CN111362939B - Preparation method of palbociclib parent nucleus structure compound - Google Patents
Preparation method of palbociclib parent nucleus structure compound Download PDFInfo
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Abstract
The invention provides a preparation method of a palbociclib mother nucleus structural compound, which comprises the step of preparing the palbociclib mother nucleus structural compound shown in a formula (I) by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw materialAn agent;
intermediate 1;
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of a palbociclib parent nucleus structure compound.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Pabulicin (trade name Ibrance) is a cyclin-dependent kinase CDK4/6 inhibitor developed by fevery, usa, which restores cell cycle control by selectively inhibiting cyclin-dependent kinase (CDK4/6), blocks tumor cell proliferation; the combination with letrozole for the advanced breast cancer in women who are estrogen receptor positive (ER +), human epidermal growth factor receptor 2 negative (HER2-), is the first approved cyclin-dependent kinase 4 and 6(CDK4/6) inhibitor, and can reduce the risk of disease progression by more than 50%.
The original patents WO2003062236, WO2012018540 and the like report synthesis methods of the palbociclib, two synthesis routes are mainly provided, the palbociclib parent nucleus is subjected to 2-position side chain reaction, and then 6-position modification is carried out to obtain the palbociclib; patent WO2014128588 reports a preparation method of a palbociclib mother nucleus (reaction route is as follows), but the inventors find that a 2,4, 5-trisubstituted pyrimidine raw material (for example, 5-bromo-2, 4-dichloropyrimidine adopted in the reported patent) as a main starting material is difficult to obtain, and halogen with similar activity causes poor selectivity, and more side reactions cause difficulty in purification, so that purity cannot be guaranteed, and difficulty in industrial production of the mother nucleus is increased generally.
The palbociclib is not on the market at home, a stable industrial production and high-quality process is sought for mother nucleus process development, and the palbociclib has important significance for the market economy and social benefits of domestic imitation drugs and the drugs.
Disclosure of Invention
Therefore, the invention aims to provide a preparation process of the parent nucleus of the palbociclib, which has the advantages of wide source of starting materials, low price, simple operation process, less side reaction and high purity and conforms to the modern green industrial production.
The parent nucleus of the palbociclib has a structure shown in a formula (I):
wherein X is selected from halogen.
Specifically, the technical scheme of the invention is as follows:
the invention provides a preparation method of a palbociclib mother nucleus structural compound, which comprises the steps of preparing the palbociclib mother nucleus structural compound shown in a formula (I) by taking cytosine (CAS number: 71-30-7) or an intermediate 1 or an intermediate 2 as a starting raw material;
wherein X groups in the formula (I), the intermediate 1 and the intermediate 2 are the same and are all selected from halogen.
In some embodiments of the present invention, the preparation method of the palbociclib core structure compound includes preparing a compound represented by formula (I) using the intermediate 2 as a starting material, specifically including: the intermediate 2 and halogenated cyclopentane are subjected to substitution reaction to prepare an intermediate 3, the intermediate 3 and crotonic acid are subjected to substitution reaction to prepare an intermediate 4, and the intermediate 4 and a bromization reagent are subjected to substitution reaction to prepare a compound shown in the formula (I);
wherein the X groups in intermediate 3 and intermediate 4 are the same as in intermediate 2.
In other embodiments of the present invention, the preparation method of the palbociclib core structure compound includes preparing a compound represented by formula (I) using the intermediate 1 as a starting material, which specifically includes: the intermediate 1 and a bromization reagent are subjected to substitution reaction to prepare an intermediate 2, the intermediate 2 and halogenated cyclopentane are subjected to substitution reaction to prepare an intermediate 3, the intermediate 3 and crotonic acid are subjected to substitution reaction to prepare an intermediate 4, and the intermediate 4 and the bromization reagent are subjected to substitution reaction to prepare a compound shown in a formula (I);
wherein the X groups in intermediate 1, intermediate 3 and intermediate 4 are the same as in intermediate 2.
When the halogenated cyclopentane reacts with the intermediate 2, the halogen is a leaving group, and can be selected by a person skilled in the art according to needs, for example, the halogen can be F, Cl, Br or I.
In still other embodiments of the present invention, the preparation method of the palbociclib core structure compound includes preparing a compound represented by formula (I) using cytosine as a starting material, which specifically includes: the method comprises the following steps of carrying out substitution reaction on cytosine and a halogenated reagent to prepare an intermediate 1, carrying out substitution reaction on the intermediate 1 and a brominated reagent to prepare an intermediate 2, carrying out substitution reaction on the intermediate 2 and halogenated cyclopentane to prepare an intermediate 3, carrying out substitution reaction on the intermediate 3 and crotonic acid to prepare an intermediate 4, and carrying out substitution reaction on the intermediate 4 and the brominated reagent to prepare a compound shown in the formula (I);
wherein the X groups or halogens in the halogenating reagent in intermediate 1, intermediate 3 and intermediate 4 are the same as in intermediate 2.
In an embodiment of the invention, the intermediate 2 is reacted with a halogenated cyclopentane in the presence of an acid-binding agent to prepare an intermediate 3; wherein the acid-binding agent is triethylamine and/or diisopropylamine.
In an embodiment of the invention, said intermediate 3 is reacted with crotonic acid
And performing Heck reaction and intramolecular amidation cyclization to obtain an intermediate 4.
Wherein, the reaction of preparing the intermediate 4 from the intermediate 3 is carried out in the presence of a palladium catalyst and an acid-binding agent; the palladium catalyst is selected from palladium chloride [ PdCl2]Bis (benzonitrile) palladium chloride [ (C)6H5CN)2PdCl2]And palladium acetate [ Pd (CH)3COO)2]One or more of; the acid-binding agent is triethylamine and/or diisopropylamine.
In an embodiment of the invention, the reaction to prepare the compound of formula (I) from the reaction of intermediate 4 with a brominating agent is reacted in a catalyst/solvent system, wherein the catalyst is selected from one or more of KBr, KI, glacial acetic acid and oxalic acid; the solvent is selected from one or more of glacial acetic acid, acetonitrile and dichloroethane. In some preferred embodiments, when the catalyst is KBr and/or KI, the solvent is glacial acetic acid; or when the catalyst is glacial acetic acid and/or oxalic acid, the solvent is acetonitrile and/or dichloroethane. The brominating agent is selected from one or more of bromine (namely liquid bromine), N-bromosuccinimide (NBS) and 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH).
In an embodiment of the present invention, the reaction of intermediate 1 with a brominating reagent to produce intermediate 2 is carried out in a catalyst/solvent system, wherein when the catalyst is KBr and/or KI, the solvent is glacial acetic acid. The brominating agent is selected from one or more of bromine, NBS and DBH.
In this step of the present invention, the inventors tried to react intermediate 1 with an iodinating reagent or a chlorinated reagent, but the reaction effect of the prepared product in the subsequent reaction was not ideal, especially with the iodinating reagent. For example, when an iodo reagent is used, the subsequent one-step coupling and cyclization reaction of the product is difficult to realize, so that the reaction route is complicated.
In this step of the present invention, the inventors tried to react with intermediate 1 using iodo reagent NIS, but the yield was not NBS high, among the bromo reagents bromine, NBS and DBH, bromine was preferred, and using bromine as the bromo reagent increased the yield from 82% to over 95% and greatly reduced the cost.
In an embodiment of the present invention, the reaction solvent in the reaction of cytosine with a halogenating agent to prepare intermediate 1 is chlorobenzene and/or toluene. Wherein, the halogenating reagent is preferably a chloro reagent selected from one or more of phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and organophosphorus chloride; the organophosphorus chloride can be, for example, triphenyl phosphorus chloride or triphenyl phosphite chloride.
In embodiments of the invention, such as when X is Cl, intermediate 1 is 2-chloro-4-aminopyrimidine (CAS number 7461-50-9); intermediate 2 is 5-bromo-2-chloro-4 aminopyrimidine (CAS number: 205672-25-9). When the intermediate 1 or the intermediate 2 is used as a starting material to prepare the palbociclib parent nucleus structure compound, the intermediate compound can be independently prepared or directly purchased to obtain the compounds.
The invention provides a more preferable method for preparing a palbociclib mother nucleus structure compound, wherein X is chlorine, the palbociclib mother nucleus structure compound is (6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one, and the method comprises the following steps:
the cytosine is subjected to chlorination reaction to prepare 2-chloro-4 aminopyrimidine; preparing 5-bromo-2-chloro-4-aminopyrimidine through bromination reaction of 2-chloro-4-aminopyrimidine; in the presence of an acid binding agent, carrying out substitution reaction on 5-bromo-2-chloro-4-aminopyrimidine and halogenated cyclopentane to prepare 5-bromo-2-chloro-4-N-cyclopentylpyrimidine; in the presence of a palladium catalyst and an acid-binding agent, reacting 5-bromo-2-chloro-4-N-cyclopentylpyrimidine with crotonic acid to prepare 8-cyclopentylalkyl-5-methyl-2-chloro-pyrido [2,3-d ] pyrimidin-7-one; brominating 8-cyclopentyl-5-methyl-2-chloro-pyrido [2,3-d ] pyrimidin-7-one to obtain 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one.
In some embodiments of the present invention, for reference, the present invention provides a material dosage range, and a better reaction effect can be obtained within the dosage range provided by the present invention, and the yield is higher:
in the preparation process of the intermediate 1, the molar weight ratio of cytosine to the halogenated reagent is 1: 1.8-1: 3.5;
in the preparation process of the intermediate 2, the molar weight ratio of the intermediate 1 to the brominating agent is 1: 1.0-1: 1.5;
in the preparation process of the intermediate 3, the molar weight ratio of the intermediate 2 to the halogenated cyclopentane is 1: 1.18-1: 1.25;
in the preparation process of the intermediate 4, the molar weight ratio of the intermediate 3 to the crotonic acid is 1: 1.25-1: 2;
in the preparation process of the intermediate 4, the dosage of the palladium chloride is 2 to 5 percent (mass percentage) of the dosage of the intermediate 3;
in the process of preparing the compound of the formula (I), the molar weight ratio of the intermediate 4 to the brominating agent is 1: 1.3-1: 1.7.
However, it should be understood that the present invention aims to provide a green process route with abundant and easily available raw material sources, simple operation, less side reactions, high purity and low cost, and based on the disclosure of the present invention, the skilled in the art can further search and adjust the material usage and parameter control in each step of reaction to obtain higher yield and output.
Of course, in the method of the present invention, in order to obtain a purer product, each step of reaction may further include operations of separation, refining and impurity removal; the separation operation can comprise the steps of extraction, washing and drying after the solvent is removed, or washing and drying after the suction filtration; the refining, impurity-removing and purifying operation can comprise recrystallization, or further steps of suction filtration, leaching and drying after crystallization.
For example, in the preparation process of the intermediate 1, the operations of removing the solvent, extracting, drying and the like to obtain the intermediate 1 after the reaction is finished, and further the operations of refining and purifying the intermediate 1 are also included, and the refining and purifying mode can be crystallization under the ice bath condition by adding n-hexane.
For example, in the preparation process of the intermediate 3, after the reaction is finished, a purification step of adding ice water to control the temperature to be 0-10 ℃ and stirring for crystallization is further included.
For example, in the process of preparing the compound of formula (I), after the reaction is finished, suction filtration is carried out, the obtained filter cake is recrystallized, and the solvent can be a mixed solution of toluene and n-hexane.
In some embodiments of the invention, the reaction to prepare intermediate 1 from cytosine comprises the steps of:
under the condition of stirring, fully and uniformly stirring cytosine, a chlorinated reagent and a solvent (such as toluene), heating to 95-110 ℃ for reflux reaction, and finishing the reaction; removing most of the solvent (e.g., by distillation under reduced pressure), cooling to room temperature, adding water, extracting with dichloromethane, combining the organic phases, drying to remove water, and removing dichloromethane (e.g., by distillation under reduced pressure) to obtain a liquid intermediate 1; or, further adding a crystallization solvent such as n-hexane into the liquid intermediate 1, stirring in an ice-water bath, crystallizing, filtering, leaching with n-hexane, and drying in vacuum to obtain the intermediate 1.
In some embodiments of the invention, the reaction to prepare intermediate 2 from intermediate 1 comprises the following steps:
adding a solvent such as glacial acetic acid into the intermediate 1, stirring and dissolving, adding a catalyst, slowly dropwise adding a bromization reagent at room temperature, after dropwise adding, enabling the reaction system to be vermilion, slowly heating to 50-60 ℃, reacting for 0.5-1 h, changing the vermilion color of the reaction liquid into white color, separating out a solid, continuing to react for 1-2 h, cooling to room temperature, adding a saturated sodium bisulfite aqueous solution, continuing stirring, performing suction filtration, leaching with purified water, and performing vacuum drying at 40-50 ℃ to obtain an intermediate 2.
In some embodiments of the invention, the reaction to prepare intermediate 3 from intermediate 2 comprises the following steps:
mixing and stirring the intermediate 2, an acid-binding agent and a solvent such as methanol for dissolving, dropwise adding halogenated cyclopentane at room temperature, controlling the temperature and stirring for reaction after the dropwise adding is finished, adding ice water after the reaction is finished, controlling the temperature to be 0-10 ℃, stirring for crystallization, performing suction filtration, rinsing with ice water, drying, and performing vacuum drying at 40-50 ℃ to obtain an intermediate 3.
In some embodiments of the invention, the reaction to prepare intermediate 4 from intermediate 3 comprises the following steps:
mixing the intermediate 3, an acid-binding agent and a solvent such as THF, stirring and dissolving, adding a palladium catalyst, heating to 55-65 ℃ for reflux, and reacting completely; adding crotonic acid to continue reacting for 2 h; and (3) cooling to 30-40 ℃, removing the solvent under reduced pressure, adding purified water, controlling the temperature to be 5-15 ℃ for crystallization, performing suction filtration, leaching with the purified water, and performing vacuum drying at 45-55 ℃ to obtain an intermediate 4.
In some embodiments of the invention, the reaction to prepare the compound of formula (I) from intermediate 4 comprises the steps of:
adding a solvent such as glacial acetic acid into the intermediate 4, stirring and dissolving, adding a catalyst, slowly dropwise adding a bromization reagent at room temperature, after dropwise adding, making the reaction system be vermilion, slowly heating to 55-65 ℃ for reaction for 0.5-1 h, changing the vermilion into white in the reaction liquid, separating out a solid, continuing to react for 1-2 h, cooling to room temperature, adding a saturated sodium bisulfite aqueous solution, continuing to stir, performing suction filtration to obtain a filter cake, recrystallizing with a mixed solution of toluene and n-hexane, performing suction filtration, leaching with a mixed solution, and drying under reduced pressure at 45-55 ℃ to obtain the palbociclib mother nucleus compound shown in the formula (I).
In the embodiment of the invention, when cytosine is used as a starting raw material to prepare the palbociclib mother nucleus structure compound, the total yield of the process can reach more than 65%, the purity is more than 99.3%, the cytosine has wide sources and low price, the cost of the process can be greatly reduced, the defects of poor selectivity, more side reactions and difficult later purification caused by using a 2,4, 5-trisubstituted pyrimidine raw material as the raw material in the prior art are overcome by using the cytosine as the starting raw material, and the method has simple operation process and less side reactions, and is particularly suitable for industrial production.
Detailed Description
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 according to conventional conditions or according to conditions recommended by the manufacturers.
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. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1Preparation of 2-chloro-4-aminopyrimidine (intermediate 1)
Under the condition of mechanical stirring, adding cytosine (57.05g, 0.5mol), phosphorus pentachloride (312.36g, 1.5mol) and 570mL of toluene into a reaction bottle, fully and uniformly stirring, heating to 110 ℃, carrying out reflux reaction, and monitoring the completion of the reaction of the raw materials by TLC; concentrating under reduced pressure to remove most of the solvent, cooling to room temperature, adding 500mL of water, extracting with dichloromethane for multiple times, combining organic phases, drying with anhydrous sodium sulfate to remove water, concentrating under reduced pressure to remove dichloromethane to obtain a light yellow transparent liquid intermediate 1(62.84g, yield 97%, purity 97.7%), and directly using in the next step without purification; or further adding 250ml of n-hexane into the mixture, stirring the mixture in an ice water bath, crystallizing the mixture for 2 hours, performing suction filtration, leaching a small amount of n-hexane, and performing vacuum drying to obtain a light yellow crystal intermediate 1(59.47g, yield 91.82% and purity 99.3%);1H NMR(400MHz,CD3OD)δ:6.41(d,1H),7.74(s,2H)7.90(d,1H).
when the molar ratio of cytosine to the halogenating agent is changed to 1:1.8 to 1:3.5, the yield of the intermediate 1 can be 90.5 to 91.9%.
Example 25-bromoPreparation of (E) -2-chloro-4-aminopyrimidine (intermediate 2)
Adding 500mL of glacial acetic acid into the light yellow transparent liquid of the intermediate 1, stirring and dissolving, adding KBr (6.2g, 10%), slowly dropwise adding 80mL of glacial acetic acid solution of bromine (81.4g, 0.51mol) at room temperature, after dropwise adding, enabling the reaction system to be vermilion, slowly heating to 55 ℃ for reaction for 1h, enabling the reaction solution to be changed from vermilion into white, and separating out a solid; continuing to react for 1h, cooling to room temperature, adding 10ml of saturated sodium bisulfite aqueous solution, continuing to stir for 0.5h, performing suction filtration, rinsing with purified water, and performing vacuum drying at 45 ℃ to obtain a white solid powder intermediate 2(97.06g, yield 96%, purity 98.73%);1H NMR(400MHz,CDCl3)δ:8.71(s,1H),5.77(s,2H)。
when the molar ratio of the intermediate 1 to the brominating agent is changed to 1:1.0 to 1:1.5, the yield of the intermediate 2 can be 95.1 to 96.4%.
Example 3Preparation of 5-bromo-2-chloro-4-N-cyclopentylpyrimidine (intermediate 3)
Dissolving the intermediate 2(83.4g, 0.4mol), triethylamine (40.5g, 0.4mol) and methanol 300ml in a reaction bottle under stirring, dropwise adding chlorocyclopentane (50.2g, 0.48mol) at room temperature, controlling the temperature to stir for reaction 2 after the dropwise adding, monitoring by TLC until the reaction is finished, adding ice water 350ml, controlling the temperature to 0-10 ℃, stirring for crystallization for 1h, performing suction filtration, leaching by using ice water, draining, performing vacuum drying at 45 ℃ to obtain a white solid powder intermediate 3(102.57g, the yield is 92.74%, the purity is 99.18%),1H NMR(400MHz，CDC13)δ：8.10(s,1H),5.47(d,J＝4.5Hz,1H),4.42(dd,J＝14.0,7.0Hz,1H),1.44～2.17(m,8H)。
when the molar ratio of the intermediate 2 to the halogenated cyclopentane is changed to be within the range of 1:1.18 to 1:1.25, the yield of the intermediate 3 can be 91.2 to 92.9%.
Example 48-Cyclopentylalkyl-5-methyl-2-chloro-pyrido [2,3-d]Preparation of pyrimidin-7-one (intermediate 4,)
Intermediate 3(83g, 0.3mol), triethylamine (121.32g, 1.2mol) and THF (400mL) were added to a reaction flask and stirred to dissolve, palladium chloride (2.1g) was added, the mixture was heated to 60 ℃ and refluxed for 5 hours, and the reaction was monitored by TLCCompletely; adding crotonic acid (61.26g, 0.6mol) and continuing to react for 2 h; cooling to 40 deg.C, removing THF under reduced pressure, adding purified water (800ml), controlling temperature at 10 + -5 deg.C for crystallization for 1h, vacuum filtering, eluting with purified water, vacuum drying at 50 deg.C to obtain yellow brown solid intermediate 4(70.48g, yield 89.08%, purity 98.28%),1H NMR(400MHz，CDC13)δ:8.76(s,1H),6.56(d,J＝2.5Hz,1H)，5.87(m,1H),2.46(d,J＝1.2Hz,3H),1.71～2.24(m,8H)。
when the molar ratio of the intermediate 3 to the crotonic acid is changed to be in the range of 1: 1.25-1: 2, the yield of the intermediate can be 88-89.7%; the catalyst or acid-binding agent is replaced to influence the reaction process, and when palladium chloride is used as a palladium catalyst and triethylamine is used as an acid-binding agent, the reaction effect is best, and the yield is relatively higher.
Example 5Parent nucleus of Palbociclib (6-bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido [2, 3-d)]Preparation of pyrimidin-7 (8H) -ones)
The method is the same as the preparation method of the intermediate 2, wherein the molar ratio of the intermediate 4 to the bromine is 1:1.5, the filter cake obtained by suction filtration is recrystallized by using a mixed solution (10v) of toluene and n-hexane, the filter cake is subjected to suction filtration, the mixed solution is used for leaching, the white solid powder of the parent nucleus of the palbociclib is obtained by decompression drying at 50 ℃, the yield is 90 percent, the purity is 99.37 percent,1H NMR(400MHz，CDC13)δ:8.88(s,1H,ArH),5.99(m,1H),2.68(s,3H),1.72～2.22(m,8H)。
changing the dosage of the intermediate 4 and the brominating agent to ensure that the molar ratio is within the range of 1: 1.3-1: 1.7; or the type of the brominating agent is changed into NBS or DBH, the yield aiming at the mother nucleus in the embodiment can be 85-90%.
Comparative example
6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one was prepared according to the procedure described in WO2014128588, the reaction scheme being as follows:
the preparation process comprises the following steps:
step A: preparation of 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine
To a vessel was added neat ethanol (3000mL, 3.0vol) followed by 5-bromo-2, 4-dichloropyrimidine (molecular weight 227.87; 1000g, 1.0 eq.). Triethylamine (612mL, 1.0 equiv.) was added, followed by slow addition of cyclopentylamine (molecular weight 85.15; 520mL,1.2 equiv.) over a 2 hour period to control the mild exotherm. After completion of the cyclopentylamine addition, the reaction was seeded with 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine (5g, 0.5 wt%) to initiate crystallization. The reaction was stirred at 25 ℃ for 2 hours.
Water (2500mL, 2.5vol) was added to the vessel at a rate of 30 mL/min at 20 to 25 ℃. The mixture was cooled to 8 to 12 ℃ at 2 ℃/min. The slurry was maintained at 8 to 12 ℃ for 1 hour and then at #2WhatmanTMFiltering on filter paper. The filter cake was washed with n-heptane (2000 mL). The filter cake was reslurried on a filter dryer with n-heptane (2000 mL). The material was dried in a vacuum oven at 50 to 55 ℃ overnight to yield 5-bromo-2-chloro-6-cyclopentyl-aminopyrimidine (984 g; yield 81%, purity 94.94%, with an isomeric impurity of 4.94%) as a white solid.
And B: preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one
5-bromo-2-chloro-6-cyclopentylamino-pyrimidine (10.0g, 1.0 eq.) and N-methylpyrrolidinone (NMP) (50mL, 5.0vol) are added to the vessel at ambient temperature. To the reaction mixture was added crotonic acid (4.7g, 1.5 equivalents) and triethylamine (20.2mL, 4.0 equivalents). The vessel was degassed and flushed with nitrogen three times. Adding Pd (OAc) to the degassed reaction mixture2(0.25g, 0.03 eq.). The vessel was degassed and flushed with nitrogen three times using the same method as step 3. The mixture was heated to 65 ℃ and allowed to stir until the starting material was consumed (at least 6 hours).
Acetic anhydride (6.8mL, 2.0 equivalents) was added to the reaction mixture. The reaction was allowed to react at 65 ℃ until the starting material was consumed (typically 1 to 2 hours).
The reaction mixture was cooled to 20 ℃ and H was added2O(100mL, 10vol) to dissolve triethylamine HBr salt and precipitate 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2, 3-d-]A pyrimidin-7-one. The mass was granulated at 20 ℃ for 1 hour. The solid was filtered and washed with H2O (20mL, 2.0vol) and 4:1 isopropanol/H2O mixture (50mL, 5.0vol) was washed. The crude product was dried under vacuum at 55 to 70 ℃ to give 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] in the form of a tan to gray solid]Pyrimidin-7-one (8.3 g; yield 86%; purity 94.28%).
And C: preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one
Adding 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] to a glass-lined vessel]Pyrimidin-7-one (9.35g, 1.0 eq.) and acetonitrile (65mL, 7.0 vol). N-bromosuccinimide (9.67g, 1.5 equivalents) and oxalic acid (0.65g, 0.2 equivalents) were added. The reaction mixture was then heated to 60 ± 5 ℃. The reaction was stirred at 60 ℃ until the starting material was consumed (at least 6 hours). The slurry was cooled to 20 ℃ and H was added2O (9mL, 1 vol). Adding to the slurry H2Sodium bisulfite solution (3.88g, 1.0 equiv) in O (38mL, 4 vol). The slurry was granulated for 1 hour and then filtered directly on a #2Whatman filter paper. The reaction vessel was rinsed with water (19mL, 2vol) followed by a 7:3 methanol/acetonitrile mixture (28mL, 3vol) and the rinse was then transferred to the filter cake. The product was dried in a vacuum oven at 50 to 55 ℃. Isolating 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d as a pale yellow solid]Pyrimidin-7-one (10.73 g; yield 88.8%; purity 96.51%).
The product was further purified by recrystallization from toluene and n-heptane. Toluene (60mL, 6vol) and 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one (10.00g, 1 eq) were added to the reaction vessel and heated to 80 ℃. The warm reaction mixture was filtered through a suitable cartridge to ensure removal of insoluble Pd and other insoluble contaminants. The filter cartridge was rinsed with 80 deg.C toluene (5mL, 0.5 vol). The slurry was cooled to 25 ℃ at 1 ℃/min. N-heptane (70mL, 7vol) was added to the reaction slurry at 1 mL/min. The slurry was further cooled to 0 ℃ at 1 ℃/min. The slurry was granulated at 0 ℃ for at least 1 hour.
The slurry was filtered directly on a #2Whatman filter paper. N-heptane (30mL, 3vol) was charged to the reaction vessel and the wash was transferred to the filter cake and the product was dried in a vacuum oven at 50 to 55 ℃. 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one was isolated as an emulsified colored solid (8.23g, 82% yield; 99.76% purity).
In the implementation process, in the step a, the reactant 5-bromo-2, 4-dichloropyrimidine is 2,4, 5-trihalo-substituted pyrimidine, the number of halogens is large, and the activities of the halogens are similar, so that the selectivity of the reaction in the step for specific halogens is poor, side reactions are easy to occur, the yield and purity are low, subsequent impurities are derived, the purity of each intermediate is not high, and although the parent nucleus with high purity is obtained after complicated purification, the overall yield is low and is about 50%. In addition, the price of the starting material 5-bromo-2, 4-dichloropyrimidine is high, and the industrial production cost is high.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (16)
1. A preparation method of a palbociclib-mother nucleus structural compound comprises the steps of preparing the palbociclib-mother nucleus structural compound shown in a formula (I) by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw material;
wherein X is chlorine;
the method comprises the following steps of preparing the compound shown in the formula (I) by taking the intermediate 2 as a starting material, and specifically comprises the following steps: carrying out substitution reaction on the intermediate 2 and halogenated cyclopentane at room temperature to prepare an intermediate 3, wherein the molar weight ratio of the intermediate 2 to the halogenated cyclopentane is 1: 1.18-1: 1.25; mixing the intermediate 3, an acid-binding agent and a solvent, stirring and dissolving, adding a palladium catalyst, heating to 55-65 ℃, refluxing, and reacting completely; adding crotonic acid to continue reacting for 2 h; cooling to 30-40 ℃, removing the solvent under reduced pressure, adding purified water, controlling the temperature to be 5-15 ℃ for crystallization, performing suction filtration, leaching with the purified water, and performing vacuum drying at 45-55 ℃ to obtain an intermediate 4; carrying out substitution reaction on the intermediate 4 and a bromization reagent to prepare a compound shown in the formula (I);
wherein the X groups in intermediate 3 and intermediate 4 are the same as in intermediate 2.
2. The preparation method of the palbociclib core structure compound according to claim 1, wherein the method comprises the step of preparing the compound shown in the formula (I) by using the intermediate 1 as a starting material, and specifically comprises the following steps: the intermediate 1 and a bromization reagent are subjected to substitution reaction to prepare an intermediate 2, the intermediate 2 and halogenated cyclopentane are subjected to substitution reaction to prepare an intermediate 3, the intermediate 3 and crotonic acid are subjected to substitution reaction to prepare an intermediate 4, and the intermediate 4 and the bromization reagent are subjected to substitution reaction to prepare a compound shown in a formula (I);
wherein the X groups in intermediate 1, intermediate 3 and intermediate 4 are the same as in intermediate 2.
3. The preparation method of the palbociclib-nucleus structural compound as claimed in claim 1, wherein the method comprises the step of preparing the compound shown in the formula (I) by taking cytosine as a starting material, and specifically comprises the following steps: the method comprises the following steps of carrying out substitution reaction on cytosine and a halogenated reagent to prepare an intermediate 1, carrying out substitution reaction on the intermediate 1 and a brominated reagent to prepare an intermediate 2, carrying out substitution reaction on the intermediate 2 and halogenated cyclopentane to prepare an intermediate 3, carrying out substitution reaction on the intermediate 3 and crotonic acid to prepare an intermediate 4, and carrying out substitution reaction on the intermediate 4 and the brominated reagent to prepare a compound shown in the formula (I);
wherein the X groups or halogens in the halogenating reagent in intermediate 1, intermediate 3 and intermediate 4 are the same as in intermediate 2.
4. The preparation method of the parent nucleus structure compound of palbociclib according to any one of claims 1 to 3, characterized in that the intermediate 2 is reacted with halogenated cyclopentane in the presence of an acid-binding agent to prepare the intermediate 3.
5. The preparation method of the palbociclib parent core structure compound as claimed in claim 4, wherein the acid-binding agent is triethylamine and/or diisopropylamine.
6. The preparation method of the palbociclib core structure compound as claimed in any one of claims 1 to 3, wherein the intermediate 3 is prepared by Heck reaction with crotonic acid and intramolecular amidation ring formation to obtain intermediate 4.
7. The method for preparing the palbociclib parent nucleus structure compound as claimed in claim 6, wherein the reaction for preparing the intermediate 4 from the intermediate 3 is carried out in the presence of a palladium catalyst and an acid-binding agent.
8. The preparation method of the palbociclib core-structure compound as claimed in claim 7, wherein the palladium catalyst is one or more selected from palladium chloride, bis (benzonitrile) palladium chloride and palladium acetate.
9. The preparation method of the palbociclib parent core structure compound as claimed in claim 7, wherein the acid-binding agent is triethylamine and/or diisopropylamine.
10. The preparation method of the palbociclib parent nucleus structural compound as claimed in any one of claims 1 to 3, characterized in that the reaction for preparing the compound of formula (I) from the reaction of the intermediate 4 with a brominating agent is carried out in a catalyst/solvent system, wherein the catalyst is selected from one or more of KBr, KI, glacial acetic acid and oxalic acid; the solvent is selected from one or more of glacial acetic acid, acetonitrile and dichloroethane.
11. The method for preparing the palbociclib-core structural compound as claimed in claim 10, wherein when the catalyst is KBr and/or KI, the solvent is glacial acetic acid; or when the catalyst is glacial acetic acid and/or oxalic acid, the solvent is acetonitrile and/or dichloroethane.
12. The method for preparing the palbociclib core structure compound as claimed in claim 10, wherein the brominating agent is selected from one or more of bromine, NBS and 1, 3-dibromo-5, 5-dimethylhydantoin.
13. The method for preparing the palbociclib core structure compound as claimed in claim 10, wherein the brominating agent is selected from one or more of bromine, NBS and 1, 3-dibromo-5, 5-dimethylhydantoin.
14. The method for preparing the palbociclib-nucleus structural compound as claimed in claim 3, wherein the reaction solvent in the reaction of preparing the intermediate 1 from cytosine and a halogenating reagent is chlorobenzene and/or toluene.
15. The method for preparing the palbociclib parent nucleus structural compound as claimed in claim 14, wherein the halogenating agent is a chlorinating agent selected from one or more of phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and organophosphorus chloride.
16. The method for preparing a parent nucleus-structured compound of pabulicin according to claim 15, wherein the organophosphorus chloride is triphenylphosphonium chloride or triphenylphosphite chloride.
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