2,6-diamino-6-methyl-heptanoic acid and derivatives, process...

Details 2,6-diamino-6-methyl-heptanoic acid and derivatives, process... 2,6-diamino-6-methyl-heptanoic acid and derivatives, process...

2001-04-25

2003-01-07

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Carboxylic acid esters

C562S561000, C564S197000, C564S198000, C560S019000

Reexamination Certificate

active

06504047

ABSTRACT:

The present invention is directed towards compounds of the general formula (I)
The invention also describes intermediates of (I), a process for the preparation thereof and the use thereof.
Compounds of formula (I) are suitable intermediates for the preparation of pharmaceuticals described in U.S. Pat. No. 5,552,397, WO 9738705 and in J. Med. Chem. 42, 305 (1999).
In J. Med. Chem. 42, 305 (1999), a synthesis route for the preparation of a structural unit—an &agr;-amino-&egr;-caprolactam derivative—of the pharmaceutically active compounds is mentioned. That structural unit is obtained with the aid of expensive reagents in a process that is rather disadvantageous for a robust commercial process.
Accordingly, the object was to provide other precursors for the preparation of &agr;-amino-&egr;-caprolactam derivatives, and to provide a process for the preparation thereof. In particular, the process is to be suitable for use on a commercial scale, that is to say advantageous from an ecological and economic point of view.
The object is achieved by compounds of the general formula (I)
wherein
R
1
, R
2
each independently of the other represents H, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxycarbonyl, (C
3
-C
8
)-cycloalkyloxycarbonyl, (C
6
-C
18
)-aryloxycarbonyl, (C
7
-C
19
)-aralkyloxycarbonyl, (C
3
-C
18
)-heteroaryloxycarbonyl, (C
4
-C
19
)-heteroaralkyloxycarbonyl, (C
3
-C
8
)-cycloalkylcarbonyl, (C
6
-C
18
)-arylcarbonyl, (C
7
-C
19
)-aralkylcarbonyl, (C
3
-C
18
)-heteroarylcarbonyl, (C
4
-C
19
)-heteroaralkylcarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
8
)-cycloalkyloxycarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
6
-C
18
)-aryloxycarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
18
)-heteroaryloxycarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
8
-cycloalkylcarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
6
-C
18
)-arylcarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
18
)-heteroarylcarbonyl, or an N-protecting group, such as, for example, formyl, Fmoc, t-Boc, Z,
R
3
represents OH, NH
2
, O—(C
1
-C
8
)-alkyl, NH—(C
1
-C
8
)-alkyl, N((C
1
-C
8
)-alkyl)
2
, O—(C
3
-C
8
)-cycloalkyl, NH—(C
3
-C
8
)-cycloalkyl, N((C
3
-C
8
)-cycloalkyl)
2
, O—(C
6
-C
18
)-aryl, NH—(C
6
-C
18
)-aryl, N((C
6
-C
18
)-aryl)
2
, O—(C
7
-C
19
)-aralkyl, NH—(C
7
-C
19
)-aralkyl, N((C
7
-C
19
)-aralkyl)
2
, or R
2
and R
3
form a ring via a —CO—NH— group,
R
4
, R
5
each independently of the other represents H, (C
1
-C
8
)-acyl, (C
3
-C
8
)-cycloalkylcarbonyl, (C
6
-C
18
)-arylcarbonyl, (C
7
-C
19
)-aralkylcarbonyl, (C
3
-C
18
)-heteroarylcarbonyl, (C
4
-C
19
)-heteroaralkylcarbonyl, ((C
1-C
8
)-alkyl)
1-3
-(C
3
-C
8
)-cycloalkylcarbonyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
6
-C
18
)-arylcarbonyl, ((C
1
-C
18
)-alkyl)
1-3
-(C
3
-C
18
)-heteroarylcarbonyl, formyl,
R
6
, R
7
each independently of the other represents (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
3
-C
8
)-cycloalkyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
8
)-cycloalkyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
6
-C
18
)-aryl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
18
)-heteroaryl, or the two radicals are bonded to one another via a (C
1
-C
8
)-alkylene bridge.
Compounds of the general formula (I) can readily be converted into the desired &agr;-amino-&egr;-caprolactam derivatives by processes known to the person skilled in the art, whereby a novel approach to obtaining that class of compounds has been opened up.
Preference is given to compounds of the general formula (I) wherein
R
1
represents H,
R
2
represents an N-protecting group, especially t-Boc, Z,
R
3
represents OH, NH
2
, O—(C
1
-C
8
)-alkyl, NH—(C
1
-C
8
)-alkyl,
R
4
represents H, R
5
represents (C
1
-C
8
)-acyl,
R
6
, R
7
represent (C
1
-C
8
)-alkyl.
Also preferred are compounds of the general formula (I) in which R
1
, R
2
=H, R
3
=OH, R
6
, R
7
=methyl, R
4
, R
5
=H or R
4
=H, R
5
=formyl, or R
4
=H, R
5
=acetyl.
In a further embodiment, the invention relates to compounds of the general formula (II)
wherein R
1
, R
2
, R
3
, R
6
, R
7
may be as defined above. Preference is given to compounds of the general formula (II) wherein R
1
, R
2
=H and R
3
=OH or NH
2
and R
6
, R
7
=methyl. Also preferred are compounds of the general formula (II) wherein R
1
=H, R
2
=acetyl and R
3
=OH and R
6
, R
7
=methyl. Also advantageous are compounds of the general formula (II) wherein R
1
=H and R
2
and R
3
form a ring via a —CO—NH— group, and R
6
, R
7
=methyl.
In another aspect, the invention is concerned with compounds of the general formula (III)
wherein R
1
, R
2
, R
3
, R
6
, R
7
may be as defined above, and R
1
, R
2
are not phthaloyl when R
3
=Obenzyl and R
6
, R
7
=methyl. Preference is given to compounds of the general formula (III) wherein R
1
, R
2
=H and R
3
=OH or NH
2
and R
6
, R
7
=methyl. Also preferred are compounds of the general formula (III) wherein R
1
=H, R
2
=acetyl and R
3
=OH and R
6
, R
7
=methyl. Also advantageous are compounds of the general formula (III) wherein R
1
=H and R
2
and R
3
form a ring via a—CO—NH— group, and R
6
, R
7
=methyl.
In a further aspect, the invention is concerned with compounds of the general formula (IV)
wherein R
6
, R
7
may have the meanings mentioned at the beginning for those radicals and R
8
represents NH
2
or OH. R
6
, R
7
preferably represent methyl.
In yet a further aspect, the invention is directed towards compounds of the general formula (V)
wherein
each of R
1
, R
2
, R
6
, R
7
may be as defined at the beginning, and R
10
, R
11
may represent (C
1
-C
8
)-alkyl, (C
2
-C
8
)-alkenyl, (C
2
-C
8
)-alkynyl, (C
3
-C
8
)-cycloalkyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
8
)-cycloalkyl, ((C
1
-C
8
)-alkyl)
1-3
-(C
6
-C
18
)-aryl, ((C
1
-C
8
)-alkyl)
1-3
-(C
3
-C
18
)-heteroaryl In (V), preferably R
1
=H and R
2
=acetyl and R
10
, R
11
=methyl or ethyl and R
6
, R
7
=methyl.
In a particular embodiment, the present invention relates to a process for the preparation of compounds of the general formula (I). The process is distinguished by the fact that compounds of the general formula (II) or of the general formula (III)
wherein R
1
, R
2
, R
3
, R
6
, R
7
may be as defined at the beginning, are reacted under acid conditions with a nitrile. Such a reaction, known as the Ritter reaction (Org. React. 17, 213-326 (1969)), makes it possible to obtain the substances of the general formula (I) in a high yield starting from the readily accessible compounds (II) or (III). The conditions under which the reaction takes place are in principle sufficiently well known to the person skilled in the art (Org. React. 17, 213-326 (1969)). More advantageously, however, the reaction is carried out in strongly acid media, preferably in from 65 to 85% sulfuric acid. The temperature in the reaction is on the one hand to be sufficiently high that the reaction proceeds sufficiently rapidly. On the other hand, however, it should not be chosen to be so high that the reactants are destroyed. A temperature range from −20 to 100° C. is therefore preferred, with the range from 20 to 40° C. being especially preferred. There may be used as nitrites all compounds that come into consideration to the person skilled in the art for that purpose. Preferred nitrites are those that are readily available commercially. Hydrocyanic acid, acetonitrile or benzonitrile are especially preferred. The use of hydrocyanic acid is very especially preferred. For the reaction with the nitrile, special preference is given to an N-acetyl derivative, an amide, a hydantoin of (II) or (III) or the free amino acids of (II) or (III).
The N
6
-acyl derivatives obtained by the reaction with nitrites can be converted into the corresponding compounds having a free amino group by hydrolysis. Hydrolysis of the N-formyl compound resulting f

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