CN109180683A - A kind of preparation method for replacing Buddhist nun according to Shandong - Google Patents
A kind of preparation method for replacing Buddhist nun according to Shandong Download PDFInfo
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- CN109180683A CN109180683A CN201811043982.7A CN201811043982A CN109180683A CN 109180683 A CN109180683 A CN 109180683A CN 201811043982 A CN201811043982 A CN 201811043982A CN 109180683 A CN109180683 A CN 109180683A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to medical processing technique fields, and disclose a kind of preparation method that Buddhist nun is replaced according to Shandong, it is successively ready to according to Shandong for the material of Buddhist nun the following steps are included: will need to prepare, 3- aminopiperidines, D- pyroglutamic acid, 4- Phenoxyphenyl vinylidene cyanide methane compounds, acryloyl chloride and cyclizing agent, 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, back flow reaction occurs, is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamate.This replaces the preparation method of Buddhist nun according to Shandong, it is made according to Shandong by the above material for Buddhist nun, react more mild during production, it is not in that reaction relatively acutely causes dangerous situation, and such placement production operation is more simple, synthetic route is convenient, it is low in cost, convenient for purifying, the advantages of environmentally friendly and optical purity of products is high and suitable industrialized production.
Description
Technical field
The present invention relates to medical processing technique field, specially a kind of preparation method that Buddhist nun is replaced according to Shandong.
Background technique
Replacing Buddhist nun according to Shandong is second new drug through the breakthrough drug channel approval of FDA, while also enjoying other two of FDA
Administrative protection in 7 years after buff, and listing, replacing Buddhist nun according to Shandong is Johnson Johnson company and Pharmacyclics company
The target anticancer new drug of R & D Cooperation is ratified to list, commodity in 13 Huo Food and Drug Adminstration of the US (FDA) November in 2013
Entitled Imbruvica, the medicine are used for the treatment of lymphoma mantle cell, and the Chinese chemical name of Buddhist nun: 1- [3 (R)-[4- ammonia is replaced according to Shandong
Base -3- (4- phenoxy phenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] piperidin-1-yl] -2- propylene -1- ketone；English language Chemical name
Claim: 1- [3 (R)-[4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl]
piperidin-1-yl]-2-propen-1-one；Molecular formula: C25H24N6O2；Molecular weight: 440.50；CAS registration number:
936563-96-1。
Traditional production replaces Buddhist nun's elapsed time longer according to Shandong, the complexity that the approach of synthesis compares, therefore can greatly reduce
The efficiency of production, while traditional fabrication can have toxicity according to Shandong for the required material part of Buddhist nun, if therefore operation error,
The case where will appear producer's poisoning or personnel's poisoning nearby, life threatening health are unfavorable for making, therefore herein propose
A kind of preparation method for replacing Buddhist nun according to Shandong.
Summary of the invention
(1) the technical issues of solving
In view of the deficiencies of the prior art, the present invention provides a kind of preparation method for replacing Buddhist nun according to Shandong, have high-efficient etc. excellent
Point solves traditional production and replaces Buddhist nun's elapsed time longer according to Shandong, the complexity that the approach of synthesis compares, therefore can greatly reduce
The efficiency of production, while traditional fabrication can have toxicity according to Shandong for the required material part of Buddhist nun, if therefore operation error,
The case where will appear producer's poisoning or personnel's poisoning nearby, life threatening health are unfavorable for the problem of making.
(2) technical solution
To realize above-mentioned high-efficient purpose, the invention provides the following technical scheme: a kind of preparation method that Buddhist nun is replaced according to Shandong,
The following steps are included:
1) it will need to prepare successively to be ready to according to Shandong for the material of Buddhist nun, 3- aminopiperidines, D- pyroglutamic acid, 4- benzene
Phenyl vinylidene cyanide methane compounds, acryloyl chloride and cyclizing agent；
2) 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, are sent out
Raw back flow reaction is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamic acid
R-3- amino piperidine pyroglutamate and (Boc) 2O adding into dichloromethane are added alkaline reagent, are stirred at room temperature by salt
To concentrated solvent after reaction, be diluted with water, then plus ethyl acetate extraction, organic phase is cleaned more with saturated sodium chloride solution
It is secondary, double boc-protected R-3- amino piperidine intermediates are concentrated under reduced pressure to give, by R-3- amino piperidine intermediate, periodic acid, wet
SiO2 and sodium nitrite adding into dichloromethane, are stirred at room temperature reaction, filter after reaction, anhydrous slufuric acid is added in filtrate
Sodium is dry, and three filter ten minutes later, remove filtrate under reduced pressure and obtain nitroso compound；
3) nitroso compound is dissolved in methylene chloride, adds glacial acetic acid and reducing agent, room temperature reaction is after
Saturated sodium carbonate solution is added and adjusts the pH of reaction system as alkalinity, ethyl acetate extraction is added, stands and is layered, pour out lower layer
Water phase, organic phase are cleaned once with saturated sodium carbonate solution again, are finally washed three times with saturated sodium chloride solution, organic phase is concentrated,
It crosses column chromatography and obtains diazanyl intermediate, which is added to the methanol for the hydrogen chloride that molar concentration is 4mol/L
In solution, it is stirred to react 0.5h in 0-30 DEG C and obtains 3R- diazanyl -1- piperidine compounds；
4) 3R- diazanyl -1- piperidine compounds are put into and fill 4- Phenoxyphenyl (methoxyl group) vinylidene cyanide first
In the reaction kettle of hydride compounds, pyrazoles cyclization occurs and obtains (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3-
Base) -1H- pyrazoles -4- carbonitrile compounds；
5) under nitrogen protection by (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazoles -4-
Carbonitrile compounds are added in cyclizing agent, are placed in constant-temperature heating magnetic stirring apparatus or microwave synthesizer and are occurred instead in 60-180 DEG C
It answers, TLC detects addition saturated sodium chloride solution dilution after fully reacting, adds ethyl acetate extraction, and washing stands and divides
Layer pours out lower aqueous layer, and organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and crosses column chromatography and obtains
Pyrimidine ring compound intermediate and sodium hydroxide solution are added to methanol under nitrogen protection by pyrimidine ring compound intermediate
In, back flow reaction to TLC detection is spin-dried for solvent after reaction, and ethyl acetate dissolution is added, adds saturated sodium chloride solution,
Washing stands and is layered, and pours out lower aqueous layer, and organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, will
To crude product and acryloyl chloride be added in dry methylene chloride, add triethylamine, be stirred at room temperature reaction to TLC detect react
After decompression be spin-dried for solvent, ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, stands and layering, pours out
Lower aqueous layer, organic phase are cleaned twice with saturated sodium chloride solution again, organic phase are concentrated, crude product is recrystallized to give through dehydrated alcohol
White solid replaces Buddhist nun's compound according to Shandong；
6) preservation processing finally is sealed for Buddhist nun according to Shandong by obtained.
(3) beneficial effect
Compared with prior art, the present invention provides it is a kind of according to Shandong replace Buddhist nun preparation method, have it is following the utility model has the advantages that
This replaces the preparation method of Buddhist nun according to Shandong, is made according to Shandong by the above material for Buddhist nun, is reacted more during production
What is added is mild, is not in that reaction relatively acutely causes dangerous situation, and such placement production operation is more simple, synthesis
Route is convenient, it is low in cost, convenient for purifying, the advantages of environmentally friendly and optical purity of products is high and suitable industrialized production.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution in the embodiment of the present invention is clearly and completely retouched
It states, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the present invention
In embodiment, every other implementation obtained by those of ordinary skill in the art without making creative efforts
Example, shall fall within the protection scope of the present invention.
A kind of embodiment one: preparation method for replacing Buddhist nun according to Shandong, comprising the following steps:
1) it will need to prepare successively to be ready to according to Shandong for the material of Buddhist nun, 3- aminopiperidines, D- pyroglutamic acid, 4- benzene
Phenyl vinylidene cyanide methane compounds, acryloyl chloride and cyclizing agent；
2) 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, are sent out
Raw back flow reaction is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamic acid
R-3- amino piperidine pyroglutamate and (Boc) 2O adding into dichloromethane are added alkaline reagent, are stirred at room temperature by salt
To concentrated solvent after reaction, be diluted with water, then plus ethyl acetate extraction, organic phase is cleaned more with saturated sodium chloride solution
It is secondary, double boc-protected R-3- amino piperidine intermediates are concentrated under reduced pressure to give, by R-3- amino piperidine intermediate, periodic acid, wet
SiO2 and sodium nitrite adding into dichloromethane, are stirred at room temperature reaction, filter after reaction, anhydrous slufuric acid is added in filtrate
Sodium is dry, and three filter ten minutes later, remove filtrate under reduced pressure and obtain nitroso compound；
3) nitroso compound is dissolved in methylene chloride, adds glacial acetic acid and reducing agent, room temperature reaction is after
Saturated sodium carbonate solution is added and adjusts the pH of reaction system as alkalinity, ethyl acetate extraction is added, stands and is layered, pour out lower layer
Water phase, organic phase are cleaned once with saturated sodium carbonate solution again, are finally washed three times with saturated sodium chloride solution, organic phase is concentrated,
It crosses column chromatography and obtains diazanyl intermediate, which is added to the methanol for the hydrogen chloride that molar concentration is 4mol/L
In solution, it is stirred to react in 15 DEG C and obtains within 20 minutes 3R- diazanyl -1- piperidine compounds；
4) 3R- diazanyl -1- piperidine compounds are put into and fill 4- Phenoxyphenyl (methoxyl group) vinylidene cyanide first
In the reaction kettle of hydride compounds, pyrazoles cyclization occurs and obtains (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3-
Base) -1H- pyrazoles -4- carbonitrile compounds；
5) under nitrogen protection by (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazoles -4-
Carbonitrile compounds are added in cyclizing agent, are placed in constant-temperature heating magnetic stirring apparatus or microwave synthesizer and are reacted in 60 DEG C,
TLC detects addition saturated sodium chloride solution dilution after fully reacting, adds ethyl acetate extraction, and washing stands and is layered,
Lower aqueous layer out, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and are crossed column chromatography and are obtained pyrimidine ring
Pyrimidine ring compound intermediate and sodium hydroxide solution are added in methanol by compound intermediate under nitrogen protection, reflux
Reaction to TLC detection is spin-dried for solvent after reaction, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, quiet
It sets and is layered, pour out lower aqueous layer, organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, thick by what is obtained
Product and acryloyl chloride are added in dry methylene chloride, add triethylamine, are stirred at room temperature and are reacted to TLC detection after reaction
Decompression is spin-dried for solvent, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, and lower water is poured out in standing and layering
Layer, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and crude product is recrystallized to give white admittedly through dehydrated alcohol
Body replaces Buddhist nun's compound according to Shandong；
6) preservation processing finally is sealed for Buddhist nun according to Shandong by obtained.
A kind of embodiment two: preparation method for replacing Buddhist nun according to Shandong, comprising the following steps:
1) it will need to prepare successively to be ready to according to Shandong for the material of Buddhist nun, 3- aminopiperidines, D- pyroglutamic acid, 4- benzene
Phenyl vinylidene cyanide methane compounds, acryloyl chloride and cyclizing agent；
2) 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, are sent out
Raw back flow reaction is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamic acid
R-3- amino piperidine pyroglutamate and (Boc) 2O adding into dichloromethane are added alkaline reagent, are stirred at room temperature by salt
To concentrated solvent after reaction, be diluted with water, then plus ethyl acetate extraction, organic phase is cleaned more with saturated sodium chloride solution
It is secondary, double boc-protected R-3- amino piperidine intermediates are concentrated under reduced pressure to give, by R-3- amino piperidine intermediate, periodic acid, wet
SiO2 and sodium nitrite adding into dichloromethane, are stirred at room temperature reaction, filter after reaction, anhydrous slufuric acid is added in filtrate
Sodium is dry, and three filter ten minutes later, remove filtrate under reduced pressure and obtain nitroso compound；
3) nitroso compound is dissolved in methylene chloride, adds glacial acetic acid and reducing agent, room temperature reaction is after
Saturated sodium carbonate solution is added and adjusts the pH of reaction system as alkalinity, ethyl acetate extraction is added, stands and is layered, pour out lower layer
Water phase, organic phase are cleaned once with saturated sodium carbonate solution again, are finally washed three times with saturated sodium chloride solution, organic phase is concentrated,
It crosses column chromatography and obtains diazanyl intermediate, which is added to the methanol for the hydrogen chloride that molar concentration is 4mol/L
In solution, it is stirred to react in 30 DEG C and obtains within 40 minutes 3R- diazanyl -1- piperidine compounds；
4) 3R- diazanyl -1- piperidine compounds are put into and fill 4- Phenoxyphenyl (methoxyl group) vinylidene cyanide first
In the reaction kettle of hydride compounds, pyrazoles cyclization occurs and obtains (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3-
Base) -1H- pyrazoles -4- carbonitrile compounds；
5) under nitrogen protection by (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazoles -4-
Carbonitrile compounds are added in cyclizing agent, are placed in constant-temperature heating magnetic stirring apparatus or microwave synthesizer and are reacted in 180 DEG C,
TLC detects addition saturated sodium chloride solution dilution after fully reacting, adds ethyl acetate extraction, and washing stands and is layered,
Lower aqueous layer out, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and are crossed column chromatography and are obtained pyrimidine ring
Pyrimidine ring compound intermediate and sodium hydroxide solution are added in methanol by compound intermediate under nitrogen protection, reflux
Reaction to TLC detection is spin-dried for solvent after reaction, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, quiet
It sets and is layered, pour out lower aqueous layer, organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, thick by what is obtained
Product and acryloyl chloride are added in dry methylene chloride, add triethylamine, are stirred at room temperature and are reacted to TLC detection after reaction
Decompression is spin-dried for solvent, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, and lower water is poured out in standing and layering
Layer, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and crude product is recrystallized to give white admittedly through dehydrated alcohol
Body replaces Buddhist nun's compound according to Shandong；
6) preservation processing finally is sealed for Buddhist nun according to Shandong by obtained.
A kind of embodiment three: preparation method for replacing Buddhist nun according to Shandong, comprising the following steps:
1) it will need to prepare successively to be ready to according to Shandong for the material of Buddhist nun, 3- aminopiperidines, D- pyroglutamic acid, 4- benzene
Phenyl vinylidene cyanide methane compounds, acryloyl chloride and cyclizing agent；
2) 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, are sent out
Raw back flow reaction is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamic acid
R-3- amino piperidine pyroglutamate and (Boc) 2O adding into dichloromethane are added alkaline reagent, are stirred at room temperature by salt
To concentrated solvent after reaction, be diluted with water, then plus ethyl acetate extraction, organic phase is cleaned more with saturated sodium chloride solution
It is secondary, double boc-protected R-3- amino piperidine intermediates are concentrated under reduced pressure to give, by R-3- amino piperidine intermediate, periodic acid, wet
SiO2 and sodium nitrite adding into dichloromethane, are stirred at room temperature reaction, filter after reaction, anhydrous slufuric acid is added in filtrate
Sodium is dry, and three filter ten minutes later, remove filtrate under reduced pressure and obtain nitroso compound；
3) nitroso compound is dissolved in methylene chloride, adds glacial acetic acid and reducing agent, room temperature reaction is after
Saturated sodium carbonate solution is added and adjusts the pH of reaction system as alkalinity, ethyl acetate extraction is added, stands and is layered, pour out lower layer
Water phase, organic phase are cleaned once with saturated sodium carbonate solution again, are finally washed three times with saturated sodium chloride solution, organic phase is concentrated,
It crosses column chromatography and obtains diazanyl intermediate, which is added to the methanol for the hydrogen chloride that molar concentration is 4mol/L
In solution, it is stirred to react in 20 DEG C and obtains within 30 minutes 3R- diazanyl -1- piperidine compounds；
4) 3R- diazanyl -1- piperidine compounds are put into and fill 4- Phenoxyphenyl (methoxyl group) vinylidene cyanide first
In the reaction kettle of hydride compounds, pyrazoles cyclization occurs and obtains (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3-
Base) -1H- pyrazoles -4- carbonitrile compounds；
5) under nitrogen protection by (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazoles -4-
Carbonitrile compounds are added in cyclizing agent, are placed in constant-temperature heating magnetic stirring apparatus or microwave synthesizer and are reacted in 150 DEG C,
TLC detects addition saturated sodium chloride solution dilution after fully reacting, adds ethyl acetate extraction, and washing stands and is layered,
Lower aqueous layer out, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and are crossed column chromatography and are obtained pyrimidine ring
Pyrimidine ring compound intermediate and sodium hydroxide solution are added in methanol by compound intermediate under nitrogen protection, reflux
Reaction to TLC detection is spin-dried for solvent after reaction, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, quiet
It sets and is layered, pour out lower aqueous layer, organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, thick by what is obtained
Product and acryloyl chloride are added in dry methylene chloride, add triethylamine, are stirred at room temperature and are reacted to TLC detection after reaction
Decompression is spin-dried for solvent, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, and lower water is poured out in standing and layering
Layer, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and crude product is recrystallized to give white admittedly through dehydrated alcohol
Body replaces Buddhist nun's compound according to Shandong；
6) preservation processing finally is sealed for Buddhist nun according to Shandong by obtained.
The beneficial effects of the present invention are: being made according to Shandong by the above material for Buddhist nun, reacted more during production
It is mild, be not in that reaction relatively acutely causes dangerous situation, and such placements production operation is more simple, synthesis road
Line is convenient, it is low in cost, convenient for purifying, the advantages of environmental-friendly and optical purity of products is high and suitable industrialized production.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (1)
1. a kind of preparation method for replacing Buddhist nun according to Shandong, which comprises the following steps:
1) it will need to prepare successively to be ready to according to Shandong for the material of Buddhist nun, 3- aminopiperidines, D- pyroglutamic acid, 4- phenoxy group
Phenyl vinylene dicyanomethane compound, acryloyl chloride and cyclizing agent；
2) 3- aminopiperidines and resolution reagent D- pyroglutamic acid are placed in the reaction kettle for being placed with dehydrated alcohol, are occurred back
Stream reaction is cooled to room temperature precipitation white solid after reaction and obtains optically pure R-3- amino piperidine pyroglutamate, will
R-3- amino piperidine pyroglutamate and (Boc) 2O adding into dichloromethane, add alkaline reagent, are stirred at room temperature to reaction
After concentrated solvent, be diluted with water, then plus ethyl acetate extraction, organic phase clean repeatedly with saturated sodium chloride solution, decompression
Double boc-protected R-3- amino piperidine intermediates are concentrated to get, by R-3- amino piperidine intermediate, periodic acid, wet SiO2 and Asia
Sodium nitrate adding into dichloromethane is stirred at room temperature reaction, filters after reaction, and anhydrous sodium sulfate drying is added in filtrate,
Three filter ten minutes later, remove filtrate under reduced pressure and obtain nitroso compound；
3) nitroso compound is dissolved in methylene chloride, adds glacial acetic acid and reducing agent, room temperature reaction is added after
Saturated sodium carbonate solution adjusts the pH of reaction system as alkalinity, and ethyl acetate extraction is added, and stands and is layered, pours out lower water
Phase, organic phase are cleaned once with saturated sodium carbonate solution again, are finally washed three times with saturated sodium chloride solution, organic phase, mistake is concentrated
Column chromatography obtains diazanyl intermediate, and the methanol which is added to the hydrogen chloride that molar concentration is 4mol/L is molten
In liquid, it is stirred to react 0.5h in 0-30 DEG C and obtains 3R- diazanyl -1- piperidine compounds；
4) 3R- diazanyl -1- piperidine compounds are put into and fill 4- Phenoxyphenyl (methoxyl group) vinylidene cyanide methanation
In the reaction kettle for closing object, pyrazoles cyclization occurs and obtains (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -
1H- pyrazoles -4- carbonitrile compounds；
5) under nitrogen protection by (R) -5- amino -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazoles -4- formonitrile HCN
Compound is added in cyclizing agent, is placed in constant-temperature heating magnetic stirring apparatus or microwave synthesizer and is reacted in 60-180 DEG C,
TLC detects addition saturated sodium chloride solution dilution after fully reacting, adds ethyl acetate extraction, and washing stands and is layered,
Lower aqueous layer out, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and are crossed column chromatography and are obtained pyrimidine ring
Pyrimidine ring compound intermediate and sodium hydroxide solution are added in methanol by compound intermediate under nitrogen protection, reflux
Reaction to TLC detection is spin-dried for solvent after reaction, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, quiet
It sets and is layered, pour out lower aqueous layer, organic phase is cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, thick by what is obtained
Product and acryloyl chloride are added in dry methylene chloride, add triethylamine, are stirred at room temperature and are reacted to TLC detection after reaction
Decompression is spin-dried for solvent, and ethyl acetate dissolution is added, adds saturated sodium chloride solution, washs, and lower water is poured out in standing and layering
Layer, organic phase are cleaned twice with saturated sodium chloride solution again, and organic phase is concentrated, and crude product is recrystallized to give white admittedly through dehydrated alcohol
Body replaces Buddhist nun's compound according to Shandong；
6) preservation processing finally is sealed for Buddhist nun according to Shandong by obtained.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020234379A1 (en) * | 2019-05-21 | 2020-11-26 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a btk inhibitor |
| CN114853662A (en) * | 2021-02-05 | 2022-08-05 | 四川青木制药有限公司 | Preparation method of chiral hydrazinylpiperidine derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233344A (en) * | 2017-07-20 | 2017-10-10 | 河南师范大学 | A kind of antineoplastic replaces the preparation method of Buddhist nun according to Shandong |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
-
2018
- 2018-09-07 CN CN201811043982.7A patent/CN109180683A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233344A (en) * | 2017-07-20 | 2017-10-10 | 河南师范大学 | A kind of antineoplastic replaces the preparation method of Buddhist nun according to Shandong |
| CN107383017A (en) * | 2017-07-20 | 2017-11-24 | 河南师范大学 | Buddhist nun's high efficiency preparation method is replaced according to Shandong |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020234379A1 (en) * | 2019-05-21 | 2020-11-26 | Janssen Pharmaceutica Nv | Processes and intermediates for preparing a btk inhibitor |
| CN113906011A (en) * | 2019-05-21 | 2022-01-07 | 詹森药业有限公司 | Processes and intermediates for preparing BTK inhibitors |
| CN114853662A (en) * | 2021-02-05 | 2022-08-05 | 四川青木制药有限公司 | Preparation method of chiral hydrazinylpiperidine derivative |
| CN114853662B (en) * | 2021-02-05 | 2024-01-12 | 四川青木制药有限公司 | Process for preparing chiral hydrazinopiperidine derivatives |
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