| US 7,566,792 B2 | ||
| Method for the manufacture of Lovastatin | ||
| Sanjay Kumar Vaishnav, Maharashtra (India); Bhupendra Harishchandra Thakur, Maharashtra (India); and Subhash Rajaram Kadam, Maharashtra (India) | ||
| Assigned to Lupin Limited, Mumbai, Maharashtra (India) | ||
| Appl. No. 10/571,192 PCT Filed Oct. 14, 2003, PCT No. PCT/IN03/00333 § 371(c)(1), (2), (4) Date Dec. 20, 2006, PCT Pub. No. WO2005/035515, PCT Pub. Date Apr. 21, 2005. |
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| Prior Publication US 2007/0238885 A1, Oct. 11, 2007 | ||
| Int. Cl. C07D 309/30 (2006.01) | ||
| U.S. Cl. 549—292 | 14 Claims |
1. A method for lactonisation of mevinolinic acid of formula II and isolation of Lovastatin of formula (I):
![]() a) adjusting the pH of a fermentation broth containing mevinolinic acid(II) to 3.5±0.1 with a mineral acid, and optionally
filtering the fermentation broth,
b) adding a hydrophobic solvent to the aqueous fermentation broth or the mycelia cake and bubbling an inert gas into the biphasic
mixture,
c) heating the fermentation broth or the mycelia cake at 55±5° C., in the presence of a hydrophobic solvent, carrying out
lactonisation of mevinolinic acid (II)
![]() and extracting Lovastatin(I) into a hydrophobic solvent, concurrently, in a time period between 12-19 hours, under constant
nitrogen bubbling,
d) isolating impure Lovastatin (I) from said hydrophobic solvent,
e) purifying impure Lovastatin (I) by dissolving impure Lovastatin (I) in a chlorinated solvent followed by removal of suspended
resinous impurities by filtration, adding a hydrophobic solvent, heating the mixture to 55±5° C., evaporating the chlorinated
solvent followed by crystallization from a hydrophobic solvent to give pure Lovastatin (I) of purity≧98.70%, or by dissolving
Lovastatin (I) in a mixture of a chlorinated solvent and a hydrophobic solvent, filtering the suspended impurities, and heating
the mixture to 55±5° C., followed by evaporating the chlorinated solvent and crystallizing from the hydrophobic solvent to
give pure Lovastatin (I) of purity≧98.70%,
f) recrystallising Lovastatin (I), from a aliphatic alcohol, by heating Lovastatin (I) with an aliphatic alcohol between 65
to 75° C. for 30 minutes, cooling the mixture between −5 to +5° C. and filtering crystalline Lovastatin (I) followed by drying
at 35-40° C. to give pure Lovastatin (I) of purity≧99.3%, substantially free from impurities and conforming to pharmacopoeial
specification.
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