JPS6242910B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to organic compounds, and more specifically to 1-aminomethyl-6-phenyl-
The present invention relates to a new process for producing 4H-s-triazolo[4,3-a][1,4]benzodiazepines and intermediates thereof. The novel process or product of the present invention can be exemplified as follows. where R′ and R″ are alkyl of 1 to 3 carbon atoms or taken together

[Formula] is pyrrolidino, piperidino, 4-methylpiperazino,
Or morpholino. In addition to the method →→→→, the present invention also includes
Includes novel intermediates of the above formulas and. A preferred intermediate class of type has the more specific formula A. In the formula, R ₁ is hydrogen, fluoro, chloro, bromo,
nitro or trifluoromethyl, R ₂ is hydrogen, fluoro, or chloro, and R ₃ is hydrogen or, if R ₂ is fluoro, fluoro. The most preferred intermediates of the type are those of formula B. In the formula, R' ₁ and R' ₂ are hydrogen or chloro. The more desirable products of the formula have the more specific formula A. where R′ ₀ and R″ ₀ are alkyl of 1 to 3 carbon atoms, R ₁ is hydrogen, fluoro, chloro, bromo, nitro, or trifluoromethyl;
R ₂ is hydrogen, fluoro, chloro, and R ₃ is hydrogen or fluoro if R ₂ is also fluoro. The most preferred intermediates of the type have the specific formula B. In the formula, R' ₁ and R' ₂ are hydrogen or chlorine. The method of the present invention comprises treating one equivalent of the compound with two equivalents of α-phthalimide acetyl chloride or bromide in an inert organic solvent to obtain the compound, and treating the compound with trifluoroacetic acid to obtain the compound. , treatment of the compound with dialkylmethylene ammonium chloride or bromide to obtain the compound, and treatment of the compound with hydrazine in ethanol to obtain the above compound. Examples of lower alkyl groups of 1 to 3 carbon atoms are methyl, ethyl, propyl, and isopropyl. The end products of the formula are known compounds that are active as tranquilizers, anxiolytics, and antidepressants useful in the treatment of mammals and birds. 0.02 and 1 as detailed in parent patent application number 332293 filed February 14, 1973.
A single unit dosage format between mg/Kg is used. The object of the present invention is compounds of the formula and new intermediates in the process and a new process for their preparation. Some of the starting compounds of the formula are described by Derieg et al., Journal of Organic Chemistry (J.Org.Chem.), Vol. 36, p. 783 (1971).
This technique has been described by (2013). Other substituted compounds of the formula are made by the same method using well known and available substituted 2-aminobenzophenones. Here, rings A and B are unsubstituted or substituted as described above. In carrying out the method of the invention, selected 3-amino-3,4-dihydro-4-hydroxy-4-
Phenylquinazoline is suspended in an inert organic solvent such as ethylene dichloride, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, etc. in the presence of an organic base. Add α-phthalimide acetyl chloride or bromide to this suspension [C. Ainsworth et al., Journal of American Chemical Society (J.Am.Chem.Soc.) Vol. 76, p. 5651 (1954)] . In a preferred embodiment of the invention, the reaction is carried out between 2 and
2.5 molar equivalents of pyridine are added as base and the same amount of α-phthalimide acetyl halide reagent in an inert solvent is added dropwise over a period of 0.5 to 3 hours, carried out under a nitrogen atmosphere. The preferred temperature during the reaction is -5 to 15°C. Once all the reagents have been added, the mixture is left at -5 to 15°C for 0.5 to 2 hours and finally at room temperature (22 to 28°) for 1 to 24 hours. At the end of the reaction, the product is recovered in a customary manner, ie by addition of water and extraction with a water-immiscible organic solvent such as chloroform, methylene chloride. The products are purified by conventional means, generally by crystallization. The compound is prepared by diluting a solution of the compound in an inert organic solvent into a halogenated acetic acid, e.g. chloroacetic acid,
It is converted to the compound by reaction with dichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, or trifluoroacetic acid, with preference given to reaction with trifluoroacetic acid. Using solvents like benzene, toluene, xylene, chlorobenzene. In a preferred embodiment of the present invention,
The solution of the compound is reacted with trifluoroacetic acid at a temperature of 80-125°C for 0.5-4 hours. The product is then recovered and purified by conventional means, namely concentrating the reaction mixture, adding water, neutralizing the acid, extracting with a water-immiscible organic solvent, chromatography and/or crystallization. Ru. The compound is H.Bohme
et al., Chem.Ber, vol. 93,
1305 pages (1960) or J. Schreiber (J.
Schreiber et al., Angew.Chem.int.
ed.) Vol. 10, p. 330 (1971), by reacting with a substituted methylene ammonium halide prepared as shown in vol. 10, p. 330 (1971). The dialkylmethylene ammonium halide can also be made in situ, rather than being pre-prepared and added to the reaction afterwards. In a preferred embodiment of the invention, a selected N,N,N',N'-tetraalkyldiaminomethane in a solvent such as dimethylformamide, diethylformamide, dimethyl- or diethylacetamide, etc. Treat with an acyl halide, usually acetyl chloride, under an atmosphere of nitrogen at °C. The mixture is allowed to warm to room temperature (approximately 25°C) and left at room temperature for 0.5-4 hours. The compounds are added to this mixture and the reaction mixture is then allowed to react for 10-48 hours at a temperature of 25-100°C. The reaction mixture is then poured into water to neutralize and the precipitated product is collected. The product is purified by conventional procedures such as recrystallization or chromatography. The compound is converted to the compound by treatment with hydrazine, usually as a hydrate, in a lower alkanol of 1 to 4 carbon atoms between 25 and 100°C. Methylamine, ethylamine, propylamine or butylamine instead of hydrazine,
Solvents such as and tetrahydrofuran, methylene chloride can be used. In a preferred method,
Hydrazine hydrate in ethanol at about reflux temperature is used for 1 to 4 hours. The product is recovered and purified by conventional procedures such as filtration, extraction, chromatography, crystallization, etc. As shown by the sharp melting points of the products of each step in the examples below, by using the method of the present invention, crystalline materials can be obtained and used to synthesize target compounds. You can get the effect you want. The following examples are illustrative of the methods and products of the invention, but are not to be considered limiting. Example 1 1,3-dioxo-2-isoindoline acetic acid,
[[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide 3-amino-6-chloro-3,4-dihydro-4- in 150 ml of dry tetrahydrofuran. A stirred mixture of hydroxy-4-phenylquinazoline (2.74 g, 0.01 mol) is cooled under nitrogen in an ice bath and treated with dry pyridine (1.77 ml, 0.0122 mol). Next, add 25ml of this mixture to tetrahydrofuran.
α-phthalimide acetyl chloride (4.92
g, 0.022 mol) dropwise over 1 hour. The mixture is kept in an ice bath for 1 hour and at ambient temperature (25°) for 4 hours. This is then poured into ice water and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate,
Concentrate. The solid residue was suspended in ethyl acetate,
When collected by filtration, washed with ethyl acetate and dried, 1,3-dioxo-2-isoindoline acetic acid [[N-(2-benzoyl-4-chlorophenyl)-1, This yields 5.36 g of 3-dioxo-2-isoindolineacetamide]methylene]hydrazide. By concentrating the ethyl acetate filtration, a second crop of 0.517 g is obtained with a melting point of 164.5-167°C (decomposition). The analytical sample was crystallized from methylene chloride-ethyl acetate and has a melting point of 196.5-198.5°C. Analysis C ₃₄ H ₂₂ ClN ₅ O ₇ Calculated value: C, 63.02; H, 3.42;
Cl, 5.47; N, 10.81 Measured value: C, 63.10; H, 3.59;
Cl, 5.50; N, 10.97 Example 2 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-4-
Chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide 3-Amino-6-chloro-3,4-dihydro-4-hydroxy-4-
When (o-chlorophenyl)quinazoline is reacted with α-phthalimide acetyl chloride together with pyridine, 1,3-dioxo-2-isoindoline acetic acid [[N-[2-(o-chlorobenzoyl]
-4-chlorophenyl]-1,3-dioxo-2
-Produces isoindolineacetamide]methylene]hydrazide. Example 3 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-4-
Nitrophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide 3-Amino-6-nitro-3,4-dihydro-4-hydroxy-4-
When (o-chlorophenyl)quinazoline is reacted with pyridine and α-phthalimide acetyl chloride, 1,3-dioxo-2-isoindoline acetic acid, [[N-[2-(o-chlorobenzoyl)]
-4-nitrophenyl]-1,3-dioxo-2
-Produces isoindolineacetamide]methylene]hydrazide. Example 4 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide 3-amino-6- Chloro-3,4-dihydro-4-hydroxy-4-
When (2,6-difluorophenyl)quinazoline is reacted with pyridine and α-phthalimide acetyl chloride, 1,3-dioxo-2-isoindoline acetic acid, [[N-[2-(2,6-difluorobenzoyl)] -4-chlorophenyl]-1,
This produces 3-dioxo-2-isoindolineacetamide]methylene]hydrazide. Example 5 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-4-
Fluorophenyl]-1,3-dioxo-2-
Isoindolineacetamide]methylene]hydrazide 3-Amino-6-fluoro-3,4-dihydro-4-hydroxy-4 by the method described in Example 1
-(o-chlorophenyl)quinazoline is reacted with α-phthalimide acetyl chloride together with pyridine to produce 1,3-dioxo-2-isoindoline acetic acid, [[N-[2-(o-chlorobenzoyl)-4-fluorophore] This produces enyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide. Example 6 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-4-
(trifluoromethyl)phenyl]-1,3-
Dioxo-2-isoindolineacetamide]
Methylene]hydrazide 3-Amino-6-trifluoromethyl-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline is reacted with α-phthalimide acetyl chloride together with pyridine in the manner described in Example 1. and 1,3-dioxo-2-
This yields isoindoline acetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide. Other compounds of formula structure can be synthesized using the methods described in the Examples above. Representative compounds thus obtained include the following. 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-fluorobenzoyl)-4-]
Chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-benzoyl-4-nitrophenyl]-1,3-dioxo -2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-
Benzoyl-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-
Benzoyl-4-fluorophenyl]-1,3-
Dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-benzoyl-3
-Nitrophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-2-(m-bromobenzoyl)-4-
Chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-bromobenzoyl)-5
-Nitrophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(p-bromobenzoyl)-6]
-Fluorophenyl]-1,3-dioxo-2-
Isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-5-bromophenyl]-1,3-dioxo-2-iso Indoline acetamide [methylene]
Hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(p-chlorobenzoyl)-3-nitrophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]
Hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(m-fluorobenzoyl)-3-fluorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide ;1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-3-chlorophenyl)-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide;
1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-5-
(Trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamide]-methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)] -6-chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-
Bromophenyl)-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide; 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoylphenyl)-1,3
-Dioxo-2-isoindolineacetamide]
methylene] hydrazide, etc. Example 7 5-chloro-2-[3-phthalimidomethyl)
-4H-1,2,4-triazol-4-yl]benzophenone 1,3-dioxo-2-isoindolineacetic acid,
[[N-(2-benzoyl-4-chlorophenyl)
-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide (8.0g, 0.0123
A stirred mixture of 200 ml of toluene and 200 ml of toluene was treated with 0.9 ml of trifluoroacetic acid and heated to 100-110°C.
Heat for 1.5 hours. Concentrate the mixture in vacuo and
The residue is mixed with cold water and chloroform and made alkaline with aqueous sodium hydroxide solution. The mixture is extracted with chloroform, the extracts are washed with brine, dried over anhydrous sodium sulfate, and concentrated.
The residue is chromatographed on 400 g of silica gel with 1.5% methanol-98.5% chloroform. When the product thus obtained is crystallized from methylene chloride-methanol, 5-chloro-2-[3-(phthalimidomethyl)-4H-
2.54 g of 1,2,4-triazol-4-yl]benzophenone with a melting point of 228-228.5℃ and a melting point of
Yields 0.361 g at 229-230°C (53% yield).
The analytical sample has a melting point of 229.5-230.5°. Analysis C ₂₄ H ₁₅ ClN ₄ O ₃ Calculated value: C, 65.09; H, 3.41;
Cl, 8.00; N, 12.65 Measured value: C, 65.01; H, 3.67;
Cl, 8.01; N, 12.84 Example 8 2',5-dichloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone 1,3-dioxo-
2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-chlorophenyl]-1,
When 3-dioxo-2-isoindolineacetamide]methylene]hydrazide is heated with trifluoroacetic acid at 100-110°C, it produces 2',5-dichloro-2-[3-(phthalimidomethyl)-4H-
This produces 1,2,4-triazol-4-yl]benzophenone. Example 9 2'-Chloro-5-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone 1,3-dioxo ―
2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-nitrophenyl]-1,
When 3-dioxo-2-isoindolineacetamide]methylene]hydrazide is heated to 100-110°C with trifluoroacetic acid, 2'-chloro-5-
Nitro-2-[3-phthalimidomethyl)-4H
-1,2,4-triazol-4-yl]benzophenone is produced. Example 10 2′,6′-difluoro-5-chloro-2-[3-
(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone 1,3-dioxo-
2-isoindolineacetic acid, [[N-[2-(2,6
-Difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide is heated to 100-110℃ with trifluoroacetic acid to produce 2',6'-
This produces difluoro-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone. Example 11 2'-Chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone 1,3-dioxo ―
2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-fluorophenyl]-
When 1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide is heated to 100-110℃ with trifluoroacetic acid, 2'-chloro-5
-Fluoro-2-[3-phthalimidomethyl)-
This produces 4H-1,2,4-triazol-4-yl]benzophenone. Example 12 2'-chloro-5-trifluoromethyl-2-
[3-(phthalimidomethyl)-4H-1,2,
4-Triazol-4-yl]benzophenone 1,3-dioxo-
2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)]
When phenyl]-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide is heated to 100-110°C with trifluoroacetic acid,
2′-chloro-5-trifluoromethyl-2-[3
-(phthalimidomethyl)-4H-1,2,4-
This produces triazol-4-yl]benzophenone. By the method described in Example 7, the other 2-
[3-(phthalimidomethyl)-4H-1,2,4
-triazol-4-yl]benzophenones can be synthesized. Representative compounds thus obtained include the following. 5-chloro-2'-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 5-nitro-
2-[3-(phthalimidomethyl)-4H-1,
2,4-triazol-4-yl]benzophenone; 5-trifluoromethyl-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 5-fluoro-2- [3-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone; 6-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazole-4
-yl]benzophenone;3'-bromo-5-chloro-2-[3-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone; 2'-bromo-4-nitro-2-[3-
(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 4'-bromo-3-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazole- 4-
benzophenone; 2′6′-difluoro-4-
Bromo-2-[3-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]benzophenone; 4'-chloro-6-nitro-2-
[3-(phthalimidomethyl)-4H-1,2,4
-triazol-4-yl]benzophenone;
3'-fluoro-6-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 6-chloro-
2-[3-(phthalimidomethyl)-4H-1,
2,4-triazol-4-yl]benzophenone; 2'-chloro-4-trifluoromethyl-2-
[3-(phthalimidomethyl)-4H-1,2,4
-triazol-4-yl]benzophenone;
2'-chloro-3-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 5-bromo-2-
[3-(phthalimidomethyl)-4H-1,2,4
-triazol-4-yl]benzophenone; 2
―[3-(phthalimidomethyl)-4H-1,
2,4-triazol-4-yl]benzophenone, etc. Example 13 5-chloro-2-[3-[(dimethylamino)
Methyl]-5-(phthalimidomethyl)-4H
-1,2,4-triazol-4-yl]benzophenone N, N, in 45 ml of dry dimethylformamide
N′,N′-tetramethyldiaminomethane (1.531
The stirred solution of 1.0 g, 0.015 mol) is cooled in an ice bath under nitrogen and treated dropwise with freshly distilled acetyl chloride (1.06 ml, 0.015 mol). The resulting suspension is allowed to warm to 25°C for about 2 hours. 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazole-4-
Benzophenone (4.429 g, 0.01 mole) is added and the resulting mixture is maintained at 50-54°C for 25 hours. This is then cooled and poured into cold water. The resulting solution is neutralized with sodium bicarbonate. The precipitated product is collected by filtration, washed with water and dissolved in methylene chloride. Wash the methylene chloride solution with water and brine,
Dry over anhydrous sodium sulfate and concentrate. The residue was crystallized from methylene chloride-methanol and decolorized with activated carbon (Darco) to give 5-chloro-2-
Melting point of [3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone 206~
Yields 4.02 g of 207.5°C and 0.224 g of 5°C, melting point 206-208. The analysis sample has a melting point of 206.5-208.5
It is ℃. Analysis C ₂₇ H ₂₂ ClN ₅ O ₃ Calculated: C, 64.87; H, 4.44;
Cl, 7.09; N, 14.01 Measured value: C, 64.51; H, 4.59;
Cl, 7.17; N, 13.90 Example 14 2',5-dichloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)
-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-
Reacting tetramethyldiaminomethane and acetyl chloride together in dimethylformamide produces a suspension of dimethylmethylene ammonium chloride. This suspension was mixed with 2′,5-dichloro-2-[3-
When reacted with (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone, 2',5-dichloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl )-4H-1,2,4-triazol-4-yl]benzophenone. Example 15 2'-chloro-5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-4
-yl]benzophenone By the method described in Example 13, N, N, N', N'-
Reacting tetramethyldiaminomethane and acetyl chloride together in dimethylformamide produces a suspension of dimethylmethylene ammonium chloride. This suspension was mixed with 2′-chloro-5-nitro-2-
[3-(phthalimidomethyl)-4H-1,2,4
-Triazol-4-yl] When reacted with benzophenone, 2'-chloro-5-nitro-2-[3
-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 16 2′,6′-difluoro-5-chloro-2-[3-
[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-
Reacting tetramethyldiaminomethane and acetyl chloride together in dimethylformamide produces a suspension of dimethylmethylene ammonium chloride. This suspension was mixed with 2′,6′-difluoro-5-chloro-2-[3-(phthalimidomethyl)-4H-
When reacted with 1,2,4-triazol-4-yl]benzophenone, 2′6′-difluoro-5-
Chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,
This produces 2,4-triazol-4-yl]benzophenone. Example 17 2'-chloro-5-fluoro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone N,N,N',N'-
Reacting tetramethyldiaminomethane and acetyl chloride together in dimethylformamide produces a suspension of dimethylmethylene ammonium chloride. This suspension was mixed with 2′-chloro-5-fluoro-2-
[3-(phthalimidomethyl)-4H-1,2,4
-triazol-4-yl] When reacted with benzophenone, 2'-chloro-5-fluoro-2-
[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 18 2′-chloro-5-trifluoromethyl-2-
[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N' ―
Reacting tetramethyldiaminomethane and acetyl chloride together in dimethylformamide produces a suspension of dimethylmethylene ammonium chloride. This suspension was mixed with 2'-chloro-5-trifluoromethyl-2-[3-(phthalimidomethyl)-4H
When reacted with -1,2,4-triazol-4-yl]benzophenone, 2'-chloro-5-trifluoromethyl-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-
This produces 4H-1,2,4-triazol-4-yl]benzophenone. By the method described in Example 13, the other 2-
[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenones can be synthesized. Representative compounds thus obtained include the following. 5-chloro-2'-fluoro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-4-
yl] benzophenone; 5-nitro-2-[3-
[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone; 5-trifluoromethyl-2-[3-[(dimethylamino)methyl]
-5-(phthalimidomethyl)-4H-1,2,
4-triazol-4-yl]benzophenone;
5-fluoro-2-[3-[(dimethylamino)
Methyl]-5-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone; 6-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]benzophenone; 3'-bromo-5-chloro-2-
[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 2'-bromo-
4-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone; 4'-bromo-3-fluoro-2-[3-
[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone; 2',6'-difluoro-4-bromo-2-[3-[(dimethylamino)
Methyl]-5-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone; 4'-chloro-6-nitro-2-[3-
[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone; 3′-fluoro-6-
Fluoro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,
2,4-triazol-4-yl]benzophenone; 6-chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]benzophenone; 2'-chloro-4-trifluoromethyl-2-[3-[(dimethylamino)methyl]
-5-(phthalimidomethyl)-4H-1,2,
4-triazol-4-yl]benzophenone;
2'-Chloro-3-chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone; 5-bromo-2 - [3-
[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-
4-yl]benzophenone; 2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone, etc. Example 19 5-chloro-2-[3-[(diethylamino)
Methyl]-5-(phthalimidomethyl)-4H
-1,2,4-triazol-4-yl]benzophenone When N,N,N',N'-tetraethyldiaminomethane and acetyl chloride are reacted together in dimethylformamide, N,N-diethylmethylene ammonium chloride is formed. Produces a suspension. By the method described in Example 13, 5-chloro-2-
[3-(phthalimidomethyl)-4H-1,2,4
-Triazol-4-yl]benzophenone is reacted with the above suspension and then neutralized with sodium bicarbonate to give 5-chloro-2-[3-[(diethylamino)methyl]-5-(phthalimidomethyl). -4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 20 2',5-dichloro-2-[3-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-4-
When N,N'-dimethyl-N,N'-diethyldiaminomethane and acetyl chloride are reacted together in dimethylformamide, N-methyl-N
-Produces a suspension of ethyl-methylene ammonium chloride. 2',5-dichloro-
2-[3-(phthalimidomethyl)-4H-1,
Reaction of 2,4-triazol-4-yl]benzophenone with the above suspension and subsequent neutralization with sodium bicarbonate yields 2',5-dichloro-2-[3
-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 21 5-chloro-2-[3-[(dipropylamino)methyl]-5-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]
Benzophenone N,N,N',N'-Tetrapropyldiaminomethane and acetyl chloride are reacted together in dimethylformamide to form a suspension of N,N-dipropylamethylene ammonium chloride. By the method described in Example 13, 5-chloro-2-
[3-(phthalimidomethyl)-4H-1,2,4
-Triazol-4-yl]benzophenone is reacted with the above suspension and then neutralized with sodium bicarbonate to give 5-chloro-2-[3-[(dipropylamino)methyl]-5-(phthalimidomethyl )-4H-1,2,4-triazole-4-
il] produces benzophenone. Example 22 2',5-dichloro-2-[3-[(diisopropylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-4
-yl]benzophenone N,N,N',N'-Tetraisopropyldiaminomethane and acetyl chloride are reacted together in dimethylformamide to form a suspension of diisopropylamethylene ammonium chloride. 2',5-dichloro-
2-[3-phthalimidomethyl)-4H-1,
Reaction of 2,4-triazol-4-yl]benzophenone with the above suspension and subsequent neutralization with sodium bicarbonate yields 2',5-dichloro-2-[3
-[(diisopropylamino)methyl]-5-
(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 23 2'-chloro-5-nitro-2-[3-(pyrrolidinomethyl)-5-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]
When benzophenone dipyrrolidinomethane and acetyl chloride are reacted together in dimethylformamide, 1
-Produces a suspension of methylene pyrrolidinium chloride. 2′-chloro-5-nitro-2-[3-(phthalimidomethyl)-4H
-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension and then neutralized with sodium bicarbonate to give 2'-chloro-5-nitro-2-[3-( pyrrolidinomethyl)-5-
(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 24 2'-chloro-5-trifluoromethyl-2-
[3-(Piperidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone When dipiperidinomethane and acetyl chloride are reacted together in dimethylformamide, 1
-Produces a suspension of methylene piperidinium chloride. 2'-chloro-5-trifluoromethyl-2-[3-(phthalimidomethyl)-4H-1,2,4-triazole-4-
Reaction of benzophenone with the above suspension and subsequent neutralization with sodium bicarbonate yields 2'-chloro-5-trifluoromethyl-2-[3-(piperidinomethyl)-5-(phthalimidomethyl).
-4H-1,2,4-triazol-4-yl]
Produces benzophenone. Example 25 2′5-dichloro-2-[3-[(4-methylpiperazino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazole-4-
yl]benzophenone Reacting bis(4-methylpiperazino)methane and acetyl chloride together in dimethylformamide produces a suspension of 4-methyl-1-methylenepiperazinium chloride. By the method described in Example 13, 2′5-dichloro-2
―[3-(phthalimidomethyl)-4H-1,
Reaction of 2,4-triazol-4-yl]benzophenone with the above suspension and subsequent neutralization with sodium bicarbonate yields 2',5-dichloro-2-[3
―[(4-Methylpiperazino)methyl]-5-
(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is produced. Example 26 2'5-dichloro-2-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-
1,2,4-triazol-4-yl]benzophenone When dimorpholinomethane and acetyl chloride are reacted together in dimethylformamide, 4
-Produces a suspension of methylenemorpholinium chloride. 2',5-dichloro-
2-[3-(phthalimidomethyl)-4H-1,
Reaction of 2,4-triazol-4-yl]benzophenone with the above suspension and subsequent neutralization with sodium bicarbonate yields 2',5-dichloro-2-[3
-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazole-4-
il] produces benzophenone. Example 27 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-chloro-2- in 10 ml of absolute ethanol [3
A stirred suspension of [(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (1.0 g, 0.002 mol) was mixed with hydrazine hydrate ( 0.145 ml, 0.003 mol) and warm in a 70-77°C bath for 2 hours. As the reaction progresses, the starting material dissolves and a second solid precipitates. Cool the mixture and filter. Wash the solid with ethanol and methylene chloride and concentrate the combined filtrates. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate, filtered through a small plug of silica gel, and crystallized from ethyl acetate-Skerisolve B hexanes to give 8-chloro-1-[(dimethylamino)methyl]-6-
Phenyl-4H-s-triazolo [4,3-a]
[1,4] 0.365 g of benzodiazepine with a melting point of 171.5 to 174° and one with a melting point of 170.5 to 174°
Two crops of 0.078g are obtained. Example 28 8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s
-Triazolo[4,3-a][1,4]benzodiazepine 2',5-dichloro-
2-[3-[(dimethylamino)methyl]-5-
When (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated with hydrazine hydrate in ethanol, the 8-
Chloro-1-[(dimethylamino)methyl]-6
-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Example 29 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s
-Triazolo[4,3-a][1,4]benzodiazepine 2'-chloro-5-nitro-2-[3-[(dimethylamino)methyl]
-5-(phthalimidomethyl)-4H-1,2,
Heating 4-triazol-4-yl]benzophenone with hydrazine hydrate in ethanol produces 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-
Produces triazolo[4,3-a][1,4]benzodiazepines. Example 30 8-Trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)
-4H-s-triazolo [4,3-a] [1,
4] Benzodiazepine 2'-chloro-5-
(trifluoromethyl)-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)
-4H-1,2,4-triazol-4-yl]
Heating benzophenone with hydrazine hydrate in ethanol produces 8-trifluoromethyl-
1-[(dimethylamino)methyl]-6-(o-
chlorophenyl)-4H-s-triazolo[4,
3-a] [1,4] produces benzodiazepines. Example 31 8-fluoro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s
-Triazolo[4,3-a][1,4]benzodiazepine 2'-chloro-5-fluoro-2-[3-[(dimethylamino)methy]
-5-(phthalimidomethyl)-4H-1,2,
Heating 4-triazol-4-yl]benzophenone with hydrazine hydrate in ethanol produces 8-fluoro-1-[(dimethylamino)
Methyl]-6-(o-chlorophenyl)-4H-
Produces s-triazolo[4,3-a][1,4]benzodiazepine. Example 32 8-chloro-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-
4H-s-triazolo [4,3-a] [1,4]
Benzodiazepines 2',6'-difluoro-5-chloro-2-[3-[(dimethylamino)]
Methyl]-5-(phthalimidomethyl)-4H-
Heating 1,2,4-triazol-4-yl]benzophenone with hydrazine hydrate in ethanol produces 8-chloro-1-[(dimethylamino)methyl]-6-(2,6-difluorophenone). enyl)-4H-s-triazolo[4,3-a]
[1,4] Produces benzodiazepines. Example 33 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine By the method described in Example 27, 5-chloro- 2-
When [3-[(diethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated with hydrazine hydrate in ethanol, it forms 8-chloro- 1-[(diethylamino)methyl]-6-
Phenyl-4H-s-triazolo [4,3-a]
[1,4] Produces benzodiazepines. Example 34 8-chloro-1-[(ethylmethylamino)methyl]-6-(o-chlorophenyl)-4H-
s-triazolo[4,3-a][1,4]benzodiazepine 2',5-dichloro-
2-[3-[(ethylmethylamino)methyl]-
5-(phthalimidomethyl)-4H-1,2,4
-Triazol-4-yl]benzophenone when heated with hydrazine hydrate in ethanol produces 8-chloro-1-[(ethylmethylamino)
Methyl]-6-(o-chlorophenyl)-4H-
Produces s-triazolo[4,3-a][1,4]benzodiazepine. Example 35 8-Chloro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine By the method described in Example 27, 5- Chloro-2-
[3-[(dipropylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]] When benzophenone is heated with hydrazine hydrate in ethanol, 8-
Chloro-1-[(dipropylamino)methyl]-
6-phenyl-4H-s-triazolo[4,3-
a] [1,4] produces benzodiazepines. Example 36 8-chloro-1-[(diisopropylamino)
Methyl]-6-(o-chlorophenyl)-4H
-s-triazolo[4,3-a][1,4]benzodiazepine 2',5-dichloro-
2-[3-[(diisopropylamino)methyl]
-5-(phthalimidomethyl)-4H-1,2,
When 4-triazol-4-yl]benzophenone is heated with hydrazine hydrate in ethanol, it produces 8-chloro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-
Produces 4H-s-triazolo[4,3-a][1,4]benzodiazepine. Example 37 8-nitro-1-[(pyrrolidinomethyl)-6
-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine 2'-chloro-5-nitro-2-[3-(pyrrolidino)] methyl)-5-
When (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated with hydrazine hydrate in ethanol, 8
-Nitro-1-(pyrrolidinomethyl)-6-(o
-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Example 38 8-trifluoromethyl-1-(piperidinomethyl)-6-(o-chlorophenyl)-4H-
s-triazolo[4,3-a][1,4]benzodiazepine 2'-chloro-5-trifluoromethyl-2-[3-(piperidinomethyl)-5-(phthalimidomethyl)] by the method described in Example 27. -4H-1,
Heating 2,4-triazol-4-yl]benzophenone with hydrazine hydrate in ethanol produces 8-trifluoromethyl-1-(piperidinomethyl)-6-(o-chlorophenyl)-
Produces 4H-s-triazolo[4,3-a][1,4]benzodiazepine. Example 39 8-chloro-1-[(4-methylpiperazino)
Methyl]-6-(o-chlorophenyl)-4H
-s-triazolo[4,3-a][1,4]benzodiazepine 2'5-dichloro-2
-[3-[(4-methylpiperazino)methyl]-
5-(phthalimidomethyl)-4H-1,2,4
-Triazol-4-yl]benzophenone when heated with hydrazine hydrate in ethanol produces 8-chloro-1-[(4-methylpiperazino)methyl]-6-(o-chlorophenyl)-
Produces 4H-s-triazolo[4,3-a][1,4]benzodiazepine. Example 40 8-chloro-1-(morpholinomethyl)-6-
(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine 2′5-dichloro-2
-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated with hydrazine hydrate in ethanol to form 8-chloro-1 -(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-
a] [1,4] produces benzodiazepines. Other 1-aminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines () can be converted to the corresponding 2-[3-() by the method described in Example 27. aminomethyl)
-5-(phthalimidomethyl)-4H-1,2,
It can be synthesized from 4-triazol-4-yl]benzophenones. Representative compounds thus obtained include the following. 8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-
Triazolo[4,3-a][1,4]benzodiazepine; 8-nitro-1-[(dimethylamino)
Methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; 8-
Trifluoromethyl-1-[(dimethylamino)
Methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; 8-
Fluoro-1-[(dimethylamino)methyl]-
6-phenyl-4H-s-triazolo[4,3-
a] [1,4]benzodiazepine; 7-nitro-
1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,
4] Benzodiazepine; 8-chloro-1-[(dimethylamino)methyl]-6-(m-bromophenyl)-4H-s-triazolo[4,3-a]
[1,4] Benzodiazepine; 9-nitro-1-
[(dimethylamino)methyl]-6-(o-bromophenyl)-4H-s-triazolo[4,3-
a] [1,4]benzodiazepine; 10-fluoro-1-[(dimethylamino)methyl]-6-(p
-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine; 9-
Bromo-1-[(dimethylamino)methyl]-6
-(2,6-difluorophenyl)-4H-s-
Triazolo[4,3-a][1,4]benzodiazepine; 7-nitro-1-[(dimethylamino)
Methyl]-6-(p-chlorophenyl)-4H-
s-triazolo[4,3-a][1,4]benzodiazepine; 7-fluoro-1-[(dimethylamino)methyl]-6-(m-fluorophenyl)
-4H-s-triazolo [4,3-a] [1,4]
Benzodiazepine; 7-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-
Toluazolo[4,3-a][1,4]benzodiazepine; 9-trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a ] [1,
4] Benzodiazepine; 10-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]
[1,4]Benzodiazepine; 8-bromo-1-
[(dimethylamino)methyl]-6-phenyl-
4H-s-triazolo[4,3-a][1,4]benzodiazepine; 1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4] Benzodiazepine; 8-
Nitro-1-[(ethylmethylamino)methyl]
-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine; 8-fluoro-1-[(pyrrolidinomethyl)
-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine; 8-trifluoromethyl-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H ―
s-Triazolo[4,3-a][1,4]benzodiazepine; 9-bromo-1-[(4-methylpiperazino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a] [1,
4] Benzodiazepine; 9-nitro-1-[(diisopropylamino)methyl]-6-phenyl-
4H-s-triazolo[4,3-a][1,4]benzodiazepine; 10-fluoro-1-[(dipropylamino)methyl]-6-phenyl-4H-s
-Triazolo[4,3-a][1,4]benzodiazepine; 7-chloro-1-[(diethylamino)methyl]-6-(o-fluorophenyl)-
4H-s-triazolo[4,3-a][1,4]benzodiazepine; etc. The present invention is a method as described in the claims, and includes the following embodiments. 1 The starting compound is 3-amino-6-chloro-
5. The method of claim 4, wherein the quinazoline is 3,4-dihydro-4-hydroxy-4-phenylquinazoline. 2 The starting compound is 3-amino-6-chloro-
3,4-dihydro-4-hydroxy-4-(o
-chlorophenyl) quinazoline. 3. Process according to claim 4, wherein the starting compound is 3-amino-3,4-dihydro-4-hydroxy-4-phenylquinazoline. 4. Claims 2, 3, and 4, wherein the substituted methylene ammonium halide is dimethyl methylene ammonium chloride.
Section method. 5. The method of item 1 above, wherein the substituted methylammonium halide is dimethylmethylene ammonium chloride. 6. The method of item 2 above, wherein the substituted methylene ammonium halide is dimethyl methylene ammonium chloride. 7. The method of item 3 above, wherein the substituted methylene ammonium halide is dimethyl methylene ammonium chloride. 8 The halogenated acetic acid is trifluoroacetic acid,
A method according to claims 3 and 4. 9 formula [wherein rings A and B are unsubstituted or substituted with one or two substituents selected from the group consisting of fluoro, chloro, bromo, nitro, and trifluoromethyl]. 10 Formula A The compound according to the above item 9 [wherein R ₁ is hydrogen,
fluoro, chloro, bromo, nitro, or trifluoromethyl, R ₂ is hydrogen, fluoro, or chloro, and R ₃ is hydrogen, or
When R ₂ is also fluoro, it is fluoro]. 11 Formula B The compound according to the above item 9 [wherein R' ₁ and R' ₂
is hydrogen or chloro]. 12 formulas [wherein R' and R'' are alkyl of 1 to 3 carbon atoms, or taken together]

[Formula] is pyrrolidino, piperidino, morpholino, or N-methylpiperazino, and rings A and B are unsubstituted or fluoro, chloro, bromo,
[substituted with one to two substituents selected from the group consisting of nitro and trifluoromethyl]. 13 Formula A The compound according to the above item 12 [wherein R′ ₀ and R″ ₀ are 1 to
alkyl of 3 carbon atoms, R ₁ is hydrogen, fluoro, chloro, bromo, nitro, or trifluoromethyl, R ₂ is hydrogen, fluoro, or chloro, and R ₃ is hydrogen, or R ₂ is also fluoro when it is fluoro]. 14 Formula B [wherein R' ₁ and R' ₂ are hydrogen or chlorine]. 15 R′ ₁ is chloro and R′ ₂ is hydrogen, so the compound is 1,3-dioxo-2-isoindoline acetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo The compound of item 11 above, which is -2-isoindolineacetamide]methylene]hydrazide. 16 R′ ₁ and R′ ₂ are chloro, so the compound is 1,3-dioxo-2-isoindoline acetic acid,
[[N-[2-(o-chlorobenzoyl)-4-
The compound according to item 11, which is chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide. 17 R′ ₁ and R′ ₂ are hydrogen, so the compound is 1,
3-dioxo-2-isoindoline acetic acid, [[N
-(2-Benzoylphenyl)-1,3-dioxo-2-isoindolineacetamide]methylene]hydrazide, the compound according to item 11. 18 R′ ₁ is chloro and R′ ₂ is hydrogen, so the compound is 5-chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-
4H-1,2,4-triazol-4-yl]
15. The compound of item 14 above, which is benzophenone. 19 R′ ₁ and R′ ₂ are chloro, so the compound
2',5-dichloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)
-4H-1,2,4-triazol-4-yl]benzophenone, the compound of item 14 above. 20 R′ ₁ and R′ ₂ are hydrogen, so the compound is 2-
[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone,
The compound of item 14 above. 21 1 formula [In the formula, rings A and B are unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, and trifluoromethyl]. Corresponding compounds by treatment with halogenated acetic acid at 80-125 °C in solvent [In the formula, rings A and B have the above meanings], and the compound is expressed as the formula [In the formula, R′ and R″ are alkyl of 1 to 3 carbon atoms, or

[Formula] is pyrrolidino, piperidino, 4-methylpiperazino, or morpholino, and Hal is chlorine or bromine]
The corresponding compounds were treated with substituted methylene ammonium halides in an inert solvent at 25-100 °C. [In the formula, R′, R″ or

[Formula] and rings A and B are as defined above], and 3 treatment of the compound with hydrazine in an alkanol of 1 to 4 carbon atoms at 25-100°C gives the corresponding compound. a formula consisting of [In the formula, R′, R″, or

A process for producing a compound of the formula: and rings A and B are as defined above. 22 1 formula A compound of the formula [wherein rings A and B are unsubstituted or substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, and trifluoromethyl] [In the formula, R′ and R″ are alkyl of 1 to 3 carbon atoms, or

[Formula] is pyrrolidino, piperidino, 4-methylpiperazino or morpholino, and Hal is chlorine or bromine], and a substituted methylene ammonium halide compound of 25 to
The corresponding compounds were treated in an inert organic solvent at 100 °C. [In the formula, R′, R″ or

[Formula] and rings A and B are as defined above].
formula V, consisting of treatment in an alkanol of ~4 carbon atoms to obtain the corresponding compound [In the formula, R′, R″ or

A process for producing a compound of the formula: and rings A and B are as defined above. 23 formula [In the formula, R′ and R″ are alkyl of 1 to 3 carbon atoms, or

[Formula] is pyrrolidino, piperidino, 4-methylpiperazino, or morpholino, and rings A and B are unsubstituted or one or more members selected from the group consisting of fluoro, chloro, bromo, nitro, and trifluoromethyl. substituted by a substituent of] with hydrazine in an alkanol of 1 to 4 carbon atoms at 25 to 100°C to obtain the corresponding compound V, [In the formula, R′, R″, or

A process for producing a compound of the formula: and rings A and B are as defined above.

Claims (1)

[Claims] 1 1 Formula [In the formula, rings A and B are unsubstituted or fluoro,
substituted with one or more substituents selected from the group consisting of chloro, bromo, nitro, and trifluoromethyl. Substitution of [wherein R' and R'' are alkyl of 1 to 3 carbon atoms, or [formula] is pyrrolidino, piperidino, 4-methylpiperazino or morpholino, and Hal is chlorine or bromine] The corresponding compound can be obtained by treatment with methylene ammonium halide in an inert organic solvent at 25 to 100°C. [wherein R′, R″, or [Formula] and rings A and B are as defined above], and the compound is dissolved in an inert organic solvent from 25 to 100%
treatment with hydrazine at °C to obtain the corresponding compound, the formula [In the formula, R′, R″, or [Formula] and rings A and B are as defined above.] A method for producing a compound of the formula. 2 1 Formula [In the formula, rings A and B are unsubstituted or fluoro,
substituted with one or more substituents selected from the group consisting of chloro, bromo, nitro, and trifluoromethyl] in an inert organic solvent.
The corresponding compound was treated with halogenated acetic acid at °C. [In the formula, rings A and B are as defined above], and converting the compound into the formula Substitution of [wherein R' and R'' are alkyl of 1 to 3 carbon atoms, or [formula] is pyrrolidino, piperidino, 4-methylpiperazino or morpholino, and Hal is chlorine or bromine] The corresponding compound can be obtained by treatment with methylene ammonium halide in an inert organic solvent at 25 to 100°C. [In the formula, R′, R″, or [Formula] and rings A and B are as defined above]. 3. The compound is heated in an inert organic solvent at 25 to 100°C.
consisting of treatment with hydrazine to obtain the corresponding compound, with the formula [In the formula, R′, R″, or [Formula] and rings A and B are as defined above] A method for producing a compound of the formula: 3 1 In an inert organic solvent [In the formula, rings A and B are unsubstituted or fluoro,
substituted with one or more substituents selected from the group consisting of chloro, bromo, nitro, and trifluoromethyl. The corresponding compound was treated with 2 molar equivalents of bromide at -5 to +15°C. [In the formula, rings A and B are as defined above], and the compound was heated at 80 to 125°C in an inert organic solvent.
The corresponding compound by treatment with halogenated acetic acid
[In the formula, rings A and B are as defined above], and converting the compound to the formula Substitution of [wherein R' and R'' are alkyl of 1 to 3 carbon atoms, or [formula] is pyrrolidino, piperidino, 4-methylpiperazino or morpholino, and Hal is chlorine or bromine] The corresponding compound can be obtained by treatment with methylene ammonium halide in an inert organic solvent at 25 to 100°C. [In the formula, R′, R″, or [Formula] and rings A and B are as defined above], and 4. The compound was heated at 25 to 100°C in an inert organic solvent.
consisting of treatment with hydrazine to obtain the corresponding compound, with the formula [In the formula, R', R'', or [Formula] and rings A and B are as defined above].