Preparation method of (S)-N-BOC-3-hydroxypiperidine

Abstract

The invention provides a preparation method of (S)-N-BOC-3-hydroxypiperidine. The preparation method comprises the following steps: carrying out a reaction on (S)-epichlorohydrin with a 2-chloroethylmagnesium bromide Grignard reagent to obtain (S)-1,5-dichloro-2-pentanol, carrying out an intramolecular cyclization reaction in the presence of an alkaline substance to generate (S)-5-chloro-1,2-epoxypentane, carrying out a reaction on the (S)-5-chloro-1,2-epoxypentane with an ammonia solution to generate (S)-1-amino-5-chloro-2-pentanol, then carrying out an intramolecular cyclization reaction onthe (S)-1-amino-5-chloro-2-pentanol to obtain (S)-3-hydroxypiperidine, and finally carrying out a reaction with BOC anhydride to obtain the product (S)-N-BOC-3-hydroxypiperidine. The preparation method disclosed by the invention has the advantages of short synthesis route, few side reactions and high yield; the product has good quality and is convenient for purification. The raw materials are easily available and has low price; the reaction conditions are mild; and safety is high. The preparation method is environmentally friendly, is simple and practice, and is suitable for industrial batchproduction.

Description

technical field

[0001] The invention belongs to the field of compound synthesis and relates to a preparation method of (S)-N-BOC-3-hydroxypiperidine. Background technique

[0002] (S)-N-Boc-3-hydroxypiperidine is an important pharmaceutical intermediate, widely used in the synthesis of analgesic, antipsychotic, antitumor drugs, etc. Synthesis of flatness, antimalarial drugs tembranine and anomaly. At present, optically active (S)-N-Boc-3-hydroxypiperidines can be obtained by chemical methods or enzymatic biological methods. However, most of the products synthesized by chemical methods are para-3-hydroxypiperidines or Therefore, N-Boc-3-hydroxypiperidine needs to be split in the synthesis process, and the limitation of the split method is that the yield is low, and the separation and extraction are also complicated, which is not conducive to industrial production. However, the biological method takes enzymatic catalysis as the main method. Through the asymmetric reduction o...

Examples

Embodiment 1

[0061] In this embodiment, a preparation method of (S)-N-BOC-3-hydroxypiperidine is provided, and the preparation method comprises the following steps:

[0062] (1) Preparation of 2-chloroethylmagnesium bromide Grignard reagent. A mixture of 1-bromo-2-ethane (177.5 g, 1.25 mol) and 500 mL of tetrahydrofuran was used for later use.

[0063] Under nitrogen protection, 29.16 g (1.2 mol) of magnesium bars, 300 mL of tetrahydrofuran, and a grain of iodine were sequentially added, and 20 mL of the 1-bromo-2-chloroethane tetrahydrofuran solution prepared above was added dropwise. Heat slowly to reflux. When the reaction night faded, the remaining 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. After dripping, the reaction was continued for 2 hours under reflux. After cooling to room temperature, the obtained 2-chloroethylmagnesium bromide Grignard reagent was protected by nitrogen for use.

[0064] (S)-epichlorohydrin (92.5g, 1mol) and 500mL of anhydrous tetra...

Embodiment 2

[0070] (1) Prepare 2-chloroethylmagnesium bromide Grignard reagent according to Example 1 for subsequent use.

[0071] (S)-epichlorohydrin (92.5g, 1mol) and 500mL of anhydrous tetrahydrofuran were stirred and mixed, cooled to -65°C, and the 2-chloroethylmagnesium bromide Grignard reagent prepared above (167.5g, 1mol) was added dropwise. . The reaction is exothermic. The dropping rate was controlled so that the reaction temperature was not higher than -55°C. After dripping, the reaction was incubated for 1.5 hours. Turn off the freezer and let it naturally warm to room temperature. Then 400 grams of saturated aqueous ammonium chloride solution was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was extracted three times with 500 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and distilled in high vacuum to obtain 120.18 ...

Embodiment 3

[0076] (1) Prepare 2-chloroethylmagnesium bromide Grignard reagent according to Example 1 for subsequent use.

[0077] (S)-epichlorohydrin (92.5 g, 1 mol) and 500 mL of anhydrous tetrahydrofuran were stirred and mixed, cooled to -30°C, and the 2-chloroethylmagnesium bromide Grignard reagent prepared above (335 g, 2 mol) was added dropwise. The reaction is exothermic. The dropping rate was controlled so that the reaction temperature was not higher than -20°C. After dripping, the reaction was incubated for 2.5 hours. Turn off the freezer and let it naturally warm to room temperature. Then 400 grams of saturated aqueous ammonium chloride solution was added dropwise. The mixture was stirred at room temperature for 2 hours, and the reaction solution was 500 mL×3 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and distilled in high vacuum to obtain 99.23 g of (S)-1,5-dichloro-...

technical field

[0001] The invention belongs to the field of compound synthesis and relates to a preparation method of (S)-N-BOC-3-hydroxypiperidine. Background technique

[0002] (S)-N-Boc-3-hydroxypiperidine is an important pharmaceutical intermediate, widely used in the synthesis of analgesic, antipsychotic, antitumor drugs, etc. Synthesis of flatness, antimalarial drugs tembranine and anomaly. At present, optically active (S)-N-Boc-3-hydroxypiperidines can be obtained by chemical methods or enzymatic biological methods. However, most of the products synthesized by chemical methods are para-3-hydroxypiperidines or Therefore, N-Boc-3-hydroxypiperidine needs to be split in the synthesis process, and the limitation of the split method is that the yield is low, and the separation and extraction are also complicated, which is not conducive to industrial production. However, the biological method takes enzymatic catalysis as the main method. Through the asymmetric reduction o...

Examples

Embodiment 1

[0061] In this embodiment, a preparation method of (S)-N-BOC-3-hydroxypiperidine is provided, and the preparation method comprises the following steps:

[0062] (1) Preparation of 2-chloroethylmagnesium bromide Grignard reagent. A mixture of 1-bromo-2-ethane (177.5 g, 1.25 mol) and 500 mL of tetrahydrofuran was used for later use.

[0063] Under nitrogen protection, 29.16 g (1.2 mol) of magnesium bars, 300 mL of tetrahydrofuran, and a grain of iodine were sequentially added, and 20 mL of the 1-bromo-2-chloroethane tetrahydrofuran solution prepared above was added dropwise. Heat slowly to reflux. When the reaction night faded, the remaining 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. After dripping, the reaction was continued for 2 hours under reflux. After cooling to room temperature, the obtained 2-chloroethylmagnesium bromide Grignard reagent was protected by nitrogen for use.

[0064] (S)-epichlorohydrin (92.5g, 1mol) and 500mL of anhydrous tetra...

Embodiment 2

[0070] (1) Prepare 2-chloroethylmagnesium bromide Grignard reagent according to Example 1 for subsequent use.

[0071] (S)-epichlorohydrin (92.5g, 1mol) and 500mL of anhydrous tetrahydrofuran were stirred and mixed, cooled to -65°C, and the 2-chloroethylmagnesium bromide Grignard reagent prepared above (167.5g, 1mol) was added dropwise. . The reaction is exothermic. The dropping rate was controlled so that the reaction temperature was not higher than -55°C. After dripping, the reaction was incubated for 1.5 hours. Turn off the freezer and let it naturally warm to room temperature. Then 400 grams of saturated aqueous ammonium chloride solution was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was extracted three times with 500 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and distilled in high vacuum to obtain 120.18 ...

Embodiment 3

[0076] (1) Prepare 2-chloroethylmagnesium bromide Grignard reagent according to Example 1 for subsequent use.

[0077] (S)-epichlorohydrin (92.5 g, 1 mol) and 500 mL of anhydrous tetrahydrofuran were stirred and mixed, cooled to -30°C, and the 2-chloroethylmagnesium bromide Grignard reagent prepared above (335 g, 2 mol) was added dropwise. The reaction is exothermic. The dropping rate was controlled so that the reaction temperature was not higher than -20°C. After dripping, the reaction was incubated for 2.5 hours. Turn off the freezer and let it naturally warm to room temperature. Then 400 grams of saturated aqueous ammonium chloride solution was added dropwise. The mixture was stirred at room temperature for 2 hours, and the reaction solution was 500 mL×3 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to remove the solvent, and distilled in high vacuum to obtain 99.23 g of (S)-1,5-dichloro-...

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