Sodium Hydroxide → N-(3-((4aS,7aS)-2-Benzamido-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide

HRID 2060758Notes

Reaction equation

HRID 2060758 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>ClCCl.CN(C=O)C>[C:18]([NH:17][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:34](=[O:35])[C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=3)[CH:3]=[CH:4][C:5]=2[F:26])[N:9]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

8

Reactant 5

HCID 14798Sodium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27628765-fluoropyridine-2-carboxylic AcidHCID 27960291-Hydroxybenzotriazole hydrateHCID 57504887N-((4aS,7aS)-7a-(5-Amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Product 1

HCID 57504891N-(3-((4aS,7aS)-2-Benzamido-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamideYield 92.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
22 °C

Procedure

A mixture of N-((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (20.4 g, 51.8 mmol), 5-fluoropicolinic acid (8.77 g, 62.2 mmol), 1-hydroxybenzotriazole hydrate (10.3 g, 67.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.2 g, 67.4 mmol) in a mixture of dichloromethane (345 mL) and DMF (6.5 mL) is stirred at 22° C. for 80 min. A solution of 2 M sodium hydroxide (129.5 mL, 259 mmol) is added and the stirring is continued for 10 min. The mixture is separated and the aqueous phase is extracted with twice with dichloromethane (2×100 mL). The organic layer is concentrated under reduced pressure and the residue is diluted with ethyl acetate (200 mL). The organic layer is washed with cooled water (2×50 mL), brine (50 mL) and filtered through a short pad of silica using 100% ethyl acetate to give title compound (23.8 g, 79%). ES/MS m/e: 495 (M+1).

Workup

  1. waitthe stirring is continued for 10 min
  2. customThe mixture is separated
  3. extractionthe aqueous phase is extracted with twice with dichloromethane (2×100 mL)
  4. concentrationThe organic layer is concentrated under reduced pressure
  5. additionthe residue is diluted with ethyl acetate (200 mL)
  6. washThe organic layer is washed with cooled water (2×50 mL), brine (50 mL)
  7. filtrationfiltered through a short pad of silica using 100% ethyl acetate

Sources & evidence

ORD record
ord-7be03ea75b8a40eea2e6b40e20564cb8
Source dataset
uspto-grants-2012_10
Patent number
US08278441B2

Reaction notes

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