Racemization of atropisomeric bis(phosphine oxide) compounds

Details Racemization of atropisomeric bis(phosphine oxide) compounds Racemization of atropisomeric bis(phosphine oxide) compounds

2000-06-15

2001-09-11

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Phosphorus containing

C549S218000

Reexamination Certificate

active

06288280

ABSTRACT:

SUMMARY OF THE INVENTION
The subject invention provides a process for the racemization of a compound of the formula:
which is present in the (R) form, the (S) form, or a non-racemic mixture of the (R) form and (S) form. In the compound of formula I, R
1
is C
1-8
-alkoxy and R
2
is hydrogen, C
1-8
-alkyl, or C
1-8
-alkoxy. Alternatively, R
1
and R
2
taken together are methylenedioxy or ethylenedioxy. R
3
is hydrogen, C
1-8
-alkyl, or C
1-8
-alkoxy. R
4
is phenyl or phenyl monosubstituted in the meta- or para-position by C
1-8
-alkyl, C
1-8
-alkoxy, di- C
1-8
-alkylamino, trialkylsilyl or phenyl. This process comprises heating the compound of formula I to a temperature of from about 260° C. to about 400° C. for a time sufficient to cause racemization of the compound of formula I.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not limiting.
The present invention is concerned with a novel process for the racemization of atropisomeric compounds of formula I,
The optical active compounds of formula I above are known, as are the intermediates for the preparation of optically active bisphosphine ligands of formula II,
which form optically active complexes with transition metals. These complexes are used as catalysts in a number of asymmetric reactions.
Synthesis of optically active intermediates of formula I and ligands of formula II by known processes typically use a racemic mixture (mixture of equal amounts of both enantiomers) of the product, that is resolved for the preparation of the optical active ligands of formula II, which are in turn used for the preparation of catalysts. The synthesis of optically active bisphosphine ligands of formula II thus involves the formation of a racemic mixture of the bis(phosphine oxide) of formula I, subsequent racemic resolution and reduction to obtain the desired enantiomer or reduction to the racemic bisphosphine of formula II followed by racemic resolution. The present invention provides a method to use the undesired enantiomer of the intermediate of formula I in order to improve the efficiency of the synthesis of optical active ligands of formula II.
The present invention is thus concerned with a novel process for the racemization of atropisomeric compounds of formula I,
which are present in the (R) or (S) form or a non-racemic mixture of the (R) and (S) form and wherein
R
1
signifies C
1-8
-alkoxy and
R
2
signifies hydrogen, C
1-8
-alkyl, C
1-8
-alkoxy or
R
1
and R
2
together signify methylenedioxy or ethylenedioxy
R
3
signifies hydrogen, C
1-8
-alkyl or C
1-8
-alkoxy and
R
4
signifies phenyl or substituted phenyl,
characterized in that the racemization is thermal and carried out at a temperature from 260 to 400° C., preferably from 280 to 380° C.
The term “racemization” signifies the transition of an optical active compound towards the corresponding racemate. A racemate signifies a mixture of equal amounts of both enantiomers. It is to be understood that racemization need not be complete to be within the scope of the invention. Thus, the transformation of a (R) to (S) mixture that is in the ratio of 10 to 1 via the subject process into a more racemic mixture of 6 to 4 would be considered within the scope of the invention.
The term “atropisomeric” indicates the stereochemistry of compounds in which the free rotation along a bond is hindered and optical activity results. Atropisomerism is a special case of axial chirality.
The term “C
1-8
-alkyl” signifies in the scope of the present invention hydrocarbons with 1 to 8 carbon atoms, i.e. straight-chain or branched alkyl groups such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, tert.-hexyl, heptyl, and octyl.
The term “C
1-8
-alkoxy” signifies a C
1-8
-alkyl group as defined above which is bonded via an oxygen atom. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like can be mentioned as example.
The term “substituted phenyl” signifies in the scope of the present invention phenyl groups which are monosubstituted in the meta- or para-position, preferably in the para-position. Suitable substituents for the phenyl group are C
1-8
-alkyl, preferably methyl; or C
1-8
-alkoxy, preferably methoxy; or di-C
1-8
-alkylamino, preferably dimetylamino; or trialkylsilyl, preferably trimethylsilyl; or substituted by a phenyl group.
According to the invention, the racemization of the compounds of the formula I is carried out by heating the compound in a solvent or in the melt at a temperature from 260 to 400° C. The “melt” means a liquid resulting from the heating of a compound of formula I. The heating is carried out in a device which allows for heating up to 400° C. For small scale the heating can be carried out e.g. with a heating/stirring mantel, an aluminum heating block, an electrically heated reactor or autoclave and the like or by microwave irradiation. For larger scale the heating can be carried out e.g. in reactors or autoclaves. The reaction is carried out batchwise or in a continuous manner.
In a preferred way, the racemization of the compounds of the formula I is carried out in a high boiling solvent at a temperature from 260 to 400° C. batchwise or in a continuous manner and optionally under pressure at 10
5
to 3.5×10
7
Pa or preferably at 10
5
to 10
7
Pa. Suitable high boiling solvents are compounds of formula
R
5
O(CH
2
CH
2
O)
n
CH
2
CH
2
OR
6
  III
wherein R
5
and R
6
each independently signify hydrogen or lower alkyl (C
1
-C
4
), and
n is 2,3,4,5,6,7 or higher to signify a polyethylenoxy chain.
Examples of solvents of formula III are tetraethylene glycol, tetraethylene glycol dimethyl ether, polyethylene glycol monomethyl ether 350, polyethylene glycol dimethyl ether 400 or polyethylene glycol 350, polyethylene glycol 400, polyethylene glycol 550 and polyethylene glycol 725.
Further suitable high boiling solvents are solvents of formula
R
5
O(CH
2
CH(CH
3
)O)
n
CH
2
CH(CH
3
)OR
6
  IV
wherein R
5
and R
6
are as mentioned above, and
wherein n is as mentioned above to signify a polypropylenoxy chain.
A preferred solvent of formula IV is polypropylene glycol 725.
A further preferred solvent is polyoxyethylen-sorbitan-monooleat. The reaction can also be carried out in inorganic salt melts.
In another preferred aspect of the invention the racemization of the compounds of the formula I is carried out in a low boiling organic solvent under pressure at 10
5
to 3.5×10
7
Pa, preferably at 10
5
to 10
7
Pa. Suitable solvents are aromatic solvents like benzene, toluene, xylene, or alcohols like methanol, ethanol, propanol, butanol, or a mixture of the mentioned solvents. Preferred solvents are toluene, ethanol or a mixture of both solvents.
According to the invention the racemization is carried out batchwise i.e. by a reaction in which the reactant is added to a reaction system (e.g. round flask) once and after the reaction the product is separated. In the alternative, according to the invention, the racemization is carried out in a continuous manner i.e. by a continuous running reaction in which the reactant is continuously added to a reaction system (e.g. reactor) and the product is continuously separated.
In a further preferred embodiment, the racemization is carried out in the melt at a temperature from 260 to 400° C. under normal or elevated pressure at 10
5
to 3×10
5
Pa or in a preferred way at a temperature from 280 to 380° C. and the same pressure.
In a preferred embodiment a specific amount of the optical active or non-racemic mixture of the intermediate of formula I is heated in a high or low boiling solvent or in the melt form under argon or under nitrogen. The heating is carried out in a device which allows for heating up to 400° C. For small scale the heating can be carried out e.g. with a heating/stirring mantel, an aluminum heating block, an electrically heated reactor or au

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