Proton sponge → NaV1.7 Blocker-801

HRID 1401917

반응식

HRID 1401917 반응식
[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:41]([CH:42]3[CH2:45][N:44](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:43]3)[N:40]=[CH:39][CH:38]=2)[CH:3]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[NH:44]1[CH2:43][CH:42]([N:41]2[C:37]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:36]=[CH:35][C:5]=3[O:6][C:7]3[C:12]([F:13])=[CH:11][C:10]([S:14]([NH:17][C:18]4[S:22][N:21]=[CH:20][N:19]=4)(=[O:15])=[O:16])=[C:9]([F:34])[CH:8]=3)=[CH:38][CH:39]=[N:40]2)[CH2:45]1

참가 물질

6

반응물 3

HCID 88675Proton spongeHCID 5213051-Chloroethyl chloroformateHCID 594365414-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

생성물 1

HCID 46841215NaV1.7 Blocker-801

시약·촉매·용매 2

HCID 887Methanol용매HCID 6344Dichloromethane용매

실험 절차

4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 688, 270 mg, 0.321 mmol) was dissolved in dichloromethane (15 ml) and N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (85 mg, 0.40 mmol) was added followed by 1-chloroethyl chloroformate (0.07 ml, 0.65 mmol) and the solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate (40 ml) and 1M aqueous citric acid solution (20 ml), the ethyl acetate was washed with water, dried over anhydrous sodium sulphate, evaporated and the solvents removed in vacuo to give an oil. The oil was dissolved in methanol (15 ml) and refluxed for 5 hours. Some of the methanol was removed in vacuo to leave about 5 ml, the precipitated solid was removed by filtration and the filtrate was adsorbed onto silica gel (5 g) and dried prior to purification by column chromatography on silica gel using 10-25% v/v methanol (containing 10% v/v 0.880 aqueous ammonia) in dichloromethane. This afforded the title compound as a pinkish solid, 80 mg.

후처리

  1. concentrationThe solution was concentrated in vacuo
  2. customthe residue was partitioned between ethyl acetate (40 ml) and 1M aqueous citric acid solution (20 ml)
  3. washthe ethyl acetate was washed with water
  4. dry with materialdried over anhydrous sodium sulphate
  5. customevaporated
  6. customthe solvents removed in vacuo
  7. customto give an oil
  8. temperaturerefluxed for 5 hours
  9. customSome of the methanol was removed in vacuo
  10. customto leave about 5 ml
  11. customthe precipitated solid was removed by filtration
  12. customdried
  13. customto purification by column chromatography on silica gel using 10-25% v/v methanol (
  14. additioncontaining 10% v/v 0.880 aqueous ammonia) in dichloromethane

출처 및 근거

ORD 기록
ord-16c296c3298d45b39d60b4c2fe9c1464
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08907101B2

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