KR102129150B1 - 이사부코나졸 또는 라부코나졸의 제조 방법 - Google Patents
이사부코나졸 또는 라부코나졸의 제조 방법 Download PDFInfo
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- KR102129150B1 KR102129150B1 KR1020157001779A KR20157001779A KR102129150B1 KR 102129150 B1 KR102129150 B1 KR 102129150B1 KR 1020157001779 A KR1020157001779 A KR 1020157001779A KR 20157001779 A KR20157001779 A KR 20157001779A KR 102129150 B1 KR102129150 B1 KR 102129150B1
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- pro
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- 238000000034 method Methods 0.000 title claims abstract description 65
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 230000008569 process Effects 0.000 title description 14
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 title description 2
- 229960000788 isavuconazole Drugs 0.000 title description 2
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 title description 2
- 229950004154 ravuconazole Drugs 0.000 title description 2
- 108090000371 Esterases Proteins 0.000 claims abstract description 48
- 150000002576 ketones Chemical class 0.000 claims abstract description 35
- 238000006680 Reformatsky reaction Methods 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims description 67
- 238000006243 chemical reaction Methods 0.000 claims description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 29
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052725 zinc Inorganic materials 0.000 claims description 26
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- 239000000203 mixture Substances 0.000 claims description 22
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- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 14
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- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 12
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 229920001184 polypeptide Polymers 0.000 claims description 10
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
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- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
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- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
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- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
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- 150000001649 bromium compounds Chemical group 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- ZTWQHVRMOJLGRW-UHFFFAOYSA-N 3-hydroxy-2-methyl-3-phenyl-4-(1,2,4-triazol-1-yl)butanoic acid Chemical compound C=1C=CC=CC=1C(O)(C(C(O)=O)C)CN1C=NC=N1 ZTWQHVRMOJLGRW-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
- 239000006184 cosolvent Substances 0.000 claims description 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- NLPHXWGWBKZSJC-UHFFFAOYSA-N 4-acetylbenzonitrile Chemical class CC(=O)C1=CC=C(C#N)C=C1 NLPHXWGWBKZSJC-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 239000011737 fluorine Substances 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- ZTWQHVRMOJLGRW-GXFFZTMASA-N (2r,3r)-3-hydroxy-2-methyl-3-phenyl-4-(1,2,4-triazol-1-yl)butanoic acid Chemical compound C([C@@](O)([C@H](C(O)=O)C)C=1C=CC=CC=1)N1C=NC=N1 ZTWQHVRMOJLGRW-GXFFZTMASA-N 0.000 claims 1
- AHYMJWOBUAYXDS-UHFFFAOYSA-N 3-phenyl-2-(triazol-1-yl)butanoic acid Chemical compound N1(N=NC=C1)C(C(=O)O)C(C)C1=CC=CC=C1 AHYMJWOBUAYXDS-UHFFFAOYSA-N 0.000 claims 1
- ASBQZLJHLBWDAI-UHFFFAOYSA-N CC(C(=O)O)C(CN1N=CN=C1)C1=CC=CC=C1 Chemical compound CC(C(=O)O)C(CN1N=CN=C1)C1=CC=CC=C1 ASBQZLJHLBWDAI-UHFFFAOYSA-N 0.000 claims 1
- 125000001391 thioamide group Chemical group 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 abstract description 30
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- 150000001875 compounds Chemical class 0.000 abstract description 8
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 abstract description 4
- 241000282326 Felis catus Species 0.000 description 48
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- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 24
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 24
- 108010034529 leucyl-lysine Proteins 0.000 description 24
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- 108010093581 aspartyl-proline Proteins 0.000 description 22
- 239000000243 solution Substances 0.000 description 16
- DINOVZWPTMGSRF-QXEWZRGKSA-N Asp-Pro-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O DINOVZWPTMGSRF-QXEWZRGKSA-N 0.000 description 14
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- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 12
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- YJIUYQKQBBQYHZ-ACZMJKKPSA-N Gln-Ala-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O YJIUYQKQBBQYHZ-ACZMJKKPSA-N 0.000 description 12
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| WO1999045008A1 (en) | 1998-03-06 | 1999-09-10 | F. Hoffmann-La Roche Ag | 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity |
| AU2002321068B2 (en) * | 2001-06-26 | 2007-11-15 | Basilea Pharmaceutica Ag | Intermediate halophenyl derivatives and their use in a process for preparing azole derivatives |
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| WO2009157418A1 (ja) * | 2008-06-25 | 2009-12-30 | 第一三共株式会社 | カルボン酸化合物 |
| MX2011000179A (es) * | 2008-07-03 | 2011-04-05 | Astellas Pharma Inc | Derivado de triazol o su sal. |
| WO2010122175A1 (en) | 2009-04-24 | 2010-10-28 | Dsm Ip Assets B.V. | Improved pig liver esterases |
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- 2013-07-31 ES ES13747999.4T patent/ES2616412T3/es active Active
- 2013-07-31 HR HRP20170171TT patent/HRP20170171T1/hr unknown
- 2013-07-31 CN CN201380038886.2A patent/CN104507917B/zh active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| PT2882723T (pt) | 2017-02-23 |
| ES2616412T3 (es) | 2017-06-13 |
| KR20150037875A (ko) | 2015-04-08 |
| JP2015527345A (ja) | 2015-09-17 |
| WO2014023623A1 (en) | 2014-02-13 |
| MX2015000744A (es) | 2015-04-14 |
| PL2882723T3 (pl) | 2017-05-31 |
| US20190077771A1 (en) | 2019-03-14 |
| EP2882723B1 (en) | 2016-11-16 |
| US10590092B2 (en) | 2020-03-17 |
| JP6334529B2 (ja) | 2018-05-30 |
| CA2878361A1 (en) | 2014-02-13 |
| CA2878361C (en) | 2020-09-22 |
| HUE031679T2 (en) | 2017-07-28 |
| CN104507917B (zh) | 2017-10-17 |
| BR112015002526A2 (pt) | 2018-06-12 |
| US20150239852A1 (en) | 2015-08-27 |
| BR112015002526B1 (pt) | 2022-09-06 |
| CN104507917A (zh) | 2015-04-08 |
| HRP20170171T1 (hr) | 2017-04-07 |
| MX360783B (es) | 2018-11-16 |
| EP2882723A1 (en) | 2015-06-17 |
| US9783508B2 (en) | 2017-10-10 |
| SI2882723T1 (sl) | 2017-04-26 |
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