Diisopropylethylamine → N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide

HRID 930293Notes

Reaction equation

HRID 930293 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH3:48])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([NH: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:45](=[O:46])[C:42]3[C:41]([CH3:48])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=3)[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 516892Sodium BicarbonateHCID 223920095-Chloro-3-methylpyridine-2-carboxylic acid2×HCID 86732123N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide

Product 1

HCID 86732125N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamideYield 15.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A round-bottomed flask was charged with N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (rac-4l, 0.233 g, 0.589 mmol), DCM (8 mL), N,N-diisopropylethylamine (0.133 mL, 0.766 mmol), 5-chloro-3-methylpicolinic acid (intermediate 6) 0.131 g, 0.766 mmol) and finally with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.347 mL, 0.589 mmol). The reaction mixture was stirred at room temperature for 15 min. The Reaction mixture was poured into aqueous saturated NaHCO3 (50 mL) and then extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over Na2SO4 and loaded onto silica gel. Purification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane) gave the title compound (50 mg). MS m/z=549.1 [M+H]+. Calculated for C26H21ClF4N4O3: 548.9

Workup

  1. extractionextracted with EtOAc (2×50 mL)
  2. washThe combined extracts were washed with brine
  3. dry with materialdried over Na2SO4
  4. customPurification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane)

Sources & evidence

ORD record
ord-b9d34e73267549b597b2067c2260d7e4
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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