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Diisopropylethylamine → 2-((3-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)-2,5,7-triazaspiro[3.4]octane-6,8-dione

HRID 1506353
Notes
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Reaction equation

HRID 1506353 reaction equation
Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.[CH2:31]1[C:34]2([C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]2)[CH2:33][NH:32]1.C(OC1C=CC(C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)=C(C(F)(F)F)C=1)(C)C.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:22]1([C:16]2[O:15][N:14]=[C:13]([C:12]3[O:11][N:10]=[C:9]4[C:28]5[C:5]([CH2:6][CH2:7][C:8]=34)=[CH:4][C:3]([CH2:2][N:32]3[CH2:31][C:34]4([C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]4)[CH2:33]3)=[CH:30][CH:29]=5)[C:17]=2[C:18]([F:21])([F:19])[F:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 666007202,5,7-Triazaspiro[3.4]octane-6,8-dioneHCID 671678437-(Bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazoleHCID 671709643-(4-Isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole

Product 1

HCID 67170833
2-((3-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)-2,5,7-triazaspiro[3.4]octane-6,8-dione
Yield 65.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred mixture of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6C, 25 mg, 0.053 mmol), 2,5,7-triazaspiro[3.4]octane-6,8-dione, hydrochloric acid (Preparation 17B, 11 mg, 0.079 mmol), and anhydrous dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.046 mL, 0.263 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 80 min. The reaction mixture was concentrated and subjected to prep HPLC conditions (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were concentrated to yield an aqueous suspension of the product, to which saturated aqueous sodium bicarbonate solution (1 mL) was added to make the mixture basic. The solid was filtered and washed with water (3×1 mL) and then lyophilized to give 2-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)-2,5,7-triazaspiro[3.4]octane-6,8-dione (19 mg, 0.034 mmol, 65.4% yield) as a white solid. The compound had an HPLC retention time=3.19 min (condition C); LC/MS M+1=536.3; 1H NMR (400 MHz, MeOD) δ ppm 7.92 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.58-7.71 (3H, m), 7.40 (1H, s), 7.37 (1H, d, J=7.7 Hz), 3.78 (2H, s), 3.75 (2H, d, J=8.6 Hz), 3.48 (2H, d, J=8.8 Hz), 3.08 (4H, s).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customHPLC conditions (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)
  3. concentrationThe desired fractions were concentrated
  4. customto yield
  5. additionan aqueous suspension of the product
  6. filtrationThe solid was filtered
  7. washwashed with water (3×1 mL)

Sources & evidence

ORD record
ord-eded28a1ed0b415788846aadb708052c
Source dataset
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09216972B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes