Pyridine → Tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

HRID 1951938Notes

Reaction equation

HRID 1951938 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.N1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>ClCCl.C(#N)C.C(OCC)(=O)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:12]([C:9]4[C:8]([C:15]([F:18])([F:17])[F:16])=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[O:11][N:10]=4)[O:13][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]

Participants

10

Reactant 6

HCID 1049PyridineHCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 468359141-(4-(5-(3-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acidHCID 580628345-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluorideHCID 76806751tert-butyl 1-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]azetidine-3-carboxylate

Product 1

HCID 66678445Tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (48 mg, 0.185 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (56.3 mg, 0.185 mmol) in dichloromethane (2 mL) was added pyridine (37.3 μL, 0.461 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then concentrated under reduced pressure, and the residue was diluted with ethyl acetate (3 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure resulted in the crude mixture which was dissolved in acetonitrile (2 mL). A 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (369 μL, 0.369 mmol) was added, and the solution was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL), washed with a saturated aqueous solution of sodium bicarbonate (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by preparative HPLC afforded tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate, which was used in the next step without any further purification. The product had an HPLC retention time=2.97 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=528.3.

Workup

  1. concentrationThe reaction mixture was then concentrated under reduced pressure
  2. additionthe residue was diluted with ethyl acetate (3 mL)
  3. washwashed with water (1 mL)
  4. washwashed with a saturated aqueous solution of sodium bicarbonate (1 mL)
  5. washwashed with brine (1 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationConcentration under reduced pressure
  8. customresulted in the crude mixture which
  9. stirringthe solution was stirred at room temperature for 30 min
  10. washwashed with water (10 mL)
  11. washwashed with a saturated aqueous solution of sodium bicarbonate (10 mL)
  12. washwashed with brine (10 mL)
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationConcentration under reduced pressure
  15. customfollowed by purification by preparative HPLC

Sources & evidence

ORD record
ord-f588e41cef2e4673bf59d251fe0c95a2
Source dataset
uspto-grants-2013_03
Patent number
US08404672B2

Reaction notes

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