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Synthesis method of clofarabine, midbody thereof and preparation method of midbody

A synthetic method, the technology of clofarabine, which is applied in the direction of preparation of sugar derivatives, chemical instruments and methods, esterified saccharides, etc., can solve the problems that are not suitable for industrial production, and achieve the effect of low price

Active Publication Date: 2013-09-25
FUZHOU NEPTUNUS FUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reported total yields are about 5%~10%, respectively, these processes are not suitable for industrial production

Method used

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  • Synthesis method of clofarabine, midbody thereof and preparation method of midbody
  • Synthesis method of clofarabine, midbody thereof and preparation method of midbody
  • Synthesis method of clofarabine, midbody thereof and preparation method of midbody

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preparation example Construction

[0026] 　　 A kind of synthetic method of clofarabine comprises the following steps:

[0027] 1) Compound Ⅰ undergoes a rearrangement reaction with a strong Lewis acid in dichloromethane, and then undergoes hydrolysis to generate compound Ⅱ;

[0028] 2) Compound II undergoes a fluorination reaction with a fluorinating agent and triethylamine in toluene to generate Compound III;

[0029] 3) Compound III reacts with hydrogen bromide to generate compound IV;

[0030] 4) Condensation reaction of compound IV with 2-chloroadenine, ROM to generate compound V;

[0031] 5) Compound V is reacted with lithium hydroxide to prepare the clofarabine;

[0032] R1 and R2 of compound I in the step 1) are benzoyl or acetyl, and the molar ratio of the fluorinating agent and triethylamine in the step 2) is: 1:1~2, the best is 1:2, R in the ROM in step 4) is a C1~C4 alkyl group, M is K, Na, Li, preferably lithium tert-butoxide.

[0033] The strong Lewis acid used in the step 1) includes titaniu...

Embodiment １

[0039] compound Ⅱ preparation of

[0040] In an ice-water bath, 30 g of the compound Ⅰ , into a 1000 mL reaction flask, add 250 mL of dichloromethane, and stir magnetically to dissolve it. 11.7 g of titanium tetrachloride was slowly added dropwise within 40 minutes at 0 °C, and continued to stir for 20 minutes. Heat up to 15°C, add 100 mL of distilled water, continue stirring at this temperature for 6 hours, separate the water phase, extract the water phase with 20 mL of dichloromethane, combine the organic phases, adjust the pH of the solution to 7 with saturated sodium bicarbonate, The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to remove the solvent under reduced pressure, dried in vacuo, added 400 mL of methanol and heated to reflux, and completely dissolved the solid, cooled slowly to room temperature, then placed in a refrigerator for crystallization, suction filtered, and vacuum-dried. Dry to obtain 18.1 g of white solid, total yiel...

Embodiment 2

[0042] compound Ⅱ preparation of

[0043] In an ice-water bath, 45 g of the compound Ⅰ, put into a 1000 mL reaction flask, add 400 mL of dichloromethane, and stir magnetically to dissolve it. 17.5 g of titanium tetrachloride was slowly added dropwise within 80 minutes at -20 °C, and continued to stir for 40 minutes. Heat up to 0°C, add 150 mL of distilled water, continue to stir at this temperature for 8 hours, separate the water phase, extract the water phase with 30 mL of dichloromethane, combine the organic phases, adjust the pH of the solution to 7 with saturated sodium bicarbonate, Dry the organic phase with anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure, dry in vacuum, add 600 mL of methanol and heat to reflux, and completely dissolve the solid, cool slowly to room temperature, then put it in the refrigerator to crystallize, filter with suction, vacuum Dry to obtain 25.4 g of white solid, total yield 58.9%

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Abstract

The invention relates to a synthesis method of clofarabine, a midbody thereof and a preparation method of the midbody. The synthesis method comprises the steps of: 1) a compound I is reacted with strong lewis acid and water in dichloromethane respectively to generate a compound II; 2) the compound II is jointly reacted with PBSF and Et3N.3HF in methylbenzene and triethylamine to be taken as a fluorination agent, and is fluoridized by adding Et3N with proper amount to generate a compound III; 3) the compound III is reacted with hydrogen bromide to generate a compound IV; 4) the compound IV is condensed with 2-arprinocide and ROM to generate a compound V; and 5) the compound V is reacted with lithium hydroxide to prepare the clofarabine. After the synthesis method is used, the strong lewis acid which can be dissolved in the methylene dichloride is taken as a rearrangement agent, so that the complex step of feeding HBr or Hcl gas is eliminated; and as raw materials for the fluoridation are low in price and are relatively stable to water, the strict water-free operation does not need, and equipment can not be corroded, so that the synthesis method is safe to use. The preparation total yield is improved to 18.3%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a synthesis method of clofarabine, an intermediate thereof and a preparation method of the intermediate. Background technique [0002] Clofarabine; English name: Clofarabine. It is an FDA-approved nucleotide analogue. It can be used to treat children with resistant or relapsed acute lymphoblastic leukemia (ALL). Clofarabine is the first new drug approved for the treatment of ALL in children in the past 10 years. Prior art: Chinese Journal of Pharmaceutical Industry 2006, 37 (8): 508-510, disclosing a synthesis method of clofarabine, see figure 2 Thereafter, Chemical Industry Times 2010, 24 (8): 36-38 also discloses a synthetic method of clofarabine, see image 3 . [0003] The defect of the above two synthetic methods is that when the first step reaction uses dichloromethane as a solvent, anhydrous gas HCl or HBr is introduced to carry out halogenation, bu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/19C07H13/08C07H1/00
Inventor 徐燕和
Owner FUZHOU NEPTUNUS FUYAO PHARMA
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