Ammonia → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate

HRID 1518269Notes

Reaction equation

HRID 1518269 reaction equation
Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[N:25]1([C:30](N2C=CN=C2)=[S:31])C=CN=C1.N.CO.Br[CH:41]([CH2:49][CH2:50][CH2:51][Cl:52])[C:42](=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.CCO>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:30]1[S:31][C:41]([CH2:49][CH2:50][CH2:51][Cl:52])=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:25]=1)[CH2:21][CH2:20]2)=[O:14]

Participants

8

Reactant 5

HCID 222AmmoniaHCID 887MethanolHCID 802641,1'-ThiocarbonyldiimidazoleHCID 59418695Ethyl 3-bromo-6-chloro-2-oxohexanoate2×HCID 86644320N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride

Product 1

HCID 59447646ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 6228DimethylformamideSolvent

Procedure

To N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (11.5 g, 30 mmol) in DMF (125 mL) was added TEA (16.7 mL, 120 mmol) and stirred at rt for 15 minutes. Di(1H-imidazol-1-yl)methanethione (6.53 g, 33 mmol) was added and the reaction mixture was stirred at rt for 1 hour. 7N Ammonia in MeOH (171 mL, 1.2 mol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated to remove ammonia, TEA, and MeOH. To the concentrate was added a solution of ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (11.4 g, 42 mmol) in EtOH (40 mL). The reaction mixture was heated at 50° C. under nitrogen for 4.5 hours. Additional ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (0.815 g, 3 mmol) in EtOH (3 mL) was added and heating was continued for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 30 to 50% EtOAc in hexanes to provide the desired product ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (2B) in 69% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.42 (4H, m), 4.83 (2H, s), 4.19 (2H, q), 3.72 (2H, t), 3.64 (2H, t), 3.13 (2H, m), 3.04 (2H, t), 2.00 (2H, m), 1.21 (3H, t).

Workup

  1. stirringthe reaction mixture was stirred at rt for 1 hour
  2. stirringthe mixture was stirred at rt overnight
  3. concentrationThe reaction mixture was concentrated
  4. customto remove ammonia, TEA, and MeOH
  5. temperatureThe reaction mixture was heated at 50° C. under nitrogen for 4.5 hours
  6. temperatureheating
  7. waitwas continued for 1.5 hours
  8. concentrationThe reaction mixture was concentrated under reduced pressure
  9. customto remove EtOH
  10. extractionextracted with EtOAc
  11. washThe combined organic extracts were washed with brine
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure
  15. customThe concentrate was purified by column chromatography on silica gel eluting with a gradient of 30 to 50% EtOAc in hexanes

Sources & evidence

ORD record
ord-15cf626e200644f087240b2cd638da79
Source dataset
uspto-grants-2012_07
Patent number
US08232273B2

Reaction notes

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