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Process for preparing gemcitabine intermediate based on sodium borohydride reduction method

A technology of gemcitabine and intermediates, which is applied in the synthesis field of important intermediates of antitumor drug gemcitabine hydrochloride, can solve the problems of flammability and explosion, dangerous operation and transportation, high price, etc., and achieves simple and safe operation, reduced production cost, and improved product quality. high purity effect

Active Publication Date: 2012-09-12
NINGBO TEAM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Similarly, the reducing agent Red-Al is very expensive, and it is also flammable and explosive. It is very dangerous to operate and transport, and is not suitable for industrial applications.
Also have the report to be the method that reducing agent carries out reduction at low temperature with lithium aluminum hydride, and the yield after our trial is only 65%, and main impurity is diol by-product (Ⅴ)
[0010] In summary, the existing preparation method of gemcitabine intermediate 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose is not suitable for industrial production, which leads to the final product hydrochloride Gemcitabine is very expensive

Method used

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  • Process for preparing gemcitabine intermediate based on sodium borohydride reduction method
  • Process for preparing gemcitabine intermediate based on sodium borohydride reduction method
  • Process for preparing gemcitabine intermediate based on sodium borohydride reduction method

Examples

Experimental program
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Effect test

Embodiment

[0047] Example VII: Preparation of 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose by sodium borohydride + zinc chloride method

[0048] 2-Deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranolide (Ⅱ) 15.0g (40mmol), dissolved in 200ml anhydrous tetrahydrofuran, add anhydrous zinc chloride 2.7g (20mmol). Cool in an ice-salt bath to below -10°C while stirring, add 1.5 g (40 mmol) of sodium borohydride in batches, and control the temperature below -5°C. After about 20 minutes of addition, stirring was continued at this temperature for 0.5 hour, and TLC showed that the reaction was complete. Add 15ml of 1NHCl dropwise to destroy, dilute with 300ml of ethyl acetate, and then use 150ml of 1NHCl, 150ml of water, and 5% NaHCO 3 150ml and 150ml of saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 16.5 g of oil, and dry to obtain 15.5 g of white solid, yield 100%. HPLC showed that the content of the product 2-deoxy-2,2-difluoro-3,5-di...

Embodiment XIII

[0059] Example XIII: Production of 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose by glacial acetic acid+cerium trichloride

[0060] 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranolactone (II) 40kg (106mol) is placed in 2000 liters of reactor, draws 540kg tetrahydrofuran (water content is about 0.5%), 40 kg (107 mol) of cerium trichloride heptahydrate, and 19 kg (317 mol) of glacial acetic acid were added. N 2 Stir evenly under air, and cool to below -10°C with ice brine. Add 4 kg (106 mol) of sodium borohydride in batches, and control the temperature below -5°C. After about 60 minutes of addition, stirring was continued at -5°C for 10 minutes. TLC showed that the reaction was complete. Add 40kg of 1N HCl dropwise to destroy, and keep the temperature below 0°C. After adding, dilute with 720kg of ethyl acetate, followed by 400kg of 1N HCl, 400kg of water, 5% NaHCO 3 400kg and 400kg of saturated brine were washed, and dried over anhydrous sodium sulfate. Filter and con...

Embodiment XIV

[0062] Example XIV: HPLC method for detection of 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose (Ⅲ)

[0063] Chromatographic conditions:

[0064] Column: C 18 Bonded silica gel column, 250x4mm

[0065] Mobile phase: 0.2% B 8 Solution (adjust pH=3.0 with phosphoric acid): acetonitrile=40:60

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Abstract

The invention discloses a method for preparing a gemcitabine important intermediate 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose by reducing 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranosyl lactone. In the method, sodium borohydride is used as a reducer and is additionally provided with glacial acetic acid or Lewis acid or combination of the glacial acetic acid and the Lewis acid. The product obtained by reduction has high purity and yield. Compared with other methods, the invention has the characteristics of easy acquisition of reagents and simple and safe operation.

Description

technical field [0001] The invention relates to a method for synthesizing an important intermediate of an antineoplastic drug gemcitabine hydrochloride, which belongs to the field of medicine and chemical industry. Background technique [0002] Gemcitabine hydrochloride (I), chemically named 2-deoxy-2,2-difluoro-β-cytidine, is a nucleoside antineoplastic drug developed and marketed by Eli-lily Company of the United States, with an annual sales volume of 2 billion US dollars. [0003] [0004] According to the preparation method of gemcitabine reported in literature Synthesis, 1992,565, the preparation of its important intermediate 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose (Ⅲ) adopts A method for reducing 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranolide (II). The reducing agent used is tri-tert-butoxy lithium aluminum hydride (reaction formula 1). [0005] [0006] Reaction 1 [0007] The reported yield is 100%, but when we repeat the reaction, we find tha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H13/08C07H1/00
Inventor 张海城邱玉峰章玲丽黄道飞
Owner NINGBO TEAM PHARMA