Methyl iodide → HCID 68283760, compound

HRID 1527425Notes

Reaction equation

HRID 1527425 reaction equation
[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][OH:13])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[H-].[Na+].IC.[C:25]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][O:13][CH3:25])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 68283566HCID 68283566, compound

Product 1

HCID 68283760HCID 68283760, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

(1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester as mixture of diastereoisomers (35:65 (1R,3S,5S)/(1S,3S,5R)) (840 mg, 2.94 mmol) were slowly added at 0° C. under Argon to a suspension of NaH (60% in mineral oil, 141 mg, 3.53 mmol) in THF (9 mL). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.28 mL, 4.42 mmol) was added slowly at 0° C. The reaction mixture was further stirred at RT overnight. Saturated NaHCO3 and CH2Cl2 were added, the layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 2:8) to give the title compound as an unseparable mixture of diastereosisomers. TLC, Rf (c-hexane/EtOAc 1:1)=0.70; MS (UPLC/MS): 300.3 [M+H]+, 599.5 [2M+H]+; tR (HPLC conditions a): 3.45 min. The absolute stereochemistry of the diastereoisomers was tentatively assigned by NMR and based on the test results for the final compounds Example 214 and Example 184 in the biological assay.

Workup

  1. stirringThe reaction mixture was further stirred at RT overnight
  2. customthe layers were separated
  3. extractionthe aqueous one back-extracted twice with CH2Cl2
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 2:8)

Sources & evidence

ORD record
ord-6e93007d1d3b49889412534097186a65
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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