(R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one → ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate

HRID 575376Notes

Reaction equation

HRID 575376 reaction equation
Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[C:12]3[S:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]([C@:28]1([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]1=[O:34])#[CH:27]>>[F:25][C:3]1[C:2]([C:27]#[C:26][C@:28]2([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]2=[O:34])=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:11][C:12]=3[C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:14][O:15][C:5]=2[CH:4]=1

Participants

3

Reactant 2

HCID 86693296(R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-oneHCID 86693423ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate

Product 1

HCID 86693424ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate

Procedure

Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (133 mg) was reacted with isopropylmagnesium 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-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (80 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-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12 mg and 13 mg (29% 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-0123ee837ae44054a4e11ec4c2d90076
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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