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Industrialized production method for high-purity decitabine

A decitabine and production method technology, applied in the field of medicinal chemistry, can solve the problems of difficult scale-up and repeated experiments in column chromatography purification operations, complicated intermediate quality control, and long production cycle, and achieve easy industrial scale-up production, operators and The effect of small environmental impact and short production cycle

Inactive Publication Date: 2011-01-19
JIANGSU AOSAIKANG PHARMA CO LTD
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Problems solved by technology

[0024] 2. The most effective way to improve the purity of decitabine intermediate products in the prior art is column chromatography purification, but column chromatography purification uses a large amount of solvent and silica gel, which will have a negative impact on production personnel and the environment; in addition, column chromatography purification Difficult to scale up repeated tests, complex intermediate quality control, cumbersome operation, high labor intensity, long production cycle, difficult to scale up industrial production

Method used

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  • Industrialized production method for high-purity decitabine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation of embodiment 1 decitabine

[0045] (1) Preparation of 2,4-bis(trimethylsilyl)-5-azacytosine (intermediate A)

[0046] Add 10 g (0.089 mol) of 5-azacytosine and 120 g of hexamethyldisilazane into the reaction flask, stir evenly, add 9.7 g (0.089 mol) of trimethylchlorosilane, heat to 100°C, and react for 6 hours Afterwards, filtered and evaporated to dryness under reduced pressure at 80°C to obtain 22.6 g of a white solid, ie Intermediate A, with a yield of 99.2%.

[0047](2) Preparation of 1-(3,5-di-O-p-chlorobenzoyl-2-deoxy-β-D-ribofuranose)-5-azacytosine (intermediate B) crude product

[0048] Add 22.6g (0.088mol) of intermediate A and 30.2g (0.07mol) of 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose to the reaction flask, add dichloromethane 600g, add 14.7g (0.066mol) of trimethylsilyl trifluoromethanesulfonate (TMSOTf), stir and react at 25°C for 12 hours, add 200ml of water to wash the reaction solution, let stand to separate layers, and ...

Embodiment 2

[0064] Embodiment 2 stability test

[0065] Get the samples of Example 1 (batch number: 100102 batches) and comparative example 1 (090501 batches), put them in a petri dish, spread them into a thin layer less than or equal to 5mm thick, place them in high temperature (60°C, 40°C), high humidity (25°C) ℃RH92.5%, 25℃RH75%±5%) for 10 days, samples were taken on the 5th and 10th day respectively. The results are shown in Table 1 below.

[0066] Table 1 The results of the decitabine influencing factors test

[0067]

[0068] Conclusion: The samples of Example 1 and Comparative Example 1 were placed at high temperature 60°C, 40°C and high humidity RH75%, 92.5% for 5 and 10 days respectively, the appearance and α isomerization of the sample of Example 1 (batch number: 100102) There is no significant change in the indicators such as body, related substance maximum single impurity and total impurity, content; the sample related substance maximum single impurity and total impurity ...

Embodiment 3

[0069] The preparation of embodiment 3 decitabine

[0070] (1) Preparation of 2,4-bis(trimethylsilyl)-5-azacytosine (intermediate A)

[0071] Add 50 g (0.446 mol) of 5-azacytosine and 1 kg of hexamethyldisilazane into the reaction flask, stir evenly, add 72.7 g (0.669 mol) of trimethylchlorosilane, heat to 30°C, and react for 10 hours Afterwards, filtered and evaporated to dryness under reduced pressure at 80°C to obtain 112.5 g of a white solid, ie Intermediate A, with a yield of 98.5%.

[0072] (2) Preparation of 1-(3,5-di-O-p-chlorobenzoyl-2-deoxy-β-D-ribofuranose)-5-azacytosine (intermediate B) crude product

[0073] Add 112g intermediate A (0.438mol) and 1-chloro-3,5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose 188.1g (0.438mol) to the reaction flask, add 1,2- Dichloroethane 9.4kg, add trimethylsilyl trifluoromethanesulfonate (TMSOTf) 97.7g (0.438mol), stir and react at 10 ℃ for 15 hours, add 3kg water to wash the reaction solution, let stand to separate layers, take The ...

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Abstract

The invention provides an industrialized production method for high-purity decitabine. The method comprises the following steps of: 1, performing silanization reaction of 5-azacytosine, bis(trimethylsilyl)amine and trimethyl chlorosilane, which serve as raw materials, to prepare 2,4-bis(trimethylsilyl)-5-azacytosine; 2, performing reaction of the product obtained by the step 1 and 1-chloro-3,5-bis-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose, which serve as raw materials, to prepare a crude product of 1-(3,5-bis-(4-chlorobenzoyl)-2-deoxy-beta-D-ribofuranose)-5-azacytosine; 3, dissolving the product obtained by the step 2 in a C5 to C7 hydrocarbon, stirring, filtering and drying to obtain a refined product; and 4, producing the high-purity decitabine by using the product obtained by the step 3, methyl alcohol and sodium methoxide as raw materials. The method overcomes the disadvantages of need of column purification, low purity, difficult industrial production in the prior art, and has the advantages of simple and convenient operation, small solvent consumption, small influence on the environment, low labor intensity, short period, high product purity, single impurity and less than 0.1 percent total impurity content.

Description

technical field [0001] The invention relates to an industrial production method of high-purity decitabine, which belongs to the technical field of medicinal chemistry. Background technique [0002] The chemical name of Decitabine is 4-amino-1-(2-deoxy-β-D-erythro-ribofuranose)-1,3,5-triazin-2(1H)-one; [0003] Structural formula: [0004] [0005] Molecular formula: C 8 h 18 N 4 o 4 [0006] Molecular weight: 228.21 [0007] Decitabine injection was developed by SuperGen Corporation of the United States, and was approved by the FDA in April 2006 for the clinical treatment of myelodysplastic syndrome (Myelodysplastic syndrome, MDS). Decitabine is a hypomethylating drug with a unique therapeutic mechanism as a methyltransferase inhibitor. Decitabine, as a 2′-deoxycytidine analogue of adenosine, can be converted into a 5′-monophosphate deoxycytidine analogue in vivo, which penetrates into DNA under the action of DNA polymerase and inhibits DNA synthesis and methylat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/00
Inventor 宗在伟李谢陈林魏佳
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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