1,4-Dioxane → 1-(4'-fluoro-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473634Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][N:35]=4)(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[C:16]([O:40][CH3:41])[CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]5[CH:39]=[CH:38][N:37]=[CH:36][N:35]=5)(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH:23]=[CH:22][N:21]=3)=[C:16]([O:40][CH3:41])[CH:15]=2)=[CH:4][C:3]=1[O:11][CH3:12]

Participants

Conditions

Temperature: 150 °C

Procedure

A microwave vial charged with PdCl2(Amphos)2 (0.025 g, 0.035 mmol), 4-fluoro-3-methoxyphenylboronic acid (0.119 g, 0.703 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.150 g, 0.351 mmol), potassium phosphate (0.298 g, 1.406 mmol), 1.5 mL dioxane, and 0.5 mL water was heated to 150° C. in the microwave for 40 minutes. LC/MS showed product, so the aqueous layer was removed. The reaction mixture was treated with excess HCl (4N in dioxane) and was allowed to stir for 10 minutes. The reaction mixture was then concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4′-fluoro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.030 g, 0.058 mmol, 16.5%). 1H NMR (MeCN-d3) δ: 8.69 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.20 (d, J=6.4 Hz, 1H), 7.89-7.98 (m, 2H), 7.80 (d, J=9.0 Hz, 1H), 7.34-7.47 (m, 4H), 7.19-7.33 (m, 2H), 7.06 (d, J=6.3 Hz, 1H), 3.98 (s, 3H), 3.71-3.75 (m, 3H) (M+H)+=517.1.

Workup

customso the aqueous layer was removed
additionThe reaction mixture was treated with excess HCl (4N in dioxane)
concentrationThe reaction mixture was then concentrated
customPurification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record: ord-09039a4a4d764e7ab999454e85f9d4e3
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09012443B2

Reaction notes

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