Process for the preparation of aryloctanoyl amides

Details Process for the preparation of aryloctanoyl amides Process for the preparation of aryloctanoyl amides

2003-01-15

2003-12-30

Davis, Brian (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S165000, C548S216000, C549S321000, C556S410000

Reexamination Certificate

active

06670507

ABSTRACT:

The invention relates to a stereospecific method for the preparation of 2(S),4(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides in the form of 5(R)- or 5(S)-diastereomers and mixtures thereof, as well as their physiologically acceptable salts; and new compounds used in the multistage process as intermediates.
In EP-A-0 678 503, &dgr;-amino-&ggr;-hydroxy-&ohgr;-aryl-alkanecarboxamides 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.
D. A. Sandham et al. describe in Tetrahedron Letters, Volume 41, Issue 51, pages 10085-10089 (2000), a synthesis for the preparation of 2(S),4(S),5(S),7(S)-2-isopropyl-4-hydroxy-5-amino-7-isopropyl-8-[(3-methoxy-n-propoxy)-4-methoxyphenyl]octanoyl amide, in which a Grignard compound of 1-[(3-methoxy-n-propoxy)-4-methoxyphenyl]-2-isopropyl-3-chloropropane is reacted with a pseudoephedrine-protected isopropylvalerolactone aldehyde, followed by hydrolysis, to form a compound of formula A
The compound of formula A is obtained in a yield of only 51%, the R:S ratio, in relation to the OH group, being 85:15. The OH group is then converted to a leaving group (brosylate). The reaction with sodum azide yields the corresponding azido compound which with 3-amino-2,2-dimethylpropionamide on opening of the lactone ring gives the corresponding amide. Catalytic hydrogenation then yields the desired amine.
It has now been surprisingly found that these alkanecarboxamides are obtainable both in high total yields and in a high degree of purity when the amino group is introduced with Grignard coupling. According to this process step, customary purification and separation procedures can if necessary be used for the preparation of pure diastereomers. The process is suitable for industrial scale manufacture.
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
-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 the steps
a) reaction of a compound of formula II,
wherein R
4
is as defined above, with a hydroxylamine of formula ZNHOH (III), wherein Z is a removable protecting group, to form a compound of formula IV,
b) reaction of a compound of formula IV with a metal organic derivative of a compound of formula V,
wherein R
1
, R
2
and R
3
are as defined above, and Y is Cl, Br or I, to form a compound of formula VI,
c) removal of the hydroxyl group to form a compound of formula VII,
d) removal of the pseudoephedrine protecting group to form compounds of formula VIII,
or the performance of step d) before step c), or the performance of steps c) and d) together in one reaction vessel,
e) reaction of a compound of formula VIII with an amine of formula R
5
—NH
2
to form a compound of formula IX
f) removal of protecting group Z for the preparation of compounds of formula I.
With the process according to the invention, preferably the 5(S)-diastereomer of formula Ia
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 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-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 alkanoyl 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 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-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
-propionylamidoeth-1-yl and 4-butyroylamidoeth-1-yl.
As a HO(O)C—C
1
-C
6
alkyl, R
5
may be li

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