Diisopropylethylamine → (R)-N-(4-((Difluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

HRID 924077Notes

Reaction equation

HRID 924077 reaction equation
[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:55][CH:56]([S:58][C:59]1[CH:65]=[CH:64][C:62]([NH2:63])=[CH:61][CH:60]=1)[F:57]>CN(C=O)C.CCOC(C)=O>[F:57][CH:56]([F:55])[S:58][C:59]1[CH:60]=[CH:61][C:62]([NH:63][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:21]=[N:20][CH:19]=[N:18][CH:17]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:64][CH:65]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 36891354-((Difluoromethyl)sulfanyl)anilineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 118195186(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid

Product 1

HCID 89908262(R)-N-(4-((Difluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 60 mg, 0.21 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 88 mg, 0.231 mmol) and DIPEA (73.2 μL, 0.419 mmol), in DMF (419 μL), was stirred at RT for 10 min. 4-Difluoromethylsulfanyl-aniline (60 mg, 0.21 mmol) was added and the RM was stirred for 2 days. The RM was diluted with EtOAc and washed with brine. The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) to obtain the title compound as a solid. UPLC-MS (Condition 3), tR=0.86 min, m/z=444.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm (TFA), 1.82 (br. s, 1H) 1.90 (d, J=8.60 Hz, 1H) 2.97 (d, J=10.95 Hz, 1H) 3.28 (d, J=7.04 Hz, 2H) 3.35-3.47 (m, 1H) 4.26 (br. s, 1H) 7.49-7.63 (m, 2H) 7.79-7.90 (m, 2H) 8.25 (br. s, 1H) 8.74 (br. s, 1H) 8.89-8.98 (m, 2H) 9.20-9.28 (m, 1H).

Workup

  1. washwashed with brine
  2. dry with materialThe organic phase was dried over MgSO4
  3. customevaporated to dryness under reduced pressure
  4. customThe crude product was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min)

Sources & evidence

ORD record
ord-4f16dbc755e3416aac5c14995cc44f9d
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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