1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Rac-((1r,2s)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclohexyl)-carbamic acid tert-butyl ester

HRID 1428956Notes

Reaction equation

HRID 1428956 reaction equation
[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@H:54]1[C:59](O)=[O:60])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]1[C:59]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:60])([CH3:48])([CH3:46])[CH3:47]

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 1512487cis-2-((tert-Butoxycarbonyl)amino)cyclohexanecarboxylic acidHCID 2773944N-Cyclopropyl-N-piperidin-4-yl-3-(trifluoromethyl)benzenesulfonamide

Product 1

HCID 69029096Rac-((1r,2s)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclohexyl)-carbamic acid tert-butyl esterYield 100%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Procedure

N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.348 g, 1.00 mmol), HOBt (0.135 g, 1.0 mmol), EDCI (0.230 g, 1.2 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid (0.276 g, 1.1 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclohexyl)-carbamic acid tert-butyl ester (573 mg, 100%). The product (0.120 g, 0.21 mmol) was taken up in 1 ml of EtOAc, and cooled in ice bath. 4N HCl-EtOAc (1.0 ml) was added slowly, and the mixture was stirred at room temperature for 5 hours. The solvent was removed and remaining material was triturated with ethyl ether to give the desired product 4 (colorless amorphous, 90 mg, 84%) as hydrochloride salt. LC: 100%. MS: m/z=473.

Workup

  1. washwashed with 10 ml of H2O
  2. dry with materialThe organic layer was dried over MgSO4
  3. concentrationconcentrated to dryness
  4. customThe crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane

Sources & evidence

ORD record
ord-9456cd9687a543799d2dda0cd6fa20ba
Source dataset
uspto-grants-2015_01
Patent number
US08937181B2

Reaction notes

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