N-methyl-2-pyrrolidone → (E)-N-(3-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-ylamino)phenyl)-4-(dimethylamino)but-2-enamide

HRID 1014143Notes

Reaction equation

HRID 1014143 reaction equation
C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:13]=1.CN1C(=O)CCC1.[CH3:37][N:38]([CH2:40]/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH3:39]>C1COCC1.CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([NH:25][C:43](=[O:44])/[CH:42]=[CH:41]/[CH2:40][N:38]([CH3:39])[CH3:37])[CH:22]=[CH:23][CH:24]=2)[CH:13]=1

Participants

7

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 65578Oxalyl chlorideHCID 10012053(2E)-4-(Dimethylamino)-2-butenoyl chlorideHCID 57708305N'-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine

Product 1

HCID 42601819(E)-N-(3-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-ylamino)phenyl)-4-(dimethylamino)but-2-enamide

Reagents, catalysts & solvents 2

HCID 21974620tetrahydrofuran N,N-dimethylformamideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Oxalyl chloride (155 mg, 1.2 mmol) was added dropwise to a mixture of 4-N, N-dimethyl aminocrotonic acid HCl salt (200 mg, 1.2 mmol) in 5 mL of THF at 0° C. To this mixture was added 3 drops of DMF/THF solution (made from 5 drops of DMF in 1 mL of THF). The reaction mixture was stirred at RT for 2 h, then was cooled to 0° C. ice bath. A solution of N1-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine (200 mg, 0.6 mmol) 2 mL of NMP) was added to the dimethylaminocrotonyl chloride solution and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 3 mL of 1N NaOH, and was extracted with EtOAc (2×25 mL). The crude product mixture was purified by flash chromatography on silica gel with MeOH/NH4OH/DCM solvent system to afford (E)-N-(3-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-ylamino)phenyl)-4-(dimethylamino)but-2-enamide (I-92) as a light colored solid. MS (m/z): MH+=442, 444 (3:1), H-NMR (DMSO) δ 10.08 (s, 1H), 9.67 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H), 7.57 (t, 1H), 7.53-7.24 (m, 4H), 6.29 (b, 1H), 6.23 (s, 1H), 3.51 (d, 2H), 2.21 (s, 6H).

Workup

  1. temperaturewas cooled to 0° C. ice bath
  2. stirringthe resulting mixture was stirred for 3 h at 0° C
  3. customThe reaction was quenched with 3 mL of 1N NaOH
  4. extractionwas extracted with EtOAc (2×25 mL)
  5. customThe crude product mixture was purified by flash chromatography on silica gel with MeOH/NH4OH/DCM solvent system

Sources & evidence

ORD record
ord-afeb80918de94906a4b86e6af506aa6d
Source dataset
uspto-grants-2011_07
Patent number
US07982036B2

Reaction notes

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