Tenofovir disoproxil fumarate synthesis method

A technology for tenofovir fumarate and dipyproxil, which is applied in the field of medicine, can solve the problems of low yield, complicated hydrolysis process, uneven mixing of materials, etc., and achieves improved purity and yield, good refining effect, Yield-enhancing effect

Inactive Publication Date: 2015-06-24
SHANDONG NEWTIME PHARMA
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Problems solved by technology

This method has the problems of low yield of (R)-9-(2-hydroxypropyl)adenine, complex hydrolysis process, and prone to side reactions.
[0006] CN200910157993.2 provides a new synthesis process of tenofovir dipivoxil, which improves the preparation process of key intermediates in the synthesis of tenofovir dipivoxil, (R)-methyl lactate and diisopropyl-p-toluenesulfonyloxy Methyl-phosphate condensation, which not only introduces diisopropyloxy-phosphono-methyl, but also can be used as a protecting group for hydroxyl, uses sodium borohydride to selectively reduce carboxylate to alcohol, and obtains key The intermediate tenofovir, but the optical purity is still not up to the drug requirements
[0007] At the same time, in the synthesis process of (R)-4-methyl-1,3-dioxolan-2-one in the current technology, there are generally inhomogeneous mixing of materials in the reaction system, resulting in the raw material (R)-1,2- The reaction effect of propylene glycol is relatively poor, which affects the yield and purity of the product
In the synthesis of (R)-9-(2-hydroxypropyl)adenine, after the reaction is complete, the solvent is directly added for crystallization, resulting in a low yield in this step
During the synthesis process of (R)-9-[2-(diethylphosphorylmethoxy)propyl]adenine and tenofovir, the target product was not controlled in the middle, which made the product purity too low, and the following The synthesis of the product and the refinement of the final product have adverse effects

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1 Preparation of (R)-4-methyl-1,3-dioxolan-2-one

[0033] 33.0g of (R)-1,2-propanediol, 1.2g of sodium methoxide, 76.9g of dimethyl carbonate, and 10ml of anhydrous methanol were added to a 200ml three-necked bottle. Turn on stirring, heat up to 80 ℃~90 ℃ and react, during which methanol in the reaction system is continuously evaporated, when basically no liquid flows out, TLC detects whether the reaction is complete [developing solvent is ethyl acetate (V / ml): petroleum ether (V / ml) ​​= 3:2; iodine smoked color]. After the reaction is complete, heat up to 110°C to 120°C, continue to evaporate the solvent under reduced pressure at -0.09MPa, distill until no fraction flows out, and filter off the insoluble matter by suction filtration to obtain a pale yellow oil (R)-4-methyl. 40.8 g of base-1,3-dioxolan-2-one, with a purity of 98.7% and a molar yield of 92.1%. 1 HNMR (500MHz, CDCl 3): δ4.87~4.86 (m, 1H), 4.58~4.55 (m, J=8.5Hz, 1H), 4.05~4.02 (m, J=8.5Hz, 1H), ...

Embodiment 2

[0034] Example 2 Preparation of (R)-4-methyl-1,3-dioxolan-2-one

[0035] 33.0g (R)-1,2-propanediol, 0.8g sodium hydroxide, 51.3g diethyl carbonate, and 10ml absolute ethanol were added to a 500ml three-necked bottle. Turn on stirring, heat up to 85 ℃~95 ℃ and react, during the period, the absolute ethanol in the reaction system is continuously evaporated, and when basically no liquid flows out, TLC detects whether the reaction is complete [developing solvent is ethyl acetate (V / ml): Petroleum ether (V / ml) ​​= 3:2; iodine smoked color]. After the reaction is complete, heat up to 110°C to 120°C, continue to evaporate the solvent under reduced pressure at -0.09MPa, distill until no fraction flows out, and filter off the insoluble matter by suction filtration to obtain a pale yellow oil (R)-4-methyl. 40.6 g of base-1,3-dioxolan-2-one, with a purity of 98.0% and a molar yield of 91.6%. 1 H NMR (500MHz, CDCl 3 ): δ4.87~4.86 (m, 1H), 4.58~4.55 (m, J=8.5Hz, 1H), 4.05~4.02 (m, J=8.5...

Embodiment 3

[0036] Example 3 Synthesis of (R)-9-(2-hydroxypropyl) adenine

[0037] Add 532ml of N,N-dimethylformamide, 40g of (R)-4-methyl-1,3-dioxolan-2-one, 47.2g of adenine and 0.85g of potassium hydroxide to a 2000ml three-necked bottle , turn on stirring, heat up to 135 ℃ ~ 145 ℃, keep the reaction for 22 hours, start TLC detection [developing solvent is dichloromethane (V / ml): methanol (V / ml) ​​= 9:1], confirm that the reaction is complete Then, cool down to 80°C~90°C and begin to evaporate 4 / 5 of the reaction solvent under reduced pressure. After the evaporation is completed, add 672 ml of isopropanol, heat up to 70°C~80°C and stir to dissolve; after dissolving, open the refrigeration facility to cool down. Stir and crystallize at 0℃~5℃ for 1 hour, filter with suction, filter off the solvent, and vacuum dry the filter cake at -0.08MPa and 40℃ for 8 hours to obtain 57.7g of white solid, which is (R)-9-(2- Hydroxypropyl) adenine, molar yield 85.5%, HPLC purity 98.3%.

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Abstract

The present invention belongs to the technical field of medicine, and relates to a tenofovir disoproxil fumarate synthesis method, wherein (R)-1,2-propanediol and carbonate are adopted as raw materials, and condensation, etherification, hydrolysis, esterification salification and other steps are performed to prepare the finished product. According to the present invention, the process improving and the reaction intermediate treatment are performed so as to easily achieve the reactions in the subsequent steps and the separation and purification, improve the yield and the corresponding purity of the target product, and obtain the tenofovir disoproxil fumarate meeting the medical standard.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for synthesizing tenofovir disoproxil fumarate, a pharmaceutical raw material used for the treatment of AIDS and hepatitis B. Background technique [0002] Tenofovir disoproxil fumarate is a novel oral broad-spectrum antiviral drug, an acyclic cluster nucleoside reverse transcriptase inhibitor, chemical name is 5-{[(1R)-2( 6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2,4,6,8-tetraoxo-5-phosphaazelate diisopropyl ester-5- Oxide fumarate, commonly known as tenofovir disoproxil fumarate, has the following structural formula: [0003] [0004] It was developed by Gilead Sciences in the United States, and its trade name is Viread. Tenofovir disoproxil fumarate is currently the first nucleotide analog approved by the FDA for the treatment of HIV-1 infection, and its importance has also been recognized by the World Health Organization and recommended as a first-line antivi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 赵志全裴洪凤史丙月陈波
Owner SHANDONG NEWTIME PHARMA
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