Novel synthesis method of palbociclib
Through the new synthesis route, ethyl 2-chloro-4-cyclopentylamine pyrimidine-5-carboxylate was used as the starting material to gradually synthesize pembrocilin, solving the problems of long synthesis routes and precious metal catalysis in the existing technology, and achieving the effects of simplifying the routes, reducing costs and improving purity.
Patent Information
- Application Number
- CN202411408486.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-10
- Publication Date
- 2025-02-25
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The existing pembrocilin synthesis methods have problems such as long routes, precious metal catalysis, harsh reaction conditions and high production costs, and are difficult to be suitable for industrial production.
Using a new synthesis route, Parbocilin was gradually synthesized through ethyl 2-chloro-4-cyclopentylamine-5-carboxylate as the starting material, and through nucleophilic substitution reaction, Grignard reaction, nucleophilic addition and endoylation.
A simplified synthesis route has been realized, the cost of raw materials is reduced, dangerous processes are avoided, the purity of the final product is improved, and it is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a new method for synthesizing palbociclib. Background Art
[0002] Palbociclib (6), chemically named 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazine-1-yl)pyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one, is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer Inc. It is used in combination with letrozole to treat postmenopausal women with advanced breast cancer who have not received systemic treatment and are estrogen receptor-positive and human epidermal growth factor receptor-2-negative.
[0003] At present, there are mainly the following synthesis schemes for the synthesis of palbociclib: Scheme 1: This route uses 2-methylthio-4-chloro-5-ethylformate pyrimidine as the starting material, undergoes nucleophilic substitution reaction with cyclopentylamine, ester group reduction, alcohol hydroxyl group oxidation to aldehyde group, and Grignard reaction with methylmagnesium bromide, secondary hydroxyl group oxidation to ketone group, condensation and ring closure with phosphate, bromination, methylthio group oxidation to sulfoxide, nucleophilic substitution with aminopyrimidine, Stille reaction and water treatment reaction to obtain palbociclib. For example: Journal of Medicinal Chemistry, 2005, 48(7): 2371-2387. This synthetic route is long, the reagents are expensive, and the industrial production cost is high.
[0004]
[0005] Scheme 2: 2,4-dichloro-5-bromopyrimidine is used as the starting material, and reacts with cyclopentylamine through nucleophilic substitution reaction, Heck coupling reaction, cyclization, bromination, and then reacts with 2-aminopyrimidine through nucleophilic substitution reaction, Stille reaction and water treatment reaction to obtain palbociclib. Such as WO 2014128588. 2014-08-28. This synthesis scheme uses multiple noble metal catalytic coupling reactions, which has harsh reaction conditions, high production costs, and strict control of metal residues.
[0006]
[0007] Scheme 3: This route uses 2-amino-6-bromo-8-cyclopentylamino-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one as the starting material, undergoes Heck reaction, reacts with 2-aminopyrimidine through nucleophilic substitution reaction, and hydrolyzes to obtain palbociclib. For example, Organic Letters, 2000, 2(15): 2253-2256. Although this synthetic scheme has a short route, the starting materials are expensive, the reagents used are costly and difficult to obtain, and it is not suitable for industrial production.
[0008]
[0009] Scheme 4: This route uses 5-acetyl-6-amino-2(1H)-pyrimidinone as the starting material, undergoes chlorination reaction, and then undergoes condensation reaction with ethyl acetoacetate under microwave conditions, and then undergoes alkylation reaction with cyclopentyl bromide under the action of potassium tert-butoxide, and finally undergoes nucleophilic substitution reaction with 2-aminopyridine and hydrolysis to obtain palbociclib. For example: WO 2016082605. 2016-06-02. This synthesis scheme uses microwave catalysis and is not suitable for industrial production.
[0010]
[0011] Scheme 5: This route uses 2-methylthio-4-amino-5-acetylpyrimidine as the starting material, undergoes oxidation, condenses with ethyl acetoacetate, alkylates with cyclopentyl iodide, undergoes nucleophilic substitution reaction with 2-aminopyrimidine, and hydrolyzes to obtain palbociclib. For example: US 20170247380. 2017-08-31. WO2016082605. 2016-06-02. This synthesis scheme also uses microwave synthesis, which is not suitable for industrial production.
[0012]
[0013] Scheme 6: This method uses 2-acetyl-2-butenoic acid methyl ester as the starting material, condenses with malononitrile, alkylates with cyclopentyl iodide, condenses with N-[5-(1-piperazinyl)-2-piperidinyl]guanidine, and finally oxidizes and dehydrogenates under the action of sodium selenate to obtain palbociclib. Such as US 20170247379. 2017-08-31. The starting materials of this synthesis scheme are expensive, the cost is high, the yield is low, and the industrialization cost is high.
[0014] Summary of the invention
[0015] Purpose of the invention: The purpose of the present invention is to solve the deficiencies in the prior art and provide a new method for synthesizing palbociclib.
[0016] Technical solution: The synthetic route of the present invention is as follows:
[0017] The specific steps are as follows: The first step is the synthesis of 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester: 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester is used as a raw material, and 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester (1) is prepared by a nucleophilic substitution reaction in THF under the action of diisopropylethylamine at room temperature; the specific reaction formula is as follows:
[0018] Step 2, synthesis of 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2): In anhydrous tetrahydrofuran, under nitrogen protection and at a temperature of 0-5°, 2-chloro-4-cyclopentylamino-5-acetylpyrimidine-5-carboxylic acid ethyl ester reacts with Grignard reagent methylmagnesium bromide to obtain 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2); the specific reaction formula is as follows:
[0019] Step 3, synthesis of 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3): 2-Chloro-4-cyclopentylamino-5-acetylpyrimidine and NaH are refluxed in THF to obtain 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3) through nucleophilic addition and intramolecular acylation. The specific reaction formula is as follows:
[0020] Step 4, synthesis of 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4): Under the condition of 0-5°, in anhydrous THF, under nitrogen protection, 6-ethylformate-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted with an equivalent amount of methylmagnesium bromide to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4); the specific reaction formula is as follows:
[0021] Step 5, synthesis of 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5): 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted in toluene with p-toluenesulfonic acid as catalyst and protective group ethylene glycol, and heated to reflux for reaction. During the reaction, the generated water is removed by a water separator to finally synthesize 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5). The specific reaction formula is as follows:
[0022] Step 6, synthesis of palbociclib (6): in anhydrous tetrahydrofuran, under nitrogen protection, isopropylmagnesium chloride is used as a base, 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one reacts with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, and finally the reaction solution is adjusted to a pH of about 2 with hydrochloric acid, and the temperature is raised to 50° for deprotection reaction to obtain palbociclib (6); the specific reaction formula is as follows:
[0023] Compared with the prior art, the novel method for synthesizing palbociclib provided by the present invention achieves at least the following beneficial effects: (1) The raw materials used are cheap and readily available, the process is easy to industrialize, and the final product is of high purity; (2) No dangerous process and simple equipment; (3) The route is novel and the synthetic route is short. DETAILED DESCRIPTION
[0024] Various exemplary embodiments of the present invention are now described in detail. It should be noted that unless otherwise specifically stated, the relative arrangement of the components and steps, the numerical expressions and the numerical values described in these embodiments do not limit the scope of the present invention, and the following description of at least one exemplary embodiment is actually only illustrative and is in no way intended to limit the present invention and its application or use. The techniques, methods and devices known to ordinary technicians in the relevant fields may not be discussed in detail, but where appropriate, the techniques, methods and devices should be considered as part of the specification. In all examples shown and discussed here, any specific value should be interpreted as being merely exemplary and not as a limitation.
[0025] A novel method for synthesizing palbociclib, the specific steps are as follows: The first step is the synthesis of 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester: 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester is used as a raw material, and 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester (1) is prepared by a nucleophilic substitution reaction in THF under the action of diisopropylethylamine at room temperature; the specific reaction formula is as follows: ; This step of the reaction is a nucleophilic substitution reaction with cyclopentylamine as a nucleophile. There are two chlorines in the molecule, both of which may participate in the reaction. Therefore, temperature has a great influence on the reaction. At low temperatures, the 4-position reaction takes precedence, so the reaction temperature is controlled at room temperature.
[0026] The solvent may be THF, DMF, dioxane, tetrachloroethylene, etc., preferably THF. The base may be sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, DBU, etc., preferably diisopropylethylamine.
[0027] Step 2, synthesis of 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2): In anhydrous tetrahydrofuran, under nitrogen protection and at a temperature of 0-5°, 2-chloro-4-cyclopentylamino-5-acetylpyrimidine-5-carboxylic acid ethyl ester reacts with Grignard reagent methylmagnesium bromide to obtain 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2); the specific reaction formula is as follows:
[0028] This step of reaction is the reaction between Grignard reagent and ester. According to the principle of the reaction, the reaction needs to control the temperature and the amount of Grignard reagent.
[0029]
[0030] According to the reaction principle, methylmagnesium bromide first condenses with the ester group to form a ketone, and then the ketone further reacts with the Grignard reagent to form an alcohol. Therefore, the reaction temperature and the amount of Grignard reagent are controlled to keep the reaction at the ketone step.
[0031] Step 3, synthesis of 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3): 2-Chloro-4-cyclopentylamino-5-acetylpyrimidine and NaH are refluxed in THF to obtain 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3) through nucleophilic addition and intramolecular acylation. The specific reaction formula is as follows:
[0032] The principle of this reaction is that diethyl malonate condenses with ketone under alkaline conditions, and then the intramolecular ester condenses based on amine.
[0033]
[0034] 2-Chloro-4-cyclopentylamino-5-acetylpyrimidine reacts with NaH in THF under reflux to give 6-carboxylic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3) through nucleophilic addition and intramolecular acylation.
[0035] The solvent may be THF, anisole, dioxane, etc., preferably THF. The base may be sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, etc., preferably sodium hydride.
[0036] Step 4, synthesis of 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4): Under the condition of 0-5°, in anhydrous THF, under nitrogen protection, 6-ethylformate-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted with an equivalent amount of methylmagnesium bromide to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4); the specific reaction formula is as follows:
[0037] The solvent may be selected from diethyl ether, tetrahydrofuran, methyl tert-butyl ether, anisole, etc., preferably THF. The temperature needs to be lowered to 0° before the methyl magnesium bromide is added dropwise.
[0038] Step 5, synthesis of 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5): 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted in toluene with p-toluenesulfonic acid as catalyst and protective group ethylene glycol, and heated to reflux for reaction. During the reaction, the generated water is removed by a water separator to finally synthesize 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5). The specific reaction formula is as follows:
[0039] This step of reaction is the carbonyl protection. Because the next step is to react with amine, the presence of carbonyl will condense with amino group, wasting the raw materials of the reaction, so alcohol is used for carbonyl protection.
[0040] Step 6, synthesis of palbociclib (6): in anhydrous tetrahydrofuran, under nitrogen protection, isopropylmagnesium chloride is used as a base, 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one reacts with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, and finally the reaction solution is adjusted to a pH of about 2 with hydrochloric acid, and the temperature is raised to 50° for deprotection reaction to obtain palbociclib (6); the specific reaction formula is as follows:
[0041] This step of the reaction undergoes nucleophilic substitution reaction and hydrolysis reaction, and is completed in one pot.
[0042] .
[0043] Example 1: Synthesis of ethyl 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylate (1).
[0044] Take 220 g of ethyl 2,4-dichloropyrimidine-5-carboxylate and dissolve it in 800 ml of THF, add 168 g of DIPEA, cool the system to 0°, add 93.5 g of cyclopentylamine dropwise, and finish the addition in 1 hour. After the addition is completed, the system is maintained at 0° for 1 hour, and then the system is slowly heated to room temperature for 2 hours. After the reaction is completed, ice water is added to the system and stirring is continued for 1 hour. A large amount of white solid is precipitated, filtered, the filter cake is washed with water and petroleum ether, and dried to obtain 252.86 g of white solid with a yield of 94%.
[0045] Example 2: Synthesis of 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2).
[0046] Take a 500 ml three-necked flask, add 26.9 g of ethyl 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylate, install a dropping funnel, connect a three-way connection, and install a rubber stopper on the empty port. Reduce pressure and ventilate, and replace the air in the bottle with nitrogen. Use a syringe to add 100 ml of anhydrous tetrahydrofuran to the bottle, stir to dissolve, add methylmagnesium bromide (1M / L-THF) ml to the dropping funnel, cool the system to 0°, slowly drop methylmagnesium bromide, and drip it in 30 minutes. After the dripping is completed, continue to react for 30 minutes. After the reaction is completed, slowly pour the reaction solution into ice water and continue to stir for 30 minutes. A large amount of white solid precipitates, filter, wash the filter cake with water until neutral, and dry to obtain a white solid. The solid is recrystallized from 50% ethanol to obtain 20.32 grams of white powdery solid, with a yield of 85%.
[0047] Example 3: Synthesis of 6-ethylcarboxylate-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3).
[0048] Take a 500 ml three-necked flask, weigh 19.2 g of diethyl malonate, add 100 ml of anhydrous THF, cool the system to 0°, slowly add 28.8 g of NaH in batches, stir for 30 minutes after the addition is complete, then add 23.9 g of 2-chloro-4-cyclopentylamino-5-acetylpyrimidine in batches to the system, keep the reaction for 2 hours, then heat the system to reflux reaction, continue the reaction for 4 hours, after the reaction is completed, slowly cool the reaction system to room temperature, then slowly pour the system into ice water, continue stirring for 30 minutes, precipitate a large amount of white solid, wash with water until neutral. Dry. The solid is recrystallized with methanol and dried to obtain 29.21 g of white solid, with a yield of 84%.
[0049] Example 4: Synthesis of 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4).
[0050] Take a 500 ml three-necked flask, add 33.5 g of 6-ethyl formate-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one, install a dropping funnel, connect a three-way valve, and install a rubber stopper on the empty port. Reduce pressure and ventilate, and replace the air in the bottle with nitrogen. Use a syringe to add 120 ml of anhydrous tetrahydrofuran to the bottle, stir to dissolve, add methylmagnesium bromide (1M / L-THF) ml to the dropping funnel, cool the system to 0°, slowly drop methylmagnesium bromide, drip it in 30 minutes, and continue to react for 30 minutes after dripping. After the reaction is completed, slowly pour the reaction solution into ice water and continue stirring for 30 minutes. A large amount of white solid precipitates, filter, wash the filter cake with water until neutral, and dry to obtain a white solid. The solid is recrystallized from methanol to obtain 27.75 g of white powdery solid, with a yield of 91%.
[0051] Example 5: Synthesis of 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5).
[0052] Take a 500 ml flask, add 30.5 g of 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one, add 200 ml of toluene, add 8.6 g of PTSA, add 10 g of ethylene glycol, install a water separator, heat and reflux to react until no water is produced and the reaction is completed. After the reaction is completed, toluene is recovered under reduced pressure, 100 ml of THF is added to the residue to dissolve it, and then slowly poured into ice-alkali water, and continued stirring for 30 minutes. A large amount of white solid precipitated, dried, and 34.2 g of white solid powder was obtained, with a yield of 98%.
[0053] Example 6: Synthesis of Palbociclib (6).
[0054] Take a 500 ml three-necked flask, add 34.9 g of 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one, install two constant pressure dropping funnels, install rubber stoppers and three-way valves, replace the air in the bottle with nitrogen, add 120 ml of anhydrous tetrahydrofuran into the bottle with a syringe, stir to dissolve, cool the system to below 10°, add 50 ml (1M / L) of isopropylmagnesium chloride dropwise, continue to stir for 30 minutes after the addition is complete, then slowly add 29.2 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (dissolved in 50 ml THF), continue to stir for 30 minutes after the addition is complete, then continue to add 50 ml (1M / L) of isopropylmagnesium chloride dropwise. Then the system was heated to room temperature and continued to react for 3 hours, then the system was slowly heated to 55° and continued to react for 2 hours. After the reaction was completed, the system was slowly cooled to room temperature, and then the reaction solution was slowly transferred to 200 ml of 3M / L dilute hydrochloric acid, stirring while adding. After the addition was completed, the system pH was tested, and then adjusted to about pH 2. The system was heated to 60° and stirred for 4 hours. After the reaction was completed, the pH was adjusted to 7-8 with sodium hydroxide solution, and a large amount of yellow solid was precipitated. The filter cake was filtered, washed with water until neutral, dried, and the solid was recrystallized with methanol and dried to obtain 38.44 grams of yellow solid powder with a purity of 99.312%. The yield was 86%.
[0055] Although some specific embodiments of the present invention have been described in detail by way of example, it will be appreciated by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the present invention. It will be appreciated by those skilled in the art that the above embodiments may be modified without departing from the scope and spirit of the present invention. The scope of the present invention is defined by the appended claims.
Claims
1. A novel method for synthesizing palbociclib, characterized in that: The specific steps are as follows: The first step is the synthesis of 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester: 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester is used as a raw material, and 2-chloro-4-cyclopentylaminopyrimidine-5-carboxylic acid ethyl ester (1) is prepared by a nucleophilic substitution reaction in THF under the action of diisopropylethylamine at room temperature; the specific reaction formula is as follows: ； Step 2, synthesis of 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2): In anhydrous tetrahydrofuran, under nitrogen protection and at a temperature of 0-5°, 2-chloro-4-cyclopentylamino-5-acetylpyrimidine-5-carboxylic acid ethyl ester reacts with Grignard reagent methylmagnesium bromide to obtain 2-chloro-4-cyclopentylamino-5-acetylpyrimidine (2); the specific reaction formula is as follows: ； Step 3, synthesis of 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3): 2-Chloro-4-cyclopentylamino-5-acetylpyrimidine and NaH are refluxed in THF to obtain 6-formic acid ethyl ester-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (3) through nucleophilic addition and intramolecular acylation. The specific reaction formula is as follows: ； Step 4, synthesis of 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4): Under the condition of 0-5°, in anhydrous THF, under nitrogen protection, 6-ethylformate-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted with an equivalent amount of methylmagnesium bromide to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one (4); the specific reaction formula is as follows: ； Step 5, synthesis of 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5): 6-acetyl-8-cyclopentyl-5-methyl-2-substituted pyrido[2,3-d]pyrimidin-(8H)-one is reacted in toluene with p-toluenesulfonic acid as catalyst and protective group ethylene glycol, and heated to reflux for reaction. During the reaction, the generated water is removed by a water separator to finally synthesize 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (5). The specific reaction formula is as follows: ； Step 6, synthesis of palbociclib (6): in anhydrous tetrahydrofuran, under nitrogen protection, isopropylmagnesium chloride is used as a base, 2-chloro-8-cyclopentyl-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one reacts with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, and finally the reaction solution is adjusted to a pH of about 2 with hydrochloric acid, and the temperature is raised to 50° for deprotection reaction to obtain palbociclib (6); the specific reaction formula is as follows: 。