Diisopropylethylamine → N-(5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

HRID 1502332Notes

Reaction equation

HRID 1502332 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:63]=[C:62]3[C:57]([CH:58]=[C:59]([NH:64][C:65]([CH:67]4[CH2:69][CH2:68]4)=[O:66])[N:60]=[CH:61]3)=[CH:56][CH:55]=2)[C:50]([CH3:53])=[N:51][CH:52]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH:67]1([C:65]([NH:64][C:59]2[N:60]=[CH:61][C:62]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[C:54]([C:49]2[CH:48]=[C:47]([NH:46][C:13](=[O:14])[C:12]4[CH:16]=[CH:17][C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=4)[CH:52]=[N:51][C:50]=2[CH3:53])[CH:63]=3)=[O:66])[CH2:68][CH2:69]1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 231458804-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acidHCID 57411326N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 71115180N-(5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamideYield 1.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (302 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (570 mg) at 0° C. A solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (318 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was mixed with N,N-diisopropylethylamine (387 mg, 3.0 mmol) and immediately added to the reaction at 0° C. It was stirred at 0° C. for 10 minutes and then at room temperature for 4-5 hours. The reaction was diluted with ethyl acetate (15 mL) and water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried, concentrated, and purified by prep-HPLC to give the product (6.4 mg, 1.1%). LCMS (ESI): RT (min)=0.760, M+H+=603.4, method=A; 1H NMR: (MeOH-d4, 400 MHz): δ 9.40 (d, J=2.0 Hz, 1H), 9.18 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8.29 (d, J=4.4 Hz, 1H), 8.19 (s, 1H), 8.07-01 (m, 2H), 7.83 (d, J=1.6 Hz, 1H), 3.88 (s, 2H), 3.51 (d, J=12.4 Hz, 2H), 3.31 (t, J=1.6 Hz, 2H), 3.22 (t, J=1.6 Hz, 2H), 3.06 (d, J=12.4 Hz, 2H), 2.92 (s, 3H), 2.72 (s, 3H), 2.51 (t, J=1.6 Hz, 2H), 2.02-1.97 (m, 1H), 1.05-1.04 (m, 2H), 0.95-093 (m, 2H).

Workup

  1. additionimmediately added to the reaction at 0° C
  2. waitat room temperature for 4-5 hours
  3. extractionthe aqueous layer was extracted with ethyl acetate (3×15 mL)
  4. customThe combined organic layers were dried
  5. concentrationconcentrated
  6. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-eec6664f3e5e413ea6cf2bfc7c96b914
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

Loading…