A preparation method of midazolam and its intermediate

Abstract

The present invention belongs to the field of pharmaceutical chemical preparation, and discloses a preparation method of midazolam and its intermediate M2. The preparation method provided by the present invention is: using SM1 as a starting material, reacting with SM2 of 1,3-diaminoacetone protected by alkoxycarbonyl or acyl, obtaining intermediate M2, undergoing reductive amination, deprotecting group under acidic conditions, in-situ alkalization ring-closing reaction, and then reacting with orthoacetic acid ester, and finally oxidizing to obtain midazolam. The preparation method of the present invention has the advantages of short steps, high yield, mild reaction conditions, simple post-processing, avoiding dangerous reactions, dangerous reagents, controlled reagents and genotoxic impurities involved in traditional routes, so the safety of operation and products is high, which is conducive to industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemical preparation, and in particular to a preparation method of midazolam and an intermediate thereof. Background Art

[0002] Benzodiazepines GABAA drugs are a class of drugs with high pharmacological activity and broad application prospects. They mainly mediate their effects by agonistically binding to γ-aminobutyric acid receptors (GABAA) in the central nervous system. Their typical pharmacological properties include: anxiolysis, sedation, hypnosis, anticonvulsant, central muscle relaxation and preoperative anesthesia.

[0003] Midazolam, its main dosage forms include tablets, injections, oral solvents, etc., and the corresponding raw materials have different drug forms such as free base, maleate, hydrochloride, etc. The main indications are used for sedation, anxiolysis and anterograde amnesia in pediatric patients (6 months to 16 years old) before diagnosis, treatment, endoscopic procedures or anesthesia induction. The chemical name of midazolam is 1-methyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine Typical benzodiazepine The parent core structure is a light yellow crystalline solid with CAS number 59467-96-8. The chemical structure of midazolam hydrochloride is as follows:

[0004]

[0005] There are many synthetic routes for midazolam, among which Route 1 (Walser A, Thomas Flynn, Mason C, et al. J Org Chem, 1978, 43 (5): 936-944.) discloses that compound 2 is used as a starting material, reacted with chloroacetyl chloride to generate intermediate 1, aminolysis and ring closure to obtain intermediate 2, condensed with methylamine in the presence of titanium tetrachloride, nitrosated to obtain 4, reacted with nitromethane in the presence of a strong base to produce 5, Raney nickel catalytic hydrogenation, maleic acid salt to obtain intermediate 6, cyclized with triethyl orthoacetate, and oxidative dehydrogenated with manganese dioxide to obtain midazolam free base. However, compound 2 is relatively expensive, and its synthesis still requires SM1 as a starting material. The route has a total of 8 steps of reaction, and the literature reports that the total yield is about 6.7%. It is the current mainstream amplified synthetic route. The synthesis of Route 1 is shown in Scheme 1.

[0006] However, the following problems exist in this route: 1) Chloroacetyl chloride is a highly toxic controlled substance, and urotropine, methylamine gas or methylamine solution are controlled reagents, which are not only difficult to purchase and transport, but also have high safety risks in operation; 2) The reaction route involves multiple steps such as halogenation, amination, nitrosation, hydrogenation, and oxidation, involving 18 key monitored reactions with high safety risks; 3) Excessive Raney nickel catalyst is used in the reaction route, which poses a great safety hazard during process scale-up; 4) Sodium nitrite reagent is used in the route, and nitrosamine impurities are easily produced during the reaction process. Nitrosamines are genotoxic impurities, and if product quality control is not utilized, there is a certain quality risk.

[0007]

[0008] Route 2 (Walser A, Fryer RI. J Heterocycl Chem, 1983, 20(3): 551-558.): The synthesis method of compounds 1, 2, 3, and 4 is the same as that of route 1. Intermediate 4 reacts with dimethyl malonate under the action of potassium tert-butoxide to generate intermediate 14, which undergoes hydrolysis and decarboxylation under the action of potassium hydroxide, and then reacts with sodium nitrite to generate intermediate 16. 16 is subjected to Raney nickel catalytic hydrogenation, trimethyl orthoacetate cyclization, hydrolysis, and decarboxylation to obtain midazolam. The synthesis of route 2 is shown in Scheme 2. However, the entire route has a total of 11 steps, is lengthy, has a low yield, and is costly, and also has the same problems as route 1.

[0009]

[0010] In summary, the existing technology for synthesizing midazolam currently has the following problems: such as complicated steps and low yield, the reaction process involves many dangerous reactions, dangerous reagents and controlled reagents, and is not suitable for industrial production; the reaction process also involves nitrosamine-type genotoxic impurities, which poses certain quality risks; therefore, researching and finding a route with short steps, reliable product quality and safety, simple operation, short production cycle, good equipment compatibility, and more suitable for industrial large-scale production is still a problem that needs to be solved. Summary of the invention

[0011] In order to overcome the above technical defects, the present invention aims to provide an intermediate compound of midazolam and a preparation method thereof, as well as a new method for preparing midazolam using the new 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, simple operation, short production cycle, good equipment compatibility, high safety, and is more suitable for industrial large-scale production.

[0012] The first aspect of the present invention provides an intermediate M2 compound, the structure of which is shown in the following formula:

[0013]

[0014] R, R' are independently selected from alkoxycarbonyl or acyl;

[0015] Further, R, R' are independently selected from alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, and acyl is trifluoroacetyl;

[0016] Furthermore, R and R' are both tert-butyloxycarbonyl.

[0017] The second aspect of the present invention provides a method for preparing an intermediate M2, comprising the following steps: in a reaction solvent, SM1 and SM2 are subjected to reductive amination under the action of a Bronsted acid catalyst and a reducing agent to obtain M2;

[0018] Furthermore, the reaction solvent of the present invention is 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile or toluene;

[0019] Further, the SM2 of the present invention is alkoxycarbonyl or acyl protected 1,3-diaminoacetone, R, R' are independently selected from alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, acyl is trifluoroacetyl;

[0020] Furthermore, the Bronsted acid of the present invention is selected from trifluoroacetic acid, oxalic acid, anhydrous oxalic acid or sulfuric acid;

[0021] Furthermore, the reducing agent of the present invention is selected from sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride.

[0022] The third aspect of the present invention provides a specific process for preparing midazolam, which comprises the following steps:

[0023]

[0024] 1) In a reaction solvent, SM1 and SM2 are subjected to reduction and amination under the action of a Brønsted acid catalyst and a reducing agent to obtain M2;

[0025] 2) Intermediate M2 is reacted with Bronsted acid and base to obtain M3;

[0026] 3) M3 and the original acetate reagent undergo high temperature cyclization reaction to obtain M4;

[0027] 4) M4 is oxidized to obtain midazolam;

[0028] Further, the reaction solvent in step 1) of the present invention is selected from 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile or toluene. In a specific embodiment of the present invention, the reaction solvent is preferably dichloromethane;

[0029] Further, the SM2 of the present invention is alkoxycarbonyl or acyl protected 1,3-diaminoacetone, R, R' are independently selected from alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, acyl is trifluoroacetyl; in a specific embodiment of the present invention, R, R' are preferably tert-butoxycarbonyl;

[0030] Further, the Bronsted acid in step 1) of the present invention is selected from trifluoroacetic acid, oxalic acid, anhydrous oxalic acid or sulfuric acid. In a specific embodiment of the present invention, the Bronsted acid is preferably trifluoroacetic acid;

[0031] Further, the reducing agent in step 1) of the present invention is selected from sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride. In a specific embodiment of the present invention, the reducing agent is preferably sodium triacetoxyborohydride;

[0032] Further, the Brønsted acid in step 2) of the present invention is selected from formic acid, acetic acid, trifluoroacetic acid, concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or perchloric acid. In a specific embodiment of the present invention, the Brønsted acid is preferably concentrated hydrochloric acid;

[0033] Furthermore, the base in step 2) of the present invention is selected from ammonia water, triethylamine, diisopropylethylamine, trimethylamine, diethylamine, and dimethylamine. In a specific embodiment of the present invention, the base is preferably ammonia water;

[0034] Furthermore, the orthoacetic acid ester reagent in step 3) of the present invention is selected from trimethyl orthoacetate or triethyl orthoacetate; in a specific embodiment of the present invention, the orthoacetic acid ester reagent is preferably trimethyl orthoacetate;

[0035] Furthermore, the high temperature in step 3) of the present invention is 80-130° C. In a specific embodiment of the present invention, the high temperature is preferably 110° C.;

[0036] Further, the reaction solvent in step 3) of the present invention can be selected as a suitable solvent as needed, and the solvent is selected from toluene, benzene, xylene (one or more of o-xylene, m-xylene or p-xylene) or mesitylene. Preferably, the reaction solvent is toluene or xylene. In a specific embodiment of the present invention, the solvent is preferably toluene;

[0037] Furthermore, the oxidant in step 4) of the present invention is selected from one or both of manganese dioxide and dimethyl sulfoxide. In a specific embodiment of the present invention, the oxidant is preferably a mixture of manganese dioxide and dimethyl sulfoxide;

[0038] Furthermore, the reaction temperature of step 4) of the present invention can be selected as needed, and the reaction temperature is 100-160° C. In a specific embodiment of the present invention, the reaction temperature is preferably 150° C.;

[0039] Furthermore, the reaction solvent in step 4) of the present invention can be selected as a suitable solvent as needed, and the solvent is selected from toluene, xylene, mesitylene, benzene or dimethyl sulfoxide. In a specific embodiment of the present invention, the solvent is preferably dimethyl sulfoxide.

[0040] The beneficial effects brought by the invention are:

[0041] 1. The present invention provides a new intermediate M2 and a new method for preparing midazolam using the intermediate. The method has the advantages of short steps, simple operation, easy scale-up, suitability for industrial large-scale production, and high purity of the prepared target product, which can reach 99.83%.

[0042] 2. The entire route of the present invention does not involve the dangerous reactions, dangerous reagents, controlled reagents and genotoxic impurities mentioned in the prior art, thereby improving the safety of reactions and operations as well as the safety of products, while reducing the generation of three wastes and lowering production costs. DETAILED DESCRIPTION

[0043] To make the present invention easier to understand, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are used to limit the scope of the present invention. The specific experimental methods not mentioned in the following examples are usually carried out by conventional experimental methods. In the present invention, except that the reagent SM2 is homemade, the reagents used are all commercially available products.

[0044] The structures of the compounds were determined by nuclear magnetic resonance ( 1 HNMR) to determine.

[0045] Nuclear magnetic resonance (NMR) 1 HNMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance (NMR) measurements are made using 1 HNMR instrument, the solvent was DMSO-d6, the internal standard was tetramethylsilane (TMS), the chemical shift was 10 -6 (ppm) is given as the unit.

[0046] The HPLC spectra were determined using an Agilent 1260DAD (or Shimadzu LC-2030) liquid chromatograph. In this application, HPLC purity was determined using the following method:

[0047] (1) Chromatographic columns with octadecylsilane bonded silica as filler

[0048] (2) Detector: UV detector (wavelength 254nm)

[0049] (3) Flow rate: 1.0 mL per minute

[0050] (4) Run time: gradient elution

[0051] (5) Test solution: Prepare freshly before use. Take an appropriate amount of the product, weigh accurately, dissolve in methanol and quantitatively dilute to make a solution containing about 1 mg per 1 ml.

[0052] (6) Injection volume: 10 μl. The sample solution was measured by automatic integration method, and the purity of XX in the sample was calculated based on the peak area.

[0053] Preparation Example: Preparation of SM2 Preparation process:

[0054]

[0055] (1) Preparation of SM2-1:

[0056] Add 2.00 kg SM2-2 and 10.0 kg dichloromethane to the reactor, start stirring, cool to 0-5 ° C, add 9.5 kg di-tert-butyl dicarbonate, raise the temperature to 20-30 ° C and react for 6-12 hours. After the reaction is completed by TLC detection, reduce the pressure and concentrate until no obvious liquid drips out, add 8.0 kg petroleum ether, stir and slurry at room temperature, centrifuge, and dry at 40-55 ° C for 6-8 hours to obtain 5.93 kg of intermediate SM2-1 with a yield of 92%.

[0057] (2) Preparation of SM2:

[0058] Add 1.64kg oxalyl chloride and 4.3kg dichloromethane to the reaction bottle, replace with nitrogen three times, cool to below -60°C, add a mixed solvent of 2.02kg DMSO and 2.0kg dichloromethane, add 2.5kg SM2-1 and 6.0kg dichloromethane again, add 3.48kg triethylamine slowly, control the temperature below -10°C to react for 2-4h, and react at room temperature for 6-8h. After the reaction is completed by TLC detection, add the reaction solution to the reactor, add 4.0kg drinking water, stir, and separate. The organic phase is concentrated to dryness under reduced pressure. Add 5.0kg petroleum ether and heat to 40°C for pulping, cool to 0-5°C for crystallization for 2-4h, and centrifuge the solid to dry at 40-55°C for 6-8h to obtain 2.2kg of the starting material SM2 with a yield of 90%.

[0059] 1 HNMR (400MHz, DMSO-d6) δ7.03(t,J=5.9Hz,1H),3.78(d,J=5.9Hz,2H),3.33(s,0H),1.38(s,10H).

[0060] The present invention will be further described below in conjunction with specific embodiments:

[0061] Example 1 Preparation of Intermediate M2

[0062] In a 50 ml reaction bottle, 200 ml of dichloromethane, 20 g (80.11 mmol) SM1, 34.7 g SM2 (120.2 mmol, 1.5 eq), 18.3 g trifluoroacetic acid (160.2 mmol, 2.0 eq.) were added in sequence. The reaction solution was slowly cooled to 0-5°C, and 25.2 g of sodium triacetoxyborohydride (400.5 mmol, 5.0 eq.) was slowly added in batches for about 2-6 hours until the reaction was complete as detected by TLC / HPLC. A 0.5 M aqueous sodium hydroxide solution was added to adjust the pH to alkaline, and the aqueous phase was extracted again with 100 ml of dichloromethane, and the organic phases were combined and concentrated to dryness under reduced pressure to obtain a light yellow oil, which was directly used in the next step.

[0063] 1 HNMR (400MHz, DMSO-d6) δ7.56(td,J=7.9,1.8Hz,1H),7.37(dddd,J=8.1,6.9,5.0,1.8Hz,1H),7.32(t,J=2.5Hz,1H),7.17(td,J= 7.6, 1.2Hz, 1H), 7.10 (ddd, J=11.7, 8.2, 1.2Hz, 1H), 7.04 (dd, J=8.6, 2.6Hz, 1H), 6.62 (d, J=8.6Hz, 1H), 3.55 (s, 1H), 3.53 (s, 6H).

[0064] Example 2 Preparation of Intermediate M2

[0065]

[0066] The above route indicates that SM1 and SM2 are used to prepare M2 under the action of a Bronsted acid catalyst and a reducing agent. Table 1 shows M2 prepared under different reaction conditions, and its structural identification is consistent with the NMR data of Example 1.

[0067] Table 1 Selection of reaction solvent, Bronsted acid, reducing agent, and reducing agent dosage used to generate M2

[0068]

[0069] Example 3 Preparation of Intermediate M3

[0070] To the intermediate M2 oil obtained in Example 1, 164 ml of anhydrous methanol was added, and 79 g (801 mmol, 10.0 eq.) of concentrated hydrochloric acid was slowly added in batches for about 1-3 hours, until the reaction was complete as detected by TLC.

[0071] The reaction solution was slowly added with concentrated ammonia to adjust the pH to 10-11, stirred at room temperature for 4-6 hours, and after TLC detection, 180 ml of drinking water was added, and the mixture was concentrated under reduced pressure until no obvious liquid flowed out. 150 ml of ethyl acetate was added, and the liquid was separated. The aqueous phase was extracted with ethyl acetate twice, 150 ml each time, and the organic phases were combined. The organic phase was concentrated under reduced pressure until no obvious droplets flowed out, and 67 ml of anhydrous ethanol and 67 ml of ethyl acetate were added. 18.6 g of maleic acid was added. After the addition was completed, the mixture was stirred at room temperature for 4-8 hours, filtered, and dried to obtain 28.9 g of the product. The total yield of the two steps was 86%.

[0072] 1 HNMR(400MHz,DMSO-d6)δ7.93(s,3H),7.63–7.45(m,2H),7.32(dddd,J=14.9,10.6,7.9,1.1Hz,3H),7.11(s,1H),6.95(d,J=8.9Hz,1H),6.76(d d,J=2.6,0.8Hz,1H),6.13(s,4H),4.23–4.02(m,3H),3.77(dd,J=11.8,1.4Hz,1H),2.97(dd,J=12.7,5.0Hz,1H),2.78(dd,J=12.6,7.2Hz,1H).

[0073] Example 4 Preparation of Intermediate M3

[0074]

[0075] The above route indicates that the intermediate M2 is deprotected by Bronsted acid and then ring-closed under the action of a base to obtain M3. Table 2 shows M3 prepared under different reaction conditions, and its structural identification is consistent with the NMR data of Example 3.

[0076] Table 2 is the reaction solvent, Bronsted acid and its dosage, and base selection used to generate M3

[0077]

[0078] Example 5 Preparation of Midazolam

[0079] (1) Preparation of intermediate M4

[0080] Add 100ml dichloromethane (5V / M), 20g M3 (1.0eq), 67ml purified water (3.3V / M) to the reaction bottle in sequence, start stirring, slowly add 20ml concentrated ammonia (1V / M), react for 0.5-1h, let stand, separate, add 67ml purified water (3.3V / M) to the organic phase, 20ml ammonia (1V / M) to separate, let stand, separate, the organic phase is concentrated under reduced pressure at 45-55℃ until obvious droplets flow out of the condenser. Add 80ml toluene (4V / M) and 20g trimethyl orthoacetate (4.5eq.) to the single-mouth bottle, heat to 110℃, react for 16-24h, until the reaction is complete when detected by TLC. The reaction system was cooled to 60±5°C, concentrated under reduced pressure at the same temperature until no large amount of organic phase dripped out of the condenser, 40g toluene (2V / M) was added to concentrate the water, and concentrated under reduced pressure at 60°C until no obvious droplets flowed out of the condenser; 40g toluene (2V / M) was added to the condenser under reduced pressure at 60°C until no large amount of organic phase dripped out. 60-120ml EA (1-2V / M) was added to the reaction flask, the temperature was raised to reflux to dissolve, recrystallize, cooled to room temperature, stirred for crystallization for 4-6h, filtered, the filter cake was rinsed with 20g EA (1V / M), vacuum dried at 50±5°C for 6-8h, and M4 was obtained as a light yellow solid of 10.4g, with a yield of 85.4%.

[0081] 1 HNMR (400MHz, DMSO-d6) δ7.68–7.59(m,2H),7.55(dddd,J=8.4,7.3,5.2,1.9Hz,1H),7.46(d,J=8.4Hz,1H),7.31(td,J=7.6,1.1Hz,1H),7.23(ddd ,J=11.4,8.3,1.1Hz,1H),7.11(d,J=2.5Hz,1H),4.67–4.54(m,1H),3.90 –3.77(m,2H),3.70(ddd,J=14.5,7.0,1.5Hz,1H),1.57(d,J=1.5Hz,3H).

[0082] (2) Preparation of Midazolam

[0083] Add 50ml, DMSO (10V / M), 10g M4 (92mmol, 1.0eq), 30g MnO2 (3.0M) in a 2L four-necked flask, heat to 150℃, react for 1-4h, until the reaction is complete by TLC. Cool the reaction system to room temperature, add 150ml ethyl acetate, filter through diatomaceous earth pad, rinse the filter cake with 50ml ethyl acetate, add 100ml purified water to wash, and separate the liquids. Extract the aqueous phase twice with ethyl acetate, 50ml each time, combine the organic phases, wash with 50ml saturated sodium chloride aqueous solution, wash with 50ml purified water, and concentrate under reduced pressure until no obvious droplets flow out.

[0084] Add 18 mL of tetrahydrofuran to the reaction flask, add 18 mL of maleic acid (7.1 g, 2.0 eq.) dissolved in anhydrous ethanol, stir for 30 min, add 44 ml of methyl tert-butyl ether, stir overnight at room temperature, filter, and vacuum dry the filter cake at 50±5°C for 6-8 h to obtain 6.9 g of light yellow midazolam maleate solid with a purity of 96.37%.

[0085] Add 6.9 g of midazolam maleate solid into the reaction bottle, add 14 ml of THF and 6.7 ml of anhydrous ethanol, heat to reflux to dissolve, slowly cool to 5±5°C, slowly drop 28 ml of methyl tert-butyl ether, stir for 1-3 hours, filter and collect the solid, dry under reduced pressure at 50±5°C, and obtain 6.5 g of refined product.

[0086] 25 ml of dichloromethane, 5 g of midazolam maleate, 20 ml of purified water (4 V / M) and 10 ml of concentrated ammonia (2 V / M) were added to the reaction flask in sequence, and the reaction was freed for 1-2 hours at room temperature, and the liquid was separated by standing. The organic phase was concentrated under reduced pressure at 45-55 ° C to the condenser tube until no large amount of droplets flowed out. 8 ml of methanol was added to the reaction flask, and 10 ml of purified water was added, and the temperature was naturally lowered to 5 ± 5 ° C, crystallized for 2-6 hours, filtered, and the filtered solid was dried under reduced pressure at 50 ± 5 ° C. 5.2 g of midazolam was obtained as a white solid with a purity of 99.83%. The total yield of this step was 52%.

[0087] 1 HNMR (400MHz, DMSO-d6) δ7.91–7.68(m,1H),7.68–7.44(m,1H),7.44–7.10(m,2H),6.90(s,1H),5.10(dd,J=12.8,2.1Hz,1H),4.05(d,J=12.6Hz,1H).

[0088] The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. an intermediate M2, R, R' are independently selected from alkoxycarbonyl or acyl; in, The alkoxycarbonyl group is methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, and the acyl group is trifluoroacetyl.

2. The intermediate M2 according to claim 1, characterized in that: The alkoxycarbonyl group is tert-butyloxycarbonyl.

3. A method for preparing the intermediate M2 as claimed in claim 1 or 2, characterized in that: The method comprises the following steps: in a reaction solvent, SM1 and SM2 are reacted with a Bronsted acid and a reducing agent to obtain M2, The reaction solvent is 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile or toluene; The Bronsted acid is trifluoroacetic acid, oxalic acid, anhydrous oxalic acid or sulfuric acid; The reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; The SM2 is 1,3-diaminoacetone protected by a carbamate or acyl protecting group, and R and R' are defined as R and R' in claim 1 or 2.

4. A method for preparing midazolam using M2 as an intermediate, characterized in that: The steps include: 1) Intermediate M2 is reacted with Bronsted acid and base to obtain M3; 2) M3 reacts with trimethyl orthoacetate to obtain M4; 3) M4 is oxidized by an oxidant to obtain midazolam; The Bronsted acid in step 1) is selected from formic acid, acetic acid, trifluoroacetic acid, concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or perchloric acid; The base in step 1) is selected from aqueous ammonia, triethylamine, diisopropylethylamine, trimethylamine, diethylamine or dimethylamine; The oxidant in step 3) is selected from manganese dioxide and / or dimethyl sulfoxide.

5. A method for preparing midazolam, characterized in that: The steps include: 1) In a reaction solvent, SM1 and SM2 are subjected to reduction and amination under the action of Brønsted acid and a reducing agent to obtain M2; 2) Intermediate M2 is cyclized to obtain M3 under the action of Bronsted acid and base; 3) M3 reacts with trimethyl orthoacetate to obtain M4; 4) M4 is oxidized by an oxidant to obtain midazolam; The Bronsted acid in step 1) is trifluoroacetic acid, oxalic acid, anhydrous oxalic acid or sulfuric acid; the reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; In step 2), the Bronsted acid is selected from formic acid, acetic acid, trifluoroacetic acid, concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or perchloric acid; the base is selected from ammonia water, triethylamine, diisopropylethylamine, trimethylamine, diethylamine or dimethylamine; In step 4), the oxidant is selected from manganese dioxide and / or dimethyl sulfoxide.

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