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Patented Nov. 5, 1946 2,416,431 UNITED STATES PATENT OFFICE , 2,410,431 ALKYL MERCAPTO SUBSTITUTED AMINO BENZOICACID ALKAMINE AMIDES, SALTS, ‘INTERMEDIATES; AND PROCESS OF PRE ' PARING SAME John J. Donleavy, Montclair, N. J., assignor to Allied Laboratories, Inc., Kansas City, M0. N0 Drawing. ‘Application April 24, 1943, Serial No. 484,472 5 Claims. (01. 260—558)' 1 2 This invention relates to a newly discovered group of organic compounds which have a local anesthetic action similar to :.cocaine or procaine and‘ the like. This'application is a continuation-in-part'of to a certain point produce intermediates but thereafter the processes are changed herein and there are produced amides having the advantages before mentioned over the esters produced by the process of that co-pending disclosure. By way of explanation only it is stated that common to the Patent No. 2,173,827, and the co the co-pending application Serial‘ No. 282,352 ?led January 1, 1939‘(now Patent No. 2,321,468), and ‘entitled Alkyl thio substitutedv amino ben‘zoic acid alkamine esters, salts,‘ intermediate and‘ pending application disclosure, now Patent No. 2,321,468, and the instant application all the process of preparing same, in turn a continua products include the introduction of an alkyl tion-in-partof Patent No. 2,173,827, dated Sep meroapto group into molecules previously known tember 26, 1939. ' to have some anesthetic power, but such intro duction in the products of the co-pending appli The chief object of this invention is to prepare _a compound which has local anesthetic proper cation disclosure, now'Patent No. 2,321,468, were ties equal or greater than that of cocaine, etc, 15 more desirable for reasons stated therein over the products of the earlier patent and in comparable and which has a toxicity equal to or less than that of the last mentionedproducts, the anes manner the products of the instant disclosure thetic property of the present newly discovered (the amides, etc.) are more desirable than the organic compounds being of local character. esters, eta, set forth in the copending application, Speci?cally the products are amides and com 20 now Patent No. 2,321,468. parable to the esters of the application herein The formula of this subsequent speci?c. dis before referred 'to and now allowed. closure is set forth as follows for one compound of one series of compounds: An amide of the examples’ hereinafter men tioned was found to have approximately four times the anesthetic power of cocaine although 25 only having a toxicity equal to that of cocaine and to that extent this amide is more suitable for anesthetic purposes-than the esters of the co-pending application, which included an ex ample that showed only twice the anesthetic 30 power of cocaine for the best comparable ester , ,In the series of compounds, the CONI-ICHzCI-IzN' product. The products herein of amide char-, (C2H5)2 may vary in position and the SC2H5 may acter have the general, form expressed algebrai vary in position relative to each other and, the cally as follows: position of NI-Ia. Also in place of (CzHs), wher RfSCsI-Ia (NI-I2) CONH(CH2) INR' 'R’”, wherein 35 ever the same appears, other alkyl groups may R’ is an alkyl radical, R," is an alkyl radical and be substituted therefor. One example of the R’” is an alkyl radical and r is an integer greater species group represented by the preceding dia than the unity and less than 4. In certain in gram is: stances R," and R'” may be combined in the form of a polymethylene chain, for examplethe group 40 Dialkylaminoealkyl amides of 3-dmino-4-dlkyl mercaptol-benzoic acids NR"R”' may be the piperidyl radical. ‘ Broadly speaking, the product is an amide of As representatives of this type there have been an aromatic acid and a dialkyl amino alkyl prepared the beta-diethylaminoalkyl amide of 3 amine, or is a salt thereof. , Inasmuch as the aforementioned allowed ap amino - .4 - methylmercaptobenzoic, 45 plication, now. Patent. No. 2,321,468, dated Sep tember 26, 1939; fully and accurately sets forth in considerable detail the highly desirable charac 3 - amino-4 ethylmercaptobenzoic andv 3-amino-4-propylmer captobenzoic acids. , A convenient method of preparing compounds of this type depends on they discovery that the teristics of the general class of products to which that disclosure and the instant disclosure is di rected, no further description or explanation is believed necessary. It may be here brie?y stated that the ?rst two products being the corresponding derivatives of processes set forth in the copending application, - 3-nitro~4-alkylmercaptobenzoic chlorine atom of derivatives of 3-nitrochloro 'benzoic acid such as its salts, esters’ and amides can readily be replaced by an alkylmercapto group by treatment with a metal mercaptide, the acids. > Subse as originally ?led, are processes which followed 55 quently the nitro group'may be converted to an 2,410,431 ' 5 acid, B. P. 180° C. at 4 mm.; the methyl ester of 3-amino-4-n-propylmercaptobenzoic acid, B. P. 182° at 5 mm.; the corresponding beta-diethyl aminoetliyl amide dihydrochlorides M. P. 149 151° C. and 145-149" C. respectively: in both cases the free amides were again oils, which did not crystallize. Method II 6 While the invention has been described in great detail in the foregoing speci?cations the same is to be considered as illustrative only of the general claims and not restrictive in char acter. Modi?cations here-of comparable to those disclosed in the earlier Patent No. 2,173,827, as well as in the co-pending application, now Pat ent No. 2,321,468, as well as others which will readily suggest themselves to persons skilled in A solution of 2.1 grams of the methyl ester of 10 this art, are to be considered as within the scope 3-nitro-¢l-ch1oro-benzoic acid in 30 cc. of 95% a1 of this invention, reference being had to the ap cohol was heated to boiling and added to a boil ing solution of sodium methyl mercaptide, pre pared by bubbling one gram of methyl mercaptan pended claims ior the de?nition thereof. The present disclosure is intended as a basic disclosure of basic compounds previously de slowly into a solution of 0.4 gram of sodium hy . scribed and the related compounds which differ droxide in a mixture of 3 cc. of water and 30 cc. in the position of the groups in the benzene ring. of 95% alcohol. The total mixture was boiled Herein the general disclosure 'is directed to under re?ux for thirty minutes. The solvent was compounds comprising as a Markush group the then removed by distillation under diminished pressure and the solid residue was washed with 2-0 amides and the acid addition compounds of said amides and wherein said amides have the gen 15 cc. of water containing a drop of hydrochloric eral formula, R’S (NI-I2) CeI-Is CONH (CI-12M NR" acid. The product, the methyl ester of 3-m'troJl R" where x is an integer greater than unity methylmercaptobenzoic acid, was purified by re and less than four and R’, R” and R’” represent crystallization from methyl alcohol. Further procedure following this method is identical with that applied to the same compound alkyl radicals of like or unlike character. The invention claimed is: 1. An organic compound having the formula in Method I. Method II, therefore, is an alter para-R’S-meta-NI-IzCeHaCONH(CH2) eNR' 'R' ' ’ native method of preparing the intermediate. In connection with the beta-diethylaminoethyl where a: is an integer greater than one and less amide of 3-amino~4-ethylmercaptobenzoic acid than four and R’, R" and R’” represent alkyl used for the production of the dihydrochloride in 30 radicals containing not more than six carbon a similar manner as before mentioned, same pro atoms. duced the corresponding dihydrochloride wherein 2. IS-Diethylaminoethyl amide of 3-amino-4 the actual nitrogen yield was 11.36% compared (n-propylmercapto) benzoic acid. with the theoretical nitrogen yield of 11.44% and 3. p-Diethylaminoethyl amide of 3-amino-4 the ionizable chlorine found was 18.80% as com pared to the calculated amount of 19.07%. The beta~diethylaminoethyl amide of 3-amino li-N-propylmercaptobenzoic acid when used to prepare the dihydrochloride thereof in a compa rable manner produced a product which upon analysis was found to contain nitrogen in the amount of 11.09%, whereas the theoretical nitro gen content was 11.02%. (ethylmercapto) benzoic acid. 4. p-Diethylaminoethyl amide of 3-amino-4 (methylmercapto) benzoic acid. 5. The method of preparing a 3-nitro-4-(alkyl mercaptolbenzoic acid by heating a sodium mer captide and the sodium salt of a 3-nitro-4 chlorobenzoic acid in aqueous alcohol solution. JOHN J.v DONLEAVY.