Diisopropylethylamine → 1-(4-(1-Acetylindolin-5-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide

HRID 528820

Reaction equation

HRID 528820 reaction equation
[Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:6]=1[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64]([N:67]1[C:75]2[C:70](=[CH:71][C:72]([S:76]([NH2:79])(=[O:78])=[O:77])=[CH:73][CH:74]=2)[CH2:69][CH2:68]1)(=[O:66])[CH3:65].C(N(C(C)C)C(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[C:64]([N:67]1[C:75]2[C:70](=[CH:71][C:72]([S:76]([NH:79][C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:5]4[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:29]([N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:39])=[N:4]4)=[C:9]([C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[O:18])[CH:10]=3)=[O:13])(=[O:77])=[O:78])=[CH:73][CH:74]=2)[CH2:69][CH2:68]1)(=[O:66])[CH3:65]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 8042081-Acetylindoline-5-sulfonamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 710621944-(4-Chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid2×

Product 1

HCID 710623151-(4-(1-Acetylindolin-5-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamideYield 24%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 1F, 30 mg, 0.054 mmol) in DMF (2.0 mL) was added HATU (29 mg, 0.076 mmol), 1-acetylindoline-5-sulfonamide (20 mg, 0.082 mmol), DMAP (7 mg, 0.054 mmol) and i-Pr2EtN (0.029 mL, 0.163 mmol). The resulting reaction mixture was stirred at room temperature for 3 h and then diluted with EtOAc and 1N aq. HCl solution. The organic layer was washed with 1N aq. NaOH solution (2×) followed by 1N aq. HCl solution (1×). The combined aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a crude oil, which was purified using preparative HPLC to give the title compound (10 mg, 24%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.19-8.16 (m, 2H), 8.08-8.06 (m, 1H), 7.89-7.86 (m, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.22-7.10 (m, 3.5H), 6.94 (d, J=7.3 Hz, 0.5H), 4.75-4.50 (m, 2H), 4.22-4.18 (m, 2H), 3.90-3.40 (m, 4H), 3.15-2.65 (m, 4H), 2.33 (s, 2H), 2.28 (s, 1H), 2.25 (s, 3H), 1.52-1.00 (m, 10H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.71-0.67 (m, 1H); MS(ESI+) m/z 773.2 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. washThe organic layer was washed with 1N aq. NaOH solution (2×)
  3. extractionThe combined aqueous layer was extracted with EtOAc (3×)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give a crude oil, which
  8. customwas purified

Sources & evidence

ORD record
ord-a45d389c4f41478fad5ad28688ef2cf1
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Linked notes

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