CN114560894A - Preparation method of anti-neocoronal medicine Molnbupiravir - Google Patents
Preparation method of anti-neocoronal medicine Molnbupiravir Download PDFInfo
- Publication number
- CN114560894A CN114560894A CN202210238256.0A CN202210238256A CN114560894A CN 114560894 A CN114560894 A CN 114560894A CN 202210238256 A CN202210238256 A CN 202210238256A CN 114560894 A CN114560894 A CN 114560894A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- trifluoromethanesulfonate
- preparing
- molar ratio
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a new crown resistant drug Molnopiravir (compound I). The preparation method takes cheap and easily available uridine (compound II) as a starting material, and the Molnupiarvir can be obtained through reaction in a plurality of steps. The invention has the advantages of simple and reliable process, low comprehensive cost, easy commercial production and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical synthetic chemistry, and particularly relates to a preparation method of a new crown resistant drug Molnnupiravir.
Background
Molnupiravir (also named MK4482 or EIDD2801) is a ribonucleoside analogue with broad-spectrum RNA virus activity developed by Emeric university, and can effectively inhibit the replication of influenza virus, hepatitis C virus, Ebola virus, respiratory syncytial virus, coronavirus such as SARS-CoV-1 and MERS virus, etc. EIDD2801 is assigned by Emmeri university to both Emersonide and Ridgeback, and is jointly developed into a candidate drug for oral administration against a novel coronavirus. Clinical trial results show that Molnupiravir can reduce the risk of hospitalization or death of new coronary patients by 30%. On 23/12/2021, the FDA awards the Molnupiravir Emergency Use Authority (EUA) for the treatment of adult patients with a positive test for the novel coronavirus (SARS-CoV-2) and a higher risk of developing severe mild or moderate new coronary pneumonia (COVID-19).
The chemical name of Molnupiravir is uridine 5' -methylpropionate-4-oxime, and the chemical structure of the Molnupiravir is shown as follows:
patent WO2019113462 first discloses a synthetic route to Molnupiravir. In the route, uridine is used as a raw material, cis-ortho-dihydroxy is protected, and then the uridine reacts with isopropyl anhydride to generate isobutyrate. The intermediate isobutyrate reacts with 1,2, 4-triazole under the action of phosphorus oxychloride to produce a triazole intermediate; and reacting the triazole intermediate with hydroxylamine, and finally removing a protecting group to obtain the Molnbupirivir with the total yield of 17%.
Synlett (2021,32,326-328) reported a route to Molnupiarvir starting with cytidine. Firstly, acetone is used for protecting cis-ortho-dihydroxy of cytidine, and then the cis-ortho-dihydroxy of cytidine reacts with isobutyric anhydride to generate an isobutyrate intermediate; the isobutyrate intermediate reacts with hydroxylamine sulfate, and then the protection is removed to obtain Molnbupiravir with the total yield of 44%.
Commun, (2020,56,13363-13364) reported an enzymatic synthesis route to Molnupriver. The route also takes cytidine as a starting material, and firstly, the cytidine is selectively esterified under the action of the novacin lipase 435 to generate an isobutyrate intermediate; the intermediate reacts with hydroxylamine sulfate to obtain Molnbupiravir, and the total yield of the two steps is 75%.
Although the chemical method or the enzymatic method synthesis of the Molnupiravir is greatly developed, the chemical method has longer synthesis steps and lower yield at present; although the enzymatic method has short steps and high yield, the enzyme dosage is large, the price is high, and the comprehensive cost is high. Therefore, it is very important to develop a synthesis route of Molnupiravir, which has the advantages of simple route, simple and reliable process, low comprehensive cost and suitability for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of Molnuprivir (compound I), which has the advantages of simple and reliable process, low comprehensive cost and easy commercial production.
The synthetic route of the invention is as follows:
the invention comprises the following steps:
1) uridine (compound II) is acylated with isobutyric anhydride (compound III) under the action of Lewis acid to obtain compound IV.
2) And reacting the compound IV with hydroxylamine hydrochloride or hydroxylamine sulfate in the presence of a silicon reagent to obtain a compound I.
In the step 1), the Lewis acid is one or more of copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, nickel trifluoromethanesulfonate and lanthanum trifluoromethanesulfonate.
Further, the molar ratio of the Lewis acid to the compound II in the step 1) is 1: 20-1: 1000.
Further, the molar ratio of the compound II to the compound III in the step 1) is 1: 1-1: 2.
Further, the temperature of the acylation reaction in the step 1) is-10 ℃ to 50 ℃.
In the step 2), the silicon reagent is one or more of hexamethyldisilazane/trimethylsilyl trifluoromethanesulfonate, hexamethyldisilazane/trimethylchlorosilane.
Further, the molar ratio of the hexamethyldisilazane to the compound IV in the silicon reagent in the step 2) is 2: 1-10: 1; the molar ratio of trimethylsilyl trifluoromethanesulfonate or trimethylchlorosilane to the compound IV is 0.01: 1-0.2: 1.
Further, the molar ratio of the compound IV to hydroxylamine hydrochloride or hydroxylamine sulfate in the step 2) is 1: 1-1: 2.
Compared with the prior art/literature, the invention has the following remarkable advantages:
1) the invention adopts Lewis acid catalyst to catalyze uridine for selective acylation, and the side products are few.
2) The method has the advantages of short steps, greatly reduced three wastes, and greener environmental protection of the whole preparation process;
3) the invention has simple and reliable process and low comprehensive production cost, thereby having good market competitiveness.
Detailed Description
The following examples are put forth so as to provide those of ordinary skill in the art with a view to making and evaluating the present invention, and are intended to be merely exemplary of the present disclosure and are not intended to limit the scope thereof. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), some errors and deviations should be accounted for. Unless otherwise specified, temperature is in units of ° c or at ambient temperature, and pressure is at or near atmospheric pressure.
The methods described in this example for the preparation of the disclosed compounds described herein are one of many and many others are possible and are not intended to limit the scope of the present application. Thus, one of skill in the art to which this disclosure pertains may readily modify the methods described or utilize different methods for preparing one or more of the disclosed compounds. The following methods are exemplary only, and the temperature, catalyst, concentration, reactant composition, and other process conditions may be varied, and one skilled in the art to which this disclosure pertains may readily select appropriate reactants and conditions for the preparation of the desired compound.
Example 1
Preparation of Compound IV
244.2g of Compound II and 3.62g of copper trifluoromethanesulfonate were dissolved in 2L of butanone, 166g of isobutyric anhydride were added dropwise at room temperature, and the reaction was stirred until completion. Butanone was removed under reduced pressure, and 1L ethyl acetate and 500mL of water were added to the residue to extract a liquid. The aqueous phase is extracted again with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/n-heptane to yield 286g of compound IV, 91% yield and 99.3% HPLC purity.
1H NMR(DMSO-d6,400MHz)δ11.38(s,1H),7.62(d,J＝8.0Hz,1H),5.75(d,J＝ 4.1Hz,1H),5.66(d,J＝7.8Hz,1H),5.52(br s,1H),5.32(br s,1H),4.28-4.14(m, 2H),4.10-4.04(m,1H),4.02-3.92(m,2H),2.62-2.52(m,1H),1.09(d,J＝6.8Hz, 6H)；
13C NMR(DMSO-d6,101MHz)δ176.4,163.5,151.0,141.1,102.4,89.1,81.5,73.2, 70.1,64.1,33.6,19.2；
HRMS(ESI):m/z calcd for C13H18N2O7[M+H]+315.1187,found:315.1182.
Example 2
Preparation of Compound IV
244.2g of Compound II and 3.64g of zinc trifluoromethanesulfonate were dissolved in 2L of butanone, 166g of isobutyric anhydride were added dropwise at room temperature, and the reaction was stirred until completion. Butanone was removed under reduced pressure, and 1L ethyl acetate and 500mL of water were added to the residue to extract a liquid. The aqueous phase is extracted again with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallised from ethyl acetate/n-heptane to yield 274g of compound IV, yield 87%, HPLC purity 99.2%.
Example 3
Preparation of Compound IV
244.2g of Compound II and 3.57g of nickel trifluoromethanesulfonate were dissolved in 2L of butanone, 166g of isobutyric anhydride were added dropwise at room temperature, and the reaction was stirred until completion. Butanone was removed under reduced pressure, and 1L ethyl acetate and 500mL water were added to the residue to extract the separated layers. The aqueous phase is extracted again with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/n-heptane to yield 226g of compound IV, yield 72% and HPLC purity 99.0%.
Example 4
Preparation of Compound IV
244.2g of compound II and 5.86g of lanthanum trifluoromethanesulfonate were dissolved in 2L of butanone, 166g of isobutyric anhydride were added dropwise at room temperature, and the reaction was stirred to completion. Butanone was removed under reduced pressure, and 1L ethyl acetate and 500mL of water were added to the residue to extract a liquid. The aqueous phase is extracted again with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/n-heptane to yield 289g of compound IV, 92% yield and 99.1% HPLC purity.
Example 5
Preparation of Compound I
To 157g of compound IV and 323g of hexamethyldisilazane suspension were added 5.5g of trimethylsilyl trifluoromethanesulfonate under a nitrogen atmosphere, and the mixture was stirred with heating (80 ℃ C.) for 3 hours. Then 100g of hydroxylamine sulfate is added, the mixture is stirred at the constant temperature until the reaction is complete, and then the temperature is reduced, and the mixture is concentrated under reduced pressure. To the residue were added 1L of ethyl acetate and 500mL of water, and the separated layers were extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to yield 147g of compound I in 89% yield and 99.8% HPLC purity.
1H NMR(DMSO-d6,400MHz)δ10.02(s,1H),9.67(s,1H),6.82(d,J＝8.2Hz, 1H),5.71(d,J＝5.5Hz,1H),5.59(d,J＝8.2Hz,1H),5.38(d,J＝5.5Hz,1H),5.23 (d,J＝4.5Hz,1H),4.2(dd,J＝12.0,3.1Hz,1H),4.13(dd,J＝12.0,4.9Hz,1H), 4.00(q,J＝5.3Hz,1H),3.92(h,J＝4.6Hz,2H),2.57(p,J＝7.0Hz,1H),1.09(d,J ＝7.0Hz,6H)；
13C NMR(DMSO-d6,101MHz)δ176.4,149.9,143.7,130.3,99.2,88.1,81.1,72.4, 70.4,64.3,33.6,19.2(4),19.2(2)；
HRMS(ESI):m/z calcd for C13H19N3O7[M+H]+330.1296,found:330.1294.
Example 6
Preparation of Compound I
To 157g of compound IV and 400g of hexamethyldisilazane suspension were added 10g of trimethylchlorosilane under nitrogen atmosphere, and the mixture was stirred with heating (80 ℃ C.) for 3 hours. Then 100g of hydroxylamine sulfate is added, the mixture is stirred at the constant temperature until the reaction is complete, and then the temperature is reduced, and the mixture is concentrated under reduced pressure. 1L of ethyl acetate and 500mL of water were added to the residue, and the mixture was extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to yield 134g of compound I in 81% yield and 99.7% HPLC purity.
Example 7
Preparation of Compound I
To 157g of compound IV and 500g of hexamethyldisilazane suspension were added 10g of trimethylsilyl trifluoromethanesulfonate under nitrogen atmosphere, and the mixture was stirred with heating (80 ℃ C.) for 3 hours. Then 42g of hydroxylamine hydrochloride is added, the temperature is kept and the stirring is carried out until the reaction is complete, the temperature is reduced, and the decompression concentration is carried out. 2L of ethyl acetate and 500mL of water were added to the residue, and the mixture was extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to yield 152g of compound I in 92% yield and 99.7% HPLC purity.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (9)
1. The preparation method of the anti-neocrown drug Molnbupiarvir (compound I) is characterized by comprising the following steps:
1) carrying out acylation reaction on uridine (compound II) and isobutyric anhydride (compound III) under the action of Lewis acid to obtain a compound IV;
2) reacting compound IV with hydroxylamine hydrochloride or hydroxylamine sulfate in the presence of a silicon reagent to give compound I:
2. the method for preparing compound I according to claim 1, wherein the lewis acid agent in step 1) is one or more of copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, nickel trifluoromethanesulfonate and lanthanum trifluoromethanesulfonate.
3. The method for preparing the compound I according to claim 1, wherein the molar ratio of the Lewis acid to the compound II in the step 1) is 1:20 to 1: 1000.
4. The method for preparing the compound I according to claim 1, wherein the molar ratio of the compound II to the compound III in the step 1) is 1:1 to 1: 2.
5. The process for the preparation of compound I according to claim 1, wherein the temperature of the acylation reaction in step 1) is from-10 ℃ to 50 ℃.
6. The method according to claim 1, wherein the silicon reagent in step 2) is one or more of hexamethyldisilazane/trimethylsilyl trifluoromethanesulfonate, hexamethyldisilazane/trimethylchlorosilane.
7. The method for preparing the compound I according to claim 1, wherein the mole ratio of hexamethyldisilazane to the compound IV in the silicon reagent of the step 2) is 2:1 to 10: 1; the molar ratio of trimethylsilyl trifluoromethanesulfonate or trimethylchlorosilane to the compound IV is 0.01: 1-0.2: 1.
8. The method for preparing the compound I according to claim 1, wherein the molar ratio of the compound IV in the step 2) to hydroxylamine hydrochloride or hydroxylamine sulfate is 1:1 to 1: 2.
9. The process for the preparation of compound I according to claim 1, wherein the temperature of the reaction in step 2) is from 20 ℃ to 120 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210238256.0A CN114560894B (en) | 2022-03-11 | 2022-03-11 | Preparation method of anti-new crown medicine Molnupiravir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210238256.0A CN114560894B (en) | 2022-03-11 | 2022-03-11 | Preparation method of anti-new crown medicine Molnupiravir |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114560894A true CN114560894A (en) | 2022-05-31 |
| CN114560894B CN114560894B (en) | 2023-06-20 |
Family
ID=81718171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210238256.0A Active CN114560894B (en) | 2022-03-11 | 2022-03-11 | Preparation method of anti-new crown medicine Molnupiravir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114560894B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397316A (en) * | 2008-10-23 | 2009-04-01 | 浙江工业大学 | Chemical synthesis method of ribavirin condensation compound |
| CN108676048A (en) * | 2018-06-04 | 2018-10-19 | 上海兆维科技发展有限公司 | A kind of preparation method of cordycepin |
| WO2019113462A1 (en) * | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
| US20210047280A1 (en) * | 2017-12-15 | 2021-02-18 | Kumiai Chemical Industry Co., Ltd. | Novel method for producing 5, 5-disubstituted-4, 5-dihydroisoxazole |
| US20210317457A1 (en) * | 2020-04-10 | 2021-10-14 | Aligos Therapeutics, Inc. | Antisense oligonucleotide (aso) molecules and uses thereof for coronavirus diseases |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
-
2022
- 2022-03-11 CN CN202210238256.0A patent/CN114560894B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397316A (en) * | 2008-10-23 | 2009-04-01 | 浙江工业大学 | Chemical synthesis method of ribavirin condensation compound |
| WO2019113462A1 (en) * | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
| US20210047280A1 (en) * | 2017-12-15 | 2021-02-18 | Kumiai Chemical Industry Co., Ltd. | Novel method for producing 5, 5-disubstituted-4, 5-dihydroisoxazole |
| CN108676048A (en) * | 2018-06-04 | 2018-10-19 | 上海兆维科技发展有限公司 | A kind of preparation method of cordycepin |
| US20210317457A1 (en) * | 2020-04-10 | 2021-10-14 | Aligos Therapeutics, Inc. | Antisense oligonucleotide (aso) molecules and uses thereof for coronavirus diseases |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
Non-Patent Citations (2)
| Title |
|---|
| 段传奇 等: "口服小分子抗新冠药物莫努匹韦和帕罗韦德合成路线综述", 《中国医药工业杂志》 * |
| 段传奇 等: "口服小分子抗新冠药物莫努匹韦和帕罗韦德合成路线综述", 《中国医药工业杂志》, vol. 52, no. 12, 31 December 2021 (2021-12-31), pages 1554 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114560894B (en) | 2023-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111116656A (en) | Preparation method of Reidesciclovir | |
| CN111440176A (en) | Metal complex promoted synthesis method of Reidesciclovir intermediate | |
| CN102584795A (en) | Preparing method of crizotinib | |
| US8193354B2 (en) | Process for preparation of Gemcitabine hydrochloride | |
| CN114292303A (en) | Preparation method of antiviral drug mupirovir | |
| Sugiyama et al. | Chemistry of neocarzinostatin-mediated cleavage of oligonucleotides. Competitive ribose C5'and C4'hydroxylation | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| González et al. | A facile chemoselective deacetylation in the presence of benzoyl and p-bromobenzoyl groups using p-toluenesulfonic acid | |
| CN114560894A (en) | Preparation method of anti-neocoronal medicine Molnbupiravir | |
| CN114437043B (en) | Preparation method of anti-new crown drug Nirmatrelvir | |
| CN101274950A (en) | Production process for preparing 1-oxy-acetyl-2,3,5-3-benzoyl-beta-Lribofuranose | |
| JPH0267295A (en) | Purine derivative | |
| CN115322120B (en) | Small molecule compound and application thereof in preparation of medicine for treating DHODH-mediated diseases | |
| CN113248465B (en) | Synthetic method of biochanin A | |
| CN112279785B (en) | 3, 3-difluorocyclobutylamine hydrochloride intermediate and synthetic method thereof, and 3, 3-difluorocyclobutylamine hydrochloride synthetic method | |
| CN102766182B (en) | Method for synthesizing dideoxynucleoside through glycosyl transfer reaction and application thereof | |
| CN112979695B (en) | Method for preparing 1, 2-di-fatty acyl-sn-glycerol-3-phosphatidylserine | |
| CN114907228B (en) | Colchicine and magnolol compound, synthesis method thereof and application thereof in resisting new coronaviruses | |
| CN107602602A (en) | A kind of synthetic method of the pinacol borate of 3 cyanopyridine 5 | |
| CN107304171A (en) | A kind of synthetic method of Oseltamivir | |
| CN103788011B (en) | A kind of febuxostat intermediate and preparation method thereof | |
| CN113292412A (en) | Synthetic method of 3, 4-difluoro-2-methylbenzoic acid and intermediate thereof | |
| CN116891450A (en) | Synthesis method of Iguratimod | |
| CN103788012B (en) | A kind of method of preparing Febuxostat | |
| Li et al. | Directed copper-catalyzed dehydrogenative C–H amination of unsaturated sialic acids |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |