Diisopropylethylamine → HCID 78318873, compound

HRID 527420Notes

Reaction equation

HRID 527420 reaction equation
FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.Cl.[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48](Cl)=[O:49].CCN(C(C)C)C(C)C>C1COCC1>[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:49]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 21917321(E)-4-(diMethylaMino)but-2-enoyl chlorideHCID 86732023HCID 86732023, compound

Product 1

HCID 78318873HCID 78318873, compoundYield 11.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 255 mg, 0.56 mmol) was added in one portion as a solid to a suspension of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (283 mg, 1.538 mmol) in THF (10 mL) at 0° C. The resulting orange suspension was treated with DIEA (0.39 mL, 2.23 mmol) slowly and stirred for 30 min at 0° C. The reaction mixture was removed from the ice bath and stirred at RT for 30 min. The reaction mixture was treated with silica gel, concentrated on the rotovap and purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow solid. This sample was repurified on the Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated in the genevac overnight and the resulting orange solid 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 again in the genevac for 3 h affording (E)-4-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)but-2-enamide (35 mg, 0.062 mmol, 11% yield) as an orange solid. m/z (ESI, +ve ion) 569.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (1H, s), 8.74 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J=9.4 Hz), 7.79-7.88 (1H, m), 7.59 (1H, s), 7.49 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.6 Hz), 6.73 (1H, dt, J=15.4, 5.8 Hz), 6.51 (1H, d, J=2.3 Hz), 6.44 (1H, Hz), 6.27 (1H, d, J=15.3 Hz), 6.02 (1H, br. s.), 3.77 (3H, s), 3.04 (6H, d, J=5.7 Hz), 2.36-2.46 (4H, m), 2.22 (3H, s), 2.16 (6H, s).

Workup

  1. customThe reaction mixture was removed from the ice bath
  2. stirringstirred at RT for 30 min
  3. additionThe reaction mixture was treated with silica gel
  4. concentrationconcentrated on the rotovap
  5. custompurified on an ISCO Combiflash RF (40 g Redisep column
  6. customaffording
  7. customThis sample was repurified on the Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water)
  8. additionThe product containing fractions
  9. concentrationwere concentrated in the genevac overnight
  10. concentrationthen concentrated
  11. customdried again in the genevac for 3 h

Sources & evidence

ORD record
ord-6a24859e8f844946917f5504a25c0481
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

Loading…