2,4,6-Trimethylpyridine → HCID 86638393, compound

HRID 1096297Notes

Reaction equation

HRID 1096297 reaction equation
[CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13].CC1C=C(C)C=C(C)N=1>CC(N(C)C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13]

Participants

5

Reactant 3

HCID 79532,4,6-TrimethylpyridineHCID 31297Methanesulfonyl chlorideHCID 66782827HCID 66782827, compound

Product 1

HCID 86638393HCID 86638393, compoundYield 129.8%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Procedure

A solution of methanesulfonyl chloride (53 mg, 0.46 mmol) in DMA (0.5 mL) was added at 0° C. to a solution of 4-(3,4-dichloro-phenyl)-1-((R)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one (160 mg, 0.46 mmol) and 2,4,6-trimethylpyridine (279 mg, 2.30 mmol) in DMA (2 mL), then after 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford crude methanesulfonic acid (R)-4-[4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-2-hydroxy-butyl ester (254 mg) as a light yellow gum. This was dissolved in DMA (2 mL), cooled to 0° C., and treated with NaH (55% dispersion in mineral oil, 41 mg, 0.94 mmol). After 15 min, as the methanesulfonate intermediate had disappeared, with mass spectrometry confirming the formation of the epoxide intermediate, 4-(3,4-dichloro-phenyl)-3-methyl-1-((R)-2-oxiranyl-ethyl)-piperazin-2-one [m/e=329, (M+H)+)], cesium carbonate (184 mg, 0.56 mmol) and a solution of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 77 mg, 0.47 mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol) in DMA (1 mL) were added. The reaction mixture was heated at 80° C. for 20 h, then diluted with EtOAc/MeOH 4:1 and filtered through diatomaceous earth. The filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient) to produce the title compound (101 mg, 47%). Light yellow foam, MS: 456.2 (M+H)+.

Workup

  1. customafter 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution
  2. washThe organic layer was washed with brine
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customevaporated

Sources & evidence

ORD record
ord-49fca420cdc644a88339a27f8f4e0a70
Source dataset
uspto-grants-2012_03
Patent number
US08138175B2

Reaction notes

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