Hydrochloric Acid → 1-(1,2,4-Oxadiazol-3-yl)cyclobutan-1-amine hydrochloride

HRID 1854745Notes

Reaction equation

HRID 1854745 reaction equation
[O:1]1[CH:5]=[N:4][C:3]([C:6]2([NH:10]S(C(C)(C)C)=O)[CH2:9][CH2:8][CH2:7]2)=[N:2]1.[ClH:17]>CO>[ClH:17].[O:1]1[CH:5]=[N:4][C:3]([C:6]2([NH2:10])[CH2:9][CH2:8][CH2:7]2)=[N:2]1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 90402384N-(1-(1,2,4-oxadiazol-3-yl)cyclobutyl)-2-methylpropane-2-sulfinamide

Product 1

HCID 904023871-(1,2,4-Oxadiazol-3-yl)cyclobutan-1-amine hydrochloride

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

N-(1-(1,2,4-oxadiazol-3-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (45 mg, 0.19 mmol) was taken up in 1 mL of MeOH and treated with 1 mL of HCl (2M in Et2O) at rt and allowed to stir for 30 min at rt. The reaction was then concentrated to dryness azeotroping with toluene 3× to give 1-(1,2,4-oxadiazol-3-yl)cyclobutanamine hydrochloride (32 mg, 0.18 mmol). Then 14 mg (0.077 mmol) of this material was combined with 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid (25 mg, 0.051 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.15 mmol) in DMF (1 mL) at rt. To this stirring solution 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (29 mg, 0.077 mmol) was added. The mixture was allowed to stir at rt for 30 min. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.2 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. retention time: 3.02 min; M+H: 608. Injection 2 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; MobilePhase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. retention time: 4.06 min; M+H: 608. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.33 (s, 1H), 8.55-8.46 (m, 1H), 8.10-8.02 (m, 2H), 7.98 (s, 3H), 7.69-7.59 (m, 2H), 7.46-7.37 (m, 2H), 3.05-2.97 (m, 2H), 2.85-2.71 (m, 5H), 2.67-2.56 (m, 4H), 2.10-1.99 (m, 2H).

Workup

  1. concentrationThe reaction was then concentrated to dryness
  2. customazeotroping with toluene 3×

Sources & evidence

ORD record
ord-c6a1997cc414465bba641d1369e52660
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

Loading…