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Diisopropylethylamine → 1-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-azetidine-3-carboxylic acid methyl ester

HRID 2110298
Notes
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Reaction equation

HRID 2110298 reaction equation
Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([C:21]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[CH2:18][CH2:19][CH2:20]2)=[O:22])[CH2:7]1)=[O:5]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 6027611-(p-Chlorophenyl)cyclobutanecarboxylic acidHCID 2733179PyBroPHCID 21100040Methyl azetidine-3-carboxylate hydrochloride

Product 1

HCID 587375011-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-azetidine-3-carboxylic acid methyl esterYield 70.6%

Reagents, catalysts & solvents

1
HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of azetidine-3-carboxylic acid methyl ester hydrochloride (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3×20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): δ 7.38-7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31-1.63 (m, 8H). LRMS: M+309.

Workup

  1. additionwas added to the stirring reaction mixture
  2. customwas quenched with water
  3. extractionThe aqueous layer was extracted with EtOAc (3×20 mL)
  4. dry with materialCombined organic layers were dried over Na2SO4
  5. concentrationconcentrated
  6. customto yield an oil
  7. customThis crude material was purified

Sources & evidence

ORD record
ord-2259dd80b002452297d354e754db6ee2
Source dataset
uspto-grants-2009_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07517892B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes