4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride → (S)-N-(2'-amino-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-7-yl)-5-chloropicolinamide

HRID 931642Notes

Reaction equation

HRID 931642 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH2:23])=[CH:12][CH:11]=3.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@:16]2([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([F:8])[C:5]=3[O:9][C:10]3[C:15]2=[CH:14][C:13]([NH:23][C:31](=[O:32])[C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)=[CH:12][CH:11]=3)[N:17]=1

Participants

4

Reactant 3

HCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideHCID 27628725-Chloro-2-picolinic acidHCID 90158687(S)-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazine]-2',7-diamine

Product 1

HCID 71542226(S)-N-(2'-amino-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-7-yl)-5-chloropicolinamideYield 37.9%

Procedure

A mixture of (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.048 g, 0.143 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.025 g, 0.158 mmol) was purged with N2 followed by the addition of THF (2 mL) and MeOH (0.5 mL). 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.046 g, 0.158 mmol) was added in one portion and the resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHCO3, diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0258 g, 0.054 mmol, 37.9% yield). MS m/z=474.0 [M+H]+.

Workup

  1. customwas purged with N2
  2. additionfollowed by the addition of THF (2 mL) and MeOH (0.5 mL)
  3. customthe resulting reaction mixture
  4. customThe reaction mixture was quenched with saturated NaHCO3
  5. additiondiluted with water
  6. extractionextracted with EtOAc
  7. dry with materialThe combined organics were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customchromatographed on silica gel using 0-4% MeOH/DCM
  11. customrepurified by HPLC

Sources & evidence

ORD record
ord-3ad92ba5725d46858b9c6f64a69deb74
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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