Triethylamine → (1R*,3S*,4R*)-alpha,alpha-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4,5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

HRID 2213065Notes

Reaction equation

HRID 2213065 reaction equation
C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([CH3:48])([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1)[C:17]([NH:19][C@:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:24][C:23](=O)[C@@H:22]([F:27])[CH2:21]1)=[O:18].Cl.[CH2:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52][O:51]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCCl>[CH3:48][C:16]([CH3:15])([C:34]1[CH:35]=[C:36]([C:44]([F:45])([F:46])[F:47])[CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[C:17]([NH:19][C@:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24][C@@H:23]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:50][O:51][CH2:52][CH2:53]3)[CH2:55][CH2:56]2)[C@@H:22]([F:27])[CH2:21]1)=[O:18]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydride2×HCID 219552642-Oxa-8-azaspiro(4.5)decane hydrochlorideHCID 87889272(1R*,3S*)-alpha,alpha-dimethyl-N-[3-fluoro-4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Product 1

HCID 87888922(1R*,3S*,4R*)-alpha,alpha-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4,5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideYield 3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

Sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added to a mixture of (1R*,3S*)-α,α-dimethyl-N-[3-fluoro-4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide (Example 58, 490 mg, 0.97 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride (Description 86, 204 mg, 1.37 mmol) and triethylamine (1.34 mL, 9.7 mmol) in 1,2-dichloroethane (15 mL) and the mixture was stirred at room temperature for 3 days. Further sodium triacetoxyborohydride (103 mg, 0.49 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was basified with aqueous sodium hydroxide (1M) and extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH (97.5:2.5), to give (1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (18 mg, 3%); 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.70 (2H, s), 7.36–7.23 (5H, m), 5.13 (1H, s), 4.98 (1H, br d, J 48.5 Hz), 3.81 (2H, t, J 7.2Hz), 2.89–2.68 (3H, m), 3.67–2.42 (4H, m), 2.41–2.38 (2H, m), 1.89–1.86 (1H, m), 1.73–1.71 (1H, m), 1.68 (2H, t, J 7.2 Hz), 1.63–1.58 (6H, m), and 1.53 (6H, d, 3.4 Hz). m/z (ES+) 615 (M+1); and (1S*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (280 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.81 (2H, s), 7.79 (1H, s), 7.32–7.21 (1H, s), 6.41 (1H, d, J 10.5 Hz), 5.06 (1H, br d, J 50.0 Hz), 3.87–3.83 (2H, m), 3.00–2.96 (1H, m), 2.60–2.39 (4H, m), 2.30–2.22 (2H, m), 2.01–1.93 (1H, m), 1.77–1.70 (3H, m), 1.65–1.50 (8H, m), and 1.60 (6H, d, J 6.9 Hz). m/z (ES+) 615 (M+1).

Workup

  1. stirringthe mixture was stirred at room temperature for 24 hours
  2. extractionextracted with dichloromethane
  3. dry with materialThe combined organic fractions were dried (MgSO4)
  4. customthe solvent was evaporated under reduced pressure
  5. customThe residue was purified by MPLC on silica gel
  6. washeluting with CH2Cl2/MeOH (97.5:2.5)

Sources & evidence

ORD record
ord-6a75b05d00f8434c90c05068e24212b9
Source dataset
uspto-grants-2006_09
Patent number
US07105507B2

Reaction notes

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