Hydrochloric Acid → Diethylamine

HRID 1400075Notes

Reaction equation

HRID 1400075 reaction equation
[F:1][C:2]([F:44])([F:43])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C@H:20]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=4)[C:35]([O:37]CC)=[O:36])[CH2:28][CH2:27]2)[CH2:19]3)=[O:17])[CH:4]=1.C[O-].[Na+].Cl>CO>[CH2:5]([NH:6][CH2:7][CH3:8])[CH3:4].[F:44][C:2]([F:1])([F:43])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C@H:20]([N:26]2[CH2:27][CH2:28][CH:29]([C:32]4[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=4)[C:35]([OH:37])=[O:36])[CH2:30][CH2:31]2)[CH2:19]3)=[O:17])[CH:4]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 10942334Sodium MethoxideHCID 86698132ethyl 3-(1-((2S,3aR,6aR)-3a-((S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate

Product 2

HCID 8021DiethylamineYield 0.05%HCID 866981313-{1-[(2S,3aR,6aR)-3a-({(1S,4S)-5-[4-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)octahydropentalen-2-yl]piperidin-4-yl}benzoic acid

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

The mixture from Example 9F (280 mg, 0.45 mmol), sodium methoxide (49.5 mg, 0.91 mmol) in methanol (10 mL) was refluxed for 12 hours. The mixture was acidified with 0.1 N aqueous hydrochloric acid to a pH around 5. The reaction mixture was partitioned with the addition of dichloromethane. The dichloromethane was collected and the aqueous solution was washed with dichloromethane (three times). The dichloromethane fractions were combined, dried and concentrated. The crude product was purified by preparative HPLC (Column: Phenomenex 150*30 mm; mobile phase: from 30% acetonitrile in H2O (0.01% TFA) to 70% acetonitrile in H2O (0.01% TFA) followed by chiral SFC purification (SFC condition: Column: AD-5 μm; Mobile phase:A, supercritical CO2; B, ethanol with 0.05% diethylamine, A:B=70:30 with a flow rate of 50 mL/min)) to give the title compound (peak 1 retention time: 5.58 minutes) and Example 10. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.24 (d, J=5.2 Hz, 1H), 7.80 (m, 2H), 7.28 (m, 2H), 6.78 (m, 2H), 5.10 (m, 2H) 3.30-3.79 (m, 6H), 3.20 (m, 1H), 2.70-2.96 (m, 3H), 2.25-2.65 (m, 1H), 1.50-2.15 (m, 15H), 1.38 (m, 1H); MS (ESI+) m/z 583 (M+H)+.

Workup

  1. customThe reaction mixture was partitioned with the addition of dichloromethane
  2. customThe dichloromethane was collected
  3. washthe aqueous solution was washed with dichloromethane (three times)
  4. customdried
  5. concentrationconcentrated
  6. customThe crude product was purified by preparative HPLC (Column
  7. custommobile phase: from 30% acetonitrile in H2O (0.01% TFA) to 70% acetonitrile in H2O (0.01% TFA) followed by chiral SFC purification (SFC condition

Sources & evidence

ORD record
ord-49b8b2ba34e247aab64fd311d00dc90d
Source dataset
uspto-grants-2014_12
Patent number
US08906911B2

Reaction notes

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