mPEG3-tenofovir disoproxil and preparation method thereof

A tenofovir disoproxil and structural formula technology, applied in the field of preparation of mPEG3- tenofovir disoproxil, can solve the problems that the solvent cannot be recycled, the difficulty of diesterization is increased, and the product quality is difficult to guarantee, so as to achieve good application development Prospects, stable product quality, and the effect of solving solvent loss

Inactive Publication Date: 2017-05-10
天津迈德新医药科技有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0004] The existing production technology of tenofovir disoproxil fumarate is to synthesize tenofovir disoproxil after esterification reaction from tenofovir monohydrate or anhydrate as starting material and chloromethyl isopropyl carbonate, and then Salify with fumaric acid to get tenofovir disoproxil fumarate, but the reaction conversion rate is low in the existing synthetic technology, the main reason is that tenofovir is first monoesterified during esterification, and then continues to react Diesterification, but after monoesterification, due to the increase in steric hindrance, the reaction activity decreases, and the difficulty of diesterification increases, resulting in the presence of monoester in the reaction and affecting 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 materials, this will greatly increase the production cost, and when the raw materials increase to a certain amount, the forward reaction will reach an equilibrium, and the conversion will not continue
In addition, the esterification reaction in the existing synthesis technology uses a solvent with a high boiling point, and tenofovir disoproxil is unstable at high temperature and cannot be directly recovered, so a large amount of ice water is generally used for salting out or a large amount of Washing with water causes a large amount of solvent to enter the sewage treatment system, which not only increases the pressure on environmental protection, but also causes the product cost to be too high because the solvent cannot be recycled

Method used

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  • mPEG3-tenofovir disoproxil and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 mPEG represented by formula II 3 Preparation of -(R)-9-(2-hydroxypropyl)adenine

[0054] (R)-9-(2-hydroxypropyl) adenine (Ia, 22.8g, 117mmol), triethylene glycol monomethyl ether p-toluenesulfonate (Ib, 67.2g, 211mmol) and K 2 CO 3 (32.4g, 234mmol) was dissolved in DMF (900mL), and heated to 100°C for 7h. After the reaction was completed, cool to room temperature, add distilled water (1200 mL), stir and mix well. Extracted with ethyl acetate (720mL×4), the mixed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column to obtain 19.6g of an oily solid product with a yield of 49.4% and a HPLC purity of 98.0%.

[0055]

Embodiment 2

[0056] Example 2 mPEG represented by formula III 3 - the preparation of tenofovir diethyl ester

[0057] mPEG 3 -(R)-9-(2-Hydroxypropyl)adenine (Formula II, 25.4g, 74.8mmol) was dissolved in DMF (150mL), and 2.0M tert-butoxylithium (53.9g, 673mmol) was added slowly Tetrahydrofuran solution, and then slowly added p-toluenesulfonyloxymethyl diethyl phosphate (Ic, 44.8g, 89.8mmol), heated to 35°C and stirred for 8h. After the reaction was completed and cooled to 20°C, glacial acetic acid (6.0 mL) was added, volatiles were removed by distillation under reduced pressure, and distilled water (200 mL) was added. use CH 2 Cl 2 The extracts were extracted in portions, and the extracts were combined and dried with anhydrous sodium sulfate. After filtration and concentration, 12.8 g of an oily solid product was obtained, with a yield of 34.9% and an HPLC purity of 95.8%.

[0058]

Embodiment 3

[0059] Example 3 mPEG represented by formula IV 3 - Preparation of tenofovir

[0060] mPEG 3 - tenofovir diethyl ester (formula III, 19.2 g, 28.8 mmol) was dissolved in acetonitrile (250 mL) and bromotrimethylsilane (25 mL), and stirred overnight at room temperature without air. The volatiles were distilled off under reduced pressure, distilled water (500 mL) was added, and the 2 Cl 2 washing. The aqueous phase was adjusted to pH 3.2 with NaOH aqueous solution, cooled and stirred for 6 h. The solid was collected by filtration, washed successively with ice water and acetone, and dried under vacuum to obtain 6.7 g of solid, with a yield of 53.7% and a purity of 98.0% by HPLC.

[0061]

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PUM

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Abstract

The invention belongs to the technical field of organic compound synthesis, and relates to a medicine compound mPEG3-tenofovir disoproxil and a preparation method thereof. The mPEG3-tenofovir disoproxil has the advantages of safety and high quality. The preparation method comprises the following steps: carrying out reaction on (R)-9-(2-hydroxypropyl) adenine serving as a raw material with triglycol monomethyl ether tosylate under the action of carbonate to obtain mPEG3-(R)-9-(2-hydroxypropyl) adenine represented by a formula II, carrying out reaction with p-benzenesulfonyloxymethyl phosphoric acid diethylester under the action of alkali to obtain mPEG-3-tenofovir diethyl ester represented by a formula III, and then carrying out hydrolysis and condensation to obtain the mPEG3-tenofovir disoproxil. The preparation method of the mPEG3-tenofovir disoproxil provided by the invention is simple; the raw materials are readily available, the reaction conditions are mild, and the production cost is low; furthermore, the whole reaction yield is high, and the product quality is relatively stable.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and relates to a pharmaceutical compound mPEG 3 - Tenofovir disoproxil and its synthesis process, specifically, relate to a kind of mPEG 3 - The preparation method of tenofovir disoproxil. Background technique [0002] Tenofovir disoproxil fumarate (TDF), the chemical name is (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl 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. [0003] Tenofovir bisphosphonate, the active ingredient of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
CPCC07F9/65616
Inventor 王菁梁兰李姣
Owner 天津迈德新医药科技有限公司
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