JPH09286773A - Production of 1,5-benzodiazepine derivative - Google Patents
Production of 1,5-benzodiazepine derivativeInfo
- Publication number
- JPH09286773A JPH09286773A JP9037210A JP3721097A JPH09286773A JP H09286773 A JPH09286773 A JP H09286773A JP 9037210 A JP9037210 A JP 9037210A JP 3721097 A JP3721097 A JP 3721097A JP H09286773 A JPH09286773 A JP H09286773A
- Authority
- JP
- Japan
- Prior art keywords
- group
- ring
- hydrogen atom
- lower alkyl
- alkyl group
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 title abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- -1 (substituted) benzene ring Chemical group 0.000 claims abstract description 53
- 239000002253 acid Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 24
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical class NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- FMAZQSYXRGRESX-UHFFFAOYSA-N Glycidamide Chemical class NC(=O)C1CO1 FMAZQSYXRGRESX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 80
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 17
- 239000008096 xylene Substances 0.000 claims description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000004193 piperazinyl group Chemical group 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000539 amino acid group Chemical group 0.000 claims description 11
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 claims description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 7
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 6
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 229940117389 dichlorobenzene Drugs 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000003151 propanoic acid esters Chemical class 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 132
- 239000002585 base Substances 0.000 abstract description 10
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000013078 crystal Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- 230000000704 physical effect Effects 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000000825 ultraviolet detection Methods 0.000 description 5
- PHIRCWWPENANBA-DTWKUNHWSA-N (2r,3s)-3-(4-methoxyphenyl)oxirane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@H](C(N)=O)O1 PHIRCWWPENANBA-DTWKUNHWSA-N 0.000 description 4
- LHBHZALHFIQJGJ-CABCVRRESA-N (2s,3s)-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)NC2=CC=CC=C2S1 LHBHZALHFIQJGJ-CABCVRRESA-N 0.000 description 4
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JDRPDUXQDCDWHT-UHFFFAOYSA-N 2-(4-methoxyphenyl)-5h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1C1=CC(=O)NC2=CC=CC=C2S1 JDRPDUXQDCDWHT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940032296 ferric chloride Drugs 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- CVZUMGUZDAWOGA-VHSXEESVSA-N methyl (2r,3s)-3-(4-methoxyphenyl)oxirane-2-carboxylate Chemical compound COC(=O)[C@@H]1O[C@H]1C1=CC=C(OC)C=C1 CVZUMGUZDAWOGA-VHSXEESVSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- YDVJMCUOWCZBTP-JKSUJKDBSA-N (2r,3r)-3-(2-amino-5-methylphenyl)sulfanyl-2-hydroxy-3-(4-methylphenyl)propanamide Chemical compound C1=CC(C)=CC=C1[C@H]([C@H](O)C(N)=O)SC1=CC(C)=CC=C1N YDVJMCUOWCZBTP-JKSUJKDBSA-N 0.000 description 2
- CRGDBZGAJCINFT-LSDHHAIUSA-N (2r,3s)-3-(4-methoxyphenyl)-n-phenyloxirane-2-carboxamide Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@H](C(=O)NC=2C=CC=CC=2)O1 CRGDBZGAJCINFT-LSDHHAIUSA-N 0.000 description 2
- GKFBHZZURPNZMH-CABCVRRESA-N (2s,3s)-3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanamide Chemical compound C1=CC(OC)=CC=C1[C@@H]([C@@H](O)C(N)=O)SC1=CC=CC=C1N GKFBHZZURPNZMH-CABCVRRESA-N 0.000 description 2
- ODMMNPYXPQWRMQ-MOPGFXCFSA-N (2s,3s)-3-[2-[2-(dimethylamino)ethylamino]phenyl]sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanamide Chemical compound C1=CC(OC)=CC=C1[C@@H]([C@@H](O)C(N)=O)SC1=CC=CC=C1NCCN(C)C ODMMNPYXPQWRMQ-MOPGFXCFSA-N 0.000 description 2
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- VUMZNLOQJGKGNE-UHFFFAOYSA-N 2-amino-5-methylbenzenethiol Chemical compound CC1=CC=C(N)C(S)=C1 VUMZNLOQJGKGNE-UHFFFAOYSA-N 0.000 description 2
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylaminoethyl chloride Chemical compound CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 description 2
- GKFBHZZURPNZMH-UHFFFAOYSA-N 3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanamide Chemical compound C1=CC(OC)=CC=C1C(C(O)C(N)=O)SC1=CC=CC=C1N GKFBHZZURPNZMH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- 150000007657 benzothiazepines Chemical group 0.000 description 2
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- 229910052700 potassium Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical group [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医薬化合物の合成
中間体として有用な１，５−ベンゾチアゼピン誘導体の
新規製法に関する。TECHNICAL FIELD The present invention relates to a novel method for producing a 1,5-benzothiazepine derivative useful as a synthetic intermediate for pharmaceutical compounds.
【０００２】[0002]
【従来の技術】塩酸ジルチアゼム［化学名：（２Ｓ，３
Ｓ）−３−アセトキシ−５−〔２−（ジメチルアミノ）
エチル〕−２，３−ジヒドロ−２−（４−メトキシフェ
ニル）−１，５−ベンゾチアゼピン−４（５Ｈ）−オン
塩酸塩］はカルシウムチャンネル遮断薬として狭心症や
本態性高血圧症等の治療に広く使用されている医薬化合
物であり、通常、シス−３−ヒドロキシ−２，３−ジヒ
ドロ−２−（４−メトキシフェニル）−１，５−ベンゾ
チアゼピン−４（５Ｈ）−オンの５位をジメチルアミノ
エチル化し、３位水酸基をアセチル化することにより製
造されている（特公昭４７−８１３号、特公昭６３−１
７８３２号）。2. Description of the Related Art Diltiazem hydrochloride [Chemical name: (2S, 3
S) -3-acetoxy-5- [2- (dimethylamino)
[Ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one hydrochloride] is a calcium channel blocker such as angina and essential hypertension. It is a pharmaceutical compound widely used for the treatment of cis, and is usually cis-3-hydroxy-2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one. Is prepared by converting dimethylaminoethyl at the 5-position and acetylating the hydroxyl group at the 3-position (Japanese Patent Publication Nos. 47-813 and 63-1).
7832).
【０００３】従来、塩酸ジルチアゼムの合成中間体であ
るシス−３−ヒドロキシ−２，３−ジヒドロ−２−（４
−メトキシフェニル）−１，５−ベンゾチアゼピン−４
（５Ｈ）−オンの製法としては、３−（４−メトキシフ
ェニル）−２、３−エポキシプロピオン酸メチルエステ
ルと２−アミノチオフェノールとを反応させ、生成する
３−（２−アミノフェニルチオ）−２−ヒドロキシ−３
−（４−メトキシフェニル）プロピオン酸メチルエステ
ルを一旦エステル加水分解後、分子内閉環する方法が知
られている［ケミカル・アンド・ファーマシューティカ
ル・ブレティン（Ｃｈｅｍｉｃａｌ ａｎｄ Ｐｈａｒ
ｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ）２０２８頁
（１９７０年）］。Conventionally, cis-3-hydroxy-2,3-dihydro-2- (4) which is a synthetic intermediate of diltiazem hydrochloride has been used.
-Methoxyphenyl) -1,5-benzothiazepine-4
As the method for producing (5H) -one, 3- (2-aminophenylthio) produced by reacting 3- (4-methoxyphenyl) -2,3-epoxypropionic acid methyl ester with 2-aminothiophenol is produced. -2-hydroxy-3
A method is known in which ester hydrolysis of methyl 4- (4-methoxyphenyl) propionate is carried out once, and then the ring is closed in the molecule [Chemical and Pharmaceutical Bulletin (Chemical and Phar).
Macau Bulletin, p. 2028 (1970)].
【０００４】３−（２−アミノフェニルチオ）−２−ヒ
ドロキシ−３−（４−メトキシフェニル）プロピオン酸
エステルのエステル加水分解を行わない方法としては、
スルホン酸を使用する次の方法が公開されている。As a method of not performing ester hydrolysis of 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid ester,
The following methods using sulfonic acids have been published.
【０００５】（１）２−アミノチオフェノ−ルと（−）
−（２Ｒ，３Ｓ）−２，３−エポキシ−３−（４−メト
キシフェニル）プロピオン酸メチルエステルを反応さ
せ、得られる（２Ｓ，３Ｓ）−３−（２−アミノフェニ
ルチオ）−２−ヒドロキシ−３−（４−メトキシフェニ
ル）プロピオン酸メチルエステルをメタンスルホン酸等
の存在下、７０℃以上の沸点を有する塩素化有機溶媒中
で分子内閉環させる方法（特開平２−２２９１８０号） （２）３−（２−アミノフェニルチオ）−２−ヒドロキ
シ−３−（４−メトキシフェニル）プロピオン酸メチル
エステルをメタンスルホン酸等の存在下、非ハロゲン化
有機溶媒中、分子内閉環する方法（特開平４−２３４８
６６号） （３）（２Ｓ，３Ｓ）−３−（２−アミノフェニルチ
オ）−２−ヒドロキシ−３−（４−メトキシフェニル）
プロピオン酸（１Ｒ，２Ｓ）−２−フェニルシクロヘキ
シルエステルをｐ−トルエンスルホン酸一水和物の存在
下に分子内閉環する方法（特開平２−１７１７０号） また、塩基を用いる分子内閉環反応により、塩酸ジルチ
アゼムの他の合成中間体である５−〔２−（ジメチルア
ミノ）エチル〕−２，３−ジヒドロ−３−ヒドロキシ−
２−（４−メトキシフェニル）−１，５−ベンゾチアゼ
ピン−４（５Ｈ）−オンを製造する方法として、次の方
法も公開されている。(1) 2-aminothiophenol and (-)
-(2R, 3S) -2,3-epoxy-3- (4-methoxyphenyl) propionic acid methyl ester is reacted to obtain (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy. Method for intramolecular ring closure of -3- (4-methoxyphenyl) propionic acid methyl ester in the presence of methanesulfonic acid or the like in a chlorinated organic solvent having a boiling point of 70 ° C or higher (JP-A-2-229180) (2) ) A method of intramolecular ring closure of 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester in the presence of methanesulfonic acid or the like in a non-halogenated organic solvent (special feature Kaihei 4-2348
No. 66) (3) (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl)
Intramolecular ring closure of propionic acid (1R, 2S) -2-phenylcyclohexyl ester in the presence of p-toluenesulfonic acid monohydrate (JP-A-2-17170). , Another synthesis intermediate of diltiazem hydrochloride, 5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-
The following method is also disclosed as a method for producing 2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one.
【０００６】（１）３−（２−アミノフェニルチオ）−
２−ヒドロキシ−３−（４−メトキシフェニル）プロピ
オン酸メチルエステルをエーテル系溶媒中、固体アルカ
リ金属水酸化物の存在下、Ｎ，Ｎ−ジメチルアミノエチ
ルクロリド又はその酸付加塩と反応させて分子内閉環す
る方法（特開平５−２０２０１３号） （２）３−（２−アミノフェニルチオ）−２−ヒドロキ
シ−３−（４−メトキシフェニル）プロピオン酸メチル
エステルを非プロトン性極性溶媒中、アルカリ金属アル
コキシドの存在下、分子内閉環し、さらに５位を２−
（ジメチルアミノ）エチル化する方法（特開平４−２２
１３７６号） また、一般的にアミドはエステルよりも、求核試薬の攻
撃を受けにくいことが知られており（ヘンドリクソン、
クラム、ハモンド著、オーガニックケミストリー（Ｏｒ
ｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ、第３版、第１３−１
章、第５０１〜５１６頁等）、１、５−ベンゾチアゼピ
ン骨格の合成例としては、活性化されたＮ−アシルアミ
ド基を有する、（−）−４−イソプロピル−３−〔３−
（２−アミノフェニルチオ）−２−メトキシエトキシメ
トキシ−３−（４−メトキシフェニル）プロピオニル〕
−２−オキサゾリジノンを塩化メチレン中、トリメチル
アルミニウムで処理して分子内閉環する方法［テトラヘ
ドロンレターズ（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅ
ｒｓ）第３２巻、第３５１９〜３５２２頁（１９９１
年）］が報告されているに過ぎない。(1) 3- (2-aminophenylthio)-
Molecules of 2-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester are reacted with N, N-dimethylaminoethyl chloride or an acid addition salt thereof in an ether solvent in the presence of a solid alkali metal hydroxide. Inner ring-closing method (JP-A-5-202013) (2) Alkyl 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester in an aprotic polar solvent In the presence of a metal alkoxide, the ring is closed in the molecule, and the 5-position is 2-
Method for (dimethylamino) ethylation (Japanese Patent Application Laid-Open No. 4-22
In addition, amides are generally known to be less susceptible to nucleophilic attack than esters (Hendrickson,
Crum, Hammond, Organic Chemistry (Or
ganic Chemistry, 3rd edition, 13-1
(Chapter 501, pages 516, etc.), as an example of the synthesis of the 1,5-benzothiazepine skeleton, (-)-4-isopropyl-3- [3-] having an activated N-acylamide group.
(2-Aminophenylthio) -2-methoxyethoxymethoxy-3- (4-methoxyphenyl) propionyl]
Method of Intramolecular Ring Closure by Treating 2-Oxazolidinone with Trimethylaluminum in Methylene Chloride [Tetrahedron Letter
rs) 32, 3519-3522 (1991).
Year)] has only been reported.
【０００７】なお、トランス−３−（４−メトキシフェ
ニル）−２，３−エポキシプロピオン酸エステルをアン
モニウムヒドロキシドで処理して、トランス−３−（４
−メトキシフェニル）−２，３−エポキシプロピオン酸
アミドを得ることは米国特許Ｎｏ．４９５９３５９に記
載されており、また、トランス−３−（４−メトキシフ
ェニル）−２，３−エポキシプロピオン酸メチルエステ
ルをリパーゼＳＰ５２３の存在下、アンモニアで処理し
て、（２Ｓ，３Ｒ）−体を選択的にアミド化することは
国際公開Ｎｏ．９５／７３５９に開示されている。Incidentally, trans-3- (4-methoxyphenyl) -2,3-epoxypropionic acid ester is treated with ammonium hydroxide to give trans-3- (4
-Methoxyphenyl) -2,3-epoxypropionic acid amide is described in US Pat. 4959359, and further, trans-3- (4-methoxyphenyl) -2,3-epoxypropionic acid methyl ester was treated with ammonia in the presence of lipase SP523 to give a (2S, 3R) -form. Selective amidation is described in International Publication No. 95/7359.
【０００８】[0008]
【発明が解決しようとする課題】本発明は、新規な３−
〔２−アミノ−（置換又は非置換フェニルチオ）〕−２
−ヒドロキシ−３−（置換又は非置換フェニル）プロピ
オン酸アミド化合物から一工程でかつ収率よく１，５−
ベンゾチアゼピン骨格を形成する方法を提供するもので
ある。DISCLOSURE OF THE INVENTION The present invention provides a novel 3-
[2-amino- (substituted or unsubstituted phenylthio)]-2
-Hydroxy-3- (substituted or unsubstituted phenyl) propionamide compound in one step and in good yield 1,5-
A method for forming a benzothiazepine skeleton is provided.
【０００９】[0009]
【課題を解決するための手段】本発明によれば、一般式
［ＩＩ］According to the present invention, the general formula [II]
【００１０】[0010]
【化１９】 Embedded image
【００１１】（式中、環Ａ及び環Ｂは置換基を有しても
よいベンゼン環、Ｒ3は水素原子、ジ低級アルキルアミ
ノ低級アルキル基又は置換基を有していてもよいピペラ
ジニル低級アルキル基を表わす。）で示される１，５−
ベンゾチアゼピン誘導体は、一般式［Ｉ］(In the formula, ring A and ring B are a benzene ring which may have a substituent, R 3 is a hydrogen atom, a di-lower alkylamino lower alkyl group or a piperazinyl lower alkyl which may have a substituent. Represents a group) 1,5-
The benzothiazepine derivative has the general formula [I]
【００１２】[0012]
【化２０】 Embedded image
【００１３】（式中、Ｒ1及びＲ2は同一又は異なって水
素原子、カルバモイル基、低級アルキル基、低級アルカ
ノイル基、低級アルキルアミノカルボニル基、アミノ酸
残基又は置換基を有してもよいアリール基であるか、あ
るいは互いに末端で結合して隣接する窒素原子と共に置
換されていてもよい複素環式基を形成していることを表
し、他の記号は前記と同一意味を有する。）で示される
プロピオン酸アミド誘導体又はその塩を分子内閉環反応
に付すことにより製造することができる。(In the formula, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group, an amino acid residue or an aryl which may have a substituent. Or other groups have the same meanings as defined above, which means that they are groups or are bonded to each other at the ends to form a heterocyclic group which may be substituted with an adjacent nitrogen atom.). It can be produced by subjecting the propionic acid amide derivative or a salt thereof to an intramolecular ring closure reaction.
【００１４】[0014]
【発明の実施の形態】本発明において、一般式［Ｉ］で
示されるプロピオン酸アミド誘導体の環Ａ及び／又は環
Ｂは置換基を有しないものであってもよいし、低級アル
キル基、低級アルコキシ基、ハロゲン原子又はフェニル
低級アルキル基から選ばれる置換基を任意の置換部位に
有しているものであってもよい。BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, ring A and / or ring B of the propionic acid amide derivative represented by the general formula [I] may have no substituent, a lower alkyl group or a lower alkyl group. It may have a substituent selected from an alkoxy group, a halogen atom or a phenyl lower alkyl group at an arbitrary substitution site.
【００１５】環Ａの具体例としては、式：Specific examples of ring A include the formula:
【００１６】[0016]
【化２１】 [Chemical 21]
【００１７】（式中、Ｒ4は水素原子、ハロゲン原子、
低級アルキル基又はフェニル低級アルキル基を表す。）
で示されるものがあげられ、環Ｂの具体例としては、４
−低級アルキルフェニル基、４−低級アルコキシフェニ
ル基であるものをあげることができる。(In the formula, R 4 is a hydrogen atom, a halogen atom,
It represents a lower alkyl group or a phenyl lower alkyl group. )
And a specific example of ring B is 4
Examples thereof include a lower alkylphenyl group and a 4-lower alkoxyphenyl group.
【００１８】これらのうち、環Ａ及び環Ｂの好ましい例
としては、（ａ）環Ａが式［ＶＩ］（Ｒ4は水素原子、
ハロゲン原子又はフェニル低級アルキル基）の部分構
造、環Ｂが４−低級アルコキシフェニル基であるもの、
又は（ｂ）環Ａが式［ＶＩ］（Ｒ4は低級アルキル基）
の部分構造、環Ｂが４−低級アルキルフェニル基である
ものがあげられる。Of these, preferred examples of ring A and ring B include (a) ring A having the formula [VI] (R 4 is a hydrogen atom,
A halogen atom or a phenyl lower alkyl group), a structure in which ring B is a 4-lower alkoxyphenyl group,
Or (b) ring A has the formula [VI] (R 4 is a lower alkyl group)
And the ring B is a 4-lower alkylphenyl group.
【００１９】また、Ｒ1及びＲ2におけるアミノ酸残基と
しては、アミノ酸の１つのアミノ基を除いた残基（当該
残基中に存する水酸基、メルカプト基、アミノ基及び／
又はカルボキシル基は保護されていてもよい）が挙げら
れ、アミノ酸としては天然又は非天然起源のものが含ま
れ、一分子中に少なくともアミノ基及びカルボキシル基
を各々１個有する化合物であって、天然起源のアミノ酸
もしくはその対掌体、合成起源のＤ−もしくはＬ−アミ
ノ酸、或いはこれらアミノ酸のラセミ混合物が挙げられ
る。具体的には、α−アミノ酸及びβ−アミノ酸が好適
に挙げられる。The amino acid residue in R 1 and R 2 is a residue except one amino group of an amino acid (a hydroxyl group, a mercapto group, an amino group and / or an amino group existing in the residue).
Or a carboxyl group may be protected), and amino acids include those of natural or non-natural origin, which are compounds having at least one amino group and one carboxyl group in one molecule, and Amino acids of origin or antipodes thereof, D- or L-amino acids of synthetic origin, or racemic mixtures of these amino acids are mentioned. Specifically, α-amino acids and β-amino acids are preferred.
【００２０】これらアミノ酸は中性アミノ酸、酸性アミ
ノ酸又は塩基性アミノ酸のいずれであってもよく、中性
アミノ酸としてはアラニン、イソロイシン、ロイシン等
のアミノ基とカルボキシル基を同数個有するアミノ酸、
セリン、スレオニン、チロシン等の水酸基を有するアミ
ノ酸又はシステイン、シスチン、メチオニン等のメルカ
プト基、ジスルフィド結合を有する含硫アミノ酸が挙げ
られ、酸性アミノ酸としてはグルタミン酸、アスパラギ
ン酸等のカルボキシル基をアミノ基より多く有するアミ
ノ酸が挙げられ、塩基性アミノ酸としてはアルギニン、
オルニチン、リジン等のアミノ基をカルボキシル基より
多く有するアミノ酸が挙げられる。水酸基、メルカプト
基、アミノ基及び／又はカルボキシル基が保護されてい
る場合、保護基として慣用の保護基を用いることがで
き、水酸基の保護基としては、例えばベンジル基、ｔ−
ブチル基、ベンジルオキシカルボニル基等を挙げること
ができ、メルカプト基の保護基としては、ベンジル基、
ベンジルオキシカルボニル基等を挙げることができ、ア
ミノ基保護基としては、ベンジルオキシカルボニル基、
ｔｅｒｔ−ブトキシカルボニル基等を挙げることがで
き、カルボキシル基保護基としては、メチル基、エチル
基、メトキシエチル基、メトキシエトキシエチル基、ア
ミノ基等を挙げることができる。These amino acids may be neutral amino acids, acidic amino acids or basic amino acids, and the neutral amino acids include amino acids having the same number of amino groups and carboxyl groups such as alanine, isoleucine and leucine.
Serine, threonine, amino acids having a hydroxyl group such as tyrosine or cysteine, cystine, mercapto groups such as methionine, sulfur-containing amino acids having a disulfide bond, and the like, glutamic acid, as the acidic amino acid, carboxyl groups such as aspartic acid more than amino groups Amino acids having, arginine as the basic amino acid,
Examples thereof include amino acids such as ornithine and lysine that have more amino groups than carboxyl groups. When a hydroxyl group, a mercapto group, an amino group and / or a carboxyl group is protected, a conventional protecting group can be used as the protecting group, and examples of the hydroxyl protecting group include a benzyl group and t-
Examples thereof include a butyl group and a benzyloxycarbonyl group. Examples of the mercapto group-protecting group include a benzyl group,
Examples of the amino group-protecting group include a benzyloxycarbonyl group and a benzyloxycarbonyl group.
Examples thereof include a tert-butoxycarbonyl group, and examples of the carboxyl group-protecting group include a methyl group, an ethyl group, a methoxyethyl group, a methoxyethoxyethyl group, and an amino group.
【００２１】Ｒ1及びＲ2におけるアリール基としては、
芳香族炭化水素環式基が挙げられ、例えば、フェニル
基、ナフチル基等を挙げることができる。The aryl group for R 1 and R 2 is
Examples of the aromatic hydrocarbon cyclic group include a phenyl group and a naphthyl group.
【００２２】上記アリール基の置換基としては、低級ア
ルキル基、低級アルコキシ基又はハロゲン原子を挙げる
ことができる。Examples of the substituent of the above aryl group include a lower alkyl group, a lower alkoxy group and a halogen atom.
【００２３】Ｒ1及びＲ2が互いに末端で結合して隣接す
る窒素原子と共に形成する複素環式基としては、単環式
基及び二環式基が挙げられ、アミドを形成する窒素原子
以外にさらに窒素原子、酸素原子及び硫黄原子から選ば
れるヘテロ原子を含有していてもよい。Examples of the heterocyclic group formed by R 1 and R 2 terminally bonded to each other to form an adjacent nitrogen atom include a monocyclic group and a bicyclic group, and in addition to the nitrogen atom forming an amide, Further, it may contain a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
【００２４】複素環式基としては、５〜６員環の一部が
飽和されていてもよい芳香族単環式基（例えば、ピロリ
ル基、ピリジル基、ピラジニル基、ピリミジニル基、ピ
リダジニル基、イミダゾリル基、ピラゾリル基、チアゾ
リル基、テトラゾリル基）、５〜６員環の脂肪族単環式
基（例えば、ピロリジニル基、ピペリジニル基、ピペラ
ジニル基、モルホリニル基、オキサゾリジニル基、チア
ゾリジニル基）、５〜６員環と５〜６員環とが縮合され
て一部が飽和されていてもよい芳香族二環式基（例え
ば、キノリル基、インドリル基、インダゾリル基、ベン
ゾオキサゾリジニル基、ベンゾチアゾリジニル基、ベン
ゾオキサジニル基、ベンゾチアジニル基）又は５〜６員
環と５〜６員環とが縮合されている脂肪族二環式基（例
えば、デカハイドロキノリル基、オクタハイドロ−１Ｈ
−インドリル基）を挙げることができる。The heterocyclic group is an aromatic monocyclic group in which a part of 5- to 6-membered ring may be saturated (eg, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, imidazolyl group). Group, pyrazolyl group, thiazolyl group, tetrazolyl group), 5- to 6-membered aliphatic monocyclic group (for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, oxazolidinyl group, thiazolidinyl group), 5 to 6-membered Aromatic bicyclic group which may be partially saturated by condensation of a ring and a 5- or 6-membered ring (for example, quinolyl group, indolyl group, indazolyl group, benzoxazolidinyl group, benzothiazolidinii group) Group, a benzoxazinyl group, a benzothiazinyl group) or an aliphatic bicyclic group in which a 5- or 6-membered ring and a 5- or 6-membered ring are condensed (for example, decahydro). Noryl group, octa hydro -1H
An indolyl group).
【００２５】上記複素環式基は置換基を有していてもよ
く、かかる置換基としては電子供与性基（例えば、アミ
ノ基、水酸基、低級アルキル基、低級アルコキシ基、シ
クロアルキル基）、電子吸引性基（例えば、オキソ基、
ニトロ基、ハロゲン原子、カルボキシル基、低級アルコ
キシカルボニル基）を挙げることができるが、電子吸引
性基で置換された複素環式基が好ましい。The above-mentioned heterocyclic group may have a substituent, and as such a substituent, an electron-donating group (eg, amino group, hydroxyl group, lower alkyl group, lower alkoxy group, cycloalkyl group), electron Withdrawing groups (eg, oxo groups,
Nitro group, halogen atom, carboxyl group, lower alkoxycarbonyl group), but a heterocyclic group substituted with an electron-withdrawing group is preferable.
【００２６】Ｒ1及びＲ2が互いに末端で結合して隣接す
る窒素原子と共に形成する置換されていてもよい複素環
式基の具体例としては、次式で示される基を挙げること
ができる。Specific examples of the optionally substituted heterocyclic group in which R 1 and R 2 are bonded to each other at the terminals and formed together with the adjacent nitrogen atom include the groups represented by the following formulas.
【００２７】[0027]
【化２２】 Embedded image
【００２８】Ｒ1及びＲ2の好ましい例としては、（ａ）
共に水素原子であるか又は（ｂ）一方が水素原子で他方
が低級アルキル基であるものがあげられ、共に水素原子
であるものがとりわけ好ましい。Preferred examples of R 1 and R 2 include (a)
Examples thereof are both hydrogen atoms or (b) one is a hydrogen atom and the other is a lower alkyl group, and those which are both hydrogen atoms are particularly preferable.
【００２９】Ｒ3におけるピペラジニル低級アルキル基
の置換基としては、フェニル基、或いは低級アルキル
基、低級アルコキシ基、低級アルキレンジオキシ基及び
ハロゲン原子から選ばれる基で置換されたフェニル基を
挙げることができる。Ｒ3における置換ピペラジニル低
級アルキル基の具体例としては、３−〔４−（２−メト
キシフェニル）ピペラジニル〕プロピル基があげられ、
Ｒ3におけるジ低級アルキルアミノ低級アルキル基の具
体例としては、２−（ジメチルアミノ）エチル基があげ
られる。Examples of the substituent of the piperazinyl lower alkyl group for R 3 include a phenyl group, or a phenyl group substituted with a group selected from a lower alkyl group, a lower alkoxy group, a lower alkylenedioxy group and a halogen atom. it can. Specific examples of the substituted piperazinyl lower alkyl group for R 3 include 3- [4- (2-methoxyphenyl) piperazinyl] propyl group,
A specific example of the di-lower alkylamino-lower alkyl group for R 3 is 2- (dimethylamino) ethyl group.
【００３０】Ｒ3の最も好ましい例としては、水素原子
があげられる。The most preferred example of R 3 is a hydrogen atom.
【００３１】プロピオン酸アミド誘導体［Ｉ］のうち、
環Ａが式［ＶＩ］（Ｒ4は水素原子、塩素原子、メチル
基又はベンジル基）の部分構造、環Ｂが４−メチルフェ
ニル基又は４−メトキシフェニル基、Ｒ3が水素原子、
２−ジメチルアミノエチル基又は３−〔４−（２−メト
キシフェニル）ピペラジニル〕プロピル基、Ｒ1及びＲ2
が共に水素原子であるか又は一方が水素原子で他方がメ
チル基であるものが好ましい。Among the propionamide derivative [I],
Ring A is a partial structure of the formula [VI] (R 4 is a hydrogen atom, chlorine atom, methyl group or benzyl group), Ring B is a 4-methylphenyl group or 4-methoxyphenyl group, R 3 is a hydrogen atom,
2-dimethylaminoethyl group or 3- [4- (2-methoxyphenyl) piperazinyl] propyl group, R 1 and R 2
Are both hydrogen atoms, or one is a hydrogen atom and the other is a methyl group.
【００３２】このうち、（ｉ）環Ａが式〔ＶＩ〕（Ｒ4
が水素原子又は塩素原子）の部分構造、環Ｂが４−メト
キシフェニル基、Ｒ3が水素原子又は２−（ジメチルア
ミノ）エチル基であるもの、（ｉｉ）環Ａが式〔ＶＩ〕
（Ｒ4がメチル基）の部分構造、環Ｂが４−メチルフェ
ニル基、Ｒ3が水素原子又は２−（ジメチルアミノ）エ
チル基であるもの、（ｉｉｉ）環Ａが式〔ＶＩ〕（Ｒ4
が塩素原子）の部分構造、環Ｂが４−メトキシフェニル
基、Ｒ3が水素原子又は３−〔４−（２−メトキシフェ
ニル）ピペラジニル〕プロピル基であると共に、Ｒ1及
びＲ2が共に水素原子であるか又は一方が水素原子で他
方が低級アルキル基であるもの、及び（ｉｖ）環Ａが式
〔ＶＩ〕（Ｒ4がベンジル基）の部分構造、環Ｂが４−
メトキシフェニル基、Ｒ3が水素原子又は２−（ジメチ
ルアミノ）エチル基であると共に、Ｒ1及びＲ2が共に水
素原子であるか又は一方が水素原子で他方がメチル基で
あるプロピオン酸アミド誘導体［Ｉ］がより好ましい。Of these, (i) ring A is of the formula [VI] (R 4
Is a hydrogen atom or chlorine atom), ring B is a 4-methoxyphenyl group, R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group, and (ii) ring A is a formula [VI].
(R 4 is a methyl group) partial structure, ring B is a 4-methylphenyl group, R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group, (iii) Ring A is of the formula [VI] (R Four
Is a chlorine atom), ring B is a 4-methoxyphenyl group, R 3 is a hydrogen atom or a 3- [4- (2-methoxyphenyl) piperazinyl] propyl group, and R 1 and R 2 are both hydrogen. An atom or one of which is a hydrogen atom and the other is a lower alkyl group, and (iv) ring A is a partial structure of formula [VI] (R 4 is a benzyl group), and ring B is 4-
A methoxyphenyl group, a propionic acid amide derivative in which R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group, and R 1 and R 2 are both hydrogen atoms, or one is a hydrogen atom and the other is a methyl group. [I] is more preferable.
【００３３】また、本発明の方法において、プロピオン
酸アミド誘導体は塩の形で閉環反応に供することもで
き、塩としては、無機酸もしくは有機酸との塩、例え
ば、塩酸塩、硫酸塩、リン酸塩、臭化水素酸塩、メタン
スルホン酸塩、ｐ−トルエンスルホン酸塩、酢酸塩、フ
マル酸塩、マレイン酸塩、シュウ酸塩、ベンゼンスルホ
ン酸塩等があげられる。In the method of the present invention, the propionic acid amide derivative can also be subjected to a ring closure reaction in the form of a salt, and as the salt, a salt with an inorganic acid or an organic acid, for example, hydrochloride, sulfate or phosphorus can be used. Examples thereof include acid salt, hydrobromide salt, methanesulfonate salt, p-toluenesulfonate salt, acetate salt, fumarate salt, maleate salt, oxalate salt and benzenesulfonate salt.
【００３４】本発明の分子内閉環反応は、酸もしくは塩
基の存在下又は非存在下で実施することができるが、酸
での実施が好ましい。酸としては、ブレンステッド酸及
びルイス酸をいずれも使用することができる。ブレンス
テッド酸としては無機又は有機の酸をいずれも使用する
ことができ、例えば、塩酸、硫酸、リン酸、フッ化水素
酸、臭化水素酸、過塩素酸等の鉱酸、ギ酸、酢酸、プロ
ピオン酸、酪酸等の低級アルカン酸、クエン酸等のヒド
ロキシ基置換低級アルカン酸、トリフルオロ酢酸等のハ
ロゲノ低級アルカン酸、メタンスルホン酸等の低級アル
カンスルホン酸、ｐ−トルエンスルホン酸、ベンゼンス
ルホン酸等のアリールスルホン酸、シュウ酸等をいずれ
も使用することができる。また、ルイス酸としては、四
塩化チタン、塩化アルミニウム、三フッ化ホウ素、塩化
スズ等を使用することができる。The intramolecular ring-closing reaction of the present invention can be carried out in the presence or absence of an acid or a base, but it is preferably carried out in an acid. As the acid, both Bronsted acid and Lewis acid can be used. As the Bronsted acid, it is possible to use any inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, mineral acids such as perchloric acid, formic acid, acetic acid, Lower alkanoic acid such as propionic acid and butyric acid, hydroxy group-substituted lower alkanoic acid such as citric acid, halogeno lower alkanoic acid such as trifluoroacetic acid, lower alkane sulfonic acid such as methane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid Any of aryl sulfonic acid, oxalic acid and the like can be used. Further, as the Lewis acid, titanium tetrachloride, aluminum chloride, boron trifluoride, tin chloride or the like can be used.
【００３５】これらの酸のうち、鉱酸、低級アルカンス
ルホン酸又はアリールスルホン酸がより好ましく、メタ
ンスルホン酸、ｐ−トルエンスルホン酸、ベンゼンスル
ホン酸、塩酸又は臭化水素酸がとりわけ好ましい。Of these acids, mineral acids, lower alkanesulfonic acids or arylsulfonic acids are more preferable, and methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid or hydrobromic acid is particularly preferable.
【００３６】また塩基としては、無機又は有機の塩基を
いずれも使用することができ、このような塩基として
は、炭酸水素アルカリ金属、炭酸アルカリ金属、水酸化
アルカリ金属、水酸化アルカリ土類金属、水素化アルカ
リ金属、アルカリ金属アミド、アルカリ金属アルコキシ
ド、アルキルアルカリ金属、アルカリ金属、アルカリ土
類金属等の無機塩基、１，８−ジアザビシクロ［５．
４．０］ウンデカ−７−エン、ジイソプロピルエチルア
ミン、トリエチルアミン、ピリジン等の有機塩基等が挙
げられる。As the base, any inorganic or organic base can be used. Examples of such a base include alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydroxide, alkaline earth metal hydroxide, Inorganic bases such as alkali metal hydrides, alkali metal amides, alkali metal alkoxides, alkyl alkali metals, alkali metals and alkaline earth metals, 1,8-diazabicyclo [5.
4.0] Organic bases such as undec-7-ene, diisopropylethylamine, triethylamine, pyridine and the like can be mentioned.
【００３７】酸又は塩基の使用量は特に制限されず、通
常化合物［Ｉ］に対し、０〜３００モル％程度の割合で
用いるのがよい。The amount of the acid or base used is not particularly limited, and it is usually preferable to use it in a ratio of about 0 to 300 mol% with respect to the compound [I].
【００３８】つまり本発明は、化合物［Ｉ］に対し、０
〜１００モル％、好ましくは０〜５０モル％程度の割合
のブレンステッド酸又は０〜３００モル％、好ましくは
５０〜２００モル％程度の割合のルイス酸、或いは０〜
３００モル％程度の割合の塩基を用いて実施するのが好
ましい。That is, the present invention relates to compound [I] with 0
To 100 mol%, preferably about 0 to 50 mol% of Bronsted acid or 0 to 300 mol%, preferably about 50 to 200 mol% of Lewis acid, or 0 to
It is preferable to use a base in a proportion of about 300 mol%.
【００３９】酸又は塩基は、一回で又は数回に分割し
て、反応混合物に加えることができるが、反応時間を短
縮するために、数回に分割して加えるのが好ましい。The acid or base can be added to the reaction mixture in one portion or in several divided portions, but it is preferable to add it in several divided portions in order to shorten the reaction time.
【００４０】本発明に用いられる溶媒としては、反応に
支障をきたさない溶媒であれば、制限がなく、例えば、
水またはメタノール、エタノール、プロパノール等のア
ルコール類、アセトン、メチルエチルケトン等のケトン
類、酢酸エチル等のエステル類、ベンゼン、ナフタレ
ン、クロロベンゼン、ｏ−ジクロロベンゼン、ｍ−ジク
ロロベンゼン、ｐ−ジクロロベンゼン、ｏ−トリクロロ
ベンゼン、ｍ−トリクロロベンゼン、ｐ−トリクロロベ
ンゼン、トルエン、メシチレンあるいはキシレン等の芳
香族炭化水素、または塩化メチレン、クロロホルム、四
塩化炭素、１，２−ジクロロエタン等のハロゲン化炭化
水素類、ｎ−ヘキサン、ｎ−ヘプタン等の脂肪族炭化水
素類、シクロヘキサン等の脂環式炭化水素類、Ｎ，Ｎ−
ジメチルホルムアミド、ジメチルスルホキシド等の非プ
ロトン性極性溶媒、ジオキサン、テトラヒドロフラン等
のエーテル類、アセトニトリル等のニトリル類があげら
れるが、反応速度の点からは、ジオキサン、メシチレ
ン、キシレン、トルエン、クロロベンゼン、ジクロロベ
ンゼン又はトリクロロベンゼン等の高沸点（沸点が１０
０℃以上）の溶媒がとりわけ好ましい。The solvent used in the present invention is not limited as long as it does not interfere with the reaction.
Water or alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, benzene, naphthalene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, o- Aromatic hydrocarbons such as trichlorobenzene, m-trichlorobenzene, p-trichlorobenzene, toluene, mesitylene or xylene, or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, n- Hexane, aliphatic hydrocarbons such as n-heptane, alicyclic hydrocarbons such as cyclohexane, N, N-
Examples include aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, ethers such as dioxane and tetrahydrofuran, and nitriles such as acetonitrile. From the viewpoint of reaction rate, dioxane, mesitylene, xylene, toluene, chlorobenzene, dichlorobenzene. Or high boiling point such as trichlorobenzene (boiling point is 10
Solvents above 0 ° C.) are especially preferred.
【００４１】これらの溶媒は、単独で用いてもよいが、
必要に応じて適当な比率で二種類またはそれ以上の種類
を混合し、単相又は２相の形で使用してもよい。Although these solvents may be used alone,
If necessary, two or more kinds may be mixed in an appropriate ratio and used in a single-phase or two-phase form.
【００４２】これらの溶媒のうち、アルコール類、芳香
族炭化水素、エーテル類、又はこれらの混合溶媒が好ま
しく、クロロベンゼン、ジクロロベンゼン、トルエン、
キシレン又はメシチレンがとりわけ好ましい。Of these solvents, alcohols, aromatic hydrocarbons, ethers, and mixed solvents thereof are preferable, and chlorobenzene, dichlorobenzene, toluene,
Xylene or mesitylene is especially preferred.
【００４３】また、溶媒の使用量は、反応物が溶解する
量であれば特に制限されないが、反応時間を短縮するた
めに、より少量であるのが好ましい。The amount of the solvent used is not particularly limited as long as it dissolves the reaction product, but a smaller amount is preferable in order to shorten the reaction time.
【００４４】本分子内閉環反応は、使用する溶媒中、０
〜２５０℃、とりわけ８０〜２００℃で実施するのが好
ましい。The intramolecular ring-closing reaction is carried out in the solvent used in 0
It is preferably carried out at ˜250 ° C., especially at 80˜200 ° C.
【００４５】本発明方法においてプロピオン酸アミド誘
導体［Ｉ］は、光学活性体であってもラセミ体であって
もよく、光学活性な化合物［Ｉ］を用いれば、ラセミ化
を伴うことなく目的物［ＩＩ］を光学活性体として得る
ことができる。また目的物［ＩＩ］は必要に応じ、酸又
は塩基で処して、塩酸塩、硫酸塩、リン酸塩、臭化水素
酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸、
酢酸塩、フマル酸塩、マレイン酸塩、シュウ酸塩、ベン
ゼンスルホン酸塩等との塩、アルカリ金属（ナトリウ
ム、カリウム等）塩、アルカリ土類金属（マグネシウ
ム、カルシウム等）塩等とすることもできる。In the method of the present invention, the propionic amide derivative [I] may be an optically active compound or a racemic compound. When the optically active compound [I] is used, the desired product can be obtained without racemization. [II] can be obtained as an optically active substance. The desired product [II] is optionally treated with an acid or a base to give a hydrochloride, a sulfate, a phosphate, a hydrobromide, a methanesulfonate, a p-toluenesulfonic acid,
It is also possible to use salts with acetate, fumarate, maleate, oxalate, benzenesulfonate, etc., alkali metal (sodium, potassium etc.) salt, alkaline earth metal (magnesium, calcium etc.) salt, etc. it can.
【００４６】こうして得られる１，５−ベンゾチアゼピ
ン誘導体［ＩＩ］又はその塩は、特公昭４６−１６９８
８号、特公昭４６−４３７８５号、特公昭４７−８１３
号、特公昭５３−１８０３８号、特公昭６３−１３９９
４号、特公昭６３−１７８３２号、特開平３−１５７３
７８号、特開平５−２０１８６５号等に記載された方法
に従って、一般式［ＩＩＩ］The thus obtained 1,5-benzothiazepine derivative [II] or a salt thereof is disclosed in Japanese Examined Patent Publication No. 46-1698.
No. 8, JP-B-46-43785, JP-B-47-813
No. 5, Japanese Patent Publication No. 53-18038, Japanese Patent Publication No. 63-1399
4, JP-B-63-17832, JP-A-3-1573.
No. 78, Japanese Patent Application Laid-Open No. 5-201865, etc., the general formula [III]
【００４７】[0047]
【化２３】 Embedded image
【００４８】（式中、Ｒ31はジ低級アルキルアミノ低級
アルキル基又は置換基を有していてもよいピペラジニル
低級アルキル基、Ｒ5は低級アルカノイル基を表わし、
他の記号は前記と同一意味を有する。）で示される３−
低級アルカノイルオキシ−５−（ジ低級アルキルアミノ
低級アルキル又は置換もしくは非置換ピペラジニル低級
アルキル）−２，３−ジヒドロ−２−（置換フェニル）
−１，５−ベンゾチアゼピン誘導体とし、所望によりそ
の薬理的に許容し得る塩とすることができる。(In the formula, R 31 represents a di-lower alkylamino lower alkyl group or a piperazinyl lower alkyl group which may have a substituent, and R 5 represents a lower alkanoyl group,
Other symbols have the same meaning as described above. ) 3-
Lower alkanoyloxy-5- (dilower alkylamino lower alkyl or substituted or unsubstituted piperazinyl lower alkyl) -2,3-dihydro-2- (substituted phenyl)
A -1,5-benzothiazepine derivative can be prepared, and if desired, a pharmacologically acceptable salt thereof can be prepared.
【００４９】すなわち、必要に応じて、１，５−ベンゾ
チアゼピン誘導体［ＩＩ］の５位にジ低級アルキルアミ
ノ低級アルキル基又は置換基を有していてもよいピペラ
ジニル低級アルキル基を導入する反応と、３位水酸基を
低級アルカノイル化する反応とを任意の順序で行い、所
望により生成物をその薬理的に許容し得る塩とすること
ができる。That is, if necessary, a reaction for introducing a di (lower alkyl) amino (lower alkyl) group or optionally substituted piperazinyl (lower) alkyl group at the 5-position of the 1,5-benzothiazepine derivative [II]. And the reaction of converting the 3-hydroxyl group to a lower alkanoyl group in any order, and the product can be converted into a pharmacologically acceptable salt thereof if desired.
【００５０】かかる薬理的に許容しうる塩としては、無
機酸もしくは有機酸の酸付加塩があげられ、具体例とし
ては、塩酸塩、硫酸塩、リン酸塩、臭化水素酸塩、メタ
ンスルホン酸塩、ｐ−トルエンスルホン酸塩、酢酸塩、
フマル酸塩、マレイン酸塩、シュウ酸塩、ベンゼンスル
ホン酸塩が挙げられる。Examples of such pharmacologically acceptable salts include acid addition salts of inorganic acids or organic acids. Specific examples include hydrochlorides, sulfates, phosphates, hydrobromides and methanesulfones. Acid salt, p-toluenesulfonate, acetate,
Examples include fumarate, maleate, oxalate, and benzenesulfonate.
【００５１】またＲ3が水素原子であるプロピオン酸ア
ミド誘導体［Ｉ］を用いて本発明の分子内閉環反応を行
う場合、ジ低級アルキルアミノ低級アルキル基又は置換
基を有していてもよいピペラジニル低級アルキル基を導
入しうる試薬（例えば、ジ低級アルキルアミノ低級アル
キルハライド又は置換基を有していてもよいピペラジニ
ル低級アルキルハライド等）を同時に加えれば、５位が
ジ低級アルキルアミノ低級アルキル基又は置換基を有し
ていてもよいピペラジニル低級アルキル基で置換された
１，５−ベンゾチアゼピン誘導体［ＩＩ］を実質的に単
一の反応操作で得ることもできる。When the intramolecular ring-closing reaction of the present invention is carried out using a propionic amide derivative [I] in which R 3 is a hydrogen atom, diperalkylamino-lower alkyl group or piperazinyl which may have a substituent may be used. If a reagent capable of introducing a lower alkyl group (for example, dilower alkylamino lower alkyl halide or optionally substituted piperazinyl lower alkyl halide) is added at the same time, the 5-position dilower alkylamino lower alkyl group or The 1,5-benzothiazepine derivative [II] substituted with an optionally substituted piperazinyl lower alkyl group can also be obtained in a substantially single reaction operation.
【００５２】本発明の原料化合物であるプロピオン酸ア
ミド誘導体［Ｉ］は新規化合物であり、例えば一般式
［ＩＶ］The propionic acid amide derivative [I], which is the starting material compound of the present invention, is a novel compound and has, for example, the general formula [IV].
【００５３】[0053]
【化２４】 Embedded image
【００５４】（式中、記号は前記と同一意味を有す
る。）で示される２−アミノチオフェノール誘導体と一
般式［Ｖ］(Wherein the symbols have the same meanings as defined above) and the general formula [V]
【００５５】[0055]
【化２５】 Embedded image
【００５６】（式中、記号は前記と同一意味を有す
る。）で示される２，３−エポキシプロピオン酸アミド
誘導体とを適当な溶媒中、鉄触媒の存在下又は非存在
下、加熱還流させて製造することができる。(Wherein the symbols have the same meanings as described above) and the 2,3-epoxypropionic acid amide derivative is heated to reflux in a suitable solvent in the presence or absence of an iron catalyst. It can be manufactured.
【００５７】溶媒としては、メタノール、ベンゼン、ト
ルエン、キシレン、メシチレン、クロロベンゼン、ジク
ロロベンゼン、トリクロロベンゼン又はナフタレンを使
用することができ、メタノール、キシレン、クロロベン
ゼン又はジクロロベンゼンをとりわけ好適に使用するこ
とができる。また、鉄触媒としては、２価又は３価の鉄
イオンを含有する無機又は有機の塩又は錯体があげら
れ、かかる鉄触媒の具体例としては硝酸第二鉄、水酸化
酸化鉄、塩化第二鉄、塩化第一鉄、硫酸鉄、ヨウ化第一
鉄、硫化鉄、４−シクロヘキシル酪酸鉄、酸化第二鉄、
臭化第二鉄、フッ化第一鉄、フッ化第二鉄が挙げられ、
塩化第二鉄、硫酸鉄、硝酸第二鉄がとりわけ好ましい。As the solvent, methanol, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, trichlorobenzene or naphthalene can be used, and methanol, xylene, chlorobenzene or dichlorobenzene can be particularly preferably used. . Examples of the iron catalyst include inorganic or organic salts or complexes containing divalent or trivalent iron ions. Specific examples of the iron catalyst include ferric nitrate, iron hydroxide oxide, and ferric chloride. Iron, ferrous chloride, iron sulfate, ferrous iodide, iron sulfide, iron 4-cyclohexylbutyrate, ferric oxide,
Ferric bromide, ferrous fluoride, ferric fluoride, and the like,
Ferric chloride, iron sulfate and ferric nitrate are especially preferred.
【００５８】またプロピオン酸アミド誘導体［Ｉ］のう
ち、Ｒ1及びＲ2が同一又は異なって水素原子、低級アル
キル基、アミノ酸残基又は置換基を有していてもよいア
リール基であるか、あるいは互いに末端で結合して隣接
する窒素原子と共に置換されていてもよい複素環式基を
形成している化合物は、一般式［ＶＩＩ］In the propionic amide derivative [I], R 1 and R 2 are the same or different and each is a hydrogen atom, a lower alkyl group, an amino acid residue or an aryl group which may have a substituent, Alternatively, the compound forming a heterocyclic group which is bonded to each other at the terminals together with the adjacent nitrogen atom is represented by the general formula [VII]
【００５９】[0059]
【化２６】 Embedded image
【００６０】（式中、Ｒは低級アルキル基を表し、他の
記号は前記と同一意味を有する。）で示されるプロピオ
ン酸エステル誘導体と、一般式［ＶＩＩＩ−ａ］(Wherein R represents a lower alkyl group, and other symbols have the same meanings as described above), and a propionic acid ester derivative represented by the general formula [VIII-a].
【００６１】[0061]
【化２７】 Embedded image
【００６２】（式中、Ｒ11及びＲ21は同一又は異なって
水素原子、低級アルキル基、アミノ酸残基又は置換基を
有してもよいアリール基であるか、あるいは互いに末端
で結合して隣接する窒素原子と共に置換されていてもよ
い複素環式基を形成されていることを表わす。）で示さ
れる化合物とを適当な溶媒中０〜８０℃で反応させて製
造することもできる。(In the formula, R 11 and R 21 are the same or different and each is a hydrogen atom, a lower alkyl group, an amino acid residue or an aryl group which may have a substituent, or they are bonded to each other at their terminals and are adjacent to each other. It represents that a heterocyclic group which may be substituted is formed together with the nitrogen atom represented by the formula (1).) In a suitable solvent at 0 to 80 ° C.
【００６３】溶媒としては、メタノール、エタノール、
テトラヒドロフラン、トルエン、キシレン、メシチレ
ン、クロロベンゼン等を使用することができる。As the solvent, methanol, ethanol,
Tetrahydrofuran, toluene, xylene, mesitylene, chlorobenzene and the like can be used.
【００６４】また上記反応において、化合物［ＶＩＩ］
のアミノ基を必要に応じ、ベンンジルオキシカルボニル
基等で保護した後、反応に供し、反応後に常法によって
脱保護してもよい。In the above reaction, compound [VII]
The amino group may be protected with a benzyloxycarbonyl group or the like, if necessary, then subjected to the reaction, and after the reaction, may be deprotected by a conventional method.
【００６５】なお、２，３−エポキシプロピオン酸アミ
ド化合物［Ｖ］のうち、一般式Among the 2,3-epoxypropionic amide compounds [V], the general formula
【００６６】[0066]
【化２８】 Embedded image
【００６７】（式中、記号は前記と同一意味を有す
る。）で示される（２Ｒ，３Ｓ）−２，３−エポキシプ
ロピオン酸アミド化合物［Ｖ−ａ］及び一般式(Wherein the symbols have the same meanings as described above) and the (2R, 3S) -2,3-epoxypropionic acid amide compound [Va] and the general formula
【００６８】[0068]
【化２９】 Embedded image
【００６９】（式中、環Ｂ1は低級アルキル基で置換さ
れているベンゼン環を表わし、他の記号は前記と同一意
味を有する。）で示される（２Ｓ，３Ｒ）−２，３−エ
ポキシプロピオン酸アミド化合物［Ｖ−ｂ］は新規化合
物である。(In the formula, ring B 1 represents a benzene ring substituted with a lower alkyl group, and other symbols have the same meanings as described above.) (2S, 3R) -2,3-epoxy The propionic amide compound [Vb] is a novel compound.
【００７０】化合物［Ｖ−ａ］及び化合物［Ｖ−ｂ］の
うち、Ｒ1及びＲ2が共に水素原子であるか又は一方が水
素原子で他方が低級アルキル基であるものがより好まし
く、Ｒ1及びＲ2が共に水素原子であるものがとりわけ好
ましい。Of the compounds [Va] and [Vb], it is more preferable that R 1 and R 2 are both hydrogen atoms, or one is a hydrogen atom and the other is a lower alkyl group. It is particularly preferable that 1 and R 2 are both hydrogen atoms.
【００７１】２，３−エポキシプロピオン酸アミド化合
物［Ｖ］のうち、Ｒ1及びＲ2が同一又は異なって水素原
子、カルバモイル基、低級アルキル基、アミノ酸残基又
は置換基を有してもよいアリール基であるか、あるいは
互いに末端で結合して隣接する窒素原子と共に置換され
ていてもよい複素環式基を形成している化合物は、例え
ば一般式In the 2,3-epoxypropionic acid amide compound [V], R 1 and R 2 may be the same or different and each may have a hydrogen atom, a carbamoyl group, a lower alkyl group, an amino acid residue or a substituent. Compounds which are aryl groups, or which are terminally bonded to one another to form a heterocyclic group which may be substituted with adjacent nitrogen atoms are, for example:
【００７２】[0072]
【化３０】 Embedded image
【００７３】（式中、記号は前記と同一意味を有す
る。）で示される化合物［ＩＸ］と化合物［ＶＩＩＩ−
ａ］とをメタノール、テトラヒドロフラン、ジメチルホ
ルムアミド、トルエン、キシレン等の溶媒中、０〜１０
０℃で反応させて製造することができる。[Wherein the symbols have the same meanings as described above] and the compound [IX] and the compound [VIII-].
a] in a solvent such as methanol, tetrahydrofuran, dimethylformamide, toluene, xylene, etc.
It can be produced by reacting at 0 ° C.
【００７４】また化合物［Ｖ］は、一般式The compound [V] has the general formula
【００７５】[0075]
【化３１】 Embedded image
【００７６】（式中、記号は前記と同一意味を有す
る。）で示される化合物［Ｘ］の反応性誘導体（例え
ば、酸クロリド、酸無水物等）と一般式[Wherein the symbols have the same meanings as defined above] and a reactive derivative of the compound [X] (eg, acid chloride, acid anhydride, etc.) and the general formula
【００７７】[0077]
【化３２】 Embedded image
【００７８】（式中、記号は前記と同一意味を有す
る。）で示される化合物［ＶＩＩＩ］とを塩基（例え
ば、炭酸カリウム、水酸化ナトリウム、炭酸水素ナトリ
ウム、トリエチルアミン、ピリジン等）の存在下、塩化
メチレン、テトラヒドロフラン、トルエン、キシレン等
の溶媒中、０〜１００℃で反応させて得られる一般式(Wherein the symbols have the same meanings as defined above) and the compound [VIII] in the presence of a base (eg potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, triethylamine, pyridine, etc.) General formula obtained by reacting in a solvent such as methylene chloride, tetrahydrofuran, toluene, xylene at 0 to 100 ° C
【００７９】[0079]
【化３３】 Embedded image
【００８０】（式中、記号は前記と同一意味を有す
る。）で示される化合物［ＸＩ］をさらに塩化メチレ
ン、テトラヒドロフラン、クロロベンゼン等の適当な溶
媒中、過酸化物（例えば、過酸化水素水、ｔｅｒｔ−ブ
チルヒドロパーオキシド）や過酸（例えば、過酢酸、メ
タクロロ過安息香酸）等の酸化剤の存在下、０〜１００
℃で反応させて製造することもできる。(Wherein the symbols have the same meanings as above), the compound [XI] is further treated with a peroxide (for example, hydrogen peroxide solution, in a suitable solvent such as methylene chloride, tetrahydrofuran or chlorobenzene). 0-100 in the presence of an oxidizing agent such as tert-butyl hydroperoxide) or peracid (eg, peracetic acid, metachloroperbenzoic acid).
It can also be produced by reacting at ° C.
【００８１】本明細書において、低級アルキル基として
は、炭素数が１〜６の直鎖又は分岐アルキル基が、低級
アルコキシ基としては、炭素数が１〜６の直鎖又は分岐
アルコキシ基が、低級アルキレンジオキシ基としては、
炭素数が１〜６の直鎖又は分岐アルキレンジオキシ基
が、低級アルカノイル基としては、炭素数が１〜７の直
鎖又は分岐アルカノイル基が、シクロアルキル基として
は、炭素数が３〜８のシクロアルキル基が、低級アルカ
ン酸としては、炭素数が１〜７の直鎖又は分岐アルカン
酸が、ハロゲン原子としては、塩素原子、臭素原子、フ
ッ素原子、ヨウ素原子等が挙げられる。In the present specification, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and the lower alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms. As the lower alkylenedioxy group,
A linear or branched alkylenedioxy group having 1 to 6 carbon atoms, a lower alkanoyl group is a linear or branched alkanoyl group having 1 to 7 carbon atoms, and a cycloalkyl group is 3 to 8 carbon atoms. Examples of the lower alkanoic acid include a linear or branched alkanoic acid having 1 to 7 carbon atoms, and examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.
【００８２】以下、実施例により具体的に説明するが、
本発明はこれらによって限定されるものではない。The present invention will be specifically described below with reference to Examples.
The present invention is not limited by these.
【００８３】[0083]
実施例１ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）プロピオ
ン酸アミド１．５９ｇ、キシレン８ｍｌ及びメタンスル
ホン酸２４ｍｇの混合物を１１時間還流する。その後室
温まで放冷撹拌晶析させ、析出晶をろ別、冷メタノール
で洗浄後５０℃で乾燥して、（２Ｓ，３Ｓ）−２，３−
ジヒドロ−３−ヒドロキシ−２−（４−メトキシフェニ
ル）−１，５−ベンゾチアゼピン−４（５Ｈ）−オン
１．４１ｇを得る。Example 1 (2S, 3S) -3- (2-aminophenylthio) -2
A mixture of 1.59 g of -hydroxy-3- (4-methoxyphenyl) propionic amide, 8 ml of xylene and 24 mg of methanesulphonic acid is refluxed for 11 hours. Then, the mixture is allowed to cool to room temperature and stirred for crystallization, and the precipitated crystals are separated by filtration, washed with cold methanol and dried at 50 ° C. to give (2S, 3S) -2,3-
1.41 g of dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one are obtained.
【００８４】融点：２０３−２０５℃ ［α］D 25：＋１１４．３゜（Ｃ＝０．５，ジメチルホ
ルムアミド）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：３．７６（３Ｈ，
ｓ），４．３０（１Ｈ，ｄｄ），４．７４（１Ｈ，
ｄ），５．０５（１Ｈ，ｄ），６．８７−７．６２（８
Ｈ，ｍ），１０．３２（１Ｈ，ｓ）。Melting point: 203-205 ° C. [α] D 25 : + 114.3 ° (C = 0.5, dimethylformamide) 1 H-NMR (DMSO-d 6 , δ): 3.76 (3H,
s), 4.30 (1H, dd), 4.74 (1H,
d), 5.05 (1H, d), 6.87-7.62 (8
H, m), 10.32 (1H, s).
【００８５】光学純度（ＨＰＬＣ）：＞９９．９％ｅｅ ＨＰＬＣ条件 カラム：キラルセルＯＤ（４．６ｘ２５０ｍｍ）〔ダイ
セル化学工業製〕 移動層：ｎ−ヘキサン：エタノール＝８５：１５ 流速：０．５ｍｌ／ｍｉｎ ＵＶ検出：２５４ｎｍ カラム温度：３５℃。Optical Purity (HPLC):> 99.9% ee HPLC Conditions Column: Chiralcel OD (4.6 × 250 mm) (manufactured by Daicel Chemical Industries) Mobile phase: n-hexane: ethanol = 85: 15 Flow rate: 0.5 ml / min UV detection: 254 nm Column temperature: 35 ° C.
【００８６】実施例２ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）プロピオ
ン酸アミド１５９ｍｇ及びキシレン３ｍｌの混合物を２
９時間還流する。その後室温まで放冷撹拌晶析させ、析
出晶をろ別、キシレンで洗浄後６０℃で乾燥して、（２
Ｓ，３Ｓ）−２，３−ジヒドロ−３−ヒドロキシ−２−
（４−メトキシフェニル）−１，５−ベンゾチアゼピン
−４（５Ｈ）−オン１１５ｍｇを得る。Example 2 (2S, 3S) -3- (2-aminophenylthio) -2
A mixture of 159 mg of hydroxy-3- (4-methoxyphenyl) propionamide and 3 ml of xylene was added to 2 parts.
Reflux for 9 hours. After that, the solution is allowed to cool to room temperature and stirred for crystallization, and the precipitated crystal is separated by filtration, washed with xylene and dried at 60 ° C.
S, 3S) -2,3-Dihydro-3-hydroxy-2-
115 mg of (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one are obtained.
【００８７】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product were in agreement with those of Example 1.
【００８８】実施例３ （２Ｓ，３Ｓ）−３−（２−アミノフェニオルチオ）−
２−ヒドロキシ−３−（４−メトキシフェニル）−Ｎ−
メチルプロピオン酸アミド、クロロベンゼン及びｐ−ト
ルエンスルホン酸・１水和物の混合物を還流した。その
後反応混合物をＨＰＬＣで分析した結果、（２Ｓ，３
Ｓ）−２，３−ジヒドロ−３−ヒドロキシ−２−（４−
メトキシフェニル）−１，５−ベンゾチアゼピン−４
（５Ｈ）−オンの生成を確認した。Example 3 (2S, 3S) -3- (2-aminophenyliothio)-
2-hydroxy-3- (4-methoxyphenyl) -N-
A mixture of methylpropionamide, chlorobenzene and p-toluenesulfonic acid monohydrate was refluxed. After that, the reaction mixture was analyzed by HPLC. As a result, (2S, 3
S) -2,3-Dihydro-3-hydroxy-2- (4-
Methoxyphenyl) -1,5-benzothiazepine-4
Generation of (5H) -one was confirmed.
【００８９】ＨＰＬＣ条件 カラム：ウォーターズピュアジル ５μ Ｃ１８ １２
０Å （４．６ｘ１５０ｍｍ）〔ウォーターズ社製〕 移動層：アセトニトリル：１０ｍＭリン酸二水素カリウ
ム（ｐＨ３）＝５０：５０ 流速：０．５ｍｌ／ｍｉｎ ＵＶ検出：２５４ｎｍ カラム温度：４０℃。HPLC conditions Column: Waters Puresil 5μ C18 12
0Å (4.6 × 150 mm) [manufactured by Waters] Mobile phase: acetonitrile: 10 mM potassium dihydrogen phosphate (pH 3) = 50: 50 Flow rate: 0.5 ml / min UV detection: 254 nm Column temperature: 40 ° C.
【００９０】実施例４ （２Ｒ，３Ｒ）−３−（２−アミノ−５−メチルフェニ
ルチオ）−２−ヒドロキシ−３−（４−メチルフェニ
ル）プロピオン酸アミドを実施例１と同様に処理して、
（２Ｒ，３Ｒ）−２，３−ジヒドロ−３−ヒドロキシ−
２−（４−メチルフェニル）−８−メチル−１，５−ベ
ンゾチアゼピン−４（５Ｈ）−オンを得る。Example 4 (2R, 3R) -3- (2-Amino-5-methylphenylthio) -2-hydroxy-3- (4-methylphenyl) propionic acid amide was treated as in Example 1. hand,
(2R, 3R) -2,3-dihydro-3-hydroxy-
2- (4-Methylphenyl) -8-methyl-1,5-benzothiazepin-4 (5H) -one is obtained.
【００９１】融点：２１２−２１４℃ ［α］D 25：−１２９．２゜（Ｃ＝１．０，ジメチルホ
ルムアミド）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：２．２９（６Ｈ，
ｓ），４．２９（１Ｈ，ｄｄ），４．６７（１Ｈ，
ｄ），５．０３（１Ｈ，ｄ），７．０２−７．４２（７
Ｈ，ｍ），１０．２０（１Ｈ，ｓ）。Melting point: 212-214 ° C. [α] D 25 : -129.2 ° (C = 1.0, dimethylformamide) 1 H-NMR (DMSO-d 6 , δ): 2.29 (6H, 6H,
s), 4.29 (1H, dd), 4.67 (1H,
d), 5.03 (1H, d), 7.02-7.42 (7
H, m), 10.20 (1H, s).
【００９２】実施例５ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド９６６ｍｇ及びキシレ
ン１０ｍｌの混合物を窒素気流下で加熱する。還流を開
始した後、すぐに２−アミノチオフェノール６８９ｍｇ
及び硫酸鉄・７水和物０．１１ｍｇのメタノール０．１
ｍｌ溶液を加え、同温で５分間反応する。さらに反応混
合物にメタンスルホン酸４８ｍｇを加え１３時間還流す
る。その後２時間氷冷し、析出晶をろ別、メタノールで
洗浄後５０℃で乾燥して、（２Ｓ，３Ｓ）−２，３−ジ
ヒドロ−３−ヒドロキシ−２−（４−メトキシフェニ
ル）−１，５−ベンゾチアゼピン−４（５Ｈ）−オン
１．０７ｇを得る。Example 5 (2R, 3S) -3- (4-methoxyphenyl) -2,
A mixture of 966 mg 3-epoxypropionamide and 10 ml xylene is heated under a stream of nitrogen. Immediately after starting the reflux, 689 mg of 2-aminothiophenol
And iron sulfate heptahydrate 0.11 mg of methanol 0.1
Add ml solution and react at the same temperature for 5 minutes. Further, 48 mg of methanesulfonic acid is added to the reaction mixture, and the mixture is refluxed for 13 hours. After cooling with ice for 2 hours, the precipitated crystals were filtered off, washed with methanol and dried at 50 ° C. to obtain (2S, 3S) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1. 1.07 g of 5,5-benzothiazepin-4 (5H) -one are obtained.
【００９３】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【００９４】実施例６ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）プロピオ
ン酸アミド、三フッ化ホウ素−ジエチルエーテル錯体及
び１，４−ジオキサンの混合物を還流する。その後反応
混合物をＨＰＬＣ分析することにより、（２Ｓ，３Ｓ）
−２，３−ジヒドロ−３−ヒドロキシ−２−（４−メト
キシフェニル）−１，５−ベンゾチアゼピン−４（５
Ｈ）−オンの生成を確認した。Example 6 (2S, 3S) -3- (2-aminophenylthio) -2
A mixture of -hydroxy-3- (4-methoxyphenyl) propionic acid amide, boron trifluoride-diethyl ether complex and 1,4-dioxane is refluxed. Then, the reaction mixture was analyzed by HPLC to give (2S, 3S)
-2,3-Dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5
H) -one formation was confirmed.
【００９５】ＨＰＬＣ条件 カラム：ウォーターズピュアジル ５μ Ｃ１８ １２
０Å（４．６ｘ１５０ｍｍ）〔ウォーターズ社製〕 移動層：アセトニトリル：１０ｍＭリン酸二水素カリウ
ム（ｐＨ３）＝５０：５０ 流速：０．５ｍｌ／ｍｉｎ ＵＶ検出：２５４ｎｍ カラム温度：４０℃。HPLC conditions Column: Waters Puresil 5μ C18 12
0Å (4.6 × 150 mm) [manufactured by Waters] Mobile phase: acetonitrile: 10 mM potassium dihydrogen phosphate (pH 3) = 50: 50 Flow rate: 0.5 ml / min UV detection: 254 nm Column temperature: 40 ° C.
【００９６】実施例７〜３１ 第１〜４表記載の化合物［Ｉ］を実施例１〜６又は３２
〜３６と同様に処理することにより、分子内閉環された
対応化合物［ＩＩ］を得る。Examples 7 to 31 Compounds [I] listed in Tables 1 to 4 were used in Examples 1 to 6 or 32.
By the same treatment as for -36, the intramolecular ring-closed corresponding compound [II] is obtained.
【００９７】[0097]
【表１】 [Table 1]
【００９８】[0098]
【表２】 [Table 2]
【００９９】[0099]
【表３】 [Table 3]
【０１００】[0100]
【表４】 [Table 4]
【０１０１】実施例３２ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）−Ｎ−フ
ェニルプロピオン酸アミド５８２ｍｇ及びクロロベンゼ
ン１０ｍｌを混合し、ｐ−トルエンスルホン酸・１水和
物１１２ｍｇを３時間おきに８回に分けて加えながら２
５時間還流する。その後反応混合物を室温まで冷却し、
クロロベンゼンを留去後、残渣にメタノール５ｍｌを加
え、１時間還流する。室温まで放冷撹拌晶析後さらに冷
却し、析出晶をろ取し、冷メタノールで洗浄後、５０℃
で乾燥することにより、（２Ｓ，３Ｓ）−２，３−ジヒ
ドロ−３−ヒドロキシ−２−（４−メトキシフェニル）
−１，５−ベンゾチアゼピン−４（５Ｈ）−オン２４３
ｍｇを得る。Example 32 (2S, 3S) -3- (2-aminophenylthio) -2
-Hydroxy-3- (4-methoxyphenyl) -N-phenylpropionic acid amide (582 mg) and chlorobenzene (10 ml) were mixed, and p-toluenesulfonic acid monohydrate (112 mg) was added every 3 hours in 8 batches of 2
Reflux for 5 hours. Then the reaction mixture is cooled to room temperature,
After distilling off chlorobenzene, 5 ml of methanol is added to the residue and refluxed for 1 hour. After cooling to room temperature with stirring and crystallization, it is further cooled, and the precipitated crystals are collected by filtration, washed with cold methanol, and then at 50 ° C.
By drying at (2S, 3S) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl)
-1,5-Benzothiazepine-4 (5H) -one 243
mg.
【０１０２】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product were the same as those of Example 1.
【０１０３】実施例３３ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド３．８６ｇ及びクロロ
ベンゼン７７ｍｌの混合物を窒素気流下で加熱する。還
流を開始した後、すぐに２−アミノチオフェノール２．
７５ｇ及び塩化第二鉄・６水和物０．５４ｍｇのメタノ
ール０．１ｍｌ溶液を加え、同温で５分間反応する。反
応混合物をＨＰＬＣで分析した結果、３−（２−アミノ
フェニルチオ）−２−ヒドロキシ−３−（４−メトキシ
フェニル）プロピオン酸アミド６．０９ｇ〔（２Ｓ，３
Ｓ）：（２Ｓ，３Ｒ）＝９１．５：８．５〕の生成を確
認した。さらに反応混合物にｐ−トルエンスルホン酸・
１水和物０．７６ｇを加え３２時間還流し、溶媒のクロ
ロベンゼンを減圧留去する。濃縮残渣にメタノール２５
ｍｌを加え１時間還流後一晩氷冷し、析出晶をろ別、メ
タノールで洗浄後５０℃で乾燥して、（２Ｓ，３Ｓ）−
２，３−ジヒドロ−３−ヒドロキシ−２−（４−メトキ
シフェニル）−１，５−ベンゾチアゼピン−４（５Ｈ）
−オン４．７６ｇを得る。Example 33 (2R, 3S) -3- (4-methoxyphenyl) -2,
A mixture of 3.86 g of 3-epoxypropionamide and 77 ml of chlorobenzene is heated under a stream of nitrogen. Immediately after starting the reflux, 2-aminothiophenol 2.
A solution of 75 g and 0.54 mg of ferric chloride hexahydrate in 0.1 ml of methanol is added, and the mixture is reacted at the same temperature for 5 minutes. As a result of analyzing the reaction mixture by HPLC, 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid amide 6.09 g [(2S, 3
S) :( 2S, 3R) = 91.5: 8.5] was confirmed. Furthermore, p-toluenesulfonic acid was added to the reaction mixture.
0.76 g of monohydrate is added and the mixture is refluxed for 32 hours, and the solvent chlorobenzene is distilled off under reduced pressure. 25 methanol in the concentrated residue
After adding ml, the mixture was refluxed for 1 hour and ice-cooled overnight. The precipitated crystals were separated by filtration, washed with methanol and dried at 50 ° C. to obtain (2S, 3S)-
2,3-Dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H)
-Getting 4.76 g on.
【０１０４】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【０１０５】ＨＰＬＣ条件 カラム：ウォーターズピュアジル ５μ Ｃ１８ １２
０Å（４．６ｘ１５０ｍｍ）〔ウォーターズ社製〕 移動層：アセトニトリル：１０ｍＭリン酸二水素カリウ
ム（ｐＨ３）＝３０：７０ 流速：１．０ｍｌ／ｍｉｎ ＵＶ検出：２５４ｎｍ カラム温度：４０℃。HPLC conditions Column: Waters Puresil 5μ C18 12
0Å (4.6 × 150 mm) [manufactured by Waters] Mobile phase: acetonitrile: 10 mM potassium dihydrogen phosphate (pH 3) = 30: 70 Flow rate: 1.0 ml / min UV detection: 254 nm Column temperature: 40 ° C.
【０１０６】実施例３４ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド９．６６ｇおよびクロ
ロベンゼン１９３ｍｌの混合物を窒素気流下で加熱す
る。還流を開始した後、すぐに２−アミノチオフェノー
ル６．８９ｇおよび塩化第二鉄・６水和物１．３５ｍｇ
のメタノール０．１ｍｌ溶液を加え、同温で５分間撹拌
する。こうして得られる（２Ｓ，３Ｓ）−３−（２−ア
ミノフェニルチオ）−２−ヒドロキシ−３−（４−メト
キシフェニル）プロピオン酸アミドを含む反応混合物
に、ｐ−トルエンスルホン酸・１水和物２．８８ｇを数
時間おきに６回に分けて加える（０．４８ｇ×６）と共
に溶媒のクロロベンゼンを留去しながら１５時間還流す
る。残存しているクロロベンゼンを減圧留去後、残さに
メタノール５０ｍｌを加え、１時間還流する。室温まで
放冷後さらに一晩冷却（３℃）し、析出晶をろ別、冷メ
タノールで洗浄後５０℃で乾燥して、（２Ｓ，３Ｓ）−
２，３−ジヒドロ−３−ヒドロキシ−２−（４−メトキ
シフェニル）−１，５−ベンゾチアゼピン−４（５Ｈ）
−オン１１．７３ｇを得る。Example 34 (2R, 3S) -3- (4-methoxyphenyl) -2,
A mixture of 9.66 g of 3-epoxypropionamide and 193 ml of chlorobenzene is heated under a stream of nitrogen. Immediately after starting the reflux, 6.89 g of 2-aminothiophenol and 1.35 mg of ferric chloride hexahydrate
0.1 ml of methanol solution is added and stirred at the same temperature for 5 minutes. The thus obtained reaction mixture containing (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid amide was added to p-toluenesulfonic acid monohydrate. 2.88 g is added in several times every several hours (0.48 g × 6) and refluxed for 15 hours while distilling off the solvent chlorobenzene. After the residual chlorobenzene was distilled off under reduced pressure, 50 ml of methanol was added to the residue and the mixture was refluxed for 1 hour. After cooling to room temperature, it was further cooled overnight (3 ° C.), the precipitated crystals were filtered off, washed with cold methanol and dried at 50 ° C., (2S, 3S)-
2,3-Dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H)
-On to get 11.73 g.
【０１０７】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【０１０８】実施例３５ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド１．９３ｇおよびクロ
ロベンゼン３９ｍｌの混合物を窒素気流下で加熱する。
還流を開始した後、すぐに２−アミノチオフェノール
１．３８ｇおよび塩化第二鉄・６水和物０．２７ｍｇの
メタノール０．０５ｍｌ溶液を加え、同温で５分間撹拌
する。こうして得られる３−（２−アミノフェニルチ
オ）−２−ヒドロキシ−３−（４−メトキシフェニル）
プロピオン酸アミド３．０８ｇ〔（２Ｓ，３Ｓ）：（２
Ｓ，３Ｒ）＝９１．３：８．７〕を含む反応混合物を１
６ｇまで濃縮し、メタンスルホン酸３８ｍｇを２〜３時
間おきに５回に分けて加えながら（３８ｍｇ×５）１３
時間還流する。残存しているクロロベンゼンを減圧留去
後、残さにメタノール１０ｍｌを加え、１時間還流す
る。室温まで放冷後さらに４０時間冷却（８℃）し、析
出晶をろ別、冷メタノールで洗浄後５０℃で乾燥して、
（２Ｓ，３Ｓ）−２，３−ジヒドロ−３−ヒドロキシ−
２−（４−メトキシフェニル）−１，５−ベンゾチアゼ
ピン−４（５Ｈ）−オン２．３８ｇを得る。Example 35 (2R, 3S) -3- (4-methoxyphenyl) -2,
A mixture of 1.93 g of 3-epoxypropionamide and 39 ml of chlorobenzene is heated under a stream of nitrogen.
Immediately after starting the reflux, a solution of 1.38 g of 2-aminothiophenol and 0.27 mg of ferric chloride hexahydrate in 0.05 ml of methanol was added, and the mixture was stirred at the same temperature for 5 minutes. 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) thus obtained
Propionic acid amide 3.08 g [(2S, 3S) :( 2
S, 3R) = 91.3: 8.7].
Concentrate to 6 g and add 38 mg of methanesulfonic acid every 2 to 3 hours in 5 batches (38 mg x 5) 13
Reflux for hours. After the residual chlorobenzene was distilled off under reduced pressure, 10 ml of methanol was added to the residue and the mixture was refluxed for 1 hour. After allowing to cool to room temperature, it is further cooled (8 ° C.) for 40 hours, the precipitated crystals are filtered off, washed with cold methanol and dried at 50 ° C.,
(2S, 3S) -2,3-dihydro-3-hydroxy-
2.38 g of 2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one are obtained.
【０１０９】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【０１１０】実施例３６ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド１５．４６ｇおよびク
ロロベンゼン３０９ｍｌの混合物を窒素気流下で加熱す
る。還流を開始した後、すぐに２−アミノチオフェノー
ル１１．０２ｇおよび塩化第二鉄・６水和物２．１６ｍ
ｇのメタノール０．１ｍｌ溶液を加え、同温で５分間撹
拌する。こうして得られる３−（２−アミノフェニルチ
オ）−２−ヒドロキシ−３−（４−メトキシフェニル）
プロピオン酸アミド２４．２４ｇ〔（２Ｓ，３Ｓ）：
（２Ｓ，３Ｒ）＝９１．３：８．７〕を含む反応混合物
の全体の４分の１量をとり、３５％塩酸１．０４ｇを加
え、溶媒を留去しながら１３時間還流する。残存してい
るクロロベンゼンを減圧留去後、残さにメタノール２５
ｍｌを加え、１時間還流する。室温まで放冷後さらに一
晩冷却（３℃）し、析出晶をろ別、冷メタノールで洗浄
後５０℃で乾燥して、（２Ｓ，３Ｓ）−２，３−ジヒド
ロ−３−ヒドロキシ−２−（４−メトキシフェニル）−
１，５−ベンゾチアゼピン−４（５Ｈ）−オン４．４９
ｇを得る。Example 36 (2R, 3S) -3- (4-methoxyphenyl) -2,
A mixture of 15.46 g of 3-epoxypropionic amide and 309 ml of chlorobenzene is heated under a stream of nitrogen. Immediately after starting reflux, 2-aminothiophenol 11.02 g and ferric chloride hexahydrate 2.16 m
A 0.1 ml solution of g of methanol is added and the mixture is stirred at the same temperature for 5 minutes. 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) thus obtained
24.24 g of propionic amide [(2S, 3S):
(2S, 3R) = 91.3: 8.7] was taken, and a quarter amount of the whole reaction mixture was taken, 1.04 g of 35% hydrochloric acid was added, and the mixture was refluxed for 13 hours while distilling off the solvent. Distill off the residual chlorobenzene under reduced pressure, and then add methanol to the residue.
Add ml and reflux for 1 hour. After cooling to room temperature, the mixture was further cooled overnight (3 ° C.), the precipitated crystals were separated by filtration, washed with cold methanol and dried at 50 ° C. to obtain (2S, 3S) -2,3-dihydro-3-hydroxy-2. -(4-methoxyphenyl)-
1,5-benzothiazepin-4 (5H) -one 4.49
get g.
【０１１１】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【０１１２】実施例３７ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミドを、塩酸の代わりに臭
化水素酸を用いること以外は実施例３６と同様に処理し
て、（２Ｓ，３Ｓ）−２，３−ジヒドロ−３−ヒドロキ
シ−２−（４−メトキシフェニル）−１，５−ベンゾチ
アゼピン−４（５Ｈ）−オンを得る。Example 37 (2R, 3S) -3- (4-methoxyphenyl) -2,
3-Epoxypropionic acid amide was treated as in Example 36 except that hydrobromic acid was used instead of hydrochloric acid to give (2S, 3S) -2,3-dihydro-3-hydroxy-2- ( 4-Methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one is obtained.
【０１１３】本品の物性値は実施例１のそれと一致し
た。The physical properties of this product agreed with those of Example 1.
【０１１４】参考例１ （１）（２Ｒ，３Ｓ）−３−（４−メトキシフェニル）
−２，３−エポキシプロピオン酸メチルエステル２．０
８ｇ及びＮ，Ｎ−ジメチルホルムアミド３ｍｌの混合物
に氷冷下２８％アンモニア水６．１ｇを加える。室温で
２時間反応後、析出晶をろ別、水洗、５０℃で乾燥する
ことにより、（２Ｒ，３Ｓ）−３−（４−メトキシフェ
ニル）−２，３−エポキシプロピオン酸アミド１．６４
ｇを得る。Reference Example 1 (1) (2R, 3S) -3- (4-methoxyphenyl)
-2,3-Epoxy propionic acid methyl ester 2.0
To a mixture of 8 g and 3 ml of N, N-dimethylformamide, 6.1 g of 28% aqueous ammonia was added under ice cooling. After reacting for 2 hours at room temperature, the precipitated crystals were separated by filtration, washed with water, and dried at 50 ° C. to give (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxypropionic amide 1.64.
get g.
【０１１５】融点：１４２−１４４℃ ［α］D 25：−１６３．７゜（Ｃ＝１．０，メタノー
ル）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：３．４９（１Ｈ，
ｄ），３．７５（３Ｈ，ｓ），３．９６（１Ｈ，ｄ），
６．９４（２Ｈ，ｄ），７．２４（２Ｈ，ｄ），７．４
１（１Ｈ，ｓ），７．５６（１Ｈ，ｓ）。Melting point: 142-144 ° C. [α] D 25 : -163.7 ° (C = 1.0, methanol) 1 H-NMR (DMSO-d 6 , δ): 3.49 (1H,
d), 3.75 (3H, s), 3.96 (1H, d),
6.94 (2H, d), 7.24 (2H, d), 7.4
1 (1H, s), 7.56 (1H, s).
【０１１６】（２）（２Ｒ，３Ｓ）−３−（４−メトキ
シフェニル）−２，３−エポキシプロピオン酸アミド
１．９３ｇ及びキシレン１５ｍｌの混合物を窒素気流下
で加熱する。還流を開始した後、すぐに２−アミノチオ
フェノール１．３８ｇ及び硫酸鉄・７水和物０．２８ｍ
ｇのメタノール０．２ｍｌ溶液を加える。同温で５分間
反応後室温まで冷却する。反応混合物をＨＰＬＣで分析
した結果、３−（２−アミノフェニルチオ）−２−ヒド
ロキシ−３−（４−メトキシフェニル）プロピオン酸ア
ミド２．６９ｇ〔（２Ｓ，３Ｓ）：（２Ｓ，３Ｒ）＝９
１：９〕の生成を確認した。溶媒を減圧濃縮後、残渣を
エタノール３ｍｌ及び水３ｍｌに加熱溶解し、０℃まで
徐冷撹拌晶析させる。析出晶をろ取、冷５０％エタノー
ルで洗浄後５０℃で乾燥して、（２Ｓ，３Ｓ）−３−
（２−アミノフェニルチオ）−２−ヒドロキシ−３−
（４−メトキシフェニル）プロピオン酸アミド０．８４
ｇを得る。(2) A mixture of (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxypropionic acid amide (1.93 g) and xylene (15 ml) is heated under a nitrogen stream. Immediately after starting the reflux, 1.38 g of 2-aminothiophenol and 0.28 m of iron sulfate heptahydrate
A solution of 0.2 g of methanol in 0.2 ml is added. After reacting for 5 minutes at the same temperature, it is cooled to room temperature. As a result of analyzing the reaction mixture by HPLC, 2.69 g of 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid amide [(2S, 3S) :( 2S, 3R) = 9
1: 9] was confirmed. After the solvent is concentrated under reduced pressure, the residue is dissolved by heating in 3 ml of ethanol and 3 ml of water, and crystallized by stirring with slow cooling to 0 ° C. The precipitated crystals were collected by filtration, washed with cold 50% ethanol, dried at 50 ° C., and then (2S, 3S) -3-
(2-Aminophenylthio) -2-hydroxy-3-
(4-Methoxyphenyl) propionic acid amide 0.84
get g.
【０１１７】融点：１１０−１１２℃ ［α］D 25：＋５０６゜（Ｃ＝１．０，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：３．７０（３Ｈ，
ｓ），４．１１（１Ｈ，ｄｄ），４．４４（１Ｈ，
ｄ），５．３５（２Ｈ，ｓ），６．０２（１Ｈ，ｄ），
６．２５−７．２８（８Ｈ，ｍ），７．３９（２Ｈ，
ｓ）。Melting point: 110-112 ° C. [α] D 25 : + 506 ° (C = 1.0, methanol) 1 H-NMR (DMSO-d 6 , δ): 3.70 (3H,
s), 4.11 (1H, dd), 4.44 (1H,
d), 5.35 (2H, s), 6.02 (1H, d),
6.25-7.28 (8H, m), 7.39 (2H,
s).
【０１１８】ＨＰＬＣ条件 カラム：ウォーターズピュアジル ５μ Ｃ１８ １２
０Å （４．６ｘ１５０ｍｍ）〔ウォーターズ社製〕 移動層：アセトニトリル：１０ｍＭリン酸二水素カリウ
ム（ｐＨ３）＝３０：７０ 流速：１．０ｍｌ／ｍｉｎ ＵＶ検出：２５４ｎｍ カラム温度：４０℃。HPLC conditions Column: Waters Puresil 5μ C18 12
0Å (4.6 × 150 mm) [manufactured by Waters] Mobile phase: acetonitrile: 10 mM potassium dihydrogen phosphate (pH 3) = 30: 70 Flow rate: 1.0 ml / min UV detection: 254 nm Column temperature: 40 ° C.
【０１１９】参考例２ （１）（２Ｒ，３Ｓ）−３−（４−メトキシフェニル）
−２，３−エポキシプロピオン酸メチルエステル２．０
８ｇにメタノール１０ｍｌを混合し、氷冷下で４０％メ
チルアミン水溶液１．４４ｇのメタノール１０ｍｌ溶液
を滴下する。次いで反応混合物を１０〜１５℃で２時間
撹拌後メタノールを留去し、エーテルを加え、析出晶を
ろ過、洗浄後５０℃で減圧乾燥することにより、（２
Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，３−
エポキシ−Ｎ−メチルプロピオン酸アミド１．７０ｇを
得る。Reference Example 2 (1) (2R, 3S) -3- (4-methoxyphenyl)
-2,3-Epoxy propionic acid methyl ester 2.0
10 g of methanol is mixed with 8 g, and a solution of 1.44 g of a 40% methylamine aqueous solution in 10 ml of methanol is added dropwise under ice cooling. Then, the reaction mixture was stirred at 10 to 15 ° C. for 2 hours, methanol was distilled off, ether was added, and the precipitated crystals were filtered, washed and dried under reduced pressure at 50 ° C. to give (2
R, 3S) -3- (4-methoxyphenyl) -2,3-
1.70 g of epoxy-N-methylpropionic acid amide are obtained.
【０１２０】融点：１３５−１３６℃ ［α］D 25：−１４５．３゜（Ｃ＝１．０，メタノー
ル）1 Ｈ−ＮＭＲ（ＣＤＣｌ3，δ）：２．８６（３Ｈ，
ｄ），３．５３（１Ｈ，ｄ），３．８１（３Ｈ，ｓ），
３．８３（１Ｈ，ｄ），６．２６（１Ｈ，ｓ）６．８４
−７．２６（４Ｈ，ｍ）。Melting point: 135-136 ° C. [α] D 25 : -145.3 ° (C = 1.0, methanol) 1 H-NMR (CDCl 3 , δ): 2.86 (3H,
d), 3.53 (1H, d), 3.81 (3H, s),
3.83 (1H, d), 6.26 (1H, s) 6.84
-7.26 (4H, m).
【０１２１】（２）（２Ｒ，３Ｓ）−３−（４−メトキ
シフェニル）−２，３−エポキシ−Ｎ−メチルプロピオ
ン酸アミド８２９ｍｇ及びキシレン１０ｍｌの混合物を
窒素気流下で加熱し、還流開始後すぐに２−アミノチオ
フェノール５５１ｍｇと無水塩化第二鉄０．０６５ｍｇ
のメタノール０．０８ｍｌ溶液の混合物を加える。同温
で５分間反応後室温まで冷却、析出晶をろ取し、さらに
キシレンで洗浄し、６０℃で乾燥することにより、（２
Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２−ヒ
ドロキシ−３−（４−メトキシフェニル）−Ｎ−メチル
プロピオン酸アミド１．０６ｇを得る。(2) A mixture of (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxy-N-methylpropionic amide (829 mg) and xylene (10 ml) was heated under a nitrogen stream, and after the start of reflux, Immediately 551 mg of 2-aminothiophenol and 0.065 mg of anhydrous ferric chloride
Add a mixture of 0.08 ml of methanol solution in. After reacting at the same temperature for 5 minutes, the mixture was cooled to room temperature, the precipitated crystals were collected by filtration, washed with xylene, and dried at 60 ° C to give (2
1.06 g of S, 3S) -3- (2-Aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) -N-methylpropionic acid amide are obtained.
【０１２２】融点：１４５−１４７℃ ［α］D 25：＋４３３゜（Ｃ＝１．０，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：２．６３（３Ｈ，
ｄ），３．７０（３Ｈ，ｓ），４．１４（１Ｈ，ｄ
ｄ），４．４５（１Ｈ，ｄ），５．３３（２Ｈ，ｓ），
６．１１（１Ｈ，ｄ），６．２５−７．２９（８Ｈ，
ｍ），７．９３（１Ｈ，ｄ）。Melting point: 145-147 ° C. [α] D 25 : + 433 ° (C = 1.0, methanol) 1 H-NMR (DMSO-d 6 , δ): 2.63 (3H,
d), 3.70 (3H, s), 4.14 (1H, d
d), 4.45 (1H, d), 5.33 (2H, s),
6.11 (1H, d), 6.25-7.29 (8H,
m), 7.93 (1H, d).
【０１２３】参考例３ （１）（２Ｓ，３Ｒ）−３−（４−メチルフェニル）−
２，３−エポキシプロピオン酸メチルエステル３．８４
ｇ及びメタノール２５ｍｌの混合物に、氷冷下で２８％
アンモニア水６．１ｇのメタノール１０ｍｌ溶液を徐々
に滴下した。次いで反応混合物を室温まで徐々に昇温し
２時間撹拌後、さらに氷冷下で１時間撹拌して析出晶を
ろ過、洗浄後５０゜Ｃで乾燥することによって（２Ｓ，
３Ｒ）−３−（４−メチルフェニル）−２，３−エポキ
シプロピオン酸アミド２．７１ｇを得る。Reference Example 3 (1) (2S, 3R) -3- (4-methylphenyl)-
2,3-Epoxypropionic acid methyl ester 3.84
g and 25 ml of methanol to a mixture of 28% under ice cooling.
A solution of 6.1 g of ammonia water in 10 ml of methanol was gradually added dropwise. Then, the reaction mixture was gradually warmed to room temperature, stirred for 2 hours, further stirred for 1 hour under ice cooling, and the precipitated crystals were filtered, washed and dried at 50 ° C. (2S,
2.71 g of 3R) -3- (4-methylphenyl) -2,3-epoxypropionic acid amide are obtained.
【０１２４】融点：１８３−１８５゜Ｃ ［α］D 25：＋１７２．５゜（ｃ＝１，メタノール）1 Ｈ−ＮＭＲ（ＣＤＣｌ3及びＤＭＳＯ−ｄ6，δ）：
２．３５（３Ｈ，ｓ），３．４７（１Ｈ，ｄ），３．９
３（１Ｈ，ｄ），６．５２（２Ｈ，ｄ），７．１６（４
Ｈ，ｓ）。Melting point: 183-185 ° C. [α] D 25 : + 172.5 ° (c = 1, methanol) 1 H-NMR (CDCl 3 and DMSO-d 6 , δ):
2.35 (3H, s), 3.47 (1H, d), 3.9
3 (1H, d), 6.52 (2H, d), 7.16 (4
H, s).
【０１２５】（２）（２Ｓ，３Ｒ）−３−（４−メチル
フェニル）−２，３−エポキシプロピオン酸アミド及び
２−アミノ−５−メチルチオフェノールを参考例１−
（２）と同様に処理して、（２Ｒ，３Ｒ）−３−（２−
アミノ−５−メチルフェニオルチオ）−２−ヒドロキシ
−３−（４−メチルフェニル）プロピオン酸アミドを得
る。(2) (2S, 3R) -3- (4-methylphenyl) -2,3-epoxypropionic acid amide and 2-amino-5-methylthiophenol were used in Reference Example 1-
The same process as (2) is performed to obtain (2R, 3R) -3- (2-
Amino-5-methylphenylthio) -2-hydroxy-3- (4-methylphenyl) propionic acid amide is obtained.
【０１２６】融点：１４５−１４６゜Ｃ ［α］D 25：−４１０゜（ｃ＝１，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：１．９６（３Ｈ，
ｓ），２．２４（３Ｈ，ｓ），４．１１（１Ｈ，ｄ
ｄ），４．４６（１Ｈ，ｄ），５．１３（２Ｈ，ｓ），
５．９９（１Ｈ，ｓ），６．５１−７．２６（７Ｈ，
ｍ），７．３７（２Ｈ，ｓ）。Melting point: 145-146 ° C. [α] D 25 : -410 ° (c = 1, methanol) 1 H-NMR (DMSO-d 6 , δ): 1.96 (3 H,
s), 2.24 (3H, s), 4.11 (1H, d
d), 4.46 (1H, d), 5.13 (2H, s),
5.99 (1H, s), 6.51-7.26 (7H,
m), 7.37 (2H, s).
【０１２７】参考例４ （１）（２Ｓ，３Ｒ）−３−（４−メチルフェニル）−
２，３−エポキシプロピオン酸メチルエステル１．９２
ｇ及びメタノール１０ｍｌの混合物に、氷冷下で４０％
メチルアミン水溶液２．３７ｇのメタノール１０ｍｌ溶
液を徐々に滴下した。氷冷下で１時間撹拌後、反応混合
物を濃縮し、エーテルを加えて析出晶をろ過、洗浄後５
０゜Ｃで乾燥することによって、（２Ｓ，３Ｒ）−３−
（４−メチルフェニル）−２，３−エポキシ−Ｎ−メチ
ルプロピオン酸アミド１．７５ｇを得る。Reference Example 4 (1) (2S, 3R) -3- (4-methylphenyl)-
2,3-Epoxy propionic acid methyl ester 1.92
g and 10 ml of methanol to a mixture of 40% under ice cooling.
A solution of 2.37 g of the methylamine aqueous solution in 10 ml of methanol was gradually added dropwise. After stirring under ice-cooling for 1 hour, the reaction mixture was concentrated, ether was added, and the precipitated crystals were filtered, washed and washed 5
By drying at 0 ° C, (2S, 3R) -3-
1.75 g of (4-methylphenyl) -2,3-epoxy-N-methylpropionic acid amide are obtained.
【０１２８】融点：１５２−１５３゜Ｃ ［α］D 25：＋１５３．７゜（ｃ＝１，メタノール）1 Ｈ−ＮＭＲ（ＣＤＣｌ3，δ）：２．３４（３Ｈ，
ｓ），２．８６（３Ｈ，ｄ），３．５２（１Ｈ，ｄ），
３．８３（２Ｈ，ｄ），６．２７（１Ｈ，ｓ），７．１
５（４Ｈ，ｓ）。Melting point: 152-153 ° C [α] D 25 : + 153.7 ° (c = 1, methanol) 1 H-NMR (CDCl 3 , δ): 2.34 (3H,
s), 2.86 (3H, d), 3.52 (1H, d),
3.83 (2H, d), 6.27 (1H, s), 7.1
5 (4H, s).
【０１２９】（２）（２Ｓ，３Ｒ）−３−（４−メチル
フェニル）−２，３−エポキシ−Ｎ−メチルプロピオン
酸アミド及び２−アミノ−５−メチルチオフェノールを
参考例１−（２）と同様に処理して、（２Ｒ，３Ｒ）−
３−（２−アミノ−５−メチルフェニオルチオ）−２−
ヒドロキシ−３−（４−メチルフェニル）−Ｎ−メチル
プロピオン酸アミドを得る。(2) (2S, 3R) -3- (4-methylphenyl) -2,3-epoxy-N-methylpropionic acid amide and 2-amino-5-methylthiophenol were used in Reference Example 1- (2). The same process as (2R, 3R)-
3- (2-amino-5-methylpheniothio) -2-
Hydroxy-3- (4-methylphenyl) -N-methylpropionic acid amide is obtained.
【０１３０】融点：１６８−１７０゜Ｃ ［α］D 25：−３７９゜（ｃ＝１，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：１．９７（３Ｈ，
ｓ），２．２５（３Ｈ，ｓ），２．６２（３Ｈ，ｄ），
４．１３（１Ｈ，ｄｄ），４．４７（１Ｈ，ｄ），５．
１２（２Ｈ，ｓ），６．１０（１Ｈ，ｄ），６．５１−
７．２７（７Ｈ，ｍ），７．９４（１Ｈ，ｄ）。Melting point: 168-170 ° C. [α] D 25 : -379 ° (c = 1, methanol) 1 H-NMR (DMSO-d 6 , δ): 1.97 (3H,
s), 2.25 (3H, s), 2.62 (3H, d),
4.13 (1H, dd), 4.47 (1H, d), 5.
12 (2H, s), 6.10 (1H, d), 6.51-
7.27 (7H, m), 7.94 (1H, d).
【０１３１】参考例５ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）プロピオ
ン酸メチルエステル及びメタノールの混合物に氷冷下ア
ンモニア水を加え、室温で反応後、析出物をろ別、水
洗、乾燥することにより、（２Ｓ，３Ｓ）−３−（２−
アミノフェニルチオ）−２−ヒドロキシ−３−（４−メ
トキシフェニル）プロピオン酸アミドを得る。Reference Example 5 (2S, 3S) -3- (2-aminophenylthio) -2
Ammonia water was added to a mixture of -hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester and methanol under ice-cooling, the mixture was reacted at room temperature, and then the precipitate was separated by filtration, washed with water, and dried (2S, 3S). ) -3- (2-
Aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid amide is obtained.
【０１３２】参考例６ 炭酸カリウムをジメチルスルホキシドに加え、７０℃で
撹拌した後に室温まで冷却し、（２Ｓ，３Ｓ）−３−
（２−アミノフェニルチオ）−２−ヒドロキシ−３−
（４−メトキシフェニル）プロピオン酸アミドを加えて
撹拌する。反応混合物に２−ジメチルアミノエチルクロ
リドを滴下し、室温で撹拌する。反応混合物を氷水中に
加えて酢酸エチルで抽出し、抽出液を乾燥後溶媒を留去
して、（２Ｓ，３Ｓ）−３−〔２−（２−ジメチルアミ
ノエチルアミノ）フェニルチオ〕−２−ヒドロキシ−３
−（４−メトキシフェニル）プロピオン酸アミドを得
る。Reference Example 6 Potassium carbonate was added to dimethyl sulfoxide, and the mixture was stirred at 70 ° C. and cooled to room temperature, then (2S, 3S) -3-
(2-Aminophenylthio) -2-hydroxy-3-
Add (4-methoxyphenyl) propionic acid amide and stir. 2-Dimethylaminoethyl chloride is added dropwise to the reaction mixture and stirred at room temperature. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was dried and the solvent was evaporated to give (2S, 3S) -3- [2- (2-dimethylaminoethylamino) phenylthio] -2- Hydroxy-3
-(4-Methoxyphenyl) propionic acid amide is obtained.
【０１３３】参考例７ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸アミド及びキシレンの混合物
を窒素気流下で還流を開始した後、すぐに２−（２−ジ
メチルアミノエチルアミノ）チオフェノール及び硫酸鉄
・７水和物のメタノール溶液を加える。同温で反応後室
温まで冷却し、溶液を減圧濃縮する。濃縮残渣をエタノ
ール及び水で加熱溶解後、０℃まで徐冷し、析出物をろ
取、冷５０％エタノールで洗浄後乾燥することにより、
（２Ｓ，３Ｓ）−３−〔２−（２−ジメチルアミノエチ
ルアミノ）フェニルチオ〕−２−ヒドロキシ−３−（４
−メトキシフェニル）プロピオン酸アミドを得る。Reference Example 7 (2R, 3S) -3- (4-methoxyphenyl) -2,
After refluxing the mixture of 3-epoxypropionic amide and xylene under a nitrogen stream, immediately, a methanol solution of 2- (2-dimethylaminoethylamino) thiophenol and iron sulfate heptahydrate is added. After reacting at the same temperature, it is cooled to room temperature, and the solution is concentrated under reduced pressure. The concentrated residue was heated and dissolved in ethanol and water, gradually cooled to 0 ° C., the precipitate was collected by filtration, washed with cold 50% ethanol, and then dried.
(2S, 3S) -3- [2- (2-Dimethylaminoethylamino) phenylthio] -2-hydroxy-3- (4
-Methoxyphenyl) propionic acid amide is obtained.
【０１３４】参考例８〜３０ 対応原料化合物を参考例１〜７、３１〜３３と同様に処
理することにより第５〜８表記載化合物を得る。Reference Examples 8 to 30 The corresponding starting compounds are treated in the same manner as in Reference Examples 1 to 7 and 31 to 33 to obtain the compounds shown in Tables 5 to 8.
【０１３５】[0135]
【表５】 [Table 5]
【０１３６】[0136]
【表６】 [Table 6]
【０１３７】[0137]
【表７】 [Table 7]
【０１３８】[0138]
【表８】 [Table 8]
【０１３９】参考例３１ （１）窒素気流下、水素化ナトリウム（６２．５％油中
分散）０．４６ｇ及びジメチルスルホキシド３ｍｌの混
合物にアニリン１．０２ｇのジメチルスルホキシド１ｍ
ｌ溶液を室温で加え、３０分間撹拌する。反応混合物に
（２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸メチルエステル２．０８ｇの
ジメチルスルホキシド４ｍｌ溶液を室温で１５分かけて
加える。さらに、同温で１時間撹拌し、水５０ｍｌを加
え、析出した黄色結晶をろ取する。この結晶を酢酸エチ
ル６０ｍｌで再結晶し、（２Ｒ，３Ｓ）−３−（４−メ
トキシフェニル）−２，３−エポキシ−Ｎ−フェニルプ
ロピオン酸アミド１．５０ｇを得る。Reference Example 31 (1) Under a nitrogen stream, a mixture of 0.46 g of sodium hydride (62.5% dispersion in oil) and 3 ml of dimethyl sulfoxide was added to 1.02 g of aniline and 1 m of dimethyl sulfoxide.
l solution is added at room temperature and stirred for 30 minutes. The reaction mixture contained (2R, 3S) -3- (4-methoxyphenyl) -2,
A solution of 2.08 g of 3-epoxypropionic acid methyl ester in 4 ml of dimethyl sulfoxide is added at room temperature over 15 minutes. Further, the mixture is stirred at the same temperature for 1 hour, 50 ml of water is added, and the precipitated yellow crystals are collected by filtration. The crystals are recrystallized from 60 ml of ethyl acetate to obtain 1.50 g of (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxy-N-phenylpropionic acid amide.
【０１４０】融点：１６２−１６３゜Ｃ ［α］D 25：−２２３．７゜（ｃ＝１，ジメチルホルム
アミド）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：３．７７（３Ｈ，
ｓ），３．７８（１Ｈ，ｄ），４．１３（１Ｈ，ｄ），
６．９５−７．６９（９Ｈ，ｍ），１０．２５（１Ｈ，
ｓ）。Melting point: 162-163 ° C. [α] D 25 : -223.7 ° (c = 1, dimethylformamide) 1 H-NMR (DMSO-d 6 , δ): 3.77 (3H,
s), 3.78 (1H, d), 4.13 (1H, d),
6.95-7.69 (9H, m), 10.25 (1H,
s).
【０１４１】（２）（２Ｒ，３Ｓ）−３−（４−メトキ
シフェニル）−２，３−エポキシ−Ｎ−フェニルプロピ
オン酸アミド５３９ｍｇ及びクロロベンゼン５ｍｌの混
合物を窒素気流下で加熱する。還流を開始した後すぐ
に、２−アミノチオフェノール２７５ｍｇ及び塩化第二
鉄・６水和物０．０５４ｍｇのメタノール０．１ｍｌ溶
液を加える。同温で５分間撹拌後、室温まで冷却し、析
出晶をろ取、クロロベンゼンで洗浄後、５０℃で乾燥
し、（２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）
−２−ヒドロキシ−３−（４−メトキシフェニル）−Ｎ
−フェニルプロピオン酸アミド５８２ｍｇを得る。(2) A mixture of (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxy-N-phenylpropionic amide (539 mg) and chlorobenzene (5 ml) is heated under a nitrogen stream. Immediately after starting the reflux, a solution of 275 mg of 2-aminothiophenol and 0.054 mg of ferric chloride hexahydrate in 0.1 ml of methanol is added. After stirring at the same temperature for 5 minutes, the mixture was cooled to room temperature, the precipitated crystals were collected by filtration, washed with chlorobenzene and dried at 50 ° C., (2S, 3S) -3- (2-aminophenylthio).
-2-Hydroxy-3- (4-methoxyphenyl) -N
582 mg of phenylpropionic acid amide are obtained.
【０１４２】融点：２１５−２１７゜Ｃ ［α］D 25：＋４３７゜（ｃ＝１，ジメチルホルムアミ
ド）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）：３．６９（３Ｈ，
ｓ），４．３５（１Ｈ，ｄ），４．５１（１Ｈ，ｄ），
５．３１（２Ｈ，ｓ），６．２４−７．６９（１３Ｈ，
ｍ），６．５２（１Ｈ，ｓ），９．８３（１Ｈ，ｓ）。Melting point: 215-217 ° C. [α] D 25 : + 437 ° (c = 1, dimethylformamide) 1 H-NMR (DMSO-d 6 , δ): 3.69 (3H,
s), 4.35 (1H, d), 4.51 (1H, d),
5.31 (2H, s), 6.24-7.69 (13H,
m), 6.52 (1H, s), 9.83 (1H, s).
【０１４３】参考例３２ （２Ｒ，３Ｓ）−３−（４−メトキシフェニル）−２，
３−エポキシプロピオン酸メチルエステル１０．４ｇ及
び１５．３ｗｔ％アンモニア／メタノール溶液５６ｇを
混合し、１５℃で２時間３０分反応する。全量が４４ｇ
になるまで溶媒を減圧留去し、冷水１１２ｇを加え、２
時間氷冷下で撹拌する。析出晶をろ別、水洗、５０℃で
乾燥し、（２Ｒ，３Ｓ）−３−（４−メトキシフェニ
ル）−２，３−エポキシプロピオン酸アミド８．９９ｇ
を得る。Reference Example 32 (2R, 3S) -3- (4-methoxyphenyl) -2,
10.4 g of 3-epoxypropionic acid methyl ester and 56 g of a 15.3 wt% ammonia / methanol solution are mixed and reacted at 15 ° C. for 2 hours and 30 minutes. The total amount is 44g
The solvent was distilled off under reduced pressure until it became, and 112 g of cold water was added.
Stir under ice cooling for an hour. The precipitated crystals were separated by filtration, washed with water, dried at 50 ° C., and (2R, 3S) -3- (4-methoxyphenyl) -2,3-epoxypropionic acid amide 8.99 g.
Get.
【０１４４】参考例３３ （２Ｓ，３Ｓ）−３−（２−アミノフェニルチオ）−２
−ヒドロキシ−３−（４−メトキシフェニル）プロピオ
ン酸メチルエステル及びアニリンを参考例５と同様に処
理して、（２Ｓ，３Ｓ）−３−（２−アミノフェニルチ
オ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−Ｎ−フェニルプロピオン酸アミドを得る。Reference Example 33 (2S, 3S) -3- (2-aminophenylthio) -2
-Hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester and aniline were treated as in Reference Example 5 to give (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3-. (4-methoxyphenyl)
-N-Phenylpropionic acid amide is obtained.
【０１４５】[0145]
【発明の効果】本発明の方法によれば、２位水酸基を保
護していないプロピオン酸アミド誘導体［Ｉ］を分子内
閉環して、塩酸ジルチアゼム等の医薬化合物の合成中間
体である、１，５−ベンゾチアゼピン誘導体［ＩＩ］を
高収率で得ることができる。とりわけ、アミド上の置換
基（Ｒ1及びＲ2）が共に水素原子である場合には、分子
内閉環反応の際に生成するアンモニアを気体として系内
から除去することができるため、酸もしくは塩基が存在
しなくても、反応混合物を単に加熱するだけで、容易に
分子内閉環反応を行うことができる。INDUSTRIAL APPLICABILITY According to the method of the present invention, 1, which is a synthetic intermediate of a pharmaceutical compound such as diltiazem hydrochloride by intramolecularly ring-closing the propionic acid amide derivative [I] in which the 2-hydroxyl group is not protected, The 5-benzothiazepine derivative [II] can be obtained in high yield. In particular, when the substituents (R 1 and R 2 ) on the amide are both hydrogen atoms, the ammonia generated during the intramolecular ring-closing reaction can be removed from the system as a gas, so that an acid or a base can be removed. Even in the absence of OH, the intramolecular ring closure reaction can be easily carried out by simply heating the reaction mixture.
【０１４６】また本発明によれば、２−アミノチオフェ
ノール誘導体［ＩＶ］と２，３−エポキシプロピオン酸
アミド誘導体［Ｖ］とを反応させた後、生成するプロピ
オン酸アミド誘導体［Ｉ］を単離せず、反応混合物をそ
のまま用いれば本発明の分子内閉環反応に付すこともで
き、その場合、２，３−エポキシプロピオン酸アミド誘
導体［Ｖ］から煩雑な操作を行うことなく、同一反応系
中で収率よく、目的物［ＩＩ］を得ることもできる。Further, according to the present invention, after the 2-aminothiophenol derivative [IV] is reacted with the 2,3-epoxypropionic amide derivative [V], the resulting propionic amide derivative [I] is converted into a simple compound. If the reaction mixture is used as it is without separation, it can be subjected to the intramolecular ring closure reaction of the present invention. In that case, in the same reaction system without performing a complicated operation from the 2,3-epoxypropionic amide derivative [V]. The desired product [II] can also be obtained with good yield.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｄ 249/08 ５１６ Ｃ０７Ｄ 249/08 ５１６ 265/22 265/22 279/08 279/08 281/10 281/10 Ｅ 295/12 295/12 Ａ 295/18 295/18 Ｚ Ａ 303/48 303/48 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location C07D 249/08 516 C07D 249/08 516 265/22 265/22 279/08 279/08 281/10 281/10 E 295/12 295/12 A 295/18 295/18 Z A 303/48 303/48
Claims (40)
環、Ｒ1及びＲ2は同一又は異なって水素原子、カルバモ
イル基、低級アルキル基、低級アルカノイル基、低級ア
ルキルアミノカルボニル基、アミノ酸残基又は置換基を
有してもよいアリール基であるか、あるいは互いに末端
で結合して隣接する窒素原子と共に置換されていてもよ
い複素環式基を形成し、Ｒ3は水素原子、ジ低級アルキ
ルアミノ低級アルキル基又は置換基を有してもよいピペ
ラジニル低級アルキル基を表わす。）で示されるプロピ
オン酸アミド誘導体又はその塩を分子内閉環反応に付
し、所望により生成物をその塩とすることを特徴とする
一般式［ＩＩ］ 【化２】 （式中、記号は前記と同一意味を有する。）で示される
１，５−ベンゾチアゼピン誘導体又はその塩の製法。1. A compound of the general formula [I] (In the formula, ring A and ring B are benzene rings which may have a substituent, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group. , An amino acid residue or an aryl group which may have a substituent, or a heterocyclic group which may be substituted with an adjacent nitrogen atom by being bonded to each other at the terminal, and R 3 is a hydrogen atom. , A di-lower alkylamino-lower alkyl group or a piperazinyl-lower alkyl group which may have a substituent)) is subjected to an intramolecular ring-closing reaction, and if desired, the product A salt of the general formula [II], which is characterized as a salt (In the formula, symbols have the same meanings as described above.) A method for producing a 1,5-benzothiazepine derivative or a salt thereof.
環、Ｒ1及びＲ2は同一又は異なって水素原子、カルバモ
イル基、低級アルキル基、低級アルカノイル基、低級ア
ルキルアミノカルボニル基、アミノ酸残基又は置換基を
有してもよいアリール基であるか、あるいは互いに末端
で結合して隣接する窒素原子と共に置換されていてもよ
い複素環式基を形成し、Ｒ3は水素原子、ジ低級アルキ
ルアミノ低級アルキル基又は置換基を有していてもよい
ピペラジニル低級アルキル基を表わす。）で示されるプ
ロピオン酸アミド誘導体又はその塩を分子内閉環反応に
付し、得られる一般式［ＩＩ］ 【化４】 （式中、記号は前記と同一意味を有する。）で示される
１，５−ベンゾチアゼピン誘導体の５位に、必要に応じ
てジ低級アルキルアミノ低級アルキル基又は置換基を有
していてもよいピペラジニル低級アルキル基を導入する
反応と、３位水酸基を低級アルカノイル化する反応を任
意の順序で行い、所望により、生成物を薬理的に許容し
うる塩とすることを特徴とする一般式［ＩＩＩ］ 【化５】 （式中、Ｒ31はジ低級アルキルアミノ低級アルキル基又
は置換基を有していてもよいピペラジニル低級アルキル
基を表わし、Ｒ5は低級アルカノイル基を表し、他の記
号は前記と同一意味を有する。）で示される３−低級ア
ルカノイルオキシ−５−〔ジ低級アルキルアミノ低級ア
ルキル又は置換もしくは非置換ピペラジニル低級アルキ
ル〕−１，５−ベンゾチアゼピン誘導体又はその薬理的
に許容し得る塩の製法。2. A compound represented by the general formula [I]: (In the formula, ring A and ring B are benzene rings which may have a substituent, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group. , An amino acid residue or an aryl group which may have a substituent, or a heterocyclic group which may be substituted with an adjacent nitrogen atom by being bonded to each other at the terminal, and R 3 is a hydrogen atom. , A di-lower-alkylamino-lower-alkyl group or a piperazinyl-lower-alkyl group which may have a substituent)) is subjected to an intramolecular ring-closing reaction to give a compound represented by the general formula: II] (Wherein the symbols have the same meanings as described above), the 5-position of the 1,5-benzothiazepine derivative may optionally have a di-lower alkylamino-lower alkyl group or a substituent at the 5-position. A general formula characterized in that a reaction for introducing a good piperazinyl lower alkyl group and a reaction for lower alkanoylating the 3-position hydroxyl group are carried out in any order to give a product as a pharmacologically acceptable salt, if desired. III] (In the formula, R 31 represents a dilower alkylamino lower alkyl group or a piperazinyl lower alkyl group which may have a substituent, R 5 represents a lower alkanoyl group, and other symbols have the same meanings as described above. ) 3-Lower alkanoyloxy-5- [dilower alkylamino lower alkyl or substituted or unsubstituted piperazinyl lower alkyl] -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof.
式［Ｉ］ 【化６】 （式中、環Ａ及び環Ｂは置換基を有してもよいベンゼン
環、Ｒ1及びＲ2は同一又は異なって水素原子、カルバモ
イル基、低級アルキル基、低級アルカノイル基、低級ア
ルキルアミノカルボニル基、アミノ酸残基又は置換基を
有してもよいアリール基であるか、あるいは互いに末端
で結合して隣接する窒素原子と共に置換されていてもよ
い複素環式基を形成し、Ｒ3は水素原子、ジ低級アルキ
ルアミノ低級アルキル基又は置換基を有していてもよい
ピペラジニル低級アルキル基を表わす。）で示されるプ
ロピオン酸アミド誘導体又はその塩が、一般式［ＩＶ］ 【化７】 （式中、記号は前記と同一意味を有する。）で示される
２−アミノチオフェノール誘導体と一般式［Ｖ］ 【化８】 （式中、記号は前記と同一意味を有する。）で示される
２，３−エポキシプロピオン酸アミド誘導体とを反応さ
せて得られる化合物である請求項１又は２記載の製法。3. The general formula [I] in the production method according to claim 1 or 2. (In the formula, ring A and ring B are benzene rings which may have a substituent, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group. , An amino acid residue or an aryl group which may have a substituent, or a heterocyclic group which may be substituted with an adjacent nitrogen atom by being bonded to each other at the terminal, and R 3 is a hydrogen atom. , A di-lower alkylamino-lower alkyl group or a piperazinyl-lower alkyl group which may have a substituent), and a propionic acid amide derivative represented by the formula [IV]: (Wherein the symbols have the same meanings as described above) and a 2-aminothiophenol derivative represented by the general formula [V] The process according to claim 1 or 2, which is a compound obtained by reacting with a 2,3-epoxypropionic amide derivative represented by the formula (wherein the symbols have the same meaning as described above).
式［Ｉ］で示される化合物が、一般式［Ｉ−ａ］ 【化９】 （式中、環Ａ及び環Ｂは置換基を有してもよいベンゼン
環、Ｒ11及びＲ21は同一又は異なって水素原子、低級ア
ルキル基、アミノ酸残基又は置換基を有してもよいアリ
ール基であるか、あるいは互いに末端で結合して隣接す
る窒素原子と共に置換されていてもよい複素環式基を形
成し、Ｒ3は水素原子、ジ低級アルキルアミノ低級アル
キル基又は置換基を有してもよいピペラジニル低級アル
キル基を表わす。）で示されるプロピオン酸アミド誘導
体であり、該化合物［Ｉ−ａ］が一般式［ＶＩＩ］ 【化１０】 （式中、Ｒは低級アルキル基を表し、他の記号は前記と
同一意味を有する。）で示されるプロピオン酸エステル
誘導体と一般式［ＶＩＩＩ−ａ］ 【化１１】 （式中、記号は前記と同一意味を有する。）で示される
化合物とを反応させて得られる化合物である請求項１又
は２記載の製法。4. The compound represented by the general formula [I] in the production method according to claim 1 or 2 is represented by the general formula [Ia]: (In the formula, ring A and ring B may have a benzene ring which may have a substituent, and R 11 and R 21 may have the same or different hydrogen atom, a lower alkyl group, an amino acid residue or a substituent. Aryl groups, or terminally bonded to each other to form a heterocyclic group which may be substituted with an adjacent nitrogen atom, and R 3 has a hydrogen atom, a di-lower alkylamino-lower alkyl group or a substituent. Which represents an optionally substituted piperazinyl lower alkyl group), wherein the compound [Ia] is a compound represented by the general formula [VII]: (In the formula, R represents a lower alkyl group, and other symbols have the same meanings as described above.) And a propionic acid ester derivative represented by the general formula [VIII-a]: The method according to claim 1 or 2, which is a compound obtained by reacting with a compound represented by the formula (wherein the symbols have the same meanings as described above).
又は４記載の製法。5. R 1, is a hydrogen atom, and is a hydrogen atom.
Or the production method described in 4.
原子又は一方が水素原子で他方が低級アルキル基である
請求項１、２、３又は４記載の製法。6. The process according to claim 1, 2, 3 or 4, wherein R 1 and R 2 or R 11 and R 21 are both hydrogen atoms or one is a hydrogen atom and the other is a lower alkyl group.
原子である請求項６記載の製法。7. The process according to claim 6, wherein R 1 and R 2 or R 11 and R 21 are both hydrogen atoms.
原子又は一方が水素原子で他方が低級アルキル基、Ｒ3
が水素原子である請求項１、２、３又は４記載の製法。8. R 1 and R 2 or R 11 and R 21 are both hydrogen atoms or one is a hydrogen atom and the other is a lower alkyl group, R 3
Is a hydrogen atom, The manufacturing method of Claim 1, 2, 3 or 4.
が水素原子である請求項８記載の製法。9. R 1 , R 2 and R 3 or R 11 , R 21 and R 3
Is a hydrogen atom, The manufacturing method of Claim 8.
子、低級アルキル基又はフェニル低級アルキル基、環Ｂ
が４−低級アルキルフェニル基又は４−低級アルコキシ
フェニル基である請求項１、２、３、４、５、６、７、
８又は９記載の製法。10. Ring A is of the formula: A benzene ring represented by, R 4 is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl lower alkyl group, and ring B
Is a 4-lower alkylphenyl group or a 4-lower alkoxyphenyl group, 1, 2, 3, 4, 5, 6, 7,
The production method according to 8 or 9.
ェニル低級アルキル基、環Ｂが４−低級アルコキシフェ
ニル基である請求項１０記載の製法。11. The method according to claim 10, wherein R 4 is a hydrogen atom, a halogen atom or a phenyl lower alkyl group, and Ring B is a 4-lower alkoxyphenyl group.
級アルキルフェニル基である請求項１０記載の製法。12. The method according to claim 10, wherein R 4 is a lower alkyl group and Ring B is a 4-lower alkylphenyl group.
チル基又はベンジル基、環Ｂが４−メチルフェニル基又
は４−メトキシフェニル基、Ｒ1及びＲ2又はＲ11及びＲ
21が共に水素原子又は一方が水素原子で他方がメチル
基、Ｒ3が水素原子、２−（ジメチルアミノ）エチル基
又は３−〔４−（２−メトキシフェニル）ピペラジニ
ル〕プロピル基である請求項１、２、３又は４記載の製
法。13. Ring A is of the formula: A benzene ring represented by, R 4 is a hydrogen atom, a chlorine atom, a methyl group or a benzyl group, a ring B is a 4-methylphenyl group or a 4-methoxyphenyl group, R 1 and R 2 or R 11 and R
21 is a hydrogen atom or one is a hydrogen atom and the other is a methyl group, and R 3 is a hydrogen atom, a 2- (dimethylamino) ethyl group or a 3- [4- (2-methoxyphenyl) piperazinyl] propyl group. The method according to 1, 2, 3 or 4.
４−メトキシフェニル基、Ｒ3が水素原子又は２−（ジ
メチルアミノ）エチル基である請求項１３記載の製法。14. The method according to claim 13, wherein R 4 is a hydrogen atom or a chlorine atom, Ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group.
ェニル基、Ｒ3が水素原子又は２−（ジメチルアミノ）
エチル基である請求項１３記載の製法。15. R 4 is a methyl group, Ring B is a 4-methylphenyl group, R 3 is a hydrogen atom or 2- (dimethylamino).
The method according to claim 13, wherein the method is an ethyl group.
フェニル基、Ｒ3が水素原子又は３−〔４−（２−メト
キシフェニル）ピペラジニル〕プロピル基である請求項
１３記載の製法。16. The process according to claim 13, wherein R 4 is a chlorine atom, ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 3- [4- (2-methoxyphenyl) piperazinyl] propyl group.
シフェニル基、Ｒ3が水素原子又は２−（ジメチルアミ
ノ）エチル基である請求項１３記載の製法。17. The method according to claim 13, wherein R 4 is a benzyl group, ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group.
４、１５、１６又は１７記載の製法。18. The method according to claim 13, wherein R 3 is a hydrogen atom.
The method according to 4, 15, 16 or 17.
項１８記載の製法。19. The method according to claim 18, wherein both R 1 and R 2 are hydrogen atoms.
溶媒、エーテル系溶媒又はこれらの混合溶媒を用いて分
子内閉環反応を行うことを特徴とする請求項１、２、
３、４、５、６、７、８、９、１０、１１、１２、１
３、１４、１５、１６、１７、１８又は１９記載の製
法。20. The intramolecular ring closure reaction is carried out using an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixed solvent thereof.
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1
The method according to 3, 14, 15, 16, 17, 18 or 19.
トルエン、キシレン又はメシチレンを用いて分子内閉環
反応を行うことを特徴とする請求項２０記載の製法。21. Chlorobenzene, dichlorobenzene,
21. The method according to claim 20, wherein the intramolecular ring closure reaction is carried out using toluene, xylene or mesitylene.
とを特徴とする請求項１、２、３、４、５、６、７、
８、９、１０、１１、１２、１３、１４、１５、１６、
１７、１８、１９、２０又は２１記載の製法。22. The intramolecular ring-closing reaction is carried out in the presence of an acid.
8, 9, 10, 11, 12, 13, 14, 15, 16,
The method according to 17, 18, 19, 20 or 21.
リールスルホン酸の存在下で分子内閉環反応を行うこと
を特徴とする請求項２２記載の製法。23. The method according to claim 22, wherein the intramolecular ring closure reaction is carried out in the presence of a mineral acid, a lower alkanesulfonic acid or an arylsulfonic acid.
ホン酸、ベンゼンスルホン酸、塩酸又は臭化水素酸の存
在下で分子内閉環反応を行うことを特徴とする請求項２
３記載の製法。24. The intramolecular ring closure reaction is carried out in the presence of methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid or hydrobromic acid.
3. The production method described in 3.
環、Ｒ1及びＲ2は同一又は異なって水素原子、カルバモ
イル基、低級アルキル基、低級アルカノイル基、低級ア
ルキルアミノカルボニル基、アミノ酸残基又は置換基を
有してもよいアリール基であるか、あるいは互いに末端
で結合して隣接する窒素原子と共に置換されていてもよ
い複素環式基を形成し、Ｒ3は水素原子、ジ低級アルキ
ルアミノ低級アルキル基又は置換基を有していてもよい
ピペラジニル低級アルキル基を表わす。）で示されるプ
ロピオン酸アミド誘導体又はその塩。25. A compound represented by the general formula [I]: (In the formula, ring A and ring B are benzene rings which may have a substituent, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group. , An amino acid residue or an aryl group which may have a substituent, or a heterocyclic group which may be substituted with an adjacent nitrogen atom by being bonded to each other at the terminal, and R 3 is a hydrogen atom. , A di-lower alkylamino-lower alkyl group or a piperazinyl-lower alkyl group which may have a substituent)), or a salt thereof.
子、低級アルキル基又はフェニル低級アルキル基、環Ｂ
が４−低級アルキルフェニル基又は４−低級アルコキシ
フェニル基である請求項２５記載の化合物。26. Ring A is of the formula: A benzene ring represented by, R 4 is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl lower alkyl group, and ring B
26. The compound according to claim 25, wherein is a 4-lower alkylphenyl group or a 4-lower alkoxyphenyl group.
ェニル低級アルキル基、環Ｂが４−低級アルコキシフェ
ニル基である請求項２６記載の化合物。27. The compound according to claim 26, wherein R 4 is a hydrogen atom, a halogen atom or a phenyl lower alkyl group, and Ring B is a 4-lower alkoxyphenyl group.
級アルキルフェニル基である請求項２６記載の化合物。28. The compound according to claim 26, wherein R 4 is a lower alkyl group and ring B is a 4-lower alkylphenyl group.
チル基又はベンジル基、環Ｂが４−メチルフェニル基又
は４−メトキシフェニル基、Ｒ1及びＲ2が共に水素原子
又は一方が水素原子で他方がメチル基、Ｒ3が水素原
子、２−（ジメチルアミノ）エチル基又は３−〔４−
（２−メトキシフェニル）ピペラジニル〕プロピル基で
ある請求項２５又は２６記載の化合物。29. Ring A has the formula: embedded image A benzene ring represented by, R 4 is a hydrogen atom, a chlorine atom, a methyl group or a benzyl group, Ring B is a 4-methylphenyl group or a 4-methoxyphenyl group, R 1 and R 2 are both hydrogen atoms or one is a hydrogen atom. And the other is a methyl group, R 3 is a hydrogen atom, 2- (dimethylamino) ethyl group or 3- [4-
The compound according to claim 25 or 26, which is a (2-methoxyphenyl) piperazinyl] propyl group.
４−メトキシフェニル基、Ｒ3が水素原子又は２−（ジ
メチルアミノ）エチル基である請求項２９記載の化合
物。30. The compound according to claim 29, wherein R 4 is a hydrogen atom or a chlorine atom, Ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group.
ェニル基、Ｒ3が水素原子又は２−（ジメチルアミノ）
エチル基である請求項２９記載の化合物。31. R 4 is a methyl group, Ring B is a 4-methylphenyl group, R 3 is a hydrogen atom or 2- (dimethylamino).
30. The compound according to claim 29, which is an ethyl group.
フェニル基、Ｒ3が水素原子又は３−〔４−（２−メト
キシフェニル）ピペラジニル〕プロピル基である請求項
２９記載の化合物。32. The compound according to claim 29, wherein R 4 is a chlorine atom, ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 3- [4- (2-methoxyphenyl) piperazinyl] propyl group.
シフェニル基、Ｒ3が水素原子又は２−（ジメチルアミ
ノ）エチル基である請求項２９記載の化合物。33. The compound according to claim 29, wherein R 4 is a benzyl group, ring B is a 4-methoxyphenyl group, and R 3 is a hydrogen atom or a 2- (dimethylamino) ethyl group.
０、３１、３２又は３３記載の化合物。34. The method according to claim 29, wherein R 3 is a hydrogen atom.
The compound according to 0, 31, 32, or 33.
及びＲ2は同一又は異なって水素原子、カルバモイル
基、低級アルキル基、低級アルカノイル基、低級アルキ
ルアミノカルボニル基、アミノ酸残基又は置換基を有し
てもよいアリール基であるか、あるいは互いに末端で結
合して隣接する窒素原子と共に置換されていてもよい複
素環式基を形成していることを表わす。）で示される
（２Ｒ，３Ｓ）−２，３−エポキシプロピオン酸アミド
誘導体又はその塩。35. The general formula [Va]: (In the formula, ring B is a benzene ring which may have a substituent, R 1
And R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group, an amino acid residue or an aryl group which may have a substituent, or they are mutually terminal. Represents that they are bonded together to form a heterocyclic group which may be substituted with an adjacent nitrogen atom. (2R, 3S) -2,3-epoxypropionamide derivative or a salt thereof.
基、Ｒ1及びＲ2が共に水素原子又は一方が水素原子で他
方が低級アルキル基である請求項３５記載の化合物。36. The compound according to claim 35, wherein Ring B is a 4-lower alkoxyphenyl group, R 1 and R 2 are both hydrogen atoms or one is a hydrogen atom and the other is a lower alkyl group.
及びＲ2が共に水素原子である請求項３６記載の化合
物。37. Ring B is a 4-methoxyphenyl group, R 1
37. The compound according to claim 36, wherein R 2 and R 2 are both hydrogen atoms.
ゼン環、Ｒ1及びＲ2は同一又は異なって水素原子、カル
バモイル基、低級アルキル基、低級アルカノイル基、低
級アルキルアミノカルボニル基、アミノ酸残基又は置換
基を有してもよいアリール基であるか、あるいは互いに
末端で結合して隣接する窒素原子と共に置換されていて
もよい複素環式基を形成していることを表わす。）で示
される（２Ｓ，３Ｒ）−２，３−エポキシプロピオン酸
アミド誘導体又はその塩。38. A compound represented by the general formula [Vb]: (In the formula, ring B 1 is a benzene ring substituted with a lower alkyl group, R 1 and R 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group, an amino acid. It represents a residue or an aryl group which may have a substituent, or represents a heterocyclic group which is bonded to each other at an end thereof and may be substituted with an adjacent nitrogen atom.). The (2S, 3R) -2,3-epoxypropionic acid amide derivative shown or its salt.
基、Ｒ1及びＲ2が共に水素原子又は一方が水素原子で他
方が低級アルキル基である請求項３８記載の化合物。39. The compound according to claim 38, wherein ring B 1 is a 4-lower alkylphenyl group, R 1 and R 2 are both hydrogen atoms or one is a hydrogen atom and the other is a lower alkyl group.
びＲ2が共に水素原子である請求項３９記載の化合物。40. The compound according to claim 39, wherein ring B 1 is a 4-methylphenyl group, and R 1 and R 2 are both hydrogen atoms.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03721097A JP3287258B2 (en) | 1996-02-23 | 1997-02-21 | Method for producing 1,5-benzothiazepine derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8-35302 | 1996-02-23 | ||
| JP3530296 | 1996-02-23 | ||
| JP03721097A JP3287258B2 (en) | 1996-02-23 | 1997-02-21 | Method for producing 1,5-benzothiazepine derivative |
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| Publication Number | Publication Date |
|---|---|
| JPH09286773A true JPH09286773A (en) | 1997-11-04 |
| JP3287258B2 JP3287258B2 (en) | 2002-06-04 |
Family
ID=26374267
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|---|---|---|---|
| JP03721097A Expired - Fee Related JP3287258B2 (en) | 1996-02-23 | 1997-02-21 | Method for producing 1,5-benzothiazepine derivative |
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| Country | Link |
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