Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

Integrin inhibitors based on the tripeptide sequence Arg–Gly–Asp (RGD) are potential therapeutics for the treatment of idiopathic pulmonary fibrosis (IPF). Herein, we describe an expeditious three-step synthetic sequence of Horner–Wadsworth–Emmons olefination, diimide reduction, and global deprotection to synthesise cores for these compounds in high yields (63–83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps.


S3
The solvents employed were: A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution, B = acetonitrile. LC-MS purities are quoted as peak area % (% a/a) seen in the chromatogram. High resolution mass spectra (HRMS) were recorded using an Acquity UPLC CSH C18 column (LC) and Waters XEVO G2-XS QTof (ES+) (MS)
The residue was dissolved in DMF (10 mL) and the flask was charged with potassium carbonate (550 mg, 3.98 mmol). The stirred suspension was heated to 100 °C and benzenesulfonyl hydrazide (514 mg, 2.98 mmol) was added portionwise over 5 min.
The reaction was stirred for 80 min and then cooled to rt. The mixture was partitioned S12 between DCM (50 mL) and sat. LiCl (50 mL
After 10 min additional potassium carbonate (276 mg, 2.0 mmol) was added followed by benzenesulfonyl hydrazide (258 mg, 1.5 mmol) portionwise over 4 min. After 1 h, the reaction mixture was cooled to rt and partitioned between DCM (20 mL) and sat.
LiCl (20 mL). The phases were separated and the aqueous phase was further extracted with DCM (2 × 30 mL). The combined organics were washed with sat. LiCl (70 mL), passed through a hydrophobic frit, and concentrated in vacuo.

S14
The residue was dissolved in 7.4 M HCl (8 mL
The residue was dissolved in DMF (10 mL) and the flask was charged with potassium carbonate (548 mg, 3.97 mmol). The stirred suspension was heated to 100 °C and benzenesulfonyl hydrazide (512 mg, 2.98 mmol) was added portionwise over 5 min.
The reaction mixture was stirred for 75 min and then cooled to rt. The mixture was partitioned between DCM (50 mL) and sat. LiCl (50 mL). The phases were separated and the aqueous phase was extracted with DCM (3 × 40 mL). The combined organics were washed with sat. LiCl (70 mL), passed through a hydrophobic frit, and concentrated in vacuo.