36916-19-5

Usage

Uses

Used in Pharmaceutical Industry:
5-CHLOOR-2-(3-METHYL-4H-1,2,4-TRIAZOOL-4-YL)BENZOFENON is used as an impurity in the production of Alprazolam, a widely prescribed medication for the treatment of anxiety and panic disorders. Its presence as an impurity is significant for quality control and safety assessments in the pharmaceutical manufacturing process.
Used in Chemical Research:
As a chemical compound with unique structural features, 5-CHLOOR-2-(3-METHYL-4H-1,2,4-TRIAZOOL-4-YL)BENZOFENON may also be utilized in chemical research for the development of new compounds or the study of its properties and potential applications in various fields, such as materials science or pharmaceuticals.

InChI:InChI=1/C16H12ClN3O/c1-11-19-18-10-20(11)15-8-7-13(17)9-14(15)16(21)12-5-3-2-4-6-12/h2-10H,1H3

Synthetic route

7-Chloro-1-methyl-5-phenyl-s-triazolo<4,3-a>quinoline (36916-18-4) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5)

Conditions	Yield
With potassium permanganate; sodium periodate; potassium carbonate In water; acetone for 100.7h;	72.1%
Multi-step reaction with 2 steps 1: 20.8 percent / ozone in oxygen / methanol; CH2Cl2 / 12 h / cooling in an ice bath 2: 59.7 percent / AgNO3, 1N NaOH / methanol; H2O / 18 h / Ambient temperature View Scheme

4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carboxaldehyde (36916-20-8) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5)

Conditions	Yield
With sodium hydroxide; silver nitrate In methanol; water for 18h; Ambient temperature;	59.7%

alprazolam (28981-97-7) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) + triazolaminoquinoleine

Conditions	Yield
In methanol at 50℃; for 360h; aq. buffer; Irradiation;	A n/a B 50.65%

7-Chloro-1-methyl-5-phenyl-s-triazolo<4,3-a>quinoline (36916-18-4) → C17H12ClN3O (75158-63-3) + 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) + 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carboxaldehyde (36916-20-8)

Conditions	Yield
With ozone In methanol; dichloromethane at 0℃; for 12h;	A 4% B 43.5% C 20.8%

7-Chloro-1-methyl-5-phenyl-s-triazolo<4,3-a>quinoline (36916-18-4) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) + 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carboxaldehyde (36916-20-8)

Conditions	Yield
With ruthenium(IV) oxide; sodium periodate In water; acetone at 0 - 4℃; for 23.5h;	A 20.8% B 18%

alprazolam (28981-97-7) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5)

Conditions	Yield
With hydrogenchloride In methanol

alprazolam (28981-97-7) → U 31957 (28910-92-1) + 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) + triazolaminoquinoleine

Conditions	Yield
With hydrogenchloride In water for 8h; pH=3.6; Kinetics; Further Variations:; pH-values; UV-irradiation;

2,6-dichloro-4-phenylquinoline (10352-30-4) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 74.5 percent / hydrazin hydrate / 1 h / Heating 2: 83.9 percent / xylene / 2.67 h / Heating 3: 20.8 percent / ozone in oxygen / methanol; CH2Cl2 / 12 h / cooling in an ice bath 4: 59.7 percent / AgNO3, 1N NaOH / methanol; H2O / 18 h / Ambient temperature View Scheme

6-chloro-2-hydrazino-4-phenylquinoline (27537-93-5) → 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 83.9 percent / xylene / 2.67 h / Heating 2: 20.8 percent / ozone in oxygen / methanol; CH2Cl2 / 12 h / cooling in an ice bath 3: 59.7 percent / AgNO3, 1N NaOH / methanol; H2O / 18 h / Ambient temperature View Scheme

5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) → 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone (38150-27-5)

Conditions	Yield
With paraformaldehyde In 5,5-dimethyl-1,3-cyclohexadiene	72.8%

N,N-dimethyl-formamide (68-12-2, 33513-42-7) + 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) → 7-Chloro-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline-4-carbaldehyde (121899-10-3) + (Z)-2-[4-(2-Benzoyl-4-chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-3-dimethylamino-propenal (121899-09-0)

Conditions	Yield
With phosphorus pentachloride In N,N-dimethyl-formamide 1) O deg C, 6 h, 2) room temperature, 4 d;	A 160 mg B 14%

acetic anhydride (108-24-7) + 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) → triazolaminoquinoleine

Conditions	Yield
Stage #1: acetic anhydride; 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone In tetrahydrofuran at 20℃; for 3h; pH=9.0; Stage #2: With potassium hydroxide In methanol at 91℃; for 6h;

5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (36916-19-5) → 2-(3-bromo-5-methyl-[1,2,4]triazol-4-yl)-5-chloro-benzophenone (55932-51-9)

Conditions	Yield
With N-Bromosuccinimide In tetrachloromethane

Upstream product

• 36916-18-4 7-Chloro-1-methyl-5-phenyl-s-triazolo<4,3-a>quinoline 
• 36916-20-8 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carboxaldehyde 
• 28981-97-7 alprazolam 
• 10352-30-4 2,6-dichloro-4-phenylquinoline 
• 27537-93-5 6-chloro-2-hydrazino-4-phenylquinoline 

Downstream Products

• 55932-51-9 2-(3-bromo-5-methyl-[1,2,4]triazol-4-yl)-5-chloro-benzophenone 
• 38150-27-5 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone 
• 121899-10-3 7-Chloro-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline-4-carbaldehyde 
• 121899-09-0 (Z)-2-[4-(2-Benzoyl-4-chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-3-dimethylamino-propenal 

Relevant academic research and scientific papers

Isolation and structural elucidation of degradation products of alprazolam: Photostability studies of alprazolam tablets

Accelerated thermal, hydrolytic, and photochemical degradations of alprazolam were performed under several reaction conditions. The stress studies revealed the photolability of the drug as the most adverse stability factor; the main photodegradation products were isolated and properly characterized as: triazolaminoquinoleine; 5-chloro-[5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, and 1-methyl-6-phenyl-4h-s-triazo- [4,3-α][1,4]benzodiazepinone. Accelerated pH-dependent studies show that the photoinstability increases as the pH decreases; at pH 9.0, photodegradation does not occur, therefore, the photochemical degradation of alprazolam was performed in buffered solutions at pH 2.0 and 3.6. The higher rate of reaction was observed at pH = 2.0; consequently, acidic conditions should be avoided and appropriate light protection is recommended during the drug-development process, storage, and handling. The main degradation route for alprazolam tablets is also photochemical.

Identification of Alprazolam and its degradation products using LC-MS-MS

An efficient LC/MS/MS methodology for the analysis of Alprazolam API and Alprazolam tablets was developed. The analysis of the MS2 fragmentation profile, obtained from only one chromatographic assay, allows the identification of Alprazolam, its main degradation product, triazoaminoquinoleine (Imp G), the analysis of the MS3 spectra allows the identification of 5-chloro-[5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (Imp C) and with SIM mode the 5-chloro-[2-(3-aminomethyl-5-methyl-1,2,4-triazol- 4-yl]benzophenone, opened-ring Alprazolam, proposed as precursor of triazoaminoquinoleine in basic and acid hydrolysis and only detected before by NMR analysis, was identified. With this method it is possible to study samples with only one chromatographic run, identifying unequivocally the impurities present, taking advantage of the MS-MS resource.

Kinetic and mechanistic studies on the hydrolysis and photodegradation of diazepam and alprazolam

The corresponding o-aminobenzophenones are usually reported as the main degradation products in the hydrolysis of 1,4-benzodiazepinones. Nevertheless, in previous studies of diazepam (DZ) in acidic aqueous medium we isolated and characterized seven unexpected degradation products. Kinetic measurements under several reaction conditions shed some light on the mechanisms of the complex reactions that are taking place, and photochemical studies give hints on the mechanisms of chlorination and annelation processes. Alprazolam (AL) seems to exhibit an unusually high stability against hydrolysis under several conditions; nevertheless, the structure is sensitive to photolytic cleavage. The photodegradation of AL was studied in aqueous and methanolic solutions. Characterization of the isolated products by 1H and 13C NMR and mass spectrometry revealed that electron transfer, oxidation and rearrangement reactions take place. The influence of several variables such as pH, solvent composition and light irradiation were examined and mechanisms for the formation of three photoproducts are proposed. A specific method for the determination of AL in the presence of photoproducts was developed, which allowed kinetic determinations of the photostability of AL. The photosensitivity observed in some patients treated with AL seems to be due to one of the characterized photoproducts. Copyright

Novel synthesis of the pharmacologically important 1-substituted-6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines

Several 6-phenyl-4H-s-triazolo[4,3-α][1,4]benzodiazepines have useful biological activity both in experimental animals and in man. This manuscript describes a novel synthesis of these compounds from intermediates that do not have a pre-formed benzodiazepine ring system.

2-[3-(Phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenones

A process to make 6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepines by converting 2-[3-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenones to 2-[3-[(phthalimido or methanesulfonyl)methyl]-4H-1,2,4-triazol-4-yl]benzophenones and converting these compounds to the highly active 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines useful as tranquilizers and sedatives.

Triazolyl benzophenone compounds

Intermediates of the formula IV: STR1 wherein R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; and wherein R2, R3, and R4 are selected from the group consisting of hydrogen, fluoro, chloro, bromo, nitro, and trifluoromethyl are produced by a multistep synthesis. The final compounds are tranquilizers and sedatives and can be used in mammals, including man, and in birds.