Water → Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-(4-cyano-3-fluorobenzyloxy)pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

HRID 526352노트

반응식

HRID 526352 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([F:52])[CH:45]=1.O>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([CH2:43][O:38][C:36]2[CH:37]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)[CH2:19]3)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[N:34][CH:35]=2)=[CH:45][C:46]=1[F:52])#[N:49]

참가 물질

8

반응물 4

HCID 962WaterHCID 24758Sodium hydrideHCID 27784664-Cyano-3-fluorobenzyl bromideHCID 71259055tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

생성물 1

HCID 71258934Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-(4-cyano-3-fluorobenzyloxy)pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate수율 4.5%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매2회HCID 8857Ethyl Acetate용매HCID 57417360Sodium chloride; water용매

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온도
0 °C

실험 절차

To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 200 mg, 0.37 mmol) in DMF (5 mL) was added sodium hydride (60%, 9.6 mg, 0.24 mmol) and the mixture was cooled to 0° C. 4-(Bromomethyl)-2-fluorobenzonitrile (70.5 mg, 0.33 mmol) in DMF (3 mL) was added while stirring and the mixture was warmed to room temperature. After one hour water, brine and ethyl acetate were added. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 10 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.

후처리

  1. temperaturethe mixture was warmed to room temperature
  2. customPhases were separated
  3. extractionthe aqueous phase was extracted with ethyl acetate
  4. dry with materialThe combined extracts were dried over sodium sulfate
  5. concentrationconcentrated in vacuum
  6. customThe residue was purified by preparative HPLC

출처 및 근거

ORD 기록
ord-37f3413513324f96983a8a58e9d413dd
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09345793B2

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