Zeranol is an anabolic agent of Formula I. It is widely used in veterinary medicine for promoting weight gain in ruminants and other animals.

Zeranol has been widely used to promote the growth of cattle and other domestic animals to maximize both rate of weight gain and the absolute amount of weight gain per average amount of food consumed, achieving higher feed efficiency.
Zeranol has been commercially available in a formulation known as Ralgro® (Intervet Schering-Plough Animal Health Corporation).
The first process for producing Zeranol, see Urry et al, Tetrahedron Letters, 1966, 27, 3109-3114, was non-specific, and was developed with a two step reduction of zearalenone using two different catalysts, and performing hydrogenation at both atmospheric pressure and elevated pressure. This route is not commercially efficient and no attempts were made to separate the resulting mixture of diastereomers.
Zeranol has been conventionally produced, see GB 1152678, using a single vessel, high pressure, high temperature hydrogenation with a Raney-nickel catalyst. Under these, conditions the ketone and alkene groups are both reduced producing both Zeranol and Taleranol. The resulting product requires multiple recrystallizations for purification and provides low recovery of the preferred Zeranol.
The process for producing Zeranol typically starts with Zearalenone of Formula III (CAS Name: (3S,11E)-3,4,5,6,9,10-hexahydro-14,16-dihydroxy-3-methyl-1H-2-benzoxacyclotetradecin-1,7(8H)-dione, CAS Number: 17924-92-4).

Reduction of the Zearalenone double bond followed by reduction of the ketone gives an equal mixture of the diastereomeric alcohols: Zeranol of Formula I and Taleranol of Formula II.

Separation of Zeranol and Taleranol by crystallization, chromatography or other means then lead to isolation of the desired Zeranol diastereomer. See The Merck Index, 14th Ed., Merck & Co., Inc, NJ, 2006, pp 1745; Urry et al, Tetrahedron Letters, 1966, 27, 3109-3114 and U.S. Pat. No. 3,239,345.
Great Britain Patent 1,152,677 teaches high pressure hydrogenation of Zearalenone with Raney Nickel to afford a mixture of Zeranol and Taleranol. Multiple crystallizations in water and water/IPA mixtures are then required to provide a low yield of Zeranol. This process is inefficient in yield and requires the use of hydrogen at high pressure.
U.S. Pat. No. 3,574,235 teaches a method for separation of the Zeranol and Taleranol diastereomers resulting from the reduction of Zearalenone. This method involves selective crystallization of the undesired Taleranol, followed by dilution and crystallization of the desired Zeranol, then a second crystallization. The yields are poor and the process laborious.
U.S. Pat. No. 3,687,982 teaches a method for reducing Zearalenone to an about 55:45 mixture of the Zeranol and Taleranol diastereomers with Raney Nickel. Separation of Zeranol from Taleranol is achieved by esterification of the aliphatic hydroxyl group, selective crystallization and de-esterification. This multi-step process demonstrates little diastereomeric reduction selectivity and achieves a poor overall Zeranol yield.
U.S. Pat. No. 3,704,248 teaches a method for selective reduction of zearalenone to a mixture of diasteriomers, of which 70% is the lower melting diastereomer, and a reference method for purifying this diastereomer. The low melting diastereomer is less active than the higher melting isomer. This method is not useful for producing the higher melting diastereomer.
U.S. Pat. No. 3,704,249 teaches the selective reduction of Zearalenone or Zearalanone of Formula IV (CAS Name: (3S)-3,4,5,6,9,10,11,12-octahydro-14,16-dihydroxy-3-methyl-1H-2-benzoxacyclotetradecin-1,7(8H)-dione, CAS Number: 5975-78-0)

with a variety of reducing agents, including aluminum alkoxides. The preferred method is to reduce the 2,4 diethers of Zearalenone or Zearalanone with aluminum tri-t-butoxide. No yields are reported. Selectivity is not defined.
U.S. Pat. No. 3,808,233 teaches a method of selective reduction of zearalenone preferentially to the more active diastereomer of Zeranol, by hydrogenation at 50 psi with a platinum catalyst in the presence of a weak acid. Selectivities of about 75:25 are noted, but no results above that selectivity are reported and the hydrogenation required elevated pressures.
U.S. Pat. No. 4,148,808 teaches a method for reduction of Zearalenone with Raney nickel in isopropanol, followed by introduction of hydrogen and further reduction of the double bond. This patent discusses the concept of slow distillation of solvent to enhance selectivity, but the best enhancement provides only a 65:35 Zeranol to Taleranol selectivity that is contaminated with unreacted Zearalanone.
Snatzke et al. reported a method for diastereoselective reduction of the dibenzylderivative of zearalenone with a chiral borane complex, followed by separation of the diastereomers by chromatography and further hydrogenation with Raney nickel. The starting material must be prepared from zearalenone in an extra synthetic step. The chiral borane complex is prepared in a multistep process. This multi-step process is not as efficient as a more direct process. (PECS Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. [Prod] 3rd (1987), Meeting Date 1985, 4, 294-298). More detail is provided in Helv. Chim. Acta, 1986, 69, 734-748, and additional chiral boranes are described, but the process suffers from the limitations noted above.
Sharkawy and Abul-Hajj (J. Org. Chem. 1988, 515-519) describe a process for microbial reduction of zearalenone to Zeranol in 20% yield.
EU 332047 (a published patent application) discloses a method for separating the diastereomers of Zeranol by crystallization from acetonitrile.
French Patent 2,668,487, teaches an economical process to reduce zearalenone to Zeranol using hydrogen and a nickel-aluminum catalyst. It results in a 50:50 mixture of diastereomers that must be separated through further crystallization.
Sunjic et al., Enzyme Microb. Technol., 1991, 13, 344-348, report the reduction of Zearalenone and Zearalanone to mixtures of Zeranol and Taleranol with some selectivity, but in low yield. This process is not practical at an industrial scale because of poor yields and the need to separate the diastereomers after reduction.
U.S. Pat. No. 5,136,056 teaches a process for catalytic reduction of Zearalenone with Raney nickel followed by double recrystallization of the mixture of Zeranol and Taleranol diastereomers. Mother liquors of each recrystallization are recycled, sometimes with additional chemical steps, to provide an overall high throughput of material to the desired Zeranol.
Sunjic (Tetrahedron, 1992, 48, 6511-6520) reports a method for separation of the acyl esters of the diastereomeric mixture of Zeranol by enzymatic kinetic separation using lipases.
In view of the prior art described above, the present invention teaches a new and novel process for manufacturing Zeranol that provides an almost three fold increase in yield and selectivity to Zeranol of 85:15 to Taleranol. The invention teaches a safe, economical and efficient process for commercial manufacture of Zeranol.
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