3,4-Dichlorophenyl isocyanate → (R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid (3,4-dichloro-phenyl)-amide

HRID 655566ノート

反応式

HRID 655566 の反応式
Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].CN1CCOCC1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]

参加物

6

反応物 4

HCID 76073,4-Dichlorophenyl isocyanate2 回HCID 79724-MethylmorpholineHCID 516892Sodium BicarbonateHCID 67080697(R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride

生成物 1

HCID 59149944(R)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid (3,4-dichloro-phenyl)-amide収率 51%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

A solution of 0.120 g (purity: 76% corresponds to 0.25 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 1E) in 2 ml N,N-dimethylformamide was treated at room temperature with 0.052 g (0.27 mmol, 1.1 eq.) of 3,4-dichlorophenyl isocyanate and 0.136 ml (1.24 mmol, 5 eq.) of 4-methylmorpholine. The reaction was stirred at room temperature overnight. To the solution was added 5 mg (0.02 mmol, 0.1 eq.) of 3,4-dichlorophenyl isocyanate. After 1 h, no starting material was left; the solution was slowly added to a solution of sat. aq. sodium hydrogencarbonate, followed by extraction with ethyl acetate (3 times). The organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum. The crude product was purified by flash chromatography (20 g SiO2-column, dichloro-methane/methanol 2:98, 5:95, 1:9, 1:4) to give 0.061 g (51%) of the title compound as white solid. MS: 483.4 (MH+, 2Cl).

後処理

  1. waitAfter 1 h
  2. waitno starting material was left
  3. extractionfollowed by extraction with ethyl acetate (3 times)
  4. washThe organic phases were washed with a solution of sat. aq. sodium hydrogencarbonate and with 10% aq. sodium chloride solution
  5. dry with materialThe combined organic phases were dried over Na2SO4
  6. customthe solvent was removed under vacuum
  7. customThe crude product was purified by flash chromatography (20 g SiO2-column, dichloro-methane/methanol 2:98, 5:95, 1:9, 1:4)

出典と根拠

ORDレコード
ord-69773a3b118247cba3a05d16b8111f74
出典データセット
uspto-grants-2011_12
特許番号
US08071586B2

反応ノート

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