Hydrochloric Acid → (3R)-3-[(1S)-1-(3,4-Dichlorophenyl)-3-(4-(2-methylsulfinylphenyl)-piperidino)propyl]-2-methyl-2,3-dihydroisoindol-1-one hydrochloride

HRID 1738935Notes

Reaction equation

HRID 1738935 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][S:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:26].C([BH3-])#N.[Na+].Cl>CO.C(=O)(O)[O-].[Na+].C(N(CC)CC)C.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:25]([CH3:24])=[O:26])[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 5003444Sodium cyanoborohydrideHCID 187003874-(2-(Methylsulfinyl)phenyl)piperidineHCID 57040947(3S)-3-(3,4-Dichlorophenyl)-3-((1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde

Product 1

HCID 70111254(3R)-3-[(1S)-1-(3,4-Dichlorophenyl)-3-(4-(2-methylsulfinylphenyl)-piperidino)propyl]-2-methyl-2,3-dihydroisoindol-1-one hydrochlorideYield 90.2%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 8471TriethylamineSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of (3S)-3-(3,4-dichlorophenyl)-3-[(1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionaldehyde (0.54 g) in methanol (10 mL) was treated with 4-(2-methylsulfinylphenyl)piperidine (0.61 g) and the pH was adjusted to 3 with acetic acid and triethylamine. After treating with sodium cyanoborohydride (189 g) the reaction mixture was stirred at ambient temperature for 16 hours, acidified with 10% hydrochloric acid, stirred for 15 minutes and then diluted with a saturated solution of sodium bicarbonate. Upon extraction with dichloromethane, the organic layer was dried and evaporated to obtain the crude product. This material was purified by chromatography, with 20:1 dichloromethane:methanol as the eluent to give the desired 3-[1-(3,4-dichlorophenyl)-3-(4-(2-methylsulfinylphenyl)piperidino)propyl]-2-methyl-2,3-dihydroisoindol-l-one (0.414 g). This material was transformed into the hydrochloride salt as follows. The material was dissolved in dichloromethane (2 mL) and treated with hydrochloric acid in ether (2 mL). The resulting solution was diluted with anhydrous ether (80 mL), stirred for 4 hours, and the resulting precipitate was collected to afford the title compound (0.35 g); mp 180-188° C.; MS: m/z=555(M+1); NMR(CD3SOCD3): 2.0 (broad,2), 2.3 (broad,2), 2.7 (s,3), 3.1 (s,3), 3.6 (t,2, J=15), 3.76 (m,1), 4.9 (d,1, J=2.4), 6.8 (d,1, J=7.8), 7.0 (s,1), 7.3-7.98 (m,9). Analysis for C30H32C.HClH2O: Calculated: C, 59.07; H, 5.78; N, 4.59; Found: C, 59.06; H, 5.72; N, 4.45.

Workup

  1. stirringstirred for 15 minutes
  2. extractionUpon extraction with dichloromethane
  3. customthe organic layer was dried
  4. customevaporated
  5. customto obtain the crude product
  6. customThis material was purified by chromatography, with 20:1 dichloromethane

Sources & evidence

ORD record
ord-03286f64a6eb448a80c1d2e49f91effe
Source dataset
uspto-grants-1999_10
Patent number
US05965576

Reaction notes

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