Hydrochloric Acid → 2-[[(2S)-1-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-piperidin-2-y]-methoxy]-1-[4-pyridin-3-yl-4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethanone hydrochloride

HRID 1645252Notes

Reaction equation

HRID 1645252 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22](O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][CH2:27][N:28]([CH:32]([CH3:34])C)[CH:29]([CH3:31])C.CCN=C=N[CH2:40][CH2:41][CH2:42][N:43]([CH3:45])C.Cl.[CH:47]1[CH:48]=[CH:49][C:50]2N(O)N=[N:53][C:51]=2C=1.[Cl:57][CH2:58]Cl>>[ClH:57].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([N:53]2[CH2:47][CH2:48][C:49]([C:58]3[CH:45]=[N:43][CH:42]=[CH:41][CH:40]=3)([CH2:34][CH2:32][N:28]3[CH2:27][CH2:26][CH2:31][CH2:29]3)[CH2:50][CH2:51]2)=[O:23])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1

Participants

7

Reactant 6

HCID 313Hydrochloric AcidHCID 6344Dichloromethane3×HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531Diisopropylethylamine2×HCID 57819715(S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid

Product 1

HCID 442524462-[[(2S)-1-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-piperidin-2-y]-methoxy]-1-[4-pyridin-3-yl-4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethanone hydrochlorideYield 43%

Procedure

To a solution of 2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)benzyloxy)acetic acid [carboxylic acid 1] (0.5 mmol) in dichloromethane (5 ml) were added DIPEA (4 eq.), EDCI. HCl (1.2 eq) and HOBt (1 eq.). Then a mixture of Boc-deprotected tert-butyl 4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate (0.62 mmol) [deprotected using standard reaction conditions: dichloromethane (3 ml), TFA (3 eq.) and concentration in vacuo] and DIPEA (2 eq.) in dichloromethane (3 ml) was added dropwise at ice-cold reaction conditions. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride, brine, saturated sodium bicarbonate solution and again brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, methanol/dichloromethane). The free base of the desired compound was dissolved in dioxane (3 ml), stirred in dioxane saturated with HCl for 1 h and then concentrated under reduced pressure to give the desired product.

Workup

  1. additionwas added dropwise at ice-cold reaction conditions
  2. washwashed with saturated ammonium chloride, brine, saturated sodium bicarbonate solution and again brine
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by column chromatography (silica, methanol/dichloromethane)
  6. dissolutionThe free base of the desired compound was dissolved in dioxane (3 ml)
  7. stirringstirred in dioxane saturated with HCl for 1 h
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-9aa444f1287448b39b4d29b3b28c6620
Source dataset
uspto-grants-2012_02
Patent number
US08124624B2

Reaction notes

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