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Diisopropylethylamine → (+/-)-4-[(3,3-Dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester

HRID 2281127
Notes
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Reaction equation

HRID 2281127 reaction equation
[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[CH:12]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[N+:23]([O-])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15]2)[NH:18][C:22]2[C:21]([CH3:20])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:7][CH:6]=1)[CH3:2]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 70214663-Methylquinoline N-oxideHCID 71243808(+/-)-4-[Amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester2×

Product 1

HCID 71243836(+/-)-4-[(3,3-Dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl esterYield 64.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2 H) 7.56-7.62 (m, 2 H) 7.46-7.53 (m, 3 H) 7.38-7.46 (m, 1 H) 7.12-7.20 (m, 1 H) 5.33 (dd, J=9.5, 6.7 Hz, 1 H) 4.77 (d, J=6.6 Hz, 1 H) 4.34 (q, J=7.2 Hz, 2 H) 2.67 (sxt, J=8.8 Hz, 1 H) 2.30 (s, 3 H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1 H) 1.74-1.85 (m, 1 H) 1.66-1.73 (m, 2 H) 1.36 (t, J=7.1 Hz, 3 H) 1.16 (s, 3 H) 1.10 (s, 3 H); MS (M+1): 403.3.

Workup

  1. custombefore partitioning between ethyl acetate and aq. sat. NaHCO3
  2. extractionThe separated aqueous layer was extracted with additional 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-7d768e7b97504ca693c6b8a806862d44
Source dataset
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09139538B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes