Carbonic ester photosensitive reagent as well as preparation method thereof and method for preparing 5'-photosensitive protected nucleoside

A carbonate type and reagent technology, which is applied in the field of carbonate type photosensitizers and their preparation, and the preparation of 5'-photosensitive protected nucleosides, can solve the problems of inconvenient operation, difficult separation, low yield and the like, and can reduce production Cost, reduction of purification process, effect of high application value

Inactive Publication Date: 2015-05-20
石平 +1
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are two common problems: (1), when introducing the 5'-photosensitive group, due to the use of acyl chloride photosensitive reagents, the reaction lacks sufficient selectivity, especially large-scale reactions, the selective reaction of acyl chloride photosensitive reagents The conditions are difficult to control. While generating 5'-Photolabile dN, there are a considerable amount of by-products 3'-Photolabile dN and 3',5' -Generation of double photosensitive protected nucleosides (3',5'-diPhotolabile dN), depending on the base, the main product 5'-photosensitive protected nucleosides and by-products (3'-photosensitive protected nucleosides and 3',5 '-Double photosensitive protected nucleosides, etc.) The ratio is generally 5:1 to 2:1 (references: Sigrid Buhler, Irene Lagoja, etc., Helvetica Chimica Acta, 2004, v87(3), 620-659)
Because the separation properties of 3'-photosensitive protected nucleosides and 5'-photosensitive protected nucleosides are very similar, it is quite difficult to separate 5'-photosensitive protected nucleosides from 3'-photosensitive protected nucleosides
Even if separated, because the two are easy to cross each other, the loss of 5'-photosensitive protected nucleoside product is relatively large, and the yield is low
Therefore, it is very important to find highly selective reagents for primary (1°) alcohols and secondary (2°) alcohols to improve the selectivity of the reaction (references: Abbas-Alli G.Shaikh, Chem Review, 1996, v96, 951- 976); (2), must use diphosgene (diphosgene) (references: Woffgang Pfleiderer&Heiner Giegrich, 1998, U.S. Patent, US5763599) when preparing acid chloride photosensitive reagent, diphosgene is very toxic, and it is very inconvenient to operate , and seriously pollute the environment, it should be avoided as much as possible in production

Method used

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  • Carbonic ester photosensitive reagent as well as preparation method thereof and method for preparing 5'-photosensitive protected nucleoside
  • Carbonic ester photosensitive reagent as well as preparation method thereof and method for preparing 5'-photosensitive protected nucleoside
  • Carbonic ester photosensitive reagent as well as preparation method thereof and method for preparing 5'-photosensitive protected nucleoside

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 5'-NPPOC-dT( 5 ) preparation

[0032] 1a. Preparation reaction steps of photosensitive reagent:

[0033]

[0034] At room temperature 25°C, in a reaction vessel, 2-o-nitrobenzene-1-propanol 1 [2-(2-nitrophenyl)propan-1-ol, 54.4g, 0.30mol] was dissolved in dichloromethane (544ml), bis(p-nitrophenyl) carbonate was added 2 [Bis(4-nitrophenyl)carbonate, 0.33mol], then added triethylamine (0.303mol); the reaction system was stirred at room temperature, and after 6 hours, HPLC showed that the reaction was complete, and the reaction was stopped. The reaction solution was successively water (2×300ml, indicated by After extraction with 300ml of water, extract once with 300ml of water (extracted twice in total) and saturated aqueous sodium chloride solution (300ml), keep the organic (dichloromethane) layer, dry the dichloromethane layer with anhydrous sodium sulfate, and filter , the filtrate was evaporated to dryness, and dried in vacuo to obtain (2-o-nitrophenyl)-1-propyl...

Embodiment 2

[0042] 5'-NPPOC-N-Ac-dC( 9 ) preparation

[0043] 2a. Preparation reaction steps of photosensitizer:

[0044]

[0045] At room temperature 20°C, in a reaction vessel, 2-o-nitrobenzene-1-propanol 1 [2-(2-nitrophenyl)propan-1-ol, 0.30mol] was dissolved in chloroform (544ml), and bis(pentafluorobenzene)carbonate was added 6 [Bis(pentafluorophenyl)carbonate0.33mol], and then added triethylamine (0.303mol). The reaction system was stirred at room temperature. After 9 hours, HPLC showed that the reaction was complete, and the reaction was stopped. The reaction solution was extracted with water (2×300ml) and saturated aqueous sodium chloride solution (300ml) successively, and the organic (chloroform) layer was retained; After drying with anhydrous sodium sulfate, filter, evaporate to dryness, and vacuum dry to obtain (2-o-nitrophenyl)-1-propyl pentafluorobenzenecarbonate 7 , 95.1g, the HPLC purity was 97%, and the yield was 81%.

[0046] 2b. Select the coupling reaction step:...

Embodiment 3

[0053] 5'-NPPOC-N-Bz-dA( 13 ) preparation

[0054] 3a. Preparation reaction steps of photosensitizer:

[0055]

[0056] At room temperature 25°C, in a reaction vessel, 2-o-nitrobenzene-1-propanol 1 [2-(2-nitrophenyl)propan-1-ol, 0.30mol] was dissolved in ethyl acetate (540ml), and N'N-carbonyldiimidazole was added 10 (1,1'-Carbonyldiimidazole, 0.33 mol), and triethylamine (0.303 mol) was added. The reaction system was stirred at room temperature. After 7 hours, HPLC showed that the reaction was complete, and the reaction was stopped. The reaction solution was extracted with water (2×300ml) and saturated aqueous sodium chloride solution (300ml) successively, and the organic (ethyl acetate) layer was retained; After drying with anhydrous sodium sulfate, filter, evaporate to dryness, and vacuum dry to obtain N-imidazole carbonate (2-o-nitrophenyl)-1-propyl ester 11 , 69.4g, the HPLC purity was 96%, and the yield was 84%.

[0057] 3b. Select the coupling reaction step:

...

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Abstract

The invention relates to a carbonic ester photosensitive reagent as well as a preparation method thereof and a method for preparing the 5'-photosensitive protected nucleoside. The structural formula of the carbonic ester photosensitive reagent is shown in the description, wherein X is -OX', imidazole group and substituted imidazole group; the method for preparing the 5'-photosensitive protected nucleoside comprises the following steps: processing the 2'-deoxynucleoside, 2-o-nitrophenyl-1-propyl carbonic ester photosensitive reagent and the triethylamine to obtain the 5'-photosensitive protected nucleoside crude product, purifying the crude product to obtain the 5'-photosensitive protected nucleoside. The method for preparing the 5'-photosensitive protected nucleoside is capable of average increasing the selectivity for 3.4 times, reducing the purifying process, increasing the yield, greatly reducing the production cost and avoiding the use of virulent diphosgene.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a carbonate photosensitive reagent, a preparation method thereof, and a preparation method of 5'-photosensitive protected nucleosides. Background technique [0002] Gene chip technology is a high-tech biotechnology formed by combining the principle of nucleic acid molecular hybridization with microelectronic technology. It can be widely used in many fields such as disease diagnosis, drug screening, biological science research, optimal breeding of crops, judicial identification, food hygiene supervision, and environmental testing. Since in situ lithography technology can prepare high-density oligonucleotide gene chips, at present, gene chips based on in situ lithography technology are widely used, 5'-photosensitive protected nucleosides and their derivatives 5'-photosensitive sub Phosphoramide monomer is one of the key raw materials for the preparation of th...

Claims

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Application Information

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IPC IPC(8): C07C205/43C07C201/12C07H19/073C07H1/00C07D233/56C07H19/173C07D213/64
CPCC07C201/12C07D213/64C07D233/56C07H1/00C07H19/073C07H19/173C07C205/43C07C205/42
Inventor 石平林金来
Owner 石平
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