Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthesis and chiral resolution method for (R)-1-t-butyloxycarbonyl-3-benzyl-3-formate piperidine

A technology for tert-butoxycarbonyl and chiral separation, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of incomplete separation, complicated and cumbersome process, and poor separation effect, and achieve convenient operation, The process is simple and the effect of improving the reaction yield

Inactive Publication Date: 2016-12-07
WUHAN INSTITUTE OF TECHNOLOGY
View PDF3 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process is cumbersome and cumbersome, and the yield is low. After two addition reactions of di-tert-butyl dicarbonate, and the chiral substances after resolution, they are prone to racemization in the subsequent reaction process.
In addition, D-tartaric acid has a certain resolution effect, but it cannot achieve the purpose of completely splitting the two isomers, and its resolution effect is relatively poor. It takes multiple resolutions to obtain better purity and optical properties. The product

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis and chiral resolution method for (R)-1-t-butyloxycarbonyl-3-benzyl-3-formate piperidine
  • Synthesis and chiral resolution method for (R)-1-t-butyloxycarbonyl-3-benzyl-3-formate piperidine
  • Synthesis and chiral resolution method for (R)-1-t-butyloxycarbonyl-3-benzyl-3-formate piperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A synthesis and chiral resolution method of (R)-1-tert-butoxycarbonyl-3-benzyl-3-formic acid piperidine, comprising the following five steps:

[0038] 1. Synthesis of ethyl 3-piperidinecarboxylate.

[0039]Add 51.6g (0.4mol) of 3-piperidinecarboxylic acid and 205ml of ethanol to a 500ml three-necked flask, slowly drop 71.4g (0.6mol) of thionyl chloride into it under temperature control, and then reflux for 3 to 5 hours after the temperature remains constant. The TLC reaction was complete, and the solution was removed, and 205 ml of ethanol was added to remove the solution again. Finally, the obtained organic phase was cooled and crystallized at room temperature to obtain 71.8 g of white solid of ethyl 3-piperidinecarboxylate, and the calculated yield was 92.78%. The product nuclear magnetic spectrum that this step makes is as figure 1 As shown, the following information can be obtained from the spectrum: H 1 NMR 1 (400MHz, CDCl 3 )δ: 1.323(s, 2H, CH 2 ), 1.581 (s, ...

Embodiment 2

[0049] A synthesis and chiral resolution method of (R)-1-tert-butoxycarbonyl-3-benzyl-3-formic acid piperidine, comprising the following five steps:

[0050] 1. Synthesis of ethyl 3-piperidinecarboxylate.

[0051] Add 929g (7.2mol) of 3-piperidinecarboxylic acid and 3.7L of ethanol to a 30L reactor, slowly drop 1274.4g (10.8mol) of thionyl chloride into it under temperature control, and then reflux for 3-5 hours after the temperature remains constant. The TLC reaction was complete, and the solution was removed, and 3.7L of ethanol was added thereto to remove the solution again. Finally, the obtained concentrate was cooled and crystallized at room temperature to obtain 1272 g of white solid of ethyl 3-piperidinecarboxylate, with a yield of 91.33%.

[0052] 2. Synthesis of piperidine ethyl 1-tert-butoxycarbonyl-3-carboxylate.

[0053] Add 1270g (6.56mol) ethyl 3-piperidinecarboxylate, 2086g Na in the 30L reactor 2 CO 3 (19.68mol) and 5715ml ethanol, stirred to dissolve and m...

Embodiment 3

[0061] A synthesis and chiral resolution method of (R)-1-tert-butoxycarbonyl-3-benzyl-3-formic acid piperidine, comprising the following five steps:

[0062] 1. Synthesis of ethyl 3-piperidinecarboxylate.

[0063] Under the condition that other parameters and conditions are constant, with reference to the reaction procedure of embodiment 2, by 929g (7.2mol) 3-piperidinecarboxylic acid and 1028g (8.64mol) sulfur oxychloride reaction 3-piperidinecarboxylic acid ethyl ester.

[0064] 2. Synthesis of piperidine ethyl 1-tert-butoxycarbonyl-3-carboxylate.

[0065] Under the condition that other parameters are constant and condition, with reference to the reaction procedure of embodiment 2, by 1270g (6.56mol) ethyl 3-piperidinecarboxylate, 787g NaOH (19.68mol) and 2145g (9.84mol) (Boc) 2 O reacts to produce piperidine ethyl 1-tert-butoxycarbonyl-3-carboxylate.

[0066] 3. Synthesis of 1-tert-butyl carboxylate-3-benzyl-3-ethyl piperidine carboxylate.

[0067] Under the condition th...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention belongs to the technical field of medical intermediate synthesis and chiral resolution, and particularly relates to a synthesis and chiral resolution method for (R)-1-t-butyloxycarbonyl-3-benzyl-3-formate piperidine. The method comprises the following steps that 3-piperidine-2-carboxylic acid is adopted as a raw material, 3-piperidinecarboxylicacid and thionyl chloride are subjected to an esterification reaction according to the molar ratio being 1:(1.2-1.5), the obtained product and di-tert-butyl dicarbonate ((Boc)2O) are firstly subjected to an addition reaction, then the obtained product and LDA (lithium diisopropylamide) are subjected to a hydrogen extracting reduction reaction, then the product obtained in the last step is subjected to the hydrolysis reaction of LiOH.H2O, and finally the product and R-(+)-alpha-methylbenzylamine are subjected to chiral resolution to obtain the target product. The method has the advantages of being cheap and available in raw material, simple in synthesis process, controllable in reaction, simple in step, low in cost, high in yield and the like, and has good application prospects.

Description

technical field [0001] The invention belongs to the technical field of synthesis and chiral resolution of N-containing heterocyclic pharmaceutical intermediates, and specifically relates to the synthesis and chirality of (R)-1-tert-butoxycarbonyl-3-benzyl-3-carboxylic acid piperidine Split method. Background technique [0002] (R)-1-tert-butoxycarbonyl-3-benzyl-3-piperidine carboxylate is an important pharmaceutical intermediate and an important synthetic raw material for anamorelin. A few days ago, the 2014 European Society for Medical Oncology (ESMO) held in Madrid, Spain announced that a new drug, anamorelin, is expected to become the first drug that can effectively improve cancer cachexia. The drug anamorelin stimulates hunger with the same effect as the so-called "ghrelin" peptide, which regulates appetite. Anamorelin can increase the patient's appetite and also help the patient maintain health. Recent research results have shown that anamorelin can help patients wit...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/62
CPCC07D211/62C07B2200/07
Inventor 黄齐茂冯瑾瑾高辉
Owner WUHAN INSTITUTE OF TECHNOLOGY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com