Chromanone derivatives

Details Chromanone derivatives Chromanone derivatives

2003-07-29

2004-11-02

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S456000

Reexamination Certificate

active

06812353

ABSTRACT:

The invention relates to chromanone derivatives of the formula I
in which
R
1
to R
4
are each, independently of one another, H, A, CN, Hal, OR
5
, COOR
5
, CF
3
, OCF
3
, NO
2
, Ar, OAr, N(R
5
)
2
or CON(R
5
)
2
,
R
5
is H or A,
A is alkyl having 1 to 6 carbon atoms,
Ar is phenyl which is unsubstituted or substituted by A, OR
5
, CN, Hal, CF
3
, OCF
3
, NO
2
or N(R
5
)
2
,
Hal is F, Cl, Br or I,
and their salts.
The invention also relates to the optically active forms, the racemates, the enantiomers, and the hydrates and solvates, for example alcoholates, of these compounds.
Similar compounds are disclosed in EP 0 707 007.
The invention had the object of finding novel compounds which can be used, in particular, as Intermediates in the synthesis of medicaments.
It has been found that the compounds of the formula I and their salts are important intermediates for the preparation of medicaments, in particular those which exhibit actions on the central nervous system.
The invention relates to the chromanone derivatives of the formula I and their salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
and R
6
have the meanings indicated under the formulae I to III, unless expressly stated otherwise.
In the above formulae, A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. A is particularly preferably methyl.
Acyl has 1 to 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms. Acyl is in particular acetyl, propionyl or butyryl.
Ar is phenyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, CF
3
, OR
5
, OCF
3
, CN, NO
2
, Hal or N(R
5
)
2
, where R
5
is H or A, and A is as defined above. Ar is preferably phenyl.
Hal is preferably F, Cl or Br.
R
1
, R
2
, R
3
and R
4
are each, independently of one another, H, A, CN, Hal, OR
5
, COOR
5
, CF
3
, OCF
3
, NO
2
, Ar, OAr, N(R
5
)
2
or CON(R
5
)
2
, where A, Hal, Ar and R
5
are as defined above. R
1
is preferably H. R
2
is particularly preferably H. R
3
is preferably H. R
4
is preferably H.
R
6
is acyl having 1 to 6 carbon atoms, —CO—Ar or an amino-protecting group, where acyl and Ar are as defined above. R
6
is particularly preferably acyl.
The term “amino-protecting group” is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size is furthermore not crucial; however, preference is given to those having 1-20 carbon atoms, in particular 1-8 carbon atoms. The term “acyl group” should be understood in the broadest sense in connection with the present process. It covers acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxy-alkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC or 2-iodoethoxycarbonyl; alkenyloxycarbonyl, such as allyloxycarbonyl (Aloc), aralkoxycarbonyl, such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2-(phenylsulfonyl)ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc), or arylsulfonyl, such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino-protecting groups are BOC, Fmoc and Aloc, furthermore CBZ, benzyl and acetyl. Particularly preferred protecting groups are BOC and Fmoc.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I covers all these forms.
Particularly preferred compounds of the formula I are
a) 2-aminomethyl-4-chromanone,
b) (R)-2-aminomethyl-4-chromanone,
c) (S)-2-aminomethyl-4-chromanone, and their salts.
The invention furthermore relates to a process for the preparation of chromanone derivatives of the formula I according to claim
1
and of their salts, characterised in that a compound of the formula II
in which
R
1
, R
2
, R
3
and R
4
are as defined in claim
1
, and
R
6
is acyl having 1 to 6 carbon atoms, —CO—Ar or an amino-protecting group,
is hydrogenated with the aid of a non-racemic chiral catalyst to give a compound of the formula III
in which R
1
to R
6
are as defined above, and the radical R
6
is cleaved off.
In particular, it has been found that (2-acetylaminomethyl)chromen-4-one can be hydrogenated with various non-racemic chiral rhodium/diphosphine complexes to give enantiomerically enriched (2-acetylaminomethyl)chroman-4-one, and the acetyl group can be cleaved off while avoiding racemisation.
The invention also relates to a process for the preparation of chromanone derivatives of the formula I, characterised in that the non-racemic chiral catalyst is a transition-metal complex.
The catalyst is particularly preferably a transition-metal complex containing a metal selected from the group consisting of rhodium, iridium, ruthenium and palladium.
The invention furthermore relates to a process for the preparation of chromanone derivatives of the formula I, characterised in that the catalyst is a transition-metal complex in which the transition metal is complexed with a chiral diphosphine ligand.
The following ligands may be mentioned by way of example:
Depending on the choice of the R) or (S)-enantiomer of the ligand in the catalyst, the (R)- or (S)-enantiomer is obtained in excess.
Precursors for the chiral ligands are compounds such as, for example, Rh(COD)
2
OTf (cyclooctadienylrhodium triflate), [Rh(COD)Cl]
2
, Rh(COD)
2
BF
4
, [Ir(COD)Cl]
2
, Ir(COD)
2
BF
4
or [Ru(COD)Cl
2
]
x
.
The compounds of the formula I and also the starting materials for their preparation are furthermore prepared by chemical reactions which are known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but are instead immediately converted further into the compounds of the formula I.
Some of the compounds of the formula II are known; the unknown compounds can easily be prepared analogously to the known compounds. The conversion of a compound of the formula II into a compound of the formula I is carried out in accordance with the invention using hydrogen gas with the aid of a non-racemic chiral catalyst in an inert solvent, such as, for example, methanol or ethanol, followed by racemisation-free removal of the radical R
6
, as defined above.
Suitable inert solvents are furthermore, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, s

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