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Industrialized preparation method for capecitabine

A technology of capecitabine and its synthesis method, which is applied in the field of preparation technology and product purification of antineoplastic drug capecitabine raw materials, and can solve the problems of low purity of capecitabine raw materials and breakage of amide bonds in capecitabine , slow dissolution of crude capecitabine, etc., to achieve the effect of reducing operational complexity, reducing the difficulty of purification, and strict temperature control

Active Publication Date: 2014-02-12
SINOPHARM A THINK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing synthetic technology, there are all the shortcomings of small reaction scale, low purity of capecitabine raw material, and a large number of impurities (including U.S. FDA standard It contains 9 known structure impurities and several unknown impurities, and its total impurity content is 1.5%); at the same time, in the last step of recrystallization and purification, the existing route mostly uses ethyl acetate single solvent recrystallization (China Journal of Medicinal Chemistry, 2005, 15, 173-187) or mixed solvent recrystallization of ethyl acetate and other solvents (Synthetic Chemistry, 2008, 16, 120 -122; N. Shimma et al.Bioorg. Med. Chem.2000, 8, 1697-1706), but found in the course of the work of the present inventors that, Ethyl acetate dissolves the crude capecitabine very slowly, which is not conducive to large-scale production. If the temperature rises and dissolves, the amide bond in capecitabine will be broken.
Although Chinese patent 201010180463.2 specifically discloses an improved post-processing method to obtain high-purity capecitabine, its HPLC purity can reach 99.86%, but its final product is composed of 2',3'-di-O-acetyl -5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine 5 pure product hydrolyzed, increased to 2',3'-di-O-acetyl-5'-deoxy- The operational difficulty and requirements of 5-fluoro-N-[(pentyloxy)carbonyl]cytidine purification 5, and the operation scale is small.

Method used

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  • Industrialized preparation method for capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 14.2 kg (110 mol, 1.1eq) 5-fluorocytosine 1 Added to 50 L reactor, then added 29.8 L HMDS (143 mol, 1.43eq), then added 20 L toluene, stirred and heated to reflux for 4h. Decompression (rotary evaporator bath temperature is not higher than 70 o C) The solvent was removed to obtain a white solid powder.

[0032] The above white solid powder and 5-deoxy-1,2,3-triacetyl deoxyribose 2 26 kg (100 mol, 1eq) was suspended in 100 L of dichloromethane, and the temperature in the reactor was lowered to below 2 oC 15.2 L (130 mol, 1.3eq) SnCl was added dropwise with a constant pressure funnel 4 10 L of dichloromethane solution (inside temperature range of 2 oC to 8 o C), slowly return to room temperature after dropping, continue to stir and react at room temperature for 12 h, then add 97.5 kg of anhydrous Na to the system at low temperature 2 CO 3 (920 mol, 9.2eq), then slowly add H 2 O 26 L (keep the internal temperature not higher than 25 oC ), keep the internal...

Embodiment 2

[0036] Compound 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine 3 19.76 kg (60 mol, 1 eq) was dissolved in 49.4 L of dichloromethane (1 kg : 2.5 L), and 9.66 L of pyridine (120 mol, 2 eq) was added, and the inner temperature of the reactor dropped to -15 o Below C, start to add n-amyl chloroformate dropwise 4 12.17 L (84 mol, 1.4 eq), while keeping the internal temperature below -5 O c. After the dropwise addition, the temperature was naturally restored and the reaction was monitored by TLC until the reaction was complete. Add 20 L H 2 O and 50 L of dichloromethane were stirred for 10 min, and then the layers were separated; the organic phase was separated and washed with water (20 L*2); the aqueous phase was back-extracted with dichloromethane (50 L*2); the organic phases were combined , dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give yellow oily product 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine 5 (d...

Embodiment 3

[0038] The crude product 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine obtained in the previous step 5 Dissolve in 28 L of methanol, and wait until the temperature in the reactor drops to -10 o Below C, start adding 9.6 kg NaOH (240 mol, 4 eq) dropwise in 24 L H 2 O solution (10 mol / L), during which the internal temperature should not be higher than -5 o C, continue to keep the low temperature after dripping (-5 o C) to react for 20 min, then add about 20 L of concentrated hydrochloric acid dropwise, adjust the pH to 4-5, and keep the internal temperature not higher than -5 o C. Add 10 L of water and 100 L of dichloromethane after the dropwise addition, let stand to separate the layers, and separate the organic phase. The organic phase was washed with water (20 L*2). The aqueous phase was back-extracted with dichloromethane (50 L*2). Combined organic phases, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to give a slightly yellow o...

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Abstract

The invention optimizes the synthesis process of capecitabine bulk drug, especially improves the purification method of capecitabine. The method involved in the invention is suitable for industrial production, remarkably reduces the quantity and limit of related impurities in the capecitabine bulk drug, and improves the quality of the capecitabine bulk drug.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, specifically, the invention relates to a preparation process and a product purification method of an antineoplastic drug capecitabine bulk drug. Background technique [0002] Capecitabine (Capecitabine), trade name Xeloda, is a 5-fluorouracil (5-FU) precursor anti-cancer drug first developed by Hoffmey Roche Co., Ltd. in Basel, Switzerland. It is suitable for paclitaxel and The further treatment of advanced primary or metastatic breast cancer that is ineffective in the treatment of anthracycline antibiotic chemotherapy is also suitable for the first-line treatment of inoperable advanced or metastatic gastric cancer, and it can also be used as a single drug for the first-line treatment of metastatic colorectal cancer. Its molecular structure and absolute configuration are shown in Formula 1: [0003] [0004] Formula 1 [0005] In the early stages of capecitabine synthesis, D-ribo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06
Inventor 不公告发明人
Owner SINOPHARM A THINK PHARMA
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