CN115124578A - Trachelospermol intermediate, preparation method and application thereof - Google Patents
Trachelospermol intermediate, preparation method and application thereof Download PDFInfo
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- CN115124578A CN115124578A CN202110336623.6A CN202110336623A CN115124578A CN 115124578 A CN115124578 A CN 115124578A CN 202110336623 A CN202110336623 A CN 202110336623A CN 115124578 A CN115124578 A CN 115124578A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 130
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- 238000006243 chemical reaction Methods 0.000 claims abstract description 222
- 239000002904 solvent Substances 0.000 claims abstract description 82
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 30
- 239000002253 acid Substances 0.000 claims abstract description 26
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 230000035484 reaction time Effects 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 152
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 129
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 120
- 235000020357 syrup Nutrition 0.000 claims description 84
- 239000006188 syrup Substances 0.000 claims description 84
- 239000000243 solution Substances 0.000 claims description 82
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 66
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 53
- 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 33
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 28
- 239000007787 solid Substances 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 23
- 238000010791 quenching Methods 0.000 claims description 23
- 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
- 238000001035 drying Methods 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000011230 binding agent Substances 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- RINHYCZCUGCZAJ-UHAHJPEESA-N (2s,3r,4s,5s,6r)-2-[(e)-3-phenylprop-2-enoxy]-6-[[(2s,3r,4s,5s)-3,4,5-trihydroxyoxan-2-yl]oxymethyl]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)CO[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC\C=C\C=2C=CC=CC=2)O1 RINHYCZCUGCZAJ-UHAHJPEESA-N 0.000 claims description 14
- 238000004537 pulping Methods 0.000 claims description 14
- JJYVNURTNGHITH-UHFFFAOYSA-N rosavin Natural products OC1COC(OCC2OC(OC(=O)C=Cc3ccccc3)C(O)C(O)C2O)C(O)C1O JJYVNURTNGHITH-UHFFFAOYSA-N 0.000 claims description 14
- IEBFEMIXXHIISM-UHFFFAOYSA-N rozarin Natural products OC1C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC=CC=2C=CC=CC=2)O1 IEBFEMIXXHIISM-UHFFFAOYSA-N 0.000 claims description 14
- RINHYCZCUGCZAJ-UHFFFAOYSA-N rozavin Natural products OC1C(O)C(O)COC1OCC1C(O)C(O)C(O)C(OCC=CC=2C=CC=CC=2)O1 RINHYCZCUGCZAJ-UHFFFAOYSA-N 0.000 claims description 14
- -1 haloalkane hydrocarbon Chemical class 0.000 claims description 13
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 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
- 239000012266 salt solution Substances 0.000 claims description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 14
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 55
- 238000003756 stirring Methods 0.000 description 40
- 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
- 239000013078 crystal Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000013557 residual solvent Substances 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 238000011031 large-scale manufacturing process Methods 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
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical group COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 6
- 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 229960004380 tramadol Drugs 0.000 description 6
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 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
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-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
- 238000010586 diagram Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-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
- 241000222354 Trametes Species 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
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004949 mass spectrometry 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
- 238000005457 optimization Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 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
- 238000012216 screening 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
- 238000001228 spectrum Methods 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
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
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- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a torsavide intermediate, a preparation method and application thereof. The preparation method of the compound shown as the formula P8 specifically 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, carrying out deprotection reaction on the compound shown as the formula P7 to obtain the compound shown as the formula P8. Also discloses application of the compound shown as the formula P6 in preparing the torsavide. The method has the advantages of low cost, short reaction time, high yield, environmental protection, avoidance of column chromatography step, easy operation and suitability for scale-up production.
Description
Technical Field
The invention relates to a torsavide intermediate, a preparation method and application thereof.
Background
The rosavin 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 rosavin are few, the general cost is high, the yield is low, and the biggest problem is that the rosavin needs to be subjected to column chromatography, so that the rosavin is not suitable for industrial production. Such as: li et al (Li X D, Kang S T, Li GY, et al. Synthesis of Some Phenyl Propanoic Glycosides (PPGs) and Their Acetylcholinesterase/xanthene oxide inhibition Activities [ J ]. Molecules,2011,16(5):3580-3596) prepared as bond intermediates:
tr is used as a hydroxyl protecting group, the reaction time for synthesizing the torsavide by using the intermediate is long, the post-treatment is complex, the step of column chromatography is required, 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 torsavide intermediate in the prior art, and provides a torsavide intermediate, and 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 step, easy operation and suitability for mass production.
The invention solves the technical problems through 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, carrying out deprotection reaction on a compound shown as a formula P7 to obtain a compound shown as a formula P8;
in the preparation method of the compound represented by the formula P8, in a preferred embodiment of the present invention, certain conditions or operations are defined as follows, and the conditions and operations not mentioned are as described in any of the embodiments of the present invention, (abbreviated as "in a certain embodiment of the present invention"), in step (1), the solvent may be a solvent conventional in such reactions in the art, preferably pyridine or a "mixed solvent of pyridine and a haloalkane hydrocarbon solvent", and further preferably a mixed solvent of pyridine and a haloalkane hydrocarbon solvent; the haloalkane solvent is preferably dichloromethane; when the mixed solvent is pyridine and halogenated alkane solvent, the volume ratio of the pyridine to the halogenated alkane solvent is preferably 1: (2-5), for example, 1: 3.
In one embodiment of the present invention, in the step (1), the amount of the solvent may be an amount conventionally used in such reactions in the art, and preferably, the volume-to-mass ratio of the solvent to the compound represented by the formula P6 is (2-10) mL/g, for example, 3mL/g or 8 mL/g.
In one embodiment of the present invention, in the preparation method of the compound represented by formula P8, in step (1), the amount of BzCl may be an amount conventionally used in such reactions in the art, and preferably, the molar ratio of BzCl to the compound represented by formula P6 is (5-10): 1, e.g. 8: 1.
In a certain scheme of the preparation method of the compound shown in the formula P8, in the step (1), the temperature of the hydroxyl protection reaction may be a reaction temperature conventional in such reactions in the field, and is preferably 20-40 ℃.
In one embodiment of the present invention, in the preparation method of the compound represented by formula P8, in step (1), the progress of the hydroxyl protection reaction may be monitored according to a conventional detection method in the art (e.g., TLC, HPLC, or GC), and generally the time when the compound represented by formula P6 disappears is used as an end point of the reaction, and the time of the hydroxyl protection reaction is preferably 4 to 10 hours (e.g., 7 hours).
In one embodiment of the present invention, step (1) of the preparation method of the compound represented by formula P8 further comprises the following post-treatment steps: quenching reaction (for example, quenching reaction by adding water), washing organic phase (for example, washing by hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and water in sequence), concentrating to obtain P7 syrup, and directly carrying out next reaction in the form of P7 syrup. The post-treatment of the step (1) does not comprise a column chromatography step, is easy to operate and is suitable for large-scale production.
In the preparation method of the compound shown in the 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 one embodiment of the present invention, in the step (2), the amount of the solvent may be an amount conventionally used in such reactions in the art, and preferably, the volume-to-mass ratio of the solvent to the compound represented by the formula P7 is (4-10) mL/g, for example, 5 mL/g.
In one embodiment of the present invention, in the preparation method of the compound represented by formula P8, in step (2), the acid is an acid that can be conventional in such reactions in the art, and is preferably hydrochloric acid; the hydrochloric acid is preferably added to the system in the form of an aqueous hydrochloric acid solution, and the molar concentration of the aqueous hydrochloric acid solution is preferably 0.8-1.5 mol/L (e.g. 1 mol/L).
In the preparation method of the compound shown as the formula P8, in one embodiment of the invention, in the step (2), the acid can be used in an amount conventional in such reactions in the field, and preferably, the molar ratio of the acid to the compound shown as the formula P7 is 1: (0.5-5).
In a certain embodiment of the present invention, in the step (2), the deprotection reaction temperature may be a reaction temperature conventional to such reactions in the art, and is preferably 20 to 40 ℃.
In a certain embodiment of the present invention, in the step (2), the progress of the deprotection reaction may be monitored by a conventional detection method in the art (e.g., TLC, HPLC, or GC), and is generally determined as an end point of the reaction when the compound shown in formula P7 disappears, and the time of the deprotection reaction is preferably 0.5 to 5 hours (e.g., 2 hours).
In one embodiment of the present invention, step (2) of the preparation method of the compound represented by formula P8 further comprises the following post-treatment steps: adding solvent to precipitate solid of the compound shown as the formula P8, and filtering. The post-treatment of the step (2) 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 post-treatment step of step (2) of the preparation method of the compound represented by formula P8 comprises the following steps: adding saturated sodium bicarbonate water solution for quenching reaction, adding ethyl acetate for extraction, adding petroleum ether (the dosage of the petroleum ether is 2-6 times of the mass of a theoretical product), then separating out a solid of a compound shown as a formula P8, and filtering to obtain the compound.
In one embodiment of the present invention, the preparation method of 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-butyldimethylsilyl chloride (TBDMSCl) to obtain a compound shown as a formula P6;
the acid-binding agent is imidazole.
In the preparation method of the compound shown in the formula P6, in one embodiment of the present invention, 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.
In a certain embodiment of the present invention, the amount of the solvent used in the preparation method of the compound represented by formula P6 may be an amount conventionally used in such reactions in the art, and preferably, the volume-to-mass ratio of the solvent to the compound represented by formula P5 is (4-10) mL/g, for example, 6 mL/g.
In a certain embodiment of the present invention, the acid-binding agent may be used in an amount that is conventional in the field of such reactions, and preferably, the molar ratio of the acid-binding agent to the compound represented by formula P5 is (1-4): 1, more preferably (2-3): 1, e.g. 2.5: 1.
in a certain scheme of the preparation method of the compound shown in the formula P6, the amount of tert-butyldimethylsilyl chloride may be the amount conventionally used in such reactions in the field, and preferably, the molar ratio of tert-butyldimethylsilyl chloride to the compound shown in 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 a certain scheme of the preparation method of the compound shown as the formula P6, the temperature of the hydroxyl protection reaction can be the reaction temperature of the reaction routine in the field, and is preferably 20-40 ℃.
In one embodiment of the preparation method of the compound represented by the formula P6, the progress of the hydroxyl protection reaction can be monitored according to detection methods (such as TLC, HPLC or GC) conventional in the art, and is generally used as the end point of the reaction when the compound represented by the formula P5 disappears, and the time of the hydroxyl protection reaction is preferably 1 to 6 hours (such as 1 hour or 5 hours).
In one embodiment of the present invention, the preparation method of the compound represented by formula P6 comprises the following steps: mixing a compound shown as a formula P5, an acid-binding agent and a solvent, and adding tert-butyldimethylsilyl chloride into a system to perform a hydroxyl protection reaction to obtain a compound shown as a 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 as 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 large-scale production.
In one embodiment of the present invention, the post-treatment step of the preparation method of the compound represented by the formula P6 comprises the following steps: adding water for quenching reaction, adding ethyl acetate for extraction, washing the organic phase with saturated salt solution, drying, filtering, concentrating to obtain solid of the compound shown as the formula P6, adding petroleum ether for pulping, filtering, and drying to obtain the compound shown as the formula P6.
In one embodiment of the present invention, the preparation method of the compound represented by formula P6 further comprises the following steps:
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 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 represented by formula P5.
In a certain embodiment of the present invention, the amount of the solvent used in the preparation method of the compound represented by the formula P5 may be an amount conventionally used in such reactions in the field, and preferably, the volume-to-mass ratio of the solvent to the compound represented by the formula P4 is (4-10) mL/g, for example, 6 mL/g.
In one embodiment of the present invention, the base may be a base conventional in such reactions in the art, and is preferably sodium methoxide. The sodium methoxide is preferably added into the system in the form of a methanol solution of the sodium methoxide, wherein the volume-to-mass ratio of the methanol to the compound shown as the formula P4 is (2-5) mL/g, for example, 3 mL/g.
In one embodiment of the present invention, the amount of the base used in the preparation method of the compound represented by formula P5 may be an amount conventionally used in such reactions in the art, and preferably, the molar ratio of the base to the compound represented by formula P4 is (1-5): 1, e.g. 3: 1.
In a certain scheme of the preparation method of the compound shown in the formula P5, the deprotection reaction temperature can be a reaction temperature conventional in the reaction in the field, and is preferably 20-40 ℃.
In a certain embodiment of the present invention, the process of the deprotection reaction may be monitored by a conventional detection method in the art (e.g., TLC, HPLC, or GC), and is generally determined as the end point of the reaction when the compound shown in formula P4 disappears, and the time of the deprotection reaction is preferably 3 to 10 hours (e.g., 6 hours).
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 by addition of methanolic hydrochloric acid) and concentrated to give P5 syrup, which is directly subjected to the next reaction in the form of 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 large-scale production.
In one embodiment of the present invention, the preparation method of the compound represented by formula P5 further comprises the following steps: reacting the compound shown as the formula P3 with cinnamyl alcohol to obtain a compound shown as the formula P4;
in one embodiment of the present invention, in the preparation method of the compound represented by formula P4, the reaction conditions and operation may be those conventional in the art.
In one embodiment of the present invention, the preparation method of the compound represented by 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;
in one embodiment of the present invention, in the preparation method of the compound represented by formula P3, the organic solvent may be a conventional organic solvent in the reactions in this field, preferably dichloromethane.
In one embodiment of the present invention, the catalyst may be a basic reagent conventional in the art, preferably 1, 8-diazabicycloundecen-7-ene (DBU), for the preparation of the compound of formula P3.
In a certain embodiment of the present invention, in the preparation method of the compound represented by formula P3, the mass-to-volume ratio of the compound represented by formula P2 to the organic solvent is preferably 2mg/mL to 8 mg/mL.
In a certain scheme of the invention, in the preparation method of the compound shown in the formula P3, the molar ratio of the catalyst to the compound shown in the formula P2 is (0.1-1): 1.
in a certain scheme of the preparation method of the compound shown in the formula P3, the molar ratio of trichloroacetonitrile to the compound shown in the formula P2 is (1-5): 1.
In one embodiment of the present invention, the progress of the substitution reaction can be monitored by conventional detection methods 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 a certain scheme of the preparation method of the compound shown in the formula P3, the time of the substitution reaction is based on the completion of the substitution reaction, and is preferably 1-5 h, for example 2 h.
In one embodiment of the present invention, the post-treatment step of the substitution reaction may be a post-treatment step conventional in the art, such as pulping, filtering and drying, in the preparation method of the compound represented by formula P3. Does not contain a column chromatography step, is easy to operate and is suitable for large-scale production.
In one embodiment of the present invention, the preparation method of the compound represented by formula P3 further comprises the following steps: in an alcohol solvent, a compound shown as a formula P1 and NH are added 3 Carrying out deprotection reaction to obtain a compound shown as a formula P2;
in a certain embodiment of the present invention, the alcohol solvent may be a solvent that is conventional in the reaction in the field, and is preferably methanol.
In one embodiment of the present invention, the amount of the solvent used in the preparation method of the compound represented by formula P2 may be the amount conventionally used in such reactions in the art, and the volume-to-mass ratio of the solvent to the P1 is preferably 5mL/g to 20 mL/g.
In one embodiment of the preparation method of the compound shown as the formula P2, the NH is 3 The amount of (A) may be that conventional in the art for such reactions, said NH 3 The amount of the compound (B) is preferably 0.05 to 0.5 times the mass of P1.
In one embodiment of the preparation method of the compound shown as the formula P2, the NH is 3 The passage time of (a) may be a passage time customary in the art for such reactions, saidNH of (2) 3 The preferred time for introducing (2) is 30-90 min.
In a certain scheme of the preparation method of the compound shown in the formula P2, the deprotection reaction temperature may be a reaction temperature conventional for such reactions in the field, preferably 20 to 40 ℃, and more preferably 25 ℃.
In the preparation method of the compound shown as the formula P2, in one embodiment of the invention, the pressure of the deprotection reaction can be adjusted according to the reaction temperature, and the reaction temperature does not exceed the "boiling point under pressure", preferably 80kPa to 120kPa, and more preferably 101 kPa.
In the preparation method of the compound shown in the formula P2, in a certain embodiment of the present invention, the progress of the deprotection reaction can be monitored by a conventional monitoring method in the art (e.g. TLC, HPLC or NMR), generally, the reaction time is 10h to 20h, and more preferably 15h, when the compound shown in the formula P1 is no longer reacted, which is the reaction endpoint.
In one embodiment of the present invention, the post-treatment of the deprotection reaction may be a post-treatment conventional in the art, and preferably, the post-treatment of the deprotection reaction includes the following steps: the organic solvent (e.g., ethyl acetate) was dissolved, washed with water, and concentrated to give P2 syrup, which was directly subjected to the next reaction in the form of P2 syrup. And the method does not comprise a column chromatography step, so that the method is easy to operate and suitable for large-scale production.
In one embodiment of the present invention, the preparation method of the compound represented by formula P2 further comprises the following steps: 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 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 represented by formula P1.
In a certain embodiment of the present invention, in the preparation method of the compound represented by formula P1, the acid-binding agent may be an acid-binding agent conventional in such reactions in the art, and is preferably pyridine.
In a certain embodiment of the present invention, the amount of the solvent may be an amount conventionally used in such reactions in the art, and preferably, the volume-to-mass ratio of the solvent to the compound represented by formula 1 is (2-10) mL/g, for example, 5 mL/g.
In a certain embodiment of the present invention, the amount of the acid-binding agent may be an amount conventionally used in such reactions in the art, and preferably, the volume-to-mass ratio of the acid-binding agent to the compound shown in formula 1 is (5-20) mL/g, for example, 10 mL/g.
In the preparation method of the compound shown in the formula P1, in a certain embodiment of the present invention, the dosage of the benzoyl chloride may be a dosage conventionally used in such reactions in the field, and preferably, the molar ratio of the benzoyl chloride to the compound shown in the formula P1 is 4-10: 1, e.g. 8: 1.
In a certain scheme of the preparation method of the compound shown as the formula P1, the reaction temperature can be a reaction temperature conventional in the field, and is preferably 20-40 ℃.
In the preparation method of the compound shown in the formula P1, in one embodiment of the present invention, the progress of the reaction can be monitored according to detection methods (such as TLC, HPLC or GC) conventional in the art, and generally the time when the compound shown in the formula 1 disappears is used as the end point of the reaction, and the reaction time is preferably 1-5 hours (such as 3 hours).
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 neutral, 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 large-scale production.
The invention also provides a compound shown as the formula P6:
the invention also provides application of the compound shown as the formula P6 in preparation of the torsavide.
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) carrying out deprotection reaction on a compound shown as a formula P9 to obtain the rosavin;
in one embodiment of the present invention, step (a) of the use employs a method for preparing a compound represented by formula P8 as described in any one of the preceding claims.
In one embodiment of the present invention, in step (B) for the use, the conditions and operations of the reaction may be those conventional in the art for such reactions.
In one embodiment of the present invention, in step (C) of the use, the conditions and operation of the deprotection reaction may be those conventional in the art for such reactions.
The positive progress effects of the invention are as follows: the method uses the specific silicon-based protective group through process optimization and condition screening, is more economic 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 X-ray diffraction spectrum of the tramadol form I
Figure 2 is a diagram of a differential scanning calorimeter for torsavid form I.
Figure 3 HPLC data for torsavid form I.
FIG. 4 is an X-ray diffraction pattern of amorphous Cellvin
Figure 5 amorphous voseville HPLC data.
FIG. 6 shows a comparison of the overlay of the novel crystalline form of torsavide with amorphous solid-XPRD.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Preparation example 1 preparation A4
To the reaction vessel was added 500g of L-arabinose, dichloromethane (2.5L) was added and the mixture was dissolved with stirring, and pyridine (2.63kg) was added. Benzoyl chloride (3.75kg, 8eq) was added dropwise in an ice bath. After reacting for 3h at room temperature, the reaction was completed, and water (1.5L) was added dropwise to quench the reaction. Separating the solution and extracting an organic phase, washing by 1M HCl, washing by saturated sodium bicarbonate solution and washing by water in sequence. 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 in acetic acid (816g, 3eq) and the reaction was complete after 2 hours at room temperature. Adding saturated sodium bicarbonate to quench the reaction, separating the solution, washing with water and concentrating. A2 syrup was obtained.
Acetone (5.24L) and water (1.74L) were added to the A2 syrup, and sodium iodide (249g, 0.5eq) was added thereto to react at room temperature for 2 hours, after which the reaction was completed. The product was extracted with ethyl acetate (5.24L) and water (5.24L), washed successively with sodium thiosulfate solution and saturated sodium bicarbonate, and concentrated to give A3 syrup.
The A3 syrup was dissolved in dichloromethane (7.7L) under stirring at room temperature, and then trichloroacetonitrile (0.962kg, 2eq) and DBU (253.7g, 0.5eq) were added to the solution to react for 2 hours under stirring at room temperature, and then the reaction was completed. The reaction solution was concentrated, ethyl acetate (4.6L) was added and stirred for 2 hours to complete the reaction, and the reaction solution was concentrated to give a4 syrup and used directly in the next feeding, product: 1.58kg, yield: 78.3 percent.
EXAMPLE 1 preparation of P3
642.78g of anhydrous glucose was added to the reaction vessel, 3.21L of methylene chloride was added thereto, and the mixture was dissolved by stirring, and 2.82kg of pyridine was added thereto. Benzoyl chloride (4kg, 8eq) was added dropwise in an ice bath. After reacting at room temperature for 3 hours, the reaction was completed, and water (1.928L) was added dropwise to quench the reaction. Separating the solution to extract an organic phase, and washing with 1M HCl, saturated sodium bicarbonate solution and water in sequence. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.1kg, HPLC purity: 95.5 percent.
3.1kg of the syrup was dissolved in absolute methanol (21L), and 200g of ammonia gas was introduced into the reaction solution for 1 hour. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction solution was concentrated to give a black P2 syrup, which was dissolved in 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give 2.3kg of a black P2 syrup, HPLC purity: 86.5 percent.
2.3kg of the P2 syrup was dissolved in 10.6L of dichloromethane under stirring, and 1.03kg of trichloroacetonitrile and 271g of DBU were added and reacted for 2 hours under stirring at room temperature, whereupon the reaction was completed. The reaction mixture was concentrated, and 7.928L of ethyl acetate was added thereto, followed by stirring for 2 hours to precipitate P3. Filtering and drying to obtain 1.61kg of P3 solid, and the three-step total yield is as follows: 60.7%, HPLC purity: 94.5 percent.
Comparative example 1 preparation of P3 Using hydrazine acetate
642.78g of anhydrous glucose was added to the reaction vessel, 3.21L of methylene chloride was added thereto, and the mixture was dissolved by stirring, and 2.82kg of pyridine was added thereto. Benzoyl chloride (4kg, 8eq) was added dropwise in an ice bath. After reacting for 3h at room temperature, the reaction was completed, and 1.928L of water was added dropwise to quench the reaction. Separating the solution to extract an organic phase, and washing with 1M HCl, saturated sodium bicarbonate solution and water in sequence. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.11kg, HPLC purity: 94.5 percent.
3.1kg of the above syrup was added to 21L of absolute methanol, and hydrazine acetate (330g) was added. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction solution was concentrated to give a black P2 syrup, which was dissolved in 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give 2.31kg of a black P2 syrup, HPLC purity: 75.7 percent.
2.31kg of the P2 syrup was dissolved in 10.6L of dichloromethane under stirring, and 1.03kg of trichloroacetonitrile and DBU271g were added and reacted for 2 hours under stirring at room temperature, after which the reaction was completed. The reaction mixture was concentrated, and 7.928L of ethyl acetate was added thereto and stirred for 2 hours to precipitate P3. Filtering and drying to obtain 0.95kg of P3 solid, and obtaining three-step yield: 35.7%, HPLC purity: 85.5 percent.
Comparative example 2 preparation of P3 using methylamine
642.78g of anhydrous glucose was added to the reaction vessel, 3.21L of methylene chloride was added thereto, and the mixture was dissolved by stirring, and 2.82kg of pyridine was added thereto. Benzoyl chloride (4kg, 8eq) was added dropwise in an ice bath. After reacting at room temperature for 3 hours, the reaction was completed, and water (1.928L) was added dropwise to quench the reaction. Separating the solution to extract an organic phase, and washing with 1M HCl, saturated sodium bicarbonate solution and water in sequence. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.15kg, purity: 94.55 percent.
3.1kg of the syrup was dissolved in 21L of anhydrous methanol, and methylamine (110g) was added to the reaction solution. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction solution was concentrated to give black P2 syrup, which was dissolved in 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give 2.3kg of black P2 syrup, HPLC purity: 68 percent. When the reaction scale is large, side reactions are obvious when methylamine is used for carrying out deprotection reaction, and the side reactions are removal of the rest benzoyl on D-glucose caused by over-strong alkalinity, so that the yield and the purity are reduced.
2.3kg of the P2 syrup was dissolved in 10.6L of dichloromethane under stirring, and 1.03kg of trichloroacetonitrile and 271g of DBU were added and reacted at room temperature for 2 hours under stirring to complete the reaction. The reaction mixture was concentrated, and 7.928L of ethyl acetate was added thereto and stirred for 2 hours to precipitate P3. Filtering and drying to obtain 0.86kg of P3 solid, and obtaining three-step yield: 32.6%, HPLC purity: 83.5 percent.
COMPARATIVE EXAMPLE 3 preparation of P3 (solvent screen: tetrahydrofuran)
642.78g of anhydrous glucose was added to the reaction vessel, methylene chloride (3.21L) was added thereto and dissolved by stirring, and pyridine (2.82kg) was added thereto. Benzoyl chloride (4kg, 8eq) was added dropwise in an ice bath. After reacting at room temperature for 3 hours, the reaction was completed, and water (1.928L) was added dropwise to quench the reaction. Separating the solution to extract an organic phase, and washing with 1M HCl, saturated sodium bicarbonate solution and water in sequence. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.05kg, HPLC purity: 93.6 percent.
3.1kg of the syrup was added to 21L of tetrahydrofuran, and ammonia gas was introduced into the reaction solution for 1 hour. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction solution was concentrated to give black P2 syrup, which was dissolved in 8.5L of ethyl acetate, washed twice with 4.25L of water, and the ethyl acetate phase was concentrated to give 2.3kg of black P2 syrup, HPLC purity: 86.5 percent.
2.3kg of the P2 syrup was dissolved in 10.6L of dichloromethane under stirring, and 1.03kg of trichloroacetonitrile and 271g of DBU were added and reacted at room temperature for 2 hours under stirring to complete the reaction. The reaction mixture was concentrated, and 7.928L of ethyl acetate was added thereto and stirred for 2 hours to precipitate P3. Filtration and drying gave 1.12kg of P3 as a solid, yield: 42.2%, HPLC purity: 94.5 percent.
COMPARATIVE EXAMPLE 4 preparation P3 (solvent screen: dichloromethane)
642.78g of anhydrous glucose was added to the reaction vessel, methylene chloride (3.21L) was added thereto and dissolved by stirring, and pyridine (2.82kg) was added thereto. Benzoyl chloride (4kg, 8eq) was added dropwise in an ice bath. After reacting at room temperature for 3 hours, the reaction was completed, and water (1.928L) was added dropwise to quench the reaction. Separating the solution to extract an organic phase, and washing with 1M HCl, saturated sodium bicarbonate solution and water in sequence. Dried over anhydrous sodium sulfate, filtered, and concentrated to give benzoyl glucose syrup (P1), 3.14kg, HPLC purity: 95.2 percent.
3.1kg of the syrup was added to 21L of dichloromethane and dissolved, and ammonia gas was introduced into the reaction solution for 1 hour. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction solution was concentrated to give 2.3kg of black P2 syrup, which was dissolved in 8.5L of ethyl acetate, washed twice with water and 4.25L of ethyl acetate, and the ethyl acetate phase was concentrated to give 2.3kg of black P2 syrup, HPLC purity: 37.3 percent.
Dissolving P2 syrup 2.3kg in dichloromethane 10.6L under stirring, adding trichloroacetonitrile 1.03kg and DBU (271 g), stirring at room temperature for 2 hr to react completely, concentrating the reaction solution, adding ethyl acetate 7.928L, stirring for 2 hr to precipitate P3, filtering, and oven drying to obtain P3 solid 0.54kg, yield 20.5%, and HPLC purity 86.3%.
Example 2
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH 7, and the reaction solution was concentrated to give 241.6g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.20 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. TBDMSCl (142.4g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after the reaction is carried out for 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L), pulping, filtering and drying to obtain P6203g with two-step yield: 78.49%, purity (HPLC): 95.44 percent.
Nuclear magnetic mass spectrometry data of P6: 1H NMR (600MHz, CDCl3) δ 7.39(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 (dt, J ═ 9.1Hz,1H), 3.48-3.43 (m,1H),3.35 (m,1H), 3.7, 7.5H, 1H).
MS：433(M+Na)。
Example 3
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH 7, and the reaction solution was concentrated to give 240g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.10 percent.
P5 syrup was dissolved in anhydrous THF (1.3L) and imidazole (107g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (142.4g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after the reaction is carried out for 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6178 g, wherein the yield of the two steps is as follows: 68.80%, purity (HPLC): 93.60 percent.
Example 4
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol hydrochloride solution was added to adjust pH 7, and the reaction solution was concentrated to give 242.8g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 94.40 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (94.9g, 1eq) was added dropwise. After the dropwise addition, the reaction is completed after 5 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6156.2g, wherein the yield of the two steps is as follows: 60.40%, purity (HPLC): 96.21 percent.
Comparative example 5
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol hydrochloride solution was added to adjust pH 7, and the reaction solution was concentrated to give P5 syrup 249g (excess weight due to concentrated residual solvent), HPLC purity: 93.95 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. Tert-butyldiphenylchlorosilane TBDPSCl (259g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after the reaction is carried out for 12 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6-1 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6-1144 g, wherein the two-step yield is as follows: 44.36%, purity (HPLC): 87.63 percent. The TBDPS group is sterically bulky, resulting in extended reaction times, lower yields and purities.
Comparative example 6
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol hydrochloride solution was added to adjust pH 7, and the reaction solution was concentrated to give 247g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 94.60 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. Trimethylsilyl chloride TMSCl (102g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after the reaction is carried out for 3 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6-2 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6-2100.4 g, and the yield of the two steps is as follows: 43.30%, purity (HPLC): 83.57 percent. The yield and the purity are lower.
Comparative example 7
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH 7, and the reaction solution was concentrated to obtain 241g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.5 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and pyridine (124g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (142.4g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after 1 hour of room temperature reaction. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P689 g, wherein the yield of the two steps is as follows: 34.40%, purity (HPLC): 86.50 percent. The yield and the purity are both low.
Comparative example 8
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol hydrochloride solution was added to adjust pH 7, and the reaction solution was concentrated to give 244g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 94.77 percent.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and triethylamine (160.5g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (142.4g, 1.5eq) was added dropwise. After the dropwise addition, the reaction is completed after reacting for 2 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6104 g with two-step yield: 40.50%, purity (HPLC): 83.27 percent, and the yield and the purity are lower.
Comparative example 9
P4(500g) was added, methylene chloride was added and dissolved with stirring (3L), and a solution of sodium methoxide (113.68g, 3eq) in methanol (1.5L) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH 7, and the reaction solution was concentrated to give 243.6g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.5 percent.
P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (190g, 2eq) was added dropwise. After the dropwise addition, the reaction is completed after the reaction is carried out for 1 hour at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give P6 as a solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6115 g, wherein the two-step yield is as follows: 44.00%, purity (HPLC): 81.70%, excess TBDMSCl produced more by-product.
Example 5
P6150 g was dissolved by addition of pyridine (288g, 10eq) and dichloromethane (900 ml). Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After the reaction is completed after 7h at room temperature, water is added to quench the reaction. The organic phase was washed sequentially with 1M HCl, saturated aqueous sodium bicarbonate, water and concentrated to give 306g of P7 syrup, yield: 115.9% (excess weight due to concentrated residual solvent), HPLC purity: 97.6 percent.
The above P7 syrup was dissolved in DMF (1.58L) and 1M aqueous HCl (150ml) was added at 5 ℃ in an ice bath. The reaction was complete after 2h at room temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted 2 times with ethyl acetate (600 ml). The resulting mixture was added dropwise to 3 times the volume of petroleum ether (1.8L) and stirred to precipitate a product. Filtration afforded P8 as a solid (184.4g), two-step overall yield: 83.06% and an HPLC purity of 97.89%.
Example 6
P6150 g, pyridine (432g, 15eq) was added. Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After the reaction is completed after 7h at room temperature, water is added to quench the reaction. The organic phase was washed with 1M HCl, saturated aqueous sodium bicarbonate, water, and concentrated to give 324g of P7 syrup, yield: 123.2% (excess weight due to concentrated residual solvent), HPLC purity: 90.40 percent.
The above P7 syrup was dissolved in DMF (1.58L) and 1M aqueous HCl (150ml) was added at 5 ℃ in an ice bath. The reaction was complete after 2h at room temperature. The reaction was quenched by addition of saturated aqueous sodium bicarbonate and extracted 2 times with ethyl acetate (600 ml). The resulting solution was added dropwise to 3 times the volume of petroleum ether (1.8L) and stirred to precipitate a product. Filtration afforded P8 as a solid (156.4g), two-step overall yield: 70.46%, HPLC purity 87.5%.
Example 7
P6150 g was dissolved by addition of pyridine (288g, 10eq) and dichloromethane (900 ml). Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After reacting for 7h at room temperature, the reaction is completed, and water is added to quench the reaction. The organic phase was washed with 1M HCl, saturated aqueous sodium bicarbonate, water, and concentrated to give 304g of P7 syrup, yield: 115.6% (excess weight due to concentrated residual solvent), HPLC purity: 97.5 percent.
The above P7 syrup was dissolved in THF (1.58L) and 1M HCl (150ml) was added at 5 ℃ in an ice bath. The reaction is complete after 12h at room temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted 2 times with ethyl acetate (600 ml). The product (177.12 g) was precipitated by stirring back into 3 volumes of petroleum ether (1.8L) in two steps in total yield: 80.06% and an HPLC purity of 97.70%. As a result, THF was used as a solvent, and the reaction time was longer than that of DMF, and THF was more expensive than DMF.
Comparative example 10
P6150 g was added to methylene chloride (900ml) and dissolved with stirring at room temperature, and triethylamine (370g, 10eq) was added. Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After the triethylamine is used for replacing pyridine, the raw materials do not react, the effect is not good, and the target product is not obtained.
Comparative example 11
P6-1150 g was dissolved by adding pyridine (288g, 10eq) and dichloromethane (900ml, 5 vol). Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. No target product is generated after the reaction is carried out for 24 hours at room temperature.
Comparative example 12
P6150 g was dissolved by addition of pyridine (288g, 10eq) and dichloromethane (900 ml). Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After the reaction is completed after 7h at room temperature, water is added to quench the reaction. The organic phase was washed with 1M HCl, saturated aqueous sodium bicarbonate, water, and concentrated to give 295g of P7 syrup, yield: 112.2% (excess weight due to concentrated residual solvent), HPLC purity: 95.5 percent.
The above P7 syrup was dissolved in acetonitrile (1.58L), and 1M HCl (150ml) was added thereto at 5 ℃ in an ice bath to react at room temperature for 12 hours, after which the reaction was completed. The reaction was quenched by addition of saturated aqueous sodium bicarbonate and extracted 2 times with EA (600 ml). The product was back-dropped into 3 volumes of petroleum ether (1.8L) and stirred to precipitate 130g of the product in two-step total yield: 59.80% and an HPLC purity of 95.40%. The results show that the reaction is incomplete in acetonitrile as solvent compared to DMF.
Comparative example 13
P610 g was dissolved by adding pyridine (13.5g, 7eq) and dichloromethane (60 ml). Pivaloyl chloride (17.6g, 6eq) was added dropwise in an ice bath. After reacting for 15h at room temperature, the reaction is completed, and water is added to quench the reaction. The organic phase was washed with 1M HCl, saturated aqueous sodium bicarbonate, water and column chromatography to give P7-1(9.8 g). Yield: and (4) 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(2g, 1eq) was dissolved in DMF (14ml) and 1M HCl (3ml) was added at 5 ℃ in an ice bath. The reaction was complete after 2h at room temperature. 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, and column chromatography gave P8-1 as a solid (0.84g), yield: 48.55 percent.
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
P6150 g was dissolved by addition of pyridine (288g, 10eq) and dichloromethane (900 ml). Acetyl chloride (372g, 8eq) was added dropwise in an ice bath. After the reaction is completed after 7h at room temperature, water is added to quench the reaction. The organic phase was washed 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 (150ml) was added at 5 ℃ in an ice bath. The reaction was complete after 2h at room temperature. The reaction was quenched by addition of saturated aqueous sodium bicarbonate and extracted 2 times with ethyl acetate (600 ml). The resulting solution was added dropwise to 3 times the volume of petroleum ether (1.8L) and stirred to precipitate a product. Filtration afforded P8-2 as a solid (88.5g), yield: 57.3%, HPLC purity: 93.4 percent.
Comparative example 15
P6150 g was dissolved by the addition of pyridine (288g, 10eq) and dichloromethane (900 ml). Benzoyl chloride (372g, 8eq) was added dropwise in an ice bath. After the reaction is completed after 7h at room temperature, water is added to quench the reaction. The organic phase was washed 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 (150ml) was added at 5 ℃ in an ice bath. The reaction was complete after 2h at room temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted 2 times with ethyl acetate (600 ml). The organic phase is washed by saturated brine, dried and filtered by anhydrous sodium sulfate, and concentrated to obtain a crude product of P8. The crude P8 was dissolved in (methanol: DCM ═ 1vol:3vol, 200 ml: 600ml) and crystallized at 25 ℃ for 3h, and filtered to give P8 as a solid (100.7g) in two steps in total yield: 45.5%, HPLC purity: 94.6 percent.
Because P7 syrup contains a large amount of benzoic anhydride as a by-product, when the reaction scale is large, the benzoic anhydride reacts with P8 by post-treatment of concentration and recrystallization, and is converted into impurities almost in half. The invention is improved, directly and reversely dripped into petroleum ether without concentration after water washing to separate out products, and has simple and convenient operation and less impurities.
EXAMPLE 8 preparation of P9
A4 (265.5 g theoretically, 1.5eq) syrup and P8(177.5g, 1eq) were mixed and dissolved by adding dichloromethane (1L, 5vol) under inert gas. A dilution of TMSOTf (9.07g, 0.14eq) in dichloromethane was added dropwise at reduced temperature. After reacting for 1 hour at room temperature, the reaction is completed, and triethylamine is added to quench the reaction. The reaction mixture was concentrated, and recrystallized from methanol to give glycosylated product P9(297g) in a yield of 96.74%.
Example 9 preparation of tramadol form I
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 154g of rosavin syrup. Methanol (300ml) and ethyl acetate (900ml) are added to be separated out, and 120g of the tramadol crystal form I is obtained by filtration, with the yield of 98.6%. HPLC purity: 98.74 percent. Standing at 25 deg.C + -1 deg.C and relative humidity of 80% + -2% for 24h, crystal form I increased in mass by 0.15% compared to the initial mass, and had almost no hygroscopicity.
The X-ray diffraction spectrogram of the obtained crystal form I is shown in figure 1, and the diffraction peak, the peak width value, the peak height percentage, the peak area and the peak area percentage are shown in the following table 1:
TABLE 1X-ray diffraction pattern of Lusseivian crystal form I expressed by 2 theta angle
A diagram of a differential scanning calorimeter of torsavid form I is shown in fig. 2.
The HPLC data of the Luoxinvitae crystal form I are shown in FIG. 3, and the test conditions are as follows: liquid phase column: agilent 5 Tc-C18250X 4.6; flow rate: 1.0 ml/min; column temperature: 35 ℃; detection wavelength: 250 nm; mobile phase A: CH (CH) 3 OH; mobile phase B: 10mM potassium dihydrogen phosphate in water, the 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 |
。
Luoshiwei: 1H NMR (400MHz, CDCl) 3 )1H NMR(400MHz,CD 3 OD)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 voseville
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. The mixture was adjusted to pH 7 by adding a methanol solution of hydrochloric acid, and the reaction solution was filtered to remove salts and concentrated to obtain 160g of trametes de-mer syrup. Adding methanol (300ml) and dichloromethane (900ml), stirring at room temperature for crystallization for 0.5h, and filtering to obtain the torsavide crystal form 117g, wherein the torsavide crystal form I is confirmed to be torsavide crystal form I, the yield is 95.9%, and the HPLC purity is as follows: 94.5 percent. When the crystal form I is placed for 24 hours under the conditions of 25 +/-1 ℃ and the relative humidity of 80% +/-2%, the mass of the crystal form I is increased by 0.16% compared with the initial mass, and the crystal form I has almost no hygroscopicity.
Example 11 preparation of tramadol form I
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 152g of rosavin syrup. Adding methanol (300ml) and dichloromethane (600ml), stirring at room temperature for crystallization for 0.5h, and filtering to obtain the tramadol crystal form I102 g with a yield of 84.5%. Purity: 76.2 percent. Standing at 25 ℃. + -. 1 ℃ for 24h with a relative humidity of 80%. + -. 2%, the crystal form I having an increased mass of 0.20% compared to the initial mass, with almost no hygroscopicity.
EXAMPLE 12 preparation of Luoxine
P9(300g) was added, methylene chloride was added and dissolved with stirring (1800ml), and sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 155g of rosavin syrup. Adding methanol (300ml) and dichloromethane (900ml), stirring at room temperature for crystallization for 15min, and filtering to obtain 100.5g of the tramadol crystal form I with the yield of 83.5%. HPLC purity: 79.2 percent. Standing at 25 ℃. + -. 1 ℃ for 24h with a relative humidity of 80%. + -. 2%, the crystal form I having an increased mass of 0.17% compared to the initial mass, with almost no hygroscopicity.
Comparative example 16 amorphous trametin preparation
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 154.2g of rosavin syrup. Ethyl acetate (900ml) was added and slurried for 2 hours, followed by filtration to give 32.46g of hygroscopic amorphous Celavide with a yield of 80%. HPLC purity: 92.5 percent.
When the amorphous rosavin is placed for 24 hours at 25 +/-1 ℃ and the relative humidity of 80 +/-2%, the amorphous rosavin has the increased mass of 15.4% compared with the initial mass and is extremely hygroscopic.
The X-ray diffraction pattern of the obtained amorphous voseivil is shown in fig. 4, and the diffraction peak, peak width, peak height percentage, peak area and peak area percentage are shown in the following table 3:
TABLE 3X-ray diffraction pattern of amorphous Cellvin expressed in 2 theta angle
| Numbering | 2θ(±0.2°) | d(A) | Peak height | Percentage of peak height (%) | Peak area | Percentage of 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 overlay of the novel crystalline form of torsavide and amorphous solid-XPRD is shown in FIG. 6, the HPLC data is shown in FIG. 5, and the testing conditions of the method are the same as those of the above torsavide form I.
Comparative example 17: the water/acetone system is recrystallized.
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900ml) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 157.2g of rosavin syrup. Acetone (900ml) and water (300ml) are added, and the mixture is stirred and crystallized for 12 hours at room temperature, and the product of the torsavide solid can not be obtained.
Comparative example 18: and recrystallizing the methanol/ether system.
P9(300g) was added, methylene chloride was added and the mixture was dissolved with stirring (1800ml), and 900ml of a methanol solution of sodium methoxide (1.5eq, 23g) was added. The reaction was complete after 6h at room temperature. Methanol solution of hydrochloric acid was added to adjust pH to 7, and the reaction solution was filtered to remove salts and concentrated to obtain 152.5g of rosavin syrup. Diethyl ether (900ml) and methanol (300ml) are added, and the mixture is stirred and crystallized for 12 hours at room temperature, thus the product of the torsavide solid can 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 that 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 spirit and scope of the invention, and these changes and modifications are within the scope of the invention.
Claims (14)
1. A method for preparing a compound shown as a formula P8, which is characterized by comprising 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, carrying out deprotection reaction on a compound shown as a formula P7 to obtain a compound shown as a formula P8;
2. the process for preparing a compound represented by the formula P8, according to claim 1, wherein in the process for preparing a compound represented by the formula P8, in the step (1), the solvent is pyridine or a mixed solvent of pyridine and a haloalkane hydrocarbon solvent, preferably a mixed solvent of pyridine and a haloalkane hydrocarbon solvent; the haloalkane solvent is preferably dichloromethane; when the mixed solvent is a mixed solvent of pyridine and a halogenated alkane solvent, the volume ratio of the pyridine to the halogenated alkane solvent is preferably 1: (2-5), for example 1: 3;
and/or in the preparation method of the compound shown as the formula P8, in the step (1), the volume-to-mass ratio of the solvent to the compound shown as the formula P6 is (2-10) mL/g, for example, 3mL/g or 8 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, e.g., 8: 1;
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 preferably 4-10 hours, such as 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: quenching reaction (for example, adding water to quench reaction), washing the organic phase (for example, sequentially washing with 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 a nitrogen-containing compound solvent and/or an ether solvent, preferably DMF and/or THF (such as DMF);
and/or in the preparation method of the compound shown as the formula P8, in the step (2), the volume-to-mass ratio of the solvent to the compound shown as the formula P7 is (4-10) mL/g, for example, 5 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; the hydrochloric acid is preferably added into the system in the form of a hydrochloric acid aqueous solution, and the molar concentration of the hydrochloric acid aqueous solution is preferably 0.8-1.5 mol/L, such as 1 mol/L;
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 to 5);
and/or in the preparation method of the compound shown as the formula P8, in the step (2), the temperature of 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, such as 2 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: adding a solvent to precipitate a solid of the compound shown as the formula P8, and filtering; preferably, the post-treatment step of step (2) of the preparation method of the compound represented by the formula P8 comprises the following steps: adding saturated sodium bicarbonate water solution for quenching reaction, adding ethyl acetate for extraction, adding petroleum ether (the using amount of the petroleum ether is 2-6 times of the mass of a theoretical product), then separating out a solid of a compound shown as a formula P8, and filtering to obtain the compound.
3. The process of claim 1 for the preparation of a compound of formula P8, wherein the process of preparation of a compound of 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-butyldimethylsilyl chloride (TBDMSCl) to obtain a compound shown as a formula P6;
the acid-binding agent is imidazole.
4. The process for preparing a compound represented by the formula P8, according to claim 3, wherein in the process for preparing a compound represented by the formula P6, the solvent is a nitrogen-containing compound solvent and/or an ether solvent, preferably DMF and/or THF;
and/or in the preparation method of the compound shown in the formula P6, the volume-to-mass ratio of the solvent to the compound shown in the formula P5 is (4-10) mL/g, for example 6 mL/g;
and/or in the preparation method of the compound shown in the formula P6, the molar ratio of the acid-binding agent to the compound shown in the formula P5 is (1-4): 1, preferably (2-3): 1, e.g. 2.5: 1;
and/or in the preparation method of the compound shown in the formula P6, the molar ratio of tert-butyldimethylsilyl chloride to the compound shown in the formula P5 is (1-1.8): 1 (e.g., 1:1 or 1.5:1), preferably (1.2 to 1.6): 1;
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 time of the hydroxyl protection reaction is 1-6 hours (such as 1 hour or 5 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-butyldimethylsilyl chloride into a system to perform a 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 as formula P6, adding solvent, pulping, filtering, and drying; preferably, the post-treatment step of the preparation method of the compound shown in the formula P6 comprises the following steps: adding water for quenching reaction, adding ethyl acetate for extraction, washing the organic phase with saturated salt solution, drying, filtering, concentrating to obtain solid of the compound shown as the formula P6, adding petroleum ether for pulping, filtering, and drying to obtain the compound shown as the formula P6.
5. The method of claim 3, wherein the method of preparing the compound of formula P8 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;
6. the process for the preparation of a compound of formula P8 according to claim 5, wherein the solvent is a halogenated hydrocarbon solvent, preferably dichloromethane;
and/or in the preparation method of the compound shown in the formula P5, the volume-to-mass ratio of the solvent to the compound shown in the formula P4 is (4-10) mL/g, such as 6 mL/g;
and/or in the preparation method of the compound shown in the formula P5, the alkali is sodium methoxide, the sodium methoxide is preferably added into a system in the form of a methanol solution of sodium methoxide, and the volume-to-mass ratio of methanol to the compound shown in the formula P4 is preferably (2-5) mL/g, for example 3 mL/g;
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, e.g., 3: 1;
and/or in the preparation method of the compound shown as the formula P5, the deprotection reaction temperature 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, such as 6 hours;
and/or the preparation method of the compound shown as the formula P5 further comprises the following post-treatment steps: the pH is adjusted to neutral (e.g. pH 7 by addition of methanolic hydrochloric acid) and concentrated to give P5 syrup, which is directly subjected to the next reaction in the form of P5 syrup.
7. The process for the preparation of a compound of formula P8 according to claim 5, further comprising the steps of: reacting the compound shown as the formula P3 with cinnamyl alcohol to obtain a compound shown as the formula P4;
the preparation method of the compound shown in 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;
8. the method of claim 7, wherein the organic solvent is dichloromethane;
and/or, in the preparation method of the compound shown as the formula P3, the catalyst is a basic reagent, preferably 1, 8-diazabicycloundecen-7-ene;
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 in the formula P3, the molar ratio of the catalyst to the compound shown in the formula P2 is (0.1-1): 1;
and/or in the preparation method of the compound shown in the formula P3, the molar ratio of the trichloroacetonitrile to the compound shown in 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, such as 2 h;
and/or, in the preparation method of the compound shown as the formula P3, the post-treatment step of the substitution reaction can be a post-treatment step which is conventional in the field reaction, such as pulping, filtering and drying.
9. The process for the preparation of a compound of formula P8 according to claim 7, further comprising the steps of: in an alcohol solvent, a compound shown as a formula P1 and NH are added 3 Carrying out deprotection reaction to obtain a compound shown as a formula P2;
10. the method of claim 9, wherein the alcoholic 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-20 mL/g;
and/or, in the preparation method of the compound shown as the formula P2, NH 3 The dosage of the compound is 0.05 to 0.5 time of the mass of the P1;
and/or, in the preparation method of the compound shown as the formula P2, NH 3 The preferred time for introducing is 30min-90 min;
and/or in the preparation method of the compound shown as the formula P2, the deprotection reaction temperature is 20-40 ℃, preferably 25 ℃;
and/or, in the preparation method of the compound shown in the formula P2, the pressure of the deprotection reaction is adjusted according to the reaction temperature, and the reaction temperature does not exceed the boiling point under pressure, preferably 80kPa-120kPa, more preferably 101 kPa;
and/or in the preparation method of the compound shown as the formula P2, the reaction time of the deprotection group is 10-20 h, preferably 15 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: the organic solvent (e.g., ethyl acetate) was dissolved, washed with water, and concentrated to give P2 syrup, which was directly subjected to the next reaction in the form of P2 syrup.
11. The process of claim 9 for the preparation of a compound of formula P8, wherein the process of preparation of 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;
12. the process for the preparation of a compound of formula P8 according to claim 11, wherein the solvent is a halogenated hydrocarbon solvent, preferably dichloromethane;
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 in the formula P1, the volume-to-mass ratio of the solvent to the compound shown in the formula 1 is (2-10) mL/g, for example 5 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, for example 10 mL/g;
and/or in the preparation method of the compound shown in the formula P1, the molar ratio of the benzoyl chloride to the compound shown in the formula P1 is 4-10: 1, e.g., 8: 1;
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, such as 3 hours;
and/or the preparation method of the compound shown as the formula P1 further comprises the following post-treatment steps: adjusting pH to neutral, concentrating to obtain P1 syrup, and directly performing the next reaction in the form of P1 syrup.
13. A compound of formula P6:
14. use of a compound according to claim 13, of formula P6, for the preparation of torsavide, 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 11;
(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) carrying out deprotection reaction on a compound shown as a formula P9 to obtain the rosavin;
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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