Hydrochloric Acid → HCID 86709320, compound

HRID 529407Notes

Reaction equation

HRID 529407 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:23]S(C(C)(C)C)=O)[CH2:17][CH2:18][O:19][CH2:20][C:21]#[N:22].Cl.C1(C)C=CC=CC=1.C[Al](C)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:17][CH2:18][O:19][CH2:20][C:21]([NH2:22])=[N:23]3)[C:6]3[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=3[O:13][C:14]2=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 1140TolueneHCID 16682925TrimethylaluminumHCID 86709319HCID 86709319, compound

Product 1

HCID 86709320HCID 86709320, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a vial was added N-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (242 mg, 0.485 mmol) and HCl (4.0M solution in 1,4-dioxane, 0.970 mL, 3.88 mmol) in dioxane (4 mL). The mixture was stirred at RT for 20 mins, then quenched with 5 mL of a saturated aqueous solution of Na2CO3 and extracted into EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude product as orange oil. The crude product was dissolved with 4 mL of toluene and trimethylaluminum solution (2M in toluene, 0.728 mL, 1.455 mmol) was added to the mixture (exothermic after addition). The mixture was heated to 90° C. in oil bath for 10 min, then quenched with Rochelle's salt (12 mL) at 0° C. and stirred overnight at RT. The reaction mixture was diluted with water and extracted with EtOAc (10 mL×2). The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as orange oil. It was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.22 (m, 4 H) 4.42 (s, 2 H) 6.18 (br. s., 2 H) 7.21 (d, J=8.51 Hz, 1 H) 7.39 (s, 1 H) 7.45-7.62 (m, 2 H) 8.36 (s, 1 H). The other stereoisomer is Example 3B in Table 1.

Workup

  1. customquenched with 5 mL of a saturated aqueous solution of Na2CO3
  2. extractionextracted into EtOAc
  3. extractionThe organic extract
  4. washwas washed with saturated NaCl aqueous solution
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the crude product as orange oil
  9. additionwas added to the mixture (exothermic after addition)
  10. temperatureThe mixture was heated to 90° C. in oil bath for 10 min
  11. customquenched with Rochelle's salt (12 mL) at 0° C.
  12. stirringstirred overnight at RT
  13. additionThe reaction mixture was diluted with water
  14. extractionextracted with EtOAc (10 mL×2)
  15. extractionThe organic extract
  16. washwas washed with saturated NaCl aqueous solution
  17. dry with materialdried over MgSO4
  18. filtrationfiltered
  19. concentrationconcentrated
  20. customto give the crude material as orange oil
  21. customIt was absorbed onto a plug of silica gel
  22. custompurified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g)
  23. washeluting with a gradient of 30% to 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane

Sources & evidence

ORD record
ord-24750cadbcd24575af9471ab645aed10
Source dataset
uspto-grants-2016_05
Patent number
US09346827B2

Reaction notes

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