Oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof
A technology of compounds and oxygen bridges, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, drug combinations, etc., can solve problems affecting drug efficacy, achieve strong inhibitory activity, and down-regulate estrogen receptor levels
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[0137] Preparation of Ethylene Sulfonate Derivatives 13b~13l
[0138] Referring to the preparation method of vinylsulfonate derivative 13a containing a covalent warhead, compound 12 and As starting materials, ethylene sulfonate derivatives 13b-13l were prepared.
[0139] 4. Synthesis of vinylsulfonamide derivatives 16a-16j:
[0140]
[0141] (1) Weigh 1.0eq. of aminophenyl derivatives in a 100mL one-mouth bottle, add 25mL of DCM, dropwise add 1.2eq. of trifluoroacetic anhydride (14g is synthesized by adding acetic anhydride), and react at room temperature for 12 hours. The reaction was quenched by adding 10 mL of water, extracted with DCM, saturated NaHCO 3 Solution washing, organic layer anhydrous NaSO 4 Drying and precipitation under reduced pressure gave crude products, and column chromatography (eluent, petroleum ether / ethyl acetate=10:1~1:1) gave compounds 14a~14g.
[0142] (2) Weigh 1.0eq. compound 14a-14g and 50mL two-necked flask, add 20mL DCM, replace with a...
Embodiment 1
[0146] [Example 1] 4-acrylamide phenyl-5,6-bis(4-hydroxyphenyl)-7-oxo bridge bicyclo-[2.2.1]-hept-5-ene-2-sulfonic acid ester 17a preparation
[0147]
[0148] Weigh 3,4-bis(4-hydroxyphenyl)furan 1.0e.q and 4-acrylamide phenylethylene sulfonate (13a) 1.0e.q into a 25mL single-necked round-bottom bottle, add 1mL tetrahydrofuran, and then slowly raise the temperature After reaction at 90°C for 12 hours, it was spin-dried, separated and purified by direct column chromatography, the eluent ratio was dichloromethane:methanol=60:1, and a yellow solid was obtained with a yield of 61%.
[0149] 1 H NMR (400MHz, Acetone-d 6 )δ9.59(s,1H),8.82(d,J=3.2Hz,1H),8.75(d,J=3.0Hz,1H),7.81–7.67(m,2H),7.30–7.13(m,6H ),6.89–6.74(m,4H),6.39(m,J=16.9,6.0Hz,2H),5.72(dd,J=9.7,2.3Hz,1H),5.64–5.62(m,1H),5.43( d,J=4.3Hz,1H),3.77(dd,J=8.3,4.5Hz,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H ).
[0150] 13 C NMR (101MHz, Acetone-d 6 )δ163.46,162.32,157.71,157.56,145.09,141.29,138.19,136.96,...
Embodiment 2
[0151] [Example 2] 4-(2-butenamido)phenyl-5,6-bis(4-hydroxyphenyl)-7-oxo-bridge bicyclo-[2.2.1]-hept-5-ene-2 - Preparation of sulfonate 17b
[0152]
[0153] Referring to the preparation method of Example 1, using 3,4-bis(4-hydroxyphenyl)furan and ethylenesulfonate derivative 13b as raw materials, the product was a yellow solid with a yield of 53%.
[0154] 1 H NMR (400MHz, Acetone-d 6 )δ9.39(s,1H),8.76(s,2H),7.77(dd,J=34.6,9.0Hz,2H),7.38–7.12(m,6H),6.97–6.88(m,1H),6.87 –6.74(m,4H),6.12(dd,J=15.1,1.5Hz,1H),5.65–5.60(m,1H),5.40(t,J=18.0Hz,1H),3.80–3.56(m,1H ),2.40(dt, J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H),1.85(dd,J=6.9,1.2Hz,3H).
[0155] 13 C NMR (101MHz, Acetone-d 6 )δ163.76,157.58,157.44,144.89,141.34,140.61,138.45,137.02,129.20,128.60,125.70,124.12,123.32,122.57,120.39,115.73,115.51,84.38,82.77,60.50,30.60,16.94.
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