GB2431640A

GB2431640A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431640A
Application number: GB0521721A
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: GB0521721D0

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

Description

PC/4-34595P I 1 2431640 Omanic Compounds The present invention provides

new methods for preparing certain 2(S),4(S),5(S),7(S)-2,7-dialkyl4hydroxy5amiflO-8-arYl-OCtan0Yl amide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediates useful in the manufacture of the same.

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

In particular, the present invention provides a method for the preparation of a compound of the formula wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkylOXy or C16alkoxy-C1.6alkyl; R2 is halogen, C1alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16alkyl, C1.6aIkanoyloxy-C16alkyl, C16aminoalkyl, C1.6alkylamino-C16alkYI, C16dialkylamino-Ci6alkYl, C1.6alkanoylamino-C16a1ky1, HO(O)C-C16alkYl, C16alkyl-O-(O)C-Ci6alkYl, H2N-C(O)-C16alkyl, C16alkyl-H N-C(O)-C16alkyl or (C16alkyl)2N-C(O)-C16alkYl or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula Ia, lb or Ic (below) and following the steps outlined in Schemes I to 3 to obtain a compound of the formula ha, lib, or Ilc for transformation to a compound of formula (A).

P0/4-34595 P1 Scheme I e.g OH (%) Rt R3 R1 R3 t::) (RO)F-_' R2-b----'--<j Ia R3 iv,v,vl R1 R3 vii R R3 ONIprOR R1 R3 R1 R3 R1__-\ R2 _b_0R [R2b_OR1 R2_b_' R2 -R> OR j ix R1 R -R2 R 2__9__> R2 R2__j__(jR. xli R4. ha

The central idea depicted in Scheme I is, to react an in-situ generated acyl nitroso dienophilic group intramolecularly with a suitably substituted diene with the result that the amino group bearing stereocenter at C5 is introduced during the reaction while the hydroxyl bearing functionality at 0-4 is derived e.g. from malic acid.

A possibility to produce the necessary hydroxamic acid precursor for the generation of the acyl-nitroso-dienophil is to start from malic acid [see Scheme I]. As shown on the scheme on the right side early introduction of the branched alkyl group R3/R4, e.g. isopropyl, could significantly help to increase the face selectivity of the Diels-Alder attack. An option can also be to use this regioselective reaction intermolecularly employing a acylnitroso dienophil build into a four carbon fragment.

In the following Scheme 2 the hetero-Diels-Alder Addition of a chiral imine to a diene prepared from succinic acid derivatives by double deprotonation with LDA or alternatively sodiumhydride/butyllithium and protection of the ester enolate moieties (analogous from aldehyde precursors) can yield adequately substituted six-membered rings suitable for the further transformation to a product according to formula A. The beauty of this concept is that PC/4-34595P1 the labile stereocenter at 05 can be additionally subjected to a dynamic kinetic resolution and the double bond at 02 subjected to an asymmetric hydrogenation.

Another option is to add an oxonium cation generated by Lewis acids from hydroxybutenolids or furanoids to introduce a five membered lactone.

Scheme 2 lb

R

RR, O A+C Aux.NH2 PGON)J IV R I R3 Aux' A OPG R Le:ic acid Rix5'o R=HorR4 R2 A H, 0 (cyclic), OR (succinic acid ester) Aux: Phenylethylamines, ephedrins, [91 Acid tert.butyl sulfinyl, sultames, Camphoric acid PG: protecting group [9] :Ib:: In the following Scheme 3 the Hetero-Diels-Alder-reaction (pressurized reaction to improve endo-selectivity) to give compounds of formulae V is known in the literature. A modification of that racemic concept is, to add a chiral Lewis acid catalyst such as e.g. transition metal selenium complexes in order to control additionally the stereochemistry of the Hetero-Diels-Alder-addition to give enantiopure compounds of formula V. The concept of this invention contains two strategies toward precursors of compounds acc. to formula Ic: a) using the Hetero Diels Alder reaction with compounds R= H and to introduce the branched C3-C6alkyl, e.g. isopropyl groups secondarily, and b) building in the isopropyl group (R) into the diene from the beginning.

Further scheme 3 depicts how the Diels-alder-Adducts of formula V are further transformed via intermediates VI -VIII to the key intermediate of formula llc.

PC/4-34595P I Scheme 3 R=H,R4 OP OMe P = Protecting group M-L: e.g. Jacobsen cataIt OMe Ic 90% (+ M.L) R C02R6 12 kbar MeOL to + IlL OP OMe Ca. 70% OP 50% in toluene, coR6 R and R6are C1 -C6 alkyl depo?yn, erize by reflux lh V *.-RO;J_sMgX R vi lie The advantage of the methods according to the invention resides in the application of mild reaction conditions which are highly stereoselective and avoid the use of elementary bromine and sodium azide.

An object of the invention is to provide key intermediates for the methods acording to the invention. Such intermediates are key intermediates in the methods of the present invention having the desired stereochemistry already at place and are claimed per Se. These intermediates include the compounds of formulae Ila and Ill (Scheme 1), lIb, D, E and G (Scheme 2), and lic (Scheme 3).

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 PC/4-34595P1 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.

The following particular description of Schemes I to 3 is intended to illustrate the invention and is not to be construed as being a limitation thereon. In general, abbreviations used are those conventional in the art. The substituents R1 to R5 have the meanings given above for formula A. Preferably R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

In Scheme I the reaction at (I) of a malic acid derivative e.g. a compound of formula Ia may be performed according to a) Corcoran, R.C. [Tetrahedron Left. 1990, 31, 2 101-2104.] or b) Thiam et.al. [Synth. Commun. 1992, 22, 83-85]. Reaction (ii) is a Wittig-Homer olefination with an R1 R2 and R3-substituted benzene-propenealdehyde wherein R1 R2 and R3 have the meanings above using a hydride such as NaH in a polar solvent such as THE at from about -20 00 to room temperature. The reductive ring opening of the resulting benzylidene acetal (iii) may be performed according to Kibayashi et al. [J. Org. Chem. 2001, 66, 3338-3347].

Reaction (iv) represents the introduction of the leaving group, e.g. MsCI in e.g. triethylamine and an apolar solvent such as dichloromethane; (v) represents nucleophilic substitution with a metal cyanide e.g. NaCN in a polar solvent such as DMSO at 5000; (vi) represents nitrile saponification by refluxing with alkali such as NaOH in aqueous alcohol e.g. methanol resulting in a compound of formula Ill wherein R1 R2 and R3 have the meanings above and R may be e.g. C1.6alkyl, preferably methyl or ethyl, (vii) represents hydroxamic acid preparation (a) with e.g. SOCI2 in an aromatic solvent e.g. toluene using e.g. DMF as catalyst and (b) hydroxylamine hydrochloride in alkali e.g. KOH and alcohol e.g. methanol at about 0 C; (viii) represents in situ oxidation of the hydroxamic acid and Diels-Alder reaction of the acylnitroso intermediate using e.g. NalO4, a catalyst such as Bu4NBr in e.g. aqueous DMA.

In Scheme 2 a compound of formula lb wherein R4 is as defined above, and A may be H, represent o-cylic or represent a succinic acid ester, is first given oxygen protecting groups PG forming a compound of formula D which is reacted with an R1 R2 and R3 substituted chiral benzene-propionaldehyde of formula B wherein R1 R2 and R3 have the meanings above to give a six membered lactone of formula E containing the said R1, R2, R3 and R4 Alternatively, a compound of formula C which is an Auxilliary substituted imine equivalent to a compound of formula B, wherein the auxilliary group Aux' may be a phenylethylamine, ephedrine, t-butyl sulfinyl sultames or camphoric acid is reacted with a compound of formula PC/4-34595P I C in the presence of a Lewis acid to produce the Auxilliary protected six membered cyclic amide of formula F containing the said R1, R2, R3 and R4 substituents.

A compound of formula E may be converted to a compound of formula F by known N for 0 substitution reactions and a compound of formula F is hydrogenated at (9) to produce a compound of formula G which can be treated with acid to give a compound of formula lib wherein R1 to R4 are as defined above. Similarly to Scheme I a compound of formula llb may be reacted with R5NH2 and the auxiliary removed to produce a compound of formula (A).

In Scheme 3 (i) represents the preparation of a protected R substituted diene from the corresponding alkylene compound of formula Ic wherein R is H or R4 is as above defined (e.g. isopropyl) and R' is C16alky1, e.g. methyl, e.g. with BuLi (90%) and a Hetero-Diels- Alder-reaction, performed e.g. according to C. Bataille et al [J. Oi. Chem. 2002, 6, 8054- 8062].; (ii) represents an enantioselective Hetero-Diels-Alder-reaction of the said diene in the presence of a chiral metal complex, e.g. the Jakobsen-complex, as described in (a) Review: Jorgensen Eur. J. Org. Chem. 2093-2102 and (b) Kwiatkowski et al [Synlett 2004, 1755- 1758] to produce a compound of formula V wherein R is defined above and R6 is e.g. C16alkyl; (iii) represents a) catalytic hydrogenation of a compound of formula V in an apolar solvent such as ethyl acetate, b) reaction with e.g. LAH in a polar solvent such as THF, c) the introduction of suitable protecting groups P, d) oxidation, e.g. with TEMPO and RuCI3 to produce a compound of formula VI wherein R is as above defined, (iv) represents the introduction of R4, e.g. ispropyl if necessary for R=H: a) by reaction with e.g. LiHMDS, in a polar solvent such as THF at about -78 C, then acetone, b) reaction with MsCI in e.g. triethylamine using e.g. DMAP as catalyst in a solvent such as dichloromethane, C) catalytic hydrogenation in a solvent such as ethyl acetate and NaHCO3, to produce a compound of formula VII (v) represents a) deprotection, b) reaction with e.g. MsCI in e.g. triethylamine and then addition of a compound of formula IX wherein R1 to R3 are as defined above to produce a compound of formula VIII wherein R1 to R4 are as defined above; (vi) represents reaction with HCI; (vii) represents a) reaction with MsCI and triethylamine, b) reaction with an azide such as sodium azide and e.g. LiCI in a solvent such as DMA to produce a compound of formula Ic wherein R1 to R4 are as defined above. Similarly to Schemes I and 2 a compound of formula (A) may be produced from a compound of formula lIc by reduction of the azide and reaction with R5NH2. (x) represents an alternative preparation of a compound of formula VI from diethyl tartrate according to Sanchez-Sancho et. al [Tetrahedron Assymm. 1996 11, 3209-3246] followed by hydrogenation.

PC/4-34595P I 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, chloromethyl, dichioromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

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

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

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

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

As a C16alkoxy-C16alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

In a preferred embodiment, R1 is methoxy-or ethoxy-C1..4alkyloxy, 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 1-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 1-propyl.

PC/4-34595P I 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 o 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-C15a1ky1, 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-Ci6alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

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

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

As C1..6alkylamino-Ci6alkyl and C16dialkylamino-C16alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C1..4alkyl 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-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.

PC/4-34595P 1 As a C16a1ky1-O-(O)C-C16alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another I to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonyipropyl, and 4-ethoxycarbonylbutyl.

As a H2N-C(O)-C15alkyI, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-1,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a Ci6alkyl-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-C16alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined herein above, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::oN NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are 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-am i benzyl]-8-methyl-nonanoic 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 PC/4-34595P1 R1 R3 R2

III

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C1.6alkyl; R2 is halogen, C1..4alkyl or C14alkoxy; R3 is branched C3alkyl and R is C16 alkyl.

Preferably R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 is isopropyl.

A compound of the formula :; H2 ha wherein R1 is halogen, C1..6halogenalkyl, C16alkoxy-C16alkyloxy or Ci6aIkoxy-C16a1ky1; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36a1ky1.

Preferably R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

A compound of the formula

PGO

A OPG

D

wherein A is H, a succinic acid ester or represents o-cyclic, PG are oxygen protecting groups and R4 is branched C36alkyl.

Preferably R4 is isopropyl.

A compound of the formula PC/4-34595P I ::; wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16aIkyl; R2 is halogen, C14a1ky1 or C14aIkoxy; R3 and R4 are independently branched C36alkyl.

A compound of the formula R4 :: wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C3alkyl.

A compound of the formula :: *ç?3 lib wherein R1 is halogen, C16halogenalkyl, C1alkoxy-C16alkyloxy or C16aIkoxy-C16a1ky1; R2 is halogen, C14a1ky1 or C1.4alkoxy; R3 and R4 are independently branched C36a1ky1 and Aux represents as an auxilliary phenylethylamine, ephedrine, tert. Butyl sulfinyl or camphoric acid.

PC/4-34595P1 Preferably R1 is 3-methoxypropyloxy; R2 is methoxy, and R3 and R4 are isopropyl.

A compound of the formula OR3 I Ic wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C1.6alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C1.4alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl.

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 Chemistry", Plenum PC/4-34595P I 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-methylpyr-rolidirie, 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/4-34595P I Vvhat is claimed is: 1. A method for preparing a compound

of the formula R4 (A) wherein R1 is halogen, C16halogerialkyl, Cl6alkoxy-Cl5aUcyIoxy or C1.6alkoxy-Cl6alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, Ciealkanoyloxy-C16alkyl, Ci6aminoalkyl, Cl6alkylamino-Cl6alkyl, Ci6dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16alkyI, Cl6alkyl-Q-(O)c-c16aucyl, H2N-C(O)-C16alkyl, C16a1ky1-H N-C(O)-C16alkyl or (Ci6aIkyl)2N-C(O)-c1.6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula Ia, lb or Ic (of Schemes 1-3) and following the steps outlined in Schemes I to 3 to obtain a compound of the formula Ila, lib, or lIc for transformation to compound A.
2. A method according to claim 1, wherein a compound of formula (A) has the formula N2 (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 (25,4S,5S,7S)-5-am nonanoic acid (2-carbamoyl-2-methyl-propyl) amide hemifumarate.

4. A compound of the formula PC/4-34595P 1 Ill wherein R1 is halogen C16halogenalkyl, C16alkoxy-C16alkyIoxy or C16alkoxy-C1.6alkyl; R2 is halogen, C14a1kyl or C14aIkoxy; R3 is branched C3aUcyl and R is C16 alkyl.

5. A compound according to claim 4 wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 is isopropyl.

6. A compound of the formula :: H2 Ha wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyI; R2 is halogen, C1.4alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl.

7. A compound according to claim 6 wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

8. A compound of the formula

A OPG

wherein A is H, a succinic acid ester or represents 0-cyclic, PG are oxygen protecting groups and R4 is branched C3.6alkyl.

9. A compound according to claim 8 wherein R4 is isopropyl.

PC/4-34595P I 10. A compound of the formula :23E wherein R1 is halogen, C16halogenalkyl, C1.6alkoxy-C16alkyloxy or Ci5alkoxy-C1.6alkyl; R2 is halogen, C1.4alkyl or C14alkoxy; R3 and R4 are independently branched C3..6alkyl.

11. A compound of the formula R4 wherein R1 is halogen, C16halogenalkyl, Ci6alkoxy-C16alkyloxy or C1..6alkoxy-C16alkyl; R2 is halogen, C14alkyl or Ci4alkoxy; R3 and R4 are independently branched C36a1ky1.

12. A compound of the formula : y' lib wherein R1 is halogen, Ci6halogenalkyl, Ci6alkoxy-C16alkyloxy or Ci6alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C1.4alkoxy; R3 and R4 are independently branched C36a1ky1 and Aux represents as an auxilliary phenylethylamine, ephedrine, ted. Butyl suphinyl sultames or camphoric acid.

PC/4-34595P 1 13. A compound of the formula N3I,1,_& OR3 R4 I Ic wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C,6alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36a1ky1.

14. A compound according to any one of claims 10 to 13 wherein R1 is 3-methoxypropyloxy; R2 is methoxy, and R3 and R4 are isopropyl.