IL24097A - 3-aminopyrazinoic acid n-oxide compounds and esters,amides and hydrazides thereof,and processes for their preparation - Google Patents

Description

3 compounds and and processes for This consists in amides and of the formula wherein X is trifl phenyl optionally with nyl or is hydroxy or 1 The compounds of invention are useful 2 mediates in the preparation of 3 guanidine compounds and guanidine which compounds possess 5 diuretic and natriuretic properties useful in of and other diseases 7 known to responsive to this The ally1 esters of this invention be converted to the corresponding 10 dine or b reaction of the ester with an unsubstituted or 12 stituted guanidine or preferably 13 under anhydrous conditions with or without a at room temperature or The 15 pyrazinoic acid compounds can be 16 converted to the corresponding 17 for by reaction with a substituted 18 or unsubstituted preferably by heating 19 together the reactants in aqueous alcohol containing 20 an a 21 The Plow Diagramson some of 22 the interrelationships in the synthesis of above In this Plow Diagram is hydrogen or and is or lowe The description which follows refers 26 to the compounds of the invention by the compound 27 numbers given on the Plow II Oxidation I hydrogen or lower alkyl hydrogen cycloalkyl or optionally 1 The allcyl esters and 2 used as starting materials for the synthesis of the compounds of this invention can be prepared by known to the 6 Allcyl Fsters The esters of 8 this invention correspond to the above 9 cribed generic structure where Z is 10 Allcyl esters 11 can be prepared by direct of the ponding allcyl esters when the latter compounds are substituted in the of the ring by which are unaffected by the oxidizing agent under the conditions employed for The include 17 trifluororaeth phenyl optionally subsituted by halogen 18 Although 19 and of 2 pyrazinoate esters could be prepared by direct oxidation of the corresponding alkyl if the latter pounds were readily the are made 6 preferably from the 7 8 as 9 inafter described for the specified page 3a 10 Any suitable oxidizing agent can be employed 11 which will effect the reaction illustrated 12 above without adversely affecting other 13 stituents in the The preferred 1k dizing agents used in the practice of this invention include organic peroxides and peroxy 16 acids such as 17 18 the The choice of oxidizing agent 19 will be largely determined by economic factors 20 as well as the chemical efficiency of the 21 ticular 2 Various solvents be enployed us 23 medium for the oxidizing the major requirement being that the oxidizing agent is soluble therein and unreactive with the 26 Typical solvents which may be employed are 27 28 and the 1 Molar ratios of the oxidizing agent to the 2 pyrazlnoic acid ester can vary about to 3 about and preferably from about to about Ratios above and below these can also 5 be employed but are less 6 The temperatures at which the oxidation of the 7 acid ester is effected are 8 tures In a range from about to about although temperatures above and below this range 10 might also be the reaction 11 takes place at room or by warming up 12 to about the reaction takes 13 place at the reflux temperature of the reaction The reaction proceeds quite rapidly and 15 is usually complete in about 1 minutes to 16 although in some longer reaction times 17 might be The alkyl product 19 can be isolated as such or in the form of 20 hydrate or a salt In a preferred 21 the product is isolated from the cooled reaction mixture by the solvent can be removed by vacuum distillation and the resulting solid from a 25 solvent such as 1 The 2 of this invention which are substituted in the able 3 by easily as the Plow Diagram by are prepared by a as hereinafter 6 the last step of which is the conversion of a into the corresponding 9 10 by reaction with an This reaction 11 takes place by heating a solution of the 12 compound in the conveniently at reflux 13 a few The solvent is removed under and the residue is stirred with dilute The product then can be recovered by 16 tralizing the cooled reaction mixture with 17 and filtering off the product which l3 The alkyl esters 19 preferably are made from the oxazine 20 mediate include the as 22 as the and 1 heating a acid 2 pound an acid Typical of 3 the anhydrides which can be used or this purpose are acetic propionic butyrio trifluoroacetic and 6 acid anhydrides such as phenylacetic acid 7 To obtain an in which is 8 the acid 9 is heated with a mixture of formic acid and acetic 10 11 acid 1 The acid compounds 13 of this invention correspond to the above described structure where Z is When the acid 16 pounds are substituted in the by groups which are unaffected by the oxidizing 18 agent they are prepared by hydrolysis 19 of the corresponding 20 ester 21 The acid compounds 22 which are substituted in the by 23 which are easily oxidized are prepared from the pteridinone compounds as hereinafter 1 The and 2 must be prepared from the pteridinone 3 in which is The and on the other may be prepared from the pteridinone 6 in which R either or 6 7 When R is Compound V can be 8 represented in its tautomeric which is named 9 as the 10 The acid compounds 11 which are substituted in the by 12 alkylsulfonyl or a are 13 obtained by oxidizing a acid l having the corresponding or 16 Compounds 17 The compounds 18 correspond to the above described generic structure vjhere Z is amino or 20 The compounds a and 21 which are substituted by that 22 unaffeoted by oxidizing agents can be prepared 23 from the corresponding ester in two steps either by verting the alkyl ester a 26 pound into 27 ID and then oxidizing the latter compound to the 28 or 1 by oxidizing the alkyl ester 2 to the alkyl ester 3 which then is converted to the pyrazinamide The compounds which are substituted by that are 7 affected by oxidizing agents can be prepared by the 8 reaction of or an amine with the 9 ing esters which in turn are prepared from the oxazine 11 mediate as hereinbefore acid hydrazide acid hydrazide compounds correspond to the above described 15 generic structure where 2 is hydrazino 1 These compounds can be prepared by heating the 17 corresponding alkyl ester with conveniently at the 19 reflux 20 21 The 22 mediate is obtained by cyclization 23 of the appropriate for by heating with a mixture of acetic anhydride and triethyl 27 The intermediates 28 are prepared from 29 by a nucleophilic displacement reaction The chlorine atom is replaced readily by a variety 1 of nucleophilic reagents to give the corresponding 2 The mediates are obtained by replacing the 5 group with an This can be 6 for by dissolving sodium in the 7 adding the 8 pound and refluxing for a few 9 The are obtained 0 upon reaction of the 1 with 2 The or 3 derivatives are prepared by reaction of the with the corresponding 5 6 When the of V is or be 8 hydrogen or when the 9 stituent is or be 0 in order to obtain ring cleavage to 1 desired acid 2 in the next step under mild conditions such that 3 the remains unaffected under the k conditions Each of the reactions described for the 6 also can be accomplished starting with the 8 pteridinone As the details concerning the actual 2 reaction conditions are provided in the 3 the above references to the Plow Diagram are provided without further 6 The following examples are illustrative 7 of the methods by which the products of this invention can be prepared and are not to be 9 considered as limiting the invention to the 0 particular procedural conditions employed or 1 to the particular compounds prepared 2 All melting points are corrected 1 EXAMPLE 1 2 Methyl 3 A suspension of methyl and acid 5 in chloroform is stirred at room temperature until 6 solution is The reaction mixture is refluxed 7 one hour and then the solvent is recovered by distillation 8 under The resulting solid is stirred with warm 9 methanol and recovered by The yield 10 After 11 from acetonitrile the compound melts at 12 Analysis calculated for C II 6 7 3 3 13 EXAMPLE 2 1 Methyl 17 A suspension of methyl 18 and acid 19 in chloroform is stirred at room temperature 20 until a solution is obtained Then the mixture 21 is refluxed for one The solid that separates upon 22 cooling is recovered by the yield is 23 After crystallization from methanol the product melts 2k at 25 Calculated for 26 3 27 1 EXAMPLE 3 2 Methyl 3 A solution of methyl and acid 5 in chloroform refluxed for one hour 6 and then The solid that separates is recovered by filtration and recrystallized from etha to yield of methyl 9 10 Analysis calculated for 0 6 6 3 3 11 12 13 EXAMPLE Methyl 1 This compound is prepared by essentially the same 16 method described in Example except that the methyl 17 of Example 1 is replaced by an ular quantity of methyl 19 EXAMPLE 20 Methyl 21 This compound is prepared by essentially the same method described in Example except that the methyl 23 of Exaraple 1 is replaced by an ular quantity of methyl 920 1 EXAMPLE 6 2 Methyl e compound Is prepared by essentially the method described in Example 1 except that 5 the methyl of 1 is re 6 placed by an equimolecular quantity of methyl 7 8 EXAMPLE 7 9 Methyl 10 This compound is prepared by essentially 11 the same method described in Example lfl except that 12 the methyl 1 is 13 placed by an equimolecular quantity of methyl EXAMPLE 8 16 acid hydrazide Methyl oxide is added to a solution 19 of hydrazine In ethanol 20 and the reaction mixture is refluxed for hours 21 during which time the product The product 22 recovered from the chilled reaction mixture by 23 filtrationp washed with a small amount of cold and The yield is of 25 acid hydrazide 26 27 Analysis calculated for Poundi EXAMPLE 9 Methyl Preparation of ia suspended in aqueous methylamine and the mixture stirred vigorously for 20 hours at room The reaction mixture is filtered and the solid washed with water and dried yielding of which after recrystalllzatlon from ethanol melts at Analysis calculated for Step Preparation of chloropyrazinamide To a suspension of in chloroform added zoic acid and the reaction is refluxed for one Upon cooling solid separates which is washed with and This solid is talliz6d several times from ethanol to yield of zinamide 170 Analysis calculated for 3 Step Preparation of 5 pteridinone 6 To a mixture of triethyl orthoformate 7 and acetic anhydride is added 8 9 The resulting solution 10 refluxed for two the reaction mixture 11 then is and the product that separates 12 is removed by washed with ethyl 13 acetate and dried yielding teridinone Preparation o 16 17 To a solution of aqueous amine in is 19 added 20 and the resulting solution 21 is heated for hours on the steam The 22 reaction mixture then is cooled in an ice bath 23 whereupon a solid This product is separated by filtratione with cold methanol 25 dried yielding 26 pteridinone 92 Step Preparation of 2 pyrazlnolc acid 3 Sodium hydroxide and 5 are and then 6 with for hours on the steam 7 The reaction is cooled to room temperature and 8 then carefully neutralized with formic acid 9 upon the product recovered by 10 tion and to yield 11 aminopyrazinoic acid 12 Step Preparation of 13 15 A mixture of 16 pyrazinoic acid and acetic anhydride is stirred and heated 18 for hours on the steam The resulting 19 solution is chilled in an ice bath whereupon a 20 30lid This product is separated by 211 washed with cold ether and dried to yield 23 Step Preparation of Methyl is added to methanol and the solution is refluxed for solvent is removed under vacuum and the residue is stirred with for minutes at room The cooled action is carefully neutralized with sodium d and the product which separates is recovered by filtration and EXAMPLE 10 Methyl Step Ai Preparation of pteridinone Sodium is solved in methanol and teridinone from Example Step is added to the which is then refluxed for Water is added to the cooled reaction mixture which then is fied with dilute hydrochloric whereupon the product The product is ized from aqueous Step Preparation of acid Sodium hydroxide 10 and are mixed and then stirrings 1 for hours on the steam The reaction 2 is cooled to room temperature and then carefully 3 neutralized with forraic acid whereupon the product recovered by filtration and 5 to yield acid 6 Step Preparation of 7 A mixture of 9 acid and acetic 10 dride is stirred and heated for hours 11 on the steam The resulting solution is 12 chilled in an ice bath whereupon a solid 13 This product Is separated by with cold ether and dried to 1 16 Step Preparation of Methyl pyrazinoate 18 The 19 is 20 added to methanol and solution is 21 refluxed for The solvent is removed 22 under vacuum and the residue is stirred with HC1 for at room The cooled reaction is carefully neutralized with 25 sodium and the product which 26 arates is recovered by filtration and 20 1 EXAMPLE 11 2 Methyl 3 Preparation of Methyl 300 5 added to 2 liters of concentrated a 6 hydroxide solution and the stirred 16 hours at room The solid product formed 8 is collected by filtration and dried yielding 260 9 of 231 232 0 Analysis Calculated for 3 Step Preparation of To a suspension of 6 amide in chloroform is 7 added acid and the reaction mixture is refluxed for 1 Upon cooling a solid separates which is 0 washed with and This solid is 1 tallized several times from ethanol to yield the 2 purified 3 Step Preparation of 5 A mixture of acetic anhydride 7 and ethyl is refluxed The is cooled and the product which precipitates is collected and recrystallized 0 from aqueous to give 1 pteridine 1 Step Preparation of 2 pteridine 3 A solution of and benzyl raercaptan in sodium hydroxide solution 6 is heated 30 minutes on the steam The solution is cooled end sodium hydroxide 8 solution is added to precipitate the 9 sodium salt of the The salt is 10 dissolved in of hot and the solution 11 is acidified to precipitate the product which is 1 recrystallized from aqueous to give Ste Preparation of pyrazinoic acid 16 A solution of topteridine in 18 sodium hydroxide solution is heated 8 19 hours on the steam The solution is chilled 20 to precipitate the sodium salt of the 21 The salt is dissolved in hot water and the 22 tion acidified to precipitate 23 mercaptopyrazinoic acid Step Ft 26 A solution of pyrazinoic acid in 28 acetic anhydride is heated 5 hours on the 29 steam Volatile materials are distilled vacuo and the residue is recrystallized 1 benzene to give 2 3 Step Preparation of Methyl 6 7 added to methanol and solution is refluxed for The solvent is under 9 vacuum and the residue is stirred IN 0 for minutes at The 1 reaction is carefully neutralized with and the product which separates is 3 covered by filtration and EXAMPLE 12 Methyl Step Preparation o teridlne Methyl mercaptan is 9 dissolved in a sodiura hydroxide solution i 0 and added to a solution of 1 from Example Step 2 in a sodium hydroxide solution The resulting solution is heated 20 minutes on the then chilled to precipitate the sodium salt of the The salt is collecteds dissolved 6 in hot water and the solution acidified to precipitate the product is recrystallized from aqueous to yield 9 Step Preparation of Methyl 2 sul 3 The added to methanol and the solution 6 for The solvent is removed under vacuum and the residue is stirred with 8 HCl for minutes at room 9 The cooled reaction is carefully neutralized with 10 sodium and the product which 11 ates is recovered by filtration and 12 the above examples describe the 13 preparation of certain compounds which are trative of the novel compounds of this 15 it is to be understood that the invention is not 16 to be limited to the specific compounds described 17 in the examples or by the specific reaction ditione described for the preparation of these but is to be understood to embrace 20 variations and modifications thereof fall within the scope of the appended insufficientOCRQuality

Claims (1)

1. 26 O acid compounds of t e formulas wherein is lo phenyl optionally substituted by or and 2 is or Kethyl Methyl laminopyraslnoate acid acid acid de acid hydrazine acid compounds according to Claim substantially as described herein with reference to the A process Claim 13 or the starting material an and end product la the corresponding chloropyrazinamide A process for the preparation o acid according to Claim 1 having the formula 0 has the same meaning as in wherein a compound of formula B in Qlsdm 13 in which is alkoxy A for the preparation of acid according to Claim 1 having the formula in which X is lower lower mercapto or wherein a pyrazinamide compound of the formula o 6 in which X is chlorine or bromine and is hydrogen or is subjected to ring closure to form a of the formula this letter subjected to a nucleophyiic reaction the chlorine or bromine atom by one of the aforesaid and the of the formula obtained is subjected to with the proviso i that where the X in the end product of is to be a lower or the group in the starting compound of formula must be lower process according to Claim wherein the ring closure in the compound of ef by heating the latter with a mixture of acetic anhydride and triethyl A process according to Claim wherein the cleavage of the compound of formul to form a compound formula VIb is effected b reaction with dilute alkali b A process according to Claim wherein a lower a a or is used the nucleophyiic 31 A process according Claim wherein the acid anhydride of is or trifluoroacetie anhydride or an acid anhydride such as acid process according to Claim 24 or wherein acetic anhydride is reacted with acid to yield ox and the latter is reacted with a lower process according to Claim 24 or wherein acetic anhydride is reacted with acid to yield and the latter reacted with a lower A process according to Claim 24 or wherein acetic anhydride reacted with a acid oxide of formula in Claim 19 yield a of fonaula in Claim wherein is or and the latter reacted with a lower A process for the preparation of alk pyrazinoate Compounds according to 1 of the formula wherein a corresponding acid of formula in Claim in I which X is as defined in Claim 19 and is reacted with 32 mixture of formic acid and acetic anhydride to form a cos und of formula VII in Claim 24 in 5 is and the latter compound reacted an A process for the preparation of acid of the formula in 1 which X has same meaning as Claim 1 and 2 wherein a corresponding alkyl ester of the ormula is reacted with A process for preparation of pyrazinamide compounds according to Claim 1 of the 0 in which has the same meaning as in Claims 19 and 23 and is hydrogen or lower wherein a corresponding alkyl amino of in 24 is reacted with ammonia or an Processes the preparation of acid compounds according to substantially as described herein with reference to the For the Applicants insufficientOCRQuality