Potassium Hydroxide → (S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

HRID 2075021Notes

Reaction equation

HRID 2075021 reaction equation
[C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2CN[C@@H]2CCCC[C@H]2NCC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:49][C:50]([F:89])([F:88])[C:51]1[CH:52]=[C:53]([CH:81]=[C:82]([C:84]([F:87])([F:86])[F:85])[CH:83]=1)[CH2:54][N:55]([CH2:62][C:63]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:64]=1[C:73]([CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)=[O:74])[C:56]1[N:57]=[N:58][N:59]([CH3:61])[N:60]=1.[OH-].[K+]>C(O)(C)C>[F:89][C:50]([F:49])([F:88])[C:51]1[CH:52]=[C:53]([CH:81]=[C:82]([C:84]([F:85])([F:86])[F:87])[CH:83]=1)[CH2:54][N:55]([CH2:62][C:63]1[CH:68]=[C:67]([C:69]([F:72])([F:71])[F:70])[CH:66]=[CH:65][C:64]=1[C@H:73]([CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)[O:74][CH3:1])[C:56]1[N:57]=[N:58][N:59]([CH3:61])[N:60]=1

Participants

5

Reactant 3

HCID 14797Potassium HydroxideHCID 10909155(1R,2R)-N1,N2-Bis(2-(diphenylphosphino)benzyl)cyclohexane-1,2-diamineHCID 58968633(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone

Product 1

HCID 58968607(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amineYield 92%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Procedure

A mixture of [IrHCl2(COD)]2 (54.4 mg, 0.073 mmol) and (1R,2R)—N,N′-bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-diamine (44.8 mg, 0.067 mmol) in isopropanol was stirred at room temperature for 30 minutes. A solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone in isopropanol was added to mixture followed by potassium hydroxide (44.8 mg, 0.799 mmol) and stirred at room temperature for 18 hours. Isopropanol was removed in vacuo and the crude product was purified on Biotage 40+M silica column, eluted with 0-30% ethyl acetate in heptane, to afford 3.7 g (92%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.17 (m, 5H) 1.24 (d, J=15.77 Hz, 1H) 1.54-1.60 (m, 1H) 1.61-1.67 (m, J=2.07 Hz, 2H) 1.73-1.79 (m, 1H) 1.93 (d, J=12.86 Hz, 1H) 2.25 (s, 1H) 4.20 (s, 3H) 4.65 (d, J=7.05 Hz, 1H) 4.70 (d, J=15.77 Hz, 1H) 4.76 (t, J=15.35 Hz, 2H) 4.86 (d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.50-7.59 (m, 2H) 7.65 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1). 95.9% ee determined by chiral HPLC on Chiralpak AD-H (4.6 mm×25 cm) eluted at 6.912 min using 90/10 heptane/IPO (1 mL/min).

Workup

  1. stirringstirred at room temperature for 18 hours
  2. customIsopropanol was removed in vacuo
  3. customthe crude product was purified on Biotage 40+M silica column
  4. washeluted with 0-30% ethyl acetate in heptane

Sources & evidence

ORD record
ord-2f43dd04a4df4edf90764729ce7826d3
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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