GB2431654A

GB2431654A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431654A
Application number: GB0521752A
Authority: GB
Inventors: Stuart John Mickel
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-10-25
Filing date: 2005-10-25
Publication date: 2007-05-02
Also published as: GB0521752D0

Abstract

An alternative synthesis of certain 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives or pharmaceutically acceptable salts thereof utilises an oxazolidinone compound of formula (1a) and the reaction scheme defined in Scheme 1 therein. Novel intermediates are used in the preparation of the above target compound.

Description

Case PC/4-34593P1 1 2431654 Organic Compounds The present invention

provides new methods for preparing certain 2(S),4(S),5(S),7(S)2,7 amide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediates useful in the manufacture of the same.

More specifically, the 2(S) ,4(S) ,5(S) ,7(S)-2 amide derivatives to which the methods of the present invention apply are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Patent No. 5,559,111.

Surprisingly, it has now been found that aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using an oxazolidinone derivative of formula (Ia) as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula :::?4205 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-Ci6aIkYIoXy or C16alkoxy-C1alkyl R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16aIkanOylOXy-Ci6alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, Cl6dialkylaminO-C16alkYl, C16alkanoylaminO-C16alkyl, HO(O)C-C16alkyl, C16alkylO(O)C-Ci6alkyl, H2N-C(O)-C16alkYl, C16a1ky1-HN-C(O)-C16aIkyl or (C16alkyl)2N-C(O)Ci6alkYl or a pharmaceutically acceptable salt thereof; which method comprises starting from an oxazolidinone derivative of the formula (Ia) and following reaction steps as outlined in Scheme 1.

Case PC/4-34593P1 Scheme 1: 0 0 1) base + R)I(j(H + LVNHRS O 2) reduction R3 R3 0 (Ia) (Ib) 0 (II) (III) if base = Ph R4 protection R(('j(5 OH 0 R R-R3 3 7 (V) (M I 1) activation (Via): H I (Vib): Y Halide R2 LI... (Vic): Y= Metal 3) deprotectiofl R4 R4 OH 0 NH2 (VIII) (VII) e.g., via HN< hydroboration cc'3 OH R4 : X3N (IX) protection R9 R4 R8

HN NHR5 NHR5

2) deprotection :;OHo 1) reduction R1 R3 R2 R (A) (X) Case PC/4-34593P1 Compounds of formulae (IV) and (VII) are key intermediates in the methods of the present invention having the desired stereochemistry already at place at carbons corresponding to position 2 and 7 in the compounds of formula (A). Likewise, compounds of formula (VIII) are useful intermediates for the synthesis of compounds of formula (A) having the desired stereochemistry already at place at carbons corresponding to position 2, 5 and 7 in the compounds of formula (A). Finally, compounds of formula (IX) possessing the desired stereochemistry already at all of the stereocenters are useful as precursors to compounds of formula (A).

Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the description, appended claims, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.

As illustrated in Scheme 1, a compound of formula (Ia) wherein R3 has a meaning as defined for formula (A), may be condensed with a compound of formula (Ib) wherein R6 is C120alkyl, C312cycloalkyl, C312cycloaIkyl-C16alkyl, C610ary1 or C610aryl-C16alkyI, and X represents a leaving group such as chloride, iodide, bromide or methanesulfonate, in the presence of a suitable base and an inert organic solvent. Subsequent reduction of the resulting ester then affords a compound of formula (II) wherein R3 has a meaning as defined herein above. Both compounds of formulae (Ia) and (Ib) are known, or if they are novel they may be prepared using methods well know in the art. As illustrated in Scheme 1, chirality is induced by employing Evans technology (oxazolidinone, e.g., R'). Suitable bases employed in the condensation include, but are not limited to, n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyl-disilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide. Commonly used solvents are, e.g., tetrahydrofuran (THF), dichloromethane, toluene, and the condensation reaction is preferably performed at a temperature ranging from about -78 C to room temperature. The subsequent reduction may be conducted using a suitable reducing agent such as Red-AL or di-isobutylaluminium hydride (DIBAL-H) in an inert organic solvent such as TI-1F to provide an aldehyde of formula (Il).

A compound of formula (II) wherein R3 has a meaning as defined herein above, may then be reacted with a compound of formula (Ill) wherein R4 and R5 have meanings as defined for formula (A), in the presence of a suitable base and an organic solvent, e.g., those described Case PC/4-34593P1 herein above for the condensation step, to give a compound of formula (IV) wherein R3, R4 and R5 have meanings as defined herein above. Compounds of formula (Ill) are known, or if they are novel they may be prepared using methods well know in the art.

A resulting compound of formula (IV) wherein R3, R4 and R5 have meanings as defined herein above, may then be converted to a compound of formula (V) wherein R3, R4 and R5 have meanings as defined herein above, and R7 represents an 0-protecting group such as (C18alkyl)3silyl, e.g., t-butyldimethylSilyl, by first protecting of the hydroxyl group in a compound of formula (IV) as a silyl ether, followed by removal of the oxazolidinone group (R'). The protection of the hydroxyl group may be conveniently achieved by employing t-butyldimethylsilyl chloride or corresponding trifluoromethanesulfOflate in the presence of a base such as triethylamine, pyridine or 2,6-lutidine in an organic solvent such as THF or dichloromethane. Removal of the oxazolidinone may be carried out according to methods well known in the art, e.g., using lithium peroxide in an organic solvent such as THF.

A resulting carboxylic acid of formula (V) wherein R3, R4, R5 and R7 have meanings as defined herein above, may then be converted to its activated derivative using methods well known in the art. A subsequent reaction with an organometallic compound of formula (Vic) wherein R1 and R2 have meanings as defined for formula (A), and Y is, e.g., lithium, or a compound of formula (VIc) represents a Grignard reagent, followed by removal of the 0-protecting group, then affords a compound of formula (VII) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above.

In the processes cited above, an activated derivative of a carboxylic acid of formula (V) include acid chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters, and activated esters thereof, and the like. Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or isobutyl analogs. Activated esters include, for example, succinimido, phthalimido or 4-nitrophenyl esters. The reaction of an activated derivative of a carboxylic acid of formula (V) with an organometallic compound of formula (Vic) may be carried out, e.g., in the presence of catalysts, e.g., palladium catalysts, and/or an additive, e.g., TMEDA, DMPU or HMPA, or a Lewis acid, e.g., ferric chloride in an organic solvent such as THF or toluene at low temperature.

Removal of the 0-protecting group may be carried out using reaction conditions well known in the art, e.g., using camphorsuiphonic acid (CSA) in methanol/water, preferably, at room temperature.

Case PC/4-34593P1 A compound of formula (VII) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, may then be converted to a compound of formula (VIII) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, through an imidate rearrangement. The rearrangement may be conducted according to methods known in the art, e.g., via reaction with trichloroacetonitrile in the presence of a base such as potassium t-butoxide.

A resulting compound of formula (VIII) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, may then be subjected to conditions of chiral hydroboration to form a compound of formula (IX) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above. The chiral hydroboration reaction may be conducted according to methods known in the art, e.g., using pinylborane followed by treatment with hydrogen peroxide and aqueous sodium hydroxide.

A compound of formula (IX) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, may be converted to a compound of formula (X) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, and R8and R9 are independently hydrogen, C16aIkyl or C610ary1, or R8 and R9 combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring, using reaction conditions well known in the art.

Finally, a compound of formula (X) may be converted to compounds of formula (A) wherein R1, R2, R3, R4 and R5 are as defined herein above, according to methods well known in the art, e.g., by first reducing the carbonyl group using hydrogen in the presence of a catalyst, e.g., palladium on carbon, and an organic solvent such as ethanol, followed by deprotection under acidic conditions, e.g., aqueous hydrochloric acid.

Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.

As an alkyl, R1 may be linear or branched and preferably comprise I to 6 C atoms, especially I or 4 C atoms. Examples are methyl, ethyl, n-and i-propyl, n-, I-and t-butyl, pentyl and hexyl.

As a halogenalkyl, R1 may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

Case PC/4-34593P1 As an alkoxy, R1 and R2 may be linear or branched and preferably comprise I to 4 C atoms.

Examples are methoxy, ethoxy, n-and i-propyloxy, n-, i-and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises I to 4 C atoms.

Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C16alkoxy-C16alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethylOxy and 2-butyloxyethyloxy.

In a preferred embodiment, R1 is methoxy-or ethoxy-C14alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula (A), wherein R1 is 3-methoxypropyloxy and R2 is methoxy.

As a branched alkyl, R3 and R4 preferably comprise 3 to 6 C atoms. Examples are i-propyl, i-and t-butyl, and branched isomers of pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula (A) are in each case i-propyl.

As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.

As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise 1 to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, i-and t-butyl are preferred.

Case PC/4-34593P1 As a C16hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms.

Some examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3-or 4-hydroxybutyl, hydroxypentyl and hydroxyhexyl.

As a C16alkoxy-C16alkyl, R5 may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.

As a C1.6alkanoyloxy-Cl6alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

As a C16aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms.

Some examples are 2-aminoethyl, 2-or 3-aminopropyl and 2-, 3-or 4-aminobutyl.

As C16alkylamino-Ci6alkyl and C16dialkylamino-C16alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C14alkyl groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2- ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C1.6alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a C16alkyl-O-(O)C-C16alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another I to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonyiprOpyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonyl propyl, and 4-ethoxycarbonylbutyl.

As a H2N-C(O)-C16alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethYl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-I,2-dimethylpropyl, 3-carbamido-3-ethylprOpyl, 3-Case PC/4-34593P1 carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a C16alkyl-HN-C(O)-C16a1ky1 or (C16a1kyl)2N-C(O)-C16alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined herein above, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.

As an alkyl, R6, R8 and R9 may be linear or branched and comprise preferably I to 12 C atoms, 1 to 8 C atoms being especially preferred. Particularly preferred is a linear C14alkyl.

Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl. Especially preferred are methyl and ethyl.

As a cycloalkyl, R6 may preferably comprise 3 to 8 ring-carbon atoms, 5 or 6 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclododecyl.

As a cycloalkyl-alkyl, R6 may comprise preferably 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred, and preferably I to 4 C atoms in the alkyl group, I or 2 C atoms being especially preferred. Some examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopentylethyl, and cyclohexylmethyl or 2-cyclohexylethyl.

As an aryl, R6, R8 and R9 are preferably phenyl or naphthyl.

As an aralkyl, R6 is preferably benzyl.

In a preferred embodiment, R6, R3 and R9 are methyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::oN NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are i-propyl; or a pharmaceutically acceptable salt thereof.

Case PC/4-34593P1 Further preferred are the methods of the present invention, wherein a compound of formula (B) is benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

Compounds of the formula R4 O 0 N NHR5 (IV) OH 0

R Ph

wherein R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C16alkyl,C16aminoalkyl, C1aIkylamino-C16aIkyl, C16dialkylamino-C16aIkyl, C16alkanoylamino-C1..6aIkyI, HO(O)C-C16a1ky1, C1..6aIkyI-O-(O)C-C16aIkyl, H2N-C(O)-C16a1ky1, C16a1kyl-H N-C(O)-C16aIkyl or (C16a1ky1)2N-C(O)-C16aIkyl: are useful as intermediates for the preparation of compounds of formula (A).

Preferred are the compounds of formula (IV) wherein R3 and R4 are i-propyl.

Compounds of the formula (VII) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C1.6alkyloxy or C1.6alkoxy-C16alkyI; R2 is halogen, C1.4aIkyI or C14aIkoxy; R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16atkyl, C16hydroxyalkyl, C16alkoxy-C16aIkyI, C16alkanoyloxy-C16alkyI, C16aminoalkyl, C16alkylamino-C16alky1, C16dialkylamino-C16a1ky1, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, C16a1ky1-O-(O)C-C15a1ky1, H2N-C(O)-C16alkyI, C16alkyl-H N-C(O)-C16aIkyl or (C16a1ky1)2N-C(O)-C16a1ky1; are also useful as intermediates for the preparation of compounds of formula (A).

Preferred are the compounds of formula (VII) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are i-propyl.

Compounds of the formula Case PC/4-34593P1 (VIII) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyIoxy or C16alkoxy-C1alkyI; R2 is halogen, C1..4aIkyI or C14aIkoxy;R3 and R4 are independently branched C3..6aIkyl; and R5 is cycloalkyl, C1aIkyI, C16hydroxyaikyl, C16aIkoxy-C16a1ky1, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16aIkyIamino-C16alkyi, C16dialkylamino-C16a1ky1, C16alkanoylamino-C16a1ky1, HO(O)C-C16alkyl, C16aIkyl-O-(O)C-C16a1ky1, H2N-C(Q)-C16a1ky1, C16a1ky1-H N-C(O)-C16alkyI or (C16alkyl)2N-C(O)-Ci6aikyI; are also useful as intermediates for the preparation of compounds of formula (A).

Preferred are the compounds of formula (VIII) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are i-propyl.

Compounds of the formula 0 OH R4 R2 (IX) wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16alkyloxy or C16alkoxy-C16aIkyl; R2 is halogen, C14a1ky1 or C14alkoxy;R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16aIkyI, C16hydroxyalkyi, C16aIkoxy-C16a1ky1, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16alkylamino-Ci6aIkyI, C16dialkylamino-Ci6alkyI, C16alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C16a1ky1-O-(O)C-C1..6aIkyl, H2N-C(O)-C16alkyl, C16a1ky1-H N-C(O)-C16a1ky1 or (C16aIkyl)2N-C(O)-Ci6aIkyl; are also useful as intermediates for the preparation of compounds of formula (A).

Preferred are the compounds of formula (IX) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are i-propyl.

As indicated herein above, compounds of the present invention can be converted into acid addition salts. The acid addition salts may be formed with mineral acids, organic carboxylic acids or organic sulfonic acids, e.g., hydrochloric acid, fumaric acid and methanesulfonic acid, respectively.

Case PC/4-34593P1 In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The present invention further includes any variant of the above process, in which an inter-mediate product obtainable at any stage thereof is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.

When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxyl, thiol etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistnj', Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.

Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, Case PC/4-34593P1 methylisobutylketone, cyctohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n-or i-propanol, n-, i-or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitrites (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyr-rolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

The processes described herein above are preferably conducted under inert atmosphere, more preferably under nitrogen atmosphere.

Compounds of the present invention may be isolated using conventional methods known in the art, e.g., extraction, crystallization and filtration, and combinations thereof.

Claims

Case PC/4-34593P1 What is claimed is: 1. A method for preparing a

compound of the formula ::oR5 (A) wherein R1 is halogen, C16halogenalkyl, C15alkoxy-C16alkyloxy or C15alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C14alkyl; and R5 is H, cycloalkyl, C1.6alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, C16a1ky1-O-(O)C-C16alkyl, H2N-C(O)-C16alkyl, C16a1ky1-HN-C(O)-C16alkyl or (C15alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from an oxazolidinone derivative of formula (Ia) and following reaction steps as outlined in Scheme 1.

2. A method according to claim 1, wherein a compound of formula (A) has the formula NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,5S,7S)- 5-amino-4-hyd roxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl] -8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

4. A compound of the formula R4 (IV) i.. R3 wherein R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16alkyl, Case PC/4-34593P1 C16hydroxyalkyl, C1alkoxy-C16alkyl, C16alkanoyloxy-C16alky1,C1..6aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16alkyI, C16alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C16alky1-O-(O)C-C16a1kyl, H2N-C(O)-C16alkyI, C16a1ky1-H N-C(O)-C16alky1 or (C16a1ky1)2N-C(O)-C16a1ky1; are useful as intermediates for the preparation of compounds of formula (A).

5. A compound according to claim 4, wherein R3 and R4are 1-propyl.

6. A compound of the formula (VU) wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16alkyloxy or C16aIkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy;R3 and R4 are independently branched C3..6aIkyI; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1.6alkoxy-C16a1ky1, C16alkanoyloxy-C1.6alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16a1ky1, C16alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C16a1ky1-O-(O)C-C16a1ky1, H2N-C(O)-C16a1ky1, C16a1ky1-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-C16aIkyl; are also useful as intermediates for the preparation of compounds of formula (A).

7. A compound according to claim 6, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4are i-propyl.

8. A compound of the formula (VIII) wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16aIkyloxy or C16alkoxy-C15a1ky1; R2 is halogen, C14a1ky1 or C14alkoxy;R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16aIkyl, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16aIkyl, C1.6alkanoylamino-C16aIkyI, HO(O)C-C1.6alkyl, C16alkyl-O-(O)C-C16alkyI, H2N-C(O)-C16a1ky1, C16alkyl-H N-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C16a1ky1; are also useful as intermediates for the preparation of compounds of formula (A).

Case PC/4-34593P1 9. A compound according to claim 8, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4are i-propyl.

10. A compound of the formula 0 OH R4 R (IX) wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy;R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16alkyl, C1..6hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-Ci6alkyl, C16dialkylamino-C16alkYl, C16alkanoylamino-C1.6aIkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16aIkYl, H2N-C(O)-C16aIkyl, C16alkyl-H N-C(O)-C16a1ky1 or (C16alkyl)2N-C(O)-C16aIkYl are also usefu' as intermediates for the preparation of compounds of formula (A).

11. A compound according to claim 10, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4are i-propyl.