N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styrene → N-{2-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline hydrochloride

HRID 268744노트

반응식

HRID 268744 반응식
Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[F:54][C:55]1[CH:56]=[C:57]2[C:61](=[CH:62][CH:63]=1)[CH2:60][NH:59][CH2:58]2>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:59]1[CH2:58][C:57]2[C:61](=[CH:62][CH:63]=[C:55]([F:54])[CH:56]=2)[CH2:60]1)=[O:6]

참가 물질

5

반응물 3

HCID 16212021N-benzyl-N-ethylethanamine;1,4-bis(ethenyl)benzene;styreneHCID 179862522-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochlorideHCID 179862865-fluoro-2,3-dihydro-1H-isoindole hydrochloride

생성물 1

HCID 17986248N-{2-Chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl}-5-fluoro-isoindoline hydrochloride수율 109.7%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.8 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline hydrochloride (D8) (0.10 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E65) as a white solid (0.14 g). MS electrospray (+ion) 430/432 (MH+). 1H NMR δ (DMSO-d6): 10.48 (1H, s), 7.46-7.06 (6H, m), 4.88-4.60 (3H, m), 4.51 (2H, m), 3.80-3.55 (1H, m), 3.46-3.18 (2H, m), 2.88 (2H, m), 2.38-1.64 (10H, m).

후처리

  1. customThe reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]
  2. additionFractions containing the required product
  3. customwere evaporated
  4. dissolutionredissolved in DCM
  5. additiontreated with excess hydrogen chloride (1M solution in diethyl ether)
  6. concentrationconcentrated
  7. customThe residue was crystallised from acetone

출처 및 근거

ORD 기록
ord-22a46e2b3ac24108851f9a5422b5e2a0
출처 데이터셋
uspto-grants-2008_11
특허 번호
US07446103B2

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