GB2431650A

GB2431650A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431650A
Application number: GB0521745A
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: GB0521745D0

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 compounds or pharmaceutically acceptable salts thereof which uses cyclooctadiene monoepoxide as a starting material. Novel intermediates are used in the preparation of the above target compound.

Description

Omanic Compounds The present invention provides methods for preparing

certain 2(S) ,4(S) ,5(S) ,7(S)-2,7-dialkyl-4hydroxy-5amino-8-arYl-OCtanOYl amide derivatives, or pharmaceuticafly 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)-2,7dialkyl4hydroxy-5-amiflO-8-arYl-octafl0YI 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(S) ,4(S) ,5(S),7(S)2,7dialkyl4hydroXY-58min08 aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity making use of cyclooctadiene and its mono epoxide as starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula ::?42oR5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C1alkyl or C14alkoxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-Ci6aIkyl, C1.6diaIkylamino-Ci6alkyl, C16alkanoylamino-C16alkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16aIkyl, H2N-C(O)-C16alkyl, C1.6alkyl-H N-C(O)-C16alkyl or (C16alkyl)2NC(O)-Ci.6alkyl or a pharmaceutically acceptable salt thereof; which method comprises making use of cyclooactdiene mono epoxide as starting material and following reaction steps as outlined in Scheme I which illustrates the preparation of a compound falling under formula (A) and having the formula ::EoN2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceuticafly acceptable salt thereof, particularly (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl7[4methoxy-3(3-methoxy-propoxy)-beflZYl1-8-methYl-flOnanOiC acid (2-carbamoy!-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

Scheme I ii III o4"9J + :::::::Ist RO'<''( 1) Base, Acetone 01 2) deoxygenation Na104 ROJ7<i0R Resolution

VI H OHV

.&. OH Chiral epoxide opening o N HO'5{ HOj -A resp. B Compounds of formulae (Ill), (IV), (V), (VI) and (VII) 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

C

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.

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 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-chioroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms.

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

As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially 1 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 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, I-and t-butyl, and branched isomers of pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula (A) are in each case i-propyl.

As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.

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

As a C16hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms.

Some examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3-or 4-hydroxybutyl, hydroxypentyl and hydroxyhexyl.

As a Ci6alkoxy-C16alkyl, R5 may be linear or branched. The alkoxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.

As a C16alkanoyloxy-C15a1ky1, 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 C16alkylamino-C16alkyl and C16dialkylamino-C16aIkyl, 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 2-methylaminoethyl, 2-dimethylaminoethyl, 2- ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C16a1ky1, 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 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-diniethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-I,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 Ci5alkyl-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-C16a1ky1, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 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-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 aliskirene, 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.

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 Chemistr'J', 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, tetrachioroethane, 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-, 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-methylpyrrolidine, 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.

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 cyclooctadiene mono epoxide with a compound of formula (II) to yield a compound of formula (Ill) according to Scheme 1: The reaction of cyclooctadiene mono epoxide with a compound of formula (II) to give a compound of formula (III) requires the presence of a "Grubbs second generation catalyst".

Solvents suitable for this reaction are chlorinated hydrocarbons, such as methylene chloride and the like, or aromatic hydrocarbons, such as toluene and the like, and the appropriate temperature is between about room temperature and the reflux temperature of the reaction mixture.

A reaction of a compound of formula (Ill) to yield a compound of formula (IV) according to Scheme 1: The conversion of a compound of formula (Ill) into a corresponding compound of formula (IV) involves -generation of a di-anion by treatment with a suitable base in an appropriate solvent, such as tetrahydrofu ran and the like, and at a temperature of preferably about -78 C; -treatment of the anion with acetone to give a hydroxylated product, solvent(s) and temperature conveniently being as for the aforesaid generation of the di-anion; and -deoxygenation of the aforesaid hydroxylated product under radical conditions, solvents suitable therefor being toluene and the like, and the appropriate temperature being between about room temperature and the ref lux temperature of the solvent utilised (see, for example, Tetrahedron (1989), 45(21), 6623-6230).

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 chain shortening at both ends of the molecule which can be conveniently brought about, for example, by periodate cleavage in mixtures of water and a suitable alcohol at about or around room temperature; and -oxidation in a suitable solvent or solvent system, such as aqueous ethanol and the like, preferably at about room temperature, to yield the racemic epoxy di-acid of formula (V), oxidizing agent suitable therefore being readily available 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 resolution of the racemic compound of formula (V) can be carried out by a standard reagent which is readily available to those skilled in the art, conveniently in an alcoholic solvent, and the optically pure enantiomer of formula (VI) can then be isolated.

A reaction of a compound of formula (VI) to yield a compound of formula (VII) according to Scheme 1: The conversion of the compound of formula (VI) to a compound of formula (VII) involves a regioselective ring opening which can conveniently carried out in an ether solvent, the appropriate temperature being preferably from about 000 to about room temperature, see, for example, Tetrahedron Assymmetry 1998, 9(10), 1747.

A reaction of a compound of formula (VII) to yield a compound of formula (B) according to Scheme 1: The conversion of a compound of formula (VII) to Aliskiren of formula (I) involves -protection of the di-acid by treatment with an alcohol under acidic conditions; or via an acid chloride, such as the chloride; or via a reaction catalysed by a standard peptide coupling reagent, such as dicyclohexylcarbodiimide, and the like, in a suitable solvent, such as dimethyl formamide and the like, the appropriate temperature being preferably about ambient temperatures; and -converting the product thus obtained to the compound of formula (B) in a further three steps which will be readily apparent to those skilled in the art.

Alternatively to what has been described herein above, cyclooctadiene is used as the starting material instead of its mono epoxide. Cyclooctadiene can be converted into its 4,8-or 3,4-dioxo derivative by means of tert-butyl peroxide or singlet oxygen in the presence of a suitable rhodium catalyst; or it can be functionalized in different ways, see, for example, Journal of Organic chemistry 2002, 67(2), 5250; JACS 2002, 124(30), 8806; Tetrahedron Letters 2000, 41(46), 8947; and Synth. Commun., 1988, 18, 617; and the compounds thus obtained can be converted into intermediates which are suitable for the manufacture of the compound of the formula (B) along the lines described hereinabove for the procedure starting with cyclooctadiene mono epoxide.

Claims

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

::.ONR5 (A) wherein R1 is halogen, C16halogenalkyl, Cl6alkoxy-Cl6alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C15alkyI, C16hydroxyalkyl, C16alkoxy-C16alkyl, Cialkanoyloxy-C15alkyl, Ci6aminoalkyl, Ci6alkylamino-C16alkyl, C16dialkylamino-C16allcyI, C16alkanoylamino- C16alkyl, HO(O)C-C16a1ky1, Ci6alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C15alkyl, C16a1ky1-HN-C(O)-C16alkyl or (Ci6alkyl)2N-C(Q)-C1.6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises making use of cyclooactadiene mono epoxide as starting material and following reaction steps as outlined in Scheme 1.

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

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,5S,75)-nonanoic acid (2-carbamoyl-2-methyfpropyI)amide hemifumarate.

4. Compounds of the formulae (Ill), (IV), (V), (VI) and (VII) as shown in Scheme 1.