Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(hydroxy)methyl]cyclopropanecarboxylate

HRID 1475679Notes

Reaction equation

HRID 1475679 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([OH:37])[C:27]2([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:29][CH2:28]2)=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]

Participants

7

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58288396(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acidHCID 67957785tert-Butyl 1-[(3-amino-4-chlorophenyl)(hydroxy)methyl]cyclopropanecarboxylate

Product 1

HCID 68006961tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(hydroxy)methyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of 2.65 g (9.92 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 1.97 g (6.62 mmol) of tert-butyl 1-[(3-amino-4-chlorophenyl)(hydroxy)methyl]cyclopropane-carboxylate and 3.27 g (8.60 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of pyridine and 10 ml of DMF was stirred at room temperature for three days. 100 ml of ethyl acetate were then added to the mixture, and the solution obtained was washed with 1 M hydrochloric acid and saturated sodium chloride solution. The solution was dried over magnesium sulphate and then filtered, and the filtrate was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→40:1→30:1). The product obtained in this manner was taken up in 100 ml of ethyl acetate, and the solution was extracted three times with saturated sodium bicarbonate solution. The organic phase was washed once more with saturated sodium chloride solution, then dried over magnesium sulphate and finally concentrated to dryness under reduced pressure. This gave 2.75 g of the target compound (76% of theory).

Workup

  1. customthe solution obtained
  2. washwas washed with 1 M hydrochloric acid and saturated sodium chloride solution
  3. dry with materialThe solution was dried over magnesium sulphate
  4. filtrationfiltered
  5. customthe filtrate was evaporated to dryness
  6. customThe crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→40:1→30:1)
  7. customThe product obtained in this manner
  8. extractionthe solution was extracted three times with saturated sodium bicarbonate solution
  9. washThe organic phase was washed once more with saturated sodium chloride solution
  10. dry with materialdried over magnesium sulphate
  11. concentrationfinally concentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-e8facd234fc648369eb27398d9ad5802
Source dataset
uspto-grants-2015_04
Patent number
US09018258B2

Reaction notes

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