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Synthesis technology for capecitabine

A synthetic process, capecitabine technology, applied in the field of chemical drug synthesis, can solve problems such as existing risks and high costs, and achieve the effect of improving quality, reducing quantity and limit

Inactive Publication Date: 2015-04-22
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] There are many synthetic methods for capecitabine in the existing synthetic technology, usually two fragment docking, in which 5-deoxy-triacetyl ribose and 5-fluorocytosine are used as raw materials to first synthesize the intermediate 2',3'- Diacetoxy-5'-deoxy-5-fluorocytidine, then synthesized capecitabine, there are two isomers α and β, the separation and purification of the two isomers requires high cost, and there are risk

Method used

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  • Synthesis technology for capecitabine

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Experimental program
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Effect test

Embodiment 1

[0018] Add 5′-deoxy-5-fluorouridine (40.7mmol) and hydroxylamine hydrochloride (40.7mmol) to methanol (100mL), add triethylamine (5mL) under stirring, react at 50-60°C for 2h, cool and filter , and washed to obtain a white solid (10 g, yield 94.4%). Dichloromethane (100mL) was added to 5'-deoxy-ribose-5-fluoro-4-hydroxylamine-3,4 dihydropyrimidine (38.3mmol) and potassium carbonate (38.3mmol), and acetic anhydride (91.9 mmol), react at 10-15°C for 5h, concentrate to dryness, wash the residue with water, filter and dry to obtain a white solid (12.9g, yield 97.7%). Add 2',3'-di-O-acetyl-5'-deoxy-ribose-5-fluoro-4-hydroxylamino-3,4 dihydropyrimidine (28.9mmol) and hydrochloric acid (10ml) to water (50mL) Add zinc chloride (57.8mmol) under stirring, react at 70-80°C for 3.5h, wash with water after cooling, filter, and dry to obtain a white solid (8.6g, yield 90.5%). Under ice-cooling, slowly drop n-pentyl chloroformate (21.5mmol) into N,N-diisopropylethylamine (0.46mL) and 2',3'...

Embodiment 2

[0020] Add 5′-deoxy-5-fluorouridine (40.7mmol) and hydroxylamine hydrochloride (40.7mmol) to ethanol (100mL), add triethylamine (5mL) under stirring, react at 70-80°C for 2h, cool and filter , and washed to obtain a white solid (9.6 g, yield 90.6%). Add 5'-deoxy-ribose-5-fluoro-4-hydroxylamino-3,4 dihydropyrimidine (38.3mmol) and triethylamine (38.3mmol) to acetic anhydride (100mL), add acetic anhydride (91.9mmol) under stirring mmol), reacted at 25-30°C for 5h, cooled and concentrated to dryness, the residue was washed with water, filtered and dried to obtain a white solid (12.3g, yield 92.8%). Add 2',3'-di-O-acetyl-5'-deoxy-ribose-5-fluoro-4-hydroxylamino-3,4-dihydropyrimidine (27.7mmol) and hydrochloric acid (10ml) to methanol (50mL) Add zinc chloride (54.9mmol) under stirring, react at 40-50°C for 3.5h, wash with water after cooling, filter, and dry to obtain a white solid (8.2g, yield 86.0%). Under ice-cooling, n-pentyl chloroformate (20.4mmol) was slowly dropped into N...

Embodiment 3

[0022]Add 5′-deoxy-5-fluorouridine (40.7mmol) and hydroxylamine hydrochloride (40.7mmol) to 50% ethanol solution (100mL), add triethylamine (5mL) under stirring, react at 65-70°C for 2h, After cooling, it was filtered and washed to obtain a white solid (9.4 g, yield 88.7%). Dichloromethane (100mL) was added to 5'-deoxy-ribose-5-fluoro-4-hydroxylamine-3,4 dihydropyrimidine (36.1mmol) and triethylamine (36.1mmol), and acetic anhydride ( 86.3 mmol), reacted at 0-5°C for 5 h, cooled and concentrated to dryness, the residue was washed with water, filtered and dried to obtain a white solid (12.1 g, yield 91.8%). Add 2',3'-di-O-acetyl-5'-deoxy-ribose-5-fluoro-4-hydroxylamine-3,4-dihydropyrimidine (27.2mmol) and hydrochloric acid (10ml) to ethanol (50mL) Add zinc chloride (57.8mmol) under stirring, react at 50-55°C for 3.5h, wash with water after cooling, filter, and dry to obtain a white solid (8.1g, yield 85.1%). Under ice-cooling, n-pentyl chloroformate (20.2 mmol) was slowly dro...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis technology for capecitabine. The synthesis technology for the capecitabine particularly comprises the first step of ketoxime synthetic reaction, the second step of acetyl protection, the third step of reduction reaction, the fourth step of condensation reaction, and the fifth step of hydrolysis reaction; accordingly, the capecitabine end products are obtained, and the capecitabine is purified by recrystallization through a single solvent. Compared with the prior art, the synthesis technology for the capecitabine revises the synthesis technology of the capecitabine active pharmaceutical ingredients, and particularly improves the intermediate protection and amination process; industrial production is applicable, the quality of the capecitabine active pharmaceutical ingredients is significantly improved, and the number and limitation of relative impurities in the capecitabine active pharmaceutical ingredients are decreased.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and specifically relates to a synthesis process of capecitabine. Background technique [0002] The trade name of capecitabine is Xeloda, which is a 5-fluorouracil precursor anticancer drug firstly developed by Hoffmey-Roche Co., Ltd. in Basel, Switzerland. Under the action, it is transformed into cytotoxic 5-fluorouracil through three steps. Enzymes related to the metabolism of capecitabine have a higher concentration in tumor tissue than in normal tissue, so high selectivity can be achieved. Capecitabine can inhibit cell division and interfere with RNA and protein synthesis, and is suitable for further treatment of advanced primary or metastatic breast cancer that is ineffective in paclitaxel and chemotherapy regimens including anthracycline antibiotics. It is mainly used for the treatment of advanced primary or metastatic breast cancer, rectal cancer, colon cancer and gastric ...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCC07H19/06C07H1/00
Inventor 李明丽李中井张萌刘新刚魏衍纲
Owner CISEN PHARMA
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