potassium (S)-3-cyano-5-methylhexanoate → Pregabalin

Temperatur

70 °C

A hydrogenator (12000 L) is charged with water (942.1 L) and with the reaction mixture from Example 12, which contains (S)-3-cyano-5-methyl-hexanoic acid potassium salt (Formula 26, 4122.9 L). A Raney nickel suspension (219.6 kg, 50% w/w in H2O) is added. The hydrogenation is conducted under 50 psig at 35° C. After 6 h, the Raney nickel is filtered and the resulting filtrate is transferred to a reactor (16000 L) for crystallization. After adding H2O (1098 L), the pH of the solution is adjusted to 7.0-7.5 using HOAc (864.7 kg). The resulting precipitate is filtered and washed once with H2O (549 L) and twice with IPA (2,586 L each). The solid is recrystallized with IPA (12296 L) and H2O (6148 L). The mixture is heated to 70° C. and subsequently cooled to 4° C. After 5-10 h, the crystalline solid is filtered, washed with IPA (5724 L), and dried in a vacuum oven at 45° C. for 24 h to give pregabalin as a white crystalline solid (1431 kg, 30.0% overall yield, 99.5% purity and 99.75% ee).

1. customis conducted under 50 psig at 35° C
2. filtrationthe Raney nickel is filtered
3. customthe resulting filtrate is transferred to a reactor
4. custom(16000 L) for crystallization
5. additionAfter adding H2O (1098 L)
6. filtrationThe resulting precipitate is filtered
7. washwashed once with H2O (549 L) and twice with IPA (2,586 L each)
8. customThe solid is recrystallized with IPA (12296 L) and H2O (6148 L)
9. temperaturesubsequently cooled to 4° C
10. waitAfter 5-10 h
11. filtrationthe crystalline solid is filtered
12. washwashed with IPA (5724 L)
13. customdried in a vacuum oven at 45° C. for 24 h

ORD-Eintrag

ord-1538b19241684ca2b2246af957873e51

Quelldatensatz

uspto-grants-2011_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08044227B2