Citric Acid → N-[2-(4-benzylpiperazin-1-yl)-2-hydroxycarbamoylethyl]-4-(2-trifluoromethylpyrazolo-[1,5-a]-pyridin-3-ylmethoxy)benzamide

HRID 517527Notes

Reaction equation

HRID 517527 reaction equation
F[B-](F)(F)F.[N:6]1([O:15]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([CH:45]([CH2:49][NH:50][C:51](=[O:73])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[C:61]([C:69]([F:72])([F:71])[F:70])=[N:62][N:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=34)=[CH:54][CH:53]=2)[C:46](O)=[O:47])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Si](ON)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([CH:45]([C:46](=[O:47])[NH:6][OH:15])[CH2:49][NH:50][C:51](=[O:73])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[C:61]([C:69]([F:71])([F:72])[F:70])=[N:62][N:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=34)=[CH:54][CH:53]=2)[CH2:41][CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1

Participants

9

Reactant 6

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 4691350O-(tert-Butyldimethylsilyl)hydroxylamineHCID 670569572-(4-Benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzoylamino]propanoic acid

Product 1

HCID 75600335N-[2-(4-benzylpiperazin-1-yl)-2-hydroxycarbamoylethyl]-4-(2-trifluoromethylpyrazolo-[1,5-a]-pyridin-3-ylmethoxy)benzamideYield 22.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

106 g (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 0.2 ml (1.2 mmol) of diisopropylethylamine are added to a solution of 190 mg (0.3 mmol) of 2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzoylamino]propanoic acid in 10 ml of dimethylformamide. After stirring for 20 minutes at ambient temperature, 53 mg (0.4 mmol) of O-tert-butyldimethylsilylhydroxylamine diluted in 3 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 18 h, then hydrolysed with 1 ml of a 5% aqueous solution of citric acid and 2 ml of water and stirred for 1 h. The mixture is then brought to pH=8 with a saturated aqueous solution of sodium hydrogen carbonate then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is precipitated in a heptane/ethyl acetate mixture then filtered. The solid obtained is recrystallized in ethyl acetate. 41 mg (21%) of N-[2-(4-benzylpiperazin-1-yl)-2-hydroxycarbamoylethyl]-4-(2-trifluoromethylpyrazolo-[1,5-a]-pyridin-3-ylmethoxy)benzamide are obtained in the form of a white solid.

Workup

  1. additionare added
  2. stirringThe reaction medium is stirred at ambient temperature for 18 h
  3. extractionthen extracted with ethyl acetate
  4. washThe organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate
  5. dry with materialwith a saturated aqueous solution of sodium chloride, dried over magnesium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe crude product obtained
  9. customis precipitated in a heptane/ethyl acetate mixture
  10. filtrationthen filtered
  11. customThe solid obtained
  12. customis recrystallized in ethyl acetate

Sources & evidence

ORD record
ord-6a0c99e9d1e24a5fbbb2ad8e0c826106
Source dataset
uspto-grants-2015_08
Patent number
US09115102B2

Reaction notes

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