1-Hydroxybenzotriazole → 2'-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-one

HRID 1056150Notes

Reaction equation

HRID 1056150 reaction equation
Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]([CH3:25])=[N:19]4)=[CH:9][C:10]=2[C:11](O)=[O:12])[CH2:5][CH2:4]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:27]([NH:26][C:17]1[C:18]([CH3:25])=[N:19][C:20]2[C:15]([N:16]=1)=[C:14]([C:8]1[NH:7][C:6]3[C:3]4([CH2:5][CH2:4]4)[NH:2][C:11](=[O:12])[C:10]=3[CH:9]=1)[C:23]([F:24])=[CH:22][CH:21]=2)([CH3:28])([CH3:30])[CH3:29]

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 897832122-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride

Product 1

HCID 717317792'-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-b]pyrrol]-4'(5'H)-oneYield 41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (295c) (140 mg, 0.32 mmol) in 8 mL of DMF and 8 mL of DCM at RT was sequentially added 1-hydroxybenzotriazole (AK Scientific, Inc., Union City, Calif.) (65 mg, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma-Aldrich) (93 mg, 0.48 mmol) and DIPEA (Sigma-Aldrich) (0.34 mL, 1.94 mmol). The reaction mixture was stirred at RT for 16 h and was then concentrated. The yellow oil was dissolved in CH2Cl2 and washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 2′-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (295) (50 mg, 0.13 mmol, 41% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 7.70 (dd, J=9.00, 5.87 Hz, 1H), 7.63 (s, 1H), 7.30 (dd, J=10.47, 8.90 Hz, 1H), 6.49-6.55 (m, 1H), 6.07 (s, 1H), 2.54 (s, 3H), 1.43 (s, 9H), 1.37-1.41 (m, 2H), 1.29-1.35 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ ppm −111.61 (s, 1F). m/z (ESI, +ve) 380.1 (M+H)+.

Workup

  1. concentrationwas then concentrated
  2. dissolutionThe yellow oil was dissolved in CH2Cl2
  3. washwashed with water, 1 M NaOH (aq.) and brine
  4. dry with materialThe organic layer was dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was absorbed onto a plug of silica gel
  8. custompurified by silica gel chromatography (0-5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-09dfc67b0cae46f2ae5969ea2eba9dc8
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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