Sodium Bicarbonate → [4(3,4-Difluoro-phenyl)-piperazin-1-yl]-[(4S,4aS,8aR)-2-(2(S)-methyl-3-quinoxalin-6-yl-propyl)-decahydro-isoquinolin-4-yl]-methanone

HRID 988750Notes

Reaction equation

HRID 988750 reaction equation
[CH3:1][C@@H:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=O.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[F:23].[BH-](O[C:42]([CH3:44])=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:7]3[C@@H:42]4[C@@H:44]([CH2:1][CH2:2][CH2:5][CH2:6]4)[CH2:10][N:9]([CH2:3][C@@H:2]([CH3:1])[CH2:5][C:6]4[CH:7]=[C:8]5[C:13](=[CH:14][CH:15]=4)[N:12]=[CH:11][CH:10]=[N:9]5)[CH2:8]3)=[O:31])[CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[F:23]

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 86588589(S)-2-methyl-3-quinoxalin-6-yl-propionaldehydeHCID 86588590[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-methanone

Product 1

HCID 20597810[4(3,4-Difluoro-phenyl)-piperazin-1-yl]-[(4S,4aS,8aR)-2-(2(S)-methyl-3-quinoxalin-6-yl-propyl)-decahydro-isoquinolin-4-yl]-methanone

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

To a solution of (S)-2-methyl-3-quinoxalin-6-yl-propionaldehyde (2.7 g, 13.48 mmol) in dichloroethane (100 ml) is added (4S,4aS,8aR)-decahydro-isoquinolin-4-yl)-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-methanone (5.36 g, 11.22 mmol) and stirred for 5 minutes. NaBH(OAc)3 (3.56 g, 16.8 mmol) is added and the mixture stirred for 1 h. A 1 M solution of NaHCO3 (100 ml) is added and intensively stirred for 15 minutes. The phases are separated, the organic phase dried over Na2SO4 and evaporated to afford 7.2 g of the crude product. MPLC purification (silicagel, EtOAc, then EtOAc/MeOH 5:1) yield pure [4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-[(4S,4aS,8aR)-2-(2(S)-methyl-3-quinoxalin-6-yl-propyl)-decahydro-isoquinolin-4-yl]-methanone. This base is dissolved in 60 ml warm MeOH and treated with maleic acid (1.3 g, 11.22 mmol) in 20 ml MeOH. The solution is diluted with Et2O (450 ml), and the slightly cloudy solution filtered through Hyflo. Crystallisation first at room temperature and then at 5° afford the maleic acid salt, m.p. 1200-1230. Recrystallization from 50 ml MeOH and 100 ml Et2O yield the pure maleic acid salt, m.p. 129°-131°.

Workup

  1. stirringthe mixture stirred for 1 h
  2. stirringintensively stirred for 15 minutes
  3. customThe phases are separated
  4. dry with materialthe organic phase dried over Na2SO4
  5. customevaporated
  6. customto afford 7.2 g of the crude product
  7. customMPLC purification (silicagel, EtOAc

Sources & evidence

ORD record
ord-403c57eb5b8e479389ac54b644917872
Source dataset
uspto-grants-2003_10
Patent number
US06635647B2

Reaction notes

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