1,2-Dimethoxyethane → N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)benzamide

HRID 924119Notes

Reaction equation

HRID 924119 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]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.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>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:3]=2)=[CH:9][CH:10]=1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899064003-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3 S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide

Product 1

HCID 118195281N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)benzamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 80 mg, 0.167 mmol), pyrimidin-5-ylboronic acid (41.5 mg, 0.335 mmol), Pd(PPh3)2Cl2 (11.76 mg, 0.017 mmol) and Na2CO3 (71.0 mg, 0.670 mmol) were added to a MW vial and treated with a mixture of DME (710 μL), water (203 μL) and EtOH (101 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min, diluted with MeOH (1 mL) and DCM (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 69.8 mg, 0.1 mmol). The solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/(MeOH-1% NH4OH), from 2% to 12% (MeOH-1% NH4OH). Product was further purified by preparative SFC (Column DEAP, from 25% to 30% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.90 min, m/z=476.9 [M+H]+, m/z=521.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.75 (d, J=10.39 Hz, 2H) 3.27 (dd, J=10.33, 3.61 Hz, 2H) 3.88 (br. s, 2H) 5.09 (d, J=3.18 Hz, 2H) 6.97 (d, J=8.93 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.17 (s, 1H) 10.11 (s, 1H).

Workup

  1. customThe vial was sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 125° C. for 10 min
  4. additiondiluted with MeOH (1 mL) and DCM (2 mL)
  5. customThe solvent was evaporated off under reduced pressure
  6. customto give a crude product that
  7. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/(MeOH-1% NH4OH)
  8. customProduct was further purified by preparative SFC (Column DEAP, from 25% to 30% in 10 min)

Sources & evidence

ORD record
ord-e7de429b50894df9bc6eefbdfe7ea9cf
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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