Dichloromethane → Dichloromethane methanol ammonium hydroxide

HRID 931632Notes

Reaction equation

HRID 931632 reaction equation
[F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=3)[C@@:7]3([CH2:21][CH2:20][S:19][C:18]([NH2:22])=[N:17]3)[C:6]=2[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=1.CCCP(=O)=O.C(OCC)(=O)C.[CH2:47]([Cl:49])[Cl:48]>CCCCCCC>[CH2:47]([Cl:49])[Cl:48].[CH3:13][OH:14].[NH4+:16].[OH-:33].[NH2:22][C:18]1[S:19][CH2:20][CH2:21][C@@:7]2([N:17]=1)[C:6]1[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([NH:16][C:32](=[O:34])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:11][CH:12]=1

Participants

8

Reactant 5

HCID 6344DichloromethaneHCID 8857Ethyl Acetate2×HCID 27628725-Chloro-2-picolinic acidHCID 16167369Propylphosphoric anhydrideHCID 89473221(S)-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthene]-2,7'-diamine

Product 2

HCID 21896990Dichloromethane methanol ammonium hydroxideYield 50%HCID 71542786(S)-N-(2-amino-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthen]-7'-yl)-5-chloropicolinamideYield 14.24%

Reagents, catalysts & solvents 1

HCID 8900HeptaneSolvent

Procedure

To a solution of (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthene]-2,7′-diamine (55 mg, 0.159 mmol), 5-chloro-2-pyridinecarboxylic acid (37.6 mg, 0.239 mmol), and TEA (0.067 mL, 0.478 mmol) in DCM (1.5 mL) was added propylphosphonic anhydride solution, 50 wt. % in ethyl acetate (0.152 mL, 0.239 mmol). The mixture was stirred at rt. 0.5 hr later, the reaction mixture was concentrated. The red residue was diluted with water and extracted with DCM. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a red solid. The crude material was purified by chromatography eluting with a gradient of DCM for 5 mins and 25% to 35% to 50% DCM/MeOH/NH4OH in (40% of EtOAc in Heptane), to provide (S)—N-(2-amino-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-7′-yl)-5-chloropicolinamide (11 mg, 0.023 mmol, 14.24% yield) as off-white solid.

Workup

  1. concentration0.5 hr later, the reaction mixture was concentrated
  2. additionThe red residue was diluted with water
  3. extractionextracted with DCM
  4. extractionThe organic extract
  5. washwas washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationThe solution was filtered
  8. concentrationconcentrated in vacuo
  9. customto give the crude material as a red solid
  10. customThe crude material was purified by chromatography
  11. washeluting with a gradient of DCM for 5 mins

Sources & evidence

ORD record
ord-e25d7456937d43178de547ff9a58c0e8
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

Loading…