Citric Acid → HCID 67341828, compound

HRID 1894844Notes

Reaction equation

HRID 1894844 reaction equation
[OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.CC([O-])(C)C.[K+].[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:21]=1[NH:22][CH:23]1[CH2:30][CH2:29][C:26]2([O:28][CH2:27]2)[CH2:25][CH2:24]1)=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C[Si](C=[N+]=[N-])(C)C>CN1C(=O)CCC1.ClCCl.CO>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:21]=1[NH:22][CH:23]1[CH2:30][CH2:29][C:26]([OH:28])([CH2:27][O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[CH2:25][CH2:24]1)=[O:16]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 167693TrimethylsilyldiazomethaneHCID 2733227(S)-(+)-3-HydroxytetrahydrofuranHCID 23665647Potassium tert-butoxideHCID 58360459HCID 58360459, compound

Product 1

HCID 67341828HCID 67341828, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 13387N-methyl-2-pyrrolidoneSolvent3×HCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of (S)-(+)-3-hydroxytetrahydrofuran (259 mg, 2.94 mmol) in dry NMP (1 mL) was added to a solution of KOtBu (271 mg, 2.42 mmol) in dry NMP (1 mL). The reaction was stirred at room temperature for 15 min, then a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(1-oxa-spiro[2.5]oct-6-ylamino]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.576 mmol) in dry NMP (4.0 mL) was added and the reaction heated in a 40° C. oil bath for 24 h. The reaction was poured into ice water, cooled to 0° C., neutralized with 5% citric acid to pH=5-6 and extracted with ethyl acetate. The organic layer was washed with 5% LiCl, brine, dried and concentrated to give a brown oil which was taken up in dichloromethane/MeOH (5.0 mL/1.0 mL) and treated with the dropwise addition of TMSCH2N2 (0.35 mL, 0.692 mmol, 2M in hexane). After 20 min, volatiles were removed under vacuum and the crude residue was purified by column chromatography on silica gel (Teledyne Isco Redisep Rf Gold™) eluting with 100% dichloromethane to 20% ethyl acetate/dichloromethane to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-hydroxy-4-(tetrahydro-furan-3-yloxymethy)-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (120 mg, 48%) as a colorless solid.

Workup

  1. temperaturethe reaction heated in a 40° C. oil bath for 24 h
  2. temperaturecooled to 0° C.
  3. extractionextracted with ethyl acetate
  4. washThe organic layer was washed with 5% LiCl, brine
  5. customdried
  6. concentrationconcentrated
  7. customto give a brown oil which
  8. waitAfter 20 min
  9. customvolatiles were removed under vacuum
  10. customthe crude residue was purified by column chromatography on silica gel (Teledyne Isco Redisep Rf Gold™)
  11. washeluting with 100% dichloromethane to 20% ethyl acetate/dichloromethane

Sources & evidence

ORD record
ord-a269816650544a00ba3869c50f6d315b
Source dataset
uspto-grants-2013_08
Patent number
US08513298B2

Reaction notes

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