Triethylamine → (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 1698354Notes

Reaction equation

HRID 1698354 reaction equation
[CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:9]=[C:8]([O:18][CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.C([N:22](CC)CC)C.[C:27]([O:31][C:32]([N:34]1[CH2:41][CH:40]2[CH2:42][CH:36](C(=O)[O:38][C:39]2=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Si](CCO)(C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:41][C@H:40]([C:39](=[O:38])[N:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:9]=[C:8]([O:18][CH3:19])[CH:7]=2)[CH2:42][C@H:36]([NH2:22])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]

Participants

8

Reactant 5

HCID 8471Triethylamine2×HCID 180132-(Trimethylsilyl)ethanolHCID 199401P,P-Diphenylphosphinic azideHCID 59778297Tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylateHCID 59817709N-(3-methoxy-5-(3-methoxypropoxy)benzyl)cyclopropanamine

Product 1

HCID 69064081(3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl esterYield 12.5%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of Cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amine (1.18 g, 4.45 mmol) and triethylamine (0.68 mL, 4.90 mmol) in THF (20 mL) at room temperature is added 2,4-Dioxo-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (1.07 g, 4.19 mmol). After stirred for 2 h, bulk of the solvent is concentrated. The residue is diluted with EtOAc, and washed with aq. KHSO4, water, and brine, dried over Na2SO4, filtered, and concentrated. To a solution of a part of the residue (673 mg, 1.29 mmol) in toluene (5 mL) at room temperature are added triethylamine (0.2 mL, 1.44 mmol) and DPPA (0.31 mL, 1.43 mmol). After stirred for 40 min, TMSCH2CH2OH (0.9 mL, 6.31 mmol) is added. The reaction mixture is refluxed for 2 h. After dilution with EtOAc, the mixture is washed with aq. KHSO4, water, aq. sat. NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to afford the desired carbamate (332 mg, 0.522 mmol), which is treated with TBAF (410 mg, 1.57 mmol) in THF (5 mL) at 50° C. for 2.5 h. After dilution with EtOAc, the mixture is washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as a pale yellow oil. MS: 491 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.67 min.

Workup

  1. concentrationbulk of the solvent is concentrated
  2. additionThe residue is diluted with EtOAc
  3. washwashed with aq. KHSO4, water, and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. stirringAfter stirred for 40 min
  8. temperatureThe reaction mixture is refluxed for 2 h
  9. washAfter dilution with EtOAc, the mixture is washed with aq. KHSO4, water, aq. sat. NaHCO3, and brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-9cb1aef430ac457f91602368cecc9a03
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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