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Method for preparing improved decitabine

A technology of decitabine and its compound, which is applied in the field of preparation of decitabine, an anti-tumor cell growth drug, can solve the problems of low yield of deprotection group, difficult removal of heavy metal tin, excessive heavy metal and burning residue, etc.

Inactive Publication Date: 2009-10-21
SHANGHAI QINGSONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem with this preparation method is that the anhydrous tin tetrachloride used in the reaction makes it difficult to remove the heavy metal tin in the final product, causing heavy metals and ignition residues to exceed the standard
[0009] The problem that this preparation method exists is: (1) protecting group fluorenylmethoxycarbonyl chloride (Fmoc-Cl) is expensive; (2) use anhydrous tin tetrachloride in the reaction, cause the heavy metal tin in the final product to be difficult to remove completely , causing excessive heavy metals and burning residues; (3) the yield of deprotection group is low (36%), and the cost is high

Method used

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  • Method for preparing improved decitabine
  • Method for preparing improved decitabine
  • Method for preparing improved decitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of 3',5'-di-p-chlorobenzoyl-5-aza-2'-deoxycytidine (Formula IV, X=Cl)

[0022] In the three-necked bottle of 1000ml, add 5-azacytosine (131 grams, 1.17mol), hexamethyldisilazane (731ml, 3.51mol), ammonium sulfate (2g), reflux under nitrogen for 5 hours, reduce The solvent was distilled off under pressure to obtain 2,4-bis-(trimethylsilyl)-5-azacytosine (Formula III). Formula III was then dissolved in chloroform (2.4 L).

[0023] Add 1-α-chloro-3,5-di-p-chlorobenzoyl-2-deoxy-D-ribose (Formula II, X=Cl) (480g, 1.12mol) to the above solution, nitrogen protection, 50-55 Reflux for 4 hours. The reaction solution was cooled to room temperature, and the solvent was evaporated to dryness under reduced pressure. Methyl tert-butyl ether (2.4 L) was added to the residue, followed by heating under reflux for 1 hour. Cool to room temperature, filter with suction, and air-dry at 45°C to obtain an off-white solid, which is the title compound (Formula IV) (423.0 g), wit...

Embodiment 2-6

[0028] Preparation of 3′,5′-di-p-halobenzoyl-5-aza-2′-deoxycytidine (Formula IV, X=Cl, Br) was performed in the same manner as in Example 1, and the results are shown in Table 1.

[0029] Table 1: Preparation of 3', 5'-di-p-halobenzoyl-5-aza-2'-deoxycytidine (Formula IV, X=Cl, Br)

[0030] Example

Embodiment 7

[0032] Preparation of Decitabine (Formula I)

[0033] 3', 5'-chlorobenzoyl-5-aza-2'-deoxycytidine (Formula IV, X=Cl) (200g, 396mmol) was added to methanol (2000ml), and sodium methoxide (1.07g, 19.8 mmol), refluxed under nitrogen for 3 hours. Cool to 0°C and stir for 2 hours, filter with suction, wash with cold methanol (200ml), and dry in vacuo to obtain white solid formula I (47.1g), yield 52%.

[0034] Melting point: 190-192°C; [α] 22 D +69.5°(C=1,H 2 O); purity 99.77%

[0035] 1 H-NMR (DMSO-d 6 )8.50(s, 1H), 7.46(bs, 2H), 6.01(t, 1H), 5.20(bs, 1H), 5.00(bs, 1H), 4.22(s, 1H), 3.80(bs, 1H), 3.51-3.61(m, 2H), 2.10-2.21(m, 2H)

[0036] Liquid Chromatography Conditions

[0037]

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Abstract

The invention discloses a method for preparing improved decitabine (formula I), comprising: using 1-alpha-chlorine-3,5-two pairs of halo-benzoyl-2-deoxidation-D-ribose (formula II) as materials, concentrating with 2-4-bi-(trimethyl silicane)-5-azacytosine (formula III) to obtain I by de-protecting group. Materials used in the invention are easy to obtain at a low price. The invention also has the advantages of convenient operation and a high reaction yield, and is suitable for industrialized production.

Description

technical field [0001] The present invention relates to the preparation method of medicine. In particular, it relates to an improved preparation method for preparing anti-tumor cell growth drug decitabine. Background technique [0002] Decitabine is a 2′-deoxycytidine analogue that can effectively inhibit the growth of tumor cells. Its chemical name is: 5-aza-2′-deoxycytidine, and its structural formula is as follows: Formula I: [0003] [0004] Formula I [0005] Decitabine is a 2′-deoxycytidine analogue developed by SuperGen Corporation of the United States. It was approved for marketing by the European EMEA and the U.S. FDA in April and May 2006, and is used for the treatment of primary and secondary Drugs for myelodysplastic syndrome (MDS), which can be converted into deoxycytidine 5-monophosphate analogs in the body, incorporated into DNA under the action of DNA polymerase, inhibit DNA synthesis, inhibit DNA methylation, Thereby inhibiting the growth of tumor cel...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00A61K31/706A61P35/00
CPCY02P20/55
Inventor 张磊张健谭宙宏杨琍苹
Owner SHANGHAI QINGSONG PHARMA
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