Triethylamine → 1-methylcyclopropyl 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carboxylate

HRID 1850735Notes

Reaction equation

HRID 1850735 reaction equation
[N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH:26](C)[CH3:27])=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:31](N(CC)CC)C.C(=O)(OC1(C)CC1)ON1C(=O)CCC1=O>ClCCl>[N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]4([CH3:31])[CH2:26][CH2:27]4)=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 577528092,5-Dioxopyrrolidin-1-yl 1-methylcyclopropyl carbonateHCID 66563045isobutyl 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carboxylate

Product 1

HCID 665631411-methylcyclopropyl 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). 2,5-Dioxopyrrolidin-1-yl 1-methylcyclopropyl carbonate (81 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 1 L). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.30-3.90 (m, 4H), 2.80-2.60 (m, 2H), 2.25-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.55 (s, 3H), 1.40-1.20 (m, 2H), 1.10-0.80 (m, 4H), 0.80-0.55 (m, 4H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 412 [M+H]+.

Workup

  1. concentrationconcentrated to dryness under reduced pressure
  2. customThe residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 1 L)
  3. additionThe product containing fractions
  4. concentrationconcentrated under reduced pressure
  5. customThe compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min)

Sources & evidence

ORD record
ord-b7ed8f9d0cad4f64903ffda56cdc1785
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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