AU2006203349B2

AU2006203349B2 - Process

Info

Publication number: AU2006203349B2
Application number: AU2006203349A
Authority: AU
Inventors: Daniel Howard Cohen; Thomas Gerard Cullen; Michael Joseph O'neill; Jignesh Patel
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2006-05-08
Filing date: 2006-08-04
Publication date: 2008-01-31
Anticipated expiration: 2026-08-04
Also published as: AU2006100658B4; NZ548934A; AU2006100658A4; AU2006203349A1; AU2006100658C4

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE

SPECIFICATION

STANDARD PATENT Invention Title: Process The following statement is a full description of this invention, including the best method of performing it known to us: 004817509 2

PROCESS

Field of the invention The present invention relates to a process for the manufacture of moxidectin.

Background of the invention Moxidectin (23-methoxime-LL-F28249-a) is a potent endectocidal agent and is of special interest for use in agriculture, horticulture and animal and human health.

Economic, efficient, environmentally friendly and safe methods to prepare moxidectin are constantly being sought.

Summary of the invention This invention seeks to provide a safe and effective process for the production of moxidectin, which affords mild reaction conditions and high product yields.

This invention also seeks to provide a process that is economical and is suitable for use in the large-scale manufacture of moxidectin, a potent endectocidal agent.

In a first aspect the present invention provides a process for preparation of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a with p-nitrobenzoyl halide to give the corresponding 5-O-(p-nitrobenzoyl)-LL-F28249-a compound; 2) oxidizing said compound to give the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in other than an isolated form; 3) reacting said 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in other than an isolated form with methoxylamine or a salt thereof to give the 23-methoxime- 5-O-(p-nitrobenzoyl)-LL-F28249-a intermediate; and 4) deprotecting said intermediate to give the moxidectin product, and 004817509 3 optionally isolating said moxidectin product in a solid form.

Optionally the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249- derivative in other than an isolated form is deprotected to give the 23-keto-LL-F28249-a compound and said 23keto compound is reacted with methoxylamine or a salt thereof to give the moxidectin product.

Preferably, the deprotection reaction occurs in the presence of a base.

The present invention also provides a moxidectin product whenever produced by a process as described hereinabove.

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 23methoxime derivative of LL-F28249-a. The 23-alkyloxime-LL-F28249 family of compounds and their use as anthelmintic, insecticidal, nematicidal, ectoparasiticidal and acaricidal agents are described in US 4,916,154. The antibiotic compounds designated as LL-F28249 are described in US 5,106,994. A process for the manufacture of moxidectin from LL-F28249-a is disclosed in US 4,988,824. Said process includes an oxidation step wherein the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative is isolated in crystalline form. These United States patent specifications are incorporated herein by reference.

004817509 4 As used herein, the term "isolate", and grammatical variations thereof, means to separate a product from the reaction mixture in which it was synthesized. Separation is for example by filtration, concentration in vacuo, or other suitable methods.

As used herein, the term "purify", and grammatical variations thereof, means to remove impurities from a product, preferably an isolated product.

Accordingly, the present invention provides a process for the preparation of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a with p-nitrobenzoyl halide to give the corresponding 5-O-(p-nitrobenzoyl)-LL-F28249-a compound; 2) oxidizing said compound to give the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in other than an isolated form; 3) reacting said 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in other than an isolated form with methoxylamine or a salt thereof to give the 23-methoxime- 5-O-(p-nitrobenzoyl)-LL-F28249-a intermediate; and 4) deprotecting said intermediate to give the moxidectin product, and optionally isolating said moxidectin product in a solid form.

Optionally the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in other than an isolated form is deprotected to give the 23-keto-LL-F28249-a compound and said 23keto compound is reacted with methoxylamine or a salt thereof to give the moxidectin product.

The reaction scheme of one embodiment of the invention is shown in flow diagram I wherein PNB represents p-nitrobenzoyl. The protecting group reagent used in the depicted embodiment is p-nitrobenzoyl chloride, the methoxylamine is presented as a methoxylamine hydrochloride salt and the deprotection reaction occurs in the presence of a base.

004817509

PNB-CI

(LL-F28249-alpha) Oxidation

I

Deprotection Base

CH

3 0NH 2

-HCI

CH

3

QNH

2 -HC1 Deprotection Base (Moxidectin) The following discussion provides further information on the reaction conditions that would be suitable for use with the depicted embodiment. It will be appreciated that the 004817509 6 described reaction conditions may be suitable for use with alternative embodiments of the invention.

In the depicted embodiment protection of the 5-hydroxy group of LL-F28249-a is achieved by the reaction of LL-F28249-a with 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. Protection of the group may also be achieved by reacting LL-F28249-a with p-nitrobenzoyl fluoride, pnitrobenzoyl bromide or p-nitrobenzoyl iodide. Oxidation of the protected LL-F28249-a compound (5-O-(p-nitrobenzoyl)-LL-F28249-a), either isolated and/or purified or as a solution of the crude reaction product in an organic solvent, such as toluene, is successfully achieved using an oxidizing system such as pyridinium dichromate and acetic anhydride; pyridinium dichromate and dimethylformamide; aluminium t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; chromium trioxide, potassium dichromate; FeBr 3 and H 2 0 2 dicyclohexylcarbodiimide and dimethyl sulfoxide; manganese dioxide; acetic anhydride and dimethyl sulfoxide; or the like, preferably manganese dioxide. A further preferred oxidizing system includes dimethyl sulfoxide and acetic anhydride. A solution of this reaction product (23-keto-5-O-(pnitrobenzoyl)-LL-F28249-a) in an organic solvent, such as toluene, without isolation or further purification, is reacted with an aqueous solution of methoxylamine or a salt thereof, in the depicted embodiment a methoxylamine hydrochloride salt, and sodium acetate to give 23-methoxime-5-O-(p-nitrobenzoyl)-LL-F28249-a. The 23-methoxime-5- O-(p-nitrobenzoyl)-LL-F28249-a compound may be isolated and/or purified or introduced to the subsequent deprotection step as a solution of the crude reaction product in an organic solvent. Deprotection is achieved by reacting a solution of said 23methoxime-5-O-(p-nitrobenzoyl)-LL-F28249-a 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. The isolated moxidectin product may then be purified using standard procedures known in the art.

004817509 7 In the present inventive process, the 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative is not isolated from the reagents of the oxidizing reaction before being reacted with methoxylamine or a salt thereof. Not isolating said derivative is advantageous as it helps to minimise the manufacturing steps required, which is of great advantage in a commercial setting, where timing and additional steps may add significantly to the costs of manufacturing veterinary medicines, pharmaceuticals and agricultural chemicals.

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.

EXAMPLE 1 Preparation of 5-O-(p-nitrobenzoyl)-LL-F28249-a 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 0 -25 0 C. After 4 hours at 20 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 the title compound as a solid foam, 7.9 g (quantitative yield), identified by liquid chromatography, proton NMR and mass spectral analyses.

EXAMPLE 2 Preparation of 23-Methoxime-5-O-(p-nitrobenzoyl)- LL-F28249-a A solution of 5-O-(p-nitrobenzoyl)-LL-F28249-a (0.19g, 0.25 mmol) in methylene chloride is treated with MnO 2 (8.0g, 92 mmol), stirred at 200-250 C for 2h, treated further with methylene chloride and stirred until oxidation was complete by HPLC analysis. The reaction mixture was filtered. The filtrate was treated with a solution of methoxylamine hydrochloride (1.5 molar equivalents) and sodium acetate (1.5 molar equivalents) in water and stirred at 20 0 -25 0 C for 10h. The phases are separated. The organic phase is 004817509 8 washed with water and evaporated to dryness to give the title product as a solid, identified by HPLC analysis.

EXAMPLE 3 Preparation of 23-Methoxime-LL-F28249-a (Moxidectin) A mixture of 23-methoxime-5-O-(p-nitrobenzoyl)-LL-F28249-a (1.58 g, 2.0 mmol) in dioxane is treated dropwise with 4% NaOH (3.0 g, 3.0 mmol NaOH) at 8°-120 C, stirred for 3 h 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 the title product as a white foam, identified by

HPLC.

EXAMPLE 4 Preparation of 23-Methoxime-LL-F28249-a (Moxidectin) A mixture of 5-O(p-nitrobenzoyl)-LL-F28249a (7.26 g, 10mmole) and pyridine (1 molar equivalent) in toluene is treated with dimethyl sulfoxide (40 molar equivalents) and trifluoroacetic acid (1.0 molar equivalent), cooled to 20 0 C, treated dropwise with acetic anhydride (5 molar equivalents) at 20 0 -25 0 C, stirred for 24 hours at 20 0 -25 0 C, and treated with toluene and water. The reaction mixture is stirred at ambient temperature for 15-30 minutes and the phases are separated. The organic phase is washed with cold dilute hydrochloric acid and 5% sodium chloride solution. The washed organic phase containing 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249a is treated with 4% sodium hydroxide (1.65 molar equivalents NaOH), stirred for 2 hours at 23 0 C, treated with toluene and water, and shaken. The phases are separated and the organic phase is washed with water. The organic phase containing 3-keto-LL-F28249a (determined by HPLC analysis) is treated with a solution of methoxyl amine hydrochloride (1.5 molar equivalents) and sodium acetate (1.5 molar equivalents) in water and stirred at 20-25 0

C

for 10 hours, diluted with toluene and water and stirred for 30 minutes. The phases are separated and the organic phase is evaporated to dryness. The resultant residue is 004817509 9 dispersed in methanol, diluted with water and filtered. The filtercake is dried to give the title compound as a white solid, identified by HPLC analysis.

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 could reasonably be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims

2. A process according to claim 1 wherein the protection reaction, oxidation reaction and/or methoxylamine reaction is performed in an organic solution and the organic solution is utilised in the subsequent reaction.
3. A process according to claim 2 wherein the organic solution is an organic phase.
4. A process according to claim 1 wherein the 23-methoxime-5-O-(p-nitrobenzoyl)- LL-F28249-a intermediate is isolated in a crystalline form. A process according to any one of the preceding claims wherein the moxidectin product is isolated in a crystalline form.
6. A process according to any one of the preceding claims wherein the 23- methoxime-5-O-(p-nitrobenzoyl)-LL-F28249-a intermediate is deprotected in the presence of a base.
7. A process for the preparation of moxidectin including: 1) protecting the 5-hydroxy group of LL-F28249-a with p-nitrobenzoyl halide to give the corresponding 5-O-(p-nitrobenzoyl)-LL-F28249-at compound; 004817509 11 IND 0 O 2) oxidizing said compound to give the 23-keto-5-O-(p-nitrobenzoyl)-LL- F28249-a derivative in other than an isolated form; 3) deprotecting said 23-keto-5-O-(p-nitrobenzoyl)-LL-F28249-a derivative in 0 other than an isolated form to give the 23-keto-LL-F28249-a intermediate; and 4) reacting said intermediate with methoxylamine or a salt thereof to give the moxidectin product, and (N 0 optionally isolating said moxidectin product in a solid form.
8. A process according to claim 7 wherein the protection reaction, oxidation reaction and/or deprotection reaction is performed in an organic solution and the organic solution is utilised in the subsequent reaction.
9. A process according to claim 8 wherein the organic solution is an organic phase. A process according to any one of claims 7 to 9 wherein the moxidectin product is isolated in a crystalline form.
11. A process according to any one of claims 7 to 10 wherein the 23-keto-5-O-(p- nitrobenzoyl)-LL-F28249-a derivative is deprotected in the presence of a base.
12. A process according to any one of the preceding claims wherein the oxidation is carried out using an oxidizing system selected from the group consisting of: pyridinium dichromate and acetic anhydride; pyridinium dichromate and dimethylformamide; aluminium t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; chromium trioxide; potassium dichromate; FeBr 3 and H 2 0 2 dicyclohexylcarbodiimide and dimethyl sulfoxide; manganese dioxide; and acetic anhydride and dimethyl sulfoxide.
13. A process according to claim 12 wherein said oxidizing system includes manganese dioxide.
14. A process according to claim 12, wherein said oxidizing system includes dimethyl sulfoxide and acetic anhydride. 004817509 12 NO A process according to claim 1 or 7, substantially as described herein with reference to any one of the examples.
16. A moxidectin product whenever produced by a process according to any one of 0 the preceding claims. r 5 Dated: 4 August 2006 SFreehills Patent Trade Mark Attorneys \Patent Attorneys for the Applicant: SWyeth