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Method for synthesizing clofarabine

A synthesis method and technology of clofarabine are applied in the directions of drug combination, sugar derivatives, organic chemistry, etc., which can solve the problems of unsuitable industrial production, high production cost, low total yield and the like, and achieve improved yield and less reaction impurities. , the effect of less side effects

Inactive Publication Date: 2008-09-17
深圳万乐药业有限公司
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Problems solved by technology

[0003] Chinese Journal of Pharmaceutical Industry 2006, 37 (8): 508~510 discloses " the synthesis of clofarabine ", and the yield of each step of the synthetic method of this prior art is low, causes total yield to be lower, only 5%, Thereby its production cost is bigger, is not suitable for industrialized production

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  • Method for synthesizing clofarabine

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Embodiment 1

[0022] (1) Preparation of 2-deoxy-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose

[0023] Under a nitrogen atmosphere, 1.6 Kg of 1-acetyl-2,3,5-tri-oxo-benzoyl-β-D-ribofuranose and 10 L of dichloromethane were added into a 20 L reactor, and stirred and mixed evenly. The temperature was lowered to -10~-5°C, and 8L of 0.4Mol / L hydrogen bromide in dichloromethane solution was added dropwise. After the dropwise addition was completed, the insulation reaction was continued for 5 h. Washed twice with water, separated, and the organic layer was spin-dried to obtain 1.2 Kg of a white solid with a yield of 81%.

[0024] (2) Preparation of 2-deoxy-2-imidazolesulfonyl-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose

[0025] Under nitrogen atmosphere, add 1.2Kg of 2-deoxy-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose, 18L of dichloromethane and 3L of N,N-dimethylformamide to 30L Reactor, stirring to dissolve. The temperature was lowered to -15~-10°C, and 900 g of sulfuryl chloride was added dropwise. After ...

Embodiment 2

[0035] (1) Preparation of 2-deoxy-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose

[0036] Under a nitrogen atmosphere, 0.8Kg of 1-acetyl-2,3,5-tri-oxo-benzoyl-β-D-ribofuranose and 5L of dichloromethane were added into a 10L reaction kettle, and stirred and mixed evenly. The temperature was lowered to 5-15°C, and 4L of 0.4Mol / L hydrogen bromide in dichloromethane solution was added dropwise. After the dropwise addition was completed, the insulation reaction was continued for 10 h. Washed twice with water, separated, and the organic layer was spin-dried to obtain 0.6 Kg of a white solid with a yield of 81%.

[0037] (2) Preparation of 2-deoxy-2-imidazolesulfonyl-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose

[0038] Under nitrogen atmosphere, add 0.6Kg of 2-deoxy-1,3,5-tri-oxo-benzoyl-β-D-ribofuranose, 9L of dichloromethane and 1.5L of N,N-dimethylformamide to 20L Reactor, stirring to dissolve. The temperature was lowered to -40~-30°C, and 450 g of sulfuryl chloride was added dropwise. Afte...

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Abstract

The invention provides a preparation method of clofarabine, which includes allowing 1-acetyl-2,3,5-tri-o-benzoyl-Beta-D-ribofuranose as the initial raw material and dichloromethane solution of hydrobromide to perform the rearrangement reaction, reacting with sulfuryl chloride and imidazole, performing the fluoridation reaction in the presence of hydrogen fluoride aqueous solution and potassium hydrogen fluoride, and performing bromination reaction in acetic acid solution of hydrogen bromide, condensing with 2-chloro adenosine in alkaline condition, and removing benzoyl in the presence of lithium hydroxide to obtain clofarabine. Compared with prior art, the method has the advantages of high yield of each step, higher total yield, and easily realized industrialized production.

Description

technical field [0001] The invention relates to a synthetic method of clofarabine. Background technique [0002] Clofarabine, chemical name 2-chloro-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl) adenine. It belongs to a kind of nucleotide analogue, which achieves anti-tumor effect by inhibiting DNA polymerase and ribonucleic acid reductase. Clofarabine is currently the only drug suitable for the treatment of childhood leukemia. It has a very high therapeutic efficiency, is well tolerated by patients, and has potential broad-spectrum anti-tumor properties. [0003] Chinese Journal of Pharmaceutical Industry 2006, 37 (8): 508~510 discloses " the synthesis of clofarabine ", and the yield of each step of the synthetic method of this prior art is low, causes total yield to be lower, only 5%, Thereby its production cost is bigger, is not suitable for industrialized production. Contents of the invention [0004] The technical problem to be solved by the present invention is to provid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/173A61P35/00
Inventor 苏军张广明
Owner 深圳万乐药业有限公司
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