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

2003-01-03

2004-05-04

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S561000, C562S471000, C562S495000, C564S191000, C560S104000

Reexamination Certificate

active

06730798

ABSTRACT:

The invention relates to a process for the preparation of 2(S),4(S),5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides and their physiologically acceptable salts; and the 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 alkane-carboxamides 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 or 2,7-dialkyl-8-aryl-4-octenic acid ester is simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the halolactone is converted to a hydroxylactone and then the hydroxy group is converted to a leaving group, the leaving group substituted with azide, the lactone amidated and then the azide converted to the amine group. Apart from the high yields and stereoselectivities in the individual process steps, particular attention is drawn to the fact that substantially fewer by-products are formed in the azidation step.
A primary object of the invention is a process for the preparation of compounds of formula I,
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
-alkanoylamido-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
1
-C
6
alkyl or (C
1
-C
6
alkyl)
2
N—C(O)—C
1
-C
6
-alkyl, comprising
a) the 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 compounds of formula II by reacting
c1) a compound of formula IV,
wherein R
6
is C
1
-C
20
alkyl, C
3
-C
12
cycloalkyl, C
3
-C
12
cycloalkyl-C
1
-C
6
alkyl, C
6
-C
10
aryl or C
6
-C
10
-aryl-C
1
-C
6
alkyl, with a halogenation agent to form a compound of formula VI, or
c2) a carboxylic acid of formula V, or a salt of this carboxylic acid,
with a halogenation agent to form a compound of formula VI,
wherein X is Cl, Br or I,
d) reaction of the compound of formula VI in the presence of an alkali metal or alkaline earth metal hydroxide or an alcohol to form a compound of formula VII,
wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group,
e) hydrolysis of the compound of formula VII in the presence of an acid to form a compound of formula VIII,
f) substitution of the hydrogen atom of the hydroxyl group in the compound of formula VIII and conversion thereof to a leaving group AO to form compounds of formula IX,
g) and then reaction of the compound of formula IX with an azidation agent to form a compound of formula II, or
h) reaction if the compound of formula VIII directly with a zinc azide/-bis-pyridine complex in the presence of a tertiary phosphine and an azodicarboxylate, if necessary in an organic solvent, 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, trichloromethyl, 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
1
-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 alkyoxy 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 in the form of alkyl 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-ethoxyprop-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 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-ethylaminoeth-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-propionylam

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