CN107722005A - A kind of process for purification of pa Berkeley - Google Patents
A kind of process for purification of pa Berkeley Download PDFInfo
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- CN107722005A CN107722005A CN201710946081.8A CN201710946081A CN107722005A CN 107722005 A CN107722005 A CN 107722005A CN 201710946081 A CN201710946081 A CN 201710946081A CN 107722005 A CN107722005 A CN 107722005A
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- berkeley
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of process for purification of pa Berkeley, including (1) to be added to pa Berkeley crude product in deionized water, is heated to 40~70 DEG C of dissolvings completely, is cooled to 0~5 DEG C of precipitation solid, filtering, obtains pa Berkeley crude product；(2) ethanol and 2 butanone mixed organic solvents are added, is heated to reflux to being completely dissolved, adds activated carbon decolorizing, filtering, filtrate is cooled to 5 DEG C~10 DEG C, static crystallization；(3) filter, elution crystal is carried out with ethanol, dry, obtain refined pa Berkeley.By the process for purification of the present invention, the pa Berkeley purity of gained can reach more than 99.9%, and total impurities and single impurity control 0.1% respectively, within 0.05%, the quality of product has obtained significant raising, and subtractive process is easy to operate, is adapted to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the process for purification of antineoplastic pa Berkeley.
Background technology
Pa Berkeley (Palbociclib) is a kind of cell cycle dependent kinase developed by Pfizer (Pfizer) company
(CDK4/6) inhibitor, in April, 2013 obtain " breakthrough sex therapy " qualification of U.S. FDA.Due to its III phase clinically good
Performance, Pfizer submit application for quotation to U.S. FDA in August, 2014, and obtain preferential examination qualification, for estrogen by
The first-line treatment of the body positive (ER+) and negative (HER2-) advanced breast cancer of human epidermal growth factor receptor 2.The research of the medicine into
Work(will provide another important new selection for metastatic breast cancer patient.
Pa Berkeley (Palbociclib, I) it is chemical entitled：6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (1-
Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one, its structural formula is：
The preparation method of prior art, complex steps, side reaction is more, is not suitable for industrial production；Or yield is low, waste former
Material, improve production cost.In addition, in some cases, because controlling of production process is improper, pharmaceutical purity is caused also not meet
It is required that.Prior art is to this without disclosing special purification process, it is therefore necessary to which so underproof product or crude product are entered
One step is purified, to improve the yield of product and purity.This area there is an urgent need to work out a kind of low cost, in high yield, it is suitable
For the process for purification of the pa Berkeley produced greatly, to overcome disadvantages mentioned above.
The technical problem to be solved in the invention is overcome the deficiencies in the prior art, there is provided a kind of purifying side of pa Berkeley
Method, this method is simple, and product purity is high, high income, is easy to industrialized production.
The content of the invention
The defects of in order to overcome above-mentioned prior art, pa Berkeley purity is improved, this is bright to provide a kind of pa Berkeley
Process for purification, it is possible to increase product quality, be suitable for industrialized production.
In general, conventional separation methods have, such as the cooling including reactant mixture, crystallization is then collected by filtration
Method；Washed including heating crystalline, and with solvent, solvent is then distilled off and cools down the method for obtaining crystallization；Solvent extraction
Method；Dilution method；Recrystallization method；Column chromatography；The methods of preparing thin-layer chromatography.And various isolation and purification methods and a variety of conditions ginseng
Number there may be varied associativity and unpredictability again.
Applicant, by the experiment largely screened, has had been surprisingly found that a kind of Pa Baike on the basis of a large amount of existing literatures
The process for purification of profit, astoundingly obtain the product of high yield high-purity.
Process for purification provided by the invention is applied to be currently known pa Berkeley crude product obtained by synthetic method, commercially available
Pa Berkeley crude product prepared by pa Berkeley bulk drug or technical solution of the present invention refines, and the present inventor has found by research,
By including the preparation method of following processing step, the purity of bulk drug pa Berkeley can be increased substantially：
(1) pa Berkeley crude product is added in deionized water, is heated to 40~70 DEG C of dissolvings completely, is cooled to 0~5 DEG C
Solid is separated out, filtering, obtains pa Berkeley crude product；
(2) ethanol and 2- butanone mixed organic solvents are added, is heated to reflux to being completely dissolved, adds activated carbon decolorizing, mistake
Filter, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization；
(3) filter, carry out elution crystal with ethanol, vacuum drying obtains refined pa Berkeley.
It the following specifically describes the present invention.
Pa Berkeley and the mass volume ratio of deionized water are 1 in step (1):1~60g/mL.
In step (2), the volume ratio of mixed organic solvents and deionized water is 1~80:1, the volume of ethanol and 2- butanone
Than for 2~4:1, the activated carbon decolorizing time is 10~30min.
Preferably, pa Berkeley crude product 30g is weighed, adds 900mL deionized waters, is heated to 60 DEG C of dissolvings completely, cooling
To 0~5 DEG C of precipitation solid, filtering, ethanol 720mL and 2- butanone 180mL are added, be heated to reflux to being completely dissolved, add activity
Carbon decoloring 30min, filtering, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, is dried in vacuo,
Obtain refined pa Berkeley.
In the building-up process of the pa Berkeley crude product of the present invention, described step a is acetyl group diethyl malonate (II)
Compounds Ⅳ is made in annulation in caustic alcohol and ethanol with compound III；Step b is compounds Ⅳ and POCl3 in first
Benzene solvent reacts, and reaction terminates, and cools down, crystallization, filtering, compound V is made；Step c is compound V and ethyl acetoacetate
30min is stirred in 40-50 DEG C in sodium hydroxide, isopropanol, cyclopentamine is added and carries out the obtained compound VII of " one kettle way " reaction；Step
Rapid d compounds VII are reacted under palladium bichloride hydroconversion condition is made finished product pa Berkeley (I).
Wherein, the mass volume ratio of step a acetyl group diethyl malonate and ethanol is 1:10~15g/mL, acetyl group third
The mol ratio of diethyl adipate (II) and compound III is 1:1~1.1.
Step b is made in compounds Ⅳ in step a and sequentially adds POCl3, toluene, N, and N- dimethyl amines are stirred at reflux
2h, 25~30 DEG C are cooled to, pour into crystallization in frozen water, filtered, compound V is made.
Step c adds ethyl acetoacetate, sodium hydroxide, isopropanol, in 40-50 in compound V made from step b
DEG C stirring 30min, add cyclopentamine, be stirred at reflux 3h, filter, obtain compound VII.
Compared with prior art, the present invention has following beneficial effect：
1. this method can prepare the pa Berkeley of high-purity, its total miscellaneous control is below 0.1%, and single miscellaneous control is 0.05%
Below.
2. the synthesis technique of pa Berkeley crude product prepared by the present invention, whole piece synthetic route, react easily operation, technique road
Line is simple, and each step accessory substance is low, is adapted to industrialized production.
Embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but therefore not limited
Determine present disclosure.Wherein, the preparation of N- [5- (1- piperazinyls) -2- piperidyls] guanidine (III) is referring to document WO2006095159
Preparation method.
Embodiment 1
(1) synthesis of pa Berkeley crude product
A, compound ii 20.2g, compound III 22g, caustic alcohol 0.2mol and absolute ethyl alcohol are sequentially added in there-necked flask
202mL, stir 40-50 DEG C of conditioned response 5h.Removal of solvent under reduced pressure, residue are washed with distilled water 600mL, are then added dropwise
10% hydrochloric acid, solid is separated out, filtering, obtains compounds Ⅳ；
B, POCl3 0.279mol, toluene 200mL, N, N- dimethyl amine are sequentially added in above-mentioned obtained compounds Ⅳ
0.15mol is stirred at reflux 2h.25~30 DEG C are cooled to, pours into crystallization in frozen water, filters and compound V is made；
C, ethyl acetoacetate 11.28g, caustic alcohol 0.173mol, isopropanol are added in compound V obtained above
200mL, 30min is stirred in 40-50 DEG C, cyclopentamine 6.71g (0.0788mol, molecular weight 85.15) is added, is stirred at reflux 3h,
Filtering, obtains compound VII；
D, reaction bulb is vacuumized and replaced 3 times with hydrogen, absolute ethyl alcohol 6.5mL, palladium bichloride are added under hydrogen atmosphere
Ethanol solution 13.5mL (3.2 × 10-3M), sodium hydroxide 2.90g (0.0724mol, molecular weight 40) and the 34.90g of compound VII
(0.0724mol).Reaction is carried out in atmospheric hydrogen, and reaction temperature is 40-50 DEG C, is reacted through 4h, filters, it is thick to obtain pa Berkeley
Product 34.82g.
(2) pa Berkeley is refined
Above-mentioned pa Berkeley crude product 30g is taken, adds 30mL deionized waters, 40 DEG C of dissolvings is heated to completely, is cooled to 0~5
DEG C solid is separated out, filtering, add ethanol 20mL and 2- butanone 10mL, be heated to reflux to being completely dissolved, add activated carbon decolorizing
10min, filtering, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, and vacuum drying obtains pa
The fine work 27.08g of Berkeley, yield 90.2%, purity 99.91%.
Embodiment 2
(1) synthesis of pa Berkeley crude product
A, compound ii 20.2g, compound III 2.42g, caustic alcohol 0.2mol and anhydrous second are sequentially added in there-necked flask
Alcohol 202mL, stir 40-50 DEG C of conditioned response 5h.Removal of solvent under reduced pressure, residue are washed with distilled water 600mL, then dripped
Add 10% hydrochloric acid, separate out solid, filtering, obtain compounds Ⅳ；
B, compounds Ⅳ 30.86g, POCl3 0.279mol, toluene are sequentially added in above-mentioned obtained compounds Ⅳ
200mL, N, N- dimethyl amine 0.15mol are stirred at reflux 2h.25~30 DEG C are cooled to, pours into crystallization in frozen water, is filtered, obtainedization
Compound V；
C, ethyl acetoacetate 11.28g, caustic alcohol 0.173mol, isopropanol are added in compound V obtained above
200mL, 30min is stirred in 40-50 DEG C, cyclopentamine 6.71g is added, is stirred at reflux 3h, filters, obtains compound VII；
D, reaction bulb is vacuumized and replaced 3 times with hydrogen, absolute ethyl alcohol 6.5mL, palladium bichloride are added under hydrogen atmosphere
Ethanol solution 13.5mL (3.2 × 10-3M), the sodium hydroxide 2.90g and 34.90g of compound VII.Reaction is entered in atmospheric hydrogen
OK, reaction temperature is 40-50 DEG C, is reacted through 4h, filters, obtains pa Berkeley crude product 35.28g.
(2) pa Berkeley is refined
Above-mentioned pa Berkeley crude product 30g is taken, adds 1.8L deionized waters, 50 DEG C of dissolvings is heated to completely, is cooled to 0~5
DEG C solid is separated out, filtering, add ethanol 1200mL and 2- butanone 600mL, be heated to reflux to being completely dissolved, add activated carbon decolorizing
10min, filtering, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, and vacuum drying obtains pa
The fine work 28.10g of Berkeley, yield 93.6%, purity 99.93%.
Embodiment 3
(1) synthesis of pa Berkeley crude product
A, compound ii 20.2g, compound III 22g, caustic alcohol 0.2mol and absolute ethyl alcohol are sequentially added in there-necked flask
303mL, stir 40-50 DEG C of conditioned response 5h.Removal of solvent under reduced pressure, residue are washed with distilled water 600mL, are then added dropwise
10% hydrochloric acid, solid is separated out, filtering, obtains compounds Ⅳ；
B, compounds Ⅳ 30.86g, POCl3 0.279mol, toluene are sequentially added in above-mentioned obtained compounds Ⅳ
200mL, N, N- dimethyl amine 0.15mol are stirred at reflux 2h.25~30 DEG C are cooled to, pours into crystallization in frozen water, is filtered, obtainedization
Compound V；
C, ethyl acetoacetate 11.28g, caustic alcohol 0.173mol, isopropanol are added in compound V obtained above
200mL, 30min is stirred in 40-50 DEG C, cyclopentamine 6.71g is added, is stirred at reflux 3h, filters, obtains compound VII；
D, reaction bulb is vacuumized and replaced 3 times with hydrogen, absolute ethyl alcohol 6.5mL, palladium bichloride are added under hydrogen atmosphere
Ethanol solution 13.5mL (3.2 × 10-3M), the sodium hydroxide 2.90g and 34.90g of compound VII.Reaction is entered in atmospheric hydrogen
OK, reaction temperature is 40-50 DEG C, is reacted through 4h, filters, obtains pa Berkeley crude product 35.28g.
(2) pa Berkeley is refined
Above-mentioned pa Berkeley crude product 30g is taken, adds 900mL deionized waters, 60 DEG C of dissolvings is heated to completely, is cooled to 0~5
DEG C solid is separated out, filtering, add ethanol 720mL and 2- butanone 180mL, be heated to reflux to being completely dissolved, add activated carbon decolorizing
30min, filtering, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, and vacuum drying obtains pa
The fine work 28.99g of Berkeley, yield 96.6%, purity 99.97%.
Embodiment 4
(1) synthesis of pa Berkeley crude product
A, compound ii 20.2g, compound III 2.42g, caustic alcohol 0.2mol and anhydrous second are sequentially added in there-necked flask
Alcohol 303mL, stir 40-50 DEG C of conditioned response 5h.Removal of solvent under reduced pressure, residue are washed with distilled water 600mL, then dripped
Add 10% hydrochloric acid, separate out solid, filtering, obtain compounds Ⅳ；
B, compounds Ⅳ 30.86g, POCl3 0.279mol, toluene are sequentially added in above-mentioned obtained compounds Ⅳ
200mL, N, N- dimethyl amine are stirred at reflux 2h.25~30 DEG C are cooled to, pours into crystallization in frozen water, is filtered, compound V is made；
C, ethyl acetoacetate 11.28g, caustic alcohol 0.173mol, isopropanol are added in compound V obtained above
200mL, 30min is stirred in 40-50 DEG C, cyclopentamine 6.71g is added, is stirred at reflux 3h, filters, obtains compound VII；
D, reaction bulb is vacuumized and replaced 3 times with hydrogen, absolute ethyl alcohol 6.5mL, palladium bichloride are added under hydrogen atmosphere
Ethanol solution 13.5mL (3.2 × 10-3M), the sodium hydroxide 2.90g and 34.90g of compound VII.Reaction is entered in atmospheric hydrogen
OK, reaction temperature is 40-50 DEG C, is reacted through 4h, filters, obtains pa Berkeley crude product 36.02g.
(2) pa Berkeley is refined
Above-mentioned pa Berkeley crude product 30g is taken, adds 1.8L deionized waters, 70 DEG C of dissolvings is heated to completely, is cooled to 0~5
DEG C solid is separated out, filtering, add ethanol 1440mL and 2- butanone 600mL, be heated to reflux to being completely dissolved, add activated carbon decolorizing
30min, filtering, filtrate are cooled to 5 DEG C~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, and vacuum drying obtains pa
The fine work 29.13g of Berkeley, yield 97.1%, purity 99.98%.
Experimental Comparison example
This test example purpose is：Compare the obtained of pa Berkeley made from process for purification of the invention and prior art
Pa Berkeley impurity situation.
Sample 1：The pa Berkeley prepared according to patent CN201510790622.3 methods；
Sample 2：The pa Berkeley prepared according to patent CN201510578741.2 methods；
Sample 3：The pa Berkeley prepared according to patent CN201510210595.8 methods；
Sample 4：The pa Berkeley prepared according to patent CN201410691233.0 methods；
Sample 5：The pa Berkeley prepared according to patent CN201410693091.1 methods；
Sample 6：The commercially available crude product in Tianjin Hua Luokang bio tech ltd, it is refined according to the embodiment of the present invention 4
It is prepared by method；
Sample 7：The commercially available crude product of Jinan million Pharmaceutical Technology Co., Ltd of treasured, according to the refined side of the embodiment of the present invention 4
It is prepared by method；
Testing result see the table below：
The pa Berkeley product impurity situation of table 1 contrasts
From table it was found from results contrast, the pa Berkeley product that process for purification of the invention obtains can be by total impurities content
Control is below 0.1%, and maximum single impurity content control is below 0.05%；And the crude product of prior art synthesis passes through this hair
Bright process for purification is refined, and can also control product impurity content below 0.1%, and maximum single impurity content control exists
Less than 0.05%.
Claims (8)
1. a kind of process for purification of pa Berkeley, including the synthesis of pa Berkeley crude product and refining for pa Berkeley, its feature exists
In the process for purification of described pa Berkeley comprises the following steps：
(1) pa Berkeley crude product is added in deionized water, is heated to 40~70 DEG C of dissolvings completely, is cooled to 0~5 DEG C of precipitation
Solid, filtering, obtains pa Berkeley crude product；
(2) ethanol and 2- butanone mixed organic solvents are added, is heated to reflux to being completely dissolved, is added activated carbon decolorizing, filter, filter
Liquid is cooled to 5 DEG C~10 DEG C, static crystallization；
(3) filter, carry out elution crystal with ethanol, vacuum drying obtains refined pa Berkeley.
2. the process for purification of pa Berkeley according to claim 1, it is characterised in that the conjunction of described pa Berkeley crude product
Into comprising the following steps：
A, compounds Ⅳ is made in the annulation in caustic alcohol and ethanol to acetyl group diethyl malonate (II) with compound III；
B, compounds Ⅳ and POCl3 react in toluene solvant, and reaction terminates, and cool down, crystallization, filtering, compound V are made；
C, compound V stirs 30min in sodium hydroxide, isopropanol with ethyl acetoacetate in 40-50 DEG C, adds cyclopentamine and enters
Compound VII is made in row " one kettle way " reaction；
D, compound VII is reacted under palladium bichloride hydroconversion condition is made finished product pa Berkeley (I).
3. the process for purification of pa Berkeley according to claim 1 or 2, it is characterised in that pa Berkeley it is refined in, step
Suddenly pa Berkeley and the mass volume ratio of deionized water are 1 in (1):1~60g/mL.
4. the process for purification of pa Berkeley according to claim 1 or 2, it is characterised in that pa Berkeley it is refined in, step
Suddenly the volume ratio of (2) mixed organic solvents and deionized water is 1~80:1, the volume ratio of ethanol and 2- butanone is 2~4:1, it is living
The property carbon decoloring time is 10~30min.
5. the process for purification of pa Berkeley according to claim 1 or 2, it is characterised in that weigh pa Berkeley crude product
30g, 900mL deionized waters are added, be heated to 60 DEG C of dissolvings completely, be cooled to 0~5 DEG C of precipitation solid, filtering, add ethanol
720mL and 2- butanone 180mL, it is heated to reflux to being completely dissolved, adds activated carbon decolorizing 30min, filtering, filtrate is cooled to 5 DEG C
~10 DEG C, static crystallization 1h；Filtering, is eluted with ethanol, is dried in vacuo, is obtained refined pa Berkeley.
6. the process for purification of pa Berkeley according to claim 2, it is characterised in that acetyl group described in step a the third two
The mass volume ratio of diethyl phthalate and ethanol is 1:10~15g/mL, acetyl group diethyl malonate (II) rub with compound III
You are than being 1:1~1.1.
7. the process for purification of pa Berkeley according to claim 2, it is characterised in that the step b is：In step a systems
POCl3, toluene, N are sequentially added in the compounds Ⅳ obtained, N- dimethyl amines are stirred at reflux 2h, are cooled to 25~30 DEG C, fall
Enter crystallization in frozen water, filter, obtain compound V.
8. the process for purification of pa Berkeley according to claim 2, it is characterised in that the step c is:In step b systems
The compound V obtained, ethyl acetoacetate, sodium hydroxide, isopropanol, 30min is stirred in 40-50 DEG C, add cyclopentamine, stirring
Flow back 3h, filtering, obtains compound VII.
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| CN201710946081.8A CN107722005B (en) | 2017-10-12 | 2017-10-12 | A kind of refining methd of pa Berkeley |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110563607A (en) * | 2019-10-25 | 2019-12-13 | 许昌远志生物科技有限公司 | refining method of MK-2866 |
| CN111157319A (en) * | 2019-10-29 | 2020-05-15 | 谢至刚 | Formula and preparation method of destaining solution of gram staining solution |
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| US20170247380A1 (en) * | 2014-11-26 | 2017-08-31 | Suzhou Miracpharma Technology Co., Ltd. | Method for preparing palbociclib |
| CN105111205B (en) * | 2015-09-12 | 2017-01-04 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Pa Boxini |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563607A (en) * | 2019-10-25 | 2019-12-13 | 许昌远志生物科技有限公司 | refining method of MK-2866 |
| CN111157319A (en) * | 2019-10-29 | 2020-05-15 | 谢至刚 | Formula and preparation method of destaining solution of gram staining solution |
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| CN107722005B (en) | 2019-05-03 |
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