CN113816972A - Preparation method of HIV inhibitor and intermediate crystal form thereof - Google Patents
Preparation method of HIV inhibitor and intermediate crystal form thereof Download PDFInfo
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- CN113816972A CN113816972A CN202111359127.9A CN202111359127A CN113816972A CN 113816972 A CN113816972 A CN 113816972A CN 202111359127 A CN202111359127 A CN 202111359127A CN 113816972 A CN113816972 A CN 113816972A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000013078 crystal Substances 0.000 title abstract description 14
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims description 91
- 238000001816 cooling Methods 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- AGMZSYQMSHMXLT-SCSAIBSYSA-N (3r)-3-aminobutan-1-ol Chemical compound C[C@@H](N)CCO AGMZSYQMSHMXLT-SCSAIBSYSA-N 0.000 claims description 5
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 5
- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 238000003756 stirring Methods 0.000 description 29
- 238000010438 heat treatment Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000000967 suction filtration Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000001291 vacuum drying Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000002386 leaching Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 238000000634 powder X-ray diffraction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229950004159 bictegravir Drugs 0.000 description 4
- SOLUWJRYJLAZCX-LYOVBCGYSA-N bictegravir Chemical compound C([C@H]1O[C@@H]2CC[C@@H](C2)N1C(=O)C1=C(C2=O)O)N1C=C2C(=O)NCC1=C(F)C=C(F)C=C1F SOLUWJRYJLAZCX-LYOVBCGYSA-N 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 229950005928 cabotegravir Drugs 0.000 description 3
- WCWSTNLSLKSJPK-LKFCYVNXSA-N cabotegravir Chemical compound C([C@H]1OC[C@@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F WCWSTNLSLKSJPK-LKFCYVNXSA-N 0.000 description 3
- 229960001976 dolutegravir sodium Drugs 0.000 description 3
- UGWJRRXTMKRYNK-VSLILLSYSA-M dolutegravir sodium Chemical compound [Na+].C([C@@H]1OCC[C@H](N1C(=O)C1=C([O-])C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F UGWJRRXTMKRYNK-VSLILLSYSA-M 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229940124524 integrase inhibitor Drugs 0.000 description 3
- 239000002850 integrase inhibitor Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 2
- 102100021202 Desmocollin-1 Human genes 0.000 description 2
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 2
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- -1 Polycyclic carbamoylpyrimidines derivatives Chemical class 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RCHOKTKXVKKNBC-UHFFFAOYSA-N (2,4,6-trifluorophenyl)methanamine Chemical compound NCC1=C(F)C=C(F)C=C1F RCHOKTKXVKKNBC-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 108010002459 HIV Integrase Proteins 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 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 1
- 229960002402 cobicistat Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- 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 1
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of an HIV inhibitor and an intermediate crystal form thereof. The preparation method has high reaction yield and simple post-treatment, and is suitable for industrial production; the intermediate crystal form is higher in yield and purity of a final product obtained by subsequent reaction.
Description
Technical Field
The invention particularly relates to a preparation method of an HIV inhibitor and an intermediate crystal form thereof.
Background
Polycyclic carbamoylpyrimidines derivatives are well known inhibitors of HIV integrase chain transfer and are used in combination with other antiretroviral drugs to treat HIV-1 infections in adults and children over 12 years of age weighing over 40 kg.
Dolutegravir Sodium (Dolutegravir Sodium) was approved by the U.S. Food and Drug Administration (FDA) on 12/8/2013. An anti-AIDS drug developed by Kulansu Schk (GSK) in cooperation with Shionogi, Japan salt wild pharmaceutical company. Is a third FDA-approved HIV integrase inhibitor following Raltegravir (Raltegravir), eltamivir (Elvitegravir). The structural formula is as follows:
cabotegravir is an integrase inhibitor and can be administered orally, intramuscularly or subcutaneously. HIV can be effectively inhibited by orally taking 30mg CAB once a day.
Bictegravir is a novel integrase inhibitor developed by Gilead corporation, and unlike previously developed integrase inhibitors, Bictegravir only needs to be used once a day and does not require the synergist cobicistat.
There are several documents currently reporting methods for the preparation of dolutegravir, wherein the preparation method disclosed in WO2010110409 is shown in scheme 1.
The total yield of the route is only 0.5%, especially the reaction yield of the sixth step is only 25%, the product is in the shape of orange powder, the subsequent condensation reaction is directly carried out without purification, the yield is 55%, and the purity of the reaction product of the sixth step is reflected to be not high. Therefore, this route is not suitable for industrial production. The problem of conversion of 7-chloro to 7-hydroxy using silanolate with low yield (25%) is that the process is not suitable for industrialization.
A currently industrially common process is the preparation method disclosed in WO2011119566, as shown in scheme 2:
Therefore, the development of a novel method for preparing the polycyclic carbamoylpyrimidine derivative, which is environment-friendly, has cost advantage and better quality control, is urgently needed in the field.
Disclosure of Invention
The invention aims to solve the problems of low key reaction yield, complex post-treatment, unsuitability for industrialization and the like of a preparation method of an HIV inhibitor in the prior art, and provides a preparation method of the HIV inhibitor and an intermediate crystal form thereof. The preparation method has high reaction yield and simple post-treatment, and is suitable for industrial production; the intermediate crystal form is higher in yield and purity of a final product obtained by subsequent reaction.
The invention provides a preparation method of a compound shown as a formula I, which comprises the following steps:
in tetrahydrofuran, in the presence of lithium bromide, carrying out deprotection reaction on the compound N-3 as shown in the specification to obtain a compound N-2;
wherein the deprotection reaction is carried out in the presence of a base or in the absence of a base;
n is 0 or 1;
a is methyl and B is hydrogen; or A, B form a five-membered ring structure with the carbon between them;
r is C2~C6An alkyl group;
the alkali is M1OH、And R1OM2One or more of; m1And M2Independently an alkali metal; r1、R2、R3And R4Independently is C1~C4An alkyl group;
the carbon marked with x is an S configuration or an R configuration chiral carbon.
When n is 0, preferably A is methyl and B is hydrogen.
When n is 1, preferably A is methyl and B is hydrogen.
Or, when n is 1, it is preferable that A, B form a five-membered ring structure with carbon between them.
C2~C6The alkyl group is preferably C2~C4Alkyl, for example ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl.
When said R is2、R3、R4And R5Independently is C1~C4When alkyl, said C1~C4The alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group, for example, an ethyl group.
The alkali metal is preferably one or more of sodium, potassium and cesium.
Said M1The OH can be sodium hydroxide and/or potassium hydroxide.
Said R1OM2Can be one or more of sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and potassium methoxide.
In a preferred embodiment, A is the same side as the hydrogen on the carbon at position 1.
In a preferred embodiment of the present invention,is composed ofN is 0, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is;
In a preferred embodiment of the present invention,is composed ofWhen n is 1, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is shown in the specification;
In a preferred embodiment, n is 1, A, B forms a five-membered ring structure with the carbon between them, and the compound of formula I has the formula。
The tetrahydrofuran is used in an amount which is conventional in the art for carrying out such reactions, and preferably in a volume molar ratio of 0.5 to 2.0L/mol, for example, 1.21L/mol, to the compound N-3.
When the deprotection reaction is carried out in the presence of a base, the base may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, the molar ratio thereof to the compound N-3 is 1.0 to 1.5, for example, 1.13.
The amount of lithium bromide may be that conventionally used in the art for such reactions, and is preferably in a molar ratio of 2.5 to 3.5, e.g., 3.02, to compound N-3.
The reaction temperature of the deprotection reaction can be a conventional temperature for carrying out the reaction in the field, and is preferably 50-80 ℃, for example, 60-70 ℃.
The progress of the deprotection reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and is generally determined as the end point of the reaction when compound N-3 is eliminated. The reaction time is preferably 18 to 36 hours, for example, 24 hours.
The deprotection reaction can further comprise post-treatment; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, cooling, adding water to quench the reaction, removing the solvent under reduced pressure, adding dilute hydrochloric acid to precipitate crystals, performing suction filtration to obtain a crude product, drying, and recrystallizing the crude product in acetonitrile/water to obtain the compound N-2.
The preparation method of the compound N-2 can also comprise the following steps: (1) reacting compound N-4 with lithium hydroxide; (2) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (3) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or(ii) a Directly carrying out the next reaction in the steps (1) and (2) without any post-treatment;
wherein n, A, B and x are as defined above.
The preparation method of the compound shown in the formula I can further comprise the following steps: in dichloromethane, in the presence of a condensing agent, the compounds N-2 andcarrying out condensation reaction as shown in the specification to obtain a compound as shown in a formula I;
The invention also provides a crystal form of a compound N-2', wherein an X-ray powder diffraction pattern expressed by 2 theta angle by using Cu-Kalpha radiation has characteristic peaks at one or more of the following positions: 7.7o±0.2o,10.3o±0.2o,13.3o±0.2o,14.3o±0.2o,17.8o±0.2o,19.0o±0.2o,20.9o±0.2o,21.9o±0.2o,27.4o±0.2o, 28.5o±0.2o,29.8o±0.2o;
Further, the X-ray powder diffraction pattern expressed in terms of 2 θ angles has characteristic peaks at one or more of the following positions: 7.7o±0.2o,10.3o±0.2o,11.5±0.2o,12.8±0.2o,13.3o±0.2o,14.3o±0.2o,15.0 o±0.2o,15.7o±0.2o,16.6o±0.2o,17.5 o±0.2o,17.8o±0.2o,19.1o±0.2o,20.9o±0.2o,21.9o±0.2o,27.4o±0.2o,28.5o±0.2o,29.8o±0.2o。
Further, the X-ray powder diffraction is shown in FIG. 1.
The differential scanning calorimetry diagram of the crystal form of the compound N-2' provided by the invention has an endothermic peak with an initial value of 273.72 ℃ and a peak value of 277.12 ℃.
The Differential Scanning Calorimetry (DSC) chart of the crystal form of the compound N-2' provided by the invention is basically shown in figure 2.
The invention provides a crystal form of compound N-2' with an infrared absorption spectrum at 3455, 3051, 2974, 2889, 1733, 1634, 1544, 1525, 1461, 1451, 1442, 1371, 1304, 1255, 1237, 1215, 1190, 1176, 996, 980, 695, 540cm-1Has an absorption peak.
Furthermore, the invention provides a crystal form of the compound N-2', the infrared absorption spectrum of which is basically shown in figure 4.
The crystal form thermogravimetric analysis (TGA) of the compound N-2' provided by the invention has the weight loss of about 15.1% in the range of 260 ℃ to 310 ℃ and 38.2% in the range of 310 ℃ to 400 ℃.
Still further, the present invention provides a crystalline form of compound N-2' having a thermogravimetric analysis (TGA) substantially as shown in figure 5.
Drawings
FIG. 1 is an XRPD pattern for a typical example of compound N-2'.
FIG. 2 is a DSC of compound N-2'.
FIG. 3 is a drawing of compound N-21HNMR atlas.
FIG. 4 is an IR spectrum of compound N-2'.
FIG. 5 is a TGA profile of Compound N-2'.
Detailed Description
The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The general method comprises the following steps:
XRPD pattern determination method
X-ray powder diffraction instrument: BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source: k α 1=1.54060 a, k α 2=1.54439 a, the strength ratio α 1/α 2 is 0.50000 a; generator (Generator) kv: 30.0 kv; generator (Generator) mA: 10.0 mA; initial 2 θ: 2.000 °, scan range: 2.0000-40.000 degree.
DSC test method
The DSC detector has the model as follows: METTLER TOLEDO DSC1 differential scanning calorimeter; temperature rising procedure: the starting temperature was 25 ℃, increased to 400 ℃ at 10 ℃/min, temperature range: 25-400 ℃.
3.1HNMR test method
The model of the nuclear magnetic detector is BRUKERAVANCEIII, 300MHz, and the deuterated reagent is DMSO-d 6.
IR test method
The infrared spectrophotometer is a PerkinElmer Spectrum Two Fourier transform infrared spectrometer; the operation method comprises the following steps: adopting a KBr tabletting method, and scanning the range of 450-4000 cm-1。
TGA test method
The TGA detector is METTLER TOLEDO TGA/DSC1 thermogravimetric analyzer; temperature rising procedure: the initial temperature is 25 ℃, and the temperature is increased to 400 ℃ at the speed of 10 ℃/min; temperature range: 25-400 ℃.
Compound N-5 reference Organic Letters (2015), 17(3), 564-567 was prepared and used directly in the subsequent step reactions.
Preparation of Compound N-5
And (3) putting the compound N-725.0 g in a reaction bottle, cooling to 0-10 ℃, dropwise adding DMFDMA20.5g, returning to room temperature after dropwise adding, and keeping the temperature until the reaction is complete. Adding 50mL of ethanol into the system, cooling to 0-10 ℃, dropwise adding 16.6g of aminoacetaldehyde dimethyl acetal, heating to room temperature after dropwise adding, and keeping the temperature to react until the reaction is complete. And (3) concentrating the system under reduced pressure until no fraction is separated out, adding 10mL of ethanol into the system, cooling to-10-0 ℃, stirring, crystallizing, filtering, leaching a filter cake with 10mL of ethanol, draining, and drying to obtain a compound N-525.8 g, wherein the HPLC purity is 99.5%.
Preparation of compound N-4
And (3) putting the compound N-781.4 g in a reaction bottle, cooling to 0-10 ℃, dropwise adding 66.9g of DMFDMA, after dropwise adding, returning to room temperature, and keeping the temperature until the reaction is complete. Adding 162mL of ethanol into the system, cooling to 0-10 ℃, dropwise adding 55.1g of aminoacetaldehyde dimethyl acetal, heating to room temperature after dropwise adding, and keeping the temperature to react until the reaction is complete. And (3) concentrating the system under reduced pressure until no fraction is separated out, adding 1300mL of ethanol into the system, adding 204.6g of diethyl oxalate, cooling to 0-10 ℃, adding 95.3g of sodium ethoxide in batches, heating to 20-30 ℃ after the addition is finished, and keeping the temperature until the reaction is complete. And (3) cooling the system to 0-10 ℃, dropwise adding 3N hydrochloric acid to adjust the pH of the system to 6-7, concentrating under reduced pressure until no fraction is separated out basically, adding 650mL of ethyl acetate and 400mL of water, stirring for 1 hour, filtering, leaching a filter cake with 160mL of ethyl acetate, filtering a mother solution, separating liquid, and concentrating an organic phase until no fraction is separated out to obtain a compound N-4138.9 g, wherein the HPLC purity is 97.2%.
Preparation of three, dolutegravir sodium
A. The preparation method of the compound N-3' is as follows:
A1. preparation of Compound N-3 from Compound N-5
Adding 27.0g of compound N-5 into 270mL of ethanol, adding 40.9g of diethyl oxalate, cooling to 0-10 ℃, adding 19.1g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 5.1g of lithium hydroxide monohydrate in batches, keeping the temperature to be 0-10 ℃ and reacting for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 150mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 120mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 360mL of acetonitrile into the concentrated system, and then adding 33g of acetic acid, adding 7.3g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 7.7g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 11.6g of (R) -3-aminobutanol into the system, heating the system to 70-80 ℃ after dropwise adding, and reacting until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated, adding 150mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with ethanol, and carrying out vacuum drying on a wet product to obtain 27.8g of a compound N-3', wherein the HPLC purity is 98.7%.
A2. Preparation of Compound N-3' from Compound N-4
Adding 34.7g of compound N-4 into 170mL of ethanol, cooling the system to 0-10 ℃, adding 5.1g of lithium hydroxide monohydrate in batches, keeping the temperature at 0-10 ℃ for reaction for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 150mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 120mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 360mL of acetonitrile into the concentrated system, and then adding 33g of acetic acid, adding 7.3g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 7.7g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 11.6g of (R) -3-aminobutanol into the system, heating the system to 70-80 ℃ after dropwise adding, and reacting until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated, adding 150mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with ethanol, and carrying out vacuum drying on a wet product to obtain 27.8g of a compound N-3', wherein the HPLC purity is 98.7%.
B. The compound N-2' is prepared as follows:
adding 140g of compound N-3' into 520mL of tetrahydrofuran, cooling to 0-10 ℃, adding 33g of sodium ethoxide in batches, adding 113g of lithium bromide in batches, heating to 60-70 ℃, keeping the temperature, reacting completely, cooling, adding 700mL of water into the system, concentrating under reduced pressure until no fraction is separated out, adding 3N hydrochloric acid dropwise into the system to adjust the pH value of the system to 3-4, and stirring for crystallization. And (4) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude product of the compound N-2'. And adding the crude product into a system of 700mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, carrying out suction filtration, washing a filter cake, and then transferring the filter cake into a vacuum drying oven for drying to obtain 110.2g of a compound N-2', wherein the HPLC purity is 99.3%.
The high-purity compound N-2 'is prepared by changing the types of the solvent, the base and the Lewis acid reagent and further using the compound N-3' in the presence of the Lewis acid reagent while keeping the mole number of each substance unchanged. Some of the conditions screened in the preparation of compound N-2' are shown in Table 1:
TABLE 1
XRPD test is carried out on the obtained compound N-2', the X-ray powder diffraction data is shown in the table 2, and the X-ray powder diffraction pattern is shown in the figure 1; performing DSC test, and the spectrum is shown in figure 2; performing H NMR test, wherein the spectrogram is shown in figure 3; performing an IR test, wherein the spectrogram is shown in FIG. 4; TGA testing was performed and the spectrum is shown in figure 5.
TABLE 2
C. The preparation method of the compound N-1' is as follows:
adding 85.0g of compound N-2' into 500mL of dichloromethane, adding 56.4g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 58.1g of 2, 4-difluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 170mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 170mL of 3% sodium bicarbonate solution, washing with 170mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 470mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 170mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 113.9g of a compound N-1', wherein the HPLC purity is 99.7%.
D. Compound N was prepared as follows:
adding 50g of compound N-1' into 400mL of solvent with ethanol/water =4/1, heating to 70-75 ℃, dropwise adding 25.0g of 20% sodium hydroxide solution, stirring at a constant temperature for 1-3 hours after dropwise adding, cooling to room temperature, stirring for 1-3 hours, performing suction filtration, leaching a filter cake with 100mL of ethanol, transferring a wet product into a vacuum drying oven for drying, and obtaining 47.2g of compound N with the HPLC purity of 99.8%.
Preparation of Cabotegravir
A. The preparation method of the compound N-3 '' is as follows:
adding 21.6g of compound N-5 into 220mL of ethanol, adding 32.7g of diethyl oxalate, cooling to 0-10 ℃, adding 15.3g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 4.1g of lithium hydroxide monohydrate in batches, keeping the temperature to be 0-10 ℃ and reacting for 3 hours, adjusting the pH of the system to 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out basically, adding 110mL of water, adjusting the pH of the system to 3-4 by using 3N hydrochloric acid, adding 110mL of ethyl acetate, stirring, separating liquid, concentrating an organic phase until no fraction is separated out, adding 110mL of acetonitrile, continuously concentrating until no fraction is separated out, adding 280mL of acetonitrile into the concentrated system, then adding 26.4g of acetic acid, adding 5.8g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature for reaction until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 6.2g of triethylamine into the system, stirring for 10 minutes after dropwise adding, continuously dropwise adding 7.8g of (S) -2-aminopropanol into the system, and heating the system to 70-80 ℃ after dropwise adding until the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated out, adding 110mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching filter cake with ethanol, and carrying out vacuum drying on wet products to obtain 22.3g of a compound N-3 '', wherein the HPLC purity is 98.8%.
B. The preparation method of the compound N-2 '' is as follows:
adding 20g of compound N-3 '' into 100mL of tetrahydrofuran, adding 4.7g of sodium ethoxide, adding 16.1g of lithium bromide, heating to 60-70 ℃ for reacting for 24 hours, cooling, adding 100mL of water into the system, concentrating under reduced pressure until no fraction is separated out, dropwise adding 3N hydrochloric acid into the system to adjust the pH of the system to 3-4, and crystallizing. And (5) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude compound N-2 ''. And adding the crude product into a system of 100mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, performing suction filtration, washing a filter cake, and drying in a vacuum drying oven to obtain 16.9g of a compound N-2', wherein the HPLC purity is 99.3%.
Preparation of cabotegravir
Adding 28.0g of compound N-2 '' into 140mL of dichloromethane, adding 19.4g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 17.2g of 2, 4-difluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 56mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 56mL of 3% sodium bicarbonate solution, washing with 56mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 140mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 56mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 37.2g of a compound N-1 '', wherein the HPLC purity is 98.9%.
Preparation of Bictegravir
A. Preparation of Compound N-3' ″
Adding 19.6g of compound N-5 into 200mL of ethanol, adding 29.7g of diethyl oxalate, cooling to 0-10 ℃, adding 13.4g of sodium ethoxide into the system in batches, and reacting for 5-10 hours under the condition of heat preservation until the reaction is complete. After the reaction is finished, controlling the temperature to be 0-10 ℃, adding 3.7g of lithium hydroxide monohydrate in batches, keeping the temperature to be 0-10 ℃, reacting for 3 hours, adjusting the pH of the system to be 6-7 by using 3N hydrochloric acid, concentrating under reduced pressure until no fraction is separated out, adding 100mL of water, adjusting the pH of the system to be 3-4 by using 3N hydrochloric acid, adding 170mL of ethyl acetate, stirring, separating liquid, and carrying out organic phase separationConcentrating the phase until no fraction is obtained, adding 120mL of acetonitrile, continuously concentrating until no fraction is obtained, adding 150mL of acetonitrile into a concentrated system, then adding 20.4g of acetic acid, adding 4.6g of methanesulfonic acid, heating to 70-80 ℃, keeping the temperature, reacting until the reaction is basically complete, cooling to 40-50 ℃, dropwise adding 5.6g of triethylamine into the system, stirring for 10 minutes after dropwise adding is finished, and continuously dropwise adding into the system8.2g, after dripping, heating the system to 70-80 ℃ for reaction till the reaction is complete. And (3) cooling, concentrating the system until no fraction is separated out, adding 100mL of ethanol into the system, heating to 70-80 ℃, keeping the temperature and stirring for 2 hours, cooling to room temperature, carrying out suction filtration, leaching filter cake with ethanol, and carrying out vacuum drying on wet products to obtain 16.7g of a compound N-3 ' ' ', wherein the HPLC purity is 99.0%.
B. The compound N-2 ' ' ' is prepared as follows:
adding 15g of compound N-3 ' ' ' into 45mL of tetrahydrofuran, adding 3.1g of sodium ethoxide, adding 11.7g of lithium bromide, heating to 60-70 ℃ for reacting for 24 hours, cooling, adding 75mL of water into the system, concentrating under reduced pressure until no fraction is separated, dropwise adding 3N hydrochloric acid into the system to adjust the pH of the system to 3-4, and crystallizing. And (5) carrying out suction filtration, and drying the crude product in a vacuum drying oven to obtain a crude compound N-2 ' ' '. Adding the crude product into a system of 75mL acetonitrile/water (acetonitrile/water =1v/1 v), heating to 70-80 ℃, preserving heat, stirring for 3 hours, cooling to room temperature, performing suction filtration, washing a filter cake, and drying in a vacuum drying oven to obtain 12.4g of a compound N-2 ' ' ', wherein the yield is as follows: 90.2% and an HPLC purity of 99.2%.
C. Preparation of Bictegravir
Adding 10.0g of compound N-2 ' ' ' into 50mL of dichloromethane, adding 6.3g of CDI, heating to reflux, keeping the temperature for 4 hours, cooling to 0-10 ℃, dropwise adding 6.9g of 2, 4, 6-trifluorobenzylamine, and after dropwise adding, returning the temperature to room temperature for reaction until the reaction is finished. And adding 20mL of 3N hydrochloric acid into the reacted system, stirring for 0.5-1 hour, separating liquid, washing an organic phase with 20mL of 3% sodium bicarbonate solution, washing with 20mL of water, separating liquid, and concentrating the organic phase until no fraction is separated. Adding 50mL of ethanol into the system, heating to 60-70 ℃, keeping the temperature, stirring for 3-4 hours, cooling to 0-10 ℃, stirring for 1-2 hours, performing suction filtration, leaching a filter cake with 20mL of ethanol, and drying a wet product in a vacuum drying oven to obtain 13.7g of a compound N-1 ' ' ', wherein the HPLC purity is 99.4%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A preparation method of a compound shown as a formula I is characterized by comprising the following steps:
in tetrahydrofuran, in the presence of lithium bromide, carrying out deprotection reaction on the compound N-3 as shown in the specification to obtain a compound N-2;
wherein the deprotection reaction is carried out in the presence of a base or in the absence of a base;
n is 0 or 1;
a is methyl and B is hydrogen; or A, B form a five-membered ring structure with the carbon between them;
r is C2~C6An alkyl group;
the alkali is M1OH, c and R1OM2One or more of; m1And M2Independently an alkali metal; r1、R2、R3And R4Independently is C1~C4An alkyl group;
the carbon marked with x is an S configuration or an R configuration chiral carbon.
2. The process according to claim 1, wherein when n is 0, A is methyl and B is hydrogen;
or, when n is 1, A is methyl and B is hydrogen;
or, when n is 1, A, B forms a five-membered ring structure with the carbon between them.
3. The method of claim 1, wherein C is2~C6Alkyl is C2~C4An alkyl group; and/or, when said R is2、R3、R4And R5Independently is C1~C4When alkyl, said C1~C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
6. The method of claim 1, wherein A is the same side as the hydrogen on the carbon at position 1.
7. The method according to claim 1, wherein the reaction mixture,
is composed ofN is 0, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is;
Or,is composed ofWhen n is 1, A is methyl, B is hydrogen, the structural formula of the compound shown in the formula I is shown in the specification;
8. The preparation method according to claim 1, wherein the volume molar ratio of the tetrahydrofuran to the compound N-3 is 0.5 to 2.0L/mol;
and/or, when the deprotection reaction is carried out in the presence of a base, the molar ratio of the base to the compound N-3 is 1.0-1.5;
and/or the molar ratio of the lithium bromide to the compound N-3 is 2.5-3.5;
and/or the reaction temperature of the deprotection reaction is 50-80 ℃.
9. The method of claim 1, further comprising the steps of: (1) reacting compound N-4 with lithium hydroxide; (2) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (3) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or(ii) a Directly carrying out the next reaction in the steps (1) and (2) without any post-treatment;
wherein n, a, B and x are as defined in any one of claims 1 to 7.
10. The method of claim 1, further comprising the steps of: (1)reacting the compound N-5 with diethyl oxalate under alkaline conditions; (2) reacting compound N-4 with lithium hydroxide; (3) adding acetic acid and methanesulfonic acid, and continuing to react at 60-80 ℃; (4) cooling to 40-50 ℃, adding triethylamine and a reagent A, and reacting at 70-80 ℃ to obtain a compound N-3; the reagent A is (R) -3-aminobutanol, (S) -2-aminopropanol or(ii) a The steps (1), (2) and (3) are directly subjected to the next reaction without any post-treatment;
wherein n, a, B and x are as defined in any one of claims 1 to 7.
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CN102933080A (en) * | 2010-03-23 | 2013-02-13 | Viiv保健公司 | Process for preparing carbamoylpridone derivatives and intermediates |
WO2019159199A1 (en) * | 2018-02-16 | 2019-08-22 | Cipla Limited | Continues flow process for the preparation of active pharmaceutical ingredients - polycyclic carbamoyl pyridone derivatives and intermediates thereof |
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WO2023087747A1 (en) * | 2021-11-17 | 2023-05-25 | 奥锐特药业(天津)有限公司 | Preparation method for hiv inhibitor and intermediate crystalline form thereof |
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