Dichloromethane → (R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

HRID 57428

Reaction equation

HRID 57428 reaction equation
Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])=[C:4]([F:18])[CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[NH4+].[Cl-].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.CCCCCCC.COCCOC>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[C:7]([F:8])=[CH:6][C:5]=1[C@@H:9]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10]

Participants

10

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 112635011-Methyl-1H-pyrazole-4-boronic acidHCID 90347558(R)-N-((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Product 1

HCID 90416139(R)-N-((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamideYield 73.7%

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolventHCID 21899848Ethylacetate heptaneSolvent

Conditions

Temperature
100 °C

Procedure

To two microwave vials with stir bars were added (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.47 mmol), 1-Methyl-4-1H-pyrazoleboronic acid, pinacol ester (917 mg, 4.41 mmol), DME (6 ml), Na2CO3 (3.67 ml, 7.35 mmol) (2.0 M aq) and PdCl2(dppf).CH2Cl2 adduct (60.0 mg, 0.07 mmol) divided evenly between the two vessels. Vessels were capped and heated by microwave irradiation for 20 min at 100° C. Reaction mixtures were combined, diluted with a saturated solution of NH4Cl and EtOAc. Phases partitioned. Aqueous phase extracted with EtOAc and organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 60 to 100%) provided (R)—N—((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 1.08 mmol, 73.7% yield). 1H NMR (400 MHz, CDCL3) δ ppm 1.23 (s, 9H) 1.57-1.60 (m, 3H) 3.33 (d, J=4.06 Hz, 1H) 3.97 (s, 3H) 4.79-4.88 (m, 1H) 7.10 (dd, J=11.20, 6.06 Hz, 1H) 7.20 (dd, J=10.78, 6.19 Hz, 1H) 7.76 (d, J=2.20 Hz, 1H) 7.82 (s, 1H). LCMS m/z 342.1 (M+H)+, Rt 0.77 min.

Workup

  1. customVessels were capped
  2. customReaction mixtures
  3. customPhases partitioned
  4. extractionAqueous phase extracted with EtOAc and organic phases
  5. washwashed with water, brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated onto silica gel

Sources & evidence

ORD record
ord-5f786cf5a3484828b2217b2c2861b086
Source dataset
uspto-grants-2016_09
Patent number
US09434719B2

Linked notes

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