CN111320598B - Preparation method of hydroxypyrone compound - Google Patents

Preparation method of hydroxypyrone compound Download PDF

Info

Publication number
CN111320598B
CN111320598B CN201811532241.5A CN201811532241A CN111320598B CN 111320598 B CN111320598 B CN 111320598B CN 201811532241 A CN201811532241 A CN 201811532241A CN 111320598 B CN111320598 B CN 111320598B
Authority
CN
China
Prior art keywords
formula
compound
acid
compound shown
reaction
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.)
Active
Application number
CN201811532241.5A
Other languages
Chinese (zh)
Other versions
CN111320598A (en
Inventor
郭朋滨
寇景平
周自洪
刘玉婷
袁希
王仲清
罗忠华
黄芳芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong HEC Pharmaceutical
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Priority to CN201811532241.5A priority Critical patent/CN111320598B/en
Publication of CN111320598A publication Critical patent/CN111320598A/en
Application granted granted Critical
Publication of CN111320598B publication Critical patent/CN111320598B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
    • 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)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a preparation method of 3-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one, belonging to the field of pharmaceutical chemicals; the method can use the reaction of the compound of the ethyl hydroxy pyran and the ketone with the p-toluenesulfonic acid monohydrate, then the treatment is carried out to obtain the product which is substituted by the alcoholic hydroxyl, and the steps of dehydration, rearrangement and the like are carried out to obtain the final product. The method provided by the invention can effectively prepare the required 3-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one, and provides favorable conditions for further preparing the target compound. The method has the advantages of high product purity, high yield, simple operation and the like.

Description

Preparation method of hydroxypyrone compound
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of a hydroxypyrone compound.
Background
Xofluza (BaloxavirMarvoxil, formerly known as S-033188) is an innovative Cap-dependent endonuclease inhibitor, is a few new drugs which can inhibit the proliferation of influenza virus in the world, is developed by Nippon salt wild-type pharmaceutical Co., Ltd, has been approved for acceleration, and is marketed in Japan. Xofluza can inhibit the CAP structure at the 5' end of host mRNA obtained from host cells aiming at the key link of influenza virus replication, thereby inhibiting the transcription of the self mRNA of the influenza virus. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell. In 2015, baloxavirmrvoxil was identified in japan as a pioneer (Sakigake) drug for preventing influenza a and b.
BaloxavirMarvoxil was first described in PCT patent WO2016175224 and has the following structural formula:
Figure BDA0001905968660000011
WO2017221869 discloses a method for preparing a fused cyclic compound, specifically as follows:
Figure BDA0001905968660000012
compound a is present in this route, as follows:
Figure BDA0001905968660000013
compound a is an essential intermediate for the synthesis of the desired product, but to prepare compound a, compound B is used, the formula is as follows:
Figure BDA0001905968660000021
the methods for synthesizing the compound B are reported less frequently at present, and the common preparation method is as follows:
Figure BDA0001905968660000022
this method has the following drawbacks:
1. the raw material pyromeconic acid is difficult to purify, resulting in poor reaction reproducibility;
2. the raw materials are expensive and are not suitable for industrial production.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a preparation method of the compound B (3-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one), which has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.
According to one aspect of the invention, the present invention proposes a process for the preparation of the intermediate 3-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one for the production of xofluza (baloxavirmarvoxil), by the following route:
Figure BDA0001905968660000023
wherein R is1、R2And R3Each independently is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
above R1、R2And R3Wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2Amino, hydroxyl, mercapto, alkyl, alkylamino, alkoxy;
R4is a protecting group such as benzoyl, phenoxyformyl, benzyloxyformyl, acetyl, pivaloyl, benzyl, alkylsilyl, carbobenzoxy and the like;
x is halogen.
The above method may comprise the steps of:
(1) mixing the compound shown in the formula I and the compound shown in the formula II with p-toluenesulfonic acid monohydrate, stirring, adding water, and stirring; adding saturated NaHCO after finishing3Distilling the aqueous solution, adding dichloromethane, filtering, and concentrating the filtrate to obtain the compound shown in the formula III
Figure BDA0001905968660000031
(2) Mixing the compound shown as the formula III, alkali and an organic solvent, adding an acylation reagent shown as the formula IV, stirring to react, adding ethyl acetate after distillation, and filtering to obtain the compound shown as the formula V
Figure BDA0001905968660000032
(3) Dissolving the compound shown as the formula V and 2-iodoacyl benzoic acid in a reaction solvent, heating for reaction, cooling to room temperature after the reaction is finished, and filtering to obtain the compound shown as the formula VI
Figure BDA0001905968660000041
(4) Mixing the compound shown as the formula VI with an acid solution, and reacting at a certain temperature to obtain the compound shown as the formula B
Figure BDA0001905968660000042
According to some embodiments of the present invention, the organic solvent in step (2) may be dichloromethane, dichloroethane, acetonitrile, acetone, alcohol, tetrahydrofuran, toluene, dioxane, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, or the like.
According to some embodiments of the present invention, the base in step (2) may be triethylamine, diazabicyclo, sodium hydrogen, potassium carbonate, ammonium carbonate, sodium hydroxide, potassium hydroxide, diisopropylethylamine, or the like.
According to some embodiments of the present invention, the reaction temperature in the step (2) may be-20 to 50 ℃.
According to some embodiments of the present invention, the reaction solvent in step (3) may be water, ethyl acetate, acetonitrile, acetone, alcohol, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, or a mixture thereof.
According to some embodiments of the present invention, the reaction temperature in the step (3) may be 40 to 90 ℃.
According to some embodiments of the invention, the molar ratio of 2-iodoxybenzoic acid to the compound of formula v in step (3) is 1:1 to 1: 10.
According to some embodiments of the present invention, the certain temperature in the step (4) may be 0 to 150 ℃.
According to some embodiments of the present invention, the certain temperature in the step (4) is preferably 40 to 90 ℃.
According to some embodiments of the present invention, the acidic solution in step (4) may be an inorganic acidic aqueous solution or an organic acidic aqueous solution, or a mixture thereof, and the like, such as an aqueous hydrochloric acid solution, an aqueous hydrobromic acid solution, an aqueous trifluoroacetic acid solution, an aqueous sulfuric acid solution, an aqueous acetic acid solution, an aqueous formic acid solution, and an aqueous oxalic acid solution.
Definition of terms
In this specification, "g" means g.
In the present specification, "room temperature" means 10 ℃ to 35 ℃.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The conditions for measuring Mass Spectrometry (MS) data were: electrospray ionization (ESI).
Measurement conditions of H spectrum: 400MHz, deuterated DMSO.
Typical synthetic procedures for preparing dialkylamine compounds according to embodiments of the present invention are shown in the following synthetic schemes:
Figure BDA0001905968660000051
EXAMPLE 1 preparation of the Compound of formula III
Compound I (5g), dimethoxypropane (50ml) and p-toluenesulfonic acid monohydrate (1g) were charged into a reaction flask at room temperature, stirred until the reaction system became clear, and water (100ml) was added for hydrolysis. After completion, saturated aqueous NaHCO3 was added and the pH was adjusted to 8. The solvent was distilled, methylene chloride (160ml) was added thereto, and the filtrate was concentrated to give 4.5g of a compound of the formula III as a solid in a yield of 75%.
EXAMPLE 2 preparation of the Compound of formula V
A reaction flask was charged with the compound of formula III (12.55g), methylene chloride (40ml) and triethylamine (7.05g) at room temperature, and benzoyl chloride (7.91g) was added thereto under stirring to complete the reaction, followed by stirring. After the reaction, water (50ml) was added, and the solution was separated to obtain an organic phase, the solution was evaporated to dryness, and the residue was added with 20ml of ethyl acetate, stirred, filtered and dried to obtain 12.02g of the compound of formula V, with a purity of 97.91% and a yield of 80.0%.
EXAMPLE 3 preparation of Compound of formula VI
A reaction flask was charged with the compound of formula V (12.0g), ethyl acetate (108ml) and 2-iodoxybenzoic acid (19.86g) at room temperature, and stirred at 78 ℃. After completion, the reaction mixture was cooled to room temperature and filtered to give 11.0g of the compound of formula VI in 92.3% yield.
MS:[M+H]+＝337.35；
1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.4Hz,2H),7.56(t,J＝7.4Hz,1H),7.43(t,J＝7.7Hz,2H),4.94(s,1H),4.77–4.62(m,2H),4.55–4.50(m,1H),4.49–4.45(m,2H),3.48(s,3H),1.49(s,3H),1.38(s,3H)。
EXAMPLE 4 preparation of Compound of formula VI
A reaction flask was charged with a compound of formula V (12.0g), acetonitrile (108ml) and 2-iodoxybenzoic acid (19.86g) at room temperature, and stirred at an elevated temperature of 78 ℃. After completion, the reaction mixture was cooled to room temperature and filtered to give 9.67g of the compound of formula VI in 81.2% yield.
EXAMPLE 5 preparation of the Compound of formula B
Adding a compound of formula VI (2.19g) and 25% hydrochloric acid aqueous solution (8.8ml) into a reaction bottle at room temperature, heating to 90 ℃, stirring for reaction, cooling to room temperature, filtering, and desolventizing an aqueous phase to obtain 1.15g of a compound of formula B with the yield of 94.1%.
MS:[M+H]+＝143.00；
1H NMR(400MHz,CDCl3)δ7.89(d,J＝5.5Hz,1H),6.60(d,J＝5.5Hz,1H),4.78(s,2H)。
EXAMPLE 6 preparation of the Compound of formula B
Adding a compound of formula VI (2.19g) and 25% acetic acid aqueous solution (8.8ml) into a reaction bottle at room temperature, heating to 90 ℃, stirring for reaction, cooling to room temperature, filtering, and desolventizing an aqueous phase to obtain 1.06g of a compound of formula B with the yield of 87.3%.
EXAMPLE 7 preparation of the Compound of formula B
At room temperature, a compound of formula VI (2.19g) and 25% trifluoroacetic acid aqueous solution (8.8ml) were added into a reaction flask, the mixture was heated to 90 ℃ and stirred for reaction, after completion of cooling to room temperature, the mixture was filtered, and the aqueous phase was exsolved to obtain 1.08g of the compound of formula B with a yield of 88.5%.
EXAMPLE 8 preparation of the Compound of formula B
Adding a compound of the formula VI (2.19g) and 25% hydrochloric acid aqueous solution (8.8ml) into a reaction bottle at room temperature, heating to 80 ℃, stirring for reaction, cooling to room temperature, filtering, and desolventizing an aqueous phase to obtain 1.01g of a compound of the formula B, wherein the yield is 82.6%.
In the description herein, references to the description of the term "one embodiment," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (8)

1. A preparation method of a compound 3-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one shown in a formula B is characterized by comprising the following steps:
Figure FDA0003470705570000011
(1) mixing the compound shown in the formula I and the compound shown in the formula II with p-toluenesulfonic acid monohydrate, stirring, adding water, and stirring; saturated NaHCO was added at the end3Distilling the aqueous solution, adding dichloromethane, filtering, and concentrating the filtrate to obtain the compound shown in the formula III
Figure FDA0003470705570000012
(2) Mixing the compound shown as the formula III, alkali and an organic solvent, adding an acylation reagent shown as the formula IV, stirring to react, adding ethyl acetate after distillation, and filtering to obtain the compound shown as the formula V
XR4
In the formula IV, the compound is shown in the specification,
Figure FDA0003470705570000021
(3) dissolving the compound shown as the formula V and 2-iodoacyl benzoic acid in a reaction solvent, heating for reaction, cooling to room temperature after the reaction is finished, and filtering to obtain the compound shown as the formula VI
Figure FDA0003470705570000022
(4) Mixing the compound shown as the formula VI with an acid solution, and reacting at a certain temperature to obtain the compound shown as the formula B
Figure FDA0003470705570000023
Wherein the content of the first and second substances,
R1、R2and R3Each independently is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
above R1、R2And R3Wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2Amino, hydroxyl, mercapto, alkyl, alkylamino, alkoxy;
R4is benzoyl, phenoxyformyl, benzyloxyformyl, acetyl, pivaloyl, benzyl, alkylsilyl, carbobenzoxy or carbobenzoxy;
x is halogen.
2. The method of claim 1, wherein the reaction temperature in step (2) is-20 to 50 ℃.
3. The method of claim 1, wherein in step (2), the base is triethylamine, diazabicyclo, sodium hydride, potassium carbonate, ammonium carbonate, sodium hydroxide, potassium hydroxide, diisopropylethylamine, or a combination thereof.
4. The method of claim 1, wherein the reaction solvent in step (3) is ethyl acetate, acetonitrile, acetone, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, or a combination thereof.
5. The method according to claim 1, wherein the certain temperature in the step (3) is 40 to 90 ℃.
6. The process of claim 1, wherein the molar ratio of 2-iodoxybenzoic acid to the compound of formula v in step (3) is from 1:1 to 1: 10.
7. The method of claim 1, wherein the temperature in step (4) is 0-150 ℃.
8. The method of claim 1, wherein the acidic solution in step (4) is an aqueous solution of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, acetic acid, formic acid, oxalic acid, or a combination thereof.
CN201811532241.5A 2018-12-14 2018-12-14 Preparation method of hydroxypyrone compound Active CN111320598B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811532241.5A CN111320598B (en) 2018-12-14 2018-12-14 Preparation method of hydroxypyrone compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811532241.5A CN111320598B (en) 2018-12-14 2018-12-14 Preparation method of hydroxypyrone compound

Publications (2)

Publication Number Publication Date
CN111320598A CN111320598A (en) 2020-06-23
CN111320598B true CN111320598B (en) 2022-04-26

Family

ID=71172343

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811532241.5A Active CN111320598B (en) 2018-12-14 2018-12-14 Preparation method of hydroxypyrone compound

Country Status (1)

Country Link
CN (1) CN111320598B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003160577A (en) * 2001-11-26 2003-06-03 Chemiprokasei Kaisha Ltd 3-hydroxy-6-(4-hydroxyphenyloxymethyl)-4h-pyran-4-one and production method thereof
CN101959873A (en) * 2008-02-25 2011-01-26 伊士曼化工公司 5-hydroxy-2-methyl-4H-pyran-4-one-esters as novel tyrosinase inhibitors
CN106083790A (en) * 2016-06-14 2016-11-09 武昌理工学院 A kind of synthetic method of 2 (1 hydroxyl 4 ketone 2,5 cyclohexadiene) pyrans 4 ketone
CN106660981A (en) * 2014-07-29 2017-05-10 广东东阳光药业有限公司 Process for preparing 2, 3-disubstituted-5-oxopyran compound

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2981269T (en) * 2013-04-04 2023-10-10 Boehringer Ingelheim Vetmedica Gmbh Treatment of metabolic disorders in equine animals

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003160577A (en) * 2001-11-26 2003-06-03 Chemiprokasei Kaisha Ltd 3-hydroxy-6-(4-hydroxyphenyloxymethyl)-4h-pyran-4-one and production method thereof
CN101959873A (en) * 2008-02-25 2011-01-26 伊士曼化工公司 5-hydroxy-2-methyl-4H-pyran-4-one-esters as novel tyrosinase inhibitors
CN106660981A (en) * 2014-07-29 2017-05-10 广东东阳光药业有限公司 Process for preparing 2, 3-disubstituted-5-oxopyran compound
CN106083790A (en) * 2016-06-14 2016-11-09 武昌理工学院 A kind of synthetic method of 2 (1 hydroxyl 4 ketone 2,5 cyclohexadiene) pyrans 4 ketone

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A New Synthesis of Maltol;Rajender K. Chawla 等;《J.Org.Chem.》;19741231;第39卷(第22期);第3281页路线1，第3282页左栏倒数第3段 *
Basic 3-hydroxypyridin-4-ones: Potential antimalarial agents;Lotfollah S. Dehkordi 等;《European Journal of Medicinal Chemistry》;20070802;第43卷;第1038页路线4，第1044页右栏第2段 *
MONOMOLAR ACETALATIONS OF METHYL α-D-MANNOSIDES-SYNTHESIS OF METHYL α-D-TALOPYRANOSIDE;MICHAEL E.EVANS;《Carbohydrate Research》;19771231;第54卷;第107页结构式和第3段，第111页第1段、第4-5段 *
Stereoselective Synthesis of 2-C-Acetonyl-2-Deoxy-D-Galactosides using 1,2-Cyclopropaneacetylated Sugar as Novel Glycosyl Donor;Qiang Tian 等;《ORGANIC LETTERS》;20091230;第12卷(第3期);Supporting Information第S6页 *
Synthesis of 2-Methyl-3-hydroxy-4H-pyran-4-one and 4-Hydroxy-5-methyl-2H-furan-3-one from Carbohydrates;Tatsuya Shono 等;《J.Org.Chem.》;19831231;第48卷(第25期);第5126-5128页 *

Also Published As

Publication number Publication date
CN111320598A (en) 2020-06-23

Similar Documents

Publication Publication Date Title
RU2397980C2 (en) Novel 2h-chromene synthesis methods
KR20150042847A (en) Process for the preparation of pyrazole carboxylic acid derivatives
CN107513031B (en) Preparation method of 2-oxo-1-pyrrolidine chiral derivative
KR102485412B1 (en) Preparation method for benzoxazoleoxazine ketone compound and intermediate and crystal form thereof
EP3530664A1 (en) Diol, process for producing diol, di(meth)acrylate, and process for producing di(meth)acrylate
CA2783587A1 (en) Method for manufacturing neuraminic acid derivatives
WO2006034641A1 (en) The process for producing simvastatin
CN111320598B (en) Preparation method of hydroxypyrone compound
CN109956956B (en) Preparation method of polycyclic pyridone compound
CN113024489A (en) Preparation method of oseltamivir synthesis process impurity
CN111170875B (en) Preparation method of dialkoxyamine compound
CN111662263B (en) Preparation method of pyrone compound
KR20140117481A (en) Industrial process for preparation of 1,2-dihydroquinoline derivative or a salt thereof, and intermediate for preparation thereof
CN108191849B (en) Preparation method of anti-epidermal growth factor receptor drug resistance mutation inhibitor, related intermediate and application
JP5357559B2 (en) Compound having dimethoxynaphthalene skeleton and process for producing the same
WO2018109775A1 (en) Improved process for the preparation of aripiprazole lauroxil
CN102924454A (en) Synthetic method of entecavir
WO2017109524A1 (en) Method and intermediate for the production of baricitinib
US20150322050A1 (en) Efficient Process for the Preparation of Lapatinib and Salts Thereof by Means of New Intermediates
EP2754662B1 (en) Efficient process for the preparation of Lapatinib and salts thereof by means of new intermediates
JPH03220195A (en) Substitution of 3-fluorosulfonyloxyceph-3-em
CN111253405B (en) Preparation method of biapenem intermediate
CN109879832B (en) 4-alkoxy-2-aryl mercaptomorpholine-3, 5-dione compound and preparation method thereof
CN114907301B (en) Ranitivir octanoate intermediate and preparation method thereof
US10889557B1 (en) Method of producing an alkoxyflavone derivative

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
CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.