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3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → Tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate

HRID 921891
Notes
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Reaction equation

HRID 921891 reaction equation
Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].[O:35]=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([C:36]2([OH:35])[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 86708662Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamateHCID 178461732HCID 178461732, compound

Product 1

HCID 89922436Tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028
Tetrahydrofuran
Solvent
2×

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Intermediate (500 mg, 1.107 mmol) in THF (2.5 ml) at 0° C. was added drop wise isopropylmagnesium lithium chloride (1.3 M in THF) (0.937 mL, 1.218 mmol) under nitrogen. After stirring at 0° C. for 30 min, removal of the cooling bath and stirred at room temperature for 30 min. The reaction mixture was cooled to −14° C. (NaCl-ice bath), to this was added drop wise a solution of tert-butyl 3-oxoazetidine-1-carboxylate (208 mg, 1.218 mmol) in THF (2 mL), and left stirring in the cooling bath for 2 h, during this time the temperature rose to −4° C. The reaction was quenched with sat, aqueous NH4Cl solution (5 ml), and diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Solvent was removed. The crude residue was purified by ISCO (12 g) column chromatography, eluting with hexane containing 0 to 40% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (408 mg).

Workup

  1. customremoval of the cooling bath
  2. stirringstirred at room temperature for 30 min
  3. temperatureThe reaction mixture was cooled to −14° C. (NaCl-ice bath)
  4. waitleft
  5. stirringstirring in the cooling bath for 2 h, during this time the temperature
  6. customrose to −4° C
  7. customThe reaction was quenched
  8. additionaqueous NH4Cl solution (5 ml), and diluted with EtOAc
  9. washwashed with water, brine
  10. dry with materialdried over Na2SO4
  11. customSolvent was removed
  12. customThe crude residue was purified by ISCO (12 g) column chromatography
  13. washeluting with hexane containing 0 to 40% EtOAc

Sources & evidence

ORD record
ord-8abcc78f0d294161b86cb4082ed6520c
Source dataset
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09273057B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes