Hydrochloric Acid → 1-(2-Methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester

HRID 1845008Notes

Reaction equation

HRID 1845008 reaction equation
C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH:18][C:19](=O)[CH2:20][CH2:21][S:22][CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl>[CH3:7][O:8][C:9]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19]([CH2:20][CH2:21][S:22][CH3:23])=[N:18]1)=[O:25]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 65578Oxalyl chlorideHCID 66940370HCID 66940370, compound

Product 1

HCID 669404581-(2-Methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl esterYield 38%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

0.882 mL (10.07 mmol) of oxalyl chloride was added dropwise to a solution of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester (from previous step) in 30 mL of dichloromethane and stirred at room temperature for 1 h. This reaction mixture was then cooled to −10° C. and treated with 1.82 g (11 mmol) of FeCl3 at this temperature in portions. This reaction mixture was allowed to warm up to room temperature overnight. 30 mL of 2 N aq. HCl was added slowly while stirring for 1 h. 20 mL of dichloromethane was added and separated, washed again with water (50 mL), and dried over sodium sulfate. The organic solvents were evaporated in vacuo. The residual red solid was mixed with 30 mL of methanol and 1.5 mL of conc. H2SO4 and heated under reflux overnight. Water was added to the reaction mixture and the methanol was evaporated under reduced pressure Ammonium hydroxide was added to adjust pH to basic. The aqueous layer (˜50 mL) was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 923 mg (38%) of 1-(2-methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 264 (M+1)+.

Workup

  1. temperatureThis reaction mixture was then cooled to −10° C.
  2. temperatureto warm up to room temperature overnight
  3. stirringwhile stirring for 1 h
  4. customseparated
  5. washwashed again with water (50 mL)
  6. dry with materialdried over sodium sulfate
  7. customThe organic solvents were evaporated in vacuo
  8. additionThe residual red solid was mixed with 30 mL of methanol and 1.5 mL of conc. H2SO4
  9. temperatureheated
  10. temperatureunder reflux overnight
  11. additionWater was added to the reaction mixture
  12. customthe methanol was evaporated under reduced pressure Ammonium hydroxide
  13. additionwas added
  14. extractionThe aqueous layer (˜50 mL) was extracted with dichloromethane (2×50 mL)
  15. dry with materialThe combined organic layers were dried over sodium sulfate
  16. customevaporated
  17. customPurification by column chromatography on silica gel

Sources & evidence

ORD record
ord-71d23024af764deeb0f98770035146c0
Source dataset
uspto-grants-2015_02
Patent number
US08946259B2

Reaction notes

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