Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
1998-09-08
2001-02-13
Vollano, Jean F (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
Reexamination Certificate
active
06187941
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for the preparation of racemic and diastereomeric oxazaphosphorine-2-amines (N-substituted tetrahydro-2H-&sgr;
4
&lgr;
5
-1,3,2-oxazaphosphorine-2-amino-2-oxides [sic]) of the general formula 1
in which R
1
can be H, 2-bromoethyl, 2-chloroethyl, 2-hydroxyethyl, 2-mesyloxyethyl and 1-phenylethyl, R
2
can be H and 2-chloroethyl and R
3
can be H, 2-bromoethyl, 2-chloroethyl and 1-phenylethyl, or R
1
and R
2
, together with the linked N atom, form an aziridine ring. The compounds prepared by the novel process are either cytostatics or immunosuppressants themselves or starting compounds for the preparation of racemic and enantiomerically pure oxazaphosphorine-2-amines having cytostatic or immunosuppressant activity.
2. Background Information
The compounds of the formula 1 include the known medicaments cyclophosphamide (R
1
=R
2
=2-chloroethyl, R
3
=H), ifosfamide (R
1
=R
3
=2-chloroethyl, R
2
=H) and trofosfamide (R
1
=R
2
=R
3
=2-chloroethyl). They have been used in cancer therapy since 1958 or the 1970s (N. Brock, Cancer Res. 49, 1-7 (1989)). Their synthesis is described in the Patent Specifications DE 1 057 119, GB 1 235 022 and DE 1 645 921. The compounds according to formula 1 furthermore include sufosfamide (R
1
=2-mesyloxyethyl, R
2
=H, R
3
=2-chloroethyl), which was developed as an immunosuppressant for autoimmune diseases (DE 2 107 936, DE-A 2 201 675), as well as compounds which are suitable for the preparation of the mentioned oxazaphosphorine-2-amines in their racemic or enantiomeric form (K. Pankiewicz et al., J. Amer. Chem. Soc. 101, 7712-7718 (1979) and K. Misiura et al. J. Med. Chem. 26, 674-679 (1983)).
It is common to the syntheses known from the literature that, as a phosphorus-containing starting compound, 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide, bis(2-chloroethyl)dichlorophosphoramide or 2-chloro-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-amino-2-oxide [sic] is reacted in one synthesis step to give oxazaphosphorine-2-amine. The three phosphorus-containing starting compounds are prepared, for their part, from phosphoryl chloride (R. H. Iwamato et al. J. Org. Chem. 26, 4743-4745 (1961), O. M. Friedman et al., J. Amer. Chem. Soc. 76, 655-658 (1954) and J. M. S. van Maanen et al., J. Labelled Compd. Radiopharm. 18, 385-390 (1981)).
These syntheses have disadvantages. The total yield of the oxazaphosphorine-2-amines, based on phosphoryl chloride, remains significantly below 50% and is therefore relatively low for a two-stage synthesis. Furthermore, the isolation of the intermediate, i.e. one of the three abovementioned phosphorus-containing starting compounds, is unfavorable, since they are thermally and hydrolytically unstable and can give rise to side reactions during preparation, storage or shortly before use. Additionally, the advantages of a two-stage one-pot reaction are not utilized.
SUMMARY OF THE INVENTION
The object was therefore to achieve a process which, compared with the known prior art, has the following advantages:
1. higher total yield,
2. avoidance of the isolation of intermediates,
3. lower outlay in terms of apparatus,
4. decreased time requirement,
5. lower substance requirement,
6. avoidance of chromatographic or other additional purification steps and
7. reduced cytostatic and chemical waste and thus lower environmental pollution.
The solution of the problem according to the invention consists in reacting a phosphoryl halide and two amines in an inert organic solvent and using an auxiliary base, with minimization of the effect of water and of alcohols and also without isolation of an intermediate compound, to give the compounds of the general formula I. As a rule, the process is carried out as a two-stage one-pot reaction in which the reaction participants are added successively to the reaction vessel.
For the successful implementation of the novel process, it is crucial that the effect of water, in particular on phosphoryl chloride, is suppressed. On the basis of the extensive investigation of the inventors, it was demonstrated that with increasing water content in the reaction mixture the number and amount of by-products increases and the yield of the target compounds is drastically reduced. The crystallization of the final products is then no longer possible or only possible after additional purification steps, e.g. chromatography. This surprising effect of water on the success of the synthesis was still not taken into account in the literature until now. Instead of this, the difficulties of a two-stage one-pot synthesis which starts from phosphoryl chloride were avoided. The only obviously advantageous one-stage synthesis was selected, in which one of the three abovementioned phosphorus-containing starting compounds was used.
In addition to water, attention is to be paid to the absence of alcohols. Thus it was possible to show that traces of methanol and ethyl alcohol in the solvents can lead to side reactions and yield reduction.
The phosphoryl halides have the general formula 2 and the two amines the general formulae 3 and 4:
in which R
1
, R
2
and R
3
have the same meaning as in formula 1, R
4
can be H, or R
3
and R
4
, together with the linked N atom, form an aziridine ring, X is chlorine or bromine, X only being bromine if R
1
or R
3
is 2-bromoethyl, and Y has no meaning or can be hydrogen chloride or hydrogen bromide. The optically active amine used for the preparation of two diastereomeric compounds of the formula 1 is thus (R)-(+)- or (S)-(−)-1-phenylethylamine or an N-3-hydroxypropyl derivative of (+)-or (−)-1-phenylethylamine.
The reaction is carried out in inert organic solvents or solvent mixtures, dichloromethane, 1,2-dichloroethane, chloroform, dioxane, acetonitrile, tetrahydrofuran and toluene, for example, being suitable.
A suitable auxiliary base or acid-binding agent is, for example, triethylamine, pyridine and sodium carbonate.
The concentration of the reaction mixture, i.e. the ratio of compound of the formula 2, 3 or 4 to the volume of the solvent, can vary between 0.1 to [sic] 6 mol per liter.
The amines of the general formulae 3 and 4 are employed, as a rule, in equimolar amount based on the compound of the formula 2, a stoichiometric deficit of up to 5% or a 20% excess being possible.
The auxiliary base is employed, as a rule, in an equivalent amount to the amine, i.e. for the condensation of the compound of the formula 3, two equivalents of auxiliary base are needed if it is present as a salt, and one equivalent of auxiliary base if it is present as a free base. For the compounds of the formula 4, correspondingly, three or two equivalents respectively are used. An up to 30 percent excess of auxiliary base is possible.
The condensation reaction of the phosphoryl halide with the amines proceeds exothermically. To control the reaction temperature, the reaction component with which the condensation is set off is slowly added with cooling. Therefore phosphoryl chloride, for example, is slowly added dropwise to an amine which is present as the free base, or the auxiliary base is slowly added to a mixture of phosphoryl chloride and an amine which is present as a salt. In the initial phase, the reaction temperature is kept, as a rule, in the temperature range from −40° C. to 20° C., in particular between −20 and +10° C., by cooling. It can increase after half of the reaction has taken place to 100° C. or up to the boiling temperature of the solvent—if appropriate by heating.
The compounds of the formulae 2 to 4 and the auxiliary base are added together at specific times. The following standard batch with its variations is intended to clarify this.
An amine of the formula 3 and the equivalent amount of auxiliary base are initially introduced in the solvent, and a compound of the formula 2 is slowly added dropwise or run in (first step). Subsequentl
Kutscher Bernard
Neda Ion
Niegel Harald
Niemeyer Ulf
Asta Medica Aktiengesellschaft
Pillsbury Madison & Sutro LLP
Vollano Jean F
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