Diisopropylethylamine → HCID 78318940, compound

HRID 527429Notes

Reaction equation

HRID 527429 reaction equation
[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.[CH3:18][C:19]1[C:28]2[CH:27]=[N:26][C:25](S(C)=O)=[N:24][C:23]=2[N:22]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=2)[C:21](=[O:43])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]3[N:26]=[CH:27][C:28]4[C:19]([CH3:18])=[CH:20][C:21](=[O:43])[N:22]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:23]=4[N:24]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 86709973HCID 86709973, compoundHCID 86732024N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

Product 1

HCID 78318940HCID 78318940, compoundYield 49%

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c; 373 mg, 1.56 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 440 mg, 1.194 mmol) in tert-butanol (10 mL) was added DIEA (0.62 mL, 3.58 mmol). The mixture was heated in an oil bath at 80° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 5-10% 2M NH3/MeOH in DCM) affording enriched product. It was then repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The desired fractions were collected, and concentrated to dryness in a genevac overnight. The resulting solid was dissolved in 9:1=DCM:MeOH and was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried under vacuum affording N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (317 mg, 0.58 mmol, 49% yield) as a yellow solid. m/z (ESI, +ve ion) 544.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.78 (1H, br. s.), 8.05 (1H, br. s.), 7.84 (1H, d, J=7.0 Hz), 7.60 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.15 (1H, d, J=9.0 Hz), 6.99 (1H, d, J=9.0 Hz), 6.41-6.51 (1H, m), 6.23-6.34 (2H, m), 6.16 (1H, d, J=2.2 Hz), 5.85 (1H, br. s.), 5.73-5.81 (1H, m), 5.57 (1H, br. s.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, 1=4.8 Hz), 3.90 (1H, br. s.), 3.73 (5H, br. s.), 2.76-2.88 (2H, m), 2.74 (1H, t, J=4.9 Hz), 2.63-2.71 (1H, m), 2.46 (3H, s).

Workup

  1. concentrationThe reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator)
  2. customthe crude residue was purified on silica gel on an ISCO Combiflash RF (40 g Redisep column
  3. customaffording
  4. customIt was then repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water)
  5. customThe desired fractions were collected
  6. concentrationconcentrated to dryness in a genevac overnight
  7. dissolutionThe resulting solid was dissolved in 9:1=DCM
  8. concentrationthen concentrated
  9. customdried under vacuum

Sources & evidence

ORD record
ord-48c459cc3e27417eb007220c09fd5089
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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