Pyridine → Ivacaftor

HRID 76796Notes

Reaction equation

HRID 76796 reaction equation
[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(=O)(OC)[O:16][C:17]1[CH:22]=[C:21]([NH2:23])[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=1[C:28]([CH3:31])([CH3:30])[CH3:29].CC1OCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1.C[O-].[Na+].CO>>[C:24]([C:20]1[CH:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:17]([OH:16])=[CH:22][C:21]=1[NH:23][C:12]([C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:14])([CH3:27])([CH3:25])[CH3:26]

Participants

7

Reactant 6

HCID 1049PyridineHCID 73012-Methyltetrahydrofuran3×HCID 111923Propylphosphonic anhydrideHCID 2208754-Quinolone-3-carboxylic acidHCID 23694274Sodium methanolate methanolHCID 46927778Carbonic acid, 5-amino-2,4-bis(1,1-dimethylethyl)phenyl methyl este

Product 1

HCID 16220172Ivacaftor

Procedure

4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/−5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20° C.+/−5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times and 2-MeTHF (16.5 vol) was charged to the reactor. This solution was charged with 30% w/w NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred at 25.0° C.+/−5.0° C. for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1.2N HCl/H2O (10.0 vol), and washed with 0.1N HCl/H2O (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor.

Workup

  1. washThe T3P charged vessel was washed with 2-MeTHF (0.6 vol)
  2. temperaturethe resulting suspension was heated to 47.5+/−5.0° C.
  3. temperatureOnce complete, the resulting mixture was cooled to 20° C.+/−5° C
  4. additionto dilute the mixture
  5. washThe reaction mixture was washed with water (10.0 vol) 2 times and 2-MeTHF (16.5 vol)
  6. additionwas charged to the reactor
  7. customOnce complete, the reaction was quenched with 1.2N HCl/H2O (10.0 vol)
  8. washwashed with 0.1N HCl/H2O (10.0 vol)
  9. filtrationfiltered
  10. customto remove any particulates
  11. customplaced in a second reactor

Sources & evidence

ORD record
ord-d82f1772d69546239fba981cd12dae9e
Source dataset
uspto-grants-2014_09
Patent number
US08835639B2

Reaction notes

Loading…