CN106083860A - A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong - Google Patents
A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong Download PDFInfo
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- CN106083860A CN106083860A CN201610460713.5A CN201610460713A CN106083860A CN 106083860 A CN106083860 A CN 106083860A CN 201610460713 A CN201610460713 A CN 201610460713A CN 106083860 A CN106083860 A CN 106083860A
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- shandong
- buddhist nun
- triphenylphosphine
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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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Abstract
The present invention relates to a kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong, it is exactly 3 (4 Phenoxyphenyl) 1H pyrazoles [3 specifically, 4 d] pyrimidine 4 amine is reacted by Mitsunobu with (s) 1 tertbutyloxycarbonyl 3 hydroxy piperidine, triphenylphosphine, DIAD, de-Boc process obtains intermediate aggregate sample, obtain crude intermediate with solvent crystallization, then crude product mixed solvent method is recrystallized to give the purity process replacing Buddhist nun's intermediate according to Shandong more than 97%.The present invention uses " one kettle way " to obtain according to Shandong for Buddhist nun's intermediate, and course of reaction is simple, and yield is high, additionally provides a kind of efficient process for purification simultaneously.
Description
Technical field
The invention belongs to medicine synthesis field, be exactly that 3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] is phonetic specifically
Pyridine-4-amine and (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine, triphenylphosphine, DIAD are reacted by Mitsunobu, de-Boc process
Obtain obtaining process according to Shandong for Buddhist nun's intermediate and recrystallization thereof.
Background technology
The treatment lymphoma mantle cell (MCL) developed jointly for Ni Shi pharmacyclics company and Johson & Johnson according to Shandong
Medicine, trade name Imbruvica, in October, 2013 through FDA approval listing.Concrete structure is as follows:
Former patent US7514444 of grinding discloses a kind of synthetic method replacing Buddhist nun according to Shandong, and concrete synthetic route is as follows:
Patent CN104557945A discloses another synthetic method replacing Buddhist nun according to Shandong, and concrete synthetic route is as follows:
Above two synthesis replaces the method for Buddhist nun all to experienced by intermediate B according to Shandong, and its Central Plains is ground in patent US7514444 and used
Be the method purification intermediate of column chromatography, purge process is time-consuming and is not suitable for large-scale production；Patent CN104557945A is also
It is not directed to clear and definite purification of intermediate method, and needs to make Grignard reagent by oneself in course of reaction, also need to price simultaneously
The palladium of costliness, the catalyst of nickel class, course of reaction is difficult to control to and cost is high.So, a kind of efficient easy-operating centre of exploitation
The purification process of body B has good market prospect.
Summary of the invention
In order to overcome defect of the prior art, this application provides a kind of new according to Shandong for the synthesis of Buddhist nun's intermediate with pure
Metallization processes, the application uses " one kettle way " to prepare the crude product of intermediate B, can avoid purification back intermediate, can be with saving of labor
Time, cost declining.It addition, use mixed solvent method recrystallization, experimentation is simple, efficient, and reaction condition is relatively mild, is suitable for big
Large-scale production.
A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong, step is as follows:
A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong, specifically comprises the following steps that
(1) preparation of Buddhist nun's crude intermediate is replaced according to Shandong
By triphenylphosphine dissolved in THF in, be cooler than at 0 DEG C, add (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 3-
(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, is dropwise added drop-wise to reactant liquor system by DIAD after stirring 20 minutes
In, react 20 hours at keeping 0 DEG C, concentrate feed liquid the most thick, the 0.5M hydrochloric acid dioxane solution of addition, anti-at 20 DEG C
Answer 4 hours, concentrate, add water and ethyl acetate, layering, aqueous phase adds solvent, more alkaline with alkali liquor furnishing, growing the grain 30min,
Filter to obtain crude product；
Described triphenylphosphine is 1g/10ml with the mass volume ratio of THF；
Described triphenylphosphine is 1g/30～50ml with the mass volume ratio of hydrochloric acid dioxane solution；
Described triphenylphosphine is 1g/10ml with the mass volume ratio of water or ethyl acetate；
Described triphenylphosphine, (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine, 3-(4-Phenoxyphenyl)-1H-pyrazoles
The ratio of the amount of the material of [3,4-d] pyrimidine-4-amine and DIAD is 1:1:1:1；
(2) preparation of Buddhist nun's intermediate fine work is replaced according to Shandong
Be dissolved in outstanding for step (1) gained crude product in mixed solvent, be heated to reflux to molten clearly, naturally be cooler than at 20 DEG C and stir 12
Hour, it is filtrated to get fine work.
Owing to the impurity in crude product is mainly raw material residual, mixed solvent reaches pure by dissolubility good to raw material
The purpose changed.
Solvent described in step (1) is the one in methanol, ethanol, isopropanol, acetone, and triphenylphosphine and solvent
Mass volume ratio is 1g/0.5～2.0ml.
Alkali liquor described in step (1) is sodium hydroxide or potassium hydroxide, and concentration is 10%～25%.
Mixed solvent described in step (2) includes two kinds in methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, and
Crude intermediate is 1g/5.0～15ml with the mass volume ratio of mixed solvent.
About the innovative point of the present invention, can be illustrated by following aspect:
(1) " one kettle way " prepares the crude product of intermediate B, can avoid purification back intermediate, can drop into saving working hour
This.Former patent of grinding is separated the intermediate before intermediate B by the method for column chromatography, and the present invention is directly with " one kettle way "
Obtain Crude Intermediate B, not only save a lot of mask work, additionally it is possible to large-scale production.
(2) using mixed solvent method recrystallization, experimentation is simple, efficient, and reaction condition is relatively mild, is suitable for extensive
Produce.
Detailed description of the invention:
Embodiment one:
By 10.0g (38.2mmol 1.0eq) triphenylphosphine dissolved in 100ml THF, it is cooler than at 0 DEG C, adds 7.67g
(38.2mmol 1.0eq) (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxy group
Phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, after stirring 20 minutes, 7.67g (38.2mmol 1.0eq) DIAD is dropwise dripped
In reactant liquor system, react 20 hours at keeping 0 DEG C.Then concentrate feed liquid the most thick, add 380ml 0.5M hydrochloric acid two
Oxygen six ring solution, reacts 4 hours at 20 DEG C, concentrates, and adds 100ml water and 100ml ethyl acetate, layering, adds in aqueous phase
20ml methanol, then it is adjusted to pH=10-11, growing the grain 30min with the sodium hydrate aqueous solution of 10%, filter to obtain crude product 8.85g, yield
60%.
8.0g crude product is hanged (methanol: ethyl acetate=1:3) in molten 80ml mixed solvent, be heated to reflux to molten clearly, natural
It is cooler than at 20 DEG C stirring 12 hours, is filtrated to get intermediate fine work 5.65, yield 63.8%.
Embodiment two:
By 10.0g (38.2mmol 1.0eq) triphenylphosphine dissolved in 100ml THF, it is cooler than at 0 DEG C, adds 7.67g
(38.2mmol 1.0eq) (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxy group
Phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, after stirring 20 minutes, 7.67g (38.2mmol 1.0eq) DIAD is dropwise dripped
In reactant liquor system, react 20 hours at keeping 0 DEG C.Then concentrate feed liquid the most thick, add 380ml 0.5M hydrochloric acid two
Oxygen six ring solution, reacts 4 hours at 20 DEG C, concentrates, and adds 100ml water and 100ml ethyl acetate, layering, adds in aqueous phase
10ml ethanol, then it is adjusted to pH=10-11, growing the grain 30min with the sodium hydrate aqueous solution of 20%, filter to obtain crude product 9.13g, yield
61.9%.
8.0g crude product is hanged (methanol: acetonitrile=1:2) in molten 64ml mixed solvent, be heated to reflux to molten clearly, be naturally cooler than
Stir 12 hours at 20 DEG C, be filtrated to get intermediate fine work 6.11, yield 76.3%.
Embodiment three:
By 10.0g (38.2mmol 1.0eq) triphenylphosphine dissolved in 100ml THF, it is cooler than at 0 DEG C, adds 7.67g
(38.2mmol 1.0eq) (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxy group
Phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, after stirring 20 minutes, 7.67g (38.2mmol 1.0eq) DIAD is dropwise dripped
In reactant liquor system, react 20 hours at keeping 0 DEG C.Then concentrate feed liquid the most thick, add 380ml 0.5M hydrochloric acid two
Oxygen six ring solution, reacts 4 hours at 20 DEG C, concentrates, and adds 100ml water and 100ml ethyl acetate, layering, adds in aqueous phase
15ml acetone, then it is adjusted to pH=10-11, growing the grain 30min with the potassium hydroxide aqueous solution of 15%, filter to obtain crude product 8.66g, yield
58.7%.
8.0g crude product is hanged (methanol: ethanol=1:1) in molten 56ml mixed solvent, be heated to reflux to molten clearly, be naturally cooler than
Stir 12 hours at 20 DEG C, be filtrated to get intermediate fine work 5.94, yield 74.3%.
Embodiment four:
By 10.0g (38.2mmol 1.0eq) triphenylphosphine dissolved in 100ml THF, it is cooler than at 0 DEG C, adds 7.67g
(38.2mmol 1.0eq) (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxy group
Phenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, after stirring 20 minutes, 7.67g (38.2mmol 1.0eq) DIAD is dropwise dripped
In reactant liquor system, react 20 hours at keeping 0 DEG C.Then concentrate feed liquid the most thick, add 380ml 0.5M hydrochloric acid two
Oxygen six ring solution, reacts 4 hours at 20 DEG C, concentrates, and adds 100ml water and 100ml ethyl acetate, layering, adds in aqueous phase
20ml isopropanol, then it is adjusted to pH=10-11, growing the grain 30min with the potassium hydroxide aqueous solution of 20%, filter to obtain crude product 8.12g, receive
Rate 55.0%.
8.0g crude product is hanged (acetonitrile: ethyl acetate=3:1) in molten 40ml mixed solvent, be heated to reflux to molten clearly, natural
It is cooler than at 20 DEG C stirring 12 hours, is filtrated to get intermediate fine work 6.02, yield 75.2%.
Claims (4)
1. synthesis and the purifying process replacing Buddhist nun's intermediate according to Shandong, it is characterised in that specifically comprise the following steps that
(1) preparation of Buddhist nun's crude intermediate is replaced according to Shandong
By triphenylphosphine dissolved in THF in, be cooler than at 0 DEG C, add (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine and 3-(4-
Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine, after stirring 20 minutes, DIAD is dropwise added drop-wise in reactant liquor system,
React 20 hours at keeping 0 DEG C, concentrate feed liquid the most thick, the 0.5M hydrochloric acid dioxane solution of addition, at 20 DEG C, react 4
Hour, concentrate, add water and ethyl acetate, layering, aqueous phase adds solvent, more alkaline with alkali liquor furnishing, growing the grain 30min, mistake
Filter to obtain crude product；
Described triphenylphosphine is 1g/10ml with the mass volume ratio of THF；
Described triphenylphosphine is 1g/30～50ml with the mass volume ratio of hydrochloric acid dioxane solution；
Described triphenylphosphine is 1g/10ml with the mass volume ratio of water or ethyl acetate；
Described triphenylphosphine, (s)-1-tertbutyloxycarbonyl-3-hydroxy piperidine, 3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-
D] ratio of amount of material of pyrimidine-4-amine and DIAD is 1:1:1:1；
(2) preparation of Buddhist nun's intermediate fine work is replaced according to Shandong
Be dissolved in outstanding for step (1) gained crude product in mixed solvent, be heated to reflux to molten clearly, naturally be cooler than at 20 DEG C that to stir 12 little
Time, it is filtrated to get fine work.
2. replace synthesis and the purifying process of Buddhist nun's intermediate as described in claim 1 according to Shandong, it is characterised in that in step (1)
Described solvent is the one in methanol, ethanol, isopropanol, acetone, and the mass volume ratio of triphenylphosphine and solvent is 1g/
0.5～2.0ml.
A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong, it is characterised in that step
(1) alkali liquor described in is sodium hydroxide or potassium hydroxide, and concentration is 10%～25%.
A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong, it is characterised in that step
(2) mixed solvent described in includes two kinds in methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, and crude intermediate with
The mass volume ratio of mixed solvent is 1g/5.0～15ml.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610460713.5A CN106083860A (en) | 2016-06-23 | 2016-06-23 | A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong |
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| CN201610460713.5A CN106083860A (en) | 2016-06-23 | 2016-06-23 | A kind of synthesis and purifying process replacing Buddhist nun's intermediate according to Shandong |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106967071A (en) * | 2017-03-24 | 2017-07-21 | 福建省微生物研究所 | It is a kind of according to Shandong replace Buddhist nun's intermediate isolation and purification method |
| CN109232581A (en) * | 2018-11-28 | 2019-01-18 | 福建省微生物研究所 | The method for replacing Buddhist nun's intermediate according to Shandong is isolated and purified with zinc chloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| WO2014176348A1 (en) * | 2013-04-23 | 2014-10-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibitors of the ire-1/xbp-1 pathway and methods of using thereof |
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
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2016
- 2016-06-23 CN CN201610460713.5A patent/CN106083860A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319488A (en) * | 2007-03-28 | 2013-09-25 | 环状药物公司 | Inhibitors of bruton's tyrosine kinase |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| WO2014176348A1 (en) * | 2013-04-23 | 2014-10-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibitors of the ire-1/xbp-1 pathway and methods of using thereof |
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
Non-Patent Citations (2)
| Title |
|---|
| NORA LIU 等: "irect and two-step bioorthogonal probes for Bruton’s tyrosine kinase based on ibrutinib: a comparative study", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| XIXIANG LI 等: "Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106967071A (en) * | 2017-03-24 | 2017-07-21 | 福建省微生物研究所 | It is a kind of according to Shandong replace Buddhist nun's intermediate isolation and purification method |
| CN109232581A (en) * | 2018-11-28 | 2019-01-18 | 福建省微生物研究所 | The method for replacing Buddhist nun's intermediate according to Shandong is isolated and purified with zinc chloride |
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Application publication date: 20161109 |