(3S,6S)-3-[2-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester → (3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one

HRID 1261839Notes

Reaction equation

HRID 1261839 reaction equation
C(OC([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][CH2:23][N:24]3[CH2:31][CH2:30][C:27]4([CH2:29][CH2:28]4)[C@H:26]([OH:32])[CH2:25]3)[CH2:20][O:21][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[OH:32][C@@H:26]1[CH2:25][N:24]([CH2:23][CH2:22][C@@H:19]2[N:14]3[C:15](=[O:18])[C@H:16]([CH3:17])[NH:11][CH2:12][CH:13]3[O:21][CH2:20]2)[CH2:31][CH2:30][C:27]21[CH2:29][CH2:28]2

Participants

4

Reactant 1

HCID 67092709(3S,6S)-3-[2-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester

Product 1

HCID 67092909(3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-hexahydro-oxazolo[3,2-a]pyrazin-5-oneYield 93.4%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

A solution of (3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (200 mg, 0.45 mmol) in EtOH (2 mL) was stirred for 3½ h at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 96 mg), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated to afford (3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (130 mg). This was redissolved in DCM (2 mL), then 3,4-dichlorophenyl isocyanate (88 mg, 0.45 mmol) was added at 0° C. The ice bath was removed, then after 30 min diethylamine (16 mg, 0.23 mmol) was added and the reaction mixture was evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced (3S,6S,8aS)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid (3,4-dichloro-phenyl)-amide [example 1; 17 mg, 8%; white solid, MS 497.3 (M+H)+] and (3S,6S,8aR)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid (3,4-dichloro-phenyl)-amide (example 2; 127 mg, 57%; white foam, MS 497.3 (M+H)+].

Workup

  1. custominsoluble material was removed by filtration through diatomaceous earth
  2. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-40fb49bb1a1a403abc22424608f9be2c
Source dataset
uspto-grants-2013_06
Patent number
US08471004B2

Reaction notes

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