CN114437050A - Deprotection agent for halofuginone intermediate and application thereof - Google Patents
Deprotection agent for halofuginone intermediate and application thereof Download PDFInfo
- Publication number
- CN114437050A CN114437050A CN202111629546.XA CN202111629546A CN114437050A CN 114437050 A CN114437050 A CN 114437050A CN 202111629546 A CN202111629546 A CN 202111629546A CN 114437050 A CN114437050 A CN 114437050A
- Authority
- CN
- China
- Prior art keywords
- halofuginone
- deprotection
- agent
- mixed solvent
- metal reducing
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
Abstract
The invention provides a deprotection agent for a halofuginone intermediate and application thereof. The deprotection agent comprises a metal reducing agent and a mixed solvent, wherein the metal reducing agent comprises zinc powder and iron powder, and the mixed solvent comprises methanol, glacial acetic acid and water. The method for deprotecting the halofuginone intermediate comprises the following steps: 1) dissolving the halofuginone intermediate in a mixed solvent; 2) adding a metal reducing agent, and carrying out reflux reaction. The deprotection agent can be selectively and efficiently removed under highly specific conditions, does not affect the rest parts of molecules, and has high product purity, high yield and high efficiency.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a deprotection agent for a halofuginone intermediate and application thereof.
Background
Halofuginone (Hal), the chemical name of which is 7-bromo-6-chloro-3- [3- (3-hydroxy-2-piperidyl) -2-oxopropyl (acetonyl) ] -4(3H) -quinazolinone hydrobromic acid, is a quinazolinone alkaloid which is a derivative of dichroine extracted from dichroa febrifuga. The chemical structure is shown as formula III:
at present, the commercial halofuginone is mainly represented by a halofuginone hydrobromide formula, the halofuginone hydrobromide is white or grey white crystalline powder, is odorless, tasteless and good in stability, is mainly used for preventing and treating coccidiosis and malaria of domesticated animals such as poultry and livestock at present, 3ppm concentration in feed can effectively control 6 species eimeria coccidia, clinical symptoms of coccidiosis can be obviously controlled after the feed is used, oocyst elimination is completely inhibited, so that the environment is not polluted any more, the possibility of reinfection is reduced, and the advantages of broad spectrum, high efficiency, irreversibly, no relapse after drug withdrawal, no cross drug resistance, low toxicity, safety and the like are achieved. Recently, halofuginone is found to be used for preventing hepatic fibrosis, pulmonary fibrosis, scleroderma and other diseases and malignant tumors such as bladder cancer, prostatic cancer, skin cancer, breast cancer, lung cancer and the like, and has wide market prospect.
Due to the complex synthesis process of halofuginone, the industrial production of halofuginone cannot be realized in China, and the halofuginone is totally imported, so that the price is up to 13000 yuan/kg at present, and the wide application of halofuginone in China is limited. At present, the method for synthesizing halofuginone is to synthesize two intermediates, wherein one intermediate is the synthesis of a quinazolinone ring part, namely the synthesis of 7-bromo-6-chloro-4 (3H) -quinazolinone, and the other is the synthesis of a piperidine ring part, then the two intermediates are butted and then subjected to N-removal protection after being butted, so that the final product halofuginone is obtained. Among the commonly used N protecting groups are the 2,2,2-trichloroethoxycarbonyl protecting group (2,2,2-trichloroethoxycarbonyl, Troc), which protects the amino group by forming a carbamate. Generally, the conditions for removing N protection are carried out under the reduction condition of zinc-acetic acid, and the reaction equation is as follows:
wherein the mechanism of Troc deprotection is as follows: the zinc metal transfers an electron to the carbon atom of trichloromethyl troc to promote the leaving of a chloride ion, the formed dichloromethyl free radical continues to receive an electron transferred by the zinc metal to form unstable carbanion, the carbanion immediately undergoes beta elimination to form 1, 1-dichloroethylene gas, and the reaction moves to the right due to obvious entropy increase, so that troc is completely decomposed, and the reaction equation is as follows:
for example, in patent CN101987843A, when the de-N protection reaction is performed, the de-protection reaction is performed using zinc powder and acetic acid as reactants, and the solvent used is a mixed solvent of an inert solvent such as tetrahydrofuran, methanol, ethanol, and acetic acid and distilled water, but this reaction has the following disadvantages:
1) in the deprotection process, bromine in the chlorine bromine quinazolinone is easily removed by a deprotection agent to generate larger impurities (the structure is shown as formula IV) which reach more than 20%, so that the side reactions are more, the product is impure and is difficult to purify;
2) the subsequent conversion into halofuginone will not occur with the progress of the reaction, thus greatly affecting the yield of the deprotection reaction, resulting in low yield and increased production cost.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a deprotection agent for a halofuginone intermediate and application thereof, and solves the problems of more side reactions, impure products and low yield in the prior art.
In one aspect of the invention, the deprotection agent for the halofuginone intermediate comprises a metal reducing agent and a mixed solvent, wherein the metal reducing agent comprises zinc powder and iron powder, and the mixed solvent comprises methanol, glacial acetic acid and water.
Preferably, the mass ratio of the zinc powder to the iron powder is 5:1-1: 5.
Preferably, the volume ratio of the methanol to the glacial acetic acid to the water is 5-10:0.2-0.5: 3-5.
Preferably, the metal reducing agent and the mixed solvent are used in a ratio of 1:50-100 in g/mL.
Preferably, the structural formula of the halofuginone intermediate is shown as formula I:
in another aspect of the present invention, a method for deprotecting a halofuginone intermediate is provided, which comprises the following steps:
1) dissolving the halofuginone intermediate in a mixed solvent;
2) adding a metal reducing agent, and carrying out reflux reaction to obtain a product, wherein the structural formula of the product is shown as a formula II:
preferably, the mass ratio of the metal reducing agent to the halofuginone intermediate is 1: 2-5.
Preferably, the reflux reaction time is 3-5h, the temperature is 70-75 ℃, and the pH value is 2-3.
Preferably, further comprising step 3): and (4) carrying out extraction and purification on the product.
In another aspect of the invention, the application of a deprotection agent for a halofuginone intermediate in the preparation of halofuginone is provided.
The technical principle of the invention is as follows: the metal reductant donates electrons during the reduction process, combining with protons provided by the proton donating agent, thereby forming a reduction product. In the previous experiments, the inventor tries a plurality of metal reducing agents to carry out deprotection reaction, and unexpectedly finds that the zinc and iron mixture can carry out directional deprotection on the N protecting group in the halofuginone intermediate and does not affect other groups which are easy to reduce, such as bromine, chlorine and the like; the side reaction is less, the product purity is high, the crude product purity reaches more than 97 percent, and the step of refining the product is omitted; the yield is high and exceeds 80 percent; the efficiency is high.
Compared with the prior art, the invention has the following beneficial effects:
1) can selectively and efficiently remove N protective groups under highly specific conditions, does not affect the rest parts of molecules, and has high product purity, and the purity of crude products reaches more than 97 percent.
2) The yield is high and exceeds 80 percent.
3) Short reaction time, mild reaction condition, high efficiency and high yield in a short time.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
EXAMPLE 1 deprotection of halofuginone intermediates
Sequentially adding 2.65g of halofuginone intermediate (represented by SD-5 and represented by a structural formula I) into a clean 100ml three-necked bottle at the temperature T of 30 ℃, 35ml of methanol, 17.5ml of purified water, 1.75ml of glacial acetic acid and 0.8g of zinc/iron powder (the mass ratio is 1:1), adjusting the pH value to 2.0, heating to 70 ℃, carrying out reflux reaction for 5 hours, and stopping the reaction. Suction filtration, filtrate concentration, concentrate transfer to separating funnel, add 20ml chloroform, take the aqueous layer, chloroform layer with 1M hydrochloric acid (10 ml-20 ml) × 3 extraction, combine aqueous layer, adjust pH with 3M NaOH to 8, the system precipitates the white solid, suction filtration, take the filter cake, add 30ml chloroform under the ultrasonic beating, filter, concentrate under reduced pressure to get the oily substance, then add 5ml ethyl acetate and precipitate the crystal, suction filtration, oven dry, get 1.71g of product, HPLC purity 97.8%, yield 92.1%.
EXAMPLE 2 deprotection of halofuginone intermediates
Sequentially adding SD-55 g, methanol 30.49ml, purified water 18.30ml, glacial acetic acid 1.21ml and zinc/iron powder (5:1)1.0g into a clean 100ml three-neck flask at the temperature of T of 30 ℃, adjusting the pH value to 2.5, heating to 75 ℃, carrying out reflux reaction for 3h, continuously stirring for 45min, and stopping the reaction. Suction filtration, filtrate concentration, concentrate transfer to separating funnel, add 20ml chloroform, take the aqueous layer, chloroform layer with 1M hydrochloric acid (10 ml-20 ml) × 3 extraction, combine aqueous layer, adjust pH with 3M NaOH to 8, the system separates out the white solid, suction filtration, take the filter cake, add 30ml chloroform under the ultrasonic beating, filter, concentrate under reduced pressure to get the oily substance, then add 5ml ethyl acetate and precipitate the crystal, suction filtration, oven dry, get 1.60g of product, HPLC purity 97.5%, yield 86.2%.
EXAMPLE 3 deprotection of halofuginone intermediates
Sequentially adding SD-52 g, methanol 64ml, purified water 32ml, glacial acetic acid 4ml and zinc/iron powder (1:5)1.0g into a clean 100ml three-neck flask at the temperature of T of 25 ℃, adjusting the pH value to 3.0, heating to 72 ℃, carrying out reflux reaction for 4h, continuously stirring for 45min, and stopping the reaction. Suction filtration, filtrate concentration, concentrate transfer to separating funnel, add 20ml chloroform, take the aqueous layer, chloroform layer with 1M hydrochloric acid (10 ml-20 ml) × 3 extraction, combine aqueous layer, adjust pH with 3M NaOH to 8, the system precipitates the white solid, suction filtration, take the filter cake, add 30ml chloroform under the ultrasonic beating, filter, concentrate under reduced pressure to get the oily substance, then add 5ml ethyl acetate and precipitate the crystal, suction filtration, oven dry, get 1.66g of product, HPLC purity 97.1%, yield 89.4%.
Comparative example 1
In a clean 100ml three-mouth bottle, SD-52.65 g, methanol 35ml, purified water 17.5ml, acetic acid 1.75ml and iron powder 0.8g are added in sequence at the temperature of T being 30 ℃, the pH value is adjusted to 2.0, the temperature is raised to 70 ℃, reflux reaction is carried out for 5 hours, and the reaction is not carried out.
Comparative example 2
In a clean 100ml three-mouth bottle, SD-52.65 g, methanol 35ml, purified water 17.5ml, acetic acid 1.75ml and zinc 0.8g are added in sequence at the temperature of T being 30 ℃, the pH value is adjusted to 2.0, the temperature is raised to 70 ℃, reflux reaction is carried out for 5h, and the reaction is stopped. Suction filtration, filtrate concentration, concentrate transfer to separating funnel, add 20ml chloroform, take the aqueous layer, chloroform layer with 1M hydrochloric acid (10 ml-20 ml) × 3 extraction, combine aqueous layer, adjust pH with 3M NaOH to 8, the system separates out the white solid, suction filtration, take the filter cake, add 30ml chloroform under the ultrasonic beating, filter, concentrate under reduced pressure to get the oily substance, then add 5ml ethyl acetate and precipitate the crystal, suction filtration, oven dry, get 1.61g of product, HPLC purity 15.2%.
From the above results, it can be seen that: the effect of adding the iron powder alone is obviously inferior to that of the example 1-3, but the deprotection reaction does not occur, so that the iron powder and the zinc powder which are used as metal reducing agents have mutual synergistic action, the N removal protection reaction of the halofuginone intermediate is promoted together, and the yield and the purity of the product are improved.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. A deprotection agent for a halofuginone intermediate, characterized by: the zinc-iron-based zinc oxide powder is characterized by comprising a metal reducing agent and a mixed solvent, wherein the metal reducing agent comprises zinc powder and iron powder, and the mixed solvent comprises methanol, glacial acetic acid and water.
2. A deprotecting agent for halofuginone intermediates according to claim 1, wherein: the mass ratio of the zinc powder to the iron powder is 5:1-1: 5.
3. A deprotecting agent for halofuginone intermediates according to claim 1, wherein: the volume ratio of the methanol to the glacial acetic acid to the water is 5-10:0.2-0.5: 3-5.
4. A deprotecting agent for halofuginone intermediates according to claim 1, wherein: and the dosage ratio of the metal reducing agent to the mixed solvent is 1:50-100 in g/mL.
5. A deprotecting agent for halofuginone intermediates according to claim 1, wherein: the structural formula of the halofuginone intermediate is shown as a formula I:
6. a method for deprotecting a halofuginone intermediate, comprising the steps of:
1) dissolving the halofuginone intermediate in a mixed solvent;
2) adding a metal reducing agent, and carrying out reflux reaction to obtain a product, wherein the structural formula of the product is shown as a formula II:
7. the method of deprotection of a halofuginone intermediate according to claim 6, wherein: the mass ratio of the metal reducing agent to the halofuginone intermediate is 1: 2-5.
8. The method of deprotection of a halofuginone intermediate according to claim 6, wherein: the reflux reaction time is 3-5h, the temperature is 70-75 ℃, and the pH value is 2-3.
9. The method of deprotection of a halofuginone intermediate according to claim 6, wherein: further comprising step 3): and (4) carrying out extraction and purification on the product.
10. An application of deprotection agent for halofuginone intermediate in preparing halofuginone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111629546.XA CN114437050B (en) | 2021-12-28 | 2021-12-28 | Deprotection agent for halofuginone intermediate and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111629546.XA CN114437050B (en) | 2021-12-28 | 2021-12-28 | Deprotection agent for halofuginone intermediate and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114437050A true CN114437050A (en) | 2022-05-06 |
| CN114437050B CN114437050B (en) | 2023-05-23 |
Family
ID=81365397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111629546.XA Active CN114437050B (en) | 2021-12-28 | 2021-12-28 | Deprotection agent for halofuginone intermediate and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114437050B (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024134A (en) * | 1971-01-29 | 1977-05-17 | Glaxo Laboratories Limited | Syn isomers of cephalosporins having α-hydroximino- or α-acyloxyiminoacylamido groups at position-7 |
| US5798311A (en) * | 1990-07-13 | 1998-08-25 | Rohm And Haas Company | N-aryl-3-aryl-4-substituted-4,5-dihydro-1H-pyrazole-1-carboxamides and methods of their production |
| CN1249307A (en) * | 1999-08-19 | 2000-04-05 | 北京工业大学 | Metallic phthalocyanine carboxylic acid derivatives and its preparing process and application |
| JP2002241393A (en) * | 2000-08-10 | 2002-08-28 | Sankyo Co Ltd | Nucleic acid reagent and medicine which contain nucleoside and oligonucleotide analogue |
| CN101987843A (en) * | 2010-08-20 | 2011-03-23 | 南开大学 | Method for synthesizing halofuginone hydrobromide and analogues thereof |
| CN102351790A (en) * | 2011-09-15 | 2012-02-15 | 南昌大学 | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone |
| WO2012145932A1 (en) * | 2011-04-29 | 2012-11-01 | Pharmaresources (Shanghai) Co., Ltd. | A novel process for the preparation of peramivir and intermediates thereof |
| CN103275063A (en) * | 2013-06-19 | 2013-09-04 | 重庆威鹏药业有限公司 | Method for preparing halofuginone hydrobromide |
| CN103772295A (en) * | 2014-01-26 | 2014-05-07 | 苏州立新制药有限公司 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine |
| AU2017315140A1 (en) * | 2016-08-24 | 2019-03-14 | Tfchem | Difluorinated compounds as depigmenting or lightening agents |
-
2021
- 2021-12-28 CN CN202111629546.XA patent/CN114437050B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024134A (en) * | 1971-01-29 | 1977-05-17 | Glaxo Laboratories Limited | Syn isomers of cephalosporins having α-hydroximino- or α-acyloxyiminoacylamido groups at position-7 |
| US5798311A (en) * | 1990-07-13 | 1998-08-25 | Rohm And Haas Company | N-aryl-3-aryl-4-substituted-4,5-dihydro-1H-pyrazole-1-carboxamides and methods of their production |
| CN1249307A (en) * | 1999-08-19 | 2000-04-05 | 北京工业大学 | Metallic phthalocyanine carboxylic acid derivatives and its preparing process and application |
| JP2002241393A (en) * | 2000-08-10 | 2002-08-28 | Sankyo Co Ltd | Nucleic acid reagent and medicine which contain nucleoside and oligonucleotide analogue |
| CN101987843A (en) * | 2010-08-20 | 2011-03-23 | 南开大学 | Method for synthesizing halofuginone hydrobromide and analogues thereof |
| WO2012145932A1 (en) * | 2011-04-29 | 2012-11-01 | Pharmaresources (Shanghai) Co., Ltd. | A novel process for the preparation of peramivir and intermediates thereof |
| CN102351790A (en) * | 2011-09-15 | 2012-02-15 | 南昌大学 | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone |
| CN103275063A (en) * | 2013-06-19 | 2013-09-04 | 重庆威鹏药业有限公司 | Method for preparing halofuginone hydrobromide |
| CN103772295A (en) * | 2014-01-26 | 2014-05-07 | 苏州立新制药有限公司 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(mercaptopropionic)-5-aminopyrimidine |
| AU2017315140A1 (en) * | 2016-08-24 | 2019-03-14 | Tfchem | Difluorinated compounds as depigmenting or lightening agents |
Non-Patent Citations (5)
| Title |
|---|
| KEITH C. COFFMAN，等: "Heterocycle-to-Heterocycle Route to Quinoline-4-amines:Reductive Heterocyclization of 3-(2-Nitrophenyl)isoxazoles", EUROPEAN J ORG CHEM. * |
| 任彦荣，等: "原位制备 SrSb2O6/ g-C3N4新型二维异质结用于可见光催化降解四环素的研究", 化学通报 * |
| 王爱华: "多西他赛原料药的开发研究", 中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑 * |
| 董浩，等: "酰胺类化合物合成的最新研究进展", 有机化学 * |
| 韩亮: "2-氨基-2-脱氧糖糖苷合成概述", 湘潭师范学院学报(自然科学版) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114437050B (en) | 2023-05-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210147335A1 (en) | Fenfluramine compositions and methods of preparing the same | |
| CN109970663B (en) | Method for preparing oxa-goril intermediate | |
| JP2011521001A (en) | Preparation method of ezetimibe and composition containing the same | |
| CN111278830A (en) | Preparation method of PARP inhibitor and intermediate thereof | |
| CN114437050A (en) | Deprotection agent for halofuginone intermediate and application thereof | |
| CN114315755B (en) | Synthesis method of key intermediate of Tubulysin and analogues thereof | |
| WO2007094007A1 (en) | An improved process for the preparation of entacapone | |
| CN112624980B (en) | Preparation method of bendamustine hydrochloride suitable for industrial production | |
| JP6947354B2 (en) | How to make linagliptin | |
| CN112552283A (en) | Preparation method of novel tinib medicine | |
| CN112409272A (en) | Preparation method and application of 6-chloro-7-bromo-4 (3H) -quinazolinone | |
| CN108864096B (en) | Istradefylline bulk drug and preparation method thereof | |
| CN112679363A (en) | Method for preparing pentazocine intermediate | |
| JP4138883B2 (en) | Method for producing acridone derivative and 8-hydroxyimidazoacridinone derivative | |
| CN111548341B (en) | Chemical synthesis method of lenalidomide key intermediate | |
| CN115850240B (en) | Synthesis method of medicine ao Lu Taxi Ni for treating acute myelogenous leukemia | |
| CN115626903B (en) | Preparation method of EED inhibitor intermediate | |
| CN115974856B (en) | Preparation method of drug valmotustat for treating adult T-cell leukemia lymphoma | |
| CN112552299B (en) | Preparation method of linagliptin for treating type II diabetes | |
| CN112521315B (en) | Preparation method of lidocaine degradation impurities | |
| KR20180123851A (en) | Novel crystal form of lenalidomide and preparation of the same | |
| CN116239529A (en) | Preparation method of N-methyltetrahydroquinoline alkaloid with participation of carbon dioxide | |
| CN110615790A (en) | Improved method of preparation process of linagliptin | |
| CN117802179A (en) | Method for preparing zimetapam by chemical-enzymatic method | |
| CN115010610A (en) | Synthesis method of miglitol intermediate N-hydroxyethyl glucosamine |
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 |