Sodium triacetoxyborohydride → Tert-butyl 3-{n-[(1r)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3s)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

HRID 489705Notes

Reaction equation

HRID 489705 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.[CH2:45]1[CH:47]([CH:48](O)C#N)[CH2:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[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][CH2:48][CH:47]3[CH2:45][CH2:46]3)[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1

Participants

5

Reactant 3

HCID 5049666Sodium triacetoxyborohydrideHCID 10189232tert-Butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)-piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}-carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylateHCID 113893592-Cyclopropyl-2-hydroxyacetonitrile

Product 1

HCID 69152283Tert-butyl 3-{n-[(1r)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3s)-1,2,3,4-tetrahydroisoquinoline-2-carboxylateYield 85.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a 50 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) followed by 1,2-dichloroethane (20 mL) and cyclopropyl-carboxaldehyde (Aldrich) (58 mg, 0.83 mmol). The reaction mixture was stirred for 6 h, then treated with sodium triacetoxyborohydride (Aldrich) (176 mg, 0.83 mmol) at 0° C. After stirring for 12 h at RT, the reaction mixture was quenched with satd NaHCO3 (20 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (2×20 mL). The organic fractions were combined, washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:10 MeOH:EtOAc) provided the title compound as a white foam (431 mg). MS (ESI, pos. ion) m/z: 671 (M+1); MS (ESI, neg. ion) m/z: 669 (M−1). Calcd for C39H47ClN4O4: 670.33.

Workup

  1. customTo a 50 round-bottomed flask equipped
  2. stirringThe reaction mixture was stirred for 6 h
  3. stirringAfter stirring for 12 h at RT
  4. customthe reaction mixture was quenched with satd NaHCO3 (20 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer extracted with CH2Cl2 (2×20 mL)
  7. washwashed with satd NaCl (50 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification by silica gel chromatography (1:10 MeOH:EtOAc)

Sources & evidence

ORD record
ord-2c6cf9be0db14575b916707c31312180
Source dataset
uspto-grants-2005_12
Patent number
US06977264B2

Reaction notes

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