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Synthesis method of capecitabine

A capecitabine and synthesis method technology, applied in the field of synthesis of small molecule chemical drug capecitabine, can solve the problems of high production cost, difficult to evaporate, highly toxic phosgene, etc., achieve mild reaction conditions, reduce treatment Loss, cost reduction effect

Active Publication Date: 2015-05-20
ARROMAX PHARMATECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] However, there are generally the following disadvantages in these methods: column chromatographic separation is required, which is not conducive to industrial production; triphosgene has the danger of generating highly toxic phosgene in actual operation; in the silanization protection reaction, hexamethyldisilazide Alkane is used as a reaction reagent and solvent, and it is not easy to evaporate after the reaction, which affects the progress of the next step of the reaction; anhydrous tin tetrachloride is highly toxic, and it is easy to absorb water and deliquescence during operation, resulting in relatively harsh industrial production conditions and high production costs. , the environment is seriously polluted, and the toxic heavy metal tin will be carried to the next product, seriously endangering human health

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Embodiment 1

[0024] 1.1 Synthesis of compound of formula (II) (method 1)

[0025] Dissolve 10g (0.08mol) of the compound of formula (I) 5-fluorocytosine in 60ml of pyridine, and slowly add 13.5ml (0.096mol) of n-pentyl chloroformate to the resulting solution in an ice bath, and the addition is complete Then transfer to 110°C oil bath for 6h reaction. After the reaction was completed, ice water was added, and 18.5 g of white solid, namely the compound of formula (II), was obtained by filtration, with a yield of 98.4%.

[0026] 1 H-NMR (DMSO-d 6 )δ: 11.13 (brs, 2H, -CONH); 7.96 (s, 1H, Ar-H); 4.05 (t, 2H, J=6.8, -CH 2 O); 1.62-1.56 (m, 2H, -CH 2 ); 1.31-1.29 (m, 4H, -CH 2 -CH 2 -); 0.89-0.85(t, 3H, -CH 3 ).

[0027] 1.2 Synthesis of compound of formula (II) (method 2)

[0028] Dissolve 10g (0.08mol) of the compound of formula (I) 5-fluorocytosine in 50ml of DMSO, and add 28.5ml (0.16mol) of diisopropylethylamine under stirring, and slowly add chloroformic acid dropwise at room te...

Embodiment 2

[0031] 2.1 Synthesis of compound of formula (III) (method 1)

[0032] Dissolve 18.5g (0.076mol) of the compound of formula (II) in 100ml of anhydrous dichloromethane, and add 20ml (0.08mol) of BSA dropwise to the resulting solution, and a mixed solution is obtained after the addition; Boron trifluoride-ether 10.6g (0.075mol) of the complex was dissolved in 150ml of anhydrous dichloromethane, and 20g (0.077mol) of 1,2,3-O-acetyl-5-deoxy-D-ribofuranose was added and stirred, and the stirred solution Add to the above mixed solution, and stir the reaction for 7 hours in an oil bath at 30°C under nitrogen protection. After the reaction, wash with saturated sodium bicarbonate (150×3ml), saturated sodium chloride (150×3ml), anhydrous sodium sulfate dry. After spin-drying, 30 g of a yellow semi-solid product, namely the compound of formula (III), was obtained, with a yield of 91%. Wherein, the product does not need to be purified and can be directly used in the next reaction.

[...

Embodiment 3

[0039] Synthesis of the compound of formula (IV)

[0040] Dissolve 30g of the compound of formula (III) in 60ml of methanol, and slowly add 165ml of 0.5mol / L lithium hydroxide solution dropwise to the resulting solution under ice-salt bath conditions, and then continue the reaction under this condition for 0.5h, and the reaction ends Then adjust the pH to about 5-6 with 1M hydrochloric acid, extract with dichloromethane (150ml), wash with saturated sodium bicarbonate (150×3ml), wash with saturated sodium chloride (150×3ml), and dry over anhydrous sodium sulfate. 21.8 g of a white solid, namely the compound of formula (IV), was obtained with a yield of 90%.

[0041] 1 H-NMR (DMSO-d6) δ: 10.53 (brs, 1H, -CONH); 8.00 (s, 1H, -ArH); 5.67-5.66 (m, 1H, 1'-H); 5.43-5.42 (m, 1H, 2'-H); 5.07-5.05(m, 1H, 4'-H); 4.04-4.02(m, 3H, -CH 2 O, 3'-H); 3.89-3.86(m, 1H, 2'-OH); 3.70-3.67(m, 1H, 3'-OH); 1.61-1.58(m, 2H, -CH 2 ); 1.32-1.29 (m, 4H, -CH 2 -CH 2 ); 1.24(s, 3H, 4'-CH 3 ); 0.88...

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Abstract

The invention provides a synthesis method of capecitabine. The method comprises the following steps of (a) carrying out anti-amidation reaction on a compound 5-flucytosine in formula (I) and pentyl chloroformate in an organic solvent in the presence of alkali to prepare a compound in formula (II); (b) dissolving the compound in formula (II) in an organic solvent, adding Lewis acid, a silylating reagent and 1,2,3-O-acetyl-5-deoxidation-D-ribofuranose, and reacting under a temperature of 25-110DEG C to prepare a compound in formula (III); and (c) carrying out hydrolysis reaction on the compound in formula (III) to prepare the compound capecitabine in formula (IV). According to the method, the key intermediates do not need to be separated, the post-processing is simple, the reaction condition is mild, the operation is simple and convenient, and safety and environmental protection property are provided, so that the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicines, and more particularly relates to a method for synthesizing small molecule chemical drug capecitabine. Background technique [0002] Capecitabine (Capecitabine, trade name: Xeloda), chemical name 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, is a 5-fluorouracil developed by Roche (5-FU) prodrug, approved by US FDA in September 1998. At present, my country has approved the import of this product, which is clinically used in the treatment of advanced breast cancer, colorectal cancer and other solid tumors. Capecitabine is an oral cytotoxic preparation that has a selective effect on tumor cells. It is not cytotoxic itself, but it can be converted into cytotoxic 5-fluorouracil, which is activated by tumor-associated vascular factor thymophosphorylase The tumor site is transformed, which greatly reduces the damage of 5-fluorouracil to normal human cells, and has good curative effect and strong safety fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/06C07H1/00
Inventor 洪健张宗华武进刘华晖
Owner ARROMAX PHARMATECH
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