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Synthetic method for (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine

A technology of hydroxymethylpiperidine and tert-butoxycarbonyl, which is applied in the field of synthesis of -N-tert-butoxycarbonyl-3-hydroxymethylpiperidine, and can solve problems such as lack of scalability, complicated methods, and harsh conditions. problems, to achieve the effects of improving ease of operation and convenience, ensuring yield and purity, and mild reaction conditions

Inactive Publication Date: 2019-07-09
CHANGZHOU VOCATIONAL INST OF ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many other methods for synthesizing (R)-N-Boc-3-piperidinemethanol are too complex or harsh and not scalable

Method used

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  • Synthetic method for (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine
  • Synthetic method for (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine
  • Synthetic method for (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine

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Embodiment 1

[0023] Prepare (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine by using the process of the present invention, comprising the steps of:

[0024] Step S1: To synthesize ethyl 3-piperidinecarboxylate (compound II), add 50 mL of absolute ethanol and 12.9 g (0.1 mol) of 3-piperidinecarboxylic acid (compound I) into the reaction flask, and control the temperature at 0°C; In the state, add thionyl chloride 13.1g (0.105mol) dropwise to the reaction flask, heat to reflux temperature of 70°C, reflux reaction until the reaction material is clear, and the reaction ends; the excess ethanol is evaporated under reduced pressure, cooled to room temperature; Adjust the pH to 12 with 5% sodium hydroxide aqueous solution, then add 25mL dichloromethane for extraction, and then extract the aqueous layer twice with dichloromethane, combine the organic phases, and pass the organic phases through saturated sodium bicarbonate, purified water, and saturated brine successively. Wash, dry with anhydr...

Embodiment 2

[0030] Prepare (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine by the process of the present invention, comprising the steps of:

[0031] Step S1: To synthesize ethyl 3-piperidinecarboxylate (compound II), add 50 mL of absolute ethanol and 12.9 g (0.1 mol) of 3-piperidinecarboxylic acid (compound I) into the reaction flask, and control the temperature at 0°C; 15 g (0.12 mol) of thionyl chloride was added dropwise to the reaction flask, heated to a reflux temperature of 70° C., refluxed until the reaction material was clear, and the reaction ended; excess ethanol was evaporated under reduced pressure and cooled to room temperature; % Potassium hydroxide aqueous solution to adjust the pH to 12, then add 25mL dichloromethane for extraction, and then extract the aqueous layer twice with dichloromethane, combine the organic phases, and wash the organic phases successively with saturated sodium bicarbonate, purified water, and saturated brine , dried with anhydrous sodium sulfat...

Embodiment 3

[0037] Prepare (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine by the process of the present invention, comprising the steps of:

[0038] Step S1: To synthesize ethyl 3-piperidinecarboxylate (compound II), add 50 mL of absolute ethanol and 12.9 g (0.1 mol) of 3-piperidinecarboxylic acid (compound I) into the reaction flask, and control the temperature at 0°C; 17.81g (0.13mol) of phosphorus trichloride was added dropwise to the reaction flask under the condition of Adjust the pH to 13 with 5% sodium hydroxide aqueous solution, then add 25mL dichloromethane for extraction, and then extract the aqueous layer twice with dichloromethane, combine the organic phases, and pass the organic phases through saturated sodium bicarbonate, purified water, and saturated brine successively. Wash, dry with anhydrous sodium sulfate for 10 h, filter with suction, and concentrate the filtrate under reduced pressure to obtain 14.2 g of oily liquid (Compound II), the yield of this step is 90% (b...

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Abstract

The invention discloses a synthetic method for (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine. The method comprises the following four steps: synthesizing ethyl 3-piperidinecarboxylate (compoundII), synthesizing ethyl (R)-nipecotate-L-tartarate (compound III), synthesizing ethyl (R)-N-Boc-3-piperidinecarboxylate (compound IV) and synthesizing the (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine (compound V); and the method comprises the following special steps: synthesizing the compound II by using 3-piperidinecarboxylic acid (compound I) as a raw material through chloroacylation andethanol esterification; performing a salt formation reaction to form the compound III; adding a Boc anhydride and performing a reaction to obtain the compound IV; and finally performing sodium borohydride reduction to obtain the compound V. The method provided by the invention has the advantages of mild reaction conditions, environmental friendliness, simple operation steps, better reproducibilityand high practicability, and is suitable for industrial mass production of the (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine. Background technique [0002] (R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine, also known as (R)-N-Boc-3-piperidinemethanol, is the key intermediate for the synthesis of vinblastine antitumor bisindole alkaloids In vivo, vinblastine antineoplastic drugs can reduce the synthesis of DNA, RNA and protein, inhibit the mitosis of cancer cells, stop the division of cancer cells in the middle stage and cannot proliferate, and have the characteristics of high curative effect and small adverse reactions, so they are widely accepted attention and has been applied clinically. (①Philip Magnus, and LeeS.Thurston.Synthesis of the vinblastine-like antitumor bis-indole alkyloidnavelbine analog desethyldihydronavelbine.J.Org.Chem.,1991,56(3),1166–1170.) Vinblastine-like antitumor bis-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
CPCC07B2200/07C07D211/22
Inventor 刘承先程进樊亚娟陆敏文艺刘长春
Owner CHANGZHOU VOCATIONAL INST OF ENG
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