CN108675969A - A kind of preparation method of SC 69124 sodium impurity - Google Patents
A kind of preparation method of SC 69124 sodium impurity Download PDFInfo
- Publication number
- CN108675969A CN108675969A CN201810455612.8A CN201810455612A CN108675969A CN 108675969 A CN108675969 A CN 108675969A CN 201810455612 A CN201810455612 A CN 201810455612A CN 108675969 A CN108675969 A CN 108675969A
- Authority
- CN
- China
- Prior art keywords
- reaction
- added
- separation
- phenyl
- sodium
- 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
- 0 CC(O)=CC(c1cc(S(*)(=*)=O)ccc1)=N Chemical compound CC(O)=CC(c1cc(S(*)(=*)=O)ccc1)=N 0.000 description 2
- LQSDCOXFNFRIBZ-UHFFFAOYSA-N Cc([o]nc1-c2cccc(S(N)(=O)=[U])c2)c1[Br]=C Chemical compound Cc([o]nc1-c2cccc(S(N)(=O)=[U])c2)c1[Br]=C LQSDCOXFNFRIBZ-UHFFFAOYSA-N 0.000 description 1
- UQDSSHAKJADYNV-UHFFFAOYSA-N Cc1cc(-c2cccc(SN)c2)n[o]1 Chemical compound Cc1cc(-c2cccc(SN)c2)n[o]1 UQDSSHAKJADYNV-UHFFFAOYSA-N 0.000 description 1
- UCGIIOJWRLQBRP-UHFFFAOYSA-N Cc1cc(-c2ccccc2)n[o]1 Chemical compound Cc1cc(-c2ccccc2)n[o]1 UCGIIOJWRLQBRP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a kind of preparation methods of 3 [3 isoxazole of (4 phenyl) 5 methyl] benzsulfamide of SC 69124 sodium impurity, the method is with 1 phenyl 1,2 propanedione are raw material, SC 69124 sodium impurity is obtained after cyclisation, sulfonation, ammonolysis, bromo, coupling, gained compound of the invention confirms structure through 1H NMR, 13C NMR, DEPT, gCOSY, HMQC, HMBC collection of illustrative plates, preparation method is novel, obtained compound is detected through HPLC, related material purity >=98%.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -
3- isoxazoles] benzsulfamide preparation method.
Background technology
Parecoxib Sodium is the cox 2 inhibitor of specificity, is mainly used for the treatment of postoperative pain, on Europe
City is mainly used for the short of postoperative pain, can be clinically used for the treatment of moderate or severe postoperative acute pain.
The preparation method of Parecoxib Sodium passes through sulfonation, ammonolysis mainly with 3,4- diphenyl -5- methylisoxazoles for raw material
Reaction synthesis Valdecoxib, then process is propionating, Parecoxib Sodium is made at salt.However, in the process of synthesis Valdecoxib
In, sulfonating reaction may greatly will produce impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide, and very likely
The related impurities similar with Parecoxib Sodium structure are generated with the reaction of subsequent acylating reagent to remain in finished product, and it is auspicious to influence pa
The quality of former times cloth sodium product.Since compound structure is more similar, brought to the Parecoxib Sodium quality control subsequently synthesized
Bigger difficulty.
Currently, the synthetic method in relation to SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide
It has not been reported, document (Synthetic Communications, 42 (5), 639-649;2012) also only in synthesis pa auspicious former times
It discloses this substance during cloth sodium intermediate Valdecoxib as by-product to occur in the reaction, yield only has 10%, hardly possible
It is separated with single.
The SC 69124 sodium impurity of high-purity can be used as the preparation of the impurity reference substance in Parecoxib Sodium finished product detection standard
Reference, can be promoted Parecoxib Sodium finished product detection analysis for impurity positioning analysis and qualitative detection, effectively control pa
The quality of auspicious former times cloth sodium finished product, ensures the safety of drug.The present invention provides a kind of synthesis high-purity SC 69124 sodium impurity 3-
[(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide (CAS:1373038-56-2) novel synthetic method, for effectively controlling
The quality of Parecoxib Sodium product processed has important practical significance.
Invention content
SC 69124 sodium impurity 3- [the different evils of (4- phenyl) -5- methyl -3- are prepared the object of the present invention is to provide a kind of
Azoles] benzsulfamide (CAS:Method 1373038-56-2), the sample that this method is novel, raw material is easy to get, is easy to operate, obtaining are pure
Degree is high, and the impurity of acquisition can be used as the impurity reference substance in Parecoxib Sodium finished product detection standard.
To realize the present invention, following embodiment is provided.
In one embodiment, of the invention a kind of to prepare impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzene sulfonyl
Amine (CAS:Method 1373038-56-2), synthetic route are as follows:
This approach includes the following steps:
A) starting material 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride are added in organic solvent by, add catalyst,
Temperature rising reflux reacts, and after reaction, separation obtains intermediate I;
B) intermediate I is added in organic solvent by, and chlorosulfonic acid is added, and drop finishes, and heat up reaction overnight, by reaction solution plus
Enter in mixture of ice and water and be quenched, separation organic phase obtains the organic solution of intermediate II;
C) dichloromethane solutions into the organic solution of intermediate II are added in reaction bulb, and ammonium hydroxide is added dropwise, reacts at room temperature,
Reaction is finished, isolated intermediate III;
D) mixes intermediate III with n,N-Dimethylformamide, and N-bromosuccinimide is added, after room temperature reaction,
Water is added and reaction is quenched in ethyl acetate, separation obtains intermediate IV;
E) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium, ethyl alcohol, a small amount of water are added to reaction bulb by
In, nitrogen protection, back flow reaction is overnight, and reaction finishes, isolated SC 69124 sodium impurity.
The method of above-mentioned invention, catalyst described in step a) are silico-tungstic acid, and the organic solvent is selected from methanol, second
One kind in alcohol, isopropanol, preferred alcohol;The step b) is dichloromethane;Separation described in the step d) includes using second
Acetoacetic ester extracts, and organic phase is concentrated under reduced pressure, column chromatography for separation;Step e) the separation includes that reaction solution, column chromatography is concentrated under reduced pressure
Separation;Base reagent described in step e) is sodium carbonate or cesium carbonate.
The method of aforementioned present invention, the reaction temperature that the reaction temperature of step a) is 60~80 DEG C or step b) is 40~
60℃。
In one embodiment, of the invention a kind of to prepare impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzene
The method of sulfonamide includes the following steps:
A) starting material 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride, organic solvent are added in reaction bulb cyclization,
The silico-tungstic acid of catalytic amount is added, temperature rising reflux reacts about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain yellow
Intermediate I;
B) intermediate I, dichloromethane are added in reaction bulb sulfonating reaction, and chlorosulfonic acid is added dropwise in cooling.Drop finishes, and heating is overnight
Reaction.Obtained system is slowly added to be quenched in mixture of ice and water, liquid separation, water phase is extracted with dichloromethane, merges organic phase,
Washing, without being further processed, directly carries out next step reaction to get to the dichloromethane solution of intermediate II;
C) dichloromethane solution of intermediate II is added in reaction bulb ammonolysis reaction, and ammonium hydroxide is added dropwise, and reacts at room temperature about 2h,
Being concentrated under reduced pressure into system has solid generation, and filtering, filtration cakes torrefaction is to get intermediate III, without processing, directly carries out next
Step;
D) intermediate III, n,N-Dimethylformamide are added in reaction bulb bromo-reaction, and N- bromo ambers are added dropwise in cooling
Acid imide.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
Intermediate IV;
E) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium, ethyl alcohol, a small amount of water are added to by coupling reaction
In reaction bulb, nitrogen protection, back flow reaction is overnight.Reaction finishes, and is directly concentrated under reduced pressure, and column chromatography for separation is to get to pa auspicious former times
Cloth sodium impurity.
In the above-described embodiment, [(4- phenyl) -5- methyl -3- is different by the SC 69124 sodium impurity i.e. 3- for preparing of the invention
Oxazole] benzsulfamide method, step a) cyclizations 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride, silico-tungstic acid mole
Amount is than being 1:1~1.5:0.01~0.1, preferably 1:1:0.01, the one kind of organic solvent in methanol, ethyl alcohol, isopropanol is excellent
It is 60~80 DEG C to select ethyl alcohol, the reaction temperature;Step b) sulfonating reactions intermediate I, the mole ratio of chlorosulfonic acid are 1:5~8,
It is preferred that 1:5, reaction temperature is 40~60 DEG C;The mole ratio of step d) bromo-reactions intermediate III, N-bromosuccinimide
It is 1:3~5, preferably 1:3;The mole of step e) coupling reactions intermediate IV, phenyl boric acid, tetrakis triphenylphosphine palladium, base reagent
Than being 1:1.2~2:0.05~0.1:0.006~0.01, preferably 1:1.2:0.05:0.006, the base reagent sodium bicarbonate, carbon
One kind in sour sodium, potassium carbonate, cesium carbonate, preferably sodium carbonate.
The method of the present invention has the following advantages:
The novel synthetic method of designed, designed, raw material is easy to get, easy to operate, and the impurity sample purity HPLC detection of acquisition >=
98%, obtained impurity sample confirms structure, Ke Yizuo by 1H-NMR, 13C-NMR, DEPT, gCOSY, HMQC, HMBC collection of illustrative plates
For reference prepared by the impurity reference substance in Parecoxib Sodium finished product detection standard, Parecoxib Sodium finished product detection point can be promoted
The positioning analysis and qualitative detection for impurity are analysed, the quality of Parecoxib Sodium finished product is effectively controlled, ensures the safety of drug.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Fig. 2~3 are that the 1H-NMR of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide schemes
Spectrum;
Fig. 4 is the 13C-NMR collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Fig. 5 is the DEPT collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Fig. 6 is the gCOSY collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Fig. 7 is the HMQC collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Fig. 8 is the HMBC collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide;
Specific implementation mode
Following embodiment is used to be explained further the essence of the present invention, but does not limit the scope of the invention.
The preparation of 1 SC 69124 sodium impurity 3- of embodiment [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide
1- phenyl -1,2- propanedione 10g is dissolved in 50mL ethyl alcohol, 4.7g hydroxylamine hydrochlorides are added, 2.0g silicon tungsten is added
Acid is warming up to 80 DEG C of back flow reaction about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain the intermediate I of yellow about
9.6g;
Intermediate I 9.6g, dichloromethane 40mL are added in reaction bulb, chlorosulfonic acid 40g is added dropwise in cooling.Drop finishes, and is warming up to
55 DEG C of reaction overnights.Obtained system is slowly added to be quenched in 80mL mixture of ice and water, liquid separation, water phase is extracted with dichloromethane
It takes, merges organic phase, washing, without being further processed, directly carries out in next step to get to the dichloromethane solution of intermediate II
Reaction;
The dichloromethane solution of intermediate II is added in reaction bulb, ammonium hydroxide 80mL is added dropwise, reacts at room temperature about 2h, decompression is dense
Being reduced in system has solid generation, and filtering, filtration cakes torrefaction directly carries out down to get the about 12.5g of intermediate III without processing
One step;
III 12.5g of intermediate, n,N-Dimethylformamide 60mL are added in reaction bulb, N- bromo succinyls are added dropwise in cooling
Imines 30g.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
The about 11.4g of intermediate IV;
IV 11.4g of intermediate, phenyl boric acid 6.5g, sodium carbonate 0.20g, tetrakis triphenylphosphine palladium 0.25g are added to reaction
In bottle, ethyl alcohol 30mL, water 1mL are added in reaction bulb, and nitrogen protection, back flow reaction is overnight.Reaction finishes, and directly depressurizes dense
Contracting, column chromatography for separation is to get to the SC 69124 sodium impurity 7.6g of title.
Obtained SC 69124 sodium impurity through 1H-NMR, 13C-NMR, DEPT, gCOSY, HMQC, HMBC collection of illustrative plates through confirming
Structure is correct (scheming see 2-8), and HPLC detects purity and is more than 98% (see Fig. 1).
The preparation of 2 SC 69124 sodium impurity 3- of embodiment [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide
1- phenyl -1,2- propanedione 10g is dissolved in 50mL ethyl alcohol, 5.0g hydroxylamine hydrochlorides are added, 2.2g silicon tungsten is added
Acid is warming up to 80v back flow reactions about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain the intermediate I of yellow about
9.5g;
Intermediate I 9.5g, dichloromethane 50mL are added in reaction bulb, chlorosulfonic acid 48g is added dropwise in cooling.Drop finishes, and is warming up to
50 DEG C of reaction overnights.Obtained system is slowly added to be quenched in 100mL mixture of ice and water, liquid separation, water phase is extracted with dichloromethane
It takes, merges organic phase, washing, without being further processed, directly carries out in next step to get to the dichloromethane solution of intermediate II
Reaction;
The dichloromethane solution of intermediate II is added in reaction bulb, ammonium hydroxide 100mL is added dropwise, reacts at room temperature about 2h, decompression
Being concentrated into system has solid generation, filtering, and filtration cakes torrefaction is to get the about 11.2g of intermediate III, without processing, directly carries out
In next step;
III 11.2g of intermediate, n,N-Dimethylformamide 45mL are added in reaction bulb, N- bromo succinyls are added dropwise in cooling
Imines 35g.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
The about 9.8g of intermediate IV;
IV 9.8g of intermediate, phenyl boric acid 6.0g, cesium carbonate 0.16g, tetrakis triphenylphosphine palladium 0.20g are added to reaction bulb
In, ethyl alcohol 20mL, water 0.8mL are added in reaction bulb, and nitrogen protection, back flow reaction is overnight.Reaction finishes, and directly depressurizes dense
Contracting, column chromatography for separation is to get to the SC 69124 sodium impurity 6.4g of title.
Claims (8)
1. a kind of method preparing SC 69124 sodium impurity, the impurity is 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzene
Sulfonamide, synthetic route are as follows:
This approach includes the following steps:
A) starting material 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride are added in organic solvent by, add catalyst, heating
Back flow reaction, after reaction, separation obtains intermediate I;
B) intermediate I is added in organic solvent by, and chlorosulfonic acid is added, and drop finishes, and heat up reaction overnight, and ice is added in reaction solution
It is quenched in aqueous mixtures, separation organic phase obtains the organic solution of intermediate II;
C) dichloromethane solutions into the organic solution of intermediate II are added in reaction bulb, and ammonium hydroxide is added dropwise, reacts at room temperature, reaction
Finish, isolated intermediate III;
D) mixes intermediate III with n,N-Dimethylformamide, and N-bromosuccinimide is added, and after room temperature reaction, is added
Reaction is quenched in water and ethyl acetate, and separation obtains intermediate IV;
E) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium, ethyl alcohol, a small amount of water are added in reaction bulb by, nitrogen
Gas shielded, back flow reaction is overnight, and reaction finishes, isolated SC 69124 sodium impurity.
2. according to the method described in claim 1, catalyst described in step a) is silico-tungstic acid.
3. according to the method described in claim 1, organic solvent described in step a) in methanol, ethyl alcohol, isopropanol one
Kind, preferred alcohol.
4. according to the method described in claim 1, the step b) is dichloromethane.
5. according to the method described in claim 1, separation described in the step d) is organic to subtract each other including being extracted with ethyl acetate
Pressure concentration, column chromatography for separation.
6. according to the method described in claim 1, the step e) separation includes that reaction solution, column chromatography for separation is concentrated under reduced pressure.
7. according to the method described in claim 1, base reagent described in step e) is sodium carbonate or cesium carbonate.
8. according to the method described in claim 1, the reaction temperature that the reaction temperature of step a) is 60~80 DEG C or step b) is
40~60 DEG C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810455612.8A CN108675969A (en) | 2018-05-14 | 2018-05-14 | A kind of preparation method of SC 69124 sodium impurity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810455612.8A CN108675969A (en) | 2018-05-14 | 2018-05-14 | A kind of preparation method of SC 69124 sodium impurity |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108675969A true CN108675969A (en) | 2018-10-19 |
Family
ID=63806435
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810455612.8A Pending CN108675969A (en) | 2018-05-14 | 2018-05-14 | A kind of preparation method of SC 69124 sodium impurity |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108675969A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113387903A (en) * | 2021-06-21 | 2021-09-14 | 宏冠生物药业有限公司 | Synthesis method of parecoxib sodium impurity |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2098593A (en) * | 1981-05-11 | 1982-11-24 | Sterling Drug Inc | Isoxazoles |
CN104193694A (en) * | 2014-09-19 | 2014-12-10 | 成都欣捷高新技术开发有限公司 | Method for preparing parecoxib sodium intermediate |
CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
CN104592141A (en) * | 2015-01-04 | 2015-05-06 | 成都克莱蒙医药科技有限公司 | Synthesis method of parecoxib sodium |
-
2018
- 2018-05-14 CN CN201810455612.8A patent/CN108675969A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2098593A (en) * | 1981-05-11 | 1982-11-24 | Sterling Drug Inc | Isoxazoles |
CN104193694A (en) * | 2014-09-19 | 2014-12-10 | 成都欣捷高新技术开发有限公司 | Method for preparing parecoxib sodium intermediate |
CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
CN104592141A (en) * | 2015-01-04 | 2015-05-06 | 成都克莱蒙医药科技有限公司 | Synthesis method of parecoxib sodium |
Non-Patent Citations (2)
Title |
---|
MAJID M. HERAVI,ET AL.: "Heteropolyacids as green and reusable catalysts for the synthesis of isoxazole derivatives", 《SYNTHETIC COMMUNICATIONS》 * |
王凯等: "帕瑞昔布的合成", 《中国医药工业杂志》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113387903A (en) * | 2021-06-21 | 2021-09-14 | 宏冠生物药业有限公司 | Synthesis method of parecoxib sodium impurity |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7368636B2 (en) | Method for synthesizing roxadustat and its intermediates and intermediates thereof | |
CN104250232A (en) | Preparation method of parecoxib sodium | |
CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
CN112020498A (en) | Buvalracetam intermediate, preparation method thereof and preparation method of Buvalracetam | |
CN114478273A (en) | Preparation method of metahydroxylamine bitartrate | |
CN108675969A (en) | A kind of preparation method of SC 69124 sodium impurity | |
CN109776407B (en) | Preparation method of 2-methyl-4-hydroxymethyl quinoline and derivatives thereof | |
CN112300073B (en) | Preparation method of isoquinoline derivative | |
CN108484516A (en) | A kind of SC 69124 sodium impurity and preparation method thereof | |
CN111995520A (en) | Synthetic method of 4-formyl-2- (trifluoromethyl) benzoic acid | |
CN109232254B (en) | Synthesis method and application of compound | |
CN112225769A (en) | Method for synthesizing and purifying tulathromycin impurity E | |
CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
CN112266348B (en) | Preparation method of L-prolinamide | |
CN112624968B (en) | Synthetic method of 5-amino-3-cyanopyridine methyl formate hydrochloride | |
CN113603693B (en) | Preparation method of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine | |
CN114105848B (en) | Preparation method of cis-D-hydroxyproline derivative | |
CN112125864B (en) | Synthesis method of 1,1 '-diamino-5, 5' -bitetrazole | |
JP7174851B2 (en) | Method for preparing (1R,3S)-3-amino-1-cyclopentanol and salts thereof | |
CN111362893B (en) | Preparation method of tasimelteon intermediate | |
CN116606260A (en) | Synthesis method of fluorine Lei Lana | |
CN110759860B (en) | Preparation method of 3-methyl formate-4-methoxy-5-cyanopyridine | |
EP1554279B1 (en) | Process for the preparation of zaleplon | |
CN115872906A (en) | Levatinib impurity and preparation method thereof | |
CN117843545A (en) | Preparation method of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile and hydrochloride thereof |
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 | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181019 |