Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → HCID 86712027, compound

HRID 1051385Notes

Reaction equation

HRID 1051385 reaction equation
[CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[CH:5][CH:4]=[N:3]1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@H:30]([NH2:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C@H:30]([NH:41][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[N:9][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:17]3)=[O:20])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1

Participants

5

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67365517HCID 67365517, compoundHCID 86712022HCID 86712022, compound

Product 1

HCID 86712027HCID 86712027, compoundYield 2.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 2-5 mL microwave vial equipped with a stirring bar was charged with 92 (94 mg, 0.3506 mmol, 1.1 equiv), (3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine (90 mg, 0.3187 mmol, 1.0 mmol, CASRN 114616-86-5), DMF (2.0 mL) and HATU (187.4 mg, 0.4780 mmol, 1.5 equiv). The reaction mixture was stirred 20 min at RT and treated with TEA (0.1347 mL, 0.956 mmol, 3.0 equiv). The microwave vial was capped, and the reaction was stirred for 2 h at RT. The DMF solution was partitioned between EtOAc and water (120 mL/40 mL). The EtOAc layer was washed twice with brine, dried, filtered, and concentrated to give a crude oil. A portion of the crude (20%) was purified by RP HPLC to give 3.5 mg of N-((3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-((1-methyl-1H-pyrazol-5-yl)amino)isoquinoline-6-carboxamide (purity=100%, 254 nM). The remainder of the crude (80%) was purified on a SiO2 column (ISCO) eluting with a MeOH/DCM gradient (2 to 8% MeOH) to afford an additional 48 mg (total 51.5 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (q, J=7.7 Hz, 4H), 7.26 (d, J=8.1 Hz, 3H), 6.92 (s, 1H), 6.86 (d, J=8.4, 2H), 6.23 (s, 1H), 4.49-4.43 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62 (d, J=10.4 Hz, 1H), 3.43 (q, J=7.5 Hz, 1H), 3.04 (m, 2H), 2.60 (m, 2H). LCMS M+H+=534.

Workup

  1. customA 2-5 mL microwave vial equipped with a stirring bar
  2. customThe microwave vial was capped
  3. stirringthe reaction was stirred for 2 h at RT
  4. customThe DMF solution was partitioned between EtOAc and water (120 mL/40 mL)
  5. washThe EtOAc layer was washed twice with brine
  6. customdried
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give a crude oil
  10. customA portion of the crude (20%) was purified by RP HPLC

Sources & evidence

ORD record
ord-e064928e64334f88869762e15c35a56d
Source dataset
uspto-grants-2016_07
Patent number
US09388171B2

Reaction notes

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