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A method for the catalytic synthesis of optically active 2h-1,4-benzoxazin-2-one derivatives by chiral spirocyclic phosphoric acid

A technology of spirocyclic phosphoric acid catalysis and benzoxazinone, which is applied in organic chemistry and other fields, and achieves the effects of wide sources, reduced preparation costs, and convenient operation

Inactive Publication Date: 2017-10-17
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Simple and convenient asymmetric catalyzed cyclization to prepare cyclic quaternary stereocenters The generation of trifluoromethyl groups has not been well studied and remains a great challenge

Method used

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  • A method for the catalytic synthesis of optically active 2h-1,4-benzoxazin-2-one derivatives by chiral spirocyclic phosphoric acid
  • A method for the catalytic synthesis of optically active 2h-1,4-benzoxazin-2-one derivatives by chiral spirocyclic phosphoric acid
  • A method for the catalytic synthesis of optically active 2h-1,4-benzoxazin-2-one derivatives by chiral spirocyclic phosphoric acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 3-Trifluoromethyl-benzoxazinone (0.05mmol), pyrrole (0.06mmol), (R)-spirophosphoric acid represented by structural formula (1) (0.0025mmol) (cas: 1372719- 95-3), inject 0.5 mL of toluene, and react at room temperature for 12 hours. After the reaction is completed, use silica gel column chromatography directly. The eluent is ethyl acetate / petroleum ether=1:8 to obtain the corresponding optical activity 2H-1 ,4-benzoxazin-2-one derivative, yield 93%; the product is characterized as follows:

[0039] Structural formula:

[0040]

[0041] Appearance: yellow solid;

[0042] m.p.104.1-105.2℃;

[0043] Optical purity: 93%ee;

[0044] HPLC analysis conditions: (Dai Road chiral column, the same below) Chiralpak OD-H (n-hexane / i-PrOH=90 / 10, 0.8mL / min), t R (minor)10.978min,t R (major)16.172min;

[0045] Optical rotation: [α] D 20 =-190.1(c=0.4,CH 2 Cl 2 );

[0046] 1 H NMR (400MHz, CDCl 3 )δ=8.77(s,1H),7.05-6.97(m,1H),6.95-6.84(m,2H),6.84-6.77(m,2H),6.26-6.15(m,1H...

Embodiment 2

[0049] 6-Fluoro-3-trifluoromethyl-benzoxazinone (0.05mmol), pyrrole (0.06mmol), (R)-spirophosphoric acid (0.0025mmol) represented by structural formula (1) were added to the reaction flask, Inject 0.5 mL of benzene, and react at room temperature for 24 hours. After the reaction is completed, use silica gel column chromatography directly. The eluent is ethyl acetate / petroleum ether=1:8 to obtain the corresponding optically active 2H-1,4-benzoyl Oxazin-2-one derivative in 95% yield; the product is characterized as follows:

[0050] Structural formula:

[0051]

[0052] Appearance: white solid;

[0053] m.p.122.5-124.7℃; Optical purity: 91%ee; HPLC analysis conditions: Chiralpak OD-H (n-hexane / i-PrOH=90 / 10, 0.8mL / min), t R (minor)13.745min,t R (major)18.205min;

[0054] Optical rotation: [α] D 20 =-127.1(c=0.9,CH 2 Cl 2 );

[0055] 1 H NMR (400MHz, CDCl 3 )δ=8.77(s,1H),6.97-6.91(m,1H),6.91-6.87(m,1H),6.72-6.64(m,1H),6.62-6.51(m,1H),6.33-6.26( m,1H),6.21–6.14(m,1H),4....

Embodiment 3

[0058] 6-chloro-3-trifluoromethyl-benzoxazinone (0.05mmol), pyrrole (0.06mmol), (R)-spirophosphoric acid (0.0025mmol) represented by structural formula (1) were added to the reaction flask, Inject 0.5 mL of xylene, and react at room temperature for 18 hours. After the reaction is completed, use silica gel column chromatography directly. The eluent is ethyl acetate / petroleum ether=1:8 to obtain the corresponding optically active 2H-1,4-benzene. The oxazin-2-one derivative, yield 91%; the product is characterized as follows:

[0059] Structural formula:

[0060]

[0061] Appearance: brown solid;

[0062] m.p.131.1-133.5℃;

[0063] Optical purity: 92%ee; HPLC analysis conditions: Chiralpak OD-H (hexane / i-PrOH=90 / 10, 0.8mL / min), t R (minor)14.620min,t R (major)29.410min;

[0064] Optical rotation: [α] D 20 =-173.8(c=1.2,CH 2 Cl 2 );

[0065] 1 H NMR (400MHz, CDCl 3 )δ=8.76(s,1H),6.95(d,J=4Hz,1H),6.94–6.88(m,2H),6.88–6.82(m,1H),6.32–6.26(m,1H),6.23– 6.15(m, 1H), 4.8...

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Abstract

The invention discloses a method for chiral spirophosphonate catalyzed synthesis of an optically active 2H-1,4-benzoxazine-2-one derivative. The method is characterized in that the 2H-1,4-benzoxazine-2-one derivative is prepared through a complete reaction of a benzoxazinone compound and a pyrrole compound as raw materials in an organic catalyst with chiral spirophosphonate as a catalyst. The method using an asymmetric catalysis aza Friedel-Crafts alkylation reaction technology to synthesize the optically active 2H-1,4-benzoxazine-2-one derivative containing a trifluoromethyl quaternary stereo center has the advantages of mild reaction conditions, simple process and convenient operation, and the above obtained product has potential good bioactivity and is of great significance to screen new drugs, and obtained chiral compounds can be used as a drug synthesis intermediate.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for synthesizing optically active 2H-1,4-benzoxazin-2-one derivatives with a chiral spirocyclic phosphoric acid catalyst. Background technique [0002] 2H-1,4-benzoxazin-2-one and its analogs are important nitrogen-containing heterocyclic compounds, and are also important skeletons of many active pharmaceutical molecules. There are antibiotics, plant disease resistance, antibacterial and pest resistance, serotonin ( 5-HT3) receptor antagonists, potassium channel modulators, anti-rheumatic and antihypertensive drugs and some enzyme inhibitors and other biological activities and pharmacological activities; thus study the optical activity of 2H-1,4-benzoxazine among them The -2-one derivatives are of particular interest. [0003] The synthesis of optically active 2H-1,4-benzoxazin-2-one derivatives by asymmetric catalytic method is one of the most straightforward me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04
CPCC07D413/04
Inventor 娄恒桥金恩泽林旭锋
Owner ZHEJIANG UNIV