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Water → (1R,3S,5R)-3-[(S)-1-(3-Chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

HRID 1527367
Notes
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Reaction equation

HRID 1527367 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])[CH2:19][OH:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 962WaterHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11020613(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidHCID 55278294(2S)-2-amino-2-(3-chloro-2-fluorophenyl)ethan-1-ol

Product 1

HCID 68283751
(1R,3S,5R)-3-[(S)-1-(3-Chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (750 mg, 3.30 mmol), (2S)-2-amino-2-(3-chloro-2-fluorophenyl)ethan-1-ol (746 mg, 3.30 mmol) and HBTU (1.75 g, 4.62 mmol) in CH2Cl2 (30 mL) was added under nitrogen DIPEA (2.31 mL, 13.20 mmol). The reaction mixture was stirred at RT overnight. CH2Cl2 and water were added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give the desired compound as a colorless oil. MS (UPLC/MS): 399.3/401.3 [M+H]+, 443.4/445.3 [M+HCOO]−; tR (HPLC conditions a): 3.28 min.

Workup

  1. additionwas added under nitrogen DIPEA (2.31 mL, 13.20 mmol)
  2. customthe layers were separated
  3. extractionthe aqueous one back-extracted with CH2Cl2 (×3)
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc)

Sources & evidence

ORD record
ord-dc52451c20ae45dca55961ce79ea8f76
Source dataset
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09085555B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes