CN112920182B - Preparation method of palbociclib - Google Patents
Preparation method of palbociclib Download PDFInfo
- Publication number
- CN112920182B CN112920182B CN201911234427.7A CN201911234427A CN112920182B CN 112920182 B CN112920182 B CN 112920182B CN 201911234427 A CN201911234427 A CN 201911234427A CN 112920182 B CN112920182 B CN 112920182B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- temperature
- acetyl
- iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of palbociclib. Specifically, the invention uses the condensation hydrolysis of the ethyl acetoacetate and the acetaldehyde to prepare the 2-acetyl-2-butenoic acid to replace crotonic acid, and does not need to carry out complex step acetyl, so that the synthetic route is simplified. The preparation method disclosed by the invention is simple and safe in synthesis method, high in product purity and high in yield.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of palbociclib.
Background
Parbuxib is the first global marketed oral targeted CDK4/6 inhibitor developed by pyroxene, and can selectively inhibit cyclin dependent kinases 4 and 6 (CDK 4/6), restore cell cycle control and block tumor cell proliferation. It can be used in combination with Femara for the 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 an Aoslercanic oncology drug Faslodex for the treatment of female patients with hormone receptor positive (HR+), human EGFR 2 negative (HER 2-) advanced or metastatic breast cancer following endocrine treatment. The drug is on the market with accelerated FDA approval in the united states for menstruation 2 in 2015. The chemical name of the compound is 6-acetyl-8-cyclopentyl-5-methyl-2- [ [5- (piperazin-1-yl) pyridin-2-yl ] amino ] -8H-pyrido [2,3-D ] pyrimidine-7-ketone, and the structure is shown as follows:
the synthesis method of palbociclib reported in patent WO2014128588 A1 is as follows:
the patent uses crotonic acid as a raw material, and the process is complicated after the step of acetyl, so that the total yield is reduced.
Therefore, it is necessary to develop a process for preparing palbociclib, which can make the synthesis procedure simple and easy to operate, 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 present invention, there is provided a method of preparing palbociclib, comprising the steps of:
(i-a) condensing ethyl acetoacetate with acetaldehyde in an inert solvent in the presence of a condensing agent, and hydrolyzing 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-pyridine pyrimidine (B);
(ii) In an inert solvent, under the action of an alkaline condition and a catalyst, the compound A reacts with the compound B 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 alkaline conditions to obtain 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) Removing Boc from the compound E to obtain the palbociclib.
In another preferred embodiment, in the step (i-a) and the step (i-b), the solvents are each independently selected from the group consisting of: absolute methanol, absolute ethanol, toluene, or a combination thereof, preferably absolute 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 a combination 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 step (i-a), the temperature of the reaction is from 0 to 70 ℃, preferably from 10 to 50 ℃, more preferably from 20 to 30 ℃.
In another preferred embodiment, in step (i-a), the reaction time is 1 to 24 hours, preferably 2 to 8 hours, more preferably 6 hours.
In another preferred embodiment, in the step (i-a), the hydrolysis is performed in the presence of a base.
In another preferred embodiment, in the step (i-a), the alkali solution is an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution, or a combination thereof, preferably an aqueous sodium hydroxide solution.
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 the 5-bromo-2, 4-dichloropyrimidine to the cyclopentylamine is 1:1.0-1.5.
In another preferred embodiment, in the step (i-b), the molar ratio of the 5-bromo-2, 4-dichloropyrimidine to the 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 embodiment, in the step (i-b), the acid-binding agent is triethylamine.
In another preferred embodiment, 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 step (i-b), the temperature of the reaction is from 0 to 70 ℃, preferably from 10 to 50 ℃, more preferably from 20 to 30 ℃.
In another preferred embodiment, in step (i-b), the reaction time is 1-4 hours, preferably 2-3 hours, more preferably 2 hours.
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 to 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 embodiment, in the step (ii), the base is triethylamine.
In another preferred embodiment, in the step (ii), the molar ratio of the compound B to the 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 step (ii), the temperature of the reaction is from 0 to 90 ℃, preferably from 50 to 70 ℃, more preferably 65 ℃.
In another preferred embodiment, in step (ii), the reaction time is 1 to 10 hours, preferably 5 to 8 hours, more preferably 6 hours.
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 step (ii), the reaction is continued for a period of 1 to 4 hours, preferably 2 to 3 hours, more preferably 2 hours after the addition of acetic anhydride.
In another preferred embodiment, in the step (iii), the molar ratio of the compound C to the compound D is 1:1.2-1.8.
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 said 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 step (iii), the temperature is from 0 to 30 ℃, more preferably from 10 to 20 ℃.
In another preferred embodiment, in step (iii), the reaction time is 10 to 24 hours, preferably 14 to 18 hours, more preferably 16 hours.
In another preferred embodiment, in 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 embodiment, in the step (iv), after removing Boc from the compound E under acidic conditions, the pH is adjusted to 10 with an alkaline solution to obtain the palbociclib.
In another preferred embodiment, in step (iv), the temperature of the reaction is from 30 to 80 ℃, preferably from 45 to 75 ℃, more preferably 75 ℃.
In another preferred embodiment, in 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 step (iv), the reaction time is 1 to 4 hours, preferably 1.5 to 3 hours, more preferably 2 hours.
In another preferred embodiment, in step (iv), the lye is selected from the group consisting of: the aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution, or a combination thereof, is preferably aqueous sodium hydroxide solution.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
Through extensive and intensive research, the inventor develops a preparation method of the palbociclib through a large number of screening and testing, and the preparation method is simple and safe to operate, high in product purity and high in yield. The present invention has been completed on the basis of this finding.
Terminology
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 volumetric 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-pyridine".
The term "compound C" is used interchangeably with "6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridin [2,3-d ] pyrimidin-7-one".
The term "compound D" is used interchangeably with "tert-butyl 4- (6-aminopyridine-3-acyl) -piperazine-1-carboxylate".
The term "compound E" is used interchangeably with "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".
The term "THF": tetrahydrofuran (THF)
The term "NMP": n-methyl-2-pyrrolidone
The term "Boc": boc-group
The term "LDA": lithium diisopropylamide
The term "LiHMDS": lithium hexamethyldisilazide
A process for preparing palbociclib comprising the steps of:
the ethyl acetoacetate is condensed and hydrolyzed with acetaldehyde to prepare 2-acetyl-2-butenoic acid, the 2-bromo-2-chloro-6-cyclopentylamine-pyridine pyrimidine prepared by the condensation reaction of 5-bromo-2, 4-dichloropyrimidine and cyclopentylamine is condensed to prepare 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridine [2,3-d ] pyrimidine-7-ketone, and the 6- (6-aminopyridine-3-acyl) -piperazine-1-carboxylic acid tert-butyl ester is reacted to prepare 4- {6- [ 6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydro-pyridine [2,3-d ] pyrimidine-2-ylamino ] -pyridine-3-yl } -piperazine-1-carboxylic acid tert-butyl ester, and the base is adjusted by removing Boc under acidic conditions to obtain the palbociclib. The preparation method of the invention using 2-acetyl-2-butenoic acid to replace crotonic acid simplifies the synthetic route, improves the product yield, has simple post-treatment, accords with the environment-friendly concept, and 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 at a proper temperature for a certain time after the reaction is completed, dripping alkali liquor, reacting for a certain time after the reaction is completed, removing the solvent by rotary evaporation, adding water, regulating acid, extracting, and removing the solvent by rotary evaporation to obtain a compound A; wherein the condensing agent may be a condensing agent commonly used in the art, 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 temperature of the reaction may be 0 to 70 ℃, preferably 10 to 50 ℃, more preferably 20 to 30 ℃; the certain time may be 1-24 hours, preferably 2-8 hours, more preferably 6 hours; the alkali liquor is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution or a combination thereof.
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 the dropwise addition is finished, adding water, stirring after the reaction is complete, and filtering to obtain a compound B; among them, the acid-binding agent may be one commonly used in the art, for example: 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 temperature of the reaction 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.
Step (3): dissolving a compound B in a solvent, adding triethylamine, a compound A, a catalyst and nitrogen for reaction for a certain time at a proper temperature, adding acetic anhydride for reaction 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; wherein the catalyst may be a conventional palladium catalyst such as palladium acetate, palladium chloride or a combination thereof; in this step, the reaction solvent, reaction temperature, reaction time, etc. may be selected according to the specific reactants, for example, the temperature of the reaction 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.
Step (4): dissolving a 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 a compound C in batches, reacting for a certain time at room temperature, adding acetic acid after the reaction is completed, precipitating a solid, and filtering to obtain a compound E; the hydrogen extracting reagent is organic strong alkali commonly used in the field, and can be LDA, liHMDS, butyl lithium 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, and for example, the temperature of the reaction may be 0 to 30 ℃, more preferably 10 to 20 ℃.
Step (5): adding the compound E into a solvent, stirring, removing Boc under an acidic condition at a certain temperature, stirring for a certain time, completely reacting, adding anisole, adjusting the pH to 10 by using alkali liquor, separating liquid, heating and refluxing an organic phase to separate out water, cooling, and filtering to obtain the palbociclib; wherein the acid is hydrogen chloride gas, concentrated hydrochloric acid, acetyl chloride, or a combination thereof; the alkali liquor is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution or a combination thereof; in this step, the reaction solvent, the reaction temperature, the reaction time, etc. may be selected depending on the specific reactants, for example, the reaction temperature is 30 to 80 ℃, preferably 45 to 75 ℃, more preferably 75 ℃.
The main advantages of the invention include:
(1) The invention adopts the preparation method that 2-acetyl-2-butenoic acid is used for replacing crotonic acid to directly obtain the product with acetyl, and the complex step of acetyl is not needed, so that the synthetic route is simplified.
(2) The preparation method of the 2-acetyl-2-butenoic acid used in the invention is simple and easy to prepare.
(3) The invention has short production cycle of the synthetic route, improved total reaction yield, mild reaction conditions and high product purity.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Examples
EXAMPLE 1 Synthesis of Compound A
Ethyl acetoacetate (100.0 g,0.7684 mol) was dissolved in absolute ethanol (500 mL,5 v) and stirred, piperidine (98.2 g,1.1526 mol) was added, acetaldehyde (44.0 g,0.9989 mol) was reacted at 20-30℃for 6 hours, after completion of the reaction, 30% aqueous sodium hydroxide solution (175 mL) was added dropwise, stirred for 2 hours, the reaction was completed, ethanol was removed by rotary evaporation, water (500 mL) was added to the rotary evaporation, ethyl acetate (300 mL) was stirred for separation, pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, extraction was performed with ethyl acetate (500 mL), and dried, and the organic phase was dried by rotary evaporation to obtain compound A81.3 g, yield: 82.6% (calculated as ethyl acetoacetate), MS (ESI): [ M+1 ]] + ＝129.14。
EXAMPLE 2 Synthesis of Compound B
5-bromo-2, 4-dichloropyrimidine (100.0 g,0.4388 mol) was dissolved in absolute ethanol (300 mL,3 v) and stirred, triethylamine (53.3 g,0.5266 mol) was added to cool to 0-5 ℃, the temperature was maintained, cyclopentylamine (44.8 g,0.5266 mol) was added dropwise, the reaction was completed at 20-30℃for 2h, water (250 ml) was added to stir, filter, and dry to give 106.5g of a white solid, yield: 87.8% (calculated as 5-bromo-2, 4-dichloropyrimidine), MS (ESI): [ M+1 ]] + ＝277.56。
EXAMPLE 3 Synthesis of Compound C
Compound B (80.0 g,0.2893 mol) was dissolved in NMP (400 mL,5 v) with stirring and triethylamine (146.4 g,1.4465 mol) was addedCompound a (92.7 g,0.7233 mol), palladium acetate (2.0 g), nitrogen protection, heating to 65 ℃ for reaction for 6h, adding acetic anhydride (53.2 g,0.5207 mol) for reaction for 2h, filtering while hot, recovering palladium acetate, cooling filtrate to 10-20 ℃, adding water (800 ml), stirring, filtering, drying to obtain 73.7g of white solid, yield: 83.3% (based on compound B), MS (ESI): [ M+1 ]] + ＝306.75。
EXAMPLE 4 Synthesis of Compound E
Compound D (95.6 g,0.3434 mol) was dissolved in anhydrous tetrahydrofuran (700 ml,10 v) and stirred to reduce the temperature to 10-20 ℃, nitrogen was used to protect, the temperature was maintained, liHMDS tetrahydrofuran solution (470 ml, 0.45778 mol) was added dropwise, stirring was performed for 1h after the addition was completed, compound C (70.0 g,0.2289 mol) was added in portions, the reaction was performed at room temperature for 15h, the reaction was completed, acetic acid (23.4 g,0.3891 mol) was added, stirring was performed for 2h, a yellow solid was precipitated, filtered, and dried to obtain yellow fixation of 117.5g, yield: 93.7% (based on compound C), MS (ESI): [ M+1 ]] + ＝548.65。
EXAMPLE 5 Synthesis of palbociclib
Compound E (110 g, 0.025 mol) was added to n-butanol (720 ml,12 v) and water (1100 ml,10 v) with stirring, heating to 70 ℃, starting to add concentrated hydrochloric acid (49.2 g,0.5013 mol) dropwise, stirring for 2h after the addition was completed, adding anisole (2000 ml,18 v) with stirring, adjusting pH to 10 with 30% aqueous sodium hydroxide solution, separating out the organic phase, heating the organic phase to reflux to separate out 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 mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (25)
1. A method for preparing palbociclib, comprising the steps of:
(i-a) condensing ethyl acetoacetate with acetaldehyde in an inert solvent in the presence of a condensing agent, and hydrolyzing 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-pyridine pyrimidine (B);
(ii) In an inert solvent, under the action of an alkaline condition and a catalyst, the compound A reacts with the compound B to obtain 6-acetyl-2-chloro-8-cyclopentyl-5-methyl-8H-pyridine [2,3-d ] pyrimidine-7-ketone (C); wherein the base is triethylamine, and the catalyst is palladium acetate, palladium chloride or a combination thereof;
(iii) Reacting compound C with compound D in an inert solvent under alkaline conditions to obtain 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) Removing Boc from the compound E to obtain the palbociclib;
wherein in the step (ii), acetic anhydride is also required to be added.
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 method of claim 1, wherein in step (i-b), the molar ratio of 5-bromo-2, 4-dichloropyrimidine to cyclopentylamine is in the range of 1:1.0 to 1.5.
4. The method of claim 1, wherein in 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.
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 according to claim 1, wherein in step (ii), the mass ratio of compound B to catalyst is from 1:0.01 to 0.04.
7. The method of claim 1, wherein in step (iii), the molar ratio of compound C to compound D is from 1:1.2 to 1.8.
8. The method of claim 1, wherein in step (iii), the base is LDA, liHMDS, butyllithium, or a combination thereof.
9. The method of claim 1, wherein in step (iv), compound E is subjected to Boc removal under acidic conditions and then adjusted to pH 10 with an alkaline solution to provide palbociclib.
10. The method of claim 1, wherein in step (i-a), the temperature of the reaction is 0 to 70 ℃.
11. The method of claim 1, wherein in step (i-a), the temperature of the reaction is 10 to 50 ℃.
12. The method of claim 1, wherein in step (i-a), the temperature of the reaction is 20 to 30 ℃.
13. The method of claim 1, wherein in step (i-a), the condensing agent is piperidine.
14. The method of claim 1, wherein in step (i-b), the temperature of the reaction is 0 to 70 ℃.
15. The method of claim 1, wherein in step (i-b), the temperature of the reaction is 10 to 50 ℃.
16. The method of claim 1, wherein in step (i-b), the temperature of the reaction is 20 to 30 ℃.
17. The method of claim 1, wherein the catalyst is palladium acetate.
18. The method of claim 1, wherein in step (ii), the temperature of the reaction is 0 to 90 ℃.
19. The method of claim 1, wherein in step (ii), the temperature of the reaction is 50 to 70 ℃.
20. The method of claim 1, wherein in step (ii), the temperature of the reaction is 65 ℃.
21. The method of claim 1, wherein in step (iii), the temperature is from 0 ℃ to 30 ℃.
22. The method of claim 1, wherein in step (iii), the temperature is 10 to 20 ℃.
23. The method of claim 1, wherein in step (iv), the temperature of the reaction is 30 to 80 ℃.
24. The process of claim 1, wherein in step (iv), the temperature of the reaction is 45-75 ℃.
25. The method of claim 1, wherein in step (iv), the temperature of the reaction is 75 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911234427.7A CN112920182B (en) | 2019-12-05 | 2019-12-05 | Preparation method of palbociclib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911234427.7A CN112920182B (en) | 2019-12-05 | 2019-12-05 | Preparation method of palbociclib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112920182A CN112920182A (en) | 2021-06-08 |
| CN112920182B true CN112920182B (en) | 2023-08-01 |
Family
ID=76161226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911234427.7A Active CN112920182B (en) | 2019-12-05 | 2019-12-05 | Preparation method of palbociclib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112920182B (en) |
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 |
|---|
| A Tandem "On-Palladium" Heck–Jeffery Amination Route Toward the Synthesis of Functionalized Indole-2-carboxylates;James McNulty et al.;《Eur. J. Org. Chem.》;第6902-6908页 * |
| An approach for quinolines via palladium-catalyzed Heck coupling followed by cyclization;Chan Sik Cho et al.;《Tetrahedron Letters》;第48卷;第3775-3778页 * |
| Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design;Ola Fjellström et al;《PLoS One》;第10卷;第1-42页 * |
| 新型抗乳腺癌药帕博西尼的合成进展;高芳等;《化工进展》;第37卷;第242-251页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112920182A (en) | 2021-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1539711B1 (en) | Process for preparing the calcium salt of rosuvastatin | |
| CN104130258B (en) | The method for transformation of a kind of dimer | |
| CN102617481A (en) | Preparation method of rosuvastatin calcium | |
| CN104610254A (en) | Low-cost preparation method for palbociclib | |
| CN106608876A (en) | Preparation method of high-purity palbociclib | |
| CN102180842B (en) | Synthesis method of 2-amino-delta 2-thiazoline-4-carboxylic acid | |
| CN102190695B (en) | Preparation method for 5'-deoxy-2',3'-diacetyl-5-fluorocytidine | |
| CN112920182B (en) | Preparation method of palbociclib | |
| CN102321086B (en) | Synthesizing method of adenine | |
| CN101565428B (en) | Preparation method of prulifloxacin | |
| CN102887902A (en) | Preparation process for synthesizing high-purity Pemedolac | |
| CN103058936B (en) | The preparation method of 4-[(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
| CN109134569B (en) | A kind of production technology of Vidarabine Monophosphate | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN110734398B (en) | New preparation method of 2-chloronicotinic acid | |
| CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
| CN101935317B (en) | Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof | |
| CN101555248B (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN106854182B (en) | Preparation method of 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine | |
| CN114230525B (en) | Preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
| CN114539085B (en) | Preparation of ureido derivatives | |
| CN103030599A (en) | Gefitinib intermediate and preparation method thereof | |
| CN114751909B (en) | Preparation method of rebaudinib intermediate | |
| CN113292506B (en) | Preparation method of 2-amino-4, 6-dichloro-5-nitropyrimidine | |
| CN113651751B (en) | Preparation method of N-methoxycarbonyl-3-trifluoromethylpyridine-2-sulfonamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |