Process for the cis-selective catalytic hydrogenation of...

Details Process for the cis-selective catalytic hydrogenation of... Process for the cis-selective catalytic hydrogenation of...

2000-09-14

2001-05-15

Richter, Johann (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S397000, C564S416000, C564S417000, C564S462000

Reexamination Certificate

active

06232501

ABSTRACT:

The present invention relates to a novel, inventive process for the cis-selective catalytic hydrogenation of cyclohexylidenamines and their precursors.
Cyclohexylamines can be used, inter alia, as antioxidants and as pharmaceutical active substances. An important cyclohexylamine is sertraline:
Sertraline: (1S,4S)-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthylamine, see
Merck Index Twelfth Edition
1996, No. 8612, is known as antidepressant. The preparation of this compound is described in U.S. Pat. No. 4,536,518. The hydrochloride is commercially available, inter alia under the registered trademarks Lustral® and Zoloft®. The cyclohexylamines of the type:
(R
2
≠H) exist in at least two isomeric forms:
In another, non-symmetrical substitution at the cyclohexyl ring, the carbon atoms are chiral in 1- and 4-position. According to the R,S-nomenclature by Cahn, Ingold and Prelog, sertaline has the 1S-, 4S-configuration.
Cyclohexylamine is obtained, for example, by the following method: Reacting the ketone
with a primary amine, e.g. methylamine, results, with elimination of water, in a cyclohexylidenamine:
The resultant imine is then catalytically hydrogenated to the amine. These reactions proceed without, or only with minor, stereoselectivity. In the case of sertraline, four enantiomers are obtained.
This invention has for its object to prepare cyclohexylamines having as high as possible a cis-isomer proportion.
To achieve this object, the above-mentioned U.S. Pat. No. 4,536,518 proposes to hydrogenate an imine of formula:
using palladium and carbon as substrates. This affords 70% of cis- and 30% of trans-racemate.
To further improve this yield, WO 93/01161 proposes to replace palladium and carbon as substrate by Raney nickel when hydrogenating the imine. This results in a cis/trans ratio of 8:1. Surprisingly, it has now been found that an even better cis/trans ratio is obtained if the imine is catalytically hydrogenated in the presence of a copper. The preparation of secondary amines from ketones and intermediate imines by hydrogenation in the presence of copper chromite catalysts is known from R. B. C. Pillai
J. Mol. Catalysis
84 (1993), 125-129. However, it is surprising that, starting from cyclohexylidenamines, which are also obtainable as intermediates from ketones, the hydrogenation by means of a copper-containing catalyst proceeds diastereoselectively and affords a high cis-isomer proportion (>95%).
This invention relates to a process for the preparation of cis-compounds of formula:
wherein R
1
and R
2
are each independently of the other hydrocarbon radicals and A is substituents, and m is an integer from 0 to 4 and defines the number of the substituents A, which process comprises
a) hydrogenating a cyclohexylidenamine of formula:
wherein n is 0 or 1 and R
1
, R
2
, A and m have the cited meanings, in the presence of a copper-containing catalyst; or
b) reacting a ketone of formula:
wherein R
2
, A and m have the cited meanings, with a compound introducing the R
1
—N→(O)
n
group, hydrogenating the imine or nitrone (II) which is obtainable as intermediate in the presence of a copper containing catalyst and isolating the cis-compound (I).
If in a compound (I) m is 0 and the cyclohexyl ring is unsubstituted, then the two structural formulae represent identical compounds:
Of the two possibilities for representing the structural formula of the cis-compound (I) in the description of this invention, only the general formula:
is used. If in a compound (I) m is 1 to 4 (m>0) and the cyclohexyl ring is unsymmetrically substituted, then a cis-enantiomer pair is selectively obtained during hydrogenation which can be separated into the optically pure antipodes by customary methods of racemate resolution, for example by crystallisation of the mandelic acid salt by the method of W. M. Welch et al in
J. Med. Chem.
1984, 27, 1508-1515. The relationship between the two cis- and trans-enantiomer pairs and the 4 optically pure antipodes is illustrated by the following formula scheme of sertraline:
In the structural formulae of the starting materials (II) and (III), the unbroken bonding dashes to the substituent R
2
signify that in the case of R
2
≠H and of different substitution at the cyclohexyl ring, these starting materials can be used in the process in the form of racemic mixtures having identical or different antipode proportions or in the form of an optically pure antipode.
The process is distinguished by a high yield of the desired cis-compounds. In the case of the synthesis of sertraline, a ratio of the cis- to the trans-enantiomer pair is obtained which is higher than 95:5. In a particularly preferred embodiment of this invention, the even better ratio of higher than 99:1 is obtained. This high cis-compound yield obviates the separation of the cis- from the trans-enantiomer pair which is otherwise necessary when different substituents A (m>0) are present.
The definitions and denotations used within the scope of the description of this invention preferably have the following meanings:
A hydrocarbon radical R
1
or R
2
is preferably selected from the group consisting of C
1
-C
20
alkyl, C
4
-C
12
cycloalkyl, C
2
-C
11
heterocycloalkyl, carbocyclic C
5
-C
16
aryl, C
2
-C
15
heteroaryl, carbocyclic C
7
-C
16
aralkyl and C
2
-C
15
heteroarylalkyl and can in addition be substituted by suitable functional groups, for example by the functional groups or derivatised functional groups consisting of amino, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, hydroxy, carboxy and halogen.
The cyclohexyl ring can be substituted by 1 to 4, preferably by 2, substituents from the group A containing the substituents R
3
, R
4
, R
5
and R
6
. Suitable substituents are listed in the List of Radical Names, valid according to IUPAC Rules, and remain unchanged under the conditions of the catalytic hydrogenation reaction. Any of the substituents may be chosen. Suitable substituents A from the group R
3
, R
4
, R
5
and R
6
are selected, for example, from the group of the functional groups or derivatised functional groups consisting of amino, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, hydroxy, carboxy and halogen, or are saturated or unsaturated aliphatic, cycloaliphatic or heterocycloaliphatic radicals, carbocyclic or heterocyclic aryl radicals, condensed carbocyclic, heterocyclic or carbocyclic-heterocyclic radicals, which can in turn be combined with any others of these radicals and which can be substituted by the cited functional groups or derivatised functional groups.
The cited substituents and radicals can furthermore be interrupted by one or more than one bivalent radical from the group consisting of —O—, —C(═O)—O—, —O—C(═O)—, —C(═O)—N(C
1
-C
4
alkyl)—, —N(C
1
-C
4
alkyl)—C(═O)—, —S(═O)
2
—, —S(═O)
2
—O—, —O—S(═O)
2
—, —S(═O)
2
—N(C
1
-C
4
alkyl)—, —(C
1
-C
4
alkyl)N—S(═O)
2
—, —P(═O)——P(═O)—O—, —O—P(═O)— and —O—P(═O)—O—.
In a preferred embodiment of this invention, two substituents A from the group R
3
, R
4
, R
5
and R
6
are bivalent, bridge-like C
2
-C
6
alkylene, C
4
-C
8
alkyldiylidene or C
4
-C
8
alkenyldiylidene groups, preferably butanediylidene, more preferably 2-butenediylidene, which is bound with the cyclohexyl ring to two adjacent carbon atoms and which forms together with these carbon atoms a phenyl ring which can be substituted by the cited functional groups or substituents.
Suitable substituents A from the group R
3
, R
4
, R
5
and R
6
are also substituents from the group C
1
-C
20
alkyl, C
4
-C
12
cycloalkyl, C
7
-C
12
bicycloalkyl, C
2
-C
11
heterocycloalkyl, carbocyclic C
6
-C
16
aryl, C
2
-C
15
heteroaryl, carbocyclic C
7
-C
16
aralkyl and C
2
-C
15
heteroarylalkyl, which can in turn be substituted by the cited functional groups and interrupted by bivalent radicals.
C
1
-C
20
Alkyl is, for example, methyl, ethyl, n-, or isopropyl or n-, sec- or tert-butyl and straight-chain or branched pentyl, hexyl, heptyl, octyl, isooctyl, nonyl, tert-nonyl, decyl, undecyl or dodecy

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