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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
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2275034
[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]
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 3283Diethyl EtherLösungsmittelHCID 6228DimethylformamideLösungsmittel2×

Versuchsvorschrift

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:

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-09c0c62c8851453c8638662524562726
Quelldatensatz
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09127003B2

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