Hydrochloric Acid → 1-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473626Notes

Reaction equation

HRID 1473626 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=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.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=3)(=[O:35])=[O:36])=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 866876591-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideHCID 866876962-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole

Product 1

HCID 866876951-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 68.4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of PdCl2(dppf)-CH2Cl2 adduct (0.127 g, 0.156 mmol), 2-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole (Intermediate OOOOO; 0.643 g, 2.026 mmol), 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG) (0.500 g, 1.559 mmol), and potassium carbonate (0.862 g, 6.24 mmol) in 6 mL dioxane/2 mL water was heated to 110° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane) (1.559 ml, 6.24 mmol). After stirring for an additional 10 minutes, 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-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.507 g, 1.066 mmol, 68.4% yield). 1H NMR (MeCN-d3) δ: 8.71 (d, J=5.7 Hz, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=6.3 Hz, 1H), 7.91-7.97 (m, 3H), 7.75-7.84 (m, 2H), 7.72 (sd, J=7.8 Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.06 (s, J=6.3 Hz, 1H), 3.75 (s, 3H); (M+H)+=476.0.

Workup

  1. customThe aqueous layer was removed
  2. concentrationthe reaction mixture was concentrated
  3. 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-f690837bd5c04398bbf83cd9d868732d
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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