Process for preparing racemic amino derivatives

Details Process for preparing racemic amino derivatives Process for preparing racemic amino derivatives

1996-08-05

2002-12-31

Badio, Barbara P. (Department: 1616)

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

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06500986

ABSTRACT:

The present invention relates to a new process for preparing racemic amino derivatives by racemization of optically active amides.
Already known is the preparation of optically active amides by enantioselectively acylating racemic amines and separating the resulting mixture of optically active amine and optically active amide (=acylated amine) (cf. DE-A 43 32 738, Chimia 48, 570 (1994)). Furthermore, it is already known that optically active amides can be obtained by enantioselective hydrolysis of racemic amides and subsequent separation of the resulting mixture of optically active amide and optically active amine (cf. EP-A 0 399 589). In order to make these processes for resolution of racemates economical, the undesired enantiomer in each case has to be racemized again and returned to the circuit. If the component which is not required is an optically active amine, the racemization can be carried out by treatment with alkoxides in the presence of dimethyl sulphoxide (cf. DE-A 40 38 356). However, if the undesired isomer is an amide, a disadvantage of the work-up is that a saponification of the optically active amide is first required and the racemization of the optically active amine formed can only be carried out in a further step.
It has now been found that racemic amino derivatives of the formula
in which
n represents the numbers 0, 1 or 2,
R
1
represents unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl,
R
2
represents unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl, but with R
1
and R
2
—(CH
2
)
n
— not being identical, and
R represents hydrogen or —CO—R
3
, where
R
3
represents hydrogen, amino, unsubstituted or substituted alkyl or unsubstituted or substituted alkoxy, with the carbon chain being able, in the case of those radicals containing more than one carbon atom, to be interrupted by heteroatoms or hetero groups, or
R
3
represents unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocyclyl,
are obtained when optically active amides of the formula
in which
R
1
,R
2
,R
3
and n are as defined above,
are reacted with strong bases, optionally in the presence of an organic diluent and, if desired, the resulting racemic amides of the formula
in which
R
1
, R
2
, R
3
and n are as defined above,
are reacted either
a) with water in the presence of a base or an acid and optionally in the presence of an organic diluent,
or
b) if the compounds of the formula (Ia) are amides in which R
3
is hydrogen, with alkali metal hydroxide or alkaline earth metal hydroxide.
It must be regarded as extremely surprising that racemic amides and amines can be prepared by the process of the invention, since it was not previously known from the prior art that racemization of optically active amides is possible without prior saponification.
The process of the invention has a series of advantages. Thus, it makes possible the preparation of racemic amides or amines from the respective undesired enantiomers in high yield. It is also advantageous that the optically active amides required as starting materials can be obtained in a simple manner and that the acyl radical can be varied within a wide range. Finally, the reaction procedure and the isolation of the desired substances also present no difficulties at all.
Alkyl represents, in the present case, unless otherwise defined, saturated aliphatic hydrocarbon radicals which can be straight-chain or branched.
Cycloalkyl represents, in the present case, unless otherwise defined, saturated, carbocyclic radicals which may optionally, together with further condensed-on or bridged rings, form a bicyclic or polycyclic ring system.
Cycloalkenyl represents, in the present case, unless otherwise defined, unsaturated, carbocyclic radicals which may optionally, together with further condensed-on or bridged rings, form a bicyclic or polycyclic ring system.
Aryl represents, in the present case, unless otherwise defined, aromatic, monocyclic, bicyclic or polycyclic hydrocarbon radicals such as phenyl, naphthyl, anthryl, phenanthryl, preferably phenyl or naphthyl, in particular phenyl.
Heterocyclyl represents, in the present case, unless otherwise defined, saturated or unsaturated, cyclic radicals in which at least one ring atom is a heteroatom, i.e. an atom different from carbon. If the ring contains a plurality of heteroatoms, these can be identical or different. Heteroatoms are preferably oxygen, nitrogen or sulphur. Optionally, the cyclic radicals together with further carbocyclic or heterocyclic, condensed-on or bridged rings, form a bicyclic or polycyclic ring system. Preference is given to monocyclic or bicyclic ring systems, in particular monocyclic or bicyclic ring systems having aromatic character.
In the definitions, the saturated or unsaturated carbon chains such as alkyl, alkanediyl, alkenyl or alkinyl, including those linked to groups bonded by heteroatoms, i.e. groups such as alkoxy, alkylthio or alkylamino are in each case straight-chain or branched.
Halogen represents, in the present case, unless otherwise defined, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.
If (S)-N-[1-(4-chlorophenyl)-ethyl]-acetamide is used as starting material and potassium hydroxide as strong base, then the course of the first stage of the process of the invention can be depicted by the following reaction scheme:
If racemic N-[1-(4-chlorophenyl)-ethyl]-acetamide is used as starting component and aqueous hydrochloric acid as reaction component, then the course of the second stage of the process of the invention can be depicted by the following reaction scheme:
The optically active amides required as starting materials for carrying out the process of the invention are generally defined by the formula (II). In this formula, the asymmetrically-substituted carbon atom is denoted by (*). In other formulae for optically active compounds, centres of chirality are also each marked in the same manner.
n also preferably represents the numbers 0, 1 or 2.
R
1
preferably represents straight-chain or branched alkyl having from 1 to 8 carbon atoms, with the alkyl radicals being able to be monosubstituted or polysubstituted, identically or differently, by halogen, amino, hydroxy, formyl, carboxy, carbamoyl, straight-chain or branched alkoxy or straight-chain or branched alkylthio each having from 1 to 6 carbon atoms;
and/or by straight-chain or branched halogenoalkoxy or straight-chain or branched halogenoalkylthio each having from 1 to 6 carbon atoms and from 1 to 13 identical or different halogen atoms;
and/or by alkylamino, dialkylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy, hydroximinoalkyl or alkoximinoalkyl which may each be straight-chain or branched and each have from 1 to 6 carbon atoms in the individual alkyl parts;
or by doubly linked alkylene having from 1 to 6 carbon atoms, or by doubly linked dioxyalkylene having from 1 to 4 carbon atoms, with the two latter radicals themselves being able to be monosubstituted or polysubstituted, identically or differently, by halogen, straight-chain or branched alkyl having from 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkyl having from 1 to 4 carbon atoms and from 1 to 9 identical or different halogen atoms, or
R
1
preferably represents cycloalkyl having from 3 to 7 carbon atoms, with these radicals being able to be monosubstituted to tetrasubstituted, identically or differently, by halogen and/or alkyl having from 1 to 4 carbon atoms, or
represents cycloalkenyl having from 3 to 7 carbon atoms, with these radicals being able to be monosubstituted to tetrasubstituted, identically or diffe

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