CN106008499B - A kind of method for preparing CDK46 kinase inhibitors Pa Boxini - Google Patents

A kind of method for preparing CDK46 kinase inhibitors Pa Boxini Download PDF

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CN106008499B
CN106008499B CN201610319207.4A CN201610319207A CN106008499B CN 106008499 B CN106008499 B CN 106008499B CN 201610319207 A CN201610319207 A CN 201610319207A CN 106008499 B CN106008499 B CN 106008499B
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pyrimidine
amino
methyl
cyclopenta
pyridine radicals
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CN106008499A (en
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刘淑兰
王晓娟
毕宝亮
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Liu Shulan
Wang Xiaojuan
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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 method for preparing CDK46 kinase inhibitors Pa Boxini, comprise the following steps：1) by compound N cyclopenta 5 methyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] 6 bromopyridines shown in formula (I) simultaneously [2,3 d] (8H) ketone of pyrimidine 7 reacts 5 methyl of compound N cyclopenta 6 acetenyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] pyrido [2,3 d] pyrimidine 7 (8H) ketone shown in generation formula (II) in the presence of the cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn；2) by step 1) 5 methyl of compound N cyclopenta 6 acetenyl 2 [[5 (1 piperazinyl) 2 pyridine radicals] amino] pyrido [2,3 d] pyrimidine 7 (8H) ketone shown in obtained formula (II) obtains Pa Boxini in acidic aqueous solution reclaimed water solution；

Description

A kind of method for preparing CDK46 kinase inhibitors Pa Boxini
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of side for preparing CDK46 kinase inhibitors Pa Boxini Method.
Background technology
Pa Boxini (Palbociclib), is the global first CDK4/6 kinase inhibitors developed by Pfizer, is used for The first-line treatment of estrogen receptor positive (ER+) and negative (HER2-) advanced breast cancer of human epidermal growth factor receptor 2.Pa Bo Chemical entitled 6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (1- the piperazinyls) -2- pyridine radicals] amino] pyrido of western Buddhist nun [2,3-d] pyrimidine -7 (8H) -one, concrete structure is as follows：
WO2008032157 discloses a kind of Pa Boxini synthetic method, and this method is with the chloro- 5- bromines of 2,4- bis- and ring penta Base amine is that initiation material obtains target product by seven steps, and specific synthetic route is as follows：
The synthetic method route is long, wherein the reaction of the 5th step has Cl and Br competitive reaction, yield is not high and purifies tired Difficulty, also and its strictly, in addition, Heck reacts this method twice, the use of precious metal palladium catalyst is also big for reaction condition requirement Improve production cost greatly.
CN104447743B discloses a kind of Pa Boxini preparation method, and this method is with 2- acetyl group -2- butenoic acid first Ester and malononitrile make initiation material, through cyclization, with Cyclopentane halide necleophilic reaction then with N- [5- (1- piperazinyls) -2- pyridines Base] guanidine condensation, the obtained Pa Boxini of the dehydrogenation reaction that then grown prosperity in the presence of sodium selenate.Although this method is preparation Pa Boxini There is provided new approach, but the overall yield of this method or relatively low, this is mainly due to the 3rd step and N- [5- (1- piperazines Base) -2- pyridine radicals] yield is relatively low, the reaction time is long for guanidine condensation, and this method dehydrogenation reaction has used hypertoxic sodium selenate in addition, no Preferably mass produce, and be unfavorable for the health of labourer.
Therefore, this area needs a kind of method for preparing Pa Boxini of simple, mild condition and high income badly.
The content of the invention
It is an object of the invention to the defect for overcoming above-mentioned prior art, there is provided a kind of new preparation Pa Boxini intermediates Method, this method is simple, mild condition, and yield is higher, is particularly suitable for industrial-scale production.
The present inventor has found under study for action, in Pa Boxini preparation process, can use and trimethyl silicane Alkyl acetylene connects alkynyl, then obtains acetyl group by the method for hydrolysis, and this method avoid use precious metal and condition is severe The heck at quarter reacts and uses toxic reagent catalytic dehydrogenation, and mild condition, overall yield is higher, while it also avoid heavy metal Residual in the product, so as to complete the present invention.
To achieve these goals, the present invention provides a kind of method for preparing CDK46 kinase inhibitors Pa Boxini, the party Method comprises the following steps：
1) by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] - Simultaneously [2,3-d] pyrimidine -7 (8H) -one reacts production to 6- bromopyridines in the presence of iodine and cesium carbonate with trimethylsilanylethyn (II) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyridine shown in And [2,3-d] pyrimidine -7 (8H) -one；
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one obtains Pa Boxi in acidic aqueous solution reclaimed water solution Buddhist nun；
Preferably, N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] -6- bromopyridines simultaneously [2, 3-d] (8H) -one of pyrimidine -7 and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide be 1：1.2~2.5：0.4 ~0.7：1.5~3.
Preferably, N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] -6- bromopyridines simultaneously [2, 3-d] (8H) -one of pyrimidine -7 and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide be 1：1.5~1.8：0.4 ~0.5：2~3.
Preferably, step 1) reaction condition include：Reaction temperature is 55~65 DEG C, and the solvent of reaction is THF.The condition Under, step 1) reaction can complete within 3~4 hours.
Although the reaction of the present invention can react under household condition, in order to avoid air etc. must influence on reacting, preferably In the case of, step 1) reaction carried out in the presence of protective gas, the protective gas be nitrogen, helium or argon gas.
Step 2 in the present invention) hydrolysis, be not particularly limited for acid solution, for example 5~15 weights Measure % aqueous sulfuric acid.Preferably, step 2) hydrolysis condition include：Reaction temperature is 70~80 DEG C, the catalyst of hydrolysis For AuCl, AuCl consumption is N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrrole Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one weight 2~5%.In the conditions of the invention, the reaction of hydrolysis 2~3 hours Complete.
In the present invention, the compound shown in initiation material formula (I) used in the present invention is commercially available or root Prepare, for example, can be prepared according to the preparation method in WO200832157 or WO2014128588 according to prior art.
In the present invention, the amount of solvent for use is not particularly limited in reaction, can be determined according to actual tests, example As added 1~10ml solvents per 1g inventorys.
Signified room temperature of the invention refers to 25 DEG C ± 5 DEG C.
In the present invention, can be monitored tracking to reaction using the conventional method in this area, such as TLC, LCMS, GCMS etc., reaction finish finger TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than 2%.
Specifically, synthetic route of the invention is as follows：
The invention provides a kind of new way for preparing Pa Boxini, it is to avoid uses precious metal or poisonous dehydrating agent Gentle Deng, reaction condition, overall yield is also higher, is more suitable for industrialized production.
Other features and advantages of the present invention will be described in detail in subsequent embodiment part.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without It is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of method for preparing CDK46 kinase inhibitors Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyrroles Piperidinyl] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 48.4g (100mmol) at cuprous bromide 5.7g (40mmol) With 55 DEG C of reactions 3 in THF with trimethylsilanylethyn 16.7g (170mmol) in the presence of potassium tert-butoxide 28g (250mmol) Hour, after reaction terminates, remove solvent under reduced pressure, wash, recrystallizing methanol, compound N-ring penta shown in dry formula (II) Base -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 34.4g, yield is 80.2%, purity 99.90% (HPLC area normalization methods).
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] (8H) -one of pyrimidine -7 20g is added to acidic aqueous solution (10% sulfuric acid The aqueous solution) under AuCl0.8g catalysis 75 DEG C hydrolyze 2 hours, reaction end is cooled to room temperature, ether extraction, concentrates, washing, Recrystallizing methanol, is dried to obtain Pa Boxini 18.5g, and yield is 88.7%, purity 99.98% (HPLC area normalization methods).
Embodiment 2
A kind of method for preparing CDK46 kinase inhibitors Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyrroles Piperidinyl] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 48.4g (100mmol) at cuprous bromide 5.7g (40mmol) With 65 DEG C of reactions 4 in THF with trimethylsilanylethyn 17.7g (180mmol) in the presence of potassium tert-butoxide 28g (200mmol) Hour, after reaction terminates, remove solvent under reduced pressure, wash, recrystallizing methanol, compound N-ring penta shown in dry formula (II) Base -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 34.2g, yield is 79.7%, purity 99.90% (HPLC area normalization methods).
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] (8H) -one of pyrimidine -7 20g is added to acidic aqueous solution (15% sulfuric acid The aqueous solution) under AuCl 0.6g (3%) catalysis 80 DEG C hydrolyze 3 hours, reaction end is cooled to room temperature, ether extraction, dense Contracting, washing, recrystallizing methanol is dried to obtain Pa Boxini 18.6g, and yield is 89.1%, and purity 99.91% (return by HPLC areas One method).
Embodiment 3
A kind of method for preparing CDK46 kinase inhibitors Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyrroles Piperidinyl] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 48.4g (100mmol) at cuprous bromide 7.2g (50mmol) With 60 DEG C of reactions in THF with trimethylsilanylethyn 14.7g (150mmol) in the presence of potassium tert-butoxide 33.7g (300mmol) 3 hours, after reaction terminates, remove solvent under reduced pressure, wash, recrystallizing methanol, compound N-ring penta shown in dry formula (II) Base -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 33.9g, yield is 78.9%, purity 99.90% (HPLC area normalization methods).
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] (8H) -one of pyrimidine -7 20g is added to acidic aqueous solution (10% sulfuric acid The aqueous solution) under AuCl1.0g (5%) catalysis 70 DEG C hydrolyze 3 hours, reaction end is cooled to room temperature, ether extraction, concentration, Washing, recrystallizing methanol is dried to obtain Pa Boxini 18.0g, and yield is 86.4%, (the HPLC area normalizations of purity 99.91% Method).
Embodiment 4
A kind of method for preparing CDK46 kinase inhibitors Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyrroles Piperidinyl] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 48.4g (100mmol) at cuprous bromide 10g (70mmol) With 55 DEG C of reactions in THF with trimethylsilanylethyn 24.6g (250mmol) in the presence of potassium tert-butoxide 16.8g (150mmol) 4.5 hours, after reaction terminates, remove solvent under reduced pressure, wash, recrystallizing methanol, compound N-ring shown in dry formula (II) Amyl group -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) - Ketone 32.4g, yield is 75.4%, purity 99.90% (HPLC area normalization methods).
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] (8H) -one of pyrimidine -7 20g is added to acidic aqueous solution (5% sulfuric acid water Solution) under AuCl0.4g (2%) catalysis 70 DEG C hydrolyze 3.5 hours, reaction end is cooled to room temperature, ether extraction, concentration, Washing, recrystallizing methanol is dried to obtain Pa Boxini 18.2g, and yield is 87.6%, (the HPLC area normalizations of purity 99.84% Method).
Embodiment 5
A kind of method for preparing CDK46 kinase inhibitors Pa Boxini, this method comprises the following steps：
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyrroles Piperidinyl] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one 48.4g (100mmol) at cuprous bromide 5.7g (40mmol) With 65 DEG C of reactions in THF with trimethylsilanylethyn 11.8g (120mmol) in the presence of potassium tert-butoxide 22.4g (200mmol) 3.5 hours, after reaction terminates, remove solvent under reduced pressure, wash, recrystallizing methanol, compound N-ring shown in dry formula (II) Amyl group -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) - Ketone 32.5g, yield is 75.6%, purity 99.90% (HPLC area normalization methods).
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in obtained formula (II) Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] (8H) -one of pyrimidine -7 20g is added to acidic aqueous solution (10% sulfuric acid The aqueous solution) under AuCl0.6g (3%) catalysis 80 DEG C hydrolyze 3 hours, reaction end is cooled to room temperature, ether extraction, concentration, Washing, recrystallizing methanol is dried to obtain Pa Boxini 17.8g, and yield is 85.6%, (the HPLC area normalizations of purity 99.87% Method).
Embodiment 6
Method as prepared CDK46 kinase inhibitors Pa Boxini in embodiment 1, except that, in step 2) in, no Make AuCl, obtain Pa Boxini 11.0g, yield is 53.2%, purity 87.91% (HPLC area normalization methods).
Comparative example 1
Method as prepared CDK46 kinase inhibitors Pa Boxini in embodiment 1, except that, in step 1) in, no Using cuprous bromide and potassium tert-butoxide, compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- shown in formula (II) are obtained Piperazinyl) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 6.6g, yield is 15.3%.
Comparative example 2
Method as prepared CDK46 kinase inhibitors Pa Boxini in embodiment 1, except that, in step 1) in, no Using cuprous bromide, compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- shown in formula (II) are obtained Pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 21.9g, yield is 51.0%, (the HPLC areas of purity 94.09% Normalization method)
Comparative example 3
Method as prepared CDK46 kinase inhibitors Pa Boxini in embodiment 1, except that, in step 1) in, make Potassium tert-butoxide is substituted with the potassium carbonate of same molar, compound N-cyclopenta -5- methyl -6- acetylene shown in formula (II) is obtained Base -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one 28.2g, yield is 65.7%, purity 97.32% (HPLC area normalization methods).
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention Close, as long as it is without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.

Claims (4)

1. a kind of method for preparing CDK46 kinase inhibitors Pa Boxini, it is characterised in that this method comprises the following steps：
1) by the compound N shown in formula (I)-cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] -6- bromines Pyrido [2,3-d] (8H) -one of pyrimidine -7 is reacted in the presence of cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn gives birth to Into the compound N shown in formula (II)-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] Pyrido [2,3-d] pyrimidine -7 (8H) -one；N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- pyridine radicals] amino] -6- Simultaneously [2,3-d] pyrimidine -7 (8H) -one and trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide are 1 to bromopyridine： 1.2~2.5：0.4~0.7：1.5~3；Step 1) reaction condition include：Reaction temperature is 55~65 DEG C, and the solvent of reaction is THF；
2) by step 1) compound N-cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazines shown in obtained formula (II) Base) -2- pyridine radicals] amino] pyrido [2,3-d] pyrimidine -7 (8H) -one obtains Pa Boxini in acidic aqueous solution reclaimed water solution；Water The catalyst of solution is AuCl；
2. according to the method described in claim 1, it is characterised in that N- cyclopenta -5- methyl -2- [[5- (1- piperazinyls) -2- Pyridine radicals] amino] -6- bromopyridines simultaneously [2,3-d] pyrimidine -7 (8H) -one and trimethylsilanylethyn, cuprous bromide, the tert-butyl alcohol The mol ratio of potassium is 1：1.5~1.8：0.4~0.5：2~3.
3. the condition of hydrolysis includes according to the method described in claim 1, it is characterised in that step 2)：Reaction temperature be 70~ 80 DEG C, the catalyst of hydrolysis is AuCl, and AuCl consumption is N- cyclopenta -5- methyl -6- acetenyls -2- [[5- (1- piperazines Base) -2- pyridine radicals] amino] and pyrido [2,3-d] pyrimidine -7 (8H) -one weight 2~5%.
4. reaction according to the method described in claim 1, it is characterised in that step 1) is carried out in the presence of protective gas, institute Protective gas is stated for nitrogen, helium or argon gas.
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CN106866666B (en) * 2017-04-06 2020-03-20 山东裕欣药业有限公司 Palbociclib crystal form compound and preparation method thereof
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