JP2016147843A - エゼチミブ及びその中間体の製造方法 - Google Patents
エゼチミブ及びその中間体の製造方法 Download PDFInfo
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- JP2016147843A JP2016147843A JP2015201131A JP2015201131A JP2016147843A JP 2016147843 A JP2016147843 A JP 2016147843A JP 2015201131 A JP2015201131 A JP 2015201131A JP 2015201131 A JP2015201131 A JP 2015201131A JP 2016147843 A JP2016147843 A JP 2016147843A
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- ezetimibe
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 30
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 26
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 16
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 125000001033 ether group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 22
- -1 triethylsilyl group Chemical group 0.000 claims description 8
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical group COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 claims description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003529 anticholesteremic agent Substances 0.000 abstract description 2
- 229940127226 anticholesterol agent Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 239000007788 liquid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- ZVTWZSXLLMNMQC-UHFFFAOYSA-N 4-phenylmethoxybenzaldehyde Chemical compound C1=CC(C=O)=CC=C1OCC1=CC=CC=C1 ZVTWZSXLLMNMQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 0 *[C@@](CC[C@](C(c(cc1)ccc1O*)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound *[C@@](CC[C@](C(c(cc1)ccc1O*)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F 0.000 description 1
- IWNBEFDVKWCBFY-HYARGMPZSA-N Fc(cc1)ccc1/N=C/c(cc1)ccc1OCc1ccccc1 Chemical compound Fc(cc1)ccc1/N=C/c(cc1)ccc1OCc1ccccc1 IWNBEFDVKWCBFY-HYARGMPZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 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 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000004079 stearyl 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])C([H])([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
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
前記濃縮物にジクロロメタン(150ml)を加え、ビストリメチルシリルアセトアミド(BSA)(36.94g,1.3eq)を加え、50℃に加熱し1時間回流させ、反応完了まで薄層クロマトグラフィー(TLC)で監視する。反応液を濃縮、乾燥して、無水エタノール(300ml)を加え、室温で1時間撹拌、洗浄して、抽出、濾過を行い、乾燥して式(III)のオフホワイトの固体(93g)が得られ、収率は93%であり、純度は99%である。
後処理は以下の通りである。即ち、酢酸(0.65eq)を加えて撹拌し、減圧下で乾燥まで脱溶媒を行って、M1が得られ、M1の残留物にイソプロパノール(5V)を加え、2Nの硫酸(0.5V)と室温で酸化を行い、原料の反応完了まで監視する。水洗、乾燥、脱溶媒を行って油状物が得られ、油状物をn−ヘキサン(360ml,18V)で一晩撹拌して固液分離され、抽出、濾過してM2の固体(16g)が得られ、収率は96%である。
第一ステップ:カップリング反応
上記濃縮物にジクロロメタン(100ml)を加え、ビストリメチルシリルアセトアミド(BSA)(26.4g,1.3eq)を加え、50℃に加熱し1時間回流させ、反応完了まで薄層クロマトグラフィー(TLC)で監視する。反応液を濃縮、乾燥して、無水エタノール(200ml)を加え、室温で1時間撹拌し、抽出、濾過し、乾燥して式(III’)のオフホワイトの固体(62.3g)が得られ、収率は94%であり、純度は99%である。
第二ステップ:水酸基の保護
Claims (7)
- R2はトリメチルシリル基、tert−ブチルジメチルシリル基、トリエチルシリル基、2−メトキシプロペン基のうちの何れか一種が選ばれることを特徴とする請求項1に記載のエゼチミブの製造方法。
- R1はベンジル基、R2はトリメチルシリル基であることを特徴とする請求項2に記載のエゼチミブの製造方法。
- エゼチミブの製造中に用いることを特徴とする、請求項6に記載の化合物中間体。
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CN201510083806.6 | 2015-02-15 | ||
CN201510083806.6A CN105985275B (zh) | 2015-02-15 | 2015-02-15 | 一种依泽替米贝及其中间体的制备方法 |
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JP2016147843A true JP2016147843A (ja) | 2016-08-18 |
JP6153209B2 JP6153209B2 (ja) | 2017-06-28 |
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JP2015201131A Active JP6153209B2 (ja) | 2015-02-15 | 2015-10-09 | エゼチミブ及びその中間体の製造方法 |
Country Status (2)
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JP (1) | JP6153209B2 (ja) |
CN (1) | CN105985275B (ja) |
Families Citing this family (1)
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CN110143928A (zh) * | 2018-02-12 | 2019-08-20 | 罗欣药业(上海)有限公司 | 一种依折麦布关键中间体的晶型及制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
CN101845010A (zh) * | 2010-02-10 | 2010-09-29 | 浙江大学 | 一种制备伊替米贝的方法 |
WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
CN102850390A (zh) * | 2011-07-01 | 2013-01-02 | 江苏豪森药业股份有限公司 | 依折麦布的中间体及其制备方法 |
CN103864708A (zh) * | 2012-12-12 | 2014-06-18 | 天津市医药集团技术发展有限公司 | 一种依折麦布中间体的制备方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CZ2008317A3 (cs) * | 2008-05-21 | 2009-12-02 | Zentiva, A. S. | Zpusob výroby (3R,4S)-1-(4-fluorfenyl)-3-[(3S)-3-(4-fluorfenyl)-3-hydroxypropyl)]-4-(4-hydroxyfenyl)-2-azetidinonu |
PL387331A1 (pl) * | 2009-02-24 | 2010-08-30 | Instytut Chemii Organicznej Polskiej Akademii Nauk | Sposób wytwarzania aldehydowego związku beta-laktamowego, związek pośredni, sposób wytwarzania związku pośredniego oraz zastosowanie związku pośredniego |
-
2015
- 2015-02-15 CN CN201510083806.6A patent/CN105985275B/zh active Active
- 2015-10-09 JP JP2015201131A patent/JP6153209B2/ja active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
CN101845010A (zh) * | 2010-02-10 | 2010-09-29 | 浙江大学 | 一种制备伊替米贝的方法 |
CN102850390A (zh) * | 2011-07-01 | 2013-01-02 | 江苏豪森药业股份有限公司 | 依折麦布的中间体及其制备方法 |
CN103864708A (zh) * | 2012-12-12 | 2014-06-18 | 天津市医药集团技术发展有限公司 | 一种依折麦布中间体的制备方法 |
Non-Patent Citations (2)
Title |
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DATABASE CAPLUS ON STN, AN 2013:420725, DN 159:259959, YU, C.-G., ET AL., NEW SYNTHESIS PROCESS FOR, JPN7016003276 * |
PETER G. M. WUTS, GREENE'S PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, FIFTH EDITION, JPN6016042043, 2014, pages 90 - 91 * |
Also Published As
Publication number | Publication date |
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CN105985275B (zh) | 2018-12-14 |
JP6153209B2 (ja) | 2017-06-28 |
CN105985275A (zh) | 2016-10-05 |
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