Hydrochloric Acid → HCID 22390522, compound

HRID 1072078Notes

Reaction equation

HRID 1072078 reaction equation
[OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][N:17]3[C:22]=2[C:21]([NH:23][C:24]2[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)[N:28]=[CH:27]4)=[N:20][CH:19]=[N:18]3)[CH2:9][CH2:8]1)=[O:6].Cl>CO.C1COCC1>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:22]4=[C:14]([CH2:13][N:10]5[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]5)[CH:15]=[CH:16][N:17]4[N:18]=[CH:19][N:20]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 44430027HCID 44430027, compound

Product 1

HCID 22390522HCID 22390522, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Aqueous NaOH (2.1 mL, 1.0 N) was added to a solution of 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid methyl ester (352 mg, 0.686 mmole) in a mixture of MeOH (0.2 ml) and THF (0.2 ml) at 0° C. After stirring at 0° C. for 1 hour, the reaction mixture was allowed to warm to RT and left stirring overnight. Aqueous HCl (2.1 ml, 1.0 N) was added dropwise and the reaction was extracted with DCM. The organic extracts were dried (Na2SO4) and the solvents were removed to leave 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid, as a solid (329 mg, purity 84% by LCMS) which was used as such. A solution of the crude acid (100 mg, 0.168 mmole) in THF (2 ml) was added dropwise to a solution of 1,1′-carbonyldiimidazole (33 mg, 0.2 mmole) in THF (0.3 ml) and this was heated at reflux for 30 min. After cooling to RT, cyclopropylsulfonamide (82 mg, 0.67 mmole, 4 equiv.) was added followed by a solution of DBU (50 uL, 0.336 mmole, 2 equiv.) in THF (0.2 ml). The reaction was stirred for 18 hr, diluted with EtOAc (120 ml), washed with pH 4.0 buffer (9 mL), brine (5 mL) and dried (Na2SO4). Removal the solvent followed by radial chromatography (2 mm silica gel plate gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (58 mg, 57%). 1H NMR (CDCl3) δ 0.98-1.00 (m, 2H), 1.22-1.27 (m, 2H), 1.84-1.92 (m, 4H), 2.03-2.16 (m, 2H), 2.24-2.3 (m, 1H), 2.83-2.92 (m, 1H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.54 (s, 2H), 6.46 (d, 1H, J=2.5 Hz), 6.81-6.97 (m, 3H), 7.20-7.27 (m, 1H), 7.36-7.51 (m, 3H), 7.84 (s, 1H), 8.06 (s, 2H), 11.82 (bs, 1H). MS: 603.7 (M+H+); HPLC Ret Time: 1.21 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).

Workup

  1. temperatureto warm to RT
  2. waitleft
  3. stirringstirring overnight
  4. extractionthe reaction was extracted with DCM
  5. dry with materialThe organic extracts were dried (Na2SO4)
  6. customthe solvents were removed

Sources & evidence

ORD record
ord-1383f581dd87482fbdf47ec9c629a9db
Source dataset
uspto-grants-2005_06
Patent number
US06908916B2

Reaction notes

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