Methanol → Nav1.7 inhibitor

HRID 508403Notes

Reaction equation

HRID 508403 reaction equation
Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:4][C:3]=1[F:19].[CH3:20][S:21]([NH2:24])(=[O:23])=[O:22].N12CCCN=C1CCCCC2.[CH3:36][OH:37]>O1CCOCC1.ClCCl.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[Cl:8][C:6]1[C:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:4][C:3]([F:19])=[C:2]([CH:7]=1)[C:36]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[O:37]

Participants

10

Reactant 4

HCID 887MethanolHCID 72879MethanesulfonamideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 666664431-Bromo-5-chloro-4-((3,4-dichlorophenoxy)methyl)-2-fluorobenzene

Product 1

HCID 56589663Nav1.7 inhibitor

Reagents, catalysts & solvents 5

HCID 98885Molybdenum carbonyl (Mo(CO)6)CatalystHCID 2734635Tri-tert-butylphosphine tetrafluoroborateCatalystHCID 11104995trans-Bis(acetato)bis[2-[bis(2-methylphenyl)phosphino]benzyl]dipalladium(II)CatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A 5 mL microwave reaction vial was charged with 1-bromo-5-chloro-4-((3,4-dichlorophenoxy)methyl)-2-fluorobenzene (Preparation 1, 206 mg, 0.54 mmol), molybdenumhexacarbonyl (139 mg, 0.53 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (25.9 mg, 0.028 mmol), tri-tert-butylphosphonium tetrafluoroborate (16.8 mg, 0.058 mmol), methanesulphonamide (159 mg, 1.67 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL, 1.56 mmol) in 1,4-dioxane (1.80 mL). The vessel was sealed under air and exposed to microwave irradiation at 140° C. for 15 minutes. Once the reaction had cooled to room temperature the reaction mixture was then concentrated in vacuo to afford a brown oil. The oil was then passed through a short plug of silica eluting with 5% methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to afford an off white solid (266 mg). A portion of this material (190 mg) was purified by reverse phase column chromatography using the ISCO™ system (30 g ISCO C-18 cartridge) using a gradient of water/0.01% formic acid/acetonitrile to 0.01% formic acid/water as eluant to give the title compound (50 mg, 22%) as a white solid.

Workup

  1. customA 5 mL microwave reaction
  2. customThe vessel was sealed under air
  3. customirradiation at 140° C. for 15 minutes
  4. concentrationwas then concentrated in vacuo
  5. customto afford a brown oil
  6. additioncontaining product
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-587c075c25c345ff81a72a9933725a71
Source dataset
uspto-grants-2015_08
Patent number
US09096500B2

Reaction notes

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