Preparation method of triazolone-14C

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of triazolone-14C. Comprising the following steps: synthesizing phenol-14C: preparing a system A: adding water and concentrated sulfuric acid into a single-mouth bottle and stirring; performing liquid separation on aniline hydrochloride-14C and a saturated sodium bicarbonate solution, performing extraction, adding an organic phase into the system A, performing reaction concentration, dropwise adding sodium nitrite, adding methylbenzene, and performing reaction at 100 DEG C; extracting, drying, filtering, concentrating, and passing through a chromatographic column; the preparation method comprises the following steps: synthesizing 4-chlorophenol-14C, namely dropwise adding N-chlorosuccinimide into 4-chlorophenol-14C, p-toluenesulfonic acid and acetonitrile, and reacting completely; extracting, drying, filtering, concentrating, and passing through a chromatographic column; 4-chlorophenol-14C, ethyl acetate, 1, 2, 4-triazole, potassium carbonate and 600 polyethylene glycol are synthesized, 1, 1-dichloropinacolone is dropwise added, and a reaction is conducted at the temperature of 85 DEG C; after the reaction is finished, cooling to room temperature, extracting, drying, filtering, concentrating, and passing through a chromatographic column; the total yield of the three steps is basically maintained between 60% and 85%, the synthetic reaction conditions are simple, and the yield is high.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a triazolone- 14 Preparation method of C. Background Technology

[0002] The description of the background art in this invention pertains to related technologies and is used merely for illustration and to facilitate understanding of the invention. It should not be construed as the applicant explicitly believing or presuming that the invention was prior art on the filing date of the first application.

[0003] Triadimefon is a highly effective, broad-spectrum, systemic fungicide with preventative, curative, and bactericidal effects. Its fungicidal mechanism primarily involves inhibiting the biosynthesis of ergosterol in pathogenic fungi, disrupting cell structure, thereby inhibiting or interfering with the development of appressorium and haustoria, and suppressing mycelial growth and spore formation. As a preferred control agent for various crop diseases, triadimefon is effective in controlling wheat rust and powdery mildew, corn and sorghum head smut, and corn spot disease; it also shows significant control effects against wheat take-all, smut, loose smut, leaf blight, and clouding disease; furthermore, it has good control effects against powdery mildew in cucurbits, tobacco, mulberry, and apple trees. It is relatively safe for fish and birds; and harmless to bees and natural enemies.

[0004] Triadimefon is mainly produced by condensing monochlorophenanthone with p-chlorophenol, followed by dichlorothioyl chlorination, and finally condensing with 1H-1,2,4-triazole to synthesize triadimefon.

[0005] Preparation Method 1: Ammonium formate is prepared by passing ammonia gas into formic acid, and then reacted with hydrazine hydrate to obtain 1,2,4-triazole. Isoamyl alcohol is dehydrated and transposed to form isopentene under the catalysis of activated alumina. 2-Methyl-1-butene and 2-methyl-2-butene are added with hydrogen chloride to form chloropentane. Then, it reacts with formaldehyde in acidic solution to form pinacolone, and chlorination is passed through it in the presence of a solvent to obtain monochloropinacolone. Monochloropinacolone reacts with p-chlorophenol in the presence of potassium carbonate in toluene to prepare 1-(4-chlorophenoxy)pinacolone, which is then chlorinated with thiocyanate to obtain 1-(4-chlorophenoxy)-1-chloropinacolone. Finally, it is reacted with 1,2,4-triazole to synthesize triazolone. The reaction can also be carried out in acetone solvent, using sodium iodide as catalyst and anhydrous potassium carbonate as acid-binding agent to synthesize ether ketones, and then reacting with thioyl chloride in carbon tetrachloride solvent to obtain α-chloroether ketones in quantitative yield, and then reacting with 1,2,4-triazole in acetone solvent to synthesize triazole ketones.

[0006] Preparation Method 2: In the presence of anhydrous sodium carbonate and carbon tetrachloride solvent, 1,2,4-triazole is chlorinated at 35°C to obtain 1-chloro-1,2,4-triazole. This 1-chloro-1,2,4-triazole is then used as a chlorine atom donor to react with a ketone ether, causing a substitution reaction at the α-position of the alkyl group to generate α-chloroketone ether. This reaction requires the presence of an initiator such as azobisisobutyronitrile (AIBN). Simultaneously, the triazole produced from the chlorotriazole precipitates from the reaction solvent. Since the triazole itself is also a pure acid, triazolone is generated during the continued reaction. After the addition of triazole or an acid-binding agent, the α-chloroketone ether is completely reacted.

[0007] The disadvantages are that it is relatively complex, requires demanding operating conditions, and has high production costs. Summary of the Invention

[0008] The purpose of this invention is to provide a triazolone- 14 The preparation method of C, in this invention, uses aniline hydrochloride- 14 C is used as a raw material to synthesize triazolone- 14 C represents a completely new synthetic route, the key being the initiation of the synthesis of phenol from labeled aniline hydrochloride. 14 C and 4-chlorophenol- 14 C reacts with dichloropinazone to give the desired labeled triazolone. 14 C, filling the gap in the domestic synthesis of isotope-labeled triazolone derivatives.

[0009] A triazolone- 14 The preparation method of C includes the following steps: Synthetic phenol- 14 C: Prepare system A, which is: add 5ml of water and 0.4ml of concentrated sulfuric acid to a 100ml single-necked bottle, stir at 0℃ and set aside for use; Aniline hydrochloride - 14 After separation and extraction of C and saturated sodium bicarbonate solution, the organic phase is added to system A for reaction and concentration. The mixture is then cooled to 0°C, sodium nitrite is added dropwise, and the temperature is controlled at 0-5°C. 5 ml of toluene is added, and the mixture is heated to 100°C for reaction. After the reaction is complete, the mixture is cooled to room temperature, extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthesis of 4-chlorophenol- 14 C: Phenol - 14 C. P-Toluenesulfonic acid and acetonitrile were reacted dropwise with N-chlorosuccinimide until the reaction was complete; the mixture was then extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthetic triazolone- 14 C: 4-Chlorophenol- 14 C and ethyl acetate 5ml, 1,2,4-triazole, potassium carbonate, 600 polyethylene glycol, 1,1-dichloropinazone added dropwise, reacted at 85℃; after the reaction was complete, cooled to room temperature, extracted, dried, filtered and concentrated and passed through a chromatography column;

[0010] Furthermore, the specific steps include the following: Synthetic phenol- 14 C: Preparation of System A: Add 5ml of water and 0.4ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; Add aniline hydrochloride to the separatory funnel. 14 C (131.6 mg, 1.0 eq) and 20 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (15 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (75.9 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 5 ml of toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (30 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 96 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (96 mg, 1.0 eq), p-toluenesulfonic acid (73 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (113.5 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with dichloromethane (30 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 121.4 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (121.4 mg, 1.0 eq) was mixed with 5 ml of ethyl acetate, 1,2,4-triazole (83.5 mg, 1.3 eq), potassium carbonate (287.5 mg, 2.24 eq), and 600% polyethylene glycol (279 mg, 0.5 eq). The mixture was heated to 85 °C, and 1,1-dichloropinazone (157.2 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with ethyl acetate (30 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 275 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 246.6 mg, with a yield of 89.66%.

[0011] Furthermore, the specific steps include the following: Synthetic phenol- 14C: Preparation of System A: Add 10ml of water and 0.8ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; add aniline hydrochloride to a separatory funnel. 14 C (263.2 mg, 1.0 eq) and 40 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (20 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (151.8 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 10 ml toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (40 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 192 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (192 mg, 1.0 eq), p-toluenesulfonic acid (146 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (227 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with dichloromethane (40 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 248 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (248 mg, 1.0 eq) was mixed with 10 ml of ethyl acetate, 1,2,4-triazole (170.6 mg, 1.3 eq), potassium carbonate (587.2 mg, 2.24 eq), and 600% polyethylene glycol (570 mg, 0.5 eq). The mixture was heated to 85 °C, and 1,1-dichloropinazone (321 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 35 ml of water was added, and the mixture was extracted with ethyl acetate (40 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 560 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 505.6 mg.

[0012] Furthermore, the specific steps include the following: Synthetic phenol- 14 C: Preparation of System A: Add 25ml of water and 2.0ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; add aniline hydrochloride to a separatory funnel. 14C (658 mg, 1.0 eq) and 100 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (30 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (379.5 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 15 ml of toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (50 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 480 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (480 mg, 1.0 eq), p-toluenesulfonic acid (365 mg, 0.425 eq) and 15 ml acetonitrile were added dropwise to N-chlorosuccinimide (567.5 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 50 ml of water was added, and the mixture was extracted with dichloromethane (50 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 613.6 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (613.6 mg, 1.0 eq) was mixed with 15 ml of ethyl acetate, 1,2,4-triazole (422 mg, 1.3 eq), potassium carbonate (1452.9 mg, 2.24 eq), and 600% polyethylene glycol (1412.4 mg, 0.5 eq). The mixture was heated to 85 °C, and 1,1-dichloropinazone (794.6 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with ethyl acetate (50 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 1390 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 1256.7 mg.

[0013] The embodiments of the present invention have the following beneficial effects: This invention uses aniline hydrochloride- 14 C is used as a raw material to synthesize triazolone- 14 C represents a completely new synthetic route, the key being the initiation of the synthesis of phenol from labeled aniline hydrochloride. 14 C and 4-chlorophenol- 14 C reacts with dichloropinazone to give the desired labeled triazolone. 14 C, filling the gap in the domestic synthesis of isotope-labeled triazolone derivatives.

[0014] 1. This invention avoids the use of reaction equipment with high airtightness requirements, and directly uses other readily available raw materials and labeled aniline hydrochloride as starting materials. The reaction conditions are mild and easy to implement. 2. This invention presents a completely new synthetic route that enables the labeling of triazolone derivatives; 3. The overall yield of the three steps in this invention is basically maintained between 60% and 85%, and the synthesis reaction conditions are simple and the yield is high. Detailed Implementation

[0015] The present application will be further described below with reference to the embodiments.

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, in the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Different embodiments can be substituted or combined, and for those skilled in the art, other implementation methods can be obtained based on these embodiments without creative effort.

[0017] A triazolone- 14 The preparation method of C includes the following steps: Synthetic phenol- 14 C: Prepare system A, which is: add 5ml of water and 0.4ml of concentrated sulfuric acid to a 100ml single-necked bottle, stir at 0℃ and set aside for use; Aniline hydrochloride - 14 After separation and extraction of C and saturated sodium bicarbonate solution, the organic phase is added to system A for reaction and concentration. The mixture is then cooled to 0°C, sodium nitrite is added dropwise, and the temperature is controlled at 0-5°C. 5 ml of toluene is added, and the mixture is heated to 100°C for reaction. After the reaction is complete, the mixture is cooled to room temperature, extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthesis of 4-chlorophenol- 14 C: Phenol - 14 C. P-Toluenesulfonic acid and acetonitrile were reacted dropwise with N-chlorosuccinimide until the reaction was complete; the mixture was then extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthetic triazolone- 14 C: 4-Chlorophenol- 14 C and ethyl acetate 5ml, 1,2,4-triazole, potassium carbonate, 600 polyethylene glycol, 1,1-dichloropinazone added dropwise, reacted at 85℃; after the reaction was complete, cooled to room temperature, extracted, dried, filtered and concentrated and passed through a chromatography column;

[0018] Example 1. Synthesis of phenol - 14 C: Prepare system A: Add 5ml of water and 0.4ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside.

[0019] Add aniline hydrochloride to the separatory funnel. 14 C (131.6 mg, 1.0 eq) and 20 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (15 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0°C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0°C, and sodium nitrite (75.9 mg, 1.1 eq) was added dropwise. The temperature was maintained at 0-5°C for 2 hours. Then, 5 ml of toluene was added, and the temperature was raised to 100°C for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (30 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 96 mg of phenol. 14 C, yield 100%.

[0020] Synthesis of 4-chlorophenol- 14 C: Phenol was added to a 50ml three-necked flask under nitrogen protection. 14 C (96 mg, 1.0 eq), p-toluenesulfonic acid (73 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (113.5 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours.

[0021] After the reaction was complete, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with dichloromethane (30 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 121.4 mg of 4-chlorophenol, with a yield of 93%.

[0022] Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (121.4 mg, 1.0 eq) and 5 ml of ethyl acetate, 1,2,4-triazole (83.5 mg, 1.3 eq), potassium carbonate (287.5 mg, 2.24 eq), and 600 polyethylene glycol (279 mg, 0.5 eq) were added. The mixture was heated to 85 °C, and 1,1-dichloropinazone (157.2 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours.

[0023] After the reaction was complete, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with ethyl acetate (30 ml × 3). It was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 275 mg of the crude compound. 14 C-triazolone was prepared and purified to obtain 246.6 mg, with a yield of 89.66% and an overall yield of 83.38%.

[0024] Example 2. Synthesis of phenol - 14 C: Prepare system A: Add 10ml of water and 0.8ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside.

[0025] Add aniline hydrochloride to the separatory funnel. 14 C (263.2 mg, 1.0 eq) and 40 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (20 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0°C for 20 minutes. The DCM was then concentrated to dryness. The mixture was cooled to 0°C, and sodium nitrite (151.8 mg, 1.1 eq) was added dropwise. The temperature was maintained at 0-5°C for 2 hours. Then, 10 ml of toluene was added, and the mixture was heated to 100°C for 2 hours. After the reaction was complete, a product was formed. The mixture was cooled to room temperature, extracted with ethyl acetate (40 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography to obtain 192 mg of phenol. 14 C, yield 100%.

[0026] Synthesis of 4-chlorophenol- 14 C: Phenol was added to a 50ml three-necked flask under nitrogen protection. 14 C (192 mg, 1.0 eq), p-toluenesulfonic acid (146 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (227 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours.

[0027] After the reaction was complete, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with dichloromethane (40 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 248 mg of 4-chlorophenol, with a yield of 95%.

[0028] Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (248 mg, 1.0 eq) and 10 ml of ethyl acetate, 1,2,4-triazole (170.6 mg, 1.3 eq), potassium carbonate (587.2 mg, 2.24 eq), and 600 polyethylene glycol (570 mg, 0.5 eq) were added. The mixture was heated to 85 °C, and 1,1-dichloropinazone (321 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours.

[0029] After the reaction was complete, the mixture was cooled to room temperature, 35 ml of water was added, and the mixture was extracted with ethyl acetate (40 ml × 3). It was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 560 mg of the crude compound. 14C-triazolone was prepared and purified to obtain 505.6 mg, with a yield of 90.01% and an overall yield of 85.49%.

[0030] Example 3. Synthesis of phenol - 14 C: Prepare system A: Add 25ml of water and 2.0ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside.

[0031] Add aniline hydrochloride to the separatory funnel. 14 C (658 mg, 1.0 eq) and 100 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (30 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0°C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0°C, and sodium nitrite (379.5 mg, 1.1 eq) was added dropwise. The temperature was maintained at 0-5°C for 2 hours. Then, 15 ml of toluene was added, and the temperature was raised to 100°C for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (50 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 480 mg of phenol. 14 C, yield 100%.

[0032] Synthesis of 4-chlorophenol- 14 C: Phenol was added to a 50ml three-necked flask under nitrogen protection. 14 C (480 mg, 1.0 eq), p-toluenesulfonic acid (365 mg, 0.425 eq) and 15 ml acetonitrile were added dropwise at 10 °C to N-chlorosuccinimide (567.5 mg, 0.85 eq), and the reaction was carried out at 30 °C for 5 hours.

[0033] After the reaction was complete, the mixture was cooled to room temperature, 50 ml of water was added, and the mixture was extracted with dichloromethane (50 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 613.6 mg of 4-chlorophenol, with a yield of 94%.

[0034] Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (613.6 mg, 1.0 eq) and 15 ml of ethyl acetate, 1,2,4-triazole (422 mg, 1.3 eq), potassium carbonate (1452.9 mg, 2.24 eq), and 600 polyethylene glycol (1412.4 mg, 0.5 eq) were added. The mixture was heated to 85 °C, and 1,1-dichloropinazone (794.6 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours.

[0035] After the reaction was complete, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with ethyl acetate (50 ml × 3). It was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 1390 mg of the crude compound. 14 C-triazolone was prepared and purified to obtain 1256.7 mg, with a yield of 90.41% and an overall yield of 84.99%.

[0036] This invention uses aniline hydrochloride- 14 C is used as a raw material to synthesize triazolone- 14 C represents a completely new synthetic route, the key being the initiation of the synthesis of phenol from labeled aniline hydrochloride. 14 C and 4-chlorophenol- 14 C reacts with dichloropinazone to give the desired labeled triazolone. 14 C, filling the gap in the domestic synthesis of isotope-labeled triazolone derivatives.

[0037] 1. This invention avoids the use of reaction equipment with high airtightness requirements, and directly uses other readily available raw materials and labeled aniline hydrochloride as starting materials. The reaction conditions are mild and easy to implement. 2. This invention presents a completely new synthetic route that enables the labeling of triazolone derivatives; 3. The overall yield of the three steps in this invention is basically maintained between 60% and 85%, and the synthesis reaction conditions are simple and the yield is high.

[0038] This invention is also applicable to the isotope labeling synthesis of triazolone derivatives. 13 Synthesis of C.

[0039] It should be noted that the above embodiments can be freely combined as needed. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A triazolone- 14 The method for preparing C is characterized by, Includes the following steps: Synthetic phenol- 14 C: Prepare system A, which is: add water and concentrated sulfuric acid to a single-necked flask, stir and set aside; Aniline hydrochloride - 14 After separation and extraction of C and saturated sodium bicarbonate solution, the organic phase is added to system A for reaction and concentration. The mixture is then cooled to 0°C, sodium nitrite is added dropwise, and the temperature is controlled at 0-5°C. Toluene is added, and the mixture is heated to 100°C for reaction. After the reaction is complete, the mixture is cooled to room temperature, extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthesis of 4-chlorophenol- 14 C: Phenol- 14 C. P-Toluenesulfonic acid and acetonitrile were reacted dropwise with N-chlorosuccinimide until the reaction was complete; the mixture was then extracted, dried, filtered, concentrated, and passed through a chromatography column. Synthetic triazolone- 14 C: 4-Chlorophenol- 14 C and ethyl acetate, 1,2,4-triazole, potassium carbonate, 600 polyethylene glycol, 1,1-dichloropinazone were added dropwise, and the reaction was carried out at 85°C. After the reaction was completed, the mixture was cooled to room temperature, extracted, dried, filtered, and concentrated before being passed through a chromatography column.

2. The triazolone- according to claim 1 14 The method for preparing C is characterized by, Specifically, the steps include the following: Synthetic phenol- 14 C: Preparation of System A: Add 5ml of water and 0.4ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; Add aniline hydrochloride to the separatory funnel. 14 C (131.6 mg, 1.0 eq) and 20 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (15 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (75.9 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 5 ml of toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (30 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 96 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (96 mg, 1.0 eq), p-toluenesulfonic acid (73 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (113.5 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with dichloromethane (30 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 121.4 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (121.4 mg, 1.0 eq) was mixed with 5 ml of ethyl acetate, 1,2,4-triazole (83.5 mg, 1.3 eq), potassium carbonate (287.5 mg, 2.24 eq), and 600% polyethylene glycol (279 mg, 0.5 eq). The mixture was heated to 85 °C, and 1,1-dichloropinazone (157.2 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 20 ml of water was added, and the mixture was extracted with ethyl acetate (30 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 275 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 246.6 mg, with a yield of 89.66%.

3. The triazolone- according to claim 1 14 The method for preparing C is characterized by, Specifically, the steps include the following: Synthetic phenol- 14 C: Preparation of System A: Add 10ml of water and 0.8ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; add aniline hydrochloride to a separatory funnel. 14 C (263.2 mg, 1.0 eq) and 40 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (20 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (151.8 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 10 ml toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (40 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 192 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (192 mg, 1.0 eq), p-toluenesulfonic acid (146 mg, 0.425 eq) and 5 ml acetonitrile were added dropwise to N-chlorosuccinimide (227 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with dichloromethane (40 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 248 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (248 mg, 1.0 eq) was mixed with 10 ml of ethyl acetate, 1,2,4-triazole (170.6 mg, 1.3 eq), potassium carbonate (587.2 mg, 2.24 eq), and 600% polyethylene glycol (570 mg, 0.5 eq). The mixture was heated to 85 °C, and 1,1-dichloropinazone (321 mg, 1.0 eq) was added dropwise. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 35 ml of water was added, and the mixture was extracted with ethyl acetate (40 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 560 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 505.6 mg.

4. The triazolone- according to claim 1 14 The method for preparing C is characterized by, Specifically, the steps include the following: Synthetic phenol- 14 C: Preparation of System A: Add 25ml of water and 2.0ml of concentrated sulfuric acid to a 100ml single-necked flask, stir at 0℃ and set aside; add aniline hydrochloride to a separatory funnel. 14 C (658 mg, 1.0 eq) and 100 ml saturated sodium bicarbonate solution were added, followed by extraction with DCM (30 ml * 4). The organic phase was added to system A, and the reaction was carried out at 0 °C for 20 minutes. The DCM was then concentrated to dryness. The temperature was lowered to 0 °C, and sodium nitrite (379.5 mg, 1.1 eq) was added dropwise. The temperature was controlled at 0-5 °C and maintained for 2 hours. 15 ml of toluene was added, and the temperature was raised to 100 °C and reacted for 2 hours. After the reaction was complete, a product was formed. The temperature was lowered to room temperature, and the product was extracted with ethyl acetate (50 ml × 3). The product was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 480 mg of phenol. 14 C; Synthesis of 4-chlorophenol- 14 C: Under nitrogen protection, add phenol to a 50ml three-necked flask. 14 C (480 mg, 1.0 eq), p-toluenesulfonic acid (365 mg, 0.425 eq) and 15 ml acetonitrile were added dropwise to N-chlorosuccinimide (567.5 mg, 0.85 eq) at 10 °C, and the reaction was carried out at 30 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 50 ml of water was added, and the mixture was extracted with dichloromethane (50 ml × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 613.6 mg of 4-chlorophenol. Synthetic triazolone- 14 C: Under nitrogen protection, add p-chlorophenol to a 100ml three-necked flask. 14 C (613.6 mg, 1.0 eq) and 15 ml of ethyl acetate, 1,2,4-triazole (422 mg, 1.3 eq), potassium carbonate (1452.9 mg, 2.24 eq), and 600% polyethylene glycol (1412.4 mg, 0.5 eq) were added. The mixture was heated to 85 °C, and 1,1-dichloropinazone (794.6 mg, 1.0 eq) was added dropwise. The reaction was carried out at 85 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, 40 ml of water was added, and the mixture was extracted with ethyl acetate (50 ml × 3). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a chromatography column to obtain 1390 mg of crude compound. 14 C-triazolone was prepared and purified to obtain 1256.7 mg.

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