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Carbonic ester type photosensitive reagent and preparation method thereof as well as preparation method of 5'-photolabile dN

A photosensitive and reagent technology, which is applied in the field of carbonate photosensitive reagents and their preparation, and the preparation of 5'-photosensitive protected nucleosides, can solve the problems of difficult separation, inconvenient operation, low yield, etc., and achieve a reduced purification process , Reduce production cost, high application value effect

Inactive Publication Date: 2016-09-28
石平 +1
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Problems solved by technology

[0004] has two common problems: (1), when introducing 5'-photosensitive groups, due to the use of acid chloride photosensitive reagents, the reaction lacks enough options Especially for large-scale reactions, it is difficult to control the reaction conditions for the selection of acyl chloride photosensitive reagents. While generating 5'-photosensitive protected nucleosides (5'-Photolabile dN), there is a considerable amount of by-product 3'-photosensitive protected Nucleoside (3'-Photolabile dN) and 3',5'-double photosensitive protected nucleoside (3',5'-diPhotolabile dN) are generated, depending on the base, the main product generated is 5'-photosensitive protected nucleoside and The ratio of by-products (3'-photosensitive protected nucleosides and 3',5'-double photosensitive protected nucleosides, etc.) is generally 5:1 to 2:1 (references: Sigrid Buhler, Irene Lagoja et al., 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 type photosensitive reagent and preparation method thereof as well as preparation method of 5'-photolabile dN
  • Carbonic ester type photosensitive reagent and preparation method thereof as well as preparation method of 5'-photolabile dN
  • Carbonic ester type photosensitive reagent and preparation method thereof as well as preparation method of 5'-photolabile dN

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Experimental program
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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 type photosensitive reagent and a preparation method thereof as well as a preparation method of 5'-photolabile dN. The structural formula of the carbonic ester type photosensitive reagent is shown in the specification, wherein X is -OX', imidazolyl or substituted imidazolyl. The preparation method of 5'-photolabile dN comprises the following steps: preparing a crude product of 5'-photolabile dN from 2'-deoxynucleoside and 2-o-nitrobenzene-1-propyl carbonic ester type photosensitive reagent and triethylamine; and purifying the crude product to obtain the 5'-photolabile dN. According to the preparation method of 5'-photolabile dN, the selectivity is improved by 3.4 times on average, the purifying process is simplified, the yield is increased, the production cost is greatly reduced, and the use of virulent diphosgene is avoided.

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