4-Methylmorpholine → Tert-Butyl (3R,4S)-3-({cyclopropyl[3-({(1R,2R)-2-[(2,3-dihydro-1H-inden-5-yloxy)-carbonyl]cyclopropyl}methoxy)-5-(3-methoxypropyl)benzyl]amino}-carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

HRID 1798466Notes

Reaction equation

HRID 1798466 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:74]1[C:82]2[C:77](=[CH:78][C:79](O)=[CH:80][CH:81]=2)[CH2:76][CH2:75]1.[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][C:79]3[CH:78]=[C:77]4[C:82](=[CH:81][CH:80]=3)[CH2:74][CH2:75][CH2:76]4)=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 151185-IndanolHCID 24758Sodium hydrideHCID 62365Isobutyl chloroformateHCID 68488708(1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-Butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic Acid

Product 1

HCID 86641741Tert-Butyl (3R,4S)-3-({cyclopropyl[3-({(1R,2R)-2-[(2,3-dihydro-1H-inden-5-yloxy)-carbonyl]cyclopropyl}methoxy)-5-(3-methoxypropyl)benzyl]amino}-carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.1 M) at −20° C. was added N-methylmorpholine (1.3 eq.) and isobutylchloroformate (1.3 eq.). The reaction was stirred at −20° C. for 45 min. Meanwhile, a solution of indan-5-ol (2 eq) in THF (0.2) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1 eq.), stirred for 30 min at rt, and added to the reaction at −15° C. The reaction was stirred at rt for 18 h and then quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.

Workup

  1. customat −20° C.
  2. stirringstirred for 30 min at rt
  3. additionadded to the reaction at −15° C
  4. stirringThe reaction was stirred at rt for 18 h
  5. customquenched with saturated aqueous NaHCO3 solution
  6. extractionThe aqueous layer was extracted with EtOAc
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex)

Sources & evidence

ORD record
ord-bc8c38e03d1446c38348ab772d692f74
Source dataset
uspto-grants-2013_01
Patent number
US08343968B2

Reaction notes

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