GB2431642A

GB2431642A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431642A
Application number: GB0521725A
Authority: GB
Inventors: Stuart John Mickel
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-10-25
Filing date: 2005-10-25
Publication date: 2007-05-02
Also published as: GB0521725D0

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 Schemes 1-3. Novel intermediates are used in the preparation of the above target compound.

Description

PC/4-34606P1 1 2431642 Organic Compounds The present invention provides

new 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-octanoyl amide derivatives to which the methods of the present invention apply are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Patent No. 5,559,111.

Surprisingly, it has now been found that 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using a simple carboxylic acid derivative of formula (I) as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula ::1?4205 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyloxy or C16alkoxy-C1alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C3..6alkyl; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C1alkyl, C16aminoalkyl, C1.6alkylamino-C1alkyl, C16dialkylamino-C1alkyl, C1alkanoylamino-C16a1ky1, HO(O)C-C1.6alkyl, C16alkyl-O-(O)C-C16aIkyl, H2N-C(O)-C16a1ky1, C16a1ky1-H N-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-Ci6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula (I) and following reaction steps as outlined in Scheme 1, Scheme 2 and Scheme 3, to obtain a compound of formula (A).

PC/4-34606P I In another aspect, the present invention relates to key intermediates in the methods according to the present invention, in particular, such as those of formulae (VI), (X) and (Xl).

Scheme I: R4 R4 R4 X.LOH X.,LOR 0 0 0 (I) (II) (Ill) R.'( (IV) R" R"-L0 R R4 HNL._J%...(NHR5 R 0

R

(VI) (I) Scheme 2: R" 0 R" R" R"-__0 R4 0 R4 RIJL, + HN.L..,,1NHR5 a-R1 NHR5

R

(IX) (VIa) (X) I R1,1Y (VIla): Y H (Vllb): Y= Halide (Vllc): Y Metal R2 (A) xJ...1 R3 (VIII) PC/4-34606P I Scheme 3: R1 R" R2 (XII) H (A) (Vib) (XI) Other aspects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the description, appended claims, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.

As illustrated in Scheme I, a racemic compound of formula (I) wherein R4 has a meaning as defined herein above, and X represents a leaving group such as halide, preferably chloride, may be resolved to give a compound of formula (II), using conventional methods, e.g., by treatment with a chiral amine to form a mixture of diastereoisomeric salts which may then be fractionally re-crystallized from, e.g., an alcoholic solvent such as ethanol, isopropanol and the like. Chiral amines suitable for the use herein are, e.g., (R)-or (S)-alpha-methylbenzylamines and the like, or alkaloids, such as quinine, brucine and the like.

Compounds of formula (I) are known, or if they are novel they may be prepared using methods well known in the art.

Conversion of a compound of formula (II) to a compound of formula (Ill) wherein R4 and X have meanings as defined herein above, and R represents C1..20alkyl, C312cycloalkyl, C3.12cycloalkyl-C16alkyl, C610ary1 or C610ary1-C16alkyl, involves an esterification which transformation may be carried out using methods well known in the art.

Alternatively, a racemic acid of formula (I) may be directly converted into an optically pure ester of formula (Ill) by treatment with an appropriate esterase in water to selectively estenfy only one of the two possible enantiomers.

Coupling of an ester of formula (Ill) wherein X is, e.g., chloro, with an acetylenic ketone of formula (IV) wherein R' represents hydrogen or a R3-CH2-group in which R3 has a meaning PC/4-34606P I as defined herein above, to form compound (V) wherein R, R' and R4 have meanings as defined herein above, can be conducted according to known methods, e.g., by means of zinc, magnesium or lithium chemistry, e.g., in a suitable solvent such as tetrahydrofuran, preferably, at a low temperature, followed by reduction of the triple bond to afford a compound of formula (V), e.g., by catalytic hydrogenation in the presence of, e.g., Pd/C and BaSO4.

Compounds of formula (IV) are known, or if they are novel they may be prepared using methods well known in the art.

Conversion of a resulting compound of formula (V) to a compound of formula (VI) wherein R', R4 and R5 have meanings as defined herein above, and R" and R" are independently hydrogen, C16alkyl 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, may be carried out, e.g., by (a) hydrolysis, followed by bromolactonization and subsequent steps thereof to afford a desired 5-hydroxylactone intermediate; (b) conversion of the hydroxyl group to a leaving group; (c) treatment of a resulting compound with an azide; (d) reaction of a resulting 5-azidolactone with an amine of formula H2NR5 in which R5 has a meaning as defined herein above; (e) reduction of the azido group; and (f) protection of the vicinal amino alcohol moiety.

Reaction conditions under which these operations can be carried out are well known in the art, and variations thereof are readily obvious to those of ordinary skill in the art.

As illustrated in Scheme 2, a compound of formula (VIII) wherein R3 has a meaning as defined herein above, and X'-CO represents an activated carboxyl group in which X' is, e.g., halide, preferably chloride, may be treated with an organometallic compound of formula (VlIc) wherein R1 and R2 have meanings as defined herein above, and Y is, e.g., lithium, or a compound of formula (Vllc) represents a Grignard reagent, to afford a compound of formula (IX) wherein R1, R2 and R3 have meanings as defined herein above.

Compounds of formula (VIIa-c) are known, or if they are novel they may be prepared using methods well known in the art.

In the processes cited above, an activated carboxyl group include acid chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters, and activated esters thereof, and the like.

Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or isobutyl analogs. Activated esters include, for example, succinimido, phthalimido or 4-nitrophenyl esters. The reaction of an activated carboxyl group with an PC/4-34606P I organometallic compound of formula (Vile) may be carried out, e.g., in the presence of catalysts, e.g., palladium catalysts, and/or an additive, e.g., TMEDA, DMPU or HMPA, or a Lewis acid, e.g., ferric chloride in an organic solvent such as THE or toluene at low temperature.

A resulting compound of formula (IX) wherein R1, R2 and R3 have meanings as defined herein above, may then be condensed with a compound of formula (VI) wherein R", R", R4 and R5 have meanings as defined herein above, and R' represents hydrogen, designated herein as a compound of formula (Via), to afford a compound of formula (X) wherein R", R", R1, R2, R3, R4 and R5 have meanings as defined herein above. The aldol condensation is preferably carried out in the presence of the following reagents: a suitable base and a catalytic amount of L-or D-proline, or any other suitable amino acid; a suitable base and a catalytic amount of a chiral compound such as quinine, strychnine or BINAP; a chiral boron reagent, e.g., (+)-or (-)-diisopinenylcamphenylchloroborane; or a chiral organolithium base.

It should be noted that the stereochemical outcome of the above aldol condensation may also be controlled solely by the two stereocenters at C-4 and C-5, thus, allowing the use of achiral organo-lithium bases or other reagents suitable for anion formation at the alpha position to a carbonyl group. These reactions are usually run in an ether solvent system such as tetrahydrofuran, or diethyl ether, dichloromethane or toluene can also be used.

Temperature range for aldol condensations typically lies between -78 C and room temperature.

A resulting compound of formula (X) wherein R", R", R1, R2, R3, R4 and R5 have meanings as defined herein above, may then be converted to a compound of formula (A) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above, by reduction of the benzylic carbonyl group and the secondary hydroxyl group at C-6, followed by deprotection of the vicinal aminoalcohol moiety, using methods well known in the art.

Alternatively, as outlined in Scheme 3, a compound of formula (XII) wherein R1 and R2 have meanings as defined herein above, may be condensed with a compound of formula (VI) wherein R", R", R4 and R5 have meanings as defined herein above, and R' represents a R3-CH2-group in which R3 has a meaning as defined herein above, designated herein as a compound of formula (VIb), to afford a compound of formula (Xl) wherein R", R", R1, R2, R3, R4 and R5 have meanings as defined herein above. The aldol condensation may be conducted under conditions as described herein in Scheme 2.

PC/4-34606P I Compounds of formula (XII) are known, or if they are novel they may be prepared using methods well known in the art.

A resulting compound of formula (Xl) may then be converted to a compound of formula (A) wherein R1, R2, R3, R4 and R5 have meanings as defined herein above analogously as described for a compound of formula (X) herein above.

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

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

As a halogenalkyl, R1 may be linear or branched and preferably comprise 1 to 4 C atoms, especially I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chioromethyl, 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 i-propyloxy, n-, i-and t-butyloxy, pentyloxy and hexyloxy.

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

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

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

PC/4-34606P I In a preferred embodiment, R1 is methoxy-or ethoxy-C1alkyIoxy, 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 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-C16alkyl, 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 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

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

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

As C16alkylamino-C16a1ky1 and C15dialkylamino-C1.6alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C14alkyI groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2-PC/4-34606P I ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C16alky1, 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 I 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-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 an alkyl, R, R" and R" may be linear or branched and comprise preferably I to 12 C atoms, I to 8 C atoms being especially preferred. Particularly preferred is a linear C14a1ky1.

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

As an aryl, R, R" and R" are preferably phenyl or naphthyl.

As an aralkyl, R is preferably benzyl.

PC/4-34606P 1 In a preferred embodiment, R, R" and R" are methyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::2i,oN 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-nonarioic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

The invention is inclusive of the following intermediates: A compound of the formula R'" R'L,LQ R HNL1..(NHR5 (VI) wherein R' is hydrogen or R3-CH2-group; R3 and R4 are independently branched, C36a1ky1; R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16alkyl, C1.6alkanoyloxy-C16alkyl,C16aminoalkyl, C16alkylamino-C1.6alkyI, C16diaIkylamino-C1alkyl, C16alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C1.6alkyI-O-(O)C-C1.6aIkyI, H2N-C(O)-C16a1ky1, C1..6alkyl-HN-C(O)Ci6alkyl or (C16alkyl)2N-C(O)-C16a1ky1; and R" and R" are independently hydrogen, C16a1ky1 or C610ary1, or R" and R" combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring.

Preferred are the compounds of formula (VI) wherein R' is hydrogen or R3-CH2-group in which R3 is isopropyl; R4 is isopropyl; R5 is 2-carbamoyl-2-methyl-propyl; and R" and R" are methyl.

A compound of the formula PC/4-34606P I R"' R"_0 R4 (X) wherein R1 is halogen, C16halogenalkyl, C1alkoxy-C1alkyloxy or C1aIkoxy-C1alkyI; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C6alkyl; R5 is cycloalkyl, C1.6alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C1alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C16a1ky1, C16alkyl-H N-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C16alkyl; and R" and R" are independently hydrogen, C16alkyl 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.

Preferred are the compounds of formula (X) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; R3 and R4 are isopropyl; R5 is 2-carbamoyl-2-methyl-propyl; and R" and R" are methyl.

A compound of the formula R"-fo R4 (Xl) wherein R1 is halogen, C1.6halogenalkyl, C16alkoxy-C1.6alkyloxy or C1aIkoxy-C16alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C3alkyl; R5 is cycloalkyl, C16alkyl C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16alkyl, H2N-C(O)-C16a1ky1, C16aIkyl-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-Ci6alkyl; and R" and R" are independently hydrogen, C1.6alkyl or C610ary1, or R" and R" combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring.

Preferred are the compounds of formula (Xl) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; R3 and R4 are isopropyl; R5 is 2-carbamoyl-2-methyl-propyl; and R" and R" are methyl.

PC/4-34606P I 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 is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.

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

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

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

Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, PC/4-34606P I benzene, toluene, xylene), halogenated hydrocarbon (dichioromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and tactones (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; nitrites (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyr-rolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

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

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

Claims

PC/4-34606P1 What is claimed is: 1. A method for preparing a compound

of the formula ::EoN5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched CalkyI; and R5 is cycloalkyl, C16alkyl, C1..6hydroxyalkyl, C16alkoxy-C1alkyl, C1.6alkanoyloxy-C1alkyl, C16aminoalkyl, C16alkylamino-C1.6alkyl, C16dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C1.6alkyl, H2N-C(O)-C1alkyl, C16alkyl-l-IN-C(O)-C16alkyl or (C1.6alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula (I) and following reaction steps as outlined in Scheme 1, Scheme 2 and Scheme 3, to obtain a compound of formula (A).

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

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,55,7S)-5amino4hydroxy2-isopropyl-7-[4-methoxy-3-(3-methOXy-PrOpOXY) -beflZyl] -8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

4. A compound of the formula R"7L0 R HNJ..A...(NHR5 (VI) PC/4-34606P1 wherein R' is hydrogen or R3-CH2-group; R3 and R4 are independently branched, C36alkyl; R5 is cycloalkyl, C16alky1, C16hydroxyalkyl, C16aIkoxy-C1aIkyI, C16aIkanoyloxy-C16alkyl,Ci6amiflOaIkYl, C16alkylamino-Ci6alkyI, C1diaIkylamino-C1aIkyl, C16alkanoylamino-C16alky1, HO(O)C-C1..6alkyl, C1alkyl-O-(O)C-C1.6alkyI, H2N-C(O)-C16aIkyl, C16alkyI-HN-C(O)-Ci6alkyl or (C1.6aIkyl)2N-C(O)-C1..6alkyl; and R" and R" are independently hydrogen, C16alkyl or C6..10aryl, or R" and R" combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring.

5. The compound according to claim 4, wherein R' is hydrogen or R3-CH2-group in which R3 is isopropyl; R4 is isopropyl; R5 is 2-carbamoyl-2-methyl-propyl; and R" and R" are methyl.

6. A compound of the formula R"../__o R4 HN/i1(L.JyNHR5 (X) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-Ci6alkyloxy or C1.6alkoxy-C1.6alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C3alkyl; R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C1..6alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C1.6dialkylamino-C16a1ky1, C1.6alkanoylamino- C1.6alkyl, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16alkyl, H2N-C(O)-C1alkyl, C1.6alkyl-H N-C(O)-C1alkyl or (C1..6alkyl)2N-C(O)-C16alkyl; and R" and R" are independently hydrogen, C16a1ky1 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.

7. The compound according to claim 6, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; R3 and R4 are isopropyl; R5 is 2-carbamoyl-2-methyl-prOpyl and R" and R" are methyl.

8. A compound of the formula PC/4-34606P1 R" R" (Xl) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C1aIkoxy-C16aIkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36alkyl; R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C1..6alkoxy-C16alkyl, C16alkanoyloxy-C1alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-Ci6alkyl, C16alkanoylamino-C16alkyl, HO(O)C-C16alkyl, C16a1kyl-O-(O)C-C16alkyl, H2N-C(O)-C16alkyl, C1aIkyl-H N-C(O)-C16alkyl or (C16aIkyl)2N-C(O)-C16aIkyI; and R" and R" are independently hydrogen, C16a1ky1 or C610ary1, or R" and R" combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring.

9. The compound according to claim 8, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; R3 and R4 are isopropyl; R5 is 2-carbamoyl-2-methyl-propyl; and R" and R" are methyl.