Diisopropylethylamine → Isobutyl 3-(5-((1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoate

HRID 1406588Notes

Reaction equation

HRID 1406588 reaction equation
[NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:28]=[CH:29][C:30]2[CH2:35][O:34][CH2:33][O:32][C:31]=2[CH:36]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl.O>[O:32]1[C:31]2[CH:36]=[C:27]([C@@H:3]([O:4][C:5]3[CH:6]=[C:7]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]4)[C@@H:2]([NH:1][C:40](=[O:41])[C:39]([F:44])([F:38])[CH3:43])[CH3:37])[CH:28]=[CH:29][C:30]=2[CH2:35][O:34][CH2:33]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 27828252,2-Difluoropropionic acidHCID 59272925HCID 59272925, compound

Product 1

HCID 59272926Isobutyl 3-(5-((1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoateYield 80.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of isobutyl 3-(5-((1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propoxy)-1H-indazol-1-yl)benzoate (420 mg, 0.84 mmol) (I5b), 2,2-difluoropropanoic acid (213 mg, 1.94 mmol) and HBTU (420 mg, 1.11 mmol) were suspended in dichloromethane (10 mL). N-ethyl-N-isopropylpropan-2-amine (0.85 mL, 5.13 mmol) was added and the mixture was stirred at room temperature overnight. Water (ca 10 mL) was added to the solution. After stirring for some minutes the mixture was added to a phase separator. The water phase was stirred with dichloromethane (5 mL) and added to the phase separator. The combined organic phases were concentrated to a brown oil. Purification by flash chromatography on silica (dichloromethane/ethyl acetate 10/1) gave the title compound as a white foam (400 mg, 80%).

Workup

  1. stirringAfter stirring for some minutes the mixture
  2. additionwas added to a phase separator
  3. additionadded to the phase separator
  4. concentrationThe combined organic phases were concentrated to a brown oil
  5. customPurification by flash chromatography on silica (dichloromethane/ethyl acetate 10/1)

Sources & evidence

ORD record
ord-9dab6b4d9c87436a9e03e4be58e09b23
Source dataset
uspto-grants-2014_12
Patent number
US08916600B2

Reaction notes

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