Preparation method of decitabine intermediate

A technology for decitabine and intermediates, applied in the preparation of sugar derivatives, chemical instruments and methods, esterified saccharides, etc., can solve the problems of high cost, low market supply, harsh reaction conditions, etc., and achieve easy operation and control , reduce operating hazards, and obtain raw materials easily

Active Publication Date: 2014-04-23
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The starting material used in this route is azacitidine, and special reagents TiPSh, phenyl thiochloroformate, and TTMSS are used. The market supply is small, the cost is high, and the reaction conditions are harsh.

Method used

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  • Preparation method of decitabine intermediate
  • Preparation method of decitabine intermediate
  • Preparation method of decitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Synthesis of Intermediate I

[0068] Add 1200g of 2-deoxy-D-ribose and 12L of anhydrous methanol into the reaction kettle, and stir at room temperature until the solid is completely dissolved, and the system is a light yellow transparent solution. 2.4 L of HCl-methanol solution with a mass fraction of HCl of 1% was added dropwise through a constant pressure funnel. After the dropwise addition was complete, it was stirred for 40 minutes. 600 ml of pyridine was added and stirring was continued for 30 minutes. After suction filtration, the filter cake was washed with anhydrous methanol, and the filtrate was evaporated to dryness under reduced pressure at 0.01Mpa to obtain 2.1Kg of intermediate I as an oil.

[0069] Synthesis of Intermediate II

[0070] Add 1.185Kg of intermediate I and 8L of anhydrous pyridine into the reaction kettle, control the reaction temperature at -20°C, add 4.552KgFmoc-Cl in three batches, each with an interval of 1 hour, after the addition is c...

Embodiment 2

[0074] Synthesis of Intermediate I

[0075] Add 1200g of 2-deoxy-D-ribose and 12L of anhydrous methanol into the reaction kettle, stir at room temperature until the solids are completely dissolved, and the system is a light yellow transparent solution. 2.4 L of HCl-methanol solution with a mass fraction of HCl of 0.5% was added dropwise through a constant pressure funnel. After the dropwise addition was complete, it was stirred for 40 minutes. 600 ml of pyridine was added and stirring was continued for 30 minutes. After suction filtration, the filter cake was washed with anhydrous methanol, and the filtrate was evaporated to dryness under reduced pressure at 0.01Mpa to obtain Intermediate I as an oil.

[0076] Synthesis of Intermediate II

[0077] Add 1.185Kg of intermediate I, 8L of anhydrous pyridine to the reaction kettle, control the reaction temperature between 0°C, add 4.552KgFmoc-Cl in two equal batches, and the interval between the two batches is half an hour. After...

Embodiment 3

[0081] Synthesis of Intermediate I

[0082] Add 1200g of 2-deoxy-D-ribose and 12L of anhydrous methanol into the reaction kettle, and stir at room temperature until the solid is completely dissolved, and the system is a light yellow transparent solution. 2.4 L of HCl-methanol solution with a mass fraction of HCl of 1.2% was added dropwise through a constant pressure funnel. After the dropwise addition was complete, it was stirred for 40 minutes. 600 ml of pyridine was added and stirring was continued for 30 minutes. After suction filtration, the filter cake was washed with anhydrous methanol, and the filtrate was evaporated to dryness under reduced pressure at 0.01Mpa to obtain 2.1Kg of intermediate I as an oil.

[0083] Synthesis of Intermediate II

[0084] Add 1.185Kg of intermediate I, 8L of anhydrous pyridine to the reaction kettle, control the reaction temperature between 10°C, add 4.552KgFmoc-Cl in two equal batches, and the interval between the two batches is half an...

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Abstract

The invention discloses a preparation method of a decitabine intermediate compound 1-acetoxyl-2-deoxidized-3,5-bi-O-fluorene methyl cyslohexyl-D-ribofuranose. The structural formula of the compound is shown in img file='DDA0000455164900000011.TIF' wi='648' he='304'/, and the preparation method comprises the following steps: o-methylation of 2'-deoxidized-D-ribose 1-bit hydroxyl; b) protection of 3,5-bit hydroxyl; and c) acylation of 1-bit-O-methyl. The invention also discloses a method for preparing decitabine employing the intermediate as a raw material.

Description

technical field [0001] The invention relates to a preparation method of a decitabine intermediate compound 1-acetyloxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose, which belongs to the field of medicine and chemical industry. Background technique [0002] Decitabine (also known as Dezocitadine), chemical name: 4-amino-1-(2-deoxy-β-D-erythrofuranose)-1,3,5-triazine-2(1H)- Ketone is an analogue of 2′-deoxycytidine, the structural formula is (I): [0003] [0004] Decitabine is a specific DNA methyltransferase inhibitor that can be phosphorylated by deoxycytidine kinase and incorporated into DNA in the form of phosphate. High concentration of decitabine incorporation can inhibit DNA synthesis to induce cell death and exert its cytotoxic effect; low concentration of decitabine incorporation can replace cytosine in tumor cells and covalently bind to DNA methyltransferase , inactivates DNA methyltransferases without causing cell death. [0005] Decitabine was de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/12C07H1/00C07H19/12
Inventor 白文钦曹守敬赵桂芳
Owner SHANDONG NEWTIME PHARMA
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