CN113614075A - 伏立康唑及其中间体的制备方法 - Google Patents
伏立康唑及其中间体的制备方法 Download PDFInfo
- Publication number
- CN113614075A CN113614075A CN202080007221.5A CN202080007221A CN113614075A CN 113614075 A CN113614075 A CN 113614075A CN 202080007221 A CN202080007221 A CN 202080007221A CN 113614075 A CN113614075 A CN 113614075A
- Authority
- CN
- China
- Prior art keywords
- compound
- voriconazole
- acid
- process according
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 40
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000000543 intermediate Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 229940126214 compound 3 Drugs 0.000 claims description 22
- 229940125782 compound 2 Drugs 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 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 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract description 8
- LKTGVRWVTAJGMS-UHFFFAOYSA-N 4-chloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC(Cl)=C1F LKTGVRWVTAJGMS-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 5
- -1 1H-1,2, 4-triazolyl Chemical group 0.000 abstract description 4
- BCEHBSKCWLPMDN-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C(=CC(F)=CC=1)F)C(C)C1=NC=NC=C1F BCEHBSKCWLPMDN-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- WNAHEVXTGAEKIY-ZDUSSCGKSA-N tert-butyl n-[(2r)-1-phenylbut-3-en-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C=C)CC1=CC=CC=C1 WNAHEVXTGAEKIY-ZDUSSCGKSA-N 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 201000009085 invasive aspergillosis Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
公开了伏立康唑及其中间体的制备方法。本发明公开了以伏立康唑缩合物异构体为原料于酸存在下反应以获得4‑氯‑6‑乙基‑5‑氟嘧啶和2',4'‑二氟‑2‑[1‑(1H‑1,2,4‑三唑基)]苯乙酮的方法。本发明还公开了利用由此获得的中间体制备伏立康唑的方法。采用本发明的方法可以大幅提高按照现有技术制备伏立康唑的原料和辅料的利用率，从而降低成本。
Description
PCT国内申请，说明书已公开。
Claims (9)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019101219610 | 2019-02-19 | ||
| CN201910121961.0A CN109705102A (zh) | 2019-02-19 | 2019-02-19 | 伏立康唑及其中间体的制备方法 |
| PCT/CN2020/075707 WO2020169025A1 (zh) | 2019-02-19 | 2020-02-18 | 伏立康唑及其中间体的制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113614075A true CN113614075A (zh) | 2021-11-05 |
Family
ID=66263809
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910121961.0A Pending CN109705102A (zh) | 2019-02-19 | 2019-02-19 | 伏立康唑及其中间体的制备方法 |
| CN202080007221.5A Pending CN113614075A (zh) | 2019-02-19 | 2020-02-18 | 伏立康唑及其中间体的制备方法 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910121961.0A Pending CN109705102A (zh) | 2019-02-19 | 2019-02-19 | 伏立康唑及其中间体的制备方法 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20220162189A1 (zh) |
| EP (1) | EP3929191A1 (zh) |
| CN (2) | CN109705102A (zh) |
| WO (1) | WO2020169025A1 (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112442017A (zh) * | 2019-08-29 | 2021-03-05 | 珠海润都制药股份有限公司 | 一种采用微通道反应器制备伏立康唑消旋体的方法 |
| WO2021127965A1 (zh) * | 2019-12-24 | 2021-07-01 | 刘杰 | 一种伏立康唑对映异构体的回收方法 |
| CN111217758A (zh) * | 2020-03-18 | 2020-06-02 | 湖南复瑞生物医药技术有限责任公司 | 一种6-乙基-5-氟-4-氯嘧啶的制备方法 |
| CN114057699B (zh) * | 2021-07-13 | 2024-05-10 | 西安丽彩医药研发有限公司 | 一种伏立康唑中间体外消旋体的制备方法 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195346A (zh) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | 通过有机金属化合物对酮及其中间体的加成合成三唑化合物 |
| CN102190628A (zh) * | 2010-03-03 | 2011-09-21 | 浙江海翔药业股份有限公司 | 一种5-氟-6-乙基-4-羟基嘧啶中间体及伏立康唑的制备方法 |
| CN103788073A (zh) * | 2013-12-18 | 2014-05-14 | 北京华禧联合科技发展有限公司 | 一种制备伏立康唑关键中间体的新方法 |
| CN105503834A (zh) * | 2015-12-23 | 2016-04-20 | 浙江华海药业股份有限公司 | 一种伏立康唑中间体的合成方法 |
| CN106117186A (zh) * | 2016-06-12 | 2016-11-16 | 重庆莱美隆宇药业有限公司 | 一种伏立康唑及其中间体的制备方法 |
| CN107827876A (zh) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | 一种伏立康唑消旋体的制备方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9002375D0 (en) | 1990-02-02 | 1990-04-04 | Pfizer Ltd | Triazole antifungal agents |
| CN1919846B (zh) | 2006-09-14 | 2013-01-02 | 大道隆达（北京）医药科技发展有限公司 | 伏立康唑及其药用盐、中间体的一种新定向合成制备方法 |
-
2019
- 2019-02-19 CN CN201910121961.0A patent/CN109705102A/zh active Pending
-
2020
- 2020-02-18 WO PCT/CN2020/075707 patent/WO2020169025A1/zh unknown
- 2020-02-18 CN CN202080007221.5A patent/CN113614075A/zh active Pending
- 2020-02-18 EP EP20758561.3A patent/EP3929191A1/en active Pending
- 2020-02-18 US US17/430,794 patent/US20220162189A1/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195346A (zh) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | 通过有机金属化合物对酮及其中间体的加成合成三唑化合物 |
| CN102190628A (zh) * | 2010-03-03 | 2011-09-21 | 浙江海翔药业股份有限公司 | 一种5-氟-6-乙基-4-羟基嘧啶中间体及伏立康唑的制备方法 |
| CN103788073A (zh) * | 2013-12-18 | 2014-05-14 | 北京华禧联合科技发展有限公司 | 一种制备伏立康唑关键中间体的新方法 |
| CN105503834A (zh) * | 2015-12-23 | 2016-04-20 | 浙江华海药业股份有限公司 | 一种伏立康唑中间体的合成方法 |
| CN106117186A (zh) * | 2016-06-12 | 2016-11-16 | 重庆莱美隆宇药业有限公司 | 一种伏立康唑及其中间体的制备方法 |
| CN107827876A (zh) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | 一种伏立康唑消旋体的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3929191A4 (en) | 2021-12-29 |
| EP3929191A1 (en) | 2021-12-29 |
| WO2020169025A1 (zh) | 2020-08-27 |
| CN109705102A (zh) | 2019-05-03 |
| US20220162189A1 (en) | 2022-05-26 |
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