Methylamine → N-(4-cyclopentyl-5-hydroxy-2-(3-(methylamino)prop-1-ynyl)phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

HRID 471998Notes

Reaction equation

HRID 471998 reaction equation
C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([CH:12]2[O:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:21][C:15]=3[NH:14][CH2:13]2)=[O:11])[C:6]([C:27]#[C:28][CH2:29]O)=[CH:5][C:4]=1[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH2:39]([N:41](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.CN>ClCCl>[CH:31]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([NH:9][C:10]([CH:12]3[O:17][C:16]4[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=4[NH:14][CH2:13]3)=[O:11])=[C:6]([C:27]#[C:28][CH2:29][NH:41][CH3:39])[CH:5]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1

Participants

7

Reactant 5

HCID 6329MethylamineHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 85257MethanesulfonateHCID 593949372-cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate

Product 1

HCID 46836518N-(4-cyclopentyl-5-hydroxy-2-(3-(methylamino)prop-1-ynyl)phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideYield 116%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

2-Cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (20 μL, 0.14 mmol) and cooled to 0° C. Methanesulfonyl chloride (4.3 mg, 2.9 μL, 0.04 mmol) in 1 mL of dichloromethane was slowly added to the reaction. Conversion to the mesylate was complete after 10 min. MeNH2 (100 μL of 2 M in THF, 0.20 mmol) was then added and the reaction stirred at room temperature for 10 h. The solution was concentrated in vacuo and purified by HPLC (10-99% CH3CN/0.035% TFA) to provide N-(4-cyclopentyl-5-hydroxy-2-(3-(methylamino)prop-1-ynyl)phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (21 mg, 97% yield). LC/MS m/z 490.4 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 7.65 (s, 1H), 7.28 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.54 (dd, J=1.8, 8.7 Hz, 1H), 4.78 (dd, J=3.0, 7.0 Hz, 1H), 4.14 (dd, J=16.6, 27.1 Hz, 2H), 3.67 (dd, J=3.0, 12.1 Hz, 1H), 3.49-3.44 (m, 1H), 3.24 (m, 1H), 2.79 (s, 3H), 2.05-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.71-1.68 (m, 2H), 1.54-1.51 (m, 2H).

Workup

  1. concentrationThe solution was concentrated in vacuo
  2. custompurified by HPLC (10-99% CH3CN/0.035% TFA)

Sources & evidence

ORD record
ord-bd8281995675478796738dd19dffd252
Source dataset
uspto-grants-2014_01
Patent number
US08633189B2

Reaction notes

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