New preparation method of palbociclib

Abstract

The invention provides a novel preparation method of palbociclib, which comprises the following steps: by taking ethyl acetoacetate as an initial raw material, carrying out condensation with paraformaldehyde, carrying out carbonyl protection and hydrolyzing to obtain an intermediate 2-(2-methyl-1, 3-dioxolame) crotonic acid, carrying out condensation with 2, 4-dichloro-5-bromopyrimidine and cyclopentylamine, then carrying out condensation with the intermediate 2-(2-methyl-1, 3-dioxolame) crotonic acid, and carrying out condensation with the intermediate 2-(2-methyl-1, 3-dioxolame) crotonic acid to obtain the palbociclib. According to the present invention, the palbociclib is prepared through HECK coupling, intramolecular acylation and final hydrolysis deprotection of (2, 3-dioxolame) crotonic acid, the preparation route is short, the reagent consumption is reduced, the reagent is easy to obtain, and the industrial production cost is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and in particular to a novel preparation method of palbociclib. Background Art

[0002] Palbociclib inhibits breast cancer cell proliferation: Palbociclib inhibits breast cancer cell proliferation by specifically inhibiting CDK4 / 6 activity and preventing the cell cycle from entering the S phase. It is particularly effective against hormone receptor-positive breast cancer because this type of cancer cell is highly dependent on estrogen; Palbociclib enhances the effect of chemotherapy: Palbociclib can inhibit cell cycle progression and make cancer cells more sensitive to the effects of chemotherapy drugs. By combining it with chemotherapy, the therapeutic effect can be improved and the patient's survival can be prolonged; compared with hormone therapy alone, palbociclib combined with hormone therapy can reduce the risk of disease progression by about 50%.

[0003] Currently, there are several main methods for preparing palbociclib:

[0004] Existing scheme 1: using 2-methylthio-4-chloro-5-ethylcarboxylate pyrimidine as a starting material, undergoing a 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 cyclization with phosphate, bromination, methylthio group oxidation to sulfoxide, and nucleophilic substitution with aminopyrimidine, Stille reaction and water treatment reaction to obtain palbociclib. This scheme has a long route, expensive reagents, and high industrial production cost.

[0005] Existing 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 preparation scheme uses multiple noble metal catalytic coupling reactions, has harsh reaction conditions, high production costs, and strict control of metal residues.

[0006] Existing Scheme 3: This scheme uses 2-amino-6-bromo-8-cyclopentylamino-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a starting material, undergoes a Heck reaction, and then undergoes a nucleophilic substitution reaction with 2-aminopyrimidine, followed by hydrolysis to obtain palbociclib. For example, Organic Letters, 2000, 2(15):2253-2256. Although this preparation scheme has a short route, the starting materials are expensive, the reagents used are costly and difficult to obtain, and are not suitable for industrial production.

[0007] Existing Scheme 4: This scheme uses 5-acetyl-6-amino-2(1H)-pyrimidinone as the starting material, undergoes a chlorination reaction, and then undergoes a condensation reaction with ethyl acetoacetate under microwave conditions, and then undergoes an alkylation reaction with cyclopentyl bromide under the action of potassium tert-butoxide, and finally undergoes a nucleophilic substitution reaction with 2-aminopyridine and hydrolysis to obtain palbociclib. For example: WO 2016082605.2016-06-02. This preparation scheme uses a microwave catalytic reaction and is not suitable for industrial production.

[0008] Existing Scheme 5: This scheme 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: US20170247380.2017-08-31.WO2016082605.2016-06-02. This preparation scheme also uses microwave synthesis, which is not suitable for industrial production.

[0009] Existing 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. For example, US20170247379.2017-08-31. The starting materials of this preparation scheme are expensive, the cost is high, the yield is low, and the industrialization cost is high. Summary of the invention

[0010] Purpose of the invention: The purpose of the present invention is to solve the deficiencies in the prior art and provide a new preparation method of palbociclib.

[0011] Technical solution:

[0012] The present invention provides a novel preparation method of palbociclib, and the specific steps are as follows:

[0013] The first step is the synthesis of methyl 2-acetyl-2-butenoate (1): ethyl acetoacetate and paraformaldehyde are condensed in ethanol under the action of sodium ethoxide to synthesize methyl 2-acetyl-2-butenoate (1); the specific reaction formula is as follows:

[0014]

[0015] Step 2, synthesis of ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2): methyl 2-acetyl-2-butenoate and ethylene glycol are reacted in toluene by PTSA catalysis to synthesize ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2); the specific reaction formula is as follows:

[0016]

[0017] Step 3, synthesis of 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3): 2-(2-methyl-1,3-dioxolanyl)crotonic acid ethyl ester is hydrolyzed in methanol by sodium hydroxide to synthesize 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3); the specific reaction formula is as follows:

[0018]

[0019] Step 4, synthesis of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (4): 2,4-dichloro-5-bromopyrimidine and cyclopentylamine are condensed in tetrahydrofuran at room temperature using DIPEA as a base to synthesize 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (4); the specific reaction formula is as follows:

[0020]

[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): Under nitrogen protection, 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine and 2-(2-methyl-1,3-dioxolan-2-yl)crotonic acid are added to NMP, DIPEA is added, and palladium acetate is added in batches to carry out HECK coupling reaction. After the reaction is completed, acetic anhydride is added to carry out intramolecular condensation to 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]

[0023] 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:

[0024]

[0025] Compared with the prior art, the novel preparation method of palbociclib provided by the present invention achieves at least the following beneficial effects:

[0026] (1) It is suitable for industrial production and the palbociclib product produced has high purity;

[0027] (2) It eliminates dangerous processes, increases yields, and reduces production costs;

[0028] (3) The preparation route is short, which reduces the amount of reagents used and is easy to obtain, thus reducing the cost of industrial production. DETAILED DESCRIPTION

[0029] 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.

[0030] A new preparation method of palbociclib, the specific steps are as follows:

[0031] The first step is the synthesis of methyl 2-acetyl-2-butenoate (1): ethyl acetoacetate and paraformaldehyde are condensed in ethanol under the action of sodium ethoxide to synthesize methyl 2-acetyl-2-butenoate (1); the specific reaction formula is as follows:

[0032]

[0033] This step of reaction is a condensation reaction. The condensation agent can be formaldehyde and paraformaldehyde. Since formaldehyde contains water, paraformaldehyde is selected during the operation.

[0034] 2-Acetyl-2-butenoic acid methyl ester (1) was synthesized by condensing ethyl acetoacetate and paraformaldehyde in ethanol under the action of sodium ethoxide.

[0035] The solvent may be selected from methanol, ethanol, THF, dioxane, etc., preferably ethanol. The base may be selected from sodium methoxide, sodium ethoxide, sodium hydride, etc., preferably sodium ethoxide.

[0036] Step 2, synthesis of ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2): methyl 2-acetyl-2-butenoate and ethylene glycol are reacted in toluene by PTSA catalysis to synthesize ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2); the specific reaction formula is as follows:

[0037]

[0038] This step of the synthesis reaction is to protect the carbonyl group. There are many methods for protecting the carbonyl group. During the operation, alcohol is selected as the protecting group. Methanol, ethanol, ethylene glycol, etc. can be used for condensation protection, and ethylene glycol is preferred as the protecting group.

[0039] Ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2) was synthesized by condensation of methyl 2-acetyl-2-butenoate and ethylene glycol in toluene using PTSA as a catalyst.

[0040] The solvent may be tetrahydrofuran, methanol, ethanol, toluene, etc., preferably toluene. The acid may be p-toluenesulfonic acid, benzenesulfonic acid, dry hydrogen chloride, trifluoroacetic acid, acetic acid, preferably p-toluenesulfonic acid.

[0041] Step 3, synthesis of 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3): 2-(2-methyl-1,3-dioxolanyl)crotonic acid ethyl ester is hydrolyzed in methanol by sodium hydroxide to synthesize 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3); the specific reaction formula is as follows:

[0042]

[0043] The solvent may be methanol, ethanol, tetrahydrofuran, etc., preferably methanol. The base may be sodium hydroxide, potassium hydroxide, sodium carbonate, etc., preferably sodium hydroxide.

[0044] Step 4, synthesis of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (4): 2,4-dichloro-5-bromopyrimidine and cyclopentylamine are condensed in tetrahydrofuran at room temperature using DIPEA as a base to synthesize 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (4); the specific reaction formula is as follows:

[0045]

[0046] 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.

[0047] 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.

[0048] 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): Under nitrogen protection, 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine and 2-(2-methyl-1,3-dioxolan-2-yl)crotonic acid are added to NMP, DIPEA is added, and palladium acetate is added in batches to carry out HECK coupling reaction. After the reaction is completed, acetic anhydride is added to carry out intramolecular condensation to 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:

[0049]

[0050] This step of the reaction first undergoes a coupling reaction under the catalysis of palladium acetate, and then undergoes an intramolecular condensation under the action of acetic anhydride.

[0051] The solvent may be DMF, NMP, DME, etc., preferably NMP.

[0052] 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:

[0053]

[0054] Example 1: Synthesis of methyl 2-acetyl-2-butenoate (1)

[0055] Take 130 grams of ethyl acetate, add 350 milliliters of ethanol, add 90 grams of paraformaldehyde, add 102 grams of sodium ethoxide, heat and reflux for 4 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and most of the solvent is recovered under reduced pressure. Ethyl acetate is added to the residue under ice bath to dissolve, and the solution is slowly poured into ice water. The liquids are separated, the organic layer is washed with water until neutral, the organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is reduced pressure to recover the solvent to obtain 146.64 grams of colorless liquid, with a yield of 94%.

[0056] Example 2: Synthesis of ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2)

[0057] Take a 500 ml flask, add 15.6 g of methyl 2-acetyl-2-butenoate, add 150 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, the reaction solution is cooled to room temperature, the reaction solution is slowly poured into ice water, separated, the organic layer is washed with water until neutral, the organic layer is dried over anhydrous magnesium sulfate, filtered, and the filtrate is decompressed to recover the solvent to obtain 19.6 g of white liquid, with a yield of 98%.

[0058] Example 3: Synthesis of 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3)

[0059] Take 20 grams of ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate, dissolve it in 60 milliliters of methanol, add 80 milliliters of water, add 4.2 grams of sodium hydroxide, heat and reflux for 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then the reaction solution is cooled to below 5° with an ice bath, and the pH of the system is adjusted to about 7 with acetic acid. 200 milliliters of ethyl acetate are extracted twice, the organic layers are combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent to obtain 17.03 grams of white solid powder with a yield of 99%.

[0060] Example 4: Synthesis of 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine (4)

[0061] Weigh 22.6 g of 2,4-dichloro-5-bromopyrimidine and dissolve it in 100 ml of THF, add 14 g of DIPEA, cool to 0°, and add 11.5 g of cyclopentylamine dropwise. Then stir at room temperature for 4 hours, and the reaction is complete by TLC detection, and a white solid is precipitated. Slowly add water (80 ml), stir in an ice-water bath for 2 hours, and then filter. Wash the filter cake with petroleum ether and vacuum dry to obtain 25.57 g of a white solid with a yield of 93%.

[0062] 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).

[0063] Weigh 27.5 g of 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine and 22.36 g of 2-(2-methyl-1,3-dioxolanyl) crotonic acid and dissolve them in NMP (100 ml), then add 10 g of triethylamine, and then add 22.45 mg of palladium acetate every three hours under nitrogen protection. Then stir the reaction mixture at 70 ° C for 15 hours under nitrogen protection, and the reaction is completed by TLC detection. Then, add 11 g of acetic anhydride, and then stir the solution at 65 ° C for 2 hours, and the reaction is completed by TLC detection. Then cool the mixture, dilute with ethyl acetate (150 ml), and then wash three times with NH4Cl aqueous solution, NaHCO3 solution and water respectively. Combine the organic phases, dry with anhydrous magnesium sulfate, filter, and distill the filtrate under reduced pressure to recover the solvent. The residue is recrystallized from 50% ethanol to obtain 31.76 g of white solid, with a yield of 91%.

[0064] Example 6. Synthesis of Palbociclib (6)

[0065] 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 completed, 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 completed, then continue to add 50 ml (1M / L) of isopropylmagnesium chloride dropwise. Then the system was heated to room temperature and the reaction continued for 3 hours. Then the system was slowly heated to 55° and the reaction continued for 2 hours. After the reaction was completed, the system was slowly cooled to room temperature. Then the reaction solution was slowly transferred into 200 ml of 3M / L dilute hydrochloric acid while stirring. 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. A large amount of yellow solid was precipitated, filtered, the filter cake was 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%.

[0066] 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 preparation method of palbociclib, characterized in that: The specific steps are as follows: The first step is the synthesis of methyl 2-acetyl-2-butenoate (1): ethyl acetoacetate and paraformaldehyde are condensed in ethanol under the action of sodium ethoxide to synthesize methyl 2-acetyl-2-butenoate (1); the specific reaction formula is as follows: ； Step 2, synthesis of ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2): methyl 2-acetyl-2-butenoate and ethylene glycol are condensed in toluene by PTSA to obtain ethyl 2-(2-methyl-1,3-dioxolanyl)crotonate (2). The specific reaction formula is as follows: ； Step 3, synthesis of 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3): 2-(2-methyl-1,3-dioxolanyl)crotonic acid ethyl ester is hydrolyzed in methanol by sodium hydroxide to synthesize 2-(2-methyl-1,3-dioxolanyl)crotonic acid (3); the specific reaction formula is as follows: ； Step 4, synthesis of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (4): 2,4-dichloro-5-bromopyrimidine and cyclopentylamine are condensed in tetrahydrofuran at room temperature using DIPEA as a base to synthesize 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (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): Under nitrogen protection, 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine and 2-(2-methyl-1,3-dioxolan-2-yl)crotonic acid were added to NMP, DIPEA was added, and palladium acetate was added in batches to carry out HECK coupling reaction. After the reaction was completed, acetic anhydride was added to carry out intramolecular condensation to 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 the reaction solution is finally 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: 。

Images