CN115124578B - Trapezium intermediate, preparation method and application thereof - Google Patents
Trapezium intermediate, preparation method and application thereof Download PDFInfo
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- CN115124578B CN115124578B CN202110336623.6A CN202110336623A CN115124578B CN 115124578 B CN115124578 B CN 115124578B CN 202110336623 A CN202110336623 A CN 202110336623A CN 115124578 B CN115124578 B CN 115124578B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 145
- 241000826860 Trapezium Species 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 309
- 238000006243 chemical reaction Methods 0.000 claims abstract description 218
- 239000002904 solvent Substances 0.000 claims abstract description 98
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000002253 acid Substances 0.000 claims abstract description 28
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000035484 reaction time Effects 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 144
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 117
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 96
- 239000006188 syrup Substances 0.000 claims description 88
- 235000020357 syrup Nutrition 0.000 claims description 88
- 239000000243 solution Substances 0.000 claims description 64
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 47
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 42
- 238000001914 filtration Methods 0.000 claims description 35
- 238000004519 manufacturing process Methods 0.000 claims description 35
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 29
- 239000012074 organic phase Substances 0.000 claims description 28
- 239000007787 solid Substances 0.000 claims description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 22
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000003208 petroleum Substances 0.000 claims description 20
- 239000011230 binding agent Substances 0.000 claims description 19
- 238000005406 washing Methods 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 150000008282 halocarbons Chemical class 0.000 claims description 15
- 238000004537 pulping Methods 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 10
- -1 nitrogen-containing compound Chemical class 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical group C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000010009 beating Methods 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 13
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 56
- 238000003756 stirring Methods 0.000 description 34
- 239000000203 mixture Substances 0.000 description 30
- 230000000052 comparative effect Effects 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229960001031 glucose Drugs 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000013557 residual solvent Substances 0.000 description 9
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000004817 gas chromatography Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000981595 Zoysia japonica Species 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 238000013341 scale-up Methods 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 2
- MXOSTENCGSDMRE-UHFFFAOYSA-N butyl-chloro-dimethylsilane Chemical group CCCC[Si](C)(C)Cl MXOSTENCGSDMRE-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- VPUGDVKSAQVFFS-UHFFFAOYSA-N coronene Chemical compound C1=C(C2=C34)C=CC3=CC=C(C=C3)C4=C4C3=CC=C(C=C3)C4=C2C3=C1 VPUGDVKSAQVFFS-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- 244000042430 Rhodiola rosea Species 0.000 description 1
- 235000003713 Rhodiola rosea Nutrition 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229930015704 phenylpropanoid Natural products 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a zoysin intermediate, a preparation method and application thereof. Specifically disclosed is a method for preparing a compound represented by the formula P8, which comprises the following steps: (1) In a solvent, carrying out hydroxyl protection reaction on a compound shown as a formula P6 and BzCl to obtain a compound shown as a formula P7; (2) And (3) in a solvent, under the action of acid, carrying out deprotection reaction on the compound shown as the formula P7 to obtain the compound shown as the formula P8. Also disclosed is the use of the compound of formula P6 for preparing the zoysin. The method has the advantages of low cost, short reaction time, high yield, environmental protection, avoidance of column chromatography steps, easy operation and suitability for large-scale production.
Description
Technical Field
The invention relates to a zoysin intermediate, a preparation method and application thereof.
Background
The zoysia japonica is one of extracts of rhodiola rosea, and is mainly used for resisting fatigue, resisting anoxia, relieving pressure, improving working efficiency and treating functional diseases of a nervous system.
At present, the synthetic patents of the zoysin are fewer, the common cost is high, the yield is low, and the biggest problem is that the process of column chromatography is needed, so that the process is not suitable for industrial production. Such as: li et al (Li X D,Kang S T,Li GY,et al.Synthesis of Some Phenylpropanoid Glycosides(PPGs)and Their Acetylcholinesterase/Xanthine Oxidase Inhibitory Activities[J].Molecules,2011,16(5):3580-3596), in this document prepared a zoysin with the following compounds as bond intermediates:
The Tr is used as a hydroxyl protecting group, the intermediate is used for synthesizing the zosai, the reaction time is long, the post-treatment is complex, the step of column chromatography is needed, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of long synthesis reaction time and complex post-treatment of a bazooka intermediate in the prior art, and provides the bazooka intermediate, a preparation method and application thereof. The method has the advantages of low cost, short reaction time, high yield, environmental protection, avoidance of column chromatography steps, easy operation and suitability for large-scale production.
The invention solves the technical problems by the following technical scheme:
the invention provides a preparation method of a compound shown as a formula P8, which comprises the following steps:
(1) In a solvent, carrying out hydroxyl protection reaction on a compound shown as a formula P6 and BzCl to obtain a compound shown as a formula P7;
(2) In a solvent, under the action of acid, a compound shown as a formula P7 is subjected to deprotection reaction to obtain a compound shown as a formula P8;
In the process for preparing the compound represented by formula P8, in a certain preferred embodiment of the present invention, certain conditions or operations are defined below, and the conditions and operations not mentioned are as described in any one of the embodiments of the present invention, (abbreviated as "in a certain embodiment of the present invention"), the solvent in step (1) may be a solvent conventional in such a reaction in the art, preferably pyridine or a "mixed solvent of pyridine and halogenated hydrocarbon solvent", further preferably a mixed solvent of pyridine and halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably methylene chloride; in the case of a mixed solvent of pyridine and halogenated hydrocarbon solvent, the volume ratio of the pyridine to the halogenated hydrocarbon solvent is preferably 1: (2-5), e.g., 1:3.
In the preparation method of the compound shown as the formula P8, in one embodiment of the invention, in the step (1), the solvent can be used in an amount conventional in the reaction in the field, preferably, the volume-mass ratio of the solvent to the compound shown as the formula P6 is (2-10) mL/g, for example, 3mL/g or 8mL/g.
In the preparation method of the compound shown as the formula P8, in one scheme of the invention, the amount of BzCl in the step (1) can be the conventional amount in the field of such reactions, and preferably, the molar ratio of BzCl to the compound shown as the formula P6 is (5-10): 1, e.g., 8:1.
In the preparation method of the compound represented by the formula P8, in one embodiment of the present invention, the temperature of the hydroxyl group protection reaction in the step (1) may be a reaction temperature conventional in the art, and preferably is 20 to 40 ℃.
In the preparation method of the compound represented by formula P8, in one embodiment of the present invention, in step (1), the progress of the hydroxyl-protecting reaction may be monitored according to a detection method conventional in the art (for example, TLC, HPLC or GC), and the time of the hydroxyl-protecting reaction is preferably 4 to 10 hours (for example, 7 hours) generally using the disappearance of the compound represented by formula P6 as the end point of the reaction.
In one embodiment of the present invention, the step (1) of the preparation method of the compound represented by formula P8 further comprises the following post-treatment steps: quenching reaction (such as quenching reaction by adding water), washing the organic phase (such as washing by hydrochloric acid water solution, saturated sodium bicarbonate water solution and water in sequence), concentrating to obtain P7 syrup, and directly carrying out the next reaction in the form of P7 syrup. The post-treatment in the step (1) does not comprise a column chromatography step, is easy to operate and is suitable for scale-up production.
In the method for preparing the compound represented by formula P8, in one embodiment of the present invention, in step (2), the solvent may be a solvent conventional in such reactions in the art, preferably a nitrogen-containing compound solvent and/or an ether solvent, and more preferably DMF and/or THF (e.g., DMF).
In the preparation method of the compound shown as the formula P8, in one embodiment of the invention, in the step (2), the solvent can be used in an amount conventional in the reaction in the field, and preferably, the volume-mass ratio of the solvent to the compound shown as the formula P7 is (4-10) mL/g, for example, 5mL/g.
In one embodiment of the present invention, in the method for preparing the compound represented by formula P8, the acid in step (2) is an acid which may be conventional in such a reaction in the art, preferably hydrochloric acid; the hydrochloric acid is preferably added to the system in the form of an aqueous hydrochloric acid solution, preferably having a molar concentration of 0.8 to 1.5mol/L (e.g., 1 mol/L).
In one embodiment of the present invention, in the method for preparing the compound represented by formula P8, the amount of the acid used in step (2) may be an amount conventional in such reactions in the art, and preferably, the molar ratio of the acid to the compound represented by formula P7 is 1: (0.5-5).
In the preparation method of the compound represented by the formula P8, in one embodiment of the present invention, the temperature of the deprotection reaction in the step (2) may be a reaction temperature conventional in such a reaction in the art, and preferably is 20 to 40 ℃.
In the preparation method of the compound represented by formula P8, in one embodiment of the present invention, in step (2), the progress of the deprotection reaction may be monitored (for example, TLC, HPLC or GC) according to a detection method conventional in the art, and the time of the deprotection reaction is preferably 0.5 to 5 hours (for example, 2 hours) when the compound represented by formula P7 disappears as the end point of the reaction.
In one embodiment of the present invention, the step (2) of the preparation method of the compound represented by formula P8 further comprises the following post-treatment steps: after the addition of the solvent, a solid of the compound represented by formula P8 is precipitated and filtered. The post-treatment in the step (2) does not comprise a column chromatography step, is easy to operate and is suitable for scale-up production.
In one embodiment of the present invention, the post-treatment step of the step (2) of the preparation method of the compound represented by formula P8 comprises the following steps: adding saturated sodium bicarbonate aqueous solution for quenching reaction, adding ethyl acetate for extraction, adding petroleum ether (the petroleum ether dosage is 2-6 times of the theoretical product mass), separating out the solid of the compound shown as the formula P8, and filtering.
In one embodiment of the present invention, the method for preparing the compound represented by formula P8 further comprises the following steps:
In a solvent, under the action of an acid binding agent, carrying out hydroxyl protection reaction on a compound shown as a formula P5 and tert-butyldimethyl chlorosilane (TBDMSCl) to obtain a compound shown as a formula P6;
The acid binding agent is imidazole.
In the preparation method of the compound shown as the formula P6, in one embodiment of the invention, the solvent can be a solvent which is conventional in the reaction in the field, preferably a nitrogen-containing compound solvent and/or an ether solvent, and more preferably DMF and/or THF.
In the preparation method of the compound shown as the formula P6, in one embodiment of the invention, the solvent can be used in an amount conventional in the reaction in the field, and preferably, the volume-mass ratio of the solvent to the compound shown as the formula P5 is (4-10) mL/g, for example, 6mL/g.
In the preparation method of the compound shown as the formula P6, in a certain scheme of the invention, the dosage of the acid-binding agent can be the dosage which is conventional in the reaction in the field, and preferably, the molar ratio of the acid-binding agent to the compound shown as the formula P5 is (1-4): 1, more preferably (2 to 3): 1, for example 2.5:1.
In the preparation method of the compound shown as the formula P6, in one scheme of the invention, the amount of the tertiary butyl dimethyl chlorosilane can be the amount which is conventional in the reaction in the field, preferably, the molar ratio of the tertiary butyl dimethyl chlorosilane to the compound shown as the formula P5 is (1-1.8): 1 (e.g., 1:1 or 1.5:1), more preferably (1.2 to 1.6): 1.
In the preparation method of the compound shown as the formula P6, in one embodiment of the invention, the temperature of the hydroxyl protection reaction can be a reaction temperature conventional in the art, and is preferably 20-40 ℃.
In the preparation method of the compound represented by formula P6, in one embodiment of the present invention, the progress of the hydroxyl-protecting reaction may be monitored according to a detection method conventional in the art (for example, TLC, HPLC or GC), and the time of the hydroxyl-protecting reaction is preferably 1 to 6 hours (for example, 1 hour or 5 hours) as the end point of the reaction when the compound represented by formula P5 disappears.
In one embodiment of the present invention, the method for preparing the compound represented by formula P6 includes the steps of: and mixing the compound shown in the formula P5, an acid binding agent and a solvent, and adding tert-butyldimethyl chlorosilane into the system to perform hydroxyl protection reaction to obtain the compound shown in the formula P6.
In one embodiment of the present invention, the preparation method of the compound represented by formula P6 further comprises the following post-treatment steps: concentrating to obtain solid of compound shown in formula P6, adding solvent, pulping, filtering, and drying. The post-treatment of the preparation method of the compound shown as the formula P6 does not comprise a column chromatography step, is easy to operate and is suitable for scale-up production.
In one embodiment of the present invention, the post-treatment step of the preparation method of the compound represented by formula P6 comprises the following steps: quenching the reaction with water, extracting with ethyl acetate, washing the organic phase with saturated saline water, drying, filtering, concentrating to obtain solid of the compound shown in formula P6, pulping with petroleum ether, filtering, and drying to obtain the compound shown in formula P6.
In one embodiment of the present invention, the method for preparing the compound represented by formula P6 further comprises the steps of:
In a solvent, under the action of alkali, carrying out deprotection reaction on a compound shown as a formula P4 to obtain a compound shown as a formula P5;
In the method for preparing the compound represented by formula P5, in one embodiment of the present invention, the solvent may be a solvent conventional in such reactions in the art, preferably a halogenated hydrocarbon solvent, and more preferably dichloromethane.
In the preparation method of the compound shown as the formula P5, in one embodiment of the invention, the solvent can be used in an amount which is conventional in the reaction in the field, and preferably, the volume-mass ratio of the solvent to the compound shown as the formula P4 is (4-10) mL/g, for example, 6mL/g.
In the preparation method of the compound shown as the formula P5, in one embodiment of the invention, the base can be a base conventional in the reaction in the field, and sodium methoxide is preferred. The sodium methoxide is preferably added to the system in the form of a methanolic solution of sodium methoxide, wherein the volume to mass ratio of methanol to the compound represented by formula P4 is (2-5) mL/g, for example 3mL/g.
In the preparation method of the compound shown as the formula P5, in one embodiment of the invention, the amount of the base can be the amount which is conventional in the reaction in the field, and preferably, the molar ratio of the base to the compound shown as the formula P4 is (1-5): 1, e.g., 3:1.
In the preparation method of the compound shown as the formula P5, in one embodiment of the invention, the temperature of the deprotection reaction can be a reaction temperature conventional in the art, and is preferably 20-40 ℃.
In the preparation method of the compound represented by formula P5, in one embodiment of the present invention, the progress of the deprotection reaction may be monitored according to a detection method conventional in the art (for example, TLC, HPLC or GC), and the deprotection reaction is preferably carried out for 3 to 10 hours (for example, 6 hours) with the end point of the reaction when the compound represented by formula P4 disappears.
In one embodiment of the present invention, the preparation method of the compound represented by formula P5 further comprises the following post-treatment steps: the pH is adjusted to neutral (e.g., ph=7 is adjusted by adding methanolic hydrochloric acid), and the mixture is concentrated to obtain P5 syrup, and the next reaction is directly carried out as P5 syrup. The post-treatment of the preparation method of the compound shown as the formula P5 does not comprise a column chromatography step, is easy to operate and is suitable for scale-up production.
In one embodiment of the present invention, the method for preparing the compound represented by formula P5 further comprises the steps of: reacting a compound shown as a formula P3 with cinnamyl alcohol to obtain a compound shown as a formula P4;
in one embodiment of the present invention, the conditions and operations of the reaction in the preparation method of the compound represented by formula P4 may be conditions and operations conventional in the art for such reactions.
In one embodiment of the present invention, the method for preparing the compound represented by formula P4 further comprises the steps of: in an organic solvent, under the action of a catalyst, carrying out substitution reaction on a compound shown as a formula P2 and trichloroacetonitrile to obtain a compound shown as a formula P3;
In the preparation method of the compound shown as the formula P3, in one scheme of the invention, the organic solvent can be a conventional organic solvent for the reaction in the field, and dichloromethane is preferred.
In the preparation method of the compound shown as the formula P3, in one scheme of the invention, the catalyst can be a conventional alkaline reagent for the reaction in the field, preferably 1, 8-diazabicyclo undec-7-ene (DBU).
In the preparation method of the compound shown as the formula P3, in a certain scheme of the invention, the mass-volume ratio of the compound shown as the formula P2 to the organic solvent is preferably 2 mg/mL-8 mg/mL.
In the preparation method of the compound shown as the formula P3, in a certain scheme of the invention, the molar ratio of the catalyst to the compound shown as the formula P2 is (0.1-1): 1.
In the preparation method of the compound shown as the formula P3, in one scheme of the invention, the mol ratio of the trichloroacetonitrile to the compound shown as the formula P2 is (1-5): 1.
In the preparation method of the compound shown as the formula P3, in one embodiment of the invention, the progress of the substitution reaction can be monitored by a detection method conventional in the art, such as Thin Layer Chromatography (TLC), gas Chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), high Performance Liquid Chromatography (HPLC), and the like.
In the method for preparing the compound represented by formula P3, in one embodiment of the present invention, the time for the substitution reaction is preferably 1 to 5 hours, for example, 2 hours, based on the completion of the substitution reaction.
In the preparation method of the compound shown as the formula P3, in a certain scheme of the invention, the post-treatment step of the substitution reaction can be a post-treatment step conventional in the art reaction, such as pulping, filtering and drying. Does not contain column chromatography step, is easy to operate and is suitable for large-scale production.
In one embodiment of the present invention, the method for preparing the compound represented by formula P3 further comprises the steps of: in an alcohol solvent, carrying out deprotection reaction on a compound shown as a formula P1 and NH 3 to obtain a compound shown as a formula P2;
in the preparation method of the compound shown as the formula P2, in one scheme of the invention, the alcohol solvent can be a conventional solvent for such reactions in the field, and is preferably methanol.
In the preparation method of the compound shown as the formula P2, in one scheme of the invention, the solvent can be used in a conventional amount for such reactions in the field, and the volume-mass ratio of the solvent to the P1 is preferably 5mL/g-20mL/g.
In the preparation method of the compound shown as the formula P2, in one embodiment of the invention, the amount of NH 3 can be the conventional amount of the reaction in the field, and the amount of NH 3 is preferably 0.05 to 0.5 times the mass of P1.
In the preparation method of the compound shown as the formula P2, in a certain scheme of the invention, the introducing time of the NH 3 can be the conventional introducing time of the reaction in the field, and the introducing time of the NH 3 is preferably 30-90 min.
In the method for preparing the compound represented by formula P2, in one embodiment of the present invention, the temperature of the deprotection reaction may be a reaction temperature conventional in such a reaction in the art, preferably 20 to 40 ℃, more preferably 25 ℃.
In the method for producing the compound represented by the formula P2, in one embodiment of the present invention, the pressure of the deprotection reaction is adjusted depending on the reaction temperature, based on the fact that the reaction temperature does not exceed the "boiling point under pressure", preferably 80kPa to 120kPa, more preferably 101kPa.
In the preparation method of the compound shown in the formula P2, in one embodiment of the present invention, the progress of the deprotection reaction may be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally, the reaction end point is when the compound shown in the formula P1 is no longer reacted, and the time of the deprotection reaction is preferably 10h to 20h, more preferably 15h.
In one embodiment of the present invention, the post-treatment of the deprotection reaction may be a conventional post-treatment of this type of reaction in the art, and preferably, the post-treatment of the deprotection reaction comprises the following steps: organic solvents (e.g., ethyl acetate) are dissolved, washed with water, and concentrated to give P2 syrup, which is directly subjected to the next reaction as P2 syrup. The method does not comprise a column chromatography step, is easy to operate and is suitable for large-scale production.
In one embodiment of the present invention, the method for preparing the compound represented by formula P2 further comprises the steps of: in a solvent, in the presence of an acid binding agent, reacting a compound shown as a formula 1 with benzoyl chloride to obtain a compound shown as a formula P1;
In the method for preparing the compound represented by formula P1, in one embodiment of the present invention, the solvent may be a solvent conventional in such reactions in the art, preferably a halogenated hydrocarbon solvent, and more preferably dichloromethane.
In the preparation method of the compound shown as the formula P1, in one scheme of the invention, the acid binding agent can be an acid binding agent conventional in the reaction in the field, and is preferably pyridine.
In the preparation method of the compound shown as the formula P1, in one embodiment of the invention, the solvent can be used in an amount conventional in the reaction in the field, and preferably, the volume-mass ratio of the solvent to the compound shown as the formula 1 is (2-10) mL/g, for example, 5mL/g.
In the preparation method of the compound shown as the formula P1, in a certain scheme of the invention, the dosage of the acid-binding agent can be the dosage which is conventional in the reaction in the field, and preferably, the volume-mass ratio of the acid-binding agent to the compound shown as the formula 1 is (5-20) mL/g, for example, 10mL/g.
In the preparation method of the compound shown as the formula P1, in one scheme of the invention, the dosage of the benzoyl chloride can be the dosage which is conventional in the reaction in the field, and preferably, the molar ratio of the benzoyl chloride to the compound shown as the formula P1 is 4-10: 1, e.g., 8:1.
In the preparation method of the compound shown as the formula P1, in one embodiment of the invention, the reaction temperature can be a reaction temperature conventional in the art, and is preferably 20-40 ℃.
In the preparation method of the compound represented by formula P1, in one embodiment of the present invention, the progress of the reaction may be monitored according to a detection method conventional in the art (for example, TLC, HPLC or GC), and the reaction time is preferably 1 to 5 hours (for example, 3 hours) when the compound represented by formula 1 disappears as an end point of the reaction.
In one embodiment of the present invention, the preparation method of the compound represented by formula P1 further comprises the following post-treatment steps: adjusting pH to neutrality, concentrating to obtain P1 syrup, and directly performing the next reaction in the form of P1 syrup. The post-treatment of the preparation method of the compound shown as the formula P1 does not comprise a column chromatography step, is easy to operate and is suitable for scale-up production.
The invention also provides a compound shown as a formula P6:
the invention also provides application of the compound shown as the formula P6 in preparing the zoysin.
In one aspect of the invention, the use comprises the steps of:
(A) Preparing a compound shown as a formula P7 from a compound shown as a formula P6; preparing a compound shown as a formula P8 from a compound shown as a formula P7;
(B) Reacting a compound shown as a formula P8 with a compound shown as a formula A4 to obtain a compound shown as a formula P9;
(C) Deprotection reaction is carried out on the compound shown as the formula P9 to obtain the zotebuxostat;
In one embodiment of the invention, step (a) of the use employs a process for the preparation of a compound of formula P8 as described in any one of the preceding claims.
In one embodiment of the invention, in step (B) of the use, the conditions and operation of the reaction may be those conventional in the art for such reactions.
In one embodiment of the invention, in step (C) of the use, the conditions and operation of the deprotection reaction may be conventional conditions and operations for such reactions in the art.
The invention has the positive progress effects that: the invention uses specific silicon-based protecting groups through process optimization and condition screening, is more economical and environment-friendly, has short reaction time and high yield, avoids the step of column chromatography, is easy to operate and is suitable for large-scale production.
Drawings
FIG. 1 is an X-ray diffraction pattern of crystalline form I of Corsev
Fig. 2 is a differential scanning calorimeter diagram of crystalline form I of bazochrome.
Fig. 3 HPLC data for crystalline form I of bazochrome.
FIG. 4 is an X-ray diffraction pattern of amorphous zoysin
Figure 5 amorphous zosev HPLC data.
Fig. 6 shows a comparison of the crystalline form of bazochrome with the amorphous solid-XPRD overlay.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
PREPARATION EXAMPLE 1 PREPARATION A4
To the reaction vessel, 500g of L-arabinose was added, methylene chloride (2.5L) was added, and the mixture was dissolved by stirring, and pyridine (2.63 kg) was added. Benzoyl chloride (3.75 kg,8 eq) was added dropwise to the ice bath. After 3h at room temperature, the reaction was complete, quenched by dropwise addition of water (1.5L). The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate and filtered to give a benzoyl-L-arabinose (A1) solution.
The above A1 solution was added to a 33% hydrobromic acid acetic acid solution (816 g,3 eq) and the reaction was completed after 2 hours at room temperature. The reaction was quenched by addition of saturated sodium bicarbonate, separated, washed with water and concentrated. A2 syrup was obtained.
The above A2 syrup was added to acetone (5.24L) and water (1.74L), and then, sodium iodide (249 g,0.5 eq) was added to the mixture to react at room temperature for 2 hours, followed by completion of the reaction. Ethyl acetate (5.24L) and water (5.24L) were added to extract the product, followed by washing with sodium thiosulfate solution, saturated sodium bicarbonate, and concentration to obtain A3 syrup.
The above A3 syrup was dissolved in methylene chloride (7.7L) by stirring at room temperature, and trichloroacetonitrile (0.962 kg,2 eq) and DBU (253.7 g,0.5 eq) were added thereto, followed by stirring at room temperature for 2 hours to complete the reaction. The reaction solution was concentrated, ethyl acetate (4.6L) was added and stirred for 2 hours, then the reaction was completed, the reaction solution was concentrated to obtain A4 syrup and was directly used for the next feeding, the product: 1.58kg, yield: 78.3%.
Example 1 preparation of P3
To the reaction vessel was added 642.78g of anhydrous glucose, 3.21L of methylene chloride was added, and the mixture was stirred and dissolved, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After 3h at room temperature, the reaction was complete, quenched by dropwise addition of water (1.928L). The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.1kg, hplc purity: 95.5%.
3.1Kg of the syrup was added to an anhydrous methanol (21L) solution, and 200g of ammonia gas was introduced into the reaction mixture for 1 hour. Then left to react at room temperature for 15 hours, and the reaction is complete. Concentrating the reaction solution to obtain black P2 syrup, adding ethyl acetate 8.5L for dissolution, washing 4.25L for two times, concentrating an ethyl acetate phase to obtain black P2 syrup 2.3kg, and carrying out HPLC (high Performance liquid chromatography) purity: 86.5%.
2.3Kg of the P2 syrup was dissolved in 10.6L of methylene chloride under stirring, 1.03kg of trichloroacetonitrile and 271g of DBU were added, and the reaction was completed after stirring at room temperature for 2 hours. The reaction mixture was concentrated, 7.928L of ethyl acetate was added thereto, and the mixture was stirred for 2 hours to precipitate P3. Filtering and drying to obtain P3 solid 1.61kg, and three steps of total yield: 60.7%, HPLC purity: 94.5%.
Comparative example 1 preparation of P3 using hydrazine acetate
To the reaction vessel was added 642.78g of anhydrous glucose, 3.21L of methylene chloride was added, and the mixture was stirred and dissolved, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After 3 hours at room temperature, the reaction is complete, and water 1.928L is added dropwise to quench the reaction. The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.11kg, HPLC purity: 94.5%.
3.1Kg of the syrup was dissolved in 21L of anhydrous methanol, and hydrazine acetate (330 g) was added. Then left to react at room temperature for 15 hours, and the reaction is complete. Concentrating the reaction solution to obtain black P2 syrup, adding ethyl acetate 8.5L for dissolution, washing 4.25L for two times, concentrating an ethyl acetate phase to obtain black P2 syrup 2.31kg, and carrying out HPLC (high Performance liquid chromatography) purity: 75.7%.
2.31Kg of the P2 syrup was dissolved in 10.6L of methylene chloride under stirring, 1.03kg of trichloroacetonitrile and 271g of DBU were added, and the reaction was completed after stirring at room temperature for 2 hours. The reaction mixture was concentrated, 7.928L of ethyl acetate was added thereto, and the mixture was stirred for 2 hours, whereby P3 was precipitated. Filtering and drying to obtain 0.95kg of P3 solid, and three steps of yield: 35.7%, HPLC purity: 85.5%.
Comparative example 2 preparation of P3 using methylamine
To the reaction vessel was added 642.78g of anhydrous glucose, 3.21L of methylene chloride was added, and the mixture was stirred and dissolved, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After 3h at room temperature, the reaction was complete, quenched by dropwise addition of water (1.928L). The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.15kg, purity: 94.55%.
3.1Kg of the syrup was added to 21L of absolute methanol solution, and methylamine (110 g) was added to the reaction mixture. Then left to react at room temperature for 15 hours, and the reaction is complete. The reaction solution was concentrated to give black P2 syrup, which was dissolved by adding 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give black P2 syrup 2.3kg, HPLC purity: 68%. When methylamine is used for deprotection reaction at a large reaction scale, side reaction is obvious, and the side reaction is that the rest benzoyl on D-glucose is removed due to over-strong alkalinity, so that the yield and purity are reduced.
2.3Kg of the P2 syrup was dissolved in 10.6L of methylene chloride under stirring, 1.03kg of trichloroacetonitrile and 271g of DBU were added, and the reaction was completed after stirring at room temperature for 2 hours. The reaction mixture was concentrated, 7.928L of ethyl acetate was added thereto, and the mixture was stirred for 2 hours, whereby P3 was precipitated. Filtering and drying to obtain 0.86kg of P3 solid, and three-step yield: 32.6%, HPLC purity: 83.5%.
Comparative example 3 preparation of P3 (solvent screening: tetrahydrofuran)
To the reaction vessel was added 642.78g of anhydrous glucose, methylene chloride (3.21L) was added and dissolved by stirring, and pyridine (2.82 kg) was added. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After 3h at room temperature, the reaction was complete, quenched by dropwise addition of water (1.928L). The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.05kg, HPLC purity: 93.6%.
3.1Kg of the syrup was added to 21L of tetrahydrofuran solution, and ammonia gas was introduced into the reaction mixture for 1 hour. Then left to react at room temperature for 15 hours, and the reaction is complete. The reaction solution was concentrated to give black P2 syrup, which was dissolved by adding 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give black P2 syrup 2.3kg, HPLC purity: 86.5%.
2.3Kg of the P2 syrup was dissolved in 10.6L of methylene chloride under stirring, 1.03kg of trichloroacetonitrile and 271g of DBU were added, and the reaction was completed after stirring at room temperature for 2 hours. The reaction mixture was concentrated, 7.928L of ethyl acetate was added thereto, and the mixture was stirred for 2 hours, whereby P3 was precipitated. Filtration and drying give 1.12kg of P3 solid, yield: 42.2%, HPLC purity: 94.5%.
Comparative example 4 preparation of P3 (solvent screening: dichloromethane)
To the reaction vessel was added 642.78g of anhydrous glucose, methylene chloride (3.21L) was added and dissolved by stirring, and pyridine (2.82 kg) was added. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After 3h at room temperature, the reaction was complete, quenched by dropwise addition of water (1.928L). The organic phase was separated and washed sequentially with 1M HCl, saturated sodium bicarbonate solution and water. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.14kg, HPLC purity: 95.2%.
3.1Kg of the syrup was added to 21L of methylene chloride solution, and ammonia gas was introduced into the reaction mixture for 1 hour. Then left to react at room temperature for 15 hours, and the reaction is complete. The reaction solution was concentrated to obtain 2.3kg of black P2 syrup, 8.5L of ethyl acetate was added for dissolution, 4.25L of water was washed twice, and the ethyl acetate phase was concentrated to obtain 2.3kg of black P2 syrup with HPLC purity: 37.3%.
2.3Kg of the P2 syrup is added with 10.6L of dichloromethane, stirred and dissolved, 1.03kg of trichloroacetonitrile and DBU (271 g of DBU are added, stirred and reacted at room temperature for 2 hours, the reaction liquid is concentrated, 7.928L of ethyl acetate is added, stirred for 2 hours, P3 is separated out, filtration and drying are carried out, and 0.54kg of P3 solid is obtained, the yield is 20.5%, and the HPLC purity is 86.3%.
Example 2
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Methanol hydrochloride was added to adjust ph=7, and the reaction was concentrated to give 241.6g of P5 syrup (due to excess solvent concentration), HPLC purity: 95.20%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107 g,2.5 eq) was added. TBDMSCl (142.4 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, P6203g is obtained by filtering and drying, and the yield of two steps is: 78.49%, purity (HPLC): 95.44%.
Nuclear magnetic mass spectrum data of P6 ：1H NMR(600MHz,CDCl3)δ7.39(d,J＝7.3Hz,2H),7.34–7.29(m,2H),7.25(t,J＝7.3Hz,1H),6.60(t,J＝17.7Hz,1H),6.30(ddd,J＝22.7,14.5,8.3Hz,1H),4.54–4.45(m,1H),4.37(t,J＝9.9Hz,1H),4.30–4.24(m,1H),3.88(qd,J＝10.8,5.1Hz,2H),3.63–3.56(m,1H),3.53(t,J＝9.1Hz,1H),3.48–3.43(m,1H),3.35(dt,J＝9.7,5.1Hz,1H).
MS：433(M+Na)。
Example 3
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Ph=7 was adjusted by adding methanol hydrochloride solution, and the reaction solution was concentrated to give 240g of P5 syrup (due to the excess of concentrated residual solvent), HPLC purity: 95.10%.
The P5 syrup was dissolved in anhydrous THF (1.3L) and imidazole (107 g,2.5 eq) was added. T-butyldimethylchlorosilane TBDMSCl (142.4 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, and the mixture is filtered and dried to obtain P6 178g, and the yield of two steps is: 68.80%, purity (HPLC): 93.60%.
Example 4
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Methanol hydrochloride was added to adjust ph=7, and the reaction was concentrated to give 242.8g of P5 syrup (due to excess residual solvent concentration), HPLC purity: 94.40%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107 g,2.5 eq) was added. T-butyldimethylchlorosilane TBDMSCl (94.9 g,1 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 5 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, and P6 156.2g is obtained by filtering and drying, and the yield of two steps is: 60.40%, purity (HPLC): 96.21%.
Comparative example 5
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Ph=7 was adjusted by adding methanol hydrochloride solution, and the reaction solution was concentrated to obtain 249g of P5 syrup (due to the excess of concentrated residual solvent), HPLC purity: 93.95%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107 g,2.5 eq) was added. Tert-butyldiphenylchlorosilane TBDPSCl (299 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 12 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6-1 solid is obtained after concentration. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6-1 144g, and obtaining the yield of two steps: 44.36%, purity (HPLC): 87.63%. The TBDPS group is sterically bulky, resulting in prolonged reaction times, lower yields and purities.
Comparative example 6
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Methanol hydrochloride was added to adjust ph=7, and the reaction was concentrated to give 247g of P5 syrup (due to excess solvent concentration), HPLC purity: 94.60%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107 g,2.5 eq) was added. Trimethylsilyl chloride TMSCl (102 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 3 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6-2 solid is obtained after concentration. Petroleum ether (1.8L) is added for pulping, and P6-2.4 g is obtained after filtration and drying, and the yield of two steps is: 43.30%, purity (HPLC): 83.57%. The yield and purity are low.
Comparative example 7
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. The ph=7 was adjusted by adding methanol hydrochloride solution, and the reaction solution was concentrated to give 241g of P5 syrup (due to the excess of concentrated residual solvent), HPLC purity: 95.5%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and pyridine (124 g,2.5 eq) was added. T-butyldimethylchlorosilane TBDMSCl (142.4 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, and P6 g is obtained by filtering and drying, and the yield of two steps is: 34.40%, purity (HPLC): 86.50%. The yield and purity are low.
Comparative example 8
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Ph=7 was adjusted by adding methanol hydrochloride solution, and the reaction solution was concentrated to give 244g of P5 syrup (due to the excess of concentrated residual solvent), HPLC purity: 94.77%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and triethylamine (160.5 g,2.5 eq) was added. T-butyldimethylchlorosilane TBDMSCl (142.4 g,1.5 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 2 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, and P6 g is obtained by filtering and drying, and the yield of two steps is: 40.50%, purity (HPLC): 83.27%, and has low yield and purity.
Comparative example 9
P4 (500 g) was added, and the mixture was dissolved (3L) in methylene chloride under stirring, and a methanol (1.5L) solution of sodium methoxide (113.68 g,3 eq) was added. After 6h at room temperature, the reaction was complete. Methanol hydrochloride was added to adjust ph=7, and the reaction was concentrated to give 243.6g of P5 syrup (due to excess solvent concentration), HPLC purity: 95.5%.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107 g,2.5 eq) was added. T-butyldimethylchlorosilane TBDMSCl (190 g,2 eq) was added dropwise. After the completion of the dropwise addition, the reaction was completed after 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase is subjected to secondary saturated saline washing, anhydrous sodium sulfate drying and filtering, and the P6 solid is obtained by concentration. Petroleum ether (1.8L) is added for pulping, and P6 115g is obtained by filtering and drying, and the yield of two steps is: 44.00%, purity (HPLC): 81.70% excess TBDMSCl produced more by-product.
Example 5
P6 g was dissolved by adding pyridine (288 g,10 eq) and methylene chloride (900 ml). Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give 306g of P7 syrup, yield: 115.9% (due to the concentration of residual solvent overweight), HPLC purity: 97.6%.
The above P7 syrup was dissolved in DMF (1.58L) and 1M aqueous HCl (150 ml) was added at 5℃in ice bath. After 2h reaction at room temperature, the reaction was complete. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with ethyl acetate. The reaction mixture was added dropwise to petroleum ether (1.8L) in an amount of 3 times the volume, followed by stirring to precipitate a product. Filtration gave P8 as a solid (184.4 g), overall yield in two steps: 83.06% HPLC purity was 97.89%.
Example 6
Pyridine (432 g,15 eq) was added to 150g of P. Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give 324g of P7 syrup, yield: 123.2% (due to the concentration of residual solvent overweight), HPLC purity: 90.40%.
The above P7 syrup was dissolved in DMF (1.58L) and 1M aqueous HCl (150 ml) was added at 5℃in ice bath. After 2h reaction at room temperature, the reaction was complete. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with ethyl acetate. The reaction mixture was added dropwise to petroleum ether (1.8L) in an amount of 3 times the volume, followed by stirring to precipitate a product. Filtration gave P8 as a solid (156.4 g), overall yield in two steps: 70.46% HPLC purity was 87.5%.
Example 7
P6 g was dissolved by adding pyridine (288 g,10 eq) and methylene chloride (900 ml). Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give 304g of P7 syrup, yield: 115.6% (due to the concentration of residual solvent overweight), HPLC purity: 97.5%.
The above P7 syrup was dissolved in THF (1.58L) and 1M HCl (150 ml) was added at 5℃in ice bath. After 12h at room temperature, the reaction was complete. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with ethyl acetate. After the reaction, the mixture was added dropwise to petroleum ether (1.8L) in 3 volumes, 177.12g of a product was precipitated under stirring, and the total yield in two steps was: 80.06% HPLC purity was 97.70%. The results showed that the reaction time was longer with THF as solvent than DMF, and the price of THF was higher than DMF.
Comparative example 10
To 150g of P6 was added dichloromethane (900 ml), and the mixture was dissolved by stirring at room temperature, and triethylamine (370 g,10 eq) was added. Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After triethylamine is used for replacing pyridine, the raw materials do not react, the effect is poor, and the target product is not obtained.
Comparative example 11
Pyridine (284 g,10 eq) and dichloromethane (900 ml,5 vol) were added to dissolve P6-1 g at 150 g. Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 24 hours of reaction at room temperature, no target product is generated.
Comparative example 12
P6 g was dissolved by adding pyridine (288 g,10 eq) and methylene chloride (900 ml). Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give 295g of P7 syrup, yield: 112.2% (due to the concentration of residual solvent overweight), HPLC purity: 95.5%.
The above P7 syrup was dissolved in acetonitrile (1.58L), and after 12 hours of reaction at room temperature with the addition of 1M HCl (150 ml) at 5℃in an ice bath, the reaction was completed. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with EA. After the reaction, the reaction mixture was added dropwise to petroleum ether (1.8L) in 3 volumes, 130g of a two-step total yield of the precipitated product was obtained by stirring: 59.80% HPLC purity was 95.40%. The results showed that the reaction was incomplete with acetonitrile as solvent, compared to DMF.
Comparative example 13
P6 g was dissolved by adding pyridine (13.5 g,7 eq) and methylene chloride (60 ml). Pivaloyl chloride (17.6 g,6 eq) was added dropwise to the ice bath. After 15 hours of reaction at room temperature, the reaction is complete, and the water is added to quench the reaction. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate and water, and column chromatography gave P7-1 (9.8 g). Yield: 64.6%.
P7-1：1H NMR(400MHz,CDCl3)δ7.41–7.17(m,138H),6.59(t,J＝13.3Hz,1H),6.20(ddd,J＝15.9,6.8,5.5Hz,1H),5.33(t,J＝9.5Hz,1H),5.13–5.01(m,2H),4.63(d,J＝8.0Hz,1H),4.49(ddd,J＝12.8,5.3,1.2Hz,1H),4.26(ddd,J＝13.0,6.9,0.8Hz,1H),3.76–3.50(m,3H).
P7-1 (2 g,1 eq) was dissolved in DMF (14 ml), ice bath 5℃and 1M HCl (3 ml) was added. After 2h reaction at room temperature, the reaction was complete. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution and extracted 2 times with ethyl acetate. The organic phase was concentrated to give P8-1 syrup, which was column chromatographed to give P8-1 as a solid (0.84 g), yield: 48.55%.
P8-1：1H NMR(600MHz,CDCl3)δ6.60(d,J＝15.9Hz,1H),6.22(dt,J＝15.9,6.1Hz,2H),5.41(t,J＝9.5Hz,1H),5.10(ddd,J＝12.5,8.9,3.6Hz,2H),4.68(d,J＝8.1Hz,1H),4.51(dd,J＝12.8,4.8Hz,1H),4.29(dd,J＝12.8,6.6Hz,1H),3.77–3.68(m,1H),3.58(q,J＝6.7Hz,2H).
Comparative example 14
P6 g was dissolved by adding pyridine (288 g,10 eq) and methylene chloride (900 ml). Acetyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give P7-2 syrup.
The above P7-2 syrup was dissolved in DMF (1.58L) and 1M HCl (150 ml) was added at 5℃in ice bath. After 2h reaction at room temperature, the reaction was complete. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with ethyl acetate. The reaction mixture was added dropwise to petroleum ether (1.8L) in an amount of 3 times the volume, followed by stirring to precipitate a product. Filtration gave P8-2 as a solid (88.5 g), yield: 57.3%, HPLC purity: 93.4%.
Comparative example 15
P6 g was dissolved by adding pyridine (288 g,10 eq) and methylene chloride (900 ml). Benzoyl chloride (372 g,8 eq) was added dropwise to the ice bath. After 7 hours of reaction at room temperature, the reaction is complete, and the reaction is quenched by adding water. The organic phase was washed successively with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give P7 syrup.
The above P7 syrup was dissolved in DMF (1.58L) and 1M HCl (150 ml) was added at 5℃in ice bath. After 2h reaction at room temperature, the reaction was complete. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted 2 times (600 ml) with ethyl acetate. And (3) drying and filtering the organic phase-dependent saturated saline water and anhydrous sodium sulfate, and concentrating to obtain a P8 crude product. The crude P8 was dissolved in (methanol: dcm=1vol:3vol, 200ml:600 ml) and crystallized at 25 ℃ for 3h, filtered to give P8 as a solid (100.7 g), two steps total yield: 45.5%, HPLC purity: 94.6%.
Because the P7 syrup contains a large amount of byproduct benzoic anhydride, when the reaction scale is large, the benzoic anhydride can react with P8 in a post-treatment mode of concentration and recrystallization, and is almost semi-converted into impurities. The invention improves, directly and reversely drops into petroleum ether to separate out the product after washing without concentrating, and has simple operation and less impurity.
Example 8 preparation of P9
A4 (theoretical 265.5g,1.5 eq) syrup and P8 (177.5 g,1 eq) were mixed and dissolved in methylene chloride (1L, 5 vol) under inert gas. A dilution of TMSOTF (9.07 g,0.14 eq) in methylene chloride was added dropwise at reduced temperature. After 1 hour at room temperature, the reaction is complete, and the reaction is quenched by adding triethylamine. The reaction mixture was concentrated and recrystallized from a methanol system to give a glycosylation product P9 (297 g) in a yield of 96.74%.
EXAMPLE 9 preparation of crystalline form I of Corona
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salt, and the reaction solution was concentrated to obtain 154g of bazochrome syrup. Methanol (300 ml) and ethyl acetate (900 ml) were added to precipitate, and the mixture was filtered to obtain 120g of crystalline form I of the zoysia japonica, with a yield of 98.6%. HPLC purity: 98.74%. The added mass of form I was 0.15% compared to the initial mass with little hygroscopicity when left for 24h at 25 ℃ + -1deg.C with a relative humidity of 80% + -2%.
The X-ray diffraction pattern of the obtained crystal form I is shown in fig. 1, and diffraction peaks, peak width values, peak heights, peak height percentages, peak areas and peak area percentages are shown in table 1 below:
TABLE 1X-ray diffraction pattern of crystalline form I of Corona
A differential scanning calorimeter diagram of the crystalline form I of the zobivaive is shown in fig. 2.
HPLC data for the crystalline form I of Corsev are shown in FIG. 3, and the test conditions are as follows: liquid phase column: agilent 5Tc-c18×4.6; flow rate: 1.0ml/min; column temperature: 35 ℃; detection wavelength: 250nm; mobile phase a: CH 3 OH; mobile phase B:10mM potassium dihydrogen phosphate aqueous solution, elution procedure is shown in Table 2 below:
TABLE 2
| Minute (min) | A％ | B％ |
| 0 | 25 | 75 |
| 5 | 25 | 75 |
| 15 | 35 | 65 |
| 40 | 35 | 65 |
| 41 | 25 | 75 |
| 45 | 25 | 75 |
。
Trapeziwei (Chinese character) ：1H NMR(400MHz,CDCl3)1H NMR(400MHz,CD3OD)δ7.45–7.41(m,2H),7.35–7.29(m,2H),7.24(ddd,J＝7.3,3.8,1.2Hz,1H),6.72(d,J＝16.0Hz,1H),6.38(ddd,J＝16.0,6.4,5.8Hz,1H),4.53(ddd,J＝12.9,5.6,1.5Hz,1H),4.39(t,J＝5.5Hz,1H),4.38–4.31(m,2H),4.13(dd,J＝11.4,2.2Hz,1H),3.91–3.86(m,1H),3.82(dt,J＝4.9,2.5Hz,1H),3.76(dd,J＝11.4,5.8Hz,1H),3.63(dd,J＝8.8,6.7Hz,1H),3.58–3.52(m,2H),3.48(ddd,J＝8.0,5.7,2.1Hz,1H),3.40–3.35(m,2H),3.28–3.23(m,1H).MS：(M+Na)+451.
EXAMPLE 10 preparation of crystalline form I of Corona
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salt, and the reaction solution was concentrated to obtain 160g of bazochrome syrup. Methanol (300 ml) and methylene dichloride (900 ml) are added, stirred and crystallized at room temperature for 0.5h, and filtered to obtain 117g of the crystalline form of the zoysin, which is proved to be crystalline form I of the zoysin, the yield is 95.9%, and the purity of HPLC: 94.5%. The added mass of form I was 0.16% compared to the initial mass with little hygroscopicity when left for 24h at 25 ℃ + -1deg.C with a relative humidity of 80% + -2%.
EXAMPLE 11 preparation of crystalline form I of Corsev
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salt, and the reaction solution was concentrated to obtain 152g of bazochrome syrup. Methanol (300 ml) and methylene dichloride (600 ml) are added, stirred and crystallized for 0.5h at room temperature, and filtered to obtain 102g of the crystalline form I of the zoysia japonica, and the yield is 84.5%. Purity: 76.2%. The added mass of form I was 0.20% compared to the initial mass, with little hygroscopicity, when left at 25 ℃ ± 1 ℃ with a relative humidity of 80% ± 2% for 24 hours.
EXAMPLE 12 preparation of Corp
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salt, and the reaction solution was concentrated to obtain 155g of bazochrome syrup. Methanol (300 ml) and methylene dichloride (900 ml) are added, stirred and crystallized at room temperature for 15min, 100.5g of the crystalline form I of the zoysia japonica is obtained by filtration, and the yield is 83.5%. HPLC purity: 79.2%. The added mass of form I was 0.17% with little hygroscopicity compared to the initial mass when left at 25 ℃ ± 1 ℃ with a relative humidity of 80% ± 2% for 24 hours.
Comparative example 16 amorphous zotebuvir preparation
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salts, and the reaction solution was concentrated to obtain 154.2g of a syrup of bazochrome. Ethyl acetate (900 ml) was added to the mixture and the mixture was beaten for 2 hours, and the resultant was filtered to obtain 32.46g of amorphous zoysia japonica having a moisture absorption property, and the yield was 80%. HPLC purity: 92.5%.
The amorphous zoysin is placed for 24 hours at the temperature of 25+/-1 ℃ and the relative humidity of 80+/-2%, and compared with the initial mass, the amorphous zoysin has 15.4% of mass and excellent moisture absorption.
The X-ray diffraction pattern of the obtained amorphous coronene is shown in fig. 4, and the diffraction peaks, peak width values, peak heights, peak height percentages, peak areas and peak area percentages are shown in the following table 3:
TABLE 3X-ray diffraction pattern of amorphous collaterals obstruction dimension expressed in terms of 2 theta angle
| Numbering device | 2θ(±0.2°) | d(A) | Peak height | Peak height percentage (%) | Peak area | Percent peak area (%) |
| 1 | 3.518 | 25.0944 | 493 | 51.4 | 2678 | 28.1 |
| 2 | 20.057 | 4.4233 | 496 | 51.7 | 249 | 2.6 |
| 3 | 27.328 | 3.2608 | 362 | 37.7 | 1194 | 12.5 |
| 4 | 31.614 | 2.8278 | 959 | 100.0 | 9534 | 100.0 |
The superimposed graph pair of the crystalline form and the amorphous solid-XPRD of the zoysin is shown in FIG. 6, the HPLC data is shown in FIG. 5, and the test conditions of the method are the same as those of the above zoysin crystalline form I.
Comparative example 17: the water/acetone system was recrystallized.
P9 (300 g) was added, and the mixture was dissolved (1800 ml) in methylene chloride under stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol (900 ml) was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salts, and the reaction solution was concentrated to obtain 157.2g of bazochrome syrup. Acetone (900 ml) and water (300 ml) were added, and stirred at room temperature for crystallization for 12 hours, thus obtaining the product, i.e., the solid of the zosev.
Comparative example 18: the methanol/diethyl ether system was recrystallized.
P9 (300 g) was added, dissolved (1800 ml) in methylene chloride with stirring, and a solution of sodium methoxide (1.5 eq,23 g) in methanol was added. After 6h at room temperature, the reaction was complete. Hydrochloric acid in methanol was added to adjust ph=7, filtered to remove salts, and the reaction solution was concentrated to obtain 152.5g of bazochrome syrup. Diethyl ether (900 ml) and methanol (300 ml) were added, and stirred at room temperature for crystallization for 12 hours, whereby a product, i.e., a solid, of the product, i.e., the zosev-vitamin, could not be obtained.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the principles and spirit of the invention, but such changes and modifications fall within the scope of the invention.
Claims (26)
1. A process for the preparation of a compound of formula P8, comprising the steps of:
(1) In a solvent, carrying out hydroxyl protection reaction on a compound shown as a formula P6 and BzCl to obtain a compound shown as a formula P7;
wherein the solvent is pyridine or a mixed solvent of pyridine and halogenated hydrocarbon solvent;
(2) In a solvent, under the action of acid, a compound shown as a formula P7 is subjected to deprotection reaction to obtain a compound shown as a formula P8;
2. the method for producing a compound represented by formula P8 according to claim 1, wherein in the method for producing a compound represented by formula P8, in step (1), the solvent is a mixed solvent of pyridine and a halogenated hydrocarbon solvent;
and/or, in the preparation method of the compound shown as the formula P8, in the step (1), the volume-mass ratio of the solvent to the compound shown as the formula P6 is (2-10) mL/g;
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the molar ratio of BzCl to the compound shown as the formula P6 is (5-10): 1, a step of;
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the temperature of the hydroxyl protection reaction is 20-40 ℃;
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the time of the hydroxyl protection reaction is 4-10 hours;
and/or, the step (1) of the preparation method of the compound shown as the formula P8 further comprises the following post-treatment steps: quenching reaction, washing and concentrating an organic phase to obtain P7 syrup, and directly carrying out the next reaction in the form of P7 syrup;
and/or, in the preparation method of the compound shown as the formula P8, in the step (2), the solvent is a nitrogen-containing compound solvent and/or an ether solvent;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the volume-mass ratio of the solvent to the compound shown as the formula P7 is (4-10) mL/g;
and/or, in the preparation method of the compound shown as the formula P8, in the step (2), the acid is hydrochloric acid;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the molar ratio of the acid to the compound shown as the formula P7 is 1: (0.5-5);
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the temperature of the deprotection reaction is 20-40 ℃;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the deprotection reaction time is 0.5-5 hours;
And/or, the step (2) of the preparation method of the compound shown as the formula P8 further comprises the following post-treatment steps: after the addition of the solvent, a solid of the compound represented by formula P8 is precipitated and filtered.
3. The method for producing a compound represented by formula P8 according to claim 2, wherein in step (1), when the compound is a mixed solvent of pyridine and a halogenated hydrocarbon solvent, the volume ratio of pyridine to halogenated hydrocarbon solvent is 1: (2-5);
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the volume-mass ratio of the solvent to the compound shown as the formula P6 is 3mL/g or 8mL/g;
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the mol ratio of BzCl to the compound shown as the formula P6 is 8:1;
And/or, in the preparation method of the compound shown as the formula P8, in the step (1), the time of the hydroxyl protection reaction is 7 hours;
And/or, the step (1) of the preparation method of the compound shown as the formula P8 further comprises the following post-treatment steps: adding water for quenching reaction, washing an organic phase sequentially by hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and water, concentrating to obtain P7 syrup, and directly carrying out the next reaction in the form of P7 syrup;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the solvent is DMF and/or THF;
and/or, in the preparation method of the compound shown as the formula P8, in the step (2), the volume-mass ratio of the solvent to the compound shown as the formula P7 is 5mL/g;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the hydrochloric acid is added into the system in the form of hydrochloric acid aqueous solution, and the molar concentration of the hydrochloric acid aqueous solution is 0.8-1.5 mol/L;
and/or, in the preparation method of the compound shown as the formula P8, in the step (2), the deprotection reaction time is 2 hours;
And/or, the post-treatment step of the step (2) of the preparation method of the compound shown as the formula P8 comprises the following steps: quenching the reaction with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, adding petroleum ether, separating out solid of the compound shown in formula P8, and filtering.
4. The method for producing a compound represented by formula P8 according to claim 3, wherein in the step (1), when the compound is a mixed solvent of pyridine and a halogenated hydrocarbon solvent, the volume ratio of pyridine to halogenated hydrocarbon solvent is 1:3;
And/or, in the preparation method of the compound shown as the formula P8, in the step (2), the solvent is DMF;
and/or, in the preparation method of the compound shown as the formula P8, in the step (2), the molar concentration of the hydrochloric acid aqueous solution is 1mol/L.
5. The method for producing a compound of formula P8 as claimed in claim 3, wherein the petroleum ether is used in an amount of 2 to 6 times the mass of the theoretical product in the post-treatment of step (2).
6. The method for preparing a compound represented by formula P8 according to claim 1, wherein the method for preparing a compound represented by formula P8 further comprises the steps of:
In a solvent, under the action of an acid binding agent, carrying out hydroxyl protection reaction on a compound shown as a formula P5 and tert-butyldimethyl chlorosilane (TBDMSCl) to obtain a compound shown as a formula P6;
The acid binding agent is imidazole.
7. The method for producing a compound represented by formula P8 according to claim 6, wherein in the method for producing a compound represented by formula P6, the solvent is a nitrogen-containing compound solvent and/or an ether solvent;
And/or, in the preparation method of the compound shown as the formula P6, the volume-mass ratio of the solvent to the compound shown as the formula P5 is (4-10) mL/g;
And/or, in the preparation method of the compound shown as the formula P6, the mol ratio of the acid binding agent to the compound shown as the formula P5 is (1-4): 1, a step of;
And/or, in the preparation method of the compound shown as the formula P6, the mol ratio of the tert-butyldimethyl chlorosilane to the compound shown as the formula P5 is (1-1.8): 1, a step of;
And/or, in the preparation method of the compound shown as the formula P6, the temperature of the hydroxyl protection reaction is 20-40 ℃;
And/or, in the preparation method of the compound shown as the formula P6, the hydroxyl protection reaction time is 1-6 hours;
and/or, the preparation method of the compound shown as the formula P6 comprises the following steps: mixing a compound shown as a formula P5, an acid binding agent and a solvent, and adding tert-butyldimethyl chlorosilane into a system to perform hydroxyl protection reaction to obtain a compound shown as a formula P6;
and/or, the preparation method of the compound shown as the formula P6 further comprises the following post-treatment steps: concentrating to obtain solid of compound shown in formula P6, adding solvent, pulping, filtering, and drying.
8. The method for producing a compound represented by formula P8 according to claim 7, wherein in the method for producing a compound represented by formula P6, the solvent is DMF and/or THF;
And/or, in the preparation method of the compound shown as the formula P6, the volume-mass ratio of the solvent to the compound shown as the formula P5 is 6mL/g;
And/or, in the preparation method of the compound shown as the formula P6, the mol ratio of the acid binding agent to the compound shown as the formula P5 is (2-3): 1, a step of;
And/or in the preparation method of the compound shown in the formula P6, the mol ratio of the tert-butyldimethyl chlorosilane to the compound shown in the formula P5 is 1:1 or 1.5:1;
and/or, in the preparation method of the compound shown as the formula P6, the hydroxyl protection reaction time is 1 hour or 5 hours;
And/or, the post-treatment step of the preparation method of the compound shown as the formula P6 comprises the following steps: quenching the reaction with water, extracting with ethyl acetate, washing the organic phase with saturated saline water, drying, filtering, concentrating to obtain solid of the compound shown in formula P6, pulping with petroleum ether, filtering, and drying to obtain the compound shown in formula P6.
9. The method for producing a compound represented by formula P8 according to claim 7, wherein in the method for producing a compound represented by formula P6, the molar ratio of the acid-binding agent to the compound represented by formula P5 is 2.5:1, a step of;
and/or, in the preparation method of the compound shown as the formula P6, the mol ratio of the tert-butyldimethyl chlorosilane to the compound shown as the formula P5 is (1.2-1.6): 1.
10. The method for preparing a compound represented by formula P8 as claimed in claim 6, wherein the method for preparing a compound represented by formula P6 further comprises the steps of:
In a solvent, under the action of alkali, carrying out deprotection reaction on a compound shown as a formula P4 to obtain a compound shown as a formula P5;
11. The method for producing a compound represented by the formula P8 according to claim 10, wherein in the method for producing a compound represented by the formula P5, the solvent is a halogenated hydrocarbon solvent;
And/or, in the preparation method of the compound shown as the formula P5, the volume-mass ratio of the solvent to the compound shown as the formula P4 is (4-10) mL/g;
And/or, in the preparation method of the compound shown as the formula P5, the alkali is sodium methoxide;
and/or, in the preparation method of the compound shown as the formula P5, the molar ratio of the alkali to the compound shown as the formula P4 is (1-5): 1, a step of;
And/or, in the preparation method of the compound shown as the formula P5, the temperature of the deprotection reaction is 20-40 ℃;
and/or, in the preparation method of the compound shown as the formula P5, the deprotection reaction time is 3-10 hours;
And/or, the preparation method of the compound shown as the formula P5 further comprises the following post-treatment steps: adjusting pH to neutrality, concentrating to obtain P5 syrup, and directly performing the next reaction in the form of P5 syrup.
12. The method for producing a compound of formula P8 according to claim 11, wherein in the method for producing a compound of formula P5, the solvent is methylene chloride;
And/or, in the preparation method of the compound shown as the formula P5, the volume-mass ratio of the solvent to the compound shown as the formula P4 is 6mL/g;
And/or, in the preparation method of the compound shown as the formula P5, the sodium methoxide is added into the system in the form of a methanol solution of sodium methoxide;
and/or, in the preparation method of the compound shown as the formula P5, the molar ratio of the alkali to the compound shown as the formula P4 is 3:1;
And/or, in the preparation method of the compound shown as the formula P5, the deprotection reaction time is 6 hours;
And/or, in the preparation method of the compound shown as the formula P5, the post-treatment further comprises the following post-treatment steps: adding hydrochloric acid methanol solution to adjust pH=7, concentrating to obtain P5 syrup, and directly carrying out the next reaction in the form of P5 syrup.
13. The method for preparing a compound represented by formula P8 according to claim 12, wherein the volume/mass ratio of the methanol to the compound represented by formula P4 is (2 to 5) mL/g.
14. The method for preparing a compound represented by formula P8 according to claim 12, wherein the volume/mass ratio of the methanol to the compound represented by formula P4 is 3mL/g.
15. The method for preparing a compound represented by formula P8 according to claim 10, wherein the method for preparing a compound represented by formula P5 further comprises the steps of: reacting a compound shown as a formula P3 with cinnamyl alcohol to obtain a compound shown as a formula P4;
The preparation method of the compound shown as the formula P4 further comprises the following steps: in an organic solvent, under the action of a catalyst, carrying out substitution reaction on a compound shown as a formula P2 and trichloroacetonitrile to obtain a compound shown as a formula P3;
16. The method for producing a compound of formula P8 according to claim 15, wherein in the method for producing a compound of formula P3, the organic solvent is methylene chloride;
And/or, in the preparation method of the compound shown as the formula P3, the catalyst is an alkaline reagent;
And/or, in the preparation method of the compound shown as the formula P3, the mass-volume ratio of the compound shown as the formula P2 to the organic solvent is 2 mg/mL-8 mg/mL;
And/or, in the preparation method of the compound shown as the formula P3, the mol ratio of the catalyst to the compound shown as the formula P2 is (0.1-1): 1, a step of;
And/or, in the preparation method of the compound shown as the formula P3, the mol ratio of the trichloroacetonitrile to the compound shown as the formula P2 is (1-5): 1;
And/or, in the preparation method of the compound shown as the formula P3, the time of the substitution reaction is 1-5 h;
And/or, in the preparation method of the compound shown as the formula P3, the post-treatment step of the substitution reaction is beating, filtering and drying.
17. The method for producing a compound represented by formula P8 according to claim 16, wherein in the method for producing a compound represented by formula P3, the catalyst is 1, 8-diazabicyclo undec-7-ene;
and/or, in the preparation method of the compound shown as the formula P3, the time of the substitution reaction is 2h.
18. The method for preparing a compound represented by formula P8 according to claim 15, wherein the method for preparing a compound represented by formula P3 further comprises the steps of: in an alcohol solvent, carrying out deprotection reaction on a compound shown as a formula P1 and NH 3 to obtain a compound shown as a formula P2;
19. the method for producing a compound of formula P8 according to claim 18, wherein in the method for producing a compound of formula P2, the alcohol solvent is methanol;
And/or, in the preparation method of the compound shown as the formula P2, the volume-mass ratio of the solvent to the P1 is 5mL/g-20mL/g;
And/or, in the preparation method of the compound shown as the formula P2, the dosage of NH 3 is 0.05-0.5 times of the mass of P1;
and/or, in the preparation method of the compound shown as the formula P2, the introducing time of the NH 3 is 30-90 min;
And/or, in the preparation method of the compound shown as the formula P2, the temperature of the deprotection reaction is 20-40 ℃;
And/or, in the preparation method of the compound shown as the formula P2, the pressure of the deprotection reaction is adjusted according to the reaction temperature, and the reaction temperature is not more than the boiling point under pressure;
And/or, in the preparation method of the compound shown as the formula P2, the deprotection reaction time is 10-20 h;
And/or, in the preparation method of the compound shown as the formula P2, the post-treatment of the deprotection reaction comprises the following steps: dissolving the organic solvent, washing with water, concentrating to obtain P2 syrup, and directly carrying out the next reaction in the form of P2 syrup.
20. The method for producing a compound represented by formula P8 according to claim 19, wherein the temperature of the deprotection reaction in the method for producing a compound represented by formula P2 is 25 ℃;
And/or, in the preparation method of the compound shown as the formula P2, the pressure of the deprotection reaction is 80kPa-120kPa;
and/or, in the preparation method of the compound shown as the formula P2, the deprotection reaction time is 15h;
and/or, in the preparation method of the compound shown as the formula P2, in the post-treatment of the deprotection reaction, the organic solvent is ethyl acetate.
21. The method for producing a compound of formula P8 as claimed in claim 19, wherein the pressure of the deprotection reaction is 101kPa.
22. The method for preparing a compound of formula P8 as claimed in claim 18, wherein the method for preparing a compound of formula P2 further comprises the steps of: in a solvent, in the presence of an acid binding agent, reacting a compound shown as a formula 1 with benzoyl chloride to obtain a compound shown as a formula P1;
23. the method for producing a compound represented by the formula P8 according to claim 22, wherein in the method for producing a compound represented by the formula P1, the solvent is a halogenated hydrocarbon solvent;
And/or, in the preparation method of the compound shown as the formula P1, the acid binding agent is pyridine;
and/or, in the preparation method of the compound shown as the formula P1, the volume-mass ratio of the solvent to the compound shown as the formula 1 is (2-10) mL/g;
And/or, in the preparation method of the compound shown as the formula P1, the volume-mass ratio of the acid binding agent to the compound shown as the formula 1 is (5-20) mL/g;
And/or, in the preparation method of the compound shown as the formula P1, the molar ratio of the benzoyl chloride to the compound shown as the formula P1 is (4-10): 1, a step of;
and/or, in the preparation method of the compound shown as the formula P1, the reaction temperature is 20-40 ℃;
and/or, in the preparation method of the compound shown as the formula P1, the reaction time is 1-5 hours;
And/or, the preparation method of the compound shown as the formula P1 further comprises the following post-treatment steps: adjusting pH to neutrality, concentrating to obtain P1 syrup, and directly performing the next reaction in the form of P1 syrup.
24. The method for producing a compound of formula P8 according to claim 23, wherein in the method for producing a compound of formula P1, the solvent is methylene chloride;
and/or, in the preparation method of the compound shown as the formula P1, the volume-mass ratio of the solvent to the compound shown as the formula 1 is 5mL/g;
and/or, in the preparation method of the compound shown as the formula P1, the volume-mass ratio of the solvent to the compound shown as the formula 1 is 10mL/g;
And/or, in the preparation method of the compound shown as the formula P1, the molar ratio of the benzoyl chloride to the compound shown as the formula P1 is 8:1;
and/or, in the preparation method of the compound shown as the formula P1, the reaction time is 3 hours.
25. A compound of formula P6:
26. use of a compound of formula P6 according to claim 25 for the preparation of a zoysin, comprising the steps of:
(A) Preparing a compound shown as a formula P7 from a compound shown as a formula P6; preparing a compound shown as a formula P8 from a compound shown as a formula P7;
the operation and conditions of step (a) are as defined in any one of claims 1 to 22;
(B) Reacting a compound shown as a formula P8 with a compound shown as a formula A4 to obtain a compound shown as a formula P9;
(C) Deprotection reaction is carried out on the compound shown as the formula P9 to obtain the zotebuxostat;
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| WO2016127874A1 (en) * | 2015-02-13 | 2016-08-18 | 上海彩迩文生化科技有限公司 | Method for preparing vorapaxar sulfate, and intermediate and preparation method therefor |
| WO2017120729A1 (en) * | 2016-01-11 | 2017-07-20 | 浙江海正药业股份有限公司 | Method and intermediate for the preparation of epirubicin hydrochloride |
| WO2017202365A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Preparation method for trifluoromethyl-substituted pyran derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016127874A1 (en) * | 2015-02-13 | 2016-08-18 | 上海彩迩文生化科技有限公司 | Method for preparing vorapaxar sulfate, and intermediate and preparation method therefor |
| WO2017120729A1 (en) * | 2016-01-11 | 2017-07-20 | 浙江海正药业股份有限公司 | Method and intermediate for the preparation of epirubicin hydrochloride |
| WO2017202365A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Preparation method for trifluoromethyl-substituted pyran derivative |
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