Hydrochloric Acid → HCID 68283128, compound

HRID 1527423Notes

Reaction equation

HRID 1527423 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=2[F:28])[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81531Diisopropylethylamine2×HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 2773614(3-Chloro-2-fluorophenyl)methanamine2×HCID 68284162HCID 68284162, compound

Product 1

HCID 68283128HCID 68283128, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH2Cl2 (6 mL) was added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under nitrogen overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCl 1N (pH-1) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.55 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.45 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.89 min.

Workup

  1. waitthe mixture was further stirred overnight at RT under N2
  2. extractionextracted with CH2Cl2 (2×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60)

Sources & evidence

ORD record
ord-ba5224ce488a497bb44a963cf5b5c63d
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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