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Sodium Carbonate → (3R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine

HRID 1484042
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1484042
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:10]=23)O1.Cl[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@H:37]2[CH3:42])[CH:33]=[C:32]([C:43]2([S@:46]([CH3:49])(=[NH:48])=[O:47])[CH2:45][CH2:44]2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.COCCOC.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:42][C@@H:37]1[CH2:38][O:39][CH2:40][CH2:41][N:36]1[C:34]1[CH:33]=[C:32]([C:43]2([S@:46]([CH3:49])(=[NH:48])=[O:47])[CH2:44][CH2:45]2)[N:31]=[C:30]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])[CH:16]=[CH:17][C:10]=23)[N:35]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 3

HCID 10340Sodium CarbonateHCID 497589261-Tosyl-1H-pyrrolo(2,3-B)pyridine-4-boronic acid pinacol esterHCID 86660219(3R)-4-(2-chloro-6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine

Produkt 1

HCID 86660218(3R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholineAusbeute 39,2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418476HCID 178418476, VerbindungKatalysatorHCID 80711,2-DimethoxyethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 18180031Water 1,2-dimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (21.15 g, 53.11 mmol) in DME (212 ml) was added to a solution of (3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (12.55 g, 37.93 mmol) in DME:water 4:1 (55 ml). 2M aqueous sodium carbonate solution (22.76 ml, 45.52 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.666 g, 0.95 mmol) were added. The resulting solution was stirred at 90° C. for 2 hours under nitrogen. The reaction mixture was diluted with EtOAc (400 ml), and washed with water (400 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and a portion was purified by flash chromatography on silica eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (8.42 g, 39%); 1H NMR (400 MHz, CDCl3) 1.36 (3H, d), 1.52 (2H, dd), 1.80 (2H, dd), 2.24-2.46 (3H, s), 3.10 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.84 (1H, d), 3.99-4.18 (2H, m), 4.47 (1H, s), 6.91 (1H, s), 7.23-7.3 (3H, m, obscured by CDCl3), 7.45 (1H, d), 7.81 (1H, d), 8.08 (3H, dd), 8.51 (1H, d); m/z: (ES+) MH+, 567.4. The rest of the material was evaporated and the residue was dissolved in DCM (500 ml) and concentrated in vacuo onto silica (100 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3R)-3-methyl-4-(6-(14(R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (4.00 g, 19%); 1H NMR (400 MHz, DMSO-d6) 1.19-1.31 (3H, m), 1.37-1.58 (3H, m), 1.75 (1H, ddd), 2.34 (3H, s), 3.04 (3H, d), 3.2-3.27 (1H, m), 3.46-3.54 (1H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.82 (1H, s), 3.99 (1H, dd), 4.16 (1H, d), 4.54 (1H, s), 7.04 (1H, s), 7.42 (2H, d), 7.54 (1H, d), 8.01 (3H, dd), 8.10 (1H, d), 8.49 (1H, d); m/z: (ES+) MH+, 567.00.

Aufarbeitung

  1. washwashed with water (400 ml)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. dissolutionThe residue was dissolved in DCM (100 ml)
  6. customa portion was purified by flash chromatography on silica eluting with a gradient of 0 to 5% MeOH in DCM
  7. customPure fractions were evaporated

Quellen und Nachweise

ORD-Eintrag
ord-6c07c18542dc4609ac2bb0c9003daec3
Quelldatensatz
uspto-grants-2016_08
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09421213B2

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