Triethylamine → (+/-)-3-{4-[(3,3-Di methyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester

HRID 2281129Notes

Reaction equation

HRID 2281129 reaction equation
[CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])[CH3:43].C(N(CC)CC)C>ClCCl>[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1)[CH3:43]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71243837(+/-)-4-[(3,3-Dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid2×

Product 1

HCID 71239546(+/-)-3-{4-[(3,3-Di methyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl esterYield 80.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26) (37 mg, 0.099 mmol) was combined with 1-hydrobenzotriazole hydrate (23.0 mg, 0.149 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29.0 mg, 0.149 mmol), and beta-alanine ethyl ester hydrochloride (18.0 mg, 0.119 mmol). Anhydrous dichloromethane (5 mL) was added followed by triethylamine (0.027 mL, 0.198 mmol). The solution was stirred at room temperature for 3 d before partitioning between ethyl acetate and aq. sat. ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (37.9 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.2 Hz, 2 H) 7.59 (t, J=3.9 Hz, 2 H) 7.46-7.52 (m, 3 H) 7.37-7.45 (m, 1 H) 7.11-7.19 (m, 1 H) 6.75 (t, J=5.8 Hz, 1 H) 5.32 (dd, J=9.7, 6.7 Hz, 1 H) 4.75 (d, J=6.6 Hz, 1 H) 4.10-4.21 (m, 2 H) 3.70 (q, J=6.0 Hz, 2 H) 2.55-2.74 (m, 3 H) 2.29 (s, 3 H) 1.96 (ddd, J=11.1, 8.2, 2.9 Hz, 1 H) 1.75-1.84 (m, 1 H) 1.64-1.73 (m, 2 H) 1.26 (m, 3 H) 1.16 (s, 3 H) 1.09 (s, 3 H); MS (M+1): 474.7.

Workup

  1. custombefore partitioning between ethyl acetate and aq. sat. ammonium chloride
  2. extractionThe separated aqueous layer was extracted with ethyl acetate
  3. dry with materialthe combined organics dried over MgSO4
  4. customPurification by silica gel flash chromatography (ethyl acetate/heptane)

Sources & evidence

ORD record
ord-45e76212a7bb414293709177afd70d74
Source dataset
uspto-grants-2015_09
Patent number
US09139538B2

Reaction notes

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