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Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning

A technology of tert-butoxycarbonyl and hydroxypiperidine, which is applied in the field of compound synthesis, can solve the problems of difficult industrialization, chiral impurities in the resolution process, and difficult purification, etc., and achieve the effect of clean reaction

Active Publication Date: 2014-06-18
ABA CHEM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the chemical resolution method, due to the water solubility of 3-hydroxypiperidine, it is not easy to purify and obtain, and it is difficult to industrialize
At the same time, chiral impurities are likely to exist during the resolution process

Method used

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  • Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning
  • Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning
  • Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate

[0040] (1) Synthesis of (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate (1)

[0041] In a 1000ml three-necked flask, add N-benzyl-3-hydroxypiperidine (95.6g, 0.5mol), add 478ml of isopropanol dropwise in 116ml of isopropanol solution of L-CSA (58g, 0.25mol), and stir at room temperature for 1 hour , a solid precipitated out, kept at 0°C for 2 hours, filtered, washed with 30 ml of cold isopropanol, and dried to obtain 75 g of (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate. (ee: 95%) (theoretical: 105.9g). (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate with 95% ee value is recrystallized with 3 times the amount of isopropanol to obtain (S)-1-benzyl-3-hydroxypiperidine Camphor Sulfonate (99% ee).

[0042] (2) Synthesis of (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate (2)

[0043] In a 1000ml three-necked flask, add N-benzyl-3-hydroxypiperidine (95.6g, 0.5mol), add 478ml of et...

Embodiment 2

[0052] Embodiment 2: the synthesis of (R)-1-benzyl-3-hydroxypiperidine camphorsulfonate

[0053] In a 1000ml three-necked flask, add N-benzyl-3-hydroxypiperidine (95.6g, 0.5mol), add D-CSA (58g, 0.25mol) in 116ml of isopropanol solution in 478ml of isopropanol, and stir at room temperature for 1 hour , a solid precipitated out, kept at 0°C for 2 hours, filtered, washed with 30 ml of cold isopropanol, and dried to obtain 75 g of (R)-1-benzyl-3-hydroxypiperidine camphorsulfonate. (ee: 95%) (theoretical: 105.9g). (R)-1-benzyl-3-hydroxypiperidine camphorsulfonate with 95% ee value is recrystallized with 3 times the amount of isopropanol to obtain (R)-1-benzyl-3-hydroxypiperidine Camphor Sulfonate (99% ee).

[0054] Step 2) Synthesis of (S) or (R)-1-benzyl-3-hydroxypiperidine

Embodiment 3

[0055] Embodiment 3: the synthesis of (S)-1-benzyl-3-hydroxypiperidine

[0056] (1) Synthesis of (S)-1-benzyl-3-hydroxypiperidine (1)

[0057] In a 1000ml three-necked bottle, add (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate (99%ee, 84.7 g, 0.2mol), dichloromethane 423ml, 1N aqueous sodium hydroxide solution (210ml) was added dropwise, stirred at room temperature for 1 hour, the water phase was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain (S)-1-benzyl -3-hydroxypiperidine 38g. (ee: 99%; LC-MS: m / e=191.3) (theoretical: 38.25 g).

[0058] (2) Synthesis of (S)-1-benzyl-3-hydroxypiperidine (2)

[0059] In a 1000ml three-necked flask, add (S)-1-benzyl-3-hydroxypiperidine camphorsulfonate (99%ee, 84.7 g, 0.2mol), ethyl acetate 423ml, 1N aqueous potassium carbonate solution (150ml) was added dropwise, stirred at room temperature for 1 hour, the water phase was separated, the organic phase was dried over anhydrous sodium sul...

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Abstract

The invention relates to preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and a method for chirality turning. The preparation mainly comprises the following steps: resolving N-benzyl-3-hydroxy piperidine as a raw material to obtain a (S) or (R)-1-benzyl-3-hydroxy piperidine camphorsulfonic acid salt, performing alkali freedom to obtain (S) or (R)-1-benzyl-3-hydroxy piperidine, performing palladium carbon hydrogenation debenzylation / t-butyloxycarboryl protection to obtain (S) or (R)-1-t-butyloxycarboryl-3-hydroxy piperidine, acylating substituting sulfonyl chloride of (R) or (S)-1-substituting-3-hydroxy piperidine as a raw material to obtain (R) or (S)-1-substituting-3-hydroxy piperidine sulfonate, substituting by using substituting carboxylate to obtain (S) or (R)-1-substituting-3-hydroxy piperidine carboxylic ester, and performing alkaline hydrolysis to obtain (S) or (R)-1-substituting-3-hydroxy piperidine. The synthesis route is gentle in reaction condition, and is applicable to industrial large-scale production.

Description

technical field [0001] The invention relates to the synthesis of a compound, in particular to a preparation of chiral-1-tert-butoxycarbonyl-3-hydroxypiperidine and a chiral inversion method. Background technique [0002] (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine is an important pharmaceutical intermediate. Its synthesis method reported in the current literature is mainly as follows: [0003] Method 1 (asymmetric synthesis): [0004] [0005] Main literature: Tetrahedron, 63, 331-336; 2007. [0006] Method 2 (enzymatic asymmetric reduction): [0007] [0008] Main literature: Organic Letters, 11(6), 1245-1248; 2009. [0009] Method 3 (chemical resolution method): [0010] [0011] Main documents: WO2004064730; WO2004072086. [0012] In the chemical resolution method, due to the water solubility of 3-hydroxypiperidine, it is not easy to purify and obtain, and it is difficult to industrialize. At the same time, chiral impurities are likely to exist in the re...

Claims

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Application Information

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IPC IPC(8): C07D211/42C07B53/00
CPCC07B53/00C07B2200/07C07D211/42
Inventor 林志刚徐军刘艳琴阙利民江岳恒蔡彤
Owner ABA CHEM CORP
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