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Method for preparing 9-(diethoxy phosphoryl methoxy ethyl)-adenine

A technology of diethoxyphosphorylmethoxyethyl and adenine, applied in the field of preparation of 9--adenine, which can solve the problems of high price and rare raw materials

Inactive Publication Date: 2006-10-25
EAST CHINA UNIV OF SCI & TECH +1
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Problems solved by technology

[0008] The main defect of this method has two, and one is: raw material is rare, and compound 3 needs to be made by reaction of chloroethyl chloromethyl ether (its structure is shown in formula 4, hereinafter referred to as compound 4) and triethyl phosphite ,
[0024] It can be seen that the synthesis of compound 8 requires the use of trifluoroethanol, which is very expensive

Method used

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  • Method for preparing 9-(diethoxy phosphoryl methoxy ethyl)-adenine
  • Method for preparing 9-(diethoxy phosphoryl methoxy ethyl)-adenine
  • Method for preparing 9-(diethoxy phosphoryl methoxy ethyl)-adenine

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preparation example Construction

[0038] The method for preparing 9-(diethoxyphosphorylmethoxyethyl)-adenine in the present invention comprises the steps of:

[0039] (1) In the presence of anhydrous aluminum trichloride, use paraformaldehyde, 2-chloroethanol, diethyl phosphite and dry hydrogen chloride gas as raw materials, and react at 90 ° C to 125 ° C for 6 to 8 hours , Distilled under reduced pressure, collecting the fraction at 140-150°C / 10mmHg to obtain diethoxyphosphorylmethoxyethyl chloride (compound 3);

[0040] Wherein: the recommended consumption of anhydrous aluminum trichloride is that its mol ratio with paraformaldehyde is 1: 3~4; The preferred mol ratio of paraformaldehyde, 2-chloroethanol and diethyl phosphite is 1: (0.5 ~1.1): (0.5 ~ 1.5), the best is 1: (0.8 ~ 1.0): (0.7 ~ 1.0); the preferred molar ratio of diethoxyphosphorylmethoxyethyl chloride and adenine is 1: (0.5 ~ 1.1), the best is 1: (0.8 ~ 1.0).

[0041] (2) The diethoxyphosphorylmethoxyethyl chloride and adenine produced by step ...

Embodiment 1

[0045] Paraformaldehyde (chemically pure, Shanghai Experimental Reagent Co., Ltd.) (94g, 3.24mol), 2-chloroethanol (255g, 3.16mol), anhydrous aluminum trichloride (139g, 1.04mol) and diethyl phosphite ( Industrial product, Yixing Manqiu Chemical Co., Ltd.) (385g, 2.5mol), at 25°C, feed dry hydrogen chloride gas (generated by concentrated sulfuric acid and concentrated hydrochloric acid) into the system under stirring, then pass through concentrated sulfuric acid and anhydrous Sodium sulfate drying), when all the solids in the mixture are dissolved, stop feeding hydrogen chloride, heat up to 90°C within 1 hour, react for 4 hours, then heat up to 125°C for 2 hours, then change the reaction device to vacuum distillation device, collect 140~150 DEG C / 10mmHg cuts, obtain yellowish liquid (250g, 1.04mol), purity 96% (gas chromatography content), yield 41.6% (based on diethyl phosphite).

[0046]Under stirring, in 2000mL DMF (900mL), add adenine (25g, 0.185mol), anhydrous potassium c...

Embodiment 2

[0048] In a 1000L glass-lined reactor, add paraformaldehyde (47kg, 1.62kmol), 2-chloroethanol (127.5kg, 1.58kmol), anhydrous aluminum trichloride (69.5kg, 520mol) and diethyl phosphite (192.5 kg, 1.25kmol), at 25°C, feed dry hydrogen chloride gas into the system under stirring (generated by concentrated sulfuric acid and concentrated hydrochloric acid, and then dried by concentrated sulfuric acid and anhydrous sodium sulfate), when all the solids in the mixture dissolve Afterwards, stop feeding hydrogen chloride, heat up to 90°C within 1 hour, react for 4 hours, then heat up to 125°C for 2 hours, then switch the reaction device to a vacuum distillation state, collect 140-150°C / 10mmHg fractions, A slightly yellow liquid (125kg, 520mol) was obtained with a purity of 96% (gas chromatography content) and a yield of 41.6% (based on diethyl phosphite).

[0049] Add DMF (450L) to a 1000L glass-lined reactor, add adenine (12.5kg, 92.5mol) and anhydrous potassium carbonate (25kg, 180mo...

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Abstract

This invention relates to 9-(bi ethoxy phosphoryl methoxyl group ethyl)-gland piaolin preparation method. (1) Materials are paraformaldehyde, 2-chlorohydrin, diethyl phosphate and dry chlorine hydride gas, they are reacted for 6-8 hours at 90-125 degree centigrade under condition of anhydrous aluminium chloride existing, and then bi ethoxy phosphoryl methoxyl group ethyl is got after decompression and distillation. (2) The bi ethoxy phosphoryl methoxyl group ethyl made in (1) is condensed reacted with gland piaolin to get the object. Comparing to existing technique, this invention simplifies preparation methods, and reduces operation cost. Furthermore, it is friendly to environment.

Description

technical field [0001] The invention relates to a preparation method of 9-(diethoxyphosphorylmethoxyethyl)-adenine. Background technique [0002] Hepatitis B is a disease that seriously threatens people's health. In order to treat patients with hepatitis B, various drugs have been developed, among which, 9-(2-phosphorylmethoxyethyl)-adenine (its structure is shown in formula 1, hereinafter referred to as compound 1) is a It is a relatively effective drug, which can quickly and effectively reduce the serum HBV DNA level of patients with hepatitis B, and can also reduce transaminases, and long-term use will not produce drug resistance. [0003] A key intermediate for the synthesis of compound 1 is 9-(diethoxyphosphorylmethoxyethyl)-adenine (its structure is shown in formula 2, hereinafter referred to as compound 2). [0004] [0005] There are mainly three methods for the synthesis of compound 2 reported in the literature so far: [0006] One: A method reported by Holy A...

Claims

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Application Information

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IPC IPC(8): C07F9/09
Inventor 沈永嘉王成云任晓莉叶传永叶波
Owner EAST CHINA UNIV OF SCI & TECH
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