WO2015133405A1 - 光学活性アゼチジノン化合物の製造方法 - Google Patents
光学活性アゼチジノン化合物の製造方法 Download PDFInfo
- Publication number
- WO2015133405A1 WO2015133405A1 PCT/JP2015/055924 JP2015055924W WO2015133405A1 WO 2015133405 A1 WO2015133405 A1 WO 2015133405A1 JP 2015055924 W JP2015055924 W JP 2015055924W WO 2015133405 A1 WO2015133405 A1 WO 2015133405A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optically active
- compound
- formula
- azetidinone compound
- group
- Prior art date
Links
- -1 azetidinone compound Chemical class 0.000 title claims abstract description 64
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 230000001939 inductive effect Effects 0.000 claims description 2
- 230000000707 stereoselective effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000014759 maintenance of location Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound 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
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- VBUZIXJFGCVTJL-UHFFFAOYSA-N azanium;methanol;formate Chemical compound [NH4+].OC.[O-]C=O VBUZIXJFGCVTJL-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 244000274847 Betula papyrifera Species 0.000 description 1
- 235000009113 Betula papyrifera Nutrition 0.000 description 1
- 235000009109 Betula pendula Nutrition 0.000 description 1
- 235000010928 Betula populifolia Nutrition 0.000 description 1
- 235000002992 Betula pubescens Nutrition 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@@](CCC([C@@](c(cc1)ccc1O*)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound C[C@@](CCC([C@@](c(cc1)ccc1O*)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- BVYNXBNCXPJQCW-PQHLKRTFSA-N O=C(CC[C@H]([C@@H](c(cc1)ccc1OCc1ccccc1)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound O=C(CC[C@H]([C@@H](c(cc1)ccc1OCc1ccccc1)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F BVYNXBNCXPJQCW-PQHLKRTFSA-N 0.000 description 1
- FOWWDYMLCOKZTN-QKBZBAIHSA-N O[C@@H](CC[C@H]([C@@H](c(cc1)ccc1OCc1ccccc1)N1C2=CC[C@H]2F)C1=O)c(cc1)ccc1F Chemical compound O[C@@H](CC[C@H]([C@@H](c(cc1)ccc1OCc1ccccc1)N1C2=CC[C@H]2F)C1=O)c(cc1)ccc1F FOWWDYMLCOKZTN-QKBZBAIHSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UTQCNMRDWASSEC-UHFFFAOYSA-L [1-[2-bis(3,5-dimethylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(3,5-dimethylphenyl)phosphane 1,1-bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine dichlororuthenium Chemical compound Cl[Ru]Cl.C1=CC(OC)=CC=C1C(N)(C(N)C(C)C)C1=CC=C(OC)C=C1.CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C(=C3C=CC=CC3=CC=2)C=2C3=CC=CC=C3C=CC=2P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)=C1 UTQCNMRDWASSEC-UHFFFAOYSA-L 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for producing an optically active azetidinone compound.
- the azetidinone compound (compound (1)) represented by the formula (1) is useful as a therapeutic agent for hyperlipidemia (see Non-Patent Document 1).
- the azetidinone compound (compound (4)) represented by formula (4) which is one of the precursors of compound (1), reduces the ketone compound (compound (2)) represented by formula (2).
- the presence of an asymmetric reduction catalyst such as RuCl 2 ((R) -xylBinap) ((R) -daipen) represented by formula (3) A method of reducing under is reported (see Patent Document 1).
- Patent Document 1 describes that the reaction conversion rate is lowered and the reaction time is extended by reducing the amount of the catalyst. Further, the hydrogen pressure during the reaction is described as 2 to 3 MPa, which is a condition requiring special equipment. Therefore, an industrially suitable improved manufacturing method has been desired.
- the present invention provides a production precursor of compound (1) and a further production method of compound (1).
- the present inventors have conducted an intensive study aimed at providing a high yield, high stereoselective and industrially useful production method of an optically active azetidinone compound.
- the inventors have found a production method capable of obtaining an optically active azetidinone compound with selectivity and high yield, and completed the present invention.
- the present invention relates to the following [1] to [10].
- Formula (5) (Wherein R represents a hydrogen atom or a hydroxy protecting group), a ketone compound represented by formula (6): (In the formula, Ar represents a 3,5-dimethylphenyl group.)
- an optically active ruthenium catalyst represented by formula (7) The manufacturing method of the optically active azetidinone compound represented by these.
- an optically active azetidinone compound represented by the formula (7) useful as a pharmaceutical intermediate can be produced in large quantities with high selectivity and high yield, and the present invention is useful as an industrial production method. Is expensive.
- n- is normal, “t-” is tertiary, “c-” is cyclo, “o-” is ortho, “Bn” is benzyl, “TBS”. Means t-butyldimethylsilyl.
- optically active azetidinone compounds (7) and (1) The production method of the optically active azetidinone compounds (7) and (1) will be described in detail below.
- the amount of the asymmetric reduction catalyst used is 1 / 100,000 mol% to 100 mol%, preferably 0.01 mol% to 5 mol% with respect to the ketone compound (5).
- a base can be added to accelerate the reaction.
- the base used include alkali metal salts of alcohols. More preferred bases are sodium methoxide, sodium ethoxide, potassium t-butoxide, and most preferred is potassium t-butoxide.
- the amount of the base to be added may be the same amount or more with respect to the asymmetric reduction catalyst to be used, and preferably 10 to 500 equivalents with respect to the catalyst.
- the solvent used in this reaction is not limited as long as it does not inhibit the progress of the reaction.
- Preferred examples include water, aprotic polar organic solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide, N, N -Dimethylacetamide, tetramethylurea, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, etc.), fat Aromatic hydrocarbon solvents (eg, pentane, n-hexane, c-hexane, octane, decane, decalin, petroleum ether, etc.), aromatic hydrocarbon solvents (benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene,
- the reaction temperature is preferably about 10 to 50 ° C, more preferably about 20 to 30 ° C.
- the reducing agent that can be used is not particularly limited as long as it is a reducing agent that is used as a reagent, and examples thereof include hydrogen gas.
- the hydrogen pressure at the time of carrying out the reaction can be carried out at an arbitrary pressure, but it is preferably in the range of 0.1 to 4.0 MPa, more preferably 0 from the viewpoint of contribution to the reaction and adaptation to industrial production.
- the range is from 1 to 1.0 MPa.
- Hydroxy protecting groups can be used in deprotection reactions (eg, Protective Groups Organic Synthesis, Fourth edition, TWGreene), John Wiley and Sons. Incorporated (see John Wiley & Sons Inc. (2006) etc.) can be removed.
- the hydroxy protecting group in this production method is not limited as long as it does not inhibit the progress of the reaction, and a protecting group usually used in organic synthesis can be used.
- Preferred hydroxy protecting groups include, for example, benzyl group, methyl group, methoxymethyl group, acetyl group, trimethylsilyl group, t-butyldimethylsilyl group, allyl group, etc., preferably benzyl group, t-butyldimethylsilyl group Or an allyl group.
- Ketone compounds (2) and (8) are known compounds and can be synthesized according to methods described in the literature, for example, methods described in International Publication No. 2007/119106, International Publication No. 2007/072088 and the like.
- the conversion rate from the compound (2) to the compound (4) was 100.00%.
- To the obtained solution was added 423.7 mg (7.06 mmol) of acetic acid and stirred, and then insoluble matter was filtered off.
- the obtained filtrate was concentrated to 104.78 g under reduced pressure, then 327.82 g of ethanol was added and heated to 71 ° C. After cooling to 22 ° C., 54.00 g of water was added and cooled to 1 ° C.
- the precipitated solid was filtered, washed with a mixed solution of 43.23 g of ethanol and 10.94 g of water, further washed with a mixed solution of 43.28 g of ethanol and 10.82 g of ion-exchanged water, and 49.73 g of Compound (4) as a white solid.
- the chemical purity of the obtained compound (4) was 99.96%, and the diastereomeric excess was 99.88% de.
- Example 3 The same operation as in Example 3 was carried out except that the hydrogen pressure was changed to 500 kPa in Example 3, to obtain 1.89 g of Compound (4).
- the conversion rate from compound (2) to compound (4) after stirring for 1 hour was 97.44%, and the diastereomeric excess was 100.00% de.
- the present invention is useful in that an optically active azetidinone compound useful as a pharmaceutical intermediate can be produced with high yield and high stereoselectivity.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
〔1〕
式(5):
で表される光学活性ルテニウム触媒の存在下、水素ガスを反応させることを特徴とする、式(7):
〔2〕
Rが水素原子である、上記〔1〕記載の光学活性アゼチジノン化合物の製造方法。
〔3〕
Rがヒドロキシ保護基である、上記〔1〕記載の光学活性アゼチジノン化合物の製造方法。
〔4〕
Rがベンジル基である、上記〔3〕記載の光学活性アゼチジノン化合物の製造方法。
〔5〕
Rがt-ブチルジメチルシリル基である、上記〔3〕記載の光学活性アゼチジノン化合物の製造方法。
〔6〕
Rがアリル基である、上記〔3〕記載の光学活性アゼチジノン化合物の製造方法。
〔7〕
式(5):
で表される光学活性ルテニウム触媒の存在下、水素ガスを反応させ、
式(7):
式(1):
で表される光学活性アゼチジノン化合物の製造方法。
〔8〕
Rがベンジル基である、上記〔7〕記載の光学活性アゼチジノン化合物の製造方法。
〔9〕
Rがt-ブチルジメチルシリル基である、上記〔7〕記載の光学活性アゼチジノン化合物の製造方法。
〔10〕
Rがアリル基である、上記〔7〕記載の光学活性アゼチジノン化合物の製造方法。
[1]1H-NMR
機種:ECP300(日本電子株式会社製品)
測定溶媒:DMSO-d6
[2]HPLC
(1)HPLC分析条件1(化学純度及び反応転化率の測定に使用)
装置:アジレント1260
カラム:L-Column ODS(財団法人化学物質評価研究機構製品)
250×4.6mmI.D. 5μm
カラムオーブン温度:40℃
溶離液:アセトニトリル、10mM酢酸アンモニウム水溶液混合溶媒
グラジェント条件(アセトニトリル体積比):20%(0min.)→20%(10min.)→50%(15min.)→50%(30min.)→95%(40min.)→95%(50min.)
かっこ内のタイムプログラムは分析開始からの総時間を表す。
流速:1.0mL/min.
検出器:紫外可視吸光光度計233nm
(2)HPLC分析条件2(光学純度の測定に使用)
装置:島津20A
カラム:CHIRALPAK IC(株式会社ダイセル製品)
250mm×4.6mmI.D. 5μm
カラムオーブン温度:35℃
溶離液:ヘキサン/2-プロパノール/トリフルオロ酢酸=900/100/1(V/V/V)
流速:1.0mL/min.
検出器:紫外可視吸光光度計233nm
ここへ20%硫酸水溶液1.37g(2.79mmol)を加えて、58~59℃で1時間撹拌後、放冷したところ、白色の固体が析出した。ここへ水8.46gを滴下し、更に、0~3℃で3時間撹拌して、析出した固体をろ過した。2-プロパノール2.09gと水2.09gの混液、2-プロパノール2.11gと水2.10gの混液、水2.11gで洗浄し、50℃で減圧乾燥して、化合物(1)1.34gを白色固体として得た。
HPLC分析条件1にて化学純度を測定したところ、97.49%であった。
また、HPLC分析条件2にてジアステレオマー過剰率を測定したところ、99.01%deであった。さらに、その保持時間は、特許第3640888号に記載の方法に準じて合成した化合物(1)の保持時間と一致した(保持時間:19.7分、ジアステレオマーの保持時間:24.6分)。
また、2段階反応の生成物である(1)のジアステレオマー過剰率が99.01%deであり、2工程目でジアステレオマー過剰率が保持されると考えられることから、1段階目生成物の化合物(9)のジアステレオマー過剰率は99.01%de以上であることが分かる。
1H-NMR分析:(300MHz,DMSO―d6)δppm:1.72-1.88(4H,m),3.06-3.08(1H,m),4.49(1H,s),4.80(1H,d,J=2.2Hz),5.28(1H,br),6.76(2H,d,J=8.5Hz),7.09-7.16(4H,m),7.19-7.24(4H,m),7.28-7.33(2H,m),9.53(1H,s)
1H-NMR分析:(300MHz,CDCl3)δppm:1.84-1.99(4H,m),2.38(1H,d,J=2.9Hz),3.00(1H,d,J=5.2Hz),4.56(1H,br),4.64(1H,br),5.04(2H,s),6.88-7.03(6H,m),7.20-7.42(11H,m)
攪拌1時間後の化合物(2)から化合物(4)への転化率は97.44%であり、ジアステレオマー過剰率は100.00%deであった。
また、この白色固体のXRDを測定したところ、特表2007-526251号に記載のフォームAの回折パターンと一致した。
1H-NMR分析:(300MHz,CDCl3)δppm:1.85-2.02(4H,m),2.24(1H,d,J=3.8Hz),3.05-3.10(1H,m)4.51-4.54(2H,m),4.57(2H,d,J=16.7Hz),4.71-4.73(1H,m)5.27-5.44(2H,m),5.98-6.10(1H,m)6.89-7.05(6H,m),7.19-7.31(6H,m)
Claims (10)
- Rが水素原子である、請求項1記載の光学活性アゼチジノン化合物の製造方法。
- Rがヒドロキシ保護基である、請求項1記載の光学活性アゼチジノン化合物の製造方法。
- Rがベンジル基である、請求項3記載の光学活性アゼチジノン化合物の製造方法。
- Rがt-ブチルジメチルシリル基である、請求項3記載の光学活性アゼチジノン化合物の製造方法。
- Rがアリル基である、請求項3記載の光学活性アゼチジノン化合物の製造方法。
- Rがベンジル基である、請求項7記載の光学活性アゼチジノン化合物の製造方法。
- Rがt-ブチルジメチルシリル基である、請求項7記載の光学活性アゼチジノン化合物の製造方法。
- Rがアリル基である、請求項7記載の光学活性アゼチジノン化合物の製造方法。
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- 2015-02-27 JP JP2016506463A patent/JP6795974B2/ja active Active
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