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Fluorocyclohexanone spiro-1, 3-dioxane chiral derivative as well as preparation method and application thereof

A technology of cyclohexanone spiro and dioxane, which is applied in the fields of organic chemistry, antibacterial drugs, local antibacterial agents, etc., can solve the problems of few synthesis methods of related compounds, change of physical and chemical properties, or harsh conditions, etc., and achieve broad Market application prospect, simple preparation method, mild reaction effect

Pending Publication Date: 2022-05-13
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The introduction of chiral fluorine atoms into the drug skeleton is an excellent modification method, which can not only increase the efficacy of the drug, but also change various physical and chemical properties of the drug, but the synthesis methods of related compounds are less or the conditions are relatively harsh

Method used

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  • Fluorocyclohexanone spiro-1, 3-dioxane chiral derivative as well as preparation method and application thereof
  • Fluorocyclohexanone spiro-1, 3-dioxane chiral derivative as well as preparation method and application thereof
  • Fluorocyclohexanone spiro-1, 3-dioxane chiral derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (2R,2'S)-2'-benzyl-2'-fluoro-4H-spiro[benzo[1,3]dioxo-2,1'-cyclohexane]-3',4-dione (synthetic Substrate using salicylaldehyde)

[0036]

[0037] White solid, yield 99%, ee 98%, dr 92:8;

[0038] 1 H NMR (600MHz, CDCl 3 )δ(ppm): 7.97(dd,J=7.8,1.2Hz,1H),7.60–7.57(m,1H),7.26–7.21(m,5H),7.18(t,J=7.2Hz,1H), 6.97(d,J=8.4Hz,1H),3.50(dd,J=15.0,13.2Hz,1H),3.41(dd,J=36.0,14.4Hz,1H),2.74–2.68(m,1H),2.58 –2.52(m,1H),2.50–2.42(m,2H),2.01–1.94(m,1H),1.82–1.75(m,1H).

[0039] 13 C NMR (151MHz, CDCl 3 )δ(ppm):200.8(C-F, 2 J C-F =21.6Hz), 158.7, 154.6, 136.7, 133.1, 130.6, 129.8, 128.2, 127.2, 123.5, 116.6, 113.6, 107.9 (C-F, 2 J C-F =21.6Hz), 99.6(C-F, 1 J C-F =198.3Hz), 37.6, 35.4(C-F, 2 J C-F =21.6Hz), 31.0, 18.5.

[0040] The single crystal data of embodiment 1 product (see figure 1 and table below):

[0041]

[0042]

[0043]

Embodiment 2

[0045] (2R,2'S)-2'-Benzyl-2'-fluoro-8-methyl-4H-spiro[benzo[1,3]dioxo-2,1'-cyclohexane]-3',4 - diketones (3-methylsalicylaldehyde is used in the synthesis of substrates).

[0046]

[0047] White solid, yield 98%, ee 99%, dr 93:7;

[0048] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.81 (dd, J = 7.8, 1.2Hz, 1H), 7.44 (d, J = 7.2Hz, 1H), 7.30–7.20 (m, 5H), 7.08 (t, J = 7.2Hz, 1H),3.52–3.41(m,2H),2.76–2.70(m,1H),2.57–2.51(m,1H),2.48–2.41(m,2H),2.24(s,3H),2.00–1.93( m,1H),1.74–1.67(m,1H).

[0049] 13 C NMR (151MHz, CDCl 3 )δ(ppm):200.9(C-F, 2 J C-F =20.1Hz), 159.0, 152.6, 137.8, 133.2, 130.7, 128.2, 127.4, 127.1, 126.2, 122.9, 113.2, 107.8 (C-F, 2 J C-F =23.0Hz), 99.2(C-F, 1 J C-F =195.3Hz), 37.6, 34.8(C-F, 2 J C-F =20.1Hz), 30.5, 18.8, 14.8.

Embodiment 3

[0051] (2R,2'S)-2'-Benzyl-2'-fluoro-8-bromo-4H-spiro[benzo[1,3]dioxo-2,1'-cyclohexane]-3',4- Diketones (3-bromosalicylaldehyde is used in the synthesis of substrates).

[0052]

[0053] White solid, yield 95%, ee 92%, dr 92:8;

[0054] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.92 (dd, J = 7.2, 1.2Hz, 1H), 7.80 (dd, J = 8.4, 1.8Hz, 1H), 7.27–7.21 (m, 5H), 7.08 (t, J = 7.8 Hz,1H),3.55(dd,J=15.0,12.6Hz,1H),3.44(dd,J=37.2,15.6Hz,1H),2.70–2.64(m,1H),2.62–2.57(m,1H) ,2.53–2.45(m,2H),2.05–1.98(m,1H),1.93–1.86(m,1H).

[0055] 13 C NMR (151MHz, CDCl 3 )δ(ppm):200.0(C-F, 2 J C-F =20.1Hz), 157.8, 151.9, 139.7, 132.6, 130.4, 128.9, 128.3, 127.4, 124.2, 115.1, 110.1, 108.6 (C-F, 2 J C-F =20.1Hz), 100.2(C-F, 1 J C-F =199.7Hz), 37.7, 36.4(C-F, 2 J C-F =21.6Hz), 31.9, 18.2.

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a fluoro-cyclohexanone spiro-1, 3-dioxane chiral derivative as well as a preparation method and application thereof, discloses the fluoro-cyclohexanone spiro-1, 3-dioxane chiral derivative, and further provides a preparation method of the compound. Comprising the following steps: adding 1.0 eq of a substrate 1, 1.5 eq of salicylaldehyde 2, 1.5 eq of an oxidant DQ, 10 mol% of an additive Add, 1.0 eq of alkali Cs2CO3 and 20 mol% of a catalyst C into a reaction sealed tube, adding 1 ml of dry diethyl ether under the protection of argon, reacting the mixture at normal temperature for 8 hours, and concentrating and purifying after the reaction is completed to obtain a target product 3. The preparation method is simple and convenient to operate, mild in reaction and high in yield. The compound provided by the invention has excellent antibacterial activity and wide market application prospect.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a fluorocyclohexanone spiro-1,3-dioxane chiral derivative and a preparation method and application thereof. Background technique [0002] Spiro compounds widely exist in natural products and synthetic drugs. Relevant studies have shown that compounds containing this skeleton have a variety of important biological and pharmaceutical activities. Substituent modification of such compounds, derivatization of structural analogs and further biological The re-evaluation of academic activity has become a research hotspot. The introduction of chiral fluorine atoms into the drug skeleton is an excellent modification method, which can not only increase the efficacy of the drug, but also change various physical and chemical properties of the drug, but the synthesis methods of related compounds are less or the conditions are relatively harsh. [0003] How to easily prepare fluori...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/08A61P31/10A61P31/04A61P31/02
CPCC07D319/08A61P31/10A61P31/04A61P31/02
Inventor 李俊龙苟川管一龙李青竹陈林戴青松张翔冷海军漆婷刘燕青寇鑫鑫
Owner CHENGDU UNIV