[1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof

A technology of methylphosphonic acid and dialkyl methylphosphonite, which is applied in [1-halo-]-methylphosphonic acid compounds and their preparation and application fields, and can solve the problem of difficult removal of monoester impurities, Poor solubility of adenine, low reaction yield and other problems, to achieve good product quality, reduce production costs, and high yield

Inactive Publication Date: 2014-12-24
SHANGHAI KEYI BIOLOGICAL MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] One is: adenine has poor solubility in DMF solvent, and the reaction yield with (R)-[1-chloro-(2-propoxy)]-methylphosphonic acid diethyl ester [9] is not high
[0019] The second is: using trimethylchlorosilane and sodium bromide instead of trimethylbromosilane to hydrolyze compound [4], there is also the problem that the hydrolysis is not complete and the monoester impurities are difficult to remove

Method used

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  • [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof
  • [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof
  • [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of [1-chloro-(2-propoxy)]-methylphosphonic acid

[0051] 1. 1-chloro-2-chloromethoxypropane

[0052] In a 1000mL reaction flask, add 378 grams (4mol) of 1-chloro-2-propanol and 144 grams (4.8mol) of paraformaldehyde, stir to form a suspension, slowly introduce dry HCl gas, and control the temperature not to exceed 40 °C until the solids are completely dissolved. Transfer the reaction solution into a separatory funnel, separate the lower organic phase, dry over anhydrous sodium sulfate, filter off the desiccant, and distill under reduced pressure to obtain 432.6 g of a colorless liquid with a yield of 75.6%.

[0053] 2. [1-Chloro-(2-propoxy)]-methylphosphonic acid diethyl ester

[0054] In a 1000mL reaction flask, add 286 grams (2mol) of 1-chloro-2-chloromethoxypropane, heat the oil bath to 100°C, drop in 365 grams (2.2mol) of triethyl phosphite, and control the rate of addition so that The temperature does not exceed 110°C. After the addition is complete...

Embodiment 2

[0058] Preparation of [1-chloro-(2-propoxy)]-methylphosphonic acid

[0059] In a 2000mL reaction flask, add 256.5 grams (1mol) of [1-chloro-(2-propoxy)]-methylphosphonite diethyl ester, 1000 grams (5mol) of 40% hydrobromic acid aqueous solution, stir and heat To reflux, react for 6 hours. Adjust the pH to 12-14 with 5M NaOH aqueous solution. Extract twice with 300 mL of dichloromethane and 300 mL of ethyl acetate. Then, the aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, and extracted three times with 300 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off and distilled to dryness under reduced pressure to obtain 157.9 g of white solid with a yield of 83.7%.

Embodiment 3

[0061] Preparation of [1-chloro-(2-propoxy)]-methylphosphonic acid

[0062] In a 2000mL reaction flask, add 256.5 grams (1mol) of diethyl [1-chloro-(2-propoxy)]-methylphosphonite, 1500mL of acetonitrile, 543 grams (5mol) of trimethylchlorosilane, bromine 515 g (5 mol) of sodium chloride was stirred and heated to reflux, and reacted for 6 hours. Concentrate to remove the acetonitrile solvent to dryness. Cool to room temperature, add 800 g of water, and adjust pH to 12-14 with 1M NaOH aqueous solution. Extract twice with 300 mL of dichloromethane and 300 mL of ethyl acetate. Then, the aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, and extracted three times with 300 mL of ethyl acetic acid. The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off and distilled to dryness under reduced pressure to obtain 149.3 g of white solid with a yield of 79.2%.

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Abstract

The invention relates to [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and an application thereof. The compounds are [1-halo-(2-propoxy)]-methylphosphoric acid, (R)-[1-halo-(2-propoxy)]-methylphosphoric acid or (S)-[1-halo-(2-propoxy)]-methylphosphoric acid, the structural formulae are respectively shown in the specification. The compounds provided by the invention are used for preparing tenofovir and can better solve the defects in the existing process. The self process has the advantages of high yield, good product quality and the like, the production cost of tenofovir can be greatly lowered, and the compounds are suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of tenofovir disoproxil fumarate, in particular to a [1-halo-(2-propoxy)]-methylphosphonic acid compound and its preparation and application. Background technique [0002] Tenofovir Disoproxil Fumarate (Tenofovir Disoproxil Fumarate, English abbreviation TDF, structural formula [1], chemical name: 5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1 -Methylethoxy] methyl}-2,4,6,8-tetraoxo-5-phosphazelaic acid diisopropyl-5-oxide fumarate) was produced by Gilead Sciences, USA Research and development, first launched in the United States in 2001, for the treatment of HIV (AIDS) infection. In 2008, the FDA approved it for the treatment of chronic HBV (hepatitis B) infection in adults. [0003] [0004] Tenofovir, English abbreviation PMPA, structural formula [5] is as follows: [0005] [0006] It is the prodrug of tenofovir disoproxil fumarate. After oral administration, the drug 1 is hydrolyzed to 5 under the action of estera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38C07F9/6561
Inventor 李舸李海林王世运张建现陈林张爱强
Owner SHANGHAI KEYI BIOLOGICAL MEDICINE CO LTD
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