Process for the manufacture of dexmedetomidine hydrochloride

Abstract

The present application relates to a method for preparing dexmedetomidine hydrochloride, which utilizes dextro- or levorotatory tartaric acid as a resolution reagent and water as a resolution solvent to resolve S-configuration dexmedetomidine d-tartaric acid salt from dexmedetomidine tartaric acid salt, and then replace it with hydrochloride. This method not only simplifies the process and greatly reduces the amount of organic solvent, but also does not require the use of organic solvents in the mother liquor recovery process, thereby providing dexmedetomidine tartaric acid salt with high purity, high yield, reduced organic solvent usage, and recovered mother liquor.

Description

Technical Field

[0001] The present invention relates to a method for producing an α2-adrenergic receptor agonist, and more particularly to a method for producing dexmedetomidine tartrate with high purity, high yield, reduced organic solvent usage, and the ability to recover mother liquor. Background Art

[0002] Dexmedetomidine is an anxiolytic, sedative, and analgesic sold under the trade name Precedex. Unlike other commonly used medications, such as propofol and fentanyl, dexmedetomidine provides sedation without the risk of respiratory depression and can provide concerted or semi-awakening sedation. Dexmedetomidine is a sympathomimetic agent, similar to clonidine, acting as an agonist of α2-adrenergic receptors in certain parts of the brain. Veterinarians use dexmedetomidine for similar purposes in cats, dogs, and horses, and the commercial product was developed by Orion Pharma.

[0003] After synthesizing medetomidine, existing processes require the use of multiple organic solvents for splitting and multiple crystallizations to purify the dextrorotatory enantiomer of medetomidine (also known as dexmedetomidine), particularly the S-configuration dexmedetomidine dextrorotatory tartrate. However, existing processes require the use of multiple organic solvents for splitting, which is complex, costly, and prone to producing genotoxic impurities. Secondly, existing processes require multiple crystallizations to improve the chiral purity of dexmedetomidine, but this also increases the cost of recrystallization. Furthermore, existing processes do not provide a mother liquor (ML) recovery process, resulting in waste of the dextrorotatory and levorotatory enantiomers, ultimately making it difficult to achieve the desired yield.

[0004] Therefore, there is an urgent need to improve the preparation method of dexmedetomidine hydrochloride to provide a process with high purity, high yield, reduced cost and the ability to recover mother liquor. Summary of the Invention

[0005] Therefore, one embodiment of the present invention provides a method for producing dexmedetomidine hydrochloride, which utilizes dextrorotatory tartaric acid as a resolving agent and water as a resolving solvent. Dexmedetomidine tartrate can be split into S-configuration dexmedetomidine dextrorotatory tartrate in one step, which is then replaced with hydrochloride. This method not only simplifies the process and significantly reduces the amount of organic solvent used, but also eliminates the need for an organic solvent in the mother liquor (ML) recovery process, thereby providing dexmedetomidine hydrochloride with high purity, high yield, and optimized process.

[0006] Another aspect of the present invention provides a method for producing dexmedetomidine hydrochloride, which utilizes L-tartaric acid as a resolving agent and water as a resolving solvent. This method allows for the immediate resolution of dexmedetomidine tartrate to yield the S-configuration dexmedetomidine L-tartrate, which is then replaced with the hydrochloride. This method also simplifies the process, significantly reduces the amount of organic solvent used, and eliminates the need for organic solvents in the mother liquor recovery process.

[0007] According to the above-mentioned method of the present invention, a method for producing dexmedetomidine hydrochloride is provided. In one embodiment, the method comprises the following steps: First, dexmedetomidine (D-(-) tartaric acid) is added to a resolution solvent to form a first mixture, wherein the dexmedetomidine (D-) tartaric acid may include racemic dexmedetomidine (D-) tartaric acid and / or enriched R-configuration dexmedetomidine (D-) tartaric acid, and the resolution solvent may be, for example, water.

[0008] Next, the first mixture is subjected to a first filtration step to obtain a first filtrate.

[0009] Then, the first filtrate is subjected to at least one recrystallization step and a second filtration step at 0° C. to obtain a first solid intermediate product and a first mother liquor. The first solid intermediate product may be, for example, S-configuration dexmedetomidine dextrorotatory tartrate, and the chiral purity of the first solid intermediate product may be, for example, not less than 97%.

[0010] The first mother liquor is then subjected to at least one recovery step. In this embodiment, the first mother liquor is subjected to a concentration step to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water. Next, the first concentrated mother liquor is subjected to a third filtration step to obtain a second filtrate. The second filtrate is then subjected to the aforementioned recrystallization step to obtain a second solid intermediate product and a second mother liquor. The second solid intermediate product may, for example, be dexmedetomidine dextrorotatory tartrate in the S configuration, and the chiral purity of the second solid intermediate product may, for example, be no less than 97%.

[0011] Subsequently, a salt exchange step is performed. In this embodiment, the first solid intermediate product and the second solid intermediate product are added to ethanol or butanone to form a second mixture. The second mixture is then added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride.

[0012] In the above embodiment, the weight ratio of the racemic dexmedetomidine dexmedetomidine tartrate to the concentrated R-configuration dexmedetomidine tartrate can be, for example, 1:1.

[0013] In the above examples, the dexmedetomidine dextrorotatory tartrate is added to the resolution solvent at 10°C to 30°C.

[0014] In the above embodiment, after the first mixture is cooled to 0° C. to 5° C., the first mixture is heated to 20° C. to 40° C. to perform the first filtration step.

[0015] In the above embodiment, seed crystals may be selectively added to the first filtrate in the recrystallization step, wherein the seed crystals may be, for example, S-configuration dexmedetomidine dextrorotatory tartrate.

[0016] In the above embodiment, after the recrystallization step, the second mother liquor can be optionally subjected to at least one recovery step to obtain a third solid intermediate product and a third mother liquor, wherein the third solid intermediate product is dexmedetomidine dextrorotatory tartrate with an S configuration and has a chiral purity of not less than 97%. In the above example, after the recovery step, the third mother liquor can be optionally added to ethanol to obtain a third mixture, and the third mixture can then be subjected to at least one recovery step to obtain a fourth solid intermediate product and a fourth mother liquor.

[0017] In the above embodiment, after the recovery step of the third mixture, at least one of the first solid intermediate product, the second solid intermediate product, the third solid intermediate product and the fourth solid intermediate product may be selectively dried, and the temperature of the drying step may be, for example, not higher than 60°C.

[0018] According to another aspect of the present invention, a method for producing dexmedetomidine hydrochloride is provided. In one embodiment, the method comprises the following steps: First, dexmedetomidine L-(+) tartaric acid is added to a resolution solvent at, for example, 10°C to 30°C to form a first mixture, wherein the dexmedetomidine L-(+) tartaric acid comprises racemic dexmedetomidine L-(+) tartaric acid and / or enriched R-configuration dexmedetomidine L-(+) tartaric acid, and the resolution solvent is water.

[0019] Next, the first mixture is subjected to a first cold filtration step to obtain a first filtrate. The first filtrate is then subjected to a concentration step and a filtration step to obtain a first solid intermediate product and a first mother liquor. The first solid intermediate product may be, for example, S-configuration dexmedetomidine levotartrate, and the chiral purity of the first solid intermediate may be, for example, not less than 90%.

[0020] Subsequently, the first mother liquor is subjected to at least one recovery step. In this embodiment, the recovery step comprises subjecting the first mother liquor to a second cooling filtration step and a concentration step at a temperature of 0°C to 10°C to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water. Next, the first concentrated mother liquor is subjected to a filtration step to obtain a second solid intermediate product and a second mother liquor, wherein the second solid intermediate product is dexmedetomidine levotartrate with an S-configuration, and the chiral purity of the second solid intermediate product can be, for example, no less than 90%.

[0021] Thereafter, the second mother liquor is subjected to at least one cycle of a mother liquor recovery step, a second cooling and filtration step, a concentration step, and a filtration step to obtain a third solid intermediate product and a third mother liquor, wherein the third solid intermediate product is S-configuration dexmedetomidine levotartrate, and the chiral purity of the third solid intermediate product may be, for example, not less than 90%.

[0022] Then, the first solid intermediate product, the second solid intermediate product, and the third solid intermediate product are dissolved in, for example, 2 to 10 volumes of a resolution solvent, and subjected to at least one recrystallization step to obtain a fourth solid intermediate product. The fourth solid intermediate product may be, for example, S-configuration dexmedetomidine levotartrate, and the chiral purity of the fourth solid intermediate may be, for example, not less than 97%.

[0023] Then, a salt exchange step is performed, and the fourth solid intermediate product is added to ethanol or butanone to form a second mixture. Then, the second mixture is added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride.

[0024] In the above embodiment, the dexmedetomidine levotartrate can be added to the resolution solvent at 10°C to 30°C, for example.

[0025] In the above embodiment, the first cold filtration step and the second cold filtration step can be performed at 0°C to 5°C, for example.

[0026] In the above embodiment, the filtration step is performed at 20°C to 40°C.

[0027] In the above embodiment, after the recrystallization step, the fourth solid intermediate product (i.e., S-configuration dexmedetomidine levotartrate) can be selectively converted into S-configuration dexmedetomidine dexotartrate, and then subjected to a salt exchange step to obtain S-configuration dexmedetomidine hydrochloride.

[0028] The method for preparing dexmedetomidine hydrochloride of the present invention utilizes dextrorotatory or levorotatory tartaric acid as a resolving agent and water as a resolving solvent. Dexmedetomidine tartrate can be split into S-configuration dexmedetomidine dextrorotatory tartrate in one step, and then replaced into hydrochloride. This method not only simplifies the process and significantly reduces the amount of organic solvent used, but also provides dexmedetomidine hydrochloride with high purity, high yield, and optimized process.

[0029] It is to be understood that the foregoing general description and the following detailed description are merely exemplary, and are intended to provide further explanation of the invention as claimed. DETAILED DESCRIPTION

[0030] Unless otherwise defined, the technical and scientific terms used below have the same meanings as understood by those skilled in the art to which this invention belongs. If a definition or usage of a term in a reference is inconsistent or contrary to the definition herein, the definition herein shall prevail and not the definition in the reference. Furthermore, unless the context otherwise requires, a singular term may include the plural, and a plural term may include the singular.

[0031] As mentioned above, the present invention provides a method for preparing dexmedetomidine hydrochloride, which comprises splitting dexmedetomidine tartrate into S-configuration dexmedetomidine dextrorotatory tartrate in one step and then replacing it with hydrochloride.

[0032] In one embodiment, the "dexmedetomidine dexmedetomidine tartrate" referred to herein may include racemic dexmedetomidine tartrate and / or enriched R-configuration dexmedetomidine tartrate.

[0033] The "racemic dexmedetomidine dextrorotatory salt" referred to herein (whose structure is shown in Formula I) refers to a mixture of equal or unequal amounts of R-configured dexmedetomidine dextrorotatory salt (whose structure is shown in Formula II) and S-configured dexmedetomidine dextrorotatory salt (whose structure is shown in Formula III):

[0034]

[0035] In the above embodiment, the weight ratio of the racemic dexmedetomidine dexmedetomidine tartrate and the concentrated R-configuration dexmedetomidine tartrate is not particularly limited, and can be, for example, 1:1 or other ratios.

[0036] As used herein, "enrichment" refers to increasing the proportion of other components in a mixture by removing one or more components without changing the concentration of the other components. In the above embodiment, enrichment of R-dexmedetomidine dextrorotatory salt means that the mixture is primarily composed of R-dexmedetomidine dextrorotatory salt. In existing processes, enriched R-dexmedetomidine dextrorotatory salt is typically discarded. However, one of the technical features of the present invention is the ability to separate high-purity S-dexmedetomidine dextrorotatory salt from the discarded mixture, thereby improving yield. The term "purity" herein refers to chiral purity, specifically the chiral purity of the S-dexmedetomidine salt.

[0037] "Resolution" as used herein refers to the separation of isomers of different configurations from a racemic compound or a compound of a specific configuration. In one embodiment, the method of the present invention relates to the resolution of the aforementioned dexmedetomidine dextrorotatory salt to obtain the S-configuration dexmedetomidine dextrorotatory salt. In one embodiment, the present invention utilizes a specific resolving agent and a specific resolving solvent to resolve the S-configuration dexmedetomidine dextrorotatory salt in a single step. The "resolving agent" referred to herein refers to dextrorotatory or levorotatory tartaric acid. The "resolving solvent" referred to herein refers to water. It should be noted that the present invention utilizes water as the resolution solvent, eliminating the use of other organic solvents, thereby significantly reducing the amount of organic solvent used and lowering costs.

[0038] The "single resolution" referred to herein means that the S-configuration dexmedetomidine dextrorotatory tartrate can be resolved by performing a single resolution step using the aforementioned resolution reagent and the aforementioned resolution solvent, thereby effectively simplifying the process.

[0039] The following describes a method for producing dexmedetomidine hydrochloride using D-(-)tartaric acid as the resolving agent. However, in other embodiments, this method may also include other existing steps upstream or downstream. In one embodiment, dexmedetomidine D-tartrate is first added to a resolving solvent at room temperature (e.g., 10°C to 30°C) to form a first mixture. In some examples, the dexmedetomidine D-tartrate may include racemic dexmedetomidine D-tartrate and / or concentrated R-configuration dexmedetomidine D-tartrate. Generally, the amount of the resolving agent (i.e., D-tartrate) used may be, for example, 0.8 to 1.2 eq. based on 50 g of dexmedetomidine. In other examples, the resolving solvent may be water. In other examples, the resolving solvent may be water with up to 10% by volume of an organic solvent, such as dimethyl sulfoxide (DMSO). In some specific examples, the volume-to-weight ratio (mL / g) of the resolution solvent to dexmedetomidine dextrorotatory tartrate can be, for example, 10 to 20, preferably 13 to 16. In other examples, the first mixture can be optionally stirred for 0.5 to 1.5 hours.

[0040] Next, the first mixture is subjected to a first filtration step to obtain a first filtrate, thereby removing the R-configuration dexmedetomidine dextrorotatory tartrate. In this embodiment, the first filtration step can be performed using existing process conditions, such as cooling the first mixture to below room temperature (e.g., 0°C to 5°C) and then heating the first mixture to room temperature (e.g., 20°C to 40°C, or 20°C to 23°C) to perform the first filtration step.

[0041] The first filtrate is then subjected to at least one recrystallization step and a second filtration step at a temperature below room temperature (e.g., 0° C. to 10° C.) to obtain a first solid intermediate product and a first mother liquor (ML). The first solid intermediate product may be, for example, S-configuration dexmedetomidine dextrorotatory tartrate, and the chiral purity of the first solid intermediate product may be, for example, not less than 97%.

[0042] In the above embodiment, seed crystals may be selectively added to the first filtrate during the recrystallization step, wherein the seed crystals may be, for example, S-configuration dexmedetomidine dextrorotatory tartrate, thereby increasing the yield of the first solid intermediate product.

[0043] Then, the first mother liquor is subjected to at least one recovery step. In this embodiment, the first mother liquor is subjected to a concentration step to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water.

[0044] As used herein, "concentrate" or "concentrated" refers to increasing the concentration of all components of a mixture by removing some or all of the solvent from the mixture, without changing the proportions of the components. In the above embodiments, the concentration step may be performed using conventional methods, such as vacuum concentration, but the present invention is not limited thereto.

[0045] Next, the first concentrated mother liquor is subjected to a third filtration step to obtain a second filtrate, thereby removing the R-configuration dexmedetomidine dextrorotatory salt. The second filtrate is then subjected to the aforementioned recrystallization step to obtain a second solid intermediate product and a second mother liquor. The second solid intermediate product may, for example, be S-configuration dexmedetomidine dextrorotatory salt, and the chiral purity of the second solid intermediate product may, for example, be not less than 97%.

[0046] Subsequently, a salt exchange step is performed. In this embodiment, the first solid intermediate product and the second solid intermediate product are added to ethanol or butanone to form a second mixture. Then, the second mixture is added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride, as shown in Formula IV:

[0047]

[0048] In some embodiments, the recrystallization step, the second filtration step, the recovery step, and the concentration step can be performed in a cyclic manner, and one or more cycles can be optionally performed to increase the yield of the S-configuration dexmedetomidine dextrorotatory salt. Specifically, in the above embodiment, after the recrystallization step, the second mother liquor can be optionally subjected to at least one recovery step to obtain a third solid intermediate product and a third mother liquor, wherein the third solid intermediate product is S-configuration dexmedetomidine dextrorotatory salt and has a chiral purity of not less than 97%. In the above example, after the recovery step, the third mother liquor can be optionally added to ethanol to obtain a third mixture, and the third mixture can then be subjected to the at least one recovery step to obtain a fourth solid intermediate product and a fourth mother liquor.

[0049] In the above embodiment, after the recovery step of the third mixture, at least one of the first solid intermediate product, the second solid intermediate product, the third solid intermediate product, and the fourth solid intermediate product may be optionally subjected to a drying step. This drying step may be performed using conventional methods and is not particularly limited, except that the temperature of the drying step is preferably no higher than 60° C. It should also be noted that the method of the present invention only requires a single drying step to synthesize S-configuration dexmedetomidine hydrochloride, thereby obtaining S-configuration dexmedetomidine hydrochloride with high purity and high yield, effectively overcoming the time-consuming drawback of the existing process, which requires multiple freeze-drying steps.

[0050] Below, the method for producing dexmedetomidine hydrochloride is illustrated using L-(+) tartaric acid as a resolving agent. However, in other embodiments, this method may also include other existing steps upstream or downstream.

[0051] In one embodiment, dexmedetomidine levotartrate is first added to a resolution solvent at room temperature (e.g., 10°C to 30°C) to form a first mixture. In some examples, the dexmedetomidine levotartrate may include racemic dexmedetomidine levotartrate and / or concentrated R-configuration dexmedetomidine levotartrate. Generally, the amount of the resolution agent (i.e., levotartrate) used may be, for example, 0.8 to 1.2 gram equivalents (eq.) based on 50 grams of dexmedetomidine. In other examples, the resolution solvent may be water; in other examples, the resolution solvent may optionally contain up to 10% by volume of an organic solvent, such as DMSO, in water. In some specific examples, the volume-to-weight ratio (mL / g) of the resolution solvent to dexmedetomidine levotartrate may be 10 to 20, preferably 13 to 16. In other examples, the first mixture may be stirred for 0.5 to 1.5 hours.

[0052] The "racemic dexmedetomidine levotartrate" referred to herein (whose structure is shown in Formula V) refers to a mixture of equal or unequal amounts of R-configured dexmedetomidine levotartrate (whose structure is shown in Formula VI) and S-configured dexmedetomidine levotartrate (whose structure is shown in Formula VII):

[0053]

[0054] In the above embodiment, the weight ratio of the racemic dexmedetomidine L-tartrate and the concentrated R-configuration dexmedetomidine L-tartrate is not particularly limited, and can be, for example, 1:1 or other ratios (e.g., 4:6 to 6:4).

[0055] Next, the first mixture is subjected to a first cold filtration step at 0° C. to 5° C. to obtain a first filtrate, thereby removing the R-configuration dexmedetomidine levotartrate. The first filtrate is then subjected to a concentration step to obtain a first concentrated solution, and the first concentrated solution is subjected to a second filtration step at room temperature (e.g., 20° C. to 40° C., or 20° C. to 23° C.) to obtain a first solid intermediate product and a first mother liquor. The first solid intermediate product may, for example, be S-configuration dexmedetomidine levotartrate, and the chiral purity of the first solid intermediate product may, for example, be not less than 90%.

[0056] Subsequently, the first mother liquor is subjected to at least one recovery step. In this embodiment, the recovery step includes performing a second cold filtration step on the first mother liquor, i.e., cooling the first mother liquor to 0 to 10° C. and performing a filtration step to remove the R-configuration dexmedetomidine levotartrate from the first mother liquor. Then, the first mother liquor after the second cold filtration step is subjected to a concentration step to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water. Then, the first concentrated mother liquor is filtered at room temperature (e.g., 20° C. to 40° C., or 20° C. to 23° C.) to obtain a second solid intermediate product and a second mother liquor, wherein the second solid intermediate product may, for example, be S-configuration dexmedetomidine levotartrate, and the chiral purity of the second solid intermediate product may, for example, be no less than 90%.

[0057] The second mother liquor is then subjected to at least one recovery step, a second cold filtration step, a concentration step, and a filtration step to obtain a third solid intermediate product and a third mother liquor. The third solid intermediate product is dexmedetomidine levotartrate with an S configuration, and the chiral purity of the third solid intermediate product may be, for example, not less than 90%. In other embodiments, the third mother liquor may be subjected to one or more cycles of recovery, concentration, and second filtration steps, similar to the treatment process for the first and second mother liquors, to obtain more solid intermediate product. The solid intermediate product is dexmedetomidine levotartrate with an S configuration, and the chiral purity of the third solid intermediate product may be, for example, not less than 90%.

[0058] Then, the first solid intermediate product, the second solid intermediate product, and the third solid intermediate product are dissolved in, for example, 2 to 10 volumes of a resolution solvent, and subjected to at least one recrystallization step to obtain a fourth solid intermediate product. The fourth solid intermediate product may be, for example, S-configuration dexmedetomidine levotartrate, and the chiral purity of the fourth solid intermediate may be, for example, not less than 97%.

[0059] Then, a salt-exchange step is performed, comprising adding ethanol or butanone to the fourth solid intermediate product to form a second mixture. Then, the second mixture is added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride. In other embodiments, before performing the salt-exchange step, the fourth solid intermediate product (i.e., S-configuration dexmedetomidine levotartrate) can be optionally replaced with S-configuration dexmedetomidine dexotartrate, and then the salt-exchange step is performed to obtain S-configuration dexmedetomidine hydrochloride.

[0060] The S-configuration dexmedetomidine hydrochloride of the present invention can exist in the form of a hydrate or a solvate. In other embodiments, the S-configuration dexmedetomidine hydrochloride can be used in pharmaceutical compositions or in combination with existing drugs.

[0061] It should be understood that the specific configurations, viewpoints, illustrations, and embodiments described below are provided for illustrative purposes only and are not intended to limit the present invention. The key features of the present invention may be employed in a variety of embodiments without departing from the spirit and scope of the present invention. Therefore, those skilled in the art will readily be able to identify the essential technical features of the present invention and make various modifications and refinements to suit different applications and conditions without departing from the spirit and scope of the present invention.

[0062] Example 1

[0063] In Examples 1 to 7, D-(-)tartaric acid was used as the resolving agent and water was used as the resolving solvent to concentrate S-dexmedetomidine D-tartaric acid salt with high chiral purity from dexmedetomidine D-tartaric acid salt.

[0064] First, 35.7 g of dexmedetomidine dextrorotatory salt and 600 mL of water are added to a suitable reactor to form a mixture, wherein the dexmedetomidine dextrorotatory salt comprises racemic dexmedetomidine (or R-dexmedetomidine) dextrorotatory salt (as shown in Formula I) and / or enriched R-configuration dexmedetomidine dextrorotatory salt (as shown in Formula II). Next, the mixture is heated to no less than (NLT) 30° C. to dissolve, and then cooled to 0° C. Then, the resulting mixture is heated to 23° C. and stirred at 23° C. overnight. Afterwards, the mixture is filtered to obtain a solid, which is R-configuration dexmedetomidine tartrate, with a chiral purity of 93.56%. Next, the filtrate is stirred at 23° C. Then, 150 mg of S-dexmedetomidine D-tartaric acid salt (shown as Formula III) was added to the filtrate as seed crystals. The mixture was then cooled to 6°C, filtered, and dried at no more than 60°C (NMT) to obtain S-dexmedetomidine D-tartaric acid salt (8.6 g) as a white to off-white solid with a chiral purity of 98.16% and a yield of 47%.

[0065] The mother liquor (ML) was concentrated to 349 g. The resulting mixture was cooled to 22° C. and stirred for 19 hours, after which the mixture was filtered. The resulting solid was R-configuration dexmedetomidine tartrate, with a chiral purity greater than 94.57%. The filtrate was then stirred at 23° C. 200 mg of S-configuration dexmedetomidine dextrorotatory tartrate was added to the filtrate as seed crystals. The mixture was then cooled to 7° C., filtered, and dried at no more than (NMT) 60° C. to obtain S-configuration dexmedetomidine dextrorotatory tartrate (3.6 g) as a white to off-white solid with a chiral purity of 97.60% and a yield of 20%. The total yield was 67%, and all mother liquor was recovered.

[0066] Next, 100 mL of dichloromethane (DCM) was added to the mother liquor, followed by the addition of 4N aqueous sodium hydroxide (NaOH(aq)) to adjust the pH to 12 to 13. Phase separation was then performed, and the aqueous layer was extracted with 50 mL of dichloromethane. The two organic layers were combined and concentrated to yield 7.6 g of an oily product. The oily product was dissolved in 100 mL of ethanol, and 5.66 g of the dexmedetomidine salt was added, followed by stirring overnight. The solid was filtered and dried at 60°C to yield concentrated R-configuration dexmedetomidine salt (10.7 g). This was subsequently used in Example 3, where the weight ratio of the R-configuration product to the S-configuration product (R / S ratio) was 57.6 / 42.4.

[0067] Example 2

[0068] In this example, the S-configuration dexmedetomidine dexmedetomidine tartrate was resolved from the racemic dexmedetomidine tartrate.

[0069] First, 19.4 g of racemic dexmedetomidine L-tartaric acid salt and 388 mL of water were added to a suitable reactor to form an aqueous solution. Next, 150 mL of dichloromethane (DCM) was added to the aqueous solution, followed by the addition of 4N sodium hydroxide (NaOH(aq)) to adjust the pH to 12. The phases were then separated, and the aqueous layer was extracted with 50 mL of dichloromethane. The two organic layers were then combined and re-extracted with water. Next, 5.86 g (0.7 eq) of dexmedetomidine L-tartaric acid was dissolved in 300 mL of water. The organic layer was then extracted with the dexmedetomidine L-tartaric acid solution. The phases were then separated, and any residual dichloromethane in the aqueous layer was removed. Then, 125 mg of dexmedetomidine L-tartaric acid was seeded into the aqueous layer at 18°C, and the mixture was cooled to 4°C. Then, 0.42 g (0.05 eq) of dexmedetomidine tartaric acid salt was added and the temperature was maintained at 4° C. for 2 days. The mixture was filtered and dried at not more than (NMT) 60° C. to obtain S-configuration dexmedetomidine tartaric acid salt (3.9 g) as a white to off-white solid with a chiral purity of 97.43% and a yield of 39%.

[0070] Next, 2.48 g (0.3 eq) of dexmedetomidine tartrate was added to the mother liquor obtained after filtering the mixture at 30°C. The resulting mixture was then cooled to 23°C and stirred for 21 hours. Afterwards, the mixture was filtered to obtain a solid, R-configuration dexmedetomidine tartrate, with a chiral purity of greater than 94.14%. The filtrate was then stirred at 23°C. 56 mg of S-configuration dexmedetomidine tartrate was then added to the filtrate as seed crystals. The mixture was then cooled to 7°C, filtered, and dried at no more than (NMT) 60°C to obtain S-configuration dexmedetomidine tartrate (2.4 g) as a white to off-white solid with a chiral purity of 97.97% and a yield of 25%. All of the mother liquor was recovered.

[0071] The mother liquor was concentrated to 87 g. The resulting mixture was cooled to 22 ° C and stirred for 19 hours, and then filtered. The resulting solid was R-configuration dexmedetomidine tartrate, with a chiral purity greater than 93.11%. The filtrate was then stirred at 23 ° C. 81 mg of S-configuration dexmedetomidine dextrorotatory tartrate was added to the filtrate as a seed crystal. The mixture was then cooled to 7 ° C, filtered, and dried at no more than (NMT) 60 ° C to obtain S-configuration dexmedetomidine dextrorotatory tartrate (1.0 g) as a white to off-white solid with a chiral purity of 98.24% and a yield of 10%. The above total yield was 74%, and all mother liquors were recovered.

[0072] Example 3

[0073] In this example, the S-configuration dexmedetomidine dextrorotatory salt was recovered from the R-configuration dexmedetomidine dextrorotatory salt concentrated in Example 1.

[0074] First, 14 g of concentrated R-configuration dexmedetomidine dextrorotatory salt (R / S = 55.42 / 44.58) and 210 mL of water were added to a suitable reactor to form a mixture. The mixture was then stirred at 23° C. for 4 hours. The mixture was then filtered to obtain a solid, R-configuration dexmedetomidine dextrorotatory salt, with a chiral purity of 92.86%. Next, 4N aqueous sodium hydroxide solution [NaOH(aq)] was added to the filtrate, and 76 mg of S-configuration dexmedetomidine dextrorotatory salt was added to the filtrate as seed crystals. The mixture was then cooled to 3° C., filtered, and dried at no more than (NMT) 60° C. to obtain S-configuration dexmedetomidine dextrorotatory salt (3.4 g) as a white to off-white solid with a chiral purity of 98.57% and a yield of 53%. All mother liquor was recovered.

[0075] Example 4

[0076] In this example, racemic dexmedetomidine dextrorotatory tartrate was used as the resolving agent, but no seed crystals were added.

[0077] First, 8 g of racemic dexmedetomidine dextrorotatory salt and 144 mL of water were added to a suitable reactor to form a mixture. The mixture was then heated to 45° C. and then cooled to 5° C. The resulting mixture was then heated to 23° C. and stirred at 23° C. for 17 hours. The mixture was then filtered to obtain a solid, R-configured dexmedetomidine tartrate, with a chiral purity of 94.34%. Next, 1.2 mL of 3N aqueous sodium hydroxide solution [NaOH(aq)] was added to the filtrate. The mixture was then cooled to 3° C. The mixture was filtered and dried at no more than (NMT) 60° C. to obtain S-configured dexmedetomidine dextrorotatory salt (1.9 g) as a white to off-white solid with a chiral purity of 98.91% and a yield of 47%. All mother liquor was recovered.

[0078] Example 5

[0079] This example prepares S-configuration dexmedetomidine dextrorotatory tartrate (chiral purity greater than 99.0%).

[0080] First, 16.9 g of S-configuration dexmedetomidine dextrorotatory salt (chiral purity greater than 98.87%) and 170 mL of water were added to a suitable reactor to form a mixture. The mixture was then heated to 52° C., cooled to 5° C., and stirred at 5° C. for not less than (NLT) 1 hour. The mixture was then filtered and dried at no more than (NMT) 60° C. to obtain S-configuration dexmedetomidine dextrorotatory salt (13.4 g) as a white to off-white solid with a chiral purity of 99.96% and a yield of 80%. All of the mother liquor was recovered.

[0081] Example 6

[0082] In this example, the mother liquor prepared from the S-configuration dexmedetomidine dextrorotatory salt (with a chiral purity greater than 99.0%) was recovered to prepare the S-configuration dexmedetomidine dextrorotatory salt.

[0083] First, the mother liquor (320 g, containing 7.1 g of S-configuration dexmedetomidine tartrate) and 170 mL of DCM were added to a suitable reactor to form a mixture. Then, 4N aqueous sodium hydroxide solution [NaOH(aq)] was added to the mixture to adjust the pH to greater than (MT) pH 9. The phases were then separated, and the aqueous layer was extracted with 35 mL of DCM. The two organic layers were then combined and extracted with 170 mL of water. The organic layer was concentrated, and 70 mL of ethanol (EtOH) was added. Next, 3.06 g (1.0 eq.) of D-(-)-tartaric acid was added to the mixture at 60°C to 65°C and stirred overnight. The mixture was then filtered and dried at no more than (NMT) 60°C to obtain S-configuration dexmedetomidine tartrate (5.5 g) as a white to off-white solid. Then, 5.5 g of S-configuration dexmedetomidine dextrorotatory salt (92% chiral purity) and 55 mL of water were added to a suitable reactor to form a mixture. The resulting mixture was then heated to 55° C. The mixture was then cooled to 3° C. and stirred at 5° C. for not less than (NLT) 1 hour. The mixture was filtered and dried at no more than (NMT) 60° C. to obtain S-configuration dexmedetomidine dextrorotatory salt (4.2 g) as a white to off-white solid with a chiral purity of 99.93% and a yield of 65%.

[0084] Example 7

[0085] Please refer to Table 1, which shows the results of mother liquor recovery in Preparation Example 7-1, Preparation Comparative Example 7-1, and Preparation Comparative Example 7-2. The results of Preparation Example 7-1 show that when the amount of dexmedetomidine salt used is 0.8 gram equivalent (eq.) and the volume-to-weight ratio of water to dexmedetomidine (mL / g) is 17.6 times, the chiral purity of the obtained first solid intermediate product is indeed not less than 97%, and the second filtrate contains dissolved S-configuration dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine salt. In contrast, the first solid intermediate products (R / S) of Preparation Comparative Examples 7-1 and Preparation Comparative Examples 7-2 cannot obtain S-configuration dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine salt with a chiral purity greater than 97%, but a concentrated first mother liquor can be obtained. If the process of Preparation Example 7-1 is subsequently carried out, S-configuration dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine salt with a chiral purity of not less than 97% can still be obtained.

[0086] Table 1

[0087]

[0088] Example 8

[0089] Please refer to Table 2, which shows the resolution results of Preparation Examples 8-1 to 8-5. The results of Preparation Example 8-1 indicate that when the amount of dextrorotatory tartrate used is 1.0 gram equivalent (eq.) and the volume-to-weight ratio of water to dexmedetomidine (mL / g) is 14.2 times, the chiral purity of the resulting first solid intermediate product is indeed no less than 97%.

[0090] Table 2

[0091]

[0092]

[0093] Example 9

[0094] In this example, L-(+)tartaric acid was used as a resolving agent to resolve the S-configuration dexmedetomidine L-tartrate.

[0095] Please refer to Table 3, which shows the resolution results of Comparative Example 9-1 and Examples 9-1 to 9-4. The results of Examples 9-1 to 9-2 show that when the amount of L-tartrate used is 0.7 to 0.85 eq. and the volume-to-weight ratio of water to dexmedetomidine (mL / g) is 14.9 times, at least 97% of the R-configuration dexmedetomidine L-tartrate (equivalent to the concentrated mother liquor) can be precipitated and removed. The results of Examples 9-3 to 9-4 show that at least 0.8 eq. of L-tartrate can be resolved into S-configuration dexmedetomidine L-tartrate with a chiral purity greater than 90%. In contrast, Comparative Example 9-1 failed to precipitate the R-configuration dexmedetomidine L-tartrate.

[0096] Table 3

[0097]

[0098]

[0099] Example 10

[0100] In this embodiment, 3.89g of racemic dexmedetomidine was dissolved in 93mL of ethanol (EtOH). 2.05g (0.7eq) of tartrate was dissolved in 7mL of water. The tartrate aqueous solution was added to the racemic dexmedetomidine ethanol solution, and the solvent was removed. Then, the solid product obtained was dissolved in 100mL of water. Then, 126mg of dexmedetomidine tartrate was added to the water layer as a seed crystal at 16°C and cooled to 4°C. Afterwards, the mixture was filtered to obtain R-configuration dexmedetomidine tartrate (3.9g) of white to off-white solid with a chiral purity greater than 97.64%. Next, the filtrate was concentrated to 71g, and 0.88g (0.3eq) of tartrate was added as a seed crystal. Then, the mixture was cooled to 22°C and stirred for 18 hours. The mixture was filtered and dried at not higher than (NMT) 60° C. to obtain S-configuration dexmedetomidine levotartrate (1.3 g) as a white to off-white solid with a chiral purity of 92.27% and a yield of 47%.

[0101] Example 11

[0102] This example converts the L-tartrate salt to the D-tartrate salt.

[0103] 1.3 g of S-configuration dexmedetomidine levotartrate was dissolved in 20 mL of water, and 50 mL of ethyl acetate was added. 4N aqueous sodium hydroxide solution (NaOH(aq)) was then added to the mixture, and the pH was adjusted to 12. The mixture was then separated, and the aqueous layer was extracted with 30 mL of ethyl acetate. The two organic layers were combined and re-extracted with 50 mL of water. The organic layer was then concentrated to yield 0.73 g of an oily product. The oily product was dissolved in 10 mL of ethanol, and 20 mL of water containing 0.55 g of dexmedetomidine levotartrate was added. The solution was concentrated to 21 g, cooled to 4°C, and stirred overnight. The solution was filtered and dried at 60°C to yield 0.81 g of S-configuration dexmedetomidine levotartrate as a white to off-white solid with a chiral purity of 99.67% and a yield of 64%.

[0104] Example 12

[0105] In this example, S-dexmedetomidine L-tartrate salt was recrystallized (second crystallization).

[0106] Please refer to Table 4, which shows the resolution results of Preparation Examples 10-1 and 10-2. The results of Preparation Examples 10-1 and 10-2 indicate that when dextrorotatory or levorotatory tartaric acid is used as the resolution reagent and the volume-to-weight ratio of water to dexmedetomidine (mL / g) is 11.7 to 15.6 times, all of Preparation Examples 10-1 and 10-2 can yield at least 97% of the S-configuration dexmedetomidine levorotatory tartrate.

[0107] Table 4

[0108]

[0109] In summary, the above-mentioned compounds of specific structures, specific reagents, specific solvents, specific processing steps, specific analysis modes or specific evaluation methods are only used to illustrate the method for producing dexmedetomidine hydrochloride. However, those skilled in the art will appreciate that, without departing from the spirit and scope of the present invention, compounds of other structures, other reagents, other solvents, other processing steps, other analysis modes or other evaluation methods may also be used in the method for producing dexmedetomidine hydrochloride, and are not limited to the above. For example, in an embodiment using dextrorotatory tartaric acid as a resolution reagent, the above-mentioned recrystallization step, second filtration step, recovery step and concentration step may be performed in a cyclic manner, and one or more cycles may be performed to increase the yield of S-configuration dexmedetomidine dextrorotatory salt. In an embodiment using levatotartaric acid as a resolution reagent, the above-mentioned recovery step, concentration step and second filtration step may be performed in a cyclic manner, and one or more cycles may be performed to increase the yield of S-configuration dexmedetomidine levatotaric salt.

[0110] As can be seen from the above examples, the method for preparing dexmedetomidine hydrochloride of the present invention has the advantage that water is used as the resolution solvent, and the S-configuration dexmedetomidine dextrorotatory tartrate can be resolved from dexmedetomidine tartrate in one step. This not only simplifies the process and significantly reduces the amount of organic solvent used, but also the mother liquor recovery process does not require the use of organic solvents, thereby providing dexmedetomidine tartrate with high purity, high yield, reduced organic solvent usage, and the ability to recover the mother liquor.

[0111] Although the present invention has been disclosed above with reference to several specific embodiments, other embodiments are possible. Therefore, the spirit and scope of the present invention as defined by the appended claims should not be limited to the embodiments contained herein.

Claims

1. A method for producing dexmedetomidine hydrochloride, characterized in that: Include: adding dexmedetomidine dextrorotatory salt to a resolving solvent at 10° C. to 30° C. to form a first mixture, wherein the dexmedetomidine dextrorotatory salt comprises racemic dexmedetomidine dextrorotatory salt and / or concentrated R-configuration dexmedetomidine dextrorotatory salt, the resolving solvent is water, and the volume-to-weight ratio (mL / g) of the resolving solvent to the dexmedetomidine dextrorotatory salt is 10 to 20; Performing a first filtration step on the first mixture to obtain a first filtrate; subjecting the first filtrate to at least one recrystallization step and a second filtration step at 0° C. to 10° C. to obtain a first solid intermediate product and a first mother liquor, wherein the first solid intermediate product is S-configuration dexmedetomidine dextrorotatory tartrate, and the chiral purity of the first solid intermediate product is not less than 97%; The first mother liquor is subjected to at least one recovery step, comprising: performing a concentration step on the first mother liquor to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water; performing a third filtration step on the first concentrated mother liquor to obtain a second filtrate; and performing the recrystallization step on the second filtrate to obtain a second solid intermediate product and a second mother liquor, wherein the second solid intermediate product is S-configuration dexmedetomidine dextrorotatory tartrate, and the chiral purity of the second solid intermediate product is not less than 97%; and Perform a salt exchange step, comprising: adding ethanol or butanone to the first solid intermediate product and the second solid intermediate product to form a second mixture; and The second mixture is added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride.

2. The method for producing dexmedetomidine hydrochloride according to claim 1, wherein The weight ratio of the racemic dexmedetomidine dextrorotatory salt to the concentrated R-configuration dexmedetomidine dextrorotatory salt is 1:

1.

3. The method for producing dexmedetomidine hydrochloride according to claim 1, wherein After the first mixture is cooled to 0° C. to 5° C., the first mixture is heated to 20° C. to 40° C. to perform the first filtering step.

4. The method for producing dexmedetomidine hydrochloride according to claim 1, wherein The recrystallization step further comprises adding a seed crystal to the first filtrate, and the seed crystal is S-configuration dexmedetomidine dextrorotatory tartrate.

5. The method for producing dexmedetomidine hydrochloride according to claim 1, wherein After the recrystallization step, the method further comprises: The second mother liquor is subjected to the at least one recovery step to obtain a third solid intermediate product and a third mother liquor, wherein the third solid intermediate product is S-configuration dexmedetomidine dextrorotatory tartrate, and the chiral purity of the third solid intermediate product is not less than 97%.

6. The method for producing dexmedetomidine hydrochloride according to claim 5, wherein After the recovery step, the method further comprises: adding ethanol to the third mother liquor to obtain a third mixture; and The recovery step is performed on the third mixture at least once to obtain a fourth solid intermediate product and a fourth mother liquor.

7. The method for producing dexmedetomidine hydrochloride according to claim 6, wherein After the step of recovering the third mixture, the method further comprises: A drying step is performed on at least one of the first solid intermediate product, the second solid intermediate product, the third solid intermediate product, and the fourth solid intermediate product, and a temperature of the drying step is not higher than 60°C.

8. A method for producing dexmedetomidine hydrochloride, characterized in that: Include: adding dexmedetomidine levotartrate to a resolving solvent at 10° C. to 30° C. to form a first mixture, wherein the dexmedetomidine levotartrate comprises racemic dexmedetomidine levotartrate and / or concentrated R-configuration dexmedetomidine levotartrate, the resolving solvent is water, and the volume-to-weight ratio (mL / g) of the resolving solvent to the dexmedetomidine levotartrate is 10 to 20; performing a first cold filtration step on the first mixture to obtain a first filtrate; performing a concentration step and a filtration step on the first filtrate to obtain a first solid intermediate product and a first mother liquor, wherein the first solid intermediate product is S-configuration dexmedetomidine levotartrate, and the chiral purity of the first solid intermediate product is not less than 90%; Performing a mother liquor recovery step, comprising: performing a second cooling filtration step and a concentration step on the first mother liquor to obtain a first concentrated mother liquor, wherein the first concentrated mother liquor contains no more than 50% by weight of water; Performing the filtration step on the first concentrated mother liquor to obtain a second solid intermediate product and a second mother liquor, wherein the second solid intermediate product is S-configuration dexmedetomidine levotartrate, and the chiral purity of the second solid intermediate product is not less than 90%; performing at least one cycle of the second cooling and filtration step, the concentration step, and the filtration step on the second mother liquor to obtain a third solid intermediate product and a third mother liquor, wherein the third solid intermediate product is S-configuration dexmedetomidine levotartrate, and the chiral purity of the third solid intermediate product is not less than 90%; performing a recrystallization step on the first solid intermediate product, the second solid intermediate product, and the third solid intermediate product to obtain a fourth solid intermediate product, wherein the fourth solid intermediate product is S-configuration dexmedetomidine levotartrate, and the chiral purity of the fourth solid intermediate product is not less than 97%; and Perform a salt exchange step, comprising: adding ethanol or butanone to the fourth solid intermediate product to form a second mixture; and The second mixture is added to an ethanol solution containing hydrochloric acid or a butanone solution containing hydrochloric acid to obtain S-configuration dexmedetomidine hydrochloride.

9. The method for producing dexmedetomidine hydrochloride according to claim 8, wherein The first cooling filtration step and the second cooling filtration step are performed at 0°C to 5°C.

10. The method for producing dexmedetomidine hydrochloride according to claim 8, wherein The filtration step is carried out at 20°C to 40°C.

11. The method for producing dexmedetomidine hydrochloride according to claim 8, wherein After the recrystallization step, the method further comprises: converting the fourth solid intermediate product into S-configuration dexmedetomidine dextrorotatory tartrate; and The salt exchange step was performed on the S-configuration dexmedetomidine dextrorotatory tartrate.

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