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A kind of industrialized preparation method of capecitabine

A technology of capecitabine and reaction, which is applied in the field of preparation technology and product purification of anti-tumor drug capecitabine raw materials, can solve the problem of low purity of capecitabine raw materials, unfavorable large-scale production, small reaction scale, etc. problems, achieve the effect of reducing operational complexity, strict temperature control, and reducing production costs

Active Publication Date: 2016-01-13
SINOPHARM A THINK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the existing synthetic technology, there are small reaction scales, low purity of capecitabine raw materials, and a large number of impurities (wherein the U.S. FDA standard contains 9 impurities with known structures and several unknown impurities, the other The total content of impurities is 1.5%); meanwhile, in the last step of recrystallization and purification, ethyl acetate single solvent recrystallization (Chinese Journal of Medicinal Chemistry, 2005,15,173-187) or ethyl acetate is mixed with other solvents in the existing route Solvent recrystallization (Synthetic Chemistry, 2008, 16, 120-122; N. Shimmaetal. Bioorg. Med. Chem. 2000, 8, 1697-1706), but found during the operation of the inventors of the present invention that ethyl acetate has no effect on capec The dissolution of the crude product of citabine is very slow, which is not conducive to large-scale production. If the temperature rises and dissolves, the amide bond in capecitabine will be broken.

Method used

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  • A kind of industrialized preparation method of capecitabine
  • A kind of industrialized preparation method of capecitabine
  • A kind of industrialized preparation method of capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 14.2kg (110mol, 1.1eq) of 5-fluorocytosine 1 was added to a 50L reactor, then 29.8L of HMDS (143mol, 1.43eq) was added, and 20L of toluene was added, stirred and heated under reflux for 4h. The solvent was removed under reduced pressure (the bath temperature of the rotary evaporator was not higher than 70° C.) to obtain a white solid powder.

[0033] Suspend the above-mentioned white solid powder and 226kg (100mol, 1eq) of 5-deoxy-1,2,3-triacetyl deoxyribose in 100L of dichloromethane, and when the temperature in the reactor is lower than 2°C, use a constant pressure funnel to Add 15.2L (130mol, 1.3eq) SnCl dropwise 4 10L of dichloromethane solution (the internal temperature range of the dropwise addition process is 2°C to 8°C), slowly return to room temperature after dropping, and continue to stir and react at room temperature for 12h, then add 97.5kg of anhydrous Na to the system at low temperature 2 CO 3 (920mol, 9.2eq), then slowly add H 2 O26L (keep the internal...

Embodiment 2

[0037] The compound 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine 319.76kg (60mol, 1eq) was dissolved in 49.4L dichloromethane (1kg:2.5L), and pyridine 9.66 L (120mol, 2eq), when the internal temperature of the reactor drops below -15°C, start to add 412.17L (84mol, 1.4eq) of n-amyl chloroformate dropwise, while keeping the internal temperature not higher than -5°C. After the dropwise addition, the temperature was naturally restored and the reaction was monitored by TLC until the reaction was complete. Add 20LH 2 O and 50L dichloromethane, after stirring for 10min, let stand to separate layers; separate the organic phase, wash with water (20L*2); the water phase is back-extracted with dichloromethane (50L*2); the organic phases are combined, anhydrous sulfuric acid Na-dried, and the solvent was removed under reduced pressure to obtain the yellow oily product 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine 5 (directly used in the next step).

Embodiment 3

[0039] Dissolve the crude product 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine 5 in 28L of methanol from the previous step, and put it in the reaction kettle When the temperature drops below -10°C, start to drop 9.6kgNaOH (240mol, 4eq) in 24LH 2 O solution (10mol / L), keep the internal temperature not higher than -5°C during the period, continue to keep the low temperature (below -5°C) to react for 20min after dropping, then add about 20L of concentrated hydrochloric acid drop by drop, adjust the pH to 4-5, During this period, keep the internal temperature not higher than -5°C, add 10L of water and 100L of dichloromethane after the dripping, let stand to separate the layers, and separate the organic phase. The organic phase was washed with water (20L*2). The aqueous phase was back extracted with dichloromethane (50L*2). Combined organic phases, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to give a slightly yellow oily substance. Ad...

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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 anticancer 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] In the early stages of capecitabine synthesis, D-ribose or D-ribose deriva...

Claims

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Application Information

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