Synthesis method of midazolam

Abstract

The invention provides a novel midazolam synthesis method, which comprises the following steps: by taking SM1 as a raw material, protecting ketal of SM1 with alcohol under the action of an acid catalyst to obtain M1; carrying out reductive amination on M1 and M2 to obtain M3; and removing the protecting group from the M3, closing the ring, reacting with orthoacetate, and finally oxidizing to obtain midazolam. The method provided by the invention has the advantages of simplicity and convenience in operation, high yield and high product purity, and is more suitable for industrial large-scale production and quality control of drugs.

Description

Technical Field

[0001] The invention relates to the field of compound synthesis, in particular to a method for synthesizing midazolam. Background Art

[0002] Midazolam is used primarily in pediatric patients for sedation, anxiolysis, and amnesia before diagnostic, therapeutic, or endoscopic procedures or before induction of anesthesia. Its chemical name is 1-methyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine The structural formula is as follows:

[0003]

[0004] Midazolam is a white to slightly yellow crystal or crystalline powder. Its medicinal forms include free base, hydrochloride and maleate, etc. Its medicinal dosage forms include injection, syrup, oral solution, buccal mucosal solution, etc.

[0005] At present, there are four main reports on the synthesis routes of midazolam:

[0006] Route 1:

[0007]

[0008] This route comes from the journal article Journal Organic Chemistry, 1978, 43(5):936-944 published by the original researcher Roche. The total yield is only 10%, and nitrite is used, which has the risk of introducing nitrosamine genotoxic impurities.

[0009] Route 2:

[0010]

[0011] This route comes from the original patent US4226771, and the reported batch size is at the milligram level. The last step uses a preparative liquid phase for separation and purification, and nitrite is used, which poses a risk of introducing nitrosamine genotoxic impurities.

[0012] Route 3:

[0013]

[0014] This route comes from the original research journal Synthesis, 2004, (16): 2697-2703, in which several steps need to be carried out at low temperatures. The last step uses a reagent containing heavy metal mercury. The total yield is reported to be 34%, and nitrite is used, which has the risk of introducing nitrosamine genotoxic impurities.

[0015] Route 4:

[0016]

[0017] This route comes from the original research patent US4401597A report. It has three more steps than Route 1 and uses nitrite twice, which poses a risk of introducing nitrosamine genotoxic impurities. Summary of the invention

[0018] In order to overcome the above technical defects, the present invention aims to provide a new method for preparing midazolam and an intermediate compound. The method solves the problems of the prior art such as long reaction route, low yield, and dangerous reactions, dangerous reagents, controlled reagents and genotoxic impurities, and achieves short steps, high yield, good product purity, and simple operation, which is more suitable for industrial large-scale production and quality control of drugs.

[0019] The present invention provides a method for synthesizing midazolam, characterized in that it comprises the following steps:

[0020]

[0021] in,

[0022] G is hydrogen, alkoxycarbonyl or acyl. The alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, preferably tert-butoxycarbonyl; the acyl may be acetyl or trifluoroacetyl;

[0023] X and Y are each independently selected from O or S;

[0024] R1 and R2 are each independently selected from H, C1-C3 alkyl;

[0025] Further, R1 and R2 are each independently selected from H, methyl, ethyl, propyl, isopropyl;

[0026] Alternatively, R1 and R2 may be connected to form a substituted or unsubstituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, wherein the substituents may be one or more C1-C3 alkyl groups;

[0027] Furthermore, R1 and R2 may be connected to form a substituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, and the substituent may be one or more methyl groups or ethyl groups;

[0028] Step 1: M3 is deprotected under acid catalysis and then adjusted to alkaline conditions to close the ring to obtain M4;

[0029] Step 2: M4 reacts with orthoacetate to obtain M5;

[0030] Step 3: M5 is oxidized with an oxidant to obtain midazolam.

[0031] in,

[0032] The acid used for deprotection in step 1 may be one or more of trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid; the solvent used may be toluene, xylene or a mixture thereof; the base used may be an inorganic base or an organic base, or an aqueous solution thereof, wherein the inorganic base is selected from ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the organic base is selected from triethylamine and diisopropylethylamine; the alkaline conditions required for ring closure require that the reaction system pH is greater than 9;

[0033] The solvent used in step 2 may be one or more of xylene, toluene, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide; the orthoacetate may be trimethyl orthoacetate, triethyl orthoacetate or tripropyl orthoacetate.

[0034] The solvent used in step 3 can be one or more of xylene, toluene, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide; the oxidant can be manganese dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone, etc., preferably manganese dioxide.

[0035] Furthermore, step 3 may include a purification step for midazolam. Conventional purification methods can be used to purify midazolam, such as column chromatography, crystallization, etc., among which crystallization is preferred. Conventional operating methods can be used in the crystallization method, and commonly used crystallization solvents, such as ether, ethanol or methyl tert-butyl ether, can achieve crystallization purification of midazolam.

[0036] Furthermore, the synthesis method can adopt a step-by-step reaction method, that is, the product of each step is purified and separated before being put into the next step reaction, or a one-pot method without purification can be adopted, such as the products of step 1 and step 2 are not separated and purified, and step 3 is continued.

[0037] Furthermore, the present application also provides a method for synthesizing intermediate M3, which specifically comprises the following steps:

[0038]

[0039] Wherein the ranges of R1, R2, G, X, and Y are as described above;

[0040] Step 1: SM1 reacts with alcohol under acid catalysis to generate M1;

[0041] Step 2: SM2 and an amino protecting group reagent are first subjected to an amino protection reaction, and then Oppenauer oxidation is performed in an acetone / aluminum isopropoxide system to obtain M2; when G is H, oxidation reaction can be directly performed to obtain M2;

[0042] Step 3: M1 reacts with M2 in the presence of an acid catalyst and a reducing agent to obtain M3.

[0043] The solvent used in step 1 may be toluene, xylene or a mixture thereof; the alcohol or thiol used may be methanol, methyl mercaptan, ethanol, ethyl mercaptan, propanol, propyl mercaptan, 2-methyl-1,3-propanediol, 2-methyl-1,3-propanedithiol, 2,2-dimethyl-1,3-propanediol, 2,2-dimethyl-1,3-propanedithiol, 1,2-propanediol, 1,2-propanedithiol, 2-methyl-1,2-propanediol, 2-methyl-1,2-propanedithiol, 1,2-dimethyl-1 ,2-propylene glycol or 1,2-dimethyl-1,2-propanediol; the amount of alcohol is 1 to 10 equivalents, which is enough to allow the reaction to proceed and to make the reaction complete. Those skilled in the art can adjust it according to actual conditions; the acid catalyst is one or more of p-toluenesulfonic acid, trifluoromethanesulfonic acid, or methanesulfonic acid, and the amount is 0.1 to 10% of the weight of the substrate SM1. Those skilled in the art can adjust it according to actual conditions; the reaction temperature is -20°C to reflux temperature, which can be adjusted by those skilled in the art according to actual conditions.

[0044] Furthermore, step 1 may include treating the reaction solution with an alkaline aqueous solution to make the pH of the reaction solution alkaline to neutralize the residual acid in the system, thereby obtaining the free state M1. Common alkaline reagents can achieve this effect, such as sodium hydroxide aqueous solution, ammonia water, sodium carbonate aqueous solution, sodium bicarbonate aqueous solution, potassium hydroxide aqueous solution, etc.

[0045] The solvent used in step 2 can be acetone; the amino protecting group reagent is di-tert-butyl dicarbonate, diethyl dicarbonate, dimethyl dicarbonate, acetic anhydride or trifluoroacetic anhydride, and the amount used is 2 to 10 equivalents, which can be adjusted by those skilled in the art according to actual conditions; the temperature is -20°C to reflux temperature, which can be adjusted by those skilled in the art according to actual conditions;

[0046] The solvent used in step 3 can be one or more of toluene, xylene or dichloromethane; the acid catalyst can be one or more of formic acid, acetic acid or trifluoroacetic acid, and the amount is 0.1 to 10 equivalents, which can be adjusted by those skilled in the art according to actual conditions; the reducing agent can be one or more of sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, and the amount is 1 to 10 equivalents, which can be adjusted by those skilled in the art according to actual conditions; the reaction temperature is -20°C to reflux temperature, which can be adjusted by those skilled in the art according to actual conditions; the molar ratio of M1:M2 is 1:1.0 to 1:10, which can be adjusted by those skilled in the art according to actual conditions;

[0047] Furthermore, step 3 may include treating the reaction solution with an alkaline aqueous solution to make the pH of the reaction solution alkaline to neutralize the residual acid in the system, thereby obtaining the free M3. Common alkaline reagents can achieve this effect, such as sodium hydroxide aqueous solution, ammonia water, sodium carbonate aqueous solution, sodium bicarbonate aqueous solution, potassium hydroxide aqueous solution, etc.

[0048] Furthermore, step 3 may include a purification step for M3. Conventional purification methods can be used to purify M3, such as column chromatography, crystallization, etc., among which crystallization is preferred. Conventional operation methods can be used in the crystallization method, and commonly used crystallization solvents, such as ether, ethanol or methyl tert-butyl ether, can be used to purify M3 by crystallization.

[0049] Furthermore, the method for synthesizing M3 can adopt a step-by-step reaction method, that is, the product of each step is purified and separated before being put into the next step reaction, or a one-pot method without purification can be adopted, such as the products of step 1 and step 2 are not separated and purified, and step 3 is continued.

[0050] On the other hand, the present invention also provides a key intermediate M3 for synthesizing midazolam:

[0051]

[0052] in,

[0053] G is hydrogen, alkoxycarbonyl or acyl; wherein the alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, preferably tert-butoxycarbonyl; the acyl may be acetyl or trifluoroacetyl;

[0054] X and Y are each independently selected from O or S;

[0055] R1 and R2 are each independently selected from H, C1-C3 alkyl;

[0056] Further, R1 and R2 are each independently selected from H, methyl, ethyl, propyl, isopropyl;

[0057] Alternatively, R1 and R2 may be connected to form a substituted or unsubstituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, wherein the substituents may be one or more C1-C3 alkyl groups;

[0058] Furthermore, R1 and R2 may be connected to form a substituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, and the substituent may be one or more methyl groups or ethyl groups.

[0059] Specifically, M3 can be any one of the following structures:

[0060]

[0061] On the other hand, the present invention provides a method for synthesizing midazolam using SM1 and SM2 as raw materials, which specifically comprises the following steps:

[0062]

[0063] Wherein, the ranges of G, X, Y, R1 and R2 are as described above. The reaction conditions of each step are as described above.

[0064] This route can be carried out in a step-by-step reaction manner, that is, the product of each step is purified and separated before being put into the next step reaction, or it can be completed in one pot.

[0065] The beneficial effects of the present invention are as follows:

[0066] 1. It solves the problems of hazardous reagents, hazardous reactions and genotoxic impurities in the prior art and has the characteristics of high safety.

[0067] 2. The intermediates are all solids with good crystallinity, which not only have the advantage of being easy to refine and purify, but also have a lower risk of residual solvents. In addition, solids are easier to package, store, accurately weigh and feed than liquids.

[0068] 3. Each step of operation is simpler.

[0069] 4. The reaction yield of each step is high.

[0070] 5. Each step of the reaction product has high purity DETAILED DESCRIPTION

[0071] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described here are only a part of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention.

[0072] Comparative Example 1: Preparation of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-1,3-dithiofuran-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate (refer to Example 3 of CN114773348A)

[0073]

[0074] (1) Add 200 mL of dichloromethane, 15.9 g of ethanedithiol and 20 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone to a reaction flask, slowly drop 30.4 g of titanium tetrachloride through a dropping funnel, heat to 30-40° C. for reaction, monitor the reaction by TLC, slowly drop 100 mL of drinking water to quench the reaction, and the product precipitates. Continue to keep warm and stir for 2 hours, filter, and dry the filter cake at 45-55° C. for 6 hours to obtain 17.5 g of a light yellow solid, which is the thioketal intermediate D-M1-1 (reported yield 82.7%, actual yield 67.0%).

[0075] (2) 150 mL of toluene, 20 g of the above-obtained D-M1-1, 26.6 g of di-tert-butyl (2-oxypropane-1,3-diyl) biscarbamate and 0.74 g of acetic acid were added to the reaction flask in sequence, and the temperature was raised to vigorous reflux, and the water was separated for reaction. The reaction was continued for about 24 hours until the reaction was complete as detected by TLC, and the temperature was lowered to 30°C, and 60 mL of anhydrous methanol was added, and 17.1 g of NaBH3CN was slowly added in batches, and the reaction was continued for about 3 hours until the reaction was complete as detected by TLC. The reaction solution was cooled to 5°C, and 80.0 mL of drinking water was slowly added dropwise, filtered, and the filter cake was concentrated under reduced pressure at 45-55°C until no large amount of organic phase dripped out, and 60 g of ethyl acetate was added for extraction, and the aqueous phase was back-extracted with 60 g of ethyl acetate. The organic phases were combined and concentrated to dryness to obtain 24 g of D-M2-1. Then, 19 g of D-M2-1 was obtained by column chromatography separation and purification, namely di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-1,3-dithiofuran-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate. The yield of this step was 51.7%, the total yield of the two-step reaction was 34.6%, and the purity was 92.3%.

[0076] D-M2-1 is a brown-yellow oily substance. After repeated attempts such as freezing, nitrogen purging, and solvent crystallization, the oily substance could not solidify and always remained in a liquid state.

[0077] Comparative Example 2: Preparation of Midazolam (refer to Example 5 of CN114773348A)

[0078]

[0079] (1) D-M2-1 obtained in Comparative Example 1 was not purified by column chromatography, and 180 mL of acetonitrile and 18 mL of drinking water were directly added, stirring was started, 10.4 g of sodium bicarbonate and 62.8 g of iodine were added, and the reaction was stirred at 35-45 ° C until completion, 25.5 g of sodium sulfite and 100 mL of drinking water were added, and the reaction was stirred for 2 hours, and the mixture was concentrated under reduced pressure at 45-55 ° C until no obvious liquid dripped out, 100 mL of ethyl acetate was added for extraction twice, the organic phases were combined, and the mixture was concentrated under reduced pressure until no obvious liquid dripped out, 100 mL of methanol was added, the temperature was lowered to 5 ° C, 48 mL of concentrated hydrochloric acid was slowly dripped in, and the temperature was raised to room temperature for reaction for 26 hours until the reaction was complete by TLC detection. The reaction system was cooled to 5 ° C, and concentrated ammonia was added to adjust the pH to > 8. After the addition, the reaction was carried out at room temperature for 6 hours until the reaction was complete by TLC detection. The condenser was concentrated under reduced pressure at 45-55°C until no large amount of organic phase dripped out, 100 mL of ethyl acetate was added, the liquid was separated, the aqueous phase was extracted again with 100 mL of ethyl acetate, the organic phase was combined, the liquid was separated, and the organic phase was concentrated under reduced pressure at 45-55°C until no large amount of organic phase dripped out. 27 mL of dichloromethane was added to the reaction flask, 12.0 g of maleic acid dissolved in 27 mL of anhydrous ethanol was added dropwise, and the reaction was stirred at room temperature for 8 hours, filtered, and the filter cake was vacuum dried at 45-55°C to obtain 9.3 g of yellow solid, which was D-M3 (the reported two-step total yield starting from D-M1-1 in Comparative Example 1 was 54.8%, and the actual total yield starting from D-M1-1 was 36.1%).

[0080] (2) Add 300mL of dichloromethane, 60g of D-M3 obtained in the previous step and 200mL of purified water to a 100mL single-mouth bottle, start stirring, slowly add 60mL of concentrated ammonia water, react for 1 hour, let stand, separate the liquids, add 200mL of purified water to the organic phase, 60mL of ammonia water is freed, let stand, separate the liquids, and concentrate the organic phase under reduced pressure at 45-55°C until no obvious droplets flow out. Add 240mL of toluene and 60.53g of trimethyl orthoacetate to the single-mouth bottle, heat to 110°C, react for 24 hours, until the reaction is complete by TLC detection. Cool the reaction system to 55-65°C, and concentrate under reduced pressure at this temperature until no large amount of organic phase drips out. Add 120g of toluene to concentrate with water, and concentrate under reduced pressure at 60°C until no obvious droplets flow out. Add 120g of toluene and concentrate under reduced pressure at 60°C until no large amount of organic phase drips out. Add 120 mL of ethyl acetate to the reaction flask, raise the temperature to reflux to dissolve, recrystallize, cool to room temperature, stir and crystallize for 6 hours, filter, rinse the filter cake with 60 g of ethyl acetate, and vacuum dry at 45-55 ° C for 8 hours to obtain 33 g of light yellow solid, which is D-M4 (reported single-step yield is 85%, actual single-step yield is 70.4%).

[0081] (3) 15 mL of dimethyl sulfoxide, 3.0 g of D-M4 obtained in the previous step and 2.4 g of manganese dioxide were added to a 50 mL reaction bottle, and the temperature was raised to 150° C. The reaction was allowed to react for 1.5 hours until the reaction was complete as detected by TLC. The reaction system was cooled to room temperature, 30 mL of ethyl acetate was added, the filter cake was rinsed with 15 mL of ethyl acetate, 20 mL of purified water was added for washing, and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, 15 mL each time, and the organic phases were combined and washed with 15 mL of saturated sodium chloride aqueous solution and 15 mL of purified water in turn, and concentrated under reduced pressure until no obvious droplets flowed out, to obtain 1.9 g of off-white solid, which was midazolam (reported single-step yield 76%, actual single-step yield 63.7%; reported HPLC purity 99.89%, actual purity 98.06%). Starting from the starting material SM1, the total yield (i.e., the total yield after combining Comparative Example 1 and Comparative Example 2) was 10.8%.

[0082] Comparative Example 3: Preparation of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate (refer to Example 4 of CN114773348A)

[0083]

[0084] (1) Add 600 mL of ethylene glycol and 100 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone to a 2L reaction bottle, and drip 218 g of trimethylsilyl chloride through a constant pressure dropping funnel. After the addition is complete, heat to 50-55° C. and react for 24 hours. HPLC detection is performed until the raw material residue is less than about 5%. The reaction solution is added dropwise to 1.2 L of saturated sodium carbonate aqueous solution, and ethyl acetate is added for extraction, 600 mL each time, for a total of three times. The organic phases are combined, washed twice with drinking water, 600 mL each time, for a total of two times, and the organic phase is concentrated to dryness to obtain 102 g of crude product, 250 mL of toluene is added, the temperature is raised to 50-60° C. for pulping, and then reduced to 10-15° C., stirred for 2 hours, filtered, and dried to obtain 81 g of yellow solid, namely D-M1-2 (reported yield 82%, actual yield 68.9%).

[0085] (2) 600 mL of dichloromethane, 60 g of the above-obtained D-M1-2, 88 g of di-tert-butyl (2-oxypropane-1,3-diyl) biscarbamate and 6.0 g of acetic acid were added to a 5 L reaction bottle in sequence, and 173.2 g of sodium triacetoxyborohydride was slowly added in batches. The reaction was allowed to proceed for 16 hours until the reaction was complete as detected by TLC. After separation and purification by column chromatography, 79 g of D-M2-2 was obtained, namely di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl] biscarbamate. The yield of this step was 68.3%, the total yield was 47.1%, and the purity was 93.7%.

[0086] D-M2-2 is a light yellow oily liquid. After repeated attempts such as freezing, nitrogen purging, and solvent crystallization, the oily liquid could not solidify and always remained in a liquid state.

[0087] Comparative Example 4: Preparation of Midazolam (refer to Example 6 of CN114773348A)

[0088]

[0089] (1) D-M2-2 obtained in Comparative Example 3 was directly added with 180 mL of anhydrous methanol without column chromatography purification, and 167 mL of concentrated hydrochloric acid was slowly added in batches, and the reaction was carried out for about 3 hours until the reaction was complete by TLC detection. Concentrated ammonia was slowly added to the reaction solution to adjust the pH to 11, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed by TLC detection, 180 mL of drinking water was added, and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, 600 mL each time, and the organic phase was combined and washed with 400 mL of saturated sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure until no obvious droplets flowed out, and 120 mL of anhydrous ethanol, 120 mL of ethyl acetate and 47.4 g of maleic acid were added. After the addition was completed, the mixture was stirred at room temperature for 8 hours, filtered, and dried to obtain 46.3 g of a yellow solid, namely D-M3 (the reported total yield was 90% based on D-M1-2, and the actual total yield was 54.0% based on D-M1-2).

[0090] (2) Add 300mL of dichloromethane, 60g of D-M3 obtained in the previous step and 200mL of purified water to a 1L single-mouth bottle, start stirring, slowly add 60mL of concentrated ammonia water, react for 1 hour, let stand, separate the liquids, add 200mL of purified water to the organic phase, 60mL of ammonia water is free, let stand, separate the liquids, and concentrate the organic phase under reduced pressure at 45-55°C until no obvious droplets flow out. Continue to add 240mL of toluene and 60.53g of trimethyl orthoacetate, raise the temperature to 110°C, react for 24h, until the reaction is complete by TLC detection. The reaction system is cooled to 55-65°C, and concentrated under reduced pressure at this temperature until no large amount of organic phase drips out, add 120g of toluene to concentrate with water, and concentrate under reduced pressure at 60°C until no obvious droplets flow out. Add 120g of toluene and concentrate under reduced pressure at 60°C until no large amount of organic phase drips out. Add 120 mL of ethyl acetate to the reaction flask, raise the temperature to reflux to dissolve the clear solution, recrystallize, cool to room temperature, stir and crystallize for 6 hours, filter, rinse the filter cake with 60 g of ethyl acetate, and vacuum dry at 45-55 ° C for 8 hours to obtain 23 g of light yellow solid, which is D-M4 (reported single-step yield is 71.2%, actual single-step yield is 49.1%).

[0091] (3) 150 mL of dimethyl sulfoxide, 30 g of D-M4 obtained in the previous step, and 90 g of manganese dioxide were added to a 2 L reaction bottle in sequence, and the temperature was raised to 150 ° C. The reaction was allowed to react for 1.5 hours until the reaction was complete when detected by TLC. The reaction system was cooled to room temperature, 450 mL of ethyl acetate was added, and the diatomaceous earth pad was used for filtering. The filter cake was rinsed with 150 mL of ethyl acetate, and 300 ml of purified water was added for washing, and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, each time with 150 mL, and the organic phases were combined and washed with 150 mL of saturated sodium chloride aqueous solution and 150 mL of purified water in sequence, and concentrated under reduced pressure until no obvious droplets flowed out.

[0092] First, add 54 mL of tetrahydrofuran to dissolve, then add a solution of 21.2 g of maleic acid dissolved in 54 mL of anhydrous ethanol, stir for 30 minutes, add 130 mL of methyl tert-butyl ether, stir overnight at room temperature, filter, and vacuum dry the filter cake at 45-55 ° C for 8 hours to obtain 19.8 g of light yellow midazolam maleate solid (the single-step yield calculated based on the reported yield is 51.4%, and the actual yield is 49.0%).

[0093] Add 20.8g of light yellow solid midazolam maleate to the reaction flask, then add 42mL of tetrahydrofuran and 20mL of anhydrous ethanol, heat to reflux to dissolve, slowly cool to 5°C, slowly drop 84mL of methyl tert-butyl ether, stir for 3 hours, filter to collect the solid, and dry under reduced pressure at 45-55°C. 18.6g of solid is obtained, which is the refined product of midazolam maleate.

[0094] 75 mL of dichloromethane, 15 g of refined midazolam maleate, 60 mL of purified water and 30 mL of concentrated ammonia were added to the reaction flask in sequence, and the reaction was allowed to proceed for 2 hours at room temperature, and the liquid was separated by standing. The organic phase was concentrated under reduced pressure at 45-55 ° C until no large amount of droplets flowed out. 24 mL of methanol and 30 mL of purified water were added to the reaction flask, and the temperature was naturally lowered to 0-10 ° C, crystallized for 6 hours, filtered, and the filter cake was dried under reduced pressure at 45-55 ° C. 10.5 g of white solid was obtained, which was midazolam (the reported single-step reaction and purification total yield was 52%, and the actual single-step reaction and purification total yield was 41.6%; the reported purity was 99.92%, and the actual purity was 99.37%). Starting from the starting material SM1, the total yield (i.e., the total yield after combining comparative example 3 and comparative example 4) was 7.6%.

[0095] Example 1: Preparation of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)dimethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0096]

[0097] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 16 g of methanol and 0.5 g of p-toluenesulfonic acid to 100 mL of toluene, heat and reflux for reaction, and monitor the completion of the reaction by TLC after 38 hours. Cool to room temperature, adjust the pH to > 8 with NaOH aqueous solution, discard the aqueous phase, and retain the organic phase to obtain M1-1 solution;

[0098] MS (ESI) m / z = 296.1 ([M+H] + ).

[0099] 1 H NMR (400M, DMSO-d6): δ7.52~7.57(m,1H),7.37~7.43(m,1H),7.14~7.24(m,3 H),6.71~7.04(m,1H),6.61~6.64(d,J=12Hz,1H),5.45(s,2H),3.29(s,6H).

[0100] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0101] 1H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0102] 3) The concentrated residue M2 obtained in the previous step was added to the M1-1 solution obtained in step 1), and 50 mL of acetic acid was added. Then, 12.6 g of sodium cyanoborohydride was added in batches at a system temperature of -5 to 5°C. After 6 hours, the reaction was monitored by TLC to be complete. After the reaction was completed, the pH was adjusted to pH>9 with an aqueous NaOH solution, and the aqueous phase was discarded. The organic phase was concentrated to no fraction and then crystallized with methyl tert-butyl ether to obtain 53.5 g of a white crystalline solid, namely di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)dimethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 94.1% and a purity of 99.5%.

[0103] MS (ESI) m / z = 568.2 ([M+H] + ).

[0104] 1 H NMR (400M, DMSO-d6): δ7.39~7.59(m,2H),7.13~7.24(m,4H),6.71~6.81(m,3H),5.92~ 5.94(d,J=8Hz,1H),4.01~4.05(m,2H),3.41~3.56(m,3H),3.30(s,6H),1.43(s,18H).

[0105] Example 2: Preparation of Midazolam

[0106]

[0107] 1) Add 30 g of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)dimethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of toluene, and then add 15 g of trifluoromethanesulfonic acid, and stir at room temperature to carry out a deprotection reaction. After 10 hours, the deprotection reaction is completed by TLC monitoring. A NaOH aqueous solution is added to adjust the pH to > 9, and the ring-closing reaction is continued by stirring at room temperature. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0108] 2) Continue to add 50g of tripropyl orthoacetate, raise the temperature to 100°C for condensation ring reaction, and after 10 hours, the reaction is completed by TLC monitoring, and then cool to room temperature and proceed to the next step without purification;

[0109] 3) Continue to add 50g of manganese dioxide, raise the temperature to 60°C for oxidative dehydrogenation reaction, and after 16 hours, the reaction is completed by TLC monitoring, and then cool to room temperature. Filter the reaction solution, concentrate the filtrate until no fraction flows out, and crystallize it twice with ethanol to obtain 14.5g of white crystalline powder, which is midazolam. The total yield of the three steps is 88.4% and the purity is 99.9%. .

[0110] MS (ESI) m / z = 326.1 ([M+H] + ).

[0111] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

[0112] Example 3: Preparation of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0113]

[0114] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 23 g of ethanol and 0.5 g of p-toluenesulfonic acid to 100 mL of toluene, heat and reflux for reaction, and monitor the completion of the reaction by TLC after 26 hours. Cool to room temperature, adjust the pH to > 8 with aqueous ammonia solution, discard the aqueous phase, and retain the organic phase to obtain M1-2 solution;

[0115] MS (ESI) m / z = 324.2 ([M+H] + ).

[0116] 1 H NMR (400M, DMSO-d6): δ7.51~7.56(m,1H),7.36~7.42(m,1H),7.13~7.23(m,3H),6.70~7.03( m,1H),6.60~6.63(d,J=12Hz,1H),5.44(s,2H),3.49~3.54(m,4H),1.17~1.19(t,J=4Hz,6H).

[0117] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0118] 1 H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0119] 3) The concentrated residue M2 obtained in the previous step was added to the M1-2 solution obtained in step 1), 50 mL of acetic acid was added, and then 42.4 g of sodium triacetoxyborohydride was added in batches at a system temperature of -5 to 5°C. After 5 hours, the reaction was monitored by TLC to complete. After the reaction was completed, the pH was adjusted to pH>9 with an aqueous ammonia solution, the aqueous phase was discarded, and the organic phase was concentrated to no fraction, and then crystallized with methyl tert-butyl ether to obtain 55 g of a white crystalline solid, namely di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 92.1% and a purity of 99.3%.

[0120] MS (ESI) m / z = 596.3 ([M+H] + ).

[0121] 1 H NMR (400M, DMSO-d6): δ7.38~7.58(m,2H),7.12~7.23(m,4H),6.70~6.80(m,3H),5.91~5.93(d,J=8Hz,1 H),4.00~4.04(m,2H),3.40~3.55(m,3H),2.88~3.06(m,4H),1.42(s,18H),1.18~1.21(t,J=12Hz,6H).

[0122] Example 4: Preparation of Midazolam

[0123]

[0124] 1) Add 30 g of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of toluene, and then add 15 g of trifluoroacetic acid, and stir at room temperature to carry out a deprotection reaction. After 9 hours, the deprotection reaction is completed by TLC monitoring. Ammonia solution is added to adjust the pH to > 9, and the ring-closing reaction is continued by stirring at room temperature. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0125] 2) Continue to add 30g of trimethyl orthoacetate, raise the temperature to 100°C for condensation ring reaction, and after 6 hours, the reaction is completed by TLC monitoring, and then cool to room temperature and proceed to the next step without purification;

[0126] 3) Continue to add 50g of manganese dioxide, raise the temperature to 60°C for oxidative dehydrogenation reaction, monitor the reaction completion by TLC after 16 hours, and cool to room temperature. Filter the reaction solution, concentrate the filtrate until no fraction flows out, and crystallize it twice with ethanol to obtain 14.5g of white crystalline powder, i.e. midazolam, with a total yield of 88.4% in three steps and a purity of 99.9%.

[0127] MS (ESI) m / z = 326.1 ([M+H] + ).

[0128] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

[0129] Example 5: Preparation of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-5-methyl-1,3-dioxan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0130]

[0131] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 45 g of 2-methyl-1,3-propanediol and 0.5 g of trifluoromethanesulfonic acid to 100 mL of toluene, heat to 80-90° C. for reaction, monitor the reaction completion by TLC after 19 hours, cool to room temperature, adjust the pH to > 8 with NaOH aqueous solution, discard the aqueous phase, and retain the organic phase to obtain M1-3 solution;

[0132] MS (ESI) m / z = 322.2 ([M+H]+ ).

[0133] 1 H NMR (400M, DMSO-d6): δ7.50~7.55(m,1H),7.35~7.41(m,1H),7.12~7.22(m,3H),6.99~7.02(m,1H),6.59~6.62( d,J=12Hz,1H),5.43(s,2H),3.99~4.03(m,2H),3.47~3.52(m,2H),1.90~2.01(m,1H),0.85~0.87(d,J=8Hz,3H).

[0134] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0135] 1 H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0136] 3) The concentrated residue M2 obtained in the previous step was added to the M1-3 solution obtained in step 1), 50 mL of acetic acid was added, and then 12.6 g of sodium cyanoborohydride was added in batches at a system temperature of -5 to 5°C. After 6 hours, the reaction was monitored by TLC to be complete. After the reaction was completed, the pH was adjusted to pH>9 with an aqueous NaOH solution, the aqueous phase was discarded, and the organic phase was concentrated to no fraction, and then crystallized with methyl tert-butyl ether to obtain 51 g of a white crystalline solid, namely di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 85.7% and a purity of 98.9%.

[0137] MS (ESI) m / z = 594.3 ([M+H] + ).

[0138] 1H NMR (400M, DMSO-d6): δ7.37~7.57(m,2H),7.11~7.22(m,4H),6.69~6.79(m,3H),5.90~5.92(d,J=8Hz,1H),3.99 ~4.03(m,2H),3.39~3.54(m,3H),2.87~3.05(m,4H),1.92~1.99(m,1H),1.39(s,18H),0.87~0.88(d,J=4Hz,3H).

[0139] Example 6: Preparation of Midazolam

[0140]

[0141] 1) Add 30 g of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-5-methyl-1,3-dioxane-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of xylene, and then add 15 g of trifluoromethanesulfonic acid, and stir at room temperature to carry out deprotection reaction. After 11 hours, the deprotection reaction is completed by TLC monitoring. Add NaOH aqueous solution to adjust the pH to > 9, continue stirring at room temperature to carry out ring-closing reaction. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0142] 2) Continue to add 40g of triethyl orthoacetate, raise the temperature to 100°C for condensation ring reaction, and after 8 hours, the reaction is completed by TLC monitoring, cool to room temperature, and proceed to the next step without purification;

[0143] 3) 50 g of manganese dioxide was added, and the temperature was raised to 70° C. for oxidative dehydrogenation reaction. After 12 hours, the reaction was completed by TLC monitoring, and the temperature was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated until no fraction flowed out. It was crystallized twice with ethanol to obtain 13 g of white crystalline powder, which was midazolam. The total yield of the three steps was 79.0%, and the purity was 99.9%.

[0144] MS (ESI) m / z = 326.1 ([M+H] + ).

[0145] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

[0146] Example 7: Preparation of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-4-methyl-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0147]

[0148] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 38 g of 1,2-propylene glycol and 0.5 g of p-toluenesulfonic acid to 100 mL of toluene, heat and reflux for reaction, and complete the reaction after 24 hours under TLC monitoring. Cool to room temperature, adjust the pH to > 8 with Na2CO3 aqueous solution, discard the aqueous phase, and retain the organic phase to obtain M1-4 solution;

[0149] MS (ESI) m / z = 308.2 ([M+H] + ).

[0150] 1 H NMR (400M, DMSO-d6): δ7.49~7.54(m,1H),7.34~7.40(m,1H),7.11~7.21(m,3H),6.98~7.01(m,1H),6. 58~6.61(d,J=12Hz,1H),5.42(s,2H),3.96~4.01(m,2H),3.46~3.52(m,1H),1.30~1.32(d,J=8Hz,3H).

[0151] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0152] 1 H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0153] 3) The concentrated residue M2 obtained in the previous step was added to the M1-4 solution obtained in step 1), and 10 mL of trifluoroacetic acid was added. Then, 42.4 g of sodium triacetoxyborohydride was added in batches at a system temperature of -5 to 5°C. After 5 hours, the reaction was monitored by TLC to be complete. After the reaction was completed, the pH was adjusted to pH>9 with a Na2CO3 aqueous solution, and the aqueous phase was discarded. The organic phase was concentrated to no fraction and then crystallized with methyl tert-butyl ether to obtain 49 g of a white solid, namely di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethoxymethyl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 84.4% and a purity of 99.1%.

[0154] MS (ESI) m / z = 580.3 ([M+H] + ).

[0155] 1 H NMR (400M, DMSO-d6): δ7.36~7.56(m,2H),7.10~7.21(m,4H),6.68~6.78(m,3H),5.89~5.91(d,J=8Hz, 1H), 3.98~4.02(m,2H), 3.38~3.53(m,2H), 2.86~3.05(m,4H), 1.45(s,18H), 1.32~1.34(d,J=8Hz,3H).

[0156] Example 8: Preparation of Midazolam

[0157]

[0158] 1) Add 30 g of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-4-methyl-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of toluene, and then add 15 g of trifluoroacetic acid, and stir at room temperature to carry out a deprotection reaction. After 10 hours, the deprotection reaction is completed by TLC monitoring. A Na2CO3 aqueous solution is added to adjust the pH to > 9, and the ring-closing reaction is continued by stirring at room temperature. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0159] 2) Continue to add 50g of tripropyl orthoacetate, raise the temperature to 100°C for condensation ring reaction, and after 10 hours, the reaction is completed by TLC monitoring, and then cool to room temperature and proceed to the next step without purification;

[0160] 3) Continue to add 50g of manganese dioxide, raise the temperature to 60°C for oxidative dehydrogenation reaction, monitor the reaction completion by TLC after 16 hours, and cool to room temperature. Filter the reaction solution, concentrate the filtrate until no fraction flows out, and crystallize it twice with ethanol to obtain 12.5g of white crystalline powder, which is midazolam, with a total yield of 74.2% in three steps and a purity of 99.9%.

[0161] MS (ESI) m / z = 326.1 ([M+H] + ).

[0162] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

[0163] Example 9: Preparation of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-4,4-dimethyl-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0164]

[0165] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 45 g of 2-methyl-1,2-propanediol and 0.5 g of trifluoromethanesulfonic acid to 100 mL of toluene, heat and reflux for reaction, and complete the reaction after 26 hours under TLC monitoring. Cool to room temperature, adjust the pH to > 8 with NaOH aqueous solution, discard the aqueous phase, and retain the organic phase to obtain M1-5 solution;

[0166] MS (ESI) m / z = 322.2 ([M+H] + ).

[0167] 1 H NMR (400M, DMSO-d6): δ7.48~7.53(m,1H),7.33~7.39(m,1H),7.10~7.20(m,3H),6.97~ 7.00(m,1H),6.57~6.60(d,J=12Hz,1H),5.41(s,2H),3.95~4.00(m,2H),1.18(s,6H).

[0168] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0169] 1 H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0170] 3) The concentrated residue M2 obtained in the previous step was added to the M1-5 solution obtained in step 1), 50 mL of acetic acid was added, and 12.6 g of sodium cyanoborohydride was added in batches at a system temperature of -5 to 5°C. After 6 hours, the reaction was monitored by TLC to complete. After the reaction was completed, the pH was adjusted to pH>9 with an aqueous NaOH solution, the aqueous phase was discarded, and the organic phase was concentrated to no fraction, and then crystallized with methyl tert-butyl ether to obtain 52 g of a white solid, namely di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-4,4-dimethyl-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 87.4% and a purity of 98.8%.

[0171] MS (ESI) m / z = 594.3 ([M+H] + ).

[0172] 1 H NMR (400M, DMSO-d6): δ7.35~7.55(m,2H),7.09~7.20(m,4H),6.67~6.77(m,3H),5.88~5.90(d,J =8Hz,1H),3.97~4.01(m,2H),3.37~3.45(m,1H),2.85~3.03(m,4H),1.43(s,18H),1.20(s,6H).

[0173] Example 10: Preparation of Midazolam

[0174]

[0175] 1) Add 30 g of di-tert-butyl [2-({4-chloro-2-[2-(2-fluorophenyl)-4,4-dimethyl-1,3-dioxolan-2-yl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of xylene, and then add 15 g of trifluoromethanesulfonic acid, and stir at room temperature to carry out deprotection reaction. After 13 hours, the deprotection reaction is completed by TLC monitoring. NaOH aqueous solution is added to adjust the pH to > 9, and the ring-closing reaction is continued by stirring at room temperature. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0176] 2) Continue to add 40 g of triethyl orthoacetate, raise the temperature to 100° C. to carry out condensation ring reaction, and after 6 hours, the reaction is completed by TLC monitoring, and then cool to room temperature and proceed to the next step without purification;

[0177] 3) 50 g of manganese dioxide was added, and the temperature was raised to 70° C. for oxidative dehydrogenation reaction. After 12 hours, the reaction was completed by TLC monitoring, and the temperature was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated until no fraction flowed out. It was crystallized twice with ethanol to obtain 15 g of white crystalline powder, which was midazolam. The total yield of the three steps was 91.2% and the purity was 99.9%.

[0178] MS (ESI) m / z = 326.1 ([M+H] + ).

[0179] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

[0180] Example 11: Preparation of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethylthiomethyl]phenyl}amino)propane-1,3-diyl]biscarbamate

[0181]

[0182] 1) Add 25 g of 2-amino-5-chlorophenyl-2'-fluorophenyl ketone, 31 g of ethanethiol and 0.5 g of p-toluenesulfonic acid to 100 mL of toluene, heat and reflux for reaction, and monitor the completion of the reaction by TLC after 26 hours. Cool to room temperature, adjust the pH to > 8 with aqueous ammonia solution, discard the aqueous phase, and retain the organic phase to obtain M1-6 solution;

[0183] MS (ESI) m / z = 356.2 ([M+H]+ ).

[0184] 1 H NMR (400M, DMSO-d6): δ7.53~7.58(m,1H),7.38~7.44(m,1H),7.15~7.25(m,3H),6.72~7.05( m,1H),6.62~6.65(d,J=12Hz,1H),5.46(s,2H),2.46~2.51(m,4H),1.14~1.16(t,J=4Hz,6H).

[0185] 2) Add 13.5 g of 1,3-diamino-2-hydroxypropane and 72 g of di-tert-butyl dicarbonate to 50 mL of acetone, stir and react at room temperature, and after 17 hours, the reaction is completed as monitored by TLC, and then 3 g of aluminum isopropoxide is added, and the temperature is raised to reflux for oxidation reaction. After 7.5 hours, the reaction is completed as monitored by TLC, and the mixture is filtered with silica gel as an auxiliary filter, and the filtrate is concentrated until no fraction flows out to obtain a concentrated residue M2;

[0186] 1 H NMR (400M, DMSO-d6): δ7.02~7.04(t,J=4Hz,2H), 3.78~3.79(d,J=4Hz,4H), 1.38(s,18H).

[0187] 3) The concentrated residue M2 obtained in the previous step was added to the M1-6 solution obtained in step 1), and 50 mL of acetic acid was added. Then, 42.4 g of sodium triacetoxyborohydride was added in batches at a system temperature of -5 to 5°C. After 5 hours, the reaction was completed by TLC monitoring. After the reaction was completed, the pH was adjusted to pH>9 with an aqueous ammonia solution, and the aqueous phase was discarded. The organic phase was concentrated to no fraction and then crystallized with methyl tert-butyl ether to obtain 59.5 g of a white crystalline solid, namely di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethylthiomethyl]phenyl}amino)propane-1,3-diyl]biscarbamate, with a total yield of 94.7% and a purity of 99.6%.

[0188] MS (ESI) m / z = 628.3 ([M+H] + ).

[0189] 1 H NMR (400M, DMSO-d6): δ7.40~7.40(m,2H),7.14~7.25(m,4H),6.72~6.82(m,3H),5.93~5.95(d,J=8Hz, 1H), 3.52~3.57(m,1H), 2.90~3.08(m,4H), 2.47~2.52(m,4H), 1.44(s,18H), 1.15~1.17(t,J=4Hz,6H).

[0190] Example 12: Preparation of Midazolam

[0191]

[0192] 1) Add 31.5 g of di-tert-butyl [2-({4-chloro-2-[(2-fluorophenyl)diethylthiomethyl]phenyl}amino)propane-1,3-diyl]biscarbamate to 100 mL of toluene, and then add 15 g of trifluoroacetic acid, and stir at room temperature to carry out a deprotection reaction. After 9 hours, the deprotection reaction is completed by TLC monitoring. Ammonia solution is added to adjust the pH to > 9, and the ring-closing reaction is continued by stirring at room temperature. After 15 hours, the ring-closing reaction is completed by TLC monitoring. The aqueous phase is discarded, and the organic phase is continued to the next step without purification;

[0193] 2) Continue to add 30g of trimethyl orthoacetate, raise the temperature to 100°C for condensation ring reaction, and after 6 hours, the reaction is completed by TLC monitoring, and then cool to room temperature and proceed to the next step without purification;

[0194] 3) 50 g of manganese dioxide was added, and the temperature was raised to 60° C. for oxidative dehydrogenation reaction. After 16 hours, the reaction was completed by TLC monitoring, and the temperature was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated until no fraction flowed out. It was crystallized twice with ethanol to obtain 15.3 g of white crystalline powder, which was midazolam. The total yield of the three steps was 95.2% and the purity was 99.9%.

[0195] MS (ESI) m / z = 326.1 ([M+H] + ).

[0196] 1 H NMR(400M, CDCl3):7.57~7.67(m,2H),7.40~7.49(m,2H),7.24~7.29(m,2H),7.02~7.07( m,1H),6.96(s,1H),5.14~5.17(d,J=12Hz,1H),4.06~4.09(d,J=12Hz,1H),2.58(s,3H).

Claims

1. A method for synthesizing midazolam, characterized in that: The following steps are involved: Step 1: M3 is deprotected under acid catalysis and then adjusted to alkaline conditions to close the ring to obtain M4; Step 2: M4 reacts with orthoacetate to obtain M5; Step 3: M5 is oxidized with an oxidant to obtain midazolam; in, G is hydrogen, alkoxycarbonyl or acyl; wherein the alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, preferably tert-butoxycarbonyl; the acyl may be acetyl or trifluoroacetyl; X and Y are each independently selected from O or S; R1 and R2 are each independently selected from H, C1-C3 alkyl; Alternatively, R1 and R2 may be connected to form a substituted or unsubstituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, and the substituents may be one or more C1-C3 alkyl groups.

2. The synthesis method as claimed in claim 1, wherein the alkaline condition required for the ring closure in step 1 is pH>9, and the reagent used to adjust to the alkaline condition can be an inorganic base or an organic base, or an aqueous solution thereof, wherein the inorganic base is selected from ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the organic base is selected from triethylamine and diisopropylethylamine.

3. The synthesis method as claimed in claim 1 can be carried out in a one-pot manner.

4. The synthesis method as claimed in claim 1, further comprising a method for synthesizing M3: Step 1: SM1 reacts with alcohol or thiol under acid catalysis to generate M1; Step 2: SM2 and an amino protecting group reagent are first subjected to an amino protection reaction, and then Oppenauer oxidation is performed in an acetone / aluminum isopropoxide system to obtain M2; when G is H, oxidation reaction can be directly performed to obtain M2; Step 3: M1 reacts with M2 in the presence of an acid catalyst and a reducing agent to obtain M3; The ranges of R1, R2, G, X and Y are as described in claim 1.

5. The synthesis method as claimed in claim 4 can be carried out in a one-pot manner.

6. The synthesis method as claimed in claim 4, wherein the alcohol or thiol used in step 1 can be methanol, methyl mercaptan, ethanol, ethyl mercaptan, propanol, propyl mercaptan, 2-methyl-1,3-propanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 1,2-propanediol, 1,2-propanediol, 2-methyl-1,2-propanediol, 2-methyl-1,2-propanediol, 1,2-dimethyl-1,2-propanediol or 1,2-dimethyl-1,2-propanediol.

7. The synthesis method according to claim 4, wherein the acid used in step 1 can be p-toluenesulfonic acid, trifluoromethanesulfonic acid, or methanesulfonic acid.

8. The synthesis method according to claim 4, wherein the acid catalyst used in step 3 can be formic acid, acetic acid or trifluoroacetic acid.

9. The synthesis method according to claim 4, wherein the reducing agent used in step 3 can be sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or a mixture thereof.

10. An intermediate M3 for synthesizing midazolam: in, G is hydrogen, alkoxycarbonyl or acyl, wherein the alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, preferably tert-butoxycarbonyl; the acyl may be acetyl or trifluoroacetyl; X and Y are each independently selected from O or S; R1 and R2 are each independently selected from H, C1-C3 alkyl; Alternatively, R1 and R2 may be connected to form a substituted or unsubstituted five-membered or six-membered ring together with the X, Y atoms and carbon atoms connected thereto, and the substituents may be one or more C1-C3 alkyl groups.

11. The M3 as claimed in claim 10 may be of the following structure:

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