Hydrochloric Acid → HCID 68173591, compound

Temperature

22.5 °C

1-Methyl-1H-tetrazole-5-thiol (5-mercapto-1-methyltetrazole, 23.3 g, 200 mmol) was added to 28.8 g of NaOH-32% and 22.0 g of water. Then (4R,6S)-6-(chloromethyl)-4-hydroxytetrahydropyran-2-one (EP 1404844, 32.9 g, 200 mmol) was added in 1 h at 25-30° C., keeping the pH between 12-12.5 by addition of NaOH-32%. The reaction mixture was stirred at 20-25° C. for 2 h. Then 200 mL of methanol was added and the pH adjusted with concentrated aqueous HCl to 0.7-0.8. The reaction was stirred for 20 h and the pH adjusted to −0.5 with concentrated aqueous HCl. Then methanol/water was removed by distillation under vacuum to give thick oil. To this oil 200 mL of methanol was added, stirred for 1 h and concentrated again. Then 150 mL of methanol was added. The precipitated salts were removed by filtration. The methanol was removed again by distillation under vacuum. Next 320 mL of toluene and 200 mL of 5% aqueous NaCl was added to the residue. The organic layer was separated and about 75 mL removed by distillation. To the clear solution was added methanesulphonic acid (0.96 g, 10 mmol) and 2,2-dimethoxy propane (31.2 g, 300 mmol). The mixture was stirred for approximately 20 h at 20-25° C. Then 200 mL of 0.5 N aqueous NaOH was added. The phases were stirred, separated and the organic phase washed with water (1×100 mL). After concentration of the organic phase, the title compound was obtained as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.40-4.22 (m, 2H), 3.92 (s, 3H), 3.68 (s, 3H), 3.40 (dd, 2H), 2.48 (dd, 2H), 1.74 (dt, 1H), 1.42 (s, 3H), 1.39-1.29 (m, 1H), 1.35 (s, 3H).

1. stirringThe reaction was stirred for 20 h
2. customThen methanol/water was removed by distillation under vacuum
3. customto give thick oil
4. stirringstirred for 1 h
5. concentrationconcentrated again
6. additionThen 150 mL of methanol was added
7. customThe precipitated salts were removed by filtration
8. customThe methanol was removed again by distillation under vacuum
9. additionNext 320 mL of toluene and 200 mL of 5% aqueous NaCl was added to the residue
10. customThe organic layer was separated
11. customabout 75 mL removed by distillation
12. stirringThe mixture was stirred for approximately 20 h at 20-25° C
13. stirringThe phases were stirred
14. customseparated
15. washthe organic phase washed with water (1×100 mL)

ORD record

ord-15e27b1bfed14ae39e302d7a018c1dc7

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09260423B2