United States Patent 119 Morwick et al. (4) (75) (73) Ry by (63) (uy (2) ba} (56) PROCESS FOR REMOVING SULFONYL GROUPS FROM BENZIMIDAZOLE ISOMERS Inventors: Tina M, Morwick, Beech Grove; James H. Wikel, Greenwood, both of Ina. Assignee: Eli Lilly and Company, Indianapolis, Ind, Appl. Nos 477,876 led: “Mar, 21, 1983, Related U.S. Application Data Continuation-in-part of Ser. No. 366,759, Apr. 8, 1982, abandoned. Int, CL COT 235/30 US. . ven $48/306 Field of Search swe 542/429, 467; 548/306 References Cited U.S. PATENT DOCUMENTS 3,825,837 7/1974 Haugwitz ota 260/243 4,008,243 2/1977 Wike! et a oe $48/306 4,018,790 4/1977 Paget et al OI sa97306 4,118,573 10/1978, 548/306 MIB 742 10/1978. Paget etal 48/906 41150028 4/1979. Paget etal 3260/3067 T 4.174484 11/1979. Paget etal 548/306 4,196,125 4/1980 Paget etal sats 4216313 8/1980 Paget etal 544/35 4,230,868 10/1980 Paget etal 48306 Patent Number: Date of Patent: my las} 4,463,181 Jul. 31, 1984 OTHER PUBLICATIONS Sidgwick, The Organic Chemistry of Nitrogen, (1966) p. 251 Smith, The Chemistry of Open-Chain Organic Nitrogen ‘Compounds, vol. 1, (1968) pp. 188-189. Wright, Chem. Reviews, 48, 486-487 (1951), Price, et al. “Some Sulfonamide Derivatives of 2- Aminobenzimidazole.” J. Org. Chem. 12, 269-274 (1947). Primary Examiner—Robert W. Ramsuer Attorney, Agent, or Firm—Karen B. Dow; Arthut R. Whale (7 ABSTRACT This invention discloses a process for removing a sulfo- nyl group from the L-position of a benzimidazole to allow conversion of 2-amino-,5-substituted-ben- zimidazole compounds into 2-amino-1,6-substituted- benzimidazole compounds. The S-isomer is reacted with an alkali metal hydroxide or carbonate in an inert aqueous organic solvent system. The reaction is acidi- fied to precipitate the base and form the intermediate benzimidazole tautomer. The intermediate is then re- acted with a sulfonyl acylating agent or a haloalkyl isothiocyanate to form a mixture of 2-amino-1,5(6)-sub- stituted-benzimidazole compounds. This invention also discloses the same process for removing a sulfonyl group from the I-position of a benzimidazole to allow conversion of 2-amino-1,6-substituted-benzimidazole ‘compounds into 2-amino-1,5-substituted-benzimidazole ‘compounds. 9c 1, No Drawings4,463,181 a PROCESS FOR REMOVING SULFONYL GROUPS FROM BENZIMIDAZOLE ISOMERS CROSS REFERENCE TO RELATED ‘APPLICATIONS, ‘This is a continuation-in-part of application Ser. No. 366,759, filed Apr. 8, 1982 now abandoned. BACKGROUND OF THE INVENTION This invention describes a process for removing a sulfonyl group from the I-position of a benzimidazole to allow conversion of the 5-isomer into the 6-isomer and, ‘also conversion of the 6-isomer into the S-isomer. 2-Amino-1,5(6)-substituted-benzimidazole _com- pounds inhibit the growth of certain viruses, such as thinoviruses, polio (types I, II, III, Coxsackie (A9, ‘All, BS), echo virus (strains 1, 2, 3, 4), and Mengo ‘virus. Although both the 5- and 6-isomers are useful as antiviral agents, ‘the 6-substituted-2-amino-ben- imidazole is generally the more active isomer. Certain ‘sulfonylbenzimidazole compounds are dis- closed in U.S. Pat. Nos. 4,118,742 and 4,174,454, The preparation of these reference compounds follows the methods disclosed in U.S. Pat. Nos. 4,018,790 and 4,118,573. Both of these patents reveal the reaction of a benzimidazole compound and a sulfonyl chloride com- pound in an organic solvent in the presence of a base. Thiazolinyl and thiaziny! benzimidazole compounds are prepared by the reaction of a I-unsubstituted-ben- imidazole with a haloalkyl isothiocyanate in an organic solvent in the presence of a base, as described in U.S. Pat. Nos. 4,008,243 and 4,150,028. The references also discuss the compounds use as antiviral agents. In Chemical Reviews, 48, 397-541 (1951), John B. Wright reports the imidazole ring of benzimidazole compounds is cleaved by an acid halide and water, forming a diamine compound, Charles Price and Robert Reitsema in “Some Sulfon- amide Derivatives of 2-Aminobenzimidazole,” Journal of Organic Chemistry, 12, 269-274 (1947) describe the formation of 2-aminobenzimidazole-3-nitrobenzenesul- fonate by treating 1-G-nitrophenylsulfonyl)-2- aminobenzimidazole with sodium hydroxide and acetic acid, SUMMARY OF THE INVENTION ‘This invention concerns a process for removing a sulfonyl group from the L-position of a benzimidazole 10 allow conversion of » 2-amino-1,5-substituted-ben- zimidazole compounds into a mixture of S- and 6-sub- stituted isomers, from which the preferred 6.isomer is recovered. The S-isomer also formed then can be recy- cled through this process to form more 5- and 6-iso- ‘mers. This invention also discloses the same process for removing a sulfonyl group from the I-position of a benzimidazole to allow conversion of the 6-isomer into the S-isomer. ‘A benzimidazole compound of the formula O S02 i 0 38 0 4 2 is reacted with an alkali metal hydroxide or carbonate in an inert aqueous organic solvent at a temperature from about 20° C. to about 100" C. to form a tautomeric benzimidazole of the formula II, s a Ore w “The tautomer (11) then can be reacted with a sulfonyl halide or a haloalkyl isothiocyanate to forma mixture of the S- and 6-isomers. In particular, the S-isomer compound of the formula, Ob ccan be reacted to form the tautomeric benzimidazole of the formula Il ‘Another aspect of this invention is removing a sulfo- yl group from the I-position of a benzimidazole to allow conversion of 2-amino-1,6-substituted-ben- zimidazole compounds into 2-amino-1,5-substituted- ‘benzimidazole compounds. The 6-isomer compound of | the formula 111 so m i is reacted in the same manner as the 5-isomer to form the tautomeric benzimidazole of the formula TL DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS ‘This invention discloses a process for removing a sulfonyl group from the I-position of a benzimidazole to allow conversion of 2-amino-1,5-substituted-ben- Zimidazole compounds into a miature of 5- and 6-sub- stituted isomers, form which the preferred 6-isomer is recovered. The $.isomer also formed then can be recy- cled through this process to form more S-and 6-isomers, This invention also discloses the same process for re- moving a sulfonyl group from the 1-position of a benz~ imidazole to allow conversion of the 6-isomer into the S-isomer, ‘The 5- and 6-isomer can be represented by formula 0 RsOp +4,463,181 3 A. L-substituted-2-amino-5-substituted-benzimidazole of the formula I 0 isettd with an aalmetalyeoxide or cron in thine aqucus rare even tem forma ate ier baimiecle oe format s 1 t LE Leen ® N 20 The taiomer I hen can be reacted with salon bale ofthe rina RISO or ala solo), anate of the formula X(CHz),NCS, optionally substi- tuted on the carbon chain with RS; to form a mixture of 5- and 6-isomers. ‘The desired 2-amino-1,6-substituted- benzimidazole is of the formula IV. x e w ‘ Sen ® A I-substituted-2-amino-6-substituted-benzimidazole 4. of the formula ITT Rs: a it \* ® pen “ N \ is reacted with an alkali metal hydroxide or carbonate in 50 an inert aqueous organic solvent system to form a tauto- meric benzimidazole of the formula II. N55 . Doe ‘The tautomer (I1) the can be reacted with a sulfonyl halide ofthe formula R'SO3X, or a haloalky isothiocy- amate of the formula X(CHa)yNCS, optionally substi- tuted on the carbon chain with RS; 10 form a minture of os 5- and 6-isomers. The desired 2-amino- of the formula V. ,S-substituted-benzimidazole is In the above formulas: Ris C)-Csalkyl, Ca-Cy cycloalkyl, furyl, or thienyl; Rlis C-Csalkyl, Cy-cr cycloalkyl, phenyl, furyl, oF thienyl; Ris RISO3 or 4 alkyl, C}-Cy alkoxy, halo, nitro, C1-Cs alkylthio, phenylthio; phenoxy, carboxy, methylsul- fonyl, trifluoromethyl, a Ré is hydrogen, C)-Cy alkyl, C3-C cycloalkyl (Cs-Cr eycloalky!)methy!, 14{Cs-Cr eycloalky!)-ethy, thienyl, benzyl, phenyl, or mono-substtuted phenyl Wherein seid phenyl substituent is selected from the group consisting of C)-Ce alkyl, C1-C¢ alkoxy, chloro, bromo, iodo, nitro, and trifluoromethyl; RS is hydrogen, C1-Cs alkyl, benzyl, or phenyl; RO is hydrogen, Cj-Cr alkyl, Cs-Cy_ cycloalkyl, (Cs-Cy eyeloalkyDmethyl, 14(C)-Cy eycloalky)ethyh, phenyl, or mono-substituted phenyl, wherein. said Phenyl substituent is selected from the group consisting Of C}-Ce alkyl, Cj-Cé alkoxy, chloro, bromo, iodo, nitro, and trifluoromethyl; RY and R¥ independently are hydrogen, halo, cyano, hydroxymethyl, nitro, Om r S—Ci-Cuathy, CHR, COR, phenyl or mono-substituted phenyl, wherein said phenyl substituent is selected from the group consisting of C}~Cs alkyl, Cj-Cs alkoxy, chloro, bromo, iodo, nitro, and trifluoromethyl B9is hydroxy, Cy-Cy alkony, halo, C3-Ce eycloalky! C1-Cy alkoxy, or (O—C}-Ce alkyl)y NR!OR! wherein RI and Ril independently are hydrogen or C1-Ce alkyl Z is oxygen, C1-Cralkylidene, oF C1-Cyalkosyimino; X is chloro or bromo; Y is hydrogen, and W is hydroxy, or together Y and W form a bond; MC is an alkali metal cation or @ hydronium ion; mis0, 1, oF 2; nis 2or3; and