Chroman derivatives

Details Chroman derivatives Chroman derivatives

2002-02-28

2003-11-11

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S407000

Reexamination Certificate

active

06646136

ABSTRACT:

This application is a 371 of PCT/EP99/09333 filed Dec. 1, 1999.
The invention relates to chroman derivatives of the formula I
in which
R
1
is acyl having 1-6 C atoms, —CO—R
5
or an amino protective group,
R
2
is H or alkyl having 1-6 C atoms,
R
3
, R
4
in each case independently of one another are H, alkyl having 1-6 C atoms, CN, Hal or COOR
2
.
R
5
is phenyl which is unsubstituted or mono- or disubstituted by alkyl having 1-6 C atoms, OR
2
or Hal,
X is H,H or O,
Hal is F, Cl, Br or I,
and their salts.
The invention also relates to the optically active forms, the racemates, the enantiomers and also the hydrates and solvates, e.g. alcoholates, of these compounds.
Similar compounds are disclosed in EP 0 707 007.
The invention was based on 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 of those which show, for example, actions on the central nervous system.
The invention relates to the chroman derivatives of the formula I and their salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
and X have the meanings indicated in the formulae I and II, if not expressly stated otherwise.
In the above formulae, alkyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms. Alkyl is preferably methyl or ethyl, furthermore propyl, isopropyl, in addition also butyl, isobutyl, sec-butyl or tert-butyl. Acyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms Acyl is in particular acetyl, propionyl or butyryl.
R
2
is preferably H, in addition also methyl, ethyl or is propyl.
R
3
and R
1
are preferably H.
R
5
is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl. The radical R
1
is acyl, —CO—R
5
or else an amino protective group which is known per se; acetyl is particularly preferred.
The expression “amino protective group” is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise uncritical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression “acyl group” is to be interpreted in the widest sense in connection with the present process and the present compounds. It includes acyl groups derived from, aliphatic, araliphacic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl: aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (carbobenzoxycarbonyl, also called 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxy-carbonyl); arylsulfonyl such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protective groups are BOC and Mtr, an addition CBZ or FMOC.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I according to claim 1 and also of their salts, in which X is O, characterized in chat a compound of the formula II
in which R
1
, R
2
, R
3
, R
4
have the meanings indicated in claim 1 and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst.
The invention also relates to a process for the preparation of chroman derivatives of the formula I according to claim 1 and also of their salts, in which X is H,H, characterized in that a compound of the formula II
in which R
1
, R
2
, R
3
, R
4
have the meanings indicated in claim 1 and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst, and then reduced in the customary manner.
In particular, it has been found that (2-acetylaminomethyl)chromen-4-one can be hydrogenated using various enantiomerically pure rhodium-diphosphane complexes to give enantiomerically enriched (2-acetylaminomethyl)chroman-4-one.
The invention also relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the enantiomerically enriched catalyst is a transition metal complex.
Particularly preferably, the catalyst is a transition metal complex comprising a metal selected from the group rhodium, iridium, ruthenium and palladium.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the catalyst is a transition metal complex in which the transition metal is complexed with a chiral diphosphane ligand.
The ligands below 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 an excess.
Precursors used for the chiral ligands are compounds such as, for example, Rh(COD)
2
OTf (rhodium-cyclooctadiene 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 substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), mainly under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds.
The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is O is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as, for example, methanol or ethanol.
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, carbon tetrachloride, 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 such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, and optionally also mixtures of the solvents mentioned with one another or mixtures with water.
The reaction time of the enantioselective hydrogenation, depending on the conditions used, is between a few minutes and 14 days; the reaction temperature is between 0 and 150°, normally between 20 and 130°.
Customarily, the catalyst/substrate ratio is between 1

Affiliated with

Also associated with

Rating

Chroman derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Chroman derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chroman derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3132914