Triethylamine → Trifluoroacetic acid

HRID 1506544Notes

Reaction equation

HRID 1506544 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:30]3[CH2:33][CH:32]([C:34](O)=[O:35])[CH2:31]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1([O:65][C:66](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:37][S:38]([NH:41][C:34]([CH:32]1[CH2:31][N:30]([CH2:29][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[C:18]2=[N:19][O:20][C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:11]=4[C:12]([F:13])([F:14])[F:15])=[C:17]2[CH2:28][CH2:27]3)[CH2:33]1)=[O:35])(=[O:40])=[O:39].[C:66]([OH:65])([C:12]([F:15])([F:14])[F:13])=[O:39]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 72879MethanesulfonamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 532354811-((3-(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Product 2

HCID 6422Trifluoroacetic acidYield 24.8%HCID 67171979N-(methylsulfonyl)-1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxamide

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (Example 7, 80 mg, 0.161 mmol), methanesulfonamide (77 mg, 0.807 mmol), DMAP (3.95 mg, 0.032 mmol), triethylamine (0.113 mL, 0.807 mmol), and anhydrous dichloromethane (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (92 mg, 0.242 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 5 h before being concentrated. The residue was dissolved in MeOH and a little dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave N-(methylsulfonyl)-1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxamide, TFA (15 mg, 0.020 mmol, 12.58% yield) as a white solid. The compound had an HPLC retention time=3.21 min (condition C); LC/MS M+1=573.1. 1H NMR (400 MHz, MeOD) δ ppm 8.08 (1H, d, J=7.9 Hz), 7.64-7.69 (2H, m), 7.54-7.64 (4H, m), 7.51 (1H, dd, J=7.9, 1.8 Hz), 4.48 (2H, s), 4.36 (4H, d, J=7.9 Hz), 3.68 (1H, quin, J=8.0 Hz), 3.27 (3H, s), 3.11-3.22 (4H, m).

Workup

  1. concentrationbefore being concentrated
  2. dissolutionThe residue was dissolved in MeOH
  3. customPurification
  4. concentrationphase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization

Sources & evidence

ORD record
ord-f14f6f21731046c6833b8a5b4a25d4bc
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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