Hydrochloric Acid → HCID 86687692, compound

HRID 1473624Notes

Reaction equation

HRID 1473624 reaction equation
[F:1][CH:2]([F:22])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([O:20][CH3:21])[CH:4]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([N:37](CC3C=CC(OC)=CC=3)[C:38]3[S:39][CH:40]=[CH:41][N:42]=3)(=[O:36])=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:22][CH:2]([F:1])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]4[S:39][CH:40]=[CH:41][N:42]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[C:5]([O:20][CH3:21])[CH:4]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 866874151-Chloro-N-(4-methoxybenzyl)-N-(thiazol-2-YL)isoquinoline-6-sulfonamideHCID 866876931443379-41-6

Product 1

HCID 86687692HCID 86687692, compoundYield 17.8%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of PdCl2(dppf)-CH2Cl2 adduct (7.78 mg, 9.53 μmol), 2-(4-(difluoromethyl)-2,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate NNNNN; 0.078 g, 0.248 mmol), 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.085 g, 0.191 mmol), and potassium carbonate (0.079 g, 0.572 mmol) in 2 mL dioxane, 1 mL water was heated to 100° C. overnight. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was then removed. The reaction mixture was treated with HCl (4N in dioxane) (0.953 ml, 3.81 mmol) and was heated to 100° C. for one hour. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(difluoromethyl)-2,5-dimethoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.016 g, 0.034 mmol, 17.58% yield). 1H NMR (MeCN-d3) δ: 8.68 (d, J=5.7 Hz, 1H), 8.51 (s, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=6.1 Hz, 1H), 6.99 (d, J=4.7 Hz, 1H), 6.61 (d, J=4.7 Hz, 1H), 3.81 (s, 3H), 3.65 (s, 3H); (M+H)+=478.0.

Workup

  1. customThe aqueous layer was then removed
  2. temperaturewas heated to 100° C. for one hour
  3. concentrationso the reaction mixture was concentrated
  4. customPurification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-a1f8e980ffca41a18c87856e307abb81
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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