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Hydrochloric Acid → (1-{6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza-bicyclo [2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 417580
ノート
印刷プレビュー

反応式

HRID 417580 の反応式
C(OC([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:46][CH2:45]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:60])([F:59])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH3:81])[C:78](O)=[O:79])=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:29]3[CH:30]=[CH:31][C:32]4[C:33]5[C:25](=[CH:24][C:23]([C:20]6[CH:21]=[CH:22][C:16]7[N:15]=[C:14]([CH:13]8[CH:12]9[CH2:61][CH:9]([CH2:10][CH2:11]9)[N:8]8[C:78](=[O:79])[CH:77]([NH:76][C:74]([O:73][CH3:72])=[O:75])[CH3:81])[NH:18][C:17]=7[CH:19]=6)=[CH:35][CH:34]=5)[C:26]([F:60])([F:59])[C:27]=4[CH:28]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:58])[CH:50]([CH3:52])[CH3:51]
参加物実験手順後処理出典と根拠反応ノート

参加物

10

反応物 5

HCID 313Hydrochloric AcidHCID 81531Diisopropylethylamine2 回HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 130483432-[(Methoxycarbonyl)amino]propanoic acidHCID 66621289
3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

生成物 1

HCID 66620929(1-{6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza-bicyclo [2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester収率 43.4%

試薬・触媒・溶媒 4

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒

実験手順

3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (57.6 mg, 0.068 mmol) was dissolved in DCM (1 mL) and HCl in dioxane (4M, 1 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (26.4 mg, 0.204 mmol) was added. A solution of 2-(L) methoxycarbonylamino-propionic acid (9.95 mg, 0.068 mmol), HATU (25.9 mg, 0.068 mmol) and DIEA (8.8 mg, 0.068 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 45 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (1-{6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (25.4 mg) as a TFA salt.

後処理

  1. customall volatiles were removed in vacuo
  2. customThe crude material was used in the next step without further purification
  3. dissolutionThe crude material was dissolved in DMF (1.0 mL)
  4. stirringThe reaction was stirred at room temperature
  5. waitAfter 45 minutes
  6. washwas washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
  7. dry with materialwas dried over sodium sulfate
  8. filtrationFiltration and removal of solvents in vacuo
  9. customgave the crude material, which
  10. customwas purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA)

出典と根拠

ORDレコード
ord-eb919a5b417541ce82119dcb007a42f0
出典データセット
uspto-grants-2012_01
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08088368B2

反応ノート

読み込み中…

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