Diisopropylethylamine → 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide

HRID 1961095ノート

反応式

HRID 1961095 の反応式
[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:25][C@H:26]([CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1

参加物

7

反応物 5

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 2761473Boc-2-(trifluoromethyl)-L-phenylalanineHCID 578263895-chloro-4-(1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acidHCID 670661172-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione

生成物 1

HCID 578264215-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide収率 53.2%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

反応条件

温度
25 °C

実験手順

To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513 (M, M+2)+.

後処理

  1. customaccording to the procedure of Preparation 6
  2. customat 25° C.
  3. customwas then partitioned between H2O-DCM
  4. washThe aqueous phase was washed several times with DCM
  5. dry with materialthe combined organic fractions were dried over Na2SO4
  6. concentrationconcentrated
  7. custompurified via column chromatography (silica, 45% EtOAc in hexanes)

出典と根拠

ORDレコード
ord-95b56a06c7f14fe986fbccb616eaacbc
出典データセット
uspto-grants-2013_04
特許番号
US08410158B2

反応ノート

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