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New synthesis method of pseudouridine

A synthesis method and compound technology, applied in the new synthesis field of pseudouridine, can solve the problems of long production cycle, long chemical synthesis steps, unsafety and the like, and achieve the effects of shortening reaction steps and reducing reaction difficulty

Pending Publication Date: 2022-07-05
南京艾斯特医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, in the preparation of pseudouridine, only the traditional chemical synthesis method can catalyze the synthesis of pseudouridine, but for the chemical synthesis of pseudouridine, there are long chemical synthesis steps, low yield, and the reagents used are flammable and explosive. , a series of problems such as less security
In terms of biosynthesis, the preparation of pseudouridine through the fermentation of prepared microbial strains has problems such as long production cycle and low yield.

Method used

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  • New synthesis method of pseudouridine
  • New synthesis method of pseudouridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1 is the preparation example of compound I

[0021] In a 100 ml single-necked flask, under nitrogen protection, add 1.36 g of D-ribose and 20 ml of DMF, stir at high speed while the temperature of the system drops to -20°C, add 4.4 g of acetyl bromide dropwise, and stir for 12 hours. 100 ml of methane was used for extraction, and the obtained organic phase was dried by adding MgSO 4 . The filtered mother liquor was distilled under reduced pressure, and compound I was obtained by thin-layer separation of silica gel with a yield of 71%. The detection parameters are:

[0022] 1H NMR (CDCl3, 300MHz): δ6, 65-6.67 (m, 1H), 6.02-6.01 (m, 1H), 5.51-5.50 (m, 1H), 4.32-4.30 (m, 1H), 4.12-4.10 ( m, 1H), 2.06(s, 9H);

Embodiment 2

[0023] Embodiment 2 is the preparation example of compound II

[0024] In a 100 ml single-necked flask, under nitrogen protection, 2.35 g of uracil and 15 g of DMF were added, the temperature of the system was lowered to 0°C, 6.5 g of 60% NaH was added in batches, and 10.1 g of (Boc)2O was added in batches while stirring at a high speed. At room temperature overnight, after spotting to confirm the end of the reaction, extract with 100 ml of dichloromethane, add MgSO4 to the obtained organic phase to dry, filter the mother liquor and distill under reduced pressure, and separate through silica gel thin layer to obtain 3.96 g of compound II with a yield of 88% . The detection parameters are:

[0025] 1H NMR (CDCl3, 300MHz): δ7.68 (dd, 1H, J=15Hz), 5.52 (d, 1H, J=15 Hz), 5.12-5.10 (m, 1H) 1.46 (s, 18H);

Embodiment 3

[0026] Embodiment 3 is the preparation example of compound III

[0027] In a 100 ml single-necked flask, under nitrogen protection, 1.26 g of compound II and 50 g of DMF were added, and the temperature of the system was lowered to 0 °C while stirring at a high speed, 4.0 g of 60% sodium hydride was added in batches, and 1.50 g of compound I was added after stirring for 30 minutes. , stirred at room temperature for 12 hours, adjusted the pH value with hydrochloric acid to be between 4-5, and extracted with 100 ml of dichloromethane, the obtained organic phase was added MgSO to dry, the mother liquor was filtered and distilled under reduced pressure, and 1.33 g of compound was obtained by thin layer separation of silica gel III, yield 64%. The detection parameters are:

[0028] 1H NMR (CDCl3, 300MHz): δ 7.68 (dd, 1H, J=15Hz), 5.62-5.51 (m, 3H), 4.42-4.40 (m, 1H), 4.22-4.20 (m, 1H), 2.03 ( s, 9H), 1.43 (s, 18H);

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Abstract

The invention discloses a novel synthesis method of pseudouridine, which comprises the following steps: 1) taking D-ribose as a reaction initiator, and dropwise adding acetyl bromide into an organic solvent to obtain an intermediate I; 2) using uracil as a reaction initiator, eliminating reactive hydrogen in an organic solvent by using strong Lewis base, and adding (Boc) 2O in batches to obtain a corresponding intermediate II; and (3) carrying out condensation reaction on the compound I and the compound II in an organic solvent under the condition of strong Lewis base to obtain an intermediate III, removing a protecting group by using trifluoroacetic acid to obtain an intermediate IV, adding acetic anhydride, carrying out chiral resolution by using lipase to obtain a compound V, and finally removing a protecting group under an alkaline condition to obtain a final product VI. The product is a pseudouridine product. According to the method, mild and safe chemical reagents and enzyme chiral resolution are adopted, the reaction steps are shortened, the reaction difficulty is reduced, and therefore the technical bottleneck of green synthesis is achieved.

Description

technical field [0001] The present application relates to the technical field of organic synthesis, in particular, to a new method for synthesizing pseudouridine. Background technique [0002] In 1957, DAVIS et al. first discovered an isomer similar to the natural structure of uridine in ribosomal RNA (ribosomal RNA, rRNA) and transfer RNA (transfer RNA, tRNA). , U) N1 linked, and linked to C5 to form pseudouridine (Pseudouridine, PU). Uridine is cleaved from the ribose base by pseudouridine synthase and religated to form a C-C glycosidic bond, isomerizing to pseudouridine. Pseudouridine is catalyzed by pseudouridine synthase, which isomerizes specific uridines in RNA after transcription, a process known as pseudouridylation. As a nucleotide metabolite, pseudouridine has been paid more and more attention by scholars. Pseudouridine can be used as a potential biomarker for the diagnosis of nephropathy and tumor, monitoring of curative effect, and also has certain reference ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C12P41/00C12P17/16
CPCC12P41/004C12P17/162C12P17/165C07D405/04C07B2200/07Y02P20/55
Inventor 金峰金美研金涛何亚杰
Owner 南京艾斯特医药科技有限公司
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