JP7109029B2 - PGE1 core block derivative and method for producing same - Google Patents
PGE1 core block derivative and method for producing same Download PDFInfo
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- JP7109029B2 JP7109029B2 JP2019521946A JP2019521946A JP7109029B2 JP 7109029 B2 JP7109029 B2 JP 7109029B2 JP 2019521946 A JP2019521946 A JP 2019521946A JP 2019521946 A JP2019521946 A JP 2019521946A JP 7109029 B2 JP7109029 B2 JP 7109029B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 37
- 125000002626 PGE1 group Chemical group 0.000 title 1
- -1 triethylsilyl group Chemical group 0.000 claims description 84
- 150000001875 compounds Chemical class 0.000 claims description 83
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical group CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 238000005576 amination reaction Methods 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052718 tin Inorganic materials 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 229910052726 zirconium Inorganic materials 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000002904 solvent Substances 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 238000000034 method Methods 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 230000001629 suppression Effects 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000007259 addition reaction Methods 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- GICDEPNVJHAZDI-UHFFFAOYSA-N 2-(diethylaminomethyl)-4-triethylsilyloxycyclopent-2-en-1-one Chemical compound CCN(CC)CC1=CC(CC1=O)O[Si](CC)(CC)CC GICDEPNVJHAZDI-UHFFFAOYSA-N 0.000 description 4
- SAXYYSFDXQHLOD-UHFFFAOYSA-N 4-hydroxy-2-(hydroxymethyl)cyclopent-2-en-1-one Chemical compound OCC1=CC(O)CC1=O SAXYYSFDXQHLOD-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- IYZLVHNXWSPYJG-QNXDVYBJSA-N (3R,4R)-2-methylidene-4-triethylsilyloxy-3-[(E,3S)-3-triethylsilyloxyoct-1-enyl]cyclopentan-1-one Chemical compound CCCCC[C@@H](/C=C/[C@H]1[C@@H](CC(=O)C1=C)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC IYZLVHNXWSPYJG-QNXDVYBJSA-N 0.000 description 3
- SAXYYSFDXQHLOD-YFKPBYRVSA-N (4r)-4-hydroxy-2-(hydroxymethyl)cyclopent-2-en-1-one Chemical compound OCC1=C[C@H](O)CC1=O SAXYYSFDXQHLOD-YFKPBYRVSA-N 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001492 aromatic hydrocarbon derivatives Chemical class 0.000 description 3
- 229940009098 aspartate Drugs 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-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
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
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- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- ICMWSAALRSINTC-UHFFFAOYSA-N penta-1,4-dien-3-ol Chemical compound C=CC(O)C=C ICMWSAALRSINTC-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- ZAEQTGTVGUJEFV-UHFFFAOYSA-N phenylmethanesulfonate;pyridin-1-ium Chemical compound C1=CC=[NH+]C=C1.[O-]S(=O)(=O)CC1=CC=CC=C1 ZAEQTGTVGUJEFV-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate 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
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- MMKOSVMWXHDGEI-CYBMUJFWSA-N tert-butyl-dimethyl-[(3s)-oct-1-yn-3-yl]oxysilane Chemical compound CCCCC[C@@H](C#C)O[Si](C)(C)C(C)(C)C MMKOSVMWXHDGEI-CYBMUJFWSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FXAKXZZXICYUQV-FNDVETGQSA-N triethyl-[(E,3S)-1-iodooct-1-en-3-yl]oxysilane Chemical compound CCCCC[C@@H](\C=C\I)O[Si](CC)(CC)CC FXAKXZZXICYUQV-FNDVETGQSA-N 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
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- General Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
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- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、新規なPGE1コアブロック誘導体およびその製造方法に関する。The present invention relates to novel PGE 1 core block derivatives and methods for their preparation.
プロスタグランジンE1（以下PGE1と略称する）は、血小板凝集抑制作用、血圧低下作用等の特徴ある作用を有し、末梢循環障害を改善するための医薬品として既に実用化されており、このため多数のPGE1類縁体も検討されている。
PGE1およびその誘導体を製造するために、これまでにコーリーラクトン法（特許文献１）、共役付加反応法（非特許文献１）、３成分連結法（非特許文献２）および２成分連結法（非特許文献３および特許文献２）が開発されている。これらの方法では、中間体やコアブロック製造では工程数が多く、効率が悪いという問題点がある。To produce PGE 1 and its derivatives, the corey lactone method (Patent Document 1), the conjugate addition reaction method (Non-Patent Document 1), the three-component ligation method (Non-Patent Document 2) and the two-component ligation method ( Non-Patent Document 3 and Patent Document 2) have been developed. These methods have the problem that the number of steps in the production of intermediates and core blocks is large and the efficiency is low.
例えば、２成分連結法においては、プロスタグランジンの重要な合成中間体としてexo-エノン化合物（ｃ）が用いられている(非特許文献４)。この方法においては、ジビニルカルビノールのエポキシ化反応によって得られるエポキシアルコール(a)を出発原料とし、数工程を経てβ-ヒドロキシケトン（ｂ）を導く。化合物（ｂ）をメシル化すると、脱離反応によりexo-エノン化合物（ｃ）を与える。この方法では、β-ヒドロキシケトン（ｂ）を介するため、この中間体（ｂ）における３つの水酸基を選択的に保護しなければならない。このように、従来の２成分連結法はコアブロック製造過程が煩雑である。また、中間体（ｃ）におけるTBS(tert－ブチルジメチルシリル)保護基は高価であり、さらに環境上の問題が懸念される。なお、exo-エノン中間体（ｃ）は不安定であるため、中間体（ｃ）を用いた２成分連結法は工業的に非効率的である。
上述のように、PGE1誘導体の製造方法は、中間体（ｂ）の３つの水酸基に対して、それぞれ選択的な保護および脱保護が必要となる。そのため生成物の単離が困難であり、また反応工程数も多く、その結果、目的物の製造コストが高くなるという問題が生じる。また、不安定な中間体（ｃ）に依存する反応行程は、工業的に不利であるが、簡便かつ安価で工業的に使用することができる中間体の開発はいまだに十分ではない。As described above, the method for preparing PGE 1 derivatives requires selective protection and deprotection for the three hydroxyl groups of intermediate (b), respectively. Therefore, it is difficult to isolate the product, and the number of reaction steps is large, resulting in the problem that the production cost of the desired product increases. Moreover, the reaction process depending on the unstable intermediate (c) is industrially disadvantageous, but the development of an intermediate that is simple, inexpensive, and industrially usable is still insufficient.
また、PGE1の工業的生産方法としては、下記の合成方法（非特許文献４、非特許文献５）が報告されているが、コアブロックである中間体（ｄ）を合成するために9工程を経らなければならなく、原料価格が高くなるといった問題点がある。また、TBS保護基は高価であるのみならず、TBS保護基を除去するためにフッ化水素を使用しているために製造コストが高くなるという問題および毒性という問題が生じる。
本発明の目的は、上記した従来技術における欠点または問題を解決することであり、PGE1およびその誘導体等の製造における工業的に好ましい新規な合成中間体を提供することにある。An object of the present invention is to solve the drawbacks or problems in the prior art described above, and to provide an industrially preferable novel synthetic intermediate in the production of PGE 1 and its derivatives.
本発明の他の目的は、工業化に適した、経済的に好ましい、PGE1およびその誘導体等の製造における新規な合成中間体の製造方法を提供することにある。Another object of the present invention is to provide a method for producing novel synthetic intermediates in the production of PGE 1 and its derivatives, etc., which is suitable for industrialization and economically preferable.
本発明の他の目的は、工業化に適した、経済的に好ましい、PGE1およびその誘導体等の新規な製造方法を提供することにある。Another object of the present invention is to provide a novel method for producing PGE 1 and its derivatives, etc., which is suitable for industrialization and economically preferable.
上記のような状況に鑑み、本発明者らは、PGE1およびその誘導体の合成中間体として利用可能なシクロペンテノン誘導体およびその製造方法について鋭意研究した。その結果、本発明者らは、単糖からの水熱反応により簡便に４－ヒドロキシ－２－ヒドロキシメチル－２－シクロペンテノンを製造することに成功した。本発明者らは、この４－ヒドロキシ－２－ヒドロキシメチル－２－シクロペンテノン(式(i')で表される化合物またはその立体異性体)を出発原料とし、ワンポットで一挙に式（II）で表される化合物を製造できることを見出した。本発明者らはこの知見に基づき本発明の完成に至った。
すなわち、本発明は、下記〔１〕から〔２２〕項に記載の発明を提供することにより上記課題を解決したものである。
〔１〕
式(II)
で表される化合物またはその立体異性体またはそれらの塩、
〔２〕
式（i’）
で表される化合物またはその立体異性体を用いることを特徴とする、式（II）
(式中、TESは、トリエチルシリル基を示し、Etは、エチル基を示す。)
で表される化合物またはその立体異性体またはそれらの塩の製造方法、
〔３〕
式（i’）で表される化合物またはその立体異性体をアミノ化反応に付すことを特徴とする、〔２〕に記載の製造方法、
〔４〕
式（i’）
で表される化合物またはその立体異性体を用いることを特徴とする、式（VII）
(式中、Ｒは、水素原子またはアルキルを示す。)で表される化合物またはその立体異性体の製造方法、
〔５〕
式（II）
で表される化合物またはその立体異性体またはそれらの塩を用いることを特徴とする、
式（VII）
(式中、Ｒは、水素原子またはアルキルを示す。)で表される化合物の製造方法、
〔６〕
式（II）で表される化合物またはその立体異性体またはそれらの塩を１，４付加反応に付すことを特徴とする、〔５〕に記載の製造方法、
〔７〕
式（ｉ’）
で表される化合物またはその立体異性体またはそれらの塩に変換することを含むことを特徴とする、式（VII）
〔８〕
Ｒは、水素原子またはメチルである、〔４〕～〔７〕のいずれか１項に記載の製造方法、
〔９〕
式(IＶ)
〔１０〕
式(ＶＩ)
〔１１〕
式（I）：
〔１２〕
Ｒ１、Ｒ２およびＲ３は、それぞれ同一または異なって置換基を有していてもよいＣ１～Ｃ６アルキル基である、〔１１〕に記載の化合物またはその立体異性体、
〔１３〕
Ｒ１、Ｒ２およびＲ３は、それぞれ同一または異なってメチル基、エチル基またはプロピル基である、〔１１〕に記載の化合物またはその立体異性体、
〔１４〕
Ｒ１、Ｒ２およびＲ３は、エチル基である、〔１１〕に記載の化合物またはその立体異性体、
〔１５〕
式（i）で表される化合物またはその立体異性体を用いることを特徴とする、式（I）で表される化合物またはその立体異性体（ここで、Ｒ１、Ｒ２およびＲ３は、それぞれ同一または異なって置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基、または置換基を有していてもよいアリールアルキル基である。）の製造方法、
式（i）で表される化合物またはその立体異性体をシリルハライドと反応させた後、ジエチルアミンと反応させ、式（I）で表される化合物またはその立体異性体を得ることを特徴とする、〔１５〕に記載の製造方法、
〔１７〕
シリルハライドが、トリエチルシリルクロライドである、〔１６〕に記載の製造方法、
〔１８〕
式（I）で表される化合物またはその立体異性体（ここで、Ｒ１、Ｒ２およびＲ３は、〔１〕で定義した通りである。）を用いることを特徴とする、PGE1またはその誘導体の製造方法、
〔１９〕
式（I）で表される化合物またはその立体異性体を１，４付加反応に付すことを特徴とする、〔１８〕に記載の製造方法、
〔２０〕
式（i）：
〔２１〕
式(i')で表される化合物またはその立体異性体を酵素と反応させることを特徴とする、式（i）で表される化合物またはその立体異性体の製造方法、
〔２２〕
式（i）で表される化合物またはその立体異性体を用いることを特徴とする、PGE1またはその誘導体の製造方法。That is, the present invention solves the above problems by providing the inventions described in items [1] to [22] below.
[1]
Formula (II)
A compound represented by or a stereoisomer thereof or a salt thereof,
[2]
expression (i')
Characterized by using a compound represented by or a stereoisomer thereof, formula (II)
(In the formula, TES represents a triethylsilyl group and Et represents an ethyl group.)
A method for producing a compound represented by or a stereoisomer thereof or a salt thereof,
[3]
The production method according to [2], characterized in that the compound represented by formula (i') or a stereoisomer thereof is subjected to an amination reaction;
[4]
expression (i')
Characterized by using a compound represented by or a stereoisomer thereof, formula (VII)
(Wherein, R represents a hydrogen atom or alkyl.) A method for producing a compound represented by or a stereoisomer thereof,
[5]
Formula (II)
Characterized by using a compound represented by or a stereoisomer thereof or a salt thereof,
Formula (VII)
(Wherein, R represents a hydrogen atom or alkyl.) A method for producing a compound represented by
[6]
The production method according to [5], characterized in that the compound represented by formula (II) or its stereoisomer or a salt thereof is subjected to a 1,4-addition reaction;
[7]
Formula (i')
or a stereoisomer thereof or a salt thereof of formula (VII)
[8]
The production method according to any one of [4] to [7], wherein R is a hydrogen atom or methyl;
[9]
Formula (IV)
[10]
Formula (VI)
[11]
Formula (I):
[12]
The compound according to [11] or a stereoisomer thereof, wherein R 1 , R 2 and R 3 are C 1 -C 6 alkyl groups which may have the same or different substituents, respectively;
[13]
The compound of [11] or a stereoisomer thereof, wherein R 1 , R 2 and R 3 are the same or different and are each a methyl group, an ethyl group or a propyl group;
[14]
The compound of [11], wherein R 1 , R 2 and R 3 are ethyl groups, or a stereoisomer thereof;
[15]
A compound represented by formula (I) or a stereoisomer thereof (wherein R 1 , R 2 and R 3 are each of which is an alkyl group optionally having the same or different substituents, an aryl group optionally having a substituent, or an arylalkyl group optionally having a substituent.).
A compound represented by formula (i) or a stereoisomer thereof is reacted with a silyl halide and then reacted with diethylamine to obtain a compound represented by formula (I) or a stereoisomer thereof, [15] The production method according to
[17]
The production method of [16], wherein the silyl halide is triethylsilyl chloride,
[18]
PGE 1 or PGE 1 or a method for producing a derivative thereof;
[19]
The production method of [18], characterized in that the compound represented by formula (I) or a stereoisomer thereof is subjected to a 1,4-addition reaction;
[20]
Formula (i):
[21]
A method for producing a compound represented by formula (i) or a stereoisomer thereof, which comprises reacting the compound represented by formula (i') or a stereoisomer thereof with an enzyme;
A method for producing PGE 1 or a derivative thereof, which comprises using a compound represented by formula (i) or a stereoisomer thereof.
本発明方法により、シクロペンテノン化合物（式(i)および式（I）で表される化合物またはその立体異性体）の新規な工業的製造方法が提供される。 The method of the present invention provides a novel industrial production method for cyclopentenone compounds (compounds represented by formula (i) and formula (I) or stereoisomers thereof).
本発明の方法によれば、４－ヒドロキシ－２－ヒドロキシメチル－２－シクロペンテノンを、その１つの水酸基にアセチル保護基を導入したアセタートに変換し、得られたアセタートに対し、１工程で緩和な条件下で水酸基を保護すると同時にアミノ化を行い、目的物とする化合物（I）を容易に得ることに成功した。 According to the method of the present invention, 4-hydroxy-2-hydroxymethyl-2-cyclopentenone is converted to an acetate having an acetyl protecting group introduced to one of its hydroxyl groups, and the resulting acetate is treated in one step with We succeeded in easily obtaining the target compound (I) by simultaneously protecting the hydroxyl group and performing amination under mild conditions.
さらに本発明の方法では、化合物（I）を用いて、目的とするPGE1またはその誘導体を高収率かつ効率的に、工業的規模で簡便に製造可能である。Furthermore, according to the method of the present invention, using compound (I), the desired PGE 1 or a derivative thereof can be easily produced on an industrial scale in high yield and efficiency.
さらには、本発明の方法により、医薬品およびその中間体として有用な、新規なシクロペンテノン化合物（式(i)および式（I）で表される化合物またはその立体異性体）を提供することができる。本発明の方法によって得られた新規な化合物（式(i)および式（I）で表される化合物またはその立体異性体）は、PGE1等の医薬品等の中間体および試薬として、その有用性が期待される。Furthermore, the method of the present invention can provide novel cyclopentenone compounds (compounds represented by formula (i) and formula (I) or stereoisomers thereof) useful as pharmaceuticals and intermediates thereof. can. Novel compounds (compounds represented by formula (i) and formula (I) or stereoisomers thereof) obtained by the method of the present invention are useful as intermediates and reagents for pharmaceuticals such as PGE 1 . There is expected.
以下、本発明について詳細に説明する。
本明細書において用いられる用語について以下に説明する。
特に言及しない限り、本明細書および特許請求の範囲で用いた用語は以下に述べる意味を有する。The present invention will be described in detail below.
Terms used in this specification are explained below.
Unless otherwise stated, the terms used in the specification and claims have the meanings set forth below.
「アルキル基」とは、特に限定しない限り、飽和脂肪族炭化水素基、例えば、炭素数が１～２０の直鎖または分岐鎖状のアルキル基を示し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ－ブチル基、イソブチル基、ペンチル基、ヘキシル基等のＣ１～Ｃ６アルキル基、ヘプチル基、１－メチルヘキシル基、５－メチルヘキシル基、１，１－ジメチルペンチル基、２，２－ジメチルペンチル基、４，４－ジメチルペンチル基、１－エチルペンチル基、２－エチルペンチル基、１，１，３－トリメチルブチル基、１，２，２－トリメチルブチル基、１，３，３－トリメチルブチル基、２，２，３－トリメチルブチル基、２，３，３－トリメチルブチル基、１－プロピルブチル基、１，１，２，２－テトラメチルプロピル基、オクチル基、１－メチルヘプチル基、３－メチルヘプチル基、６－メチルヘプチル基、２－エチルヘキシル基、５，５－ジメチルヘキシル基、２，４，４－トリメチルペンチル基、１－エチル－１－メチルペンチル基、ノニル基、１－メチルオクチル基、２－メチルオクチル基、３－メチルオクチル基、７－メチルオクチル基、１－エチルヘプチル基、１，１－ジメチルヘプチル基、６，６－ジメチルヘプチル基、デシル基、１－メチルノニル基、２－メチルノニル基、６－メチルノニル基、１－エチルオクチル基、１－プロピルヘプチル基、ｎ－ノニル基、ｎ－デシル基等の基を挙げることができるが、Ｃ１～Ｃ６アルキル基が好ましい。Ｃ１～Ｃ６アルキル基の好ましい例は、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ－ブチル基、イソブチル基、ペンチル基またはヘキシル基である。The term "alkyl group" means, unless otherwise specified, a saturated aliphatic hydrocarbon group, for example, a linear or branched alkyl group having 1 to 20 carbon atoms, such as methyl group, ethyl group, propyl group , isopropyl group, butyl group, sec-butyl group, isobutyl group, pentyl group, C 1 to C 6 alkyl group such as hexyl group, heptyl group, 1-methylhexyl group, 5-methylhexyl group, 1,1-dimethyl pentyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 1-ethylpentyl group, 2-ethylpentyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group , 1,3,3-trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, Octyl group, 1-methylheptyl group, 3-methylheptyl group, 6-methylheptyl group, 2-ethylhexyl group, 5,5-dimethylhexyl group, 2,4,4-trimethylpentyl group, 1-ethyl-1- methylpentyl group, nonyl group, 1-methyloctyl group, 2-methyloctyl group, 3-methyloctyl group, 7-methyloctyl group, 1-ethylheptyl group, 1,1-dimethylheptyl group, 6,6-dimethyl Groups such as heptyl group, decyl group, 1-methylnonyl group, 2-methylnonyl group, 6-methylnonyl group, 1-ethyloctyl group, 1-propylheptyl group, n-nonyl group and n-decyl group can be mentioned. but C 1 -C 6 alkyl groups are preferred. Preferred examples of C 1 -C 6 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl or hexyl groups.
「アリール基」とは、単環式または二環式芳香族性炭化水素基を示し、好ましくはフェニル基、ナフチル基等のＣ６～１０アリール基であり、より好ましくはフェニル基である。The “aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group, preferably a C 6-10 aryl group such as a phenyl group or a naphthyl group, more preferably a phenyl group.
「アリールアルキル基」とは、アリール基により置換されたアルキル基を意味する。好ましくはフェニルＣ１～Ｃ６アルキル基である。フェニルＣ１～Ｃ６アルキル基の例は、ベンジル基、１－フェニルエチル基、２－フェニルエチル基、３－フェニルプロピル基、４－フェニルブチル基、５－フェニルペンチル基、６－フェニルヘキシル基等を含むが、これらに限定されるものではない。An "arylalkyl group" means an alkyl group substituted with an aryl group. A phenyl C 1 -C 6 alkyl group is preferred. Examples of phenyl C 1 -C 6 alkyl groups are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl. etc., but not limited to these.
「置換基を有していてもよい」とは、置換基を有していても、または無置換であってもよいことを意味する。置換基を有している場合、置換基は前記の置換可能な位置に、１～５個、好ましくは１～３個を有していてもよく、置換基数が２個以上の場合は、各置換基はそれぞれ同一または異なっていてもよい。置換基としては、アルキル基、アルコキシ基、ハロゲン原子、シアノ基、ニトロ基等が挙げられるが、好ましい置換基の例は、Ｃ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基またはハロゲン原子である。"Optionally having a substituent" means that it may have a substituent or may be unsubstituted. When it has a substituent, the substituent may have 1 to 5, preferably 1 to 3 at the substitutable position, and when the number of substituents is 2 or more, each Each substituent may be the same or different. Examples of substituents include alkyl groups, alkoxy groups, halogen atoms, cyano groups, nitro groups, etc. Preferred examples of substituents are C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups or halogen atoms. is.
式（I）で表される化合物におけるＲ１、Ｒ２およびＲ３の具体例としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ－ブチル基、イソブチル基、ペンチル基またはヘキシル基が挙げられ、エチル基は好ましいが、これらに限定されるものではない。Specific examples of R 1 , R 2 and R 3 in the compound represented by formula (I) include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, pentyl group or Examples include, but are not limited to, hexyl groups, preferably ethyl groups.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等を示し、好ましくはフッ素原子および塩素原子である。 "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, preferably a fluorine atom and a chlorine atom.
「塩」とは、無機酸塩または有機酸塩から成り；該無機酸塩が、好ましくは塩酸塩、硫酸塩、臭化水素酸塩、フッ化水素酸塩、ヨウ化水素酸塩およびリン酸塩から成る群から選択され、より好ましくは塩酸塩、硫酸塩およびリン酸塩から成る群から選択され；該有機酸塩が、好ましくは２，５－ジヒドロキシベンゼンギ酸塩、１－ヒドロキシ－２－ナフタレンギ酸塩、酢酸塩、ジクロロ酢酸塩、トリクロロ酢酸塩、アセトヒドロキサム酸塩、アジピン酸塩、ベンゼンスルホン酸塩、４－クロロベンゼンスルホン酸塩、ベンゼンギ酸塩、４－アセトアミドベンゼンギ酸塩、４－アミノベンゼンギ酸塩、カプリン酸塩、カプロン酸塩、カプリル酸塩、桂皮酸塩、クエン酸塩、シクロヘキシルスルファミン酸塩、カンファースルホン酸塩、アスパラギン酸塩、樟脳酸塩、グルコン酸塩、グルクロン酸塩、グルタミン酸塩、エリソルビン酸塩、乳酸塩、アスパラギン酸塩、リンゴ酸塩、マンデル酸塩、ピログルタミン酸塩、酒石酸塩、ラウリル硫酸塩、ジベンゾイル酒石酸塩、エチル－１，２－ジスルホン酸塩、エシレート、ギ酸塩、フマル酸塩、ガラクトン酸塩、ゲンチジン酸塩、グルタル酸塩、２－オキソグルタル酸塩、グリコール酸塩、馬尿酸塩、イセチオン酸塩、ラクトビオン酸塩、アスコルビン酸塩、アスパラギン酸塩、ラウリン酸塩、樟脳酸塩、マレイン酸塩、マロン酸塩、メシル酸塩、１，５－ナフタレンジスルホン酸塩、ナフタレン－２－スルホン酸塩、ニコチン酸塩、オレイン酸塩、オロチン酸塩、シュウ酸塩、パルミチン酸塩、エンボン酸塩、プロピオン酸塩、サリチル酸塩、４－アミノサリチル酸塩、セバシン酸塩、ステアリン酸塩、ブタンジオアート、チオシアン酸塩、ウンデシレン酸塩、トリフルオロ酢酸塩、コハク酸塩およびp-トルエンスルホン酸塩から成る群から選択され、より好ましくはメシル酸塩、p-トルエンスルホン酸塩および１，５－ナフタレンジスルホン酸塩から成る群から選択される。 "Salt" consists of inorganic or organic acid salts; the inorganic acid salts are preferably hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide and phosphate. salts, more preferably selected from the group consisting of hydrochlorides, sulfates and phosphates; said organic acid salts are preferably 2,5-dihydroxybenzeneformate, 1-hydroxy-2- naphthaleneformate, acetate, dichloroacetate, trichloroacetate, acetohydroxamate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzeneformate, 4-acetamidobenzeneformate, 4-amino Benzeneformate, caprate, caproate, caprylate, cinnamate, citrate, cyclohexylsulfamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, Glutamate, Erythorbate, Lactate, Aspartate, Malate, Mandelate, Pyroglutamate, Tartrate, Lauryl Sulfate, Dibenzoyl Tartrate, Ethyl-1,2-Disulfonate, Esylate, Formic Acid salt, fumarate, galactonate, gentisate, glutarate, 2-oxoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, lauric acid salt, camphorate, maleate, malonate, mesylate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, nicotinate, oleate, orotate, oxalate , palmitate, embonate, propionate, salicylate, 4-aminosalicylate, sebacate, stearate, butanedioate, thiocyanate, undecylenate, trifluoroacetate, succinate and p-toluenesulfonate, more preferably mesylate, p-toluenesulfonate and 1,5-naphthalenedisulfonate.
「PGE1誘導体」とは、例えば、式（VII）
本明細書に記載の化合物は不斉中心を含んでいてもよく、したがって鏡像異性体として存在してもよい。本明細書に記載の化合物が２つ以上の不斉中心を有する場合、それらはさらにジアステレオマーとして存在してもよい。鏡像異性体およびジアステレオマーはより広いクラスの立体異性体に入る。実質的に純粋な分割された鏡像異性体、そのラセミ混合物、ならびにジアステレオマーの混合物等のすべての可能な立体異性体は含まれることが意図される。本明細書において開示する化合物のすべての立体異性体は、含まれることが意図される。特に記載がないかぎり、1つの異性体への言及は任意の可能な異性体に適用される。異性体組成が明記されていない場合はいつも、すべての可能な異性体が含まれる。 The compounds described herein may contain asymmetric centers and therefore exist as enantiomers. Where the compounds described herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers, are intended to be included. All stereoisomers of the compounds disclosed herein are intended to be included. Unless otherwise stated, references to one isomer apply to any possible isomer. Whenever the isomeric composition is not specified, all possible isomers are included.
［本発明の化合物（i）の製造方法］
例えば、以下に記す方法またはこれに準じた方法等（例えば、J. J. Gridley et al., Snylett., 1397. 1997; S.Akai et al., J. Org. Chem., 67, 441, 2002; E. W. Holla, J. Carbohydr. Chem. 9, 113, 1990等）によって酵素と酢酸ビニルにより位置選択的に1級アリルアルコール(i')をアセチル化し、（i）を製造することができる。
For example, the method described below or a method based thereon (e.g., JJ Gridley et al., Snylett., 1397. 1997; S.Akai et al., J. Org. Chem., 67, 441, 2002; EW Holla, J. Carbohydr. Chem. 9, 113, 1990, etc.) can regioselectively acetylate primary allyl alcohol (i') with an enzyme and vinyl acetate to produce (i).
［本発明の化合物（I）の製造方法］
化合物（i）の水酸基の保護(化合物(ia)の合成)
化合物（i）の水酸基の保護は、例えば、以下に示す方法またはこれに準じた方法等（例えば、Ｃｏｒｅｙ， Ｅ．Ｊ． ｅｔ ａｌ．， Ｊ． Ａｍ． Ｃｈｅｍ． Ｓｏｃ．， ９４， ６１９０， １９７２； Ｍｏｒｉｔａ， Ｔ． ｅｔ ａｌ．， Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．， ２１， ８３５， １９８０； Ｙ． Ｋｉｔａ， ｅｔ ａｌ．， Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．， ４３１１， １９７９に記載されたシリルエーテル化等。総説として、Ｌａｌｏｎｄｅ， Ｍ．，Ｃｈａｎ， Ｔ．Ｈ．， Ｓｙｎｔｈｅｓｉｓ， ８１７－８４５， １９８５等も参照のこと）によって化合物(i)をシリルハライド化合物と反応させて行うことができる。
Protection of hydroxyl group of compound (i) (synthesis of compound (ia))
The hydroxyl group of compound (i) can be protected by, for example, the method shown below or a method analogous thereto (e.g., Corey, EJ et al., J. Am. Chem. Soc., 94, 6190, 1972 Morita, T. et al., Tetrahedron Lett., 21, 835, 1980; Y. Kita, et al., Tetrahedron Lett., 4311, 1979. As a review, see Lalonde, M.; , Chan, TH, Synthesis, 817-845, 1985) by reacting compound (i) with a silyl halide compound.
シリルハライド化合物
シリルハライド化合物の種類は特に限定されず、当業界で用いられるものはいずれも本発明の方法に使用できる。例えば、トリアルキルシリルハライド化合物、モノアルキルジアリールシリルハライド化合物、トリアリールシリルハライド化合物等を用いることができる。シリルハライド化合物がアルキル基を有する場合には、アルキル基として、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、イソブチル基、またはtert－ブチル基等を用いることができる。これらのうち、メチル基またはエチル基が好ましい。シリルハライド化合物がアリール基を有する場合にはフェニル基等を用いることができる。シリルハライド化合物を構成するハロゲン原子としては、塩素原子、臭素原子、またはヨウ素原子等を用いることができ、塩素原子を用いることが好ましい。シリルハライド化合物として、より具体的には、トリメチルシリルクロライド（トリメチルクロロシランと呼ばれる場合もある。以下の化合物についても同様である。）、トリエチルシリルクロライド、tert－ブチルジメチルシリルクロライド、tert－ブチルジフェニルシリルクロライド、トリフェニルシリルクロライド等を挙げることができる。Silyl Halide Compound The type of silyl halide compound is not particularly limited, and any one used in the art can be used in the method of the present invention. For example, trialkylsilyl halide compounds, monoalkyldiarylsilyl halide compounds, triarylsilyl halide compounds, and the like can be used. When the silyl halide compound has an alkyl group, the alkyl group may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, or tert-butyl group. etc. can be used. Among these, a methyl group or an ethyl group is preferred. When the silyl halide compound has an aryl group, a phenyl group or the like can be used. As the halogen atom constituting the silyl halide compound, a chlorine atom, a bromine atom, an iodine atom, or the like can be used, and a chlorine atom is preferably used. More specifically, the silyl halide compounds include trimethylsilyl chloride (sometimes called trimethylchlorosilane; the same applies to the following compounds), triethylsilyl chloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride. , triphenylsilyl chloride and the like.
（塩基）
使用塩基としては、有機塩基および無機塩基が挙げられ、有機塩基としては、これらに限られないが、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、イミダゾール、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）、ｎ－ブチルリチウム、カリウムtert－ブトキシドが挙げられ、イミダゾールおよびピリジンが好ましい。無機塩基としては、これらに限られないが、水素化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウムまたは炭酸セシウムが挙げられる。塩基の使用量としては、原料化合物の当量以上が好ましい。さらには、原料化合物１モルに対して通常１．０～１０．０モルの範囲を例示できるが、好ましくは２．０～６．０モルの範囲が良く、より好ましくは２．０～４．０モルの範囲であることが良い。(base)
Bases used include organic and inorganic bases, including but not limited to triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine (DMAP), n- Butyllithium, potassium tert-butoxide, imidazole and pyridine are preferred. Inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate. The amount of the base to be used is preferably equal to or more than the amount of the raw material compound. Further, the range of 1.0 to 10.0 mol is usually exemplified per 1 mol of the raw material compound, preferably 2.0 to 6.0 mol, more preferably 2.0 to 4.0 mol. It is preferably in the range of 0 mol.
（溶媒）
反応の円滑な進行等の観点から、本発明の反応は溶媒の存在下で実施することが好ましい。本発明の反応における溶媒は、反応が進行する限りは、いずれの溶媒でもよい。(solvent)
From the viewpoint of smooth progress of the reaction, etc., the reaction of the present invention is preferably carried out in the presence of a solvent. Any solvent may be used in the reaction of the present invention as long as the reaction proceeds.
本発明の反応における溶媒としては、例えば、アミド類（例えば、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡＣ）、Ｎ，Ｎ－ジエチルアセトアミド、Ｎ－メチルピロリドン（ＮＭＰ）等、好ましくはＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡＣ）、Ｎ－メチルピロリドン（ＮＭＰ）、より好ましくはＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ））、スルホキシド類（例えば、ジメチルスルホキシド（ＤＭＳＯ）等）を含むが、これらに限定されるものではない。溶媒の使用量は、反応が進行する限りは、いずれの量でもよい。本発明の反応における溶媒の使用量は当業者により適切に調整されることができる。 Solvents in the reaction of the present invention include, for example, amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP) etc., preferably N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), more preferably N,N-dimethylformamide (DMF)), sulfoxides (for example , dimethylsulfoxide (DMSO), etc.). Any amount of the solvent may be used as long as the reaction proceeds. The amount of solvent used in the reaction of the present invention can be appropriately adjusted by those skilled in the art.
（反応温度）
本発明の反応温度は、特に制限されない。一つの態様においては、収率の向上、副生成物の抑制および経済効率等の観点から、－２０℃～５０℃（すなわち、マイナス２０℃～プラス５０℃）、好ましくは－１０℃～３０℃（すなわち、マイナス１０℃～プラス３０℃）の範囲を例示できる。(reaction temperature)
The reaction temperature of the present invention is not particularly limited. In one embodiment, -20°C to 50°C (that is, -20°C to +50°C), preferably -10°C to 30°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. (that is, minus 10° C. to plus 30° C.) can be exemplified.
（反応時間）
本発明の反応時間は、特に制限されない。一つの態様においては、収率の向上、副生成物の抑制および経済効率等の観点から、０．５時間～１２０時間、好ましくは１時間～７２時間、より好ましくは１時間～４８時間、さらに好ましくは１時間～２４時間の範囲を例示できる。しかしながら、本発明の反応時間は当業者により適切に調整されることができる。(reaction time)
The reaction time of the present invention is not particularly limited. In one aspect, from the viewpoints of yield improvement, suppression of by-products, economic efficiency, etc., 0.5 to 120 hours, preferably 1 to 72 hours, more preferably 1 to 48 hours, and further Preferably, the range of 1 hour to 24 hours can be exemplified. However, the reaction time of the present invention can be adjusted appropriately by those skilled in the art.
化合物（ia）のアミノ化反応
化合物（I）は、公知の方法またはそれに準ずる方法によって製造することができる。例えば、式（ia）の化合物を、適切な溶媒中でジエチルアミンと塩基存在下で反応させることにより、目的とする式（I）の化合物を得ることができる。
（ジエチルアミンの使用量）
ジエチルアミンの使用量は、反応が進行する限りは特に制限されない。収率、副生成物の抑制および経済効率等の観点から、式（I）の原料１モルに対して、通常は０．８～３．０モル、好ましくは０．９～２．０モル、より好ましくは０．９～１．５モルの範囲を例示することができる。(Amount of diethylamine used)
The amount of diethylamine used is not particularly limited as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is usually 0.8 to 3.0 mol, preferably 0.9 to 2.0 mol, per 1 mol of the starting material of formula (I). More preferably, the range of 0.9 to 1.5 mol can be exemplified.
（塩基）
使用することができる塩基としては、例えば、アルカリ金属水酸化物、アルカリ土類金属水酸化物、アルカリ金属炭酸塩、アルカリ土類金属炭酸塩、アルカリ金属炭酸水素塩、アルカリ土類金属炭酸水素塩等の無機塩基類、ピリジン類、キノリン類、イソキノリン類、３級アミン類、２級アミン類、１級アミン類、芳香族アミン類、環状アミン類、カルボン酸アルカリ金属塩、カルボン酸アルカリ土類金属塩等の有機塩基類が挙げられるが、これらに限定されない。(base)
Bases that can be used include, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydrogencarbonates inorganic bases such as pyridines, quinolines, isoquinolines, tertiary amines, secondary amines, primary amines, aromatic amines, cyclic amines, alkali metal carboxylates, alkaline earth carboxylates Examples include, but are not limited to, organic bases such as metal salts.
反応性、収率、価格および取り扱いの容易さ等の観点から、使用する塩基の例としては、好ましくはアルカリ金属水酸化物、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩、３級アミン類、カルボン酸アルカリ金属塩、より好ましくはアルカリ金属水酸化物、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩、さらに好ましくはアルカリ金属水酸化物が挙げられる。使用する塩基の好ましい例としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、トリエチルアミン、酢酸ナトリウム、酢酸カリウムが挙げられ、より好ましくは水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等が挙げられる。 From the viewpoint of reactivity, yield, price and ease of handling, examples of the base to be used are preferably alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, tertiary amines, carboxylic acid Acid alkali metal salts, more preferably alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, more preferably alkali metal hydroxides. Preferred examples of the base used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, sodium acetate, potassium acetate, more preferably sodium hydroxide, water Potassium oxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like.
使用する塩基の形態は、反応が進行する限りは特に制限されない。使用する塩基の形態としては、例えば、塩基のみの固体もしくは液体、または任意の濃度の水溶液もしくは水以外の溶媒の溶液等が挙げられる。また、用いる塩基は単独でまたは２種以上を任意の割合で混合しても良い。 The form of the base to be used is not particularly limited as long as the reaction proceeds. The form of the base to be used includes, for example, a solid or liquid form of the base alone, an aqueous solution of any concentration, or a solution of a solvent other than water. Also, the bases to be used may be used alone or in combination of two or more at any ratio.
（溶媒系）
使用することができる溶媒系としては、例えば、芳香族炭化水素誘導体類、脂肪族炭化水素類、ハロゲン化脂肪族炭化水素類、エーテル類、アルコール類、ニトリル類、アミド類、アルキル尿素類、スルホキシド類、スルホン類、ケトン類、カルボン酸エステル類、カルボン酸類、芳香族複素環類、水およびこれらの２種以上の組み合わせを、任意の割合で混合した混合溶媒系が挙げられる。(solvent system)
Solvent systems that can be used include, for example, aromatic hydrocarbon derivatives, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, ethers, alcohols, nitriles, amides, alkyl ureas, sulfoxides , sulfones, ketones, carboxylic acid esters, carboxylic acids, aromatic heterocycles, water, and combinations of two or more of these in any proportion.
価格、取り扱いの容易さ、反応性および収率等の観点から、使用する溶媒系の例としては、好ましくは芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類、エーテル類、アルコール類、ニトリル類、アミド類、アルキル尿素類、スルホキシド類、スルホン類、水およびそれらからなる溶媒系、より好ましくは芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類、エーテル類、アルコール類、ニトリル類、アミド類、水およびそれらからなる溶媒系、さらに好ましくはニトリル類と水からなる溶媒系が挙げられる。溶媒系の具体的な好ましい例としては、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼン、ジクロロメタン、テトラヒドロフラン（ＴＨＦ）、ジイソプロピルエーテル、ジブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）、メチル－tert－ブチルエーテル、メタノール、エタノール、プロパノール、２－プロパノール、ブタノール、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡＣ）、Ｎ－メチルピロリドン（ＮＭＰ）、Ｎ，Ｎ’－ジメチルイミダゾリジノン（ＤＭＩ）、ジメチルスルホキシド（ＤＭＳＯ）、スルホラン、水およびそれらからなる溶媒系、より好ましくはトルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼン、ジクロロメタン、テトラヒドロフラン（ＴＨＦ）、ジイソプロピルエーテル、ジブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）、メチル－tert－ブチルエーテル、メタノール、エタノール、プロパノール、２－プロパノール、ブタノール、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡＣ）、Ｎ－メチルピロリドン（ＮＭＰ）、水およびこれらの２種以上からなる溶媒系、さらに好ましくはアセトニトリルと水からなる溶媒系が挙げられる。 From the viewpoint of cost, ease of handling, reactivity, yield, etc., preferred examples of the solvent system to be used include aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, ethers, alcohols, nitriles amides, alkyl ureas, sulfoxides, sulfones, water and solvent systems consisting thereof, more preferably aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, ethers, alcohols, nitriles, Examples include amides, water and solvent systems comprising them, more preferably solvent systems comprising nitriles and water. Specific preferred examples of solvent systems include toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloromethane, tetrahydrofuran (THF), diisopropylether, dibutylether, cyclopentylmethylether (CPME), methyl-tert-butylether, methanol, ethanol, propanol, 2-propanol, butanol, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone ( DMI), dimethyl sulfoxide (DMSO), sulfolane, water and solvent systems consisting thereof, more preferably toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloromethane, tetrahydrofuran (THF), diisopropyl ether, dibutyl ether, cyclopentyl methyl ether ( CPME), methyl-tert-butyl ether, methanol, ethanol, propanol, 2-propanol, butanol, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP) , water and a solvent system consisting of two or more of these, more preferably a solvent system consisting of acetonitrile and water.
（溶媒の使用量）
溶媒系を形成する溶媒の使用量としては、反応系の撹拌が十分にできる限りは特に制限されない。反応性、副生成物の抑制および経済効率等の観点から、式（I）の原料１モルに対して、水の量が通常は０（ゼロ）～１０．０Ｌ（リットル）、好ましくは０．０１～１０．０Ｌ、より好ましくは０．１～５．０Ｌ、さらに好ましくは０．２～３．０Ｌの範囲を例示することができる。さらに、同様の観点から、式（I）の原料１モルに対して、水以外の上記した溶媒の量が、通常は０（ゼロ）～１０．０Ｌ（リットル）、好ましくは０．０１～１０．０Ｌ、より好ましくは０．１～５．０Ｌ、さらに好ましくは０．２～３．０Ｌの範囲を例示することができる。なお、水および水以外の溶媒の混合割合は、反応が進行する限りは特に制限されない。水以外の２種以上の溶媒を用いる場合は、溶媒の混合割合は、反応が進行する限りは特に制限されない。(Amount of solvent used)
The amount of the solvent used to form the solvent system is not particularly limited as long as the reaction system can be sufficiently stirred. From the viewpoint of reactivity, suppression of by-products, economic efficiency, etc., the amount of water is usually 0 (zero) to 10.0 L (liter), preferably 0.0 L (liter), per 1 mol of the raw material of formula (I). A range of 01 to 10.0 L, more preferably 0.1 to 5.0 L, and even more preferably 0.2 to 3.0 L can be exemplified. Furthermore, from the same point of view, the amount of the above solvent other than water is usually 0 (zero) to 10.0 L (liter), preferably 0.01 to 10 .0L, more preferably 0.1 to 5.0L, more preferably 0.2 to 3.0L. The mixing ratio of water and a solvent other than water is not particularly limited as long as the reaction proceeds. When using two or more solvents other than water, the mixing ratio of the solvents is not particularly limited as long as the reaction proceeds.
（反応温度）
反応温度は、特に制限されない。収率、副生成物の抑制および経済効率等の観点から、通常は１０℃～１００℃、好ましくは４０℃～９５℃、より好ましくは４５℃～８５℃、さらに好ましくは５０℃～７０℃の範囲を例示することができる。(reaction temperature)
The reaction temperature is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the Ranges can be exemplified.
（反応時間）
反応時間は、特に制限されない。収率、副生成物の抑制および経済効率等の観点から、通常は０．５時間～４８時間、好ましくは０．５時間～２４時間、より好ましくは１時間～１２時間の範囲を例示することができる。(reaction time)
Reaction time is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time range is usually 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours, more preferably 1 hour to 12 hours. can be done.
上記に示す本発明の化合物（I）の製造方法において、化合物（Ia）を単離精製することなく、化合物（i）をシリルハライドと反応させた後、さらにジエチルアミンと反応させ、一挙に本発明の化合物（I）を製造することができる。
本発明の化合物（II）のワンポット
式（i’）で表される化合物またはその立体異性体をアミノ化反応に付すことにより、式（II）で表される化合物またはその立体異性体またはそれらの塩をワンポットで製造することができる。
ハロゲン化反応に用いるハロゲン化剤としては、例えば、オキシ塩化リン、三塩化リン、五塩化リン、塩化チオニル、三臭化リン等が挙げられる。ハロゲン化剤の使用量は、化合物（i’）に対して、通常１～５モルである。
ジエチルアミンの使用量は、反応が進行する限りは特に制限されない。収率、副生成物の抑制および経済効率等の観点から、式（i’）の原料１モルに対して、通常は０．８～３．０モル、好ましくは１．０～２．０モルである。
本発明の化合物（II）のワンポット反応は、反応に悪影響を及ぼさない溶媒中で行われる。反応に悪影響を及ぼさない溶媒としては、例えば、ハロゲン化炭化水素類（例えば、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、１，１，２，２－テトラクロロエタン等）、エーテル類（例えば、エチルエーテル、イソプロピルエーテル、テトラヒドロフラン、ジオキサン等）、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エステル類（酢酸メチル、酢酸エチル等）、芳香族炭化水素類（例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、ニトロベンゼン、ベンゾトリフルオリド等）、ピリジン等が用いられる。これら溶媒は、２種以上を適宜の割合で混合して用いてもよい。反応温度は、通常-１０℃～３０℃、好ましくは、０℃～２５℃である。反応時間は、通常３０分間～２０時間である。The compound represented by formula (II) or its stereoisomer or their Salt can be produced in one pot.
Halogenating agents used in the halogenation reaction include, for example, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and phosphorus tribromide. The amount of the halogenating agent to be used is generally 1-5 mol relative to compound (i').
The amount of diethylamine used is not particularly limited as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is usually 0.8 to 3.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of the starting material of formula (i'). is.
The one-pot reaction of compound (II) of the present invention is carried out in a solvent that does not adversely affect the reaction. Examples of solvents that do not adversely affect the reaction include halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.), ethers (eg, ethyl ether , isopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g., acetonitrile, propionitrile, etc.), esters (methyl acetate, ethyl acetate, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride, etc.), pyridine and the like are used. Two or more of these solvents may be mixed in an appropriate ratio and used. The reaction temperature is usually -10°C to 30°C, preferably 0°C to 25°C. The reaction time is usually 30 minutes to 20 hours.
［式（II）の化合物からPGE1誘導体等(式（VII）)への変換］
下記の図で示されるように、式(II)（式中、TESは、トリエチルシリル基を示し、Etは、エチル基を示す。）の化合物に対して、式（III）（式中、Ｍは、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示す。）で表される金属有機化合物を用いて、１，４付加反応を進行させることにより、シクロペンテノンの３位に側鎖が導入される。それと同時にシクロペンテノン誘導体の2位にメチリデン化がおこり、効率よく式（IV）で表されるプロスタグランジン誘導体等の中間体に導くことができる。さらに式（IV）化合物に対して、式（V）（式中、Ｍ’は、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示す。）で表される有機金属化合物を用いて、１，４付加反応を進行させることにより、式（VI）で表される化合物式に導くことができる。式（VI）の化合物のシリル基を除去することにより、式（VII）で示されるPGE1誘導体を製造することができる。
As shown in the diagram below, for compounds of formula (II) (wherein TES denotes a triethylsilyl group and Et denotes an ethyl group), formula (III) (where M represents a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, and Sn, or a group containing the metal.) Using a metal organic compound represented by A side chain is introduced at the 3-position of cyclopentenone by proceeding with the 1,4-addition reaction. At the same time, methylidenation occurs at the 2-position of the cyclopentenone derivative, which can efficiently lead to an intermediate such as a prostaglandin derivative represented by formula (IV). Furthermore, for the compound of formula (IV), formula (V) (wherein M' is a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, Sn, or The compound represented by the formula (VI) can be obtained by proceeding the 1,4-addition reaction using the organometallic compound represented by the group containing the metal. PGE 1 derivatives of formula (VII) can be prepared by removing the silyl group of compounds of formula (VI).
前記反応工程式において、化合物（III）および（V）はそれ自体公知であるか、あるいは公知の方法により容易に製造することができる。
また、前記反応工程における１，４付加反応は、例えば、非特許文献４および非特許文献５に記載された方法に準じて、行うことができる。
なお、使用される化合物（VI）のシリル基の切断剤としては、好適には、ピリジニウムトルエンスルホン酸、トルエンスルホン酸等のアリールスルホン酸、メタンスルホン酸等のアルカンスルホン酸、希塩酸、希硫酸のような希鉱酸、またはテトラブチルアンモニウムフルオライドのようなアンモニウムフルオライドであり、より好適には、パラピリジニウムトルエンスルホン酸である。使用される不活性溶剤は、例えば、水、アセトン、メチルエチルケトン、メチルイソプロピルケトンまたはメチルイソブチルケトン（ＭＩＢＫ）等のケトン類、テトラヒドロフラン、ジオキサン、エ－テル、ジメトキシエタンのようなエーテル類、塩化メチレン、クロロホルム、四塩化炭素、ジクロロエタンのようなハロゲン化炭化水素類、ベンゼン、トルエン、キシレンのような芳香族炭化水素類および任意の割合のそれらの任意の組み合わせを含むが、これらに限定されるものではない。好適には、アセトンと水の混合溶媒である。反応温度は、通常０℃～８０℃（好適には、１０℃～４０℃）であり、反応時間は、通常１０分間～２４時間（好適には、３０分間～８時間）である。
本明細書中の各反応において、反応生成物は通常の精製手段、例えば、常圧下または減圧下における蒸留、シリカゲルまたはケイ酸マグネシウムを用いた高速液体クロマトグラフィー、薄層クロマトグラフィー、あるいはカラムクロマトグラフィーまたは洗浄、再結晶等の方法により精製することができる。精製は各反応ごとに行なってもよいし、いくつかの反応終了後に行なってもよい。In the above reaction scheme, compounds (III) and (V) are known per se or can be easily produced by known methods.
In addition, the 1,4-addition reaction in the reaction step can be performed, for example, according to the methods described in Non-Patent Document 4 and Non-Patent Document 5.
The silyl group cleaving agent of compound (VI) to be used is preferably pyridinium toluenesulfonic acid, arylsulfonic acid such as toluenesulfonic acid, alkanesulfonic acid such as methanesulfonic acid, dilute hydrochloric acid, or dilute sulfuric acid. or an ammonium fluoride such as tetrabutylammonium fluoride, more preferably parapyridinium toluenesulfonic acid. The inert solvents used are, for example, water, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone (MIBK), ethers such as tetrahydrofuran, dioxane, ether, dimethoxyethane, methylene chloride, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene and any combination thereof in any proportion. do not have. A mixed solvent of acetone and water is preferred. The reaction temperature is generally 0° C. to 80° C. (preferably 10° C. to 40° C.), and the reaction time is generally 10 minutes to 24 hours (preferably 30 minutes to 8 hours).
In each of the reactions herein, the reaction product can be purified by conventional means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography. Alternatively, it can be purified by methods such as washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of some reactions.
以下に実施例を挙げて、本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されない。本明細書中、室温は１０℃から３５℃を示す。なお、実施例および参考例の各物性の測定には次の機器を用いた。融点：Ｙａｎａｃｏ Ｍｐ－５００Ｖ（アナテック・ヤナコ社製）。１Ｈ核磁気共鳴スペクトル(１Ｈ‐ＮＭＲ)：ＡＶＡＮＣＥ－４００（Ｂｕｒｋｅｒ）。内部基準物質：テトラメチルシラン。質量分析：ｍｉｒｃＯＴＯＦ－Ｑ II－Ｓ１（Ｂｕｒｋｅｒ）EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples. In this specification, room temperature indicates 10°C to 35°C. The following instruments were used to measure physical properties in Examples and Reference Examples. Melting point: Yanaco Mp-500V (manufactured by Anatech Yanaco). 1 H nuclear magnetic resonance spectrum ( 1 H-NMR): AVANCE-400 (Burker). Internal reference substance: tetramethylsilane. Mass spectrometry: mircOTOF-Q II-S1 (Burker)
製造方法１
(R)2-(ジエチルアミノ)メチル)-4-(トリエチルシリル)オキシ)シクロペント-2-エン-1-オン
[α]D = +18.7 (c = 1.0 in CHCl3); 1H NMR (400 Mz, CDCl3) δ 0.65 (dd, J = 8.0, 15.8 Hz, 6H), 0.96-1.04 (m, 15H), 2.32 (dd, J = 2.0, 18.4 Hz, 1H), 2.47-2.53 (m, 4H), 2.77 (dd, J = 6.0, 18.2 Hz, 1H), 3.15-3.25 (m, 2H), 4.90-4.92 (m, 1H), 7.24-7.25 (m, 1H); 13C NMR (100 Mz, CDCl3) δ 4.8, 6.9 12.1, 45.9, 47.4, 47.5, 68.8, 145.1, 158.9, 206.2; IR(neat): 1147, 1716, 2960 cm-1; HRMS (m/z): ([M + H]+) C16H32NO4Si2 calcd. for 298.2197, found 298.2196
製造方法２
(R)-2-(ジエチルアミノ)メチル)-4-(トリエチルシリル)オキシ)シクロペント-2-エン-1-オン
製造方法３
(R)-2-((ジエチルアミノ)メチル)-4-(トリエチルシリル)オキシ)シクロペント-2-エン-1-オン
(R)2-(Diethylamino)methyl)-4-(triethylsilyl)oxy)cyclopent-2-en-1-one
[α] D = +18.7 (c = 1.0 in CHCl 3 ); 1 H NMR (400 Mz, CDCl 3 ) δ 0.65 (dd, J = 8.0, 15.8 Hz, 6H), 0.96-1.04 (m, 15H), 2.32 (dd, J = 2.0, 18.4 Hz, 1H), 2.47-2.53 (m, 4H), 2.77 (dd, J = 6.0, 18.2 Hz, 1H), 3.15-3.25 (m, 2H), 4.90-4.92 ( m, 1H), 7.24-7.25 (m, 1H); 13C NMR (100 Mz, CDCl3 ) δ 4.8, 6.9 12.1, 45.9, 47.4, 47.5, 68.8, 145.1, 158.9, 206.2; IR(neat): 1147 , 1716, 2960 cm -1 ; HRMS (m/z): ([M + H] + ) C 16 H 32 NO 4 Si 2 calcd. for 298.2197, found 298.2196
Manufacturing method 2
(R)-2-(Diethylamino)methyl)-4-(triethylsilyl)oxy)cyclopent-2-en-1-one
Manufacturing method 3
(R)-2-((diethylamino)methyl)-4-(triethylsilyl)oxy)cyclopent-2-en-1-one
(3R,4R)-2-メチレン-4-[(トリエチルシリル)オキシ]-3-{(S,E)-3-[(トリエチルシリル)オキシ]オクト-1-エン-1-イル}シクロペンタン-1-オン
Rf = 0.33; [α]D = -40.8 (c = 0.30 in CHCl3); 1H NMR (400 Mz, CDCl3) δ 0.56-0.62 (m, 12H), 0.88 (t, J =6.8 Hz, 3H), 0.93-0.97 (m, 18H), 1.26-1.51 (m, 8H), 2.34 (dd, J = 6.4, 17.8 Hz, 1H), 2.63 (dd, J = 6.4, 17.8 Hz, 1H), 3.30-3.33 (m, 1H), 4.10-4.15 (m, 2H), 5.24-5.25 (m, 1H), 5.45-5.65 (m, 2H), 6.12-6.13 (m, 1H); 13C NMR (100 Mz, CDCl3) δ 4.9, 5.1, 6.9, 7.0, 14.2, 22.8, 25.2, 32.0, 38.7, 47.1, 54.6, 72.79, 72.83, 77.4, 119.5, 127.6, 137.7, 146.8, 203.7; HRMS (m/z): ([M + Na]+) C26H48O3Si2Na calcd. for 487.3034, found 487.3029
(3R,4R)-2-methylene-4-[(triethylsilyl)oxy]-3-{(S,E)-3-[(triethylsilyl)oxy]oct-1-en-1-yl}cyclopentane -1-on
R.f = 0.33; [α]D. = -40.8 (c = 0.30 in CHCl3);1H NMR (400 Mz, CDCl3) δ 0.56-0.62 (m, 12H), 0.88 (t, J =6.8 Hz, 3H), 0.93-0.97 (m, 18H), 1.26-1.51 (m, 8H), 2.34 (dd, J = 6.4, 17.8 Hz, 1H), 2.63 (dd, J = 6.4, 17.8 Hz, 1H), 3.30-3.33 (m, 1H), 4.10-4.15 (m, 2H), 5.24-5.25 (m, 1H), 5.45-5.65 ( m, 2H), 6.12-6.13 (m, 1H);13C NMR (100 Mz, CDCl3) δ 4.9, 5.1, 6.9, 7.0, 14.2, 22.8, 25.2, 32.0, 38.7, 47.1, 54.6, 72.79, 72.83, 77.4, 119.5, 127.6, 137.7, 146.8, 203.7; +Na]+) C26H.48O3Si2Na calcd. for 487.3034, found 487.3029
メチル7-((1R,2R,3R)-5-オキソ-3-((トリエチルシリル)オキシ)-2-((S,E)-3-((トリエチルシリル)オキシ)オクト-1-エン-1-イル）シクロペンチル）ヘプタノエート
[α]D = -29.0 (c = 0.24 in CHCl3); 1H NMR (400 Mz, CDCl3) δ 0.55-0.62 (m, 12H), 0.88 (t, J =6.8 Hz, 3H), 0.92-0.99 (m, 18H), 1.21-1.63 (m, 18H), 1.91-1.97 (m, 1H), 2.18 (dd, J = 8.0, 18.4 Hz, 1H), 2.28 (t, J =7.6 Hz, 2H), 2.42-2.49 (m, 1H), 2.62 (ddd, J = 1.2, 7.2, 18.2 Hz, 1H), 3.66 (s, 3H), 4.1-4.13 (m, 2H), 5.49-5.61 (m, 2H); 13C NMR (100 Mz, CDCl3) δ 4.9, 5.1, 6.7 6.9, 7.1, 14.2, 22.8, 25.1, 25.2, 26.8, 28.0, 29.1, 29.3, 29.7, 32.0, 34.2, 38.7, 51.6, 53.2, 53.9, 73.0, 77.4, 129.0, 136.3, 174.4, 216.5; HRMS (m/z): ([M + Na]+) C33H64O5Si2Na calcd. for 619.4184, found 619.4203
Methyl 7-((1R,2R,3R)-5-oxo-3-((triethylsilyl)oxy)-2-((S,E)-3-((triethylsilyl)oxy)oct-1-ene- 1-yl)cyclopentyl)heptanoate
[α]D. = -29.0 (c = 0.24 in CHCl3);1H NMR (400 Mz, CDCl3) δ 0.55-0.62 (m, 12H), 0.88 (t, J =6.8 Hz, 3H), 0.92-0.99 (m, 18H), 1.21-1.63 (m, 18H), 1.91-1.97 (m, 1H), 2.18 (dd, J = 8.0, 18.4 Hz, 1H), 2.28 (t, J =7.6 Hz, 2H), 2.42-2.49 (m, 1H), 2.62 (ddd, J = 1.2, 7.2, 18.2 Hz, 1H) , 3.66 (s, 3H), 4.1-4.13 (m, 2H), 5.49-5.61 (m, 2H);13C NMR (100 Mz, CDCl3) δ 4.9, 5.1, 6.7 6.9, 7.1, 14.2, 22.8, 25.1, 25.2, 26.8, 28.0, 29.1, 29.3, 29.7, 32.0, 34.2, 38.7, 51.6, 53.2, 53.9, 73.0, 77.4, 129.0, 136.3, 174.4 , 216.5; HRMS (m/z): ([M + Na]+) C33H.64OFiveSi2Na calcd. for 619.4184, found 619.4203
PGE1-メチルエステル
[α]D = -46.8 (c = 0.93 in MeOH); 1H NMR (400 Mz, CDCl3) δ 0.89 (t, J =6.4 Hz, 3H), 1.21-1.69 (m, 18H), 1.96-2.04 (m, 1H), 2.17-2.38 (m, 5H), 2.73 (ddd, J = 1.2, 7.2, 18.4 Hz, 1H), 3.22 (brs, 1H), 3.66 (s, 3H), 4.01-4.14 (m, 2H), 5.52-5.70 (m, 2H); 13C NMR (100 Mz, CDCl3) δ 14.2, 22.8, 25.0, 25.3 26.7, 27.8, 29.0, 29.5, 31.8, 34.1, 37.5, 51.6, 54.6, 54.9, 72.0, 73.1, 131.9, 136.9, 174.5, 214.8; HRMS (m/z): ([M + Na]+) C21H36O5Na calcd. for 391.2455, found 391.2459
PGE1-methyl ester
[α]D. = -46.8 (c = 0.93 in MeOH);1H NMR (400 Mz, CDCl3) δ 0.89 (t, J =6.4 Hz, 3H), 1.21-1.69 (m, 18H), 1.96-2.04 (m, 1H), 2.17-2.38 (m, 5H), 2.73 (ddd, J = 1.2, 7.2 , 18.4 Hz, 1H), 3.22 (brs, 1H), 3.66 (s, 3H), 4.01-4.14 (m, 2H), 5.52-5.70 (m, 2H);13C NMR (100 Mz, CDCl3) δ 14.2, 22.8, 25.0, 25.3 26.7, 27.8, 29.0, 29.5, 31.8, 34.1, 37.5, 51.6, 54.6, 54.9, 72.0, 73.1, 131.9, 136.9, 174.5, HRMS:[m/8; M + Na]+) Ctwenty oneH.36OFiveNa calcd. for 391.2455, found 391.2459
4-ヒドロキシ-2-(アセトキシメチル)シクロペンタ-2-エン-1-オン
1H NMR (400 Mz, CDCl3) δ = 2.11 (s, 3H), 2.38 (dd, J = 2.0, 18.4 Hz, 1H), 2.88 (dd, J = 6.4, 18.4 Hz, 1H), 4.78-4.79 (m, 1H), 5.02 (bra, 1H), 7.38-7.39 (m, 1H) ppm. 13C NMR (100 Mz, CDCl3) δ = 20.9, 45.1, 57.8, 68.8, 142.7, 185.1, 170.7, 204.0 ppm. HR-MS (ESI-TOF): m/z C8H10O4Na ([M + Na]+) calcd. for 193.0471, found 193.04714-Hydroxy-2-(acetoxymethyl)cyclopent-2-en-1-one
1 H NMR (400 Mz, CDCl 3 ) δ = 2.11 (s, 3H), 2.38 (dd, J = 2.0, 18.4 Hz, 1H), 2.88 (dd, J = 6.4, 18.4 Hz, 1H), 4.78-4.79 (m, 1H), 5.02 (bra, 1H), 7.38-7.39 (m, 1H) ppm. 13 C NMR (100 Mz, CDCl 3 ) δ = 20.9, 45.1, 57.8, 68.8, 142.7, 185.1, 170.7, 204.0 ppm. HR-MS (ESI-TOF): m/z C8H10O4Na ([M + Na] + ) calcd . for 193.0471 , found 193.0471
2-(ジエチルアミノメチル)-4-(トリエチルシリルオキシ)シクロペンタ-2-エン-1-オン
1H NMR (400 Mz, CDCl3) δ = 0.65 (dd, J = 8.0, 15.8 Hz, 6H), 0.96-1.04 (m, 15H), 2.32 (dd, J = 2.0, 18.4 Hz, 1H), 2.47-2.53 (m, 4H), 2.77 (dd, J = 6.0, 18.2 Hz, 1H), 3.15-3.25 (m, 2H), 4.90-4.92 (m, 1H), 7.24-7.25 (m, 1H) ppm. 13C NMR (100 Mz, CDCl3) δ = 4.8, 6.9 12.1, 45.9, 47.4, 47.5, 68.8, 145.1, 158.9, 206.2 ppm. HR-MS (ESI-TOF): m/z C16H32NO4Si2 ([M + H]+) calcd. for 298.2197, found 298.21962-(Diethylaminomethyl)-4-(triethylsilyloxy)cyclopent-2-en-1-one
1 H NMR (400 Mz, CDCl 3 ) δ = 0.65 (dd, J = 8.0, 15.8 Hz, 6H), 0.96-1.04 (m, 15H), 2.32 (dd, J = 2.0, 18.4 Hz, 1H), 2.47 -2.53 (m, 4H), 2.77 (dd, J = 6.0, 18.2 Hz, 1H), 3.15-3.25 (m, 2H), 4.90-4.92 (m, 1H), 7.24-7.25 (m, 1H) ppm. 13C NMR (100 Mz, CDCl3 ) δ = 4.8, 6.9 12.1, 45.9, 47.4, 47.5, 68.8, 145.1 , 158.9, 206.2 ppm. HR-MS (ESI - TOF): m/z C16H32NO4 Si2 ( [M + H] + ) calcd. for 298.2197, found 298.2196
PGE1誘導体
アルゴン雰囲気下、ノルマルブチルリチウム（1.25 mL, 1.93 mmol）を(S)-tert-ブチルジメチル-(オクト-1-イン-3-イロキシ)シラン（500 mg, 2.08 mmol）の乾燥トルエン溶液（4 mL）に0℃で加え、30分間攪拌させた後、塩化ジエチルアルミニウムヘキサンの溶液（1.0M）（2.08 mL, 2.08 mmol）を加え、室温でさらに30分間攪拌させた。調製した有機アルミニウム試薬を-78℃に冷却し、2-(ジエチルアミノメチル)-4-(トリエチルシリルオキシ)シクロペンタ-2-エン-1-オン（412 mg, 1.38 mmol）の乾燥トルエン溶液（5 mL）を滴下した。同温度で30分間攪拌した後、さらに室温で1時間攪拌した。反応混合物に１Ｎ塩酸水溶液および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝50：1）で精製し、(3R,4R）および（3S,4S）-3-（（S）-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル）-2-メチレン-4-((トリエチルシリル)オキシ)シクロペンタン-1-オン(トランス体)（408 mg, 64%）を淡黄色の油状物質として、(3S,4R)および(3R,4S)-3-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-2-メチレン-4-((トリエチルシリル)オキシ)シクロペンタン-1-オン（シス体）(156 mg, 24%)を淡黄色の油状物質として得た。
トランス体
1H NMR (400 Mz, CDCl3) δ = 0.091 (s, 3H), 0.10 (s, 3H), 0.64 (dd, J = 7.6, 15.4 Hz, 6H), 0.87-0.99 (m, 21H), 1.28-1.69 (m, 8H), 2.34 (dd, J = 7.2, 18.6 Hz, 1H), 2.72 (dd, J = 6.4, 18.0 Hz, 1H), 3.53-3.55 (m, 1H), 4.25-4.35 (m, 2H), 5.55-5.56 (m, 1H), 6.14 (d, J = 2.8 Hz, 1H) ppm. HR-MS (ESI-TOF): m/z C26H48O3Si2Na ([M + Na]+ ) calcd. for 487.3034, found 487.3029
シス体
1H NMR (400 Mz, CDCl3) δ = 0.010 (s, 3H), 0.12 (s, 3H), 0.61 (dd, J = 8.0, 16.4 Hz, 6H), 0.88-0.97 (m, 21H), 1.26-1.69 (m, 8H), 2.41-2.44 (m, 2H), 3.68-3.69 (m, 1H), 4.38-4.41 (m, 1H), 4.52-4.54 (m, 1H), 5.56-5.60 (m, 1H), 6.17 (d, J = 3.2 Hz, 1H) ppm. 1HR-MS (ESI-TOF): m/z C26H48O3Si2Na ([M + Na]+) calcd. for 487.3034, found 487.3030
メチル7-((1R,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-5-オキソ-3-((トリエチルシリル)オキシ)シクロペンチル)ヘプタノエートの製造
アルゴン雰囲気下、１，４付加体（310 mg, 0.661 mmol）、メチル6-ヨードヘキサノエート(508 mg, 1.98 mmol)、トリブチルスズ（0.53 mL, 1.98 mmol）およびAIBN(10.8 mg, 0.0661 mmol)の脱酸素トルエン溶液（1.3 mL）を80℃で4時間攪拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝30：1→20：1）で精製し、メチル7-((1R,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-5-オキソ-3-((トリエチルシリル)オキシ)シクロペンチル)ヘプタノエート（160 mg, 40%）（トランス体）を淡黄色の油状物質として、メチル7-((1S,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル）オキシ)オクト-1-イン-1-イル)-5-オキソ-3-((トリエチルシリル）オキシ）シクロペンチル）ヘプタノエート(40.9 mg, 10%）（シス体）を淡黄色の油状物質として得た。
トランス体
1H NMR (400 Mz, CDCl3) δ = 0.090 (s, 3H), 0.10 (s, 3H), 0.63 (dd, J = 7.6, 15.8 Hz, 6H), 0.87-0.98 (m, 21H), 1.28-1.63 (m, 18H), 2.15-2.31 (m, 2H), 2.29 (t, J = 7.6, 2H), 2.68-2.69 (m, 2H), 3.66 (s, 3H), 4.25-4.35 (m, 2H) ppm. 13C NMR (100 Mz, CDCl3) δ = 4.9, 6.9, 13.7, 14.2, 16.5, 18.4, 22.7, 25.05, 21.1, 25.9, 26.8, 26.9, 29.1, 29.2, 29.3, 29.4, 31.6, 34.2, 38.9, 42.3, 47.6, 51.6, 55.1, 55.2, 63.2, 73.5, 84.0, 85.0, 174.4, 215.5 ppm. HR-MS (ESI-TOF): m/z C33H62O5Si2Na ([M + Na]+) calcd. for 617.4028, found 617.4027
シス体
1H NMR (400 Mz, CDCl3) δ = 0.061 (s, 3H), 0.070 (s, 3H), 0.59 (dd, J = 8.0, 16.0 Hz, 6H), 0.85-0.96 (m, 21H), 1.26-1.79 (m, 18H), 2.19 (d, J = 18.4 Hz, 1H), 2.27-2.34 (m, 2H), 2.56 (dd, J = 4.8, 18.6 Hz, 1H), 3.12 (d, J = 7.6 Hz, 1H), 3.34 (t, J = 6.8, 1H), 3.65 (s, 3H), 4.26-4.29 (m, 1H), 4.46 (d, J = 4.8 Hz, 1H) ppm. 13C NMR (100 Mz, CDCl3) δ = 4.5, 6.9, 14.1, 18.4, 22.7, 24.2, 25.0, 25.1, 25.9, 26.1, 27.7, 27.8, 29.2, 29.4, 31.5, 31.53, 32.5, 33.6, 33.94, 34.2, 38.9, 41.4, 46.0, 49.4, 51.6, 51.7, 63.1, 63.2, 72.4, 80.5, 88.0, 174.4, 217.5 ppm. HR-MS (ESI-TOF): m/z C33H62O5Si2Na ([M + Na]+) calcd. for 617.4028, found 617.4028
メチル7-((1R,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-3-ヒドロキシ-5-オキソシクロペンチル)ヘプタノエート（脱TES体）の製造
メチル7-((1R,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-5-オキソ-3-((トリエチルシリル)オキシ)シクロペンチル)ヘプタノエート(10.0 mg, 0.0169 mmol)を酢酸-ＴＨＦ-H2O（3：1：1）の混液（1.0 mL）に加え、1.5時間攪拌した。H2Oで希釈し、酢酸エチルで抽出した後、有機層を硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣を少量のシリカゲルで溶出し、メチル7-((1R,2S,3R)-2-((S)-3-((tert-ブチルジメチルシリル)オキシ)オクト-1-イン-1-イル)-3-ヒドロキシ-5-オキソシクロペンチル)ヘプタノエート（8.0 mg, 99%）を無色の油状物質として得た。
1H NMR (400 Mz, CDCl3) δ = 0.11 (s, 3H), 0.13 (s, 3H), 0.87-91 (m, 12H), 1.20-1.68 (m, 18H), 2.19-2.37 (m, 5H), 2.62-2.77 (m, 2H), 3.66 (s, 3H), 4.28-4.38 (m, 2H) ppm PGE1 derivative
trans body
1 H NMR (400 Mz, CDCl 3 ) δ = 0.091 (s, 3H), 0.10 (s, 3H), 0.64 (dd, J = 7.6, 15.4 Hz, 6H), 0.87-0.99 (m, 21H), 1.28 -1.69 (m, 8H), 2.34 (dd, J = 7.2, 18.6 Hz, 1H), 2.72 (dd, J = 6.4, 18.0 Hz, 1H), 3.53-3.55 (m, 1H), 4.25-4.35 (m , 2H), 5.55-5.56 (m, 1H), 6.14 (d, J = 2.8 Hz, 1H) ppm. HR-MS (ESI-TOF): m/z C 26 H 48 O 3 Si 2 Na ([M + Na] + ) calcd. for 487.3034, found 487.3029
cis form
1 H NMR (400 Mz, CDCl 3 ) δ = 0.010 (s, 3H), 0.12 (s, 3H), 0.61 (dd, J = 8.0, 16.4 Hz, 6H), 0.88-0.97 (m, 21H), 1.26 -1.69 (m, 8H), 2.41-2.44 (m, 2H), 3.68-3.69 (m, 1H), 4.38-4.41 (m, 1H), 4.52-4.54 (m, 1H), 5.56-5.60 (m, 1H), 6.17 (d, J = 3.2 Hz, 1H) ppm. 1 HR-MS (ESI-TOF): m/z C26H48O3Si2Na ( [M + Na] + ) calcd. for 487.3034 , found 487.3030
Methyl 7-((1R,2S,3R)-2-((S)-3-((tert-butyldimethylsilyl)oxy)oct-1-yn-1-yl)-5-oxo-3-(( Preparation of triethylsilyl)oxy)cyclopentyl)heptanoate 1,4 adduct (310 mg, 0.661 mmol), methyl 6-iodohexanoate (508 mg, 1.98 mmol), tributyltin (0.53 mL, 1.98 mmol) under argon atmosphere. and AIBN (10.8 mg, 0.0661 mmol) in deoxygenated toluene (1.3 mL) was stirred at 80° C. for 4 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 30:1 → 20:1), methyl 7-((1R,2S,3R)-2-(( S)-3-((tert-butyldimethylsilyl)oxy)oct-1-yn-1-yl)-5-oxo-3-((triethylsilyl)oxy)cyclopentyl)heptanoate (160 mg, 40%) ( trans form) as a pale yellow oily substance, methyl 7-((1S,2S,3R)-2-((S)-3-((tert-butyldimethylsilyl)oxy)oct-1-yn-1- yl)-5-oxo-3-((triethylsilyl)oxy)cyclopentyl)heptanoate (40.9 mg, 10%) (cis form) was obtained as a pale yellow oil.
trans body
1 H NMR (400 Mz, CDCl 3 ) δ = 0.090 (s, 3H), 0.10 (s, 3H), 0.63 (dd, J = 7.6, 15.8 Hz, 6H), 0.87-0.98 (m, 21H), 1.28 -1.63 (m, 18H), 2.15-2.31 (m, 2H), 2.29 (t, J = 7.6, 2H), 2.68-2.69 (m, 2H), 3.66 (s, 3H), 4.25-4.35 (m, 2H) ppm. 13 C NMR (100 Mz, CDCl 3 ) δ = 4.9, 6.9, 13.7, 14.2, 16.5, 18.4, 22.7, 25.05, 21.1, 25.9, 26.8, 26.9, 29.1, 29.2, 29.3, 29.4, 31. 34.2, 38.9, 42.3, 47.6, 51.6, 55.1, 55.2, 63.2, 73.5 , 84.0, 85.0 , 174.4 , 215.5 ppm. M + Na] + ) calcd. for 617.4028, found 617.4027
cis form
1 H NMR (400 Mz, CDCl 3 ) δ = 0.061 (s, 3H), 0.070 (s, 3H), 0.59 (dd, J = 8.0, 16.0 Hz, 6H), 0.85-0.96 (m, 21H), 1.26 -1.79 (m, 18H), 2.19 (d, J = 18.4 Hz, 1H), 2.27-2.34 (m, 2H), 2.56 (dd, J = 4.8, 18.6 Hz, 1H), 3.12 (d, J = 7.6 Hz, 1H), 3.34 (t, J = 6.8, 1H), 3.65 (s, 3H), 4.26-4.29 (m, 1H), 4.46 (d, J = 4.8 Hz, 1H) ppm. Mz, CDCl3 ) δ = 4.5, 6.9, 14.1, 18.4, 22.7, 24.2, 25.0, 25.1, 25.9, 26.1, 27.7, 27.8, 29.2, 29.4, 31.5, 31.53, 32.5, 33.6, 31.9, 33.94, , 46.0, 49.4, 51.6, 51.7, 63.1, 63.2, 72.4, 80.5, 88.0, 174.4, 217.5 ppm. HR-MS (ESI-TOF): m/ z C33H62O5Si2Na ( [M + Na ] + ) calcd. for 617.4028, found 617.4028
Methyl 7-((1R,2S,3R)-2-((S)-3-((tert-butyldimethylsilyl)oxy)oct-1-yn-1-yl)-3-hydroxy-5-oxocyclopentyl ) production of heptanoate (de-TES form) methyl 7-((1R,2S,3R)-2-((S)-3-((tert-butyldimethylsilyl)oxy)oct-1-yn-1-yl) -5-oxo-3-((triethylsilyl)oxy)cyclopentyl)heptanoate (10.0 mg, 0.0169 mmol) was added to a mixture of acetic acid-THF-H 2 O (3:1:1) (1.0 mL) and stirred for 1.5 hours. Stirred. After diluting with H2O and extracting with ethyl acetate, the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was eluted with a small amount of silica gel and treated with methyl 7-((1R,2S,3R)-2-((S)-3-((tert-butyldimethylsilyl)oxy)). Oct-1-yn-1-yl)-3-hydroxy-5-oxocyclopentyl)heptanoate (8.0 mg, 99%) was obtained as a colorless oil.
1 H NMR (400 Mz, CDCl 3 ) δ = 0.11 (s, 3H), 0.13 (s, 3H), 0.87-91 (m, 12H), 1.20-1.68 (m, 18H), 2.19-2.37 (m, 5H), 2.62-2.77 (m, 2H), 3.66 (s, 3H), 4.28-4.38 (m, 2H) ppm
(3R,4R)および(3S,4R)-2-メチレン-4-((トリエチルシリル)オキシ)-3-((S,E)-3-((トリエチルシリル)オキシ)オクト-1-エン-1-イル）シクロペンタン-1-オン
1H NMR (400 Mz, CDCl3) δ = 0.55-0.63 (m, 12H), 0.86-0.97 (m, 21H), 1.23-1.50 (m, 8H), 2.35 (dd, J = 3.2, 18.4 Hz, 1H), 2.64 (dd, J = 6.0, 18.4 Hz, 1H), 3.22-3.35 (m, 1H), 4.07-4.13 (m, 2H), 5.24-5.27 (m, 1H), 5.44-5.65 (m, 2H), 6.11-6.12 (m, 1H) ppm. 13C NMR (100 Mz, CDCl3) δ = 4.9, 5.1, 6.9, 14.2, 14.2, 22.8, 25.0, 31.9, 32.0, 38.6, 47.3, 54.6, 54.7, 72.8, 73.2, 119.5, 127.6, 137.7, 146.8, 203.5 ppm. HR-MS (ESI-TOF): m/z C26H48O3Si2Na ([M + Na]+) calcd. for 487.3034, found 487.3029(3R,4R) and (3S,4R)-2-methylene-4-((triethylsilyl)oxy)-3-((S,E)-3-((triethylsilyl)oxy)oct-1-ene- 1-yl)cyclopentan-1-one
1 H NMR (400 Mz, CDCl 3 ) δ = 0.55-0.63 (m, 12H), 0.86-0.97 (m, 21H), 1.23-1.50 (m, 8H), 2.35 (dd, J = 3.2, 18.4 Hz, 1H), 2.64 (dd, J = 6.0, 18.4 Hz, 1H), 3.22-3.35 (m, 1H), 4.07-4.13 (m, 2H), 5.24-5.27 (m, 1H), 5.44-5.65 (m, 2H), 6.11-6.12 (m, 1H) ppm. 13 C NMR (100 Mz, CDCl 3 ) δ = 4.9, 5.1, 6.9, 14.2, 14.2, 22.8, 25.0, 31.9, 32.0, 38.6, 47.3, 54.6, 54.7 , 72.8, 73.2, 119.5, 127.6, 137.7, 146.8, 203.5 ppm. HR-MS (ESI-TOF): m/z C26H48O3Si2Na ([M + Na] + ) calcd. for 487.3034 , found 487.3029
（非特許文献４）有機合成化学協会誌第57巻第5号、頁422－428(1999)では、PGE1製造の最終工程において非常に腐食性、毒性の高いフッ化水素を用いてTBS基を除去している。そのため、精製処理により厳密に取り除く必要がある。それに比べ、TES基は酢酸水溶液中で簡便に除去可能である。また、Eur. J. Org. Chem. 1999, 2655 にも記載の通り、２成分連結法から合成したPGE1の最終工程でPPTS触媒存在下、水-アセトン溶媒で反応を行うことでもTES基の除去が可能である。分液操作で容易に精製可能であるため、環境および製造の観点からも優れているといえる。
(Non-Patent Document 4) Journal of Synthetic Organic Chemistry, Vol. 57, No. 5, pp. 422-428 (1999) describes the use of hydrogen fluoride, which is highly corrosive and highly toxic, in the final process of producing PGE 1 to form a TBS group. are removed. Therefore, it must be strictly removed by purification treatment. In comparison, the TES group can be easily removed in aqueous acetic acid. Also, as described in Eur. J. Org. Chem. 1999, 2655, the TES group can also be synthesized by a reaction in water-acetone solvent in the presence of a PPTS catalyst in the final step of PGE 1 synthesized from the two-component ligation method. Removal is possible. Since it can be easily purified by a liquid separation operation, it can be said to be excellent from the viewpoint of environment and production.
Claims (8)
で表される化合物またはその立体異性体またはそれらの塩。 Formula (II)
A compound represented by or a stereoisomer thereof or a salt thereof.
で表される化合物またはその立体異性体またはそれらの塩の製造方法。 expression (i')
A method for producing a compound represented by or a stereoisomer thereof or a salt thereof.
で表される化合物またはその立体異性体またはそれらの塩に変換する工程、
式(II)の化合物と、式（III）（式中、Ｍは、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示す。）で表される金属有機化合物を反応させ、式（IV）の化合物を得る工程、
式（IV）化合物を式（V）（式中、Ｍ’は、Ｌｉ、Ｎａ、Ｋ、Ｍｇ、Ｃａ、Ｔｉ、Ｚｒ、Ｎｉ、Ｃｕ、Ｚｎ、Ａｌ、Ｓｎより選ばれる金属または該金属を含む基を示し、Ｒは、水素原子またはアルキル基を示す。）で表される有機金属化合物と反応させ、式（VI）の化合物を得る工程、
および式（VI）の化合物のシリル基を除去する工程を含む、式（VII）で示されるPGE1誘導体の製法方法。
Converting to a compound represented by or a stereoisomer thereof or a salt thereof,
A compound of formula (II) and formula (III) (wherein M is a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, Sn, or a metal selected from A step of reacting a metal organic compound represented by a group containing) to obtain a compound of formula (IV),
The compound of formula (IV) is converted to the formula (V) (wherein M' is a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, Sn, or contains the metal and R represents a hydrogen atom or an alkyl group) to obtain a compound of formula (VI);
and removing the silyl group of the compound of formula (VI).
8. The production method according to claim 7 , wherein the silyl halide is triethylsilyl chloride.
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