Process for the preparation of substituted octanoyl amides

Details Process for the preparation of substituted octanoyl amides Process for the preparation of substituted octanoyl amides

2003-01-24

2004-10-05

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Azides

C554S036000, C554S051000, C554S062000

Reexamination Certificate

active

06800769

ABSTRACT:

The invention relates to a stereospecific method for the preparation of 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides and their physiologically acceptable salts; and new compounds used as intermediates in the multistage process.
In EP-A-0 678 503, &dgr;-amino-&ggr;-hydroxy-&ohgr;-aryl-alkanecarbox-amides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
It has now been surprisingly found that these alkanecarboxamides can be prepared both in high total yields and in a high degree of purity, and that selectively pure diastereomers are obtainable, if the double bond of 2,7-dialkyl-8-aryl-4-octenic acid amides is simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the lactone ring is opened with an amine during the formation of the carboxamide, then the hydroxy group is replaced with azide, if necessary after protection of the hydroxy group, the resulting compound is lactonized, the lactone amidated and then the azide group converted to the amine group.
A first object of the invention is a process for the preparation of compounds of formula I and their physiologically acceptable salts,
wherein
R
1
and R
2
are, independently of one another, H, C
1
-C
6
alkyl, C
1
-C
6
halogenalkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, or C
1
-C
6
alkoxy-C
1
-C
6
alkyloxy, R
3
is C
1
-C
6
alkyl, R
4
is C
1
-C
6
alkyl, and R
5
is C
1
-C
6
alkyl, C
1
-C
6
hydroxyalkyl, C
1
-C
6
alkoxy-C
1
-C
6
-alkyl, C
1
-C
6
alkanoyloxy-C
1
-C
6
alkyl, C
1
-C
6
aminoalkyl, C
1
-C
6
alkylamino-C
1
-C
6
-alkyl, C
1
-C
6
-dialkylamino-C
1
-C
6
-alkyl, C
1
-C
6
-alkanoyl-amido-C
1
-C
6
-alkyl, HO(O)C—C
1
-C
6
-alkyl, C
1
-C
6
alkyl-O—(O)C—C
1
-C
6
alkyl, H
2
N—C(O)—C
1
-C
6
alkyl, C
1
-C
6
alkyl-HN—C(O)C—C
6
alkyl or (C
1
-C
6
alkyl)
2
N—C(O)—C
1
-C
6
-alkyl, comprising the steps
a) reaction of a compound of formula II,
with an amine of formula R
5
—NH
2
to form a compound of formula III,
and
b) reduction of the azide group of the compound of formula III to the amine group and isolation of the compounds of formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of the compound of formula II by reacting
c) a compound of formula IV
wherein X is Cl, Br or I, with an amine to form a carboxamide of formula V,
wherein R
6
is an amino group,
d1) azidating a compound of formula V to form a compound of formula VI
d2) protecting the hydroxyl group in the compounds of formula V, and azidating the resulting compound of formula VII
wherein S is a protecting group, to form a compound of formula VIII,
e) and then lactonizing the compound of formula VI or VIII in the presence of an acid to form a compound of formula II.
As an alkyl, R
1
and R
2
may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
As a halogenalkyl, R
1
and R
2
may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro-methyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
As an alkoxy, R
1
and R
2
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, R
1
and R
2
may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
As a C
2
-C
6
alkoxy-C
1
-C
6
alkyloxy, R
1
and R
2
may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R
1
is methoxy- or ethoxy-C
1
-C
4
alkyloxy, and R
2
is preferably methoxy or ethoxy. Particularly preferred are compounds of formula I, wherein R
1
is 1-methoxyprop-3-yloxy and R
2
is methoxy.
As an alkyl, R
3
and R
4
may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R
3
and R
4
in compounds of formula I are in each case isopropyl.
As an alkyl, R
5
may be linear or branched and preferably comprise 1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl are preferred.
As a C
1
-C
6
hydroxyalkyl, R
5
may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or 4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.
As a C
1
-C
6
alkoxy-C
1
-C
6
alkyl, R
5
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-methoxyethy-1-yl, 2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl, 2-ethoxyethy-1-yl, 2-ethoxy-prop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or 4-ethoxybut-1-yl.
As a C
1
-C
6
alkanoyloxy-C
1
-C
6
alkyl, R
5
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, acetyloxy-ethyl, propionyloxyethyl and butyroyloxyethyl.
As a C
1
-C
6
aminoalkyl, R
5
may be linear or branched and preferably comprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or 3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.
As a C
1
-C
6
alkylamino-C
1
-C
6
alkyl and C
1
-C
6
dialkylamino-C
1
-C
6
-alkyl, R
5
may be linear or branched. The alkylamino group preferably comprises C
1
-C
4
alkyl groups and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylamino-eth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl, 3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and 4-dimethylaminobut-1-yl.
As a C
1
-C
6
alkanoylamido-C
1
-C
6
alkyl, R
5
may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl, 2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and 4-butyroylamidoeth-l-yl.
As a HO(O)C—C
1
-C
6
-alkyl, R
5
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 C
1
-C
6
-alkyl-O—(O)C—C
1
-C
6
alkyl, R
5
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-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl, 4-methoxycarbonylbut-1-yl, ethoxy-carbonylmethyl, 2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl-prop-1-yl, and 4-ethoxycarbonylbut-1-yl.
As a H
2
N—C(O)—C
1
-C
6
alkyl, R
5
may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl, 2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1

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