Hydrochloric Acid → Bms-777607

HRID 1043040Notes

Reaction equation

HRID 1043040 reaction equation
[Cl:1][C:2]1[C:3]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:34])[N:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=1[F:35].CO.Cl.[OH-].[Na+]>CC(OC)(C)C.O>[NH2:36][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:34])[N:20]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=2[F:35])[CH:6]=[CH:5][N:4]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 86659921N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Product 1

HCID 24794418Bms-777607Yield 88%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
10 °C

Procedure

To a 250 mL vessel, N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (100.0 g, 147.7 mmoles, 1.0 eq) and methanol (900 mL) were charged. The white slurry was cooled to 10° C. and concentrated HCl (16.3 g, 163.3 mmoles, 1.105 eq) was added, maintaining the reaction temperature below 10° C. The reaction mixture was held at 10° C. for approximately 2.5 h, until HPLC indicated ≦0.5 relative area percent of starting material. Water (500 mL) and MTBE (500 mL) were added and the reaction mixture was warmed to 20° C. Next, 1N NaOH (184.08 g, 177.0 mL, 177 mmoles, 1.20 eq), was added dropwise over 20 minutes while maintaining the temperature between 15 and 20° C. The resulting slurry was cooled to 10° C. and aged for at least 10 minutes. The precipitate was filtered off, and the cake washed with water (2×350 mL), followed by a mixture of methanol:MTBE (10:90) (1×300 mL). Next, the cake was dried in a vacuum oven at 50-60° C. until LOD analysis indicated less than 1 wt % of volatiles. N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide: 79.5 g (95% yield with 98.1 AP and 99.4 wt % potency). The resulting product (35.0 g) was subsequently re-crystallized from THF (367.2 mL)/EtOH (200 proof, 244.8 mL)/n-heptane (350 mL) to obtain N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30.8 g) in 88% yield with >99.9 AP and 99.7 wt % potency.

Workup

  1. temperaturemaintaining the reaction temperature below 10° C
  2. temperaturethe reaction mixture was warmed to 20° C
  3. temperaturewhile maintaining the temperature between 15 and 20° C
  4. temperatureThe resulting slurry was cooled to 10° C. and aged for at least 10 minutes
  5. filtrationThe precipitate was filtered off
  6. washthe cake washed with water (2×350 mL)
  7. additionfollowed by a mixture of methanol:MTBE (10:90) (1×300 mL)
  8. customNext, the cake was dried in a vacuum oven at 50-60° C. until LOD analysis
  9. customThe resulting product (35.0 g) was subsequently re-crystallized from THF (367.2 mL)/EtOH (200 proof, 244.8 mL)/n-heptane (350 mL)

Sources & evidence

ORD record
ord-fe1090fc61274f0aa7e9d121ac0b58db
Source dataset
uspto-grants-2013_10
Patent number
US08558000B2

Reaction notes

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