Pyridine → Ivacaftor

HRID 446150Notes

Reaction equation

HRID 446150 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[C:17]1C=CC=[CH:19][C:18]=1[CH2:23]CCC.[CH3:30][CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1.C(P1(=O)OP(CCC)(=O)OP([CH2:50][CH2:51][CH3:52])(=O)O1)CC.[N:54]1C=CC=C[CH:55]=1.[CH3:60][O-].[Na+].CO>>[C:51]([C:34]1[CH:33]=[C:32]([C:18]([CH3:17])([CH3:19])[CH3:23])[C:31]([OH:35])=[CH:30][C:55]=1[NH:54][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])([CH3:52])([CH3:60])[CH3:50]

Participants

7

Reactant 6

HCID 1049PyridineHCID 73012-Methyltetrahydrofuran3×HCID 111923Propylphosphonic anhydrideHCID 2208754-Quinolone-3-carboxylic acidHCID 20192410HCID 20192410, compoundHCID 23694274Sodium methanolate methanol

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 25.0° C.+/−2.5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (˜16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10% H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0° C.+/−5.0° C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0° C.+/−5° C. over 5 hours, and filtered. The cake was washed with 0.0° C.+/−5.0° C. CH3CN (5 vol) 4 times. The resulting solid (compound 34) was dried in a vacuum oven at 50.0° C.+/−5.0° C. 1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H).

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 25.0° C.+/−2.5° C
  4. additionto dilute the mixture
  5. washThe reaction mixture was washed with water (10.0 vol) 2 times
  6. addition2-MeTHF was added
  7. customthe total volume of reaction
  8. additionto 40.0 vol (˜16.5 vol charged)
  9. customOnce complete, the reaction was quenched with 1 N HCl (10.0 vol)
  10. washwashed with 0.1 N HCl (10.0 vol)
  11. filtrationfiltered
  12. customto remove any particulates
  13. customplaced in a second reactor
  14. concentrationThe filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN
  15. additionwas added to 40 vol
  16. concentrationthe solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20
  17. additionThe addition of CH3CN and concentration cycle
  18. concentrationfor a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final
  19. concentrationconcentration to 20 vol, 16.0 vol of CH3CN
  20. additionwas added
  21. temperatureThis slurry was heated to 78.0° C.+/−5.0° C.
  22. temperature(reflux)
  23. stirringThe slurry was then stirred for no less than 5 hours
  24. temperatureThe slurry was cooled to 0.0° C.+/−5° C. over 5 hours
  25. filtrationfiltered
  26. washThe cake was washed with 0.0° C.+/−5.0° C
  27. dry with materialThe resulting solid (compound 34) was dried in a vacuum oven at 50.0° C.+/−5.0° C

Sources & evidence

ORD record
ord-3985cee199284d1a91032d7084b5729a
Source dataset
uspto-grants-2013_07
Patent number
US08476442B2

Reaction notes

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