GB2431643A

GB2431643A - Synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431643A
Application number: GB0521726A
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: GB0521726D0

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=715 LY=772 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/4-34584P1 Methods for the Preparation of Orcianic 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-aryI-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)-2,7dialkyl-4-hydroxy-5-amino-8-arYl-OCtaflOYl 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-4-hYdrOXY-5-amiflO- 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 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-Ci6alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14a1ky1 or C1..4alkoxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C16aIkyl, C16aminoalkyl, C16alkylamino-C16alkYl, C16dialkylamino-Ci6alkYl, C1aIkanoylamino-C16aIkyl, HO(O)C-C1..6alkyl, C16alkyl-O-(O)C-Ci6alkYl, H2N-C(O)-C1alkyI, C1alkyI-HN-C(O)-C16alkyI or (C16alkyl)2N-C(O)-Ci6alkYl or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid and following reaction steps as outlined in Scheme 1.

Case PC/4-34584P1 Scheme 1: A method for preparing a compound of formula (A) starting from tartaric acid.

R R R R' R R' OH o ><o o><o HOJLOH RO4OR [1:3) HO)J\OH (la-c) ([Ia-c) (lila-c) (lVa-c) a: 2R, 3R; L-tartaric acid I1 d b: 2S, 3S; D-tartaric acid c: meso-tartaric acid o (A) R4 (X) (Va-d) a: 2S,4R,5R,7S b: 2S,4S,5S,7S C: 2S,4R,5S,7S d: 2S,4S,5R,7S Reaction conditions: a) e.g. (i) thionyichioride, R"OH, e.g. methanol; (ii) e.g. 2,2-dimethoxypropane, p-TsOH, MeOH (R and R' are methyl) [1,2,3]; b) e.g. NaBH4, MeOH [3] or LAH, THF [2]; C) e.g. (i) methansulfonyl chloride (MsCI), NEt3 (XOMs) [2]; (ii) LiCI, 50 C [3]; d) e.g. Iithiumdisopropylamide, isovalerianic acid esters (Z=0R6 in which R6 is methyl; R3 and R4 are i-propyl), THF.

[1] A.K. Gosh et.al Synthesis 2001, 1281; [2] E.A. Mash et.al Organic Synthesis Coil Vol VIII, p155- 161; [3] B.M. Kim et.aI Org. Letters 3(2001)2349-2351; [4] EP 0678503 A. Compounds of formula (Va-d), wherein R3 and R4 are as defined for formula (A); R and R' are independently hydrogen, C16alkyI or C610aryl; or R and R' combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; and Z is OR6 in which R6 is C120a1ky1, C312cycloalkyl, C312cycloalkyI-C16aIkyl, C610ary1 or C10aryl-C16alky1; or Z represents -NR7R8 in which R7 and R8 are independently C120a1kyl, C312cycloalkyl, C312cycloalkyI-C16a1ky1, C610ary1 or C610aryI-C1alkyI; are key intermediates in the methods of the present invention. Compounds of formula (Va-d) may be converted to compounds of formula (X) wherein R1, R2, R3 and R4 are as defined herein above by three different routes, Routes A, B and C, as outlined in Schemes 2, 3 and 4, respectively.

Subsequently, compounds of formula (A), or pharmaceutically acceptable salts thereof, may Case PC/4-34584P1 be obtained from compounds of formula (X) according to methods well known in the art, e.g using methods disclosed in U.S. Patent No. 5,559,111.

It should be understood that the stereo-configuration at carbons 2 and 7 in compounds of formula (Va-d) is the result of an asymmetric induction in the course of the diastereoselective alkylation reaction of compounds of formula (lVa-c) with a carboxylic acid derivative, e.g isovalerianic acid derivatives, which may also carry a suitable chiral ester or amide group Z like the Evans or Seebach auxilliary groups. Such diastereoselective alkylation reactions of a carboxylic acid derivative, in particular isovalerianic acid derivatives, have been reported with several I,4-dihalo alkyl compounds (e.g in EP 0678503 A).

Because of the possibilities for matched and mismatched reactant pairs in the transition states of the diastereoselective alkylation reaction it is understood that, if a chiral Z-auxilliary group in the carboxylic acid derivative is used, its respective stereochemistry essentially must fit with that of the tartaric acid derived compounds of formula (lVa-c), in such a combination that the desired (S)-configuration at carbons 2 and 7 in the resulting compounds of formula (Va-d) is obtained.

Scheme 2: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route A. a R4 b HO (Va-d) (VIa-d) (VIIa-d) aI R4 (VIIi a-d) e Case PC/4-34584P1 ::ii0R4::1R4 (X) (IXa-d) Reaction conditions: a) e.g. (I) NaOH; (ii) H2SO4ltoluene; 50 C; b) e.g. diisobutylaluminium hydride, THF; c) e.g. T1CI4 or Aid3 or other Lewis acid, (Xlc); d) e.g. (I) compound (Xlc), THF; (ii) hydrogenation; e) MsCl, NEt3 (R90 is methanesulfonate).

As illustrated in Scheme 2, compounds of formula (Va-d) wherein Z, R, R', R3 and R4 have meanings as defined herein above, may first be converted to compounds of (lXa-d) wherein R1, R2, R3 and R4 have meanings as defined herein above, and OR9 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 (lXa-d) as inherited from the tartaric acid used as the starting material: (lXa): 2S,4R,5R,7S from L-tartaric acid; (lXb): 2S,4S,5S,7S from D-tartaric acid; (lXc): 2S,4R,5S,7S from meso-tartaric acid; (lXd): 2S,4S,5R,7S from meso- tartaric acid; Compounds of formula (lXa-d) may then be converted to compounds of formula (X) wherein R1, R2, R3 and R4 have meanings as defined herein above, and the transformation requires specific chemistry for each stereoisomer of formula (lXa-d). For example, a compound of formula (lXd) 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 (X). A compound of formula (lXb) 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 (X). Alternatively, a compound of formula (lXb) 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, Case PC/4-34584P1 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 (X). Similarly, a compound of formula (IXa) 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 hydroxy lactone of formula (VIlib) which may be converted to a compound of formula (lXb) and further transformed to compound (X) as described above. Alternatively, (IXa) 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,75) 5-azido-4-hydroxy intermediate, which will readily cyclize on acidic treatment to give a compound of formula (X). A compound of (lXc) may be subjected to alkaline treatment, e.g. with sodium hydroxide, that induces the inversion of the 5S-stereocenter via lactone ring opening and intramolecular formation of an (4R,5R)-epoxide, which upon 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 lactone of formula (VIlId) which is further transformed to a compound of formula (X) as described above.

Similarly, compounds of formula (Va-d) wherein Z, R, R', R3 and R4 have meanings as defined herein above, may be converted to compound of formula (lXa-d) wherein R1, R2, R3, R4 and OR9 have meanings as defined herein above, following the reaction sequence as outlined in Scheme 3, Route B. Compounds of formula (tXa-d) may then be transformed to a compound of formula (X) as described herein above for Route A. Case PC/4-34584P1 Scheme 3: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route B. R' a (Va-d) (XlIa-d) b,c 4? 0 R9O2R4 (lXa-d) Reaction conditions: a) a compound (XIc) (Scheme 2), THF; b) e.g. (I) hydrogenation; (ii) sulfuric acid; and C) e.g. MsCI, NEt3.

Finally, Scheme 4 illustrates Route C according to which the functionalization and stereochemistry at carbon 4 and 5 takes place before the aromatic fragment, characteristic to compounds of formulae (X) and (A), is introduce by addition of a compound of formula (Xlc). The key step in Route C is the selective monolactonization of compounds of formula (Va-c) wherein Z, R, R', R3 and R4 have meanings as defined herein above, to give compounds of formula (Xllla-d) which are subsequently converted to compounds of formula (XIVa-d) wherein Z, R3, R4 and OR9 have meanings as defined herein above. For Route C, the type of protecting group of the vicinal diol motive may be used advantageously, e.g. R is hydrogen and R' is aryl, to cleave that protecting moiety in a sequential way so that a half protected diol transient results. The further conversion compounds of formula (XIVa-d) to a compound of the formula (X) encompasses the introduction of the aromatic fragment according to methods known in the art, e.g. as described in EP 0678503 Al.

Case PC/4-34584P1 Scheme 4: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route C. a, b H2 "R4 c (Va-d) (XIIIa-d) (XIVa-d) (X) (XV) Reaction conditions: a) e.g. NaOH; b) e.g. H2S04/toluene, 50 C; c) e.g. MsCI, NEt3.

Analogously as described herein above, the stereochemistry at carbon 4 and 5 is maintained in compounds of formula (XlVa-d) as inherited from the tartaric acid used as the starting material: (XIVa): 2S,4R,5R,7S from L-tartaric acid; (XlVb): 2S,4S,5S,7S from D-tartaric acid; (XlVc): 2S,4R,5S,7S from meso-tartaric acid; (XlVd): 2S,4S,5R,7S from meso-tartaric acid; Compounds of formula (XIVa-d) may then be converted to compounds of formula (XV) wherein Z, R3 and R4 have meanings as defined herein above, and the transformation requires specific chemistry for each stereoisomer of formula (XIVa-d). For example, a compound of formula (XIVd) may be treated directly with a suitable nitrogen nucleophile, e.g a metal azide, such as NaN3, KN3 or L1N3, to give the required (2S,4S,5S,7S) configuration of a compound of formula (XV). A compound of formula (XIVb) may be treated with a metal halide, e.g lithium chloride, to give the 5-halo intermediate with (2S,4S,5R,7S) configuration, Case PC/4-34584P1 which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, gives the desired compound of formula (XV). Alternatively, a compound of formula (XlVb) 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 (XV).

Similarly, a compound of formula (XIVa) 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 hydroxy lactone of formula (Xlllb) which may be converted to a compound of formula (XIVb) and further transformed to compound (XV) as described above. Alternatively, (XlVa) 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 (XV). A compound of (XlVc) may be subjected to alkaline treatment, e.g. with sodium hydroxide, that induces the inversion of the 5S-stereocenter via lactone ring opening and intramolecular formation of an (4R,5R)-epoxide, which upon 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 lactone of formula (Xllld) which is further transformed to a compound of formula (XV) as described above.

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.

Case PC/4-34584P1 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 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, dichloromethyl, trichloromethyl, 2-chioroethyl 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 C16alkoxy-C1..6alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5- ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

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

Case PC/4-34584P1 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-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-C16alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

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

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

As C16alkylamino-C16alkyl and C16dialkylamino-C16a1ky1, 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.

Case PC/4-34584P1 As a HO(Q)C-C16alkyl, 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)-C16a1ky1, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-I,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-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 (C16alkyl)2N-C(O)-C16a1ky1, 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, R6, R7 and R8 may be linear or branched and comprise preferably I to 12 C atoms, I to 8 C atoms being especially preferred. R6 is particularly preferred as 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, R7 and R8 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, R7 and R8 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.

Case PC/4-34584P1 -12 -As an aryl, R, R', R6, R7 and R8 is preferably phenyl or naphthyl.

As an aralkyl, R6, R7 and R5 is preferably benzyl or phenyl ethyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::EoN NH2 (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.

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 (Va-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.

Case PC/4-34584P1 -13-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.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistt', 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 Case PC/434584P1 -14 -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.

Claims

Case PC/4-34584P1 -15-What is claimed is: 1. A method for preparing a

compound of the formula :::EoNR5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1kyl; R2 is halogen, C1..4alkyl or C14alkoxy; R3 and R4 are independently branched C6alkyl; and R5 is cycloalkyl, C16alky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C1alkanoyloxy-C1alkyI, Ci6aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16a1kyl, C16alkanoylamino-C16alkyl, HO(O)C-C16a1ky1, C16alky1-O-(O)C-C16a1ky1, H2N-C(O)-C16aIkyl, C1aIkyl-HN-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C16a1ky1; 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 (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
2.

3. A method according to claim 2, wherein a compound of formula (A) has the formula ::EoNNH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

4. A method according to claim 3, wherein a compound of formula (B) is (2S,4S,5S, 7S)-S-amino-4-hydroxy-2-isopropyl-7-[4-methoxy3(3methoxypropoxy)benzyl] 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

5. Method according to claim 1, wherein a compound of formula (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
3.

Case PC/4-34584P1 -16 - 6. A method according to claim 5, wherein a compound of formula (A) has the formula :H2Eo NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

7. A method according to claim 6, wherein a compound of formula (B) is (2S,4S, 5S, 7S)-5-amino-4-hyd roxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl] -8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

8. Method according to claim 1, wherein a compound of formula (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
4.

9. A method according to claim 8, wherein a compound of formula (A) has the formula NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9, 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.

11. A compound of the formula R' (Va-d) Case PC/4-34584P1 wherein R and R' are independently hydrogen, C16alkyl, C610ary1; or R and R' combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; Z is OR6 in which R6 is C120 alkyl, C312cycloalkyl, C312cycloalkyl-C1aIkyl, C610ary1 or C610ary1-C16alkyl; or Z represents -NR7R8 in which R7 and R8 are independently C120 alkyl, C3..12cycloalkyl, C312cycloalkyl-C16a1ky1, C6.10aryl or C610ary1-C16alkyl; and R3 and R4 are independently branched C1..4alkyl; and R6 is C120 alkyl, C312cycloalkyl, C12cycloalkyI-C16a1ky1, C610ary1 or C610ary1-C16alkyl.