Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate

A technology of tert-butyl formate and aminophenyl, which is applied in the field of preparation of tert-butyl-3-piperidine-1-carboxylate, can solve the problems of difficult separation of by-products, high cost, and low resolution yield, and achieve the product Yield and improvement, ee value improvement, and the effect of easy availability of raw materials

Inactive Publication Date: 2017-02-22
QINGDAO YUNTIAN BIOTECH
View PDF6 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, this method needs to use 2 times the amount of resolving agent L-dibenzoyl tartaric acid, and the cost is high. In this case, the resolution yield is still extremely low, and the ee value is only about 80% after repeated refining.
[0012] In addition, the above method also has the optically pure (S)-4-(piperidin-3-yl)aniline obtained by using the Boc2O reaction process and still reacts with the amino group on the phenyl group, resulting in waste of optically pure products, and the side effect The product is not only difficult to separate but also cannot carry out the reaction of subsequent intermediates

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
  • Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate
  • Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate
  • Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A method for preparing (3S)-3-(4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester, the method comprises the following steps:

[0031] 1) 27.6 g (100 mmol) of tert-butyl 3-(4-aminophenyl) piperidine-1-carboxylate, 38.3 g (110 mmol) of (R)-(-)-binaphthol phosphate, CuI3 .8g (20mmol) was added to 150ml of mixed solvent, the mixed solvent was made up of DMF and water with a volume ratio of 5:1, then was heated to 75°C for contact reaction for 1 hour, after the contact reaction, continued stirring and naturally cooled to 50°C Incubate for 1 hour, then naturally cool to room temperature, and filter to obtain solid compound A.

[0032] 2) The solid compound A obtained in step 1) was hydrolyzed in 50 ml of 10% hydrochloric acid solution. After the hydrolysis reaction was completed, sodium hydroxide was added to adjust the pH of the reaction solution to 10, extracted with ethyl acetate, concentrated, recrystallized from petroleum ether, and vacuumized. Dry to obtain (...

Embodiment 2

[0034] A method for preparing (3S)-3-(4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester, the method comprises the following steps:

[0035]1) 27.6 g (100 mmol) of tert-butyl 3-(4-aminophenyl) piperidine-1-carboxylate, 41.8 g (120 mmol) of (R)-(-)-binaphthol phosphate, CuI7 .6g (40mmol) is added in 150ml mixed solvent, and described mixed solvent is made up of DMF and water that volume ratio is 7:1, then be warming up to 80 ℃ of contact reactions for 1 hour, after the contact reaction, continue to stir and naturally cool to 45 ℃ Incubate for 1 hour, then naturally cool to room temperature, and filter to obtain solid compound A.

[0036] 2) The solid compound A obtained in step 1) was hydrolyzed in 60 ml of 5% hydrochloric acid solution. After the hydrolysis reaction was completed, sodium hydroxide was added to adjust the pH of the reaction solution to 9, extracted with ethyl acetate, concentrated, recrystallized from petroleum ether, and dried in vacuo 12.5 g of ter...

Embodiment 3

[0038] A method for preparing (3S)-3-(4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester, the method comprises the following steps:

[0039] 1) 27.6g (10mmol) of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate, 36.6g (105mmol) of (R)-(-)-binaphthol phosphate, CuCl2 .8g (30mmol) was added in 180ml mixed solvent, the mixed solvent was made up of DMF and water with a volume ratio of 8:1, then was heated to 85°C for contact reaction for 1.5 hours, after the contact reaction, continued stirring and naturally cooled to 50°C Incubate for 0.5 hours, then naturally cool to room temperature, and filter to obtain solid compound A.

[0040] 2) The solid compound A obtained in step 1) was hydrolyzed in 50 ml of 10% hydrochloric acid solution, and after the hydrolysis reaction was completed, cesium carbonate was added to adjust the pH of the reaction solution to 8, extracted with ethyl acetate, concentrated, recrystallized from petroleum ether, and dried in vacuo to obtain (...

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 discloses a method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate. The method is characterized by comprising the following steps: 1) performing a contact reaction on a 3-(4-aminophenyl)-piperidyl-1-tert-butyl formate racemate and (R)-(-)-binaphthyl-2,2-diyl hydrogen phosphate, cooling, crystallizing, and filtering to obtain a solid compound A; (2) hydrolyzing the solid compound A obtained in the step (1) under an acidic condition, adjusting the pH to be 8 to 10 after the hydrolysis reaction is completed, extracting with ethyl acetate, and concentrating to obtain the (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate. The method provided by the invention is high in yield and high in product optical purity, and provides a new way for preparing the (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for preparing (3S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester. Background technique [0002] Niraparib is a targeted inhibitor of PARP gene, its chemical name is 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-methyl Amide, the specific structural formula is shown in formula X. Nirapabb has been clinically proven to be effective against a variety of cancers, such as ovarian, breast, and prostate cancers. Nirapabb will become the second PARP inhibitor on the market, with huge potential application value. [0003] [0004] PARP is a cleavage substrate for caspases, a core member of apoptosis. It plays an important role in DNA damage repair and apoptosis. If the DNA damage is not repaired, the cell can die. For cancer cells with mutations in the BRCA gene, if PARP activity is further inhibited, these cells will produce large amounts of DNA damag...

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): C07D211/26
CPCC07D211/26
Inventor 王传秀
Owner QINGDAO YUNTIAN BIOTECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap