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Preparation method of (2R,3S)-epoxidation amino-benzene butane

A technology of epoxy group and phenylbutane, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of large solvent loss and difficult drying of products, and achieve the effects of easy operation, low cost and reduced solvent loss

Active Publication Date: 2014-08-06
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The present invention aims at the above existing problems in the prior art, and provides a preparation method of (2R,3S)-epoxidized aminobenzenebutane, which solves the problem of using a large amount of solvents that are easily soluble in water as reaction solvents. Water crystallization leads to large solvent loss and technical problems that the product is not easy to dry

Method used

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  • Preparation method of (2R,3S)-epoxidation amino-benzene butane

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Embodiment 1

[0027] Add (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane 125.0g (417.36mmol) into the reactor, and then add the non-polar solvent petroleum ether 500mL, then add a mixed solvent of 125mL acetone and 125mL methanol as a polar solvent, slowly raise the temperature to 20°C, stir until it dissolves, then, control the temperature within 15°C to 25°C, and dropwise add a concentration of 10 % sodium hydroxide aqueous solution 200g (dissolve 20g sodium hydroxide in water to prepare 200g sodium hydroxide aqueous solution with a mass concentration of 10%). After the end, stand for stratification, remove the water phase, wash the organic phase with 300mL deionized water each time, wash 3 times, then slowly cool the organic phase to -5°C for stirring and crystallization, after the crystallization is complete, filter , the filter cake was washed with 50mL of petroleum ether, the obtained wet product was placed in an oven, and the temperature was controlled to dry at ...

Embodiment 2

[0029] Add (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane 125.0g (417.36mmol) into the reactor, and then put it into the non-polar solvent ring Add 500mL of hexane, then add a mixed solvent of 125mL acetone and 125mL methanol as a polar solvent, slowly raise the temperature to 30°C, stir to dissolve, then, control the temperature within 25°C to 30°C, and add dropwise within 1 hour 200g of 25% sodium carbonate aqueous solution (dissolve 50g of sodium carbonate in water to prepare 200g of sodium carbonate aqueous solution with a mass concentration of 25%). , standing for stratification, removing the water phase, washing the organic phase with 300mL deionized water 3 times each time, then slowly cooling the organic phase to -5°C for stirring and crystallization, after the crystallization is complete, filter, and filter cake Wash with 50mL cyclohexane, put the obtained wet product into an oven, and dry it at 40°C under controlled temperature to obtain the fin...

Embodiment 3

[0031] Add (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane 125.0g (417.36mmol) into the reactor, and then add the non-polar solvent n-hexane 500mL and a polar solvent, the polar solvent is a mixed solvent of acetone 125mL and ethanol 125m, slowly warming up to 20°C, stirring until dissolved, then controlling the temperature within 15°C to 25°C, and within 1 hour Add 250g of potassium hydroxide aqueous solution with a mass concentration of 10% (dissolve 25g of potassium hydroxide in water to prepare 250g of potassium hydroxide aqueous solution with a mass concentration of 10%). The cyclization reaction was 8 hours. After the reaction was completed, the layers were left to stand, and the water phase was removed. The organic phase was washed with 300 mL of deionized water for 3 times, and then the organic phase was slowly cooled to -5°C for crystallization. After completion, filter, wash the filter cake with 50mL of n-hexane, put the obtained solid wet produc...

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Abstract

The invention relates to a preparation method of a (2R,3S)-epoxidation amino-benzene butane, and belongs to the technical field of drug intermediate synthesis. To solve the technical problems in the conventional method that a water-soluble solvent is completely used as a reaction solvent and a great deal of water is used for devitrification, the invention provides the preparation method of the (2R,3S)-epoxidation amino-benzene butane, and the method comprises the following steps: in a nonpolar solvent, carrying out cyclization reaction on the formula (2R,3S)-3-t-butyloxycarboryl amino-1-halogen-2-hydroxy-4-phenyl butane under the action of an alkali water solution; standing, layering, removing aqueous phase and devitrifying so as to obtain the (2R,3S)-epoxidation amino-benzene butane. The method provided by the invention is short in synthetic route, simple in process, small in solvent consumption and low in production cost; the (2R,3S)-epoxidation amino-benzene butane can be dried more easily through crystallization with the solvent, the mole rate of a final product is more than 96%, and the purity is more than 99.5%.

Description

technical field [0001] The invention relates to an intermediate used for preparing atazanavir, more specifically, relates to a preparation method of (2R,3S)-epoxidized aminobenzenebutane, which belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Atazanavir (Atazanavir) is a heterocyclic azahexane derivative with antiviral activity developed by Swiss Novartis in 1996-1997. In 1998, Bristol-Myers Squibb developed a new azapeptide protease inhibitor Aza Navir, which was launched in the U.S. in June 2003, is mainly used in combination with other antiretroviral drugs to treat HIV infection. Because it is only taken once a day, it is absorbed more quickly than other anti-HIV infection drugs, and blood lipids The abnormality is mild, and it can reduce the cardiovascular risk of HIV patients. Compared with other protease inhibitors, it does not interfere with the normal diet during the medication period. It is currently the preferre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D303/36C07D301/26
Inventor 王玉钢徐斌谭良志
Owner 江苏八巨药业有限公司
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