Aryl nitrogen mustard-domide conjugate and preparation method and pharmaceutical application thereof
A kind of aromatic nitrogen mustard and conjugate technology, applied in the field of biomedicine
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Embodiment 1
[0047] 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl) butanamide (I 1 ) preparation
[0048] Lenalidomide (1a, 259mg, 1.0mmol) was dissolved in 10ml of anhydrous CH 2 Cl 2 , then sequentially added chlorambucil (2a, 333mg, 1.1mmol), EDCI (384mg, 2.0mmol) and DMAP (25.9mg, 10%), and heated to 40°C for reflux reaction after all of them were dissolved. After the reaction was detected by TLC, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase ethyl acetate:petroleum ether=2:1-4:1) to obtain 338mg of white solid, yield 62%.ESI-MS (m / z):545[M+H] + . 1 H NMR (DMSO-d 6 ,400MHz): δ11.04(s,1H,NH),9.79(s,1H,NH),7.81(d,1H,J=8.0Hz,Ar-H),7.52(d,1H,J=8.0Hz ,Ar-H),7.49(m,1H,Ar-H),7.06(d,2H,J=8.0Hz,Ar-H),6.68(d,2H,J=8.0Hz,Ar-H),5.15 (m,1H,CH),4.37(m,2H,CH 2 ),3.70(m,8H,CH 2 ),2.59(m,2H,CH 2 ),2.51(m,2H,CH 2 ),2.36(m,2H,CH 2 ),2.03(m,2H,CH 2 ),1.87(m,2H,CH 2 ...
Embodiment 2
[0050] 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-(2,6-dioxopiper Pyridin-3-yl)-1-oxoisoindoline-4-yl)butanamide (I 2 ) preparation
[0051] Lenalidomide (1a, 259mg, 1.0mmol) was dissolved in 10ml of anhydrous CH 2 Cl 2 , and then sequentially added bendamustine hydrochloride hydrate (2b, 454mg, 1.1mmol), HATU (2.0mmol), DMAP (130mg, 50%) and triethylamine (404mg, 4.0mmol), until it was completely dissolved After heating to 40 ° C reflux reaction. After the reaction was detected by TLC, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase methanol: dichloromethane = 1:30-1:15) to obtain 305 mg of a light yellow solid with a yield of 51%. ESI-MS (m / z):599[M+H] + . 1 H NMR (DMSO-d 6 ,400MHz):δ11.03(s,1H,NH),9.87(s,1H,NH),7.81(m,1H,Ar-H),7.50(m,1H,Ar-H),7.34(d, 1H,J=8.0Hz,Ar-H),6.93(m,1H,Ar-H),6.79(m,1H,Ar-H),5.15(m,1H,CH),4.37(m,2H,CH 2 ),3.71(s,8H,CH 2 ),3.69(s,3H,CH...
Embodiment 3
[0053] 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-4-yl)butanamide (I 3 ) preparation
[0054] Referring to compound (I) in Example 1 1 ) preparation method, pomalidomide (1b, 273mg, 1.0mmol) was substituted for lenalidomide and chlorambucil to react to obtain light yellow solid 301mg, yield 54%, ESI-MS (m / z): 559[M+H] + . 1 HNMR (DMSO-d 6 ,400MHz):δ11.15(s,1H,NH),9.69(s,1H,NH),8.45(d,1H,J=8.0Hz,Ar-H),7.82(t,1H,J=8.0Hz ,Ar-H),7.61(d,1H,J=8.0Hz,Ar-H),7.05(d,2H,J=8.0Hz,Ar-H),6.67(d,2H,J=8.0Hz,Ar -H),5.15(m,1H,CH),3.69(s,8H,CH 2 ),2.90(m,2H,CH 2 ),2.62(m,2H,CH 2 ),2.46(t,2H,J=8.0Hz,CH 2 ),2.05(m,2H,CH 2 ),1.89(m,2H,CH 2 ).
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