4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride → N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3-chloro-5-cyano-2-pyridinecarboxamide

HRID 930295Notes

Reaction equation

HRID 930295 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1

Participants

6

Reactant 3

HCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideHCID 508531763-Chloro-5-cyanopyridine-2-carboxylic acidHCID 86732112(4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 71668048N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3-chloro-5-cyano-2-pyridinecarboxamideYield 48.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2b, 0.093 g, 0.301 mmol) and 3-chloro-5-cyano-2-pyridinecarboxylic acid (Bionet Research, 0.056 g, 0.307 mmol) in THF (1 mL) and MeOH (0.25 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Aldrich, 0.084 g, 0.304 mmol). The reaction mixture was warmed to room temperature, stirred for 17 h and concentrated. Purification by flash column chromatography on silica gel (24 g, 10% to 60% EtOAc (10% 2M NH3 in MeOH) in hexanes) afforded the title compound (0.069 g, 0.146 mmol, 48.4% yield) as a pale yellow solid. MS m/z=474.0 (M+H); Calculated mass for C19H13ClF5N5O2: 473.1

Workup

  1. concentrationconcentrated
  2. customPurification by flash column chromatography on silica gel (24 g, 10% to 60% EtOAc (10% 2M NH3 in MeOH) in hexanes)

Sources & evidence

ORD record
ord-b7be85f8932e46e88f18030ef014dbc7
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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