CN116375595A - Preparation method and refining method of oseltamivir phosphate - Google Patents
Preparation method and refining method of oseltamivir phosphate Download PDFInfo
- Publication number
- CN116375595A CN116375595A CN202310341353.7A CN202310341353A CN116375595A CN 116375595 A CN116375595 A CN 116375595A CN 202310341353 A CN202310341353 A CN 202310341353A CN 116375595 A CN116375595 A CN 116375595A
- Authority
- CN
- China
- Prior art keywords
- oseltamivir phosphate
- reaction
- water
- organic layer
- ammonium chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 title claims abstract description 47
- 229960002194 oseltamivir phosphate Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 42
- 238000007670 refining Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000047 product Substances 0.000 claims abstract description 18
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- 238000001953 recrystallisation Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012044 organic layer Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- 235000019270 ammonium chloride Nutrition 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000007858 starting material Substances 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 17
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 12
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000004593 Epoxy Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 239000010410 layer Substances 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000011835 investigation Methods 0.000 description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 2
- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 description 2
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940061367 tamiflu Drugs 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- KTPJSJOTUGLYAS-UHFFFAOYSA-N CC(C)(C)[P] Chemical compound CC(C)(C)[P] KTPJSJOTUGLYAS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- PEZBJHXXIFFJBI-UHFFFAOYSA-N ethanol;phosphoric acid Chemical compound CCO.OP(O)(O)=O PEZBJHXXIFFJBI-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/26—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The invention discloses a preparation method and a refining method of oseltamivir phosphate, which are characterized in that a commercially available epoxy intermediate (SM) is used as a starting raw material to synthesize oseltamivir phosphate crude product through three-step reaction, and finally oseltamivir phosphate Wei Chunpin is obtained through recrystallization in an acetone/water mixed solvent. The preparation method and the refining method of oseltamivir phosphate provided by the invention are simple and convenient to operate, safe and controllable, high in conversion rate, low in impurity content and high in purity of the obtained intermediate and pure product, and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method and a refining method of oseltamivir phosphate.
Background
Oseltamivir phosphate, developed and produced by the rogowski company, marketed in switzerland in 1999, and approved by the FDA in 2000 as Tamiflu in the united states, chinese name Tamiflu. Oseltamivir phosphate is mainly used for influenza a and b in adults and children over one year of age. At present, the synthetic route of the product is more, but the method for realizing industrialization is not more.
The route reported in the literature mainly comprises the following three routes:
the synthesis reported in Drugs Fut 1999,24 (11): 1189:
the quinolinic acid is used as a starting material to obtain a target product through 11 steps of reactions, and the related operation steps are simpler, so that large-scale production is possible. The disadvantage of this route is that: (1) the highly toxic borane is needed to be used for ketal opening, the stereoselectivity is poor, and the yield is obviously reduced; (2) when the trimethylphosphine is used for preparing aziridine, the requirement on moisture is extremely high, and the industrial production is difficult to control; and the trimethylphosphine is a highly flammable and explosive substance, so that the potential safety hazard is high; (3) the preparation of oseltamivir phosphate free base by hydrogenation reduction of azido with Lindlar and Raney nickel as catalysts requires long-time reaction, and has long production period and potential safety hazard due to long-time hydrogen gas introduction in the production process.
The synthetic route disclosed in patent application WO1996026933 is as follows:
the method uses shikimic acid as a starting material, methyl esterification is carried out on shikimic acid, then a series of reactions are carried out to modify the structure, methyl ester is converted into ethyl ester, and finally azido is reduced to obtain oseltamivir, 16 steps of reactions are carried out, the reaction route is long, and the total yield is low.
Org Process Res Dev 1999,3 (4): 266 the process route reported below is as follows:
the route is shorter, column chromatography is not needed in the whole reaction process, three intermediates capable of forming good crystals are provided, and compared with the first two routes, the yield is higher; use of Et 3 SiH/TiCl 4 High selectivity ketal opening to construct chirality of molecular structure. The disadvantage is that the impurity content of the obtained product is high.
In addition, patent documents such as ZL2020105492953 disclose a method for preparing oseltamivir phosphate by an azide process:
in the method, tributylphosphine is adopted to reduce azido, so that the impurity content of the obtained product is high, and the total yield is low. ZL2009100478436 uses triphenylphosphine to reduce azido and the like, and has the problems of large potential safety hazard and low reaction conversion rate.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide another preparation method of oseltamivir phosphate, which has the advantages of simple reaction conditions, high yield, low potential safety hazard, safe and controllable operation and low impurity content of the obtained intermediate and finished product. The invention also aims to provide a refining method of oseltamivir phosphate, which has high yield and high purity of finished products.
In order to achieve the above purpose, the invention is realized by the following technical scheme: the preparation method of oseltamivir phosphate is characterized by comprising the following steps:
1) Dissolving a starting material SM in a mixed solution of alcohol and water, adding ammonium chloride and sodium azide under stirring, and reacting at 60-70 ℃ to obtain an intermediate state; adding the obtained intermediate into N, N-dimethylformamide, stirring and dissolving, controlling the temperature to be less than 50 ℃, adding triphenylphosphine and triethylamine hydrochloride, heating to 50-60 ℃ and reacting to obtain an intermediate I;
2) Adding the intermediate I into N, N-dimethylformamide, stirring and dissolving, sequentially adding ammonium chloride, sodium azide and triethylamine hydrochloride, heating to 50-60 ℃, and reacting to obtain an intermediate state; adding dichloromethane into the obtained intermediate state for dissolution, adding acetic anhydride under stirring, dropwise adding triethylamine at the temperature of-5-10 ℃, and then carrying out heat preservation reaction to obtain an intermediate II;
3) Adding the intermediate II into a mixed solvent of alcohol and water, stirring and dissolving, adding ammonium chloride and zinc powder, and reacting at 10-30 ℃ to obtain an intermediate state; adding alcohol into the intermediate state, then, dropwise adding an ethanol solution of phosphoric acid at the temperature of 20-30 ℃ for crystallization at the temperature to obtain crude oseltamivir phosphate; adding the crude oseltamivir phosphate product into a mixed solvent of acetone and water for crystallization to obtain oseltamivir phosphate Wei Chunpin; the reaction formula is:
in the scheme, the method comprises the following steps: the alcohol is one of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.
In the scheme, the method comprises the following steps: in the step 1), the mol ratio of the reaction of the starting materials SM, ammonium chloride and sodium azide is 1:2.5-3.2:2.5-3.2, transferring the reaction solution into a separating funnel after the reaction is finished, adding water, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering by suction, and concentrating under reduced pressure to obtain intermediate oily substance.
In the scheme, the method comprises the following steps: in the step 1), the mol ratio of the starting materials SM, triphenylphosphine and triethylamine hydrochloride is 1:1.0-1.1:1.0-1.1, after the reaction is finished, the reaction mixture is cooled to 20-25 ℃, suction filtration is carried out, the filtrate is transferred into a separating funnel, ethyl acetate and saturated saline water are added for layering, and an oily substance is obtained by concentrating an organic layer under reduced pressure, and is the intermediate I.
In the scheme, the method comprises the following steps: in the step 2), the molar ratio of the intermediate I to the ammonium chloride to the sodium azide to the triethylamine hydrochloride is 1:1.5-1.8:1.5-1.8:0.3-0.5; after the reaction, cooling to 20-25 ℃, adding water into the mixture, extracting the mixture with ethyl acetate, drying an organic layer, and concentrating the organic layer under reduced pressure to obtain an intermediate oily substance.
In the scheme, the method comprises the following steps: in the step 2), the mol ratio of the intermediate I to the acetic anhydride to the triethylamine is 1:1.0-1.1:1.0-1.1; after the reaction is finished, adding water into the reaction mixture, layering, drying an organic layer by using anhydrous sodium sulfate, evaporating to dryness under reduced pressure, adding a mixed solution of ethyl acetate and normal hexane, heating to 50-60 ℃, stirring for dissolution, cooling to 20-25 ℃, crystallizing, filtering, and drying a filter cake to obtain an intermediate II.
In the scheme, the method comprises the following steps: in step 3), intermediate II: the mol ratio of Zn powder to ammonium chloride is 1:4.5-5.5:3.0-5.0, after the reaction is finished, the solution is filtered, water is added into the filtrate, dichloromethane is used for extraction, and the organic layer is decompressed and concentrated to obtain intermediate oily substance.
In the scheme, the method comprises the following steps: in the step 3), the concentration of phosphoric acid in the phosphoric acid ethanol solution is 83-85%.
In the scheme, the method comprises the following steps: in the step 3), the volume ratio of the acetone to the water is 5:1.
In the scheme, the method comprises the following steps: in the step 3), the mass/volume (w/v) ratio of the oseltamivir phosphate crude product to the mixed solvent is 1:10.
the second object of the invention is to provide a refining method of oseltamivir phosphate, which is characterized in that: and (3) recrystallizing by adopting a mixed solution of acetone and water according to a volume ratio of 5:1, wherein the crystallization temperature is 25+/-2 ℃.
In the scheme, the refining operation comprises the following specific steps: adding oseltamivir phosphate crude product into a container, then adding acetone and water, heating to 50+/-2 ℃ for dissolving, adding active carbon, filtering while the active carbon is hot, cooling filtrate to 25+/-2 ℃ for crystallization, filtering, and drying under reduced pressure to obtain a pure product.
The beneficial effects of the invention are as follows: the method comprises the steps of selecting the initial raw material to prepare the crude oseltamivir phosphate, reducing an azido group into an amino group by using Zn powder in one step of reduction, and then salifying with phosphoric acid to obtain the crude oseltamivir phosphate. The reduction with ammonium chloride and zinc powder eliminates the protection of the tert-butyl group and eliminates the deprotection step compared with patent application ZL 2020105492953. Compared with the method of the document J.org.chem.1998,63,4545-4550, the method not only reduces the cost and simplifies the operation, but also ensures that the reaction condition is mild and controllable, the raw materials are cheap and easy to obtain, and the industrialization is easier to realize; in addition, in the step of oseltamivir phosphate crystallization, acetone is adopted: water = 5:1, and the yield and purity of the obtained product are higher.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
The first step:
(1) 35g of the starting material, 150mL of ethanol and 150mL of water are sequentially added into a 500mL three-necked flask, 20g of ammonium chloride and 26.8g of sodium azide are added under stirring, the temperature is raised to 60-70 ℃ for 16h, and TLC detects that the reaction of the starting material is complete as the reaction end point. The reaction solution was transferred to a separating funnel, 200mL of water was added, 200mL of ethyl acetate was used for extraction, the aqueous layer was discarded, the organic layer was dried over 25g of anhydrous sodium sulfate for 1h, suction filtration was performed, and the solution was concentrated under reduced pressure (not less than 0.08 MPa) at 50.+ -. 2 ℃ and evaporated to dryness to give an oil.
(2) 120mL of N, N-dimethylformamide is added into the obtained oily substance, stirring and dissolving are carried out, the temperature is controlled to be less than 50 ℃, 37g of triphenylphosphine and 19.9g of triethylamine hydrochloride are added, the temperature is increased to 50-60 ℃ for reaction for 8 hours, and TLC detects that the intermediate reaction is complete as the reaction end point. The reaction mixture was cooled to 20-25℃and filtered with suction, the filtrate was transferred to a separatory funnel, 150mL of ethyl acetate was added, 250mL of saturated brine was layered, the aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (0.08 MPa or more) at 55.+ -. 2℃to give a brown oil, 30.2g of intermediate I, 86.5% yield.
Second step
Step (1): adding 24.2g of the intermediate I obtained in the first step into a 500mL three-necked flask, adding 170mL of dry N, N-dimethylformamide, stirring for dissolving, sequentially adding 8.1g of ammonium chloride, 9.8g of sodium azide and 4.1g of triethylamine hydrochloride, heating to 50-60 ℃, reacting for 14h, and detecting that the intermediate I is completely reacted by TLC (thin layer chromatography), thus obtaining the reaction end point. Cooling to 20-25deg.C, adding 200mL of water, extracting with 150mL of ethyl acetate, discarding water layer, drying the organic layer with 25g of anhydrous sodium sulfate for 1 hr, vacuum filtering, and evaporating filtrate under reduced pressure (more than or equal to 0.08 Mpa) at 50+ -2deg.C to obtain oily substance.
Step (2): to the resulting oil was added 100mL of methylene chloride to dissolve, 9.2mL of acetic anhydride was added under stirring to cool the reaction liquid to 0-5℃and 14mL of triethylamine was added dropwise at-5-10 ℃. After the dripping is finished, the reaction is carried out for 1h under the heat preservation. 200mL of water is added into the reaction mixture, layering is carried out, the water layer is discarded, the organic layer is evaporated to dryness under reduced pressure (more than or equal to 0.08 Mpa) at 50+/-2 ℃, 70mL of ethyl acetate and 175mL of normal hexane are added, the temperature is raised to 50-60 ℃ and stirred for 1h, the temperature is reduced to 20-25 ℃ and crystallized for 2h, suction filtration is carried out, the filter cake is dried under reduced pressure (more than or equal to 0.08 Mpa) at 50+/-2 ℃ for 6h, 28.9g of white solid is obtained, and the yield is 89.5% as intermediate II.
Third step
Step (1): 15g of intermediate II,290mL of ethanol and 95mL of water are sequentially added into a 250mL three-necked flask, stirring is carried out, then 12.0g of ammonium chloride and 15.4g of zinc powder are added, the reaction is carried out for 5h at 20-30 ℃, and TLC (thin layer chromatography) detects that the reaction of intermediate II is complete, namely the reaction end point. Suction filtration, adding 200mL of water into the filtrate, extracting with 150mL×2 of dichloromethane, discarding the water layer, and evaporating the organic layer at 50+ -2deg.C under reduced pressure (not less than 0.08 Mpa) to obtain oily substance.
Step (2): 160mL of ethanol is added into the obtained oily substance, then an ethanol solution of phosphoric acid (4.9 mL (the mass concentration is 83-85%) and phosphoric acid are diluted by 45mL of ethanol) is dropwise added at the temperature of 20-30 ℃, crystallization is carried out for 1h at the temperature, suction filtration is carried out, and a filter cake is dried for 6h at 50+/-2 ℃ to obtain 15.45g of oseltamivir phosphate crude product, and the yield is 84.98%.
Step (3): adding 15.0g of oseltamivir phosphate crude product into a 250mL dry three-port bottle, then adding 125mL of acetone and 25mL of water, heating to dissolve at 50+/-2 ℃, adding 1g of active carbon, filtering while the active carbon is hot, cooling the filtrate to 25+/-2 ℃ for crystallization for 6h, filtering, drying under reduced pressure at 50+/-2 ℃ for 6h to obtain 14.7g of pure product, wherein the yield is 78.6%, and the HPLC purity is 99.80%.
Example 2
The first step:
(1) 32g of the starting material, 135mL of isopropanol and 135mL of water are sequentially added into a 500mL three-necked flask, 16.9g of ammonium chloride and 20.5g of sodium azide are added under stirring, the temperature is raised to 60-70 ℃ for reaction for 17 hours, and TLC (thin layer chromatography) detects that the reaction of the starting material is complete as the reaction end point. The reaction solution was transferred to a separating funnel, 200mL of water was added, 200mL of ethyl acetate was used for extraction, the aqueous layer was discarded, the organic layer was dried over 25g of anhydrous sodium sulfate for 1h, suction filtration was performed, and the solution was concentrated under reduced pressure (not less than 0.08 MPa) at 50.+ -. 2 ℃ and evaporated to dryness to give an oil.
(2) 120mL of N, N-dimethylformamide is added into the oily matter, stirring and dissolving are carried out, the temperature is controlled to be less than 50 ℃, 36.3g of triphenylphosphine and 19g of triethylamine hydrochloride are added, the temperature is increased to 50-60 ℃ for reaction for 8 hours, and TLC detects that the intermediate reaction is complete as the reaction end point. The reaction mixture was cooled to 20-25℃and filtered with suction, the filtrate was transferred to a separatory funnel, 150mL of ethyl acetate was added, 250mL of saturated brine was layered, the aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (0.08 MPa or more) at 55.+ -. 2℃to give a brown oil, 27.7g of intermediate I, yield 87.2%.
Second step
Step (1): adding 24.0g of the intermediate I obtained in the first step into a 500mL three-necked flask, adding 170mL of dry N, N-dimethylformamide, stirring for dissolving, sequentially adding 9.1g of ammonium chloride, 11g of sodium azide and 6.5g of triethylamine hydrochloride, heating to 50-60 ℃, reacting for 14h, and detecting that the intermediate I is completely reacted by TLC (thin layer chromatography) to obtain a reaction end point. Cooling to 20-25deg.C, adding 200mL of water, extracting with 150mL of ethyl acetate, discarding water layer, drying the organic layer with 25g of anhydrous sodium sulfate for 1 hr, vacuum filtering, and evaporating filtrate under reduced pressure (more than or equal to 0.08 Mpa) at 50+ -2deg.C to obtain oily substance.
Step (2): to the resulting oily matter was added 100mL of methylene chloride to dissolve, 10.6g of acetic anhydride was added under stirring, the reaction solution was cooled to 0-5℃and 10.5g of triethylamine was added dropwise at-5-10℃to react for 1 hour at a constant temperature. 200mL of water is added into the reaction mixture, layering is carried out, the water layer is discarded, the organic layer is evaporated to dryness under reduced pressure (more than or equal to 0.08 Mpa) at 50+/-2 ℃, 70mL of ethyl acetate and 175mL of normal hexane are added, the temperature is raised to 50-60 ℃ and stirred for 1h, the temperature is reduced to 20-25 ℃ and crystallized for 2h, suction filtration is carried out, the filter cake is dried under reduced pressure (more than or equal to 0.08 Mpa) at 50+/-2 ℃ for 6h to obtain 28.8g of white solid which is 28.5g of intermediate II, and the yield is 89.2%.
Third step
Step (1): 15.0g of intermediate II,290mL of ethanol and 95mL of water are sequentially added into a 250mL three-necked flask, the mixture is stirred and dissolved, 7.0g of ammonium chloride and 15.8g of zinc powder are added, the mixture is reacted for 5 hours at 20-25 ℃, and the reaction end point is obtained after TLC detection of the completion of the reaction of the intermediate II. Suction filtration, adding 200mL of water into the filtrate, extracting with 150mL×2 of dichloromethane, discarding the water layer, and evaporating the organic layer at 50+ -2deg.C under reduced pressure (not less than 0.08 Mpa) to obtain oily substance.
Step (2): 160mL of ethanol is added into the obtained oily substance, then an ethanol solution of phosphoric acid (4.9 mL of phosphoric acid (the mass concentration is 83% -85%) is added dropwise at the temperature of 20-30 ℃ and diluted by 45mL of ethanol), crystallization is carried out for 1h at the temperature, suction filtration is carried out, and a filter cake is dried for 6h at 50+/-2 ℃ to obtain 15.5g of crude oseltamivir phosphate with the yield of 85.3%.
Step (3): adding 15.0g of oseltamivir phosphate crude product into a 250mL dry three-mouth bottle, then adding 125mL of acetone and 25mL of water, heating to dissolve at 50+/-2 ℃, adding 1g of active carbon, filtering while the active carbon is hot, cooling the filtrate to 25+/-2 ℃ for crystallization for 6h, filtering, and drying under reduced pressure at 50+/-2 ℃ for 6h to obtain 14.55g of pure product with HPLC purity of 99.85%.
Comparative example 1
Oseltamium phosphate Wei Chengpin was prepared by the method of reference J.org.chem.1998,63,4545-4550 using t-butylphosphorus.
Impurity and purity studies
Determination of oseltamivir phosphate obtained in example 1 and example 2, purity and impurity content determination were performed with the intermediate and final product obtained in comparative example 1, as shown in the following table:
TABLE 1 purity of oseltamivir phosphate and its intermediates prepared in examples 1 and 2 and comparative example
TABLE 2 oseltamivir phosphate related substances and content prepared in examples 1 and 2 and comparative example
Comparative example 2 investigation of crystallization solvent
(1) Referring to the refining method of patent document CN111499536a, ethyl acetate-petroleum ether is used for recrystallization.
(2) Referring to the purification method of patent document CN101538221a, ethanol-ethyl acetate 1:1 recrystallization was used.
(3) Reference is made to the purification method of patent document CN113307744a, which uses absolute ethanol and distilled water for recrystallization.
(4) Method for refining example 2
(5) Referring to the purification method of patent document CN111747861a, acetone recrystallization was used.
EXAMPLE 4 investigation of other crystallization conditions
TABLE 1 investigation of other crystallization solvents
TABLE 2 investigation of crystallization temperatures
Experiments show that the crystallization temperature has a great influence on the purity and yield of oseltamivir phosphate: when the temperature is 5+/-2 ℃, part of impurities are separated out along with the product, so that the purity of the product is reduced; when the temperature is raised to 15+/-2 ℃, the yield is reduced; when the temperature is 25+/-2 ℃, the refining purity is best, and the yield reaches 97.2 percent. Therefore, we choose the crystallization temperature 25.+ -. 2 ℃.
Therefore, the crystallization conditions used in the invention are better in view of the purity and conversion rate of the product, and the purity and the yield of the obtained product are better.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. The preparation method of oseltamivir phosphate is characterized by comprising the following steps:
1) Dissolving a starting material SM in a mixed solution of alcohol and water, adding ammonium chloride and sodium azide under stirring, and reacting at 60-70 ℃ to obtain an intermediate state; adding the obtained intermediate into N, N-dimethylformamide, stirring and dissolving, controlling the temperature to be less than 50 ℃, adding triphenylphosphine and triethylamine hydrochloride, heating to 50-60 ℃ and reacting to obtain an intermediate I;
2) Adding the intermediate I into N, N-dimethylformamide, stirring and dissolving, sequentially adding ammonium chloride, sodium azide and triethylamine hydrochloride, heating to 50-60 ℃, and reacting to obtain an intermediate state; adding dichloromethane into the obtained intermediate state for dissolution, adding acetic anhydride under stirring, dropwise adding triethylamine at the temperature of-5-10 ℃, and then carrying out heat preservation reaction to obtain an intermediate II;
3) Adding the intermediate II into a mixed solvent of alcohol and water, stirring and dissolving, adding ammonium chloride and zinc powder, and reacting at 10-30 ℃ to obtain an intermediate state; adding alcohol into the intermediate state, then, dropwise adding an ethanol solution of phosphoric acid at the temperature of 20-30 ℃ for crystallization at the temperature to obtain crude oseltamivir phosphate; adding the crude oseltamivir phosphate product into a mixed solvent of acetone and water for recrystallization to obtain oseltamivir phosphate Wei Chunpin;
the reaction formula is:
2. the method for preparing oseltamivir phosphate according to claim 1, wherein: the alcohol is one of methanol, ethanol, isopropanol and tert-butanol.
3. The method for preparing oseltamivir phosphate according to claim 2, wherein: in the step 1), the mol ratio of the reaction of the starting materials SM, ammonium chloride and sodium azide is 1:2.5-3.2:2.5-3.2, transferring the reaction solution into a separating funnel after the reaction is finished, adding water, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering by suction, and concentrating under reduced pressure to obtain intermediate oily substance.
4. A process for the preparation of oseltamivir phosphate according to claim 3, wherein: in the step 1), the mol ratio of the starting materials SM, triphenylphosphine and triethylamine hydrochloride is 1:1.0-1.1:1.0-1.1, after the reaction is finished, the reaction mixture is cooled to 20-25 ℃, suction filtration is carried out, the filtrate is transferred into a separating funnel, ethyl acetate and saturated saline water are added for layering, and an oily substance is obtained by concentrating an organic layer under reduced pressure, and is the intermediate I.
5. The process for the preparation of oseltamivir phosphate according to any one of claims 1 to 4, characterized in that: in the step 2), the molar ratio of the intermediate I to the ammonium chloride to the sodium azide to the triethylamine hydrochloride is 1:1.5-1.8:1.5-1.8:0.3-0.5; after the reaction, cooling to 20-25 ℃, adding water into the mixture, extracting the mixture with ethyl acetate, drying an organic layer, and concentrating the organic layer under reduced pressure to obtain an intermediate oily substance.
6. The method for preparing oseltamivir phosphate according to claim 5, wherein: in the step 2), the mol ratio of the intermediate I to the acetic anhydride to the triethylamine is 1:1.0-1.1:1.0-1.1; after the reaction is finished, adding water into the reaction mixture, layering, drying an organic layer by using anhydrous sodium sulfate, evaporating to dryness under reduced pressure, adding a mixed solution of ethyl acetate and normal hexane, heating to 50-60 ℃, stirring for dissolution, cooling to 20-25 ℃, crystallizing, filtering, and drying a filter cake to obtain an intermediate II.
7. The method for preparing oseltamivir phosphate according to claim 6, wherein: in step 3), intermediate II: the mol ratio of Zn powder to ammonium chloride is 1:4.5-5.5:3.0-5.0, after the reaction is finished, the solution is filtered, water is added into the filtrate, dichloromethane is used for extraction, and the organic layer is decompressed and concentrated to obtain intermediate oily substance.
8. The method for preparing oseltamivir phosphate according to claim 7, wherein: in the step 3), the concentration of phosphoric acid is 83-85%.
9. The method for preparing oseltamivir phosphate according to claim 8, wherein: in the step 3), the volume ratio of the acetone to the water is 5:1, and the crystallization temperature is 25+/-2 ℃.
10. A refining method of oseltamivir phosphate is characterized in that: recrystallizing by adopting a mixed solution of acetone and water according to a volume ratio of 5:1, wherein the crystallization temperature is 25+/-2 ℃; the method for refining oseltamivir phosphate according to claim, wherein the refining comprises the following specific operations: adding oseltamivir phosphate crude product into a container, then adding acetone and water, heating to 50+/-2 ℃ for dissolving, adding active carbon, filtering while the active carbon is hot, cooling the filtrate to 25+/-2 ℃ for crystallization, filtering, and drying under reduced pressure to obtain a pure product.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310341353.7A CN116375595A (en) | 2023-03-31 | 2023-03-31 | Preparation method and refining method of oseltamivir phosphate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310341353.7A CN116375595A (en) | 2023-03-31 | 2023-03-31 | Preparation method and refining method of oseltamivir phosphate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116375595A true CN116375595A (en) | 2023-07-04 |
Family
ID=86962871
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310341353.7A Pending CN116375595A (en) | 2023-03-31 | 2023-03-31 | Preparation method and refining method of oseltamivir phosphate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116375595A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999055664A1 (en) * | 1998-04-24 | 1999-11-04 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
CN1272105A (en) * | 1997-09-17 | 2000-11-01 | 吉里德科学公司 | Compound containing six-membered rings, processes for their preparation, and their use as medicaments |
WO2011021223A2 (en) * | 2009-08-19 | 2011-02-24 | Msn Laboratories Limited | Novel salts of ethyl (3r, 4s, 5r)-4,5-imino-3-(l-ethylpropoxy)-1- cvclohexene-1-carboxylate and its use |
KR20150095970A (en) * | 2014-02-12 | 2015-08-24 | 주식회사 경보제약 | Improved process for preparing Oseltamivir |
CN111747861A (en) * | 2020-06-16 | 2020-10-09 | 宜昌东阳光长江药业股份有限公司 | Method for preparing oseltamivir phosphate by using azide process |
-
2023
- 2023-03-31 CN CN202310341353.7A patent/CN116375595A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1272105A (en) * | 1997-09-17 | 2000-11-01 | 吉里德科学公司 | Compound containing six-membered rings, processes for their preparation, and their use as medicaments |
WO1999055664A1 (en) * | 1998-04-24 | 1999-11-04 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
WO2011021223A2 (en) * | 2009-08-19 | 2011-02-24 | Msn Laboratories Limited | Novel salts of ethyl (3r, 4s, 5r)-4,5-imino-3-(l-ethylpropoxy)-1- cvclohexene-1-carboxylate and its use |
KR20150095970A (en) * | 2014-02-12 | 2015-08-24 | 주식회사 경보제약 | Improved process for preparing Oseltamivir |
CN111747861A (en) * | 2020-06-16 | 2020-10-09 | 宜昌东阳光长江药业股份有限公司 | Method for preparing oseltamivir phosphate by using azide process |
Non-Patent Citations (2)
Title |
---|
李行舟等: "磷酸奥司米韦的合成", 中国医药工业杂志, vol. 38, no. 6, 31 December 2007 (2007-12-31), pages 393 - 397 * |
龚晓明等: "抗流感病毒新药oseltamivir的合成改进", 中国新药杂志, vol. 12, no. 6, 31 December 2003 (2003-12-31), pages 454 - 456 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112125805B (en) | Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate | |
CN113754665A (en) | Preparation method of nucleoside compound | |
CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
CN104513256B (en) | A kind of preparation method of Cefditoren pivoxil Cephalosporins | |
CN112661736B (en) | Synthetic method of tylosin intermediate | |
CN113214320A (en) | Preparation method of Reidesciclovir compound | |
CN116375595A (en) | Preparation method and refining method of oseltamivir phosphate | |
CN111138351A (en) | Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate | |
US20050203287A1 (en) | Process for the preparation of sulfamate derivatives | |
CN109535210A (en) | A kind of method of synthesizing and purifying Tulathromycin impurity E | |
CN108727445B (en) | Synthesis method of azithromycin impurity F | |
CN110551064B (en) | Preparation method of isavuconazole sulfate and intermediate thereof | |
CN113024398A (en) | Preparation method of capsaicin and capsaicin prepared by using same | |
CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
CN111018928A (en) | Synthetic method and application of gastrodin hemihydrate | |
CN115555034B (en) | Composite catalyst for converting carbonyl into methylene and preparation method for efficiently catalyzing synthesis of cholesterol by composite catalyst | |
CN115073313B (en) | Method for synthesizing terbutaline sulfate impurity C | |
CN109912552B (en) | Preparation method of brewage furan and intermediate thereof | |
CN111909136A (en) | Preparation method of candesartan cilexetil | |
CN114349600B (en) | Preparation method of L-enriched isopulegol | |
CN100556906C (en) | A kind of preparation method of proteinase inhibitor important intermediate | |
KR20170123132A (en) | Process for Preparing Treprostinil | |
CN112110868A (en) | Preparation method of Fmoc-beta-Ala-AA-OH | |
CN108084049B (en) | Preparation method of posaconazole intermediate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |