NZ548932A - Intermediates and processes using them for preparing moxidectin - Google Patents

Abstract

Disclosed herein is a compound of formula (I) and the use thereof in the preparation of moxidectin, wherein the variables shown in formula (I) are as defined in the specification.

Description

New Zealand Paient Spedficaiion for Paient Number 548932 04/08/2006 04:55 PM fraehl I Is 1 2345678 25/56 004853961 548932 *10052293964* 1 Intermediates and processes using them Field of the invention The present invention relates to processes for preparing moxidectin and intermediate compounds related to these processes.

Moxidectin (23[E]-methoxime-LL-F28249-a) is a potent endectocidal agent and is of special interest for use in agriculture, horticulture and animal and human health. Readily available, economic and efficient intermediates useful to prepare moxidectin are of great need in the art.

This invention seeks to provide an intermediate compound useful in the production of moxidectin.

This invention also seeks to provide a process for the manufacture of moxidectin which affords mild reaction conditions and high product yields, that is economical and suitable 15 for use in the large scale manufacture of moxidectin, a potent endectocidal agent.

The present invention provides a compound of formula I Background of the invention Summary of the invention (i) wherein INTELLECTUAL PROPERTY OFFICE OF N.Z.

-S AUG 2006 X is CHOH, OO or C=NOCH3; CEIVED ,rrT'--.rng.-.--.(TrT- ' V 'HUM ' 111 II— 04/08/2006 04:55 PM f r e e h I 1 Is 1 2345678 26/56 004853961 2 R is CORi, p-methoxybenzyloxymethyl, methoxymethyl, methylthiomethyl, [phenyldi(Cr C4)silyl]methoxymethyl, o-nitrobenzylmethyl, 2,2,2-trihalo- ethoxymethyl; o-nitrobenzyloxymethyl, 4-methoxyphenoxymethyl, 2,4-dinitrophenylsulfonyl, guaiacoimethyl, t-butoxymethyl, 4-pentenyloxymethyl, silyloxymethyl, 2-5 ethoxyethoxymethyl, 2,2,2-trichloroethyl, or 2-(trimethylsilyi)ethoxymethyl, and Ri is a substituted phenyl or substituted heteroaryl group with the proviso that when X is C=0 or C=NOCH3 then Ri must be other than phenyl and when X is CHOH then Ri must be other than p-nitrophenyl; or a stereoisomer thereof.

The present invention also provides a compound of formula I (0 ' wherein X is C=NOCH3; R is CORi, CrC4alkoxy-diphenylsilyl, Ci-C4alkoxydi(Ci-C4alkyl)silyl, Cr 15 C4alkyldiphenylsilyl, or di(Ci-C4alkyl)phenylsilyl; and Ri is a heteroaryl group; or a stereoisomer thereof.

The present invention further provides the use of said formula I compound in processes to prepare moxidectin. 04/08/2006 04:55 PM f r e a h I I is 1 234567 8 27/56 004653961 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 r10 23[E]-methoxime derivative of LL-F28249-a. The 23-imino derivatives of the 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 15 process utilizes the 5-0-p-nitrobenzoyl-LL-F28249-a derivative as an intermediate. It has now been determined that moxidectin may be prepared using a further range of 5-O-protected compounds as intermediates. These United States patent specifications are incorporated herein by reference.

Accordingly, the present invention provides a compound of formula I H3CI«"' (I) wherein X is CHOH, C=0 or C=NOCH3; 04/08/2006 04:55 PM fraehllls 12345678 28/56 004853961 4 R is COR-i, p-methoxybenzyloxymethyl, methoxymethyl, methylthiomethyl, [phenyldi(C-r C^silyQmethoxymethyl, o-nitrobenzylmethyl, 2,2,2-trihalo- ethoxymethyl; o-nitrobenzyloxymethyl, 4-methoxyphenoxymethyl, 2,4-dinitrophenylsulfonyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, silyloxymethyl, 2-5 ethoxyethoxymethyl, 2,2,2-trichloroethyl, or 2-(trimethylsilyl)ethoxymethyl, and Ri is a substituted phenyl or substituted heteroaryl group with the proviso that when X is C=0 or C=NOCH3 then must be other than phenyl and when X is CHOH then R! must be other than p-nitrophenyl; or a stereoisomer thereof.

Preferred compounds of the invention are those compounds of formula I wherein R is CORi. Another group of preferred compounds is those formula I compounds wherein R is 2,2,2-trihalo-ethoxymethyl.

More preferred compounds of the invention are those formula I compounds wherein R is CORi and Ri is p-halophenyl or p-methoxyphenyl. Another group of more preferred 15 compounds are those compounds of formula I wherein R is ferf-butoxydiphenylsilyl, ethoxydiphenylsilyl, or 2,2,2-trichloroethoxymethyl.

Further preferred compounds of the invention are those compounds of formula 1 wherein X is ONOCH3 and R is Ci-C4alkoxy-diphenylsilyl, CrC4alkoxydi(Ci-C4alkyl)silyl, Ci-C4alkyldiphenylsilyl; or 2,2,2-trihalo-ethoxymethyl.

Among the preferred compounds of the invention are: -0-Methyl-LL-F28249-a; 5-0-p-chlorobenzoyl-LL-F28249-a; 5-O-p-cyanobenzoyl-LL-F28249-a; 5-0-p-fluorobenzoyl-LL-F28249-a; 5-0-isonicotinoyl-LL-F28249-a; 5-0-isonicotinoyl-23-keto-LL-F28249-a; 5-0-isonicotinoyl-23[E]-methoxime-LL-F28249-a; 5-0-nicotinoyl-LL-F28249-a; 5-0- nicotinoyl-23-keto-LL-F28249-a; 5-0-nicotinoyl -23[EJ-25 methoxime-LL-F28249, 5-0-(5-chlorothiophene-2-carbonyl)-LL-F28249-a; 5-0-(5-chlorothiophene-2-carbonyl)-23-keto-LL-F28249-a; 5-0-(5-chlorothiophene-2-carbonyl)-23[E]-methoxime-LL-F28249-a; 5-0-(methoxydiphenylsilyl)-LL-F28249a; 5-0-(methoxydiphenylsilyl)-23-keto-LL-F28249a; 5-0-(methoxydiphenylsilyl)-23[E]- methoxime-LL-F28249a; 5-0-(ethoxydiphenylsilyl)-LL-F28249a; 5-0- 04/08/2006 04:55 PM freehills 12345678 29/56 004853961 (ethoxdiphenylsilyl)-23-keto-LL-F28249a; 5-0-(ethoxdipheny(silyl)-23[E]-methoxime-LL-F28249a; 5-0-(tert-butoxydipheny!silyl)- LL-F28249a; 5-0-(te/f-butoxydiphenylsilyl)-23-keto-LL-F28249a; 5-0-(fert-butoxydiphenylsilyl)-23[E]-methoxime-LL-F28249a; 5-0-(methyldiphenylsilyl)- LL-F28249a; 5-0-(methyldiphenylsilyl)-23-keto-LL-F28249a; 5-0-5 (methyldiphenylsilyl)-23[E]-methoxime-LL-F28249a; 5-0-(2,2,2- trichloroethoxymethyl)-LL-F28249-a ; 5-0-(2,2,2- trichloroethoxymethyl)-23-keto-LL-F28249-a; 5-0-(2,2,2-trichloroethoxymethyl)-23[E]-methoxime-LL-F28249-a; or a stereoisomer thereof.

^ In the specification and claims, when the terms phenyl or heteroaryl are designated as 10 being optionally substituted, the substituent groups which are optionally present may be one or more e.g. two or three, the same or different of those customarily employed in the development of protecting groups in organic synthetic procedures. Specific examples of such substituents include halogen atoms, nitro, cyano, alkyl, haloalkyi, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, 15 alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl, heterocyclyl or cycloalkyl groups, preferably halogen atoms, nitro, cyano or lower alkyl groups. Typically, 0-3 substituents may be present.

The term "halogen", as used herein, designates fluorine, chlorine, bromine, and iodine. ^20 The term "halophenyl", as used herein, designates chlorophenyl, fluorophenyl, iodophenyl or bromophenyl.

As used herein, the term "alkyl" includes both a (C1-C4) straight chain and a (C3-C5) branched-chain saturated hydrocarbon moiety. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, /7-butyl, 25 fe/f-butyl, isobutyl, sec-butyl, or the like.

The term "heteroaryl" as used herein designates an aromatic heterocyclic ring system, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together. Preferably, heteroaryl is a 5- to 6-membered ring system containing from one to four hetero atoms selected from N, O or S, wherein the nitrogen or sulfur 04/08/2006 04:5$ PM freehllls 12345678 30/56 004853961 6 atom is optionally oxidized, or the nitrogen atom is optionally quarternized. Examples of heteroaryl moieties include, but are not limited to, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzimidazole, benzoxazofe, benzisoxazole, 5 benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzofuran, dibenzothiophene, indole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, or the like.

Compounds of formula I include all stereoisomeric forms of the structure; i.e., the R and S configurations for each asymmetric center and the E and 2 forms for those compounds wherein X is C=NOCH3. Single enantiomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. The compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. The present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and E and Z isomers. Where a stereoisomer is preferred, it may in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. "Substantially free", as used herein, means that the compound is made up of a significantly greater proportion of one stereoisomer, preferably greater than about 50%, more preferably greater than about 75%, and even more preferably greater than about 90%.

Compounds of formula I may be prepared using conventional synthetic methods and, if 25 required, standard isolation or separation techniques. For example, the compound of formula I may be prepared by reacting a compound of formula II with a suitable halide of formula III, optionally in the presence of a solvent, to give the desired compound of formula I. The reaction is shown hereinbelow in flow diagram I wherein Hal is CI, Br or I and R is as described above. 04/08/2008 04:56 PM D04853961 f rtthl I Is 12345678 31/56 7 FLOW DIAGRAM I Advantageously, the formula I compounds of the invention are useful for the manufacture of moxidectin. For example, compounds of formula I wherein X is CHOH 5 (la), may be used to prepare moxidectin by: oxidizing said formula la compound with a suitable oxidizing agent optionally in the presence of a solvent to give the compound of formula I wherein X is C=0 (lb); reacting said formula lb compound with methoxylamine or a salt thereof to give the compound of formula I wherein X is ONOCH3 (Ic); and deprotecting said formula Ic compound in the presence of an acid or base, preferably a 10 base, to yield the desired moxidectin product.

Alternatively, the compound of formula lb may be deprotected in the presence of an I acid or base, preferably a base, to give the 23-keto-LL-F28249-a compound of formula IV and the formula IV compound may be reacted with methoxylamine or a salt thereof to give the desired moxidectin product.

An embodiment of each of the reactions are shown in flow diagram II. 04/08/2006 04:56 PM 004853961 f r e«h I I Is 12345678 32/56 FLOW DIAGRAM II H,CI«« (Moxidectin) Accordingly, the present invention also provides a process for the preparation of moxidectin including: 04/08/2006 04:56 PM f r a eh I I Is 12345678 33/56 004853961 1) oxidizing a compound of formula I wherein X is CHOH to give the ketone compound of formula I wherein X is C=0; 2) reacting said ketone with methoxylamine or a salt thereof to give the methoxime compound of formula I wherein X is C=NOCH3; and 3) deprotecting said methoxime to yield the moxidectin product.

The present invention further provides a process for the preparation of moxidectin including: 1) oxidizing a compound of formula I wherein X is CHOH to give the ketone compound of formula I wherein X is C=0; 2) deprotecting said ketone to give the 23-keto-LLF28249-a compound; and 3) reacting said 23-keto-LLF28249-a compound with methoxylamine or a salt thereof to yield the moxidectin product.

Oxidizing agents suitable for use in the process of the invention include pyridinium dichromate and acetic anhydride; pyridinium dichromate and dimethylformamide; 15 aluminium t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; chromium trioxide, potassium dichromate; FeBr3 and H2O2; dicyclohexylcarbodiimide and dimethyl sulfoxide; manganese dioxide; acetic anhydride and dimethyl sulfoxide; pyridinium fluorochromate; pyridinium chlorochromate; quinolinium fluorochromate; 3,5-dimethylpyrazolium fluorochromate; supported oxidizing 20 agents such as polymer-supported sulfoxides, i.e., 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 like; polymer-supported pyridinium chromates such as polymer-supported pyridinium chlorochromate, polymer-supported pyridinium dichromate or the like; polystyrene-25 supported 4-hydroxyiodobenzene diacetate; polymer-supported permanganate; polystyrene-supported perruthenate; or the like; solid-supported oxidizing agents, i.e.,alumina-supported oxidizing agents such as BaMn04AI203; K2Fe04Al203; K2Mn04Al203; alumina-supported pyridinium chlorochromate; alumina-supported pyridinium dichromate; or the like; or silica-supported oxidizing agents, such as silica- 04/08/2006 04:56 PM f reeh i I is 12345678 34/56 004353981 supported pyridinium chlorochromate; silica-supported pyridinium dichromate; or the like; pyridinium chlorochromate supported on copper(ll)sulfate; chromium trioxide supported on solid NaHS04'H20; pyridinium dichromate supported on molecular sieves; pyridinium dichromate supported on Zeolite 3A; or the like.

The oxidizing agent in an amount of at least one molar equivalent may be admixed with a compound of formula la, optionally in the presence of a solvent, at a temperature range of about 20° C to the reflux temperature of the solvent, until oxidation is complete, to give the compound of formula lb. A solution of the crude reaction product, lb, in an organic solvent, such as toluene, may then be reacted with an aqueous solution of JO methoxylamine hydrochloride and sodium acetate and stirred until oxime formation is complete to give the compound of formula Ic. Optionally, the thus-formed Ic intermediate may be isolated and purified by recrystallization from a suitable solvent.

The Ic intermediate may be deprotected by reaction with a base such as sodium hydroxide, or an acid such as hydrochloric acid, preferably a base, at 0°-25° C to give 15 the desired moxidectin product. For example, a solution of the intermediate, Ic, in an organic solvent such as toluene, dioxane, n-butanol or the like, preferably dioxane, is admixed with an aqueous solution of sodium hydroxide or hydrochloric acid, preferably sodium hydroxide, at 0°-25° C and the moxidectin product is isolated from the organic phase using standard procedures such as concentration, filtration, removal of the 20 solvent, or the like.

Unless otherwise noted, in the following examples, all parts are parts by weight. The terms HPLC and HNMR designate, high performance liquid chromatography and nuclear magnetic resonance, respectively 04/08/2006 04:56 PM freehllls 12345678 004853961 u EXAMPLE 1 Preparation of 5-0(p-chIorobenzovn-LL-F28249-g o V CI A solution of LL-F28249-a (6.36 g, 10.4 mmol) in methylene chloride at 20°-25° C is treated with pyridine (1.98 g, 25.0 mmol) and 4-chlorobenzoyl chloride (2.31 g, 13.2 mmol), stirred for 4 hours at 2°-25° C and treated with saturated sodium bicarbonate and methylene chloride. The phases are separated. The organic phase is washed sequentially with saturated sodium bicarbonate, 5% hydrochloric acid and brine and concentrated under reduced pressure to give the title compound, characterized by HPLC and mass spectral analyses. 04/08/2006 04:56 PM frtahllls 12345678 36/56 004853961 12 EXAMPLES 2-92 Preparation of 5-0-fProtected)-LL-F28249-a Using essentially the same procedure described in Example 1 and employing the 5 appropriate acid chloride, RiCOCI, the compounds shown on Table I are obtained and identified by HPLC and mass spectral analyses.

TABLE I Example Number R1 2 2-NOrC6H4 3 3-N02-C6H4 4 4-Br-C6H4 4-CF3-C6H4 04/08/2006 04:56 PM f raeh ills 1 2345678 37/56 004853961 13 TABLE t. cont Example Number R1 6 4-OCF3-C6H4 7 4-OCHF2-C6H4 7 2-CI-C6H4 9 3-CI-C6H4 4-CI-C6H4 11 2,4-diCI-C6H3 12 3,4- diCI-CeHs 13 3,5- diCI-C6H3 14 2,5- diCI-C6H3 2,6- diCI-C6H3 16 4-SF6-C6H4 17 4-SCF3-C6H4 18 4-SOCF3- qH4 19 4-SO2CF3-C6H4 4-CN-C6H4 21 4-(cyclopropyl-CH20)-C6H4 22 2-F-C6H4 23 3-F-C6H4 04/08/2006 04:56 PM 004853961 14 TABLE I. cont hUC"" Example Number R1 24 4-F-C6H4 2,4-diF-C6H3 26 3,4-diF-C6H3 27 3,5-diF-C6H3 28 4-SCH3-C6H4 29 4-SOCH3-C6H4 4-S02CH3-C6H4 31 4-N(CH3)2-C6H4 32 4-NHC(0)CH3-C6H4 33 4-NHC(0)NH2-C6H4 34 4-CH3-C6H4 furan-2-yl 36 thiophen-2-yl 37 -Cl-thiophen-2-yl 38 -C6H5-thiophen-2-yl 39 pyridin-2-yl 40 pyridin-2-yl-N-oxide 41 6-F-4-CI-pyridin-2-yl 42 4-N02-pyridin-2-yl 43 pyridin-3-yl TABLE I. cont.

QH Example Number R1 44 pyridin-3-yl-N-oxide 45 2-CI-pyridin-3-yl 46 4-CI-pyridin-3-yl 47 4-NC>2-pyridin-3-yl 48 4-CN-pyridin-3-yl 49 4-F-pyridin-3-yl 50 4-CF3-pyridin-3-yl 51 4-C H 3-py rid i n-3-y I 52 4,5-diCI-pyridin-3-yl 53 pyridin-4-yl 54 pyridin-4-yl-N-oxide 55 3-CI-pyridin-4-yl 56 3-N02-pyridin-4-yl 57 3-CN-pyridin-4-yl 58 3-F-pyridin-4-yl 59 3-N02-pyridin-4-yl 60 3,5-diCI-pyridin-4-yl 61 4-Morpholino 62 Piperazin-1-yl 63 4-CH3-piperazin-1 -yl 04/08/2006 04:56 PM f r a®h I I Is 1 2345678 40/56 004853961 Example Number 16 TABLE I. cont.

R1 64 pyrimidin-2-yl 65 4,6-di-OCH3-2-pyrimidine 66 pyridazin-3-yl 67 pyrimidin-4-yl 68 2-CI-pyrimidin-4-yl 69 2,5-diCI-pyrimidin-4-yl 70 thiazol-2-yl 71 -CH3-thiazol-2-yl 72 4-CH3-thiazol-2-yl 73 -NC>2-thiazol-2-yl 74 benzothiazol-2-yl 75 4,5-diCH3-Oxazol-2-yl 76 benzoxazol-2-yl 77 isothiazol-3-yl 78 -N02-isothiazol-3-yl 79 thiazol-4-yl 80 2-C l-th iazo l-4-y t 81 2-CeH5-thiazol-4-yl 82 2-N02-thiazol-4-yl 83 2-CH3-thiazol-4-yl 17 TABLE \. cont.

OH Example Number R1 84 5-CH3-thiazol-4-yl 85 5-CI-isothiazol-3-yl 86 5-CH3-isothiazol-3-yl 87 5-CN-isoth iazol-3-y I 88 5-cyclopropyl-isothiazol-3-yl 89 5-C6H5-isothiazol-3-yl 90 5-C6H5-1,3,4-oxadiazol-2-yl 91 5-SC2H5-1,3,4-oxadiazol-2-yl 92 5-CH3-piperazin-1-yl 04/08/2006 04:56 PM fr«ehllls 12345678 42/56 004853961 18 EXAMPLE 93 Preparation of 23-Keto-5-0-(p-chlorbenzovn-LL-F28249-g A solution of 5-0-(p-chlorobenzoyl)-LL-F28249-a (0.19g, 0.25 mmol) in toluene is 5 treated with Mn02 (8.0g, 92 mmol), stirred at 20°-25° C for 2h, treated further with toluene and stirred until the oxidation is complete. The reaction mixture is filtered and the filtercake is washed with toluene. The filtrates are combined and concentrated to dryness in vacuo to give the title compound, identified by HPLC and mass spectral analyses. 04/08/2006 04:57 PM f rsehills 1 2345678 43/56 0O48539S1 19 EXAMPLES 94 Preparation off 23rE1-Methoxgme-5-0-(p-chlorbenzovD-LL-F28249-g A solution of 23-keto-5-0-(p-chlorbenzoyl)-LL-F28249-a (7.48 g, 10 mmole) in toluene 5 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°-25°C for 10 hours. The phases are separated. The organic phase is washed with water and concentrated to dryness under reduced pressure to give the title product, identifed by HPLC and mass spectral analyses.

EXAMPLE 95 Preparation of 23rEl-Methoxime-LL-F28249-a (Moxidectin) H30'" 04/08/200 004853981 6 04:57 PM f r«fthills 1 2345878 44/5S A mixture of 23[E]-methoxime-5-0-(p-chlorobenzoyl)-LL-F28249-a (1.58 g, 2.0 mmol) in dioxane is treated dropwise with 4% aqueous NaOH (3.0 g, 3.0 mmol NaOH) at 8°-12° C, stirred for 3 h at 8°-12° C, treated with toluene and water, and stirred for 5 minutes at ambient temperatures. The phases are separated. The organic phase is washed with 5 10% NaCI and concentrated in vacuo to give the title product, identified by HPLC and mass spectral analyses.

A stirred mixture of LL-F28249-a (6.13 g, 10 mmol) and triethylamine (10 mmol) in methylene chloride at 0° C is treated with te/f-butoxydiphenylsilyl chloride (11 mmol) is added. The reaction mixture is allowed to warm to room temperature. After 30 minutes at roomtemperature, the mixture is treated with saturated aqueous sodium bicarbonate. The phases are separated. The organic phase is washed sequentially with water and 15 brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title product, identified by HPLC and mass spectral analyses.

EXAMPLE 96 Preparation of 5-0-fte/f-Butoxvdiphenvlsilvn-LL-F28249-a 04/08/2006 04:57 PM 004853961 f reehI I Is 1 2345678 45/56 21 EXAMPLES 97-109 Preparation off 5-CMProtectedl-LL-F28249-« QH OR Using essentially the same procedure described in Example 96 and employing 5 the appropriate silyl chloride, the compounds shown in Table II are obtained and identified by HPLC and mass spectral analyses.

TABLE II OH OR Example Number R 97 diphenylmethoxysilyl 98 diphenylethoxysilyl 99 diphenylisopropoxysilyl 100 dimethyl(4-methyl-2,6-di-t-butylphenoxy)silyl 101 methoxy (phenyl)t-butylsilyl 102 diphenyl-t-butylsilyl 04/08/2006 04:57 PM 004853961 f rash I I Is 1 2345678 46/56 22 TABLE II. cont.

Example Number R 103 104 105 106 107 108 109 dimethyl-t-butylsilyl triisopropylsilyl triethylsilyl diphenylmethylsilyl dimethylphenylsilyl dimethylhexylsilyl diphenyl(2,6-dimethylphenoxy)silyl EXAMPLE 110 Preparation of 23-Keto-5-0-ffert-ButoxvdiDhenvlsilvn-LL-F28249-a 04/08/2006 04:57 PM 004653961 f reehI I Is 1 2345678 47/56 23 A solution of 5-0-(terf-butoxydiphenylsilyl)-LL-F28249-<x (4.00 g, 4.61 mmol) In toluene is treated with Mn02 (120.30 g, 1.384 mol), stirred at 20°-25° C for 2h, treated further with toluene, stirred until oxidation is complete by HPLC analysis and filtered. The filtercake is washed with toluene. The filtrates are combined and concentrated under 5 reduced pressure to give the title product, identified by HPLC and mass spectal analyses.

EXAMPLE 111 Preparation of 23rEl-Methoxime-5-0-ffe/f-Butoxvdiphenvisilvn-LL-F28249-a A solution of 5-0-(ferf-butoxydiphenylsilyl)-23-(keto)-LL-F28249a (3.46 g, 4.00 mmol) in dichloromethane is treated with a solution of methoxylamine hydrochloride (0.50 g, 6.00 mmol) and sodium acetate (0.49 g, 6.00 mmol) in water and stirred at 20°-25°C for 10 hours. The phases are separated. The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to give the title, identified by 15 HPLC and mass spectral analyses. 04/08/2006 04:57 PM fraehllls 12345678 48/56 004853961 24 EXAMPLE 112 Preparation of 5-0-(2.2.2-Trichloroethoxvmethvn-LL-F28249-a ccu To a solution of LL-F28249-a (6.13 gF 10 mmol) and freshly fused lithium iodide (1.33 g, 5 10 mmol) in tetrahydrofuran is added 2,2,2-trichloroethoxy- methyl chloride (2.96 g, 15 mmol), stirred for 5 hours at room temperature and diluted with water and ether. The phases are separated. The organic phase is washed with dilute aqueous NaHS03, dried over magnesium sulfate and concentrated under reduced pressure to give the title product, identified by HPLC and mass spectral analyses.

EXAMPLE 113 Preparation of 23-Keto-5-CM2.2.2-trichloroethoxvmethvn-LL-F28249-a CClj 04/08/200 004853961 6 04:57 PM f reeh I I Is 1 2345678 49/56 A solution of 5-0-(2,2,2-trichloroethoxymethyl)-LL-F28249-a (5.5 g, 7.10 mmol) in dichloromethane (250 mL) is treated with Mn02 (185.28 g, 2.131 mol), stirred at 20°-25° C for 2h, treated further with dichloromethane, stirred until oxidation is complete by HPLC analysis and filtered. The filtercake is washed with dichloromethane. The filtrates 5 are combined and concentrated in vacuo to give the title product, identified by HPLC and mass spectral analyses.

EXAMPLE 114 Preparation of 23rEl-Methoxime-5-0»f2.2.2-trichloroethoxvmethvl)-LL-F28249-a cci3 A solution of 23-keto-5-0-(2,2,2-trichloroethoxymethyl)-LL-F28249a (3.3 g, 4.27 mmol) in methylene chloride is treated with a solution of methoxylamine hydrochloride (0.535 g, 6.41 mmol) and sodium acetate (0.526 g, 6.41 mmol) in water and stirred at 20°-25°C for 10 hours. The phases are separated. The organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo to give the title product, identified by 15 HPLC and mass spectral analyses.

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.

Claims (5)

04/08/2006 04:57 PM 004853961 f r e•h I I Is 1 2345678 50/56 26 Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in New Zealand or any other jurisdiction. 04/08/2006 04:57 PM 004853961 freehllls 1234 5678 51/56 27 The claims defining the invention are as follows:

1. A compound of formula I

(i)

wherein

X is CHOH, C=0 or C=NOCH3;

R is CORi, p-methoxybenzyloxymethyl, methoxymethyl, methylthiomethyl, [phenyldi(CrC4)silyl]methoxymethyl, o-nitrobenzylmethyl, 2,2,2-trihalo-ethoxymethyl; o-nitrobenzyloxymethyl, 4-methoxyphenoxymethyl, 2,4-dinitrophenylsulfonyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, silyioxymethyl, 2-ethoxyethoxymethyl, 2,2,2-trichloroethyl, or 2-(trimethylsilyl)ethoxymethyl, and

Ri is a substituted phenyl or substituted heteroaryl group with the proviso that when X is C=0 or C=NOCH3 then Ri must be other than phenyl and when X is CHOH then Ri must be other than p-nitrophenyl; or

15 a stereoisomer thereof.

2. A compound according to claim 1 wherein X is CHOH.

3. A compound according to claim 1 wherein X is C=0.

4. A compound according to claim 1 wherein X is C=NOCH3.

5. A compound according to any one of the preceding claims wherein R is CORi.

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6. A compound according to claim 5 wherein Ri is p-halophenyl or p-methoxyphenyl.

7. A compound according to any one of claims 1 to 4 wherein R is 2,2,2-trihalo-ethoxymethyl.

5 8. A compound of formula I

(i)

wherein

X is C=NOCH3;

R is COR-i, CrC4alkoxy-diphenylsilyl, Ci-C4alkoxydi(Ci-C4alkyl)silyl, Cr 10 C4alkyldiphenylsilyl, or di(CrC4alkyl)phenylsilyl; and

Ri is a heteroaryl group; or a stereoisomer thereof.

9. A compound according to claim 8 wherein R is Ci-C4alkoxy-diphenylsilyl, Cr C4alkoxydi(Ci-C4alkyl)silyl, CrC4alkyldiphenylsilyl; or 2,2,2-trihalo-ethoxymethyl.

15 10. A compound selected from the group consisting of:

5-0-Methyl-LL-F28249-a; 5-0-p-chlorobenzoyl-LL-F28249-a; 5-O-p-cyanobenzoyl-LL-F28249-a; 5-0-p-fluorobenzoyl-LL-F28249-a; 5-0-isonicotinoyl-LL-F28249-a; 5-0-isonicotinoyl-23-keto-LL-F28249-a; 5-0-isonicotinoyl-23[E]-methoxime-LL-F28249-a; 5-0-nicotinoyl-LL-F28249-a; 5-0- nicotinoyl-23-keto-LL-F28249-a; 5-0-nicotinoyl-23[E]-

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methoxime-LL-F28249, 5-0-(5-chlorothiophene-2-carbonyl)-LL-F28249-a; 5-0-(5-chlorothiophene-2-carbonyl)-23-keto-LL-F28249-a; 5-0-(5-chlorothiophene-2-carbonyl)-23[E]-methoxime-LL-F28249-a; 5-0-(methoxydiphenylsilyl)-LL-F28249a; 5-0-(methoxydiphenylsilyl)-23-keto-LL-F28249a; 5-0-(methoxydiphenylsilyl)-23[E]-

> methoxime-LL-F28249a; 5-0-(ethoxydiphenylsilyl)-LL-F28249a; 5-0-

(ethoxdiphenylsilyl)-23-keto-LL-F28249a; 5-0-(ethoxdiphenylsilyl)-23[E]-methoxime-LL-F28249a; 5-0-(ferf-butoxydiphenylsilyl)-LL-F28249a; 5-0-(te/f-butoxydiphenylsilyl)-23-keto-LL-F28249a; 5-0-(ferf-butoxydiphenylsilyl)-23[E]-methoxime-LL-F28249a; 5-0-(methyldiphenylsilyl)- LL-F28249a; 5-0-(methyldiphenylsilyl)-23-keto-LL-F28249a; 5-0-0 (methyldiphenylsilyl)-23[E]-methoxime-LL-F28249a; 5-0-(2,2,2-trichloroethoxymethyl)-LL-F28249-a; 5-0-(2,2,2-trichloroethoxymethyl)-23-keto-LL-F28249-a; 5-0-(2,2,2-trichloroethoxymethyl)-23[E]-methoxime-LL-F28249-a; and a stereoisomer thereof.

11. A process for the preparation of moxidectin including:

15

1) oxidizing a compound of formula 1 according to claim 1 wherein X is CHOH to give the ketone compound of formula I according to claim 1 wherein X is C=0;

2) reacting said ketone with methoxylamine or a salt thereof to give the methoxime compound of formula I according to claim 1 wherein X is C=NOCH3; and

20

3) deprotecting said methoxime to yield the moxidectin product.

12. A process according to claim 11 wherein said methoxime is deprotected in the presence of an acid or a base.

13. A process according to claim 11 or 12 wherein said methoxime is deprotected in the presence of a base.

25 14. A process for the preparation of moxidectin including:

1)

oxidizing a compound of formula 1 according to claim 1 wherein X is CHOH to give the ketone compound of formula I according to claim 1 wherein X is C=0;

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2) deprotecting said ketone to give the 23-keto-LL-F28249-a compound; and

3) reacting said 23-keto-LL-F28249-a compound with methoxylamine or a salt thereof to yield the moxidectin product.

15. A process according to claim 14 wherein said ketone is deprotected in the 5 presence of an acid or a base.

16. A process according to claim 14 or 15 wherein said ketone is deprotected in the presence of a base.

cess for the preparation of moxidectin including:

reacting LL-F28249-a with a compound R-Hal wherein R is CORi, p-methoxybenzyloxymethyl, methoxymethyl, methylthiomethyl, [phenyldi(Ci-C^silyljmethoxymethyl, o-nitrobenzylmethyl, 2,2,2-trihalo- ethoxymethyl; o-nitrobenzyloxymethyl, 4-methoxyphenoxymethyl, 2,4-dinitrophenylsulfonyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, silyloxymethyl, 2-ethoxyethoxymethyl, 2,2,2-trichloroethyl, or 2-(trimethylsilyl)ethoxymethyl, and Ri is a substituted phenyl or substituted heteroaryl group with the proviso that Ri must be other than p-nitrophenyl; and Hal is CI, Br or I to give a compound according to claim 1 wherein X is CHOH;

oxidizing said compound wherein X is CHOH to give the ketone compound of formula I according to claim 1 wherein X is C=0;

reacting said ketone with methoxylamine or a salt thereof to give the oxime compound of formula I according to claim 1 wherein X is C=NOCH3j and deprotecting said oxime to yield the moxidectin product.

18. A process according to claim 17 wherein said methoxime is deprotected in the presence of an acid or a base.

25 19. A process according to claim 17 or 18 wherein said oxime is deprotected in the presence of a base.

17. Apro<

1)

10

15

2)

20 3)

4)

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20. A compound according to claim 1 or 8, substantially as described herein with reference to any one of the examples.

21. A process according to claim 11,14 or 17, substantially as described herein with reference to any one of the examples.

5 22. A moxidectin product whenever produced by a process according to any one of claims 11 to 19 or 21.

10

Dated: 4 August 2006 Freehills Patent & Trade Mark Attorneys

Patent Attorneys for the Applicant: Wyeth