AU2006100664B4 - Oxidation process and use thereof - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION INNOVATION PATENT Invention Title: 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: 004817905 2 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-oa 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 oxidizing agents which are suitable for solvent-free reaction conditions. The use of oxidizing agents suitable for solvent-free reaction conditions offers the ability of introducing a selective, mild, high yielding oxidation step into the moxidectin manufacturing process, which has minimal environmental impact and minimal disposal costs. Further, an oxidizing agent system which allows for the use of a stoichiometric amount of a co-oxidant, or the use of a recyclable co-oxidant, in a manufacturing process would be highly desirable.

This invention seeks to provide an 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 be economical and have minimal environmental impact.

The present invention provides a process for the selective oxidation of a LL-F28249-a compound of formula II 004880987 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 halochromate oxidizing agent selected from the group consisting of: pyridinium fluorochromate; quinolinium fluorochromate; and fluorochromate.

The present invention also provides a process for the selective oxidation of a protected-LL-F28249-a compound of formula II 004817905 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 halochromate oxidizing agent in the presence of a co-oxidant.

Also provided is the use of the above oxidation processes in the manufacture of moxidectin and moxidectin products whenever produced by such processes.

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.

004817905

INO

0 0 Detailed description of the embodiments

(N

t 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 Slivestock. 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 NO process includes an oxidation step wherein the oxidizing agents disclosed are conventional agents such as pyridinium dichromate, aluminum t-butoxide, obenzoquinone, phophorous 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 workup procedures, possible use of a large excess of the oxidizing agent, and the like, can by problematic on a commercial manufacturing scale.

Surprisingly, it has now been found that a halochromate oxidizing agent may be used to selectively oxidize a 5-O-protected-LL-F28249-a( compound to the corresponding protected-23-ketone compound under mild reaction conditions. Advantageously, in preferred embodiments this oxidation may occur under solvent-free reaction conditions, with high product yield. Further, in alternative embodiments of the invention, halochromate oxidizing agents, such as pyridinium fluorochromate or pyridinium chlorochromate, may be used in catalytic amounts in the presence of a co-oxidant, such as periodic acid, to enable the use of stoichiometric amounts of the co-oxidant without producing complex product mixtures and to allow the use of a recyclable agent, such as periodic acid, as the co-oxidant.

Accordingly, 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 004817905 wherein R is a protecting group to the corresponding 23-keto compound of formula I (1) wherein R is as described for formula II which process includes reacting said formula II compound with a halochromate oxidizing agent, optionally in the presence of a cooxidant, with the proviso that, when no co-oxidant is present the halochromate oxidizing agent is other than pyridinium chlorochromate. The reaction is shown in flow diagram I wherein R represents a protecting group.

004817905 7 FLOW DIAGRAM I

OH

CH,

CH, H- 2 3 H HH CH, 23 H CH, H H H 3 C "I H 3 C H 3 C H j'H H H 3

CH

3 O H J'H OH A H 0 Halochromate Oxidizing Agent U 0 OH H

)-CH

3 R -i CH 3

R

(II)

(I)

Halochromate oxidizing agents suitable for use in the process of the invention include pyridinium fluorochromate (Journal of Fluorine Chemistry, 81 (1997) 211-213); quinolinium fluorochromate (Bulletin of the Chemical Society of Japan, 1994, 67(7), 1894); 3,5-dimethylpyrazolium fluorochromate (Tetrahedron, 2001, 57(12), 2445); pyridinium chlorochromate (Synthesis, 2001, (15) 2273); or the like.

Co-oxidants suitable for use in the process of the invention include recyclable oxidizing agents such as periodic acid (Journal of Fluorine Chemistry, 126(2005) 1356-1360); or 0 the like.

Catalytic amounts suitable for use in the process of the invention include amounts of about 0.2 mole%-2.0 mole% or the minimum amount required to catalyze an oxidation process.

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- (trimethylsilyl)ethoxymethyl, trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, or any 004817905 8 protecting group known to protect an hydroxy group in organic synthesis, preferably pnitrobenzoyl.

If the halochromate oxidizing agent is the sole oxidant, the halochromate 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 200 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 halochromate 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 halochromate oxidizing agent is suitable for use in the inventive process.

In the instance when the halochromate oxidizing agent is a co-oxidant, the halochromate oxidizing agent in a catalytic amount of about 0.2-2.0 mole may be added to a mixture of a compound of formula II and a stoichiometric amount of a cooxidant, such as periodic acid, in the presence of a solvent, at ambient temperatures, until oxidation is complete. Reaction times for the process of the invention may vary according to the co-oxidant used, the halochromate 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.

Advantageously, the oxidation process of the invention may be used in the manufacture of moxidectin. Accordingly, the present invention further provides aprocess for the manufacture of moxidectin which includes: 1) protecting the 5-hydroxy group of LL-F28249-cc to give the compound of formula II; 2) selectively oxidizing said formula II compound by an oxidation 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 004817905 9 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: 1) protecting the 5-hydroxy group of LL-F28249-a to give the compound of formula II; 2) selectively oxidizing said formula II compound by an oxidation process as described above to give the ketone of formula I; 3) deprotecting said formula I ketone to give the compound of formula IV; and 4) reacting said formula IV compound with methoxylamine or a salt thereof to 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.

004817905 Flow Diagram 11 Protection (LL-F2849-alpha) (11) Halochromnate Oxidizing Agent

CH

3 0NH 2

-HCI

Basel Deprotection

NO

Base IDeprotection

CH

3

ONH

2

-HCI

(Moxidectin) In the depicted embodiments, protection of the 5-hydroxy group of LL-F28249-aX is achieved by the reaction of LL-F28249-a with a halide precursor of a protecting group 004817905 11 0 0 as described hereinabove, for example p-nitrobenzoyl chloride, trimethylsilyl chloride,

(N

tb methoxymethylbromide, or the like, preferably p-nitrobenzoyl chloride, in the presence of an organic solvent such as toluene, methylene chloride, ethyl acetate, acetonitrile, or l- the like, preferably, toluene and an organic base such as pyridine, triethylamine, N-

O

methylpyrrolidone, or the like, preferably triethylamine. Oxidation of the protected LLj F28249-a compound of formula II is successfully achieved using the improved oxidation IN process described hereinabove, i.e. reacting said formula II compound with a

O

0 halochromate oxidizing agent optionally in the presence of a co-oxidant to give the I0 ketone of formula I. The formula I compound (either isolated and purified or as a O 10 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 Ill. 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 examples, unless otherwise noted, all parts are parts by weight. The terms HPLC and !0 H 1 NMR designate high performance liquid chromatography and proton nuclear magnetic resonance spectroscopy, respectively.

004817905 12 EXAMPLE 1 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Dimethylpyrazolium Fluorochromate Under a nitrogen atmosphere to an efficiently stirred suspension of dimethylpyrazolium fluorochromate (1.57 g, 7.26 mmol) in 10 mL of methylene chloride is rapidly added a solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (5.02 g, 6.6 mmol) in mL methylene chloride. The stirring is continued for 6-8 hours. After the completion of the reaction, 50 mL of dry diethyl ether is added and the whole mass is well shaken.

The mixture is filtered through a pad of Celite®. The filter cake is washed with dry diethyl 0 ether. The filtrates are combined and concentrated under reduced pressure to give the title product.

EXAMPLE 2 Preparation 23-Keto-5-O-(p-nitrobenzovl)-LL-F28249-a Using Pyridinium Fluorochromate To an efficiently stirred suspension of pyridinium fluorochromate (1.89 g, 9.5 mmol) in mL of anhydrous methylene chloride is added a solution of F28249-cc (5.78 g, 07.6 mmol) in 15 mL anhydrous methylene chloride. The reaction is stirred at room temperature for 6-8 hours and filtered through a pad of Celite®. The filter cake is washed with anhydrous methylene chloride. The filtrates are combined and concentrated under reduced pressure to give the title product.

004817905 13 EXAMPLE 3 Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Quinolinium Fluorochromate To an efficiently stirred suspension of quinolinium fluorochromate (2.37 g, 9.5 mmol) in 5 mL of anhydrous methylene chloride is added a solution of F28249-a (5.78 g, 07.6 mmol) in 15 mL anhydrous methylene chloride. The reaction is stirred at room temperature for 6-8 hours and filtered through a pad of Celite®. The filter cake is washed with anhydrous methylene chloride. The filtrates are combined and concentrated under reduced pressure to give the title product.

0 EXAMPLE 4 Preparation 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Periodic Acid Catalyzed by Pyridinium Fluorochromate Under a nitrogen atmosphere, a mixture of H 5 10 6 (1.20 g, 5.2 mmol) in acetonitrile is stirred rapidly for 15 minutes at room temperature, cooled with an ice-bath and treated with a solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a 3.80 g, 5.0 mmol) in acetonitrile.

The reaction mixture is treated with pyridinium fluorochromate (22 mg, 2.0 mol percent), stirred at room temperature for 6-8 hours, diluted with ethyl acetate and washed sequentially with saturated sodium chloride, saturated aqueous sodium sulfate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product.

004817905 14 0 EXAMPLE ;Z Preparation of 23-Keto-5-O-(p-nitrobenzoyl)-LL-F28249-a Using Pyridinium Fluorochromate To an efficiently stirred suspension of pyridinium fluorochromate (2.05 g, 9.5 mmol) in .O 5 mL of anhydrous methylene chloride is added a solution of F28249-a (5.78 g, 07.6 mmol) in 15 mL anhydrous methylene chloride. The reaction is IN stirred at room temperature for 6-8 hours and filtered through a pad of Celite®. The filter cake is washed with anhydrous methylene chloride. 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 Periodic Acid Catalyzed by Pyridinium Chlorochromate Under a nitrogen atmosphere, a mixture of H 5 10 6 (1.20 g, 5.2 mmol) in acetonitrile is stirred rapidly for 15 minutes at room temperature, cooled with an ice-bath and treated with a solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a 3.80 g, 5.0 mmol) in acetonitrile.

The reaction mixture is treated with pyridinium chlorochromate (24 mg, 2.0 mol percent), stirred at room temperature for 6-8 hours, diluted with ethyl acetate and washed sequentially with saturated sodium chloride, saturated aqueous sodium sulfate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product.

004817905 EXAMPLE 7 Preparation of Moxidectin Using Pyridinium Fluorochromate A stirred 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 20 0 -25 0 C. After 4 hours at 2 0 -25 0 C, the reaction mixture is 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, 5% hydrochloric acid, and saturated sodium chloride and concentrated in vacuo to give 5-O-(p-nitrobenzoyl-LL-F28249-a.

To an efficiently stirred suspension of pyridinium fluorochromate (3.78 g, 19.0 mmol) in anhydrous methylene chloride was added 5-O-(p-nitrobenzoyl-LL-F28249-a (11.44 g, 15.2.6 mmol) in anhydrous methylene chloride. The reaction is stirred at room temperature for 8 hours and filtered through a pad of Celite®. The filter cake is washed anhydrous methylene chloride. The filtrates are combined and concentrated under reduced pressure to give 23-keto-5-O-(p-nitrobenzoyl)- LL-F28249-ta.

A solution of 23-keto-5-O-(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°-250C for 10 hours. The phases are separated. The organic phase is washed with water and concentrated under reduced pressure to give 23-methoxime-5-O-(p-nitrobenzoyl)- LL-F28249-a.

A mixture of 23-methoxime-5-O-(p-nitrobenzoyl)- LL-F28249-a (12.64 g, 8.0 mmol) in dioxane is treated dropwise with 4% NaOH (24.0 g, 3.0 mmol NaOH) at 8°-120 C, stirred for 3 h at 8°-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 NaCl and concentrated in vacuo to give 23-methoxime-LL-F28249-a (moxidectin).

004817905 16 0 EXAMPLE 8 ;Z Preparation of Moxidectin Using Periodic Acid Catalyzed by Pyridinium Fluorochromate A stirred solution of LL-F28249a (6.36 g, 10.4 mmole) in methylene chloride is treated 0 5 with pyridine (1.98 g, 25.0 mmole) and p-nitrobenzoyl chloride (2.45 g, 13.2 mmole) at 0 20 0 -25 0 C. After 4 hours at 2 0 -25 0 C, the reaction mixture is treated with saturated sodium bicarbonate and methylene chloride and stirred until reaction is complete. The phases are separated, the organic phase is washed sequentially with saturated sodium bicarbonate, 5% hydrochloric acid, and saturated sodium chloride and concentrated in vacuo to give 5-O-(p-nitrobenzoyl)-LL-F28249-a as a solid foam, 7.9 g A mixture of H 5 10 6 acid (2.40 g, 10.42 mmol) in acetonitrile, under a nitrogen atmosphere, is stirred rapidly for 15 minutes at room temperature, cooled with an icebath, treated sequentially with 5-O-(p-nitrobenzoyl)-LL-F28249-a 7.61 g, 10.0 mmol) in acetonitrile and 44 mg of pyridinium fluorochromate (2.0 mol percent) The reaction mixture is stirred at room temperature for 6-8 hours, diluted with ethyl acetate, washed sequentially with saturated sodium chloride, saturated aqueous sodium sulfate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to give 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a.

A solution of 23-keto-5-O-(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-O-(p-nitrobenzoyl)- LL-F28249-a.

A mixture of 23-methoxime-5-O-(p-nitrobenzoyl)- LL-F28249-ca (12.64 g, 8.0 mmol) in dioxane is treated dropwise with 4% NaOH (24.0 g, 3.0 mmol NaOH) at 8°-120 C, stirred for 3 h at 8°-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).

004817905 17 O 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 S 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 I acknowledgement, or any form of suggestion, that this prior art forms part of the IND common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims (4)

1. A process for the selective oxidation of a 5-O-protected-LL-F28249-a compound of formula II 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 halochromate oxidizing agent selected from the group consisting of: pyridinium fluorochromate; quinolinium fluorochromate; and fluorochromate; or reacting said formula II compound with a halocharmate oxidizing agent in the presence of a co-oxidant. S00480987 19

2. A process according to claim 1 wherein, when said co-oxidant is absent, said halochromate oxidizing agent is present in an amount of about 1.0-1.5 molar equivalents.

3. A process according to claim 1 or 2 wherein, when said co-oxidant is present, said co-oxidant is periodic acid.

4. A process according to claim 3 wherein, when said periodic acid is present, the halochromate is present in an amount of about 0.2 to 2.0 mol%. A process for the manufacture of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-ca to give the compound of 0 formula II wherein R is a protecting group; 2) selectively oxidizing said formula II compound by a process according to any one of the preceding claims to give the ketone of formula I 004817905 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 wherein R is as defined for formula II; and 4) deprotecting said formula III compound to yield the moxidectin product. Dated: 4 August 2006 Freehills Patent Trade Mark Attorneys Patent Attorneys for the Applicant: Wyeth