Methyl 4-iodobenzoate → (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-yl}-benzoic acid methyl ester

HRID 507111Notes

Reaction equation

HRID 507111 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+].[F:35][C:36]([F:72])([F:71])[C:37]1[CH:38]=[C:39]([CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1)[CH2:40][N:41]([C:58]1[N:59]=[N:60][N:61]([CH3:63])[N:62]=1)[C@H:42]1[CH2:48][CH2:47][CH2:46][NH:45][C:44]2[CH:49]=[C:50]([C:54]([F:57])([F:56])[F:55])[C:51]([CH3:53])=[CH:52][C:43]1=2.[CH3:73][O:74][C:75](=[O:83])[C:76]1[CH:81]=[CH:80][C:79](I)=[CH:78][CH:77]=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:73][O:74][C:75](=[O:83])[C:76]1[CH:81]=[CH:80][C:79]([N:45]2[CH2:46][CH2:47][CH2:48][C@H:42]([N:41]([CH2:40][C:39]3[CH:64]=[C:65]([C:67]([F:70])([F:68])[F:69])[CH:66]=[C:37]([C:36]([F:71])([F:35])[F:72])[CH:38]=3)[C:58]3[N:59]=[N:60][N:61]([CH3:63])[N:62]=3)[C:43]3[CH:52]=[C:51]([CH3:53])[C:50]([C:54]([F:55])([F:56])[F:57])=[CH:49][C:44]2=3)=[CH:78][CH:77]=1

Participants

8

Reactant 4

HCID 69273Methyl 4-iodobenzoateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 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 59432356(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-yl}-benzoic acid methyl esterYield 40.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

Combine tris(dibenzylideneacetone)dipalladium (0) (16 mg, 0.018 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (14 mg, 0.036 mmol) and sodium t-butoxide (43 mg, 0.452 mmol) in toluene (5 mL) and purge this suspension with nitrogen at room temperature for 5 min. Add (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 (Example 3, Step 18) (100 mg, 0.181 mmol) followed by methyl-4-iodobenzoate (47 mg, 0.181 mmol) and heat this mixture at 100° C. under nitrogen for 2 h. Cool the mixture to room temperature, dilute with dichloromethane, filter through Celite®, and concentrate under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound as an off-white solid (50 mg, 40%). mp 101-105° C.; TLC Rf 0.50 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.72-1.89 (m, 1H), 2.00-2.32 (m, 3H), 2.29 (s, 3H), 3.33-3.40 (m, 1H), 3.89 (s, 3H), 3.99-4.09 (m, 1H), 4.19 (s, 3H), 4.69-5.33 (m, 3H), 6.68-6.73 (m, 2H), 7.15 (s, 1H), 7.45 (s, 1H), 7.62-7.72 (m, 2H), 7.79 (s, 1H), 7.96-8.05 (m, 2H); ESI MS m/z 687 [C31H27F9N6O2+H]+.

Workup

  1. temperatureCool the mixture to room temperature
  2. filtrationfilter through Celite®
  3. concentrationconcentrate under reduced pressure
  4. washChromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 1:2)

Sources & evidence

ORD record
ord-d95133e1db614e8d8377ab33baad4e31
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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