Diisopropylethylamine → Icenticaftor

HRID 444902Notes

Reaction equation

HRID 444902 reaction equation
[NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:18][CH2:19][C@:20]([CH3:26])([OH:25])[C:21]([F:24])([F:23])[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C@:20]([OH:25])([CH3:26])[CH2:19][NH:18][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([O:12][CH3:13])[N:4]=1)=[O:16]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 584423203-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid2×HCID 86657664(S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

Product 1

HCID 58442344Icenticaftor

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a solution of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) (10 g, 42.3 mmol) and (S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate RA)(7.60 g, 42.3 mmol) in NMP (400 ml) was added HATU (19.3 g, 50.8 mmol) followed by dropwise addition of DIPEA (22.19 ml, 127 mmol) over ˜1 hr. After stirring at room temperature for 30 min, the mixture was added to EtOAc (2 L), washed with 1M NaOH (2×1 L), water (1 L), brine (1 L), dried (MgSO4) and evaporated under reduced pressure to give the crude product as a dark brown oil. Purification by chromatography on silica eluting with a gradient of 1 to-25% of EtOAc in iso-hexane afforded a yellow oil. Recrystallisation of the oil from iso-hexane/DCM afforded 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide as a crystalline solid;

Workup

  1. washwashed with 1M NaOH (2×1 L), water (1 L), brine (1 L)
  2. dry with materialdried (MgSO4)
  3. customevaporated under reduced pressure
  4. customto give the crude product as a dark brown oil
  5. customPurification by chromatography on silica eluting with a gradient of 1 to-25% of EtOAc in iso-hexane
  6. customafforded a yellow oil
  7. customRecrystallisation of the oil from iso-hexane/DCM

Sources & evidence

ORD record
ord-0478defb0218448b849e810dcab93cf2
Source dataset
uspto-grants-2013_07
Patent number
US08476269B2

Reaction notes

Loading…