Methanol → 6-Chloro-2-(3-(N-methylmethylsulfonamido)-4-(morpholine-4-carbonyl)phenylamino)nicotinamide

HRID 2044102Notes

Reaction equation

HRID 2044102 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.CO>C1COCC1.C(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=2)[N:20]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 2733832Lithium Hexamethyldisilazide2×HCID 221427782,6-Dichloropyridine-3-carboxamideHCID 57489649N-(5-Amino-2-(morpholine-4-carbonyl)phenyl)-N-methylmethanesulfonamide

Product 1

HCID 574896506-Chloro-2-(3-(N-methylmethylsulfonamido)-4-(morpholine-4-carbonyl)phenylamino)nicotinamideYield 58.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A 1 M THF solution of LiHMDS (0.762 mL, 0.762 mmol) was added dropwise to a suspension of 2,6-dichloronicotinamide (54.0 mg, 0.283 mmol) and N-(5-amino-2-(morpholine-4-carbonyl)phenyl)-N-methylmethanesulfonamide (68.2 mg, 0.218 mmol) in THF (0.5 mL) at 0° C. After 21 h at room temperature, LCMS analysis showed that the reaction was less than 50% complete. Additional portions of LiHMDS (0.054 mL) were added at 22, 23, and 24 h time points. After a total of 28 h, the mixture was quenched by saturated NH4Cl (2 mL) and extracted with EtOAc (3×2 mL). The combined extracts were loaded onto a silica gel cartridge and dried in vacuo. The dry cartridge was then connected to an ISCO cartridge and eluted with 30-100% EtOAc in hexanes, then 10% MeOH in CH2Cl2 to give a brown powder (59.3 mg, 58% yield). LCMS: (M+H)+=468.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, s), 8.38 (1H, br. s.), 8.21 (1H, d, J=8.28 Hz), 7.95 (1H, d, J=2.26 Hz), 7.85 (1H, br. s.), 7.55 (1H, dd, J=8.41, 2.13 Hz), 7.30 (1H, d, J=8.28 Hz), 7.01 (1H, d, J=8.03 Hz), 3.64-3.78 (2H, m), 3.45-3.59 (4H, m), 3.23 (2H, m), 3.16 (6H, s).

Workup

  1. customAfter a total of 28 h, the mixture was quenched by saturated NH4Cl (2 mL)
  2. extractionextracted with EtOAc (3×2 mL)
  3. customdried in vacuo
  4. washeluted with 30-100% EtOAc in hexanes

Sources & evidence

ORD record
ord-262ab536b32640d39a83cc54af75b244
Source dataset
uspto-grants-2013_11
Patent number
US08586751B2

Reaction notes

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