Pyridine → (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 1-ethyl-propyl ester

HRID 507043Notes

Reaction equation

HRID 507043 reaction equation
[CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[C:7](Cl)(Cl)=[O:8].C1(C)C=CC=CC=1.[F:18][C:19]([F:55])([F:54])[C:20]1[CH:21]=[C:22]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:23][N:24]([C:41]1[N:42]=[N:43][N:44]([CH3:46])[N:45]=1)[C@H:25]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]2[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:26]1=2.N1C=CC=CC=1>ClCCl>[CH2:2]([CH:3]([O:6][C:7]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:25]([N:24]([CH2:23][C:22]2[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=[C:20]([C:19]([F:18])([F:55])[F:54])[CH:21]=2)[C:41]2[N:42]=[N:43][N:44]([CH3:46])[N:45]=2)[C:26]2[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([F:39])([F:38])[F:40])=[CH:32][C:27]1=2)=[O:8])[CH2:4][CH3:5])[CH3:1]

Participants

7

Reactant 5

HCID 1049PyridineHCID 1140TolueneHCID 6371PhosgeneHCID 114283-PentanolHCID 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 11707331(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 1-ethyl-propyl esterYield 59%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a mixture of pentan-3-ol (0.117 ml, 1.08 mmol) di-isopropyl ethyl amine (0.189 ml, 1.08 mmol) in dichloromethane at 0° C. with 20% phosgene in toluene (0.480 ml, 0.905 mmol). Stir the mixture at 0° C. for 10 minutes, and then warm up to room temperature for an hour. Add a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (0.100 mg, 0.181 mmol) (Example 3, Step 18)) in dichloromethane (1.00 ml) followed by pyridine (0.0730 ml, 0.905 mmol). Continue the reaction at room temperature overnight. Dilute the mixture with dichloromethane (5.05 ml), wash with 1N hydrochloric acid (5.00 ml) and water (3×5.00 ml), dry over Na2SO4 and concentrated. Purify by silica gel chromatography (gradient eluent, 0-25% ethyl acetate in hexane) to provide the titled compound (0.0710 g, 59%). MS (ES+): 667 (M+H).

Workup

  1. temperaturewarm up to room temperature for an hour
  2. customthe reaction at room temperature overnight
  3. washwash with 1N hydrochloric acid (5.00 ml) and water (3×5.00 ml)
  4. dry with materialdry over Na2SO4
  5. concentrationconcentrated
  6. customPurify by silica gel chromatography (gradient eluent, 0-25% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-81145fc154574cc68e170e60666a0ad2
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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