Methanesulfonyl chloride → 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-(methylsulfonyl)-piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

HRID 449696Notes

Reaction equation

HRID 449696 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][N:39]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 566563386-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one

Product 1

HCID 566563916-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(1-(methylsulfonyl)-piperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-oneYield 45%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

In a 10 mL round-bottomed flask, 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one (35.03 mg, 57.5 μmol, Eq: 1.00) was combined with DCM (3 ml) and cooled to 0° C. DIPEA (8.91 mg, 12.0 μl, 68.9 μmol, Eq: 1.2) was added, followed by addition of methanesulfonyl chloride (6.58 mg, 4.48 μl, 57.5 μmol, Eq: 1). The reaction mixture was stirred at 0° C. to room temperature for 1 hr. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane) to afford white solid (16 mg, 45%). (M+H)+=688.4 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.56 (s, 1H), 8.48 (br. s., 1H), 8.29 (br. s., 1H), 8.20 (br. s., 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m, 4H), 1.42 (s, 9H).

Workup

  1. customThe crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane)

Sources & evidence

ORD record
ord-4d5fa46d69284d4a9bab1f69668036f4
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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