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Preparation method of cytarabine 5'-O-L-valine ester hydrochloride

A technology of cytarabine ester and cytarabine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of low selectivity, need column chromatography purification, small scale and the like, and achieves high selectivity, low cost and reaction yield high effect

Active Publication Date: 2016-01-27
KUNMING JIDA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of this method are low selectivity, small scale, and the need for column chromatographic purification

Method used

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  • Preparation method of cytarabine 5'-O-L-valine ester hydrochloride
  • Preparation method of cytarabine 5'-O-L-valine ester hydrochloride
  • Preparation method of cytarabine 5'-O-L-valine ester hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] N 4 Preparation of -(N,N-dimethylaminomethylene)-cytarabine

[0022] Add 82mL of N,N-dimethylformamide dimethyl acetal (DMF-DMA) into a mixture of 60g of cytarabine and 240mL of ethanol, raise the temperature to 65°C for reaction, and the reaction ends after 4 hours. The reaction solution was lowered to room temperature, filtered, the solid was washed with methyl tert-butyl ether (MTBE), and dried under vacuum at 45°C to obtain N 4 -(N,N-Dimethylaminomethylene)-cytarabine ( N 4 -DMA-cytarabine) 69.5g, as a white solid, with a yield of 96% and a purity of 99.6% (HPLC).

Embodiment 2

[0024] 5′ -O -( N -tert-butoxycarbonyl-L-valine)-N 4 Preparation of -(N,N-dimethylaminomethylene)-cytarabine ester

[0025] Will 66.0g N 4 -DMA-Cytarabine was added to 660mL of dry DMF and stirred to dissolve, 124.3g of potassium valine was added and stirred at room temperature for 1 hour, the temperature was lowered to -10℃~-5℃, 48.2g of ethyl chloroformate was added dropwise, and After the addition, the temperature was gradually raised to 0°C to continue the reaction for 4 hours, and then gradually raised to room temperature for 2 hours, then 6.6L of isopropyl ether was added, stirred at 0°C for 2 hours, and filtered. Add 1.7L chloroform to the solid, wash with 15% sodium carbonate solution (300mLx2), saturated brine (300mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 5' -O -( N -tert-butoxycarbonyl-L-valine)-N 4 -(N,N-dimethylaminomethylene)-cytarabine ester 97.2g, liquid phase purity 94%. The compound was detect...

Embodiment 3

[0027] Cytarabine 5'-O-L -Preparation of valine ester hydrochloride

[0028] will be 5' -O -( N -tert-butoxycarbonyl-L-valine)-N 4 -(N,N-Dimethylaminomethylene)-cytarabine ester 103g was added to 800mL isopropanol, stirred to dissolve, hydrogen chloride gas was passed into the reaction liquid until saturated, stirred overnight, and the solvent was evaporated under reduced pressure , add 800mL of acetonitrile to beat for 2 hours, filter, and blow dry at 45°C to obtain cytarabine 5'-O-L -Valine ester hydrochloride 64g, is white solid, yield 74.4%, liquid phase purity 97%.

[0029] Refined: Cytarabine 5'-O-L - 64g of valine ester hydrochloride was added with 640mL of 95% ethanol, heated at 50°C for beating, cooled to room temperature, and filtered to obtain 50g of product with a purity of 99%.

[0030] The compound was detected by mass spectrometry (ESI-MS) and nuclear impact resonance (HNMR). ESI-MS detection conditions are: m / z=343[M+H] + ,172[M+2H] ++ ,685[2M+H] + , ...

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Abstract

The invention provides a preparation method of cytarabine 5'-O-L-valine ester hydrochloride (structural formula 1) and an intermediate thereof. According to the invention, cytarabine (formula 5) is adopted as a raw material, and a one-step amino protection reaction is carried out, such that a substance represented by a structural formula 3 is obtained; the substance represented by the structural formula 3 and N'-tert-butoxycarbonyl-L-valine are subjected to a reaction with chloroformate or acyl chloride under the existence of alkali, or the substance represented by the structural formula 3 and N'-tert-butoxycarbonyl-L-valine salt are subjected to an esterification reaction under the effect of chloroformate or acyl chloride, such that a substance represented by a structural formula 2 is obtained; and protection group is removed under the effect of hydrogen chloride, such that the substance represented by the structural formula 1 is obtained. The method provided by the invention has the advantages of easy operation, simple post-treatment, no need of column chromatography purification, high selectivity, high reaction yield, and low cost. The method is suitable for industrialized productions.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of cytarabine prodrug and its intermediate. Background technique [0002] Cytarabine is one of the most effective drugs clinically used in the treatment of acute myeloid leukemia, acute lymphoblastic leukemia and lymphoma. Cytarabine also has antiviral effects and is used to treat various herpes virus infections. In nervous system research, cytarabine has been used to control the proliferation of glial cells. [0003] Due to the extremely low oral bioavailability, less than 20% of cytarabine is absorbed by the digestive system, and, after oral administration, due to the first-pass effect, it is rapidly metabolized into inactive uracil by cytosine deaminase in the liver Cytarabine, therefore, clinically, cytarabine is mainly administered by injection, which brings great inconvenience to patients. [0004] Cytarabine 5'...

Claims

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Application Information

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IPC IPC(8): C07H19/09C07H1/00
Inventor 李德耀冯朴纯王春水郭雷雷
Owner KUNMING JIDA PHARMA
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