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A low-cost preparation method of palbocyb
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A low-cost, compound technology, applied in the field of medicine and biochemical industry, can solve problems such as increasing synthesis cost
Active Publication Date: 2017-02-01
XINFA PHARMA
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[0012] The disadvantage of this synthetic route 2 is that the Heck reaction is used twice, which requires the use of noble metal palladium chloride or palladium acetate, and more expensive ligands, which increases the synthesis cost
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Embodiment 1
[0074] Example 1: Preparation of 2,4-dichloropyrimidine-5-(ethylenedioxy)ethylpyrimidine (Ⅲ-1)
[0075] The initial raw material 2,4-dichloro-5-cyanopyrimidine 34.8g, dissolved in 100ml tetrahydrofuran solution, warmed up to 55-60°C, began to add equimolar methylmagnesium bromide tetrahydrofuran Grignard solution dropwise, and the dropwise addition was completed After 65°C, keep warm for 3 hours, then cool down to 15-20°C, add 50mL of dilute hydrochloric acid, stir, separate layers, dry the oil layer with anhydrous sodium sulfate, recover tetrahydrofuran, and the residue is 2,4-dichloro-5-acetyl The base pyrimidine (II) was 34.4 g, and the yield was 90%.
[0076] Dissolve 34.4g of 2,4-dichloro-5-acetylpyrimidine (II) in 120mL of toluene, add 11.5g of ethylene glycol, add 0.17g of p-toluenesulfonic acid, reflux with water until a theoretical amount of water is generated , stop the reaction, cool down to room temperature, add 0.5g of sodium methoxide, add 20mL of water to wash,...
Embodiment 2
[0079] Example 2: Preparation of 5-acetyl-2-dichloro-4-cyclopentylaminopyrimidine (IV)
[0080]Dissolve the compound (III-1) of Example 1 in 100ml of NMP, add 30mL of triethylamine, add 65g of cyclopentylamine, raise the temperature to 20-25°C for 8h, and then recover the remaining cyclopentylamine, tri Ethylamine and NMP, add 50mL of water to the residue, then add 6mL of concentrated hydrochloric acid, heat up to 60-70°C, react for 2h, adjust the pH to 9-10 with sodium carbonate solution, add 100mL of ethyl acetate for extraction, extract three times, and combine the oil layers , part of the ethyl acetate was recovered by distillation, cooled, suction filtered, and dried to obtain 34.5 g of 5-acetyl-2-dichloro-4-cyclopentylaminopyrimidine (IV), with a two-step yield of 80%.
Embodiment 3
[0081] Example 3: Preparation of 5-acetyl-4-acetoacetamido-2-chloropyrimidine (V)
[0082] 5-acetyl-2-dichloro-4-cyclopentylaminopyrimidine (IV) 34.5g, dissolved in 200mL tetrahydrofuran, 5-10 ° C, dropwise added a mixed solution of 12.7g diketene and 50mL tetrahydrofuran, dropwise After completion, react at room temperature for 4h, then raise the temperature to 60°C for 2h. Part of the solvent was concentrated under reduced pressure, and the temperature was reduced by suction filtration to obtain 43.3 g of compound 5-acetyl-4-acetoacetamido-2-chloropyrimidine (V), with a yield of 93%.
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Abstract
The invention relates to a low-cost preparation method for palbociclib. The low-cost preparation method comprises the following steps: by taking 2,4-dichloro-5-cyanopyrimidine as an initial raw material, performing cyano Grignard and hydrolysis so as to obtain 5-acetyl-2,4-dichloropyrimidine, protecting carbonyl, performing amination, removing carbonyl, performing acylation reaction by using diketene and amino so as to obtain 5-acetyl-4-acetoacetamide-2-chloropyrimidine, performing intramolecular dehydration on the product so as to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-chlorine-8H-pyridino-[2,3-d] pyrimidine-7-ketone, protecting 6 acetyl groups by using carbonyl, further realizing reaction with an aminopyridine derivative so as to obtain 4-{6-[(6-1,1 dialkoxyl) ethyl-8-cyclopentyl-5-methyl-7-keton-7,8 dihydropyridino-[2,3-d]pyrimidine-2-amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester, and finally performing acid hydrolysis and neutralization to obtain palbociclib free alkali. By adopting the low-cost preparation method, the raw materials are easy to obtain, the cost is low, and the environment can be protected.
Description
technical field [0001] The invention relates to a preparation method of palbocyb, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Palbociclib is an oral, targeted agent developed by Pfizer that selectively inhibits cyclin-dependent kinase 4 and 6 (CDK4 / 6), restores cell cycle control, and blocks tumor cell proliferation. The data from the phase II clinical study of Palbociclib 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 (Letrozole) treatment group In comparison, the progression-free survival (PFS) of the combination group of palboceb and letrozole achieved a statistically significant prolongation (20.2 months vs 10.2 months, p=0.0004), reaching the primary endpoint of the study . Preliminary data on overall survival (OS) at the time of the final PFS a...
Claims
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