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Ribociclib intermediate and preparation method thereof

A dimethyl and methoxy technology, applied in the field of preparation of the drug ribociclib, can solve the problems of cumbersome preparation process, difficult industrialized production, etc., and achieve the effects of easy availability of raw materials, promotion of development, and simple process

Active Publication Date: 2015-11-11
北京华众恩康医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Obviously, the preparation process is very cumbersome, and more unconventional reagents are used, especially the use of precious metal catalysts and the use of highly toxic compound sodium cyanide, which brings great difficulties to industrial production.

Method used

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  • Ribociclib intermediate and preparation method thereof
  • Ribociclib intermediate and preparation method thereof
  • Ribociclib intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add N,N-dimethyl-2-carbonyl-propionamide (IV) (5.75g, 50mmol), 0.1g of 98% concentrated sulfuric acid and 30mL of tetrahydrofuran into a dry reaction flask, and heat up to 50-55°C. Bromine (7.9 g, 55 mmol) dried with concentrated sulfuric acid was added dropwise under stirring. After the drop was completed, the reaction was continued with stirring at the temperature for 3-5 hours until the color of bromine basically faded and the reaction was completed. The solvent was recovered under reduced pressure, the residue was recrystallized from ethyl acetate and n-hexane (1:1, V / V), and dried in vacuo at room temperature to obtain a pale yellow solid N,N-dimethyl-1-halogen-2-carbonyl-propane Amide (V) 8.3g, yield 86.0%; EI-MSm / z: 193[M+H] + .

Embodiment 2

[0034] Add N,N-dimethyl-1-halogen-2-carbonyl-propionamide (V) (5.8g, 30mmol), malononitrile (2.2g, 33mmol), diethylamine (6.6g, 90mmol) and silicon dioxide 15g, ground and stirred at room temperature for 30 minutes, and TLC detected that the reaction was complete. Add 100 mL of chloroform into the reaction flask, stir and filter, then wash the filter cake three times with chloroform, combine the organic phases, wash with water and saturated brine in turn, dry over anhydrous sodium sulfate, concentrate, and dry in vacuo to obtain off-white solid N,N- Dimethyl-1,1-dinitrile-3-carbonyl-butanamide (VI) 4.5g, yield 83.8%; EI-MSm / z: 180[M+H] + .

Embodiment 3

[0036] Add N,N-dimethyl-1,1-dinitrile-3-carbonyl-butanamide (VI) (3.6g, 20mmol) and 50mL of methanol into the reaction flask, cool to 4-7°C in an ice bath, and stir Hydrogen chloride gas (5.4 g, 0.15 mol) was slowly introduced under low pressure, and after the completion of the passage, it was raised to room temperature, and the stirring reaction was continued for 24-26 hours. TLC detected that the reaction was complete. Nitrogen was introduced to drive off excess hydrogen chloride gas, concentrated to obtain a viscous solid, and recrystallized with methanol and water (1:1) to obtain light yellow solid 2-methoxy-5-(N,N-dimethyl-formazan Amino)-3-pyrrolecarbonitrile (VII) 3.3g, yield 90.2%; mass spectrum (EI): EI-MSm / z: 194[M+H] + .

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Abstract

The invention discloses an intermediate N-cyclopentyl-2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (II) for preparing ribociclib and a preparation method thereof. The preparation method comprises the following steps: carrying out halogenating reaction on N,N-dimethyl-2-carbonyl-propanamide (IV) to obtain N,N-dimethyl-1-halo-2-carbonyl-propanamide (V); carrying out substitution reaction on the intermediate (V) and malononitrile to obtain N,N-dimethyl-1,1-dicyano-3-carbonyl-butyramide (VI); carrying out cyclization reaction on the intermediate (VI) to obtain 2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (VII); and carrying out coupling reaction on the intermediate (VII) and bromocyclopentane to obtain the ribociclib intermediate N-cyclopentyl-2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (II). The intermediate (II) and N-[5-(1-piperazino)-2-piperidyl]guanidine (III) are subjected to condensation reaction to obtain the ribociclib. The preparation method has the advantages of accessible raw materials, simple technique, high economy and environment friendliness, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Ribociclib, which may be used to treat breast cancer. Background technique [0002] Ribociclib (Ribociclib) is an orally effective, highly specific cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Novartis, code-named LEE011. LEE011, a CDK4 / 6 dual inhibitor, can significantly inhibit the growth of 12 out of 17 types of neuroblastoma. The drug is currently in phase III clinical testing for the treatment of advanced breast cancer. The drug's successful research will provide another important option for patients with metastatic breast cancer. Because the drug does not have a standard Chinese translation, the applicant hereby transliterates it as "ribociclib". [0003] Ribociclib (Ribociclib, I) chemical name: 7-cyclopentyl-N, N-dimethyl-2-{[5-(piperazin-1-yl)pi...

Claims

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Application Information

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IPC IPC(8): C07D207/34C07D487/04
CPCC07D207/34C07D487/04C07D207/36C07D471/04
Inventor 许学农
Owner 北京华众恩康医药技术有限公司
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