Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-26
2002-06-18
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S341500, C548S342500
Reexamination Certificate
active
06407258
ABSTRACT:
DESCRIPTION
Process for the preparation of S-alkyl(aryl)-substituted imidazole derivatives
The invention relates to a process for the preparation of S-alkyl(aryl)-substituted imidazole derivatives, and their use as an intermediate for the synthesis of active compounds.
In the preparation of active compounds such as, for example, pharmaceuticals for ,cardiac and circulatory disorders, S-alkyl(aryl)-substituted imidazole derivatives have proven themselves to be important intermediates in the preparation process. For example, U.S. Pat. No. 5,350,751, U.S. Pat. No. 5,482,957 or U.S. Pat. No. 5,604,251 describes the preparation of hypotensive preparations which, as active compound, contain compounds of the angiotensin II receptor antagonist type, which have an S-alkyl(aryl)-substituted imidazole radical.
European patent application application number 98100595.2 discloses S-alkyl(aryl)-substituted imidazole derivatives having a biphenylsulfonylcyanamide side chain as sodium-dependent chloride/bicarbonate exchangers, which as a result of their pharmacological properties are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component, inter alia for infarct prophylaxis, for infarct treatment and for the treatment of angina pectoris.
A process for the preparation of S-alkyl(aryl)-substituted imidazole derivatives by reaction of the acyclic aminoacrylic acid ester precursor with 4-dimethylaminopyridine (DMAP) and PCl
5
to give the corresponding imidazole compound is disclosed in U.S. Pat. No. 5,350,751, U.S. Pat. No. 5,482,957, U.S. Pat. No. 5,604,251 or J. C. Caille et al.,
Synthesis 1995, 635-637, P. Deprez et al., J. Med. Chem. 1995, 38, 2357-2377. The S-alkyl(aryl)imidazole derivatives obtained are then purified by chromatography on silica gel, the described yields being 43-84% (J. C. Caille et al. supra).
The known process for the cyclization and purification of the S-alkyl(aryl)imidazole derivatives has a number of disadvantages.
Thus the yields obtained are very low in many cases. Furthermore, the very expensive reagent DMAP used for the cyclization must be employed in a large excess (about 2 equivalents). The S-alkyl(aryl)imidazole derivatives also cannot be obtained in a chemical purity of >99% without laborious chromatography on silica gel, and crystallization or recrystallization in the majority of cases does not lead to the desired chemical purity; moreover, large amounts of solvents are necessary for this. The process is therefore not very suitable for the production of active compound on the industrial scale (preparation of kilo to ton amounts).
The object of the present invention was the development of a simple and economical method for the cyclization of the readily accessible aminoacrylic acid esters (J. C. Caille et al., supra) to give the desired S-alkyl(aryl)imidazole derivatives, and a practicable method for the purification of these compounds.
Surprisingly, it has been found that S-alkyl(aryl)imidazole derivatives can be prepared in high yields and very high purities by cyclization of the corresponding aminoacrylic acid esters in the presence of alkylphosphonic anhydrides which are inexpensive and readily available in industrial amounts, in particular of n-propylphosphonic anhydride (PPA), and subsequent purification by means of a suitable salt.
The invention therefore relates to a process for the preparation of compounds of the formula I,
in which
R(1) is hydrogen;
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, which 4s unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, methyl, methoxy, NO
2
or NR(6)R(7);
—C
n
H
2n
-cycloalkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
where n is equal to 0, 1, 2 or 3;
—C
n
H
2n
-phenyl, which is unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1, 2 or 3;
—C
n
H
2n
-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1, 2 or 3;
R(2) and R(3) independently of one another are —SR(4) or —COOR(5);
R(4) and R(5) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, which is unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, methyl, NO
2
, methoxy or NR(6)R(7);
—C
n
H
2n
-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
where n is equal to 0, 1, 2 or 3;
—C
n
H
2n
-phenyl, which is unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, CN, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1, 2 or 3;
—C
n
H
2n
-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or is substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, CF
3
, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1, 2 or 3;
R(6) and R(7) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms;
or a salt thereof,
which comprises cyclizing compounds of the formula II
in which R(1), R(2) and R(3) have the meaning defined above, in the presence of alkylphosphonic anhydrides to give compounds of the formula (I), then purifying these in as is known per se by salt formation and, if appropriate, subsequent recrystallization and optionally removing radicals introduced for the protection of other functional groups in a manner known per se.
Suitable anhydrides according to the novel process are those of the straight- or branched-chain, optionally cyclic alkylphosphonic acids having chain lengths of 1-8 carbon atoms, preferably up to 4 carbon atoms.
The alkylphosphonic anhydrides used according to the invention are stable at room temperature. They are readily soluble in most nonaqueous solvents, in particular in lipid solvents such as chloroform or methylene chloride, but also in polar solvents such as DMF and DMA.
Particularly suitable anhydrides of the alkylphosphonic acids within the meaning of the invention are methylphosphonic anhydride, ethylphosphonic anhydride, n-propylphosphonic anhydride, n-butylphosphonic anhydride, in particular n-propylphosphonic anhydride.
The alkylphosphonic anhydrides can be prepared in a manner known per se, as formulated, for example, in Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], G. Thieme Verl., Stuttgart 1963, Vol. XII, p. 612. The preparation of n-propylphosphanic anhydride (PPA) is possible, for example, by the process described by Wissmann and Kleiner (Angew. Chem. 92 (1980) No. 2, pp. 129-130).
The acyclic precursors (II) necessary for the preparation of the compounds of the formula (I) can easily be prepared by methods known from the literature (J. C. Caille et al., Synthesis 1995, 635; P. Deprez et al., J. Med. Chem. 1995, 38, 2357).
A preferred embodiment is one wherein compounds of the formula I are prepared in which
R(1) is hydrogen;
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, which is unsubstituted or is substituted by 1 or 2 identical or different radicals from the group consisting of F, Cl, CF
3
, methyl, methoxy, NO
2
or NR(6)R(7);
—C
n
H
2n
-cycloalkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
where n is equal to 0, 1 or 2;
—C
n
H
2n
-phenyl, which is unsubstituted or is substituted by 1 or 2 identical or different radicals from the group consisting of F, Cl, CF
3
, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1 or 2;
—C
n
H
2n
-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or is substituted by a radical from the group consisting of F, Cl, CF
3
, NO
2
, methyl, methoxy, hydroxyl or NR(6)R(7);
where n is equal to 0, 1 or 2;
R(2) and R(3) independently of one ano
Holla Wolfgang
Napierski Bernd
Rebenstock Heinz-Peter
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Higel Floyd D.
Saeed Kamal
LandOfFree
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