Dimethylacetamide → 6-(1-(4-chlorobenzyl)-1H-pyrazol-4-ylamino)-N-(thiazol-2-yl)pyridine-3-sulfonamide

HRID 1644667Notes

Reaction equation

HRID 1644667 reaction equation
[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)(=[O:9])=[O:8].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl.Cl.[Cl:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH:71]=[C:70]([NH2:72])[CH:69]=[N:68]2)=[CH:64][CH:63]=1.CN(C)C(=O)C.CC(C)([O-])C.[Na+]>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]>[Cl:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH:71]=[C:70]([NH:72][C:13]3[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:9])=[O:8])=[CH:15][CH:14]=3)[CH:69]=[N:68]2)=[CH:64][CH:63]=1

Participants

7

Reactant 5

HCID 31374DimethylacetamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 9431916-chloro-N-(1,3-thiazol-2-yl)pyridine-3-sulfonamideHCID 23676156Sodium t-butoxideHCID 667761751-(4-chlorobenzyl)-1H-pyrazol-4-amine dihydrochloride

Product 1

HCID 866263606-(1-(4-chlorobenzyl)-1H-pyrazol-4-ylamino)-N-(thiazol-2-yl)pyridine-3-sulfonamideYield 35.8%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
120 °C

Procedure

Into a Vial was added the 6-Chloro-pyridine-3-sulfonic thiazol-2-ylamide (82 mg, 0.00030 mol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (21 mg, 0.000036 mol), Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.000012 mol), [B] 1-(4-chlorobenzyl)-1H-pyrazol-4-amine dihydrochloride (1.0E2 mg, 0.00036 mol) and N,N-Dimethylacetamide (4.0 mL, 0.043 mol). The mixture was sparged with argon for ˜5 min. Sodium tert-butoxide (140 mg, 0.0015 mol) was added and the reaction mixture was heated at 120° C. for 30 min in microwave. The reaction mixture was filtered through celite. The filtrate was diluted with Ethyl acetate and washed with 0.1 N HCl solution. The aqueous phase was neutralized with 1.0 N NaOH solution, extracted with Ethyl acetate. The combined organic phase was washed with water (3×) and brine, dried over Na2SO4, filtered and was concentrated to give the crude product that was purified on Gilson (Prep LC, reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS and combined accordingly. LC/MS showed the product was only ˜90% pure. The combined product solution was concentrated to remove the acetonitrile, neutralized with 1.0 N NaOH solution and then extracted with Ethyl acetate (3×). The combined organic layers were dried over sodium sulfate, filtered and was concentrated to give the product as free base, which was purified again on ISCO (0% to 100% Ethyl acetate in DCM). 48 mg of the product was obtained as a pale yellow solid.

Workup

  1. customThe mixture was sparged with argon for ˜5 min
  2. filtrationThe reaction mixture was filtered through celite
  3. additionThe filtrate was diluted with Ethyl acetate
  4. washwashed with 0.1 N HCl solution
  5. extractionextracted with Ethyl acetate
  6. washThe combined organic phase was washed with water (3×) and brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationwas concentrated
  10. customto give the crude product that
  11. customwas purified on Gilson (Prep LC, reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8)
  12. concentrationThe combined product solution was concentrated
  13. customto remove the acetonitrile
  14. extractionextracted with Ethyl acetate (3×)
  15. dry with materialThe combined organic layers were dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationwas concentrated
  18. customto give the product as free base, which
  19. customwas purified again on ISCO (0% to 100% Ethyl acetate in DCM)

Sources & evidence

ORD record
ord-a5d308aa9c2f4eb8b47fb58d7b1b7178
Source dataset
uspto-grants-2012_02
Patent number
US08124610B2

Reaction notes

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