Preparation method for optically pure aminoalcohol hydrochloride

Abstract

The invention relates to a preparation method for optically pure aminoalcohol hydrochloride. The optically pure aminoalcohol hydrochloride is any one selected from optically pure aminoalcohol hydrochloride 1 and optically pure aminoalcohol hydrochloride 2 and is prepared by subjecting a compound 4 to an esterification ring-opening reaction, an amino protection reaction, an ester reduction reaction and a deprotection salt forming reaction. The optically pure aminoalcohol hydrochloride 1 or optically pure aminoalcohol hydrochloride 2 prepared in the invention can be directly used for synthesis of abacavir and carbovir. The preparation method provided by the invention has the advantages of high product optical purity, stable product quality, high product yield, a small amount of environmental pollution, low production cost, easy industrialization, etc.

Description

technical field

[0001] The invention relates to the technical field of compound synthesis, in particular to a preparation method of optically pure amino alcohol hydrochloride. Background technique

[0002] Optically pure amino alcohols (structure shown in formula 3) are key intermediates for the preparation of anti-AIDS drugs such as abacavir (Abacavir, EP434450) and carbovir (Carbovir, JOC1995, 60, 4602-16.).

[0003]

[0004] There are as many as a dozen asymmetric synthetic routes for optically pure amino alcohols, but all of them have defects such as lengthy preparation steps, harsh reaction conditions, difficult availability of raw materials, and high manufacturing costs.

[0005] Racemic amino alcohol (±)-3 can be prepared from racemic compound (±)-4 (also known as compound 4) through protection (see WO2005075426A), reduction (see WO2006040625A), deprotection (see EP0878548A) reaction steps (see figure 1 ), and chiral resolution of racemic aminoalcohol (±)-3 to obt...

Examples

Embodiment 1

[0059] Example 1 Preparation of compound 5 and compound 6

[0060] The preparation method of compound 5 and compound 6 of this embodiment comprises the following steps:

[0061] 1) Dissolve 100g (±)-2-azabicyclo[2.2.1]hept-5-en-3-one ((±)-4) in 80ml of methanol, add 110g dropwise at 0°C with stirring After thionyl chloride, continue to stir the reaction mixture at room temperature for 1 h, then add 82.5 g of L-tartaric acid and 50 g of water, and adjust the pH of the reaction solution to 1.8-2 with 60.3 g of triethylamine at 50°C, and then It was cooled to room temperature, continued to stir for 2 hours, vacuum filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 112 g of optically pure compound 5, whose optical purity was ≥ 99% ee;

[0062] 2) Add 123.8g of D-tartaric acid to the filtrate, adjust the pH of the filtrate to 1.5 with 83.5g of triethylamine at 50°C, cool it to room temperature, and continue to stir for 2h; filter under re...

Embodiment 2

[0063] Example 2 Preparation of compound 5 and compound 6

[0064] The preparation method of compound 5 and compound 6 of this embodiment comprises the following steps:

[0065] 1) Dissolve 100g (±)-2-azabicyclo[2.2.1]hept-5-en-3-one ((±)-4) in 80ml methanol, add 110g dropwise at 0°C under stirring After thionyl chloride, continue to stir the reaction mixture at room temperature for 1 h, then add 82.5 g of D-tartaric acid and 50 g of water, and adjust the pH of the reaction solution to 1.8-2 with 60.3 g of triethylamine at 50°C, and then It was cooled to room temperature, continued to stir for 2 hours, vacuum filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 112.1 g of optically pure compound 6, with an optical purity of ≥99% ee;

[0066] 2) Add 123.8g of L-tartaric acid to the filtrate, adjust the pH of the filtrate to 1.5 with 83.5g of triethylamine at 50°C, cool it to room temperature, and continue to stir for 2h; After washing ...

Embodiment 3

[0067] Example 3 Preparation of Optically Pure Amino Alcohol Hydrochloride (1)

[0068] A preparation method of optically pure amino alcohol hydrochloride (1), comprising the steps of:

[0069] 1) Disperse 100g of optically pure compound 5 in 500ml of ethyl acetate, add 75g of triethylamine and 75g of di-tert-butyl dicarbonate (Boc 2 After (0), continue to stir at room temperature for 5 h, and filter off the insoluble matter; the organic layer is washed with water, dried, and spin-dried under reduced pressure to obtain compound 7;

[0070] 2) Dissolve the compound 7 prepared in step 1) in 250ml of tetrahydrofuran, add 20g of sodium borohydride, stir under reflux, add 30ml of methanol dropwise, continue to stir and reflux for 5h, cool to room temperature, quench the reaction with acetic acid, and depressurize The solvent and volatile matter were removed by rotary evaporation, ethyl acetate and water were added, stirred for 30 minutes, and the organic phase was taken; the ...

technical field

[0001] The invention relates to the technical field of compound synthesis, in particular to a preparation method of optically pure amino alcohol hydrochloride. Background technique

[0002] Optically pure amino alcohols (structure shown in formula 3) are key intermediates for the preparation of anti-AIDS drugs such as abacavir (Abacavir, EP434450) and carbovir (Carbovir, JOC1995, 60, 4602-16.).

[0003]

[0004] There are as many as a dozen asymmetric synthetic routes for optically pure amino alcohols, but all of them have defects such as lengthy preparation steps, harsh reaction conditions, difficult availability of raw materials, and high manufacturing costs.

[0005] Racemic amino alcohol (±)-3 can be prepared from racemic compound (±)-4 (also known as compound 4) through protection (see WO2005075426A), reduction (see WO2006040625A), deprotection (see EP0878548A) reaction steps (see figure 1 ), and chiral resolution of racemic aminoalcohol (±)-3 to obt...

Examples

Embodiment 1

[0059] Example 1 Preparation of compound 5 and compound 6

[0060] The preparation method of compound 5 and compound 6 of this embodiment comprises the following steps:

[0061] 1) Dissolve 100g (±)-2-azabicyclo[2.2.1]hept-5-en-3-one ((±)-4) in 80ml of methanol, add 110g dropwise at 0°C with stirring After thionyl chloride, continue to stir the reaction mixture at room temperature for 1 h, then add 82.5 g of L-tartaric acid and 50 g of water, and adjust the pH of the reaction solution to 1.8-2 with 60.3 g of triethylamine at 50°C, and then It was cooled to room temperature, continued to stir for 2 hours, vacuum filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 112 g of optically pure compound 5, whose optical purity was ≥ 99% ee;

[0062] 2) Add 123.8g of D-tartaric acid to the filtrate, adjust the pH of the filtrate to 1.5 with 83.5g of triethylamine at 50°C, cool it to room temperature, and continue to stir for 2h; filter under re...

Embodiment 2

[0063] Example 2 Preparation of compound 5 and compound 6

[0064] The preparation method of compound 5 and compound 6 of this embodiment comprises the following steps:

[0065] 1) Dissolve 100g (±)-2-azabicyclo[2.2.1]hept-5-en-3-one ((±)-4) in 80ml methanol, add 110g dropwise at 0°C under stirring After thionyl chloride, continue to stir the reaction mixture at room temperature for 1 h, then add 82.5 g of D-tartaric acid and 50 g of water, and adjust the pH of the reaction solution to 1.8-2 with 60.3 g of triethylamine at 50°C, and then It was cooled to room temperature, continued to stir for 2 hours, vacuum filtered, the filter cake was washed with a small amount of methanol, and dried to obtain 112.1 g of optically pure compound 6, with an optical purity of ≥99% ee;

[0066] 2) Add 123.8g of L-tartaric acid to the filtrate, adjust the pH of the filtrate to 1.5 with 83.5g of triethylamine at 50°C, cool it to room temperature, and continue to stir for 2h; After washing ...

Embodiment 3

[0067] Example 3 Preparation of Optically Pure Amino Alcohol Hydrochloride (1)

[0068] A preparation method of optically pure amino alcohol hydrochloride (1), comprising the steps of:

[0069] 1) Disperse 100g of optically pure compound 5 in 500ml of ethyl acetate, add 75g of triethylamine and 75g of di-tert-butyl dicarbonate (Boc 2 After (0), continue to stir at room temperature for 5 h, and filter off the insoluble matter; the organic layer is washed with water, dried, and spin-dried under reduced pressure to obtain compound 7;

[0070] 2) Dissolve the compound 7 prepared in step 1) in 250ml of tetrahydrofuran, add 20g of sodium borohydride, stir under reflux, add 30ml of methanol dropwise, continue to stir and reflux for 5h, cool to room temperature, quench the reaction with acetic acid, and depressurize The solvent and volatile matter were removed by rotary evaporation, ethyl acetate and water were added, stirred for 30 minutes, and the organic phase was taken; the ...

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