Diisopropylethylamine → (1R,3S,5S)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

HRID 1527432Notes

Reaction equation

HRID 1527432 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[F:33][C:34]1[C:40]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:15])[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][C:42]([F:43])([F:44])[F:45])[C:34]=2[F:33])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 252105032-Fluoro-3-(trifluoromethoxy)anilineHCID 68284002(1R,3S,5S)-5-(Tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester

Product 1

HCID 68283049(1R,3S,5S)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (1R,3S,5S)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.29 mmol) in dry CH2Cl2 (1 mL) under argon at 0° C. was added 1-chloro-N,N,2-trimethylpropenylamine (58 μL, 0.44 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. 2-Fluoro-3-(trifluoromethoxy)aniline (86 mg, 0.44 mmol) was added, followed by DIPEA (100 μL, 0.59 mmol) and the mixture was stirred at RT overnight. Then poured into water and extracted with CH2Cl2 (×2), the organics were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15). TLC, Rf (c-hexane/EtOAc 2:1)=0.45; MS (UPLC/MS): 519.3 [M+H]+, 536.3 [M+NH4]+, 517.4 [M−H]−, 563.3 [M−HCOO]−; tR (HPLC conditions f): 2.51 min.

Workup

  1. stirringthe mixture was stirred at RT overnight
  2. extractionextracted with CH2Cl2 (×2)
  3. dry with materialthe organics were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15)
  7. custom2.51 min.

Sources & evidence

ORD record
ord-f13495b3515d4ccf98c61e0c693ae1b1
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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