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Hydrochloric Acid → (3-Cyano-1-{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-carbonyl}-propyl)-carbamic acid methyl ester

HRID 417581
ノート
印刷プレビュー

反応式

HRID 417581 の反応式
C([O:5][C:6]([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.C[CH2:64][N:65](C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH:81]([C:83]#N)C)C(O)=O)=[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>[CH3:72][O:73][C:74](=[O:75])[NH:76][CH:77]([C:6]([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([CH2:45][CH2:46]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:51])[CH3:52])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:59])([F:60])[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:5])[CH2:81][CH2:83][C:64]#[N:65]
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 666212893-[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
HCID 86648886
Methoxycarbonylamino-3-cyano-butyric acid

生成物 1

HCID 66620199(3-Cyano-1-{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-carbonyl}-propyl)-carbamic acid methyl ester収率 49.7%

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 (61.9 mg, 0.074 mmol) was dissolved in DCM (1 mL) and HCl in dioxane (4M, 1 mL) was added and stirring at room temperature was continued. After 30 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 (28.5 mg, 0.186 mmol) was added. A solution of 2-(L) Methoxycarbonylamino-3-cyano-butyric acid (13.8 mg, 0.074 mmol), HATU (28.3 mg, 0.074 mmol) and DIEA (9.5 mg, 0.074 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 30 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 (3-Cyano-1-{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-carbonyl}-propyl)-carbamic acid methyl ester (33.1 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 30 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-19fa6db1948d4cb8ada372cbc92b2e4e
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

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