AU2006203346B8 - Improved oxidation process and use thereof - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE

SPECIFICATION

STANDARD

PATENT

Invention Title: Improved oxidation process and use thereof The following statement is a full description of this invention, including the best method of performing it known to us: 004816478.

2 Improved Oxidation process and use thereof Field of the invention The present invention relates to processes for oxidising secondary alcohols, in particular the 23-hydroxy group of 5-O-protected-LL-F28249-a compounds.

Background of the invention Moxidectin (23-methoxime-LL-F28249-a) is a potent endectocidal agent. An important step in the manufacture of moxidectin is the oxidation of the 5-O-protected-LL-F28249-a intermediate compound. Oxidizing agents which may be used in this manufacturing step are disclosed in US 4,988,824.

Summary of the invention None of the oxidizing agents or oxidizing agent systems disclosed in US 4,988,824 include supported oxidizing agents such as polymer-supported agents or solidsupported agents. The use of supported oxidizing agents offers the ability of introducing a selective, mild, high yielding oxidation step into the moxidectin manufacturing process.

Moreover, in many cases the supported oxidizing agent may be recycled, thus minimizing the production and handling of waste products.

This invention seeks to provide an improved oxidation process for the production of moxidectin, which affords mild reaction conditions and high product yields.

It is a feature of particular embodiments of this invention that the oxidation process may utilize a recyclable oxidizing reagent.

In a first aspect, the present invention provides a process for the selective oxidation of a 5-O-protected-LL-F28249-a compound of formula II 004816478.

wherein R is a protecting group, to the corresponding 23-keto compound of formula I

(I)

wherein R is as described for formula II, which process includes reacting said formula II compound with a supported oxidizing reagent, optionally in the presence of a solvent.

Preferably, the supported oxidizing agent is a polymer-supported oxidizing agent or a solid-supported oxidizing agent.

Optionally, the supported oxidizing agent is selected from the group consisting of: poly(styrene-co-4-vinyl methyl sulfoxide); poly(styrene-co-4-vinyl benzyl 3- [methylsulfinyl]propanoate); polymer-supported pyridinium chlorochromate; polymer- 004816478.

4 supported pyridinium dichromate; polystyrene-supported 4-hydroxyiodobenzene diacetate; polymer-supported permanganate; and polystyrene-supported perruthenate.

Alternatively, the supported oxidising agent is selected from the group consisting of: BaMnO 4 AI20 3

K

2 FeO 4

AI

2 0 3

K

2 MnO 4 -AI20 3 alumina-supported pyridinium chlorochromate; alumina-supported pyridinium dichromate; silica-supported pyridinium chlorochromate; silica-supported pyridinium dichromate; pyridinium chlorochromate supported on Cu(II)S0 4 chromium trioxide supported on solid NaHSO 4 H20; pyridinium dichromate supported on molecular sieves; and pyridinium dichromate supported on Zeolite 3A.

Also provided is the use of the improved oxidation process in the manufacture of moxidectin.

The present invention will now be described with reference to particular embodiments and examples. Nothing in the following discussion is intended to limit the scope of the invention as claimed.

Detailed description of the embodiments Moxidectin is a potent broad-spectrum endectocide of the macrocyclic lactone antimicrobial class. The unique activity of moxidectin against endo- and ectoparasites in both humans and animals, along with its high margin of safety, has had a tremendous impact on the control of internal and external parasites in companion animals and livestock. Therefore, availability of this compound is highly desired. Moxidectin is the 23oxime derivative of LL-F28249-a. A process for the manufacture of moxidectin from LL- F28249-a is disclosed in US 4,988,824, which is incorporated herein by reference. Said process includes an oxidation step wherein the oxidizing agents disclosed are conventional agents such as pyridinium dichromate, aluminium t-butoxide, obenzoquinone, phosphorous pentoxide, dicyclohexylcarbodiimide, manganese dioxide, acetic anhydride, dimethyl sulfoxide and the like or mixtures thereof. Some common difficulties encountered in using these reagents, such as long reaction times, difficult 00481647& workup procedures, possible use of a large excess of the oxidizing agent, and the like, can be problematic on a commercial manufacturing scale.

Surprisingly, it has now been found that a supported oxidizing agent may be used to selectively oxidize a 5-O-protected-LL-F28249-a compound to the corresponding protected-23-ketone compound. Advantageously, in preferred embodiments this oxidation may occur under mild reaction conditions, with high product yield and without the hazardous chemical properties generally associated with conventional oxidizing agents.

Accordingly, the present invention provides an improved process for the selective oxidation of a 5-0-protected-LL-F28249-oa compound of formula II

OH

H 23 H

SCH

3

C

H HI j'H SOH AH

CH

R

(oI) wherein R is a protecting group, to the corresponding 23-keto compound of formula I 004816478.

wherein R is as described for formula II, which process includes reacting said formula II compound, with a supported oxidizing reagent, optionally in the presence of a solvent.

The reaction is shown in flow diagram I wherein R represents a protecting group.

FLOW DIAGRAM I o01 Supported Oxidizing Agent

(II)

Supported oxidizing agents suitable for use in the process of the invention include polymer supported oxidizing agents. Useful polymer-supported oxidizing agents include polymer-supported and co-polymer-supported sulfoxides such as polystyrene-supported sulfoxides or polyethylene glycol-supported sulfoxides, including poly(styrene-co-4-vinyl methyl sulfoxide), poly(styrene-co-4-vinyl benzyl 3-[methylsulfinyl]propanoate), or the 00481647.8 7 like (Bioorganic Medicinal Chemistry Letters, 12 (2002) 1791-1793 and Tetrahedron 59 (2003) 7171-7176); 4-(N-t-butylchloro- sulfonimidoyl)polystyrene (Chemistry Letters, (2002), 250-251 and Bull Chem. Soc. Jpn., 76 (2003) 1433-1440); polymersupported pyridinium chromates such as polymer-supported pyridinium chlorochromate, polymer-supported pyridinium fluorochromate, polymer-supported pyridinium dichromate or the like (Journal of Organic Chemistry, 43 (1978) 2618; Synthetic Communications 30 (2000) 4397-4404 and Journal of the American Chemical Society, 107 (1985) 4792); polystyrene-supported 4-hydroxyiodobenzene diacetate (Bioorganic and Medicinal Chemistry Letters 12 (2002) 2047-2049); polymer-supported permanganate (Journal of Macromolecular Science, Pure and Applied Chemistry (2003) 1035-1105); polystyrene-supported perruthenate (Synthesis 1998, 977); or the like. Supported oxidizing agents suitable for use in the process of the invention also include solid-supported oxidizing agents, such as alumina-supported oxidizing agents such as BaMnO 4 Al 2 0 3 (Tetrahedron Letters, 30 (1989) 2559); K 2 FeO 4 A1 2 0 3 (Tetrahedron Letters, 27 (1986) 2875); K 2 MnO 4

AI

2 0 3 (Tetrahedron Letters, 30 (1989) 2559); alumina-supported pyridinium chlorochromate (Synthesis (1980) 223-4); alumina-supported pyridinium dichromate; or the like; or silica-supported oxidizing agents, such as silica-supported pyridinium chlorochromate (Journal of Organic Chemistry, 58 (1993) 2966-71); silica-supported pyridinium dichromate; or the like.

Other solid-supported oxidizing agents considered for use in the process of the invention include pyridinium chlorochromate supported on copper(l )sulfate(Asian Journal of Chemistry, 17 (2005) 2810); chromium trioxide supported on solid NaHSO 4

H

2 0 (Letters in Organic Chemistry, 6 (2005), 544); pyridinium chlorochromate supported on molecular sieves Chem Soc., Perkin Trans 1(1982) 1967-1973); pyridinium dichromate supported on molecular sieves (Journal of Organic Chemistry, 58 (1993) 165); pyridinium dichromate supported on Zeolite 3A (Tetrahedron Letters, 31 (1990) 1735); or the like.

As used in the specification and claims, the term protecting group designates pnitrobenzoyl, acetyl, benzyl, methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, p-methoxybenzyloxymethyl, o-nitrobenzylmethyl, onitrobenzyl-oxymethyl, 4-methoxyphenoxymethyl, guaiacolmethyl, t-butoxymethyl,4pentenyloxymethyl, siloxymethyl, 2-ethoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- 004816478.

O 8 (trimethylsilyl)ethoxymethyl, trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, or any protecting group known to protect an hydroxy group in organic synthesis, preferably pnitrobenzoyl.

The supported oxidizing agent in an amount of at least one molar equivalent may be admixed with a compound of formula II, optionally in the presence of a solvent, at a temperature range of about 20 0 C to the reflux temperature of the solvent, until oxidation is complete. Reaction times for the process of the invention may vary according to the supported oxidizing agent used, the concentration of the formula II compound, the reaction temperature, or the like. In general reaction times of one hour or less are sufficient. For optimum product yield, at least 1.0, preferably about 1.0 1.5 molar equivalents of the supported oxidizing agent is suitable for use in the inventive process.

Advantageously, the oxidation process of the invention may be used in the manufacture of moxidectin. Accordingly, the present invention further provides a process for the manufacture of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a to give the compound of formula II; 2) oxidizing said formula II compound by a process as described above to give the ketone of formula I 3) reacting said formula I ketone with methoxylamine or a salt thereof to give the compound of formula III; and 4) deprotecting said formula III compound to yield the moxidectin product.

Alternatively, the compound of formula I may be deprotected to give the compound of formula IV and the formula IV compound may be reacted with methoxylamine or a salt thereof to give the desired moxidectin product. Accordingly, the invention also provides a process for the manufacture of moxidectin including: 004816478; S9 1) protecting the 5-hydroxy group of LL-F28249-a to give the compound of Sformula II; 2) oxidizing said formula II compound by a process as described above to give the ketone of formula I; 5 3) deprotecting said formula I ketone to give the compound of formula IV; and

IN

S4) reacting said formula IV compound with methoxylamine or a salt thereof to

C

yield the moxidectin product.

Preferably, the deprotection reactions are performed in the presence of a base.

The processes of the invention are described with reference to the embodiments shown in flow diagram II, wherein R is a protecting group as described hereinabove.

0048 1647Q Flow Diagram 11 Protection (LL-F2849-alpha) Supported Oxidizing Agent

CH

3

ONH

2

-HCI

(111) Base 1 Deprotection 'Base, Deprotection

CH

3

ONH

2

-HCI

(Moxidectin) 004816478 11 In the depicted embodiments, protection of the 5-hydroxy group of LL-F28249-a is achieved by the reaction of LL-F28249-a with a halide precursor of a protecting group as described hereinabove, for example p-nitrobenzoyl chloride, trimethylsilyl chloride, methoxymethylbromide, or the like, preferably p-nitrobenzoyl chloride, in the presence of an organic solvent such as toluene, methylene chloride, ethyl acetate, acetonitrile, or the like, preferably, toluene and an organic base such as pyridine, triethylamine, Nmethylpyrrolidone, or the like, preferably triethylamine. Oxidation of the protected LL- F28249-a compound of formula II is successfully achieved using the improved oxidation process described hereinabove, i.e. reacting said formula II compound with at least one molar equivalent of a supported oxidizing agent optionally in the presence of a solvent to give the ketone of formula I. The formula I compound (either isolated and purified or as a solution of the crude reaction product in an organic solvent, such as toluene) is reacted with an aqueous solution of methoxylamine or a salt thereof and sodium acetate to give the protected moxidectin compound of formula III. Deprotection is achieved by reacting a solution of said formula III compound in an organic solvent such as toluene, dioxane, n-butanol or the like, preferably dioxane, with an aqueous solution of sodium hydroxide at 0 0 -25 0 C and isolating the desired moxidectin product from the organic phase using standard procedures such as concentration and filtration or removal of the solvent.

In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof. In the following examples, unless otherwise noted, all parts are parts by weight. The terms HPLC and HNMR designate high performance liquid chromatography and proton nuclear magnetic resonance spectroscopy, respectively.

004816478 12 EXAMPLE 1 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Polymer- Supported Sulfinimidoyl Chloride And Recycling of the Oxidizing Agent A stirred suspension of the 4-(N-t-butylchlorosulfonimidoyl)polystyrene (0.72 mmol/g, 540 mg, 0.39 mmol) in methylene chloride is treated with a solution nitrobenzoyl)-LL-F28249-a (144.6 mg, 0.19 mmol) and di-isopropylethylamine (50 mg, 0.39 mmol) in methylene chloride at -78 0 C, stirred at -78 0 C for 30 minutes and quenched with a solution of di-isopropylethylamine (50 mg, 0.39 mmol) in ethanol. The reaction mixture is filtered through Celite® and the filtercake is washed with methylene chloride. The combined filtrates are concentrated under reduced pressure to give the title product.

The washed filtercake is dried under vacuum for two hours, suspended in methylene chloride, treated with a solution of N-chlorosuccinimide (60 mg, 0.45 mmol) in methylene chloride at room temperature and stirred for one hour to regenerate the oxidizing agent. The thus-regenerated oxidizing agent may be used directly for further oxidations.

EXAMPLE 2 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using a Catalytic Amount of Polymer-Supported Sulfinimidoyl Chloride and N-Chloro- succinimide A stirred suspension of potassium carbonate (950 mg, 6.87 mmol), 4 Angstrom molecular sieves (687 mg), N-chlorosuccinimide (184 mg, 1.38 mmol) and 4-(N-tertbutylchlorosulfonimidoyl)polystyrene (1.25 mmol/g, 0.11 g) in methylene chloride is treated with a solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (525 mg, 0.69 mmol) in methylene chloride at 0°C, stirred overnight at room temperature and filtered through a Celite® pad. The filtercake is washed with methylene chloride. The filtrates are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title product.

004816478 13 EXAMPLE 3 Preparation of 23-Keto-5-O-(D-n itrobenzoyl)-LL-F28249-a Using Poly(styrene-co-4vinviphenvi Methyl Sulfoxide) A solution of poly(styrene-co-4-vinylphenyl methyl sulfoxide) (2.37 g, 2.0 mnmol) in methylene chloride at -70 0 C is treated dropwise with oxalyl chloride 25.2 mg, 0.19 mol), stirred for 30 minutes, treated with a solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 mg, 1.00 mmol) in methylene chloride, stirred at -70 0 C to -400 C for 1 hour, and treated with triethylamine (30.3 mg, 3.00 mmol). The reaction mixture is held at -40 0

C

for 1 hour, allowed to warm to room temperature and is concentrated in vacuo. The resultant residue is dispersed in tetrahydrofuran, poured into cold hexanes (to precipitate the polymer) and filtered through Celiteo. The filtercake is washed with hexane. The filtrates are combined and concentrated under reduced pressure to give the title product.

EXAMPLE 4 Preparation of 23-Keto-5-O-f P-n itrobenzoyl)-LL-F28249-a Using Polly(styrene-co-4vinylphenyl 3-rMethylsullfinylipropanoate Using essentially the same procedure described in Example 3 and employing poly(styrene-co-4-vinylphenyl 3-[methylsulfinyljpropanoate) as oxidant, the title product is obtained.

EXAMPLE Preparation 23-Keto-5-0-(P-nitrobenzoyl)-LL-F28249-a Using Polly(vinyllpyrid in jum Dich romate) A suspension of poly(vinylpyridiniumn dichromate) (1 gram, 2.2 mmol/g, 100-200 mesh) in hexanes is treated with 5-O-(p-nitrobenzoyl)-LL-F28249-ca (0.761 mg, 1.00 mmol) in hexanes, heated to reflux temperature, stirred for 6-8 hours, cooled to room 004816478 14 temperature and filtered through Celite. The filtercake is washed with hexanes. The filtrates are combined and concentrated under reduced pressure to give the title product.

EXAMPLE 6 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Poly(vinylpyridinium Chlorochromate) A suspension of poly(vinylpyridinium chlorochromate)_(380 mg, 3.5 mmol/g, 100-200 mesh) in hexanes is treated with 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 mg, 1.00 mmol) in hexanes, heated to reflux temperature, stirred for 6-8 hours, cooled to room temperature and filtered through Celite®. The filtercake is washed with hexanes. The filtrates are combined and concentrated under reduced pressure to give the title product.

EXAMPLE 7 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Poly(vinvlpyridinium fluorochromate) Using essentially the same procedure described in Examples 5 and 6 and employing poly(vinylpyridinium fluorochromate) as oxidant, the title product is obtained.

EXAMPLE 8 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Polymer-Bound 4- Hvdroxyiodobenzene Diacetate A suspension of polymer-bound 4-hydroxyiodobenzene diacetate (650 mg, 0.5-1.5 mmol/g,100-200 mesh) in methylene is treated with 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 mg, 1.00 mmol) in methylene chloride, stirred at room temperature for 8 hours and filtered. The filtercake is washed with methylene chloride. The filtrates are combined and concentrated under reduced pressure to give the title product.

004816478' EXAMPLE 9 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Polymer-Bound Permanganate A suspension of polymer-bound quaternary ammonium permanganate (1000 mg, 2.0 mmol/g,16-50 mesh) in acetonitrile is treated with 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 mg, 1.00 mmol) in acetonitrile, stirred at room temperature for temperature for 8 hours and filtered. The filtercake is washed with acetonitrile. The filtrates are combined and concentrated under reduced pressure to give the desired product.

EXAMPLE Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Polymer- Supported Perruthenate A stirred solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (1.52 mg, 0.20 mmol) in toluene is treated with polymer-supported perruthenate(200 mg, 0.02 mmol, 16-50 mesh), heated at 75-80 0 C under oxygen for 8 hours, cooled to room temperature and filtered.

The filtercake is washed with toluene. The filtrates are combined and concentrated under reduced pressure to give the title product.

EXAMPLE 11 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Alumina- Supported Pyridinium Chlorochromate A suspension of alumina-supported pyridinium chlorochromate_(2.2 gram, 2.00 mmol weight percent) in 10 methylene chloride is treated with F28249-ca (0.761 mg, 1.00 mmol) in methylene, stirred at reflux temperature 8 hours, cooled to room temperature and filtered through a pad of Celite®. The filtercake is washed with methylene chloride. The filtrates are combined and concentrated under reduced pressure to give the title product.

004816478 16 EXAMPLE 12 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Silica-Supported Pyridinium Chlorochromate Using essentially the same procedure described in Example 11 and employing silicasupported pyridinium chlorochromate as oxidant, the title product is obtained.

EXAMPLE 13 Preparation of 23-Keto-5-O-(p-nitrobenzovl)-LL-F28249-a Using Pyridinium Dichromate With Molecular Sieves A solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (1 mmol) in dichloromethane is treated with pyridinium dichromate (0.56 g, 1.5 mmol), freshly activated molecular sieve powder (0.8 g, 3 angstrom), and acetic acid (0.1 mL, anhydrous), stirred for 16 minutes, treated with Celite®, stirred for 20 minutes and filtered. The filtrate is evaporated under reduced pressure, with added toluene to ensure removal of pyridine and/or acetic acid. The resulting residue is treated with diethyl ether or ethyl acetate, filtered through MgSO 4 (anhydrous, powdered), and evaporated under reduced pressure to give the title product.

EXAMPLE 14 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Pyridinium Chlorochromate With Molecular Sieves A mixture of pyridinium chlorochromate (0.43 g, 2 mmol), F28249-a (0.761 g, 1 mmol), and 3 angstrom molecular sieves (1 g) in anhydrous dichloromethane is vigorously stirred under nitrogen for 1.5 hours, or until all of the starting alcohol is consumed. The reaction mixture is diluted with diethyl ether, the liquid is decanted and filtered through a sintered glass funnel containing 10% sulfated silica 004816478 17 gel. The filtercake is washed with diethyl ether. The filtrates are combined and concentrated in vacuo to give the title product.

EXAMPLE Preparation of 23-Keto-5-0-(p-nitrobenzoyl)-LL-F28249-a Using Chromium Trioxide Supported With Sodium Hydrogen Sulfate Monohydrate Without Solvent A mixture of 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 g, 1 mmol) and sodium hydrogensulfate monohydrate supported chromium trioxide reagent (0.25 g, Cr0 3 content 5 mmol) is vigorously shaken at room temperature for 4 hours. The reaction mixture is triturated with methylene chloride and filtered through a pad of Celite®. The filtercake is washed with methylene chloride. The filtrates are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title product.

EXAMPLE 16 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Chromium Trioxide Supported With Sodium Hydrogen Sulfate Monohydrate A solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.761 g, 1 mmol) in anhydrous acetone is treated with sodium hydrogensulfate monohydrate supported chromium trioxide reagent (0.25 g, Cr0 3 content 5 mmol), stirred at room temperature for 4 hours and filtered through a pad of Celite®. The filtercake is washed with acetone. The filtrates are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title product.

EXAMPLE 17 Preparation of Moxidectin A solution of LL-F28249a (6.36 g, 10.4 mmole) in methylene chloride is treated with pyridine (1.98 g, 25.0 mmole) and p-nitrobenzoyl chloride (2.45 g, 13.2 mmole) at 004816478' 0 18 0 25 0 C, stirred for 4 hours at 2 0 -25 0 C, treated with saturated sodium bicarbonate and methylene chloride and stirred until solution is complete. The phases are separated, the organic phase is washed sequentially with saturated sodium bicarbonate, hydrochloric acid, and saturated sodium chloride and concentrated in vacuo to give \0 5 (p-nitrobenzoyl)-LL-F28249-a.

A suspension of poly(vinylpyridinium dichromate) (10 gram, 2.2 mmol/g,100-200 mesh) in hexanes is treated with 5-O-(p-nitrobenzoyl)-LL-F28249-a (7.61 mg, 10.0 mmol) in O hexanes, heated at reflux temperature for 8 hours, cooled to room temperature and filtered through Celite®. The filtercake is washed with hexane. The filtrates are combined and concentrated under reduced pressure to give 5-O-(p-nitrobenzoyl)-23keto-LL-F28249-a.

A solution of 23-keto-5-0-(p-nitrobenzoyl)-LL-F28249-a (7.59 g, 10 mmole) in toluene is treated with a solution of methoxylamine hydrochloride (1.25 g,15 mmole) and sodium acetate (1.23 g,15 mmole) in water and stirred at 20 0 -25 0 C for 10 hours. The phases are separated. The organic phase is washed with water and concentrated under reduced pressure to give 23-methoxime-5-0-(p-nitrobenzoyl)- LL-F28249-a.

A mixture of 23-methoxime-5-0-(p-nitrobenzoyl)- LL-F28249-ao (12.64 g, 8.0 mmol) in dioxane is treated dropwise with 4% NaOH (24.0 g, 3.0 mmol NaOH) at 80-120 C, stirred for 3 hours at 80-120 C, treated with toluene and water, and stirred for 5 minutes at ambient temperatures. The phases are separated and the organic phase is washed with NaCI and concentrated in vacuo to give 23-methoxime-LL-F28249-a (moxidectin).

It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art 004816478 I 19 Scould reasonably be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims (11)

1. A process for the selective oxidation of a 5-O-protected-LL-F28249-a compound of formula II (H) wherein R is a protecting group, to the corresponding 23-keto compound of formula I wherein R is as defined for formula II, which process includes reacting said formula II compound with a supported oxidizing reagent, optionally in the presence of a solvent.

2. A process according to claim 1 wherein said supported oxidizing agent is a polymer-supported oxidizing agent or a solid-supported oxidizing agent. 004816478 0 21 0

3. A process according to claim 1 or 2 wherein said supported oxidizing agent is selected from the group consisting of: poly(styrene-co-4-vinyl methyl sulfoxide); poly(styrene-co-4-vinyl benzyl 3-[methylsulfinyl]propanoate); polymer-supported pyridinium chlorochromate; polymer-supported pyridinium dichromate; polystyrene- 5 supported 4-hydroxyiodobenzene diacetate; polymer-supported permanganate; and c polystyrene-supported perruthenate. N 4. A process according to claim 1 or 2 wherein said supported oxidizing agent is selected from the group consisting of: BaMnO 4 AI203; K 2 FeO 4 A1 2 0 3 K 2 MnO 4 Al 2 0 3 alumina-supported pyridinium chlorochromate; alumina-supported pyridinium dichromate; silica-supported pyridinium chlorochromate; silica-supported pyridinium dichromate; pyridinium chlorochromate supported on Cu(ll)S0 4 chromium trioxide supported on solid NaHSO 4 H 2 0; pyridinium dichromate supported on molecular sieves; and pyridinium dichromate supported on Zeolite 3A. A process according to claim 2 wherein said polymer supporting the oxidizing agent is polyethylene glycol or polystyrene.

6. A process according to claim 2 wherein said solid supporting the oxidizing agent is selected from the group consisting of: alumina, silica, NaHSO 4 H 2 0; Cu(II)S0 4 molecular sieves; and Zeolite 3A.

7. A process according to any one of the preceding claims wherein R is p- nitrobenzoyl.

8. A process for the manufacture of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a to give the compound of formula II 004816478 wherein R is a protecting group; 2) oxidizing said formula II compound by a process according to any one of claims 1 to 6 to give the ketone of formula I (I) wherein R is as defined for formula II; 3) reacting said formula I ketone with methoxylamine or a salt thereof to give the compound of formula III 004816478 0 23 CH, Cliz 23 H -OCH CH H 'O I OH A H CKl (III) wherein R is as defined for formula II; and 4) deprotecting said formula III compound to yield the moxidectin product.

9. A process according to claim 8 wherein said formula III compound is deprotected in the presence of a base. A process for the manufacture of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a to give the compound of formula II OH H Iii 3 S C CH H (R33 wherein R is a protecting group 004816478 24 2) oxidizing said formula II compbund by a process according to any one of claims 1 to 6 to give the ketone of formula I wherein R is as defined for formula II; 3) deprotecting said formula I ketone to give the compound of formula IV (IV) and 4) reacting said formula IV compound with methoxylamine or a salt thereof to yield the moxidectin product. 1 004816478

11. A process according to claim 10 wherein said formula I ketone is deprotected in the presence of a base.

12. A process according to any one of the preceding claims, further including recycling the supported oxidizing agent.

13. A process according to claim 1, substantially as described herein with reference to any one of the examples.

14. A process according to claim 8 or 10, substantially as described herein with reference to any one of the examples. A moxidectin product whenever produced by a process according to any one of claims 8 to11, or14. Dated: 4 August 2006 Freehills Patent Trade Mark Attorneys Patent Attorneys for the Applicant: Wyeth