GB2431646A

GB2431646A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431646A
Application number: GB0521735A
Authority: GB
Inventors: Gottfried Sedelmeier
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: GB0521735D0

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. Novel intermediates are used in the preparation of the above target compound.

Description

PC/4-34602P I 1 2431646 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-octaflOYl 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 (A) wherein R1 is halogen, C1..6halogenalkyl, C16alkoxy-C16alkyloxy or C1alkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C6alkyl; and R5 is cycloalkyl, C16alkyl, C15hydroxyalkyl, C16alkoxy-C1alkyl, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16alkyl, C1alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16alkyl, H2N-C(O)-C16a1ky1, C1alkyl-HN-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 in Scheme I (below) and following the steps outlined in any of Schemes I to 5 (below) to obtain a compound of formula X of Scheme I which is then transformed into a compound of formula (A).

PC/4-34602P I Scheme 1

OR

QNRR R4 + NRR.. NRR CHO (LCO2R dlv. Lit 7sps:Ri -:2c:r'5 -II

I R

OR 3 steps R NRR PTC OR 3 steps o.LL1 HN.r* ? R( R II R1 R1 R(' R iii R(' R3 IV R(1' R X OR 3 RR TrNH, Tr-NH,, o 4 -:: A xx XVI PC/4-34602P I Scheme 2 R4 R1 0

XI

HO

R/H0 NaH (R=CBz) RPR3X 1. Enolphosphonate OH 0 N. 2 Kumada R1_(k.1L.

o R2 R3 VIII

TMS R'

2. Oxidation 1. Hydroboration OR NRR' CHO R1 ____ R _____ R R'1-R II R2 R3 R2 -R3 NRR' X, V 7 0 0 R1 (.-y1A NR"0 R' R R(" R NRR' R2

VI VII

PC/4-34602P I Scheme 3 NRR)L#-R1.---...) CO2R 6 steps R11f" R('L' R R2 -R3 X' I Nagata Hydrocyanation

OR

0 OHCN 04 NRR'l O NRR R4 NRR' -Ri1J"R4 R1 RB1 R2 R3 R( R3

II

0 CO2R RlXflJ3 R2 R Hydrogenation (5,61 R1 -R2 R Laonng opening (Epimerisation [8J) XIV xv N-Deprotection Scheme 4 0 b) OR R/H OR4 Tr-N1)1.

Tr-NH ó Tr-NH,)t.,JLOH R1 OR RO RO R-'-R3 2 HO1 XVI HO" R XVII R,R'Tr/H XX I, R4 R4 [Rl:1OH1 R1 R2 R3

-

R2 R(R3

IV x

PC/4-34602P1 Scheme 5 3 steps [e.g 9] NaH 2. BrCH2COOR R,R = Bn/Bn; Tr/H. 9Li 3. TFA oo 1.NaH II 2. Pd(PPh3)4, Morphobn R4 TfO1CO2R 3. TEA 0 H4 CO2R ______ XVIa R,R =

A X IV

The strategic idea of the specific proposals depicted in Schemes 1-5 is to build the target molecule from the aromatic end in a linear fashion in such a way that formally a glutaminic acid equivalent has been added to the aromatic catechol fragment. Several proposals follow that aim and build the amino acid intermediate either e.g. by a chiral PTC catalysed addition of a glycine equivalent to the current "Synthon A" or by addition of the metallated catechol fragment to a glutaminic acid or pyroglutaminic acid derivative. Based on literature on related molecules there are several possibilities how such an e.g. isopropylated aryl glutaminic derivative could be further reacted to a compound according to formula A. Some of the possibilities are depicted.

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.

PC/4-34602P I An object of the invention is also to provide key intermediates for the methods acording to the invention. Such intermediates are novel chemical compounds which are claimed per Se.

These intermediates include the compounds of formula I and II (Scheme 1).

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 the following particular description of Schemes I to 5.

In the following, the substituents R1 to R5 have the meaning given in formula A above. X may be e.g. halogen or another leaving group and R, R', or R" (unless otherwise stated) may be C16alkyI or C16alkylbenzyl. In certain contexts R may be H. In Scheme I a compound of formula I referred to above as Synthon A' may itself be prepared from e.g. a brominated pyrocatechol derivative containing the substituents R1 and R2 of a compound of formula (A) above by substitution of an R3 substituted chiral propane derivative. A compound of formula I is reacted with the glutaminic ester shown wherein R may be H or C16alkyI or C16alkylbenzyl by e.g. Grignard to give a compound of formula II wherein R1 and R2 have the above meanings.

In the upper row, the ester grouping is removed from a compound of formula II to give the corresponding aldehyde. This is reacted with the R4 substituted e.g. halogenated ethanoic ester of formula VIII to give the lactone compound of formula X wherein R1 to R4 have the above meanings. A compound of formula X may be converted to a compound of formula (A) by reaction with R5-NH2.

In the central row a compound of formula II is reacted with an ester in PTC catalysed reactions to give a compound of formula III wherein R1 and R2 have the above meanings. By a series of known steps, ring closure and substitution of R4 are obtained to give a compound of formula IV wherein R1 to R4 have the above meanings. This may be converted to a compound of formula X (compare Scheme 4) by reduction with (a) Selectride and (b) catalytic hydrogenation e.g. with a palladium catalyst to give the intermediate compound shown in brackets in Scheme 4 and then with acid e.g. 6 N HCI. A compound of formula X can be converted to a compound of formula (A) as already described.

PC/4-34602P I In the lower row, a compound of formula Ills given nitrogen protection (Tr) and reacted with an R4 substituted derivative e.g. in PTC catalyzed reactions. This undergoes ring closure by known means to give a compound of formula IV, conversion of which to a compound of formula (A) is already described.

In Scheme 2, R' is preferably methylbenzyl and R may be H or C1aIkyI. The said compound of formula II is obtained from the said compound of formula I as above described and the upper line of Scheme I is repeated in the central line of Scheme 2 except that a compound of formula X' differs from a compound of formula X in that the amine N is shown as being protected by R, R'. A compound of formula (A) can be obtained from a compound of formula X' as described in Scheme I after deprotection.

In the lower line, reaction of the said compound of formula II with a hydroxylamine derivative (R" is preferably methyl) to obtain a compound of formula VI wherein R1, R2 and R3 have the above meanings. This may be reacted with a glycine derivative e.g. in PTC catalysed reactions to give a compound of formula VII where R1, R2 and R3 have the above meanings.

Conversion of a compound of formula VII to a compound of formula X' requires removal of the indicated methylene group by known means prior to reaction with a compound of formula VIII of Scheme 1.

In the upper rows, reaction of an R4 substituted ester or acid with an enolphosphonate and further reaction according to Kumada givesa compound of formula IX wherein R4 has the meaning above. This is reacted with the said compound of formula V to give a compound of formula VIII wherein R1 to R4 have the above meanings. This is subjected to hydroboration and oxidation to give the said compound of formula X' which can be converted to a compound of formula (A) as already described. Alternatively it can be converted to a compound of formula Xl by reaction with e.g. sodium hydride.

In Scheme 3, R and R' may have the meanings given in Scheme 2. The said compound of formula II (Schemes 1 and 2) is reacted with LiCH2-PO(OR)2 to give a compound of formula B' where R1, R2, and R3 have the above meanings. This is reacted with R4-CHO to give a compound of formula XII wherein R1 to R4 have the above meanings. Conversion of this compound to a compound of formula (A) may be accomplished via hydrocyanation according to Nagata.

In the upper row, the said compound B' is reacted with OHC-COOR to give a compound of formula XIII wherein R is C1.6alkyl (preferably methyl) and R1 to R3 have the above meanings.

PC/4-34602P I The said compound of formula XIII can be converted by a known series of steps to compound X' which in turn can be converted to a compound of formula (A) as described above.

In the lower row, the said compound B' is reacted with R4-CO-COOR wherein R is C16a1ky1 (preferably methyl) in alkali to give a compound of formula XIV wherein R1 to R4 have the above meanings. Reaction of this compound with NaBH4 in a solvent such as methanol gives a compound of formula XV where R1 to R4 have the above meanings. This requires hydrogenation and epimerisation to convert it to the chiral compound X' which in turn can be converted to a compound of formula (A) as described above.

In Scheme 4, the said compound of formulall is given N protection with Tr to give a compound of formula XX as in the lower row of Scheme I and reacted (a) with LiCH2PO(OR)2 and (b) with R4-CO-COOR/H wherein R is C16a1ky1 (preferably methyl) to give a compound of formula XVI wherein R1 to R4 have the above meanings. This is subjected to rearrangement with e.g. LiOH to give a compound of formula XVI wherein R1 to R4 have the above meanings. This is treated with an acid, e.g. 6 N HCI to give the ring a compound of formula IV described above. As in Scheme I this may be converted to the said compound of formulaX by reduction with (a) Selectride and (b) catalytic hydrogenation e.g. with a palladium catalyst to give the intermediate compound shown in brackets and then with acid e.g. 6 N HCI. A compound of formula X can be converted to a compound of formula (A) as described above.

In Scheme 5, R and R' are preferably Bn. A compound of formula II as described above is reacted (a) with CDI and (b) with C(R)-O-CO-OLi to give a compound of formula XVIII wherein R1 to R3 have the above meanings and R' is a Ci-C6 alkyl group. This is reacted with (a) NaH, (b) BrCH2COOR' and (C) TFA to give a compound of formula XIX wherein R1 to R3 have the above meanings. As indicated a compound of formula XIX can be obtained from a compound of formula II by introducing the group through alternative routes.

Treatment of the said compound of formula XVIII with (a) hydride, e.g. NaH, and (b) Pd catalyst, e.g. Pd(PPh3)4, morpholin and C(R4, TfO)COOR' and (c) TEA gives a compound of formula XVIa which differs from a compound of formula XVI (Scheme I) only in the nitrogen protection employed. Reduction of this compound with e.g. NaBH4 in a solvent like an alcohol such as methanol gives a compound of formula XXI already described, from which a compound of formula (A) may be obtained as already described.

PC/4-34602P 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 I 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 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-C14alkyloxy, 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.

PC/4-34602P 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 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 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-C16alkyl, 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 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-dimethytaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C1.6alkyl, 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/4-34602P I As a C16alky1-O-(O)C-C16a1ky1, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl.

As a H2N-C(O)-C16alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-1,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a C16aIkyl-HN-C(O)-C16alkyl or (C16alkyl)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 ::EoN2 (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.

The invention is inclusive of the following intermediates: A compound of the formula PC/4-34602P I NRR' R(L3

II

where R1 is halogen, C16halogenalkyl, C16aIkoxy-C16aIkyIoxy or C1alkoxy-C1alkyI; R2 is halogen, C14a1ky1 or C14alkoxy; R3 is branched CalkyI, R and R' are H or C1aIkyl or a nitrogen protecting group.

Preferably the nitrogen protecting groups comprise C16alkylbenzene.

A compound of the formula R4 where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16aIkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched Calkyl.

A compound of the formula 2 XVIa where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C6alkyl, Rand R' are H, Tr, C1alkyl or C16alkyl or C16alkylbenzene.

A compound of the formula PC/4-34602P I OHR4 where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyIoxy or C16aIkoxy-C1aIkyI; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C6alkyl, R and R'are H, Tr, C16a1ky1 or C16alkylbenzene.

A compound of the formula where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C1aIkyl; R2 is halogen, C1alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl.

Preferably in the above RI is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

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 PC/4-34602P I 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 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-PC/4-34602P I 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/4-34602P I What is claimed is: I. A method for preparing a compound

of the formula ::oR5 (A) wherein R1 is halogen, C16halogenalkyl, C1aIkoxy-C1aIkyloxy or C16alkoxy-C1alkyI; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C1.6alkyl, C16hydroxyalkyl, C1alkoxy-C16alkyl, C1alkanoyloxy-C1alkyI, C1aminoalkyl, C16alkylamino-C16alkyl, C1dialkylamino-C1alkyl, C16alkanoylamino- C1.6alkyl, HO(O)C-C16a1ky1, C1.6alkyl-O-(O)C-C16alkyl, H2N-C(O)-C16alkyl, C1alkyl-H N-C(O)-C16a1ky1 or (C16alkyl)2N-C(O)-Ci6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula I in Scheme I (below) and following the steps outlined in any of Schemes I to 5 (below) to obtain a compound of the formula X of Scheme I which is then transformed into a compound of formula A.
2. A method according to claim 1, wherein a compound of formula (A) has the formula ::oN2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,5S,7S)-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

PC/4-34602P I 4. A compound of the formula where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C1alkoxy-C1alkyl; R2 is halogen, C14a1ky1 or C1alkoxy; R3 is branched C3alkyl, R and R' are H or C1alkyl or a is a nitrogen protecting group.

5. A compound according to claim 4 wherein the nitrogen protecting groups comprise C16alkylbenzene.

6. A compound of the formula R4 where R1 is halogen, C16halogenalkyl, C1.6alkoxy-C1alkyloxy or C16alkoxy-C1alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

7. A compound of the formula 2 XVIa where R1 is halogen, C1halogenalkyl, C16alkoxy-C16alkyloxy or C1alkoxy-C16alkyl; R2 is halogen, C1alkyl or C14alkoxy; R3 and R4 are independently branched C3alkyl, R and R' are H, Tr, C16alkyl or C1alkylbenzene.

8. A compound of the formula PC/4-34602P I OHR4 where R1 is halogen, C16halogenalkyl, C1.6alkoxy-C16alkyIoxy or C1alkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched Calkyl, R and R' are H, Tr, C1alkyl or C16alkylbenzene.

9. A compound of the formula where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C1alkoxy-C1alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched Calkyl.

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

11. A compound according to any one of claims 6 to 9 wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.