1,2-Dichloroethane → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

HRID 924016Notes

Reaction equation

HRID 924016 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.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl:36][C:37]([F:47])([F:46])[O:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>CN1CCOCC1.CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]([F:46])([F:47])[O:38][C:39]1[CH:40]=[CH:41][C:42]([NH:43][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]3)=[N:8][CH:9]=2)=[CH:44][CH:45]=1

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 5727934-(Chlorodifluoromethoxy)anilineHCID 118195186(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid

Product 1

HCID 89908140(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 79724-MethylmorpholineSolventHCID 8857Ethyl AcetateSolvent

Procedure

(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinic acid (Stage 170.1, 57.3 mg, 0.2 mmol), HOBT (43.5, 0.284 mmol) and EDC (42.2 mg, 0.22 mmol) were dissolved in 0.3 M NMM in DMF (0.8 mL) at RT. 4-(Chlorodifluoromethoxy)aniline (36.8 mg, 0.19 mmol) was added and the RM was stirred for 5 h. The RM was then diluted with EtOAc and washed with 10% NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2 to 5% MeOH) and treated with Si-Thiol (50 mg) in MeOH to afford the title compound. HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH/MeOH (50:50), 0.5 mL/min, UV 210 nm) tR=21.89 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=462.2/464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.33-3.44 (m, 1H) 4.12-4.24 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.77-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.17 (s, 1H).

Workup

  1. washwashed with 10% NaHCO3
  2. dry with materialThe organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. customevaporated to dryness under reduced pressure
  5. customThe residue was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2 to 5% MeOH)
  6. additiontreated with Si-Thiol (50 mg) in MeOH

Sources & evidence

ORD record
ord-86e95d02e3fe46fd9d2167ab16555a73
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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