PROCESS FOR MAKING BENZIMIDAZOLES

Abstract: Method for making 5-membered ring compounds con­ taining N, O or S atoms by reacting certain (thio)cyanate or cyanamide salts with compounds having NH₂, OH or SH functionality vicinal to an -NH₂ group, in the presence of an acid except where said cyanate is an ammonium salt.

Description: PROCESS FOR MAKING 5-MEMBERED HETEROCYCLICS This invention relates to a method for making 5-membered ring compounds containing N, O or S atoms by reacting certain (thio)cyanate salts or cyanamide salts with compounds having NH2, OH or SH functionality vicinal to an -NH2 group, in the presence of an acid except where said cyanate, thiocyanate or cyanamide is an ammonium salt. The following references are of interest: 1. Org. Syn. Col. Vol. IV, p. 180 which discloses a process for preparing a thiourea from an amine HC1 and ammonium thiocyanate. 2. U.S. patent 3,455,948, Stedman, July 15, 1969, particularly the preparation of a thiourea in Example 7. 3. EPO 0-005-276, Nov. 14, 1979, Hoechst AG, describing preparation of a thiourea. 4. Heterocyclic Compounds, Vol. 5, Elderfield, p. 285, disclosing preparation of 2-mercaptobenzimidazoles, etc. 5. Thiourea, D.C. Schroeder, Chem. Rev. Vol. 55, pp. 181-228, which contains a review of thiourea chemistry. 6. EPO 0-012-933, July 9, 1980, Hoechst AG, disclosing production of amino-benzimidazqlone. In one aspect the invention is concerned with a one step process for the preparation of such compounds as 2-hydroxy, 2-amino or 2-mercapto benzimidazoles, benzothiazoles, benzoxazoles, imidazoles, thiazoles or oxazoles by reacting such materials as o-phenylenediamines, o-aminothiophenols, o-aminophenols, 1,2-aminoalcohols or the like with an inorganic cyanate, thiocyanate or cyanamide. An acid is used with the cyanate, thiocyanate or cyanamide in those cases where the anion is not the ammonium ion. The reaction is run in an organic solvent which enables removal of impurities and color by extracting the product into aqueous sodium hydroxide as its sodium salt and then precipitating the product from the aqueous phase with acid. In accordance with the present state of the prior art 2-mercaptobenzimidazole is prepared by reacting o-phenylenediamines with carbon disulfide. This reaction generates one mole of highly toxic hydrogen sulfide per mole of product and this hydrogen sulfide must be disposed of. In the process of this invention only a trace of hydrogen sulfide is formed, while the or joy by-product is ammonia. The invention may accordingly be characterized as a process for making a 5-membered heterocyclic compound having the structural formula EMI2.1 wherein n is 1 or zero, X is oxygen, sulfur or NR5; Y is oxygen, NH or sulfur; and if n is 1, R1, R2, R3, R4 and R5 may be the same or different and are hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, C6-C10 aryl, C7-Cg alkaryl or C7-Cg aralkyl, or R and R to- gether form a polymethylene group having 3 to 6 carbon atoms; and if n is 0, R1 and R4 together with the carbon atoms to which they are attached form a benzene ring or a benzene ring substituted with C1-C alkyl, by reacting a compound having the structural formula, ZYCN(II), wherein Z is an alkali metal or ammonium moiety, and Y is as defined above, with a compound having the structural formula EMI2.2 wherein n, R1, R2, R3, R4 and X have the meanings above; in the presence of a solvent and, except when Z is NH4, in the presence of an acid. The process of the invention is of particular interest ps allowing production of such useful compounds as antioxidants (e.g., 2-mercapto-benzimidazole) at high yields and purity, at low cost and essentially without hydrogen sulfide by-product. One preferred practice of the invention may be outlined as follows: To a suitable reaction vessel equipped with agitation and temperature determining means, as well as with condensing means, are added the solvent (e.g., water, C1-C10 alcohol, C6-C10 alkane, C6-C8 cycloalkane, benzene, toluene, xylene and the like), the ZYCN compound (e.g. ammonium or alkali metal cyanate, thiocyanate or cyanamide) and the vicinally functional compound (e.g., oarylenediamine, o-aminophenol, o-aminothiophenol, 1,2-diaminoalkanes, 1-aminoalkane-2-thiol, 1-aminoalkane-2-ol etc.) at essentially stoichiometric amounts. If the ZYCN compound is not an ammonium salt, an about equimolar (to the cyanate compound) amount of acid (usually mineral acid such as HC1, H2SO9, etc.) is charged, and, while agitating, the reaction mixture is heated to about 90-2000C for about 2 to 8 hours. After completion of the reaction, the reaction mixture is treated with aqueous caustic. The aqueous layer is separated and it is neutralized with acid. The precipitate (product) is removed by filtration. In those cases where the product is water soluble, the water is stripped off, and the solid residue is recrystallized from an appropriate solvent such as chloroform. In many cases the preferred solvent for the reaction is a C4-C8 alkanol or xylene. The concentration of reactants in the solvent is usually within the range of about 200 or less to about 900 or more g/l, preferably about 400 to about 700, more preferably about 600. Reaction temperatures are ordinarily within the range of about 110 to about 200"C or more, depending on the particular reactants, preferably about 1400 to about 180"C, more preferably from about 140 to about 1600. Reaction times within the range of from about 2 hours or less to about 12 hours or more, preferably about 4 to about 8 hours, more preferably about 6 hours. The reaction may be carried out at any desired pressure, usually atmospheric, although sub-atmospheric or superatmospheric pressure (e.g. 10 atmospheres or more) may be used if desired. Valuable products which may be prepared by the method of the invention include but are not limited to 2-mercapto-4 ,4,5, 5-tetrahexyloxazoline 4,5 -dimethyl - 2-mercaptothiazoline 2-mercapto-N,4, 5-trimethylimidazoline 2-mercapto-4-methyloxazoline 2-mercapto- 5-methyloxazoline 4-ethyl-2-mercaptothiazoline 5-ethyl-2-mercaptothiazoline 1-hexyl-2-mercapto-4-propylimidazoline 1 -hexyl -2-mercapto-5 -propylimidazoline 4-butyl-2-mercaptooxazoline 5-butyl-2-mercaptooxazoline 2-mercapto-4-pentylthiazoline 2-mercapto-5-pentylthiazoline N-cycloh exyl-4-hexyl-2-mercaptoimidazoline N - cycloh exyl -5 -hexyl- 2-mercaptoimidazoline 4-cyclopentyl-2-hydroxyoxazoline 5-cy clopentyl-2-hydroxyoxazoline 4-cyclohexyl- 2-hydroxythiazoline 5-cyclohexyl- 2- hydroxythiazoline 2-hydroxy-N - , 5-triphenylimidazoline 2-hydroxy-4-naphthyloxazoline 2-hydroxy-5-naphthyloxazoline 4-benzyl-2-hydroxy -5-phenylthiazoline 5-benzyl-2-hydroxy -4 -phenylthiazoline 1-benzyl-2-hydroxy -4-tolylimidazoline 1-benzyl-2-hydroxy -5-tolylimidazoline 2-hydroxy-l -thia-3-azabicyclo [3.3.0]oct-2-ene 1 , 3-diaza-2-hydroxy-1-tolylbicyclo [3.4.0] non-2-ene 2-hy droxy -4 -isopropylphenyloxazoline 2-hydroxy-5-isopropylphenyloxazoline butyl-2-mercaptobenzoxazole methyl-2-hydroxybenzothiazole 2-mercapto-1-phenylpropylimidazoline 2-hydroxy-4-cumyloxazoline 2-aminobenzothiazole 2-aminobenzoxazole 2-aminobenzimidazole In one preferred practice of the invention the solvent is selected from C4-C8 alkanol and xylene, the reaction temperature is from 1400 to 1800C and the reaction time is from 4 to 8 hours. Particularly preferred solvents are hexanol and 2-ethylhexanol. Of particular interest is a process including the following product purification steps: (a) Extraction of product from the organic phase with aqueous caustic; (b) Neutralizing the caustic solution from (a) with acid; (c) Isolating the product from step (b) by filtration. Preferably, prior to step (b), the mixture of product in hot aqueous caustic is treated with charcoal in order to remove impurities. The following examples will serve to illustrate the practice of the invention in more detail. Example 1 Preparation of 2-Mercapto-4(5)-methylbenzimidazole To a one liter round-bottom, three-necked flask equipped with an agitator, a thermometer, a reflux condenser and a Stark and Dean trap were added 122 g (1.0 mole) ortho-toluenediamine (mixture of 34% 2,3-toluenediamine, 63% 3,4-toluenediamine, 2% other isomers and 1% water), 244 g 2-ethylhexanol and 145.2 g 50% aqueous ammonium thiocyanate. The mixture was heated to reflux (ca. 1640C), and the water was azeotroped out for about one hour. The reaction mixture was kept at 1640C for 6 hours. The mixture was cooled to about 1000C, and 41 g of solid sodium hydroxide in 500 ml of water was added while stirring. The mixture was transferred to a separating funnel, and the aqueous layer was removed. The alcohol layer was washed with 500 ml of water, and the water drawn off. The combined water layers were neutralized with acid and the title product was removed by filtration and dried. Example 2 PrSparation of 2-Mercapto-4(5)-methylbenzimidazole To a two-liter, three-necked round bottom flask equipped with a thermometer, agitator, dropping funnel nd a Stark and Dean trap with condenser were added 122 g (1.0 mol) o-toluenediamine, 81 g (1.0 mol) sodium thiocyanate and 500 ml n-hexanol. While stirring, 84 ml concentrated hydrochloric acid was added, and the mixture was then heated to 1600C. The water present was azeotroped out of the flask during said heating period (ca. 1 hour). The mixture was refluxed (ca. 1600C) for five hours and then no further heat was applied. 170 ml of 6N sodium hydroxide (diluted to 250 ml) was slowly added to the reaction mixture which continued to reflux. After cooling the aqueous layer was removed and neutralized. A small amount (ca. 8 g) of a white solid was isolated by filtration. The hexanol portion was treated with about two liters of water. This aqueous portion was acidified causing a white solid product to precipitate. The product was isolated by filtration and dried. Total product yield was 159.5 g (97.3% of theory). Examples 3-16 Following essentially the procedures of Examples 1 and 2 respectively, additional preparations were undertaken using various reactants, solvents and process conditions, all summarized in Table I. In examples 3-6 and 9-14 the product is 2-mercapto-4(5)-methylbenzimidazole. In Example 7 the product is 2-hydroxybenzoxazole. In Example 8 the product is 2-hydroxyimidazoline. In Example 15 the product is 2-mercaptobenzimidazole. In Example 16 the product is 2-mercaptobenzothiazole. The results demonstrate the usefulness of the process of this invention for the preparation of 5-membered heterocyclic chemicals in an easy and efficient manner. Example 17 To a 2-liter Hastalloy (trademark) autoclave were added 122 g o-toluenediamine, 76 g ammonium thiocyanate and 600 ml water. The mixture was heated at 1500C for 8 hours (pressure ca. 570 kPa), after which time it was washed with ca. 300 ml methanol. The methanol was then removed from the mixture by distillation. To the remaining portion of that mixture was added 170 ml sodium hydroxide (6N), and the total volume of the mixture was increased to two liters by the addition of water. The resultant mixture was shaken with 150 ml hexanol. The water layer was removed from the mixture and neutralized with sulfuric acid (6N) which caused precipitation of the product, 2-mercapto-4(5)-methylbenzimidazole. The product was filtered out and dried. Yield: 67 g (41%). EXAMPLE 18 Preparation of 2-Aminobenzimidazole Using the same equipment as described in Example 1, 183 g 2-ethylhexanol, 122 g o-toluenediamine, 64 g sodium cyanamide and 84.3 ml concentrated HC1 were placed into the reactor. While heating the mixtures to 1640C the water was azeotroped off 1 and then the reaction mixture was kept at 1640C for 5 hours. The mixture was cooled to room temperature. The title product was extracted from the solvent with aqueous acid followed by neutralization which caused crystallization of the product. The product was isolated by filtration. TABLE I Example 3 4 5 6 7 8 9 TDA(1), mol 1 1 1 1 - - 1 pDA(2), mol - - - - - - - APO(3), mol - - - mol 1 ATP(4), mol - - - - - - - EDO(5), mol - - - - - 1 XSCN, mole 1 1 1 1 1 1 1 X of XYCN K Na Na Na Na Na Na Y of XWCN S S S S O O S Acid: Hcl, mol 1 - 1 1 1 1 Acid: H2S04, mcl - 1 - - - - 1 Solvent H2O hexanol xylene hexanol 2EH(6) 2EH NBU(7) Solvent, ml 400 150 500 220 220 220 500 Reaction temp., Or 150 147 135 162 164 164 115 Reaction time, hrs. 6 19 4 5.5 5 5 8 Yield, g 83 150 125 162 56 38 106 Yield, %(8) 51 92 76 99 42 45 65 TABLE I (continued) Example 10 11 12 13 14 15 16 TDA(1), mol 1 1 1 1 1 - PDA (2), mol - - - - - 1 APO(3), mol - - - - - - - ATP(4), mol - - - - - - 1 EDo(5), mol - - - - - - XSCN, mole 1 1 1 1 1 1 1 X of XYCN NH4 NH4 NH4 NH4 NH4 NH4 NH4 Y of XYCN S S S S S S S Acid: Hcl, mol - - - - - - - Acid: H2SO4, mol. - - - .- - - - Solvent 2EH NBU hexanol xylene decanol 2EH 2EH Solvent, ml 222 400 220 400 170 220 150 Reaction temp., C 164 117 160 130 164 164 164 Reaction time, hrs. 6 7 6 6 6 5 5 Yield, g 152 123 152 132 130 128 Yield, %(8) 93 75 93 81 79 85 29 Remarks: (1) o-toluenediamine (5) 1,2-ethylenediamine (2) o-phenylenediamine (6) 2-ethylhexanol (3) o-aminophenol (7) n-butanol (4) o-aminothiophenol (8) of theoretical yield based on appropriate (1) through (@@

Claims: CLAIMS: 1. A process for making a 5-membered heterocyclic compound characterised in that the compound has the structural formula EMI10.1 wherein n is 1 or zero, X is oxygen, sulfur or NR5; Y is oxygen, NH or sulfur; and if n is 1, R1, R2, R3, R4 and R5 may be the same or different and are hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, C6-C10 arty, C7-Cg alkaryl or C7-Cg aralkyl, or R and R together form a polymethylene group having 3 to 6 carbon atoms; and if n is 0, R1 and R4 together with the carbon atoms to which they are attached form a benzene ring or a benzene ring substituted with C1-C4 alkyl, and the process comprising reacting a compound having the structural formula, ZYCN(II), wherein Z is an alkali metal or ammonium moiety, and Y is as defined above, with a compound having the structural formula EMI10.2 wherein n, R1, R2, R3, R4 and X have the meanings above; in the presence of a solvent and, except when Z is NH4, in the presence of an acid. 2. A process according to claim 1 characterised in that II is NaSCN, KSCN or NH4SCN, III is o-tolyldianine and I is 2-mercapto-4(5)methylbenzimidazole 3. A process according to claim 1 characterised in that II is NaOCN, III is o-aminophenol and I is 2-hydroxybenzoxazole. 4. A process according to claim 1 characterised in that II is NaOCN, III is ethylenediamine and I is 2-hydroximidazoline. 5. A process according to claim 1 characterised in that II is NH4SCN, III is o-phenylenediamine and I is 2-mercaptobenzimidazole. 6. A process according to claim 1 characterised in that II is NH4SCN, III is o-aminothiophenol and I is 2-mercaptobenzothiazole. 7. A process according to claim 1 characterised in that II is NaNHCN, III is o-toluenediamine and I is 2-amino-4 (5) -methylbenzimidazole. 8. A process according to any of the preceding claims characterised in that said solvent is selected from water, C1-C10 alcohol, C6 C10 alkane, 8 cycloalkane, benzene, toluene and xylene, the reaction temperature is from 110 to 20OOC, and the reaction period is from 2 to 12 hours. 9. A process according to any of claims 1 to 7 characterised in that said solvent is a C4-C8 alkanol or xylene, the reaction temperature is from 140 to 1800C and the reaction time is from 4 to 8 hours. 10. A process according to claim 9 characterised in that'said solvent is hexanol or 2-ethylhexanol. 11. A process according to any of the preceding claims characterised in that the process also includes the following product purification steps: (a) extraction of product from organic phase with aqueous caustic; (b) neutralizing the caustic solution of (a) with acid; and (c) isolating the product from (b) by filtration; provided Y is not NH. 12. A process according to claim 11 characterised in that prior to step (b) the mixture of product in hot aqueous caustic is filtered through charcoal.

Inventors: GENCARELLI, RICHARD A., WHEELER, EDWARD L.
Applicants: UNIROYAL, INC.
Application year: 1982
Main classification: C07D235
IPC codes: C07D277, C07D235, C07D233, C07D263