Synthesis method of midazolam

Abstract

The invention discloses a midazolam synthesis method, which comprises: carrying out a chlorination reaction on a compound represented by a formula M-VI and a chlorination reagent to generate a compound represented by a formula M-VII, and carrying out a salt forming reaction and a hydrolysis ring closing reaction on the compound represented by the formula M-VII and urotropine to generate midazolam. The method is mild in reaction condition, simple and convenient to operate, high in product purity and yield and low in industrial production cost, and industrial production in workshops is realized. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for synthesizing midazolam. Background Art

[0002] Midazolam, with the chemical name of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-α][1,4]-benzodiazepine As a new type of benzodiazepine drug containing an imidazole ring, it was developed by Roche AG of Switzerland and was first marketed in the UK in 1983. It has the effects of sedation, hypnosis, anti-anxiety and anti-convulsion. At the same time, it can produce a short-term anterograde amnesia, making the patient unable to recall what happened during the drug peak period. Midazolam can also be used for general anesthesia induction before the administration of other anesthetics. In the case of using narcotic premedication, anesthesia induction can be achieved within a relatively narrow dose range and a short time. Midazolam has the advantages of rapid onset, no delayed awakening, less disturbance to respiratory and circulatory systems, reduction of intracranial pressure and intraocular pressure, and is an ideal intravenous anesthetic with great development potential and broad market prospects.

[0003] Ranbaxy Laboratories disclosed two synthetic routes of midazolam in US Patent US5792874 as follows:

[0004]

[0005] Summary of the Invention

[0006] The two synthetic routes of midazolam in US5792874 have the following defects:

[0007] (1) The synthesis of the compound shown in Formula V from the compound shown in Formula III is carried out in two steps, with a long production cycle and low conversion rate;

[0008] (2) The synthesis of the chloro product intermediate shown in Formula VIII from the compound shown in Formula V. The generated chloro product intermediate is easy to absorb moisture, making its filtration and drying operations difficult. At the same time, this intermediate is also extremely easy to hydrolyze, resulting in low purity of the chloro product intermediate and complex post-treatment procedures;

[0009] (3) The synthesis of the compound shown in Formula IX from the compound shown in Formula VIII. Ammonia is introduced for amination. Since ammonia is not easy to control, bis-substitution side reactions on the amino group are likely to occur, resulting in low yield. At the same time, ammonia is easy to leak, causing safety accidents;

[0010] (4) The synthesis of midazolam from the compound shown in Formula IX. Ceric ammonium nitrate is used as a deprotecting agent, with low conversion rate and many side reactions.

[0011] The present invention provides a method for synthesizing midazolam. Compared with the defects in the prior art, such as complicated operation procedures, high production costs, many side reactions, low yields, high risks, and being not conducive to industrial production, the synthesis method of the present invention has simple operation procedures, easy control of the test process, few side reactions, low costs, high safety, high yields, and high product purity, and is more suitable for industrial production.

[0012] The present invention provides a method for synthesizing midazolam, and the synthesis route comprises the following steps:

[0013] The compound shown by formula M-VI reacts with a chlorinating reagent through a chlorination reaction to generate the compound shown by formula M-VII, and then the compound shown by formula M-VII reacts with hexamethylenetetramine through a salt-forming reaction and a hydrolysis ring-closing reaction to generate midazolam.

[0014]

[0015] In some embodiments, the salt-forming reaction is carried out in a first solvent, and the first solvent is dichloromethane, chloroform or tetrahydrofuran. Optionally, the first solvent is dichloromethane; in some embodiments, the weight-to-volume ratio of the compound shown by formula M-VI to the first solvent is 1:(2-6) kg / L; in an exemplary embodiment, the weight-to-volume ratio of the compound shown by formula M-VI to dichloromethane is 1:4 kg / L.

[0016] In some embodiments, the hydrolysis ring-closing reaction is carried out in a second solvent, and the second solvent is one or a mixture of two or more of methanol, ethanol and water. Optionally, the second solvent is a mixture of ethanol and water; in some embodiments, the volume ratio of ethanol to water in the mixture of ethanol and water is (1-4):1, or 2.5:1; in some embodiments, the weight-to-volume ratio of the compound shown by formula M-VI to the second solvent is 1:(3-7) kg / L; in an exemplary embodiment, the weight-to-volume ratio of the compound shown by formula M-VI to the second solvent is 1:5 kg / L.

[0017] In some embodiments, the reaction temperature of the salt-forming reaction is 40°C to 70°C, optionally 50°C to 60°C.

[0018] In some embodiments, the reaction temperature of the hydrolysis ring-closing reaction is 20°C to 40°C, optionally 20°C to 30°C.

[0019] In some embodiments, the chlorinating reagent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or sulfonyl chloride. Optionally, the chlorinating reagent is thionyl chloride.

[0020] In some embodiments, the chlorination reaction, the salt formation reaction, and the hydrolysis ring closure reaction are carried out in one pot.

[0021] In some embodiments, a method for synthesizing midazolam provided by the present invention further comprises the following steps:

[0022] S1: The compound represented by formula M-III reacts with 2-bromomalonaldehyde through a cyclization reaction to form a compound represented by formula M-IV, and the compound represented by formula M-IV further reacts under the action of a reducing agent to form a compound represented by formula M-V.

[0023]

[0024] S2: The compound represented by formula M-V reacts under the action of a deprotecting agent to form a compound represented by formula M-VI.

[0025]

[0026] In some embodiments, the reducing agent in step S1 is sodium borohydride.

[0027] In some embodiments, the deprotecting agent in step S2 is N-chlorosuccinimide / iron(III) nitrate nonahydrate, N-chlorosuccinimide / silver nitrate, N-chlorosuccinimide / copper(II) chloride, or ammonium cerium(IV) nitrate. Optionally, the deprotecting agent is N-chlorosuccinimide / iron(III) nitrate nonahydrate.

[0028] In some embodiments, step S1 is carried out in one pot.

[0029] In some embodiments, the present invention provides a method for synthesizing midazolam, and the synthetic route comprises the following steps:

[0030] S1: The compound represented by formula M-III reacts with 2-bromomalonaldehyde through a cyclization reaction to form a compound represented by formula M-IV, and the compound represented by formula M-IV further reacts under the action of a reducing agent to form a compound represented by formula M-V.

[0031]

[0032] S2: The compound represented by formula M-V reacts under the action of a deprotecting agent to form a compound represented by formula M-VI.

[0033]

[0034] S3: The compound represented by formula M-VI reacts with a chlorinating agent through a chlorination reaction to form a compound represented by formula M-VII, and the compound represented by formula M-VII reacts with hexamine first under the condition of a first solvent for a salt formation reaction, and further under the condition of a second solvent for a hydrolysis ring closure reaction to form midazolam.

[0035]

[0036] Among them, both step S1 and step S3 are one-pot methods; and / or

[0037] In step S2, the deprotecting agent is N-chlorosuccinimide / iron(III) nitrate nonahydrate, N-chlorosuccinimide / silver nitrate, N-chlorosuccinimide / copper(II) chloride, or ammonium cerium(IV) nitrate,

[0038] In step S3, the chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, or sulfonamide,

[0039] In step S3, the first solvent is dichloromethane, chloroform, or tetrahydrofuran,

[0040] In step S3, the second solvent is methanol, ethanol, or water, or a combination thereof,

[0041] Further, the deprotecting agent in step S2 is N-chlorosuccinimide / iron(III) nitrate nonahydrate,

[0042] Further, the chlorinating agent in step S3 is thionyl chloride,

[0043] Further, the first solvent in step S3 is dichloromethane,

[0044] Further, the second solvent in step S3 is a composition of ethanol and water.

[0045] Compared with the prior art, the present application has the following advantages:

[0046] 1. Both step S1 and step S3 are one-pot methods, which shortens the production cycle, reduces the quality control points, improves the conversion rate and product purity, and saves production costs;

[0047] 2. In step S2, N-chlorosuccinimide / iron(III) nitrate nonahydrate is used as the deprotecting agent, which further reduces side reactions and improves the conversion rate and product purity;

[0048] 3. In step S3, the compound shown in formula M-VI first undergoes a chlorination reaction with the chlorinating agent to form the compound shown in formula M-VII, and the compound shown in formula M-VII then forms a salt with hexamine and further undergoes hydrolysis and ring closure to obtain midazolam, which not only avoids the formation of disubstituted by-products caused by the difficult control of ammonia gas, but also avoids potential safety accidents caused by ammonia gas leakage.

[0049] Other features and advantages of the present application will be set forth in the following description, and in part will be obvious from the description, or can be learned by practicing the present application. Other advantages of the present application can be realized and obtained by the solutions described in the description and the drawings. Description of the Drawings

[0050] The drawings are used to provide an understanding of the technical solutions of the present application, and constitute a part of the description. Together with the embodiments of the present application, they are used to explain the technical solutions of the present application, and do not constitute a limitation to the technical solutions of the present application.

[0051] Figure 1 It is the HPLC chromatogram for detecting the purity of the compound shown by formula M-V by high performance liquid chromatography in Example 1;

[0052] Figure 2 It is the HPLC chromatogram for detecting the compound shown by formula M-VI by high performance liquid chromatography in Example 2-1;

[0053] Figure 3 It is the HPLC chromatogram for detecting the purity of midazolam by high performance liquid chromatography in Example 2-2. Detailed Embodiments

[0054] To make the objectives, technical solutions and advantages of the present application clearer and more understandable, the embodiments of the present invention will be described in detail below. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined arbitrarily with each other.

[0055] Example 1 Synthesis of 5-Hydroxymethyl-1-[4-chloro-2-(2-(2-fluorophenyl)-1,3-dithiolan-2-yl)phenyl]-2-methyl-1H-imidazole (V)

[0056]

[0057] Add 340.0 L of isopropanol, 85.0 kg of the compound shown by Formula M-III, 15.3 kg of acetic acid, 25.8 kg of triethylamine, and 42.2 kg of 2-bromomalonaldehyde into the reaction kettle, heat up to reflux for reaction for 2.5 hours. After the reaction is completed, concentrate under reduced pressure until no liquid droplets flow out, then add 340.0 L of dichloromethane and 340.0 L of water into the reaction kettle, stir and separate the liquid, combine the organic layers, add anhydrous sodium sulfate and stir for drying for more than 2 hours. Filter the obtained material, combine the filtrate and washing liquid, concentrate under reduced pressure until no liquid droplets flow out, add 850.0 L of 95% ethanol (v / v) to dissolve, and add sodium borohydride in portions for reaction for 7 hours. After the reaction is completed, add acetic acid dropwise to quench the reaction, then concentrate under reduced pressure until no liquid droplets flow out, add water into the reaction kettle, and adjust the pH to 7 - 8 with ammonia water, stir at 20°C - 30°C for 1 hour, and filter by centrifugation to obtain the wet powder of the reduction product. Add 95% ethanol into the reaction kettle, add the wet powder of the reduction product obtained in the previous step under stirring, heat up to reflux for reaction for 2 hours, cool down to -10°C - 0°C, stir for crystallization for more than 4 hours, and filter by centrifugation. Dry the obtained solid under reduced pressure at 55°C - 65°C to obtain 81 kg of the compound shown by Formula M-V, with a yield of 83% and a purity of 99.06%.

[0058] The conversion rate and product purity of the reaction were determined by high performance liquid chromatography. The specific chromatographic conditions are as follows:

[0059] Chromatographic conditions:

[0060] Chromatographic column: Octadecylsilyl silica gel as the packing material (Agilent ZORBAX SB C8 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency);

[0061] Mobile phase A: Acetate buffer solution (Take 7.7 g of ammonium acetate and 10 ml of 40% tetrabutylammonium hydroxide solution, dissolve in water and dilute to 1000 ml, adjust the pH value to 5.3 with glacial acetic acid)

[0062] Mobile phase B: Methanol

[0063] Elution mode: Isocratic elution, mobile phase A: mobile phase B = 44:56

[0064] Flow rate: 1 ml / min

[0065] Column temperature: 30°C

[0066] Detection wavelength: 220 nm

[0067] Injection volume: 10 μl

[0068] Injection time: 60 min.

[0069] Conclusion: For the synthesis of the compound shown in Formula M-V, we prepared the compound shown in Formula M-V by the two-step synthesis method in Patent Document US5792874, with an overall yield of 70.76% and a purity of approximately 94%. In contrast, the present invention adopts a one-pot method, which reduces the filtration and drying operation procedures of the intermediate compound shown in Formula M-IV, shortens the production cycle, reduces the quality control points, saves the production cost, and at the same time increases the final overall yield to 83% and the product purity reaches 99.06%.

[0070] Example 2

[0071] Example 2-1 Synthesis of 2-{5-(hydroxymethyl)-2-methyl-1H-imidazol-1-yl}-5-chloro-2-fluorobenzophenone (VI).

[0072]

[0073] Add 468.0 L of acetonitrile, 93.6 L of water, 78.0 kg of the compound shown in Formula M-V and iron(III) nitrate nonahydrate to the reaction kettle, and add 99.1 kg of N-chlorosuccinimide in batches for desulfurization reaction for 2 hours. After the reaction is completed, carry out vacuum concentration until no liquid droplets flow out. Add the prepared aqueous solution of trisodium citrate dihydrate to the reaction kettle of the above concentrated solution, control the temperature at 35°C - 45°C and stir for 1 hour, then slowly drip the sodium carbonate solution into the above reaction kettle, adjust the pH = 6.5 - 7.0, cool down to 20°C - 30°C and stir for 1 hour, then filter by centrifugation to obtain the wet powder of the desulfurized product. Weigh 3.8 times the amount (w / v) of anhydrous methanol of the wet powder of the desulfurized product and add the wet powder of the desulfurized product to the reaction kettle, heat up to 40°C - 50°C and stir until dissolved and clear, add activated carbon, filter through a titanium rod filter, cool down to 25°C - 35°C, slowly add water with stirring, stir, and filter by centrifugation. The obtained material is dried under reduced pressure at 60°C - 70°C to obtain 56 kg of the compound shown in Formula M-VI, with a yield of 88.15% and a purity of 99.57%.

[0074] The conversion rate of the reaction and the product purity were determined by high performance liquid chromatography. The specific chromatographic conditions are as follows:

[0075] Chromatographic conditions:

[0076] Chromatographic column: Octadecylsilyl-bonded silica gel as the filler (YMC-Triart C18 4.6 mm × 250 mm, 5 μm)

[0077] Mobile phase A: Phosphoric acid solution with pH 2.5

[0078] Mobile phase B: Acetonitrile

[0079] Flow rate: 1 ml / min

[0080] Column temperature: 45°C

[0081] Detection wavelength: 210 nm

[0082] Sample injection volume: 5 μl.

[0083] Perform gradient elution according to the following table:

[0084]

[0085] Synthesis of Midazolam in Example 2-2

[0086]

[0087] Weigh 217.2 L of dichloromethane and 54.3 kg of the compound shown in Formula M-VI and add them to the reaction kettle. Cool down to 0 °C - 10 °C, and slowly add 22.6 kg of thionyl chloride while stirring (temperature controlled at 0 °C - 20 °C). After addition, react at 0 °C - 10 °C for 4 hours. After the reaction is completed, concentrate under reduced pressure until no liquid droplets flow out. Add 434.4 L of dichloromethane, cool down to 0 °C - 5 °C, and add 88.5 kg of hexamine in batches. After addition, heat up to 25 °C - 35 °C and react for 7 hours. Concentrate under reduced pressure, then add 272 L of absolute ethanol and 109 L of water, stir until dissolved clearly, heat up to 50 °C - 60 °C and react for 3 hours. Concentrate under reduced pressure until no liquid droplets flow out. Add 272 L of dichloromethane and 217 L of water, maintain the temperature at 20 °C - 30 °C and stir for 30 minutes. Dropwise add ammonia water to adjust the pH to 7 - 8, separate the liquid layers, combine the organic layers, add anhydrous sodium sulfate and stir to dry for more than 2 hours, filter under pressure, concentrate under reduced pressure until no liquid droplets flow out, then add 91.8 L of isopropanol, heat up to reflux until the solid completely dissolves, add activated carbon, heat up to reflux for decolorization, and then quickly press the material into the reaction kettle through a titanium rod filter while it is hot. Cool down to 45 °C - 55 °C, stir and crystallize for 1 hour, then cool down to 35 °C - 45 °C, stir and crystallize for 1 hour, then cool down to 25 °C - 35 °C, stir and crystallize for 1 hour, then cool down to 15 °C - 25 °C, stir and crystallize for more than 6 hours, filter by centrifugation. The obtained solid is dried under reduced pressure at 50 °C - 60 °C to obtain 39 kg of midazolam, with an overall yield of 77.53% and a purity of 99.86%.

[0088] The conversion rate of the reaction and the purity of the product were determined by high performance liquid chromatography. The specific chromatographic conditions are as follows:

[0089] Chromatographic column: Octadecylsilyl silica gel as the packing material (Agilent ZORBAX SB C8 4.6 mm × 150 mm);

[0090] Mobile phase: Use acetate buffer solution (take 7.7 g of ammonium acetate and 10 ml of 40% tetrabutylammonium hydroxide solution, dissolve in water and dilute to 1000 ml, adjust the pH value to 5.3 with glacial acetic acid, filter by suction) - methanol (44:56) as the mobile phase

[0091] Flow rate: 1 ml / min

[0092] Column temperature: 30 °C

[0093] Detection wavelength: 220 nm

[0094] Sample injection volume: 10 μL

[0095] Conclusion: Through comprehensive analysis of Examples 2-1 and 2-2, similarly, we adopted the method for synthesizing midazolam reported in Patent Document US5792874A, that is, the compound shown in Formula V was first subjected to chlorination reaction to generate the compound shown in Formula VIII, then ammonia gas was introduced for amination reaction to generate the amide intermediate shown in Formula IX, and then the compound shown in Formula IX was deprotected and cyclized under the action of ammonium cerium nitrate to obtain midazolam. The total yield was only 29.68%, and the purity was about 93%.

[0096] In the present invention, the compound shown in Formula M-V is first desulfurized under the action of a deprotecting agent to obtain the compound shown in Formula M-VI, the compound shown in Formula M-VI is then subjected to chlorination reaction to generate the compound shown in Formula M-VII, and the compound shown in Formula M-VII continues to react with hexamine through salification, hydrolysis and cyclization to obtain midazolam. The total yield is increased to 77.53%, and the purity reaches 99.86%.

[0097] Thus, it can be seen that for the method for synthesizing midazolam in the present invention, on the one hand, the treatment procedure of the chlorinated product intermediate shown in Formula VIII is reduced, and the problem of low conversion rate caused by side reactions due to the deliquescence of the chlorinated product intermediate is avoided. On the other hand, the disubstitution reaction on the amino group caused by the difficult control of ammonia gas and the potential safety accident problem caused by ammonia gas leakage are also avoided.

[0098] Although the embodiments disclosed in the present application are as above, the content described is only the embodiments adopted for facilitating the understanding of the present application and is not intended to limit the present application. Any person skilled in the art within the scope of the present application can make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in the present application. However, the scope of patent protection of the present application shall still be subject to the scope defined by the appended claims.

Claims

1. A synthetic method of midazolam, characterized in that, the synthetic method comprises the following steps: The compound shown in formula M-VI reacts with a chlorinating reagent through a chlorination reaction to generate the compound shown in formula M-VII, and the compound shown in formula M-VII then reacts with hexamine through a salt-forming reaction and a hydrolysis ring-closure reaction to generate midazolam, 2. The synthetic method according to claim 1, characterized in that, the salt-forming reaction is carried out in a first solvent, the first solvent is dichloromethane, chloroform or tetrahydrofuran, optionally, the first solvent is dichloromethane; and / or the weight-volume ratio of the compound shown in formula M-VI to the first solvent is 1:(2-6) kg / L; and / or the hydrolysis ring-closure reaction is carried out in a second solvent, the second solvent is one or a mixture of two or more of methanol, ethanol and water, optionally, the second solvent is a mixture of ethanol and water; and / or the weight-volume ratio of the compound shown in formula M-VI to the second solvent is 1:(3-7) kg / L.

3. The synthetic method according to claim 1 or 2, characterized in that, the reaction temperature of the salt-forming reaction is 40°C to 70°C, optionally, 50°C to 60°C; and / or the reaction temperature of the hydrolysis ring-closure reaction is 20°C to 40°C, optionally, 20°C to 30°C.

4. The synthetic method according to any one of claims 1 to 3, characterized in that, the chlorinating reagent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or sulfonyl chloride, optionally, the chlorinating reagent is thionyl chloride.

5. The synthetic method according to any one of claims 1 to 4, characterized in that, the chlorination reaction, the salt-forming reaction and the hydrolysis ring-closure reaction are one-pot methods.

6. The synthetic method according to any one of claims 1 to 5, characterized in that, the synthetic method further comprises the following steps: S1: The compound shown in formula M-III reacts with 2-bromomalonaldehyde through a cyclization reaction to generate the compound shown in formula M-IV, and the compound shown in formula M-IV further reacts under the action of a reducing agent to generate the compound shown in formula M-V, S2: The compound shown in formula M-V reacts under the action of a deprotecting agent to generate the compound shown in formula M-VI, 7. The synthetic method according to claim 6, characterized in that, the reducing agent is sodium borohydride; and / or the deprotecting agent is N-chlorosuccinimide / iron(III) nitrate nonahydrate, N-chlorosuccinimide / silver nitrate, N-chlorosuccinimide / copper(II) chloride, or ammonium cerium(IV) nitrate, optionally, the deprotecting agent is N-chlorosuccinimide / iron(III) nitrate nonahydrate.

8. The synthetic method according to claim 6 or 7, characterized in that, the step S1 is a one-pot method.

9. The synthetic method according to claim 1, characterized in that, the synthetic method comprises the following steps: S1: The compound shown in formula M-III reacts with 2-bromomalonaldehyde through a cyclization reaction to generate the compound shown in formula M-IV, and the compound shown in formula M-IV further reacts under the action of a reducing agent to generate the compound shown in formula M-V, S2: The compound shown in formula M-V reacts under the action of a deprotecting agent to generate the compound shown in formula M-VI, S3: The compound shown by formula M-VI undergoes a chlorination reaction with a chlorinating reagent to form a compound shown by formula M-VII, and the compound shown by formula M-VII then undergoes a salt formation reaction and a hydrolysis ring closure reaction with hexamine to form midazolam. Wherein, both the steps S1 and S3 are one-pot methods; and / or The reducing agent in the step S1 is sodium borohydride; and / or The deprotecting agent in the step S2 is N-chlorosuccinimide / ferric nitrate nonahydrate; and / or In the step S3, the chlorinating reagent is thionyl chloride; and / or, the salt formation reaction is carried out in dichloromethane; and / or, the reaction temperature of the salt formation reaction is 50°C to 60°C; and / or, the hydrolysis ring closure reaction is carried out in a mixture of ethanol and water; and / or, the reaction temperature of the hydrolysis ring closure reaction is 20°C to 30°C.

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