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The synthetic method of ribociclib intermediate

A technology of ribociclib and a synthesis method, which is applied in the new synthesis field of intermediate compounds, can solve the problems of inconvenient process amplification, high risk of worker operation, unfavorable process amplification, etc., and achieves optimization of coupling conditions and shortening of reaction steps. , the effect of simple operation

Active Publication Date: 2018-07-24
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this route selects propynyl alcohol as the side chain for coupling, the reaction yield of this step is still relatively low, and a large dose of noble metal catalyst is also used, and the process cost is high; A large amount of manganese dioxide solid is used as an oxidant, which is inconvenient for process scale-up and operation, and highly toxic sodium cyanide is used, which not only makes the operation dangerous for workers, but also requires high standards for reaction equipment, waste liquid and waste gas treatment, which is not conducive to The process is enlarged, so it is still necessary to find a simpler and more efficient new synthesis method

Method used

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  • The synthetic method of ribociclib intermediate
  • The synthetic method of ribociclib intermediate
  • The synthetic method of ribociclib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Add 5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine 1a (27.66g, 100mmol) in the three-necked flask, ethyl propiolate 2a (19.62g, 200mmol), DABCO (2.24g, 20mmol) and Acetonitrile (277mL), stirred evenly, cooled to 0-5°C, switched nitrogen three times under vacuum, added newly prepared cuprous iodide (1.9g, 10mmol) and dichloroditriphenylphosphine palladium (702mg, 1mmol) under nitrogen protection After the addition, the temperature was raised to 55-60°C for 6-8 hours. After the reaction, most of the acetonitrile was rotated off, and 277 mL of water was added to quench the reaction. The aqueous phase was extracted 3 times with ethyl acetate (138 mL), and the combined organic phase was washed with saturated brine for 1 (138 mL), dried over sodium sulfate, concentrated and separated by column chromatography with a mixed solvent of dichloromethane and methanol to obtain compound 3a (21.44 g, 73%). ESIm / z=294.10(M+1), 1 HNMR(CDCl3,400MHz)δ8.25(s,1H),4.28(q,J=7.2H...

Embodiment 2

[0037]

[0038] Add 5-iodo-2-chloro-4-(cyclopentylamino) pyrimidine 1b (32.36g, 100mmol) in the three-necked flask, ethyl propiolate 2b (19.62g, 200mmol), DABCO (2.24g, 20mmol) and Acetonitrile (324mL), stirred evenly and cooled to 0-5°C, switched nitrogen three times under vacuum, added newly prepared cuprous iodide (1.9g, 10mmol) and dichloroditriphenylphosphine palladium (702mg, 1mmol) under nitrogen protection After the addition, the temperature was raised to 55-60°C for 6-8 hours. After the reaction, most of the acetonitrile was spun off, and 324 mL of water was added to quench the reaction. The aqueous phase was extracted 3 times with ethyl acetate (162 mL), and the combined organic phase was washed with saturated brine for 2 (162 mL), dried over sodium sulfate, concentrated and separated by column chromatography with a mixed solvent of dichloromethane and methanol to obtain compound 3b (23.71 g, 81%). ESIm / z=293.11(M+1), 1HNMR(CDCl3,400MHz)δ8.27(s,1H),3.82-3.70(m,1H...

Embodiment 3

[0041]

[0042] Add 3a (29.37g, 100mmol) and dimethylformamide (147mL) into the three-necked flask, stir evenly, switch nitrogen in vacuum for 3 times, and add new cuprous chloride (0.99g, 10mmol) and DBU (3.04g , 20mmol), after the addition was completed, the temperature was raised to 85-90°C to react overnight. At the end of the reaction, 294 mL of water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate (147 mL), the combined organic phase was washed 2 times with saturated brine (147 mL), dried over sodium sulfate, concentrated and separated by column chromatography with dichloromethane methanol mixed solvent Compound 4a (25.26 g, 86%) was obtained.

[0043] Cuprous chloride in embodiment 3 can be replaced by cuprous bromide, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can be used diisopropylethylamine, triethylamine amine or triethylenediamine (DABCO) instead; the solvent dimethylformamide can be replaced by dimethylacetamide,...

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Abstract

The invention discloses preparation of a ribociclib key intermediate A; propiolic acid ester or amide 2 is directly used as a Sonogashira coupling side chain, coupling conditions are optimized, an intermediate 3 is obtained with relatively high yield, the intermediate 3 is directly subjected to ring closing under simple conditions to complete construction of a mother ring molecule, to obtain a structural formula A or a precursor ester 4 of the structural formula A, and the precursor ester 4 is subjected to hydrolysis and condensation to obtain the structural formula A. The route has simple operation, reaction steps are shorted, the yield is relatively high, and the purity of the obtained product is relatively high, and the method is suitable for enlarged production, wherein the reaction route is described in the specification.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new synthesis method for preparing an intermediate compound of Ribociclib. Background technique [0002] Ribociclib is a new type of high-efficiency oral anti-cancer drug developed by Novartis. It is a highly specific cell cycle-dependent kinase (CDK4 / 6 dual inhibitor), which can significantly inhibit the growth of a variety of neuroblastomas, and is used for the treatment of advanced breast cancer. Recent clinical research results have shown that the efficacy is significant, so it has broad application market expectation. [0003] Ribociclib chemical name: 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)-piperidin-2-yl]amino}-7H-pyrrole[ The structure of 2,3-d] pyrimidine-6-carboxamide is shown below. In the synthesis methods reported in the literature, the key reaction is how to quickly prepare the key intermediate parent ring molecule A. [0004] [0005] P...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 俞炜蒋怀志
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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