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Method for preparing gemcitabine hydrochloride

A technology of gemcitabine hydrochloride and its synthesis method, which is applied in the field of synthesis of new anti-cancer drug gemcitabine hydrochloride, and can solve the problems of relatively expensive price and high cost of the protecting group TBS

Inactive Publication Date: 2007-08-29
HUBEI YITAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The protective base TBS used in this method is more expensive and the cost is high

Method used

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

Examples

Experimental program
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Embodiment 1

[0092] Example 1: (1S, 2S)-2-((4R)-2-methoxy-2-methyl-1,3-dioxocyclopentyl)-1-((4S)-2-methyl Synthesis of oxy-2-methyl-1,3-dioxocyclopentyl)-1,2-ethanediol

[0093] After dissolving 180 g of D-mannitol in 1000 ml of DMF, add 2 g of p-toluenesulfonic acid and 300 g of trimethyl orthoacetate, react at room temperature for 24 hours, and adjust the pH of the solution to 7.5 with 15% ammonia water. Filter, concentrate the filtrate to 100ml under reduced pressure, add 500ml of water, stir evenly, add 300ml*3 dichloromethane for extraction, combine the dichloromethane layer, add 50g of anhydrous sodium sulfate, stir for 2 hours, filter to obtain the target product dichloromethane solution.

Embodiment 2

[0094] Example 2: Synthesis of (4S)-2-methoxy-2-methyl-1,3-dioxocyclopentyl-4-aldehyde

[0095] In the dichloromethane solution obtained in Example 1, 700ml aqueous solution containing 180g of sodium periodate was added in portions, stirred at room temperature for 4 hours, filtered, and the dichloromethane layer was collected by standing, dried over anhydrous sodium sulfate, and then heated at 30°C Concentrate under reduced pressure until no liquid flows out of the condenser. Control the external temperature at 120°C to collect distillates at 30-100°C under reduced pressure, combine the distillates, add 50 g of anhydrous sodium sulfate, stir for 2 hours, filter, and concentrate the filtrate below 30°C to dryness under reduced pressure to obtain 95-100 g of the target product.

Embodiment 3

[0096] Example 3: (R)-2,2-difluoro-3-hydroxyl-3-((4S)-2-methoxy-2-methyl-1,3-dioxocyclopentyl)propionic acid Synthesis of Ethyl Ester

[0097] In 200ml tetrahydrofuran, add 45g of activated zinc powder, control the internal temperature of 45-50°C and add dropwise the product obtained in Example 2 and 104g ethyl difluorobromoacetate mixture in 200ml tetrahydrofuran solution, drop it in about 1 hour, and keep warm for 2 hours. TLC detected that the reaction was complete. After the reaction solution was lowered to around 0°C, it was poured into a mixture of 200g ice, 400g water and 72g concentrated hydrochloric acid, stirred for 30 minutes, filtered, extracted with 160ml*2 dichloromethane, 5% carbonic acid After the dichloromethane layer was washed with 200 ml of sodium hydrogen, it was washed once with 150 ml of saturated brine. The collected organic layers were dried over 50 g of anhydrous sodium sulfate, filtered, and concentrated to dryness in vacuo. Petroleum ether: ethyl ...

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Abstract

The invention discloses the compounding method for hydrochloric acid Gemcitabine. It uses D-mannitol as raw material and takes the processes of hydroxyl protection, oxidation, and addition of reformatsky, hydroxy benzoylation, hydrolysis, hydroxyl sulfonylation, ring closure, carbonyl reduction, hydroxyl sulfonylation, condensation, hydrolysis and crystallization to gain hydrochloric acid Gemcitabine. It has the advantages of high yield, simple operation, and is suitable to industrial producing.

Description

technical field [0001] The invention relates to a synthesis method of a novel anticancer drug gemcitabine hydrochloride (2'-deoxy-2', 2'-difluorouridine nucleoside hydrochloride). Background technique [0002] Gemcitabine is a new antimetabolite antineoplastic drug, which has a good inhibitory effect on human leukocytes, some solid tumors in mice and human tumor xenografts. As a difluoronucleoside antimetabolite anticancer drug that disrupts cell replication, gemcitabine is a water-soluble analogue of deoxycytidine, an inhibitory substrate for ribonucleotide reductase Alternatives for DNA, an enzyme that is critical for the production of deoxynucleotides needed during DNA synthesis and repair. Clinically, gemcitabine is especially suitable for the treatment of inoperable advanced or metastatic pancreatic cancer and the treatment of locally advanced or metastatic non-small cell lung cancer. [0003] The key to the synthesis of gemcitabine is to synthesize the intermediate c...

Claims

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Application Information

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IPC IPC(8): C07H19/073
Inventor 王非余永柱何海兵栾振中
Owner HUBEI YITAI PHARMA
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