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Chiral 3-amino-4-arylpyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction

A technology of arylpyridine nitrogen oxide catalyst and aryl pyridine nitrogen oxide, which is applied in the synthesis of chiral 3-amino-4-arylpyridine nitrogen oxide catalyst to catalyze the synthesis of tetrazole hemiaminal ester, a new type In the field of chiral DMAP catalysts, it achieves the effects of strong adjustability, simple synthesis and good yield

Pending Publication Date: 2021-12-10
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above experimental results show that it is very difficult and challenging to construct chiral 2,5-disubstituted tetrazole hemiaminal esters through three-component dynamic kinetic resolution of 5-substituted tetrazole, aldehyde and anhydride

Method used

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  • Chiral 3-amino-4-arylpyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction
  • Chiral 3-amino-4-arylpyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction
  • Chiral 3-amino-4-arylpyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Synthesis of chiral 4-phenyl-3-(2-(2,6 diisopropylbenzamido) pyrrolidinyl) pyridine nitrogen oxide

[0034]

[0035] Under nitrogen protection, chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide (125mg, 0.31mmol), phenylboronic acid (152mg, 1.24mmol), potassium carbonate (171mg, 1.24mmol) were sequentially added into a 25mL sealed tube ), Pd(PPh 3 ) 4 (17.90mg, 0.015mmol), Xant-Phos (14.4mg, 0.031mmol) and 2.5mL of toluene were placed in a 120°C oil bath, and the stirring was stopped after 40min of reaction. Monitored by TLC, after the reaction of the raw materials was completed, the crude product was concentrated in vacuum to obtain a crude product, and then separated by column chromatography to obtain a light brown solid. The raw material chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide in this example can be synthesized by referring to Angew.Chem.Int.Ed.2019, 58, 2839. 1 H NMR (400MHz, CDCl 3 )δ8.35(s,1H),8.08(s,1H),7.85(d,J=6.4Hz,1H),7.46-7....

Embodiment 2

[0036] Example 2 Chiral 4-phenyl-3-(2-(3,5-bistrifluoromethylbenzamido)pyrrolidinyl)pyridine nitrogen oxide

[0037]

[0038] Under nitrogen protection, chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide (125 mg, 0.27 mmol), phenylboronic acid (134 mg, 1.10 mmol), potassium carbonate (1.10 mmol), Pd(PPh 3 ) 4 , (15.59mg, 0.0135mmol), Xant-Phos (17.4mg, 0.027mmol) and 2.5mL of toluene were placed in a 120°C oil bath, and the stirring was stopped after 40min of reaction. Monitored by TLC, after the reaction of the raw materials was completed, the crude product was concentrated in vacuum to obtain a crude product, and then separated by column chromatography to obtain a light brown solid. The raw material chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide in this example can be synthesized by referring to Angew.Chem.Int.Ed.2019, 58, 2839. 1 H NMR (400MHz, CDCl 3 )δ10.98(s,1H),8.64(s,1H),7.85(d,J=6.4Hz,1H),7.61-7.47(m,6H),7.46-7.41(m,1H),7.31(s ,1H),7.18(d,J=6.4Hz,1H)...

Embodiment 3

[0039] Example 3 Chiral 4-(3,5-dimethylphenyl)-3-(2-(2,6 diisopropylbenzamido)pyrrolidinyl)pyridine nitrogen oxide

[0040]

[0041] Under nitrogen protection, chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide (125 mg, 0.31 mmol), 3,5-dimethylphenylboronic acid (186 mg, 1.24 mmol), and Potassium carbonate (171mg, 1.24mmol), Pd(PPh 3 ) 4 (17.90mg, 0.015mmol), Xant-Phos (14.44mg, 0.031mmol) and 2.5mL of toluene were placed in a 120°C oil bath, and the stirring was stopped after 40min of reaction. Monitored by TLC, after the reaction of the raw materials was completed, the crude product was concentrated in vacuum to obtain a crude product, and then separated by column chromatography to obtain a light brown solid. 1 H NMR (400MHz, CDCl 3 )δ8.20(s,1H),7.83(dd,J=6.4,1.6Hz,1H),7.72(s,1H),7.23(d,J=8.0Hz,1H),7.11(d,J=8.0 Hz, 2H), 7.02(d, J=6.8Hz, 1H), 6.98(s, 1H), 6.95(s, 2H), 4.20(t, J=7.2Hz, 1H), 3.25(dt, J=9.6 ,7.6Hz,1H),2.93-2.75(m,3H),2.48-2.34(m,1H),2.27(s,6H),2.14-2....

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Abstract

The invention discloses a chiral 3-amino-4-arylpyridine nitrogen-oxygen catalyst and an application thereof in tetrazole hemiacetal amine ester reaction, and belongs to the technical field of organic synthesis. A Suzuki coupling reaction is performed on 4-chloropyridine nitrogen oxide and arylboronic acid, aryl is introduced at a C4 site of a pyridine ring to construct a chiral 4-arylpyridine nitrogen oxide catalyst, and the 4-arylpyridine nitrogen oxide can also be used as an acyl transfer catalyst. The catalyst has good regioselectivity and enantioselectivity in a reaction for synthesizing 2, 5-disubstituted tetrazole hemiacetal amine ester through challenging dynamic kinetic resolution of three components including tetrazole, aldehyde and anhydride. The product is subjected to derivation to obtain a small molecule PCSK9 inhibitor PF-07556769.

Description

technical field [0001] The invention relates to a novel chiral DMAP catalyst, in particular to a chiral 3-amino-4-arylpyridine nitrogen oxide catalyst and its application in catalyzing the synthesis of tetrazolium hemiaminal ester, which belongs to the field of organic chemistry Asymmetric synthesis technology field. Background technique [0002] The chiral 4-dialkylaminopyridine (DMAP) catalyst is a classic acyl transfer catalyst, and its structure is characterized by a N,N'-dialkylamino substituent at the C4 position of the pyridine ring (such as N,N'-dimethyl ylamino or pyrrolidinyl). Since the first chiral DMAP reagent was reported in 1996, chiral DMAP catalysts with central chirality, planar chirality, spiral chirality and axial chirality have been reported successively (Angew.Chem.Int.Ed.2011, 50, 6012; Organic Chemistry, 2008, 28, 574; Tetrahedron Lett. 2018, 59, 1787; Org. Chem. Front. 2019, 6, 2624). It should be emphasized that the C4 positions of these chiral D...

Claims

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Application Information

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IPC IPC(8): B01J31/02C07D401/04C07D257/04
CPCB01J31/0271B01J31/0247C07D401/04C07D257/04B01J2231/4283B01J2231/4288
Inventor 谢明胜王笑冰单梦武晓霞渠桂荣郭海明
Owner HENAN NORMAL UNIV
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