Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus containing
Reexamination Certificate
2001-11-13
2002-12-03
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus containing
C568S017000
Reexamination Certificate
active
06489513
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the preparation of enantiomerically pure (5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine -oxides) starting from 5-bromo-2-chloro-anisole and phosphorus oxychlorides of the type O═P(phenyl)
2
(Cl).
Such bis-diphenylphosphine oxides can be reduced to give the corresponding bis-diphenylphosphines, which are used as ligands for metal complexes. Such metal complexes are for their part of importance as catalysts for enantioselective hydrogenations (see DE-A1 195 22 293 and the corresponding U.S. Pat. No. 5,710,339 and 5,801,261).
Likewise known from this literature is a multi-stage process for the preparation of enantiomerically pure (5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine oxides). In this process, in a first stage, 5-bromo-2-chloroanisole is reacted by a selective monometalation with a phosphorus oxychloride of the type O═P(phenyl)
2
(Cl), giving a (4-chloro-3-methoxyphenyl)diphenylphosphine oxide. The metalation is carried out with magnesium in tetrahydrofuran, the phosphorus oxychloride is used as a solution in tetrahydrofuran, and the product is isolated by concentrating a solution in methylene chloride by evaporation and stirring with tert-butyl methyl ether. The product is produced in a yield of 70%.
In a second stage, the (4-chloro-3-methoxyphenyl)diphenyl-phosphine oxide is converted into the corresponding 2-iodo compound.
For this purpose, lithium diisopropylamide, dissolved in tetrahydrofuran, is added to a solution of the starting phosphine oxide in tetrahydrofuran at −70° C., the mixture is heated to 0° C., cooled to −76° C., and then, at this temperature, a solution of iodine in tetrahydrofuran is added dropwise. Work-up is carried out by treating with aqueous sodium sulfite solution, then extracting with ethyl acetate and stripping off the extractant. This gives the product in a yield of 80%.
In a third stage, the (4-chloro-2-iodo-3-methoxyphenyl)diphenyl-phosphine oxide is reacted with copper powder in dimethylformamide over the course of 16 hours to give racemic (5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine oxide). The latter compound is isolated by filtration, removal of the dimethylformamide from the filtrate, and stirring with tert-butyl methyl ether.
Finally, in a fourth stage, the racemic (5,5′-dichloro-6,6′-dimethoxy-biphenyl-2,2-diyl)-bis(diphenylphosphine oxide) is separated into its enantiomers using enantiomerically pure mono- or dicarboxylic acids. Here, both forms of enantiomerically pure mono- or dicarboxylic acid have to be used one after the other and complex extractions and filtrations have to be carried out.
The known overall process for the preparation of the bis-diphenyl-phosphine oxides is disadvantageous, not very suitable, and uneconomic for use on a relatively large scale, since it produces products in unsatisfactory yields, in many cases requires partly toxic solvents, is very complicated in terms of process engineering, requires the use of very low temperatures (down to −76° C.) and long reaction times, and requires the use of large amounts of solvents and auxiliaries.
There is therefore still the need for a process for the preparation of such bis-diphenylphosphine oxides, with which the latter are accessible in a more simple, more efficient and more cost-effective manner, and with which a preparation on a relatively large scale can also be carried out without problems.
SUMMARY OF THE INVENTION
We have now found a process for the preparation of enantiomerically pure bis-diphenylphosphine oxides of the formula (I)
in which
R
1
is phenyl, naphthyl, heteroaryl having 4 or 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or cyclohexyl, wherein each R
1
is optionally substituted by R′, OR′, NO
2
, NH
2
, NHR′, or NR′
2
in which each R′is C
1
-C
6
-alkyl,
R
2
is C
1
-C
4
-alkoxy,
R
3
is hydrogen, fluorine, chlorine, or bromine, and
R
4
and R
5
, independently of one another, are hydrogen, fluorine, chlorine, bromine, C
1
-C
6
-alkyl, or C
1
-C
6
-alkoxy,
comprising
(1) in a first stage, selectively monometalating a bromine compound of the formula
in which R
2
to R
5
have the meanings given for formula (I), in a solvent comprising a mixture of tetrahydrofuran and an aromatic hydrocarbon and reacting the resultant metalated compound with a diphenylphosphinic chloride of the formula (II)
in which R
1
has the meaning given for formula (I), which is added without solvent to the metalated compound, to give a diphenylphosphine oxide of the formula (III)
in which R
1
to R
5
have the meanings given in formula (I), which is isolated from a solution in an aromatic hydrocarbon by adding a saturated aliphatic hydrocarbon,
(2) in a second stage, metalating the diphenylphosphine oxide of the formula (III) in the 6-position and reacting the resultant metalated compound with iodine at a temperature of not less than −25° C., wherein the metalated diphenylphosphine oxide of the formula (III) and iodine are metered in simultaneously such that a small amount of iodine is always present in excess, to give a 2-iodo-diphenyl-phosphine oxide of the formula (IV)
in which R
1
to R
5
have the meanings given for formula (I), which is separated off in dissolved form in an aromatic hydrocarbon,
(3) in a third stage, converting the 2-iodo-diphenylphosphine oxide of the formula (IV) with copper (preferably dendritic copper) in an aromatic hydrocarbon solvent into a racemic bis-diphenylphosphine oxide of the formula (I), which is crystallized from absolution in an aromatic hydrocarbon, and
(4) in a fourth stage, separating the racemic bis-diphenylphosphine oxide of the formula (I) into its enantiomers by crystallization with an enantiomerically pure mono- or dicarboxylic acid, wherein a first enantiomer is obtained by crystallization from a solution in an aromatic hydrocarbon and a second enantiomer is obtained by hydrolysis and subsequent crystallization from a solution in an aromatic hydrocarbon.
DETAILED DESCRIPTION OF THE INVENTION
In the formulas (I) to (IV), R
1
is preferably unsubstituted phenyl, unsubstituted naphthyl, heteroaryl having 4 or 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of oxygen and sulfur, or unsubstituted cyclohexyl.
In the formulas (I), (IIa), (III) and (IV)
R
2
is preferably methoxy,
R
3
is preferably fluorine, chlorine, or bromine (particularly chlorine), and
R
4
and R
5
are preferably hydrogen.
The aromatic hydrocarbons are, for example, benzene, toluene, or xylenes. Preference is given to toluene.
The saturated aliphatic hydrocarbons may, for example, be those having boiling points of more than 30° C. (at atmospheric pressure). Preference is given to straight-chain or branched pentanes, hexanes, heptanes, and octanes. Particular preference is given to n-pentane.
In the first stage, the metalation can be carried out, for example, using magnesium, which can be activated, where necessary, for example, by adding a small amount of iodine. For the metalation, it is possible to use, for example, 1 to 1.5 mol of magnesium, based on 1 mol of bromine compound of the formula (IIa). The solvent mixture to be used for the metalation can comprise, for example, 20 to virtually 100% by volume of tetrahydrofuran and brought to 100% by volume using aromatic hydro-carbon. The solvent mixture preferably comprises 40 to 60% by volume (particularly 45 to 55% by volume) of tetrahydrofuran and brought to 100% by volume using aromatic hydrocarbon.
The procedure can be carried out, for example, by additionally introducing magnesium, a small amount of iodine, and the solvent mixture, heating the mixture to a temperature in the range from 30 to 80° C., then metering in a bromine compound of the formula (IIa) dissolved in the same solvent mixture at a temperat
Giffels Guido
Pohl Torsten
Prinz Thomas
Sirges Wolfram
Akorli Godfried R.
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Vollano Jean F.
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