Diisopropylethylamine → 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide

HRID 2381530Notes

Reaction equation

HRID 2381530 reaction equation
I[C:2]1[CH:3]=[N:4][N:5]([CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)[C:6](=[O:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:33]1([O:42][P+](N(C)C)(N(C)C)N(C)C)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.[CH3:53][C:54]1([CH3:66])[O:58][C@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]2)[CH2:56][O:55]1>CN(C)C=O.C(OCC)(=O)C>[CH3:53][C:54]1([CH3:66])[O:58][C@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH:65][C:10](=[O:12])[CH:9]([N:5]3[C:6](=[O:8])[CH:7]=[C:2]([O:42][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[N:34]4)[CH:3]=[N:4]3)[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:61]2)[CH2:56][O:55]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 579193122-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid2×HCID 59344941(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amine2×

Product 1

HCID 669004582-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amideYield 51%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid (Intermediate 86, 1.93 g, 5.74 mmol) in N,N-dimethylformamide (26 mL, 0.22M) at 25° C. was treated with N,N-diisopropylethylamine (2.8 mL, 16.94 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (3.81 g, 8.61 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 1.31 g, 6.64 mmol). The reaction was stirred at 25° C. over 2 nights. After this time, the reaction was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous ammonium chloride solution (150 mL), a saturated aqueous sodium bicarbonate solution (150 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 25-75% gradient ethyl acetate/hexanes) afforded 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (1.52 g, 51%) as a light yellow solid as a mixture of diastereomers.

Workup

  1. washwas washed with a saturated aqueous ammonium chloride solution (150 mL)
  2. dry with materiala saturated aqueous sodium bicarbonate solution (150 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate
  3. filtrationfiltered
  4. washrinsed
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3995d4e35e644c15a2608b155797e404
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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