Water → N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-fluoro-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzamide

HRID 1808162

반응식

HRID 1808162 반응식
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(#N)C.[S:29]1[C:33]([NH2:34])=[N:32][CH:31]=[N:30]1.[OH-].[Na+].O1CCOCC1.O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:34][C:33]4[S:29][N:30]=[CH:31][N:32]=4)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

참가 물질

7

반응물 6

HCID 962WaterHCID 6342AcetonitrileHCID 14798Sodium HydroxideHCID 312751,4-DioxaneHCID 2902745-Amino-1,2,4-thiadiazoleHCID 577322534-[({[1-(4-Chlorophenyl)cyclopropyl]methyl}amino)carbonyl]-2-fluorobenzenesulfonyl chloride

생성물 1

HCID 57731988N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-fluoro-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzamide수율 15.5%

실험 절차

A solution of 4-[({[1-(4-chlorophenyl)cyclopropyl]methyl}amino)carbonyl]-2-fluorobenzenesulfonyl chloride (Preparation 93, 205 mg, 0.510 mmol) in acetonitrile (1.0 mL, 19 mmol) was added dropwise to a solution of 1,2,4-thiadiazol-5-amine (155 mg, 1.53 mmol) and sodium hydroxide (61.1 mg, 1.53 mmol) in 1,4-dioxane (1.6 mL, 2.01 mmol) and water (0.32 mL, 18 mmol). After stirring 30 min at ambient temperature, the reaction mixture was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (37 mg, 15%).

후처리

  1. customthe reaction mixture was quenched with 2 N HCl
  2. customThe mixture was partitioned with methylene chloride
  3. washThe aqueous layer was washed with methylene chloride
  4. dry with materialthe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated onto Celite
  7. customThe residue was purified
  8. additionThe product containing fractions
  9. concentrationwere concentrated in vacuo
  10. dissolutionthe residue was dissolved in 1 mL of DMSO
  11. filtrationfiltered
  12. custompurified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA)
  13. additionThe product containing fractions

출처 및 근거

ORD 기록
ord-3cd9e8fee24f41949768202975b356dd
출처 데이터셋
uspto-grants-2013_01
특허 번호
US08357711B2

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