GB2431652A

GB2431652A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431652A
Application number: GB0521748A
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: GB0521748D0

Abstract

An alternative synthesis of 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 which utilises a palladium coupling reaction as defined in Scheme 1 therein. Novel intermediates are used in the preparation of the above target compound.

Description

se PC/4-34589P1 Organic Compotiri The present invention provides

methods for preparing certain 2(S),4(S),5(S),7(S)2,7Y'-4hydroxy5amiflO8a0ctahb0YI 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 applies are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Patent No. 5,559,111.

Surprisingly it has now been found that 2(5),4(5),5(S),7(S)2,7dialkY41y0xY5mu10B aryl-octanOYl amide derivatives are obtainable in high diastereOmeric and enantiomeric purity making use of Pd coupling reactions.

In particular, the present invention provides a method for the preparation of a compound of the formula (A) wherein R1 is halogen, C16halogenalkYl, 16alkoxyCj6alkyl0Xy or Cl6alkoxY-Cl6alkYI R2 is halogen, C14a1ky1 or C14a1koXy R3 and R4 are independently branched C36aIkyl; and R5 is cycloalkyl, C16alkyl, C16hydrOXyalkYI, C1 6alkoxyCi6alkyl, 1.6alkanOylOXy-C16alkYl, C16aminoalkYl, C16alkylamin0-Ci-eY', C1..6dialkyIamifloC16alkyI, C16alkanoylamiflo- C1alkyl, HO(O)C-Cl.6alkYl, C16alkyl-O-(O)CC1-6l H2N-C(O)-C16aIkYl, C16a1ky1-H N-C(O)-C16alkYl or (C16alkyl)2NC(O)-C16alkY or a pharmaceutically acceptable salt thereof; which method comprises making use of Pd coupling reactions and following reaction steps as outlined in Scheme I which illustrates the preparation of a compound falling under formula (A) and having the formula Case PC/4-34589P1 (B) wherein R1 is 3methoxyprOPYlOXY R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof, particularly (2S,4S,5S,7S)5amin04Ydb0xY2 acid (2-carbamoyl2methYlPrOPYl)ami hemifumarate, also known as aliskiren.

Scheme I II Ill lv + 5OoC,Na2C,O2 1) resolution 1 SOCI2 2, MeOH, Acid 2, H2 CBr4, PPh, DIBAL-H, Toluene, -78 C dichiorometharle MeO'-...)I MeO Br 2O C (ase PC/4-34589P1 Scheme 2 + XOH THF,-78 C:00H :0o0H 2SOCIPthne:bo0H 2 2,0 then Na104, RuC3 1, NaN3, EtOH, H20 acetonitrile 2) L1AIH4, THF -78 -0 C 3) S0C2, then LiAIH4 THF, -78 -0 C 2,pd,EHor B In Schemes I and 2, R can be e.g. methyl, R' can be e.g. 3-methoxyProPYl and X represents a leaving atom or group, such as chloro, bromo, iodo or a suitable sulfonyl group, e.g. tosyl, mesyl, nosyl or the like.

Compounds of the above formulae (IV), (V), (VI), (VII), (VIII), (X), (Xl), (XII), (XIII) and (IV) are novel and also form part of the present invention.

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.

rase PC/4-34589P1 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, dichioromethyl, trichioromethyl, 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.

Exam pies 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 C1.6alkoxy-Ci6alkYloXY, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloXy, 2-methoxyethyloXY, 3-methoxypropyloxy, 4-methoxybUtyloXy, 5-methoxypentYlOxY, 6-methoxyheXylOXy, ethoxymethylOxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloXy, 5-ethoxypentylOXy, 6-ethoxyhexyloxy, propyloxymethylOxY, butyloxymethyloXY, 2-propyloxyethyloxY and 2-butyloxyethylOXY.

In a preferred embodiment, R1 is methoxy-or ethoxy-Ci4alkYloXY, 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 i-propyl.

Case PC/4-34589P1 As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cydopentyl, 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 C1.6alkoxy-Ci6alkYl, 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 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 C15alkylaminO-C16alkyl and C16dialkylamiflO-C16alkYI, R5 may be linear or branched. The alkylamino group preferably comprises C14alkyl groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2methylaminOethYl, 2dimethylamifloethYl, 2- ethylaminoethyl, 2-ethylaminoethYl, 3-methylaminoproPYl, 3-dimethylaminoproPYl, 4-methylaminobutyl and 4dimethylaminObUtyl.

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.

As a C16alkyl-O-(O)C-C16alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are Case PC/4-34589P1 methoxycarbonylmethYl, 2methoxycarbOnYIethYI, 3-methoxycarboflyiProPYl, 4- methoxycarboflylbUtYl, ethoxycarboflylmethYl, 2-ethoxyCarbOflYlethYl, 3-ethoxycarbonyiproPYl, and 4-ethoxycarboflylbutYl.

As a H2N-C(O)-C16aIkyI, 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, 3carbamidO-3-ethYlpropYl, 3-carbamido-2,2-dimethYlprOPYl, 2-, 3-, 4-or 5-carbamidopentYl, 4-carbamido-33-or -2,2-dimethylbutyl.

As a Cl6alkyl-HN-C(O)-Cl6alkYl 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 the above formula (B) or a pharmaceutically acceptable salt thereof is prepared. Further preferred are the methods of the present invention, wherein (2S,4S,5S,7S)-5-aminO-4- acid (2-carbamoyl2methyl-proPYl)amide hemifumarate, also known as aliskiren, is prepared.

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 intermediate product obtainable at any stage 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.

rq PC/4-34589P1 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, cyclohexafle, methylcyclohexafle, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethafle, chloroform, tetrachioroethafle, chlorobenzefle) 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-methylpYrrOlidOfle) ketones (acetone, methylisobutylketone, cyclohexanOne) sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n-or i-propanol, n-, or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexaflediol, 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-methylpyrrolidifle, 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.

Case PC/4-34589P1 Compounds of the present invention may be isolated using conventional methods known in the art, e.g., extraction, crystallization and filtration, and combinations thereof.

The following Examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 5 and 50 mmHg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR and NMR. In general, abbreviations used are those conventional in the art.

A reaction of the compound of formula (II) with a compound of formula (Ill) to yield a compound of formula (IV) according to Scheme 1: The reaction of a compound of formula (II) with a compound of formula (Ill) to give a compound of formula (IV) requires the presence of an appropriate palladium derivative, such as Pd(OAc)2 and the like, of an appropriate oxygen source, such as 02 and the like, and of a suitable base, such as sodium carbonate and the like. This reaction is conveniently carried out in an inert solvent, such as dimethyl formamide and the like, the appropriate temperature being from about preferably about 50 C. Reference is made to Org. Letts. 2003, 5, 231, where similar reactions and suitable conditions therefore are described.

A reaction of a compound of formula (IV) to yield a compound of formula (V) according to Scheme 1: The conversion of a compound of formula (IV) to a compound of formula (V) involves -a racemate resolution which can conveniently be carried out by methods which are readily available to those skilled in the art; followed by -esterification of the carboxy to the methoxycarbonyl group which can conveniently be carried out by means of methanol in the presence of an appropriate acid, reaction conditions suitable therefor being readily apparent to those skilled in the art.

A reaction of a compound of formula (V) to yield a compound of formula (VI) according to Scheme 1: The conversion of a compound of formula (V) to a compound of formula (VI) can be conveniently carried out by means of a reducing system, such as DIBAL-H and the like, in the presence of a suitable inert solvent, such as toluene, and the like, the appropriate temperature being preferably about -78 C.

Case PC/4-34589P1 A reaction of a compound of formula (IV) to yield a compound of formula (VI) according to Scheme 1: The direct conversion of a compound of formula (IV) to a compound of formula (VI) involves -treatment with an appropriate agent, such as SOCI2 and the like; -hydrogenation of the product thus formed; and -racemate resolution at the appropriate stage.

Methods suitable for carrying out these operations are readily available to those skilled in the art.

A reaction of a compound of formula (VI) to yield a compound of formula (VII) according to Scheme 1: The conversion of a compound of formula (VI) to a compound of formula (VII) can be carried out by reagent systems such as CBr4/PPh3 and the like, solvents suitable therefor including dichloromethane and the like, and details of the appropriate conditions are readily apparent to those skilled in the art..

A reaction of a compound of formula (VII) to yield a compound of formula (VIII) according to Scheme 1: The conversion of a compound of formula (VII) to a compound of formula (VIII) is conveniently carried out by means of an appropriate strong base, such as butyl lithium, LDA and the like, solvents suitable therefor including tetrahydrofuran and the like, and the appropriate temperature being preferably from about -78 C to about -20 C.

A reaction of a compound of formula (VI) to yield a compound of formula (VIII) according to Scheme 1: The direct conversion of a compound of formula (VI) to a compound of formula (VIII) can be conveniently carried out by means of reagents such as (CH3O)2P(0)-C(N2)-COO-CH3 and the like, suitable reaction conditions being readily apparent to those skilled in the art.

A reaction of a compound of formula (VIII) with a compound of formula (IX) to yield a compound of formula (X) according to Scheme 2: The symbol "X" in a compound of formula (IX) represents a suitable leaving group. The reaction of a compound of formula (VIII) with a compound of formula (IX) to givea compound of formula (X) requires the presence of an appropriate organic zinc compound, such as diethyl zinc and the like, solvents suitable therefor including tetrahydrofuran and the like, and the appropriate temperature being preferably about -78 C.

Case PC/4-34589P1 A reaction of a compound of formula (X) to yield a compound of formula (Xl) according to Scheme 2: The conversion of a compound of formula (X) to a compound of formula (Xl) involves a stereoselective reduction of the acetylenic triple bond to an olefinic double bond, the two substituents attached thereto showing cis-stereochemistry. This reduction can be carried out by methods which are readily available to those skilled in the art.

A reaction of a compound of formula (Xl) to yield a compound of formula (XII) according to Scheme 2: The conversion of a compound of formula (Xl) to a compound of formula (Xli) involves -treatment with an appropriate osmium salt, such as K20s04 and the like, in the presence of a reagent such as (DHQ)2PHAL and the like, and of an appropriate aqueous alcohol, such as aqueous tert.-butanol and the like, the appropriate temperature being preferably about room temperature; -treatment of the product thus obtained with an appropriate halogenating agent, such as SOCI2 and the like, in the presence of an appropriate base, such as pyridine and the like and of a suitable solvent, such as dichloromethane and the like, the appropriate temperature being preferably about 0 C; followed by -treatment with a suitable iodate, such as NalO4 and the like, and an appropriate ruthenium salt, such as RuCI3 and the like, solvents suitable therefor including acetonitrile and the like.

A reaction of a compound of formula (XII) to yield a compound of formula (XIII) according to Scheme 2: The conversion of a compound of formula (XII) to a compound of formula (XIII) involves -treatment with an appropriate azide, such as NaN3 and the like, in a suitable solvent or solvent system, such as aqueous ethanol and the like; -treatment with an appropriate complex hydride reducing agent, such as LiAIH4 and the like, solvents suitable therefor including tetrahydrofuran and the like, and the appropriate temperature being preferably from about -78 C to 0 C; and -treatment with SOd2 or the like followed by treatment with LiAIH4 or the like, solvents suitable therefor including tetrahydrofuran and the like, and the appropriate temperature being preferably from about -78 C to 0 C.

A reaction of a compound of formula (XIII) to yield a compound of formula (XIV) according to Scheme 2: The conversion of a compound of formula (XIII) to a compound of formula (XIV) involves the reduction of an azido group to an amino group. This reduction can be conveniently be Case PC/4-34589P1 carried out by hydrogenation in the presence of a suitable catalyst, such as palladium and the like, solvents therefor including ethanol and the like; or, alternatively, by means of an organic phosphorus compound, such as triphenylphosphine and the like, solvents therefor including toluene and the like.

A reaction of a compound of formula (XIV) to yield a compound of formula (B) according to Scheme 1: The conversion of a compound of formula (XIV) to a compound of formula (B) can be carried out by means of 3-amino-2,2-dimethylpropionic acid amide, reaction conditions suitable therefor being readily apparent to those skilled in the art.

Claims

Case PC/4-34589P1 What is claimed is: 1. A method for preparing a

compound of the formula ::E0R5 (A) wherein R1 is halogen, C16halogenalkyl, C1.6alkoxy-C16aikyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14a!koxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C1.6alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16alkyl, C16alkanoylamino- C16alkyl, HO(O)C-C16alkyl, C16a1ky1-O-(O)C-C16alkyl, H2N-C(O)-C16a1ky1, C16alkyl-H N-C(O)-C16alkyl or (C1.6alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises making use of Pd coupling reactions and following reaction steps as outlined in Schemes 1 and
2.

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 (25,4S,5S,7S)-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

4. Compounds of formulae (IV), (V), (VI), (VII), (VIII), (X), (Xl), (XII), (XIII) and (IV) as shown in Schemes I and 2.