Formaldehyde → racemic (2'S,3S,4'R)-4'-[5-bromo-2-(1-methyl-4-piperidinyloxy)-phenyl]-6-chloro-2'-(3-fluorophenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione

HRID 504507Notes

Reaction equation

HRID 504507 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 74928442Racemic (2'S,3S,4'R)-4'-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2'-(5-fluorophenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione

Product 1

HCID 74928443racemic (2'S,3S,4'R)-4'-[5-bromo-2-(1-methyl-4-piperidinyloxy)-phenyl]-6-chloro-2'-(3-fluorophenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dioneYield 65.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.25 mmol) in methanol (10 mL) was added an aqueous solution (37 wt %, Aldrich) of formaldehyde (0.03 mL, 0.38 mmol) and NaCNBH3 (25 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc:triethylamine=12:88:5) to give racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-methyl-4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 65%).

Workup

  1. concentrationconcentrated
  2. customThe residue was partitioned between ethyl acetate and water
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with ethyl acetate
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography (MeOH:EtOAc:triethylamine=12:88:5)

Sources & evidence

ORD record
ord-dedb24bc86a24b0088a74c3692023df4
Source dataset
uspto-grants-2010_08
Patent number
US07776875B2

Reaction notes

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