Dimethylacetamide → 6-(Difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline

HRID 2176632Notes

Reaction equation

HRID 2176632 reaction equation
Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].Cl[C:16]1[N:21]=[C:20]2[C:22]([C:25]([F:37])([F:36])[C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[CH:31][CH:30]=[CH:29]4)=[N:23][O:24][C:19]2=[CH:18][CH:17]=1.CC(N(C)C)=O>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:37][C:25]([F:36])([C:22]1[C:20]2=[N:21][C:16]([C:2]3[S:6][N:5]=[C:4]([CH3:7])[CH:3]=3)=[CH:17][CH:18]=[C:19]2[O:24][N:23]=1)[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[CH:29]2

Participants

10

Reactant 4

HCID 31374DimethylacetamideHCID 6009595-Bromo-3-methylisothiazoleHCID 576909876-((5-Chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinolineHCID 178461732HCID 178461732, compound

Product 1

HCID 576910776-(Difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinolineYield 3.5%

Reagents, catalysts & solvents 5

HCID 3007855ZincchlorideCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-40 °C

Procedure

To a solution of 5-bromo-3-methylisothiazole (0.19 g, 1.1 mmol) in anhydrous THF (3 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 1.5 mL, 1.5 mmol) at −40° C. The mixture was stirred at −40° C. for twenty minutes followed by the addition of zinc chloride (0.5 M in THF, 3.1 mL, 1.6 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of Q-Phos (0.12 g, 0.17 mmol), Pd2(dba)3 (0.097 g, 0.110 mmol), 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol), and anhydrous dimethylacetamide (3.5 mL). The mixture was stirred at 50° C. for ninety minutes then was diluted with ethyl acetate and washed with water. Organic extracts were dried over magnesium sulfate and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes), then purified by HPLC (eluted with a gradient of 15 to 90% acetonitrile in water) to afford the product as a white solid (4.2 mg, 3%). MS m/z=395.2 [M+1]+ Calc'd for C23H15F2N3O: 394.4.

Workup

  1. customwas brought to room temperature
  2. stirringstirred for thirty minutes
  3. stirringThe mixture was stirred at 50° C. for ninety minutes
  4. washwashed with water
  5. dry with materialOrganic extracts were dried over magnesium sulfate
  6. custompurified by MPLC (
  7. washeluted with a gradient of 10 to 50% ethyl acetate in hexanes),
  8. customthen purified by HPLC (
  9. washeluted with a gradient of 15 to 90% acetonitrile in water)

Sources & evidence

ORD record
ord-50550a2147db49d19ef79b794b92991b
Source dataset
uspto-grants-2015_06
Patent number
US09066954B2

Reaction notes

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