Hydrochloric Acid → 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid

HRID 1056231Notes

Reaction equation

HRID 1056231 reaction equation
[CH:1]1([NH:4][C:5]2[C:6]([CH3:28])=[N:7][C:8]3[C:13]([N:14]=2)=[C:12]([C:15]2[NH:19][C:18]4[C@H:20]([C@H:24]([OH:26])[CH3:25])[NH:21][C:22](=[O:23])[C:17]=4[CH:16]=2)[C:11]([F:27])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[Li+].[OH-:30].Cl>O1CCOCC1.O>[NH2:21][C@H:20]([C:18]1[NH:19][C:15]([C:12]2[C:11]([F:27])=[CH:10][CH:9]=[C:8]3[C:13]=2[N:14]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:6]([CH3:28])=[N:7]3)=[CH:16][C:17]=1[C:22]([OH:23])=[O:30])[C@H:24]([OH:26])[CH3:25]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 89783316(6R)-2-(3-(cyclopropylamino)-6-fluoro-2-methyl-5-quinoxalinyl)-6-((1R)-1-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one

Product 1

HCID 897937832-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 312751,4-DioxaneSolvent3×

Conditions

Temperature
100 °C

Procedure

The yellow foam (352b) (184.5 mg) in 1,4-dioxane (6.0 mL) was treated with 1.0 M aq. LiOH (3.0 mL, 3.0 mmol). The mixture was heated at 100° C. for 16 h. The mixture was lyophilized to give a yellow solid containing m/z (ESI, +ve) 614.1 (M+H). The yellow solid was dissolved in 1 mL of dioxane and treated with a solution of 4 M HCl in 1,4-dioxane (5 mL) with a few drops of water added to aid solubility. The mixture was stirred at RT for 4 h, after which time bis-deprotection was observed by LC-MS. The mixture was lyophilized to give 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) as a brown solid. A solution of the 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) in DMF (3.0 mL) was treated with TEA (0.20 mL, 1.44 mmol) followed by PyBOP (NovaBiochem) (300 mg, 0.57 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated, dissolved in DMSO (5.0 mL), and purified by preparative HPLC (Gradient: 10-100% MeCN in H2O, modified with 0.1% TFA) to give (R)-2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6-((R)-1-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one bis(2,2,2-trifluoroacetate) (352) (54 mg, 0.089 mmol) as a red gum. LC-MS m/z 382.1, [M+H]+; 19F NMR (DMSO-d6; 376 MHz): δ −108.08 (s, 1F), −74.95 (s, 6F).

Workup

  1. customto give a yellow solid
  2. additioncontaining m/z (ESI, +ve) 614.1 (M+H)
  3. additionadded

Sources & evidence

ORD record
ord-45dcb8a5c7fe4b2480929524a76cce48
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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