Diisopropylethylamine → (S)-N-(2'-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-7-yl)-5-chloropicolinamide

HRID 931646Notes

Reaction equation

HRID 931646 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([F:13])[C:10]3[O:14][C:15]4[C:20]([C@@:21]5([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]5)[C:9]=3[CH:8]=2)=[CH:19][C:18]([NH2:28])=[CH:17][CH:16]=4)[CH2:2]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:27][C:23]1[O:24][CH2:25][CH2:26][C@:21]2([C:9]3[CH:8]=[C:7]([C:3]4[CH2:2][O:1][CH2:6][CH2:5][CH:4]=4)[N:12]=[C:11]([F:13])[C:10]=3[O:14][C:15]3[C:20]2=[CH:19][C:18]([NH:28][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][N:34]=2)=[CH:17][CH:16]=3)[N:22]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 27628725-Chloro-2-picolinic acidHCID 117600889(S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazine]-2',7-diamine

Product 1

HCID 71506897(S)-N-(2'-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-7-yl)-5-chloropicolinamideYield 25.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.095 g, 0.248 mmol) in DMF (1 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.043 g, 0.273 mmol), 0-(−7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium pf6 (0.099 g, 0.261 mmol) and Hunig's base (0.086 ml, 0.497 mmol) and the resulting mixture was stirred at rt for 15 h. The mixture was quenched with 5 drops of 2 N HCl and stirred for 1 min followed by the addition of water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM. The product was repurified by HPLC to afford (S)—N-(2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0334 g, 0.064 mmol, 25.8% yield). MS m/z=522.0 [M+H]+.

Workup

  1. customThe mixture was quenched with 5 drops of 2 N HCl
  2. stirringstirred for 1 min
  3. additionfollowed by the addition of water
  4. extractionextracted with EtOAc
  5. dry with materialThe combined organics were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customchromatographed on silica gel using 0-3% MeOH/DCM
  9. customThe product was repurified by HPLC

Sources & evidence

ORD record
ord-7cfb41a02ea44ddd913fd5f678463c57
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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