Reaktion #73447

Reaktionsgleichung

Methylamine

oxalyl chloride

4-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester

LiOH

→

(±)-4-[1-(5-Cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid methylamide

Lösungsmittel

THF EtOH H2O

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigeis consumed
2. 2
   SonstigeAt this point the reaction is quenched with 1N HCl (2 mL)
3. 3
   Extraktionextracted with EtOAc
4. 4
   SonstigeAfter drying
5. 5
   Sonstigeevaporation
6. 6
   workup.DISSOLUTIONthe crude product is dissolved in DCM (3 mL) at 0° C.
7. 7
   workup.STIRRINGthe reaction stirred for 1 h at rt
8. 8
   ExtraktionAfter work up with water and extraction with EtOAc the crude product
9. 9
   workup.DISSOLUTIONis dissolved in DCM (2 mL)
10. 10
    workup.ADDITIONTFA (1 mL) is added
11. 11
    SonstigeAfter removing the solvent in vacuo
12. 12
    Sonstigethe product is separated
13. 13
    Wascheneluting with DCM:MeOH:NH4OH 100:0:0 to 90:8:2

Vorschrift

To a solution of 4-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (110 mg, 0.196 mmol) in THF/EtOH/H2O (3:1:1 mL) LiOH (0.016 g, 0.392 mmol) is added and the reaction stirred until starting material is consumed. At this point the reaction is quenched with 1N HCl (2 mL) and extracted with EtOAc. After drying and evaporation, the crude product is dissolved in DCM (3 mL) at 0° C., oxalyl chloride (0.026 mL, 0.294 mmol) and DMF (2 drops) are added. At this point Methylamine (2 M in THF) (0.49 mL, 0.981 mmol) is added and the reaction stirred for 1 h at rt. After work up with water and extraction with EtOAc the crude product is dissolved in DCM (2 mL) and TFA (1 mL) is added. After removing the solvent in vacuo, and basifying with NH4OH, the product is separated using FCC eluting with DCM:MeOH:NH4OH 100:0:0 to 90:8:2. MS (ESI) m/z 474.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (s, 1 H)8.43 (s, 1 H)8.21-8.33 (m, 1 H)8.15 (d, J=3.79 Hz, 1 H)7.94 (d, J=5.81 Hz, 1 H)7.44 (d, J=2.27 Hz, 1 H)7.12 (d, J=9.09 Hz, 1 H)6.75 (d, J=3.03 Hz, 1 H)6.65 (s, 1 H) 3.91-4.15 (m, 2 H)3.61 (br. s, 1 H)2.83-2.95 (m, 2 H)2.66 (d, J=4.80 Hz, 3 H)2.12-2.24 (m, 1 H) 1.03-1.17 (m, 2 H)0.94 (dd, J=4.80, 2.53 Hz, 2 H).

Quelle