Hydrochloric Acid → N2,4-dimethyl-N-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide

HRID 2363617Notes

Reaction equation

HRID 2363617 reaction equation
[F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(O[C:25]([N:27](C)[C@@H:28]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:29](O)=[O:30])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.O1CCOCC1>ClCCl>[CH3:25][NH:27][C@H:28]([C:29]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)=[O:30])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 312751,4-DioxaneHCID 27960291-Hydroxybenzotriazole hydrateHCID 66590059(3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amineHCID 86641984N-Boc-N-methyl-3-tert-butyl-L-alanine

Product 1

HCID 86659288N2,4-dimethyl-N-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (95.7 mg, 0.353 mmol) was combined with (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid (101 mg, 0.388 mmol) and 1-hydroxybenzotriazole hydrate (59.4 mg, 0.388 mmol) in dichloromethane (1 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.068 mL, 0.388 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane. The resulting oil was treated with 4 N hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) for 3 hours at room temperature. The solvent was removed under a stream of nitrogen and the residue basified with aqueous sodium bicarbonate and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.36 (d, J=7.3, 1H), 7.51 (t, J=7.9, 1H), 6.98 (d, J=7.2, 1H), 6.52 (d, J=8.6, 1H), 4.45-4.35 (m, 1H), 3.74 (dd, J=10.9, 2.8, 1H), 3.62 (dd, J=10.8, 7.5, 1H), 3.52 (dd, J=10.7, 7.8, 1H), 3.29 (dd, J=10.8, 3.4, 1H), 3.24-3.18 (m, 1H), 2.79-2.64 (m, 2H), 2.42 (s, 3H), 2.14 (td, J=12.5, 7.0, 1H), 2.01-1.79 (m, 3H), 1.69 (dq, J=12.8, 8.0, 1H), 1.51 (dd, J=14.1, 6.6, 1H), 1.44-1.33 (m, 1H), 1.00 (s, 9H); MS (ESI+) m/z 413 (M+H)+.

Workup

  1. customThe reaction mixture was quenched with water
  2. extractionextracted with 2×2 mL of dichloromethane
  3. custompurified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane
  4. customThe solvent was removed under a stream of nitrogen
  5. extractionextracted with 2×2 mL of dichloromethane
  6. custompurified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane

Sources & evidence

ORD record
ord-438c16459c9b496692f93a07218d455b
Source dataset
uspto-grants-2014_04
Patent number
US08691865B2

Reaction notes

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