Lithium Chloride → HCID 59272343, compound

HRID 1970352Notes

Reaction equation

HRID 1970352 reaction equation
FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:36]#[C:37][C:38]([O:41][CH3:42])([CH3:40])[CH3:39])[CH:28]=3)[O:23][C:20]2=[CH:21][CH:22]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:51]1[CH:56]=[CH:55][N:54]=[N:53][CH:52]=1)CCC>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:42][O:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:27]1[CH:28]=[C:29]2[C@@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:19]3[C:20](=[CH:21][CH:22]=[C:17]([C:51]4[CH:56]=[CH:55][N:54]=[N:53][CH:52]=4)[CH:18]=3)[O:23][C:24]2=[N:25][CH:26]=1

Participants

7

Reactant 3

HCID 433294Lithium ChlorideHCID 64097334-(Tributylstannyl)pyridazineHCID 86640730HCID 86640730, compound

Product 1

HCID 59272343HCID 59272343, compound

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

A vial was charged with (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (102 mg, 0.158 mmol), copper(i) iodide (3.01 mg, 0.016 mmol), tetrakis(triphenylphosphine)palladium (18.24 mg, 0.016 mmol), and lithium chloride (10.96 mg, 1.579 mmol). The vial was purged with Ar (g), then DMF (790 μL) and 4-(tributylstannyl)pyridazine (146 μL, 0.474 mmol) were added in sequence. The vial was sealed and placed in a 110° C. oil bath for 4 hours. The mixture loaded onto a 2-g SCX-2 column and eluted 4× with methanol to remove impurities. The product was then eluted with 2M ammonia in methanol. The filtrate was evaporated, and the residue was chromatographed on a 40-g Redi-Sep column, eluting with 0-100% EtOAc/Hexane, then with 0-10% MeOH/DCM. The resulting material was still impure, so the material was dissolved in methanol and purified by reverse-phase HPLC (15-80% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (R)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyridazin-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.

Workup

  1. customThe vial was purged with Ar (g)
  2. customThe vial was sealed
  3. customplaced in a 110° C.
  4. customfor 4 hours
  5. washeluted 4× with methanol
  6. customto remove impurities
  7. washThe product was then eluted with 2M ammonia in methanol
  8. customThe filtrate was evaporated
  9. customthe residue was chromatographed on a 40-g Redi-Sep column
  10. washeluting with 0-100% EtOAc/Hexane
  11. dissolutionwas dissolved in methanol
  12. custompurified by reverse-phase HPLC (15-80% CH3CN/H2O with 0.1% TFA)
  13. additionThe fractions containing product
  14. extractionextracted with DCM (3×)
  15. dry with materialThe combined organic extracts were dried over sodium sulfate
  16. filtrationfiltered
  17. customevaporated

Sources & evidence

ORD record
ord-b9410ca3cb2544ca9b1d12aac7865b0f
Source dataset
uspto-grants-2013_04
Patent number
US08426447B2

Reaction notes

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