GB2431645A

GB2431645A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431645A
Application number: GB0521728A
Authority: GB
Inventors: Wolfgang Marterer
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: GB0521728D0

Abstract

An alternative synthesis of 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds or pharmaceutically acceptable salts thereof which uses the synthetic pathway detailed in Scheme 1, starting with 3-D-hydroxyaspartic acid. Novel intermediates are used in the preparation of the above target compound.

Description

Case PC/4-34586P1 Methods for the Preparation of Organic Compounds The

present invention provides methods for preparing certain 2(S),4(S),5(S),7(S)-2,7-diaIkyI4hydroxy-5-aminO-8-arYl-OCtanOYI 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 applies are any of those having lenin 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 2(S) ,4(S) , 5(S),7(S)2,7dialkyl4hydrOXY-5-aminO- 8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using 3-hydroxyaspartiC acid, in particular, D-3-hydroxyaspartic acid, as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula ::42oR5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkylOXY or C16alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched Calkyl; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-Ci-6alkyI, C16aminoalkyl, C16aIkylamiflO-C16alkYl, C16dialkylamino-C16alkyl, C1aIkanoylamino-C16alkyl, HO(O)C-C16alkYl, C16a1ky1-O-(O)C-Ci 6alkyl, H2N-C(O)-C16alkyl, C1alkyl-HN-C(O)-C16alkyl or (C16alkyl)2N-C(O)-Cl6alkYl or a pharmaceutically acceptable salt thereof; which method comprises starting from D-3-hydroxyaspaltic acid and following reaction steps as outlined in Scheme 1.

Case PC/4-34586P1 Scheme 1: A method for preparing a compound of formula (A) starting from 0-3-hydroxyaspartic acid.

HOIiOH a R\OR6 o N R\H H2NOH R9 R9 0 (Ia) (I') (IV) R-co R y 2R10 (Ib) R4 HO c R4 R1002C C02R10 R10O2cco2R10 .4 -/2 R4 -N R8 -N R9 R( R7 R9 (VII) (VI) R4 : Xlb: Y= Hal R RR7 R9 "R7 R1)(Y I Xla:Y=H R2 L__. Xlc: Y Metal (VIII) (XlIa-c) (IX) OH R4 (A) :REoN R5 (X) Compounds of formula (V), wherein R3 and R4 are as defined for formula (A); R6 is C1.

20alkyl, C312cycloalkyl, C312cycloalkyl-C16alkyl C610ary1 or C610ary1-C16alkyI; R7 and R9 are Case PC/4-34586P1 N-protecting groups independent from each other such as C6..10aryl-C1alkyI, C1aIkyl-carbonyl, C610aryl-carbonyl, C16alkoxy-carbonyl, C610aryl-C16alkoxycarbonyl; or R7 and R9 combined form phthalimide; R8 is 0-protecting group such as C16alky1, C1alkoxy-C1 6alkyloxy, C6..10aryl-C1.6aIkyl or (C18alkyl)3silyl; or R7 and R8 combined together represent CR11R12 in which R11 and R12 are independently hydrogen, C16a1kyl or C610ary1; or R11 and R12 combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; and R10 is C120alkyl, C312cycloaIkyl, C312cycIoaIkyI-C16alkyl, C 10aryl or C610ary1-C16a1kyl; are key intermediates in the methods of the present invention having the desired stereochemistry at carbons 4 and 5 already at place as inherited from the starting material, D-3-hydroxyaspartiC acid of formula (Ia). Furthermore, compounds of formula (V) are suitable substrates for an asymmetric hydrogenation reaction affording compounds of formula (VI) under which conditions the desired stereochemistry at carbons 2 and 7 may be induced. Such asymmetric hydrogenation reactions are well known in the art.

As illustrated in Scheme 1, compounds of formula (V) may be obtained starting by esterification of D-3-hydroxyaspartic acid of formula (Ia), followed by simultaneous or sequential protection of the hydroxyl and the amino group depending on the nature of R7, R8 and R9 to afford a compound of formula (Ill) wherein R7, R8 and R9 are as defined herein above, and R6 is C120alky1, C3.12cycloalkyl, C312cycloalkyl-C16alkyl, C6..10aryl or C610aryl-C16alkyl as further illustrated in Scheme 2 below.

Scheme2: Conversion of a compound of formula (Ia) to a compound of formula (Ill).

Case PC/4-34586P1 HOOH HO1OR R8O1OR R8OOR H2N R7HN,L1OR6 R9R7N 0 0 0 0 (Ia) (II) (III') (III) H0OH HOOR R9HN,.L..,OH R9HN 0 0 (I') (II') Subsequent reduction of the ester groups in a compound of formula (Ill) under reaction conditions well known in the art then yields an aldehyde of formula (IV). Finally, a Wittig-Horner-Wadsworth-Emmons-reaction of an aldehyde of formula (IV) with a compound of formula (Ib) wherein R10 has a meaning as defined herein above, and R' represents either R3 or R4, affords a compound of formula (V). It should be noted that when R3 and R4 are different two sequential Wittig-reactions may be carried out using the appropriate phosphine derivative of formula (Ib).

Subsequently, compounds of formula (VI) may be converted to compounds of formula (A) wherein R1, R2, R3 and R4 are as defined herein above, by carrying out the remaining steps as outlined in Scheme I using reaction conditions as described herein or according to methods well known in the art.

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.

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 Case PC/4-34586P1 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 I to 4 C atoms, especially I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichioromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

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 C1..6alkoxy-C16alkyloxy, R1 and R8 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially 1 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.

Case PC/4-34586P1 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 I to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, i-and t-butyl are preferred.

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-C16aIkyl, R5 may be linear or branched. The alkoxy group preferably comprises I 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 C16alkanoyloxy-C16a1ky1, 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 C1aminoalkyI, 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-C16alkyl and C16dialkylamino-C16aIkyl, 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-methylam i nopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

Case PC/4-34586P1 As a HO(O)C-C16a1ky1, 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 C16a1ky1-O-(O)C-C16a1ky1, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, 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-1,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a C16a1ky1-HN-C(O)-C16alkyl or (C16a1ky1)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, R7, R8, R9, R10, R11 and R12 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 and R10 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 and R10 may comprise preferably 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1 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 cyclohexyl methyl or 2-cyclohexylethyl.

Case PC/4-34586P1 As an alkoxycarbonyl, R7 and R9 may comprise a linear or branched alkyl group which preferably comprises I to 4 C atoms. Examples are methoxy, ethoxy, n-and i-propyloxy, n-i-and t-butyloxy, pentyloxy and hexyloxy.

In a preferred embodiment, R9 is t-butoxy-or benzyloxycarbonyl, and R7 and R8 combined together represent CR11R12 in which R11 and R12 are methyl; or R11 is hydrogen and R12 is phenyl.

As an aryl, R6, R10, R11 and R12 are preferably phenyl or naphthyl.

As an aralkyl, R6, R8 and R10 are preferably benzyl or phenethyl.

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

Further preferred are the methods of the present invention, wherein a compound of formula (B) is (2S,4S, 5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

Preferably, the key intermediate of formula (V) has the formula R10O2CCOR a) R11 R12 wherein R3 and R4 are independently branched C14a1ky1; R9 is C16alkoxy-carbonyl or C6aryl-C1alkoxy-carbonyl; R11 and R12 are C16a1ky1; and R10 is C16alkyl.

Case PC/4-34586P1 Further preferred are the compound of formula (Va), wherein R3 and R4 are isopropyl; R9 is t-butoxy-or benzyloxycarbonyl; R10 is methyl or ethyl; and R11 and R12 are methyl.

Preferably, the key intermediate of formula (VI) has the formula R10O2C (Via) R11 R12 wherein R3 and R4 are independently branched C14alkyl; R9 is C16alkoxy-carbonyl or C6aryl-C1alkoxy-carbonyl; R11 and R12 are C16alkyl; and R10 is C16alkyl.

Further preferred are the compound of formula (Via), wherein R3 and R4 are isopropyi; R9 is t-butoxy-or benzyloxycarbonyl; R10 is methyl or ethyl; and R11 and R12 are methyl.

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.

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, e.g. a compound of formula (III), formula (IV), formula (V), formula (Vi), formula (VII), formula (VIII), formula (IX) or formula (X) 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 -10-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 Chemist,'J', 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, di methylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); 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; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

Case PC/4-34586P1 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.

A reaction of compound (Ia) to yield compound (II) according to Scheme 2 and a reaction of compound (I') to yield compound (II') according to Scheme 2: A compound of formula (Ia) and a compound of formula (I') can be esterified by treatment of the corresponding carboxylic acids by heating with alcohols in the presence of an acid catalyst such as hydrogen chloride (Fisher esterification), or with an alkylating agent such as trimethylsilyldiazomethane (Angewandte Chemie International Edition 1999, 38, 3197 - 3201). A compound of formula (II) and a compound of formula (II') can also be made from other carboxylic acid derivatives, especially acyl halides and anhydrides, by reacting them with the appropriate alcohol in the presence of a weak base. The reaction is preferably carried out with hydrogen chloride in methanol or ethanol as a solvent at temperatures between 0 C and the boiling point of the reaction mixture, preferably at 20 C-80 C to provide compounds of formula (II) and (II').

A reaction of a compound of formula (II) to yield a compound of formula (Ill') according to Scheme 2 and a reaction of compound of formula (II') to yield a compound of formula (Ill) according to Scheme 2: Synthetic methods to prepare the compounds of the presents invention employ protective groups to mask a reactive functionality or minimize unwanted side reactions. In certain cases the protecting groups can additionally cause the reactions to proceed selectively, for example stereoselectively. Such protective groups are described in T.W. Green, in Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, 1999. The amino and hydroxyl groups present in a compound of formula (Ila) and a compound of formula (IlIb) can be protected simultaneouslyr by means of a bivalent protecting group, e.g. lower alkylidene such as isopropylidene, cyclohexylidene, or benzylidene. As there are several protecting groups involved in the synthesis of a compound of formula (Ill), they can be selected such as more than one protecting group can be removed simultaneously, for example by acidolysis, e.g. trifluoroacetic acid, or with hydrogen and an hydrogenation catalyst, such as palladium-on-carbon catalyst. These protecting groups can also be selected in such a way they are not all removed simultaneously, but rather removed in the Case PC/4-34586P1 -12 -desired sequence or only some of them are removed (WO 2004/013035). Compounds of formula (II) and (II') can be treated for example with 2,2-dimethoxypropane in the presence of an acid such as methylbenzensulfonic acid or p-toluenesulfonic acid to provide compounds of formula (Ill) (WO 2004/013035). The reaction is carried out preferably at temperatures between 20 C and the boiling point of the reaction mixture.

A reaction of compound of formula (I) to yield compound of formula (I') according to Scheme 2 and a reaction of compound of formula (III') to yield compound of formula (Ill) according to Scheme 2: Protective groups for the amino group are described in T.W. Green, in "Protective Groups in Organic Synthesis", 3' edition, John Wiley & Sons, 1999. The amino protecting group can refer to carbamates such as tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthalimide, or amides derivatives such as acetamide and benzamide and derivatives thereof as known to the art. The amino group is preferably protected as benzyloxycarbamate, or as another carbamate derivative. The reaction is preferably carried out in the presence of sodium bicarbonate or triethylamine in a mixture of solvent, preferably water/dioxane or water/tetrahydrofuran, at temperatures between -10 C and the boiling point of the reaction mixture, preferably at 0 C-20 C (Tetrahedron Lett.

1966, 7, 4765-4768).

Reaction of compound (Ill) to yield compound (IV) according to Scheme 1: Reacting a compound of formula (Ill) to yield a compound of formula (IV) is for the reduction of the carboxylic acid ester functions to carbonyl functions. The reduction of a carboxylic acid ester to an aldehyde can be achieved either a) directly or b) indirectly by reduction of the carboxylic acid ester to the corresponding alcohol and its subsequent oxidation, or C) indirectly by hydrolysis of the carboxylic acid ester to the corresponding carboxylic acids or carboxylate, its conversion to an acyl halogenide followed by hydrogenation. The reduction of esters to aldehydes and alcohols are known per se and for example described in "Organikum, organisch-chemisches Grundpraktikum', 17th revised edition, VEB Deutscher Verlag derWissenschaften, Berlin 1988.

a) Generally the reduction of carboxylic acid esters to aldehydes is carried out with aluminumhydrides in aliphatic or aromatic hydrocarbons such as hexane, toluene, and xylenes, and cyclic or acyclic ethers such as tetrahydrofuran and diethylether as solvent at Case PC/4-34586P1 -13-temperatures between -78 C and the boiling point of the reaction mixture, preferably with diisobutylaluminumhydride in toluene at -78 C (J. Org. Chem. 1994, 59, 932).

b) Generally the reduction of esters to alcohols is carried out with aluminum hydrides or trialkylborohydrides in cyclic or acyclic ethers (inert to these hydrides) such as tetrahydrofuran or diethylether as solvent at temperatures between -78 C and the boiling point of the reaction mixture, preferably with lithiumaluminum hydride in tetrahydrofuran at 20 C-30 C (J. Org. Chem. 1994, 59, 932-934). Also hydrogen in the presence of suitable catalysts may be used. Catalysts suitable for hydrogenation are metals, for example nickel, iron, cobalt or ruthenium, or noble metals or their oxides, such as palladium or rhodium or their oxides, optionally supported on a suitable carrier such as Raney nickel. The oxidation of alcohols to aldehydes can be achieved with any agent able to oxidize the primary alcohol group to the corresponding aldehyde without preventing the further reaction of the aldehyde. Thus, the oxidizing agent may be any sLlitable chemical agent or biological agent. Preferably the oxidizing agent is a chemical agent. Oxidation reactions of alcohols to aldehydes are known per se and for example described by M. Hudlicky in "Oxidations in Organic Chemistry", ACS: Washington 1990. The oxidation of alcohols to aldehydes can be carried out for instance with dimethylsulfoxide and acetic anhydride, with dimethylsulfoxide and dicyclohexylcarbodiimide in the presence of an acid, with dimethylsulfoxide and oxalyl chloride and a base such as triethylamine, with dimethylsulfoxide and sulfur trioxide and a base such as pyridine, with aqueous sodium hypochlorite in the presence of potassium bromide and 2,2,6,6-tetramethylpiperidin-1-oxyl, with n-methylmorpholine-N-oxide/sodium hypochlorite in the presence of tetrapropylammoniurn perruthernate, with pyridinium chlorochromate in the presence of sodium acetate, with o-iodoxyperbenzoic acid, or with manganese dioxide in solvents such as dichloromethane at temperatures between -78 C and 30 C, preferably with dimethylsulfoxide and acetic anhydride at ambient temperature (Carbohydr. Res. 1988, 174, 369).

c) The hydrolysis of esters are also known per se and for example described by T. W: Green in "Protective Groups in Organic Synthesis", 3Id edition, John Wiley&Sons 1999, p. 377. Generally the hydrolysis of esters to carboxylic acids or carboxylates are carried out for example with metal hydroxides or alkoxide in aqueous solvent mixtures such as water/ethanol or water/dimethylformamide at temperatures between -30 C and the boiling point of the reaction mixture, with metal halogens in the presence of a trimethylsilyl halogenide in a polar aprotic solvent such as acetonitrile or dimethylformamide at Case PC/4-34586P1 -14-temperatures between 000 and the boiling point of the reaction mixture, with Lewis acids such as boron halogenides, aluminum trihalogenides in the presence of thiols, alkyltinoxides in apolar solvents such as dichloromethane or benzene at temperatures between -20 C and the boiling point of the reaction mixture, preferably with sodium hydroxide in ethanol at 60 C-100 C (Tetrahedron 1997, 53, 13757). The conversion of a carboxylic acid or carboxylate to an acyl hatogenide sLich as an acyl chloride is generally performed with oxalyl chloride alone or in presence of a base such as pyridine in a solvent such as dimethylformamide, by deprotonation of the carboxylic acid with a base such as lithium hydroxide followed by treatment of the obtained carboxylate with trimethylsilyichioride and oxalylchloride, with thionyl chloride alone or in presence of a base such as lithium hydride, in anhydrous solvents such as toluene or benzene, preferably by treatment of a carboxylate with oxalyl chloride at 5 C-65 C (Tetrahedron 1997, 53, 13757). The reduction of acyl chlorides to aldehydes is generally performed with hydrogen in the presence of a metal catalyst such as palladium under atmospheric pressure or at higher pressure usually between 0 C and the boiling point (or apparent boiling point at elevated pressure) of the best boiling component of the reaction mixture. A typical catalyst is palladium on barium sulfate (Rosenmund reduction -Rec. Tray. Chim 1981, 100, 21). Other metal support catalysts such as palladium on carbon or on a polymer in the presence of quinoline and sulfur, preferably with hydrogen at atmospheric pressure in the presence of palladium on poly(p-phenylene terephthalamide) in acetone at 300-90 C can be used (Org.Process Research & Development 1997, 1, 226). Furthermore, the reduction of acyl halogenides to aldehydes can be done for example in the presence of a metal hydride derivative such as lithium tri-(tert-butoxy)aluminum hydride (LiAIH(O-t-Bu)3) in ethanol at -78 C (J. Org. Chem. 2002, 67, 9186-9191) or using sodium borohydride and pyridine in N,N-dimethylformamide (Synthetic Communications 1982, 12, 839-846) A reaction of compound of formula (IV) to yield compound of formula (V) according to Scheme 1: The reaction of a compound of formula (IV) to yield compound (V) is known as Wittig-Horner-Wadsworth-Emmons-reaction and has been described for analogous compounds (Compr. Org. Synth. 1991, 1, 755). The alkene double bond formed in the compound (V) may be cis or trans depending of the Horner-Wadsworth-Emmons phosphonate reacting with the aldehyde. A ompound of formula (IV) reacts preferably under an inert gas such as argon or nitrogen, in a solvent not adversely affecting the reaction, such as tetrahydrofuran Case PC/4-34586P1 or dimethylformamide, if necessary by addition of a halide of an alkali metal or an alkaline earth metal, such as lithium chloride, lithium bromide or magnesium bromide, and further by addition of a base, e.g. a tertiary amine such as 1,8-diazabicyclo[5.4.O]undec-7-ene, triethylamine or diisopropylethylamine, or a hydride, hydroxide, alcoholate, or alkylated product of an alkali metal such as sodium hydride, sodium hydroxide, sodium ethoxide, an alkoxide salt such as butyl lithium or an alkali metal 1,1,1,3,3,3-hexamethyldisilazane salt at temperatures between -78 C and the boiling point of the reaction mixture, preferably by reacting compound (IV) with bis-(2, 2, 2-trifluoroethoxy)phosphoryl)-3-methylbutyric acid methyl ester and potassium 1,1,1,3,3,3-hexamethyldisilazane in tetrahydrofuran at a temperature between -78 C and 30CC (Tetrahedron Lett. 1992, 33, 1411) in order to obtain the Z,Z-configured bis olefine of formula (V).

A reaction of compound of formula (V) to yield a compound of formula (VI) according to Scheme 1: The C=C-bond in a compound of formula (V) can be reduced with hydrogen in the presence of a chiral or achiral metal catalyst to obtain a compound of formula (VI). The hydrogenation of C=C-bonds is typically run at atmospheric pressure or at elevated pressure, from 0.5 to 200 bar and preferably 1 to 50 bar. Pure hydrogen or hydrogen diluted with an inert gas may be used for the reaction. The amount of catalyst added to the reactions will depend upon the reaction conditions as well as the reactivity of the substrate (i.e. compound to be hydrogenated), typically in the range of 1:100-5000 (metal-substrate molar ratio). The reaction is usually run in the presence of a solvent chosen from aliphatic hydrocarbons such as hexane, heptane and the like, aromatic hydrocarbons such as toluene, xylenes and the like, cyclic or acylic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, lower alcohols such as methanol, ethanol, n-propanol, isopropanol and the like, halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chloroform and the like, dialkyl ketones such as acetone, methyl isobutyl ketone and the like or polar aprotic solvents such as dimethylformamide, dimethylsulfoxide and the like. The reaction is run at temperatures which afford a reasonable rate of conversion and can be as low as -200 but is usually between 0 C and the boiling point (or apparent boiling point at elevated pressure) of the best boiling component of the reaction mixture. Achiral hydrogenation catalysts are for instance rhodium on carbon, palladium black, palladium on carbon or platinum oxide.

Case PC/4-34586P1 -16-Thus, a compound of formula (V) is preferably hrydrogenated in the presence of rhodium on carbon at 1-5 bar in methanol (Tetrahedron Letters 2001 42(46), 8207-8210; J. Org. Chem. 1988, 53, 4505). The diastereoselectivity of a hydrogenation can be improved by using a homogeneous or heterogeneous catalysts bearing one or more chiral ligands. For the asymmetric hydrogenation, the metal complex is typically a metal such as rhodium, ruthenium, or iridium, and preferably rhodium. The diastereoselectivity of the hydrogenation of a given substrate is influenced in some cases by parameters such as the reaction temperature, the hydrogen pressure, the nature of the solvent and the presence of additives. Thus, the hydrogenation of a compound of formula (V) is preferably carried out with a chiral catalysts such as for example BINAP-Ru, BINAP-Rh or DIPHOS-Rh in the presence of iso-propanol at 20 C-60'C at 1-5 bar (Tetrahedron:Asymmetry 1997, 8, 863- 871, Tetrahedron Letters 1998, 39, 233-236).

A reaction of a compound of formula (VI) to yield a compound of formula (VII) according to Scheme 1: The reaction of a compound of formula (VI) to a compound of formula (VII) involves the deprotection of the hydroxyl-function and the intramolecular substitution of an alkylester under formation of a lactone. The deprotection of hydroxyl and amino functions protected as acetal is known per se and has been described by T. W. Green, in "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, 1999. In the case of an N,O-acetal, the deprotection is generally performed with Bronsted acids such as hydrochloric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic or other sulfonic acids in protic solvents such as methanol, ethanol, water with or without a co-solvent such as tetrahydrofuran or another ether, or with a Lewis acid such as boron trichioride, iron trichloride, or trimethylaluminum in an aliphatic or aromatic hydrocarbon as solvent such as hexane, heptane, toluene or xylene followed by an aqueous work-up. The cleavage of the N, C acetal in compound VII is preferably carried out in methanol at 20 C-30'C in the presence of p-toluenesulfonic acid (J. Org. Chem. 1992, 59, 5811), reaction conditions which lead to the intramolecular substitution of a carboxylic acid ester by the deprotected hydroxyl-function and the formation of the lactone.

A reaction of a compound of formula (VII) to yield a compound (VII) according to Scheme 1: The conversion of a compound of formula (VII) to a compound of formula (VIII) involves the reduction of a carboxylic acid to an alcohol. Carboxylic acids are reduced to the Case PC/4-34586P1 -17-corresponding alcohols in a solvent such as methanol, ethanol, tetrahydrofuran, dimethylformamide or dimethylacetamide by means of a metal hydride complex compound such as sodium borohydride or diisobutylaluminum hydride, in a temperature range of approximately from -78 C to the boiling point of the reaction mixture, preferably from -10 C to 50 C for diisobutylaluminuni hydride. Especially borane is commonly used for the reduction of carboxylic acids in the presence of others reactive functionalities such as lactones (J. Am. Chem. 1977, 99, 8218-8226, J. Org. Chem 1973, 38, 2786). The reaction can be carried out with borane as a complex with tetrahydrofuran or with borane as a complex with dimethylsulfide in tetrahydrofuran as solvent in a temperature range of approximately from -60 C to the boiling point of the reaction mixture, preferably from -20 C to 50 C. Alternatively, a compound of formula (VIT) can be transformed into the corresponding mixed anhydride followed by its reduction with sodium borohydride in a mixture of tetrahydrofuran and methanol (Synthesis 1987; 647-64). This reaction is typically carried out in a temperature range of approximately from -60 C to the boiling point of the reaction mixture, preferably from -20 C to 50 C. Compounds of formula (VII) can also be converted into the corresponding Weinreb amide derivative followed by its reduction with LiEt3BH. This reaction is typically carried out in a temperature range from -60 C to the boiling point of the reaction mixture, preferably from -20 C to 50 C.

A reaction of a compound of formula (VIII) to yield a compound of formula (IX) according to Scheme 1: The transformation of a compound of formula (VIII) involves the conversion of the hydroxyl-function to a halide. Such transformations are typically carried out with reagents such thionyl chloride, phosphorus halides, phenylmethyleneiminium halides, benzoxazolium halides, Vilsmeier-Haack and Viehe salts (Organic Letters 2002, 4, 553-555 and references cited therein).

Alternatively, a compound of formula (VIII) may be treated with a mineral acid such as hydrogen chloride or hydrogen bromide in organic solvents, preferably a polar organic solvent, at temperatures between 300C to the boiling point of the solvent, preferably in the presence equivalent of a base, preferably in the presence of triethylamine or dimethylaminopyridine, for bonding he acid.

A reaction of a compound of formLlla (IX) to yield a compound of formula (X) according to Scheme 1: Case PC/4-34586P1 A compound of formula (X) can be prepared from a compound of formula (IX) using cross coupling reactions. Such reaction are catalysed by iron-, palladium-or nickel complexes (Comprehensive Coordination Chemistry II, 2004; Metal-Catalyzed Cross Coupling Reactions, Eds: F. Diederich, P.J. Stang, Wiley-WCH, 1998). The reaction can be performed in any solvent that is inert to the substrates and the reagents. Preferred solvents are etheral solvents, hydrocarbons or aprotic dipolar solvents. Typically reaction temperature are in a wide range between -78 C and the boiling point of the reaction mixture, preferably in a range from -10 C to 120 C (US 2003/0220498 Al and references cited therein; JACS, 2004, 126,12, 3686).

A reaction of a compound of formula (X) to yjeld a compound of formulae (Xl) and (A) according to Scheme 1: The conversion of a compound of formula (X) to a compound of formula (Xl) and has been described in EP 0678503 Al and involves the treatment of compound (X) with an amine of formula R5NH2 in a mixture of water and an organic solvent such as methanol, tetrahydrofuran, acetonitrile, dimethylformamide, N-methylpyrolidinone at a temperature between 20 C and 100 C in the presence of a cata!yst such as 2-hydroxypyridine. A compound of formula (A) may then be obtained from a compound of formula (XI) by deprotection of the 5-amino group, which can be carried out as described by T. W. Green, in "Protective Groups in Organic Synthesis". 3d edition, John Wiley & Sons, 1999.

Claims

Case PC/4-34586P1 -19-What is claimed is: 1. A method for preparing a

compound of the formula OH R,

H (A)

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16aIkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36aIkyI; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16a1 koxy-C balkyl, C 16alkanoyIoxy-C1alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C16d ial kyla mino-C1 6alkyl, C16alkanoylamino- C16a1ky1, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C16a1ky1, C1alkyl-HN-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-Ci6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from 3-D-hydroxyaspartic 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 OH R4 (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-hydroxy-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 Case PC/4-34586P1 -20 -RIOO2C4COR (V) RN\RRs wherein R3 and R4 are as defined for formula (A); R7 and R9 are independently C10aryI- C16alkyl, C16a1ky1-carbonyl, C610ary1-carbonyl, C16a I koxy-carbonyl, C10aryl- C1..6alkoxycarbonyl; or R7 and R9 combined form phthalimide; R3 is C16a1ky1, C10aryl-C16a1ky1 or (C18a1ky1)3silyl; or R7 and R8 combined together represent CR11R12 in which R11 and R12 are independently hydrogen, C16a1ky1 or C610ary1; or R11 and R12 combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; and R10 is C120a1ky1, C312cycloalkyl, C312cycloalkyl-C16alkyl, C610ary1 or C610ary1-C16a1ky1.

5. A compound according to claim 4 having the formula R10O2CCOR a) R/ R11 R12 wherein R3 and R4 are independently branched C14alkyl; R9 is C1.6alkoxy-carbonyl or C6aryl-C1alkoxy-carbonyl; R11 and R12 are C16alkyl; and R10 is C16alkyl.

6. A compound according to claim 5, wherein R3 and R4 are isopropyl; R9 is t-butoxy-or benzyloxycarbonyl; R10 is methyl or ethyl; and R11 and R12 are methyl.

7. A compound of the formula

ROC

2 /CO2R10 R)-__(R (VIa) Rxç R11 R12 wherein R3 and R4 are independently branched C14a1ky1; R9 is C16alkoxy-carbonyl or C6aryl-C1alkoxy-carbonyl; R11 and R12 are C16alkyl; and R10 is C16a1ky1.

Case PC/4-34586P1 -21 - 8. A compound according to claim 7, wherein R3 and R4 are isopropyl; R9 is t-butoxy-or benzyloxycarbonyl; R10 is methyl or ethyl; and R11 and R12 are methyl.