4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide → ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate
Reaction equation
[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13](=[O:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:23][Mg]Br.OC1(C)C2SC(C(N)=O)=NC=2C2C=C(C#CC(O)(C)C)C=CC=2OC1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:16])([CH3:23])[C:12]3[S:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1Participants
Reactant 3
Product 1
Procedure
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (415 mg) was reacted with methylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo{e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (272 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 23.3 mg and 27.4 mg (17.4% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined
Sources & evidence
- ORD record
- ord-4de896d22c834ddfbde675daa9e7af2e
- Source dataset
- uspto-grants-2015_05
- Patent number
- US09034866B2
Reaction notes
Loading…