5-fluorocytidine complete cell enzymatic synthesis method

A flucytosine and enzymatic synthesis technology, which is applied in the field of 5-fluorocytosine synthesis, can solve the problems of long time consumption, low overall yield, unfavorable large-scale continuous production and the like, and achieves improved yield, The effect of shortened time and convenient recycling

Inactive Publication Date: 2009-11-04
DONGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The technical problem to be solved by the present invention is to provide a whole-cell enzymatic synthesis method of 5-fluorocytosine nucleoside to solve the problem that the overall yield in the existing chemical method and enzymatic synthesis is lower than 25%, which takes a long time and is not conducive to Disadvantages of industrialized large-scale continuous production

Method used

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  • 5-fluorocytidine complete cell enzymatic synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] 1mL 50mmol / / L NaH with pH=8 2 PO 4 Add D-D4T 5.6mg (25mmol / L), 5-FC 6.4mg (50mmol / L), and 1.2g Lactobacillus into a 5mL Erlenmeyer flask to the buffer, and seal it with multiple layers of gauze. The reaction was shaken at 120r / min in an air shaker at 40°C for 12.5h. After the reaction was completed, the reaction system was frozen and stored at -20°C to terminate. After the sample was thawed, it was centrifuged at 10,000 r / min for 15 minutes to remove the whole cells, and the obtained supernatant was filtered and used for HPLC detection.

Embodiment 2

[0019] 1mL 50mmol / / L NaH with pH=6.85 2 PO 4 Add 5.6mg (25mmol / L) of D-D4T, 6.4mg (50mmol / L) of 5-FC, and 2g of Lactobacillus to the buffer solution in a 5mL Erlenmeyer flask, and seal it with multiple layers of gauze. The reaction was shaken at 120r / min in an air shaker at 40°C for 12.5h. After the reaction was completed, the reaction system was frozen and stored at -20°C to terminate. After the sample was thawed, it was centrifuged at 10,000 r / min for 15 minutes to remove the whole cells, and the obtained supernatant was filtered and used for HPLC detection.

Embodiment 3

[0021] 1mL 50mmol / / L NaH with pH=6.85 2 PO 4 Add 5.6mg (25mmol / L) of D-D4T, 6.4mg (50mmol / L) of 5-FC, and 1.2g of Lactobacillus to the buffer solution in a 5mL Erlenmeyer flask, and seal it with multiple layers of gauze. The reaction was shaken at 120r / min in an air shaker at 40°C for 100h. After the reaction was completed, the reaction system was frozen and stored at -20°C to terminate. After the sample was thawed, it was centrifuged at 10,000 r / min for 15 minutes to remove the whole cells, and the obtained supernatant was filtered and used for HPLC detection.

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Abstract

The invention discloses a whole cell enzymatic synthesis method of 5-fluorocytosine nucleoside, which comprises the step of synthesizing thymidine with 5-fluorocytosine in a buffer solution in which the whole cell (containing N-deoxyribose transferase) exists For base exchange reaction, react at 37°C-50°C for 10-20 hours to obtain fluorine-containing nucleoside analogs, namely 5-fluorocytidine nucleoside. In this method, the yield of 5-fluorocytosine nucleoside can reach 49.4% within 20 hours. Compared with other synthetic methods, the yield is improved and the time is shortened. Moreover, the method uses whole cell catalysis, which is convenient for recovery and can be used continuously. It is conducive to industrialized large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing 5-fluorocytosine nucleoside, in particular to a whole-cell enzymatic synthesis method for 5-fluorocytosine nucleoside. Background technique [0002] D-D4FC (β-D-2',3'-didehydrodideoxy-5-fluorocytidine nucleoside) is a new type of anti-HIV nucleoside drug. Taken once / day or twice / day, it can effectively inhibit HIV protobacteria, anti-AZT (zidofuridine, 3'-deoxy-3'-azidethymidine) strains and anti-3TC (Lami Furidine, 3'-thiocytidine) strains and HIV variant strains resistant to other NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), PIs (protease inhibitors) drugs ( Antimicrob Agents Chemother, 2002, 46(5): 1394-1401.). So far, no new HIV mutant strains have been found in patients taking D-D4FC. Importantly, the combination of D-D4FC and other virus inhibitors except DDI (2', 3'-dideoxyinosine) has no mutual inhibitory effect and almost no ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P19/40
Inventor 朱利民戚娜
Owner DONGHUA UNIV
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