Reaktion #2011027

Reaktionsgleichung

tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate

HCl

→

(R)-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydro furan-2-carboxamide hydrochloride

Ausbeute 21.0%

Lösungsmittel

methanol

TFA

ether

CH2Cl2

Reaktionsbedingungen

Aufarbeitung

1. 1
   Einengenconcentrated in vacuo
2. 2
   SonstigeThe residue obtained
3. 3
   Sonstigewas purified by C-18 reverse phase chromatography (Biotage Flash 12 M+, C-18) on Biotage SP4 unit
4. 4
   Wascheneluting with a gradient of 1-50% CH3CN/water (14 CV)
5. 5
   workup.ADDITIONThe pure fractions containing the R-isomer (
6. 6
   Einengenconcentrated in vacuo
7. 7
   Sonstigeevaporated from CH3CN (3×5 mL)
8. 8
   SonstigeThe solid residue obtained
9. 9
   EinengenThe resulting suspension was concentrated in vacuo
10. 10
    Sonstigeevaporated from CH2Cl2 (3×5 mL)
11. 11
    Sonstigedried under high vacuum for 24 hours

Vorschrift

A solution of tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate in TFA (3 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue obtained was purified by C-18 reverse phase chromatography (Biotage Flash 12 M+, C-18) on Biotage SP4 unit eluting with a gradient of 1-50% CH3CN/water (14 CV). The pure fractions containing the R-isomer (by comparing the retentions times of S-isomer, Example 71A) were pooled, concentrated in vacuo and evaporated from CH3CN (3×5 mL). The solid residue obtained was dissolved in minimal methanol, diluted with CH2Cl2 (1 mL) and treated with 2M HCl in ether (3 mL). The resulting suspension was concentrated in vacuo and evaporated from CH2Cl2 (3×5 mL) and dried under high vacuum for 24 hours to provide (R)-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydro furan-2-carboxamide hydrochloride (16 mg, 21% yield) as a solid. NMR (400 MHz, (CD3)2SO) δ 11.72 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 8.16 (br s, 3H), 7.89 (s, 1H), 4.37 (t, 1H), 3.96-3.91 (m, 1H), 3.85-3.79 (m, 1H), 3.55-3.48 (m, 3H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.28-2.20 (m, 1H), 2.15-2.09 (m, 1H), 1.94-1.81 (m, 5H), 1.48-1.40 (m, 1H); LCMS (APCI+) m/z 408.1, 410.1 (M+H)+, Retention time=2.32 minutes (Method 2).

Quelle