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Novel tenofovir disoproxil intermediate and preparation method thereof

A technology for tenofovir disoproxil and intermediates, applied in the field of new tenofovir disoproxil intermediates and its preparation, can solve the problems of reduced reactivity, difficult handling, increased production costs, etc., and achieve mild reaction conditions and process operation The effect of simplicity and safe production process

Active Publication Date: 2018-06-19
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason is that tenofovir first undergoes monoesterification during esterification, and then continues to react into diester, but after monoesterification, because of the increase in steric hindrance, the reactivity decreases, and the difficulty of diesterification increases, resulting in The presence of monoester all the time affects the reaction yield
And because there are a large number of single-substituted products, post-reaction treatment is also more difficult, and product quality is more difficult to guarantee
Although the positive progress of the reaction is promoted by increasing the amount of raw material charged, this will greatly increase the production cost, and along with the progress of the reaction, the relevant impurities (impurities shown in Figure 1) of tenofovir disoproxil begin to appear
In a word, there are disadvantages such as low yield, high cost and many impurities in the existing method for preparing tenofovir disoproxil

Method used

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  • Novel tenofovir disoproxil intermediate and preparation method thereof
  • Novel tenofovir disoproxil intermediate and preparation method thereof
  • Novel tenofovir disoproxil intermediate and preparation method thereof

Examples

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preparation example Construction

[0029] The preparation method of the new intermediate of tenofovir disoproxil adopts the synthetic route shown below:

[0030] .

Embodiment 1

[0032] Preparation of compound p-toluenesulfonyloxymethylphosphonic acid as shown in formula (Ⅲ):

[0033] Add 15g (0.046mol) of diethyl p-toluenesulfonyloxymethylphosphonate and 450ml of acetonitrile into a 1L reaction flask, stir, and slowly add 56.4g (0.37mol) of trimethylbromosilane in an ice bath, dropwise Complete, heat up to 30°C, keep warm at 30°C and react for 24 hours. After the reaction is over, concentrate under reduced pressure to remove acetonitrile, add 100ml of toluene to the concentrated solution and transfer it to a 500ml three-necked flask, cool down to 10-20°C in an ice bath, and then add 100ml of pre-cooled water, keep warm at 10-20°C and stir for 10 minutes, let stand, separate layers, and remove the organic layer. Wash the water layer with 100ml ethyl acetate for 3 times, keep warm at 10-20°C, remove the water layer after washing, combine the ethyl acetate layer, then add 100ml saturated brine to the ethyl acetate layer, keep warm at 10-20°C and stir for...

Embodiment 2

[0035] Preparation of compound p-toluenesulfonyloxymethylphosphonic acid as shown in formula (Ⅲ):

[0036] Add 20g (0.06mol) of diethyl p-toluenesulfonyloxymethylphosphonate, 500ml of N,N-dimethylformamide, and 21.7g (0.882mol) of sodium bromide into a 1L reaction flask, stir and place in an ice bath Slowly add 32.6g (1.26mol) of trimethylchlorosilane dropwise under low temperature. After the dropwise addition is completed, the temperature is raised to 60°C and reacted for 16 hours. After the reaction is completed, the reaction solution is cooled to room temperature and filtered. For methyl formamide, add 100ml of toluene to the concentrated solution and transfer it to a 500ml three-neck flask, cool down in an ice bath to 10-20°C, then add 100ml of pre-cooled water, keep warm at 10-20°C and stir for 10min, let stand, separate layers, remove organic layer. Wash the water layer with 100ml ethyl acetate for 3 times, keep warm at 10-20°C, remove the water layer after washing, com...

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Abstract

The invention discloses a novel tenofovir disoproxil intermediate with a structure shown as the formula (II) in the description. The invention further discloses a preparation method of the novel tenofovir disoproxil intermediate. According to the novel tenofovir disoproxil intermediate, a new preparation path is developed for tenofovir disoproxil preparation, purification of a follow-up step is not needed, tenofovir disoproxil related substances which are associated with phosphate part in pharmacopeia can be controlled effectively, yield is high, few impurities are produced, and preparation ofhigher-purity tenofovir disoproxil is facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new intermediate of tenofovir disoproxil and a preparation method thereof. Background technique [0002] Tenofovir disoproxil fumarate (TDF), chemical name (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methanol Base] phosphonic acid diisopropoxycarbonyloxy methyl ester fumarate is a new type of nucleotide reverse transcriptase inhibitor developed by Gilead Sciences in the United States. It mainly inhibits the activity of HIV-1 reverse transcriptase. Inhibits the replication of HIV virus. The preparation was first launched in the United States in 2001, and has been launched in Canada, Europe and other countries and regions. As a first-line drug for treating HIV, it has a good application prospect. Although the proportion of HIV-infected people in my country to the total population is very low, the number of HIV-infected people ranks second in Asia, and there is an increasin...

Claims

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Application Information

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IPC IPC(8): C07F9/40
CPCC07F9/4006
Inventor 姜春阳李惠谢军崔赛德陈俊李红昌许全胜
Owner SHANGHAI SCIENPHARM CO LTD