Trifluoroacetic acid → rac-N-(2-Amino-4-fluoro-2-methylbutyl)-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

HRID 1486336Notes

Reaction equation

HRID 1486336 reaction equation
[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:18]CC)[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:21])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[F:62][CH2:63][CH2:64][C:65]([CH3:69])([NH2:68])[CH2:66][NH2:67].C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(#N)C>[NH2:68][C:65]([CH3:69])([CH2:64][CH2:63][F:62])[CH2:66][NH:67][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:7][C:8]([CH3:21])=[CH:9][C:10]=12)=[O:16]

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 117857875rac-4-Fluoro-2-methylbutane-1,2-diamine dihydrochlorideHCID 117859730HCID 117859730, compound

Product 1

HCID 117859650rac-N-(2-Amino-4-fluoro-2-methylbutyl)-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Procedure

200 mg (0.45 mmol, about 75% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-methyl-2-propylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged together with 274 mg (0.72 mmol) of HATU and 0.42 ml (2.41 mmol) of N,N-diisopropylethylamine in 2.8 ml of DMF, and the mixture was stirred for 20 min. A solution of 330 mg (1.27 mmol assuming a purity of about 75%) of rac-4-fluoro-2-methylbutane-1,2-diamine dihydrochloride from Example 86A in 1.4 ml of DMF and 0.63 ml (3.61 mmol) of N,N-diisopropylethylamine was added to the first reaction mixture and the mixture was stirred at RT for 1 h. The reaction solution was admixed with acetonitrile, water and TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined and concentrated. Subsequently, the residue was taken up in dichloromethane and a little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. 75 mg of the target compound were obtained (37% of theory, 98% purity).

Workup

  1. additionwas added to the first reaction mixture
  2. stirringthe mixture was stirred at RT for 1 h
  3. custompurified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA)
  4. concentrationconcentrated
  5. washa little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution
  6. extractionThe aqueous phase was extracted twice with dichloromethane
  7. dry with materialThe combined organic phases were dried over sodium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-462b5f5f46cf4b759f49fe4856db097c
Source dataset
uspto-grants-2016_08
Patent number
US09422285B2

Reaction notes

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