Methyl 4-Formylbenzoate → (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl ester

HRID 507107Notes

Reaction equation

HRID 507107 reaction equation
[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[F:13][C:14]([F:50])([F:49])[C:15]1[CH:16]=[C:17]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:18][N:19]([C:36]1[N:37]=[N:38][N:39]([CH3:41])[N:40]=1)[C@H:20]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:21]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:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][C@H:20]([N:19]([CH2:18][C:17]3[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=[C:15]([C:14]([F:13])([F:50])[F:49])[CH:16]=3)[C:36]3[N:37]=[N:38][N:39]([CH3:41])[N:40]=3)[C:21]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][C:22]2=3)=[CH:6][CH:5]=1

Participants

7

Reactant 3

HCID 15294Methyl 4-FormylbenzoateHCID 5049666Sodium triacetoxyborohydrideHCID 59432408(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine

Product 1

HCID 11600101(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl esterYield 52.5%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

Add 4-formylbenzoic acid methyl ester (133 mg, 0.815 mmol) to a solution of (S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 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 white solid (100 mg, 52%): mp 71-74° C. dec; 1H NMR (CDCl3, 300 MHz) δ 1.61-1.65 (m, 2H), 2.02-2.22 (m, 2H), 2.29 (s, 3H), 2.71-2.80 (m, 1H), 3.02-3.11 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.22-4.40 (m, 2H), 4.89-5.10 (m, 2H), 5.55-5.60 (m, 1H), 6.90 (s, 1H), 7.21 (s, 1 H), 7.45-7.49 (m, 2H), 7.65-7.70 (m, 2H), 7.75-7.80 (m, 1H), 7.97-7.81 (m, 2H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 98.3%, tR 19.6 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-342df8db5f504c38b8b921124cec1fb1
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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