Preparation method and use of myocardial perfusion imaging agent precursor

Abstract

The present application provides a preparation method and use of a myocardial perfusion imaging agent precursor. The method of the present application avoids the use of explosive sodium azide by redesigning the synthesis route of the myocardial perfusion imaging agent precursor, thereby increasing production safety. At the same time, all materials involved in the route are commercialized products, which are cheap and easy to obtain, thereby reducing production costs.

Description

[0001] This case is a divisional application of a case with an application date of July 26, 2022, an invention name of "Method for preparing myocardial perfusion imaging agent precursor and its use", and an application number of 202210886122.X. Technical Field

[0002] The present application belongs to the field of biomedicine, and specifically relates to a preparation method of a myocardial perfusion imaging agent precursor and its use. Background Art

[0003] A novel fluorine-18 labeled myocardial perfusion imaging agent, the structural formula of which is as follows:

[0004]

[0005] 2-(2-((1-(3-((((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy-4-toluenesulfonate is an important intermediate for preparing the novel fluorine-18 labeled myocardial perfusion imaging agent. The structural formula of 2-(2-((1-(3-((((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy-4-toluenesulfonate is as follows:

[0006]

[0007] So far, the synthesis route of the precursor is reported as follows: Chinese patent CN103113354B discloses a method of preparing the precursor by multi-step reaction using furfural as the starting material. The route is as follows:

[0008]

[0009] This patented route uses the explosive substance sodium azide in the process of constructing the triazole ring, which has low operational safety and is difficult to produce commercially. Summary of the invention

[0010] In view of the above problems existing in the prior art, the present application provides a method for preparing a myocardial perfusion imaging agent precursor to overcome the shortcomings of the prior art products such as high production cost, complicated production operation and low safety.

[0011] Specifically, this application involves the following aspects:

[0012] 1. A method for preparing compound VI, characterized in that compound I and compound V are reacted to obtain compound VI,

[0013] Wherein compound VI is as follows:

[0014]

[0015] Compound I is shown below:

[0016]

[0017] Compound V is shown below:

[0018]

[0019] 2. The method according to item 1, characterized in that the method comprises the step of reacting compound IV with 1H-1,2,3-thiazole-4-methanol to obtain compound V:

[0020]

[0021] 3. The method according to item 2, characterized in that compound IV reacts with 1H-1,2,3-thiazole-4-methanol in the presence of a base,

[0022] Preferably, the base used in the reaction of compound IV with 1H-1,2,3-thiazole-4-methanol is potassium carbonate, and the solvent is acetone.

[0023] More preferably, the reaction temperature of compound IV and 1H-1,2,3-thiazole-4-methanol is 50-60°C.

[0024] 4. The method according to item 2, characterized in that the method comprises the step of reacting compound III with phosphorus tribromide to obtain compound IV:

[0025]

[0026] Preferably, the solvent used for the reaction of compound III with phosphorus tribromide is toluene, and the reaction temperature is 80-100°C.

[0027] 5. The method according to item 4, characterized in that the method comprises the step of reacting compound II with 1,3-benzenedimethanol to obtain compound III:

[0028]

[0029] Preferably, compound II is reacted with 1,3-benzenedimethanol in the presence of a base.

[0030] More preferably, the base used in the reaction of compound II with 1,3-benzenedimethanol is cesium carbonate, and the solvent is acetonitrile.

[0031] More preferably, the reaction temperature of compound II and 1,3-benzenedimethanol is 80-90°C.

[0032] 6. The method according to item 5, characterized in that the method comprises the step of reacting furochloric acid with tert-butylhydrazine hydrochloride to obtain compound II:

[0033]

[0034] Preferably, furochloric acid is reacted with tert-butylhydrazine hydrochloride at a temperature below 10° C., and the resulting product is refluxed with glacial acetic acid in dichloromethane for 4 to 6 hours to obtain compound II.

[0035] 7. The method according to item 1, characterized in that the method further comprises the step of reacting diethylene glycol with p-toluenesulfonyl chloride to obtain compound I:

[0036]

[0037] Preferably, diethylene glycol reacts with p-toluenesulfonyl chloride in the presence of an acid binding agent and a catalyst.

[0038] More preferably, the acid binding agent is triethylamine, and the catalyst is DMAP.

[0039] More preferably, the solvent used in the reaction of diethylene glycol and p-toluenesulfonyl chloride is one or both of dichloromethane and dichloroethane, and the reaction temperature is 20-40°C.

[0040] 8. The method according to item 1, characterized in that compound I and compound V react in the presence of a base,

[0041] Preferably, the base used in the reaction of Compound I and Compound V is sodium hydride, and the solvent is tetrahydrofuran. More preferably, the reaction temperature of Compound I and Compound V is 60-70°C.

[0042] 9. A compound VI, which is prepared by the method described in any one of items 1 to 8, wherein the compound VI is as follows:

[0043]

[0044] 10. Use of the compound VI prepared by the method of any one of items 1 to 8 or the compound VI described in item 8 for preparing a myocardial perfusion imaging agent.

[0045] The method of the present application avoids the use of explosive sodium azide by redesigning the synthesis route of the myocardial perfusion imaging agent precursor, thereby increasing production safety. At the same time, all materials involved in this route are commercialized products, which are cheap and easy to obtain, thereby reducing production costs. DETAILED DESCRIPTION

[0046] The present application is further described below in conjunction with examples. It should be understood that the examples are only used to further describe and illustrate the present application and are not used to limit the present application.

[0047] Unless otherwise defined, the technical and scientific terms in this specification have the same meaning as those generally understood by those skilled in the art. Although similar or identical methods and materials as described herein may be used in experiments or practical applications, materials and methods are described herein below. In the event of a conflict, the present specification including the definitions therein shall prevail. In addition, materials, methods and examples are provided for illustration only and are not restrictive. The present application is further described below in conjunction with specific embodiments, but is not intended to limit the scope of the present application.

[0048] The purpose of the present application is to provide a novel method for synthesizing compound VI, wherein compound VI is 2-(2-((1-(3-((((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy-4-toluenesulfonate, which is an important intermediate of a novel fluorine-18 labeled myocardial perfusion imaging agent. The structural formula of compound VI is as follows:

[0049]

[0050] The method of the present application is to obtain compound VI by reacting compound I and compound V, wherein compound I is as follows:

[0051]

[0052] Compound V is shown below:

[0053]

[0054] In a specific embodiment, compound I and compound V react in the presence of a base in a solvent. The base and the solvent may be bases and solvents well known in the art. Preferably, the base is sodium hydride and the solvent is tetrahydrofuran. Further preferably, the reaction temperature is 60 to 70°C, for example, 60°C, 62°C, 65°C, 68°C, or 70°C.

[0055] In a specific embodiment, compound I, sodium hydride and anhydrous tetrahydrofuran are mixed and stirred evenly, and the temperature is raised to 60-70°C. Then the mixed solution of compound V is slowly added dropwise to the reaction system, and the reaction is carried out at 60-70°C for 2 hours after the addition is completed. The reaction solution is cooled to room temperature, stirred with water, and then extracted twice with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is spin-dried to obtain compound VI.

[0056] Furthermore, the method of the present application may also include the step of reacting compound IV with 1H-1,2,3-thiazole-4-methanol to obtain compound V. The specific reaction is as follows:

[0057]

[0058] In a specific embodiment, compound IV reacts with 1H-1,2,3-thiazole-4-methanol in the presence of a base in a solvent. The base and the solvent may be bases and solvents well known in the art. Preferably, the base is potassium carbonate and the solvent is acetone. Further preferably, the reaction temperature is 50 to 60°C, for example, 50°C, 52°C, 55°C, 58°C, 60°C.

[0059] In a specific embodiment, compound IV is mixed with acetone (200 ml) and stirred evenly, and 1H-1,2,3-thiazole-4-methanol and potassium carbonate are added. After the addition, the temperature is raised to 50-60° C. and reacted for 12 hours. The reaction solution is cooled to room temperature and filtered, and the filtrate is crystallized after adding water, and filtered to obtain compound V.

[0060] Furthermore, the method of the present application may also include the step of reacting compound III with phosphorus tribromide to obtain compound IV, and the specific reaction is as follows:

[0061]

[0062] In a specific embodiment, the solvent used for the reaction of compound III with phosphorus tribromide is toluene, and the reaction temperature is 80-100°C, for example, 80°C, 82°C, 85°C, 88°C, 90°C, 92°C, 95°C, 98°C, or 100°C.

[0063] In a specific embodiment, compound III is mixed with toluene and stirred evenly, phosphorus tribromide is slowly added dropwise, and after the addition is completed, the temperature of the reaction system is raised to 80-100° C. for 6 hours. The reaction solution is cooled to 15-30° C., saturated sodium bicarbonate aqueous solution is added dropwise until the pH of the reaction solution is 7-8, the liquids are separated, the organic phase is washed with water, and the solvent is removed by rotary evaporation to obtain compound IV.

[0064] Furthermore, the method of the present application may also include the step of reacting compound II with 1,3-benzenedimethanol to obtain compound III. The specific reaction steps are as follows:

[0065]

[0066] In a specific embodiment, compound II reacts with 1,3-benzenedimethanol in a solvent in the presence of a base. The base and the solvent may be bases and solvents well known in the art. Preferably, the base is cesium carbonate and the solvent is acetonitrile. Further preferably, the reaction temperature is 80 to 90°C, for example, 80°C, 82°C, 85°C, 88°C, 90°C.

[0067] In a specific embodiment, compound II is mixed with acetonitrile (180 ml) and stirred evenly, 1,3-benzenedimethanol and cesium carbonate are added, and the temperature is raised to 80-90° C. for reaction for 5 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed with acetonitrile, the filtrate is combined, and the solvent is removed by rotary evaporation to obtain compound III.

[0068] Furthermore, the method of the present application may also include the step of reacting furochloro acid with tert-butylhydrazine hydrochloride to obtain compound II, and the specific reaction steps are as follows:

[0069]

[0070] In a specific embodiment, furochloroic acid and tert-butylhydrazine hydrochloride are reacted at a temperature below 10°C (for example, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, 1°C, or 0°C), and the resulting product is refluxed with glacial acetic acid in dichloromethane for 4 to 6 hours to obtain compound II.

[0071] In a specific embodiment, furochloric acid is mixed with water, anhydrous sodium carbonate is added in batches in an ice-water bath with stirring, and the solution is stirred until it becomes clear. Tert-butylhydrazine hydrochloride is added in batches, stirred for 4 to 6 hours, and filtered. The filter cake is washed with cold water, and air-dried for 12 hours to 16 hours at 30 to 40°C to obtain a yellowish brown solid. The obtained solid is mixed with dichloromethane, glacial acetic acid is added, and heated to reflux for 4 to 6 hours. After cooling to room temperature, the reaction solution is washed with water, 1N NaOH solution, and water in turn, and then allowed to stand for stratification. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to remove the solvent to obtain compound II.

[0072] Furthermore, the method of the present application may also include the step of reacting diethylene glycol with p-toluenesulfonyl chloride to obtain compound I. The specific reaction steps are as follows:

[0073]

[0074] In a specific embodiment, diethylene glycol reacts with p-toluenesulfonyl chloride in the presence of an acid binding agent and a catalyst in a solvent.

[0075] The role of the acid binding agent is to absorb the acid in the reaction so that it does not affect the reaction. The acid binding agent, catalyst and solvent in the present application can be acid binding agents and catalysts well known in the art. Preferably, the acid binding agent is triethylamine, the catalyst is DMAP, i.e. 4-dimethylaminopyridine, and the solvent is one or both of dichloromethane and dichloroethane. Further preferably, the reaction temperature is 20 to 40 ° C, for example, it can be 20 ° C, 22 ° C, 25 ° C, 28 ° C, 30 ° C, 32 ° C, 35 ° C, 38 ° C, 40 ° C.

[0076] In a preferred embodiment, as shown in the following flow chart, the method for preparing compound VI of the present application comprises the following steps:

[0077] Step 1: react diethylene glycol with p-toluenesulfonyl chloride to obtain compound I.

[0078] Step 2: react furochloric acid with tert-butylhydrazine hydrochloride to obtain compound II.

[0079] Step 3: Compound II is reacted with 1,3-benzenedimethanol to obtain compound III.

[0080] Step 4: react compound III with phosphorus tribromide to obtain compound IV.

[0081] Step 5: Compound IV is reacted with 1H-1,2,3-thiazole-4-methanol to obtain compound V.

[0082] Step 6: Compound I and Compound V are reacted to obtain Compound VI.

[0083] Wherein, the specific reaction reagents and reaction conditions of each step are as described above. Step 2, step 3, step 4, and step 5 are performed sequentially, that is, step 2 is completed first, then step 3, then step 4, and then step 5. The execution order of step 1 has no order relationship with step 2, step 3, step 4, and step 5. For example, step 1 can be performed before step 2, after step 5, or at any time between step 2 and step 5.

[0084]

[0085] The present application also provides a compound VI, which is prepared by the above method.

[0086] Wherein compound VI is as follows:

[0087]

[0088] The present application also provides the compound VI prepared by the above method or the use of the compound VI for preparing a myocardial perfusion imaging agent.

[0089] The raw materials used in the method for preparing compound VI of the present application are diethylene glycol, p-toluenesulfonyl chloride, furochloric acid, tert-butylhydrazine hydrochloride, 1,3-benzenedimethanol, phosphorus tribromide, 1H-1,2,3-thiazole-4-methanol, etc. These raw materials are cheap, easy to obtain, common commercially available products, avoiding the use of explosive sodium azide, increasing production safety, and reducing production costs. At the same time, the method of the present application can obtain a yield of more than 70%.

[0090] Example

[0091] Example 1

[0092] Preparation of Compound I

[0093] The reaction formula is as follows:

[0094]

[0095] The steps are as follows:

[0096] DMAP (0.72 g, 5.9 mmol) and diethylene glycol (20 g, 188.5 mmol) were placed in a reaction vessel, 400 mL of dichloromethane was added and stirred, and then (79.09 g, 414.8 mmol) of p-toluenesulfonyl chloride was added, and (42 g, 414.8 mmol) of triethylamine was slowly dripped into the reaction bottle. The reaction was stirred at 20°C to 40°C for 6 hours. The reaction solution was washed twice with 200 mL of water, and the organic phase was dried with 20 g of anhydrous sodium sulfate and filtered. The solution was evaporated to dryness under reduced pressure to obtain yellow oily compound I (72.38 g, 174.8 mmol) with a yield of 92.7%.

[0097] Preparation of Compound II

[0098] The reaction formula is as follows:

[0099]

[0100] The steps are as follows:

[0101] Mix furochloric acid (20 g, 118 mmol) and water (200 ml), add anhydrous sodium carbonate (6.4 g, 60 mmol) in batches in an ice-water bath (below 10°C) and stir until the solution becomes clear. Add tert-butylhydrazine hydrochloride (16.8 g, 134.8 mmol) in batches, stir for 4-6 hours, and filter with suction. Wash the filter cake with 50 ml of cold water and dry it with forced air at 30-40°C for 12-16 hours to obtain 30.12 g of khaki solid.

[0102] The obtained solid was mixed with dichloromethane (160 ml), glacial acetic acid (10 ml) was added, and the mixture was heated under reflux for 4 to 6 hours. The heating was stopped, and the mixture was cooled to room temperature. The reaction solution was washed with 200 ml of water, 200 ml of 1N NaOH solution, and 200 ml of water in sequence, and then allowed to stand for stratification. The organic phase was dried with 10 g of anhydrous sodium sulfate, filtered, and the filtrate was evaporated (temperature not higher than 40°C) to remove the solvent to obtain a light yellow oily substance, which was cooled to room temperature and solidified to obtain a yellow solid compound II (21.98 g, 99 mmol), with a yield of 84%.

[0103] Preparation of compound III

[0104] The reaction formula is as follows:

[0105]

[0106] The steps are as follows:

[0107] Compound II (17.6 g, 79.6 mmol) was mixed with acetonitrile (180 ml) and stirred evenly, 1,3-benzenedimethanol (22 g, 159.3 mmol) and cesium carbonate (10 g, 122.7 mmol) were added, and the temperature was raised to 80-90°C for reaction for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 40 ml of acetonitrile. The filtrate was combined and the solvent was removed by rotary evaporation (temperature not higher than 40°C) to obtain white solid compound III (15.6 g, 48.3 mmol) with a yield of 60.7%.

[0108] Preparation of Compound IV

[0109] The reaction formula is as follows:

[0110]

[0111] The steps are as follows:

[0112] Compound III (15.6 g, 48.3 mmol) and toluene (200 ml) were mixed and stirred evenly, and phosphorus tribromide (15.7 g, 58 mmol) was slowly added dropwise. After the addition, the temperature was raised to 80-100°C and the reaction was allowed to react for 6 hours. The reaction solution was cooled to 15-30°C, and a saturated sodium bicarbonate aqueous solution was added dropwise until the pH of the reaction solution was 7-8. The liquids were separated, and the organic phase was washed with 100 ml of water. The solvent was removed by rotary evaporation (temperature not higher than 60°C) to obtain a yellow solid compound IV (16.2 g, 42 mmol) with a yield of 87%.

[0113] Preparation of Compound Ⅴ

[0114] The reaction formula is as follows:

[0115]

[0116] The steps are as follows:

[0117] Compound IV (16.2 g, 42 mmol) was mixed with acetone (200 ml) and stirred evenly, 1H-1,2,3-thiazole-4-methanol (5 g, 50.4 mmol) and potassium carbonate (6.97 g, 50.4 mmol) were added, and the temperature was raised to 50-60°C for reaction for 12 hours after the addition. The reaction solution was cooled to room temperature and filtered, and water (200 ml) was added to the filtrate, and crystallized at 5-10°C for 2 hours, and filtered to obtain yellow solid compound V (13.4 g, 33 mmol), with a yield of 79%.

[0118] Preparation of Compound VI

[0119] The reaction formula is as follows:

[0120]

[0121] The steps are as follows:

[0122] Compound I (12.3 g, 29.7 mmol), sodium hydride (1.2 g (60% content), 29.7 mmol) and anhydrous tetrahydrofuran (96 ml) were mixed and stirred evenly, and the temperature was raised to 60-70°C. The mixed solution of compound V (12 g, 29.7 mmol) and anhydrous tetrahydrofuran (96 ml) was slowly added dropwise to the reaction system, and the mixture was reacted at 60-70°C for 2 hours. The reaction solution was cooled to room temperature, water (100 ml) was added, stirred for 10 minutes, and then ethyl acetate (100 ml) was added for extraction twice. The organic phase was dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate was spin-dried (the temperature was not higher than 40°C) to obtain a colorless viscous liquid (13.82 g, 31.4 mmol), with a yield of 72%.

[0123] Embodiment 2-4

[0124] The difference between Example 2-4 and Example 1 is that the molar ratio of diethylene glycol to p-toluenesulfonyl chloride, the molar ratio of furochloric acid to tert-butylhydrazine hydrochloride, the molar ratio of compound II to 1,3-benzenedimethanol, and the molar ratio of compound III to phosphorus tribromide are different during the reaction, and the other reaction conditions are the same as those in Example 1.

[0125] Specifically, in Example 2, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride is 1:2, the molar ratio of furochloric acid to tert-butylhydrazine hydrochloride is 1:1.3, the molar ratio of compound II to 1,3-benzenedimethanol is 1:1.8, and the molar ratio of compound III to phosphorus tribromide is 1:1.3. In Example 3, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride is 1:3, the molar ratio of furochloric acid to tert-butylhydrazine hydrochloride is 1:1.1, the molar ratio of compound II to 1,3-benzenedimethanol is 1:2.2, and the molar ratio of compound III to phosphorus tribromide is 1:1.5. In Example 4, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride is 1:2.5, the molar ratio of furochloric acid to tert-butylhydrazine hydrochloride is 1:1.2, the molar ratio of compound II to 1,3-benzenedimethanol is 1:1.9, and the molar ratio of compound III to phosphorus tribromide is 1:1.4.

[0126] The main reaction conditions of the above examples are shown in Table 1, and the yields of the compounds in the examples are shown in Table 2.

[0127] Table 1

[0128]

[0129] Table 2

[0130]

[0131] The present application adopts a novel method to prepare a myocardial perfusion imaging agent precursor, 2-(2-((1-(3-((((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy-4-toluenesulfonate. The method adopts raw materials such as diethylene glycol, p-toluenesulfonyl chloride, furochloric acid, tert-butylhydrazine hydrochloride, 1,3-benzenedimethanol, phosphorus tribromide, 1H-1,2,3-thiazole-4-methanol, etc., avoids the use of explosive sodium azide, increases production safety, and reduces production costs. At the same time, the method of the present application can obtain a target compound yield of more than 70% and is simple to operate.

Claims

1. A method for preparing compound VI, wherein compound VI is as follows: The method comprises the following steps: Diethylene glycol is reacted with p-toluenesulfonyl chloride to obtain compound I: Reacting furochloro acid with tert-butylhydrazine hydrochloride to obtain compound II; Reacting compound II with 1,3-benzenedimethanol to obtain compound III; Compound III is reacted with phosphorus tribromide to obtain compound IV; compound IV is reacted with 1H-1,2,3-thiazole-4-methanol to obtain compound V; and compound I and compound V are reacted to obtain compound VI: wherein diethylene glycol reacts with p-toluenesulfonyl chloride in the presence of an acid-binding agent and a catalyst at a reaction temperature of 20 to 40°C; The furochloric acid reacts with tert-butylhydrazine hydrochloride at a temperature below 10° C., and the obtained product is refluxed with glacial acetic acid in dichloromethane for 4 to 6 hours to obtain compound II; Compound II reacts with 1,3-benzenedimethanol in the presence of a base at a reaction temperature of 80 to 90°C; The reaction temperature of compound III and phosphorus tribromide is 80-100°C; Compound IV reacts with 1H-1,2,3-thiazole-4-methanol in the presence of a base at a reaction temperature of 50 to 60° C.; Compound I and compound V react in the presence of a base at a reaction temperature of 60-70°C.

2. The method according to claim 1, characterized in that The base used in the reaction of compound IV with 1H-1,2,3-thiazole-4-methanol is potassium carbonate, and the solvent is acetone.

3. The method according to claim 1, characterized in that The solvent used for the reaction of compound III with phosphorus tribromide is toluene.

4. The method according to claim 1, characterized in that The base used in the reaction of compound II with 1,3-benzenedimethanol is cesium carbonate, and the solvent is acetonitrile.

5. The method according to claim 1, characterized in that The acid binding agent is triethylamine, and the catalyst is DMAP.

6. The method according to claim 1, characterized in that The solvent used in the reaction of diethylene glycol and p-toluenesulfonyl chloride is one or both of dichloromethane and dichloroethane.

7. The method according to claim 1, characterized in that The base used in the reaction of compound I and compound V is sodium hydride, and the solvent is tetrahydrofuran.

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