Trimethylaluminum → 3-(4-{[5-(4-Chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 2384902Notes

Reaction equation

HRID 2384902 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:42][C:36]3[C:37](=[O:41])[O:38][CH2:39][CH2:40][C:35]=3[CH:34]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:37]([C:36]3[S:42][C:33]([C:30]4[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=4)=[CH:34][C:35]=3[CH2:40][CH2:39][OH:38])=[O:41])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 16682925TrimethylaluminumHCID 46835556Tert-butyl 3-(4-amino-2-methoxyphenoxy)azetidine-1-carboxylateHCID 689489532-(4-Chloro-phenyl)-4,5-dihydro-thieno[2,3-c]pyran-7-one

Product 1

HCID 689523253-(4-{[5-(4-Chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 99.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

Dissolve 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2.27 mmol, 667 mg) in toluene (35 mL) and add 2M trimethylaluminum in toluene (2.27 mmol 1.13 mL). Add to this solution 2-(4-chloro-phenyl)-4,5-dihydro-thieno[2,3-c]pyran-7-one (1.51 mmol 400 mg) and heat the reaction at 80° C. for 5 h. Cool the reaction to room temperature and slowly quench with 10 mL of saturated Rochelle's salt. Stir the mixture for 10 min and dilute with 40 mL of water. Separate the organic portion and extract the aqueous portion with EtOAc (2×25 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography (hexane to 70% ethyl acetate/hexane) to afford 840 mg (99%) of the title compound. MS/ES m/z (35Cl) 557.0 [M−H]−.

Workup

  1. temperatureheat
  2. customthe reaction at 80° C. for 5 h
  3. temperatureCool
  4. customthe reaction to room temperature
  5. customslowly quench with 10 mL of saturated Rochelle's salt
  6. additiondilute with 40 mL of water
  7. customSeparate the organic portion
  8. extractionextract the aqueous portion with EtOAc (2×25 mL)
  9. dry with materialDry the combined organics over Na2SO4
  10. filtrationfilter
  11. concentrationconcentrate to dryness
  12. customPurify by chromatography (hexane to 70% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-4215903d65704bcfb2e472254e24f7af
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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