Triethylamine → Methyl (+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate

HRID 2281118Notes

Reaction equation

HRID 2281118 reaction equation
[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:33][CH2:32][CH2:31][C:30]([O:29][CH3:27])=[O:34])=[O:22])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 71239463(+/-)-4-(1-((3-Methylquinolin-2-yl)amino)butyl)benzoic acid

Product 1

HCID 71239461Methyl (+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Intermediate 5 (31.64 g, 94.61 mmol), β-alanine ethyl ester hydrochloride (45.9 g, 284 mmol), and 1-hydroxybenzotriazole hydrate (80%, 20 wt % water, 47.9 g, 284 mmol) were suspended in dichloromethane (946 mL). Triethylamine (119 mL, 852 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.0 g, 237 mmol) were added, and the solution was stirred at room temperature for 10 h. The reaction mixture was washed with water (3×900 mL), then sat. aq NaCl (300 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 30×250, 20% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) gave methyl (+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 6, analytical chiral SFC 4.6 min retention) and methyl (−)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 7, analytical chiral SFC 6.5 min retention)—note that ethyl ester was converted to methyl ester during the reaction and/or purification sequence. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.4 Hz, 2H), 7.64-7.58 (m, 2 H), 7.55-7.48 (m, 3 H), 7.44 (t, J=7.7 Hz, 1 H), 7.16 (t, J=7.4 Hz, 1 H), 6.76 (t, J=5.5 Hz, 1 H), 5.48 (q, J=7.2 Hz, 1 H), 4.78 (d, J=7.0 Hz, 1 H), 3.76 (q, J=6.0 Hz, 2 H), 3.70 (s, 3 H), 2.64 (t, J=5.9 Hz, 2 H), 2.29 (s, 3 H), 2.04-1.82 (m, 2 H), 1.52-1.29 (m, 2 H), 0.98 (t, J=7.3 Hz, 3 H).

Workup

  1. additionwere added
  2. washThe reaction mixture was washed with water (3×900 mL)
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customPurification by silica gel flash chromatography (ethyl acetate/heptane)

Sources & evidence

ORD record
ord-af22b2cc42cf44e6acac819d708ab5dc
Source dataset
uspto-grants-2015_09
Patent number
US09139538B2

Reaction notes

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