• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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  • 优先权
    • 专利摘要:
    This disclosure describes novel substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines useful as anxiolytic agents.
    公开号:SU793399A3
    申请号:SU772523706
    申请日:1977-09-21
    公开日:1980-12-30
    发明作者:Роджер Аллен Младший Джордж；Вильям Ханифин Младший Джон；Брайан Моран Даниэль；Дональд Олбрайт Джей
    申请人:Американ Цианамид Компани (Фирма)；
    IPC主号:
    专利说明:

    in the medium of a solvent selected from the group of lower limit alcohols, at boiling with the release of the target product. Example 1. A mixture of 14.6 g of p- (b-chloro-4-methyl-3-pyridazinyl) -ben zonitril, 9.4 g of formyl hydrazine and 175 ml of butyl alcohol is stirred under reflux for 18 h. The reaction mixture is concentrated By removing the solvent, the concentrate is triturated with petroleum ether and filtered. The filtered precipitate is air-dried and the yellow solid is recrystallized twice from methyl alcohol obtained; light yellow crystals are recrystallized again from methanol to obtain the product indicated at the beginning of the measure; m.p. 240-243 ° C. PRI mme R 2. Preparation of p- (3-ethyl-7-methyl-1, 2,4-triazole | 4,3-B pyridazin-6-yl) -benzonitrile. A portion of 1.48 g of hydrazine acetic acid is dissolved in 50 ml of butyl alcohol with heating, then 4.58 g of p- (b-chloro-4-methyl-3-pyridazinyl) -benzonitrile is added, and after heating, additionally within 10 minutes ri, complete dissolution takes place. The solution is then heated with a counter for 18 hours. The reaction mixture is concentrated and 5.8 g of an orange solid is obtained, which is washed with petroleum ether. Then the product is dissolved in a mixture of ethyl alcohol and acetone in a ratio of 1: 1 and filtered through a layer of silica gel. The filter is washed extensively with acetone and the combined filtrates are concentrated to a yellow solid. This substance is dissolved in 100 ml of acetone and the solution is cooled in a mixture of dry ice and acetone and a brown solid is obtained, which is collected by filtration, washed extensively with petroleum ether and dried. the air. The product is dissolved in methyl alcohol, treated with activated charcoal and filtered. The filtrate is used to recrystallize from methanol, which is repeated two times and the resulting product, dried under vacuum, is the desired compound; T.SH1. 242-244s. Example 3. Getting 7-methyl-b- (m-nitrophenyl) -1,2,4-triazole 4, 3 pyridazine. 14.97 g of 3-chloro-5-methyl-b- (m-nitrophenyl) -pyridazine as a brownish solid, 7.2 g of the form of milgidrazine and 200 MP of butyl alcohol are mixed with countercurrent c. for 18 h. The reaction mixture is poured into another vessel and released from the insoluble part, then. the liquid fraction is cooled in an ice bath and 13.28 g of a brown crystalline substance are obtained. This product is dissolved in 300 ml of methyl methanol, then diluted to remove insoluble residue. The filtrate is clarified with activated carbon and filtered. the filtrate is concentrated to a small volume and a reddish-brown solid is obtained as the final product indicated in the title of the example; m.p. 213-218 C. Example 4. Preparation of b- (p-bromophenyl) -1,2,4-triazole 4, 3-6 pyridazine. A mixture of 3.76 g of 3- (p-bromophenyl) -6-chloropyridazine, 1.80 g of formylhydrazime and 50 ml of butyl alcohol is heated to reflux and left countercurrent overnight. Then the reaction mixture is cooled and the precipitated product is washed with water, dried in air and subjected to recrystallization from methyl alcohol; m.p. 209-21lc. EXAMPLE 5 A weighed portion of 2.5 g of H-chloro-6- (p-fluorophenyl) pyridazine is mixed with 1.46 g of formyl hydrazine and 40 ml of butyl alcohol. The mixture is heated with counter flow and left overnight. The mixture is then cooled in an ice bath and the precipitated product is collected by filtration, washed with butyl alcohol and left to dry overnight. The dried material is recrystallized from methyl alcohol and get the product specified at the beginning of the example, in the form of crystals; m.p. 197-198 ° C. EXAMPLE 6 Preparation of p- (1,2,4-triazole {4,3-in pyridazin-6-yl) -benzoritrile. A mixture of 1.00 g of p- (6-chloro-3-pyridazinyl) -benzonitrile in the form of crystals with m.p. 236-238c, 0.84 g of formylhydrazine and 25 MP of n-butyl alcohol are stirred at reflux for 17 hours and 45 minutes. The solvent is removed under reduced pressure, and the residue is triturated with ethyl alcohol. The mixture is filtered and the solid is recrystallized from dimethylformamide and water to give p- (1,2,4-triazole, 3-pyridazin-6-yl) -benzonitrile in the form of an orange solid; m.p. 272-274s. EXAMPLE 7 Preparation of m- (7-methyl-1, 2,4-triazole 4,3-B pyridazin-6-yl) -benzonitrile. A mixture of 3.0 g of m- (6-chloro-4-methyl-3-pyridazinylbenzonitrile as a creamy solid, 1.57 g of formyl hydrazine and 100 ml of butyl alcohol is heated in countercurrent with stirring for 18 hours. The reaction mixture is cooled in an ice bath and filtered to collect the formed solid. The final product of this example is then recrystallized from methyl alcohol and a cream-colored solid is obtained, mp 214216 0. Example. Mixture consisting of 6.0 g of 3-chloro -6- (with | 1, -triftor-m-tolyl) -pyridazine in the form of a solid substance The color of the mixture, 4.74 g of hydrazine butyric acid and 75 ml of butyl alcohol are mixed with countercurrent for 48 hours. The reaction mixture is concentrated, the solvent is removed, and the concentrate is dissolved in ethyl alcohol, treated with activated charcoal and filtered on ice. bath, and the resulting solid is filtered to obtain the product specified in the title of the example.The material is subjected to recrystallization from ethyl alcohol and dried in vacuum. Crystals are obtained; m.p. 118-120c. EXAMPLE 9 Preparation of phenyl) -7-methyl-1, 2, 4-triazole 4, 3-B pyridazine 6-fn-6pO. A mixture of 1.5 g of 3- (p-tromophenyl) -b-chloro-4-methylpyridazine as a gray solid, 0.64 g of formyl hydrazine and 25 ml of butyl alcohol are heated with stirring for 18 hours with countercurrent. The reaction mixture is cooled in an ice bath, filtered, and the solid is recrystallized from methyl alcohol and the product is obtained as a yellow solid; m.p. 219-222 ° C. PRI me R 10. Getting 6- (3-bro. M-p-me: toxiphenyl) -1,2, 4-triazole1, H-B pyridazine. A mixture consisting of 3- (3-bromo-4-methoxyphenyl) b-chloropyridazine, 75 ml of butyl alcohol and 2.88 g of the form of milgidrazine is heated to reflux and left overnight in a counter. The reaction mixture is cooled to room temperature and the product is collected by filtration. Then it is re-installed from methanol and the final product of the example is obtained in the form of crystals; m.p. 226-228 ° C. EXAMPLE 11 Preparation of b- (p-chlorophenyl) -8-methyl-1,2,4-triazole, 3-e3 pyridazine. A weighed portion of 2.0 g of 3-chloro-b- (p-chloro-phenyl) -4-methylpyridazine as a pinkish solid with 1.08 g of formyl hydrazine and 60 ml of butyl alcohol. The mixture was heated under reflux for 48 hours. The reaction mixture was cooled in an ice bath, the resulting solid was filtered, washed with petroleum ether and air dried. A brownish solid is obtained. The product is recrystallized from methyl alcohol after treatment with activated carbon and get white crystals; m.p. 230-233s. Example 12. Preparation of 3-methyl-6- (d4), k-trifluoro-m-tolyl) -1,2,4-tri azole 4, 3-8 pyridaein. A weighed portion of 6.0 g of 3-chloro-6 - (, "k, i-trifluoro-m-tolyl) -pyridazine, 3.44 g of acetylhydrazine and 75 ml of normal butyl alcohol is heated under reflux for 48 hours. The solvent is removed under vacuum, and the residue is dissolved in ethyl alcohol and treated with activated charcoal. The filtrate is concentrated, quenched, and filtered to give an orange-colored solid. By recrystallization from methyl alcohol, the product is obtained in the form of crystals: mp. 193-194 C. Example 9. Preparation of 6- (rj-chlorophenyl) -, 2, 4-triazo; 1 4.3-6 pyridazine. A mixture of 9.0 g of 3-chloro-6- (p-chlorophenyl) -pyridazine, 5.1 g of formyl hydrazine and 60 ml of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid is washed with petroleum ether and water. Then the product is heated with 125 ml of ethyl alcohol, and the insoluble part is collected by filtration. The filtrate is cooled and the precipitate is collected and mixed with insoluble material collected previously. The combined solid is recrystallized from 130 ml of ethanol to give the product; mp.216218 ° C in the form of crystals. PRI me R 14. Preparation of 6- (d4d, Jv-trifluoro-m-tolyl) -1,2, 4g-triazole 4, 3-pyridazine. A mixture of 6.0 g of 3-chloro-6 - (. (. (K-trifluoro-m-tolyl) -pyridazine, 2.78 g of formyl hydrazine and 75 ml of butyl alcohol is heated under reflux with stirring for 48 hours at a temperature of countercurrent. The reaction mixture is concentrated, removing the solvent, the residue is dissolved in ethyl alcohol, treated with activated carbon and filtered. The filtrate is cooled in an ice bath and a cream-colored solid is collected. The substance is heated with diethyl ether and the mixture is filtered. The solid is recrystallized from ethyl alcohol acetic acid ester and get the product in the form of cream colored crystals; mp 140-143 ° C. EXAMPLE 15 Preparation of 6- (p-chlorophenyl) -3-methyl-1,2, 4-triazole, 3-B pyridazine A mixture of 9.0 g of 3-chloro-6- (p-chlorophenyl) -pyridazine, 7.4 g of propionic hydrazide and 60 ml of butyl alcohol is stirred at reflux temperature for 48 h. The mixture is cooled rapidly, filtered and the solid precipitate is washed with petroleum ether and water. The substance is recrystallized from 50 ml of ethyl alcohol and get the product in the form of crystals; m.p. 197-199 ° C. Example: p. 16. Preparation of b- (p-fluorophenyl) -3-methyl-1,2,4-triazole p, 3-8J pyridazine.
    A mixture of 6/25 g of 3-chloro-b- (p-fluoromethyl) pyridazine, 4.65 g of acetylhydrazine, and 50 ml of parbolev butyl alcohol under reflux until a clear solution is obtained. The reaction mixture is cooled, filtered and the solid precipitate is washed with hexane and water. The solid is recrystallized from 50 ml of ethanol and the product is obtained in the form of crystals; mp 227229 ° C.
    PRI me R 17. Obtaining 3-methylg6- (m-nitrophenyl) -1,274-triazole 4, Zpyridaine.
    A mixture of 3.0 g H-chloro-6 (m-nitrophenyl) -pyridazine (mp. 206-208C; 2.0 g acetylhydrazine and 30 ml of butyl alcohol is heated at reflux temperature for about 72 hours and then cooled, the precipitate is filtered off, washed successively with hexane and water and dried in air. The product is boiled in 100 ml of 95% ethanol and filtered. The insoluble fraction is 3-methyl-6- (m-nitrophenyl) -1,2 , triazole G4, 3-L pyridazine; mp. 241243 ° C.
    PRI me 18. Obtaining 6- (m-nitrophenyl) -, 2,4-triazole 4, 3-6 pyridazine.
    This compound with a heat of 231-233C is prepared by replacing acetylhydrazine in Example 17 with formylhydrazine.
    Example 19: Preparation of 3-methyl-6- (p-tert-butylphenyl) -1,2,4-triazole, 3-B pyridazine.
    A mixture of 5.0 g of 3- (p-tert-butylphenyl} -b-chloropyridazine, 3.13 g of acetylhydrazine and 50 ml of n-butanol is heated under reflux for 48 hours. The mixture is concentrated in vacuo and the residue is stirred with 100m of water and 100 ml of diethyl ether.The mixture is filtered and 3.0 g of brownish solid are obtained with a melting point of 144-146 ° C. Recrystallization from a mixture of acetone and hexane gives the product as pale yellow crystals of mp 142-145 ° C.
    Example 8: Preparation of 6- {p-tert-butylphenyl) -1,2,4-triazole 4, Zpiridazine.
    A mixture of 5.0 g 3 (p-tert-butylphenyl) -6-chloropyridazine, 2.54 g of formyl hydrazine and 50 ml of n-butyl alcohol is heated under reflux with NICOM while stirring for 48. The mixture is cooled rapidly and filtered. The solid is washed with petroleum ether and water and dried in vacuo. 0.80 g of product is obtained. Filtrate
    concentrated in vacuo at a temperature below 80 ° C to obtain an additional amount of product, which is stirred with 150 ml of water and 150 ml of diethyl ether, collected by filtration and dried in vacuo. The yield is 3.0 g of an orange solid. By recrystallization from ethyl alcohol, the product is obtained in the form of white crystals with a hue; m.p. 270-275 ° C.
    EXAMPLE 21 Preparation of 6- (p-chlorophenyl) -3,8-dimethyl-1,2,4-triazole 4.3-6 pyridazine.
    A mixture of 1.0 g H-chloro-6- (p-chlorophenyl) -4-methylpyridazine, 0.62 g of acetic acid hydrazine and 10 ml of n-butanol is heated under reflux for 48 hours. The solvent is removed, the residue is dissolved They are taken in dichloromethane and filtered through magnesol. The solid fraction is recrystallized from a mixture of dichloromethane and hexane to obtain 0.6 g of a solid product with a melting point of 209-212 ° C. Recrystallization from dichloromethane and hexane gives the product in the form of light colored pinkish crystals; m.p. 215-217 ° C.
    PRI me R 22. Preparation of 6- (K, D-trifluoro-G-tolyl) -, 2, 4-triazole, 3-6 pyridazine.
    A mixture of 4.50 g of 3-chloro-6 - (d,., A-trifluoro-p-tolyl) -pyridazine, 2.09 g formyl hydrazine and 100 ml of n-butanol is stirred at reflux and heated for three days. reflux condenser. The solvent is removed and the residue is dissolved in methylene chloride, passed through magnesol, and the filtrate’s solid fraction is recrystallized from a mixture of methylene chloride and hexane to obtain the product (final) as white crystals, m.p. 160161 ° C.
    Example 23. Preparation of 3-methyl-6- (A.c.-trifluoro-p-tolyl) -1,2,4-triazole 0,4-g pyridazine.
    A mixture of 4.50 g of 3-chloro-6- (t ... -trifluoro-p-tolyl) -pyridazine, 2.5 g of acetic acid hydrazine and 100 ml of nbutanol is heated under reflux for 3 days. The solvent is removed and the residue is dissolved in methylene chloride, skip over magnesol, the solid fraction from the filtrate is recrystallized from a mixture of methylene chloride and hexane and get the final product as brownish crystals; m.p. 199-201 S.
    EXAMPLE 24 Preparation of 6- {m-chlorophenyl) -8-methyl-1,2,4-triazole p, -3-Bi pyridazine.
    权利要求:
    Claims (2)
    [1]
    A mixture of 2.0 g H-chloro-6- (mg chloro-N-4-methylpyridazine, 50 m) of 1 n-butanol and 1.08 g of formyl hydrazine is heated under reflux for 18 hours. The mixture is concentrated to dryness under vacuum and the residue is dissolved in methylene chloride. The solution is passed through a low column with hydrous magnesium silicate. The eluent is heated with countercurrent, gradually adding hexane until the crystals precipitate. After cooling and filtration, 1.20 g of crystals is obtained, the melting point is 173-178 ° C. The crystals in methylene chloride are passed through a low head of aqueous magnesium silicate, and the eluent is concentrated with the addition of hexane and 0.82 g of crystals are obtained; m.p. 181-182s. Example 25. Preparation of 6- (m-chlorophenyl) -3-methyl-1,2,4-triazole, 3-B pyridazine. A mixture of 2.0 g of 3-chloro-b- (m-chlorpheny pyridazine, 50 ml of n-butanol and 1.32 g of acetylhydrazine is heated under reflux for 18 hours. The mixture is concentrated to dryness under vacuum, the residue is dissolved in methylene chloride. Solution The column is passed through a low column of hydrous magnesium silicate. The element is heated with a countercurrent by gradually adding hexane until the crystals are separated. After cooling and filtration, obtain 1.50 g of crystals, mp 171-172.50 p. 26. Preparation of 6- (m-chlorophenyl) -3,8-dimethyl-1,2, 4-triaza §, 3-Vzpiridazina. A mixture of 7.17 g of 3-chloro-6- (m-chlorophenyl) -4-methyl pyrid 100 ml of n-butanol and 6.96 g of acetylhydrazine are heated under reflux overnight, the mixture is covered, filtered and a solid is obtained. The substance is dissolved in methylene chloride, the solution is passed through a low column of hydrous magnesium silicate. are refluxed by NICOM, gradually adding hexane until the crystals are separated. After cooling and filtering, 3.30 crystals are obtained; 193, 5-195, 5 ° C. Example 27. Getting 6- (o-fluorophenyl) -1,2,4-triazole 4, dazin. A mixture of 5.0 g of 3-chloro-6- {o-fluorophenyl) -pyridazine and 2.88 g of formyl hydrazine in 75 ml of n-butanol is heated under reflux for 48 hours and processed as described in example 35. The final product is obtained in cream colored crystals; m.p. 161-163 ° C. Example 28. Obtaining 3-methyl-6- (o-fluorophenyl) -1,2,4-triazole, 3 pyridazine. As in Example 23, a mixture of 2.5 g of H-chloro-6- (o-fluorophenyl) pyridazine and 1.76 g of acetylhydrazine in 50 ml of nb tanol is heated under reflux for 48 hours and 2 are obtained. 0g of the product in the form of white with a tint of crystals; m.p. 147-149s. Example 29. Preparation of 6- (m-fluorophenyl) -1,2,4-triazole 4, 3-6 pyridazine. A mixture of 3.6 g of H-chloro-6- (m-fluorophenyl) -pyridazine (mp. 133-135 ° C) and 2.06 g of fluoromylhydrazine in 50 ml of n-butanol is heated under reflux for 48 h, treated as described in example 35 and receive the crystalline end product; m.p. 159161 C. Example 30. Obtaining 3-methyl-6- (m-fluorophenyl) -1,2, 4-triazole 4, pyridazine. As in example 22, a mixture of 3.0 g of H-chloro-6- (m-fluorophenyl) -pyridazine, 2.14 g of acetylhydrazine and 50 ml of n-butanol is heated under reflux for 48 hours. Obtain 2.0 g crystalline product; mp.184186C. Example 31. Preparation of 6- {o-chlorophenyl) -, 2, 4-triazole 4, H-B pyridazine. A mixture of 5.67 g of 3-chor-6-1o-chlorophenyl; 1) pyridazine; m.p. 145-147s, 3.03 g formyl hydrazine in 50 mg. butanol is heated under reflux for 48 hours and 2.3 g of product are obtained in the form of pale yellow crystals; m.p. 156-158 ° C. Example 32. Preparation of 3-methyl-6-f o-chlorophenyl) -1, 2, 4-triazole 4, 3-B pyridazine. As in Example 23, a mixture of 5.5 g of H-chloro-6- (o-chlorophenyl) -pyridazine, 3.6 g of acetylhydrazine in 75 ml of n-butanol is heated under reflux for 72 hours to obtain 2.2 g of product in the form of white with a tinge of crystals; m.p. 146-148 ° C. Example 33. Preparation of 8-methyl-6- (L, h A-trifluoro-m-tolyl) -1,2,4-triazole 4.3-8 pyridazine. A mixture of 8.0 g of 3-chloro-4-methyl-6- (, (k, ol, trifluoro-m-tolyl) -pyridazine as cream crystals (mp. 123126 ° C) j3.52 g of formyl hydrazine and 125 ml of n-butanol is heated under reflux for 48 hours, then concentrated to dryness in vacuo.The residue in chloroform is passed through a column of aqueous magnesium silicate, the eluent is concentrated and the residue is crystallized from a mixture of NSB and hexane and get the final product in the form of crystals; mp 181-188 ° C. Example 34. Preparation of 3,8-dimethyl-6- (ol., ci, α-trifluoro-m-tolyl) -1, 2,4-triazole G4, 3-8 pyridazine. How and in example 23, a mixture of 8.0 g of 3-chloro p-4-methyl-6- (X, ot, I-trifluoro-mtolyl.) - pyridazine, 4.34 g of acetylhydrazine and 125 ml of n-butanol are heated under reflux for 48 h and receive 3.9 g of product in all crystals; mp. 196-198 ° C. Example 35. Preparation of 3,7-di methyl-b- (, dk, dL-trifluoro-m-tolyl) -1, 2,4-triazole 4, 3- In pyridazine. As in Example 23, a mixture of 8.0 g of 3-chloro-5-methyl-6-Cc (, A, ck-trifluoro-m-tolyl) -pyridaine and 4.34 g of acetylhydrazine in 125 ml of n- butanol is heated under reflux for 48 hours and gives 6.2 g of cream colored crystals; m.p. 185-187s. PRI me R 36. Getting 6- (m lil) -1,2-triazole 4, 3-B pyridazine. A mixture of 6.0 g of 3-chloro-6- (m-tolyl) -pyridazine (mp. 112-113 s) and 3.52 g of formyl hydrazine in 100 ml of n-butanol is heated under reflux for 48 h and treated as in example 35. Obtain 2.0 g of white crystals (from a mixture of CHSb2 and hexane); m.p. 164-166 “C. Example 37. Preparation of 3-methyl-6- (m-tolyl) -1,2,4-triazole J4, 3-B pyridazine. As in Example 23, a mixture of 6.0 g of 3-chloro-6- (m-tolyl) -pyridazine and 4.84 acetylhydrazine in 100 ml of n-butanol is heated in countercurrent for 48, and 2.0 g of cream-colored crystals are obtained; m.p. 160-162 p. Example 38. Preparation of 3-propyl-6 - (rf, dv, c-trifluoro-m-tolyl) -1,2, -triazole 4, 3-B pyridazine. A mixture of 5.0 g H-chloro-6- (ok, oC.oL-trip-tor-m-tolyl) -pyridazine, 3.94 g of hydrazide, butyric acid and 100 ml of n-butanol is heated under reflux for 48 h The solvent was removed in vacuo, and the residue was dissolved in chloroform. The solution is passed through a column of aqueous silica and magnesium, the eluent is concentrated and 3.2 g of product are obtained. Recrystallizing the mixture from a mixture of chloroform and hexane gives crystals; m.p. 173-175 ° C. Example 39. Preparation of 3-ethyl-6 {dL, ok, (-triftor-m-tolyl) -1,2,4-triazole 4, 3-b1 pyridazine. A mixture of 5.0 g of 3-chloro-b-C | C D-trifluoro-m-tolyl) -pyridazine, 3.40 g of the propionic acid hydroxide and 100 ml of n-butanol is heated under reflux for 48 hours. The body is removed in vacuo, and the residue is dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate, the eluent is concentrated and 3.0 g of crystals are obtained (from a mixture of chloroform and hexane), m.p. 183las c. PRI me R 40. Getting 2-ethyl -b - {tAiJv A-trifluoro-m-tolyl) -1,2; 4-three azole p, 3-BJ pyridazine. As in Example 38, 5.0 g 3-chloro-b- {cJk, ct., Ol. trifluoro-m-tolyl) -pyridazine and 3.40 g of propionic acid hydrazide in 100 ml of butanol are heated under reflux for 48 hours. Obtains white crystals (from a mixture of chloroform and hexane); .pl. 194-19bs. PRI me R 41. Preparation of 6- (4 chloro-cl. 1, o1, ok-trifluoro-m-tolyl) -1,2,4-triazole 4,3-B pyridazine. A mixture of 2.2 g of 3-chloro-6-4-chloro-3 (trifluoromethyl) -phenyl} pyridazine in cream-colored crystals (mp. 145-147 ° C) 0.9 g of formyl hydrazine and 50 ml n-butanol is heated under reflux for 48 hours and yields 2.1 g of the final product with a melting point of 211-214 ° C. Recrystallization from n-butanol gives cream crystals with a melting point of 217-2180 ° C. EXAMPLE 42. Preparation of 3-methyl-6- (4-chloro-o, c1, c-trifluoro-m-tolyl) -1, 2,4-triazole 0, H-B of pyridazine. As in Example 23, a mixture of 2.2 g of H-chloro-6- | 4-chloro-3- (trifluoromethyl) -phenyl-pyridazine and 1.11 g of acetylhydrazine in 50 ml of butaiol is heated under reflux for 48 h and get the final product in the form of crystals; m.p. 267-269®C. Example 43. Preparation of 6- (3,4-dichlorophenyl) -1, 2, 4-triazole J4, Z-B pyridazine. Example 44. Preparation of 3-methyl-6- (3,4-dichlorophenyl) -1,2,4-triazole §, West-Pyridazine. A mixture of 2.6 g of 3-chloro-6- (3,4, -dichlorophenyl) -pyridazine and 1.8 g of acetic acid hydrazide is heated in 50 g of n-butanol for 24 hours to obtain the product; m.p. 267-269 ° C. PRI me R 45. Preparation of 3,7,8-trimethyl-6-phenyl-1, 2,4-triazole 4, 3-b pyridazine. A weighed portion of 10 g H-chloro-4,5-dimethyl-6-phenylpyridazine in the form of a pink solid and 8 g of acetylhydrazine and 100 ml of n-butanol by heating under reflux for 48 hours. The reaction mixture is cooled in a water bath and the resulting solid is filtered under vacuum, washed first with petroleum ether, then with water and dried in air. After treatment with activated carbon, the solid is recrystallized from ethyl alcohol and dried in a vacuum. 3,7,8-trimethyl-6-phenyl-1, 2,4-triazole 4, 3-B pyridazine is obtained in the form of a white solid. EXAMPLE 46. Preparation of 7-methyl-6-phenyl-1, 2,4-triazole J4.3-6 pyridazine. A mixture of 1.5 g of 3- (p-bromophenyl) -6-chloro-4-methylpyridazine as a gray solid, 0.64 g of formyl hydrazine and 25 ml of n-butanol is stirred under heating at reflux for 18 h. The reaction mixture is cooled in an ice bath, filtered and the solid is recrystallized from methyl alcohol to give 6- (p-bromophenyl) -7-methyl-1,2,4-triazole 4, 3-6 pyridazine, 10 g mixture of this product, 30 ml of ammonium hydroxide, 250 ml of ethyl alcohol and catalytic amounts of 10% palladium on charcoal are shaken in an agitator for 18 hours. The absorption of 35 pounds of hydrogen (16.876 kg) was completed in 2 hours. Then the reaction mixture filtered to remove the catalyst, and the filtrate is condensed to a white solid , Which was triturated with petroleum ether. The solid is collected by filtration, dried in air and recrystallized from a mixture of methanol and ethyl acetate to give 7-methyl-6-phenyl-1,2,4-triazole, 3-B pyridazine as white crystals; m.p. 188-190 ° C. Example 47. Preparation of 6-phenyl -1,2, 4-triazole 4, 3-B pyridazine. 10 g of 3-chloro-6-phenylpyridazine, 6.6 g of formyl hydrazine and 100 ml of n-butanol are heated under reflux with NIKOM for 48 hours. The reaction mixture is cooled in an ice bath. The resulting solid is filtered, washed with petroleum ether and water and dried in air to give 6-phenyl-1, 2, 4-triazole 4, 3-Bj pyridazine as brownish crystals; m.p. 138-139 ° C. Example 48. Preparation of 8-methyl-6-phenyl-1, 2, 4-triazole 4, 3-pyridazine. A mixture of 2.05 g of 3-chloro-4-methyl-6-phenylpyridazine as a cream-colored solid, 1.2 g of formyl hydrazine and 50 ml of n-butanol are stirred and heated under reflux for 48 hours. The reaction mixture is concentrated, freeing yes from the solvent, the residue is stirred with diethyl ether. The mixture is filtered to give a cream colored solid. This substance is recrystallized from methanol. After treatment with activated charcoal. The methanolic filtrate is slowly evaporated at room temperature and the formation of white needles is observed along with dark yellow oil. The oil is removed, and the needles are washed with a small amount of diethyl ether, which is drained, then the needles are recrystallized from a mixture of methanol diethyl ether and petroleum ether to obtain 8-methyl-6-phenyl-1,2,4-triazole | 4.3-8 pyridazine as white crystals; m.p. 150-151 ° C. Example 49. Preparation of 3-p-pro-6-phenyl-1,2,4-triazole 4, 3-8 pyridazine. A mixture of 10 g H-chloro-6-phenylpyridisium, 11.2 g of hydrazine butyric acid and 100 ml of n-butanol is heated under reflux for 40 h. The solution is cooled and the precipitate is filtered and washed with petroleum ether and water. The filtrate is concentrated to an oil that has formed a precipitate over additional petroleum ether. The precipitate is collected and washed with petroleum ether and water. The solids are combined and recrystallized from 30 ml of ethanol to give 3-n-propyl-6-phenyl-1, 2, 4-triazole 4, 3-81 pyridazine as crystals; m.p. 123-125 C. PRI me R 50. Obtaining 3-ethyl-6-phenyl-1, 2,4-triazole 4, 3-8J pyridazine. A mixture of 7.6 g of 3-chloro-6-phenylhydrazine, 7.4 g of propionic hydrazide and 60 ml of n-butanol is stirred at reflux for 48 hours. The solution is cooled in a refrigerator, concentrated to remove the solvent and triturated with water, getting cristoshly. The mixture is filtered, washed with petroleum ether, water and dried. The product is recrystallized from 20 ml of tanol and 3-α-ethyl-6-phenyl-1, 2,4-triazole 4, H-Pyridazine is obtained; m.p. 133-135p. A mixture of the obtained compound and formylhydrazine in n-butanol is heated under reflux for 24 hours and 6- (3,4-dichlorophenyl) -1,2, 4-triazole (4, 3-6J) pyridazine is obtained. EXAMPLE 51 Preparation of 3-methyl-6- (3,4-dichlorophenyl) -1,2,4-triazole 4, 3-6 pyridazine. A mixture of 2.6 g of H-chloro-6- (3,4-dichlorophenyl) -pyridazine and 1.8 g of acetic hydrazide is heated in 50 ml of n-butanol for 24 hours to obtain the product indicated in the title of the example. Example 52. Preparation of 6- 2-chloro-6- (trifluoromethyl) -phenyl-triazole 4, 3-8 pyridazine. A mixture of H-chloro-6-2-chloro-5- (trifluoromethyl) -phenyl-pyridazine as cream-colored crystals, 2.2 g, 0.9 g of formyl hydrazine and 50 ml of n-butanol are heated under reflux for 48 h and get the product specified in the title of the example. PRI me R 53. Preparation of 3-methyl-6-2-chloro-5- (trifluoromethyl) phenyl -1, 2,4-triazole 4, 3-B pyridazine. As in example 23, a mixture of 2.2 g of H-chloro-6-2-HLOR-5- (trifluoromethyl phenyl} -pyridazine and 1.11 g of acetyl hydrazine in 50 MP n-butanol is heated under reflux for 48 h and get the product, indicated in the title of the example. Example 54. Preparation of 6-4nitro-3-ethrifluoromethyl-phenyl -1, 2,4-triazole 4, 3-B pyridazine, 7.2 g of 3-chloro-6-4-nitro H- (trifluoromethyl) -phenyl-3-pyridazine as crystals (m.p. ISl-lBS C is reacted with formylhydrazine in anti-n-butanol for 24 hours and the product is given as indicated in the Title of the Example. P and m e 55. Preparation of 3-methyl-6- | 4-nor ro-3-Striftormethyl) -phenyl -1, 2,4-triazole 4, 3-6 pyridazine. A mixture of 4.0 g of 3-chloro-6-4-nitro-3- {trifluoromethyl) -phenyl 3-pyridazine 1.95 g of acetylhydrazine in 40 ml of n-butanol is heated under reflux for 18 hours to obtain a crystalline product; mp. 293-295s Prim-er56. Preparation of b-4-fluoro-3- (trifluoromethyl) -phenyl -1,2,4-triazole, 3-B pyridazine. 3-Chloro-b-4-fluoro-3- (trifluoromethyl) -phenyl-pyridazine is reacted with formyl hydrazine, as described in example 34, and the product is obtained as indicated in the title of the example. Example 57. Obtaining 3-methyl- | 4-fluoro-3- (trifluoromethyl) -phenyl-, 2 4-triazole 4,3-B pyridazine. As described in Example 23, 3-chloro-6- 4-fluoro-3- (trifluoromethyl) -phenyl-pyridazine is reacted with acetic acid hydrazine in n-butanol to form the product indicated in the title of the example. Example 58. Preparation of 3-methyl 4-chloro-3-etrifluoromethyl) -phenyl -1,2, -triazole J4, 3-6} pyridazine. 3-Chloro-b-4-chloro-3- (trifluoromethyl) -phenyl-pyridazine, which is reacted with acetic acid hydrazine, as in Example 23, to form the final product with m.p. 2b7-269 ° C. Example59. Preparation of 3-methyl-b- (2-chloro-5-methylphenyl) -1,2,4-triazole, 3-in pyridazine. 3-Chloro-b- (2-chloro-5-methylphenyl) -pyridazine is reacted with acetic acid hydrazine in countercurrent n-butanol for 24 hours to form an example product of the title. For example. Preparation of 3-methyl-b- (2,3-dichlorophenyl) -1,2,4-triazole §, 3-B pyridazine. A mixture of 3-chloro-b- (2,3-dichlorophenyl) -pyridazine and hydrazine acetic acid in n-butanol is heated under reflux for 24 hours to obtain the product indicated in the title of the example. EXAMPLE 61 Preparation of b- (2-methyl-b-chlorophenyl) -1,2,4-triazole 4,3-B pyridazine. A mixture of 3-chloro-6- (2-methyl-5-chlorophenyl) -pyridazine and formylhydrazine in n-butanol is heated under reflux for 24 hours and is prepared. the final product of this example. Example 62. Preparation of b- {3-chloro5- (trifluoromethyl) -phenyl} -, 2, 4-triazole, 3-L1 pyridazine. 3-Chloro-b-p-chloro-B- (trifluorophenyl) -phenyl-pyridazine is reacted with formyl hydrazine in countercurrent n-butanol for 24 hours to form the final product of example b
    [2]
    2. Example 63 p. Preparation of 3-methyl-6-3-chloro-5- (trifluoromethyl) phenyl} -, 2,4-triazole / 4,3-B pyridazine. A mixture of 3-chloro-b- (3-chloro-5- (trifluoromethyl) -phenyl-pyridazine and acetic acid hydrazide in n-butanol is heated under reflux for 24 hours to obtain the final product indicated in the title of the example. substituted 6-phenyl-, 2,4-triazole 4, 3-B pyridazine of the general formula where R, R2 and Rj are each selected from the group consisting of hydrogen and alkyl Cj, R hydrogen, fluorine, chlorine bromine, cyano, trifluoromethyl, nitro, amino, acetamido, pa, carbamoyl, thiocarbamoyl, or Ci-Cj alkyl, provided that at least one of the radicals R and R is hydrogen and provided that if Rj is hydrogen, then R may not be methyl, and provided that RI and RJ are both methyl, then R cannot be hydrogen, characterized in that A compound of the formula where R / I, Rj and Kj. are as defined above, they are reacted with a compound of formula Er - NH
    779339918
    where Rj is as defined by the Information Sources,
    above, in a solvent environment, chosen-taken into account in the examination of the group of lower limit spirits- 1. i. Elderfield. Heterocyclitis at the boil with the release of the ester compounds. M., World, 1965,
    left product. 7. p.305.
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    同族专利:
    公开号 | 公开日
    BE858949A|1978-03-22|
    IS2407A7|1977-10-05|
    ZA775110B|1979-03-28|
    MC1168A1|1978-06-02|
    ZM6677A1|1979-07-19|
    PH13960A|1980-11-12|
    SE7710595L|1978-05-25|
    US4230705A|1980-10-28|
    MW2177A1|1979-06-13|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/725,597|US4230705A|1976-09-22|1976-09-22|6-Phenyl-1,2,4-triazolo[4,3-b]pyridazines and their uses in treating anxiety|
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