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Diisopropylethylamine → tert-Butyl((cis)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate

HRID 2275034
ノート
印刷プレビュー

反応式

HRID 2275034 の反応式
[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]([O:66][C:67](=[O:76])[NH:68][CH:69]1[CH2:74][CH2:73][CH:72]([CH3:75])[NH:71][CH2:70]1)([CH3:65])([CH3:64])[CH3:63]>CN(C=O)C.CCOCC.O>[C:62]([O:66][C:67](=[O:76])[NH:68][C@H:69]1[CH2:74][CH2:73][C@@H:72]([CH3:75])[N:71]([C:24]([C:22]2[CH:21]=[C:20]([O:27][CH3:28])[C:17]3[N:18]([CH3:19])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:15][C:16]=3[CH:23]=2)=[O:25])[CH2:70]1)([CH3:65])([CH3:63])[CH3:64]
参加物実験手順後処理出典と根拠反応ノート

参加物

8

反応物 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 42609251tert-butyl N-(6-methylpiperidin-3-yl)carbamateHCID 863401542-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

生成物 1

HCID 118178631
tert-Butyl((cis)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 3283Diethyl Ether溶媒HCID 6228Dimethylformamide溶媒2 回

実験手順

To a solution of 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (250 mg, 0.498 mmol) in DMF (2.3 mL) was added HATU (189 mg, 0.498 mmol) followed by DIPEA (0.174 mL, 0.996 mmol) and the reaction stirred at room temperature for 15 min. tert-Butyl(6-methylpiperidin-3-yl)carbamate (107 mg, 0.498 mmol) was added in DMF (2.3 mL) and the reaction stirred at rt for 16 h. Water (20 mL) and Et2O (20 mL) were added and the layers separated. The aqueous layer was extracted with further Et2O (2×20 mL) and the combined organics washed with water (2×20 mL), dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash chromatography on silica (25 g) using a gradient of DCM→100% (20% MeOH/DCM)/DCM. The appropriate fractions were combined and evaporated under vacuum to give the product as a yellow oil. This material was purified further by high pH MDAP (Method E). Accordingly, the sample (160 mg) was dissolved in DMSO/MeOH (1:1, 1.8 mL) and injected in two batches. The appropriate fractions were collected and concentrated in vacuo to afford a white solid—tert-butyl(1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate (93 mg, 0.162 mmol, 32.6% yield). This material was sent for chiral resolution. 4 components were successfully resolved. However analysis showed only 1-2% of the presumed minor diastereomers. The mixture was submitted for chiral preparative chromatography (Chiral Method D) and only the two major components were collected:

後処理

  1. customthe layers separated
  2. extractionThe aqueous layer was extracted with further Et2O (2×20 mL)
  3. washthe combined organics washed with water (2×20 mL)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customto afford a yellow oil
  7. customThe crude product was purified by flash chromatography on silica (25 g)
  8. customevaporated under vacuum

出典と根拠

ORDレコード
ord-09c0c62c8851453c8638662524562726
出典データセット
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09127003B2

反応ノート

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