Sodium triacetoxyborohydride → (4-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester

HRID 507116Notes

Reaction equation

HRID 507116 reaction equation
[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[F:14][C:15]([F:51])([F:50])[C:16]1[CH:17]=[C:18]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:19][N:20]([C:37]1[O:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C@H:21]1[CH2:27][CH2:26][CH2:25][NH:24][C:23]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:22]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:24]2[CH2:25][CH2:26][CH2:27][CH:21]([N:20]([CH2:19][C:18]3[CH:43]=[C:44]([C:46]([F:48])([F:49])[F:47])[CH:45]=[C:16]([C:15]([F:14])([F:50])[F:51])[CH:17]=3)[C:37]3[O:41][N:40]=[C:39]([CH3:42])[CH:38]=3)[C:22]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][C:23]2=3)[CH2:7][CH2:6]1

Participants

7

Reactant 3

HCID 5049666Sodium triacetoxyborohydrideHCID 59432390(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amineHCID 86087385Methyl 2-(4-formylcyclohexyl)acetate

Product 1

HCID 11664840(4-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl esterYield 85%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

Add (4-formyl-cyclohexyl)-acetic acid methyl ester (68 mg, 0.368 mmol) to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (80 mg, 0.122 mmol) in acetic acid (0.5 mL) and 1,2-dichloroethane (5 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (103 mg, 0.488 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless semi-solid (73 mg, 85%). 1H NMR (CDCl3, 300 MHz) δ 0.72-2.34 (m, 21H), 2.60-2.65 (m, 1H), 2.82-2.90 (m, 1H), 3.00-3.10 (m, 2H), 3.89 (s, 3H), 4.60-4.89 (m, 3H), 5.12-5.18 (m, 1H), 6.89 (s, 1H), 7.15 (s, 1H), 7.68-7.71 (m, 3H), 7.82 (s, 1H); ESI MS m/z 720 [C35H38F9N3O3+H]+; HPLC 96.1%, tR 22.1 min.

Workup

  1. washwash with saturated aqueous sodium bicarbonate solution (2×10 mL)
  2. extractionExtract the combined aqueous washes with methylene chloride (20 mL)
  3. washwash the combined organic extracts with brined (20 mL)
  4. dry with materialdry over anhydrous sodium sulfate
  5. customRemove the solvents under reduced pressure
  6. custompurify the residue by column chromatography on silica gel
  7. washeluting with ethyl acetate/hexanes (1:2)

Sources & evidence

ORD record
ord-e3ab2e0c4f0d4072b4b1fcd1482b5b4d
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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