CN107513046A - 一种可比司他的合成方法 - Google Patents
一种可比司他的合成方法 Download PDFInfo
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- CN107513046A CN107513046A CN201610423418.2A CN201610423418A CN107513046A CN 107513046 A CN107513046 A CN 107513046A CN 201610423418 A CN201610423418 A CN 201610423418A CN 107513046 A CN107513046 A CN 107513046A
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- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 11
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical group C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
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- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000000047 product Substances 0.000 description 10
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- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
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- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 229960002402 cobicistat Drugs 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 3
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 3
- 229960003586 elvitegravir Drugs 0.000 description 3
- 229960000366 emtricitabine Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 description 3
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 244000248349 Citrus limon Species 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- YSIBYEBNVMDAPN-CMDGGOBGSA-N (e)-4-oxo-4-(3-triethoxysilylpropylamino)but-2-enoic acid Chemical compound CCO[Si](OCC)(OCC)CCCNC(=O)\C=C\C(O)=O YSIBYEBNVMDAPN-CMDGGOBGSA-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
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 0 CC(CN(C)C(N*C(CCN1CCOCC1)*(NCCC[C@@](NC(OCc1cnc[s]1)=O)Nc1ccccc1)O)=O)NC(C(C)(C)C)SC Chemical compound CC(CN(C)C(N*C(CCN1CCOCC1)*(NCCC[C@@](NC(OCc1cnc[s]1)=O)Nc1ccccc1)O)=O)NC(C(C)(C)C)SC 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229960003796 atazanavir sulfate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
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- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940009102 tybost Drugs 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (10)
Priority Applications (1)
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CN201610423418.2A CN107513046B (zh) | 2016-06-15 | 2016-06-15 | 一种可比司他的合成方法 |
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CN201610423418.2A CN107513046B (zh) | 2016-06-15 | 2016-06-15 | 一种可比司他的合成方法 |
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CN107513046A true CN107513046A (zh) | 2017-12-26 |
CN107513046B CN107513046B (zh) | 2019-12-13 |
Family
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CN201610423418.2A Active CN107513046B (zh) | 2016-06-15 | 2016-06-15 | 一种可比司他的合成方法 |
Country Status (1)
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109912426A (zh) * | 2017-12-13 | 2019-06-21 | 上海奥博生物医药技术有限公司 | 用于合成抗艾滋病药物增强剂可比司他(cobicistant)的新中间体 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679325A (zh) * | 2007-02-23 | 2010-03-24 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
WO2012088178A1 (en) * | 2010-12-21 | 2012-06-28 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 (cyp3a4) |
WO2014057498A2 (en) * | 2012-10-08 | 2014-04-17 | Mylan Laboratories Ltd. | Process for the preparation of cobicistat intermediates |
WO2014105777A1 (en) * | 2012-12-26 | 2014-07-03 | Assia Chemical Industries Ltd. | Cobicostat dichlohydrate salt |
CN104093702A (zh) * | 2012-02-03 | 2014-10-08 | 吉里德科学公司 | 用于制备药物试剂的方法和中间体 |
CN105198829A (zh) * | 2015-08-15 | 2015-12-30 | 浙江永宁药业股份有限公司 | 一种可比司他中间体的制备方法及其中间体和用途 |
-
2016
- 2016-06-15 CN CN201610423418.2A patent/CN107513046B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679325A (zh) * | 2007-02-23 | 2010-03-24 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
WO2012088178A1 (en) * | 2010-12-21 | 2012-06-28 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 (cyp3a4) |
CN104093702A (zh) * | 2012-02-03 | 2014-10-08 | 吉里德科学公司 | 用于制备药物试剂的方法和中间体 |
WO2014057498A2 (en) * | 2012-10-08 | 2014-04-17 | Mylan Laboratories Ltd. | Process for the preparation of cobicistat intermediates |
WO2014105777A1 (en) * | 2012-12-26 | 2014-07-03 | Assia Chemical Industries Ltd. | Cobicostat dichlohydrate salt |
CN105198829A (zh) * | 2015-08-15 | 2015-12-30 | 浙江永宁药业股份有限公司 | 一种可比司他中间体的制备方法及其中间体和用途 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109912426A (zh) * | 2017-12-13 | 2019-06-21 | 上海奥博生物医药技术有限公司 | 用于合成抗艾滋病药物增强剂可比司他(cobicistant)的新中间体 |
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Address after: 223800 Suqian Eco-chemical Science and Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu Alpha Group Furui Pharmaceutical (Suqian) Co.,Ltd. Country or region after: China Address before: 223800 Suqian Eco-chemical Science and Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: Jiangsu Furui Kangtai Pharmaceutical Co.,Ltd. Country or region before: China |
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