Lefamulin synthesis

11synthesis methods

Product Name:Lefamulin
CAS Number:1061337-51-6
Molecular formula:C28H45NO5S
Molecular Weight:507.73

Lefamulin, also known as BC-3781, is a semi-synthetic compound that inhibits the synthesis of bacterial protein, which is required for bacteria to grow. Lefamulin acts by binding to the peptidyl transferase center, or PTC, on the bacterial ribosome in such a way that it interferes with the interaction of protein production at two key sites known as the “A” site and the “P” site, resulting in the inhibition of bacterial proteins and the cessation of bacterial growth. Lefamulin’s binding occurs with high affinity, high specificity and at molecular sites that are different than other antibiotic classes. Lefamulin exhibited MIC50 and MIC90 values of 0.12 and 0.25 μg/ml, respectively, against the entire collection (n = 822). Similar results were obtained for lefamulin against each of the most common serotypes as well as against multidrug-resistant isolates and strains that are nonsusceptible to ceftriaxone or erythromycin. Lefamulin may be useful for the treatment of community-acquired respiratory tract infections. Synthetic Description Reference: Heilmayer, Werner; Mang, Rosemarie; Badegruber, Rudolf; Stickmann, Dirk; Novak, Rodger; Ferencic, Mathias; Bulusu, Atchyuta Rama Chandra Murty. Synthesis of pleuromutilin derivatives for the treatment of diseases mediated by microbes. MX 2010009451. (2012). Synthetic Description Reference: Mang, Rosemarie; Heilmayer, Werner; Spence, Lee. Process for the preparation of pleuromutilins. Assignee Nabriva Therapeutics AG, Austria. EP 2399904. (2011). Synthetic Description Reference: Riedl, Rosemarie; Heilmayer, Werner; Spence, Lee. Process for the preparation of pleuromutilins in crystalline form. Assignee Nabriva Therapeutics AG, Austria. WO 2011146954. (2011).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

Reference: Heilmayer, Werner; Mang, Rosemarie; Badegruber, Rudolf; Stickmann, Dirk; Novak, Rodger; Ferencic, Mathias; Bulusu, Atchyuta Rama Chandra Murty. Synthesis of pleuromutilin derivatives for the treatment of diseases mediated by microbes. MX 2010009451. (2012).

5709-98-8 Synthesis

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Yield:-

Steps:

Multi-step reaction with 7 steps
1.1: triethylamine; diphenyl phosphoryl azide / toluene / 0.58 h / 20 - 95 °C / Reflux
2.1: copper(l) chloride / 0.83 h / 80 - 100 °C
3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3.5 h / 15 - 40 °C / Industry scale
4.1: tetrabutyl-ammonium chloride / toluene / 4 h / 30 - 45 °C / Industry scale
5.1: hydrazine hydrate; DL-dithiothreitol / dichloromethane / 3 h / 18 - 22 °C / Industry scale
6.1: sodium hydroxide / benzyltri(n-butyl)ammonium chloride / water; tert-butyl methyl ether / 3 h / 17 - 23 °C / Industry scale
7.1: phosphoric acid / isopropyl alcohol / 16 h / 50 °C / Industry scale
7.2: 1.5 h / 0 - 25 °C / Industry scale

References:

NABRIVA THERAPEUTICS AG;RIEDL, Rosemarie;HEILMAYER, Werner;SPENCE, Lee WO2011/146954, 2011, A1