Methyl chloroformate → tert-Butyl 3-[N-((1R)-1-[(4-chlorophenyl)-methyl]-2-{4-[2-(methoxycarbonylamino)-phenyl]-piperidyl}-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

HRID 489703Notes

Reaction equation

HRID 489703 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH3:58])=[O:56]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:55]([O:57][CH3:58])=[O:56])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 81531DiisopropylethylamineHCID 10189232tert-Butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)-piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}-carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

Product 1

HCID 69151559tert-Butyl 3-[N-((1R)-1-[(4-chlorophenyl)-methyl]-2-{4-[2-(methoxycarbonylamino)-phenyl]-piperidyl}-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylateYield 81.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) and CH2Cl2 (15 mL) followed by DIEA (0.16 mL, 0.9 mmol). The reaction mixture was stirred for 5 min at RT then treated with methyl chloroformate (Aldrich) (84.6 mg, 0.9 mmol) at 0° C. The reaction mixture was stirred at RT for 12 h then quenched with satd NaHCO3 (15 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The organic fractions were combined, washed with satd NaCl (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (412 mg). MS (ESI, pos. ion) m/z: 675 (M+1); MS (ESI, neg. ion) m/z: 673 (M−1). Calc'd for C11H13ClN4O6: 674.29.

Workup

  1. customTo a 50 mL round-bottomed flask equipped
  2. stirringThe reaction mixture was stirred for 5 min at RT
  3. stirringThe reaction mixture was stirred at RT for 12 h
  4. customthen quenched with satd NaHCO3 (15 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer was extracted with CH2Cl2 (2×15 mL)
  7. washwashed with satd NaCl (15 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification by silica gel chromatography (100% EtOAc)

Sources & evidence

ORD record
ord-2fa30c9aad7346989d4393ccdd84b594
Source dataset
uspto-grants-2005_12
Patent number
US06977264B2

Reaction notes

Loading…