GB2431648A

GB2431648A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431648A
Application number: GB0521740A
Authority: GB
Inventors: Murat Acemoglu
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: GB0521740D0

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

1 2431648 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, phamiaceutical 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, C1..6alkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C1..4alkyI or C14alkoxy; R3 and R4 are independently branched C3.6alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16alkyl, C1..6alkanoyloxy-Cl6alkyl, Ci6aminoalkyl, C16alkylamino-C1alkyl, C16dialkylamino-C16a1ky1, C.6alkanoylamino-C16alkyl, HO(O)C-C16alkyl, C16a1ky1-O-(O)C-C16alkyl, H2N-C(O)-C16a1ky1, C1.6alkyl-H N-C(O)-C16alkyl or (Ci6alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula Ia, lb, Ic, Id, le, If, Ig or lh (below) and following the steps outlined in any one of Schemes 1 to 4a/b (below) to obtain a compound of formula X, Va, XXI, XXVI, XXVIII or XXXI which is then transformed into a compound of formula A. Scheme I Ia 0 0 OL1 0L11 [A] x /LyO

II R4 R H/R

0 0 R4 0 0 R4 HIR OH H/R NHAc 0 HOrN 0 lv V HIR O 0 via O R R R4 NAc NHAc NHAc NHAc VIII Vii Vi 23 LDATHF R HA R4 (A) R2 x Scheme 2

R R

R

+ xo RIH 0 0 I 0 XI lb R/H 0 xii o

XIII R 0 0

R R P/H P/H I R/H 0 R/H:o 0 O * xIL 0 Xv Ic XIa XIV 0 OH _____ P/H II (A)

C Va

In the following Scheme 3 the two concepts depicted involve in its preferred version the preassembly of all carbon atoms of a compound of formula A in the trion compound XVIII prepared from Ic by alkylation with XVI or XVII. The further steps could involve the Genet technique (Acc. Chem. Res. 2003, 36, 906-918) either in its conventional form or a new extension generating a conjugated tetraene.

Scheme 3 0 OH OH R (A) XXXI R/H I

I

XVIII

(A) .. OH OH R -R/H RIH

XXI

The strategic idea of the proposals depicted in Schemes 1-3 is to use a dynamic kinetic resolution technique by asymmetric hydrogenation developed by Genet et.al (Acc. Chem. Res. 36 (2003) 908-918) for readily accessable aipha-hydroxyimino beta-ketoesters from which by hydrogenation a prochiral hydroxyl-enamide compound is generated that directly is hydrogenated in an asymmetric hydrogenation step in the presence of a chiral catalyst. The resulting chiral building blocks could be useful as intermediates for the synthesis of a compound according to formula A. In the following Schemes 4a/b several preparation possibilities for chiral precursors are depicted which could be used e.g. for the proposals mentioned in schemes 1-3 or also for other synthesis options to produce enamides.

A related idea to enantioselectively hydrogenate an enamide compound derived from a diketone is outlined in Scheme 4aIb.

Scheme 4a R4 R4 R4 Rf H _____ OLRIH R/H R/H R/H o 0 0 le XXII _________ R4 _________ _________ -E R4 R4

XXIII 0 0

JR/H HOo HOOH 0' THF R3 R3 Rhodia

XXIV R4 R4 0 OH R/H R/H

NHAc R/H R3

XXVI

XXV

heme 4b RdRI R 1R4 R31R1

XXVIII R/H

RJH

Rfl-I ___________

RIH

0 RJR4 RIR4

XXVII If R31R4

R31R4 OH2 R/H RIH R/H R31R4 XHaI R3IR1 0 +

HCCH XXIX Ih

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.

Another object of the invention is 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 IV, V, VIII and X (Scheme 1), XIII, Va and XV (Scheme 2), XVIII, XIX, XXX and XXXI (Scheme 3) and XXII, XXVI, XXVII and XXVIII (Scheme 4a/b).

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.

In Scheme I a double deprotonated 3-oxo butyric acid ester or amide derivative is suitably activated e.g. by LDA and THF and alkylated with a two carbon building block II carrying the chiral stereocenter R4 where R4 has the meaning indicated in formula A above. R4 is preferably isopropyl derived e.g. from valine. There results compound Ill where R' is e.g. C1 6aIkyI, A is 0 or NR, and X is a reactive group such as CI, Br or J. The next step is the introduction of the hydroxyimino group by reaction with e.g. Na NO2 and acid such as HCI to give the hydroxyiminohexanoic acid derivative IV where R' and R4 have the above meanings.

This is subjected to two catalytic hydrogenation steps firstly with Pd/C in e.g. Ac2O and secondly with RuX2 in P-P, as described for related substances by Genet et. al (Acc. Chem. Res. 2003, 36, 906-9 18) to give compound V where R' and R4 have the above meanings. Ac represents C16acyI, preferably acetyl. Treatment with acid, e.g. 6N HCI yields compound VI where Ac, R' and R4 have the above meanings.

Compound VI is reacted with (a) with MsCI, triethylamine and DMAP and (b) hydrogen with a Pd/C catalyst in a solvent such as ethyl acetate giving a lactone derivative VII bearing the stereochemically correct R4-functionality. R4, Ac and A have the above meanings.

Compound VII is reacted with (a) LiOH, (b) Cyanuryl chloride, N-methylmorpholin and DME, (c) with sodium borohydride and water and (d) with MsCI, triethylamine and DMAP to give compound VIII where R4 has the above meaning and X is e.g. CI, Br or J. The said compound VIII is then substituted by compound IX where R1 to R4 have the meanings in formula A using e.g. LDA and a polar solvent such as THF, yielding compound X where R1 to R3 have the meanings in formula A. This may be converted to a compound of formula A in a known manner by reaction with R5-NH2.

Scheme 2 shows two routes by which a compound Va, may be built up. Compound Va differs from compound V of scheme I only in the absence of the group A and R4. Compound lb where the group X is a reactive group such as Br and R is as defined above is reacted with the cyclic ester compound Xl in e.g 89 percent sodium acetate and DMF to obtain compound XII. Reaction with e.g. (a) lithium chloride and DMSO and (b) an alcohol such as methanol and an acid such as 40 percent sulphuric acid gives compound XIII. This in turn may be reacted with e.g. sodium nitrite and an acid such as HCI to add the necessary nitrogen containing group at compound XV. Hydrogenation of compound XV with (a) e.g. Pd/C and Ac20 where Ac denotes C16acy1, preferably acetyl and (b) ruthenium halide and P-P yields compound Va where Ac is defined above. Compound Va can then be converted to give compound A. Compound Va may alternatively be built up from the scheme in the lower row by first reacting compound Ic with compound XIa, a reactive, e.g. halogenated derivative of compound XI of Scheme 2 with LDA and THF to give compound XIV. Reaction of compound XIV with e.g. sodium nitrite and acid as above gives compound XV which may be reacted as already described to give compound Va.

In Scheme 3 a compound Id where R1 to R3 have the meanings in formula A above is alkylated with a compound XVI or XVII where R4 has the meaning in formula A above, using e.g. LDA and a polar solvent such as THF to give compound XVIII where R1 to R4 have the meanings in formula A above. This may be reacted with e.g. sodium nitrite in acid such as HCI to substitute the hydroxyl imine group at compound XIX. Hydrogentation with e.g. Pd/C and Ac20 where Ac has the above meaning, and subsequently reaction with LDA and R'3SiX where X may be e.g. halogen and R' e.g. C1.6alkyI gives compound XX where R1 to R4 and R' have the above meanings. Further hydrogenation with e.g. ruthenium halide and P-P which may proceed directly gives compound XXI where R1 to R4 have the meanings in formula A above. Conversion of the said compound XXI to a compound of formula A requires replacement of -O-R/H by NH-R5, where R5 has the meaning in Formula A, replacement of -NH.-CO-R/H by -NH2 and removal of a hydroxyl group all of which may be accomplished by known reactions.

The said compound XIX may alternatively be treated with hydrogen and Pd/C together with Ac20 where Ac has the above meaning to give compound XXX where R1 to R4 have the meanings in formula A above. This may be further reduced with hydrogen and RuX2 and P-P to compound XXXI. Conversion of the said compound XXXI to a compound of formula A requires replacement of -O-R/H by NH-R5, where R5 has the meaning in Formula A, removal of the carboxyl group and hydroxyl group on the sides of R3 and replacement of -NHAc by -NH2 all of which may be accomplished by known reactions.

Schemes 4a and 4b show possibilities for preparing chiral precursors which may be used as building blocks containing the groups R3 and R4 of formula A in the preparation of compounds of formula A. In these Schemes, R3 and R4 generally have the meaning given in formula A, i.e they are branched C3.6alkyl. However in Scheme 4a R3 is most suitably isopropyl. Scheme 4b is most suitable where R3 and R4 are the same group, e.g. isopropyl. R may be e.g. C16a1ky1 or C16alkylaryI.

In Scheme 4a the compound le where R4 has the above meaning may be reduced with e.g. hydrogen and Ru(BiNAP)Cl followed by L1AIH4 to give compound XXII. This may be subjected to ring closure and isomerised with e.g. Rh(BiNAP) and reduced with e.g. hydrogen and Pd/C to give the lactone compound XXIII. In the next row Rhodia is reacted with (R3)2CuLi in a polar solvent such as THF, where R3 is preferably isopropyl and the product reduced with LiAIH4 to give compound XXIV. Compounds XXIII and XXIV may then be combined to form compound XXV which is reduced to compound XXVI with e.g. Ru(BiNAP). Compound XXVI may be reacted with a R1, R2 substituted benzene derivative to form the skeleton of formula A. In Scheme 4b the compound If where R3 and R4 represent the same branched C36aIkyl group, preferably isopropyl, is dimerised by treatment with Ti according to McMurry or pinacol and oxidised with e.g. Cr03 to compound XXVII. Treatment with ammonia gives compound XXVIII. Compound XXVIII may be used similarly to compound XXVI above after reduction of the first carboxyl group.

Alternatively compound Ig may be dimerised with an intermediate acetylene group by reaction with acetylene and BuLi in a polar solvent such as THF to give compound XXIX.

Oxidation with KMnO4 and FeCI3 or with MTO and H202 yields the said compound XXVII.

The said compound XXVII may also be obtained as shown by dimerisation of the compound lh using (a) Mg and ether, (b) Pd(Ph3)4 and (c) oxygen.

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 1 to 6 C atoms, especially 1 or4 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 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 1 to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms.

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

As a Ci6alkoxy-C16alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises 1 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.

As a branched alkyl, R3 and R4 preferably comprise 3 to 6 C atoms. Examples are i-propyl, 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 cycloailçyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especiafly preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy! and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.

As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise 1 to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, i-and t-butyl are preferred.

As a C1.6hydroxyalkyl, 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 Cl5alkoxy-Cl6aIkyl 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-methoxypropyi, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.

As a C16alkanoyloxyC16aIkyl 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 Ci6aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms.

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

As Cl6alkylamino-Cl6aJkyI and C1.6dialkylaminoC16alkyl, 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-dimethylamjnoethyl 2- ethylaminoethyl 2-ethylaminoethyl 3-methylaminopropyl, 3-dimethylaminopropyp 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.

As a C1.6alkyl-Q-(o)CCi6alkyl 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 Cl6alkyl-HN-C(O)-Cl6alkyl or (Cl6alkyI)2N-C(O)-Cl6alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alky 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, ethy', 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 i-propyl; 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, benzyl]-8-methyl- nonanojc acid (2-carbamoyl-2-methyl-propyl)amjde hemifumarate, also known as aliskiren.

The invention is inclusive of the following intermediates: A compound of the formula wherein R4 is branched C36a1ky1, R' is C16a1ky1 or C16alkylaryl and A is 0 or NR'.

A compound of the formula NHAc o

V

wherein R4 is branched C36alkyl, R' is C16alkyl or C16alkylaryl and A is 0 or NR' and Ac is C16acy1.

A compound of the formula

R NHAc

wherein R4 is branched C3..6alkyl, X is halogen and Ac is C16acyl.

Preferably R4 is isopropyl.

A compound of the formula R1 R4 R2' NHAc x wherein R1 is halogen, C1.6halogenalkyl, Cl6alkoxy-Cl6allcyloxy or Ci6alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and 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 R/H o R/H 0.

wherein R is C1.6alkyl or C16alkylaryl.

A compound of the formula R/H[I) NR NHAc 0 Va wherein R is C16alkyl or C16alkylaryl and Ac is C acyl.

A compound of the formula R/H wherein R is C16a1ky1 or C16alkylaryl.

A compound of the formula 0 0 0 R 2 XVIII wherein R is C1..6alkyl or C16alkylary;, R1 is halogen, Ci6halogenalkyl, C16alkoxy-Ci6alkyloxy or Ci.6alkoxy-C16alkyp; R2 is halogen, C1.4alkyl or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

A compound of the formula R10R4

OH XIX

wherein R is C16a1kyl or C16alkylaryl, R, is halogen, Cl6halogenalkyl, C16alkoxy-Ci6alkyloxy or Cl6alkoxy-Cl6aIkyl; R2 is halogen, C14alkyl or Cl4alkoxy; and R3 and R4 are independently branched C36alkyl.

A compound of the formula R20 RIH

XXI

wherein R is C16aIkyl or C16alkylaryl, R1 is halogen, Cl6halogenallcyl, Cl6alkoxy-Ci6alkyloxy or C1..6alkoxy-Cl6alkyI R2 is halogen, C14aIkyl or Ci4alkoxy; and R3 and R4 are independently branched C36alkyl.

A compound of the formula

RIH XXX

wherein R is Ci6alkyI or C16alkylaryl, R1 is halogen, Cl6halogenallcyl, C6aIkoxy-Ci6alkyloxy or Cl6alkoxy-Cl6alkyl R2 is halogen, C14alkyI or Ci4alkoxy; and R3 and R4 are independently branched C36alkyl and Ac is C6acyl.

A compound of the formula R3NHA RIH 2 xxxi wherein R is C16alky1 or C6alkylaryl, R1 is halogen, Cl6halogenalkyl, ClGalkoxy-Cl6alkyloxy or C1.6alkoxy-c1681kyl* R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36a1ky1 and Ac is Ci6acyl.

Preferably in the above RI is 3-methoxypropyloxy; R2is methoxy; and R3and R4are isopropyl.

A compound of the formula RIH iyO H R3 0 XXVI wherein R is C16alkyl or Cj6alkylaryl,; R3 and R4 are independently branched C36aIky1 and Ac is C1.6 acyl.

A compound of the formula 0 R31R4 R/H R/H

XXVII

wherein R is C16aIkyl or C16alkylary:,; and R3 and R4 are the same branched C36alkyl.

A compound of the formula 0 0 R31R4 R/H R/H R3/R4 2 0 XXVIII wherein R is C16alkyl or Ci6alkylaryl,; and R3 and R4 are the same branched C36alkyl.

Preferably in any of the above where appropriate, R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl. R is preferably methyl.

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 dose 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 Chemisfnj', 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, cycohexanecijoI, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanedjol, 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-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

What is claimed is: 1. A method for preparing a compound of the formula

R4 ::E0R5 (A) wherein R1 is halogen, Ci6halogenalkyl, Cl6alkoxy-Cl6aIlcy:oxy or C16alkoxy-C16aIkyI; R2 is halogen C14alkyl or C14alkoxy; R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16alkyl, Cl6alkanoyloxy-Cl6aIIcyl, Cl6aminoalkyl, Cl6alkylamino-Cl6aIkyl, Cl6dialkylamino-C1.6aIkyI, C16alkanoylamino- C16a1ky1, HO(O)C-C16alkyl, Cl6aJkyI-O-(O)C-Cl6aljçyI, H2N-C(O)-Cl6alkyI, C16a1ky1-HN-C(O)-C16aIIcyI or (Cl6alkyl)2N-C(O)-Cl6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula Ia, lb, or Ic, Id, le, If, Ig or Ih and following the steps outlined in any of Schemes I to 4a/b to obtain a compound of the formula X, Va, XXI XXVI, XXVIII or XXXI 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 ::EoN 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,5S,7s) 5-am nonanoic acid (2-carbamoyI2methyIpropyI)amide hemifumarate.

4. A compound of the formula wherein R4 is branched C36alkyI, R' is C16alkyl or C16alkylaryl and A is 0 or NR'.

5. A compound of the formula 0 OH H/R' R4 NHAc o

V

wherein R4 is branched C36alkyl, R is C16alkyl or C16aIkylaryl and A is 0 or NR' and Ac is C16acy1.

6. A compound of the formula

R NHAc

wherein R4 is branched C36alkyl, X is halogen and Ac is C15acy1.

7. A compound according to claim 4, 5 or 6, wherein R4 is isopropyl.

8. A compound of the formula R1 " R4 R27 R NHAc x wherein R1 is halogen, C16halogenalkyl, Cl6alkoxy-Cl6alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyI or C14alkoxy; and R3 and R4 are independently branched C3.6alkyl.

9. A compound according to claim 8, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

10. Acompoundoftheformula F/H o o O R/H wherein R is C16a1ky1 or C16alkylaryl.

Ii. A compound of the formula 0 OH R/H

O

NHAc o Va wherein R is C16alkyI or C16alkylaryl and Ac is C16 acyl.

12. A compound of the formula R/H wherein R is C16alkyl or C16alkylaryl.

13. A compound of the formula R/H 2 xviii wherein R is C16alkyl or C16alkylaryl, R1 is halogen, Ci6halogenalkyl, C16alkoxy-C16alkyloxy or Cl6alkoxy-Cl6aIkyl R2 is halogen, C14alkyI or C14alkoxy; and R3 and R4 are independently branched C36alkyl.

14. A compound of the formula R23NO

OH XIX

wherein R is C16a1ky1 or C16alkylaryl, R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyI; R2 is halogen, C14a1kyl or C14aIkoxy; and R3 and R4 are independently branched C36alkyl.

15. A compound of the formula

OH OH OH R 2 R3J

XXI

wherein R is C1alkyl or C16alkylaryl, R1 is halogen, C16halogenalkyl, C16aIkoxy.* C16alkyloxy or Ci..6alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyI.

16. A compound of the formula O OH 0 R Il Il R/H R2 R NHAc 0 xxx wherein R is C16alkyl or C16alkylaryl, R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl and Ac is 01-6 acyl.

17. A compound of the formula 0 OH OH R R1 I R/H R( R3 NHAc 0

XXXI

wherein R is C16a1kyl or C16alkylaryl, R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyloxy or C16aIkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl and Ac is C16 acyl.

18. A compound according to any one of claims 13 to 17, wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl.

19. A compound of the formula R3 XXVI wherein R is C16aIkyl or C16alkylaryl,; and R3 and R4 are independently branched C36alkyl and Ac is C16 acyl.

20. A compound of the formula R31R4 R/H R/H xxvii wherein R is C16alkyi or C16alkylaryl,; and R3 and R4 are the same branched C36alkyl.

21. A compound of the formula o RIR R/H R/H R!R NH2 0 xxviii wherein R is C16alkyl or C16aIkylaryl,; and R3 and R4 are the same branched C36alkyl.

22. A compound according to any one of claims 19 to 21, wherein, R1 is 3-methoxypropyloxy; R2 is methoxy; R3 and R4 are isopropyl; and R is methyl.