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

HRID 1850734Notes

Reaction equation

HRID 1850734 reaction equation
[N:1]1([C:6]2[CH:23]=[CH:22][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][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][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:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:18][CH2:17]3)=[CH:22][CH:23]=2)[CH:5]=[N:4][N:3]=[N:2]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 867111854-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine

Product 1

HCID 66563045isobutyl 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 A, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). Isobutyl chloroformate (52 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, 500 mL). 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) 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), 4.20-4.10 (m, 4H), 3.86 (d, J=6.6 Hz, 2H), 2.85-2.60 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H), 1.10-0.90 (m, 2H), 0.94 (d, J=6.7 Hz, 6H), 0.80-0.65 (m, 2H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 414 [M+H]+. GPR119 Human EC50:1.6 nM

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, 500 mL)
  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-82079b10cfbb49dd8ed7ecbf6ef83a69
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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