性体を含む）、ヘプチルオキシ基（異性体を含む）、オクチルオキシ基（異性体を含む）、ノニルオキシ基（異性体を含む）、デシルオキシ基（異性体を含む）のような炭素原子数１〜１０個のアルコキシ基などを挙げることができ、好ましくはメトキシ基、エトキシ基、プロポキシ基（異性体を含む）、ブトキシ基（異性体を含む）、ペンチルオキシ基（異性体を含む）、ヘキシルオキシ基（異性体を含む）、ヘプチルオキシ基（異性体を含む）、オクチルオキシ基（異性体を含む）であり、特に好ましくは、メトキシ基、エトキシ基、プロポキシ基（異性体を含む）、ブトキシ基（異性体を含む）、ペンチルオキシ基（異性体を含む）、ヘキシルオキシ基（異性体を含む）である。
【００３５】
本発明の製法において使用する一般式（１）で表されるα、β−エポキシスルホン類において、Ｒ４は、同一または異なって、
炭素原子数１〜１０個の直鎖状または分枝状のアルキル基、
炭素原子数１〜６個の直鎖状または分枝状のアルキル基部分を持つ炭素原子数７〜１２個のアラルキル基；
炭素原子数１〜１０個の直鎖状または分枝状のアルキル基、炭素原子数１〜１０個の直鎖状または分枝状のアルコキシ基、ハロゲン原子で置換されていてもよいフェニル基、
であればよい。
【００３６】
前記のＲ４ の炭素原子数１〜１０個の直鎖状または分枝状のアルキル基、炭素原子数１〜６個の直鎖状または分枝状のアルキル基部分を持つ炭素原子数７〜１２個のアラルキル基は、前記のアルキル基、アラルキル基でよい。
本発明の製法において使用する一般式（１）で表されるα，β−エポキシスルホン類において、Ｒ４ の炭素原子数１〜１０個の直鎖状または分枝状のアルキル基、ハロゲン原子、炭素原子数１〜１０個の直鎖状または分枝状のアルコキシ基で置換されていてもよいフェニル基は、前記の置換されていてもよいフェニル基であり、『置換基を有するフェニル基の置換基』の炭素原子数１〜１０個の直鎖状または分枝状のアルキル基、炭素原子数１〜１０個の直鎖状または分枝状のアルコキシ基、ハロゲン原子も、前記の『置換基を有するフェニル基の置換基』のアルキル基、ハロゲン原子、アルコキシ基であればよい。
【００３７】
本発明の製法で使用される一般式（１）で表されるα，β−エポキシスルホン類としては、例えば、１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルエタン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルプロパン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルブタン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルペンタン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルヘキサン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルヘプタン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルオクタン、４，５−エポキシ−５−フェニル−５−フェニルスルホニル−１−ペンテン、４，５−エポキシ−５−フェニル−５−フェニルスルホニル−１−ヘキセン、４，５−エポキシ−５−フェニル−５−フェニルスルホニル−１−ヘプテン、４，５−エポキシ−５−フェニル−５−フェニルスルホニル−１−オクテン、
【００３８】
１，２−エポキシ−１，３−ジフェニル−２−フェニルスルホニルプロパン、２，３−エポキシ−１，３−ジフェニル−２−フェニルスルホニルプロパン、２，３−エポキシ−１，３−ジフェニル−２−フェニルスルホニルペンタン、１，２−エポキシ−１，３−ジフェニル−２−フェニルスルホニルブタン、２，３−エポキシ−２−フェニル−３−フェニルスルホニルプロパン、２，３−エポキシ−３−シクロプロピル−２−フェニルスルホニルプロパン、２，３−エポキシ−２−フェニル−２−フェニルスルホニルブタン、２，３−エポキシ−２−フェニル−３−フェニルスルホニルペンタン、２，３−エポキシ−２−フェニル−３−フェニルスルホニルヘキサン、２，３−エポキシ−２−フェニル−３−フェニルスルホニルオクタン、４，５−エポキシ−５−フェニル−４−フェニルスルホニル−１−ヘキセン、４，５−エポキシ−５−フェニル−４−フェニルスルホニル−１−ペンテン、７，８−エポキシ−８−フェニル−７−フェニルスルホニル−１−オクテン、
【００３９】
１−シクロヘキシル−１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルプロパン、１−シクロヘキシル−１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルブタン、１−シクロヘキシル−１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルペンタン、１−シクロヘキシル−１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルヘキサン、１−シクロヘキシル−１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルオクタン、
【００４０】
５−シクロヘキシル−４，５−エポキシ−４−フェニルスルホニル−１−ペンテン、６−シクロヘキシル−５，６−エポキシ−５−フェニルスルホニル−１−ヘキセン、８−シクロヘキシル−７，８−エポキシ−７−フェニルスルホニル−１−オクテン、１−シクロヘキシル−１，２−エポキシ−３−フェニル−２−フェニルスルホニルプロパン、１−シクロヘキシル−１，２−エポキシ−４−フェニル−２−フェニルスルホニルブタンなどのα，β−エポキシスルホン類（分子内のフェニル基は、前記の置換基を有していてもよい）を挙げることができ、
【００４１】
好ましくは、
１，２−エポキシ−２−シクロプロピル−１−フェニル−２−フェニルスルホニルエタン、４，５−エポキシ−５−フェニル−４−フェニルスルホニル−１−ペンテン、１，２−エポキシ−１−フェニル−２−フェニルスルホニルプロパンなどのα，β−エポキシスルホン類〔分子内のフェニル基は、前記の置換基（好ましくはハロゲン原子）を有していてもよい〕であり、
【００４２】
特に好ましくは、１，２−エポキシ−２−シクロプロピル−１−（２−フルオロフェニル）−２−フェニルスルホニルエタン、４，５−エポキシ−５−（２−フルオロフェニル）−４−フェニルスルホニル−１−ペンテン、１，２−エポキシ−１−（２−フルオロフェニル）−２−フェニルスルホニルプロパンである。
【００４３】
本発明の製法で使用される一般式（１）で表されるα，β−エポキシスルホン類は、例えば参考例に記載した方法に準じて、α−ハロゲン化アルキルスルホン類と対応するアルデヒド又はケトン類とを塩基の存在下に反応させる、例えばカナディアン ジャ−ナル オブ ケミストリ−（Ｃａｎａｄｉａｎ Ｊｏｕｒｎａｒ ｏｆ Ｃｈｅｍｉｓｔｒｙ、第４７巻、２８７５頁、１９６９年）に記載されている、いわゆるダルツェン反応により誘導される。
【００４４】
本発明の製法で使用される一般式（１）で表されるα，β−エポキシスルホン類のような、脱離基としてスルホニル基を分子内に持つ化合物を使用した場合は、副生するスルフィン酸は安定であり、スルフィニル基を脱離基として分子内に持つ化合物を使用した場合と異なり、悪臭は発生せず、かつ反応終了時に水洗することで簡単に除去可能なという利点がある。
【００４５】
本発明の製法において使用される一般式（２）で表される２級アミンのＲ４は、同一または異なって、
炭素原子数１〜１０個である直鎖状または分枝状のアルキル基、
炭素原子数１〜１０個である直鎖状または分枝状のアルキル基部分を持つ炭素数７〜１２個のアラルキル基、
炭素原子数２〜１０個である直鎖状または分枝状のアルケニル基、
であればよい。
【００４６】
このようなアルキル基、アラルキル基、アルケニル基は、前記のアルキル基、アラルキル基、アルケニル基であればよい。
【００４７】
本発明の製法で使用される一般式（２）で表される２級アミンのＲ５ 、Ｒ６ が、結合して置換されていてもよい複素環基を形成している場合の複素環としては、置換基を有していない複素環、置換基を有していてもよい複素環であればよい。
【００４８】
前記の置換基を有していない複素環としては、例えばピロ−ル、２Ｈ−ピロ−ル、ピリジンのような芳香族複素単環、ピロリン、ピロリジン、ピペリジンのような脂環式複素単環、インド−ル、イソインド−ル、キノリン、イソキノリンのような芳香族縮合複素環、インドリン、イソインドリン、１，２，３，４−テトラヒドロイソキノリン、４，５，６，７−テトラヒドロチエノ〔３，２−ｃ〕ピリジンのような脂環式縮合複素環、モルホリンのようなヘテロ原子２個以上含む複素環を挙げることができ、好ましくはピペリジン、モルホリン、１，２，３，４−テトラヒドロイソキノリン、４，５，６，７−テトラヒドロチエノ〔３，２−ｃ〕ピリジンである。
【００４９】
前記の『置換基を有する複素環の置換基』としては、複素環上の任意の位置に置換した、例えば、前記のアルキル基、
一般式（４）
【００５０】
【化８】
（式中、Ｒ７ 、Ｒ８ 、Ｒ９ は、同一または異なって、アルキル基、芳香族基を示す。）で表されるトリ置換シリルオキシ基を挙げることができる。
【００５２】
一般式（４）で表されるトリ置換シリルオキシ基のＲ７ 、Ｒ８ 、Ｒ９ は、アルキル基、フェニル基を示す。このような、アルキル基、フェニル基は前記のアルキル基、置換基を有していないフェニル基であればよい。
【００５３】
前記のトリ置換シリルオキシ基としては、例えばトリメチルシリルオキシ基、トリエチルシリルオキシ基、トリプロピルシリルオキシ基、トリイソプロピルシリルオキシ基、ｔ−ブチルジメチルシリルオキシ基、ｔ−ブチルジフェニルシリルオキシ基などを挙げることができ、好ましくはトリイソプロピルシリルオキシ基、ｔ−ブチルジメチルシリルオキシ基、ｔ−ブチルジフェニルシリルオキシ基であり、特に好ましくはｔ−ブチルジメチルシリルオキシ基である。
【００５４】
本発明の製法で使用される一般式（２）で表される２級アミンとしては、例えば、ジメチルアミン、ジエチルアミン、ジプロピルアミン（異性体を含む）、ジブチルアミン（異性体を含む）、ジペンチルアミン（異性体を含む）、ジヘキシルアミン（異性体を含む）、ジペンチルアミン（異性体を含む）、ジオクチルアミン（異性体を含む）、メチルエチルアミン、メチルプロピルアミン（異性体を含む）、メチルブチルアミン（異性体を含む）、ジアリルアミン、ジエタノ−ルアミン、
【００５５】
Ｎ−メチル−１−フェニルエチルアミン、Ｎ−メチル−２−フェニルエチルアミン、ピペリジン、２−メチルピペリジン、４−メチルピペリジン、モルホリン、１，２，３，４−テトラヒドロイソキノリン、４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、２−トリイソプロピルシリルオキシ−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、ｔ−ブチルジメチルシリルオキシ−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、ｔ−ブチルジフェニルシリルオキシ−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジンのような２級アミンを挙げることができ、
好ましくは、ピペリジン、ｔ−ブチルジメチルシリルオキシ−４，５，６，７−テトラチエノ〔３，２−ｃ〕ピリジンである。
【００５６】
本発明の製法で使用される一般式（２）で表される２級アミンは、その使用量が、α，β−エポキシスルホン類１モルに対して通常０．５〜５モルの割合となる量が好ましく、特に１．０〜３．０モルの割合となる量が好ましく、更に１．０〜１．５モルの割合となる量が好ましい。
【００５７】
本発明の製法において使用される一般式（２）で表される２級アミンは、市販されているものはそのまま使用できるが、例えばｔ−ブチルジメチルシリルオキシ−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンのようなｔ−ブチルジメチルシリルオキ基で置換されている化合物は、例えば特開平０８−８１１２０３（ＷＯ ９６／１１２０３）に記載された方法に準じて、５、６、７、７ａ−テトラチエノ［３，２−ｃ］ピリジン−２−オンとｔ−ブチルジメチルクロロシランとを、トリエチルアミンの存在下に、反応させてｔ−ブチルジフェニルシリルオキシ−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンに誘導できる。
【００５８】
本発明の製法で使用される塩基としては、例えば炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カルシウムのような無機塩基、ピリジン、キノリン、トリメチルアミン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、エチルジイソプロピルアミン、トリエタノ−ルアミン、ジメチルアニリン、Ｎ−メチルピペリジン、４−ピロジノピリジン、１，５−ジアザビシクロ〔４．３．０〕−５−ノネン、１，８−ジアザビシクロ〔５．４．０〕−５−ウンデセン、ジアザビシクロ〔２．２．２〕−オクタンなどの有機塩基などを挙げることができ、好ましくは炭酸カリウム、炭酸水素カリウム、トリメチルアミン、トリエチルアミンであり、特に好ましくは炭酸カリウム、トリエチルアミンである。
【００５９】
本発明の製法で使用される有機溶媒としては、反応に関与しないものであればとくに限定されないが、例えばジメチルエ−テル、ジエチルエ−テル、ジプロピルエ−テル、ジブチルエ−テル、テトラヒドロフラン、ジオキサンなどのエ−テル系極性有機溶媒、アセトニトリル、ベンゾニトリルのようなニトリル系極性有機溶媒、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピリドン、ジメチルイミダゾリドンなどのアミド系極性有機溶媒、塩化メチレン、１，２−ジクロロエタンなどのハロゲン化炭化水素系極性有機溶媒を挙げることができ、好ましくはアセトニトリル、ベンゾニトリルのようなニトリル系極性有機溶媒、塩化メチレン、１，２−ジクロロエタンなどのハロゲン化炭化水素系極性有機溶媒であり、特に好ましくはアセトニトリル、塩化メチレンである。
【００６０】
本発明の製法で使用される極性有機溶媒の使用量は、通常α，β−エポキシスルホン類に対して、１．５〜１５倍量（重量／重量）の割合になる量が好ましく、特に５〜１０倍量（重量／重量）の割合になる量が好ましい。
【００６１】
本発明の製法における反応温度としては、通常使用する有機極性溶媒の沸点までの温度であればよいが、好ましくは０〜２００℃の範囲であり、特に好ましくは１０〜１００℃の範囲である。
本発明の製法における反応時間は、反応温度により著しく影響を受けるが、通常０．５〜４８時間で反応は完結する。
【００６２】
前記の本発明の製法で得られる一般式（３）で表される目的化合物のα−アミノケトン類は、前記のα，β−エポキシスルホン類および２級アミン類によって規定される。そのような目的化合物のα−アミノケトン類としては、例えば
１−シクロプロピル−２−フェニル−２−（１−ピペリジノ）エタン、１−フェニル−１−（１−ピペリジノ）プロパン−２−オン、１−フェニル−１−（１−ピペリジノ）ブタン−２−オン、１−フェニル−１−（１−ピペリジノ）ペンタン−２−オン、１−フェニル−１−（１−ピペリジノ）ヘキサン−２−オン、１−フェニル−１−（１−ピペリジノ）ヘプタン−２−オン、１−フェニル−１−（１−ピペリジノ）オクタン−２−オン、１−フェニル−１−（１−ピペリジノ）−４−ペンテン−２−オン、１−フェニル−１−（１−ピペリジノ）−４−ヘキセン−２−オン、１−フェニル−１−（１−ピペリジノ）−４−ヘプテン−２−オン、
【００６３】
１−フェニル−１−（１−ピペリジノ）−４−オクテン−２−オン、１，３−ジフェニル−（１−ピペリジノ）プロパン−２−オン、１，４−ジフェニル−１−（１−ピペリジノ）−２−オン、１−シクロヘキシル−２−（１−ピペリジノ）プロパン−２−オン、１−シクロプロピル−２−フェニル−２−ジメチルアミノエタノン、１−フェニル−１−ジメチルアミノプロパン−２−オン、
【００６４】
１−フェニル−１−ジメチルアミノブタン−２−オン、１−フェニル−１−ジメチルアミノペンタン−２−オン、１−フェニル−１−ジメチルアミノヘキサン−２−オン、１−フェニル−１−ジメチルアミノヘプタン−２−オン、１−フェニル−１−ジメチルアミノオクタン−２−オン、１−フェニル−１−ジメチルアミノ−４−ペンテン−２−オン、１−フェニル−１−ジメチルアミノ−５−ヘキセン−２−オン、１−フェニル−１−ジメチルアミノ−６−ヘプテン−２−オン、１−フェニル−１−ジメチルアミノ−６−オクテン−２−オン、１，３−ジフェニル−１−ジメチルアミノプロパン−２−オン、
【００６５】
１，４−ジフェニル−１−ジメチルアミノブタン−２−オン、１−シクロヘキシル−１−ジメチルアミノプロパン−２−オン、Ｎ−（２−オキソ−１−フェニルプロピル）−１，２，３，４−テトラヒドロイソキノリン、５−（２−オキソ−１−フェニルプロピル）−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、２−（ｔ−ブチルジメチルシリルオキシ）−５−（１−フェニル−２−オキソプロピル）−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、２−トリイソプロピルシリルオキシ−５−（１−フェニル−２−オキソプロピル）−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、ｔ−ブチルジメチルシリルオキシ−５−（１−フェニル−２−オキソプロピル）−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジン、ｔ−ブチルジフェニルシリルオキシ−５−（１−フェニル−２−オキソプロピル）−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジンのようなα−アミノケトン類、およびこれらのα−アミノケトン類の分子内のフェニル基が、任意の位置において前記のハロゲン原子、アルキル基、アルコキシ基で置換されている化合物を挙げることができ、
【００６６】
好ましくは、α−アミノケトン類の分子内のフェニル基が、任意の位置においてハロゲン原子で置換されている化合物であり、
特に好ましくは、
１−シクロプロピル−２−（２−フルオロフェニル）−２−（１−ピペリジノ）エタン、１−（２−フルオロフェニル）−（１−ピペリジノ）−４−ペンテン−２−オン、２−（ｔ−ブチルジメチルシリルオキシ）−５−〔１−（２−フルオロフェニル）−２−オキソプロピル〕−４，５，６，７−テトラヒドロ〔３，２−ｃ〕チエノピリジンである。
【００６７】
本発明の製法において、生成したα−アミノケトン類を含む反応混合物を得る方法は、通常の洗浄操作、分離操作を組合わせて行えばよく、例えば反応液に有機溶媒を添加し、水洗などにより無機塩基を除いた後に、溶媒抽出、減圧濃縮により粗生成物が得られる。さらに精製する場合には、例えばカラムクロマトグラフィ−などで精製すればよいが、精製方法は各化合物について適宣選択すればよい。
【００６８】
【発明の効果】
本発明によれば、前記一般式（１）のα，β−エポキシスルホン類と一般式（２）の２級アミンまたはその塩とを、塩基存在下に、有機溶媒中で、反応させることにより、目的化合物であるα−アミノケトン類を、穏和な条件下、収率、選択率よく製造することができる。また、特にα，β−エポキシスルホン類は、脱離基としてスルホニル基を分子内に持つ化合物を使用しているので、副生するスルフィン酸は安定であり、スルフィニル基を脱離基として分子内に持つ化合物を使用した場合と異なり、悪臭は発生せず、かつ反応終了時に水洗することで簡単に除去可能である。
【００６９】
【実施例】
以下に実施例および参考例を示す。
【００７０】
参考例１；１，２−エポキシ−２−シクロプロピル−１−（２−フルオロフェニル）−２−フェニルスルホニルエタンの製造
（１−クロロ−１−シクロプロピルメチル）フェニルスルホン７６０ｍｇ（３．３ミリモル）と２−フルオロベンズアルデヒド４０６ｍｇ（３．３ミリモル）とを、ｔ−ブタノ−ル６ミリリットルとエチルエ−テル３ミリリットルとからなる混合溶剤に溶解し、得られた混合溶液を１０℃に冷却し、同温度を保ったまま、カリウム ｔ−ブトキシド３６９ｍｇ（３．３ミリモル）を含むｔ−ブタノ−ル溶液４ミリリットルを滴下した。滴下終了後の混合溶液を、室温（２０℃）で３時間攪拌して反応させた。
得られた反応溶液に水１０ミリリットルを加えて水洗し、抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮し、残渣を得た。得られた残渣を薄層クロマトグラフィ−（展開液；ｎ−ヘキサン：酢酸エチル＝１０：３）に付して１，２−エポキシ−２−シクロプロピル−１−（２−フルオロフェニル）−２−フェニルスルホニルエタン７５１ｍｇ（２．４ミリモル）を得た。（１−クロロ−１−シクロプロピルメチル）フェニルスルホン基準の収率＝７２．７％）
ＩＲ（ｎｅａｔ、ｃｍ−１）；１３２５、１１５５、１２３７、９１０、８２８
ＭＳ（ＣＩ：ｍ／ｚ）；３１９（ＭＨ＋ ）、１７７
実施例１
前記の参考例１で得られた１，２−エポキシ−２−シクロプロピル−１−（２−フルオロフェニル）−２−フェニルスルホニルエタン５８７ｍｇ（１．８ミリモル）と炭酸カリウム７６３ｍｇ（５．５ミリモル）とをアセトニトリル５ミリリットルに溶解し、得られたアセトニトリル溶液に、ピペリジン１７２ｍｇ（２ミリモル）を溶解したアセトニトリル５ミリリットルを滴下した後、６時間攪拌して反応させた。
得られた反応溶液に、水１０ミリリットルと塩化メチレン１０ミリリットルとを加えて、抽出し、得られた有機層を、無水硫酸マグネシウムで乾燥し、濾過した後、減圧濃縮して１−シクロプロピル−２−（２−フルオロフェニル）−２−（１−ピペリジノ）エタン４１０ｍｇ（１．６ミリモル）を無色油状物として得た。〔１，２−エポキシ−２−シクロプロピル−１−（２−フルオロフェニル）−２−フェニルスルホニルエタン基準の収率＝８８．９％〕
ＩＲ（ｎｅａｔ、ｃｍ−１）；１７００（Ｃ＝Ｏ）
ＭＳ（ＣＩ：ｍ／ｚ）；２６２（ＭＨ＋ ）、１９２
参考例２；４−クロロ−４−フェニルスルホニル−１−ブテンの製造
クロロメチルフェニルスルホン４．０ｇ（２１ミリモル）をテトラヒドロフラン２０ミリモルに溶解して、得られたテトラヒドロフラン溶液を−７０℃に冷却し、１．６Ｍ ｎ−ブチルリチウム ｎ−ヘキサン溶液１５．８ミリリットル（２５．２ミリモル）を滴下した後、同温度を保ちながら３０分間攪拌した。次いでアリルクロライド１．８ｇ（２３．１ミリモル）を、該テトラヒドロフラン溶液の温度が−７０℃を保つ速度で滴下した後、同温度を保ちながら１時間攪拌した後、０℃に昇温させ、同温度を保ったままさらに３０分間攪拌した。
得られた反応溶液を、減圧濃縮し、得られた残渣に１Ｎ−塩酸５０ミリリットルと酢酸エチル３０ミリリットルとを加えて、抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過した後、減圧濃縮してオイル５．１ｇを得た。得られたオイルをシリカゲルカラムクロマトグラフィ−（展開液；ｎ−ヘキサン：酢酸エチル＝２：１）に付して、４−クロロ−４−フェニルスルホニル−１−ブテン１．６ｇ（６．９ミリモル）を得た。（クロロメチルフェニルスルホン基準の収率＝３２．９％）
ＭＳ（ＣＩ：ｍ／ｚ）；２３１（ＭＨ＋ ）
ＮＭＲ（ＣＤＣｌ３ 、δ）；
２．５３〜２．６５（１Ｈ，ｍ）
３．１４〜３．２３（１Ｈ，ｍ）
４．６４〜４．６９（１Ｈ，ｄｄ，Ｊ＝１０．３ＨＺ）
５．２１〜５．２８（２Ｈ，ｄｄ，Ｊ＝６．７，１．２ＨＺ、：ｄｄ，Ｊ＝１５．９，１．２ＨＺ）
５．７３〜５．８５（１Ｈ，ｍ）
７．５７〜７．６４（２Ｈ，ｍ）
７．６９〜７．７５（１Ｈ，ｍ）
７．９５〜７．９９（２Ｈ，ｍ）
【００７３】
参考例３；４，５−エポキシ−５−（２−フルオロフェニル）−４−フェニルスルホニル−１−ペンテンの製造
参考例２で得られた４−クロロ−４−フェニルスルホニル−１−ブテン１．６ｇ（６．７ミリモル）と２−フルオロベンズアルデヒド８３９ｍｇ（６．７ミリモル）とを、ｔ−ブタノ−ル１２ミリリットルとエチルエ−テル６ミリリットルとからなる混合溶剤に溶解し、得られた混合溶液を１０℃に保ったまま、カリウム ｔ−ブトキシド７５９ｍｇ（６．７ミリモル）を含むｔ−ブタノ−ル溶液４ミリリットルを滴下した。滴下終了後の混合溶液を、アルゴン雰囲気下、室温（２０℃）に戻した後４時間攪拌して反応させた。
得られた反応溶液に水２３ミリリットルを加えて、水洗し、抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮し、残渣を得た。得られた残渣を薄層クロマトグラフィ−（展開液；ｎ−ヘキサン：酢酸エチル＝４：１）に付して４，５−エポキシ−５−（２−フルオロフェニル）−４−フェニルスルホニル−１−ペンテン７３４ｍｇ（２．３ミリモル）を得た。（４−クロロ−４−フェニルスルホニル−１−ブテン基準の収率＝３４．３％）
ＭＳ（ＣＩ：ｍ／ｚ）；１７７（ＭＨ−Ｃ６ Ｈ５ ＳＯ２ Ｈ）
ＮＭＲ（ＣＤＣｌ３ 、δ）；
２．３２〜２．４１（１Ｈ，ｍ）
２．５１〜２．６０（１Ｈ，ｍ）
４．６２〜４．７０（１Ｈ，ｄｄ，Ｊ＝１７．１，１．２ＨＺ）
４．８１〜４．８６（１Ｈ，ｄｄ，Ｊ＝１０．４，１．２ＨＺ）
４．９５（１Ｈ，ｓ）
５．４０〜５．５３（２Ｈ，ｍ）
７．０４〜７．３５（４Ｈ，ｍ）
７．５７〜７．７５（３Ｈ，ｍ）
７．９８〜８．０２（１Ｈ，ｍ）
【００７４】
実施例２
参考例３で得られた４，５−エポキシ−５−（２−フルオロフェニル）−４−フェニルスルホニル−１−ペンテン７３４ｍｇ（２．３ミリモル）と炭酸カリウム９５４ｍｇ（６．９ミリモル）とをアセトニトリル６ミリリットルに溶解し、得られたアセトニトリル溶液に、ピペリジン１９６ｍｇ（２．３ミリモル）を含むアセトニトリル溶液４ミリリットルを滴下し６時間攪拌した後、４５℃に昇温させ、同温度を保ったまま、さらに６時間加熱攪拌して反応させた。
得られた反応溶液を室温（２０℃）まで冷却した後、水１０ミリリットルと塩化メチレン２０ミリリットルとを加えて、抽出して有機層を得た。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮して油状物９５３ｍｇを得た。得られた油状物をシリカゲルカラムクロマトグラフィ−（展開液；ｎ−ヘキサン：酢酸エチル：トルエン＝５：１：３）に付して、１−（２−フルオロフェニル）−１−（１−ピペリジノ）−４−ペンテン−２−オン３９７ｍｇ（１．５ミリモル）を得た。〔４，５−エポキシ−５−（２−フルオロフェニル）−４−フェニルスルホニル−１−ペンテン基準の収率＝６５．２％〕
ＭＳ（ＣＩ：ｍ／ｚ）；２６２（ＭＨ＋ ）
ＮＭＲ（ＣＤＣｌ３ 、δ）；
１．３４〜１．３８（２Ｈ，ｔ，Ｊ＝５．５ＨＺ）
１．４９〜１．５７（４Ｈ，ｑ）
１．７６〜１．８１（２Ｈ，ｍ）
２．２９〜２．３１（４Ｈ，ｄ，Ｊ＝４．９ＨＺ）
４．４６（１Ｈ，ｓ）
６．３４〜６．８４（１Ｈ，ｍ）
６．８４〜７．３９（６Ｈ，ｍ）
【００７５】
参考例４：１−クロロ−１−フェニルスルホニルエタンの製造
クロロメチルフェニルスルホン４．０ｇ（２１ミリモル）をテトラヒドロフラン２０ミリリットルに溶解し、得られたテトラヒドロフラン溶液を、−７０℃に冷却した後、１．６Ｍ ｎ−ブチルリチウム ｎ−ヘキサン溶液１４．４ミリリットル（２３．１ミリモル）を滴下し−７０℃に保ったまま１時間攪拌した。さらに、０℃に昇温させ、同温度を保ったまま１時間攪拌した後、ヨウ化メチル３．３ｇ（２３．１ミリモル）を同温度を保ったまま滴下した後１時間攪拌し、溶液の温度を０℃に昇温させ、０℃を保ったままさらに１時間攪拌して反応させた。
【００７６】
得られた反応溶液を、減圧濃縮し、得られた残渣に２Ｎ−塩酸３０ミリリットルと塩化メチレン３０ミリリットルとを加えて、抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液３０ミリモルで洗浄した後、乾燥硫酸マグネシウムで乾燥し、濾過し、減圧濃縮してオイル状の１−クロロ−１−フェニルスルホニルエタン４．４ｇ（純度６５．６％、１−クロロ−１−フェニルスルホニルエタンとして１４．２ミリモル）を得た。（クロロメチルフェニルスルホンを基準とする１−クロロ−１−フェニルスルホニルエタン収率＝６７．６％）
ＭＳ（ＣＩ：ｍ／ｚ）；２０５（ＭＨ＋ ）
ＮＭＲ（ＣＤＣｌ３ 、δ）；
１．８３〜１．８３（３Ｈ，ｄ，Ｊ＝６．７２ＨＺ）
４．７７〜４．８４（１Ｈ，ｑ）
７．５８〜７．６３（２Ｈ，ｍ）
７．６９〜７．７６（１Ｈ，ｍ）
７．９５〜８．０２（２Ｈ，ｍ）
【００７７】
実施例３
４，５，６，７−テトラヒドロ−４Ｈ−チエノ〔３，２−ｃ〕ピリジン−２−オン・ｐ−トルエンスルホン酸塩６５５ｍｇ（２．０ミリモル）とｔｅｒｔ−ブチルジメチルシリルクロライド３２２ｍｇ（２．２ミリモル）とを塩化メチレン１．２ミリリットルに懸濁させ、得られた塩化メチレン懸濁液に、トリエチルアミン２２３ｍｇ（２．２ミリモル）を滴下し、１時間攪拌して反応させて、反応溶液１を得た。
【００７８】
２−（ｔ−ブチルジメチルシリルオキシ）−４，５，６，７−テトラヒドロ−４Ｈ−チエノ〔３，２−ｃ〕ピリジン（特願平６−２４４１４１号公報参照）を含む反応溶液１に、参考例５で得られた１，２−エポキシ−１−（２−フルオロフェニル）−２−フェニルスルホニルプロパン５８５ｍｇ（２．０ミリモル）とトリエチルアミン４０５ｍｇ（４．０ミリモル）とを加え、４５℃に昇温させた後、同温度を保ちながら２０時間加熱攪拌して反応させた。
【００７９】
得られた反応溶液２に、０．１Ｍリン酸緩衝液１０ミリリットル（ｐＨ＝６．８７）と塩化メチレン１０ミリリットルとを加えて抽出し、有機層を得た。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮して油状物１．４ｇを得た。得られた油状物をシリカゲルカラムクロマトグラフィ−（溶離液：ｎ−ヘキサン：酢酸エチル＝５：２）に付して、２−（ｔ−ブチルジメチルシリルオキシ）−５−〔１−（２−フルオロフェニル）−２−オキソプロピル〕−４，５，６，７−テトラヒドロチエノ〔３，２−ｃ〕ピリジン４１５ｍｇ（１．０ミリモル）を得た。（４，５，６，７−テトラヒドロ−４Ｈ−チエノ〔３，２−ｃ〕ピリジン−２−オン・ｐ−トルエンスルホン酸塩基準の収率＝５０．０％）
ＭＳ（ＣＩ：ｍ／ｚ）；４２０（ＭＨ＋ ）、３７２、２６１
参考例６：（１−クロロ−１−シクロプロピルメチル）フェニルスルホンの製造
２８％ナトリウムメトキシド（ナトリウムメトキシドとして３．９ｇ、２０．０ミリモル）メタノ−ル溶液４ミリリットルにベンゼンチオ−ル２．２ｇ（２０．０ミリモル）を含むメタノ−ル溶液８ミリリットルを滴下し、０．５時間攪拌した。得られたメタノ−ル混合液を０〜５℃に冷却し、同温度を保つ速度でシクロプロピルブロマイド２．７ｇ（２０．０ミリモル）を含むメタノ−ル溶液８ミリリットルを滴下した後、保温せず１０時間攪拌して反応させた。
得られた反応溶液１に、６Ｎ−水酸化ナトリウム水溶液１０ミリリットルとヘキサン１２ミリリットルとを加えて抽出し、有機層を得た。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮して（シクロプロピルメチル）フェニルスルフィド３．１ｇを得た。
沸点：９６℃／３．５ｍｍＨｇ
【００８１】
前記の（シクロプロピルメチル）フェニルスルフィド３．０ｇ（１８．５ミリモル）を酢酸３８ミリリットルに溶解し、得られた酢酸溶液に３５％過酸化水素水２．２ｇ（２２．２ミリモル）を含む酢酸３８ミリリットルを滴下して、２０時間攪拌して反応させた。
得られた反応溶液２に、水２５０ミリリットルと塩化メチレン１２５ミリリットルと加えて、抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧乾燥してオイル状の粗精製（シクロプロピルメチル）フェニルスルホキシド５．９ｇを得た。
【００８２】
前記の粗精製（シクロプロピルメチル）フェニルスルホキシド１．７ｇ（１５ミリモル）、炭酸カルシウム１．２ｇ（９．０ミリモル）、Ｎ−クロロスクシイミド４．０ｇ（３０ミリモル）と塩化メチレン２０ミリリットルとを混合して、４０℃で１０時間攪拌した後、さらに室温（２０℃）で４８時間静置して反応させた。
得られた反応溶液３に、４％ヨウ化ナトリウム水溶液１６ミリリットルとエチルエ−テル１６ミリリットルとを加えて、抽出した。得られた有機層を、１０％チオ硫酸ナトリウム水溶液２５ミリリットル、飽和食塩水１６ミリリットルで洗浄した後、無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮して残渣を得た。得られた残渣をシリカゲルクロマトグラフィ−（溶離液；ｎ−ヘキサン：酢酸＝１０：３）に付し、（１−クロロ−１−シクロプロピルメチル）フェニルスルホキシド１．６ｇを得た。
【００８３】
ｍ−クロロ過安息香酸１．６ｇ（９．０ミリモル）と塩化メチレン１６ミリリットルとの混合溶液を、０〜５℃に冷却し、前記（１−クロロ−１−シクロプロピルメチル）フェニルスルホキシド１．５ｇ（６．９ミリモル）を含む塩化メチレン溶液１６ミリリットルを滴下して、同温度を保ったまま１０時間攪拌して反応させた。
得られた反応溶液４に飽和炭酸水素ナトリウム水溶液１５ミリリットルと塩化メチレン１５ミリリットルとを加えて、抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過し、減圧濃縮してオイル状の（１−クロロ−１−シクロプロピルメチル）フェニルスルホンを２．３ｇ（１０．０ミリモル）を得た。（ベンゼンチオ−ル基準の収率＝５０．０％）
ＩＲ（ｎｅａｔ、ｃｍ−１）；１３２５、１１５２
ＭＳ（ＣＩ：ｍ／ｚ）；３１９（ＭＨ＋ ）、１７７
１ＨＮＭＲ（ＣＤＣｌ３ 、δ）；
０．６１〜０．８６（４Ｈ，ｍ）
１．３４〜１．４１（１Ｈ，ｍ）
４．２３〜１．２７（１Ｈ，ｄ、Ｊ＝８．５４Ｈｚ）
７．５７〜８．００（５Ｈ，ｍ）[0001]
[Industrial applications]
The production method of the present invention can be carried out, for example, using 2- (t-butyldimethylsilyloxy) -5- [1- (2-fluorophenyl) -2-oxopropyl] -4,5,6,7-tetrahydrothieno [3,2 -C] relates to a method for producing α-aminoketones such as pyridine.
The aforementioned α-aminoketones are useful as intermediates when synthesizing an antithrombotic agent having a platelet aggregation inhibitory action.
[0002]
In the target compound obtained by the production method of the present invention, for example, 2- (t-butyldimethylsilyloxy) -5- [1- (2-fluorophenyl) -2-oxopropyl] -4,5,6,7-tetrahydro Thieno [3,2-c] pyridine is, for example,JP-A-08-811203 (WO 96/11203)2-Acyloxy-5- [1- (2-fluorophenyl) having a platelet aggregation-inhibiting action by reacting an acid anhydride with a base in the presence of an acylation catalyst according to the method described in JP -2-oxopropyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine.
[0003]
[Prior art]
Conventional methods for producing 2-aminoketones include the following methods.
▲ 1 ▼. Journal of Organic Chemistry (Vol. 24, p. 478, 1956) describes a method of reacting secondary amines with α-haloketones. However, this method has a problem in that regioselectively halogenated carbonyl compounds are limited to compounds that are easily available and thermally stable, and the yield is low due to side reactions. there were.
▲ 2 ▼. Chemical Reviews (Chemical Reviews, Vol. 64, p. 81, 1964) include oximutosylates (for example, benzyl methyl ketone oximutosylate) obtained from ketoxime and p-toluenesulfonyl chloride and sodium ethyl acetate. Describes a Neber rearrangement reaction in which an α-aminoketone (eg, 1-amino-1-phenyl-2-propanone) is obtained by an intramolecular nucleophilic substitution reaction via an azirine or nitrene intermediate using a compound.
However, this method is limited to the introduction of only an unsubstituted amino group, and has a problem in that the yield is low.
(3). Tetrahedron Letters (Tetrahedron Letters, Vol. 25, p. 2977, 1984) discloses acyl cyanides (eg, 1-cyano-2-phenyl-1-ethanone) obtained by treating acyl chloride with copper cyanide. ) In the presence of excess acetic anhydride in a selective reduction reaction with zinc / acetic acid, followed by acid hydrolysis to give an α-aminoketone (eg, 1-amino-3-phenyl-2-propanone). Has been described.
However, although this method is useful for the synthesis of α-acylmethylamines, it has a problem in that it has a narrow application range and cannot be applied to the present application.
[0004]
▲ 4 ▼. Journal of Organic Chemistry (Vol. 27, p. 4392, 1962) includes epoxy ethers (eg, 1,2-epoxy-1-methoxy-2-methyl-1-phenylpropane). ) And an amine (eg, piperidine) to obtain an α-aminoketone (eg, 1-phenyl-2-methyl-2- (1-piperidino) -1-propanone).
However, although this method is useful for the synthesis of phenyl α-aminoketones, it has a problem in that it has a narrow range of application and cannot be applied to the present application.
▲ 5 ▼. Chemistry Letters (Vol. 585, 1982) describes an aminolysis reaction of an α, β-epoxysulfoxide having a sulfinyl group as a leaving group introduced as an epoxy compound. .
However, although this reaction has the advantage that the desired product can be obtained under mild conditions, sulfenic acid generated by the elimination of sulfoxide in this reaction is generally unstable, and thiolsulfinamide is dehydrated by dehydration of two molecules of sulfenic acid. However, there is a disadvantage that disulfides and thiolsulfonates having extremely bad odors are generated and disproportionately generated, and in order to obtain aminoketones with a high yield, it is necessary to add a large excess of amine. There was a problem in the point.
[0005]
Therefore, any of the known (1) to (5) has been unsatisfactory as an industrial production method for producing α-aminoketones.
[0006]
[Problems to be solved by the invention]
[0007]
The present inventors have intensively studied a method for producing α-aminoketones in order to solve the problems in the known production method, and as a result, as an epoxy compound, α, β-epoxy in which a sulfonyl group which is a leaving group was introduced. The present inventors have found that α-aminoketones can be produced with a good yield and selectivity under mild conditions by using an aminolysis reaction using sulfones and secondary amines, thereby completing the present invention.
[0008]
An object of the present invention is to provide a method for producing α-aminoketones in which α, β-epoxysulfones are reacted with secondary amines in the presence of a base.
[0009]
The present invention
General formula (1)
[0010]
Embedded image
[Wherein, R1, R2Are the same or different,Hydrogen atom, alkyl group having 1 to 10 carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl group having 7 to 12 carbon atoms; carbon atom An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, and a phenyl group which may be substituted with a halogen atomAnd R3IsAn alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms; 10 alkyl groups, alkenyl groups having 2 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, and phenyl groups which may be substituted with halogen atomsAnd R4IsAn alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms; an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom Phenyl groupIs shown. Α, β-epoxysulfonic acids represented by the formula:
[0012]
General formula (2)
[0013]
Embedded image
[Wherein, R5, R6Are the same or different,An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atomsOr R5, R6May be bonded to represent an optionally substituted heterocyclic ring. The secondary amine or a salt thereof represented by the formula: in the presence of a base in an organic solvent.
[0015]
Embedded image
[Wherein, R1, R2, R3, R5, R6Has the same meaning as described above. And a method for producing α-aminoketones represented by the formula:
[0017]
Preferred embodiments of the present invention are as follows.
[0018]
1) R1, R2Are the same or different, and include a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and 7 to 12 carbon atoms. Aralkyl groups; alkyl groups having 1 to 10 carbon atoms, alkenyl groups having 2 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, and may be substituted with halogen atomsPhenylA group represented by R3Is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms; It may be substituted by 1 to 10 alkyl groups, alkenyl groups having 2 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, and halogen atoms.PhenylA group represented by R4Is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms; substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, and a halogen atom Α, β-epoxysulfonic acids represented by the general formula (1) representing a phenyl group which may be
[0019]
R5, R6Is the same or different and has an alkyl group having 1 to 10 carbon atoms,
An alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms,
R5, R6The production method according to claim 1, wherein the secondary amine is a secondary amine represented by the general formula (2) or a salt thereof, which represents a heterocyclic ring which may be substituted by bonding.
[0020]
2) R1, R2Are the same or different, and include a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and 7 to 10 carbon atoms. Aralkyl groups, a phenyl group which may be substituted with a halogen atom,
R3Is substituted with an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and a halogen atom Represents a phenyl group which may be
R4Is an α, β-epoxysulfone represented by the general formula (1), which is a compound showing a phenyl group;
R5, R6Is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or is bonded and optionally substituted piperidine , An optionally substituted 4,5,6,7-tetrahydro [3,2-c] thienopyridine, morpholine, and a secondary represented by the general formula (2) representing 1,2,3,4-tetrahydroisoquinoline The production method according to claim 1, which is an amine or a salt thereof.
[0021]
3) R1, R2May be the same or different and include a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and 7 to 8 carbon atoms Aralkyl groups, a phenyl group which may be substituted with a fluorine atom,
R3Is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aralkyl group having 7 to 8 carbon atoms, and a fluorine atom. Represents a phenyl group which may be substituted,
R4Is an α, β-epoxy sulfone represented by the general formula (1), which is a compound showing a phenyl group;
R5, R6Is a secondary amine represented by the general formula (2), which represents piperidine, 2- (t-butyldimethylsilyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. Or the salt thereof.
[0022]
The main reaction in the production method of the present invention is, for example, the following reaction formula (1)
[0023]
Embedded image
Can be indicated by
[0025]
In the α, β-epoxysulfones represented by the general formula (1) used in the production method of the present invention, R1, R2, R3Are the same or different,
A linear or branched alkyl group having 1 to 10 carbon atoms,
A linear or branched cycloalkyl group having 3 to 10 carbon atoms,
A linear or branched alkenyl group having 2 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms having a linear or branched alkyl group portion having 1 to 6 carbon atoms,
May have a substituentPhenyl group,
Should be fine.
[0026]
As the alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl group having 1 to 8 carbon atoms (particularly, 1 to 4 carbon atoms) is preferable. Group, ethyl group, propyl group (including isomer), butyl group (including isomer), pentyl group (including isomer), hexyl group (including isomer), heptyl group (including isomer), Examples include an octyl group (including an isomer), a nonyl group (including an isomer), a decyl group (including an isomer), and the like, preferably a methyl group, an ethyl group, a propyl group (including an isomer), A butyl group (including an isomer), a pentyl group (including an isomer), a hexyl group (including an isomer), a heptyl group (including an isomer), and an octyl group (including an isomer). Methyl, ethyl, propyl (including isomers) ), A butyl group (including isomers).
[0027]
As the cycloalkyl group having 3 to 10 carbon atoms, a linear or branched cycloalkyl group having 3 to 8 carbon atoms (especially 3 to 6 carbon atoms) is preferable, For example, cyclopropyl group, cyclobutyl group (including isomer), cyclopentyl group (including isomer), cyclohexyl group (including isomer), cycloheptyl group (including isomer), cyclooctyl group (including isomer) ), A cyclononyl group (including isomers), a cyclodecyl group (including isomers), and the like, preferably a cyclopropyl group, a cyclobutyl group (including isomers), a cyclopentyl group (including isomers), A cyclohexyl group (including isomers), a cycloheptyl group (including isomers), and a cyclooctyl group (including isomers), particularly preferably a cyclopropyl group Cyclobutyl (including isomers) group, (including isomers) cyclopentyl group, a cyclohexyl group (including isomers).
[0028]
As the alkenyl group having 2 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms (particularly, 3 to 5 carbon atoms) is preferable. , Propylene group (including isomer), butene group (including isomer), pentene group (including isomer), hexene group (including isomer), heptene group (including isomer), octene group (including isomer) , A nonene group (including isomers), a decene group (including isomers), and the like, preferably a propylene group (including isomers), a butene group (including isomers), and pentene. Groups (including isomers), hexene groups (including isomers), heptene groups (including isomers), particularly preferably propylene groups (including isomers), butene groups (including isomers), pentene Group (including isomers), hexene A (including isomers), more preferably (including isomers) propylene, (including isomers) butene group, a pentene group (including isomers).
[0029]
The aralkyl group having 7 to 12 carbon atoms having a linear or branched alkyl group portion having 1 to 6 carbon atoms includes 7 to 10 carbon atoms (particularly, 7 to 8) aralkyl groups having 7 to 12 carbon atoms having a linear or branched alkyl group moiety such as phenylmethyl group, phenylethyl group (including isomers), and phenylpropyl group ( Phenylbutyl group (including isomer), phenylpentyl group (including isomer), phenylhexyl group (including isomer), and the like, preferably phenylmethyl group and phenylethyl. Group (including isomers), phenylpropyl group (including isomers), and phenylbutyl group (including isomers), and particularly preferably phenylmethyl group and phenylethyl group (including isomers). Is included).
[0030]
The phenyl group which may be substituted may be a phenyl group having no substituent or a phenyl group having a substituent.
[0031]
The “substituent of the phenyl group having a substituent” described above may be any substitution position on the ring of the phenyl group, and may be the above-mentioned alkyl group, halogen atom or alkoxy group described below.
[0032]
Examples of the halogen atom of the above-mentioned "substituent of the phenyl group having a substituent" include, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and are preferably a fluorine atom and a chlorine atom. A fluorine atom is preferred.
[0033]
In the α, β-epoxy sulfones represented by the general formula (1), the alkoxy group of the “substituent of the phenyl group having a substituent” is a straight-chain or branched-chain having 1 to 10 carbon atoms. Any alkoxy group having an alkyl group portion may be used.
[0034]
Examples of the alkoxy group having 1 to 10 carbon atoms include an alkoxy group having a linear or branched alkyl group portion having 1 to 8 carbon atoms (particularly, 1 to 6 carbon atoms). Preferably, for example, methoxy, ethoxy, propoxy (including isomers), butoxy (including isomers), pentyloxy (including isomers), hexyloxy (including isomers), heptyloxy Groups (including isomers), octyloxy groups (including isomers), nonyloxy groups (including isomers), and alkoxy groups having 1 to 10 carbon atoms such as decyloxy groups (including isomers). Preferred are methoxy, ethoxy, propoxy (including isomers), butoxy (including isomers), pentyloxy (including isomers), and hexyloxy (including isomers). ), A heptyloxy group (including isomers), an octyloxy group (including isomers), and particularly preferably a methoxy group, an ethoxy group, a propoxy group (including isomers), and a butoxy group (including isomers) ), A pentyloxy group (including isomers), and a hexyloxy group (including isomers).
[0035]
In the α, β-epoxysulfones represented by the general formula (1) used in the production method of the present invention, R4Are the same or different,
A linear or branched alkyl group having 1 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms having a linear or branched alkyl group having 1 to 6 carbon atoms;
A linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a phenyl group which may be substituted with a halogen atom,
Should be fine.
[0036]
R4A straight-chain or branched alkyl group having 1 to 10 carbon atoms, or an aralkyl having 7 to 12 carbon atoms having a straight-chain or branched alkyl group portion having 1 to 6 carbon atoms The group may be the aforementioned alkyl group or aralkyl group.
In the α, β-epoxy sulfones represented by the general formula (1) used in the production method of the present invention,4A phenyl group which may be substituted by a linear or branched alkyl group having 1 to 10 carbon atoms, a halogen atom, a linear or branched alkoxy group having 1 to 10 carbon atoms Is a phenyl group which may be substituted as described above, and is a linear or branched alkyl group having 1 to 10 carbon atoms of "substituent of phenyl group having a substituent", The up to 10 linear or branched alkoxy groups and halogen atoms may be the alkyl groups, halogen atoms and alkoxy groups of the above-mentioned "substituents of phenyl group having a substituent".
[0037]
The α, β-epoxysulfones represented by the general formula (1) used in the production method of the present invention include, for example, 1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylethane, 1,2-epoxy-1-phenyl-2-phenylsulfonylpropane, 1,2-epoxy-1-phenyl-2-phenylsulfonylbutane, 1,2-epoxy-1-phenyl-2-phenylsulfonylpentane, 1, 2-epoxy-1-phenyl-2-phenylsulfonylhexane, 1,2-epoxy-1-phenyl-2-phenylsulfonylheptane, 1,2-epoxy-1-phenyl-2-phenylsulfonyloctane, 4,5- Epoxy-5-phenyl-5-phenylsulfonyl-1-pentene, 4,5-epoxy-5-phenyl-5-phenyl Sulfonyl-1-hexene, 4,5-epoxy-5-phenyl-5-phenylsulfonyl-1-heptene, 4,5-epoxy-5-phenyl-5-phenylsulfonyl-1-octene,
[0038]
1,2-epoxy-1,3-diphenyl-2-phenylsulfonylpropane, 2,3-epoxy-1,3-diphenyl-2-phenylsulfonylpropane, 2,3-epoxy-1,3-diphenyl-2- Phenylsulfonylpentane, 1,2-epoxy-1,3-diphenyl-2-phenylsulfonylbutane, 2,3-epoxy-2-phenyl-3-phenylsulfonylpropane, 2,3-epoxy-3-cyclopropyl-2 -Phenylsulfonylpropane, 2,3-epoxy-2-phenyl-2-phenylsulfonylbutane, 2,3-epoxy-2-phenyl-3-phenylsulfonylpentane, 2,3-epoxy-2-phenyl-3-phenyl Sulfonylhexane, 2,3-epoxy-2-phenyl-3-phenylsulfonyloctane, , 5-Epoxy-5-phenyl-4-phenylsulfonyl-1-hexene, 4,5-epoxy-5-phenyl-4-phenylsulfonyl-1-pentene, 7,8-epoxy-8-phenyl-7-phenyl Sulfonyl-1-octene,
[0039]
1-cyclohexyl-1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylpropane, 1-cyclohexyl-1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylbutane, 1-cyclohexyl-1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylpentane, 1-cyclohexyl-1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylhexane, 1-cyclohexyl-1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonyloctane,
[0040]
5-cyclohexyl-4,5-epoxy-4-phenylsulfonyl-1-pentene, 6-cyclohexyl-5,6-epoxy-5-phenylsulfonyl-1-hexene, 8-cyclohexyl-7,8-epoxy-7- Α, such as phenylsulfonyl-1-octene, 1-cyclohexyl-1,2-epoxy-3-phenyl-2-phenylsulfonylpropane and 1-cyclohexyl-1,2-epoxy-4-phenyl-2-phenylsulfonylbutane; β-epoxy sulfones (the phenyl group in the molecule may have the substituent described above),
[0041]
Preferably,
1,2-epoxy-2-cyclopropyl-1-phenyl-2-phenylsulfonylethane, 4,5-epoxy-5-phenyl-4-phenylsulfonyl-1-pentene, 1,2-epoxy-1-phenyl- Α, β-epoxy sulfones such as 2-phenylsulfonylpropane [the phenyl group in the molecule may have the above-mentioned substituent (preferably a halogen atom)],
[0042]
Particularly preferably, 1,2-epoxy-2-cyclopropyl-1- (2-fluorophenyl) -2-phenylsulfonylethane, 4,5-epoxy-5- (2-fluorophenyl) -4-phenylsulfonyl- 1-pentene and 1,2-epoxy-1- (2-fluorophenyl) -2-phenylsulfonylpropane.
[0043]
The α, β-epoxysulfones represented by the general formula (1) used in the production method of the present invention can be obtained, for example, according to the method described in Reference Examples, by using α-halogenated alkylsulfones and corresponding aldehydes or ketones. The compound is reacted in the presence of a base, for example, by the so-called Dalzen reaction described in Canadian Journal of Chemistry, Vol. 47, p. 2875, 1969.
[0044]
When a compound having a sulfonyl group as a leaving group in the molecule, such as α, β-epoxysulfone represented by the general formula (1) used in the production method of the present invention, sulfin is a by-product. The acid is stable, has an advantage that, unlike the case where a compound having a sulfinyl group as a leaving group in the molecule is used, no odor is generated, and it can be easily removed by washing with water at the end of the reaction.
[0045]
R of the secondary amine represented by the general formula (2) used in the production method of the present invention4Are the same or different,
A linear or branched alkyl group having 1 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms having a linear or branched alkyl group portion having 1 to 10 carbon atoms,
A linear or branched alkenyl group having 2 to 10 carbon atoms,
Should be fine.
[0046]
Such an alkyl group, an aralkyl group and an alkenyl group may be the above-mentioned alkyl group, aralkyl group and alkenyl group.
[0047]
R of the secondary amine represented by the general formula (2) used in the production method of the present invention5, R6However, when the heterocyclic ring is bonded to form an optionally substituted heterocyclic group, the heterocyclic ring may be an unsubstituted heterocyclic ring or an optionally substituted heterocyclic ring. Good.
[0048]
Examples of the heterocyclic ring having no substituent include, for example, pyrrole, 2H-pyrrol, aromatic heteromonocycles such as pyridine, pyrroline, pyrrolidine, alicyclic heteromonocycles such as piperidine, Aromatic fused heterocycles such as indole, isoindole, quinoline, isoquinoline, indoline, isoindoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrothieno [3,2 -C] alicyclic fused heterocycles such as pyridine, and heterocycles containing two or more heteroatoms such as morpholine, preferably piperidine, morpholine, 1,2,3,4-tetrahydroisoquinoline, , 5,6,7-tetrahydrothieno [3,2-c] pyridine.
[0049]
As the "substituent of a heterocyclic ring having a substituent", the substituent at any position on the heterocyclic ring, for example, the alkyl group,
General formula (4)
[0050]
Embedded image
(Where R7, R8, R9Represents the same or different alkyl groups and aromatic groups. )).
[0052]
R of the trisubstituted silyloxy group represented by the general formula (4)7, R8, R9Represents an alkyl group or a phenyl group. Such an alkyl group and a phenyl group may be any of the above-mentioned alkyl groups and phenyl groups having no substituent.
[0053]
Examples of the tri-substituted silyloxy group include, for example, a trimethylsilyloxy group, a triethylsilyloxy group, a tripropylsilyloxy group, a triisopropylsilyloxy group, a t-butyldimethylsilyloxy group, and a t-butyldiphenylsilyloxy group. And are preferably a triisopropylsilyloxy group, a t-butyldimethylsilyloxy group, and a t-butyldiphenylsilyloxy group, and particularly preferably a t-butyldimethylsilyloxy group.
[0054]
The secondary amine represented by the general formula (2) used in the production method of the present invention includes, for example, dimethylamine, diethylamine, dipropylamine (including isomers), dibutylamine (including isomers), dipentyl Amine (including isomers), dihexylamine (including isomers), dipentylamine (including isomers), dioctylamine (including isomers), methylethylamine, methylpropylamine (including isomers), methylbutylamine (Including isomers), diallylamine, diethanolamine,
[0055]
N-methyl-1-phenylethylamine, N-methyl-2-phenylethylamine, piperidine, 2-methylpiperidine, 4-methylpiperidine, morpholine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7 -Tetrahydro [3,2-c] thienopyridine, 2-triisopropylsilyloxy-4,5,6,7-tetrahydro [3,2-c] thienopyridine, t-butyldimethylsilyloxy-4,5,6,7 Secondary amines such as -tetrahydro [3,2-c] thienopyridine and t-butyldiphenylsilyloxy-4,5,6,7-tetrahydro [3,2-c] thienopyridine;
Preferred are piperidine and t-butyldimethylsilyloxy-4,5,6,7-tetrathieno [3,2-c] pyridine.
[0056]
The amount of the secondary amine represented by the general formula (2) used in the production method of the present invention is usually 0.5 to 5 mol per 1 mol of α, β-epoxysulfones. The amount is preferably, particularly preferably an amount of 1.0 to 3.0 mol, more preferably an amount of 1.0 to 1.5 mol.
[0057]
As the secondary amine represented by the general formula (2) used in the production method of the present invention, commercially available secondary amines can be used as they are, for example, t-butyldimethylsilyloxy-4,5,6,7-tetrahydro. Compounds substituted with a t-butyldimethylsilyloxy group such as thieno [3,2-c] pyridine include, for example,JP-A-08-811203 (WO 96/11203)And reacting 5,6,7,7a-tetrathieno [3,2-c] pyridin-2-one with t-butyldimethylchlorosilane in the presence of triethylamine according to the method described in Butyldiphenylsilyloxy-4,5,6,7-tetrahydrothieno [3,2-c] pyridine can be derived.
[0058]
As the base used in the production method of the present invention, for example, an inorganic base such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, calcium hydroxide, pyridine, quinoline, trimethylamine, triethylamine, tripropyl Amine, tributylamine, ethyldiisopropylamine, triethanolamine, dimethylaniline, N-methylpiperidine, 4-pyridinopyridine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [ And organic bases such as 5.4.0] -5-undecene and diazabicyclo [2.2.2] -octane. Preferred are potassium carbonate, potassium hydrogen carbonate, trimethylamine and triethylamine, and particularly preferred. Potassium carbonate, bird It is ethylamine.
[0059]
The organic solvent used in the production method of the present invention is not particularly limited as long as it does not participate in the reaction, and examples thereof include solvents such as dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, and dioxane. Ter polar organic solvent, nitrile polar organic solvent such as acetonitrile, benzonitrile, amide polar organic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyridone, dimethylimidazolidone, chloride Examples thereof include halogenated hydrocarbon-based organic solvents such as methylene and 1,2-dichloroethane, and preferred are nitrile-based polar organic solvents such as acetonitrile and benzonitrile; and halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane. With hydrocarbon-based polar organic solvents Ri, particularly preferably acetonitrile, methylene chloride.
[0060]
The amount of the polar organic solvent used in the production method of the present invention is preferably 1.5 to 15 times (weight / weight) the amount of the α, β-epoxysulfone, and particularly preferably 5 to 15 times. An amount that gives a ratio of 10 to 10 times (weight / weight) is preferable.
[0061]
The reaction temperature in the production method of the present invention may be a temperature up to the boiling point of a commonly used organic polar solvent, but is preferably in the range of 0 to 200 ° C, particularly preferably in the range of 10 to 100 ° C.
The reaction time in the production method of the present invention is significantly affected by the reaction temperature, but the reaction is usually completed in 0.5 to 48 hours.
[0062]
The α-aminoketones of the target compound represented by the general formula (3) obtained by the above-mentioned production method of the present invention are defined by the above α, β-epoxysulfones and secondary amines. Examples of such α-aminoketones of the target compound include, for example,
1-cyclopropyl-2-phenyl-2- (1-piperidino) ethane, 1-phenyl-1- (1-piperidino) propan-2-one, 1-phenyl-1- (1-piperidino) butan-2- On, 1-phenyl-1- (1-piperidino) pentan-2-one, 1-phenyl-1- (1-piperidino) hexane-2-one, 1-phenyl-1- (1-piperidino) heptane-2 -One, 1-phenyl-1- (1-piperidino) octan-2-one, 1-phenyl-1- (1-piperidino) -4-penten-2-one, 1-phenyl-1- (1-piperidino) ) -4-Hexen-2-one, 1-phenyl-1- (1-piperidino) -4-hepten-2-one,
[0063]
1-phenyl-1- (1-piperidino) -4-octen-2-one, 1,3-diphenyl- (1-piperidino) propan-2-one, 1,4-diphenyl-1- (1-piperidino) -2-one, 1-cyclohexyl-2- (1-piperidino) propan-2-one, 1-cyclopropyl-2-phenyl-2-dimethylaminoethanone, 1-phenyl-1-dimethylaminopropane-2- on,
[0064]
1-phenyl-1-dimethylaminobutan-2-one, 1-phenyl-1-dimethylaminopentan-2-one, 1-phenyl-1-dimethylaminohexane-2-one, 1-phenyl-1-dimethylamino Heptane-2-one, 1-phenyl-1-dimethylaminooctane-2-one, 1-phenyl-1-dimethylamino-4-penten-2-one, 1-phenyl-1-dimethylamino-5-hexene- 2-one, 1-phenyl-1-dimethylamino-6-hepten-2-one, 1-phenyl-1-dimethylamino-6-octen-2-one, 1,3-diphenyl-1-dimethylaminopropane- 2-one,
[0065]
1,4-diphenyl-1-dimethylaminobutan-2-one, 1-cyclohexyl-1-dimethylaminopropan-2-one, N- (2-oxo-1-phenylpropyl) -1,2,3,4 -Tetrahydroisoquinoline, 5- (2-oxo-1-phenylpropyl) -4,5,6,7-tetrahydro [3,2-c] thienopyridine, 2- (t-butyldimethylsilyloxy) -5- (1 -Phenyl-2-oxopropyl) -4,5,6,7-tetrahydro [3,2-c] thienopyridine, 2-triisopropylsilyloxy-5- (1-phenyl-2-oxopropyl) -4,5 , 6,7-Tetrahydro [3,2-c] thienopyridine, t-butyldimethylsilyloxy-5- (1-phenyl-2-oxopropyl) -4,5,6,7-tet Such as hydro [3,2-c] thienopyridine, t-butyldiphenylsilyloxy-5- (1-phenyl-2-oxopropyl) -4,5,6,7-tetrahydro [3,2-c] thienopyridine α-aminoketones, and compounds in which the phenyl group in the molecule of these α-aminoketones is substituted at any position with the halogen atom, alkyl group, or alkoxy group,
[0066]
Preferably, a compound in which a phenyl group in a molecule of an α-aminoketone is substituted with a halogen atom at an arbitrary position,
Particularly preferably,
1-cyclopropyl-2- (2-fluorophenyl) -2- (1-piperidino) ethane, 1- (2-fluorophenyl)-(1-piperidino) -4-penten-2-one, 2- (t -Butyldimethylsilyloxy) -5- [1- (2-fluorophenyl) -2-oxopropyl] -4,5,6,7-tetrahydro [3,2-c] thienopyridine.
[0067]
In the production method of the present invention, a method for obtaining a reaction mixture containing the produced α-aminoketones may be performed by a combination of ordinary washing operation and separation operation. After removing the base, a crude product is obtained by solvent extraction and concentration under reduced pressure. In the case of further purification, purification may be performed by, for example, column chromatography or the like, but the purification method may be appropriately selected for each compound.
[0068]
【The invention's effect】
According to the present invention, by reacting the α, β-epoxy sulfone of the general formula (1) with the secondary amine of the general formula (2) or a salt thereof in the presence of a base in an organic solvent. Α-aminoketones, which are target compounds, can be produced under mild conditions with good yield and selectivity. In particular, since α, β-epoxy sulfones use a compound having a sulfonyl group as a leaving group in the molecule, by-product sulfinic acid is stable, and the sulfinyl group is a leaving group as a leaving group. Unlike the case of using the compound having the above, no odor is generated, and it can be easily removed by washing with water at the end of the reaction.
[0069]
【Example】
Examples and reference examples are shown below.
[0070]
Reference Example 1; Production of 1,2-epoxy-2-cyclopropyl-1- (2-fluorophenyl) -2-phenylsulfonylethane
760 mg (3.3 mmol) of (1-chloro-1-cyclopropylmethyl) phenyl sulfone and 406 mg (3.3 mmol) of 2-fluorobenzaldehyde were converted from 6 ml of t-butanol and 3 ml of ethyl ether. The resulting mixed solution was cooled to 10 ° C., and while maintaining the same temperature, 4 ml of a t-butanol solution containing 369 mg (3.3 mmol) of potassium t-butoxide was added dropwise. . After completion of the dropwise addition, the mixed solution was reacted by stirring at room temperature (20 ° C.) for 3 hours.
10 ml of water was added to the obtained reaction solution, washed with water, and extracted. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to thin-layer chromatography (developing solution; n-hexane: ethyl acetate = 10: 3) to give 1,2-epoxy-2-cyclopropyl-1- (2-fluorophenyl) -2-. 751 mg (2.4 mmol) of phenylsulfonylethane were obtained. (Yield based on (1-chloro-1-cyclopropylmethyl) phenylsulfone = 72.7%)
IR (neat, cm-1); 1325, 1155, 1237, 910, 828
MS (CI: m / z); 319 (MH+), 177
Example 1
587 mg (1.8 mmol) of 1,2-epoxy-2-cyclopropyl-1- (2-fluorophenyl) -2-phenylsulfonylethane obtained in Reference Example 1 and 763 mg (5.5 mmol) of potassium carbonate ) Was dissolved in 5 mL of acetonitrile, and 5 mL of acetonitrile in which 172 mg (2 mmol) of piperidine was dissolved was added dropwise to the obtained acetonitrile solution, and the mixture was stirred and reacted for 6 hours.
To the obtained reaction solution, 10 ml of water and 10 ml of methylene chloride were added and extracted, and the obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-cyclopropyl-. 410 mg (1.6 mmol) of 2- (2-fluorophenyl) -2- (1-piperidino) ethane were obtained as a colorless oil. [Yield based on 1,2-epoxy-2-cyclopropyl-1- (2-fluorophenyl) -2-phenylsulfonylethane = 88.9%]
IR (neat, cm-1); 1700 (C = O)
MS (CI: m / z); 262 (MH+), 192
Reference Example 2: Production of 4-chloro-4-phenylsulfonyl-1-butene
4.0 g (21 mmol) of chloromethylphenylsulfone was dissolved in 20 mmol of tetrahydrofuran, and the obtained tetrahydrofuran solution was cooled to -70 ° C, and 15.8 ml of a 1.6 M n-butyllithium n-hexane solution (25 ml) was added. .2 mmol), and the mixture was stirred for 30 minutes while maintaining the same temperature. Then, 1.8 g (23.1 mmol) of allyl chloride was added dropwise at a rate to keep the temperature of the tetrahydrofuran solution at -70 ° C, and the mixture was stirred for 1 hour while maintaining the same temperature, and then heated to 0 ° C. The mixture was further stirred for 30 minutes while maintaining the temperature.
The obtained reaction solution was concentrated under reduced pressure, and the obtained residue was extracted by adding 50 mL of 1N hydrochloric acid and 30 mL of ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5.1 g of an oil. The obtained oil was subjected to silica gel column chromatography (developing solution; n-hexane: ethyl acetate = 2: 1) to give 1.6 g (6.9 mmol) of 4-chloro-4-phenylsulfonyl-1-butene. Got. (Yield based on chloromethylphenylsulfone = 32.9%)
MS (CI: m / z); 231 (MH+)
NMR (CDCl3, Δ);
2.53 to 2.65 (1H, m)
3.14 to 3.23 (1H, m)
4.64 to 4.69 (1H, dd, J = 10.3HZ)
5.21 to 5.28 (2H, dd, J = 6.7, 1.2HZ, dd, J = 15.9, 1.2HZ)
5.73 to 5.85 (1H, m)
7.57 to 7.64 (2H, m)
7.69 to 7.75 (1H, m)
7.95 to 7.99 (2H, m)
[0073]
Reference Example 3: Production of 4,5-epoxy-5- (2-fluorophenyl) -4-phenylsulfonyl-1-pentene
1.6 g (6.7 mmol) of 4-chloro-4-phenylsulfonyl-1-butene obtained in Reference Example 2 and 839 mg (6.7 mmol) of 2-fluorobenzaldehyde were mixed with 12 ml of t-butanol. And 6 ml of ethyl ether, and 4 ml of a t-butanol solution containing 759 mg (6.7 mmol) of potassium t-butoxide while maintaining the obtained mixed solution at 10 ° C. It was dropped. After the completion of the dropwise addition, the mixed solution was returned to room temperature (20 ° C.) under an argon atmosphere, and then reacted by stirring for 4 hours.
23 ml of water was added to the obtained reaction solution, which was washed with water and extracted. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was subjected to thin-layer chromatography (developing solution; n-hexane: ethyl acetate = 4: 1) to give 4,5-epoxy-5- (2-fluorophenyl) -4-phenylsulfonyl-1-. 734 mg (2.3 mmol) of pentene were obtained. (Yield based on 4-chloro-4-phenylsulfonyl-1-butene = 34.3%)
MS (CI: m / z); 177 (MH-C6H5SO2H)
NMR (CDCl3, Δ);
2.32 to 2.41 (1H, m)
2.51-2.60 (1H, m)
4.62 to 4.70 (1H, dd, J = 17.1, 1.2HZ)
4.81 to 4.86 (1H, dd, J = 10.4, 1.2HZ)
4.95 (1H, s)
5.40 to 5.53 (2H, m)
7.04 to 7.35 (4H, m)
7.57 to 7.75 (3H, m)
7.98 to 8.02 (1H, m)
[0074]
Example 2
734 mg (2.3 mmol) of 4,5-epoxy-5- (2-fluorophenyl) -4-phenylsulfonyl-1-pentene obtained in Reference Example 3 and 954 mg (6.9 mmol) of potassium carbonate were mixed with acetonitrile. After dissolving in 6 ml, 4 ml of acetonitrile solution containing 196 mg (2.3 mmol) of piperidine was added dropwise to the obtained acetonitrile solution, and the mixture was stirred for 6 hours. Then, the temperature was raised to 45 ° C. The mixture was further heated and stirred for 6 hours to react.
After the obtained reaction solution was cooled to room temperature (20 ° C.), 10 ml of water and 20 ml of methylene chloride were added and extracted to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 953 mg of an oil. The obtained oil was subjected to silica gel column chromatography (developing solution; n-hexane: ethyl acetate: toluene = 5: 1: 3) to give 1- (2-fluorophenyl) -1- (1-piperidino). 397 mg (1.5 mmol) of -4-penten-2-one were obtained. [Yield based on 4,5-epoxy-5- (2-fluorophenyl) -4-phenylsulfonyl-1-pentene = 65.2%]
MS (CI: m / z); 262 (MH+)
NMR (CDCl3, Δ);
1.34 to 1.38 (2H, t, J = 5.5HZ)
1.49 to 1.57 (4H, q)
1.76 to 1.81 (2H, m)
2.29 to 2.31 (4H, d, J = 4.9HZ)
4.46 (1H, s)
6.34 to 6.84 (1H, m)
6.84 to 7.39 (6H, m)
[0075]
Reference Example 4: Production of 1-chloro-1-phenylsulfonyleethane
4.0 g (21 mmol) of chloromethylphenylsulfone was dissolved in 20 ml of tetrahydrofuran, and the obtained tetrahydrofuran solution was cooled to -70 ° C, and then 14.4 ml of a 1.6 M n-butyllithium n-hexane solution ( 23.1 mmol) was added dropwise, and the mixture was stirred for 1 hour while maintaining at -70 ° C. Further, the temperature was raised to 0 ° C., and the mixture was stirred for 1 hour while maintaining the same temperature. Then, 3.3 g (23.1 mmol) of methyl iodide was added dropwise while maintaining the same temperature, and the mixture was stirred for 1 hour. The temperature was raised to 0 ° C., and the mixture was further stirred for 1 hour while maintaining 0 ° C. to react.
[0076]
The obtained reaction solution was concentrated under reduced pressure, and the obtained residue was extracted by adding 30 ml of 2N hydrochloric acid and 30 ml of methylene chloride. The obtained organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (30 mmol), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4.4 g of oily 1-chloro-1-phenylsulfonylethane (purity: 65). 6.6%, 14.2 mmol) as 1-chloro-1-phenylsulfonylethane. (Yield of 1-chloro-1-phenylsulfonylethane based on chloromethylphenylsulfone = 67.6%)
MS (CI: m / z); 205 (MH+)
NMR (CDCl3, Δ);
1.83 to 1.83 (3H, d, J = 6.72HZ)
4.77 to 4.84 (1H, q)
7.58 to 7.63 (2H, m)
7.69 to 7.76 (1H, m)
7.95 to 8.02 (2H, m)
[0077]
Example 3
655 mg (2.0 mmol) of 4,5,6,7-tetrahydro-4H-thieno [3,2-c] pyridin-2-one.p-toluenesulfonate and 322 mg of tert-butyldimethylsilyl chloride (2. 2 mmol) was suspended in 1.2 ml of methylene chloride, 223 mg (2.2 mmol) of triethylamine was added dropwise to the resulting suspension of methylene chloride, and the mixture was stirred for 1 hour to cause a reaction. Got.
[0078]
Reaction solution 1 containing 2- (t-butyldimethylsilyloxy) -4,5,6,7-tetrahydro-4H-thieno [3,2-c] pyridine (see Japanese Patent Application No. 6-244141) 585 mg (2.0 mmol) of 1,2-epoxy-1- (2-fluorophenyl) -2-phenylsulfonylpropane obtained in Reference Example 5 and 405 mg (4.0 mmol) of triethylamine were added, and the mixture was heated to 45 ° C. After the temperature was raised, the mixture was heated and stirred for 20 hours while maintaining the same temperature to react.
[0079]
To the obtained reaction solution 2, 10 ml of a 0.1 M phosphate buffer (pH = 6.87) and 10 ml of methylene chloride were added and extracted to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.4 g of an oil. The resulting oil was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 5: 2) to give 2- (t-butyldimethylsilyloxy) -5- [1- (2-fluoro There was obtained 415 mg (1.0 mmol) of phenyl) -2-oxopropyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. (Yield based on 4,5,6,7-tetrahydro-4H-thieno [3,2-c] pyridin-2-one.p-toluenesulfonate = 50.0%)
MS (CI: m / z); 420 (MH+), 372, 261
Reference Example 6: Production of (1-chloro-1-cyclopropylmethyl) phenyl sulfone
To 4 ml of a 28% sodium methoxide (3.9 g as sodium methoxide, 20.0 mmol) methanol solution was added dropwise 8 ml of a methanol solution containing 2.2 g (20.0 mmol) of benzenethiol, Stirred for 0.5 hour. The resulting methanol mixture was cooled to 0 to 5 ° C., and 8 ml of a methanol solution containing 2.7 g (20.0 mmol) of cyclopropyl bromide was added dropwise at a rate keeping the temperature, followed by keeping the temperature. The mixture was stirred and reacted for 10 hours.
To the obtained reaction solution 1, 10 ml of a 6N-sodium hydroxide aqueous solution and 12 ml of hexane were added and extracted to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 3.1 g of (cyclopropylmethyl) phenyl sulfide.
Boiling point: 96 ° C / 3.5mmHg
[0081]
The above (cyclopropylmethyl) phenyl sulfide (3.0 g, 18.5 mmol) was dissolved in acetic acid (38 ml), and the resulting acetic acid solution contained 2.2 g (22.2 mmol) of 35% hydrogen peroxide in acetic acid. 38 ml was dropped, and the mixture was stirred and reacted for 20 hours.
250 ml of water and 125 ml of methylene chloride were added to the obtained reaction solution 2 for extraction. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and dried under reduced pressure to obtain 5.9 g of oily crude purified (cyclopropylmethyl) phenylsulfoxide.
[0082]
1.7 g (15 mmol) of the above crudely purified (cyclopropylmethyl) phenylsulfoxide, 1.2 g (9.0 mmol) of calcium carbonate, 4.0 g (30 mmol) of N-chlorosuccinimide and 20 ml of methylene chloride Were mixed and stirred at 40 ° C. for 10 hours, and then allowed to react at room temperature (20 ° C.) for 48 hours.
To the obtained reaction solution 3, 16 ml of a 4% aqueous solution of sodium iodide and 16 ml of ethyl ether were added for extraction. The obtained organic layer was washed with 25 ml of a 10% aqueous sodium thiosulfate solution and 16 ml of saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to silica gel chromatography (eluent; n-hexane: acetic acid = 10: 3) to obtain 1.6 g of (1-chloro-1-cyclopropylmethyl) phenylsulfoxide.
[0083]
A mixed solution of 1.6 g (9.0 mmol) of m-chloroperbenzoic acid and 16 ml of methylene chloride was cooled to 0 to 5 ° C., and the above solution of (1-chloro-1-cyclopropylmethyl) phenylsulfoxide was added. 16 ml of a methylene chloride solution containing 5 g (6.9 mmol) was added dropwise, and the mixture was stirred and reacted for 10 hours while maintaining the same temperature.
15 ml of a saturated aqueous solution of sodium hydrogen carbonate and 15 ml of methylene chloride were added to the obtained reaction solution 4 for extraction. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.3 g (10.0 mmol) of (1-chloro-1-cyclopropylmethyl) phenylsulfone as an oil. (Yield based on benzenethiol = 50.0%)
IR (neat, cm-1); 1325, 1152
MS (CI: m / z); 319 (MH+), 177
1HNMR (CDCl3, Δ);
0.61 to 0.86 (4H, m)
1.34 to 1.41 (1H, m)
4.23 to 1.27 (1H, d, J = 8.54 Hz)
7.57 to 8.00 (5H, m)
Claims (3)
一般式（２）
General formula (2)
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| JP09666295A JP3564791B2 (en) | 1995-04-21 | 1995-04-21 | Method for producing α-aminoketones |
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| JP09666295A JP3564791B2 (en) | 1995-04-21 | 1995-04-21 | Method for producing α-aminoketones |
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| JP3564791B2 true JP3564791B2 (en) | 2004-09-15 |
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