GB2431651A

GB2431651A - Synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431651A
Application number: GB0521747A
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: GB0521747D0

Abstract

A method for the preparation of certain 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds of formula (A): <EMI ID=1.1 HE=30 WI=69 LX=715 LY=769 TI=CF> <PC>wherein R1 is halogen, haloalkyl, alkoxy-alkoxy, alkoxyalkyl; R2 is halogen, alkyl or alkoxy; R3 and R4 are branched C1-4alkyl; and R5 is H2N-C(O)-C1-6alkyl or substituents; or a pharmaceutically acceptable salt thereof; which method comprises starting from a Boc-protected homo-tyrosine-3-isopropyl derivative of formula (I) and following the reaction sequence set out in Scheme 1. Preferred compounds of formula (A) are aliskiren and salts thereon particularly (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate. Intermediates prepared as part of this synthesis are also claimed.

Description

Organic Compounds The present invention provides 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, 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)-2,7-dialkyl-4.hydroxy-5-amino- 8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using bis-homo-tyrosin-3-isopropyl-analogueS, as the starting material.

In particular, the present invention provides a method for the manufacture of intermediates of formulae (II) to (IV) of Scheme I for the preparation of compounds of the formula (A) wherein R1 is halogen, C16halogenalkyl, C1.6alkoxy-C16alkyloxy or C16alkoxy-C1..6alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36aIkyI; and R5 is cycloalkyl, C1aIkyl, C16hydroxyalkyl, C16alkoxy-C16aIkyl, C16alkanoyloxy-C16alkyI, C1 6aminoalkyl, C16alkytamino-C16alkyl, C16dialkylamino-C16alkyl, C16alkanoylamino-C16aIkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C16alkyl, C16alkyl-H N-C(O)-C1.6alkyl or (C16alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a homo-tyrosin-3-isopropylderivative of formula (I) of Scheme 1 and following reaction steps as outlined in Scheme 1 to obtain a compound of formula (II) of Scheme I which is then transformed into a compound of formula (A).

Scheme 1 Ester MOP

MOP

cleavage Decarboxylation 2 C0

BOC BOC CD 0

\\\ Diastereo-Malonester Acylierung H (NaBH, THF, EtOH)

E E

_________________________ 2 VerselfunE -Route A] / III ci + c-Routel H,ThF, selective Reduion -CO2 N, Th/Llt: lOP 0 V Lft.: R.V. Hoffman at. ff' pH BOC-Lacton precursor I Sp 819 DW,et * 0 BOC 1. Base, BH2CO2R I 1 NaBH4, THF, ROH ROH -CO, versedunco2 _________________

COC

________________) .Aceton MOP 00 MOP 0 X H, OH, Cl, P, -O-C02R L It.: i31'),"J MOP etc. spaltung" NMe(OMe), BuLi \\ I BOC [c3.Rou // /i. Ester-BOC:::::: ; 2. Decarboxy.

lierung

____ BOCO

OH H2, Pd-C MOP 2. NaH selektlvlt I! Ethanol)j.._N(Z 1. BuLi, THF MOP IV OO'XN 3. CICO2Bn schiechte Dastereo.

4. NaH ...-\HN COOR o BOC 5 i-Pr-X

I BOC I

A preferred compound of formula (A) is a compound of the formula R4 H2N R1 OH

R (B)

wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof; and the most preferred compound is (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyI-7-[4-methoxy3(3methoxypropoxy)

benzyl] 8-methyl-nonanoic acid (2-carbamoyl-.2-methyl-propyl)-amide hemifumarate...DTD: The main purpose of the methods according to the invention is the building up of the side chain starting from 5 carbon atoms and adding three further carbon atoms while generating a second chiral center at the 2-position. One possibility consists in adding the three carbon atoms in one step as illustrated in Scheme I by the upper and lower routes (C-3-Route A and C-3-Route B), the other possibility is the sequential chain elongation by adding first one carbon atom and then two further atoms as illustrated in Scheme I by the middle route (+ Cl + C2 -Route).

For the diastereoselective introduction of an isopropyl group in the 0-2-position, again two possibilities are offered: a) after addition of the thre carbon atoms, ring closure to the lactone, activation of the 2-position by introduction of an ester group and alkylation with isopropyl halogenide (0-3-Route B); b) after building a valerolactam in different steps, acidification leads to the desired lactone.

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 are the compounds of formulae (I) to (IV) of 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 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 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 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 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 C1..6alkoxy-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 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-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-C16a1ky1, 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-C1..6alkyl and C16dialkylamino-C16alkyl, R5 may be linear or branched.

The alkylamino group preferably comprises C1.4alkyl groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C16alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a C16alkyl-O-(O)C-C16a1ky1, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another I to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonyipropyl, 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 C16a1ky1-HN-C(O)-C16a1ky1 or (C16alkyl)2N-C(O)-C16a1kyl, 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.

As indicated herein above, compounds of the present invention can be converted into acid addition salts. The acid addition salts may be formed with mineral acids, organic carboxylic acids or organic sulfonic acids, e.g., hydrochloric acid, fumaric acid and methanesulfonic acid, respectively.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The present invention further includes any variant of the above process, in which an inter-mediate product obtainable at any stage thereof, is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.

When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxyl, thiol etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistry', Plenum 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-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.

Claims

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

::E0R5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16alkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16a1ky1, C16alkanoylamino- C1..6alkyl, HO(O)C-C16alkyl, C1..6alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C16alkyl, C16alkyl-H N-C(O)-C16a1ky1 or (C16alkyl)2N-C(O)-C1alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting from a homo-tyrosin-3-isopropyl-derivative of formula (I) of Scheme 1 and following reaction steps as outlined in Scheme I to obtain a compound of formula (II) of Scheme 1 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 ::oN 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-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -benzyl]- 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

4. A compound of formula (II) of Scheme 1.

5. A compound of formula (Ill) of Scheme 1.

6. A compound of formula (I) of Scheme 1.

7. A compound of formula (IV) of Scheme 1.