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A kind of high stereo and high enantioselectivity thiazolidinedione compound, its preparation method and application

An enantioselective, thiazolidinedione technology, applied in the field of drug synthesis, can solve problems such as unreported development, and achieve the effects of low cost, high reaction efficiency, and high stereoselectivity

Active Publication Date: 2017-08-25
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the asymmetric synthesis of 5-phenyl-5-substituent thiazolidinedione structural compounds with heteroatom-bearing quaternary carbon centers at the 5-position of chiral thiazolidinedione has not been reported.

Method used

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  • A kind of high stereo and high enantioselectivity thiazolidinedione compound, its preparation method and application
  • A kind of high stereo and high enantioselectivity thiazolidinedione compound, its preparation method and application
  • A kind of high stereo and high enantioselectivity thiazolidinedione compound, its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The structural formula of compound 3a is as follows:

[0026]

[0027] The synthetic route of compound 3a is as follows:

[0028]

[0029] The synthetic steps of compound 3a are as follows:

[0030] (1) 5-(4-methoxyphenyl)-3-phenylthiazolidine-2,4-dione 1a (0.1mmol, 1.0equiv.), catalyst A (0.01mmol, 0.1equiv.), Sodium chloride (0.1eq) and Molecular sieves (50mg) were dissolved in 1.0mL m-xylene, and kept stirring at -20°C for 15 minutes;

[0031] (2) Add trans-nitrostyrene 2a (0.12 mmol, 1.2 equiv.), keep at -20°C and continue to react for 96 hours, monitor by TLC until the raw material 1a completely disappears;

[0032] (3) spin off the solvent, pass through a silica gel column (eluent: petroleum ether and ethyl acetate volume ratio from 20:1 to 5:1) to obtain a white solid (S)-5-((S)-2-nitro -1-Phenyl)-2,4-dione-3,5-diphenylthiazolidine 3a (94% yield).

[0033] White solid, melting point: 143.4–146.1°C, 97%ee, dr=94:6, (c 1.00, CHCl 3 ). 1 H NMR (300MH...

Embodiment 2

[0036]

[0037] Product name: (S)-3-(4-methoxyphenyl)-5-((S)-2-nitro-1-(p-methylphenyl)ethyl)-5-phenyl- 2,4-Diketothiazolidine.

[0038] In step (2), p-methyl-β-nitrostyrene 2b was used to replace trans-nitrostyrene 2a, and other experimental steps and purification methods were carried out with reference to Example 1; white solid, melting point: 158.7-161.1°C, 92 %ee,dr=93:7, 89% yield, (c 1.00, CHCl 3 ), 1 H NMR (300MHz, CDCl 3 )δ8.09–7.85(m,1H),7.59–7.26(m,2H),7.28–7.09(m,1H),6.78(d,J=9.0,1H),6.41(t,J=6.0,1H ),4.95–4.66(m,1H),4.36(d,J=9.5,0H),3.75(d,J=19.8,1H),2.33(d,J=12.2,1H), specifically as figure 2 shown; 13 C NMR (75MHz, CDCl 3 ( h + ) Calcd for C 25 h 22 N 2 o 5 S: 463.1328.

[0039] The ee value of the compound is obtained by high performance liquid chromatography (HPLC) analysis, CHIRALPAK IA (4.6mm×250mmi.d.)+CHIRALPAK IE (4.6mm×250mm i.d.), n-hexane / isopropanol=80 / 20 (V / V), flow rate 1.0mL / min, 25℃, 254nm, t R = 46.6 min, 69.0 min (small peak...

Embodiment 3

[0041]

[0042] Product name: (S)-3-(4-methoxyphenyl)-5-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-5-phenyl -2,4-diketothiazolidine.

[0043]In step (2), trans-nitrostyrene 2a is replaced by p-methoxy-β-nitrostyrene 2c, and other experimental steps and purification methods refer to the steps in Example 1; white solid, melting point, 81-90°C , 93%ee, dr=92:8, 92%yield, (c 1.00, CHCl 3 ), 1 H NMR (300MHz, CDCl 3 )δ8.04(dd, J=8.1,1.2,2H),7.65–7.36(m,5H),7.06–6.70(m,4H),6.66–6.27(m,2H),4.83(dd,J=10.6 ,7.1,2H),4.39(dd,J=11.6,2.5,1H),3.88–3.79(m,3H),3.76(s,3H), specifically as image 3 shown; 13 C NMR (75MHz, CDCl 3 )δ173.0, 167.8, 160.4, 160.1, 134.4, 131.2, 129.8, 129.6, 129.5, 128.3, 128.0, 124.7, 124.1, 114.2, 75.8, 69.2, 55.5, 55.4, 52.4; HRMS (ESI, m / z1): 2707 ( M+H + ) Calcd for C 25 h 22 N 2 o 6 S: 479.1277. The ee value of the compound is analyzed by high performance liquid chromatography (HPLC), CHIRALPAKIA (4.6mm×250mm i.d.)+CHIRALPAK ID-3 (4.6mm×250mm i.d.)...

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Abstract

The invention discloses a high-stereoscopic high-mapping selective thiazolidinedione compound, as well as a preparation method and application thereof. The structural formula of the compound is shown in the description, wherein Ar=4-MeOPh, and Ar'=Ph, p-MePh, p-MeOPh, p-ClPh or p-FPh. The high-stereoscopic high-mapping selective thiazolidinedione compound synthesized by adoption of the method has the characteristic of inhibiting activity of H22, HCT116 and K562 cells in different degrees, and the type of method is not reported in documents so far. The method has the advantages of universally and efficiently preparing the type of compound, is short in reaction path, high in reaction efficiency, simple in after-treatment and low in cost, and can be used for obtaining the chiral compound with high stereoselectivity and optical purity.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a thiazolidinedione compound with high stereo and high enantioselectivity, its preparation method and application. Background technique [0002] As a class of important heterocyclic compounds in the clinical treatment of diabetes, the anti-type 2 diabetes activity of thiazolidinediones has attracted the interest of many researchers in the pharmaceutical field, so the synthesis of related derivatives and more complex compounds are also becoming more important. The 5-phenyl-5-substituent thiazolidinedione structural derivatives of the quaternary carbon center bearing heteroatoms on the carbon 5 of thiazolidinedione are widely used, such as lactamase and aldose reductase inhibitors, pesticides Pesticides and angiotensin II receptor antagonists both belong to this subgroup. In addition, compounds with this structure can also be used as precursor compounds of pest...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/34A61K31/426A61P35/00
CPCC07D277/34
Inventor 江智勇朱博赵筱薇李骞焦立辉李江涛
Owner HENAN UNIVERSITY