2,6-Lutidine → HCID 68678071, compound

HRID 1992207Notes

Reaction equation

HRID 1992207 reaction equation
[CH:1]1([CH:7](O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.Cl.Cl.[F:53][C:54]1[CH:55]=[C:56]([C:60]2([CH2:66][CH2:67][N:68]3[C@H:73]4[CH2:74][CH2:75][C@@H:69]3[CH2:70][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:72]4)[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH:1]1([CH:7]([N:63]2[CH2:62][CH2:61][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=3)([CH2:66][CH2:67][N:68]3[C@H:69]4[CH2:75][CH2:74][C@@H:73]3[CH2:72][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:70]4)[CH2:65][CH2:64]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 5

HCID 79372,6-LutidineHCID 67749Trifluoromethanesulfonic anhydrideHCID 81531DiisopropylethylamineHCID 16726584Phenylmethyl α-hydroxycyclohexaneacetateHCID 68675921HCID 68675921, compound

Product 1

HCID 68678071HCID 68678071, compoundYield 20%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a −78° C. solution of benzyl cyclohexyl(hydroxy)acetate (61 mg, 0.25 mmol) and 4A molecular sieves in 1.2 mL CH2Cl2 was added trifluoromethanesulfonic anhydride (0.05 mL, 0.30 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.06 mL, 0.49 mmol) was added. After 15 min, diisopropylethylamine (0.09 mL, 0.49 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (153 mg, 0.30 mmol) in 1 mL CH2Cl2 was added. The reaction mixture was stirred at −78° C., then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by preparatory TLC using 5% MeOH in CHCl3 to afford benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (33 mg, 20%) as an oil. 1H NMR (400 MHz, CDCl3), δ 7.68-7.64 (m, 1H), 7.33-7.23 (m, 7H), 7.20-7.12 (m, 2H), 7.05 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 5.05 (ABq, 2H, J=12.3 Hz), 4.61 (m, 1H), 3.26-3.18 (m, 2H), 2.92 (d, 1H, J=10.4 Hz), 2.70 (m, 1H), 2.64-2.50 (m, 2H), 2.57 (s, 3H), 2.46-2.30 (m, 3H), 2.12-0.81 (m, 25H); ESI-MS 677 (M+H).

Workup

  1. additionwas added
  2. temperatureto warm to room temperature overnight
  3. washwashed with saturated aqueous NaHCO3
  4. custompurified by preparatory TLC

Sources & evidence

ORD record
ord-bd472ca05ba14f5288910e42d16c4404
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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