2-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide → 2-(4-((2-(6-Fluoroimidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide

HRID 1922973

Reaktionsgleichung

Reaktionsgleichung von HRID 1922973
[N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][C:44]=1[F:52]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S1C=CC=C1C([O-])=O.[Cu+]>[F:52][C:44]1[CH:45]=[CH:46][C:47]2[N:48]([CH:49]=[CH:50][N:51]=2)[C:43]=1[C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[C:8]2[S:28][C:27]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]3)=[CH:26][C:9]=2[N:10]=1

Komponenten

6

Edukt 2

HCID 575067302-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramideHCID 596052135-Bromo-6-fluoroimidazo[1,2-a]pyridine

Produkt 1

HCID 498324362-(4-((2-(6-Fluoroimidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamideAusbeute 37,1 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 11194830Cuprous 2-thiophenecarboxylateKatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
150 °C

Versuchsvorschrift

A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (69 mg, 0.10 mmol), 5-bromo-6-fluoro-imidazo[1,2-a]pyridine (25 mg, 0.12 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and copper(I) thiophene-2-carboxylate (4 mg, 0.02 mmol) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 214 as a white solid (20 mg, 37%). LCMS (Method G) RT 4.52 min; [M+H]+ 539. 1H NMR (400 MHz, CHCl3-d): 8.20 (s, 1 H); 7.71-7.62 (m, 2 H); 7.35 (s, 1 H); 7.25-7.16 (t, J=9.5 Hz, 1 H); 7.18-6.91 (m, 1 H); 5.22 (s, 1 H); 4.05 (t, J=4.7 Hz, 4 H); 3.87 (t+m, J=4.7 Hz, 6 H); 2.62 (s, 8 H); 1.25 (s, 6 H)

Aufarbeitung

  1. customwas purged with argon gas
  2. washwashed with MeOH
  3. washthen eluted with 2 M NH3 in MeOH
  4. customThe resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90)

Quellen und Nachweise

ORD-Eintrag
ord-1e8798c7d5354a03ba55e52aa4593e7c
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08173650B2

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