N-Hydroxyacetamidine → 5-(3-Azabicyclo[3.1.0]hexan-1-yl)-3-methyl-1,2,4-oxadiazole
Reaction equation
[C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].Cl.CCO.CN1C2C(N=C(N)NC=2NCC1CNC1C=[CH:32][C:31]([C:34]([NH:36][CH:37](C(O)=O)[CH2:38][CH2:39]C(O)=O)=O)=CC=1)=O>>[C:31]12([C:32]3[O:5][N:4]=[C:1]([CH3:2])[N:3]=3)[CH2:39][CH:38]1[CH2:37][NH:36][CH2:34]2Participants
Procedure
The N-benzyl-2,5-dihydropyrrole ester was prepared, as described (Chem. Pharm. Bull. 1985, 33(7), 2762) by treating ethyl propiolate and N-(methoxymethyl)-N-(trimethylsilylmethyl)-N-benzylamine in DCM with 0.1M TFA in DCM, followed by aqueous work up and silica gel chromatography, in 44% yield. The cyclopropyl group was furnished by treatment with trimethylsulfoxonium Iodide and NaH in DMSO at room temperature, followed by aqueous work up and silica gel chromatography, in 43% yield as described in the literature (Korean J. of Med. Chem. 1994, 4(2), 119). The N-benzyl group was removed with palladium on carbon and ammonium formate in methanol. The Boc protecting group was directly installed with DMAP, TEA and Boc2O in DCM, followed by silica gel chromatography, in 60% yield for both steps. The oxadiazole ring was prepared as described above, by reaction with acetamide oxime and sodium methoxide in methyl THF. Aqueous work up and silica gel chromatography provided the intermediate in 54% yield. Standard deblocking with HCl-EtOH provided the desired product, as the HCl salt, in 82% yield.
Workup
- customThe N-benzyl group was removed with palladium on carbon and ammonium formate in methanol
- customThe oxadiazole ring was prepared
- customAqueous work up and silica gel chromatography provided the intermediate in 54% yield
Sources & evidence
- ORD record
- ord-7d592d008cea4a9ea657f8ec39559c84
- Source dataset
- uspto-grants-2016_08
- Patent number
- US09403806B1
Reaction notes
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