Potassium Phosphate, Tribasic → Methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate

HRID 2401431Notes

Reaction equation

HRID 2401431 reaction equation
Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[O:24][N:23]=1>CO.O1CCOCC1.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>[C:42]([O:41][C:40]([NH:39][C:36]1([C:25]2[O:24][N:23]=[C:22]([CH3:21])[C:26]=2[C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:37]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 280500Methyl 2-Bromo-5-chlorobenzoateHCID 67814800Tert-butyl (1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)isoxazol-5-YL)cyclopropyl)carbamate

Product 1

HCID 67811790Methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoateYield 86%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3×). To the solids was added a solution of tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3×), the vial was sealed, and the contents heated to 80° C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3×) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic 30% EtOAc:70% Hexanes). The product methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z 407 [M+H]+.

Workup

  1. customwas evacuated
  2. custompurged with N2 (g) (3×)
  3. customThe suspension was evacuated
  4. custompurged with N2 (g) (3×)
  5. customthe vial was sealed
  6. customwith in 4 h
  7. temperaturethe reaction mixture was cooled to room temperature
  8. filtrationfiltered over Celite
  9. washThe filter cake was washed with MeOH (3×)
  10. concentrationthe filtrate was concentrated
  11. customto give a brown oil
  12. customThe oil was purified on Biotage system (5% EtOAc

Sources & evidence

ORD record
ord-938746327a234996b094bb5cb57dece1
Source dataset
uspto-grants-2014_08
Patent number
US08796261B2

Reaction notes

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