Sodium Hydroxide → HCID 68157525, compound

HRID 1892770Notes

Reaction equation

HRID 1892770 reaction equation
[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.[OH-].[Na+].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.[NH2:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72]>CO.[Cl-].[Na+].O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[N:12]2)=[CH:9][CH:10]=1

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68178642HCID 68178642, compound

Product 1

HCID 68157525HCID 68157525, compoundYield 91.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
20 °C

Procedure

To a solution of (+\−)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinate (800 mg, 1.85 mmol) in methanol (5 mL) was added 2N aqueous sodium hydroxide (9.2 mL, 18.4 mmol). The resulting mixture was stirred at 20° C. for 2 h. Methanol was removed under reduced pressure and the residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (30 mL×2). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). HATU (1.36 mg, 3.58 mmol) and N,N-di-iso-propylethylamine (1.15 mg, 8.95 mmol) were added. Methyl 3-aminopropanoate hydrochloride (370 mg, 2.68 mmol) was added. The resulting mixture was stirred at 30° C. for 1 h. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with 1N aqueous HCl (30 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude residue was purified silica gel chromatography to give (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate (850 mg) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.37 (d, J=12.0 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.76-7.70 (m, 2H), 6.52 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.86 (d, J=9.2 Hz, 1H), 3.62-3.58 (m, 5H), 2.54 (t, J=5.6 Hz, 2H), 1.77-1.59 (m, 3H), 1.75-1.63 (m, 2H), 0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H). (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate was resolved by SFC (column: Chiralpak AD-3, 50×4.6 mm×3 μm; mobile phase: 40% methanol in CO2; modifier: 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (450 mg, retention time: 0.62 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, isomer 2 (400 mg, retention time: 1.30 min).

Workup

  1. customMethanol was removed under reduced pressure
  2. additionthe residue was acidified by addition of 1N aqueous HCl to pH 3-4
  3. extractionextracted with dichloromethane (30 mL×2)
  4. concentrationThe combined organic layers were concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in DMF (10 mL)
  6. stirringThe resulting mixture was stirred at 30° C. for 1 h
  7. extractionextracted with ethyl acetate (30 mL×2)
  8. washThe combined organic layers were washed with 1N aqueous HCl (30 mL)
  9. dry with materialdried over anhydrous Na2SO4
  10. concentrationconcentrated to dryness
  11. customThe crude residue was purified silica gel chromatography

Sources & evidence

ORD record
ord-9f8492a057184e87a3d353fb9e09d8e1
Source dataset
uspto-grants-2013_08
Patent number
US08507533B2

Reaction notes

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