1,1'-Carbonyldiimidazole → methyl 4-((R)-((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoate

HRID 451909Notes

Reaction equation

HRID 451909 reaction equation
[NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.C1N=CN([C:34]([N:36]2[CH:40]=N[CH:38]=[CH:37]2)=[O:35])C=1.[Cl:41][C:42]1[CH:43]=[C:44]([C@@H:48]([C@@H:57]2CCCN[CH2:58]2)[O:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[C:7]([O:6][C:5]([N:4]([CH3:12])[CH2:3][C@@H:2]([NH:1][C:34]([N:36]1[CH2:37][CH2:38][CH2:58][C@@H:57]([C@H:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[CH:43]=2)[O:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH2:40]1)=[O:35])[CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:11])([CH3:9])([CH3:10])[CH3:8]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 59201313tert-butyl (S)-2-amino-3-cyclohexylpropylmethylcarbamateHCID 59201430methyl 4-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)butanoate

Product 1

HCID 59201638methyl 4-((R)-((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoateYield 22.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (165 mg, 0.61 mmol) and DIEA (3 mL) in anhydrous CH2Cl2 (10 mL) was added CDI (98 mg, 0.61 mmol) with ice bath. After addition, the mixture was stirred for 1 h at 0° C., followed by the addition of methyl 4-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)butanoate (165 mg, 0.51 mmol) in anhydrous CH2Cl2 (2 mL). The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was washed with water (10 mL) and the aqueous layer extracted with CH2Cl2 (15 mL×2), the combined organic layers was washed with saturated brine, dried over Na2SO4, filtered, then evaporated to give a residue, which was purified via preparative TLC to afford methyl 4-((R)—((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoate (70 mg, 22% yield). 1H NMR (CD3OD, 400 MHz) δ 7.34-7.28 (m, 3H), 7.19 (t, 1H), 4.25 (d, 1H), 4.11 (d, 1H), 3.95 (m, 2H), 3.64 (t, 3H), 3.27 (m, 1H), 3.10 (m, 1H), 2.87 (s, 2H), 2.69 (m, 2H), 2.43 (t, 1H), 1.84 (t, 2H), 1.72-1.52 (m, 6H), 1.45 (d, 9H), 1.39-1.22 (m, 10H), 1.14 (d, 1H), 0.97 (d, 2H), 0.85 (t, 1H).

Workup

  1. additionAfter addition
  2. temperatureto warm to rt
  3. stirringstirred overnight
  4. washThe reaction mixture was washed with water (10 mL)
  5. extractionthe aqueous layer extracted with CH2Cl2 (15 mL×2)
  6. washthe combined organic layers was washed with saturated brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customto give a residue, which
  11. customwas purified via preparative TLC

Sources & evidence

ORD record
ord-67ec4d9dedfb4c2c8ac7462edd5684ef
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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