1,2-Dimethoxyethane → 4-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-(1H-pyrrol-2-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

HRID 525684Notes

Reaction equation

HRID 525684 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:37]2[N:38](C(OC(C)(C)C)=O)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:37]2[NH:38][CH:39]=[CH:40][CH:41]=2)[CH2:23]1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 467391081-Boc-pyrrole-2-boronic acid, pinacol esterHCID 899064793-Bromo-4-((3 S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Product 1

HCID 1180450144-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-(1H-pyrrol-2-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 28.1, 100 mg, 0.217 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.434 mmol), Pd(PPh3)2Cl2 (15.22 mg, 0.022 mmol), Na2CO3 (92 mg, 0.867 mmol), DME (920 μL), water (263 μL) and EtOH (131 μL) were added to a MW vial, which was 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 at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 90 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, 4 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column NH2, from 25% to 30% in 10 min) to yield the title compound as a grey solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=448.1 [M+H]+, m/z=446.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (d, J=11.00 Hz, 2H) 3.28-3.34 (m, 6H) 3.86 (br. s, 2H) 4.97 (d, J=3.42 Hz, 2H) 6.03-6.07 (m, 1H) 6.07-6.12 (m, 1H) 6.75-6.77 (m, 1H) 6.78 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 2H) 7.82 (dd, J=8.80, 2.45 Hz, 1H) 7.85 (d, J=2.20 Hz, 1H) 7.86-7.91 (m, 2H) 10.07 (s, 1H) 10.97 (d, J=1.71 Hz, 1H).

Workup

  1. customwas sealed
  2. customevacuated/purged with argon
  3. additionMeOH (0.5 mL) was added
  4. waitthe RM was subjected to MW 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, 4 g, cyclohexane/EtOAc from 40% to 100% EtOAc)
  10. customfollowed by preparative SFC (Column NH2, from 25% to 30% in 10 min)

Sources & evidence

ORD record
ord-379070889b854db69e31add5ab9b5e8a
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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