Hydrochloric Acid → HCID 24985577, compound

HRID 544930Notes

Reaction equation

HRID 544930 reaction equation
[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C1(C)C=CC(S([O:38][CH2:39][C@H:40]2[CH2:44]OC(C)(C)[O:41]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O.CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:28])=[C:11]([NH:13][C:14]([C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:44][C@H:40]([OH:41])[CH2:39][OH:38])[CH:22]=4)=[CH:19][CH:20]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 6993835(R)-(-)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-ToluenesulfonateHCID 59761472HCID 59761472, compound

Product 1

HCID 24985577HCID 24985577, compoundYield 31.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-5-(3-hydroxyphenyl)thiophene-2-carboxamide (Example 144, 80 mg, 0.20 mmol), (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (70 mg, 0.24 mmol) and K2CO3 (84 mg, 0.61 mmol) in DMF (0.3 mL) was stirred and heated at 80° C. for 17 h. After cooling to rt, the mixture was diluted with water (˜5 mL) and extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine, dried over anhyd. Na2SO4, filtered, and concentrated under vacuum to afford a brown oil. This material was purified by reverse-phase Prep HPLC to isolate the major product which was dissolved in MeOH (˜3 mL) and 2 N aq HCl (0.3 mL) was added. The solution was warmed to 65° C. for 45 min then cooled to rt and concentrated under vacuum to remove most of the MeOH. The resulting heterogeneous mixture was diluted with water (˜2-3 mL) and stirred for 1 h. The resulting solid was collected by vacuum filtration, rinsed with water (˜5 mL), and air dried in funnel then under vacuum to afford 29 mg (30%) of an off-white solid as the title compound (Example 193). HPLC Ret. Time=2.90 min, LCMS [M+H]+ 467.29.

Workup

  1. temperatureAfter cooling to rt
  2. extractionextracted with EtOAc (3×10 mL)
  3. washthe combined extracts were washed with brine
  4. customdried over anhyd
  5. filtrationNa2SO4, filtered
  6. concentrationconcentrated under vacuum
  7. customto afford a brown oil
  8. customThis material was purified by reverse-phase Prep HPLC
  9. customto isolate the major product which
  10. temperatureThe solution was warmed to 65° C. for 45 min
  11. temperaturethen cooled to rt
  12. concentrationconcentrated under vacuum
  13. customto remove most of the MeOH
  14. additionThe resulting heterogeneous mixture was diluted with water (˜2-3 mL)
  15. stirringstirred for 1 h
  16. filtrationThe resulting solid was collected by vacuum filtration
  17. washrinsed with water (˜5 mL), and air
  18. customdried in funnel

Sources & evidence

ORD record
ord-7c465faaf92c4116917ae631694ea0c8
Source dataset
uspto-grants-2011_05
Patent number
US07935696B2

Reaction notes

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