Trifluoroacetic acid → tert-Butyl (3R)-3-[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-5-methylhexanoate

HRID 1486334Notes

Reaction equation

HRID 1486334 reaction equation
[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:54][C@H:55]([CH2:64][CH:65]([CH3:67])[CH3:66])[CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:54][C@H:55]([CH2:64][CH:65]([CH3:67])[CH3:66])[CH2:56][C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 2733825tert-Butyl (3R)-3-amino-5-methyl-hexanoateHCID 117859510HCID 117859510, compound

Product 1

HCID 117859497tert-Butyl (3R)-3-[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-5-methylhexanoateYield 56.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of 100 mg (0.30 mmol, 1.0 eq.) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A, 116 mg of TBTU (0.36 mmol, 1.2 eq.) and 0.132 ml (1.2 mmol, 4.0 eq.) of 4-methylmorpholine in 2.2 ml of DMF was admixed with 121 mg (0.60 mmol, 2.0 eq.) of tert-butyl (3R)-3-amino-5-methylhexanoate, and the mixture was stirred at RT overnight. The reaction mixture was admixed with 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. 88 mg of the target compound were obtained (57% of theory).

Workup

  1. custompurified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA)
  2. concentrationconcentrated
  3. washa little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution
  4. extractionThe aqueous phase was extracted twice with dichloromethane
  5. dry with materialThe combined organic phases were dried over sodium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-69d050a9ca68412c98abc5486ceb8288
Source dataset
uspto-grants-2016_08
Patent number
US09422285B2

Reaction notes

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