methyl 2-bromo-3-chloro-5-{N-[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1-benzofuran-6-yl]methanesulfonamido}benzoate → HCID 131732335, 화합물

HRID 2272390노트

반응식

HRID 2272390 반응식
[Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[Li+].[BH4-].C1COCC1>C1COCC1.CO.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:8][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:33][CH3:34])=[O:35])=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:11]=1[Cl:12]

참가 물질

6

반응물 2

HCID 122643076methyl 2-bromo-3-chloro-5-{N-[5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1-benzofuran-6-yl]methanesulfonamido}benzoateHCID 131718764lithium borohydride THF

생성물 1

HCID 131732335HCID 131732335, 화합물수율 104.3%

시약·촉매·용매 3

HCID 887Methanol용매HCID 8028Tetrahydrofuran용매HCID 57417360Sodium chloride; water용매

실험 절차

A solution of 54.3 g (84.0 mmol) of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate in 351 mL of anhydrous THF and 39 mL of anhydrous MeOH was cooled in an ice water/brine bath to −5° C. (internal temperature). To the stirred solution was added 125 mL (251 mmol) of 2M LiBH4/THF via addition funnel at a rate so as to maintain the temperature below 5° C. The addition required 35 minutes. The brine bath was then replaced by an ice water bath and stirring of the solution continued. After another 1.5 hours LCMS indicated complete reaction. The solution was quenched by addition of 200 mL of saturated aqueous sodium bicarbonate followed by 400 mL of water and 600 mL of EtOAc. The mixture was stirred vigorously for 30 minutes and then transferred to a separatory funnel. After the phases separated, solid remained in the aqueous phase so an additional 200 mL of water was added and the mixture shaken, and the phases again separated. The aqueous solution was extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×), saturated brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure to afford 54.5 g of 6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as an orange-brown foam. The crude material was carried forward to the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.54 (m, 1H) 8.12 (s, 1H) 7.98 (dd, J=8.93, 5.41 Hz, 2H) 7.59 (d, J=2.73 Hz, 1H) 7.54 (d, J=2.63 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.22 (s, 1H) 5.64 (t, J=5.56 Hz, 1H) 4.48 (d, J=5.56 Hz, 2H) 3.45 (s, 3H) 2.84 (d, J=4.59 Hz, 3H) 2.06-2.17 (m, 1H) 0.75-1.06 (m, 3H) 0.47 (br. s., 1H). LCMS(ESI): 623 (M+H+).

후처리

  1. additionvia addition funnel at a rate so as
  2. temperatureto maintain the temperature below 5° C
  3. additionThe addition required 35 minutes
  4. customreaction
  5. customThe solution was quenched by addition of 200 mL of saturated aqueous sodium bicarbonate
  6. stirringThe mixture was stirred vigorously for 30 minutes
  7. customtransferred to a separatory funnel
  8. customAfter the phases separated
  9. additionwas added
  10. stirringthe mixture shaken
  11. customthe phases again separated
  12. extractionThe aqueous solution was extracted with EtOAc (2×200 mL)
  13. washThe combined EtOAc solutions were washed with 5% aqueous NaCl (1×), saturated brine (1×)
  14. dry with materialdried over sodium sulfate
  15. concentrationconcentrated to dryness at reduced pressure

출처 및 근거

ORD 기록
ord-5b1c312474014edcbeee47a6b6af3d5b
출처 데이터셋
uspto-grants-2015_09
특허 번호
US09119868B2

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