CN112920182A - Preparation method of palbociclib - Google Patents
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- 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
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Abstract
The invention provides a preparation method of palbociclib. Specifically, the 2-acetyl-2-butenoic acid is prepared by condensing and hydrolyzing ethyl acetoacetate and acetaldehyde instead of crotonic acid, and acetyl is not required to be carried out through complicated steps, so that the synthetic route is simplified. The preparation method of the invention has the advantages of simple and safe synthesis method, high product purity and high yield.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of palbociclib.
Background
The palbociclib is the first global marketed oral targeting CDK4/6 inhibitor developed by fevered, can selectively inhibit cyclin dependent kinases 4 and 6(CDK4/6), restores cell cycle control and blocks tumor cell proliferation. It may be used in combination with Femara for first-line treatment of HR +/HER 2-advanced or metastatic breast cancer in postmenopausal women who have not previously received systemic treatment to control advanced disease. Can also be combined with Aslicon oncology drug Faslodex for treating female patients with hormone receptor positive (HR +), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer after endocrine therapy. The drug is on the market with accelerated FDA approval in the us at 2 menses in 2015. Its chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2- [ [5- (piperazin-1-yl) pyridin-2-yl ] amino ] -8H-pyrido [2,3-D ] pyrimidin-7-one, the structure of which is shown below:
the synthesis method of palbociclib reported in patent WO2014128588 a1 is as follows:
in the patent, crotonic acid is used as a raw material, and acetyl is added to the raw material to carry out a complicated step, so that the total yield is reduced.
Therefore, it is necessary to develop a preparation method of palbociclib, which can simplify the synthesis steps and improve the yield and purity.
Disclosure of Invention
The invention aims to provide a novel preparation method of palbociclib.
In a first aspect of the invention, a preparation method of palbociclib is provided, which comprises the following steps:
(i-a) in an inert solvent, in the presence of a condensing agent, condensing and hydrolyzing ethyl acetoacetate and acetaldehyde to obtain 2-acetyl-2-butenoic acid (A);
(i-B) reacting 5-bromo-2, 4-dichloropyrimidine with cyclopentylamine in an inert solvent in the presence of an acid-binding agent to obtain 5-bromo-2-chloro-6-cyclopentylamine-pyridylpyrimidine (B);
(ii) reacting the compound A with the compound B in an inert solvent under the action of a catalyst under the alkaline condition to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridine [2,3-d ] pyrimidine-7-ketone (C);
(iii) reacting compound C with compound D in an inert solvent under basic conditions to give 4- {6- [ 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyridin [2,3-D ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (E);
(iv) compound E was Boc-removed to give palbociclib.
In another preferred embodiment, in the step (i-a) and the step (i-b), the solvent is independently selected from the group consisting of: anhydrous methanol, anhydrous ethanol, toluene, or a combination thereof, preferably anhydrous ethanol.
In another preferred embodiment, in the step (ii), the solvent is selected from the group consisting of: NMP, n-butanol, dioxane, or a combination thereof, more preferably NMP.
In another preferred embodiment, in the step (iii), the solvent is selected from the group consisting of: anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous toluene, or combinations thereof, more preferably anhydrous tetrahydrofuran.
In another preferred embodiment, in the step (i-a), the molar ratio of acetaldehyde to ethyl acetoacetate is 1: 1.2-1.5.
In another preferred embodiment, in the step (i-a), the molar ratio of acetaldehyde to ethyl acetoacetate is 1: 1.3.
In another preferred embodiment, in the step (i-a), the condensing agent is piperidine.
In another preferred embodiment, in the step (i-a), the reaction temperature is 0 to 70 ℃, preferably 10 to 50 ℃, and more preferably 20 to 30 ℃.
In another preferred embodiment, in the step (i-a), the reaction time is 1-24h, preferably 2-8h, more preferably 6 h.
In another preferred embodiment, in the step (i-a), hydrolysis is carried out in the presence of a base.
In another preferred example, in the step (i-a), the alkali solution is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a combination thereof, preferably, an aqueous solution of sodium hydroxide.
In another preferred embodiment, in the step (i-a), after hydrolysis in the presence of a base, the pH is adjusted with an acid.
In another preferred embodiment, in the step (i-a), the pH is adjusted with hydrochloric acid.
In another preferred embodiment, in the step (i-b), the molar ratio of 5-bromo-2, 4-dichloropyrimidine to cyclopentylamine is 1: 1.0-1.5.
In another preferred embodiment, in the step (i-b), the molar ratio of 5-bromo-2, 4-dichloropyrimidine to cyclopentylamine is 1: 1.1-1.3; more preferably 1: 1.2.
In another preferred embodiment, in the step (i-b), the acid-binding agent is selected from the group consisting of: triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate, sodium carbonate, or a combination thereof.
In another preferred example, in the step (i-b), the acid-binding agent is triethylamine.
In another preferred example, in the step (i-b), the molar ratio of the 5-bromo-2, 4-dichloropyrimidine to the acid-binding agent is 1: 2.5-8.0; preferably, 1: 4-6; more preferably, 1: 5.
In another preferred embodiment, in the step (i-b), the reaction temperature is 0 to 70 ℃, preferably 10 to 50 ℃, and more preferably 20 to 30 ℃.
In another preferred embodiment, in the step (i-b), the reaction time is 1-4h, preferably 2-3h, more preferably 2 h.
In another preferred embodiment, in the step (ii), the molar ratio of the compound B to the compound A is 1: 2-4.
In another preferred embodiment, in the step (ii), the molar ratio of the compound B to the compound a is 1: 2.3-2.8; preferably 1: 2.5.
In another preferred embodiment, in the step (ii), the volume mass ratio of the inert solvent to the compound B is 1: 2-10; preferably, 1: 3-7; more preferably, 1: 5.
In another preferred embodiment, the catalyst is palladium acetate, palladium chloride or a combination thereof, preferably palladium acetate.
In another preferred example, in the step (ii), the base is triethylamine.
In another preferred embodiment, in the step (ii), the molar ratio of the compound B to triethylamine is 1: 3-9; preferably, 1: 4-6; more preferably, 1: 5.
In another preferred embodiment, in the step (ii), the mass ratio of the compound B to the catalyst is 1: 0.01-0.04.
In another preferred embodiment, in the step (ii), the mass ratio of the compound B to the catalyst is 1: 0.02-0.03; more preferably 1: 0.025.
In another preferred embodiment, in the step (ii), the reaction temperature is 0 to 90 ℃, preferably 50 to 70 ℃, and more preferably 65 ℃.
In another preferred embodiment, in the step (ii), the reaction time is 1-10h, preferably 5-8h, and more preferably 6 h.
In another preferred embodiment, in the step (ii), acetic anhydride is further added.
In another preferred embodiment, the molar ratio of the compound B to the acetic anhydride is 1: 1.3-2.5; preferably, 1: 1.6-1.9; more preferably, 1: 1.8.
In another preferred embodiment, in the step (ii), after adding acetic anhydride, the reaction is continued for 1 to 4 hours, preferably 2 to 3 hours, and more preferably 2 hours.
In another preferred embodiment, in the step (iii), the molar ratio of the compound C to the compound D is 1:1.2 to 1.8.
In another preferred embodiment, in the step (iii), the molar ratio of the compound C to the compound D is 1: 1.4-1.6; preferably 1: 1.5.
In another preferred embodiment, in the step (iii), the mass ratio of the volume of the solvent to the compound C is 1: 6-20; preferably, 1: 8-12; more preferably, 1: 10.
In another preferred embodiment, in the step (iii), the temperature is 0 to 30 ℃, more preferably 10 to 20 ℃.
In another preferred embodiment, in the step (iii), the reaction time is 10-24h, preferably 14-18h, and more preferably 16 h.
In another preferred embodiment, in the step (iii), the base is LDA, LiHMDS, butyllithium, or a combination thereof.
In another preferred embodiment, in the step (iii), the molar ratio of the compound C to the base is 1: 1.5-3.0; preferably, 1: 1.8-2.2; more preferably, 1: 2.0.
In another preferred embodiment, in the step (iii), the base is LiHMDS.
In another preferred example, in the step (iv), after the compound E is subjected to de-Boc under acidic conditions, the pH is adjusted to 10 by using alkaline solution to obtain the palbociclib.
In another preferred embodiment, in the step (iv), the reaction temperature is 30 to 80 ℃, preferably 45 to 75 ℃, and more preferably 75 ℃.
In another preferred embodiment, in the step (iv), the acid is selected from the group consisting of: hydrogen chloride gas, concentrated hydrochloric acid, acetyl chloride, or a combination thereof, preferably concentrated hydrochloric acid.
In another preferred embodiment, in the step (iv), the reaction time is 1 to 4 hours, preferably 1.5 to 3 hours, and more preferably 2 hours.
In another preferred embodiment, in the step (iv), the alkali solution is selected from the group consisting of: aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, aqueous potassium carbonate, or a combination thereof, preferably aqueous sodium hydroxide.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor develops a preparation method of palbociclib through extensive and intensive research and a large number of screening and tests, and the preparation method is simple and safe to operate, high in product purity and high in yield. The present invention has been completed based on this finding.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein;
"v" refers to the volume to mass ratio.
The term "compound a" is used interchangeably with "2-acetyl-2-butenoic acid".
The term "compound B" is used interchangeably with "5-bromo-2-chloro-6-cyclopentylamine-pyridylpyrimidine".
The term "compound C" is used interchangeably with "6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one".
The term "compound D" is used interchangeably with "4- (6-aminopyridine-3-acyl) -piperazine-1-carboxylic acid tert-butyl ester".
The term "compound E" is used interchangeably with "4- {6- [ 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyrido [2,3-d ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester".
The term "THF": tetrahydrofuran (THF)
The term "NMP": n-methyl-2-pyrrolidone
The term "Boc": tert-butyloxycarbonyl radical
The term "LDA": lithium diisopropylamide
The term "LiHMDS": hexamethyldisilazane-based aminolithium salt
A preparation method of palbociclib comprises the following steps:
performing condensation hydrolysis on ethyl acetoacetate and acetaldehyde to obtain 2-acetyl-2-butenoic acid, performing condensation reaction on 5-bromo-2-chloro-6-cyclopentylamine-pyridinopyrimidine prepared by reacting 5-bromo-2, 4-dichloropyrimidine with cyclopentylamine to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridino [2,3-d ] pyrimidin-7-one, and reacting on 4- (6-aminopyridine-3-acyl) -piperazine-1-carboxylic acid tert-butyl ester to obtain 4- {6- [ 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyridino [2 ], 3-d ] pyrimidine-2-amino ] -pyridine-3-yl } -piperazine-1-carboxylic acid tert-butyl ester is subjected to Boc removal and alkali adjustment under acidic conditions to obtain the palbociclib. The preparation method of the invention uses 2-acetyl-2-butenoic acid to replace crotonic acid, so that the synthesis route is simplified, the product yield is improved, the post-treatment is simple, the green environmental protection concept is met, and the preparation method is suitable for industrial production.
More specifically, the method comprises the following steps:
step (1): dissolving ethyl acetoacetate in a solvent, adding a condensing agent, adding acetaldehyde, reacting for a certain time at a proper temperature after the addition is finished, dropwise adding alkali liquor after the reaction is finished, reacting for a certain time, removing the solvent by rotary evaporation after the reaction is finished, adding water, adjusting acid, extracting, and removing the solvent by rotary evaporation to obtain a compound A; wherein, the condensing agent can be a condensing agent commonly used in the field, such as piperidine; in this step, the reaction solvent, the reaction temperature, the reaction time, etc. may be selected according to the specific reactants, for example, the reaction temperature may be 0 to 70 ℃, preferably 10 to 50 ℃, more preferably 20 to 30 ℃; the certain time can be 1-24h, preferably 2-8h, more preferably 6 h; the alkali solution is sodium hydroxide water solution, potassium hydroxide water solution, sodium carbonate water solution, potassium carbonate water solution or their combination.
Step (2): dissolving 5-bromo-2, 4-dichloropyrimidine in a solvent, adding an acid-binding agent, cooling, dropwise adding cyclopentylamine, reacting for a certain time at a proper temperature after dropwise adding, adding water, stirring and filtering to obtain a compound B; wherein, the acid-binding agent can be an acid-binding agent commonly used in the field, such as: triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate, sodium carbonate, or a combination thereof; in this step, the reaction solvent, the reaction temperature, the reaction time, etc. may be selected according to the specific reactants, for example, the reaction temperature may be 0 to 70 ℃, preferably 10 to 50 ℃, more preferably 20 to 30 ℃; the reaction time may be 1 to 4 hours, preferably 2 to 3 hours, more preferably 2 hours.
And (3): dissolving a compound B in a solvent, adding triethylamine, a compound A, a catalyst and nitrogen protection, reacting for a certain time at a proper temperature, adding acetic anhydride to react for a certain time after the reaction is completed, filtering after the reaction is completed, recovering the catalyst, adding water, stirring, and filtering to obtain a compound C; among them, the catalyst may be a commonly used palladium catalyst such as palladium acetate, palladium chloride or a combination thereof; in this step, the reaction solvent, the reaction temperature, the reaction time, etc. may be selected according to the specific reactants, for example, the reaction temperature may be 0 to 90 ℃, preferably 50 to 70 ℃, more preferably 65 ℃; the reaction time may be 1 to 10 hours, preferably 5 to 8 hours, more preferably 6 hours.
And (4): dissolving the compound D in a solvent, dropwise adding a hydrogen drawing reagent (alkali) under the protection of nitrogen at a certain temperature, stirring for a certain time, adding the compound C in batches, reacting for a certain time at room temperature, adding acetic acid after the reaction is completed, separating out a solid, and filtering to obtain a compound E; the hydrogen-withdrawing agent is an organic strong base commonly used in the art, and can be, for example, LDA, LiHMDS, butyllithium, or a combination thereof; in this step, the reaction solvent, the reaction temperature, the reaction time, and the like may be selected according to the specific reactants, for example, the reaction temperature may be 0 to 30 ℃, and more preferably 10 to 20 ℃.
And (5): adding the compound E into a solvent, stirring, removing Boc under an acidic condition at a certain temperature, stirring for a certain time to react completely, adding anisole, adjusting the pH to 10 with an alkali solution, separating liquid, carrying out organic phase thermal reflux to separate water, cooling, and filtering to obtain palbociclib; wherein the acid is hydrogen chloride gas, concentrated hydrochloric acid, acetyl chloride, or a combination thereof; the alkali solution is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, or their combination; in this step, the reaction solvent, the reaction temperature, the reaction time, and the like may be selected according to the specific reactants, for example, the reaction temperature is 30 to 80 ℃, preferably 45 to 75 ℃, and more preferably 75 ℃.
The main advantages of the invention include:
(1) the invention adopts the preparation method of replacing crotonic acid with 2-acetyl-2-butenoic acid to directly obtain the product with acetyl, and does not need to add acetyl through complicated steps, thereby simplifying the synthetic route.
(2) The preparation method of the 2-acetyl-2-butenoic acid used in the invention is simple and easy to prepare.
(3) The synthetic route of the invention has short production period, high total reaction yield, mild reaction conditions and high product purity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Examples
EXAMPLE 1 Synthesis of Compound A
Dissolving ethyl acetoacetate (100.0g, 0.7684mol) in absolute ethyl alcohol (500mL, 5v), stirring, adding piperidine (98.2g, 1.1526mol), reacting acetaldehyde (44.0g, 0.9989mol) at the temperature of 20-30 ℃ for 6h, after the reaction is completed, dropwise adding 30% sodium hydroxide aqueous solution (175mL), stirring for 2h, completing the reaction, removing ethanol by rotary evaporation, adding water (500mL) into the rotary evaporation, stirring and separating ethyl acetate (300mL), adjusting the pH of the aqueous phase to 3-4 by using dilute hydrochloric acid, extracting by using ethyl acetate (500mL), drying, and spin-drying the organic phase to obtain 81.3g of compound A, wherein the yield is as follows: 82.6% (calculated as ethyl acetoacetate), MS (ESI): [ M +1 ]]+＝129.14。
EXAMPLE 2 Synthesis of Compound B
Dissolving 5-bromo-2, 4-dichloropyrimidine (100.0g, 0.4388mol) in absolute ethanol (300mL, 3v) and stirring, adding triethylamine (53.3g, 0.5266mol), cooling to 0-5 ℃, keeping the temperature, dropwise adding cyclopentylamine (44.8g, 0.5266mol), reacting at the temperature of 20-30 ℃ for 2 hours until the reaction is complete, adding water (250mL), stirring, filtering and drying to obtain 106.5g of white solid, wherein the yield is as follows: 87.8% (based on 5-bromo-2, 4-dichloropyrimidine), MS (ESI): [ M +1 ]]+＝277.56。
EXAMPLE 3 Synthesis of Compound C
Dissolving a compound B (80.0g, 0.2893mol) in NMP (400mL, 5v), stirring, adding triethylamine (146.4g, 1.4465mol), a compound A (92.7g, 0.7233mol), palladium acetate (2.0g), protecting with nitrogen, heating to 65 ℃, reacting for 6h, completely reacting, adding acetic anhydride (53.2g, 0.5207mol), reacting for 2h, filtering while hot, recovering the palladium acetate, cooling the filtrate to 10-20 ℃, adding water (800mL), stirring, filtering, and drying to obtain 73.7g of white solid, wherein the yield is as follows: 83.3% (based on compound B), ms (esi): [ M +1 ]]+＝306.75。
EXAMPLE 4 Synthesis of Compound E
Dissolving a compound D (95.6g, 0.3434mol) in anhydrous tetrahydrofuran (700mL, 10v), stirring and cooling for 10-20 ℃, under the protection of nitrogen, maintaining the temperature, dropwise adding LiHMDS tetrahydrofuran solution (470mL, 0.4578mol), stirring for 1h after the dropwise adding is finished, adding a compound C (70.0g, 0.2289mol) in batches, reacting for 15h at room temperature, completely reacting, adding acetic acid (23.4g, 0.3891mol), stirring for 2h, precipitating yellow solid, filtering, drying to obtain 117.5g of yellow fixation, yield: 93.7% (based on Compound C), MS (ESI): [ M +1 ]]+＝548.65。
Example 5 Synthesis of Palbociclib
Adding compound E (110g, 0.2005mol) into n-butanol (1320mL, 12v) and water (1100mL, 10v), stirring, heating to 70 ℃, beginning to dropwise add concentrated hydrochloric acid (49.2g, 0.5013mol), stirring for 2h after dropwise addition, reacting, adding anisole (2000mL, 18v), stirring, adjusting pH to 10 with 30% sodium hydroxide aqueous solution, separating an organic phase, heating the organic phase to reflux to separate water, cooling to 10 ℃, filtering, drying to obtain 76.1g of yellow solid, yield: 84.8% (based on compound E), 99.82% purity ms (esi): [ M +1 ]]+＝448.53。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A preparation method of palbociclib is characterized by comprising the following steps:
(i-a) in an inert solvent, in the presence of a condensing agent, condensing and hydrolyzing ethyl acetoacetate and acetaldehyde to obtain 2-acetyl-2-butenoic acid (A);
(i-B) reacting 5-bromo-2, 4-dichloropyrimidine with cyclopentylamine in an inert solvent in the presence of an acid-binding agent to obtain 5-bromo-2-chloro-6-cyclopentylamine-pyridylpyrimidine (B);
(ii) reacting the compound A with the compound B in an inert solvent under the action of a catalyst under the alkaline condition to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridine [2,3-d ] pyrimidine-7-ketone (C);
(iii) reacting compound C with compound D in an inert solvent under basic conditions to give 4- {6- [ 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyridin [2,3-D ] pyrimidin-2-ylamino ] -pyridin-3-yl } -piperazine-1-carboxylic acid tert-butyl ester (E);
(iv) compound E was Boc-removed to give palbociclib.
2. The process of claim 1, wherein in step (i-a), the molar ratio of acetaldehyde to ethyl acetoacetate is from 1:1.2 to 1.5.
3. The process of claim 1, wherein in step (i-b), the molar ratio of 5-bromo-2, 4-dichloropyrimidine to cyclopentylamine is from 1:1.0 to 1.5.
4. The method of claim 1, wherein in step (i-b), the acid scavenger is selected from the group consisting of: triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate, sodium carbonate, or a combination thereof.
5. The method of claim 1, wherein in step (ii), the molar ratio of compound B to compound a is 1: 2-4.
6. The process of claim 1, wherein in step (ii), the mass ratio of compound B to catalyst is 1: 0.01-0.04.
7. The process of claim 1, wherein in step (ii), acetic anhydride is also added.
8. The method of claim 1, wherein in step (iii), the molar ratio of compound C to compound D is 1:1.2 to 1.8.
9. The method of claim 1, wherein in step (iii), the base is LDA, LiHMDS, butyllithium, or a combination thereof.
10. The method of claim 1, wherein in step (iv), after Boc removal of compound E under acidic conditions, the pH is adjusted to 10 with lye to provide palbociclib.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032157A2 (en) * | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN104496983A (en) * | 2014-11-26 | 2015-04-08 | 苏州明锐医药科技有限公司 | Palbociclib preparation method |
| CN104610254A (en) * | 2015-01-26 | 2015-05-13 | 新发药业有限公司 | Low-cost preparation method for palbociclib |
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
| CN104910149A (en) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | Palbociclib preparation method |
| 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 |
| CN106565707A (en) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | Novel synthetic method of Palbociclib |
| CN107759596A (en) * | 2017-12-05 | 2018-03-06 | 安庆奇创药业有限公司 | A kind of synthesis Pa Boxini method |
| CN108341774A (en) * | 2017-01-25 | 2018-07-31 | 北京赛林泰医药技术有限公司 | Substituted quinolinones inhibitor |
-
2019
- 2019-12-05 CN CN201911234427.7A patent/CN112920182B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032157A2 (en) * | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| CN104447743A (en) * | 2014-11-26 | 2015-03-25 | 苏州明锐医药科技有限公司 | Preparation method for palbociclib |
| CN104496983A (en) * | 2014-11-26 | 2015-04-08 | 苏州明锐医药科技有限公司 | Palbociclib preparation method |
| CN104610254A (en) * | 2015-01-26 | 2015-05-13 | 新发药业有限公司 | Low-cost preparation method for palbociclib |
| CN104910149A (en) * | 2015-04-28 | 2015-09-16 | 上海百奇医药科技有限公司 | Palbociclib preparation method |
| CN104892604A (en) * | 2015-06-19 | 2015-09-09 | 北京康立生医药技术开发有限公司 | Novel synthesis method of CDK4 (cyclin-dependent kinase 4) inhibitor |
| 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 |
| CN106565707A (en) * | 2016-11-03 | 2017-04-19 | 杭州科巢生物科技有限公司 | Novel synthetic method of Palbociclib |
| CN108341774A (en) * | 2017-01-25 | 2018-07-31 | 北京赛林泰医药技术有限公司 | Substituted quinolinones inhibitor |
| CN107759596A (en) * | 2017-12-05 | 2018-03-06 | 安庆奇创药业有限公司 | A kind of synthesis Pa Boxini method |
Non-Patent Citations (4)
| Title |
|---|
| CHAN SIK CHO ET AL.: "An approach for quinolines via palladium-catalyzed Heck coupling followed by cyclization", 《TETRAHEDRON LETTERS》, vol. 48, pages 3775 - 3778, XP022058978, DOI: 10.1016/j.tetlet.2007.04.001 * |
| JAMES MCNULTY ET AL.: "A Tandem "On-Palladium" Heck–Jeffery Amination Route Toward the Synthesis of Functionalized Indole-2-carboxylates", 《EUR. J. ORG. CHEM.》, pages 6902 - 6908 * |
| OLA FJELLSTRÖM ET AL: "Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design", 《PLOS ONE》, vol. 10, pages 1 - 42 * |
| 高芳等: "新型抗乳腺癌药帕博西尼的合成进展", 《化工进展》, vol. 37, pages 242 - 251 * |
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