CN111848505A - Preparation method of vatacostat intermediate - Google Patents
Preparation method of vatacostat intermediate Download PDFInfo
- Publication number
- CN111848505A CN111848505A CN201910341763.5A CN201910341763A CN111848505A CN 111848505 A CN111848505 A CN 111848505A CN 201910341763 A CN201910341763 A CN 201910341763A CN 111848505 A CN111848505 A CN 111848505A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- vad05
- base
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
Abstract
The invention relates to a preparation method of a valdoxat intermediate, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of taking 3-methoxy-5- (3-chlorphenyl) -2-cyanopyridine as a starting material, and obtaining a compound intermediate through hydrolysis reaction and condensation reaction; the intermediate compound can be further reacted to obtain vadadustat (kovatat); the method has the advantages of short route, simple and easily-obtained raw materials, low cost and mild reaction conditions, and is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a valdoxat intermediate.
Background
Vadadustat (valdustat) is an oral Hypoxia Inducible Factor (HIF) stabilizer and is currently used in phase 3 clinical trials to treat anemia associated with chronic kidney disease. The chemical name is N- (5- (3-chlorphenyl) -3-hydroxypyridine-2-carbonyl) glycine, and the chemical structural formula is as follows:
the synthetic route of Vadadustat disclosed in US20070299086, the route is 7 steps in total, and the total yield is 9%.
The route is long and the yield is low. The benzyl substitution reaction in the first step is harsh and cannot be amplified, and in addition, one-step hydrogenation reaction and one-step coupling reaction are also adopted, so that the operation is inconvenient, the cost is high, and the route is not suitable for amplification.
A synthetic route for the preparation of Vadadustat is disclosed in US patent US 20120309977: 3-chlorobenzoic acid and 3, 5-dichloro-2-cyanopyridine are used as initial raw materials, Vadadustat is obtained through catalytic coupling, methoxy substitution, cyano hydrolysis, condensation and ester hydrolysis reaction for 5 steps,
the strong acid reaction and the strong base reaction exist in the route, and the reaction environment has higher requirements on a reaction vessel.
Therefore, research on a preparation method of Vadadustat and an intermediate thereof is still needed to obtain a preparation method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost, environment-friendly and suitable for industrial scale-up production.
Disclosure of Invention
The invention provides a preparation method of a vatacostat intermediate, which has a structure shown in a formula R4-VAD 07:
the preparation method can use 3-methoxy-5- (3-chlorphenyl) -2-cyanopyridine (compound VADB-004) as a starting material, obtain 5- (3-chlorphenyl) -3-methoxy-2-picolinic acid (compound R4-VAD05) through hydrolysis reaction, and obtain N- (5- (3-chlorphenyl) -3-methoxypyridine-2-carbonyl) glycine (compound R4-VAD07) through condensation reaction. Compound R4-VAD07 gave vadadustat (Vanadostat) by further reaction. The specific reaction route is as follows:
In one aspect, the invention provides a preparation method of a valdoxat intermediate compound R4-VAD07,
which comprises reacting compound R4-VAD05 with glycine or a salt thereof in a reaction solvent in the presence of a condensing agent and a base, and subjecting to a post-treatment to obtain compound R4-VAD 07. The method for preparing the intermediate R4-VAD07 does not need nitrogen protection, and has mild reaction conditions and high yield.
In some embodiments, the condensing agent is selected from at least one of CDI, EDCI, DCC, and PyBOP. In some embodiments, the condensing agent is CDI.
In some embodiments, the base is an organic base or an inorganic base.
In some embodiments, the base is selected from DIPEA, TEA, DMAP, DABCO, and NaHCO3At least one of (1). In some embodiments, the base position is DIPEA or TEA.
In some embodiments, the reaction solvent is an organic solvent, and may be selected from at least one of DMSO, DMF, DMAC, DCM, and THF. In some embodiments, the reaction solvent is DMSO.
In some embodiments, the compound R4-VAD05 is in a 1:1.0-1:3.0 molar ratio to condensing agent; or the molar ratio is 1:1.2-1: 2.0.
In some embodiments, the molar ratio of compound R4-VAD05 to base is 1:2.0-1: 6.0; or the molar ratio is 1:2.5-1: 5.5; or the molar ratio is 1:3.0-1: 5.0.
In some embodiments, the molar ratio of compound R4-VAD05 to glycine or salt thereof is 1:1.0-1: 3.0; or the molar ratio is 1:1.2-1: 2.5; or the molar ratio is 1:1.5-1: 2.0.
In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 100 ℃; or the reaction temperature is 10-80 ℃; or the reaction temperature is 20-60 ℃; or the reaction temperature is 30-50 ℃.
In some embodiments, the reaction time of the reaction is from 10min to 10 h; or the reaction time is 20min-8 h; or the reaction time is 30min-5 h; or the reaction time is 1h-3 h.
In some embodiments, the post-processing comprises: stopping reaction, adding hydrochloric acid dropwise while stirring until pH is 1-4, crystallizing, and filtering.
In some embodiments, the post-processing comprises: washing the filter cake with water, and vacuum drying; or adding 10mL-100mL of water into the filter cake, washing, and then drying in vacuum at 60-100 ℃ for 12h-24 h.
In some embodiments, a method of preparing a vatacostat intermediate compound R4-VAD07 comprises: reacting a compound R4-VAD05 with glycine or a salt thereof in a reaction solvent at 0-100 ℃ in the presence of a condensing agent and alkali, after the reaction is finished, dropwise adding hydrochloric acid while stirring to adjust the pH value to 1-4, crystallizing, carrying out suction filtration, washing a filter cake with water, and carrying out vacuum drying to constant weight to obtain a compound R4-VAD 07.
In some embodiments, a method of preparing a vatacostat intermediate compound R4-VAD07 comprises: reacting the compound R4-VAD05 with a condensing agent in a reaction solvent at 0-100 ℃; then reacting with glycine or a salt thereof at 0-100 ℃ in the presence of alkali; after the reaction is finished, hydrochloric acid is added dropwise to adjust the pH value to 1-4 under stirring for crystallization, the mixture is filtered, filter cakes are washed by water and then dried in vacuum to constant weight, and the compound R4-VAD07 is prepared.
In some embodiments, a method of preparing a vatacostat intermediate compound R4-VAD07 comprises: reacting a compound R4-VAD05 with glycine or a salt thereof in DMSO in the presence of CDI and DIPEA at 0-60 ℃, after the reaction is finished, dropwise adding hydrochloric acid while stirring to adjust the pH to 1-3 for crystallization, performing suction filtration, washing a filter cake with water, heating and drying in vacuum to constant weight to obtain a compound R4-VAD 07.
In some embodiments, a method of preparing a vatacostat intermediate compound R4-VAD07 comprises: in DMSO, compound R4-VAD05 was first reacted with CDI at 0 ℃ -60 ℃; then reacting with glycine or a salt thereof at 0-60 ℃ in the presence of DIPEA; after the reaction is finished, hydrochloric acid is added dropwise to adjust the pH value to 1-3 under stirring for crystallization, the mixture is filtered, a filter cake is washed by water, and the mixture is dried under heating and vacuum to constant weight to prepare a compound R4-VAD 07.
In some embodiments, a method of preparing a vatacostat intermediate compound R4-VAD07 comprises: reacting a compound R4-VAD05 with glycine or a salt thereof in DMSO at 0-60 ℃ in the presence of CDI and DIPEA, after the reaction is finished, dropwise adding hydrochloric acid while stirring to adjust the pH to 1-3 for crystallization, performing suction filtration, washing a filter cake with water, heating and drying in vacuum to constant weight to obtain a compound R4-VAD 07; wherein, the molar ratio of the compound R4-VAD05 to the condensing agent is 1:1.0-1:3.0, the molar ratio of the compound R4-VAD05 to the alkali is 1:2.0-1:6.0, and the molar ratio of the compound R4-VAD05 to the glycine or the salt thereof is 1:1.0-1: 3.0.
In some embodiments, the preparation method provided by the invention can further comprise reacting the compound VADB-004 in the presence of alkali, and performing post-treatment to obtain R4-VAD05,
the base is an alkali metal hydroxide.
In some embodiments, the base is sodium hydroxide or potassium hydroxide, or a combination thereof. The feeding molar ratio of the alkali to the compound VADB-004 is 1:1.0-1: 4.0; or the molar ratio is 1:2.0-1: 3.0.
In some embodiments, the aqueous solution of the base has a concentration of 1.0mol/L to 2.0 mol/L.
In some embodiments, the post-processing comprises: Stopping reaction, cooling to room temperature, regulating pH to 1-4 with concentrated hydrochloric acid, separating out solid, suction filtering, and adding H to filter cake2O, washing and then drying in vacuum; or the post-processing comprises: stopping reaction, cooling to room temperature, adjusting pH to 1-4 with concentrated hydrochloric acid, precipitating solid, filtering, adding 100-300 mL H into filter cake2And after O washing, vacuum drying for 12-24 h at 60-100 ℃.
In some embodiments, compound VADB-004 is reacted at 40 ℃ to 100 ℃ in the presence of aqueous sodium hydroxide, after completion of the reaction, the reaction is stopped, cooled to room temperature, adjusted to pH 1-3 with hydrochloric acid, the solid is precipitated, filtered, the filter cake is washed with water and dried under vacuum to give R4-VAD 05.
In another aspect of the present invention, there is provided a compound having the structure shown in R4-VAD 05:
the compound R4-VAD07 can be prepared quickly and conveniently by R4-VAD05, and is favorable for improving the yield.
The preparation method of the valdoxat intermediate provided by the invention can obtain an intermediate compound R4-VAD07 to achieve the purpose of the invention, and has the advantages of short reaction route, high yield, simple and easily obtained raw materials, lower cost, controllable reaction condition and temperature, and suitability for industrial scale-up production.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "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.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol; min represents minutes; h represents an hour; g represents g; ml means ml; DMF for N, N-dimethylformamide, THF for tetrahydrofuran; CDI represents N, N' -carbonyldiimidazole; EDCI represents 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DCC denotes dicyclohexylcarbodiimide; PyBOP represents benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; DIPEA represents N, N-diisopropylethylamine; TEA represents triethylamine; DMAP represents 4-dimethylaminopyridine; DABCO represents triethylenediamine; DMSO represents dimethyl sulfoxide; DMAC denotes N, N-dimethylacetamide.
EXAMPLE 1 preparation of the Compound 5- (3-chlorophenyl) -3-methoxy-2-pyridinecarboxylic acid (R4-VAD05)
80.0g of VADB-004, 47.9g of sodium hydroxide and 800mL of water are added into a reaction bottle at room temperature,heating to 100 ℃, stirring for reaction for 4H, sampling, detecting HPLC results to show that the raw materials completely react, stopping the reaction, cooling to room temperature, adjusting pH to about 2 with concentrated hydrochloric acid, separating out solids, performing suction filtration, and adding 160mL of H into filter cakes2O washing, vacuum drying at 80 deg.C for 12h to obtain off-white solid 82.2g, yield 95.3%, purity 97%. MS: [ M +1 ] ]Nuclear magnetic 1H NMR (400MHz, DMSO)8.49(s,1H),7.94(s,1H),7.86(s,1H),7.80(s,1H),7.54(s,2H),3.97(s,3H) 264.0.
EXAMPLE 2 preparation of the Compound N- (5- (3-chlorophenyl) -3-methoxypyridine-2-carbonyl) glycine (R4-VAD07)
Adding 25g R4-VAD05, 30.7g CDI and 150mL DMSO into a reaction bottle at room temperature, stirring and reacting for 1h after finishing heating up to 45 ℃, then cooling to 30 ℃, adding 21.4g glycine and 58.2g DIPEA, reacting for 3h after finishing adding 30 ℃, sampling and detecting HPLC results show that the raw materials completely react, stopping the reaction, dropwise adding concentrated hydrochloric acid while stirring to adjust the pH to about 2 for crystallization, performing suction filtration, washing a filter cake with 50mL of water, and performing vacuum drying at 80 ℃ for 12h to obtain 27.5g of an off-white solid product, wherein the yield is 90.6 percent, and the purity is 98 percent]321.1 nuclear magnetism1H NMR(400MHz,DMSO)8.51(s,1H),8.24(s,1H),7.92(s,1H),7.86(s,1H),7.79(d,J＝7.2Hz,1H),7.60–7.47(m,2H),3.97(s,3H),3.59(s,2H).
EXAMPLE 3 preparation of the Compound N- (5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl) glycine (Vadadustat)
Adding 20g R4-VAD07, 50.6g of concentrated hydrochloric acid and 105.0g of acetic acid mixed acid into a reaction bottle at room temperature, heating to 100 ℃ for reaction, sampling for 24 hours, detecting HPLC results to show that raw materials are completely reacted, stopping the reaction, cooling the reaction liquid to 0-5 ℃, dropwise adding 50% sodium hydroxide solution to adjust the pH to 2, keeping the temperature at 0-5 ℃ for crystallization for 3 hours, carrying out suction filtration, recrystallizing the filter cake by using ethyl acetate and n-hexane mixed solvent to obtain a white-like solid, and carrying out vacuum drying at 60 ℃ for 12 hours to obtain 18g of finished product Vadadustat, the yield of which is 94.1%, and pure Vadadustat The degree is 98%. MS: [ M +1]307.0 nuclear magnetism1H NMR(400MHz,DMSO)12.37(s,1H),9.35(t,J＝5.6Hz,1H),8.82–8.39(m,1H),7.93(d,J＝24.3Hz,1H),7.85–7.68(m,2H),7.65–7.44(m,2H),4.12–3.95(m,2H).
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A process for the preparation of compound R4-VAD07,
which comprises reacting compound R4-VAD05 with glycine or a salt thereof in a reaction solvent in the presence of a condensing agent and a base, and carrying out post-treatment to obtain compound R4-VAD 07; wherein the condensing agent is at least one selected from CDI, EDCI, DCC and PyBOP, and the base is DIPEA, TEA, DMAP, DABCO and NaHCO3At least one of (1).
2. The method according to claim 1, wherein the molar ratio of compound R4-VAD05 to condensing agent is 1:1.0-1:3.0, or the molar ratio of compound R4-VAD05 to base is 1:2.0-1:6.0, or the molar ratio of compound R4-VAD05 to glycine or a salt thereof is 1:1.0-1: 3.0.
3. The process of claim 1, wherein the reaction solvent is selected from at least one of DMSO, DMF, DMAC, DCM, and THF.
4. The process of claim 1, wherein the reaction is carried out at a reaction temperature of from 20 ℃ to 60 ℃.
5. The process according to claim 1, wherein the reaction time is from 30min to 5 h.
6. The method of claims 1-5, the post-processing comprising: stopping reaction, dropping concentrated hydrochloric acid while stirring to regulate pH value to 1-4 for crystallization, suction filtering, washing the filter cake with water and vacuum drying.
7. The method of claim 1, further comprising reacting the compound VADB-004 in the presence of a base, and post-treating to obtain R4-VAD05,
the base is an alkali metal hydroxide.
8. The method of claim 7, the post-processing comprising: stopping the reaction, cooling to room temperature, adjusting the pH value to 1-4 with concentrated hydrochloric acid, precipitating a solid, performing suction filtration, washing a filter cake with water, and performing vacuum drying.
9. The method of claim 7, wherein the compound VADB-004 is present in a molar ratio to base of from 1:1.0 to 1: 4.0.
10. A compound having the structure shown in R4-VAD 05:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910341763.5A CN111848505A (en) | 2019-04-26 | 2019-04-26 | Preparation method of vatacostat intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910341763.5A CN111848505A (en) | 2019-04-26 | 2019-04-26 | Preparation method of vatacostat intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111848505A true CN111848505A (en) | 2020-10-30 |
Family
ID=72951553
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910341763.5A Pending CN111848505A (en) | 2019-04-26 | 2019-04-26 | Preparation method of vatacostat intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111848505A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021179540A1 (en) * | 2020-03-11 | 2021-09-16 | 东莞市东阳光仿制药研发有限公司 | Method for preparing vadadustat and intermediate thereof |
| WO2022018450A1 (en) * | 2020-07-23 | 2022-01-27 | Johnson Matthey Public Limited Company | Crystalline forms of vadadustat and methods for their preparation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1655779A (en) * | 2002-03-29 | 2005-08-17 | 希龙公司 | Substituted benzazoles and methods of their use as inhibitors of Raf kinase |
| CN105837502A (en) * | 2016-04-05 | 2016-08-10 | 湖南欧亚生物有限公司 | Synthesis method of Vadadustat |
| CN108473478A (en) * | 2015-06-29 | 2018-08-31 | 默克专利有限公司 | TBK/IKK epsilon inhibitor compounds and application thereof |
-
2019
- 2019-04-26 CN CN201910341763.5A patent/CN111848505A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1655779A (en) * | 2002-03-29 | 2005-08-17 | 希龙公司 | Substituted benzazoles and methods of their use as inhibitors of Raf kinase |
| CN108473478A (en) * | 2015-06-29 | 2018-08-31 | 默克专利有限公司 | TBK/IKK epsilon inhibitor compounds and application thereof |
| CN105837502A (en) * | 2016-04-05 | 2016-08-10 | 湖南欧亚生物有限公司 | Synthesis method of Vadadustat |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021179540A1 (en) * | 2020-03-11 | 2021-09-16 | 东莞市东阳光仿制药研发有限公司 | Method for preparing vadadustat and intermediate thereof |
| WO2022018450A1 (en) * | 2020-07-23 | 2022-01-27 | Johnson Matthey Public Limited Company | Crystalline forms of vadadustat and methods for their preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN111333633B (en) | Intermediate compound of Rayleigh Lu Geli and preparation method and application thereof | |
| ES2208265T3 (en) | TELMISARTAN POLYMORPHES, PROCEDURE FOR PREPARATION AND USE FOR THE PREPARATION OF A MEDICINAL PRODUCT. | |
| CN109320474B (en) | Preparation method of febuxostat | |
| CN111848505A (en) | Preparation method of vatacostat intermediate | |
| CN109180595A (en) | A kind of preparation method of posaconazole intermediate | |
| CN106220648B (en) | A kind of synthesis of tertbutyloxycarbonyl Cefcapene diisopropylamine and purification process | |
| CN113387882A (en) | Preparation method of vatacostat and intermediate thereof | |
| CN103145632A (en) | Preparation method of 1H-1,2,4-triazole-3-methyl formate | |
| CN114736154B (en) | Process for preparing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide | |
| CN113354551A (en) | Preparation method of amide compound | |
| JPS587620B2 (en) | Monomale Imidoid Mataha Polymalein Imidoidino Seizouhouhou | |
| JP6284942B2 (en) | Improved method for preparing 2-amino-5,8-dimethoxy [1,2,4] triazolo [1,5-c] pyrimidine from 4-amino-2,5-dimethoxypyrimidine | |
| CN111574520A (en) | Riagliptin intermediate compound V | |
| CN105017287B (en) | A kind of preparation method of cephamycin intermediate | |
| CN114315800B (en) | Preparation method of topiroxostat | |
| CN114524802B (en) | Synthesis method of quinoline compound | |
| JPH09143169A (en) | Production of 4,6-diamino-1,3,5-triazin-2-yl-benzoic acids | |
| CN108997327A (en) | The preparation method of aztreonam ethyl ester | |
| CN108658896B (en) | Synthesis method of hydrochlorothiazide | |
| CN109153652A (en) | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone | |
| KR20110054670A (en) | A process for preparing 2-cyano-3-hydroxy-n-[(4-trifluoromethyl)phenyl] but-2-enamide | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| CN117486878A (en) | Preparation method of ennafilat | |
| WO2003057681A1 (en) | Process for producing 2-cyanoimino-1,3-thiazolidine |
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 | ||
| CB02 | Change of applicant information |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Applicant after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Applicant before: SUNSHINE LAKE PHARMA Co.,Ltd. |
|
| CB02 | Change of applicant information |