Hydrochloric Acid → Trandolaprilat

A solution of NaOH (144.8 g, 3.42 mol; assay=94.5%), water (2573 ml), ethanol (2187 ml) and Trandolapril (680 g, 1.58 mol; assay=99.81%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 18 hours. After an in process control showed an almost complete saponification (by HPLC), the pH of the clear solution was adjusted to 3.8 by addition of 2N aqueous hydrochloric acid at a temperature ranging from about 20° C. to about 25° C. (The solution was seeded according to the general seeding procedure, see Example 2). The suspension was stirred at a temperature ranging from about 20 to about 25° C. for 5.5 hours, and then filtered off, and the wet product was washed with water (2149 ml) and ethanol (2198 ml). Then, a suspension of the wet product in ethanol (6046 ml) was stirred at a temperature ranging from about 38° C. to about 43° C. for 14 hours, and then at a temperature ranging from about 20° C. to about 25° C. for 2 hours. After filtration, the wet product was washed with ethanol (2224 ml) and dried in vacuo (<1 mbar) at 40° C. until the ethanol content was <0.5% (4 days) to give Trandolaprilat as crystalline Form E (yield: 582 g, 1.44 mol, 91.3%; assay (NaOH)=99.74%; HPLC purity: 99.33%, Trandolaprilat diketopiperazine: 0.52%; water content: 0.54%, ethanol content: 955 ppm, chloride content=not detected).

1. customranging from about 20° C. to about 25° C.
2. waitranging from about 20 to about 25° C. for 5.5 hours
3. filtrationfiltered off
4. washthe wet product was washed with water (2149 ml) and ethanol (2198 ml)
5. additionThen, a suspension of the wet product in ethanol (6046 ml)
6. stirringwas stirred at a temperature
7. waitranging from about 38° C. to about 43° C. for 14 hours
8. waitat a temperature ranging from about 20° C. to about 25° C. for 2 hours
9. filtrationAfter filtration
10. washthe wet product was washed with ethanol (2224 ml)
11. dry with materialdried in vacuo (<1 mbar) at 40° C. until the ethanol content
12. custom<0.5% (4 days)

ORDレコード

ord-b847a31459d14ece950e7f42d231c1f7

出典データセット

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07943655B2