4'-Amino-5'-methoxy-N,2'-dimethylbiphenyl-4-carboxamide → Methyl 2-(5-chloro-2-(5-methoxy-2-methyl-4'-(methylcarbamoyl)biphenyl-4-ylamino)pyrimidin-4-ylamino)benzoate

HRID 2091955Notes

Reaction equation

HRID 2091955 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH3:38])=[O:36])=[CH:31][CH:30]=2)=[C:23]([CH3:39])[CH:22]=1>CC(O)C.Cl>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:36])[NH:37][CH3:38])=[CH:31][CH:30]=3)=[C:23]([CH3:39])[CH:22]=2)=[N:3][CH:4]=1

Participants

5

Reactant 2

HCID 595867914'-Amino-5'-methoxy-N,2'-dimethylbiphenyl-4-carboxamide2×HCID 86647794Methyl 2-((2,5-dichloropyrimidin-4-yl)amino)benzoate

Product 1

HCID 68512573Methyl 2-(5-chloro-2-(5-methoxy-2-methyl-4'-(methylcarbamoyl)biphenyl-4-ylamino)pyrimidin-4-ylamino)benzoate

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of methyl 2-(2,5-dichloropyrimidin-4-ylamino)benzoate (Step 1, 50 mg, 0.16 mmol) and 4′-amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (Intermediate 31, 46 mg, 0.16 mmol) in 2-propanol is treated with conc. aqueous HCl (4 drops). The mixture is sealed and heated in a microwave at 120° C. for 20 min. The mixture is concentrated, and the residue is partitioned between ethyl acetate and sodium carbonate aqueous solution. The organic layer is concentrated to afford crude methyl 2-(5-chloro-2-(5-methoxy-2-methyl-4′-(methylcarbamoyl)biphenyl-4-ylamino)pyrimidin-4-ylamino)benzoate as a brown solid. The obtained crude product is treated with neat cyclopropylamine (0.5 mL). The mixture is heated in a sealed tube at 110° C. overnight. The mixture is concentrated and the residue is applied to RP-HPLC for purification to afford the 4′-(5-chloro-4-(2-(cyclopropylcarbamoyl)phenylamino) pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (m, 1H), 8.49 (m, 1H), 8.15 (s, 1H), 7.91 (d, 2h0, 7.73-7.71 (m, 1H), 7.60 (m, 1H), 7.46 (d, 2H), 7.30-7.26 (m, 1H), 6.98 (s, 1H), 3.88 (s, 3H), 2.96 (s. 3H), 2.90-2.86 (m, 1H), 2.15 (s, 3H), 0.86-0.83 (m, 2H), 0.67-0.65 (m, 2H); ESMS m/z 557.2 (M+H+).

Workup

  1. customThe mixture is sealed
  2. concentrationThe mixture is concentrated
  3. customthe residue is partitioned between ethyl acetate and sodium carbonate aqueous solution
  4. concentrationThe organic layer is concentrated

Sources & evidence

ORD record
ord-45d3eb3b15624197bb2ea26c42fd1534
Source dataset
uspto-grants-2013_05
Patent number
US08440681B2

Reaction notes

Loading…