Ammonium Chloride → (racemic) N-(4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Temperature

-78 °C

Phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 105 mg, 0.222 mmol) and 6-amino-4-(oxetan-2-ylmethoxy)nicotinonitrile (intermediate 34A, 54.7 mg, 0.267 mmol) were dissolved in THF (2 ml) under argon. The resulting solution was cooled to −78° C. and treated slowly with LHMDS (1 M in THF, 0.489 ml, 0.498 mmol). The reaction mixture was stirred at −78° C. for 45 min and then slowly warmed up to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). The 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated and then dissolved in THF (2 ml) and water (2 ml) and treated with conc. HCl (0.39 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was quenched with aq. sat. NaHCO3 and extracted 3× with DCM. The org layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was treated with a small quantity of DCM and then the product was precipitated by addition of heptanes. The solid was collected by centrifugation and dried under vacuum to obtain the title compound as a white solid.

1. temperatureslowly warmed up to room temperature
2. extractionextracted twice with DCM
3. dry with materialThe organic phase was then dried over Na2SO4
4. filtrationfiltered
5. customevaporated
6. customThe crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column)
7. concentrationThe 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated
8. dissolutiondissolved in THF (2 ml)
9. additionwater (2 ml) and treated with conc. HCl (0.39 ml)
10. stirringThe reaction mixture was stirred 16 h at room temperature
11. customThe reaction mixture was quenched with aq. sat. NaHCO3
12. extractionextracted 3× with DCM
13. dry with materialThe org layer was dried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated under vacuum
16. additionThe crude material was treated with a small quantity of DCM
17. customthe product was precipitated by addition of heptanes
18. customThe solid was collected by centrifugation
19. customdried under vacuum

ORD record

ord-6c413dbe06b64c85b7f57c515eb5c2e9

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266883B2