반응 #2148351

반응 방정식

picolinic acid

HATU

DIPEA

Na2SO4

17

(E)-1-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-2-hydroxyguanidine

→

precipitate

수율 33.0%

1,7-dimethyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one

수율 33.0%

용매

DMF

반응 조건

후처리

1. 1
   기타The consumption of 17
2. 2
   workup.ADDITIONAdditional anhydrous DMF (50 mL) was added
3. 3
   여과Solid was filtered off and most of DMF
4. 4
   기타was removed under vacuum
5. 5
   기타The residue was partitioned between a mixture of water (200 mL), aqueous Na2CO3 (2 M, 20 mL), EtOAc (300 mL) and MeOH (30 mL)
6. 6
   세척The organic phase was washed further with water (2×50 mL)
7. 7
   기타After drying
8. 8
   기타removal of EtOAc
9. 9
   workup.ADDITIONthe residue was treated with mixtures of DCM/MeOH (30 mL/3 mL)
10. 10
    세척washed with DCM

실험 절차

To a solution of picolinic acid (1.35 g, 11 mmol), HATU (4.18 g, 11 mmol) and DIPEA (2.09 mL, 12 mmol) in dry DMF (50 mL) at rt in the presence of anhydrous Na2SO4 (7 g, 50 mmol) was added 17 (3.37 g, 10 mmol) slowly. The consumption of 17 was determined to be completed by LC/MS. Additional anhydrous DMF (50 mL) was added and the mixture was heated at 100° C. for 16 h. Solid was filtered off and most of DMF was removed under vacuum. The residue was partitioned between a mixture of water (200 mL), aqueous Na2CO3 (2 M, 20 mL), EtOAc (300 mL) and MeOH (30 mL). The organic phase was washed further with water (2×50 mL). After drying and removal of EtOAc, the residue was treated with mixtures of DCM/MeOH (30 mL/3 mL) and washed with DCM to yield A52 as a solid precipitate (1.4 g). The mother liquor was purified by silica gel chromatography (8% MeOH in DCM) to remove most impurities. Most fractions containing product were combined to obtain solid product which was further trituated in ACN (60 mL) and washed several time with ACN to give 0.9 g of product A52. Fractions containing some product but more impurities were combined to get a crude residue which was purified with preparative HPLC to recover an additional 0.3 g A52. All three batches of 1,7-dimethyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A52) had identical NMR and LC/MS. 1H NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.83 (m, 2H), 8.18 (dt, J=8.8, 1 Hz, 1H), 8.1 (td, J=7.7, 1.7 Hz, 1H), 7.97 (s, 1H), 7.71 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 7.47 (dd, J=8.3, 2.4 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.66 (s, 3H), 3.34 (s, 3H), 2.01 (s, 3H). MS m/z 425.1 (M+1).

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