Process for preparing amidines

Details Process for preparing amidines Process for preparing amidines

1999-03-01

2001-03-20

Aulakh, Charanjit S. (Department: 1612)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S131000, C548S240000, C546S286000, C546S332000, C564S225000, C564S244000, C564S245000

Reexamination Certificate

active

06204385

ABSTRACT:

The present invention relates to a novel process for preparing amidines.
Amidines can be prepared by many routes. One of the best-tried methods is the Pinner reaction followed by ammonolysis of the iminocarboxylic ester (Ber. 18, (1885) 2845). A disadvantage of this method is the two-step reaction. As a rule, a large excess of hydrogen chloride is used, which ultimately gives rise to large amounts of concomitant salts and can sometimes cause separation problems. Finally, the reaction times in this reaction sequence are relatively long and conversions and yields are only moderate. In a manner similar to the Pinner reaction, mercaptans can be employed as auxiliary reagents for preparing amidines (R. C. Schnur, J. Org. Chem. 44, (1979) 3726). One variant of this synthesis is the addition of hydrogen sulfide to nitrites to give thiocarboxamides, followed by alkylation of the sulfur and ammonolysis (H. Rappoport, J. Org. Chem. 46, (1981) 2455; M. Ohno, Tetrahedron Lett. (1979) 2517). In all these cases, extremely malodorous and highly toxic compounds have to be handled. For the alkylation, methyl iodide or dimethyl sulfate are normally used. Both chemicals have been shown to be potent carcinogens.
Ammonia can be added directly under pressure in liquid ammonia to heteroaromatic or aromatic nitriles, but, this requires long reaction times (16 h) and gives only poor product yields (40%) (P. C. Srivastava, J. Med. Chem. 27, (1984) 266). Amidines can further be synthesized from nitriles by reaction with hydroxylamine and reductive cleavage of the intermediate carboxamide oximes (H. Jendralla, Tetrahedron 51, (1995) 12047). The reductive cleavage, however, considerably limits the substitution pattern of the nitrile. Double bonds or nitro groups are likewise easily hydrogenated. Protecting groups, for example the benzyl group, are also easily cleaved.
In 1986, A. Eschenmoser published a cysteine-catalyzed amidine synthesis (Helv. Chim. Acta 69, (1986) 1224). However, the experimental examination of this synthesis showed the yield to be only about 58%.
The simplest synthesis of amidines is the direct addition of ammonia to nitrites. Studies with substituted nitrites showed, however, that there is limited conversion even under pressure and that the amidine yield is therefore correspondingly low.
It is an object of the present invention to develop a simple method by which it is possible to convert even nitrites having complicated substitution patterns, which cannot be used by conventional amidine synthesis, into the corresponding amidines.
We have found that this object is achieved by to a process for preparing amidines and their salts with inorganic or organic acids, which comprises reacting the corresponding nitrile with ammonia, a C
1
-C
6
-alkylamine or hydrazine in the presence of a mercaptocarboxylic acid carrying, apart from the SH and the COOH groups, no other groups reactive under the reaction conditions, and in the presence or absence of an inorganic or organic ammonium salt.
By this process, virtually all amidines of the formula I
R—C(NHR′)=NH   (I)
where R is an aliphatic, aromatic or heterocyclic radical and R′ is a hydrogen atom, a C
1
-C
6
-alkyl radical or an amino group, can be prepared.
In the formula I, R can be a derivative of benzene, for example phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl or p-methoxyphenyl.
R can further be a heterocyclic system, in particular a derivative of pyridine, pyrimidine, thiophene, furan, pyrrole, isoxazole, 1,2,4-oxadiazole, pyrroline or pyrrolidine, for example pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyrimidin-2-yl, pyrimidin-4-yl or thiophen-2-yl.
Of the rings mentioned, the pyridine ring is preferred, in particular when substituted in the 2-position by a cyano group. Preference is also given to the isoxazole ring with a cyano function in the 3-position and to the 1,2,4-oxadiazole ring with a cyano function in the 3-position.
Finally, R can also be an oligopeptide structure consisting of up to 12 natural amino acids, the corresponding D-amino acids or compounds which are very similar to natural amino acids. Specifically, these are the following amino acids: glycine, alanine, phenylalanine, proline, valine, 2,3-, 3,4- or 4,5-dehydroproline, cyclohexylalanine.
The process is of very particular interest for preparing the recently published thrombin inhibitors carrying an amidine radical, which are mentioned for example in the patent applications WO 94/29335, WO 94/29336, WO 95/23609, EP 669,317 and WO 95/35309. Most of them have the structure below:
where X is the radical of a substituted or unsubstituted amino acid, preferably proline or dehydroproline, and
where
Y and Z are CH or NH groups.
Asymmetric centers in the compounds of the formula I do not interfere with the reaction and remain unaffected by the reaction.
The reaction is carried out in an inert solvent, preferably in solvents in which the solubility of ammonia at 0° C. and 1 bar is more than 2% by weight. Such solvents are in particular alcohols, such as methanol and ethanol. The same considerations are applicable for the use of amines and hydrazine.
The reaction is generally carried out at a temperature in the range from −10 to 200° C. and at a pressure in the range from 1 to 20 bar. Preference is given to the boiling point of the reaction mixture and 1 bar. The reaction is very particularly preferably carried out at autogenous pressure. Carrying out the reaction without employing superatmospheric pressure requires occasional resaturation with ammonia or amines.
The reaction can be carried out in the presence of an ammonium salt. This generally affords the corresponding amidinium salts. If an ammonium salt is used, this should be the salt of an acid which is stronger than the mercaptocarboxylic acid used. Specifically, these are the salts of the hydrohalic acids (in particular hydrochloric acid), sulfuric acid, phosphoric acid, nitric acid and C
1-6
-carboxylic acids.
Preferably, however, the reaction is carried out in the absence of an ammonium salt. In this case, the reaction product is the amidinium salt of the mercaptocarboxylic acid. In addition to the catalytic effect, the mercaptocarboxylic acid also exercises a stabilizing action on the amidine. In the reaction, the mercaptocarboxylic acid is generally employed in an amount of from 0.05 to 5 mol, preferably about 1 mol per mole of nirile.
A particular advantage of mercaptocarboxylic acids is that they have little, if any, odor, while the processes described in the literature often require malodorous and highly toxic substances.
Suitable mercaptocarboxylic acids are those not carrying any other reactive groups apart from the SH and the COOH groups. These are in particular those of the formula HS-R′-COOH where R′ is a C
1-12
-alkylene radical and where the hydrocarbon chain contains up to 3 rings and may be substituted or interrupted by heteroatoms which are inert under the reaction conditions, such as nitrogen and oxygen. Preferably, R′ is a C
1-6
-alkylene radical or a phenylene group which may be mono- or disubstituted by the following radicals: methyl, methoxy, ethoxy, n-propoxy, i-propoxy, C
1-6
-alkylamino, C
1-6
-dialkylamino, halogen, nitro.
Specifically, these are mercaptoacetic acid, &agr;- and &bgr;- mercaptopropionic acid, N-acylated aminothiocarboxylic acids—such as N-acylated cysteines—, mercaptoalkyleneprolines—such as N-(3-mercaptopropyl)proline—, mercaptoalkanoylprolines—such as N-(3-mercaptopropionyl)proline—, or cyclic thiocarboxylic acids —such as mercaptobenzoic acid.
Captopril and acetylcysteine have proved to be particularly advantageous for the process.
Generally, the reaction is terminated in a customary manner when no more nitrile can be detected (for example by GC, HPLC, TLC) in the reaction mixture.
Work-up to isolate the product is normally carried out by convention

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