Processes for 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)

Details Processes for 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl) Processes for 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)

1989-04-20

1991-03-05

Gerstl, Robert

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

Organic compounds

Amino nitrogen containing

548198, 564 27, C07C33528

Patent

active

049979817

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention is directed to advantageous processes for the preparation of 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and analogs, and to a crystalline, hydrated dihydrochloride salt thereof having advantageous properties.
Reiter, U.S. Pat. No. 4,560,690 has described 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and various analogs, compounds having valuable antiulcer activity. That patent, which further details pharmaceutical compositions and a method of inhibiting ulcers with these compounds, is included herein by reference.
Reiter prepared the subject compounds via the following reaction scheme: ##STR1## wherein R is benzyl or (C.sub.1 -C.sub.5)alkyl and R.sup.1 is (C.sub.1 -C.sub.5)alkyl. The products were generally isolated as their dihydrobromide salts and converted to preferred dihydrochloride salts via their free base forms. This route employs toxic reagents, sodium dicyanamide and hydrogen sulfide, presenting environmental problems. In particular, the use of large excesses of hydrogen sulfide (or alternatively hydrogen sulfide under pressure) presents particular problems which limit batch sizes. This old scheme further lacks flexibility, it being necessary to carry out the entire sequence for each compound of the formula (I) that is desired.


SUMMARY OF THE INVENTION

The present invention is directed to highly flexible routes to compounds of the formula (I) which avoid toxic sodium dicyanimide and hydrogen sulfide, and employ an unprecedented acid catalyzed amine exchange reaction, carried out by action of an amine RNH.sub.2 either on a 2-guanidino-4-(2-alkyl-4-imidazolyl)thiazole, of the formula ##STR2## directly forming the compound of the formula (I), as defined above; or on an amidinothiourea ##STR3## to form the N-substituted aminothiourea of the formula (II), as defined above; neat or in the presence of a reaction-inert solvent.
In one of the preferred embodiments of the present invention, an acid salt of (III), e.g., the dihydrochloride, is reacted with at least one molar equivalent of the amine neat or in the presence of a reaction-inert solvent or solvents (preferably in an excess of the amine) to directly form the corresponding acid salt of (I).
In a second preferred embodiment of the present invention, amidinothiourea is reacted with at least one molar equivalent of the amine RNH.sub.2 in a reaction-inert solvent such as a lower alkanol in the presence of a molar excess of an acid, conveniently acetic acid.
The expression "reaction-inert solvent" refers to a solvent which does not interact with starting materials, intermediates or products in a manner which adversely affects the yield of the desired product (C.sub.1 -C.sub.5)Alkyl refers to straight chain or branched alkyl groups containing from 1 to 5 carbon atoms. The preferred value of R.sup.1 is methyl; the preferred values of R are benzyl, pentyl and 2-methylbutyl.
The present invention is also directed to crystalline 2-(1-pentyl-3-guanidino-4-imidazolyl)thiazole dihydrochloride trihydrate, having distinct advantages over the prior anhydrous dihydrochloride of Reiter, which is amorphous, less readily purified, and possesses properties which are generally less suitable for formulation and use as a medicinal agent in man.


DETAILED DESCRIPTION OF THE INVENTION

The processes of the present invention are readily carried out. When the product is directly the guanylthiazole derivative (I), the reaction is conveniently carried out employing an isolated mono or diacid salt of the compound (III), thus providing the source of the required acid catalyst. The acid catalyst can be a strong acid (e.g. HBr, HCl, pCH.sub.3 C.sub.6 H.sub.4 SO.sub.3 H) or a weak acid (e.g. CH.sub.3 COOH, NH.sub.4 Cl). It is most preferred to use the dihydrochloride salt of (III). The salt is heated with at least one molar equivalent of the amine RNH.sub.2. The temperature which is generally well above ambient temperature, is not a critical feature of the present invention, temperatures in the ran

REFERENCES:
patent: 4234735 (1980-11-01), Jones et al.
patent: 4262122 (1981-04-01), Lees
patent: 4427685 (1984-01-01), Stemp
patent: 4560690 (1985-12-01), Reiter
Wegard, "Preparative Organic Chemistry" 3rd ed., 1985, John Wiley (New York), pp. 540, 541.
March, "Advanced Organic Chemistry" 3rd ed., 1985, John Wiley (New York), pp. 315 and 371-377.

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