Method for preparing capecitabine intermediate 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine by enzymatic composite chemical method

A capecitabine and chemical method technology, applied in the field of medicinal chemistry, can solve the problems of complicated and complicated preparation method of -deoxy-5-fluorocytidine, unsuitable for production conditions, unsuitable for environmental protection requirements, etc. The effect of high purity, easy control and few by-products

Active Publication Date: 2014-01-15
北京六盛合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method 3 of 5 ’ - The preparation method of deoxy-5-fluorocytidine is cumbersome and complicated, which is not suitable for the current domestic actual production conditions, and the production cost is high
Moreover, the above three methods do not meet environmental protection requirements, so it is necessary to find an intermediate that can improve yield and quality, reduce costs, and meet environmental protection requirements. ’ , 3 ’ -Di-O-acetyl-5 ’ -New preparation method of deoxy-5-fluorocytidine

Method used

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  • Method for preparing capecitabine intermediate 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine by enzymatic composite chemical method
  • Method for preparing capecitabine intermediate 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine by enzymatic composite chemical method
  • Method for preparing capecitabine intermediate 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine by enzymatic composite chemical method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 5mM 5 ’ -Deoxyribose-1-phosphate was reacted with 5mM 5-fluorocytosine, 25 units / mL pyrimidine nucleoside phosphorylase, 5mM CaCl2, at 28°C for 12 hours. After the end of the reaction, a white precipitate was visible at the bottom of the reactor. The white precipitate was filtered off, and the filtrate was concentrated to dryness at 55°C under reduced pressure. The obtained residue was dissolved in 5ml of methanol, dried by adding 2g of anhydrous sodium sulfate, filtered, and 5ml of isopropyl ether was added dropwise to the filtrate while stirring, and filtered after 2h. The solid was mixed with 40 ℃ vacuum drying for 4 hours, that is, 4.8mM of 5 ’ - Deoxy-5-fluoro-cytidine (yield 96%, HPLC 99.4%). mp192-193°C (literature: 192-194°C). HNMR(DMSO-d6)δ: 1.276 (d, 3H, H-11), 3.644 (m, 1H, H-3), 3.809 (m, 1H, H-4), 3.992 (m, 1H, H-2 ), 4.980 (d, 1H, H-10), 5.277 (d, 1H, H-9), 5.677 (s, 1H, H-1) 7.559 (s, J=7.0Hz, 1H, H-8), 7.753 (m, 2H, H-12).

[0021]

Embodiment 2

[0023] Add 5mM 5 ’ -Deoxyribose-1-phosphate was reacted with 5mM 5-fluorocytosine, 25 units / mL pyrimidine nucleoside phosphorylase, 5mM CaCl2, at 28°C for 12 hours. After the end of the reaction, a white precipitate was visible at the bottom of the reactor. The white precipitate was filtered off, and the filtrate was concentrated to dryness at 55°C under reduced pressure. The obtained residue was dissolved in 5ml of methanol, dried by adding 2g of anhydrous sodium sulfate, filtered, and 5ml of isopropyl ether was added dropwise to the filtrate while stirring, and filtered after 2h. The solid was mixed with 40 ℃ vacuum drying for 4 hours, that is, 4.6mM of 5 ’ -Deoxy-5-fluoro-cytidine (yield 92%, HPLC 99.2%).

Embodiment 3

[0025] Add 5mM 5 ’ -Deoxyribose-1-phosphate was reacted with 5mM 5-fluorocytosine, 25 units / mL pyrimidine nucleoside phosphorylase, 5mM CaCl2, at 28°C for 12 hours. After the end of the reaction, a white precipitate was visible at the bottom of the reactor. The white precipitate was filtered off, and the filtrate was concentrated to dryness at 55°C under reduced pressure. The obtained residue was dissolved in 5ml of methanol, dried by adding 2g of anhydrous sodium sulfate, filtered, and 5ml of isopropyl ether was added dropwise to the filtrate while stirring, and filtered after 2h. The solid was mixed with 40 ℃ vacuum drying for 4 hours, that is, 4.7mM of 5 ’ -Deoxy-5-fluoro-cytidine (yield 94%, HPLC 99.5%).

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Abstract

The invention provides a preparation method of a capecitabine intermediate 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, which is suitable for actual industrial mass production and has the advantages of relatively high yield, quality and good stability. The preparation method of the capecitabine intermediate comprises the following steps: creatively converting substrates 5-fluorocytosine and 5-deoxyribose-1-phosphate to 5'-deoxy-5-fluoro-cytidine by using an enzyme catalyst pyrimidine nucleoside phosphorylase (EC2.4.2.2), and further performing acetylation reaction on the 5'-deoxy-5-fluoro-cytidine to obtain the 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine. The method has the advantages of high yield and good quality and is in line with environmental protection requirements; the process is simple and easy to operate.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically related to capecitabine intermediate 2 ’ , 3 ’ -Di-O-acetyl-5 ’ - A process for the preparation of deoxy-5-fluorocytidine. Background technique [0002] The chemical name of capecitabine is 5 ’ -deoxy-5-fluoro-N4-pentyloxycarbonyl cytidine, namely 5 ’ -deoxy-5-fluoro-N4-(pentyloxycarbony)cytidine. [0003] 2 ’ , 3 ’ -Di-O-acetyl-5 ’ -Deoxy-5-fluorocytidine is an important intermediate raw material for the preparation of antineoplastic drug capecitabine. Its structural formula is as follows: [0004] [0005] Capecitabine intermediates reported in current literature and patents 2 ’ , 3 ’ -Di-O-acetyl-5 ’ There are three main synthetic routes of -deoxy-5-fluorocytidine, which are first listed as follows: [0006] [0007] Reference: Bioorganic & Medicinal Chemistry 8(2000):1697-1706 [0008] [0009] Reference: EP0602454 [0010] [0011] Referen...

Claims

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Application Information

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IPC IPC(8): C12P19/38
Inventor 田永强叶祥
Owner 北京六盛合医药科技有限公司
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