Hydrochloric Acid → HCID 71730240, compound

HRID 1056190Notes

Reaction equation

C(O[C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH:34]3[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.O[Li].O.Cl.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O1CCOCC1.O.C(Cl)Cl>[CH:34]1([NH:33][C:25]2[C:26]([CH3:32])=[N:27][C:28]3[C:23]([N:24]=2)=[C:22]([C:14]2[NH:13][C:12]4[C:9]5([CH2:11][CH2:10]5)[NH:8][C:6](=[O:7])[C:16]=4[CH:15]=2)[CH:31]=[CH:30][CH:29]=3)[CH2:36][CH2:35]1

Participants

Conditions

Temperature: 110 °C

Procedure

A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (325c; 190 mg, 0.39 mmol) in 2 mL of dioxane and 1.5 mL of water was added LiOH hydrate (81 mg, 1.93 mmol) and heated in a microwave at 110° C. for 80 min. It was lyophilized to give a yellow solid. m/z (ESI, +ve) 464.1 (M+H)+. To the yellow solid suspended in 3 mL of dioxane was added 3 mL of 4 N HCl in dioxane and stirred at RT for 1.5 h. The reaction mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×3 mL of hexanes/ether in 1/1 ratio. The filtrate was discarded. The orange solid was dried in a vacuum oven at RT for 18 h to 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d). m/z (ESI, +ve) 364.1 (M+H)+. This material was used as crude. At 0° C., a suspension of 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d) in 8 mL of DMF and 8 mL of DCM was sequentially treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (146 mg, 0.76 mmol), 1-hydroxybenzotriazole (103 mg, 0.76 mmol) and DIEA (0.40 mL, 2.28 mmol). The homogeneous reaction mixture was stirred at RT for 18 h. It was diluted with 100 mL of DCM, washed sequentially with 5 mL of water, 5 mL of 1 N NaOH, and 5 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM) to give 2′-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (325) (86 mg, 60% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (1H, br.), 7.97 (1H, dd, J=7.5, 1.3 Hz), 7.69 (1H, s), 7.62 (1H, dd, J=8.0, 1.2 Hz), 7.51 (1H, d, J=2.2 Hz), 7.38 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=1.4 Hz), 2.94 (1H, dd, J=6.5, 3.7 Hz), 2.53 (3H, s), 1.45 (2H, m), 1.35 (2H, m), 0.817 (2H, m), 0.68 (2H, m). m/z (ESI, +ve) 346.1 (M+H)+.

Workup

customto give a yellow solid
concentrationThe reaction mixture was concentrated to half of its volume
filtrationThe insoluble solid was filtered
washrinsed with 2×3 mL of hexanes/ether in 1/1 ratio
dry with materialThe orange solid was dried in a vacuum oven at RT for 18 h to 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d)
additionAt 0° C., a suspension of 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (325d) in 8 mL of DMF and 8 mL of DCM
stirringThe homogeneous reaction mixture was stirred at RT for 18 h
washwashed sequentially with 5 mL of water, 5 mL of 1 N NaOH, and 5 mL of brine
dry with materialdried over Na2SO4
concentrationconcentrated
customThe residue was purified by silica gel chromatography (50-100% EtOAc in DCM followed by 1-5% MeOH in DCM)

Sources & evidence

ORD record: ord-436d5362d88944c8b23adf745ea53830
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09394297B2

Reaction notes

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