Citric Acid → 5-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(1-oxa-spiro[2.5]oct-6-yl)-amino]thiophene-2-carboxylic acid methyl ester

HRID 1053491Notes

Reaction equation

HRID 1053491 reaction equation
[Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=1[N:18]([C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]([CH3:34])=[CH:30][CH2:29]1)=[O:27])[CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C1COCC1>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=1[N:18]([C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]([CH3:34])=[CH:30][CH2:29]1)=[O:27])[CH:19]1[CH2:20][CH2:21][C:22]2([O:25][CH2:2]2)[CH2:23][CH2:24]1)=[O:12]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 197819Trimethyloxosulphonium chlorideHCID 679837405-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester

Product 1

HCID 866989545-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(1-oxa-spiro[2.5]oct-6-yl)-amino]thiophene-2-carboxylic acid methyl esterYield 70%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Trimethylsulfoxonium chloride (79 mg, 0.62 mmol) in DMSO (1.5 mL) was treated with sodium hydride (21 mg, 60% oil dispersion, 0.53 mmol) and stirred at ambient temperature for 10 min. 5-(3,3-Dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester 507 in THF (1 mL+0.5 mL) was added dropwise and the reaction mixture was stirred for 45 min. The orange solution was treated with 5% citric acid until pH 3 and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organics were washed with 5% LiCl, water and brine, and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography (20-75% EtOAc:hexanes) to afford 0.134 g (70% yield) of 5-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(1-oxa-spiro[2.5]oct-6-yl)-amino]-thiophene-2-carboxylic acid methyl ester 508 as a white powder.

Workup

  1. stirringthe reaction mixture was stirred for 45 min
  2. custompartitioned between water and ethyl acetate
  3. customThe organic layer was separated
  4. extractionthe aqueous was extracted again with ethyl acetate
  5. washThe combined organics were washed with 5% LiCl, water and brine
  6. dry with materialdried over sodium sulfate
  7. filtrationAfter filtration and concentration
  8. customthe residue was purified by flash chromatography (20-75% EtOAc:hexanes)

Sources & evidence

ORD record
ord-527aac3c98fb4e5298b35d546181d7dc
Source dataset
uspto-grants-2016_07
Patent number
US09393256B2

Reaction notes

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