1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → HCID 86659852, compound

HRID 2402760Notes

Reaction equation

HRID 2402760 reaction equation
[CH3:1][C@@:2]1([NH2:20])[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=3)[CH2:8]2)[CH2:4][CH2:3]1.[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([F:33])[CH2:30][C@H:29]1[C:34]([OH:36])=[O:35])=[O:27])([CH3:24])([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[F:33][C@H:31]1[CH2:32][NH:28][C@H:29]([C:34]([NH:20][C@:2]2([CH3:1])[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=4)[CH2:8]3)[CH2:4][CH2:3]2)=[O:35])[CH2:30]1.[F:33][C@H:31]1[CH2:32][N:28]([C:26]([O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:27])[C@H:29]([C:34](=[O:36])[NH:20][C@:2]2([CH3:1])[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=4)[CH2:8]3)[CH2:4][CH2:3]2)[CH2:30]1

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 27960291-Hydroxybenzotriazole hydrateHCID 12043048(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acidHCID 54674494HCID 54674494, compound

Product 2

HCID 86659852HCID 86659852, compoundHCID 86659853HCID 86659853, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The title compound is prepared by treating a solution of (3aR,4S,6aS)-4-methyl-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 27 (0.075 g, 0.263 mmol) in 1 mL dichloromethane with (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (0.067 g, 0.289 mmol) followed by of 1-hydroxybenzotriazole hydrate (0.044 g, 0.289 mmol). The reaction was stirred for 5 minutes, and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.051 mL, 0.289 mmol) was added to the reaction mixture followed by stirring at ambient temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate, and the crude material was chromatographed using a 12 g silica gel cartridge eluted with 3%-100% ethyl acetate/hexanes over 30 minutes to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-4-methyl-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate which was treated with 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol). An oil slowly gummed out of solution. The reaction was stirred at room temperature for 18 hours, and the solvent was removed under a stream of nitrogen. The crude material was purified using a 12 g silica gel cartridge eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.03 (bs, 1H), 7.52 (m, 1H), 7.00 (d, J=7.2, 1H), 6.55 (d, J=8.5, 1H), 5.22 (dt, J=54.3, 3.5, 1H), 4.22-4.14 (m, 1H), 3.75-3.45 (m, 4H), 3.41-3.27 (m, 2H), 3.22-3.12 (m, 1H), 3.02-2.74 (m, 2H), 2.58 (dddd, J=23.7, 15.0, 8.5, 2.3, 1H), 2.32-2.11 (m, 2H), 1.99 (dq, J=13.3, 8.7, 1H), 1.78 (dt, J=13.2, 8.7, 1H), 1.48 (s, 3H), 1.46-1.13 (m, 1H); MS (ESI+) m/z 401 (M+H)+.

Workup

  1. stirringby stirring at ambient temperature overnight
  2. customThe reaction was quenched with saturated aqueous sodium bicarbonate
  3. customthe crude material was chromatographed
  4. washeluted with 3%-100% ethyl acetate/hexanes over 30 minutes

Sources & evidence

ORD record
ord-816331c13ee64518b29760385b4e0c62
Source dataset
uspto-grants-2014_08
Patent number
US08796470B2

Reaction notes

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