Potassium Phosphate, Tribasic → Methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate

HRID 1987165Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:14]([CH3:13])[S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

Conditions

Temperature: 100 °C

Procedure

Sulfonamide Incorporation Methyl 2,6-dichloroisonicotinate (5.0 g, 24.3 mmol), methyl(methylsulfonyl)amine (3.18 g, 29.12 mmol), potassium phosphate (7.22 g, 34.0 mmol), Xantphos (0.87 g, 1.50 mmol) and tris(dibenzylideneacetone)dipalladium (0.68 g, 0.51 mmol) were added to a dry, argon flushed flask. Dioxane (195 mL) was added, the solution degassed with argon and the reaction was heated to 100° C. for 16 hours. The reaction was cooled to rt, filtered through celite and evaporated in vacuo. Flash chromatography (silica, 0-50% EtOAc/CH2Cl2) gave methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.68 (s, 1H), 3.96 (s, 3H), 3.44 (s, 3H), 3.11 (s, 3H). Step B: Amination A solution of methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate (1.2 g, 4.30 mmol), amine XI (1.0 g, 5.60 mmol), potassium phosphate (2.74 g, 12.9 mmol), and palladium bis(tri-t-butylphosphine) (0.11 g, 0.22 mmol) in degassed toluene (15 mL) was sealed in a glass tube and heated to 110° C. for 16 hours. The reaction was filtered through celite, rinsed with ethyl acetate and concentrated in vacuo. Flash chromatography (silica, 20% EtOAc/hexanes) gave methyl 2-{benzyl[(2-trans-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinate: 1H NMR (400 MHz, MeOD) δ 7.28 (m, 5H), 7.01 (d, J=0.8 Hz, 1H), 6.98 (d, J=0.8 Hz, 1H), 4.83 (s, 2H), 3.87 (s, 3H), 3.62 (dd, J=6.0, 14.8 Hz, 1H), 3.30 (dd, J=7.2, 14.8 Hz, 1H), 3.23 (s, 3H), 2.88 (s, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.81 (m, 1H), 0.62 (m, 1H), 0.39 (m, 1H), 0.22 (m, 1H) Step C: Hydrogenation A solution of 2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinate (0.93 g, 2.23 mmol), 20% palladium hydroxide on carbon (0.042 g, 0.06 mmol) and trifluoroacetic acid (0.13 g, 1.11 mmol) in ethanol (10 mL) was placed under a hydrogen atmosphere and heated to 60° C. for 3 hours. The reaction was cooled to ambient emperature, filtered over celite, rinsed with methanol and evaporated in vacuo to give methyl 2-{[(2-trans-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinate: LCMS [M+H]=328.1 Step D: Saponification A solution of methyl 2-{[(2-trans-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinate (0.8 g, 2.44 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N NaOH (4.9 mL, 4.9 mmol) and the reaction was heated to 50° C. for 1 hour. The reaction was evaporated in vacuo and partitioned between 1M HCl and ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give 2-{[(2-trans-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinic acid (A) as a white solid: 1H NMR (400 MHz, CD3OD) δ 6.89 (s, 1H), 6.83 (s, 1H), 3.30 (s, 3H), 3.17 (d, J=6.8 Hz, 2H), 3.15 (s, 3H), 1.03 (d, J=6.0 Hz, 3H), 0.81 (m, 1H), 0.64 (m, 1H), 0.39 (m, 1H), 0.22 (m, 2H); HRMS (ES, M+H) calcd. for C13H19N3O4S: 314.1169, found: 314.1171.

Workup

customthe solution degassed with argon
temperatureThe reaction was cooled to rt
filtrationfiltered through celite
customevaporated in vacuo

Sources & evidence

ORD record: ord-f81fc2cb925a4c14aab048eccb096fe9
Source dataset: uspto-grants-2009_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07550481B2

Reaction notes

Loading…