Synthesis method of flumazenil EP impurity B

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a synthesis method of a flumazenil EP impurity B. The synthesis method comprises the following steps: step 1, reacting a compound 1 as shown in a formula (11) with a compound 2 as shown in a formula (12) at 50-130 DEG C for 8-24 hours; separating and purifying the reaction liquid to obtain a compound 3; 2, carrying out a free radical bromination reaction on the compound 3 in an inert gas environment to obtain a compound 4; step 3, the compound 4 and methylamine are subjected to a heating reaction in an inert gas environment, and a compound 5 is obtained; and 4, heating the compound 5 and bis-pinacol borate in an inert gas environment to react to obtain a compound 6, and oxidizing to obtain a compound 7. A catalyst, a reagent and the like in the method are easy to obtain and low in toxicity, and the yield of the obtained compound 7 is high.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and more specifically, to a method for synthesizing flumazenil EP impurity B. Background Art

[0002] Flumazenil as a benzodiazepine Drug-like antagonists mainly act on the central benzodiazepine (BZD) receptors and can block benzodiazepine receptors without BZD-like effects. Currently, there are many synthetic methods for preparing flumazenil, but there are few studies on the synthesis of its analogs or various impurity compounds in the synthesis process of flumazenil. For example, 8-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[F]imidazo[1,5-A][1,4]diazepine-3-carboxylic acid ethyl ester and (8-hydroxy-5-methyl-6-oxonium-5,6-dihydro-4H-benzo[F]imidazo[1,5-A][1,4]diazepine-3-carboxylic acid ethyl ester) (flumazenil EP impurity B), 8-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[F]imidazo[1,5-A][1,4]diazepine-3-carboxylic acid ethyl ester (Compound 5) are important intermediates in pharmaceutical synthesis and have certain applications. For example, flumazenil EP impurity B is an important reference substance for flumazenil activity data. It has certain biological activity itself, and its hydroxyl functional group can be derivatized with radioactive isotopes, and then radioactive isotope tracking can be performed. At the same time, its analogue 8-bromo-5-methyl-6-oxo-5,6-dihydro-4H-benzo[F]imidazo[1,5-A][1,4]diazepine-3-carboxylic acid ethyl ester can be transformed into various functional groups through metal-catalyzed coupling, substitution, etc., thereby realizing the functional group derivatization of various organic compounds.

[0003] However, the synthesis process of flumazenil EP impurity B is rarely reported, as shown in formula (01):

[0004] In this process, in step 1 (i.e., step 1), diethyl chlorophosphate is used, which is a highly toxic substance, making this synthesis step very dangerous; in addition, the yield of compound 2 obtained in this step is not particularly high. In step 2 (i.e., step 2), boron tribromide is used to demethylate the compound 7 in formula (01), and its yield is no more than 10%. At the same time, when handling a large amount of boron tribromide, it is necessary to be careful and slowly add methanol or water to avoid generating a large amount of acid gas.

[0005] In addition, there are some synthetic processes that use flumazenil analogs (compound 5) to catalyze the reaction through Rockphos Pd G3 precursor catalyst to directly convert the bromide into hydroxyl. Although the yield of the product in this synthetic process is relatively high, the Rockphos Pd G3 precursor catalyst used therein has the problems of high price, few manufacturers, and difficulty in obtaining; in addition, this process is only a laboratory-level (i.e., small-scale) synthetic study, so whether this synthetic route can be scaled up has not yet been reported. Based on the shortcomings of the catalyst, the process shown in formula (02) was used in related studies to synthesize flumazenil EP impurity B (i.e., compound 7 in formula (02)). This process uses a copper catalyst to convert the bromine substituent into a hydroxyl group to obtain compound 7, and the yield of compound 7 is relatively considerable. However, in this synthetic route, ligand L4 needs to be obtained through multi-step synthesis, rather than being directly commercially available; that is, before synthesizing compound 7, this process first needs to synthesize ligand L4, so the synthesis of ligand L4 will directly increase the process steps, making the process route more complicated and difficult to achieve industrialization.

[0006]

[0007] Therefore, considering the difficulty and price of raw material acquisition, the safety and non-toxicity of reactants and catalysts, and the yield of products, it is necessary to provide a method for synthesizing flumazenil EP impurity B with free raw material and catalyst acquisition, safety, low toxicity, and high product yield. Summary of the invention

[0008] In order to reduce the toxicity during the synthesis process of flumazenil EP impurity B and improve the product yield, the present application provides a method for synthesizing flumazenil EP impurity B.

[0009] The present application provides a method for synthesizing a flumazenil EP impurity B using the following technical solution: A method for synthesizing a flumazenil EP impurity B, comprising the following steps: Step 1, reacting compound 1 represented by formula (11) and compound 2 represented by formula (12) at 50-130° C. for 8-24 hours; the reaction solution is separated and purified to obtain compound 3 represented by formula (13); Wherein, in formula (11), R1 is a halogen, and the halogen is selected from any one of Cl and Br; in formula (13), R2 is a halogen, and the halogen is selected from any one of Cl and Br; Step 2, subjecting the compound 3 to a free radical bromination reaction in an inert gas environment to obtain a compound 4 represented by formula (14); In formula (14), R3 is a halogen, and the halogen is selected from any one of Cl and Br; Step 3: Heat and react the compound 4 and methylamine in an inert gas environment to obtain the compound 5 shown in formula (15); In formula (15), R4 is a halogen, and the halogen is selected from any one of Cl and Br; Step 4: Heat and react the compound 5 and bis(pinacolato)diboron in an inert gas environment to obtain the compound 6 shown in formula (16); Step 5: Oxidize the compound 6 at room temperature to obtain the compound 7 shown in formula (17);

[0010] In the current synthesis methods of related compounds, basically nitro-substituted compounds are used as the initial reactants to synthesize flumazenil or flumazenil derivatives. However, in the synthesis process of this application, halogen-substituted compounds (i.e., compound 1) are used as the original reaction raw materials, and finally flumazenil EP impurity B with high yield is obtained, providing a new idea and route for the synthesis of this kind of substance. Specifically, in this application, compound 3 is prepared from cheaper compound 1 and compound 2, and the operation is simple; further, compound 3 is used as the reaction substrate, and after radical bromination substitution, compound 4 is obtained; compound 4 undergoes ring closure with methylamine to obtain compound 5; compound 5 further reacts with bis(pinacolato)diboron to displace the halogen, and then through oxidation, the halogen on the original benzene ring is finally replaced by a hydroxyl group to obtain compound 7. In this synthesis route, the synthesis process is simple and easy to implement, and the product yield is relatively high; moreover, no highly toxic or specially synthesized catalysts are used, which has the advantages of safety, environmental protection and low cost.

[0011] Optionally, the reaction in step 1 is carried out in solvent 1 under the catalysis of catalyst 1, and the catalyst 1 is selected from any one or more of sodium hydride, cesium carbonate, potassium carbonate and 1,8-diazabicyclo[5,4,0]undec-7-ene; The solvent 1 is selected from any one or more of dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidone; preferably, the solvent 1 is dimethyl sulfoxide, and the catalyst 1 used is cesium carbonate.

[0012] By adopting the above technical solution, when synthesizing compound 3 in step 1, the selected catalyst and solvent are safe, non-toxic, easy to obtain and low in price, making this synthesis step easy to industrialize.

[0013] Optionally, the reaction temperature in step 1 is 80 - 110 °C, and the reaction time is 8 - 16 h.

[0014] Optionally, a purification treatment of Compound 3 is further included between Step 1 and Step 2; the purification treatment of Compound 3 specifically includes the following steps: Perform solid-liquid separation on the reaction solution obtained in Step 1, and retain the liquid phase; add water to the obtained liquid phase, and then extract with Extractor 1 to obtain a separated organic phase and aqueous phase; take the organic phase, wash it with saturated brine, then dry it with a desiccant, perform solid-liquid separation, and take the filtrate for concentration; remove the solvent from the concentrated solution to obtain a solid, which is the purified Compound 3.

[0015] Optionally, Extractor 1 is selected from any one or two of ethyl acetate and dichloromethane; the desiccant is selected from any one or two of anhydrous sodium sulfate, anhydrous magnesium sulfate, and silica powder.

[0016] Optionally, the reaction in Step 2 specifically includes: reacting Compound 3 and N-bromosuccinimide in the presence of an initiator and Solvent 2; Solvent 2 is selected from any one or more of carbon tetrachloride, 1,2-dichloroethane, acetonitrile, and chloroform; the initiator is selected from any one or two of azobisisobutyronitrile and benzoyl peroxide; Preferably, Solvent 2 is carbon tetrachloride; the initiator is azobisisobutyronitrile.

[0017] Optionally, the reaction conditions in Step 2 include: the reaction temperature is 50-80 °C, and the reaction time is 6-24 h.

[0018] Optionally, a purification treatment of Compound 4 is further included between Step 2 and Step 3; the purification treatment of Compound 4 specifically includes the following steps: Add water to the reaction solution obtained in Step 2, and extract with Extractor 2 to obtain a separated organic phase and inorganic phase; take the organic phase, wash it with saturated brine, then add a desiccant, stir and perform solid-liquid separation, take the filtrate for concentration; then remove the solvent from the concentrated solution to obtain the purified Compound 4.

[0019] Optionally, Extractor 2 is selected from any one or more of ethyl acetate, dichloromethane, and chloroform.

[0020] Optionally, when Solvent 2 is carbon tetrachloride, the reaction solution between Step 2 and Step 3 is cooled, solid-liquid separation is performed, the filtrate is taken for concentration, and the crude Compound 4 is obtained. Without performing the purification treatment of Compound 4, the crude product obtained in Step 2 is directly used as the raw material for Step 3.

[0021] In the above solution, when Solvent 2 is carbon tetrachloride, due to the difference in solubility of impurities and Compound 4 in carbon tetrachloride, Compound 4 is easily soluble in carbon tetrachloride, while the impurities are not easily soluble in this solvent. Therefore, the purification treatment can be omitted and it can be directly used for the next reaction to obtain better reaction results.

[0022] Optionally, the reaction in step 3 includes: cyclization with methylamine catalyzed by catalyst 2 in solvent 3; the reaction conditions in step 3 include: the reaction temperature is 40-60 °C, and the reaction time is 0.5-5 h; The solvent 3 is selected from any one or both of methanol and ethanol; the catalyst 2 is selected from one or more of N,N-diisopropylethylamine, methylamine ethanol solution, and triethylamine; Preferably, the solvent 3 is ethanol and the catalyst 2 is N,N-diisopropylethylamine; Preferably, in step 3, the reaction temperature is 40-60 °C and the reaction time is 0.5-1 h.

[0023] Optionally, a purification treatment of compound 5 is also included between step 3 and step 4; the purification treatment of compound 5 specifically includes the following steps: Water is added to the reaction solution obtained in step 3, and then extracted with extractant 3 to obtain a separated organic phase and inorganic phase; the organic phase is taken and washed with saturated brine, and then extractant 3 is added and stirred, and solids gradually precipitate; then, after solid-liquid separation, the solids are dried to obtain purified compound 5.

[0024] Optionally, the extractant 3 is selected from any one or more of petroleum ether, ethyl acetate, dichloromethane, chloroform, methanol, and ethanol.

[0025] Optionally, the reaction in step 4 is carried out in solvent 4 in the presence of catalyst 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; the solvent 4 is selected from any one or more of dioxane, toluene, and isopropyl acetate.

[0026] Optionally, the reaction conditions in step 4 include: the reaction temperature is 80-120 °C, and the reaction time is 8-24 h; Preferably, in step 4, the reaction temperature is 80-100 °C and the reaction time is 8-12 h.

[0027] Optionally, the reaction in step 5 is carried out in solvent 5 and an oxidant is added; the solvent 5 is selected from any one or more of tetrahydrofuran, acetonitrile, water, dichloromethane, and dioxane; the oxidant is selected from any one or both of hydrogen peroxide and sodium chlorite.

[0028] Optionally, the reaction conditions in step 5 include: the reaction time is 0.5-8 h.

[0029] Optionally, the reaction solution containing compound 6 obtained in step 4 is directly used for the reaction in step 5 without purification, or the reaction solution obtained in step 4 is used for the reaction in step 5 after separation and purification treatment; The treatment during the purification of the reaction solution containing Compound 6 specifically includes the following steps: The reaction solution containing Compound 6 is filtered with diatomaceous earth, and the filtrate is concentrated and then purified by a C18 column to obtain purified Compound 6; the treatment when the reaction solution containing Compound 6 is not purified specifically includes the following steps: The reaction solution containing Compound 6 is filtered with diatomaceous earth, and the filtrate is concentrated to obtain the crude product of Compound 6, and the crude product of Compound 6 is directly used for the next reaction.

[0030] Optionally, the purification treatment of Compound 7 specifically includes the following steps: Water and Solvent 5 are added to the reaction solution obtained in Step 6, and stirred to obtain the precipitated solid; after solid-liquid separation, the solid is washed with water and dried to obtain purified Compound 7.

[0031] Further optionally, Solvent 5 is selected from any one or more of ethyl acetate, dichloromethane, chloroform, petroleum ether, and tetrahydrofuran.

[0032] In summary, the present application has the following beneficial effects: In the current synthesis methods of related compounds, basically nitro-substituted compounds are used as the initial reactants to synthesize flumazenil or flumazenil derivatives. However, in the synthesis process of the present application, a halogen-substituted compound (i.e., Compound 1) is used as the original reaction raw material, and finally flumazenil EP impurity B with a high yield is obtained, providing a new idea and route for the synthesis of such substances. In this synthesis route, the synthesis process is simple and easy to implement, and the product yield is relatively high; and no highly toxic or specially synthesized catalysts are used, having the advantages of safety, environmental protection, and low cost. Description of the Drawings

[0033] Figure 1 is the synthesis process route diagram of flumazenil EP impurity B in Example 4 of the present application; Figure 2 is the nuclear magnetic resonance diagram of Compound 3 in Example 4 of the present application; Figure 3 is the nuclear magnetic resonance diagram of Compound 5 in Example 4 of the present application; Figure 4 is the nuclear magnetic resonance diagram of Compound 7 in Example 4 of the present application. Detailed Embodiments

[0034] The following further elaborates the present application in detail with reference to the drawings and examples. It should be specifically noted that: for those not indicating specific conditions in the following examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. Except for special instructions, the raw materials used in the following examples can all be obtained from ordinary commercial sources.

[0035] DMSO refers to dimethyl sulfoxide, DMF refers to N,N-dimethylformamide, NMP refers to N-methylpyrrolidone for short; DBU is 1,8-diazabicycloundec-7-ene, with the chemical formula C9H 16 N2; AIBN refers to azobisisobutyronitrile, NBS refers to N-bromosuccinimide, DIPEA refers to N,N-diisopropylethylamine, DCM refers to dichloromethane, MeOH refers to methanol, KOAc refers to potassium acetate, Pd(dppf)Cl2 refers to 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; MeCN refers to the organic solvent acetonitrile, with the chemical formula C2H3N; NMP refers to N-methylpyrrolidone, THF is tetrahydrofuran, TFA is trifluoroacetic acid; TEA is triethylamine.

[0036] Example 1 A synthesis method of flumazenil EP impurity B specifically includes the following steps: Step 1: Dissolve compound 1 (2.45 g, 10 mmol) and compound 2 (1.54 g, 10 mmol) in 10 mL of DMF, and add DBU (3.04 g, 20 mmol). After addition, stir this reaction at 100 °C for 12 h. After detecting the completion of the reaction by TLC, terminate the reaction. Cool, filter off the solid. Add 15 mL of water to this reaction, and extract with ethyl acetate twice, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (PE:EA = 3:1) to obtain white solid compound 3 (1.0 g, yield 26.3%).

[0037] Step 2: Dissolve compound 3 (3.8 g, 10 mmol) in 60 mL of 1,2-dichloroethane, and add benzoyl peroxide (440 mg, 1.83 mmol) and NBS (1.8 g, 10.1 mmol). After addition, displace with nitrogen three times and stir at 80 °C for 12 h. After detecting the completion of the reaction by TLC, terminate the reaction. Add 80 mL of water to this reaction, and extract with dichloromethane twice, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (PE:EA = 8:1) to obtain colorless oily compound 4 (0.9 g, yield 19.6%).

[0038] Step 3: Dissolve compound 4 (4.57 g, 10 mmol) in 40 mL of ethanol, and add 7 mL of aqueous methylamine solution (40 wt%). After addition, protect the reaction with nitrogen and stir at 50 °C for 1 h. After the reaction is completed as detected by TLC, terminate the reaction. Add 150 mL of water to this reaction, and extract twice with ethyl acetate, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid compound 5 (0.9 g, yield 24.8%).

[0039] Step 4: Dissolve compound 5 (3.63 g, 10 mmol) in 30 mL of anhydrous toluene, and successively add bis(pinacolato)diboron (2.8 g, 11.1 mmol), KOAc (1.0 g, 11.9 mmol) and Pd(dppf)Cl2 (0.58 g, 0.79 mmol). After addition, displace with nitrogen three times and stir at 120 °C for 12 h. After the reaction is completed as detected by TLC, terminate the reaction. Cool, and filter off the solid with diatomaceous earth. Concentrate the filtrate and purify it by C18 column (MeCN in water is 30 - 60%) to obtain white solid compound 6 (1.2 g, yield 29.2%).

[0040] Step 5: Dissolve compound 6 (1.0 g, 2.4 mmol) in 8 mL of acetonitrile, add 3 mL of water and sodium chlorite (0.5 g, 5.56 mmol). After addition, stir at 25 °C for 0.5 h. After the reaction is completed as detected by TLC and LCMS. Add 10 mL of water to this reaction, and extract twice with ethyl acetate, 50 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (DCM:MeOH = 10:1) to obtain white solid compound 7 (0.1 g, yield 13.8%).

[0041] Example 2 A method for synthesizing flumazenil EP impurity B, specifically including the following steps: Step 1: Dissolve compound 1 (2.45 g, 10 mmol) and compound 2 (1.54 g, 10 mmol) in 10 mL of DMSO, and add K2CO3 (2.76 g, 20 mmol). After addition, stir this reaction at 70 °C for 24 h. After the reaction is completed as detected by TLC, terminate the reaction. Cool, and filter off the solid. Add 30 mL of water to this reaction, and extract 2 times with ethyl acetate, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (PE:EA = 3:1) to obtain white solid compound 3 (1.5 g, yield 39.4%).

[0042] Step 2: Dissolve compound 3 (3.8 g, 10 mmol) in 60 mL of chloroform, add AIBN (300 mg, 1.83 mmol) and NBS (1.8 g, 10.1 mmol). After addition, displace the air with nitrogen three times and stir at 50 °C for 24 h. After the reaction is completed as detected by TLC, terminate the reaction. Add 80 mL of water to this reaction, extract twice with chloroform, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (PE:EA = 8:1) to obtain colorless oily compound 4 (1.4 g, yield 30.6%).

[0043] Step 3: Dissolve compound 4 (4.57 g, 10 mmol) in 60 mL of ethanol, add 5 mL of aqueous methylamine solution (40 wt%) and triethylamine (1.57 g, 15.5 mmol). After addition, protect with nitrogen and stir at 20 °C for 5 h. After the reaction is completed as detected by TLC, terminate the reaction. Add 150 mL of water to this reaction, extract twice with ethyl acetate, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid compound 5 (1.3 g, yield 35.8%).

[0044] Step 4: Dissolve compound 5 (3.63 g, 10 mmol) in 30 mL of dioxane, sequentially add bis(pinacolato)diboron (2.8 g, 11.1 mmol), KOAc (1.0 g, 11.9 mmol) and Pd(dppf)Cl2 (0.58 g, 0.79 mmol). After addition, displace the air with nitrogen three times and stir at 80 °C for 24 h. After the reaction is completed as detected by TLC, terminate the reaction. Filter off the solid with diatomaceous earth. Concentrate the filtrate and purify it on a C18 column (30 - 60% MeCN in H2O) to obtain white solid compound 6 (1.4 g, yield 34.1%).

[0045] Step 5: Dissolve compound 6 (1.0 g, 2.4 mmol) in 8 mL of dichloromethane, add 0.5 mL of water, 0.2 mL of trifluoroacetic acid and 0.5 mL of hydrogen peroxide (30 wt%). After addition, stir at 60 °C for 4 h. After the reaction is completed as detected by TLC and LCMS. Add 10 mL of water to this reaction, extract twice with dichloromethane, 50 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (DCM:MeOH = 10:1) to obtain white solid compound 7 (0.2 g, yield 27.7%).

[0046] Example 3 A method for synthesizing flumazenil EP impurity B, specifically comprising the following steps: Step 1: Dissolve compound 1 (2.45 g, 10 mmol) and compound 2 (1.54 g, 10 mmol) in 10 mL of NMP, and add K2CO3 (2.76 g, 20 mmol). After addition, stir this reaction at 120 °C for 8 h. After the reaction is completed as detected by TLC, terminate the reaction. Cool, filter off the solid. Add 30 mL of water to this reaction, and extract with dichloromethane twice, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and after concentrating the filtrate under reduced pressure, perform silica gel column chromatography (PE:EA = 3:1) to obtain white solid compound 3 (1.6 g, yield 42.1%).

[0047] Step 2: Dissolve compound 3 (3.8 g, 10 mmol) in 60 mL of acetonitrile, and add AIBN (700 mg, 4.26 mmol) and NBS (1.8 g, 10.1 mmol). After addition, displace with nitrogen three times, and stir at 50 °C for 12 h. After the reaction is completed as detected by TLC, terminate the reaction. Add 80 mL of water to this reaction, and extract with ethyl acetate twice, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and after concentrating the filtrate under reduced pressure, perform silica gel column chromatography (PE:EA = 8:1) to obtain colorless oily compound 4 (0.8 g, yield 17.5%).

[0048] Step 3: Dissolve compound 4 (4.57 g, 10 mmol) in 50 mL of methanol, and add 3 mL of methylamine ethanol solution (30 wt%) and DIPEA (5.16 g, 40.0 mmol). After addition, protect with nitrogen, and stir at 70 °C for 0.5 h. After the reaction is completed as detected by TLC, terminate the reaction. Add 150 mL of water to this reaction, and extract with dichloromethane twice, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and after concentrating the filtrate under reduced pressure, perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid compound 5 (1.5 g, yield 41.3%).

[0049] Step 4: Dissolve compound 5 (3.63 g, 10 mmol) in 40 mL of isopropyl acetate, and successively add bis(pinacolato)diboron (2.8 g, 11.1 mmol), KOAc (1.0 g, 11.9 mmol), and Pd(dppf)Cl2 (0.58 g, 0.79 mmol). After addition, displace with nitrogen three times, and stir at 100 °C for 8 h. After the reaction is completed as detected by TLC, terminate the reaction. Concentrate the reaction solution, and perform silica gel column chromatography (DCM:MeOH = 8:1) to obtain white solid compound 6 (0.9 g, yield 21.9%).

[0050] Step 5: Dissolve compound 6 (1.0 g, 2.4 mmol) in 4 mL of dioxane and 2 mL of water, add 1 mL of hydrogen peroxide and 0.5 mL of trifluoroacetic acid, and stir at 25 °C for 8 h after addition. After the reaction is completed as detected by TLC and LCMS, add 10 mL of water to this reaction, extract twice with DMC / MeOH (v / v = 10 / 1), 50 mL each time. The organic phase is washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and then subjected to silica gel column chromatography (DCM:MeOH = 10:1) to obtain white solid compound 7 (0.3 g, yield 41.5%).

[0051] Example 4 A method for synthesizing flumazenil EP impurity B, the synthesis process of which is as shown in formula (A) (which is also Figure 1 )

[0052] , formula (A).

[0053] The specific steps are as follows: Step 1: Dissolve compound 1 (400.0 g, 1.63 mol) and compound 2 (300.0 g, 1.95 mol) in 3 L of DMSO, and add cesium carbonate (550.0 g, 1.68 mol). After the addition is completed, stir this reaction at 100 °C for 12 h. After the reaction is completed as detected by TLC, terminate the reaction. Cool, filter off the solid. Add 5 L of water and 1 L of brine to this reaction, extract twice with ethyl acetate, 2 L each time. The organic phase is washed with 1 L of saturated brine, add 500 g of anhydrous sodium sulfate and silica gel powder (100 mesh, 500 g) to the organic phase, stir for 0.5 h, filter, concentrate the filtrate under reduced pressure, add a mixture of petroleum ether and ethyl acetate (PE / EA volume ratio is 2 / 1, total 1.5 L) and stir, a large amount of solid will precipitate, filter the solid and dry it to obtain white solid compound 3 (450.0 g, yield 72.5%). The nuclear magnetic resonance spectrum of this compound 3 is as Figure 2 shown: 1H-NMR (400 MHz, DMSO-D6) δ 8.17 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 8.4, 2.4 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 4.27 - 4.22 (m, 2H), 4.11 - 4.05 (m, 2H), 2.20 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.0 Hz, 3H).

[0054] Step 2: Dissolve compound 3 (400.0 g, 1.05 mol) in 8 L of carbon tetrachloride, add AIBN (18.0 g, 0.11 mol) and NBS (210.0 g, 1.18 mol). After addition, displace with nitrogen three times and stir at 80 °C for 6 h. After detecting the completion of the reaction by TLC, terminate the reaction. Cool and filter off the solid. The filtrate is concentrated to obtain the crude product, brown oily compound 4 (460.0 g, crude product). This crude product is directly used for the next cyclization step without purification.

[0055] Step 3: Dissolve compound 4 (460.0 g, crude product) in 4 L of ethanol, add 400 mL of methylamine ethanol solution (methylamine concentration is 30%) and DIPEA (380.0 g, 2.95 mol). After addition, protect with nitrogen and stir at 50 °C for 1 h. After detecting the completion of the reaction by TLC, terminate the reaction. The reaction solution is concentrated to remove a large amount of ethanol. Add 2 L of water to this reaction and extract with ethyl acetate twice, 2 L each time. The organic phase is washed with 0.5 L of saturated brine, add 800 mL of ethyl acetate and stir for 2 h, a large amount of solid will precipitate. The solid is filtered and dried to obtain the yellow solid compound 5 (190.0 g, yield 52.0%). The NMR spectrum of this compound 5 is as follows Figure 3 shown: 1H-NMR (400 MHz, DMSO-D6) δ 8.38 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 5.20 - 4.44 (m, 2H), 4.40 - 4.20 (m, 2H), 3.09 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0056] Step 4: Dissolve compound 5 (120.0 g, 0.33 mol) in 1.3 L of dioxane, and successively add bis(pinacolato)diboron (110.0 g, 0.43 mol), KOAc (90.0 g, 0.92 mol) and Pd(dppf)Cl2 (16.0 g, 0.02 mol). After addition, displace with nitrogen three times and stir at 100 °C for 12 h. After detecting the completion of the reaction by TLC, terminate the reaction. Cool and filter off the solid with diatomaceous earth. The filtrate is concentrated to obtain the crude product, black oily compound 6 (150 g, crude product). This crude product is directly used for the next cyclization step without purification.

[0057] Step 5: The crude product compound 6 (150 g, crude product) was dissolved in 1.5 L of tetrahydrofuran, 0.35 L of water was added, and the mixture was placed in an ice bath. 150 mL of trifluoroacetic acid and 110 mL of hydrogen peroxide were added successively. After addition, the mixture was stirred at 25 °C for 6 h. After TLC detection showed the reaction was complete, the reaction system was placed in an ice bath to cool down, and then an aqueous sodium bicarbonate solution (obtained by dissolving 190.0 g of sodium bicarbonate in 1 L of water) was slowly added. Then 1 L of dichloromethane was added. The mixture was stirred for 0.5 h, and a large amount of solid precipitated. The solid was filtered, washed 3 times with 500 mL of water each time. After the solid was collected, it was dissolved in dichloromethane and ethanol, and silica gel was added for sample mixing. Purification by silica gel column chromatography (DCM:MeOH = 15:1) gave a white solid compound 7 (60.0 g, yield 48.5%). The nuclear magnetic resonance spectrum of this compound 7 is as Figure 4 shown: 1H-NMR (400 MHz, DMSO-D6) δ 10.18 (s, 1H), 8.25 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.08 (dd, J = 8.8, 2.8 Hz, 1H), 5.05 - 4.39 (m, 2H), 4.38 - 4.25 (m, 2H), 3.07 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0058] Examples 5 - 8 and Comparative Examples 1 - 2 The synthesis reaction specifications in Step 1 of Example 4 were scaled down proportionally. Specifically, Step 1 after scaling down was as follows: Step 1: Compound 1 (2.00 g, 8.16 mmol) and compound 2 (1.26 g, 8.16 mmol) were dissolved in 15 mL of DMSO, and cesium carbonate (2.75 g, 8.4 mmol) was added. After the addition, the reaction was stirred at 100 °C for 12 h. After TLC detection showed the reaction was complete, the reaction was terminated. It was cooled, and the solid was filtered off. 30 mL of water was added to this reaction, and it was extracted 2 times with 30 mL of ethyl acetate each time. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (PE:EA = 3:1) was carried out to obtain a white solid compound 3 (2.5 g, yield 69.8%).

[0059] The following examples differed from Example 4 scaled down proportionally in that the reaction temperature in Step 1 was different. Specifically, as follows: In Step 1 of Comparative Example 1, the reaction temperature was 40 °C and the reaction time was 12 h; In Step 1 of Example 5, the reaction temperature was 50 °C and the reaction time was 12 h; In Step 1 of Example 6, the reaction temperature was 80 °C and the reaction time was 12 h; The reaction temperature in Step 1 of Example 7 was 110 °C, and the reaction time was 12 h; The reaction temperature in Step 1 of Example 8 was 130 °C, and the reaction time was 12 h; The reaction temperature in Step 1 of Comparative Example 2 was 140 °C, and the reaction time was 12 h; Others were the same as Example 4.

[0060] The yields of Compound 3 in each scheme were measured, and the specific results are shown in Table 1.

[0061] Table 1 Yields of Compound 3 at Different Synthesis Temperatures Embodiment Example 4 Comparative Example 1 Example 5 Example 6 Example 7 Example 8 Comparative Example 2 Yield of Compound 3 / % 69.8 10.5 37.5 60.8 65.1 52.8 30.6 It can be seen from the data results in Table 1 that when synthesizing Compound 3, the reaction temperature has a greater influence on the yield. When the reaction temperature is controlled within the range of 50 - 130 °C, the yield of Compound 3 is guaranteed to be more than 35%; when the reaction temperature is further controlled within the range of 80 - 110 °C, the yield of Compound 3 is at least 60.8%.

[0062] Examples 9 - 11 The synthesis reaction specifications in Step 2 of Example 4 were scaled down proportionally. After scaling down, Step 2 was specifically as follows: Step 2: Dissolve Compound 3 (3.10 g, 8.16 mmol) in 62 mL of carbon tetrachloride, add AIBN (0.14 g, 0.85 mmol) and NBS (1.63 g, 9.14 mmol). After adding, replace with nitrogen three times and stir at 80 °C for 6 h. After detecting the completion of the reaction by TLC, terminate the reaction. Add 80 mL of water to this reaction, extract with ethyl acetate 2 times, 30 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (PE:EA = 8:1) to obtain Compound 4 (2.59 g, yield 69.5%).

[0063] The differences between the following examples and Example 4 after proportional reduction are that, under the same Step 1, the solvent 2 for dissolving Compound 3 in Step 2 is different, and the post-treatment and purification steps are different. Specifically as follows: Example 9 replaced carbon tetrachloride with an equal volume of 1,2-dichloroethane. The specific procedure for step 2 in Example 9 was as follows: Compound 3 (3.10 g, 8.16 mmol) was dissolved in 62 mL of 1,2-dichloroethane, and AIBN (0.14 g, 0.85 mmol) and NBS (1.63 g, 9.14 mmol) were added. After addition, the mixture was purged with nitrogen three times and stirred at 80 °C for 6 h. After the reaction was completed as detected by TLC, the reaction was terminated. 80 mL of water was added to the reaction, and the mixture was extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, silica gel column chromatography (PE:EA = 8:1) was performed to obtain Compound 4.

[0064] Example 10 replaced carbon tetrachloride with an equal volume of acetonitrile. The specific procedure for step 2 in Example 10 was as follows: Compound 3 (3.10 g, 8.16 mmol) was dissolved in 62 mL of acetonitrile, and AIBN (0.14 g, 0.85 mmol) and NBS (1.63 g, 9.14 mmol) were added. After addition, the mixture was purged with nitrogen three times and stirred at 80 °C for 6 h. After the reaction was completed as detected by TLC, the reaction was terminated. 80 mL of water was added to the reaction, and the mixture was extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, silica gel column chromatography (PE:EA = 8:1) was performed to obtain Compound 4.

[0065] Example 11 replaced carbon tetrachloride with an equal volume of chloroform. The specific procedure for step 2 in Example 11 was as follows: Compound 3 (3.10 g, 8.16 mmol) was dissolved in 62 mL of chloroform, and AIBN (0.14 g, 0.85 mmol) and NBS (1.63 g, 9.14 mmol) were added. After addition, the mixture was purged with nitrogen three times and stirred at 80 °C for 6 h. After the reaction was completed as detected by TLC, the reaction was terminated. 80 mL of water was added to the reaction, and the mixture was extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, silica gel column chromatography (PE:EA = 8:1) was performed to obtain Compound 4.

[0066] Table 2 Yields of Compound 4 under Different Solvents Embodiment Example 4 Example 9 Example 10 Example 11 Yield of Compound 4 / % 69.5 29.1 32.1 48.2 It can be seen from the data results in Table 2 that when carbon tetrachloride was used as the solvent in the synthesis of Compound 3 in this application, a high yield of Compound 3 could be obtained. In addition, in Example 4, the product was directly used in the next step without purification. The reason is that carbon tetrachloride can directly dissolve out the impurities and cause the impurities to crystallize. Therefore, when carbon tetrachloride was used as the solvent, the crude product of Compound 3 obtained could be directly used in the next synthesis reaction.

[0067] Example 12 - 13 The synthesis reaction specifications in Step 3 of Example 4 were scaled down in equal proportion. Specifically, Step 3 after scaling down is as follows: Step 3: Dissolve Compound 4 (4.57 g, 10 mmol) in 40 mL of ethanol, add 4 mL of methylamine ethanol solution (methylamine concentration is 30 wt%) and DIPEA (3.76 g, 29.05 mmol). After adding, protect with nitrogen and stir at 50 °C for 1 h. After detecting the completion of the reaction by TLC, terminate the reaction. Add 150 mL of water to this reaction, extract twice with dichloromethane, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid Compound 5 (1.89 g, yield 52.0%).

[0068] The differences between the following examples and Example 4 with scaled - down specifications are that, with the same Steps 1 and 2, the bases added in Step 3 are different, and while their post - treatment and purification schemes are the same, specifically as follows: In Example 12, an equimolar methylamine ethanol solution was used to replace DIPEA, that is, no additional base was added. Step 3 in Example 12 is specifically as follows: Dissolve Compound 4 (4.57 g, 10 mmol) in 40 mL of ethanol, add 7 mL of methylamine ethanol solution (methylamine concentration is 30 wt%). After adding, protect with nitrogen and stir at 50 °C for 1 h. After detecting the completion of the reaction by TLC, terminate the reaction. Add 150 mL of water to this reaction, extract twice with dichloromethane, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid Compound 5.

[0069] In Example 13, an equimolar proportion of TEA was used to replace DIPEA. Step 3 in Example 13 is specifically as follows: Dissolve Compound 4 (4.57 g, 10 mmol) in 40 mL of ethanol, add 4 mL of methylamine ethanol solution (methylamine concentration is 30 wt%) and TEA (2.94 g, 29.05 mmol). After adding, protect with nitrogen and stir at 50 °C for 1 h. After detecting the completion of the reaction by TLC, terminate the reaction. Add 150 mL of water to this reaction, extract twice with dichloromethane, 100 mL each time. Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then perform silica gel column chromatography (DCM:MeOH = 20:1) to obtain white solid Compound 5.

[0070] Table 3 Effects of different bases on the yield of Compound 5 Embodiment Example 4 Example 12 Example 13 Yield of Compound 5 / % 52.0 32.5 44.1 It can be seen from the data results in Table 3 that when synthesizing Compound 5 with different alkalis added, a higher yield can be obtained with the solution of methylamine in ethanol + DIEPA in Example 4.

[0071] This specific embodiment is only an interpretation of the present application and does not limit the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A method for synthesizing flumazenil EP impurity B, characterized in that, It includes the following steps: Step 1: React compound 1 shown in formula (11) and compound 2 shown in formula (12) at 50 - 130 °C for 8 - 24 h; after separation and purification of the reaction solution, compound 3 shown in formula (13) is obtained; Among them, R1 in formula (11) is a halogen, and the halogen is selected from any one of Cl and Br; R2 in formula (13) is a halogen, and the halogen is selected from any one of Cl and Br; Step 2: Subject compound 3 to a radical bromination reaction in an inert gas environment to obtain compound 4 shown in formula (14); In formula (14), R3 is a halogen, and the halogen is selected from any one of Cl and Br; Step 3: Heat and react compound 4 and methylamine in an inert gas environment to obtain compound 5 shown in formula (15); In formula (15), R4 is a halogen, and the halogen is selected from any one of Cl and Br; Step 4: Heat and react compound 5 and bis(pinacolato)diboron in an inert gas environment to obtain compound 6 shown in formula (16); Step 5: Oxidize compound 6 at room temperature to obtain compound 7 shown in formula (17); 2. The synthesis method of a flumazenil EP impurity B according to claim 1, characterized in that, The reaction in Step 1 is carried out under the catalysis of catalyst 1 in solvent 1, and catalyst 1 is selected from any one or more of sodium hydride, cesium carbonate, potassium carbonate, and 1,8 - diazabicyclo[5,4,0]undec - 7 - ene; Solvent 1 is selected from any one or more of dimethyl sulfoxide, N,N - dimethylformamide, and N - methylpyrrolidone; preferably, solvent 1 is dimethyl sulfoxide, and catalyst 1 used is cesium carbonate.

3. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, In Step 1, the reaction temperature is 80 - 110 °C, and the reaction time is 8 - 16 h.

4. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction in Step 2 specifically includes: reacting compound 3 and N - bromosuccinimide in the presence of an initiator and solvent 2; solvent 2 is selected from any one or more of carbon tetrachloride, 1,2 - dichloroethane, acetonitrile, and chloroform; the initiator is selected from any one or two of azobisisobutyronitrile and benzoyl peroxide; Preferably, solvent 2 is carbon tetrachloride; the initiator is azobisisobutyronitrile.

5. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction conditions in Step 2 include: the reaction temperature is 50 - 80 °C, and the reaction time is 6 - 24 h.

6. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction in Step 3 includes: carrying out cyclization with methylamine under the catalysis of catalyst 2 in solvent 3; the reaction conditions in Step 3 include: the reaction temperature is 20 - 70 °C, and the reaction time is 0.5 - 5 h; Solvent 3 is selected from any one or two of methanol and ethanol; catalyst 2 is selected from one or more of N,N - diisopropylethylamine, methylamine ethanol solution, and triethylamine; Preferably, solvent 3 is ethanol, and catalyst 2 is N,N - diisopropylethylamine; Preferably, in Step 3, the reaction temperature is 40 - 60 °C, and the reaction time is 0.5 - 1 h.

7. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction in Step 4 is carried out in solvent 4 and in the presence of catalyst 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; solvent 4 is selected from any one or more of dioxane, toluene, and isopropyl acetate.

8. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction conditions in Step 4 include: the reaction temperature is 80 - 120 °C, and the reaction time is 8 - 24 h; Preferably, in step 4, the reaction temperature is 80-100 °C and the reaction time is 8-12 h.

9. A method for synthesizing flumazenil EP impurity B according to claim 1, characterized in that, The reaction of step 5 is carried out in solvent 5 and an oxidizing agent is added; the solvent 5 is selected from any one or more of tetrahydrofuran, acetonitrile, water, dichloromethane, and dioxane; the oxidizing agent is selected from any one or two of hydrogen peroxide and sodium chlorite.

10. The synthesis method of a flumazenil EP impurity B according to claim 1, characterized in that, The reaction solution containing compound 6 obtained in step 4 is directly used in the reaction of step 5 without purification, or the reaction solution obtained in step 4 is subjected to separation and purification treatment and then used in the reaction of step 5; The treatment during the purification of the reaction solution containing compound 6 specifically includes the following steps: The reaction solution containing compound 6 is filtered with diatomaceous earth, and the filtrate is concentrated and then purified with a C18 column to obtain purified compound 6; the treatment of the reaction solution containing compound 6 without purification specifically includes the following steps: The reaction solution containing compound 6 is filtered with diatomaceous earth, and the filtrate is concentrated to obtain the crude product of compound 6, and the crude product of compound 6 is directly used in the next reaction.

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