CN106008499A - Method for preparing CDK46 kinase inhibitor Palbociclib - Google Patents
Method for preparing CDK46 kinase inhibitor Palbociclib Download PDFInfo
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- CN106008499A CN106008499A CN201610319207.4A CN201610319207A CN106008499A CN 106008499 A CN106008499 A CN 106008499A CN 201610319207 A CN201610319207 A CN 201610319207A CN 106008499 A CN106008499 A CN 106008499A
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- piperazinyl
- pyrimidine
- methyl
- amino
- cyclopenta
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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 method for preparing the CDK46 kinase inhibitor Palbociclib. The method includes the following steps that 1, the compound N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6- bromopyridine -[2,3-d]-pyrimidine-7(8H)-ketone shown in the formula (I) reacts with trimethylsilylacetylene in the presence of cuprous bromide and potassium tert-butoxide to generate the compound N-cyclopentyl-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyridino-[2,3-d] pyrimidine-7(8H)-ketone shown in the formula (II); 2, the compound N-cyclopentyl-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyridino-[2,3-d] pyrimidine-7(8H)-ketone shown in the formula (II) and obtained in the step 1 is hydrolyzed in an acid water solution to obtain Palbociclib. By means of the method, a new way for preparing Palbociclib is developed, conditions are mild, and the yield is high.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of method preparing CDK46 inhibitors of kinases Pa Boxini.
Background technology
Pa Boxini (Palbociclib), is the whole world developed by Pfizer first CDK4/6 inhibitors of kinases, is subject to for estrogen
Body positive (ER+) and the first-line treatment of negative (HER2-) advanced breast cancer of human epidermal growth factor receptor 2.Pa Boxini's
Entitled 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine of chemistry
-7 (8H)-one, concrete structure is as follows:
WO2008032157 discloses the synthetic method of a kind of Pa Boxini, and the method is with 2, and 4-bis-chloro-5-bromine and cyclopenta amine are
Beginning raw material obtains target product through seven steps, and concrete synthetic route is as follows:
This synthetic method route is long, and wherein the 5th step reaction exists the competitive reaction of Cl Yu Br, and yield is the highest and purification difficult, instead
Answer condition to require also and strictly, it addition, twice Heck reaction of the method, the use of precious metal palladium catalyst is also greatly improved
Production cost.
CN104447743B discloses the preparation method of a kind of Pa Boxini, and the method is with 2-acetyl group-2-butylene acid methyl ester and the third two
Nitrile makees initiation material, through cyclization and Cyclopentane halide necleophilic reaction, is then condensed with N-[5-(1-piperazinyl)-2-pyridine radicals] guanidine,
Then in the presence of sodium selenate, flouring dehydrogenation reaction prepares Pa Boxini.Although the method is to prepare Pa Boxini to provide new way
Footpath, but the overall yield of the method or relatively low, this contracts with N-[5-(1-piperazinyl)-2-pyridine radicals] guanidine mainly due to the 3rd step
Closing that yield is relatively low, the response time is long, additionally the method dehydrogenation reaction employs severe toxicity sodium selenate, unsuitable large-scale production, and
It is unfavorable for the health of labourer.
Therefore, this area needs a kind of simple, mild condition and the high method preparing Pa Boxini of yield badly.
Summary of the invention
It is an object of the invention to overcome the defect of above-mentioned prior art, it is provided that a kind of new method preparing Pa Boxini intermediate,
The method is simple, mild condition, and yield is higher, is particularly suitable for industrial-scale production.
The present inventor finds under study for action, in the preparation process of Pa Boxini, can use and TMS second
Alkynes connects alkynyl, then obtains acetyl group by the method for hydrolysis, this method avoid and uses precious metal and the heck of condition harshness
Reaction and use toxic reagent catalytic dehydrogenation, mild condition, overall yield is higher, it also avoid heavy metal in the product simultaneously
Residual, thus complete the present invention.
To achieve these goals, the present invention provides a kind of method preparing CDK46 inhibitors of kinases Pa Boxini, and the method includes
Following steps:
1) by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] ,-6-bromopyridine is also
[2,3-d] pyrimidine-7 (8H)-one reacts generation chemical combination shown in formula (II) in the presence of iodine and cesium carbonate with trimethylsilanylethyn
Thing N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one；
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one hydrolyzes in acidic aqueous solution and obtains Pa Boxini；
Preferably, N-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino]-6-bromopyridine also [2,3-d] pyrimidine
-7 (8H)-one is 1:1.2～2.5:0.4～0.7:1.5～3 with trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide.
Preferably, N-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino]-6-bromopyridine also [2,3-d] pyrimidine
-7 (8H)-one is 1:1.5～1.8:0.4～0.5:2～3 with trimethylsilanylethyn, cuprous bromide, the mol ratio of potassium tert-butoxide.
Preferably, step 1) condition reacted includes: reaction temperature is 55～65 DEG C, and the solvent of reaction is THF.Under the conditions of Gai,
Step 1) reaction 3～within 4 hours, can complete.
Although the reaction of the present invention under household condition can be reacted, affect reacting to obtain in order to avoid air etc., under preferable case,
Step 1) reaction carry out in the presence of protective gas, described protective gas is nitrogen, helium or argon.
Step 2 in the present invention) hydrolysis, acid solution is not particularly limited, the sulfur of such as 5～15 weight %
Aqueous acid.Preferably, step 2) condition that hydrolyzes includes: reaction temperature is 70～80 DEG C, and the catalyst of hydrolysis is AuCl,
The consumption of AuCl is N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine
The 2～5% of-7 (8H)-one weight.In the conditions of the invention, the reaction 2 of hydrolysis～can complete for 3 hours.
In the present invention, the compound shown in initiation material formula (I) used in the present invention is commercially available or according to existing skill
Art prepares, such as, can prepare according to the preparation method in WO200832157 or WO2014128588.
In the present invention, in reaction, the amount of solvent for use is not particularly limited, and can determine according to actual tests, the most often
1g inventory adds 1～10ml solvent.
The room temperature of indication of the present invention refers to 25 DEG C ± 5 DEG C.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS, GCMS
Deng, react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue less than 2%.
Specifically, the synthetic route of the present invention is as follows:
The invention provides a kind of new way preparing Pa Boxini, it is to avoid use precious metal or poisonous dehydrating agent etc.,
Reaction condition is gentle, and overall yield is the highest, is more suitable for industrialized production.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments are only limitted to illustrate rather than this
The further restriction of the protection domain of invention.
Embodiment 1
A kind of method preparing CDK46 inhibitors of kinases Pa Boxini, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one 48.4g (100mmol) is cuprous bromide 5.7g (40mmol) and uncle
With trimethylsilanylethyn 16.7g (170mmol) 55 DEG C of reactions in THF in the presence of butanol potassium 28g (250mmol)
3 hours, after reaction terminates, remove solvent under reduced pressure, washing, recrystallizing methanol, it is dried to obtain the compound shown in formula (II)
N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one
34.4g, yield is 80.2%, purity 99.90% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 20g joins in acidic aqueous solution (10% aqueous sulfuric acid) at AuCl
Lower 75 DEG C of 0.8g catalysis hydrolyzes 2 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, recrystallizing methanol,
Being dried to obtain Pa Boxini 18.5g, yield is 88.7%, purity 99.98% (HPLC area normalization method).
Embodiment 2
A kind of method preparing CDK46 inhibitors of kinases Pa Boxini, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one 48.4g (100mmol) is cuprous bromide 5.7g (40mmol) and uncle
With trimethylsilanylethyn 17.7g (180mmol) 65 DEG C of reactions in THF in the presence of butanol potassium 28g (200mmol)
4 hours, after reaction terminates, remove solvent under reduced pressure, washing, recrystallizing methanol, it is dried to obtain the compound shown in formula (II)
N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one
34.2g, yield is 79.7%, purity 99.90% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 20g join in acidic aqueous solution (15% aqueous sulfuric acid)
AuCl 0.6g (3%) is catalyzed lower 80 DEG C and hydrolyzes 3 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, first
Alcohol recrystallization, is dried to obtain Pa Boxini 18.6g, and yield is 89.1%, purity 99.91% (HPLC area normalization method).
Embodiment 3
A kind of method preparing CDK46 inhibitors of kinases Pa Boxini, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one 48.4g (100mmol) is cuprous bromide 7.2g (50mmol) and uncle
In the presence of butanol potassium 33.7g (300mmol) with trimethylsilanylethyn 14.7g (150mmol) in THF 60 DEG C anti-
Answer 3 hours, after reaction terminates, remove solvent under reduced pressure, washing, recrystallizing methanol, it is dried to obtain the compound shown in formula (II)
N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one
33.9g, yield is 78.9%, purity 99.90% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 20g joins in acidic aqueous solution (10% aqueous sulfuric acid) at AuCl
1.0g (5%) is catalyzed lower 70 DEG C and hydrolyzes 3 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, and washing, methanol is heavily tied
Crystalline substance, is dried to obtain Pa Boxini 18.0g, and yield is 86.4%, purity 99.91% (HPLC area normalization method).
Embodiment 4
A kind of method preparing CDK46 inhibitors of kinases Pa Boxini, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one 48.4g (100mmol) is cuprous bromide 10g (70mmol) and uncle
In the presence of butanol potassium 16.8g (150mmol) with trimethylsilanylethyn 24.6g (250mmol) in THF 55 DEG C anti-
Answer 4.5 hours, after reaction terminates, remove solvent under reduced pressure, washing, recrystallizing methanol, it is dried to obtain the chemical combination shown in formula (II)
Thing N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one
32.4g, yield is 75.4%, purity 99.90% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 20g joins in acidic aqueous solution (5% aqueous sulfuric acid) at AuCl
0.4g (2%) is catalyzed lower 70 DEG C and hydrolyzes 3.5 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, washing, methanol weight
Crystallization, is dried to obtain Pa Boxini 18.2g, and yield is 87.6%, purity 99.84% (HPLC area normalization method).
Embodiment 5
A kind of method preparing CDK46 inhibitors of kinases Pa Boxini, the method comprises the following steps:
1) under nitrogen protection, by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one 48.4g (100mmol) is cuprous bromide 5.7g (40mmol) and uncle
In the presence of butanol potassium 22.4g (200mmol) with trimethylsilanylethyn 11.8g (120mmol) in THF 65 DEG C anti-
Answer 3.5 hours, after reaction terminates, remove solvent under reduced pressure, washing, recrystallizing methanol, it is dried to obtain the chemical combination shown in formula (II)
Thing N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one
32.5g, yield is 75.6%, purity 99.90% (HPLC area normalization method).
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 20g joins in acidic aqueous solution (10% aqueous sulfuric acid) at AuCl
0.6g (3%) is catalyzed lower 80 DEG C and hydrolyzes 3 hours, and reaction end is cooled to room temperature, and ether extracts, and concentrates, and washing, methanol is heavily tied
Crystalline substance, is dried to obtain Pa Boxini 17.8g, and yield is 85.6%, purity 99.87% (HPLC area normalization method).
Embodiment 6
Such as the method preparing CDK46 inhibitors of kinases Pa Boxini in embodiment 1, except that, in step 2) in, do not make
AuCl, obtains Pa Boxini 11.0g, and yield is 53.2%, purity 87.91% (HPLC area normalization method).
Comparative example 1
Such as the method preparing CDK46 inhibitors of kinases Pa Boxini in embodiment 1, except that, in step 1) in, do not make
With cuprous bromide and potassium tert-butoxide, obtain the compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 6.6g, yield is 15.3%.
Comparative example 2
Such as the method preparing CDK46 inhibitors of kinases Pa Boxini in embodiment 1, except that, in step 1) in, do not make
With cuprous bromide, obtain the compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals]
Amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 21.9g, yield is 51.0%, purity 94.09% (HPLC area normalization method)
Comparative example 3
Such as the method preparing CDK46 inhibitors of kinases Pa Boxini in embodiment 1, except that, in step 1) in, use
The potassium carbonate of same molar substitutes potassium tert-butoxide, obtains the compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl
-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one 28.2g, yield is 65.7%, purity 97.32%
(HPLC area normalization method).
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to the tool in above-mentioned embodiment
Body details, in the technology concept of the present invention, can carry out multiple simple variant to technical scheme, these
Simple variant belongs to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable feelings
Under condition, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention is to various possible groups
Conjunction mode illustrates the most separately.Additionally, combination in any can also be carried out between the various different embodiment of the present invention, as long as
It is without prejudice to the thought of the present invention, and it should be considered as content disclosed in this invention equally.
Claims (6)
1. the method preparing CDK46 inhibitors of kinases Pa Boxini, it is characterised in that the method comprises the following steps:
1) by the compound N shown in formula (I)-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] ,-6-bromopyridine is also
[2,3-d] pyrimidine-7 (8H)-one reacts generation formula (II) institute in the presence of cuprous bromide and potassium tert-butoxide with trimethylsilanylethyn
The compound N shown-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridine radicals] amino] pyrido [2,3-d] pyrimidine
-7 (8H)-one；
2) by step 1) compound N shown in formula (II)-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-of obtaining
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one hydrolyzes in acidic aqueous solution and obtains Pa Boxini；
Method the most according to claim 1, it is characterised in that N-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine
Base] amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one and trimethylsilanylethyn, cuprous bromide, the rubbing of potassium tert-butoxide
That ratio is 1:1.2～2.5:0.4～0.7:1.5～3.
Method the most according to claim 2, it is characterised in that N-cyclopenta-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine
Base] amino]-6-bromopyridine also [2,3-d] pyrimidine-7 (8H)-one and trimethylsilanylethyn, cuprous bromide, the rubbing of potassium tert-butoxide
That ratio is 1:1.5～1.8:0.4～0.5:2～3.
Method the most according to claim 1, it is characterised in that step 1) condition reacted includes: reaction temperature is 55～65 DEG C,
The solvent of reaction is THF.
5. according to the method described in claim 1-3, it is characterised in that step 2) condition that hydrolyzes includes: reaction temperature is
70～80 DEG C, the catalyst of hydrolysis be the consumption of AuCl, AuCl be N-cyclopenta-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-
Pyridine radicals] amino] pyrido [2,3-d] pyrimidine-7 (8H)-one weight 2～5%.
Method the most according to claim 1, it is characterised in that step 1) reaction exist in protective gas, described
Protective gas is nitrogen, helium or argon.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866666A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Pa Boxini crystal-form compounds and preparation method thereof |
| CN109394767A (en) * | 2017-12-19 | 2019-03-01 | 清华大学 | The purposes of compound in medicine preparation |
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| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN104557499A (en) * | 2013-10-15 | 2015-04-29 | 南京理工大学 | Method for synthesizing methyl ketone |
| CN105111205A (en) * | 2015-09-12 | 2015-12-02 | 山东罗欣药业集团股份有限公司 | Preparation method of palbociclib |
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| CN104557499A (en) * | 2013-10-15 | 2015-04-29 | 南京理工大学 | Method for synthesizing methyl ketone |
| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN105111205A (en) * | 2015-09-12 | 2015-12-02 | 山东罗欣药业集团股份有限公司 | Preparation method of palbociclib |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866666A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Pa Boxini crystal-form compounds and preparation method thereof |
| 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 |
| CN109394767A (en) * | 2017-12-19 | 2019-03-01 | 清华大学 | The purposes of compound in medicine preparation |
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