Synthesis method of palbociclib

Abstract

The present invention discloses a process of the present invention, which uses cheap 2-chloro-4-bromopyrimidine as a starting material, and then couples with a cheap intermediate (7) through acetylation, cyclopentyl amination, diketene cyclization, and acidic conditions to remove the protecting group, thereby obtaining palbociclib (chemical purity ≥ 99%) with high yield and low cost. The process of the present invention avoids the use of precious metal palladium chloride or palladium acetate and relatively expensive ligands in the Heck reaction, which increases the synthesis cost. The process route of the present invention is short, low in cost, beneficial to the environment, and suitable for industrial mass production. The use of precious metal palladium chloride or palladium acetate is avoided during the reaction process, reducing concerns about the genotoxicity of metal palladium, which is conducive to further improving the safety of palbociclib preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis route design and raw material medicine and intermediate preparation, and particularly relates to a synthesis method of palbociclib. Background Art

[0002] Palbociclib is an oral, targeted agent developed by Pfizer that can selectively inhibit cyclin-dependent kinases 4 and 6 (CDK4 / 6), restore cell cycle control, and block tumor cell proliferation. Palbociclib Phase II clinical study data for the treatment of advanced estrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancer in postmenopausal women showed that compared with the standard treatment drug letrozole treatment group, the combination of palbociclib and letrozole achieved a statistically significant extension of disease progression-free survival (PFS) (20.2 months vs 10.2 months, p = 0.0004). Preliminary data on overall survival (OS) at the time of the final PFS analysis showed that the average overall survival of the combination group was 37.5 months. The FDA has approved the new drug application (NDA) for palbociclib in 2015. The combination of palbociclib and letrozole provides an important new option for patients with metastatic breast cancer.

[0003]

[0004] The current literature reports that the route for synthesizing palbociclib is as follows:

[0005]

[0006] 1. This route 1 uses 2-methylthio-4-chloro-5-carboxylic acid ethyl ester pyrimidine as the starting material, and undergoes multiple steps such as amination, reduction, oxidation, Grignard, oxidation, etc., and obtains 5-acetyl 4-cyclopentylamino-2-methylthio-pyrimidine through multiple steps. The reaction steps are long, and expensive lithium aluminum hydride is used as a reducing agent. Although the literature reports a high yield, it is difficult to achieve in practice. Using sulfoxide as a leaving group, the nucleophilic substitution reaction of pyrimidine with an aminopyridine derivative (J) has a very low yield of 28-35%, which greatly increases the synthesis cost. Using stille coupling to introduce acetyl groups, the yield reaches 80%, but it is necessary to use expensive Pd as a catalyst, as well as ethoxyvinyl tributyltin, triphenylphosphine and other not cheap reagents. The total yield is 9.49% (relative to 2-methylthio-4-chloro-5-carboxylic acid ethyl ester pyrimidine), the yield is low, the steps are lengthy, and the process is cumbersome.

[0007] 2. WO2008032157 and WO2014128588A1 have improved the synthesis method of this product, using 2,4-dichloro-5-bromopyrimidine as the starting material, introducing the cyclopentylamine group by amination of cyclopentylamine at the 4-position of pyrimidine, and using the Heck reaction twice to introduce the double bond and the acetyl group respectively, making the synthesis steps very simple. The precursor of the acetyl group is vinyl butyl ether, which can be easily removed at the same time as the amino protecting group Boc under acidic conditions, and the generated by-products are very easy to separate, and the deprotection and salt formation can be completed in one pot. The nucleophilic substitution reaction of aminopyridine and pyrimidine uses strong base lithium amide or isopropyl magnesium chloride, and the yield is increased to 92-93%. WO2014128588 reported that the total yield was increased to 43.55% (based on 2,4-dichloro-5-bromopyrimidine). The reaction formula of this route is as follows

[0008]

[0009] The disadvantage of this synthetic route 2 is that the Heck reaction is used twice, and noble metal palladium chloride or palladium acetate and relatively expensive ligands are required, which increases the synthesis cost.

[0010] So far, the problems with the routes reported in the literature are as follows:

[0011] 1. Synthesis Route-1 uses sulfoxide as a leaving group to carry out nucleophilic substitution reaction of pyrimidine with aminopyridine derivative (J), and the yield is very low 28-35%, which greatly increases the synthesis cost. The acetyl group is introduced by stille coupling, and the yield reaches 80%, but it is necessary to use expensive Pd as a catalyst, as well as ethoxyvinyl tributyltin, triphenylphosphine and other not cheap reagents. The total yield is 9.49% (relative to 2-methylthio-4-chloro-5-carboxylic acid ethyl ester pyrimidine), the yield is low, the steps are lengthy, and the process is cumbersome.

[0012] 2. Route-2 uses the Heck reaction twice, which requires the use of precious metal palladium chloride or palladium acetate, as well as more expensive ligands, increasing the synthesis cost. Summary of the invention

[0013] In order to solve the deficiencies of the prior art, the present invention provides a new synthesis method. The process of the present invention uses cheap 2-chloro-4-bromopyrimidine as the starting material, and through acetylation, cyclopentyl amination, diketene cyclization, and further coupling with a cheap intermediate (7), the protective group is removed under acidic conditions, and palbociclib (chemical purity ≥ 99%) is obtained with high yield and low cost. The process of the present invention avoids the use of precious metal palladium chloride or palladium acetate and more expensive ligands in the Heck reaction, which increases the synthesis cost. The process route of the present invention is short, the cost is low, it is beneficial to the environment, and it is suitable for industrial mass production.

[0014] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, wherein 2-chloro-4-bromopyrimidine is used as a starting material, and palbociclib is prepared by acetylation, cyclopentyl amination, diketene cyclization, coupling with 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7), and removing the protecting group under acidic conditions. 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7) is an intermediate (7).

[0015] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, comprising the following steps: the starting material 2-chloro-4-bromopyrimidine (1) is dissolved in chloroform, acetyl chloride is added, aluminum chloride is slowly added, the temperature is controlled at 0-10°C, and the reaction is carried out by heat preservation. After the reaction is completed, the reaction is washed with water, the layers are separated, and the chloroform is recovered by vacuum distillation. The residue is 5-acetyl-2-chloro-4-bromopyrimidine (2), which is directly used in the next reaction without purification.

[0016] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, the method further comprising the following steps: dissolving the above-mentioned 5-acetyl-2-chloro-4-bromopyrimidine (2) in NMP, adding triethylamine, adding cyclopentylamine, heating to 20-25°C for reaction, then recovering the remaining cyclopentylamine, triethylamine and NMP under reduced pressure, adding water to the residue, adding ethyl acetate for extraction, extracting, combining the oil layers, distilling and recovering part of the ethyl acetate, cooling, filtering, and drying to obtain 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3).

[0017] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, the method further comprising the following steps: the above-mentioned 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3) is dissolved in tetrahydrofuran at 5-10°C, a mixed solution of diketene and tetrahydrofuran is added dropwise thereto, after the addition is complete, the mixture is reacted at room temperature, and then the temperature is raised to 60°C for reaction; part of the solvent is concentrated under reduced pressure, the temperature is lowered and filtered, and the compound 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4) is obtained.

[0018] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, the method further comprising the following steps: the above-mentioned 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4) is dissolved in tetrahydrofuran, a mixture of triethylamine and DMAP is added at 5-15°C, the reaction is stirred for 4 hours, the temperature is then raised to 35-40°C for reaction, the reaction is then refluxed and kept warm, the temperature is lowered to room temperature, water is added, the mixture is filtered, washed, and dried to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (5).

[0019] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, the method further comprising the following steps: dissolving 5.0 g of the above-mentioned 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one in DMF, adding potassium carbonate and the above-mentioned 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7), stirring and heating, and keeping the temperature and stirring; monitoring by TLC, after the raw material point disappears, cooling to room temperature; pouring the feed liquid into water to precipitate a large amount of orange-yellow solid, filtering, washing the filter cake with a large amount of water until the mother liquor is neutral, drying, drying to obtain a yellow solid crude product, recrystallizing, and drying to obtain a bright yellow Boc-protected palbociclib (6).

[0020] According to one aspect of the present invention, a method for synthesizing palbociclib is provided, the method further comprising the following steps: adding 5.0 g of Boc-protected palbociclib (6) to a mixed solution of acetone and water, stirring until the liquid is evenly dispersed, adding concentrated hydrochloric acid, and heating to 50° C. for reaction. TLC monitoring until the raw material point disappears. Cooling to 10° C., slowly adding triethylamine to the system until pH>9, stirring fully until a large amount of solid precipitates, continuing stirring, filtering, and washing the filter cake with water until neutral. Drying at 40° C. to obtain a crude product, recrystallizing with n-butanol and anisole, adding activated carbon for decolorization, filtering, and drying to obtain a bright yellow solid compound I, palbociclib (8).

[0021] After acetylation of 2-chloro-4-bromopyrimidine of the present invention, it reacts with cyclopentylamine and then with diketene. After cyclization under alkaline conditions, it is coupled with (7) under alkaline conditions and then deprotected to obtain palbociclib (chemical purity ≥ 99%) in high yield.

[0022] The process route is simple and avoids the use of precious metal palladium chloride or palladium acetate and relatively expensive ligands in the Heck reaction.

[0023] DETAILED DESCRIPTION

[0024] The following embodiments are intended to further illustrate some preferred embodiments of the present invention, but are not all embodiments. Other embodiments based on the present invention made by professionals in this field without creative work are all within the scope of protection of the present invention.

[0025] Example 1) Preparation of 5-acetyl-2-chloro-4-bromopyrimidine (2)

[0026]

[0027] 19.3 g of the starting material 2-chloro-4-bromopyrimidine (1) was dissolved in 200 mL of chloroform, 10.0 g of acetyl chloride was added, and 15.0 g of aluminum chloride was slowly added. The temperature was controlled at 0-10°C and the reaction was kept warm. After the reaction was completed, the mixture was washed with water, separated and distilled under reduced pressure to recover the chloroform. The residue was 5-acetyl-2-chloro-4-bromopyrimidine (2), which was directly used in the next reaction without purification.

[0028] Example 2) Preparation of 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3)

[0029]

[0030] The compound (2) of Example 1 was dissolved in 100 ml of NMP, 30 ml of triethylamine and 65 g of cyclopentylamine were added, the temperature was raised to 20-25° C. and the reaction was performed for 8 h. The remaining cyclopentylamine, triethylamine and NMP were recovered under reduced pressure, and the residue was added to

[0031] 50mL of water, add 100mL of ethyl acetate for extraction, extract three times, combine the oil layers, distill and recover part of the ethyl acetate, cool, filter,

[0032] After drying, 21.5 g of 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3) was obtained, with a two-step yield of 90%.

[0033] Example 3) Preparation of 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4)

[0034]

[0035] 12.0 g of 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3) was dissolved in 100 mL of tetrahydrofuran, and a mixed solution of 4.7 g of diketene and 40 mL of tetrahydrofuran was added dropwise at 5-10°C. After the addition was complete, the mixture was reacted at room temperature for 4 h, and then heated to 60°C for 2 h. Part of the solvent was concentrated under reduced pressure, and the mixture was filtered off with suction to obtain 13.3 g of the compound 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4) with a yield of 82%.

[0036] Example 4) Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (5)

[0037] 16.2 g of 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4) was dissolved in 40 mL of tetrahydrofuran. A mixture of 3 g of triethylamine and 2 g of DMAP was added at 5-15°C, and the mixture was stirred for reaction for 4 h. The mixture was then heated to 35-40°C for reaction for 2 h. The mixture was then refluxed for 3 h, cooled to room temperature, and 80 mL of water was added. The mixture was filtered, washed, and dried to obtain 12.3 g of 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (5) with a yield of 80%.

[0038] Example 5) Preparation of Boc-protected Palbociclib (6)

[0039]

[0040] Dissolve 5.0 g of 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one in 80 ml of DMF, add 5.0 g of potassium carbonate and 6.0 g of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7), stir and heat to 80°C, keep at 85°C and stir for 4 hours. Monitor by TLC, and cool to room temperature after the raw material point disappears. Pour the feed liquid into water, and a large amount of orange-yellow solid precipitates. Filter, wash the filter cake with a large amount of water until the mother liquor is neutral, dry at 50°C, and dry to obtain 6.8 g of yellow solid crude product. Recrystallize and dry to obtain 6.2 g of bright yellow Boc-protected palbociclib (6), with a total yield of 69%.

[0041] Example 6) Preparation of Palbociclib (8)

[0042]

[0043] 5.0 g of Boc-protected palbociclib (6) was added to a mixed solution of 60 ml of acetone and 100 ml of water, stirred until the liquid was evenly dispersed, 6 ml of 35% concentrated hydrochloric acid was added, and the temperature was raised to 50°C for reaction for 10 hours. TLC was monitored until the raw material point disappeared. The temperature was lowered to 10°C, triethylamine was slowly added to the system until pH>9, and the mixture was stirred until a large amount of solid precipitated. Stirring was continued for 3 hours, filtered, and the filter cake was washed with water until it was neutral. The crude product was dried at 40°C, recrystallized with n-butanol and anisole, decolorized with activated carbon, filtered, and dried to obtain 3.3 g of bright yellow solid compound I, with a yield of 81%.

[0044] It should be pointed out that the above preferred embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing palbociclib, characterized in that: The method uses 2-chloro-4-bromopyrimidine as a starting material, and through acetylation, cyclopentyl amination, diketene cyclization, coupling with 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7), and removing the protecting group under acidic conditions, palbociclib is prepared; The synthetic route of the palbociclib is as follows: The method comprises the following steps: The starting material 2-chloro-4-bromopyrimidine (1) is dissolved in chloroform, acetyl chloride is added, aluminum chloride is slowly added, and the temperature is controlled at 0-10° C. for reaction. After the reaction is completed, the mixture is washed with water, separated, and chloroform is recovered by vacuum distillation. The residue is 5-acetyl-2-chloro-4-bromopyrimidine (2), which is directly used in the next reaction without purification. The 5-acetyl-2-chloro-4-bromopyrimidine (2) is dissolved in NMP, triethylamine and cyclopentylamine are added, and the temperature is raised to 20-25° C. for reaction, and then the remaining cyclopentylamine, triethylamine and NMP are recovered under reduced pressure, and water is added to the residue, and ethyl acetate is added for extraction, and the oil layers are combined, and part of the ethyl acetate is recovered by distillation, and the temperature is lowered, and the mixture is filtered and dried to obtain 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3); The 5-acetyl-2-chloro-4-cyclopentylaminopyrimidine (3) is dissolved in tetrahydrofuran, and a mixed solution of diketene and tetrahydrofuran is added dropwise at 5-10°C. After the addition is complete, the mixture is reacted at room temperature, and then the temperature is raised to 60°C for reaction. Part of the solvent is concentrated under reduced pressure, and the temperature is lowered and filtered to obtain the compound 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4). The 5-acetyl-4-acetoacetylcyclopentylamino-2-chloropyrimidine (4) is dissolved in tetrahydrofuran, and a mixture of triethylamine and DMAP is added at 5-15° C., and the mixture is stirred for reaction for 4 hours, and then the mixture is heated to 35-40° C. for reaction, and then refluxed and kept warm, and then cooled to room temperature, and water is added, and the mixture is filtered, washed, and dried to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (5); The 6-acetyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one is dissolved in DMF, potassium carbonate and the 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (7) are added, the temperature is raised with stirring, and the mixture is kept warm with stirring; TLC monitoring is performed, and after the raw material point disappears, the mixture is cooled to room temperature; the feed liquid is poured into water to precipitate a large amount of orange-yellow solid, which is filtered, and the filter cake is washed with a large amount of water until the mother liquor is neutral, and then dried to obtain a yellow solid crude product, which is recrystallized and dried to obtain bright yellow Boc-protected palbociclib (6); Add Boc-protected palbociclib (6) to a mixed solution of acetone and water, stir until the feed liquid is evenly dispersed, add concentrated hydrochloric acid, and heat to 50°C for reaction; monitor by TLC until the raw material point disappears; cool to 10°C, slowly add triethylamine to the system until pH>9, stir thoroughly until a large amount of solid precipitates, continue stirring, filter with suction, wash the filter cake with water until it is neutral, dry at 40°C to obtain a crude product, recrystallize with n-butanol and anisole, add activated carbon for decolorization, filter, and dry to obtain a bright yellow solid compound 8.

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