Novel method for synthesizing 9-substituted adenine compound

An adenine and compound technology, which is applied in the field of synthesis of 9-substituted adenine compounds, can solve the problems of limited product cost advantage, high price and the like, and achieves the effects of cheap raw materials, mild reaction conditions and high overall yield

Inactive Publication Date: 2013-01-09
北京六盛合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route has shorter steps, the price of the raw material (R)-glycidyl alcohol used is quite expensive, which limits the cost advantage of the product

Method used

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  • Novel method for synthesizing 9-substituted adenine compound
  • Novel method for synthesizing 9-substituted adenine compound
  • Novel method for synthesizing 9-substituted adenine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Synthesis of (R)-2-Benzyloxypropanol

[0022] Add 1.0kg of benzyl alcohol and 50g of ZrO2 / SO4 into a three-necked flask, heat the reaction solution to 50°C, slowly add 580g of (R)-propylene oxide dropwise, keep the temperature not exceeding 50°C, and continue to keep React at high temperature for 2 hours, remove the solid by filtration, rectify the residue under reduced pressure with a glass rectification column, collect fractions from 124 to 130°C (12mmHg), and obtain 369g of a colorless oily liquid, which is (R)-2-benzyl Oxypropanol solidifies as a solid at about 20°C with a yield of 24%.

Embodiment 2

[0024] Synthesis of (R)-2-benzyloxypropanol p-toluenesulfonate

[0025] Mix 166g (R)-2-benzyloxypropanol with 1000ml DMF, add 200g triethylamine, 200g p-toluenesulfonyl and 2g 4-dimethylaminopyridine, heat to 80°C for 4 hours, cool to room temperature ,

[0026] Add 10L of water to it, extract with ethyl acetate, 1L each time, three times in total, combine the ethyl acetate layers, wash with water, dry and evaporate to dryness to obtain a light yellow solid, which is (R)-2-benzyloxypropanol p-toluene Sulfonic acid ester, weight is 278g, and yield is 87%.

Embodiment 3

[0028] Synthesis of (R)-9-(2-benzyloxypropyl)adenine

[0029] Mix 133g of adenine with 1500ml of DMSO, add 350g of (R)-2-benzyloxypropanol p-toluenesulfonate and 700g of cesium carbonate, stir and react at 100°C for 10 hours, filter after cooling, and add the filtrate to 20L of water , filtered the precipitated white solid, fully washed with water, and dried in vacuo to obtain a white solid, namely (R)-9-(2-benzyloxypropyl)adenine, with a weight of 177g and a yield of 63%.

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Abstract

The invention provides a novel method for synthesizing tenofovir disoproxil fumarate key intermediate (R)-9-(2-hydroxide-propyl)adenine. According to the invention, (R)-epoxypropane is taken as an initial raw material and reacted to benzylalcohol to obtain (R)-2-benzyloxy propanol under the catalysis of ZrO2 / SO4, (R)-2-benzyloxy propanol is reacted to p-toluene sulfonyl chloride to obtain sulfonate, under the effect of cesium carbonate, the sulfonate is reacted to adenine to obtain (R)-9-(2-benzyloxy-propyl)adenine, and benzyl is removed under the catalysis of palladium-carbon to obtain (R)-9-(2-hydroxide-propyl)adenine. The method of the invention is characterized in that the step is short, the reaction condition of each step is mild, the yield is high, and the industrialization value is provided.

Description

technical field [0001] The invention relates to a synthesis method of a 9-substituted adenine compound, which belongs to the technical field of medicines. technical background [0002] At present, a large number of patents and patent applications have disclosed the method of synthesizing (R)-9-(2-hydroxypropyl) adenine (structural formula I), which is a synthetic antiviral drug tenofovir disoproxil (structural formula II) key intermediates. [0003] [0004] Tenofovir disoproxil is a new type of nucleotide reverse transcriptase inhibitor, which inhibits reverse transcriptase in a similar way to nucleoside reverse transcriptase inhibitors, so it has potential anti-HIV-1 activity. Tenofovir bisphosphonate, the active ingredient of tenofovir, can inhibit viral polymerase by directly competitively combining with natural deoxyribose substrates, and can be used to treat HIV and HBV infections by inserting into DNA to terminate the chain , combined with other reverse transcrip...

Claims

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Application Information

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IPC IPC(8): C07D473/34
Inventor 曾裕建陈应春蒲刚杨眉黎鹏胡林
Owner 北京六盛合医药科技有限公司
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