New process for synthesizing tenofovir disoproxil fumarate

A technology of tenofovir disoproxil and a new process, which is applied in the field of synthetic process of pharmaceutical compounds, can solve problems such as high price, dangerous use, product racemization, etc., and achieve safe production process, mild reaction conditions, and avoid product racemization Effect

Active Publication Date: 2013-09-18
APELOA PHARM CO LTD +1
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Strong bases such as sodium hydroxide and potassium hydroxide are used in this process, and a large amount of use will easily cause the product to racemize, resulting in the optical purity of the product not meeting the standard
[0012] 4. Application number 201010611703.X, title of invention: a method for preparing tenofovir, discloses a method for preparing tenofovir disoproxil, including: A, using adenine and (R)-propylene carbonate as raw materials , carry out condensation reaction, generate (R)-9-(2-hydroxypropyl) adenine; B, carry out condensation reaction with p-toluenesulfonyloxyphosphonic acid diethyl ester again under the catalysis of potassium alkoxide, make ( R)-9-[2-(diethylphosphonomethoxy) propyl] adenine; C, step B obtained and p-toluenesulfonic acid chloride reacted to protect the amino group on the 4-position to prepare (R)-4- (p-toluenesulfonyl)-9-[2-(diethylphosphonomethoxy)propyl]adenine; D, the obtained step C is hydrolyzed under strong acid conditions to obtain (R)-4-(p-toluenesulfonyl )-9-[2-(dihydroxyphosphonomethoxy) propyl] adenine; E, step D gain and mercaptobenzene react in weakly alkaline conditions to remove the p-toluenesulfonic acid group to obtain tenofovir ; In this process, strong bases such as sodium hydroxide and potassium hydroxide are used many times, and the product is easily racemized, resulting in the optical purity of the product not reaching the standard
[0013] In addition, Chinese patent CN200510099916.8 discloses "composition containing nucleotide analogs and its synthesis method", and CN200610056926.8 discloses "a group of tenofovir monodivoxil with activity of inhibiting HIV-1 / HBV virus replication Compound", and CN200710014625.3 disclosed "tenofovir disoproxil fumarate new crystal form and pharmaceutical preparation thereof", although some new improved methods have been proposed for the synthesis process of tenofovir disoproxil fumarate, but Basically, expensive and dangerous reagents such as n-butyllithium and sodium hydride are still used, or some strong acids and strong bases are used, which will easily cause the product to racemize, resulting in the optical purity of the product not meeting the pharmaceutical standard

Method used

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  • New process for synthesizing tenofovir disoproxil fumarate
  • New process for synthesizing tenofovir disoproxil fumarate
  • New process for synthesizing tenofovir disoproxil fumarate

Examples

Experimental program
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Effect test

Embodiment 1

[0066] Example 1: Preparation of (R)-2-O-(diethoxy-phosphono-methyl)-1-amino-2-propanol (II)

[0067] Add 30g (0.4mol) of (R)-(-)-1-amino-2-propanol and 300ml of DMF into a 500ml reaction flask, stir mechanically, add 136.4g (0.8mol) of magnesium tert-butoxide under stirring, and heat up to 70~80°C, slowly add 193.2g (0.6mol) of diethyl p-toluenesulfonyloxymethylphosphonate dropwise, after the dropwise addition, keep warm at 70~80°C for 6 hours, stop the reaction, and the reaction solution drops to room temperature , 100ml of acetic acid was added dropwise to neutralize the reaction solution, the reaction solution was distilled under high vacuum to remove the solvent DMF, the residual solution was added with 400ml of ethyl acetate and 200ml of water, stirred for 30 minutes, left to stand for layers, the water layer was extracted with 200ml of ethyl acetate, combined The ethyl acetate layer was washed successively with 300 ml of ice water and 300 ml of saturated brine, dried ov...

Embodiment 2

[0068] Example 2: Preparation of (R)-2-O-(diethoxy-phosphono-methyl)-1-amino-2-propanol (II)

[0069] Add 30g (0.4mol) of (R)-(-)-1-amino-2-propanol and 300ml of DMF into a 500ml reaction flask, stir mechanically, add 67.2g (0.6mol) of potassium tert-butoxide under stirring, and heat up to 70~80°C, slowly add 193.2g (0.6mol) of diethyl p-toluenesulfonyloxymethylphosphonate dropwise, after the dropwise addition, keep warm at 70~80°C for 6 hours, stop the reaction, and the reaction solution drops to room temperature , 40ml of acetic acid was added dropwise to neutralize the reaction solution, the reaction solution was distilled under high vacuum to remove the solvent DMF, the residue was added with 400ml of ethyl acetate and 200ml of water, stirred for 30 minutes, left to stand for layers, the water layer was extracted with 200ml of ethyl acetate, combined The ethyl acetate layer was washed successively with 300 ml of ice water and 300 ml of saturated brine, dried over anhydrous...

Embodiment 3

[0070] Example 3: Preparation of (R)-2-O-(dihydroxy-phosphono-methyl)-1-amino-2-propanol (Ⅲ)

[0071] Add 56.7g (0.252mol) of the compound of formula (II), 560ml DMF, and 91g (0.882mol) of sodium bromide into a 1L reaction flask, stir, and slowly add 137g (1.26mol) of trimethylchlorosilane dropwise under ice bath, and dropwise add After completion, the temperature was raised to 60°C to react for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was distilled off under high vacuum to remove the solvent DMF. Added 300ml of water and 300ml of ethyl acetate to the residue, stirred for 0.5 hours, and allowed to stand for stratification. Wash the water layer once more with 300ml of ethyl acetate, lower the temperature of the obtained water layer to 3~6°C, adjust the pH to 3~4 with 40% sodium hydroxide, and crystallize, keep warm at 5~8°C, stir and crystallize for 2 hours, filter , the filter cake was vacuum-d...

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Abstract

The invention discloses a new process for synthesizing tenofovir disoproxil fumarate. The new process comprises the following steps of: reacting (R)-(-)-1-amino-2-propanol serving as a raw material with p-benzenesulfonyloxymethyl phosphoric acid diethylester, and then performing hydrolysis and condensation to obtain (R)-2-O-[bis(isopropoxycarbonyloxomethyl)phosphon-methyl]-1-amino-2-propanol (IV); and condensing the compound shown in the formula (IV) with 5-amino-4,6-dichloropyrimidine, and then performing cyclization and aminolysis, thereby obtaining the tenofovir disoproxil fumarate. The new process for synthesizing tenofovir disoproxil fumarate provided by the invention is low in production cost, safe in process, good in product quality and suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis process of a pharmaceutical compound, in particular to a new synthesis process of tenofovir disoproxil, belonging to the technical field of compound synthesis methods. 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. [0003] Tenofovir bisphosphonate, the active ingredient of tenofovir, inhibits viral polymerase by directly competitively bind...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07F9/6512
Inventor 杨勤邹海华刘剑胡键
Owner APELOA PHARM CO LTD
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