1,2-Dimethoxyethane → (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrrol-2-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

HRID 525678Notes

Reaction equation

HRID 525678 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 467391081-Boc-pyrrole-2-boronic acid, pinacol esterHCID 86702604(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

Product 1

HCID 89908429(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrrol-2-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.1, 100 mg, 0.216 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.433 mmol) Pd(PPH3)2Cl2 (15.18 mg, 0.022 mmol), Na2CO3 (92 mg, 0.865 mmol), DME (918 μL), water (262 μL) and EtOH (131 μL) were added to a MW vial, which sealed, evacuated/purged with argon and the RM was stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 91 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column DEAP, from 24% to 29% in 10 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=449.2 [M+H]+, m/z=447.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (dd, J=6.48, 2.57 Hz, 1H) 1.83 (dd, J=8.68, 4.28 Hz, 1H) 2.98 (d, J=11.98 Hz, 1H) 3.22-3.29 (m, 2H) 3.37-3.50 (m, 1H) 4.19 (d, J=2.45 Hz, 1H) 4.81 (d, J=3.42 Hz, 1H) 5.94-6.17 (m, 2H) 6.67-6.87 (m, 1H) 7.67 (d, J=8.80 Hz, 2H) 7.83-7.99 (m, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.25 (s, 1H) 11.11 (br. s, 1H).

Workup

  1. customsealed
  2. customevacuated/purged with argon
  3. additionMeOH (0.5 mL) was added
  4. customthe RM was subjected to MW irradiation at 150° C. for 5 min
  5. additionThe RM was diluted with DME (3 mL)
  6. filtrationthe supernatant was filtered
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a residue which
  9. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 40% to 100% EtOAc)
  10. customfollowed by preparative SFC (Column DEAP, from 24% to 29% in 10 min)

Sources & evidence

ORD record
ord-bf7f3497f3a146638eb249dd280caa7b
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

Loading…