IL27897A - Preparation of pyrazinoylguanidines and pyrazinamidoguanidines - Google Patents

Description

'nitui ffiD TJinrn ·π PATENT ATTORNEYS · □ ' Q ] Q D ' □ 1 DR. REINHOLD COHN I Π 3 TJini' · Ί ' Π DR. MICHAEL COHN in. 1 N a · D m ISRAEL SHACHTER B.Sc. .0.1 T D 3 LU IN T CU ' PATENTS AND DESIGNS ORDINANCE SPECIFICATION Preparation of Fyrazlnoylguanidines and Pyrazinamidoguanidines MERC & CO., Inc. a corporation of New Jerse ,U.S.A. , fiahway. New Jersey U.S.A. do hereby declare the nature of this invention and in what manner the same is to be performed, to particularly described and ascertained in and by th following statement : - This invention is concerned with a novel process for the preparation of ( 3, 5-diamino-6-chloropyrazinoyl)guani- other abnormalities resulting from the retention of excess quantities of sodium and/or fluid by the animal organism.

The novel process of this invention involves the chlorination of a ( 3* 5-diaminopyrazinoyl)guanidine or a .(3* 5- diaminopyrazinamldo)guanidine compound. This novel process presents a simple and highly economical method of producing an important group of diuretic or natriuretic products.

The novel process of this invention advantageousl is carried out by preparing a solution of the ( 3, 5-diaminopy- razinoyl)guanidine or the ( 3, 5-diaminopyrazinamido)guanidine product in an aqueous or organic solvent such as a mixture of water and acetic acid or water and dloxane, acetonitrile, formic acid and the like. Chlorine gas then is .passed through the solution thus prepared for sufficient time to ensure chlor- inatlon of the starting material. Chlorination is- acilita- ted by vigorous stirring of the reaction mixture during the addition of chlorine. In some instances and under certain reaction conditions chlorine is added to one or more of the amino groups of the starting material and, If desired, these chlorines can be removed by treating the product of chlorina- tion with sodium bisulfite or some related reducing agent which will remove all of the chlorines except that which is - lb - It Is known from Dutch Patent Application No. 6,409,717 (C.A. Vol.64, p. 8208 e) to introduce chlorine atoms into the 5- and/or 6-positions of a 3-amino-pyraisinoic acid derivative' , by means of sulphuryl chloride. This known process, however, has the disadvantage of employing the highly noxious and corrosive sulphuryl chloride reagent, of the formation of many colored impurities necesoitating lengthy., and difficult purification steps and, consequently, of rele ively low yields.

In contrast to the above mentioned known process, the novel process according to the present invention is less!¾onsum-ing and affords higher yields. It can be carried out with most ordinary equipment without hazards to operator or reaction vessels; impurities are not formed and as the end product precipitates from the reaction mixture, it can be separated merely by filtration and no additional purification steps are required.

While the novel method of this invention can be em-ployed to produce substantially any ( 3, 5-diamino-6-chloropy-razinoyl)guanidine or ( 3, 5-diamino-6-chloropyrazinamido)guani~ dine product, the reaction is particularly suited to the prepa-ration of products having the following structural formula wherein R1 and R2 can be the same or dissimilar groups selec-ted from hydrogen, lower alkyl advantageously having from 1 to 5 carbon atoms as methyl, ethyl, propyl, isopropyl, butyl, amyl, or any of the branched or 5 carbon alkyl groups, or a phenyl-lower alkyl advantageously having 1 or 2 carbons in the alkyl moiety; R3 represents hydrogen, a lower alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, iso-propyl, butyl, amyl or any of the branched 4 or 5 carbon lower alkyl groups, or substituted lower alkyl groups having from 1 to 5 carbon atoms and particularly those containing hydroxy or a heterocyclic substituent such as the pyrridyl substituent or a phenyl substituent, the phenyl-lower alkyl advantageously having an alkyl moiety of 1 to 2 carbon atoms and the phenyl moiety being either unsubstituted or substituted with one or more halogens (preferably chlorine, ( bromine, fluorine), lower alkyl (having 1 to 2 carbon atoms) and/or lower alkoxy (having 1 to 2 carbon atoms) groups; R4 advantageously is hydrogen, lower alkyl having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, amyl or any of the branched 4 or carbon alkyl groups, phenyl-lower alkyl wherein the alkyl moiety advantageously has from 1 to 2 carbon atoms and the from 1 to 2 carbon atoms) and/or lower alkoxy (having 1 to 2 carbon atoms) groups; when R3 and R4 are each lower alkyl they can be linked together to form a cyclic structure with the nitrogen atjom to which they are attached thereby forming a group ,( wherein x preferably is one of the numerals from 4 through 7 thus yielding, for example, the pyrrolidinyl group; R5 ad-vantageously is hydrogen or lower alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, amyl or any of the branched 4 or 5 carbon alkyl groups; and when Rs and R4 each are lower alkyl they can be linked together o form the structure wherein _ preferabl " is one of the numerals 2 or 3; and n is either 0 or 1.

The novel process of this invention can be illustra-ted by the following reaction scheme wherein the variable radi-cals have the meaning assigned to each of them above.

The starting materials (ll) are, for the most part, known com-pounds, or can be prepared by the reaction of a lower alkyl ester of S-amino-S-NR^-R^-pyrazinoate with the desired guani-dine or aminoguanidine having the structure · R3 1 wherein the variable radicals n, R3, R4 and Rs have the mean- 2 ing assigned above. The guanidine or aminoguanidine reactants 9 While the following examples illustrate the novel .0 process of this invention, it is to be understood that the 1 examples are not to be considered as limiting the invention 2 to the particular products prepared nor to the particular re- 3 action conditions described, but are to be understood as illus- trating solely a particular embodiment of the invention fall- 5 ing within the scope of the reaction conditions and products 6 described hereinabove. 7 EXAMPLE 1 8 ( 3J 5-Diamino-6-chloropyrazlnoyl)guanidine 9 Step A: Preparation of ( .5-diaminopyrazinoyl)guanidine 0 Absolute alcohol (2 liters) is flushed with dry ni- 1 trogen and to it is added 0.6 mole of clean sodium. Guanidine 2 hydrochloride (θ.β mole) then is added with stirring. After 3 precipitation of the sodium chloride is complete, the mixture 4 is filtered under a nitrogen atmosphere and anhydrous condi- 5 tions. Methyl 3,5-diaminopyrazinoate (θ.β mole) is added to 6 the filtrate with stirring and the mixture is heated to 60° C. 7 and then allowed to cool to room temperature spontaneously. 8 The precipitate is collected, washed, with ethanol and dried 9 to give (3, -diaminopyrazinoyl)guanidine, ir p. 286-288° C. 0 (dec. ) . 1 acid and 0.6 mole of ( 3, 5-diaminopyrazinoyl)guanidine is heat- 2 ed to 40° C. While vigorously stirring the reaction medium, 3 about 140 g. of chlorine gas is passed through the solution 4 over a period of about 30 minutes. The precipitate that forms on cool|ng is collected and stirred with a solution of 6 150 g. of sq jium bisulfite in 1 liter of water. After about 7 one-half houf, the precipitate is collected, washed with water 8 and dried to give (3, 5-diamino-6-chloropyrazinoyl)guanidine, 9 m.p. 240.5-241.5° C (dec).

EXAMPLE 2 11 ( 3-Amino-5-dimethylamino-6»chloropyrazinoyl)guanidine 12 By replacing the pyrazinoate employed in Example 1, 13 Step A, by an equimolecular' quantity of methyl 3-amino-5-di- 14 methylaminopyrazinoate and ihen following substantially the same conditions and employing the other reactants of Example l6. 1, Step A, there is obtained ( 3-ajnino-5-dimethylaminopyrazin- 17 oyl)guanidine, m.p. 224-225° C. (dec). Upon chlorinating 18 this product by the procedure described in Example 1, Step B, 19 there is obtained ( 3-amino-5-dimethylamino-6-pyrazinoyl)guani- 0 dine, m.p. 216-217° C. (dec). 1 EXAMPLE 3 2 ' ( 3-Amino-5-benzylamino-6-chloropyrazinoyl)guanidine 3 By replacing the ester used in Example 1, Step A, 4 by an equimolecular quantity of methyl 3-amino-5-benzylam~ino- 5 pyrazinoylguanidine and then following substantially the same 6 procedure and using the other reactants called for in Example 7 l, Step A, there is obtained ( 3-amino-5-benzylaminopyrazinoyl)- 8 guanidine, m.p. 231-233° C. (dec). This product can be chlor- 9 inated by substantially the same procedure described. in 1 Example 1, Step B, to give ( 3-amino-5-benzylamino-6-chloro- 2 pyrazinoyl)guanidine. 3 EXAMPLE ( 3> 5"Piamino-6-»chloropyrazinamldo)guanidine This product is prepared following substantially the same procedures described in Example 1, Steps A and -B, f with the exception that in place of ^guanidine employed in J3 Step A an equimolecular quantity of aminoguanidine is substi- tuted therefor. The ( 3* 5-diamino-6-chloropyrazinamido)guani- 10 dine thus obtained, in the form of its hydrochloride salt, 11 melts at 281-282° C. 12 EXAMPLE 5 13 ( 3-Amino-5-dimethylamino-6-pyrazinamido)guanidine 1 This product is prepared following substantially . the same procedures described in Example 2 except in place 1β of guanidine employed in Example 2 an equimolecular quantity 17 of aminoguanidine is substituted therefor. The ( 3~amino-5~ 18 dimethylamino-6-chloropyrazinamido)guanidine product thus ob- 19 tained melts at 221° C.

EXAMPLE 6 21 ( 3-Amino-5-benzylamino-6-chloropyrazlnamldo)- 22 j guanidine 23 This product is prepared following substantially the same procedure described in Example 3 with the exception that aminoguanidine is substituted for the guanidine reactant 26 and ( 3-amino-5-benzylamino-6-chloropyrazinamido)guanidine is 27 obtained. 28 .By replacing the aminoguanidine reactant employed 29 in Example , 5, and 6 by an equimolecular quantity of ' ' l-amino-3-methylguanidine, - - - 2-h drox eth l uanidine l-amino-2, 3-ethyleneguanidine, and l-amino-3, 3-dimethylguanidine, and then following substantially the same procedures and us- ing the other reactants, reagents and reaction conditions described in Examples 4, 5 and 6, there are ^obtained (a) by employing Example 4 conditions: 3j 5?;piamino-6-chloropyrazinamido -3-methylguanidine, : l-( 3, 5-diamino-6-chloropyrazinamido) -3-( 2-hydroxyethyl)- < guanidine · 1- ( 315-diamino-6-chloropyrazinamido) -3-phenethylguanidine, l-( 3* 5-diamino-6-chloropyrazinamido) -3~benzylguanidine, l-( 3i 5-diamino-6-chloropyrazinamido) -2, 3-ethyleneguani- · dine and l-( 3^ 5-diamino-6-chloropyrazinamido) -3* 3-dimethylguani- · dine; (b) by employing Example 5 conditions: l-( 3-amino-5-dimethylamino-6-chloropyrazinamid6) -3-methyl- · guanidine, l- ( 3-amino-5-dimethylamino-6-chloropyrazinamido) -3- ( 2- · · hydroxyethyl)guanidine, l-( 3-amino-5-dimethylamino-6-chloropyrazinamido) -3-phen- · ethylguanidine, l-( 3-amino-5-dimethylamino-6-chloropyrazinamido) -3-benzyl- · guanidine, l-( 3-amino-5-dimethylamino-6-chloropyrazinamido) -2, 3- « ethyleneguanidinei'.and 1- ( 3-amino-5-dimethylamino-6-chloropyrazinamido) -3, 3- · dimethylguanidine; (c) by employing Example 6 conditions: l-( 3-amino-5-benzylamino-6-chloropyrazinamido) -3-methyl-■ · guanidine, l-( 3-amino-5-benzylamino-6-chloropyrazinamido) -3- (2-hy- · droxyethyl)guanidine, l-( 3-amino-5-benzylamino-6-chloropyrazinamido) -3-phen- · ethylguanidine, l-( 3-amino-5-benzylamino-6-chloropyrazinamido) -3-benzyl- 1 l-(3-amino-5-benzylamino-6-chloropyrazinamldo)-3*3-di- 2 · methylguanidine . 3 The! following table identifies other products that 4 can be prepared by the process of this invention'. The method II is replaced by the guanidine or aminoguanidine reactant (ill) 12 identified in the table. In all other respects the reactants 13 and reaction conditions are as described in Example 1, Steps A 1 and B.

CH3 H H 252-25 CH3 CH3 H 295 C2Hs C2Hs ' H 265 (HCI -CH2-@ H H 215-216 -CH2-£¾ Ή ' H 220-223 ■ tf : .

-CH2- -F H H 216-219.5 -CH2-@-CH3 H H 210-212 -CH2CH2-@ H H ■ 219-22I.5 (2 HCl) ' CH3 CH3. H 279-28Ο m.p. is given for the free base unless otherwise noted

Claims (1)

1. HAVING NOW particularly described and ascertalnd the n$$ure o our said Invention and in what manner the same is to be performed, we ; declare that what we claim Is: WHAT IS CLAIMED IS: 1 1. A process comprising the reaction of a product 2 I selected from a (3> 5-dlaminopyrazinoyl)guanldine and a (3,5- 3 diaminopyrazinamido)guanidine with chlorine to give the (3,5- '; 4 diamino-6-chlo:tjfopyrazinoyl)guanidlne and (3i -diamino-6-chlo- 5 ropyrazinamido)guanidine products. 1 2. A process as claimed in claim 1 wherein the 2 product I is dissolved in a solvent and agitation of the re- 3 action mixture is continued throughout the chlorination pro- 4 cedure. 1 · 3. A process as claimed in claim 2 wherein the sol- 2 vent is selected from a mixture of water and acetic acid, a 3 mixture of water and dioxane, acetonitrile and formic acid. 1 . A process as claimed in claim 1 wherein product 2 I has the structural formula 4 wherein R1 and R2 are either similar or dissimilar groups and 5 are separately selected from hydrogen, lower alkyl and phenyl- 6 lower alkyl; R3 is selected from the group consisting of hy- 7 drogen, lower alkyl, hydroxy-lower alkyl, phenyl-lower alkyl, 8 halo-phenyl-lower alkyl, lower-(alkylphenyl)alkyl, and lower- 9 (alkoxyphenyl)alkylj R4 is selected from the group, consistin 10 of hydrogen, lower alkyl, phenyl-lower alkyl, halophenyl-low- 11 er alkyl, lower-(alkylphenyl)alkyl and lower-(alkoxyphenyl) - 12 alkylj R5 is selected from the group consisting of hydrogen, 13 and lower alkyl; and when R4 and R5 each are lower alkyl they 14 can he linked to ether to form the structure -C-→I 3wherein 5· process as claimed in claim 3 wherein (3*5-diaminopyrazijfioyl)guanidine is chlorinated to give (3*5~di-aminp-6-chloropyrazinoyl)guanidine. 6. A process as claimed in claim 3 wherein (3-amino-5-dimethylaminopyrazinoyl)guanidine is chlorinated to give (3-amino-5-dimethylamino-6-chloropyrazinoyl)guanidine . 7. A process as claimed in claim 3 wherein (3*5-diaminopyrazinamido)guanidine is chlorinated to give (3*5-/ diamino-6-chloropyrazlnamido)guanidine. Dated this 50th day of April,1967