Dichloromethane → N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

HRID 527434

Reaction equation

HRID 527434 reaction equation
[C:1]([NH:5][C:6]1[CH:7]=[C:8]([N:12]2[C:17]3[N:18]=[C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][C:24]=4[O:42][CH3:43])[N:20]=[CH:21][C:16]=3[C:15]([CH3:44])=[CH:14][C:13]2=[O:45])[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.CC#N>C(O)(C(F)(F)F)=O.O>[CH3:43][O:42][C:24]1[CH:25]=[C:26]([N:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[CH:27]=[CH:28][C:23]=1[NH:22][C:19]1[N:20]=[CH:21][C:16]2[C:15]([CH3:44])=[CH:14][C:13](=[O:45])[N:12]([C:8]3[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:11]=[CH:10][CH:9]=3)[C:17]=2[N:18]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 21924481TFA acetonitrileHCID 86732036Tert-butyl 4-(4-((8-(3-acrylamidophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate

Product 1

HCID 78319000N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

Reagents, catalysts & solvents 1

HCID 22392675Trifluoroacetic acid waterSolvent

Procedure

Crude tert-butyl 4-(4-((8-(3-acrylamidophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (18b) from the previous step was treated with DCM (5 mL) and TFA (5.0 mL, 64.9 mmol) and allowed to stir at RT for 30 min. The reaction mixture was concentrated and purified on the on an ISCO Combiflash RF (24 g Redisep Gold column, using a gradient of 5-20% 2 M NH3/MeOH in DCM) affording enriched product. It was repurifed on a Gilson (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in the genevac overnight and then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 20% MeOH/DCM to remove any residual salt then dried under vacuum affording N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (18) (20.6 mg, 0.040 mmol) as a bright yellow amorphous solid. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.80 (1H, s), 8.08 (1H, s), 7.87 (1H, d, J=8.2 Hz), 7.57 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=8.8 Hz), 6.97 (1H, d, J=8.6 Hz), 6.50 (1H, d, J=2.3 Hz), 6.38-6.48 (1H, m), 6.20-6.35 (2H, m), 5.99 (1H, br. s.), 5.76 (1H, dd, J=10.1, 1.9 Hz), 3.77 (3H, s), 2.87-2.99 (4H, m), 2.74-2.85 (4H, m), 2.46 (3H, s).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. custompurified on the on an ISCO Combiflash RF (24 g Redisep Gold column
  3. customaffording
  4. concentrationconcentrated in the genevac overnight
  5. customto remove any residual salt
  6. customthen dried under vacuum

Sources & evidence

ORD record
ord-9516989bc48840128c9228fda3d662bc
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Linked notes

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