CN115141237A - Preparation method of torsavide intermediate - Google Patents
Preparation method of torsavide intermediate Download PDFInfo
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- CN115141237A CN115141237A CN202110336631.0A CN202110336631A CN115141237A CN 115141237 A CN115141237 A CN 115141237A CN 202110336631 A CN202110336631 A CN 202110336631A CN 115141237 A CN115141237 A CN 115141237A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 158
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 140
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 111
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 108
- 239000006188 syrup Substances 0.000 claims description 79
- 235000020357 syrup Nutrition 0.000 claims description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 24
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 11
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 10
- 238000004537 pulping Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 2
- 150000008282 halocarbons Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical group C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 74
- 238000004128 high performance liquid chromatography Methods 0.000 description 46
- 238000003756 stirring Methods 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 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 description 13
- 239000013078 crystal Substances 0.000 description 13
- 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 description 13
- 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 description 13
- 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 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000013557 residual solvent Substances 0.000 description 12
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 12
- 229960001031 glucose Drugs 0.000 description 11
- 238000010791 quenching Methods 0.000 description 10
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- 238000004440 column chromatography Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- -1 benzoyl glucose Chemical compound 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 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 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
- 238000001514 detection method Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229960004380 tramadol Drugs 0.000 description 3
- 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 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
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011734 sodium Substances 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
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 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
- 238000010586 diagram Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 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
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011261 inert gas Substances 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
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a torsavide intermediate. The preparation method specifically comprises a preparation method of a compound shown as a formula P2 and a preparation method of a compound shown as a formula P3, wherein the preparation method of the compound shown as the formula P2 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 the compound shown as the formula P2. The method for preparing the torsavide intermediate has high yield and is environment-friendly and suitable for industrialization.
Description
Technical Field
The invention relates to a preparation method of a torsavide intermediate.
Background
Luoshiwei (rosavin) is one of the extracts of rhodiola rosea and is mainly used for resisting fatigue, resisting anoxia, relieving pressure, improving work efficiency and treating functional diseases of the nervous system.
At present, the synthesis 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 and is not suitable for industrial production. Such as: egusa Kj et al Eur.J. org.chem.2003,3435-3445, provides a voseivil intermediate
The reaction steps are as follows.
In MeOH/THF solvent, using CH 3 NH 2 Deprotection reaction to obtain
Deprotection reagent CH 3 NH 2 Has certain toxicity and is easy to cause environmental pollution, and the method is used for preparation in scale-up production
The yield is low due to the occurrence of side reaction, and the method is not favorable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of high pollution, inconvenience for industrial production and the like in the preparation process of the torsavide intermediate in the prior art, and provides the preparation method of the torsavide intermediate.
The invention provides a preparation method of a compound shown as a formula P2, which 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 the preparation method of the compound shown in the formula P2, in a preferred embodiment of the present invention, certain conditions or operations are defined as follows, and the conditions and operations that are not mentioned are as described in any embodiment of the present invention, (abbreviated as "in a certain embodiment of the present invention"), and 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 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 20mL/g.
In a certain embodiment of the present invention, in the preparation method of the compound represented by formula P2, the NH is 3 The amount of (A) can 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 a certain embodiment of the present invention, in the preparation method of the compound represented by the formula P2, the NH is 3 The passage time of (A) may be that conventional in the art for such reactions, the NH being mentioned 3 The preferred time for introducing (2) is 30-90 min.
In the preparation method of the compound shown in the formula P2, in a certain embodiment of the present invention, the deprotection reaction may be at a reaction temperature conventional in such reactions in the art, preferably at a temperature of 20 to 40 ℃, and more preferably at a temperature of 25 ℃.
In one embodiment of the present invention, the pressure of the deprotection reaction may be adjusted depending on the reaction temperature, and the reaction temperature is not higher than the "boiling point under pressure", preferably 80kPa to 120kPa, and more preferably 101kPa.
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 a 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: dissolving with organic solvent (such as ethyl acetate), washing with water, and concentrating to obtain P2 syrup.
In a certain embodiment of the present invention, the preparation method of the compound represented by the 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 a certain embodiment of the present invention, the acid-binding agent may be an acid-binding agent conventional in such reactions in the art, and is preferably pyridine.
In one 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, 5mL/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 P1 is 5-20 mL/g, for example, 10mL/g.
In one embodiment of the present invention, the dosage of the benzoyl chloride may be the dosage that is conventional in such reactions in the field, and preferably, the molar ratio of the benzoyl chloride to the compound shown in formula P1 is 4 to 10:1, e.g. 8.
In the preparation method of the compound represented by the formula P1, in a certain embodiment of the present invention, the reaction temperature may be a reaction temperature conventional in such a reaction in the art, and is preferably 20 to 40 ℃.
In the preparation method of the compound represented by 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) which are conventional in the art, and generally the time when the compound represented by 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 in 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 preparation method of the compound shown as the formula P3, which comprises the following steps:
the method comprises the following steps: preparing a compound shown as a formula P2 by adopting the preparation method;
step two: 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, the first step further comprises the following post-treatment steps: the organic solvent (e.g., ethyl acetate) is dissolved, washed with water, and concentrated to give P2 syrup, which is directly subjected to the next reaction in the form of P2 syrup. Because column chromatography step is not included, the method is easy to operate and suitable for large-scale production.
In a certain embodiment of the present invention, in the second step, the organic solvent may be a conventional organic solvent, preferably dichloromethane, of the reaction in this field.
In one embodiment of the present invention, in the second step, the catalyst may be a basic reagent conventional in the art, preferably 1, 8-diazabicycloundecen-7-ene (DBU).
In a certain embodiment of the present invention, in the second step, the mass-to-volume ratio of the compound represented by formula P2 to the organic solvent is preferably 2mg/mL to 8mg/mL.
In one embodiment of the present invention, in the second step, the molar ratio of the catalyst to the compound represented by the formula P2 is (0.1-1): 1.
in one scheme of the invention, in the second step, the molar ratio of the trichloroacetonitrile to the compound shown in the formula P2 is (1-5): 1.
In one embodiment of the present invention, in the second step, the progress of the substitution reaction can be monitored by a detection method conventional in the art, such as Thin Layer Chromatography (TLC), gas Chromatography (GC), nuclear magnetic resonance spectroscopy (NMR), high Performance Liquid Chromatography (HPLC), and the like.
In one embodiment of the present invention, in the second step, the time of the substitution reaction is based on the completion of the substitution reaction, and is preferably 1 to 5 hours, for example, 2 hours.
In one embodiment of the present invention, in the second step, the post-treatment step of the substitution reaction may be a post-treatment step conventional in the art, such as pulping, filtering and drying. Does not contain a column chromatography step, is easy to operate and is suitable for large-scale production.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the method has high yield, high purity, easily available raw materials, and suitability for industrial production.
Drawings
FIG. 1 is X-ray diffraction spectrum of the tramadol form I
Figure 2 differential scanning calorimetry trace of torsavide 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 crystal 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 (2.63 kg) was added. Benzoyl chloride (3.75kg, 8eq) was added dropwise in an ice bath. After reacting for 3h at room temperature, the reaction was complete and quenched by the addition of water (1.5L). 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 and filtered to give a benzoyl-L-arabinose (A1) solution.
The solution A1 was added to a 33% hydrobromic acid-acetic acid solution (816g, 3eq) and reacted at room temperature for 2 hours to complete the reaction. 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 syrup A2, and sodium iodide (249g, 0.5eq) was added thereto to react at room temperature for 2 hours, after which the reaction was completed. Ethyl acetate (5.24L) and water (5.24L) were added to extract the product, which was washed successively with sodium thiosulfate solution and saturated sodium bicarbonate solution, 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 thereto, followed by reaction under stirring at room temperature for 2 hours to complete the reaction. Concentrating the reaction solution, adding ethyl acetate (4.6L), stirring for 2 hours, reacting completely, concentrating the reaction solution to obtain A4 syrup, and directly using the syrup in the following feeding steps to obtain a product: 1.58kg, yield: 78.3 percent.
EXAMPLE 1 preparation of P3
642.78g of anhydrous glucose and 3.21L of dichloromethane were added to the reaction vessel, and the mixture was dissolved by stirring, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After reacting at room temperature for 3h, the reaction was complete and quenched by the addition of water (1.928L). 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 anhydrous 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 was concentrated to give a black P2 syrup, dissolved in 8.5L of ethyl acetate, washed twice with 4.25L of water, 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 is added with 10.6L of dichloromethane to be stirred and dissolved, 1.03kg of trichloroacetonitrile and 271g of DBU are added, and the mixture is stirred at room temperature to react for 2 hours and then completely react. 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 1.61kg of P3 solid, wherein the total yield of the three steps is as follows: 60.7%, HPLC purity: 94.5 percent.
Comparative example 1 preparation of P3 Using hydrazine acetate
642.78g of anhydrous glucose and 3.21L of dichloromethane were added to the reaction vessel, and the mixture was dissolved by stirring, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After reacting for 3h at room temperature, the reaction was complete 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.
3.11kg of the above syrup was added to 21L of absolute methanol, and hydrazine acetate (330 g) was added. Then, the reaction was allowed to stand at room temperature for 15 hours, and the reaction was completed. The reaction 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 black P2 syrup, HPLC purity: 75.7 percent.
2.31kg of the P2 syrup was dissolved in 10.6L of dichloromethane by stirring, and 1.03kg of trichloroacetonitrile and 271g of DBU were added and reacted at room temperature for 2 hours by 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 0.95kg of P3 solid, wherein the yield in three steps is as follows: 35.7%, HPLC purity: 85.5%.
Comparative example 2 preparation of P3 using methylamine
642.78g of anhydrous glucose and 3.21L of dichloromethane were added to the reaction vessel, and the mixture was dissolved by stirring, followed by addition of 2.82kg of pyridine. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After reacting at room temperature for 3h, the reaction was complete and quenched by the addition of water (1.928L). 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.
3.15kg of the syrup was added to 21L of absolute methanol to dissolve it, and methylamine (110 g) was added to the reaction solution. Then, the reaction was allowed to stand at room temperature for 15 hours and then was completed. The reaction 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 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 is added with 10.6L of dichloromethane and stirred to dissolve, 1.03kg of trichloroacetonitrile and 271g of DBU are added, and the mixture is stirred at room temperature and reacted for 2 hours 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 screening: 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 (2.82 kg) was added thereto. Benzoyl chloride (4 kg,8 eq) was added dropwise in an ice bath. After reacting at room temperature for 3h, the reaction was complete and quenched by the addition of water (1.928L). 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.
3.05kg 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 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 black P2 syrup, HPLC purity: 86.5 percent.
2.3kg of the P2 syrup is added with 10.6L of dichloromethane and stirred to dissolve, 1.03kg of trichloroacetonitrile and 271g of DBU are added, and the mixture is stirred at room temperature and reacted for 2 hours 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 solid, yield: 42.2%, HPLC purity: 94.5 percent.
COMPARATIVE EXAMPLE 4 preparation of 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 (2.82 kg) was added thereto. Benzoyl chloride (4 kg, 8eq) was added dropwise in an ice bath. After reacting at room temperature for 3h, the reaction was complete and quenched by the addition of water (1.928L). 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.
3.14kg of the syrup was dissolved in 21L of dichloromethane, 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 was concentrated to give 2.3kg of black P2 syrup, dissolved by addition of 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: and 37.3 percent.
Adding 10.6L of dichloromethane into 2.3kg of the P2 syrup, stirring for dissolving, adding 1.03kg of trichloroacetonitrile and DBU (271 g), stirring at room temperature for 2 hours to react completely, concentrating the reaction solution, adding 7.928L of ethyl acetate, stirring for 2 hours to precipitate P3, filtering and drying to obtain 0.54kg of P3 solid, wherein the yield is 20.5 percent, and the HPLC purity is 86.3 percent.
Example 2
P4 (500 g) 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 241.6g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.20 percent.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and imidazole (107g, 2.5eq) was added. TBDMSCl (142.4 g,1.5 eq) 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6203g, wherein the yield of the two steps is as follows: 78.49%, purity (HPLC): 95.44 percent.
Nuclear magnetic mass spectrometry data for 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 (d, J =10.8,5.1hz, 2h), 3.63-3.56 (m, 1H), 3.53 (t, J = 9.1qh), 3.48-3.43 (m, 1H), 3.35 (dt, J =9.1h, 1h).
MS：433(M+Na)。
Example 3
P4 (500 g) was added, methylene chloride was added and the mixture was 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 240g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.10 percent.
The P5 syrup was dissolved in anhydrous THF (1.3L) and imidazole (107g, 2.5 eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (142.4 g, 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6 178g, and the two-step yield is as follows: 68.80%, purity (HPLC): 93.60 percent.
Example 4
P4 (500 g) was added, methylene chloride was added and the mixture was 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.
The 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain 156.2g of P6, and obtaining the two-step yield: 60.40%, purity (HPLC): 96.21 percent.
Comparative example 5
P4 (500 g) 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 249g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 93.95 percent.
The 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 dripping is finished, the reaction is completed after the room temperature reaction for 12 hours. 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 P6-1 144g, and obtaining two-step yield: 44.36%, purity (HPLC): 87.63% of the total weight of the composition. The TBDPS group is highly hindered, resulting in extended reaction times, lower yields and purities.
Comparative example 6
P4 (500 g) was added, methylene chloride was added and the mixture was 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.
The 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 is washed by saturated saline solution, dried and filtered by anhydrous sodium sulfate, and concentrated to obtain P6-2 solid. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6-2.4g, 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 (500 g) 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 241g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.5 percent.
The P5 syrup was dissolved in anhydrous DMF (1.3L) and pyridine (124g, 2.5eq) was added. Tert-butyldimethylsilyl chloride TBDMSCl (142.4 g, 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6 89g, wherein the two-step yield is as follows: 34.40%, purity (HPLC): 86.50 percent. The yield and the purity are lower.
Comparative example 8
P4 (500 g) was added, methylene chloride was added and the mixture was 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 (142.4 g, 1.5eq) was added dropwise. After the dropwise addition is finished, the reaction is completed after the reaction is carried out 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6 104g, wherein the two-step yield is as follows: 40.50%, purity (HPLC): 83.27 percent, and the yield and the purity are lower.
Comparative example 9
P4 (500 g) was added, methylene chloride was added and the mixture was 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 obtain 243.6g of P5 syrup (overweight due to concentration of residual solvent), HPLC purity: 95.5 percent.
The 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 a solid P6. Adding petroleum ether (1.8L) for pulping, filtering and drying to obtain P6 g, wherein the two-step yield is as follows: 44.00%, purity (HPLC): 81.70%, excess TBDMSCl produced more by-product.
Example 5
P6 g was dissolved by adding pyridine (288g, 10eq) and methylene chloride (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 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 (150 ml) 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 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 (184.4 g), two-step overall yield: 83.06% and an HPLC purity of 97.89%.
Example 6
Pyridine (432g, 15eq) was added to P6 (150 g). Benzoyl chloride (372g, 8eq) was added dropwise in this 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 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 (150 ml) 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 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 (156.4 g), two-step overall yield: 70.46% and an HPLC purity of 87.5%.
Example 7
P6 g was dissolved by adding pyridine (288g, 10eq) and methylene chloride (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 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 (150 ml) was added at 5 ℃ in an ice bath. The reaction was 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). 177.12g of the product was precipitated by stirring back into 3 volumes of petroleum ether (1.8L), with two-step total yield: 80.06% and the HPLC purity is 97.70%. The results show that the reaction time is longer with THF as a solvent than with DMF, and THF is more expensive than DMF.
Comparative example 10
150g of P6 was dissolved in methylene chloride (900 ml) at room temperature with stirring, 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
P6-1 150g was dissolved by adding pyridine (288g, 10eq) and dichloromethane (900ml, 5vol). 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
P6 g was dissolved by adding pyridine (288g, 10eq) and methylene chloride (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 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 reacted at 5 ℃ in ice bath with 1M HCl (150 ml) at room temperature for 12 hours to complete the reaction. 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 95.40% HPLC purity. The results show that the reaction is incomplete in acetonitrile as solvent compared to DMF.
Comparative example 13
P6 g was dissolved by adding pyridine (13.5g, 7eq) and methylene chloride (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 (14 ml) and 1M HCl (3 ml) 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 solid (0.84 g), 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
P6 g was dissolved by adding pyridine (288g, 10eq) and methylene chloride (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. And washing the organic phase by using 1M HCl, saturated sodium bicarbonate water solution and water in sequence, and concentrating to obtain P7-2 syrup.
The above P7-2 syrup was dissolved in DMF (1.58L), and 1M HCl (150 ml) was added thereto 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 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 (88.5 g), yield: 57.3%, HPLC purity: 93.4 percent.
Comparative example 15
P6 g was dissolved by adding pyridine (288g, 10eq) and methylene chloride (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 (150 ml) 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). Washing the organic phase with saturated salt solution, drying and filtering the organic phase with anhydrous sodium sulfate, and concentrating the organic phase to obtain a P8 crude product. The crude P8 was dissolved in (methanol: DCM =1vol 3vol,200ml: 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, benzoic anhydride reacts with P8 in a post-treatment mode of concentration and recrystallization, and the reaction is almost converted into impurities in half. The invention is improved, directly and reversely drops into petroleum ether without concentration after washing, and separates out products, the operation is simple and convenient, and the impurities are few.
EXAMPLE 8 preparation of P9
A4 (theoretical 265.5g, 1.5eq) syrup and P8 (177.5g, 1eq) were mixed and dissolved by adding dichloromethane (1L, 5vol) under inert gas protection. A dichloromethane dilution of TMSOTf (9.07g, 0.14eq) 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 a glycosylated product P9 (297 g) in a yield of 96.74%.
Example 9 preparation of crystalline form I of voseville
P9 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 154g of rosavin syrup. Methanol (300 ml) and ethyl acetate (900 ml) are added to separate out, 120g of the crystal form I of the rosavin is obtained by filtration, and the yield is 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 by 0.15% compared with the initial mass, and hardly had 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 torsavide form I are shown in fig. 3, with the following test conditions: liquid phase column: agilent 5 Tc-C18X 4.6; flow rate: 1.0ml/min; column temperature: 35 ℃; detection wavelength: 250nm; 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
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 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5 eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 160g of rosavin syrup. Adding methanol (300 ml) and dichloromethane (900 ml), 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. Standing at 25 ℃. + -. 1 ℃ for 24h with a relative humidity of 80%. + -. 2%, form I increased in mass by 0.16% compared to the initial mass, with almost no hygroscopicity.
Example 11 preparation of crystalline form I of voseville
P9 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5 eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 152g of rosavin syrup. Adding methanol (300 ml) and dichloromethane (600 ml), 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 vosevin
P9 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 155g of rosavin syrup. Adding methanol (300 ml) and dichloromethane (900 ml), 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 under the condition that the relative humidity is 80% +/-2%, wherein compared with the initial mass, the mass of the crystal form I is increased by 0.17%, and the crystal form I has almost no hygroscopicity.
Comparative example 16 amorphous trametin preparation
P9 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5 eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 154.2g of rosavin syrup. Ethyl acetate (900 ml) 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 under the conditions of 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 very 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
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 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and a solution of sodium methoxide (1.5eq, 23g) in methanol (900 ml) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 157.2g of rosavin syrup. Acetone (900 ml) and water (300 ml) 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 (300 g) was added, methylene chloride was added thereto and the mixture was dissolved with stirring (1800 ml), and 900ml of a methanol solution of sodium methoxide (1.5 eq, 23g) was added. The reaction was complete after 6h at room temperature. A methanol solution of hydrochloric acid was added to adjust pH =7, and the reaction solution was filtered to remove salts and concentrated to obtain 152.5g of rosavin syrup. Adding diethyl ether (900 ml) and methanol (300 ml), stirring at room temperature and crystallizing for 12h, thus the product of the torsavide solid cannot 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 (9)
1. A preparation method of a compound shown as a formula P2 is characterized by comprising 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;
2. the method according to claim 1, wherein the alcohol solvent is methanol;
and/or in the preparation method of the compound shown as the formula P2, the volume-mass ratio of the solvent to the P1 is 5-20 mL/g;
and/or, in the preparation method of the compound shown as the formula P2, NH 3 The dosage of the P1 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 time for introducing is 30min-90min;
and/or in the preparation method of the compound shown as the formula P2, the deprotection reaction temperature is 20-40 ℃;
and/or in the preparation method of the compound shown as the formula P2, the pressure of the deprotection reaction is adjusted according to the reaction temperature, and the reaction temperature does not exceed the boiling point under the pressure;
and/or in the preparation method of the compound shown in the formula P2, the reaction time of the deprotection reaction is 10-20 h;
and/or in the preparation method of the compound shown in the formula P2, the post-treatment of the deprotection reaction comprises the following steps: dissolving with organic solvent (such as ethyl acetate), washing with water, and concentrating to obtain P2 syrup.
3. The process according to claim 1 for producing a compound represented by the formula P2, wherein the pressure for the deprotection reaction is 80kPa to 120kPa, preferably 101kPa;
and/or in the preparation method of the compound shown as the formula P2, the deprotection reaction temperature is 25 ℃;
and/or in the preparation method of the compound shown as the formula P2, the reaction time of the deprotection reaction is 15h.
4. The process of claim 1, wherein the process of preparation of the 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;
5. the process according to claim 4, wherein the solvent is a halogenated hydrocarbon solvent;
and/or in the preparation method of the compound shown as the formula P1, the acid-binding agent is pyridine;
and/or in the preparation method of the compound shown in the formula P1, the volume-mass ratio of the solvent to the compound shown in the formula 1 is (2-10) mL/g;
and/or in the preparation method of the compound shown in the formula P1, the volume-mass ratio of the acid-binding agent to the compound shown in the formula 1 is (5-20) mL/g;
and/or in the preparation method of the compound shown as the formula P1, the molar ratio of the benzoyl chloride to the compound shown as the formula 1 is (4-10): 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 in the formula P1, the reaction time is 1-5 hours;
and/or the preparation method of the compound shown as the formula P1 further comprises the following post-treatment steps: adjusting pH to neutral, concentrating to obtain P1 syrup, and directly performing the next reaction in the form of P1 syrup.
6. The process according to claim 4, wherein the solvent is dichloromethane;
and/or in the preparation method of the compound shown in the formula P1, the volume-mass ratio of the solvent to the compound shown in the formula 1 is 5mL/g;
and/or in the preparation method of the compound shown in the formula P1, the volume-mass ratio of the acid-binding agent to the compound shown in the formula 1 is 10mL/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 1 is 8;
and/or in the preparation method of the compound shown as the formula P1, the reaction time is 3 hours.
7. A preparation method of a compound shown as a formula P3 is characterized by comprising the following steps:
the method comprises the following steps: preparing a compound shown as a formula P2 by adopting the preparation method of any one of claims 1 to 6;
step two: 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 process according to claim 7, wherein the first step of the process for preparing the compound of formula P3 further comprises the following post-treatment steps: dissolving with organic solvent (such as ethyl acetate), washing with water, and concentrating to obtain P2 syrup, and directly carrying out the next reaction in the form of P2 syrup;
and/or in the preparation method of the compound shown as the formula P3, in the second step, the organic solvent is dichloromethane;
and/or in the preparation method of the compound shown as the formula P3, in the second step, the catalyst is an alkaline reagent;
and/or in the preparation method of the compound shown as the formula P3, in the second step, 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, in the second step, 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 as the formula P3, in the second step, the molar ratio of the trichloroacetonitrile to the compound shown as the formula P2 is (1-5): 1;
and/or in the preparation method of the compound shown as the formula P3, in the second step, the time of the substitution reaction is 1-5 h;
and/or in the preparation method of the compound shown as the formula P3, in the second step, the substitution reaction further comprises the following post-treatment steps: pulping, filtering and drying.
9. The method according to claim 7, wherein in the step two of the method for preparing the compound represented by the formula P3, the catalyst is 1, 8-diazabicycloundec-7-ene (DBU);
and/or in the preparation method of the compound shown as the formula P3, in the second step, the time of the substitution reaction is 2h.
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