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Acetic Acid → (1S,2R)-5'-(4-chlorophenyl)-2-(methoxymethyl)-6',7'-dimethylspiro[cyclopropane-1,3'-thieno[2,3-e][1,4]diazepin]-2'(1'H)-one

HRID 1772333
Notes
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Reaction equation

HRID 1772333 reaction equation
[NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O.C1(C(=[N:31][C@@:32]2([C:38](OCC)=[O:39])[CH2:34][C@H:33]2[CH2:35][O:36][CH3:37])C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1.C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=3[NH:1][C:38](=[O:39])[C@@:32]3([CH2:34][C@H:33]3[CH2:35][O:36][CH3:37])[N:31]=2)=[CH:10][CH:11]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 719710(2-Amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanoneHCID 23665647Potassium tert-butoxideHCID 86706920(1S,2R)-ethyl 1-((diphenylmethylene)amino)-2-(methoxymethyl)cyclopropanecarboxylate

Product 1

HCID 136338064(1S,2R)-5'-(4-chlorophenyl)-2-(methoxymethyl)-6',7'-dimethylspiro[cyclopropane-1,3'-thieno[2,3-e][1,4]diazepin]-2'(1'H)-one

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (7.09 g, 26.7 mmol) and (1S,2R)-ethyl 1-((diphenylmethylene)amino)-2-(methoxymethyl)cyclopropanecarboxylate (6 g, 17.78 mmol) in anhydrous THF (100 mL) was slowly (over 5 min) added a solution of potassium tert-butoxide (1 M in THF) at rt. The reaction was heated to 60° C. for approximately 20 h before acetic acid (10.68 g, 178 mmol) and absolute ethanol (20 mL) were added at 60° C. THF was distilled off, and the reaction was heated to reflux for 3 h. The reaction was cooled to rt before silica gel was added, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by flash chromatography (EtOAc/hexane 1:19 to 6:14) to give (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one a solid (3.7 g). LRMS (M+H)+: 375 m/z.

Workup

  1. custom(over 5 min)
  2. additionwere added at 60° C
  3. distillationTHF was distilled off
  4. temperaturethe reaction was heated
  5. temperatureto reflux for 3 h
  6. additionwas added
  7. customthe solvent was removed under vacuum
  8. customthe product was purified by flash chromatography (EtOAc/hexane 1:19 to 6:14)

Sources & evidence

ORD record
ord-42b200e45a4d42a6bf1ac9e82aa1c07c
Source dataset
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09249161B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes