Boron tribromide → (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester

HRID 1469615노트

반응식

HRID 1469615 반응식
[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([O:30]C)=[C:25]([F:32])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:21][C:22](=[O:33])[C:23]1[CH:24]=[C:25]([F:32])[C:26]([OH:30])=[C:27]([F:29])[CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]

참가 물질

4

반응물 2

HCID 25134Boron tribromideHCID 59608113(2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester

생성물 1

HCID 67506121(2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester수율 82.3%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 mL) is slowly added BBr3 (2.60 mL, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (30 mg, 0.064 mmol) in MeOH (2 mL) at room temperature is added aqueous 1M NaOH (4 mL, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1M HCl (4 mL, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCl salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.56 minutes (condition B); MS 440 (M+1); 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.19 (d, J=7.07 Hz, 3 H) 1.55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1.90-1.96 (m, 1 H) 2.54-2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25-4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33-7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1.26 Hz, 2 H).

후처리

  1. customThe reaction is quenched with MeOH
  2. additiondiluted with EtOAc
  3. washwashed with H2O and brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated under reduced pressure
  6. customThe obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM)

출처 및 근거

ORD 기록
ord-0028ee04e66d4e64a0a324ea45f8ef83
출처 데이터셋
uspto-grants-2015_04
특허 번호
US09006249B2

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