Hydrochloric Acid → 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide formate

HRID 1616519Notes

Reaction equation

HRID 1616519 reaction equation
[CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[CH:5]=[C:6]([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH:7]=[C:8]([C:11](=[O:26])[NH:12][CH2:13][C:14]2[C:15](=[O:25])[NH:16][C:17]([CH3:24])=[C:18]([F:23])[C:19]=2[CH:20]([CH3:22])[CH3:21])[C:9]=1[CH3:10])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH:39]([OH:41])=[O:40].[CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[C:9]([CH3:10])=[C:8]([CH:7]=[C:6]([C:27]2[CH:32]=[N:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:5]=1)[C:11]([NH:12][CH2:13][C:14]1[C:15](=[O:25])[NH:16][C:17]([CH3:24])=[C:18]([F:23])[C:19]=1[CH:20]([CH3:22])[CH3:21])=[O:26])[CH3:2]

Participants

5

Reactant 3

HCID 313Hydrochloric Acid2×HCID 312751,4-Dioxane2×HCID 70872613tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate

Product 1

HCID 708726253-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide formateYield 15.6%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (450 mg, 0.639 mmol) in ethanol (4.3 mL) at room temperature was added 4 M HCl in dioxane (2 mL, 8.00 mmol). LC/MS after 2 h showed both product and remaining starting material. Additional 4 M HCl in 1,4-dioxane (1.5 ml, 6.00 mmol) was added, and LC/MS after total 4 h showed that reaction was completed. The reaction mixture was concentrated to dryness, azeotroped with toluene-methanol to give crude hydrochloride salt (454 mg, 111%). A 125 mg sample of crude hydrochloride salt was purified by reverse phase HPLC/MS (ACN—H2O, 0.1% formic acid) to give 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide formate (65 mg) as a colorless glassy film. 1H-NMR (400 MHz, CD3OD) δ ppm 8.35-8.40 (m, 2H), 7.86 (dd, J=2.4, 8.8 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.92 (m, 2H), 3.84 (m, 4H), 3.54 (m, 1H), 3.30-3.38 (m, 6H), 3.07-3.18 (m, 3H), 2.33 (s, 3H), 2.24 (d, J=2.8 Hz, 3H), 1.73-1.76 (m, 2H), 1.62-1.68 (m, 2H), 1.37 (d, J=6.8 Hz, 6H), 0.89 (t, J=6.8 Hz, 3H); MS (ES)(M+H) 605.6.

Workup

  1. customLC/MS after total 4 h showed that reaction
  2. concentrationThe reaction mixture was concentrated to dryness
  3. customazeotroped with toluene-methanol
  4. customto give crude hydrochloride salt (454 mg, 111%)
  5. customA 125 mg sample of crude hydrochloride salt was purified by reverse phase HPLC/MS (ACN—H2O, 0.1% formic acid)

Sources & evidence

ORD record
ord-3d74ed64dd524f1da044b996a4517939
Source dataset
uspto-grants-2014_07
Patent number
US08765732B2

Reaction notes

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