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1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound and synthetic method and application thereof

The technology of a butenyl phosphonate and a synthesis method, which is applied in the field of phosphonate compounds, can solve the problems of complex preparation process, unsatisfactory biological activity, poor regioselectivity, etc., and achieve high regioselectivity, excellent yield, The effect of mild conditions

Active Publication Date: 2018-08-28
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although there have been studies on fluorine-containing phosphonate compounds in the prior art, there are also defects such as unsatisfactory biological activity, complicated preparation process and poor regioselectivity.

Method used

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  • 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound and synthetic method and application thereof
  • 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound and synthetic method and application thereof
  • 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound and synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Ar or N 2 Under protection, add allene (0.4mmol), benzenesulfonyl chloride (1.2mmol), fac-Ir(ppy) to the reaction tube in sequence 3 (5% mmol), acetonitrile 4mL, normal temperature, reaction under 5W blue light irradiation, TLC monitoring to the end of the reaction, quenching with water, extraction with ethyl acetate, combined organic phases, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated The product was separated by column chromatography with dichloromethane-ethyl acetate as eluent. reaction

[0030]

[0031] The obtained 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate has the following structure and the yield is 84%.

[0032]

[0033] (2-chloro-1,1-difluoro-4-methyl-3-(phenylsulfonyl)pent-3-en-1-yl)phosphonate IR(neat): 2984,2922,1612,1450,1304,1150,1080, 1033,895,834,756,717,687,602cm -1 ; 1 H-NMR (400MHz, CDCl 3 ): δ7.87-7.85 (m, 2H), 7.58-7.49 (m, 3H), 6.24 (dd, J H-F = 20.2, 11.4 Hz, 1H), 4.35-4.30 (m, 4H), 2.17 (s, ...

Embodiment 2

[0035]

[0036] The structure of the obtained 3-sulfonyl-2-chlorodifluoromethylene allyl phosphonate is as follows, and the yield is 83%.

[0037]

[0038] Diethyl(2-chloro-1,1-difluoro-4-methyl-3-((4-(trifluoromethyl)phenyl)sulfonyl)pent-3-en-1-yl)phosphonate

[0039] IR(neat): 3064, 2983, 2925, 1617, 1453, 1371, 1306, 1151, 1085, 1036, 889, 831, 758, 692, 603cm -1 ; 1 H-NMR (400MHz, CDCl 3 ): δ8.01(d,J=8.0Hz,2H), 7.78(d,J=8.0Hz,2H), 6.19(dd,J H-F = 19.4, 11.8 Hz, 1H), 4.34-4.29 (m, 4H), 2.20 (s, 3H), 2.03 (s, 3H), 1.39 (t, J = 7.0 Hz, 6H); 13 C-NMR (100MHz, CDCl 3 ):δ164.0,146.0,134.6(q,J C-F = 33.1Hz), 130.7, 127.4, 126.2(q, J C-F =3.6Hz),123.0(q,J C-F =271.3Hz),117.3(ddd,J C-F =271.4Hz, J C-F =266.4Hz,J C-P =212.9Hz), 65.2(d, J C-P =6.6Hz),65.1(d,J C-P =6.8Hz),52.7(td,J C-F =J C-P =24.5Hz), 26.1(t, J C-F =5.7Hz),25.1,16.2(d,J C-P =5.0Hz), 16.2(d, J C-P =5.0Hz); 19 F-NMR(376MHz, CDCl 3 ):δ-63.2(s,3F), -105.0to-106.1(m,1F),-107.9to-109.0(m,1F); 31 P-NMR(162MHz, CDCl 3 ...

Embodiment 3

[0041] The operation is the same as before, and the reaction process is as follows:

[0042]

[0043] The structure of the obtained 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate is as follows, and the yield is 70%.

[0044]

[0045] Diethyl(2-chloro-3-cyclopentylidene-1,1-difluoro-3-tosylpropyl)phosphonate IR(neat): 2984,2930,1720,1604,1450,1288,1141,1018,887,810,656cm -1 ; 1 H-NMR (400MHz, CDCl 3 ): δ7.74(d,J=8.4Hz,2H), 7.29(d,J=8.0Hz,2H), 6.09(ddd,J H-F = 20.6, 10.4 Hz, J H-P =1.4Hz, 1H), 4.36-4.26 (m, 4H), 3.04-2.90 (m, 2H), 2.63-2.55 (m, 1H), 2.40 (s, 3H), 2.27-2.18 (m, 1H), 1.76-1.69(m,1H),1.66-1.55(m,2H),1.51-1.44(m,1H),1.38(t,J=7.2Hz,6H); 13 C-NMR (100MHz, CDCl 3 ):δ173.4,144.0,138.4,129.5,127.3,117.5(td,J C-F =271.2Hz,J C-F =266.1Hz,J C-P =212.8Hz), 65.1(d, J C-P =6.6Hz),65.0(d,J C-P =6.9Hz),53.5(td,J C-F = 25.6Hz, J C-P =22.0Hz),36.1(t,J C-P =5.8Hz),35.3,25.9,25.7,21.5,16.3(d,J C-P =5.3Hz), 16.2(d, J C-P =4.4Hz); 19 F-NMR(376MHz, CDCl 3 )δ:-104.2to-105....

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Abstract

The invention discloses a 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound, a sulfonylation reaction synthetic method which adopts photoinduction and has high regioselectivity and application of the 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound serving as an enzyme inhibitor in preparation of antitumor drugs. A structural formula of the compound is shown in the description, wherein substituent groups R1 and R2 are alkyl groups, or R1 and R2 are connected to form a C3-C6 naphthenic base, and R3 is selected from an alkyl group, a heterocyclic aromatic group and asubstituent or non-substituent aromatic group. Compared with the prior art, the method is a green, efficient, simple and high-regioselectivity method for synthesis of 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate. The method is simple, mild in condition, great in substrate applicability and high in regioselectivity, the yield of target objects can reach 45-84%, and under an inductive effect of visible light, a sulfonylation reaction is carried out selectively on a 2,3-double bond of allene.

Description

Technical field [0001] The invention relates to a 1,1-difluoro-3-sulfonyl-2-chloro-3-butenyl phosphonate compound, a synthesis method and application thereof, and belongs to the technical field of phosphonate compounds. Background technique [0002] Sulfone compounds have unique chemical, biological and pharmaceutical activities. Sulfone skeletons exist in a variety of natural products. They have great potential in the synthesis of biologically active molecules and are widely used in medicine, pesticides and material chemistry. Therefore, the construction of C-S bonds has attracted the research interest of many chemists. On the other hand, phosphates are the active groups of natural phosphates. Such compounds play an important role in the organism, and play a very important role in the regulation of intracellular metabolism and signal transduction across cell membranes. But phosphate groups are generally not used in drug design, because phosphate esters are easily hydrolyzed by ...

Claims

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Application Information

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IPC IPC(8): C07F9/40C07F9/6553A61P35/00
CPCA61P35/00C07F9/4006C07F9/4015C07F9/655345
Inventor 林云李花蒋旭
Owner NANJING NORMAL UNIVERSITY
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