Highly efficient method for producing remimazolam besylate

Abstract

The present invention relates to a method for efficiently producing a compound derived from the commercially available and readily available 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propionate methyl ester, namely, the compound 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionate methyl ester benzenesulfonate (remimazolam besylate).

Description

Technical Field

[0001] The present invention relates to a method for producing remimazolam besylate with high efficiency. More specifically, the present invention relates to a method for synthesizing remimazolam besylate (compound of the following formula (P)) using commercially available and easily obtainable methyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propionate (compound of the following formula (P-3)). Specifically, the present invention oxidizes the compound of the following formula (P-3) to a mixture of compounds of the formulas (P-2) and (P-1) by a novel oxidation reaction, and provides a method for synthesizing the compound of the formula (P) by treating this mixture with benzenesulfonic acid:

Chemical formula

Background Art

[0002] Remimazolam besylate is an imidazobenzodiazepine-type psychotropic drug developed by GlaxoSmithKline in the UK and Piion in Germany. It is used as a sedative during surgical anesthesia. Compared with existing propofol, it has a lower risk of cardiovascular depression and respiratory depression and is also safe for patients with renal and liver dysfunction, so it has attracted attention as a new anesthetic. Remimazolam besylate can be produced from the readily available methyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propionate of the following compound (P-3) through a synthetic route of two to three steps as shown in the following Reaction Scheme 1.

[0003]

Chemical formula

[0004] Previously, an oxidation reaction using the hypervalent iodine compound (DM) (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodooxol-3(1H)-one (Dess-Martin periodinane)) disclosed in Patent Document 1 can yield the compound of formula (P-1), or a mixture thereof, in 76% yield and good purity (93.91%) via the compound of formula (P-2). However, Dess-Martin periodinane is an expensive reagent, poses an explosion risk, and requires 1.5 equivalents of reactant, making it unsuitable for industrial-scale production from a cost and safety standpoint. Furthermore, the Swarn oxidation using oxalyl chloride in dimethyl sulfoxide (DMSO) and the Albright-Goldmann oxidation reagent (anhydride acetate / DMSO) presented in the aforementioned document are sensitive to moisture and require ultra-low temperatures below -60°C, thus requiring special manufacturing equipment. Furthermore, the use of DMSO, which is difficult to handle after the reaction due to the odor and explosive hazard of its gas by-product dimethyl sulfide (DMS), limits its application to production processes.

[0005] [ka] The oxidation reaction using chromium trioxide and sulfuric acid in reaction scheme 2 described in Patent Document 2 can synthesize the compound of formula (P-1) in high yield (90%) and purity (99.94%). However, this method uses sulfuric acid, which is a strong acid, and chromium trioxide, which is a heavy metal harmful to the human body and the environment, making it difficult to apply to processes in the pharmaceutical industry.

[0006] As an alternative to these problems, Patent Documents 1, 3, and 4 propose a method for synthesizing the compound of formula (P-2). This method selectively oxidizes the secondary alcohol of the compound of formula (P-3) using a combination of hypochlorite and an N-oxyl oxidation catalyst. This combination is economical and safe, and unlike oxidizing agents that are harmful to humans and the environment or are expensive, it does not require special equipment.

[0007] Patent Document 1 describes a method for synthesizing the compound of formula (P-2) by selectively oxidizing the secondary alcohol of the compound of formula (P-3) using sodium hypochlorite (NaOCl), tetramethylpiperidine-1-oxyl (hereinafter referred to as TEMPO), sodium bromide (NaBr), and sodium bicarbonate (NaHCO3), as shown in reaction scheme 3 below. The oxidation conversion rate of this reaction is not described and is therefore unknown. However, it has been reported that when the compound of formula (P) is synthesized from the compound of formula (P-2) in a single step using benzenesulfonic acid, the yield is 50%. [ka]

[0008] Patent Document 3 describes the synthesis of compound (P-2) from compound (P-3) using a combination of sodium hypochlorite (NaOCl) and a catalytic amount of TEMPO, as shown in reaction scheme 4 below. The subsequent synthesis yield to besylate was reported to be 58.43% (purity: 98.75%). [ka]

[0009] Patent Document 4 describes a method for synthesizing compound (P-2) from compound (P-3) using sodium hypochlorite (NaOCl) and 2-azaadamantane-N-oxyl (hereinafter referred to as AZADO), as shown in reaction scheme 5 below. The yield is unknown, and the oxidation conversion rate by HPLC is stated to be 99.9%. When experiments were directly conducted under these conditions and the results were analyzed according to test method 1 described in the following examples, the oxidation conversion rate after 1 hour of stirring was low at 32.8%. Stirring was continued for up to 5 hours thereafter, but no further reaction occurred. [ka] The reactions described in Patent Documents 1, 3, and 4 have the advantage of using sodium hypochlorite (NaOCl), an economical and non-toxic oxidizing agent, for oxidation reactions, and do not require special equipment. However, these require maintaining low temperatures for extended periods, and to ensure the reaction proceeds smoothly, it is necessary to add a base such as sodium bicarbonate (NaHCO3) or a salt such as sodium bromide or potassium bromide, and carry out the reaction under acidic conditions (pH 8.6-9.5). These basic conditions increase the instability of the ester portion of the compound, leading to the disadvantage of increased side reactions and impurities. Furthermore, because sodium hypochlorite (NaOCl) in aqueous solution is used, which is more easily decomposed than the pentahydrate form, quantitative analysis by titration is required before use. Due to its aqueous solution characteristics, the volumetric efficiency is usually low, with a maximum sodium hypochlorite (NaOCl) content of 12-13 wt%, which reduces volumetric efficiency and inevitably increases the water content of the reaction mixture, thus increasing the possibility of impurity generation.

[0010] As a result, when the final substance, remimazolam, was synthesized from the compound of formula (P-2) obtained by this method, the yield was low, at less than 60%, indicating the need to research a more efficient process.

[0011] One oxidation reaction used to obtain the compound of formula (P-2) (remimazolam besylate, a synthetic intermediate for the compound of formula (P)) from the compound of formula (P-3) involves using a hypochlorite and an N-oxyl oxidation catalyst (tetramethylpiperidine-1-oxyl (hereinafter referred to as TEMPO) or 2-azaadamantane-N-oxyl (hereinafter referred to as AZADO) or an analog thereof), which allows for the safe, economical, and successful acquisition of the target compound.

[0012] However, these methods require maintaining low temperatures, and as described in Patent Document 5, the reaction proceeds smoothly under basic conditions, requiring the addition of a base to adjust the pH. However, under these basic conditions, the properties of remimazolam containing ester groups increase the instability of both the starting material and the product, potentially leading to the generation of numerous impurities. As a result, the synthesis yield to the final compound may be low. In fact, the synthesis yield to the final compound described in Patent Documents 1 and 3 was low, below 60%. The synthesis yield in Patent Document 4 is not reported. After directly experimenting based on the patented method and confirming the results according to Test Method 1, the oxidation conversion rate was low at 32.8%.

[0013] The sodium hypochlorite (NaOCl) aqueous solution used in the aforementioned literature has a maximum concentration of 13 wt%, resulting in low volumetric efficiency and poor convenience during storage and use. Furthermore, sodium hypochlorite (NaOCl) in aqueous solution form is unstable, and its concentration continuously decreases, requiring proper preparation before use. This low storage stability and low volumetric efficiency are disadvantages from the perspective of industrial manufacturing, which requires long-term storage and continuous large-scale use. In addition, using an aqueous solution inevitably introduces a large amount of water into the reaction mixture, changing the pH to 13, thus increasing the possibility of impurity generation. The description of the properties of the sodium hypochlorite (NaOCl) aqueous solution is based on Non-Patent Document 1. [Prior art documents] [Patent Documents]

[0014]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

[0019] In the oxidation reaction of the present invention, experiments were conducted to find the optimal combination and amount of oxidizing agent to improve reaction efficiency, thereby completing the present invention.

[0020] The aforementioned solution ultimately led to a reaction that did not require low-temperature maintenance, completed within 30 minutes at room temperature, reduced impurity generation, and improved purity and yield. Furthermore, the compound of formula (P-1), an important intermediate in the synthesis of remimazolam besylate, was co-produced during the reaction. This subsequently underwent a cyclization reaction, inducing a reaction pathway favorable for the synthesis of remimazolam besylate. [Effects of the Invention]

[0021] According to the present invention, the limitations of the conventional reaction are improved by using sodium hypochlorite pentahydrate (NaOCl·5H2O), which is a superior oxidizing agent to aqueous solution in terms of oxidizing power, cost-effectiveness, stability, volume efficiency, and ease of use, in the oxidation reaction of the compound of formula (P-3).

[0022] Unlike unstable sodium hypochlorite (NaOCl) aqueous solutions, sodium hypochlorite pentahydrate (NaOCl·5H2O) exhibits minimal concentration fluctuations, eliminating the inconvenience of requiring titration before use. Furthermore, it achieves superior volumetric efficiency, reaching a maximum concentration of 44 wt%, compared to the maximum concentration of 12-13 wt% achievable in aqueous solutions. These advantages, such as storage stability and volumetric efficiency, are extremely important from the perspective of industrial manufacturing requiring long-term storage and continuous large-scale use.

[0023] Furthermore, using an aqueous solution of sodium hypochlorite (NaOCl) inevitably results in the addition of a large amount of water to the reaction mixture, creating a basic environment with a pH of 13. However, replacing this with sodium hypochlorite pentahydrate (NaOCl·5H2O) significantly reduces the water content of the reaction solution, and the pH also drops to 11. As the reaction conditions become relatively milder, the possibility of impurity formation decreases, and it becomes unnecessary to maintain a low temperature during the reaction. This has led to the invention of reaction conditions that achieve a higher oxidation conversion rate and a higher yield of the target compound.

[0024] Furthermore, by adding alkaline earth metal peroxides, which are economical, environmentally friendly, and have low toxicity to humans, as auxiliary oxidizing agents, and by identifying the appropriate amount to use, a low-cost and highly efficient weak oxidation reaction was achieved.

[0025] In the embodiments of the present invention, experiments to determine the optimal amount of calcium peroxide (CaO2), one of the alkaline earth metal peroxides, to achieve maximum efficiency showed that the oxidation conversion rate did not increase proportionally to the amount added, but rather significantly improved at a specific equivalent. In fact, comparative experiments under identical conditions with and without calcium peroxide (CaO2) addition, and optimization of the amount used, confirmed that the production rate of the target compound increased by more than 9% at a specific position. This indicates that calcium peroxide (CaO2) acts as an appropriate catalyst when used in the reaction of the present invention at the equivalent amount proposed by the inventors.

[0026] By appropriately combining the sodium hypochlorite pentahydrate (NaOCl·5H2O), calcium peroxide (CaO2), oxone, ammonium salt, and N-oxyl oxidation catalyst mentioned above, a 98.9% oxidation conversion rate can be achieved within 30 minutes at room temperature, without the need for maintaining low temperatures or pH adjustments, which were limitations of conventional techniques. Since basic conditions are not required, the instability of the ester groups constituting the compound is eliminated, impurities are reduced, and the target compound can be produced in high purity and high yield without purification.

[0027] One of the important effects of the above combination is that the compound of formula (P-1), which is an important intermediate in the synthesis of remimazolam besylate, is co-produced during the reaction. This facilitates the subsequent cyclization reaction, which is advantageous for the synthesis of remimazolam besylate. Patent documents 1 and 4, which are comparable to the present invention, provide only the compound of formula (P-2) under N-oxyl oxidizing agent conditions. While only the compound of formula (P-2) is produced under N-oxyl oxidizing agent conditions, in the embodiments of the present invention, the compound of formula (P-1) is produced in a high ratio of up to approximately 2:98 to the compound of formula (P-2).

[0028] This invention was completed by demonstrating that by synthesizing the product obtained under the conditions of the present invention into remimazolam besylate, a yield improvement of 1.6 to 1.9 times or more can be obtained in both steps compared to the conventional technique. [Brief explanation of the drawing]

[0029] [Figure 1] The results of HPLC analysis of the reaction solution after stirring for 30 minutes in Example 3-3 are shown. The peak area of ​​compound (P-2), which appears at 8.925 minutes, and the peak area of ​​compound (P-1), which appears at 11.771 minutes, account for 91.5% of the total peak area. The ratio of these two is 41:59, indicating that compound (P-1) is produced in a larger quantity. Compound (P-3), shown at 8.464 minutes, was produced in small quantities of 1.06%, and other impurities accounted for 7.4%. [Figure 2] The HPLC analysis of remimazolam besylate obtained in Example 4 is shown. The purity of remimazolam besylate, which appears at 12.553 minutes, is 98.49%. [Figure 3] This graph shows a comparison of the results of Comparative Example 1 and Example 1 at different temperatures. [Figure 4] This graph shows the rate of production of the target compound in Comparative Example 1 and Example 1, both conducted at 15°C, against the reaction time. [Figure 5] This graph shows the production rate of the target compound in Comparative Example 1 and Example 1, conducted at room temperature, against the response time.

[0030] (Best mode for carrying out the invention) The present invention will be described in more detail below. The present invention relates to a method for producing remimazolam besylate (formula (P)), comprising: (a) oxidizing 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propionate methyl ester of formula (P-3) (selectively an alcohol group) in the presence of an organic solvent using a hypochlorite hydrate, an N-oxyl oxidation catalyst, an ammonium salt, and an inorganic oxidizing agent; and (b) treating the reaction product obtained in step (a) with benzenesulfonic acid in an organic solvent or a mixture of organic solvents. In this case, the reaction product obtained in step (a) is a mixture of formulas (P-1) and (P-2). [ka]

[0031] The compound of formula (P-3) is readily available commercially and can be synthesized according to the method described in Patent Document 1.

[0032] The reaction in step (a) is a reaction in which the compound of formula (P-3) is oxidized using a hypochlorite hydrate and an N-oxyl oxidation catalyst in the presence of an organic solvent. In step (a), an ammonium salt, an inorganic oxidizing agent, or an alkaline earth metal peroxide may be used further. The reaction conditions are set such that the oxidizing agent oxidizes the secondary alcohol to a ketone to produce formula (P-2), which does not react with other functional groups of the compound of formula (P-3), and at the same time, a portion of the compound of formula (P-2) undergoes a cyclization reaction under these conditions and is converted to the compound of formula (P-1).

[0033] Therefore, the product of step (a) may be a mixture of the compound of formula (P-2) and the compound of formula (P-1).

[0034] The compounds of formula (P-1) and formula (P-2) can be separated by methods commonly used in organic synthesis, but the product (mixture) from step (a) can proceed to step (b) without further purification after workup. Since the cyclization to compound (P-1) and the synthesis of remimazolam besylate of formula (P) are carried out in a single step under acidic conditions in step (b), the formation of compound (P-1) is advantageous for the synthesis of the final compound.

[0035] For the purposes of the present invention, it is preferable to stop the reaction when 90% or more, preferably 95% or more, and more preferably 98% or more of the compound of formula (P-3) has been consumed, while simultaneously maintaining the rate of impurity generation at 10% or less, preferably 6%.

[0036] The reaction described above is stirred for at least 15 minutes and completed within 180 minutes. More preferably, it is stirred for at least 40 minutes, most preferably for at least 20 minutes, and completed within 35 minutes to obtain the purest product.

[0037] The above reaction can be carried out at room temperature (0°C to 30°C) without any special temperature setting, but 20°C to 25°C is most preferable considering the oxidation conversion rate and the possibility of impurity generation.

[0038] The oxidizing agent in step (a) above is a hydrate of hypochlorite, and may be one selected from the group consisting of sodium hypochlorite (NaOCl) hydrate, potassium hypochlorite (KOCl) hydrate, and calcium hypochlorite (Ca(OCl)2) hydrate, or a mixture of the aforementioned oxidizing agents if necessary.

[0039] Specifically, it is preferable to use sodium hypochlorite pentahydrate (NaOCl·5H2O) among the oxidizing agents mentioned above.

[0040] The oxidizing agent can be used in an amount of 0 to 10 equivalents, preferably 0.1 to 5 equivalents, relative to the compound of formula (P-3).

[0041] The reaction behavior differs depending on the form of sodium hypochlorite used in the reaction. When sodium hypochlorite pentahydrate (NaOCl·5H2O) was used, the oxidation conversion rate in the reaction was higher and the amount of impurity generated was significantly reduced compared to aqueous sodium hypochlorite (NaOCl) solution (12-14 wt%).

[0042] The N-oxyl oxidation catalyst used in step (a) above includes 2,2,6,6,-tetramethylpiperidine N-oxyl (TEMPO), 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-acetoxy-TEMPO, 4-acetamino-TEMPO, 4-hydroxy-TEMPO, 4-benzoyloxy-TEMPO, 4-amino-TEMPO, N,N-dimethylamino-TEMPO, 4-oxo-TEMPO, and their 4-substituted derivatives, as well as poly[(6-[1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl)], Chimasorb The N-oxyl oxidation catalyst of step (a) is a mixture obtained by combining the aforementioned catalysts as needed.

[0043] The N-oxyl oxidation catalyst is preferably one selected from AZADO, Me-AZADO, AZADOH, Nor-AZADO, TEMPO, and ABNO, and more preferably AZADO, Me-AZADO, and ABNO. The N-oxyl oxidation catalyst can be used with respect to the compound of formula (P-3) in an equivalent ratio of 0.001 to 1, preferably 0.01 to 0.2.

[0044] The structure of the compound represented by 2-azadamantane-N-oxyl (AZADO) used in the present invention is as shown in formula (1) below. [ka] (1)

[0045] The structure of the compound represented by 1-methyl-2-azadamantane-N-oxyl (Me-AZADO) used in the present invention is as shown in formula (2) below. [ka] (2)

[0046] The structure of the compound represented by 2-hydroxy-2-azadamantane (AZADOH) used in the present invention is as shown in formula (3) below. [ka] (3)

[0047] The structure of the compound represented by 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) used in the present invention is as shown in formula (4) below. [ka] (4)

[0048] The structure of the compound represented by 9-azabicyclo-[3.3.1]nonane-N-oxyl (ABNO) used in the present invention is as shown in formula (5) below. [ka] (5)

[0049] The ammonium salt assisting the oxidation reaction in step (a) above may be one selected from the group consisting of compounds represented by tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI), their salts, and their solvates, and preferably tetrabutylammonium bromide (TBAB).

[0050] The ammonium salt can be used with respect to the compound of formula (P-3) in an equivalent ratio of 0.001 to 10, preferably 0.01 to 0.5, and most preferably 0.01 to 0.2.

[0051] The alkaline earth metal peroxide that assists the oxidation reaction in step (a) may be one selected from the group consisting of compounds represented by calcium peroxide (CaO2), magnesium peroxide (MgO2), their salts, and their solvates, and preferably calcium peroxide (CaO2).

[0052] The aforementioned alkaline earth metal peroxide can be used in a ratio of 0 to 1 equivalent, preferably 0.01 to 0.5 equivalents, and most preferably 0.05 to 0.2 equivalents, relative to the compound of formula (P-3).

[0053] The reaction in step (a) differs depending on whether or not calcium peroxide (CaO2) is added. When calcium peroxide (CaO2) was added, the rate of production of the target compound increased compared to when it was not added.

[0054] The oxidation conversion rate and the yield of the target compound varied depending on the amount of calcium peroxide (CaO2) added. Experiments were conducted with calcium peroxide (CaO2) added at 0.037 equivalents (3.7 mol%), 0.075 equivalents (7.5 mol%), 0.1 equivalents (10 mol%), and 0.15 equivalents (15 mol%). The results showed that the optimal result was obtained at 0.1 equivalents (10 mol%), and using more than necessary decreased the oxidation conversion rate. Also, the yield of the compound of formula (P-1) was highest at this point. This indicates that when using calcium peroxide (CaO2) as a catalyst for mild oxidation reactions, there is an optimal amount, and identifying this amount and applying it to the reaction is an important factor.

[0055] The inorganic oxidizing agent used to assist the reaction in step (a) is a commercially available oxone (2KHSO4). 5· KHSO 4· It may be one selected from the group consisting of compounds represented by K2SO4, salts thereof, and solvates thereof.

[0056] The inorganic oxidizing agent can be used in a ratio of 0.1 to 10 equivalents, preferably 0.01 to 3 equivalents, relative to the compound of formula (P-3).

[0057] The organic solvent in step (a) above may be one selected from the group consisting of ethyl acetate, methyl acetate, methylene chloride, dichloroethane, toluene, acetone, diethyl ether, methyl tert-butyl ether, pentane, hexane, acetonitrile, and tetrahydrofuran, or a mixture obtained by combining the above solvents as needed.

[0058] Specifically, the aforementioned organic solvent is preferably one or more selected from ethyl acetate, methylene chloride, acetonitrile, and tetrahydrofuran, and more specifically, excellent results can be obtained by using acetonitrile.

[0059] In the present invention, the term "post-treatment" in the expression "the product (mixture) of step (a) can proceed to step 2) without purification after post-treatment" refers to the general post-treatment procedure performed in organic synthesis using aqueous solutions and organic solvents for reaction termination and washing. In the above reaction, washing and reaction termination are induced using an aqueous solution of sodium thiosulfate and ethyl acetate, the separated organic layer is extracted and dried, and the process proceeds to step (b).

[0060] In the production of remimazolam besylate (compound of formula (P)), the concentrated residue obtained after the post-treatment of step (a) can be produced without purification steps such as distillation, silica gel chromatography, or recrystallization. This is because the oxidation reaction in step (a) proceeds with a high conversion rate and good reproducibility.

[0061] The reaction in step (b) is a step in which, after carrying out the reaction in step (a), the concentrated residue obtained in step (a) is reacted with an organic acid in the presence of an organic solvent to produce remimazolam besylate (a compound of formula (P)).

[0062] The reaction in step (b) is a one-pot reaction comprising the steps of cyclizing the compound of formula (P-2) to convert it to the compound of formula (P-1), and forming a salt of the compound of formula (P-1), which is either converted or present as a product of step (a), to synthesize the remimazolam besylate of formula (P).

[0063] The organic acid in step (b) above may be one selected from the group consisting of benzenesulfonic acid, its salts, its hydrates, and its solvates.

[0064] The aforementioned organic acid can be used in a ratio of 0.9 to 2 equivalents, preferably 0.9 to 1.3 equivalents, relative to the compound of formula (P-3).

[0065] The reaction in step (b) can be carried out at 0°C to 100°C, preferably 20°C to 50°C, for 1 to 72 hours, preferably 24 to 48 hours.

[0066] The organic solvent in step (b) may be one selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, t-butyl alcohol, ethyl acetate, methyl acetate, methylene chloride, acetonitrile, and methyl ethyl ketone, or it may be a mixture obtained by combining the above solvents as needed. The aforementioned organic solvent is preferably one selected from methanol, ethanol, ethyl acetate, or a mixture thereof.

[0067] The remimazolam besylate (compound of formula (P)) produced during the reaction in step (b) can be separated by methods commonly used in organic synthesis. It can be formed as crystals from the reaction mixture during the reaction, or separated by crystallization from a solvent selected from methanol, ethanol, ethyl acetate, or a mixture thereof.

[0068] Examples The following is information regarding the main reagents used in the examples described herein. Sodium hypochlorite (NaOCl) aqueous solution (hereinafter referred to as NaOCl aqueous solution) Manufacturer: Sigma-Aldrich, Content: 10-15 wt% Sodium hypochlorite pentahydrate (hereinafter, NaOCl·5H2O) Manufacturer: WAKO, Content: 39% Calcium peroxide (CaO2) Manufacturer: Sigma-Aldrich, Purity: 75% 2-Azaadamantane-N-oxyl (hereinafter referred to as AZADO) Manufacturer: Sigma-Aldrich, Purity: 90% Oxone (hereinafter referred to as OXONE) Manufacturer: TCI Corporation, Purity: Approximately 45% or higher as KHSO5 Tetrabutylammonium bromide (hereinafter referred to as TBAB) Manufacturer: JUNSEI, Purity: 98% Benzenesulfonic acid Manufacturer: Sigma-Aldrich, Purity: 90% The HPLC analysis of the examples described in this document was performed under the following conditions. HPLC conditions Column: YMCODS-AQ, 250 x 4.6 mm, particle size 3 μm mobile phase Mobile phase A: Water containing 0.01% trifluoroacetic acid Mobile phase B: Acetonitrile containing 0.01% trifluoroacetic acid [Table 1] Flow rate: 1.0mL / min Column temperature: 40℃ Autosampler: Ambient Detection: U (230nm) Injection volume: 10μL Analysis time: 40 minutes Under the conditions described above, the residence time for compound (P-3) was approximately 8.4 minutes, the residence time for compound (P-2) was approximately 9.2 minutes, and the residence times for compound (P-1) and remimazolam besylate were both approximately 11.9 minutes.

[0069] The oxidation conversion rate and the rate of formation of the target compound used to derive the results of the examples were calculated according to the methods described in Test Method 1 and Test Method 2 below. Test Method 1: Method for Calculating the Oxidation Conversion Rate

number

number

[0070] Comparative Example 1 Comparative Example 1 shows a comparative oxidation reaction experimented at various temperatures using the method described in Patent Document 4 (Korean Patent Publication No. 10-2015-0120453) filed by Paion GmbH of Germany, but it was rejected.

[0071] Comparative Example 1-1: Same experiment as Example 3-1 of Patent Document 4 The compound of formula (P-3) (100 mg, 0.22 mmol) was suspended in a mixed solution of 0.77 mL of methyl acetate and 1.3 mL of toluene. To the reaction mixture, 14 wt% aqueous sodium hypochlorite solution (0.12 mL, 0.26 mmol), AZADO (0.112 mg, 0.00066 mmol), 0.41 mL aqueous solution of sodium bicarbonate (7.7 wt%), and potassium bromide (1.31 mg, 0.011 mmol) were added, and the mixture was stirred at 0°C for 1 hour. Subsequently, the oxidation conversion rate and the target compound were measured by HPLC according to Test Method 1 and Test Method 2, respectively.

[0072] Comparative Example 1-2: Experiment conducted at 15°C according to Example 3-1 of Patent Document 4. Compound (P-3) (500 mg, 1.1 mmol) was suspended in a mixed solution of 3.9 mL of methyl acetate and 6.5 mL of toluene. To the reaction mixture, 14 wt% sodium hypochlorite aqueous solution (0.6 mL, 1.3 mmol), AZADO (0.56 mg, 0.0033 mmol), 2.1 mL of sodium bicarbonate (7.7 wt%) aqueous solution, and potassium bromide (6.6 mg, 0.055 mmol) were added, and the mixture was stirred at 15°C for 24 hours. The reaction mixture was analyzed by HPLC at 5 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, and 24 hours after the start of the reaction. The oxidation conversion rate and the target compound were calculated according to Test Method 1 and Test Method 2 described above, respectively. Figure 1 shows the HPLC results at each time point that showed the highest rate of target compound formation.

[0073] Comparative Examples 1-3: Experiments conducted at room temperature according to Example 3-1 of Patent Document 4. The procedure was the same as in Comparative Example 1-2, except that the reaction temperature was changed to room temperature (25-30°C).

[0074] Comparative Example 1-4: Experiment conducted at 40°C according to Example 3-1 of Patent Document 4. The procedure was the same as in Comparative Examples 1-2, except that the reaction temperature was changed to 40°C.

[0075] Comparative Examples 1-5: Experiments were conducted at 50°C according to Example 3-1 of Patent Document 4. The procedure was the same as in Comparative Examples 1-2, except that the reaction temperature was changed to 50°C.

[0076] Comparative Examples 1-6: Experiment conducted at 60°C according to Example 3-1 of Patent Document 4. The procedure was the same as in Comparative Examples 1-2, except that the reaction temperature was changed to 60°C.

[0077] Example 1: Comparison of reaction patterns when sodium hypochlorite aqueous solution is replaced with sodium hypochlorite pentahydrate. Example 1 demonstrated that sodium hypochlorite in hydrate form is more effective than aqueous solution in this oxidation reaction by carrying out Comparative Example 1 using sodium hypochlorite pentahydrate.

[0078] Experiment in Example 1-1: The experiment was carried out in the same manner as in Comparative Example 1-1, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate.

[0079] Experiment in Example 1-2: The experiment was carried out in the same manner as in Comparative Example 1-2, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate.

[0080] Experiments in Examples 1-3: The same procedure as in Comparative Examples 1-3 was followed, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate.

[0081] Experiments in Examples 1-4: The same procedure as in Comparative Examples 1-4 was followed, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate.

[0082] Experiments in Examples 1-5: The same procedure as in Comparative Examples 1-5 was followed, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate.

[0083] Experiments in Examples 1-6: The same procedure as in Comparative Examples 1-6 was followed, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate. The results of Comparative Example 1 and Example 1 were compared at different temperatures and are shown in Graph 1 of Figure 3.

[0084] Graph 1 shows that the results of Example 1 are excellent in all temperature ranges from 0°C to 60°C. Example 1 shows optimal results with a target compound formation rate exceeding 90% in the temperature range of 25°C to 40°C, which corresponds to a typical room temperature, indicating that the reaction can be carried out at room temperature without separate temperature control equipment. In contrast, the experimental results of Comparative Example 1 showed that the target compound formation rate was low, at 30-40%, in most temperature ranges. The optimal temperature among these was 15°C. Patent Document 4 (Korean Patent Publication No. 10-2015-0120453) also maintains a low temperature of 0°C to carry out Comparative Example 1, indicating that a separate low-temperature maintenance device is necessary when using an aqueous sodium hypochlorite solution in this reaction.

[0085] The rate of target compound formation in Comparative Example 1 and Example 1, conducted at two different temperatures (15°C and room temperature), is shown as a function of reaction time (Graph 2 in Figure 4 and Graph 3 in Figure 5). In Comparative Examples 1-3, which used an aqueous sodium hypochlorite solution, the rate of target compound formation decreased sharply within 2 hours at room temperature. In contrast, in Examples 1-3, which used sodium hypochlorite hydrate, the product was maintained for more than 24 hours. Comparative Example 1-2 was conducted at a low temperature of 15°C, and therefore showed a longer product residence time compared to Comparative Examples 1-3. However, the product began to decrease after 7 hours, whereas the product in Example 1-2 was maintained for more than 24 hours. This indicates that, in this oxidation reaction, when sodium hypochlorite is used as an aqueous solution, maintaining a low temperature is essential for product maintenance, while using the hydrate allows the product to remain stable even at room temperature.

[0086] Example 2: Oxidation reaction using calcium peroxide (CaO2) / OXONE / TBAB complex Example 2 demonstrates that the calcium peroxide (CaO2) / OXONE / TBAB complex is effective as an auxiliary catalyst in the AZADO / hypochlorite oxidation reaction.

[0087] Experiment in Example 2-1: The experiment was conducted under the same conditions as in Comparative Examples 1-3, except that a calcium peroxide (CaO2) / OXONE / TBAB complex was added.

[0088] 3 mL of acetonitrile was mixed with 14 wt% sodium hypochlorite aqueous solution (0.16 mL, 0.264 mmol) and AZADO (0.84 mg, 0.005 mmol), and the mixture was stirred at room temperature for 1 to 2 minutes. To the reaction mixture, P-3 (100 mg, 0.22 mmol), OXONE (298 mg, 0.484 mmol), TBAB (11.2 mg, 0.035 mmol), and calcium peroxide (CaO2) (1.59 mg, 0.016 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, the oxidation conversion rate and the rate of target compound formation were determined by HPLC according to Test Method 1 and Test Method 2, respectively. Oxidation conversion rate: 75.3% / Target compound formation rate: 55.9%

[0089] Experiment in Example 2-2: The experiment was carried out in the same manner as in Example 2-1, except that the 14 wt% sodium hypochlorite aqueous solution was replaced with the same molar amount of sodium hypochlorite pentahydrate. The oxidation conversion rate and the rate of target compound formation were determined according to Test Method 1 and Test Method 2, respectively. Oxidation conversion rate: 98.2% / Target compound formation rate: 94.3% [Table 2]

[0090] Table 1 above shows that the reaction is improved when sodium hypochlorite pentahydrate and a compound agent (CaO2 / OXONE / TBAB) are used.

[0091] In Comparative Example 1-3 and Example 2-1, the sodium hypochlorite aqueous solution was replaced with sodium hypochlorite pentahydrate in Examples 1-3 and 2-2, respectively. The rate of target compound formation increased by approximately 4.8 times and 1.7 times, respectively. This indicates that sodium hypochlorite pentahydrate is more effective than aqueous solution in this oxidation reaction.

[0092] In Examples 2-1 and 2-2, where the composite agent was added to the conditions of Comparative Examples 1-3 and Examples 1-3, the rate of target compound formation increased by approximately 3 times and 1.2 times, respectively. This indicates that the addition of the composite agent improves this oxidation reaction.

[0093] Example 3: Study on the effect of calcium peroxide (CaO2) addition amount Experiment in Example 3-1: Without the addition of calcium peroxide (CaO2) The same method as in Example 2-2 was used, except that the addition of calcium peroxide (CaO2) was omitted. The oxidation conversion rate and the rate of target compound formation were measured according to Test Method 1 and Test Method 2 described above, respectively.

[0094] Experiment in Example 3-2: Use of 3.7 mol% calcium peroxide (CaO2) The procedure was the same as in Example 2-2, but the amount of calcium peroxide (CaO2) used was changed to (3.7 mol%, 0.0082 mmol, 0.79 mg). The oxidation conversion rate and the rate of target compound formation were measured according to Test Method 1 and Test Method 2 described above, respectively.

[0095] Experiment in Example 3-3: Use of 10 mol% calcium peroxide (CaO2) The procedure was the same as in Example 2-2, except that the amount of calcium peroxide (CaO2) used was changed to (10 mol%, 0.022 mmol, 2.11 mg). The oxidation conversion rate and the rate of target compound formation were measured according to Test Method 1 and Test Method 2 described above, respectively. Next, an aqueous solution of sodium thiosulfate was added to the reaction mixture and the layers were separated. The resulting organic layer was washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.

[0096] Experiments in Examples 3-4: Use of 15 mol% calcium peroxide (CaO2) The procedure was the same as in Example 2-2, except that the amount of calcium peroxide (CaO2) used was changed to (15 mol%, 0.033 mmol, 3.17 mg). The oxidation conversion rate and the rate of target compound formation were measured according to Test Method 1 and Test Method 2 described above, respectively.

[0097] The results of Examples 3-1 to 3-4 are shown in Table 2 below, in comparison with the results of Example 2-2. [Table 3]

[0098] From the results in Table 2 above, it was confirmed that when calcium peroxide (CaO2) was excluded (Example 3-1), both the oxidation conversion rate and the rate of target compound formation were the lowest. This confirmed that calcium peroxide (CaO2) not only induces a stable oxidation reaction in this oxidation reaction but also reduces the generation of impurities.

[0099] However, this oxidation efficiency did not increase in proportion to the amount of calcium peroxide (CaO2). Instead, high efficiency was observed with an appropriate amount. Furthermore, the ratio of P-1 produced during the reaction also changed with the amount of calcium peroxide (CaO2). When the amount of calcium peroxide (CaO2) was approximately 10 mol% (Example 3-3), the oxidation reaction showed the highest conversion rate, and the ratio of P-1 also reached its highest value.

[0100] Example 4: Synthesis of remimazolam besylate from the product of Example 3-3 Benzenesulfonic acid (38.3 mg, 0.24 mmol), methanol, and ethyl acetate mixed solvent (mixing ratio 1:30) were added to the concentrated residue of Example 3-3, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered with 100% ethyl acetate, and the obtained solid was dissolved in methanol. Activated carbon (30 mg) was added, and the mixture was stirred at room temperature for 2 hours, then filtered. The filtrate was redissolved in a mixed solvent of MEOH and EA (mixing ratio: 1:10), and the mixture was stirred overnight at room temperature. The precipitated crystals were filtered and washed to obtain 124.3 mg of remimazolam besylate (P). (Yield: 95%, Purity: 98.49%) The results of HPLC analysis of the obtained remimazolam besylate are shown in Figure 2.

[0101] Example 5: Oxidation reaction using ABNO Example 5 demonstrates that various N-oxyl oxidation catalysts can be used in this oxidation reaction by using ABNO, which functions similarly to AZADO, instead of AZADO. Experiment in Example 5-1: Sodium hypochlorite pentahydrate (2.7 g, 16.3 mmol) was suspended in 90 mL of tetrahydrofuran. To the reaction mixture, ABNO (96.4 mg, 0.65 mmol) and the compound of formula (P-3) (3.0 g, 6.5 mmol) were added and the mixture was stirred at room temperature for 1 hour. The oxidation conversion rate and the rate of target compound formation were then measured by HPLC according to the test methods 1 and 2 described above, respectively. Subsequently, 90 mL of 20% sodium thiosulfate aqueous solution was added and stirred for 30 minutes, and then 45 mL of ethyl acetate was added and stirred for another 30 minutes. The separated organic layer was extracted using a separatory funnel, dried with sodium sulfate, and concentrated using a rotary evaporator. Oxidation conversion rate: 99.1% / Target compound formation rate: 98.0%

[0102] Experiment in Example 5-2: Synthesis of remimazolam besylate from the product of Example 5-1 To the concentrated residue of Example 5-1, benzenesulfonic acid (516 mg, 3.3 mmol), ethanol, and ethyl acetate mixed solvent (mixing ratio 1:5) were added and the mixture was stirred overnight at room temperature. The precipitated solid was filtered and washed with the same solvent as the reaction solvent to obtain 1.57 g of remimazolam besylate (P) (yield: 81%, purity: 98%). [Table 4]

[0103] Table 3 shows comparative experiments between the prior art equivalent to the present invention (Comparative Example 1-1) and Examples 1-3, 3-3, and 5-1, demonstrating that the oxidation efficiency and reaction conditions of the present invention were significantly improved by the use of sodium hypochlorite pentahydrate. The effectiveness of this compound can be explained by the fact that it eliminates the need for low-temperature maintenance and pH adjustment, and increases the production rate of the target compound by more than three times within a reaction time of 30 minutes.

[0104] Furthermore, the ratio of the compound of formula (P-1) calculated according to Test Method 3 was better than that of Comparative Example 1-1, which is more advantageous in the subsequent cyclization reaction and the synthesis of remimazolam besylate. Figure 1 shows the P-2:P-1 ratio and the degree of impurity generation in the reaction solution of Example 3-3, which were analyzed by HPLC according to Test Method 3. [Table 5]

[0105] Examples 4 and 5-2 demonstrate that, as shown in Examples 3-3 and 5-1, synthesizing remimazolam besylate from the product obtained under the optimal conditions of the present invention significantly increases the overall yield compared to the prior art. The results in Table 4 represent the two-step purification yield for producing remimazolam besylate from the compound of formula (P-3). The results in Patent Documents 1 and 3 refer to the yields reported in the literature. Since the results in Patent Document 4 were unavailable, an independent experiment was conducted. However, the yield in the oxidation step was low (oxidation conversion rate: 32.8%), and it was not possible to proceed to the final reaction.

Claims

1. The following formula (P) 【Chemistry 1】 A method for producing remimazolam besylate of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]-benzodiazepine-4-yl]propionate methyl benzenesulfonate, comprising the following steps: (a) The following formula (P-3) 【Chemistry 2】 A step of oxidizing methyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridine-2-yl)-3H-benzo[e][1,4]diazepine-3-yl)propionate, represented by [formula], in the presence of an organic solvent using a hypochlorite hydrate and an N-oxyl oxidation catalyst; and (b) A step of treating the reaction product obtained in step (a) with benzenesulfonic acid in an organic solvent.

2. The aforementioned hypochlorite hydrates include sodium hypochlorite (NaOCl) hydrate, potassium hypochlorite (KOCl) hydrate, and calcium hypochlorite (Ca(OCl) 2 The manufacturing method according to claim 1, characterized in that it is one or more selected from the group consisting of hydrates of ).

3. The aforementioned hypochlorite hydrate is sodium hypochlorite pentahydrate (NaOCl·5H 2 The manufacturing method according to claim 1, characterized in that it is O).

4. The method for producing the product according to claim 1, characterized in that the hypochlorite hydrate is used in a ratio of 0.1 to 5 equivalents with respect to the compound represented by formula (P-3).

5. The N-oxyl oxidation catalyst is 2-Azaadamantane-N-oxyl (AZADO), represented by the following formula (1), The manufacturing method according to claim 1, characterized in that it is one or more selected from the group consisting of 1-methyl-2-azaadamantane-N-oxyl (Me-AZADO) represented by the following formula (2), 2-hydroxy-2-azaadamantane (AZADOH) represented by the following formula (3), 2,2,6,6,-tetramethylpiperidine N-oxyl (TEMPO) represented by the following formula (4), and 9-azabicyclo-[3.3.1]nonane-N-oxyl (ABNO) represented by the following formula (5), their salts, and their solvates: 【Transformation 3】

6. The production method according to claim 1, characterized in that the N-oxyl oxidation catalyst is used in an equivalent ratio of 0.01 to 0.2 units relative to the compound of formula (P-3).

7. The manufacturing method according to claim 1, characterized in that an ammonium salt is further used in step (a).

8. The manufacturing method according to claim 7, characterized in that the ammonium salt is one or more selected from the group consisting of tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI), salts thereof, and solvates thereof.

9. The manufacturing method according to claim 7, characterized in that the ammonium salt is used in an equivalent ratio of 0.01 to 0.5 with respect to the compound of formula (P-3).

10. The manufacturing method according to claim 1, characterized in that an inorganic oxidizing agent is further used in step (a).

11. The inorganic oxidizing agent is Oxon (2KHSO 5・ KHSO 4・ K 2 SO 4 The manufacturing method according to claim 10, characterized in that it is one or more selected from the group consisting of the salts and solvates thereof.

12. The manufacturing method according to claim 10, characterized in that the inorganic oxidizing agent is not used with respect to the compound of formula (P-3), or is used in a ratio of 0.01 to 3 equivalents.

13. The manufacturing method according to claim 1, characterized in that an alkaline earth metal peroxide is further used in step (a).

14. Alkaline earth metal peroxides are calcium peroxide (CaO 2 ), magnesium peroxide (MgO 2 The manufacturing method according to claim 13, characterized in that it is one or more selected from the group consisting of salts thereof and solvates thereof.

15. The manufacturing method according to claim 13, characterized in that an alkaline earth metal peroxide is not used with respect to the compound of formula (P-3), or is used in an equivalent ratio of 0.01 to 0.

5.

16. The manufacturing method according to any one of claims 1 to 15, characterized in that the organic solvent used in step (a) is selected from ethyl acetate, methyl acetate, methylene chloride, dichloroethane, toluene, acetone, diethyl ether, methyl tert-butyl ether, pentane, hexane, acetonitrile, tetrahydrofuran, and mixtures thereof.

17. The manufacturing method according to any one of claims 1 to 15, characterized in that the oxidation reaction in step (a) proceeds with a conversion rate of 98% or more, and then step (b) is carried out using the product obtained by post-treating the reaction mixture.

18. The manufacturing method according to claim 17, characterized in that the oxidation reaction in step (a) is carried out within 15 to 180 minutes.

19. The manufacturing method according to any one of claims 1 to 15, characterized in that the oxidation reaction in step (a) is carried out in a range of 0 to 30°C.

20. The manufacturing method according to any one of claims 1 to 15, characterized in that in step (b), the organic solvent is selected from the group consisting of ethyl acetate, methyl acetate, methanol, ethanol, methyl ethyl ketone, and mixtures thereof.

21. The manufacturing method according to any one of claims 1 to 15, characterized in that in step (b), benzenesulfonic acid is used in an amount of 0.9 to 1.1 equivalents relative to the compound of formula (P-3).

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