GB2431644A

GB2431644A - Synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431644A
Application number: GB0521727A
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: GB0521727D0

Abstract

A method for the preparation of certain 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds of formula (A): <EMI ID=1.1 HE=30 WI=69 LX=711 LY=769 TI=CF> <PC>wherein R1 is halogen, haloalkyl, alkoxy-alkoxy, alkoxyalkyl; R2 is halogen, alkyl or alkoxy; R3 and R4 are branched C1-4alkyl; and R5 is H2N-C(O)-C1-6alkyl or substituents; or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid or a tartrate ester and following the reaction sequence set out in Scheme 1. Preferred compounds of formula (A) are aliskiren and salts thereof, particularly (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate. Intermediates prepared as part of this synthesis are also claimed.

Description

Case PC/4-34585P1 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-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl 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)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyI amide derivatives to which the methods of the present invention applies 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 2(S),4(S),5(S),7(S)-2,7-dialkyl-4hydroxy-5-amino- 8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using tartaric acid as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula :H242oR5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C15alkyloxy or C16aIkoxy-C16a1ky1, R2 is halogen, C14alkyl. or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16alky, C1..6hydroxyalkyl, C16alkoxy-C15a1ky1, C16alkanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16alkyI, C15alkanoylamino-C1..6alkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16alkyI, H2N-C(O)-C16a1ky1, C16alkyl-HN-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from D-tartaric acid and following reaction steps as outlined in Scheme 1.

Case PC/4-34585P1 Scheme 1: A method for preparing a compound of formula (A) starting from tartarate,

HO OH RO OR RO OR

ROZOR" R"OL_LJOR" O/\O (Ia-c) (Ha-c) (lila-c) a: 2R,3R; L-tartarate b: 2S,3S; D-tartarate C: meso-tartarate :R8::* (VIa-d) (Va-d) (iVa-c) a: 2S4R5R7S I b: 2S4S,5S7S 1' c: 2S4R,5S,7S ::R4 d 4S5R,7S (VII) Compounds of formula (lVa-c), wherein R3' and R4' represents R3 and R4 as defined for formula (A); or R3' and R4' are groups convertible to R3 and R4, respectively; R and R' are independently C16alkyl, C610ary1-C16a1ky1 or (C18alkyl)3silyl; or R and R' combined together represent CR9R10 in which R9 and R10 are independently hydrogen, C16a1ky1 or C610ary1; or R9 and R10 combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; R" and R7 are independently C120a1ky1, C312cycloalkyl, C312cycloalkyl-C16alkyl, C610aryl or C6.10aryl-C16alkyl; and R6 represents -C(O)0R11 in which R11 is C120a1ky1, C312cycloalkyl, C312cycloalkyl-C16a1ky1, C610ary1 or C61oaryl-C16a1ky1; or R6 represents -CH2-4-R1-3-R2-C6H4 in which R1 and R2 have meanings as defined for formula (A); are key intermediates in the methods of the present invention. Compounds of formula (lVa-c) may be converted to compounds of formula (VII) wherein R1, R2, R3 and R4 are as defined herein above, by three different routes, namely Route A, B and C, as outlined in Schemes 2, 3 and 4, respectively. Subsequently, compounds of formula (A), or pharmaceutically acceptable salts thereof, may be obtained from compounds of formula Case PC/4-34585P1 (VII) according to methods well known in the art, e.g., using methods disclosed in U.S. Patent No. 5,559,111.

As illustrated in Scheme 1, compounds of formula (lVa-c) wherein R, R', R3. R4' R and R have meanings as defined herein above, may first be converted to compounds of (Vla-d) wherein R1, R2, R3 and R4 have meanings as defined herein above, and OR8 represents a leaving group such as halide, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. It should be noted that the stereochemistry at carbons 4 and 5 is maintained in compounds of formula (Vla-d) as inherited from the tartaric acid used as the starting material: (VIa): 2S,4R,5R,7S from L-tartarate; (Vib): 2S,4S,5S,7S from D-tartarate; (VIc): 2S,4R,5S,7S from meso-tartarate; (VId): 2S,4S,5R,7S from meso-tartarate; Compounds of formula (Vla-d) may then be converted to compounds of formula (VII) wherein R1, R2, R3 and R4 have meanings as defined herein above, and the transformation requires specific chemistry for each stereoisomer of formula (Vla-d). For example, a compound of formula (Vld) may be treated directly with a suitable nitrogen nucleophile, e g a metal azide, such as NaN3, KN3 or LiN3, to give the required (2S,4S,5S,7S) configuration of a compound of formula (VII). A compound of formula (VIb) may be treated with a metal halide, e.g., lithium chloride, to give the 5-halo intermediate with (2S,4S,5R,7S) configuration, which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, gives the desired compound of formula (VII). Alternatively, a compound of formula (VIb) may be subjected to alkaline treatment, e.g. with sodium hydroxide, which induces inversion of the 5S-stereocenter via lactone ring opening followed by intramolecular formation of an (4S,5R)-epoxide, which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, affords an (2S,4S,5S,7S) 5-azido-4-hydroxy intermediate, which will readily cyclize upon acidic treatment to give the desired (2S,4S,5S,7S) compound of formula (VII). Similarly, a compound of formula (VIa) may be subjected to alkaline treatment, e.g., with sodium hydroxide, that induces inversion of the 5R-stereocenter via lactone ring opening and intramolecular formation of an (4R,5S)-epoxide, which upon treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the configuration is inverted to give the (2S,4S,5S,7S) configurated Case PC/4-34585P1 hydroxy lactone of formula (Vb) which may be converted to a compound of formula (VIb) and further transformed to compound (VII) as described above. Alternatively, (Via) may be treated with a metal halide, e.g., lithium chloride, to give the 5S-halo intermediate, which upon alkaline treatment, e.g. with sodium hydroxide, generates an (2S,4S,5R,7S)-epoxide which may be treated with a suitable nitrogen nucleophile, e.g. a metal azide, to give an (2S,4S,5S,7S) 5-azido-4-hydroxy intermediate, which will readily cyclize on acidic treatment to give a compound of formula (VII). A compound of (Vlc) may be subjected to alkaline treatment, e.g. with sodium hydroxide, that induces the inversion of the 5S-stereocenter via Iactone ring opening and intramolecular formation of an (4R,5R)-epoxide, which UOfl treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the stereoconfiguration is inverted to give a (2S,4S,5R,7S) configurated hydroxy Iactone of formula (Vd) which is further transformed to a compound of formula (VII) as described above.

As illustrated in Schemes 2 and 3, compounds of formula (IVa-c) wherein R, R', R3', R4', R6 and R7 have meanings as defined herein above, may first be converted to compounds of (XIa-d) wherein R3 and R4 have meanings as defined herein above (Route A and Route B).

Compounds of formula (XIa.-d) may then be transformed to compounds of formula (V II) wherein R1, R2, R3 and R4 have meanings as defined herein above, by two alternative routes as outlined in Schemes 5 and 6, respectively.

Scheme 4 exeplifies how compounds of formula (lVa-c) wherein R, R', R3', R4', R5 and R7 have meanings as defined herein above, may be converted to compounds of formula (Va-d) wherein R1, R2, R3 and R4 have meanings as defined herein above (Route C). Compounds of formula (Va-d) may then be transformed to compounds of formula (VII) wherein R1, R2, R3 and R4 have meanings as defined herein above, as illustrated herein in Scheme 1.

Case PC/4-34585P1 Scheme 2: Conversion of a compound of formula (IV'a-c) to a compound of formula (Xla-c), Route A.

RO OR RO OR

R11O OR7 R11OOR7 (IV'a-c) (Villa-c) (lXa-c) o o 0 O j -R4 R R4a R3 R3b (Xla-d) (Xa-c) Scheme 3: Conversion of a compound of formula (IV"a-c) to a compound of formula (Xla-d), Route B. RO OR' RO OR R3 R4 R110(O)C C(O)0R7 R1O(O)C C(O)0R7 -0'

-P.

(V"a-c) (XIIa-d) çXla-d) Scheme 4: Conversion of a compound of formula (IV"a-c) to a compound of formula (Va-d), Route C. Case PC/4-34585P1

RO OR RO OR

(IVa-c) (XIlla-d) (VII) (Vla-d) R4 (Va-d) Scheme 5: Conversion of a compound of formula (XIa-d) to a compound of formula (VII). HO.

O a HO borc (Xla-d) (XIVa-d) (Va-d) RiyY (XVa): Y H d )I_i (XVb): Y Hal R2 (XVc): Y= Metal (XVa-c) R4 R8O)2 RR3 (VII) (Vla-d) Case PC/4-34585P1 Reaction conditions: a) e.g. diisobutylaluminium hydride, Ti-IF; b) e.g. T1CI4 or Aid3 or other Lewis acid, (XVc); c) e.g. (i) compound (XVc), Ti-IF; (ii) hydrogenation; d) methansulfonyl chloride (MsCI), NEt3 (R80 is methanesulfonate).

Scheme 6: Conversion of a compound of formula (Xla-d) to a compound of formula (VII). 0 0 0

0 R LIR a, b R11 " R4 R11oi J (XIa-d) (XVIa-d) (XVIIa-d) (VII) ":4 R11O (XIX) (XVIII) Reaction conditions: a).e.g. NaOH, R110H; b) e.g. H2S04/toluene, 5000; C) e.g. MsCI, NEt.

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, R, R', R1 and R2 may be linear or branched and preferably comprise 1 to 6 C atoms, especially 1 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 I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms.

Examples are methoxy, ethoxy, n-and 1-propyloxy, n-, I-and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypenty, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C16alkoxy-C16alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 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-C14aIkyloxy, 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/4-34585P1 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-C16a1ky1, 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 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 formyloxymethyt, 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-C16alkyl and C16dialkylamino-C16alkyl, R5 may be linear or branched.

The alkylamino group preferably comprises C14a1ky1 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-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-C16alkyl, 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-methoxycarbonyipropyl, 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-Case PC/4-34585P1 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 C16alkyl-HN-C(O)-Ci6alkyl or (C16alky1)2N-C(O)-Ci6alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.

As an alkyl, R", R7, R9, R10 and R11 may be linear or branched and comprise preferably 1 to 12 C atoms, 1 to 8 C atoms being especially preferred. R", R7, R9, R10 and R11 are particularly preferred as a linear C14alkyl. Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, hepty!, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl.. Especially preferred are methyl and ethyl.

As a cycloalkyl, R", R7 and R11 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, R", R7 and R11 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, 1 or 2 C atoms being especially preferred. Some examples are cyclopropylmethyl, cyclobutylmethyl.

cyclopentylmethyl or cyclopentylethyl, and cyclohexylmethyl or 2-cyclohexylethyl.

As an aryl, R", R7, R9, R10 and R11 is preferably phenyl or naphthyl.

As an aralkyl, R, R', R", R7 and R11 is preferably benzyl or phenyl ethyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::0NH2 (B) Case PC/4-34585P1 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)-benzylj-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

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 processes, in which an inter-mediate product obtainable at any stage thereof, e.g. a compound of formula (lVa-c), (Va-d) and (Xla-d), 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.

Compounds of the invention and intermediates can also be converted into each other according to methods generally known perse.

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.

Case PC/4-34585P1 Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organ/c Chemistry' 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, 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).

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.

Case PC/4-34585P1 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.

Reaction of a compound of formula (I) to a compound of formula (II): Reacting a compound of formula (I) to yield a compound (II) is for protecting the diol motives of tartaric acid ester either with a bridging protective group, such as isopropylidene, or with a bulky protecting group, such as tert-butyldimethylsilyl or dimethylthexylsilyl. in order to improve the stereoselectivity of the subsequent steps. The protection of diols as isopropylideneacetals and the protection of alcohols as tert-butyldimethyls;Iylethers or dimethyithexylsilylether is known per se and has been described in "Protective Groups in Organic Synthesis", 3Id edition, John Wiley & Sons, New York 1999, pp. 127 and pp. 207.

Generally the protection of a diol as isopropylidene acetal is carried out with acetone, 2- methoxypropene, or 2,2-dimethoxypropane in the presence of an acid catalyst such as 4-toluenesulfonic acid, CuSO4/sulfuric acid, HBr, in acetone itself as solvent and/or xylene, benzene, or DMF at temperatures between 2000 and the boiling point of the reaction mixture, preferably with 2,2-dimethoxypropane in xylene containing a catalytic amount of 4-toluenesulfonic acid (Tetrahedron Lett. 1988, 29, 551-554.

The protection of alcohols as ter-butyldimethylsilylethers or as dimethylthexylsilytethers is generally carried out with the corresponding chloride or trifluormethansulfonic acid ester in the presence of a base such as imidazole, triethylamine alone or in the presence of dimethylaminopyridine, potassium hydride in the presence of a crown ether. pyridine. or 2,6-lutidine in a solvent such as dimethylformamide, acetonitrile, or dichioromethane at temperatures between 0 C and 30 C, preferably with tert-butyldimethylsilylchloride or dimethylthexylsilylchloride and imidazole in dimethylformamide at approximatively 25"C (Angew. Chem. 1990, 102, 64).

Reaction of a compound of formula (Il) to a compound of formula (Ill): Reacting a compound of formula (II) to yield a compound of formula (Ill) is for the reduction of the ester groups to aldehydes. Aldehydes can be obtained from esters either a) directly Case PC/4-34585P1 by reduction or b) indirectly by reduction to the corresponding alcohol and subsequent oxidation, or c) indirectly by hydrolysis to the corresponding carboxylic acids or carboxylate, activation of the carboxylate groups for example as acyl halogenides, and the subsequent 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 der Wissenschaften, Berlin 1988: a) Generally the reduction of esters to aldehydes is carried out with aluminiumhydrides in aliphatic or aromatic hydrocarbons such as hexane, toluene, or xylenes, and cyclic or acyclic ethers such as tetrahydrofurane or diethylether as solvent at temperatures between -78 C and the boiling point of the reaction mixture, preferably with diisobutylaluminiumhydride in toluene at -78 (J. Org. Chem. 1994, 59, 932-934).

b) Generally the reduction of esters to alcohols is carried out with aluminiumhydrides or trialkylborhydridrides in cyclic or acyclic ethers such as tetrahydrofurane or diethylether as solvent at temperatures between -78 C and the boiling point of the reaction mixture, preferably with lithium aluminiumhydride in tetrahydrofurane at approximately 25 C (J. Org. Chem. 1994, 59, 932-934). The oxidation reaction of alcohols to aldehydes are known per se and for example described in "Oxidations in Organic Chemistry", ACS: Washington 1990.

The oxidation of alcohols to aldehydes can be achieved with any agent able to oxidize the primary alcohol group to the corresponding aldehyde preventing the further reaction of the aldehyde. Thus, the oxidizing agent may be any suitable chemical agent or biological agent.

Preferably the oxidizing agent is a chemical agent. The oxidation of alcohols to aldehydes is generally achieved with dimethylsulfoxide/acetic anhydride, dimethylsulfoxide/ dicyclohexylcarbodiimid in the presence of an acid, dimethylsulfoxide/oxalylchloride in the presence of a base such as triethylamine, or dimethylsulfoxide/sulfurtrioxide in the presence of a base such as pyridine, with aqueous sodium hypochlorite in the presence of potassium bromide and 2,2,6,6-tetramethylpiperidin-1-oxyl, with sodium hypochlorite/n-methylmorpholine-N-oxide in the presence of tetrapropylammoniumperruthernate, with pyridiniumchlorochromate in the presence of sodium acetate, with 2-iodoxyperbenzoic acid, or with manganese dioxide in organic solvents such as dichloromethane at temperatures between -78 and 30 , preferably with dimethylsulfoxide/acetic anhydride at approximately 25 C (Carbohydr. Res. 1988, 174, 369).

Case PC/4-34585P1 c) The hydrolysis reaction of esters is also known per se and for example described in Protective Groups in Organic Synthesis", 3d edition, John Wiley & Sons 1999, pp. 377. The conversion of carboxylic acids or caboxylates into acyl chlorides and their reduction to aldehydes is known as Rosenmund reduction and described for example in Rec. Tray Chim. Pays-Bas 1981, 100, 21. Generally the hydrolysis of esters to carboxylic acids or carboxylates is carried out with metal hydroxides or alkoxides in aqueous solvent mixtures such as water/ethanol or water/dimethylformamide at temperatures between 200 and the boiling point of the reaction mixture, with metal halogens in the presence of a trimethylsiyllhalogenide in a polar aprotic solvent such as acetonitrile or dimethylformarnide at temperatures between 0 and the boiling point of the reaction mixture, with Lewis acids such as bortrihalogenides, aluminum trihalogenides in the presence of thiols, alkyltinoxides in apolar solvents such as dichloromethane, toluene, or xylene at temperatures between - 20 C and the boiling point of the reaction mixture, preferably with sodium hydroxide in ethanol between 60 C and 100 (Tetrahedron 1997, 53, 13757). The conversion of carboxylates to acyl chlorides is generally performed with oxalyl chloride alone or in a polar solvent such as dimethylformamide, with thionyl chloride in aromatic hydrocarbons such as benzene, toluene, or xylenes as solvent, preferably with oxalyl chloride between 50 C and 65 C (Tetrahedron 1997, 53, 13757). The reduction of acyl chlorides to aldehydes is generally performed with hydrogen at atmospheric or higher pressure in the presence of a catalyst such aspalladium on bariumsulfate or 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 between 30 C and 90 C (Org. Process Research & Development 1997, 1, 226).

Reaction of a compound of formula (Ill) to yield a compound of formLila (lVi The reaction of a compound of formula (Ill) to yield a compound of formula (IV) is known as Wittig-Horner-Wadsworth-Emmons-reaction and is described for example in Compr. Org. Synth. 1991, 1, 755, the conformation of the formed double bond in compound of formula (IV) depending on the used reagent. In a Wadsworth-Horner-Emmons-reaction an aldehyde is generally reacted with an appropriate phosphonate preferably under an inert gas such as argon or nitrogen, in a solvent not adversely affecting the reaction, such as tetrahydrofurane or dimethylformamide, if necessary by an addition of a halide of an alkali metal or an alkaline earth metal, such as lithium chloride, lithium bromide or magnesium Case PC/4-34585P1 -16-bromide, and further by an addition of a base such as 1,8-diazabicyclo[5.4.0]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 of formula (Ill) 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 3000 (Tetrahedron Lett. 1992, 33, 1411) or bis-(2,2,2- trifluoroethoxy)phosphoryl)-acetic acid methyl ester and potassium 1,1,1,3,3,3-hexamethyldisilazane in tetrahydrofurane at a temperature between -78 C and 30 C (Tetrahedron Letters (1995), 36(23), 4105-8; Jpn. Kokai Tokkyo Koho (1998), JP10265486 A2) in order to get the Z,Z-configured bis olefine of formula (IV"). In analogy compounds of formula (IV') and compounds of formula (IV") can be obtained by reacting a compound of formula (Ill) with the appropriate phosphonates under analogous conditions as described for the synthesis of compound of formula (IV").

Reaction of a compound of formula (IV') to yield a compound of formula (Xl), Scheme 2 The transformation of a compound of formula (IV') to a compound of formula (V) involves a) the reduction of the C=C-bond in a compound of formula (IV') to compound (VIII), b) the deprotection of the diol-function in compound of formula (VIII) with the concomittant intramolecular subtitution of OR7 and OR11 and the formation of the bis-lactone of formula (IX), c) the alkylation of the bis-lactone of formula (IX) to a compound of formula (X), and d) the stereoselective reduction of the 0=0-bond in a compound of formula (X) to a compound of formula (Xl).

The reduction of 0=0-bonds is known per se. It is generally achieved by hydrogenation in the presence of a catalyst and has been described for example in "Catalysis of Organic Reactions", Marcel Dekker, New York 1988.

The hydrogenation of a C=C-bond is generally achieved under an atmosphere of hydrogen or of hydrogen diluted with an inert gas at a pressure between 0.5 an 200 bars in the presence of a chiral or achiral palladium, platin, rhodium, ruthenium, or iridium catalyst (the amount of catalyst depending upon the reaction conditions as well as the reactivity of the compound to be hydrogenated, typically in the range of metal/compound to be hydrogenated of 1:100-5000) in a solvent or a mixture of solvents chosen from aliphatic Case PC/4-34585P1 hydrocarbons such as hexane or heptane, aromatic hydrocarbons such as toluene or xylenes, ethers such as tert-butyl methyl ether, dilsopropyl ether, or tetrahydrofuran, lower alcohols such as methanol, ethanol, n-propanol, or isopropanol, halogenated aliphatic or aromatic hydrocarbons such as dichloromethane or chloroform, dialkyl ketones such as acetone or methyl isobutyl ketone, or polar aprotic solvents such as dimethylformamide or dimethylsulfoxide, at temperatures between -20 C and the boiling point (or apparent boiling point at elevated pressure) of the reaction mixture, preferably with rhodium on carbon at 1-5 bars in methanol at ambient temperature (Tetrahedron Letters (2001), 42(46), 8207-82 10, J. Org. Chem. 1988, 53, 4505).

The deprotection of dihydroxy-functions protected as acetals or as silylethers is known per se and has been described for example in Protective Groups in Organic Synthesis", 31C edition, John Wiley & Sons, 1999, pp. 127 and pp. 211. The deprotection of a dihydroxy-function protected as acetal is generally performed with BrOnstedt acids sLich as hydrochloric acid, acetic acid, trifluoroacetic acid, 4-toluenesuflonic or another sulfonic acid in protic solvents such as methanol, ethanol, water with or without an organic co-solvent such as tetrahydrofuran, or with a Lewis acid such as boron trichloride, iron trichloride, or trimethylaluminum in an aliphatic or aromatic hydrocarbon such as hexane, heptane, toluene or xylenes as solvent, followed by an aqueous work-up, preferably with aqueous sulfuric or aqueous hydrochloric acid in a mixture of water and tetrahydrofuran, which allows the concomitant intramolecular substitution of an alkylester under formation of a lactone (Liebigs Ann. Chem. 1992, 10, 1069). The deprotection of a hydroxyl-function protected as tert-butyldimethylsilylether, dimethylthexylsilylether or as another silylether is generally performed with reagents providing a source of fluoride such as tetrabutylammonium fluoride, tetrabutylammonium chloride and potassium fluoride, potassium fluoride alone or in presence of a crown-ether, ammonium fluoride, in organic solvents such as tetrahydrofuran, acetonitrile, or dimethylformamide alone or in presence of water at temperatures between 0 C and 70 C, or with Brönsted acids such as acetic acid, formic acid, trifluoroacetic acid 4-toluenesulfonic or another sulfonic acid, or hydrochloric acid in aqueous mixtures of protic solvents such as methanol/water or ethanol/water or in aqueous mixtures of polar aprotic solvents such as tetrahydrofuran/water or acetonitrile/water at temperatures between 20C and the boiling point of the reaction mixture, preferably with trifluoroacetic acid in tetrahydrofuran between 40 C and 60 C, which allows the concomitant intramolecular substitution of an alkylester under formation of a lactone (Helv. Chim. Acta 1991, 74, Case PC/4-34585P1 343).The alkylation of a compound of formula (IX) to afford a compound of formula (X) can be achieved by the aldol condensation of a compound of formula (IX) with acetone. Aldol condensations are known per se and have been described for example in "Organic Reactions", Vol. 28, Wiley, New York 1982, pp. 203. In order to increase the selectivity of an intermolecular aldol condensation of one carbonyl compound with another, it is generally of advantage to generate first the enolate of the (nucleophilic) carbonyl compound and then to add the second (electrophilic) carbonyl compound. Such directed aldol condensations are generally performed by the treatment of the nucleophilic carbonyl compound with a strong base such as lithium diisopropylamide, lithium hexamethyldisilazide, methylmagnesium bromide in the presence or not of a metal derivative such as zinc chloride, trimethylsilyl chloride, dibutylbor trifluoromethansulfonate, or tris-(isopropiloxy)titanium chloride, in an anhydrous aprotic solvent such as tetrahydrofuran at temperatures between -78 C and 0 C, and to react the formed enolate with the electrophilic carbonyl compound in presence or not of a Lewis acid such as titanium tetrachloride, tin tetrachloride, aluminum trichioride, boron trifluoride or zinc dichloride to obtain the addition product, which generally either spontaneously, or upon warming the reaction, or upon activation with for instance thionyl chloride or acetic anhydride and a base will dehydrate to the condensation product. Thus.

the aldol condensation of a compound of formula (IX) with acetone is preferably done by the treatment of a compound of formula (IX) with lithium diisopropylamide in the presence of zinc dichioride in tetrahydrofuran between -78 and 0 C, followed by the addition of acetone, and warming up the reaction.

The stereoselective reduction of the diene of formula (X) to compound of formula (XI) can be achieved by hydrogenation in the presence of an achiral or chiral catalyst as described herein above. In the case of the diastereoselective reduction of a diene, the stereoselectivity of the hydrogenation can be improved by using a homogeneous or heterogeneous chiral catalyst, consisting of a metal such as rhodium, ruthenium, or iridium, bearing one or more chiral ligands. The stereoselectivity of the hydrogenation can be influenced by parameters such as the reaction temperature, the hydrogen pressure, the nature of the solvent and the presence of additives. Several isomers can be obtained, which can by purified by chromatographic techniques or crystallization, preferably by crystallization. Thus, the diastereoselective hydrogenation of the diene of formula (X) will preferably be carried out with at 1-5 bar in the presence of a chiral catalyst such as BINAP-Ru or Rh(NDB)DIPHOS-4 in iso-propanol between 20 C and 60 C (J. Org. Chem. 1990, 55, Case PC/4-34585P1 2776, Tetrahedron Lett. 1998, 39, 223) followed by the isolation of compound (V) by crystallization.

Reaction of a compound of formula (IV") to yield a compound of formula (Xl), Scheme 3: The transformation of a compound of formula (IV") to a compound of formula (Xl) involves a) the stereoselective reduction of a diene of formula (IV") to afford a compound of formula (XII), and b) the deprotection of the diol-function in a compound of formula (XII) with the concomitant intramolecular substitution of OR7 and OR11 and the formation of a bis-lactone of formula (XI).

a) The stereoselective reduction of the diene (IV') to compound (XII) may be achieved as described for the reduction of a diene of formula (X) to compound of formula (Xl), preferably by hydrogenation at 1-5 bar in the presence of a chiral catalysts such as for example BINAP-Ru or BINAP-Rh in iso-propanol at 20-60 C.

b) The deprotection of the diol-function in a compound of formula (XII) with the concomitant formation of the bis-lactone may be achieved as described for the conversion of a compound of formula (VIII) to a compound of formula (IX), in the case of R and R' combined are isopropylidene, preferably with aqueous sulfuric or aqueous hydrochloric acid in a mixture of water and tetrahydrofurane (W. Tochtermann et al., Liebigs Ann. Chem. 1992, 10, 1069), in the case of R and R' are terl-butyldimethylsilsl, dimethylthexylsilyl or another trialkylsilyl group preferably with trifluoracetic acid in tetrahydrofurane at 40-60 followed by a methanolic work-up (B. I. Glänzeretal., He/v. Chim. Acta 1991, 74, 343).

Reaction of a compound of formula (IV") to yield a compound of formula (Vjcheme 4: The reaction of a compound of formula (IV") to a compound of formula (V) involves a) the stereoselective reduction of the diene (IV") to compound (XIII) and b) the deprotection of the diol-function in compound (XIII) with the concomitant intramolecular substitution of OR7 and the formation of a lactone of formula (V).

a) The stereoselective reduction of the diene of formula (IV") to afford a compound of formula (XIII) may be achieved as described herein above, preferably by hydrogenation at 1-5 bar in the presence of a chiral catalysts such as for example BINAP-Ru or BINAP-Rh in iso-propan'oI at 20-60 C (J. Org. Chem. 1990, 55, 2776; Tetrahedron Lett. 1998, 39, 223).

Case PC/4-34585P1 b) The deprotection of the dihydroxy-function in a compound of formula (XIII) with the concomitant formation of a lactone can be achieved as described herein above. In the case of R and R' combined are isopropylidene, the dihydroxy-function of a compound of formula (XIII) is preferably deprotected with aqueous sulfuric or aqueous hydrochloric acid in a mixture of water and tetrahydrofuran (Liebigs Ann. Chem. 1992, 10, 1069). In the case of R and R' are tert-butyldimethylsilyl, dimethyithexylsilyl or another trialkylsilyl group, the silylethers in a compound of formula (XIII) are preferably cleaved with a fluoride based reagent such as tetrabutylammonium fluoride in acetic acid at approximately 25 C (J. Am. Chem. Soc. 1996, 118, 13095).

In order to exclude the elimination of ROH and R'OH, the protection of the 1,2-dihydroxy-function with easily removable protecting groups may be of adventage for the synthetic Route C. Examples of easily removable bridging protecting groups for a 1,2-dihydroxy-function are described for instance in "Protective Groups in Organic Synthesis", 3" edition, John Wiley & Sons, 1999, pp. 201, and include cyclopentylidene, which is preferably introduced by treating a compound of formula (I) with cyclopentanone and sulfuric acid in an aromatic hydrocarbon as solvent such as xylenes (J. Am. Chem. Soc. 1992, 114, 1438) and preferably removed by treating a compound of formula (XIII) with acetic acid in water at approximately 25 C (Tetrahedron Lett. 1987, 28, 2309), or 4-methoxybenzylidene, which is preferably introduced by treating a compound of formula (I) with 4-anisaldehyde and zinc chloride at approximatively 25 C and removed by treating a compound of formula (XIII) with acetic acid in water between 0 C and 30 C (J. Am. Chem. Soc. 1962, 430, 84).

Reaction of a compound of formula (Xl) to yield a compound of formula (VII), Scheme 5: The conversion of a compound of formula (XI) to a compound of formula (V) involves a) the reduction of the lactone (Xl), b) the addition of an organometallic derivative of formula (XVc) to the lactol (XIV), followed by the reduction of the benzylic hydroxyl group, c) conversion of the C-5 hydroxyl group to a leaving group, and d) displacement with an azido group.

The reduction of lactones to lactols is known per se and has been described for example in Synthesis 1976, 526. Generally, lactones are reduced to lactols with aluminum hydrides, such as lithium diisopropylaluminum hydride or sodium bis-(2-methoxyethoxy)aluminum hydride in the presence or not of an alcohol such as ethanol or 2-hydroxypyridine in aprotic solvents such as tetrahydrofuran, dichioromethane, or toluene at temperatures between - 78 C and 0 C, or with borohydrides and boranes such as sodiumborohydride, lithium tn-Case PC/4-34585P1 sec-butylborohydride, borane, or disiamylborane in the presence or not of an alkene such as 2,3-dimethyl-2-butene or an alcohol such as 2-hydroxypyridine, in aprotic solvents such as tetrahydrofuran or protic solvents such as water and ethanol, at temperatures between - 60 C and -30 C, preferably with bis-(2-methoxyethoxy)aluminum hydride in the presende of 2-hydroxypyridine in tetrahydrofuran between -30 C and OC (Tetrahedron Lett 2001 42.

4787).

The addition of an organometallic derivative of an alkyl or aryl halogenide to lactols or other (masked) aldehydes is known per se and described for instance by J. March in "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th edition, John Wiley & Sons, New York 1992, pp. 920. The organometallic derivative is generally prepared either by the addition of the alkyl or aryl halogenide to a suspension of magnesium or by addition of an organolithium derivative such as butyl lithium to the alkyl or aryl halogenide followed or not by the addition of magnesiumbromide in a cyclic or acyclic ether as solvent such as tetrahydrofuran or diethylether at temperatures between -78 C and the boiling boint of the reaction mixture, preferably by the addition of butyl lithium to the compoLind (XVc; X = Cl, Br) between -50 C and 20 C in tetrahydrofuran. The addition of the organometallic reagent to the aldehyde is generally done in a cyclic or acyclic ether as solvent, such as tetrahydrofuran or diethylether, at temperatures between -78 C and the boiling point of the reaction mixture, preferably in tetrahydrofurane between -78 C and 25 C (WO 2003103653).

The reduction of benzylic hydroxyl groups is known perse and, e.g. described in "Organikum, organisch-chemisches Grundpraktikum", 17th revised edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1988. It is generally achieved either by hydrogenation under an atmosphere of hydrogen or of hydrogen diluted with an inert gas at a pressure between 0.5 an 200 bars in the presence of a metal catalyst such as palladium on carbon, palladium hydroxide on carbon, platinium or (Raney) nickel in a solvent or a mixture of solvents chosen from aliphatic hydrocarbons such as hexane or heptane, aromatic hydrocarbons such as toluene or xylenes, ethers such as tert-butyl methyl ether, diisopropyl ether, or tetrahydrofuran, lower alcohols such as methanol, ethanol, n-propanol, or isopropanol, organic acids such as acetic acid, and water at temperatures between -20 C and the boiling point (or apparent boiling point at elevated pressure) of the reaction mixture, by reduction with a metal such as zinc in the presence of a mineral acid such as hydrogen chloride in acetic acid, by reduction with a metal hydride such as sodium borohydride in a Case PC/4-34585P1 -22 -solvent or mixture of solvents chosen from aliphatic hydrocarbons such as hexane or heptane, aromatic hydrocarbons such as toluene or xylenes, ethers such as tert-butyl methyl ether, diisopropyl ether, or tetrahydrofuran, lower alcohols such as methanol, ethanol, n-propanol, or by reduction with a silane or borane such as triethylsilane in the presence of an acid such as trifluoroacetic acid in an organic solvent such as dichioromethane, tetrahydrofuran, or acetonitrile, preferably by hydrogenation at atmospheric pressure in the presence of palladium hydroxide on carbon in a mixture of tetrahydrofuran, water, and acetic acid between 2000 and 30 C (Tetrahedron Lett. 2001, 42, 8207-8210), The conversion of a hydroxyl group to a leaving group is known per se and has been described for example in "Comprehensive Organic Transformations", 2 edition, John Wiley & Sons, 1999. Generally it is achieved by a reaction with sulfonyl chlorides, thionyl chloride, phosphorus halides, phenylmethyleneiminium halides, benzoxazolium halides, and Viismeier-Haack and Viehe salts, advantageously in the presence of a base such as triethylamine or dimethylaminopyridine in polar organic solvents at temperatures between - 30 C and the boiling point of the reaction mixture (Org. Lett. 2002, 4, 553).

The displacement of a leaving group with an azido group to afford a compound of formula (VII) is known per Se, and described for example in "Advanced Organic Chemistry Reactions, Mechanisms, and Structure", 41h edition, John Wiley & Sons, New York 1992.

Generally it is achieved with metal azides such as sodium azide, potassium azide or trimethylsilylazide in a polar high boiling organic solvent such as N-methylpyrrolidone or 1,3-dimethyl-3,4,5,6-tetrahydro(1 H)-pyridimone at temperatures between 20 C and the boiling point of the reaction mixture, preferably with sodium azide in N-methylpyrrolidinone between 20 C and 100 C.

Reaction of a compound of formula (Xl) to yield a compound of formula (VII), Scheme 6 Aternatively to the synthetic route outlined in scheme 5, a compound of formula (VII) can also be prepared from a compound of formula (XI) by a) alcoholysis of one lactone to the corresponding monoester and b) substitution the hydroxyl group in a compound of formula (XVI) by an azido group before the aryl substituent is introduced, i.e before c) the activation of the ester function as for instance an acyl halide, followed by an electrophilic Case PC/4-34585P1 aromatic substitution reaction with a compound of formula (XVa), and d) the reduction of the benzylic carbonyl-function in a resulting compound of formula (XIX).

The alcoholysis of lactones to hydroxy esters is known per se and has been described for instance in Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4 edition, John Wiley & Sons, New York 1992. It is generally performed with an alkali metal or alkaline metal carbonate, hydrogencarbonate, alkoxide, or hydroxide in an alcohol such as methanol or ethanol as solvent at temperatures between 0 C and the boiling point of the reaction mixture, preferably with potassium carbonate in methanol at temperatures between 0 C and 25 C (Tetrahedron Lett. 1991, 32, 547).

The electrophilic aromatic substitution of a compound of formula of formula (XVIII) with a compound of formula (XVa) necessitates the activation of the ester function as for instance an acyl halide. The conversion of the carboxylic acid ester in a compound of formula (XVIII) to an acyl halogenide involves the hydrolysis of the carboxylic acid ester to an carboxylic acid or carboxylate followed by the conversion of the carboxylic acid or carboxylate to an acyl halide. The hydrolysis of carboxylic acid esters is known perse and for example described in "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons 1999, pp. 377. Generally it is carried out with metal hydroxides or alkoxides in aqueous solvent mixtures such as water/ethanol or water/dimethylformamide at temperatures between 20 C and the boiling point of the reaction mixture, with metal halogenides in the presence of a trimethylsilyl halide in a polar aprotic solvent such as acetonitrile and dimethylformamide at temperatures between 0 C and the boiling point of the reaction mixture, with Lewis acids such as boon trihalides, aluminum trihalides in the presence of thiols, alkyltinoxides in apolar solvents such as dichloromethane, toluene, or xylene at temperatures between - 20 C and the boiling point of the reaction mixture, preferably with sodium hydroxide in ethanol between 60 C and 100 C (Tetrahedron 1997, 53, 13757). The conversion of carboxylates to acyl chlorides is known perse and generally performed with oxalyl chloride alone or in a polar solvent such as dimethylformamide, with thionyl chloride in aromatic hydrocarbons such as benzene, toluene, and xylenes as solvent, preferably with oxalyl chloride between 50 C and 65 C (Tetrahedron 1997, 53, 13757). The electrophilic aromatic substitution of aromatic hydrocarbons with an acyl halide or another activated carboxylic acid derivative is known perse as Friedel-Crafts acylation and has been described for instance in "Friedel-Crafts and Related Reactions", Vol. 1-4, lnterscience, New York 1963- 1965. It is generally achieved by treating an aromatic hydrocarbon with an acyl halide or Case PC/4-34585P1 carboxylic acid anhydride in the presence of a Lewis acid, preferably by reacting a compound of formula (XVIII) with a compound of formula (XVa) in the presence of aluminum trichloride.

Finally, the reduction of the benzylic carbonyl-function in a compound of formula (XIX) is preferably achieved as described herein above for the reduction of the benzylic hydroxyl groups, i.e. preferably by hydrogenation at atmospheric pressure in the presence of palladium hydroxide on carbon in a mixture of tetrahydrofu ran, water, and acetic acid between 20 C and 30 C.

Claims

Case PC/4-34585P1 What is claimed is: 1. A method for preparing a

compound of the formula RO (A) wherein R1 is halogen, C16halogenalkyl, C15alkoxy-C16alkylOxy or C16alkoxy-C16alkyl, R2 is halogen, C14alkyI or C14alkoxy; R3 and R4 are independently branched C35a1ky1; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C1.6alkyl C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-Ci6aIkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16alkYl, H2N-C(O)-C16a1ky1, C16a1ky1-H N-C(O)-C16alkyl or (C16alkyI)2N-C(O)-C16alkYl; or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid and following reaction steps as outlined in Scheme 1.

2. A method according to claim 1, wherein a compound of formula (lVa-d) is converted to a compound of formula (Xla-d) following reaction steps as outlined in Scheme
2.

3. A method according to claim 2, wherein a compound of formula (Xla-d) is converted to a compound of formula (VII) following reaction steps as outlined in Scheme 5 4. A method according to claim 3, wherein a compound of formula (A) has the formLila ::EoN2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

5. A method according to claim 3, wherein a compound of formula (B) is 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-proPyl)-amide hemifumarate.

Case PC/4-34585P1 6. A method according to claim 2, wherein a compound of formula (Xla-d) is converted to a compound of formula (VII) following reaction steps as outlined in Scheme 6.

7. A method according to claim 6, 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.

8. A method according to claim 7, wherein a compound of formula (B) is 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-prOPYI)-amide hemifumarate.

9. A method according to claim 1, wherein a compound of formula (lVa-d) is converted to a compound of formula (Xla-d) following reaction steps as outlined in Scheme
3.

10. A method according to claim 9, wherein a compound of formula (Xla-d) is converted to a compound of formula (VII) following reaction steps as outlined in Scheme 5.

11. A method according to claim 10, wherein a compound of formula (A) has the formula :: >NH. (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

12. A method according to claim 11, wherein a compound of formula (B) is 8-methyl-nonanoic acid (2carbamoyl-2-methyl-proPYl)-amide hemifumarate.

Case PC/4-34585P1 -27 - 13. A method according to claim 9, wherein a compound of formula (Xla-d) is converted to a compound of formula (VII) following reaction steps as outlined in Scheme 6 14. A method according to claim 13, wherein a compound of formula (A) has the formula ::or2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

15. A method according to claim 14, 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.

16. A method according to claim 1, wherein a compound of formLila (lVa-d) is converted to a compound of formula (XIa-d) following reaction steps as outlined in Scheme 4 17. A method according to claim 16, 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.

18. A method according to claim 17, 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.

19. A compound of the formula Case PC/4-34585P1 -28 -RO OR' (IVa-c) wherein R3' and R4' represents R3 and R4 as defined for formula (A); or R3' and R4 are groups convertible to R3 and R4; R and R' are independently C16a1ky1, C610aryl-C6alkyl or (C18a1ky1)3silyl; or R and R' combined together represent CR9R10 in which R9 and R10 are independently hydrogen, C16alkyl or C610ary1; or R9 and R10 combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; R6 represents -C(O)0R11 in which R11 is C120alky1, C312cycloalkyl, C312cycloalkyl-C13alkyl, C610ary1 or C610ary1-C16a1ky1; or R6 represents -CH2-4-R1-3-R2-C6H4 in which R is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14a1ky1 or C14alkoxy; and R7 is C120a1ky1, C312cycloalkyl, C312cycloalkyl-C16a1ky1, C610ary1 or C610aryl-C16a1ky1;.