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Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine

A technology of cyclopropylmethylpiperazine and propylmethyl, which is applied in the field of drug synthesis, can solve the problems of low molecular molar utilization, poor activity, high cost, etc., and achieve the effect of simple method, convenient operation and good product quality

Active Publication Date: 2018-07-31
苏州莱克施德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The activity of chloromethylcyclopropane is poor, while the molecular molar utilization rate of bromomethylcyclopropane is low, and the price of the two is relatively expensive, and the cost is high
Another common method is to condense cyproacetic acid and piperazine, but the yield is very low

Method used

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  • Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine
  • Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine

Examples

Experimental program
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Effect test

Embodiment 1

[0027] A preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine, comprising the following steps:

[0028] S1: Add N-Boc-piperazine (1.82kg, 9.77mol), triethylamine (1.48kg, 14.66mol), dichloromethane 5.46Kg in a 20L four-necked flask with mechanical stirring and a thermometer, and cool to At 0°C, cyclopropylformyl chloride (1.12kg, 10.75mol) was slowly added dropwise, and the temperature was controlled at 0°C-10°C. After the dropwise addition, the reaction was carried out at 10°C-20°C for 3 hours. Add 5kg of water, add sodium carbonate to adjust the pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg to the water phase, extract once with dichloromethane, combine the dichloromethane phase, wash once with 2kg of 0.05M dilute hydrochloric acid, and then use Wash once with 2 kg of water, concentrate to remove dichloromethane to obtain 2.43 kg of tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate, yield 98%. The NMR is consistent with t...

Embodiment 2

[0032] A preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine, comprising the following steps:

[0033] S1: Add N-Boc-piperazine (1.82kg, 9.77mol), pyridine (1.16kg, 14.66mol), and 5.46Kg of dichloromethane into a 20L four-necked flask with mechanical stirring and a thermometer, and cool to 0°C. Cyclopropylformyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled at 0°C-10°C. After the dropwise addition, the reaction was carried out at 10°C-20°C for 3 hours. Add 5kg of water, add sodium carbonate to adjust the pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg to the water phase, extract once with dichloromethane, combine the dichloromethane phase, wash once with 2kg of 0.05M dilute hydrochloric acid, and then use Wash once with 2 kg of water, concentrate to remove dichloromethane to obtain 2.40 kg of tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate, yield 96.8%. The NMR is consistent w...

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Abstract

The invention provides a preparation method of a Volasertib intermediate 1-cyclopropyl methyl piperazine. The preparation method comprises the following steps: S1, adding N-Boc-piperazine into an inert solvent and triethylamine or pyridine, dropwise adding cyclopropanecarbonyl chloride, adding water for extraction after the reaction ends, obtaining an organic phase, and concentrating the organic phase to remove an organic solvent to obtain a solid; S2, adding the solid obtained in S1 into an ether solvent, then adding sodium borohydride, dropwise adding boron trifluoride-diethyl ether for reaction, quenching the mixture, then extracting the mixture, and concentrating the mixture to remove an organic solvent to obtain a solid; S3, adding the solid obtained in S2 into an alcohol solvent, dropwise adding concentrated hydrochloric acid for reaction, alkalizing the mixture with sodium hydroxide or potassium hydroxide aqueous solution, and performing extraction and concentration in sequenceto obtain the compound 1-cyclopropyl methyl piperazine. The raw materials used in the preparation method are readily available, and the preparation method is low in cost, easy to operate, high in safety, high in product quality and yield, and convenient for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine. Background technique [0002] 1-Cyclopropylmethylpiperazine (CAS No.: 57184-25-5) is an intermediate raw material for the synthesis of the orphan drug Volasertib. On April 17, 2014, Boehringer Ingelheim (BI) announced that the U.S. Food and Drug Administration (FDA) and the European Commission granted Volasertib orphan drug qualifications for the treatment of patients with acute myeloid leukemia (AML). AML is an aggressive cancer of the bone marrow and blood, mostly in adults, with an average age of 65 to 70 years. At present, the recommended treatment standard for this disease is intensive chemotherapy, with limited treatment options, most patients cannot tolerate it, and the prognosis is relatively poor. By inhibiting Polo-like kinase 1 (Plk1), Volasertib will block the extre...

Claims

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Application Information

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IPC IPC(8): C07D295/023C07D295/03
CPCC07D295/023C07D295/03
Inventor 刘同昶俞菊荣
Owner 苏州莱克施德药业有限公司
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