Cesium carbonate → HCID 59159302, compound

HRID 1096298Notes

Reaction equation

HRID 1096298 reaction equation
[H-].[Na+].CS([O-])(=O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]3[CH2:26][O:25]3)[C:18](=[O:27])[CH:17]2[CH3:28])[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:36]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][C@H:39]2[OH:44])[CH2:37]1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.CCOC(C)=O.CO>[Cl:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]([OH:25])[CH2:26][N:41]3[CH2:42][CH2:43][C:38]4([CH2:36][CH2:37]4)[C@H:39]([OH:44])[CH2:40]3)[C:18](=[O:27])[CH:17]2[CH3:28])[CH:12]=[CH:13][C:14]=1[Cl:15]

Participants

9

Reactant 6

HCID 10796Cesium carbonateHCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 85257MethanesulfonateHCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochloride2×HCID 86638394HCID 86638394, compound

Product 1

HCID 59159302HCID 59159302, compoundYield 47%

Reagents, catalysts & solvents 2

HCID 31374DimethylacetamideSolvent2×HCID 21584119Ethylacetate methanolSolvent

Conditions

Temperature
0 °C

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. temperatureThe reaction mixture was heated at 80° C. for 20 h
  2. filtrationfiltered through diatomaceous earth
  3. customThe filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient)

Sources & evidence

ORD record
ord-9902a164120a4a619564d92ba01aa8b0
Source dataset
uspto-grants-2012_03
Patent number
US08138175B2

Reaction notes

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