HCID 86684774, compound → HCID 66685241, compound

HRID 579208Notes

Reaction equation

HRID 579208 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[O:24])[C:11]1=[O:25])=[O:4].[CH3:32][Mg+].[Br-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@H:23]([OH:24])[CH3:32])[C:11]1=[O:25])=[O:4].[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@@H:23]([OH:24])[CH3:32])[C:11]1=[O:25])=[O:4]

Participants

5

Reactant 2

HCID 86684774HCID 86684774, compoundHCID 178418689HCID 178418689, compound

Product 2

HCID 66683972HCID 66683972, compoundYield 29%HCID 66685241HCID 66685241, compoundYield 40.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-10 °C

Procedure

To a solution of 3-[(2R,5R)-5-cyclohexyl-3-oxo-2-(2-oxo-ethyl)-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.9 g, 4.26 mmol, 1.0 equiv) in THF (200 mL) at −10° C., was added MeMgBr (1.85 mL, 3.0 M solution in THF, 5.54 mmol, 1.3 equiv). The resulting solution was stirred at −10° C. for 20 minutes. The reaction was quenched by addition of 3.0 N HCl aqueous solution until pH=1. The volatile solvent was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and brine (5 mL). The separated organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography [Et2O (2% EtOAc)/Heptane, 25% to 50%] to give 3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.57 g, 29.0%) and 3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.80 g, 40.7%). MS: 462.4 [M−H+].

Workup

  1. customThe reaction was quenched by addition of 3.0 N HCl aqueous solution until pH=1
  2. customThe volatile solvent was removed under vacuum
  3. customthe residue was partitioned between EtOAc (100 mL) and brine (5 mL)
  4. dry with materialThe separated organic layer was dried over Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel column chromatography [Et2O (2% EtOAc)/Heptane, 25% to 50%]

Sources & evidence

ORD record
ord-ecd8a7672bf740e69cb85edc9e9206a5
Source dataset
uspto-grants-2015_05
Patent number
US09040690B2

Reaction notes

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