Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst

A technology catalyzed by dihydroquinazolinone and spirocyclic phosphoric acid, which is applied in organic chemistry and other fields, can solve the problems of low reaction yield, poor enantioselectivity, and lack of atom economy, and achieve mild reaction conditions and high The effect of optical activity

Inactive Publication Date: 2013-12-04
ZHEJIANG UNIV
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Problems solved by technology

Among them, the chiral binaphthylphosphonic acid-catalyzed method developed by the List research group and the Rueping research group does not have good enantioselectivity for benzaldehyde substrates with substituents in the ortho position; the chiral binaphthylphosphonic acid developed by the Tian research group The method of

Method used

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  • Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst
  • Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst
  • Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add anthranilamide compound (0.05mmol), benzaldehyde (0.055mmol) containing a substituent in the ortho position, (S)-spirocyclic phosphoric acid (0.005mmol) of structural formula (1) in the reaction flask, Molecular sieves (75 mg), inject 1 mL of chloroform, and react at room temperature for 24 hours. After the reaction is completed, directly use silica gel column chromatography, and the eluent is ethyl acetate / petroleum ether=1:2 to obtain the corresponding optically active 2,3- Dihydroquinazolin-4(1H)-one derivatives; and product characterization. In this example, "anthranilamide compound" is anthranilamide, and "benzaldehyde containing a substituent at the ortho position" is o-bromobenzaldehyde. (S)-2-(2-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one

[0019]

[0020] White solid;m.p.176-178℃;99%yield;98%ee,determined by HPLC[Daicel Chiralpak AD-H,n-hexane / i-propanol=80 / 20,1.0mL / min,λ=254nm,t( major)=15.479min,t(minor)=23.275min].[α] D 20 =+151.2°(c=1.0,THF); ...

Embodiment 2

[0022] The steps are the same as in Example 1. In this example, the "anthranilamide compound" is anthranilamide, and the "benzaldehyde containing a substituent in the ortho position" is o-nitrobenzaldehyde.

[0023] (S)-2-(2-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one

[0024]

[0025] Yellow solid;m.p.192-193℃;99%yield;95%ee,determined by HPLC[Daicel Chiralpak AS-H,n-hexane / i-propanol=50 / 50,0.7mL / min,λ=254nm,t( minor)=26.489min,t(major)=40.962min].[α] D 20 =+195.2°(c=0.75,THF); 1 H NMR (400MHz, DMSO-d 6 )δ6.34(s,1H),6.72(t,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),7.01(s,1H),7.24-7.28(m,1H), 7.61-7.67(m,2H),7.77-7.81(m,1H),7.86(dd,J 1 =8.0Hz,J 2 =1.2Hz,1H),8.07(dd,J 1 =8.4Hz,J 2 =1.2Hz,1H),8.22(s,1H); 13 C NMR (100MHz, DMSO-d 6 )δ62.6, 115.0, 115.4, 118.1, 125.2, 127.8, 129.4, 130.3, 134.0, 134.4, 136.4, 147.6, 148.1, 163.8; IR (KBr, cm -1 )3422,3188,3061,2934,1670,1612,1514,1342,1152,855,742,697;HRMS(EI-TOF):calcd for C 14 h 11 N 3 o 3 269.0800,found269.0802.

Embodiment 3

[0027]The steps are the same as in Example 1. In this example, the "anthranilamide compound" is anthranilamide, and the "benzaldehyde containing a substituent in the ortho position" is o-chlorobenzaldehyde.

[0028] (S)-2-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one

[0029]

[0030] White solid;m.p.208-210℃;99%yield;98%ee,determined by HPLC[Daicel Chiralcel OD-H,n-hexane / i-propanol=80 / 20,1.0mL / min,λ=254nm,t( major)=13.066min,t(minor)=16.992min].[α] D 20 =+172.6°(c=0.82,THF); 1 H NMR (400MHz, DMSO-d 6 )δ6.15(s,1H),6.70-6.78(m,2H),7.02(s,1H),7.24-7.28(m,1H),7.38-7.42(m,2H),7.48-7.51(m, 1H),7.66-7.69(m,2H),8.22(s,1H); 13 C NMR (100MHz, DMSO-d 6 )δ64.2, 115.0, 115.2, 117.9, 127.8, 127.9, 129.2, 130.1, 130.8, 132.3, 133.9, 138.4, 148.1, 164.1; IR (KBr, cm -1 ) 3361, 3197, 3065, 1647, 1614, 1502, 1390, 1256, 1188, 1051, 739, 539; HRMS (EI-TOF): calcd for C 14 h 11 ClN 2 O258.0560,found258.0567.

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Abstract

The invention discloses a method for synthesizing an optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as a catalyst. The optically-active 2,3-dihydro quinazolinone derivative is synthesized by taking anthranilamide and aldehyde as raw materials, the chiral spiro phosphoric acid as the catalyst and chloroform as a reaction solvent, reacting for 24 hours at room temperature in the presence of molecular sieve powder, and purifying and separating by column chromatography. The method is mild in reaction condition, simple in process and convenient and rapid to operate; the synthesized optically-active 2, 3-dihydro quinazolinone derivative has potential good bioactivity and can be used as an intermediate in medicine synthesis.

Description

technical field [0001] The invention relates to a method for catalytically synthesizing optically active 2,3-dihydroquinazolinone derivatives with chiral spirocyclic phosphoric acid. Background technique [0002] 2,3-Dihydroquinazolin-4(1H)-ones and their analogs (DHQZs) are important nitrogen-containing heterocyclic compounds, and are also important skeletons of many active pharmaceutical molecules. , diuretic, antihistamine, antidepressant, antihypertensive and antivasodilator and other biological and pharmacological activities, such as Aquamox and Thiabutazide, see [J.Med.Chem.,1968,11,1136; J.Med. Chem., 1968, 11, 348; J. Am. Chem. Soc., 1959, 81, 5508; Bioorg. Med. Chem. Lett., 1994, 4, 1141; Ann. Pharm., 2006, 40, 1040]. Judging from the structure of DHQZs, it has a chiral center of a cyclic aminal. The racemate and the single configuration often show different or even completely opposite biological activities. Recently, scientists have discovered that DHQZs has ant...

Claims

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Application Information

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IPC IPC(8): C07D239/91
Inventor 黄丹徐方曦李炉航王彦广林旭锋
Owner ZHEJIANG UNIV
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