Methanol → HCID 178499250, compound

HRID 2388263Notes

Reaction equation

HRID 2388263 reaction equation
[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([Br:31])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:22][CH2:23][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:29][CH2:30]1)[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])=[O:14]

Participants

7

Reactant 4

HCID 887MethanolHCID 1049Pyridine2×HCID 597523595-Bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl esterHCID 178461265HCID 178461265, compound

Product 2

HCID 178461265HCID 178461265, compoundHCID 178499250HCID 178499250, compoundYield 32%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
5 °C

Procedure

The 1M solution of trans-4-methylcyclohexyl carboxylic acid chloride is added to a solution of 5-bromo-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (24.79 g, 65 mmol) in toluene (25 mL) followed by pyridine (5.78 mL, 71.5 mmol). The resulting mixture is then stirred for 16 h at reflux. The reaction mixture is diluted with toluene (60 mL) and cooled down to 5° C. After the addition of pyridine (12 mL) and MeOH (5.6 mL), the mixture is stirred 2 h at 5° C. The white suspension is filtered off and the toluene is added to the mother liquor. The organic phase is washed with 10% citric acid, aq. Sat NaHCO3, dried (Na2SO4) and concentrated. The residue is triturated in boiling hexane (1500 mL). The reaction mixture is allowed to cool down to room temperature. The reaction flask is immersed into ice bath, and stirred for 30 min; white solid is filtered off, and washed with cold hexane (225 mL). The solid is purified by silica gel column chromatography using 20% EtOAc:hexane as eluent to furnish the final compound 5-bromo-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.5 g, 32%).

Workup

  1. temperatureat reflux
  2. stirringthe mixture is stirred 2 h at 5° C
  3. filtrationThe white suspension is filtered off
  4. additionthe toluene is added to the mother liquor
  5. washThe organic phase is washed with 10% citric acid, aq. Sat NaHCO3
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe residue is triturated
  9. temperatureto cool down to room temperature
  10. customThe reaction flask is immersed into ice bath
  11. stirringstirred for 30 min
  12. filtrationwhite solid is filtered off
  13. washwashed with cold hexane (225 mL)
  14. customThe solid is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-c29cedab3dc8495c919ed0a7e5a0240d
Source dataset
uspto-grants-2012_09
Patent number
US08269014B2

Reaction notes

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