Formaldehyde → (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

HRID 131430Notes

Reaction equation

HRID 131430 reaction equation
[F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][NH:22][C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][N:22]([CH3:34])[C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 10388301(S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine

Product 1

HCID 10343743(S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepineYield 82.3%

Reagents, catalysts & solvents 2

HCID 63651,1-DichloroethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

Combine (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.259 g, 0.593 mmol), formaldehyde (67 μL, 0.831 mmol, 37%), and sodium triacetoxyborohydride (0.189 g, 0.890 mmol) in dichloroethane (10 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.220 g, 0.488 mmol, 82%) as a yellow oil. Mass spectrum (APCI): m/z=451.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine dihydrochloride.

Workup

  1. extractionextract three times with methylene chloride
  2. dry with materialdry over sodium sulfate
  3. concentrationconcentrate under reduced pressure
  4. customto give the crude product
  5. customPurification by flash chromatography
  6. washeluting with a step gradient

Sources & evidence

ORD record
ord-c266fed7040148b7ae479f8bcf1a6d54
Source dataset
uspto-grants-2008_06
Patent number
US07384934B2

Reaction notes

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