Water → HCID 60142472, compound

HRID 2404604Notes

Reaction equation

HRID 2404604 reaction equation
[CH3:1][N:2]([CH2:4][C@@H:5]1[C@:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)([OH:12])[CH2:10][C@H:9]2[CH2:20][C@@H:6]1[CH2:7][CH2:8]2)[CH3:3].CCN([CH2:26][CH3:27])CC.O.[C:29]([O-:32])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:5]1([C@H:26]([CH3:27])[C:29]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C@@:11]3([OH:12])[CH2:10][C@H:9]4[CH2:20][C@H:6]([CH2:7][CH2:8]4)[C@@H:5]3[CH2:4][N:2]([CH3:1])[CH3:3])[CH:14]=2)=[O:32])[CH:11]=[CH:10][CH:9]=[CH:20][CH:6]=1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 60142469HCID 60142469, compound

Product 1

HCID 60142472HCID 60142472, compoundYield 84.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removal of solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pole yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400 mg, 1.45 mmol) and Et3N (293 mg, 2.9 mmol) to the solution. Stir the resultant mixture at room temperature for additional 3 hours. After addition of 20 mL of water, basify the mixture with K2CO3 to pH=10, and extract the aqueous mixture with EtOAc (20 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (250 mg, 0.61 mmol) with H2O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochlorid (215 mg, Yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by x-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7.14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1.80 (m, 2H), 1.51-1.59 (m, 6H).

Workup

  1. extractionextract the aqueous mixture with EtOAc (20 mL×3)
  2. washThe combined organic layers are washed with brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customPurify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1)

Sources & evidence

ORD record
ord-7d5dcfbaa58846edb01dd2d922866634
Source dataset
uspto-grants-2014_08
Patent number
US08802728B2

Reaction notes

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