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Method for preparing gemcitabine hydrochloride

A technology of gemcitabine hydrochloride and hydrochloride, which is applied in the pharmaceutical field and can solve the problems of high industrialization cost and low overall yield

Active Publication Date: 2012-07-25
江苏八巨药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The primary problem to be solved by the present invention is that the industrialization cost of the existing gemcitabine hydrochloride is relatively high, and the overall yield is low. For this reason, the present invention provides a method for preparing gemcitabine hydrochloride. The anomer mixture of formula (I) is a starting material, comprising:

Method used

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  • Method for preparing gemcitabine hydrochloride
  • Method for preparing gemcitabine hydrochloride
  • Method for preparing gemcitabine hydrochloride

Examples

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Embodiment

[0042] 1. Configuration transformation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-ditoluoyl-1-methanesulfonate anomer mixture of formula i

[0043]

[0044] 1.64 g of triethylamine and 24.3 g of acetonitrile were added to the reaction flask and stirred. At 20°C-30°C, 1.56 g of methanesulfonic acid was added dropwise. After the dropwise addition, 6.25 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-ditoluoyl-1-mesylate i-anomer mixture (wherein the α-terminal The molar ratio of isomer to beta anomer is 1:1) was dissolved in 24 g of acetonitrile and charged into the reaction flask.

[0045] The temperature rises to room temperature, continues to heat up to reflux, and keeps warm for 20-24 hours. After the heat preservation is over, cool down to 20-30°C, and recover acetonitrile by vacuum distillation. After recovery, add 75g of water and 16g of dichloromethane, stir, separate layers, The phase was extracted twice with 10g×2 dichloromethane, the combined organic phases were w...

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Abstract

The invention belongs to technical field of pharmacy and provides a method for preparing gemcitabine hydrochloride, which solves the problems that the industrialization cost is high and the total yield is low in the original preparation method of gemcitabine hydrochloride. The method comprises the steps of a. converting and extracting alpha anomer of a formula (II) from a formula (I); b. coupling the formula (II) and a formula (III); and c. obtaining the gemcitabine hydrochloride of a formula (V). The step a comprises the steps of (1) dissolving the compound with the formula (I) in an aprotic solvent at least containing R1OH and three-level organic amine salified by R1OH, heating and reflowing, then reducing temperature so as to increase the mole ratio of the Alpha anomer of the formula (II) in the Alpha anomer mixer of the formula (I); (2) extracting the compound with the formula (I), reducing the temperature under recrystallization liquid so as to recrystallize the extracted product to obtain a solid Alpha anomer of the formula (II) and recrystallization liquid of the formula (I).

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and relates to a method for preparing gemcitabine hydrochloride. The molecular structural formula of gemcitabine hydrochloride is shown in formula V. [0002] Background technique [0003] Gemcitabine hydrochloride, the chemical name is 2-deoxy-2,2-dioxycytidine hydrochloride, is a pyrimidine nucleoside analog developed by Eli Lilly, USA. It belongs to nucleoside antimetabolite and antitumor drugs. It is suitable for Non-small cell carcinoma, pancreatic cancer, bladder cancer, breast cancer, and other solid tumors. [0004] As the precursor of gemcitabine hydrochloride, the synthesis of gemcitabine base is very important. The preparation method of gemcitabine hydrochloride has been recorded in the literature. Since gemcitabine hydrochloride specifically refers to the β isomer, the α isomer generated by the reaction needs to be excluded. Some can be described by the following reaction schemes...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
Inventor 徐汉青姚小勇徐斌俞恒李正波吴金跃
Owner 江苏八巨药业有限公司
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