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Method for chiral spirophosphonate catalyzed synthesis of optically active 2H-1,4-benzoxazine-2-one derivative

A technology of spirophosphoric acid catalysis and spirophosphoric acid catalyst, which is applied in directions such as organic chemistry to achieve the effects of convenient operation, mild reaction conditions and reduced preparation cost

Inactive Publication Date: 2015-11-04
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
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  • 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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  • Method for chiral spirophosphonate catalyzed synthesis of optically active 2H-1,4-benzoxazine-2-one derivative
  • Method for chiral spirophosphonate catalyzed synthesis of optically active 2H-1,4-benzoxazine-2-one derivative
  • Method for chiral spirophosphonate catalyzed synthesis of optically active 2H-1,4-benzoxazine-2-one derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 3-trifluoromethyl-benzoxazinone (0.05mmol), pyrrole (0.06mmol), (R)-spirocyclic phosphoric acid (0.0025mmol) shown in structural formula (1) (cas: 1372719- 95-3), inject 0.5mL toluene, and react at room temperature for 12 hours. After the reaction is completed, directly use silica gel column chromatography, and the eluent is ethyl acetate / petroleum ether=1:8 to obtain the corresponding optically active 2H-1 , 4-benzoxazin-2-one derivatives, yield 93%; Product characterization is as follows:

[0039] Structural formula:

[0040]

[0041] Properties: yellow solid;

[0042] m.p.104.1-105.2°C;

[0043] Optical purity: 93%ee;

[0044] HPLC analysis conditions: (Dailu 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....

Embodiment 2

[0049] Add 6-fluoro-3-trifluoromethyl-benzoxazinone (0.05mmol), pyrrole (0.06mmol), (R)-spirocyclic phosphoric acid (0.0025mmol) shown in structural formula (1) in the reaction flask, Inject 0.5mL of benzene and react at room temperature for 24 hours. After the reaction is completed, directly use silica gel column chromatography with ethyl acetate / petroleum ether=1:8 as the eluent to obtain the corresponding optically active 2H-1,4-benzo Oxazin-2-one derivatives, yield 95%; product characterization as follows:

[0050] Structural formula:

[0051]

[0052] Properties: 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),4.87(s,1H)...

Embodiment 3

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

[0059] Structural formula:

[0060]

[0061] Appearance: brown solid;

[0062] m.p.131.1-133.5°C;

[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),4.82(s,1H;

...

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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, and in particular relates 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 analogues are important nitrogen-containing heterocyclic compounds, and are also important skeletons of many drug active molecules. There are antibiotics, plant resistance, antibacterial, and pest resistance. 5-HT3) receptor antagonists, potassium channel modulators, antirheumatic drugs and antihypertensive drugs and some enzyme inhibitors and other biological and pharmacological activities; thus study the optical activity of 2H-1,4-benzoxazine -2-one derivatives are of particular interest. [0003] Synthesis of optically active 2H-1,4-benzoxazin-2-one derivatives by asymmetric catalytic method is one of the most straightforward methods. Chiral phosphoric acid catalysts...

Claims

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Application Information

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IPC IPC(8): C07D413/04
CPCC07D413/04
Inventor 娄恒桥金恩泽林旭锋
Owner ZHEJIANG UNIV
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