Racemization method of dexmedetomidine hydrochloride resolution by-product

Abstract

The invention relates to a racemization method of dexmedetomidine hydrochloride resolution byproducts, which comprises the following steps: converting mother liquor (containing a large amount of optical levomedetomidine and dexmedetomidine) after dexmedetomidine resolution into racemized medetomidine, and further splitting to obtain dexmedetomidine hydrochloride. According to the invention, waste levomedetomidine is converted into dexmedetomidine hydrochloride again, the method has great significance for controlling the production cost of the dexmedetomidine hydrochloride bulk drug, and the preparation method has the advantages of being simple, mild in condition and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a racemic method for resolving dexmedetomidine hydrochloride byproducts. Background Technology

[0002] Dexmedetomidine hydrochloride, chemically named (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazolium monohydrochloride, has the following structural formula:

[0003]

[0004] Dexmedetomidine hydrochloride injection is an α2-adrenergic receptor agonist jointly developed by Orion Pharma (Finland) and Abott (USA), and was first marketed in the United States in March 2000. This product is the dextrorotatory isomer of dexmedetomidine and is clinically used for sedation in surgical patients undergoing general anesthesia during endotracheal intubation and mechanical ventilation.

[0005] There are currently many methods for synthesizing dexmedetomidine hydrochloride reported in literature and materials. The commonly used methods reported in existing technologies require the separation of the racemic mixture after obtaining dexmedetomidine.

[0006] US4544664 discloses a method that uses methyl 4-imidazolium carboxylate as a starting material, reacts sequentially with Grignard reagents 2,3-dimethylphenyl magnesium bromide and methyl magnesium bromide to obtain 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol, which is then eliminated and hydrogenated to obtain medetomidine, and resolved to obtain dexmedetomidine.

[0007]

[0008] Alex A. Cordi et al. disclosed a method using 4-(1-triphenylmethyl)imidazolaldehyde as a starting material, reacting it with 2,3-dimethylmagnesium bromide via a Grignard reaction, followed by oxidation with manganese dioxide to obtain 4-(2,3-dimethylbenzoyl)-1-triphenylmethylimidazolium, which was then reacted with methylmagnesium bromide to prepare 1-(2,3-dimethylphenyl)-1-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol. After further elimination, deprotection, reduction, and resolution, dexmedetomidine was obtained (see Synthetic Communications, 26(8), 1585-1593(1996)).

[0009]

[0010] Patent CN201610627337.4 discloses a process using 4-iodo-1-triphenylmethylimidazole and 2,3-dimethylacetophenone as starting materials. First, the compound 4-iodo-1-triphenylmethylimidazole is reacted with ethyl magnesium bromide to prepare a Grignard reagent. Then, it is reacted with 2,3-dimethylacetophenone to obtain a key intermediate. Finally, the product is obtained through elimination, deprotection, reduction, and resolution steps.

[0011]

[0012] There are also numerous reports in patents and literature regarding chiral resolution reagents:

[0013] Patent CN103694175A reports the use of (+)-di-p-toluyl tartaric acid for chiral resolution;

[0014] Patent CN104151249B reports the use of L-(-)camphorsulfonic acid to form salts for chiral resolution;

[0015] Patent CN105175339B reports the use of S-(+)-mandelic acid and L-(-)-dibenzoyl tartaric acid for chiral resolution.

[0016] Existing chiral resolution technologies report yields below 50%, resulting in low raw material utilization and high costs for dexmedetomidine hydrochloride API. Furthermore, the mother liquor after dexmedetomidine resolution contains significant amounts of levomedetomidine and unprecipitated dexmedetomidine. Therefore, this study explores a racemic reaction method for dexmedetomidine hydrochloride resolution byproducts, allowing for the reuse of the mother liquor to further resolve dexmedetomidine, thereby reducing the production cost of dexmedetomidine hydrochloride API. This method is of great significance to pharmaceutical manufacturers. Summary of the Invention

[0017] The purpose of this invention is to provide a method for racemizing the byproducts of dexmedetomidine hydrochloride separation, thereby achieving raw material recycling, improving raw material utilization, and reducing the production cost of active pharmaceutical ingredients.

[0018] The technical solution adopted by this invention to solve its technical problem is:

[0019] A method for preparing a compound as shown in Formula II, characterized by comprising the following steps:

[0020] (1) After the mother liquor of dexmedetomidine was separated, it was freed by adding alkali, then extracted and concentrated to recover dexmedetomidine;

[0021] (2) Then, after dissolving the compound in a solvent, bromine was added dropwise under light to carry out a bromination reaction to obtain compound I.

[0022] (3) Hydrolysis with sodium hydroxide aqueous solution yields compound II;

[0023]

[0024] Preferably, the alkali used in step (1) is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and more preferably sodium hydroxide; the extraction solvent is selected from dichloromethane, chloroform, 2-methyltetrahydrofuran or ethyl acetate, and more preferably dichloromethane.

[0025] Preferably, the solvent used in step (2) is selected from dichloromethane, chloroform or 2-methyltetrahydrofuran, and more preferably dichloromethane; the amount of bromine used is 1.0 to 1.2 equivalents, preferably 1.05 equivalents; and the light source used for illumination is a 100W high-pressure mercury lamp.

[0026] Preferably, the method for preparing the compound represented by Formula II is characterized in that the concentration of the sodium hydroxide aqueous solution used in step (3) is 5% to 20%, and more preferably 10% sodium hydroxide aqueous solution.

[0027] A method for racemizing dexmedetomidine hydrochloride resolution byproducts, characterized by comprising the following steps:

[0028] (1) After the mother liquor of dexmedetomidine was separated, it was freed by adding alkali, then extracted and concentrated to recover dexmedetomidine;

[0029] (2) Then, after dissolving the compound in a solvent, bromine was added dropwise under light to carry out a bromination reaction to obtain compound I.

[0030] (3) Hydrolysis with sodium hydroxide aqueous solution yields compound II;

[0031] (4) Compound II is dehydroxylated to obtain compound III;

[0032] (5) The compound of formula III was reduced by hydrogenation to obtain racemic metomididine;

[0033] (6) Medetomidine is resolved into salts to obtain dexmedetomidine hydrochloride;

[0034]

[0035] The compound shown in Formula II was prepared according to the preparation method described in claim 1.

[0036] Preferably, the racemic reaction method for resolving dexmedetomidine hydrochloride byproducts is characterized in that the base used in step (1) is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, more preferably sodium hydroxide; the extraction solvent is selected from dichloromethane, chloroform, 2-methyltetrahydrofuran or ethyl acetate, more preferably dichloromethane.

[0037] Preferably, the solvent used in step (2) is selected from dichloromethane, chloroform or 2-methyltetrahydrofuran, and more preferably dichloromethane; the amount of bromine used is 1.0 to 1.2 equivalents, and more preferably 1.05 equivalents; the light source used for illumination is a 100W high-pressure mercury lamp.

[0038] Preferably, the racemic reaction method for resolving dexmedetomidine hydrochloride byproducts is characterized in that the concentration of the sodium hydroxide aqueous solution used in step (3) is 5% to 20%, preferably 10% sodium hydroxide aqueous solution.

[0039] Preferably, the racemic reaction method for resolving dexmedetomidine hydrochloride byproducts is characterized in that the dehydroxylation step (4) uses a trifluoroacetic acid / triethylsilane system.

[0040] Preferably, the racemic method for resolving dexmedetomidine hydrochloride byproducts is characterized in that step (5) uses Pd / C for catalytic hydrogenation reduction; and step (6) uses L-(+)-tartaric acid for chiral resolution.

[0041] The present invention has the following beneficial effects:

[0042] By reprocessing and converting the waste generated during the separation process of dexmedetomidine hydrochloride, the mother liquor can be recycled and reused, being converted back into an intermediate for the preparation of dexmedetomidine, and then further processed to obtain dexmedetomidine hydrochloride. This significantly improves raw material utilization and reduces production costs. The reagents used for recycling and conversion are inexpensive, the reaction conditions are mild, and the operation is simple, making it suitable for industrial production. Detailed Implementation

[0043] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the nature and scope of the present invention are not limited thereto.

[0044] Example 1: Recovery of metoprimidine from the mother liquor

[0045] Two L of dexmedetomidine dissociation mother liquor (ethanol solution containing 54.5 g dexmedetomidine tartrate) was concentrated to dryness under reduced pressure. 500 ml of dichloromethane and 500 ml of purified water were added, and the pH was adjusted to 9–10 with 10% sodium hydroxide aqueous solution. The mixture was separated, and the organic layer was concentrated to dryness under reduced pressure to recover 30.6 g of dexmedetomidine, with a yield of 98.3%. HPLC isomerization analysis showed that the content of levomedetomidine in the sample was 88.6%, and the content of dexmedetomidine was 10.5%.

[0046] Example 2: Preparation of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0047]

[0048] Dissolve 20g (0.1mol) of recovered metoprimidine in 120ml of dichloromethane. Under irradiation with a 100W high-pressure mercury lamp, add 16.8g (0.105mol, 1.05eq) of bromine dropwise at 0-5℃. After the addition is complete, continue the reaction under light for 2h. Then, add 60ml of 2% sodium thiosulfate aqueous solution to terminate the reaction. Separate the liquids, retain the dichloromethane phase, and proceed directly to the next step.

[0049] Add 120 ml of 10% sodium hydroxide aqueous solution to the above dichloromethane solution, heat to 40-45℃ and react for 5 h, then cool to 20-30℃, separate the liquid and retain the dichloromethane phase, wash once with 120 ml of saturated brine, add 300 ml of n-heptane dropwise to the dichloromethane phase, precipitate a solid, filter, dry to obtain 18.9 g of off-white solid, yield 87.3%, HPLC purity 98.9%.

[0050] Example 3: Preparation of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0051] Dissolve 20g (0.1mol) of recovered metoprimidine in 120ml of chloroform. Under irradiation with a 100W high-pressure mercury lamp, add 16.0g (0.10mol, 1.0eq) of bromine dropwise at 0-5℃. After the addition is complete, irradiate the reaction for 1h. Then, add 60ml of 2% sodium thiosulfate aqueous solution to terminate the reaction. Separate the liquids, retain the chloroform phase, and proceed directly to the next step.

[0052] Add 120 ml of 10% sodium hydroxide aqueous solution to the above chloroform solution, heat to 60-65℃ and react for 2 h, then cool to 20-30℃, separate the liquid and retain the chloroform phase, wash once with 120 ml of saturated brine, add 150 ml of n-heptane to the chloroform phase, precipitate a solid, filter, and dry to obtain 17.6 g of off-white solid, yield 81.5%, HPLC purity 99.2%.

[0053] Example 4: Preparation of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0054] Dissolve 20g (0.1mol) of recovered metoprimidine in 120ml of dichloromethane. Under irradiation with a 100W high-pressure mercury lamp, add 19.2g (0.12mol, 1.2eq) of bromine dropwise at 0-5℃. After the addition is complete, continue the reaction under light for 2h. Then, add 60ml of 2% sodium thiosulfate aqueous solution to terminate the reaction. Separate the liquids, retain the dichloromethane phase, and proceed directly to the next step.

[0055] Add 100 ml of 20% sodium hydroxide aqueous solution, stir at 25-30℃ for 2 h, separate the layers, retain the upper 2-methyltetrahydrofuran phase, wash once with 100 ml of saturated saline, add 300 ml of methyl tert-butyl ether, cool to 0-5℃ to crystallize for 4 h, filter, and dry to obtain 18.1 g of off-white solid, yield 83.8%, HPLC purity 99.1%.

[0056] Example 5: Preparation of 4-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole

[0057]

[0058] 15.1 g (0.07 mol) of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol was dissolved in 100 mL of dichloromethane. 40.7 g of triethylsilane was added, and the mixture was cooled to -5 to 0 °C. 30 mL of trifluoroacetic acid was added dropwise over approximately 0.5 h. The mixture was then slowly heated to 20-25 °C and reacted for 5 h. The mixture was washed with 150 mL of saturated sodium bicarbonate and once with 100 mL of saturated brine. The solution was concentrated under reduced pressure to obtain 12.6 g of the product, with a yield of 91.0% and an HPLC purity of 98.8%.

[0059] Example 6: Preparation of Medemidin

[0060]

[0061] 12 g of 4-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole was dissolved in 60 ml of 2N hydrochloric acid. 1.2 g of 10% palladium on carbon was added, and the mixture was pressurized to 0.15 MPa with hydrogen and reacted at 20-30 °C for 10 h. The palladium on carbon was removed by filtration. 60 ml of ethyl acetate was added, and the pH was adjusted to 9-10 with sodium hydroxide aqueous solution. The mixture was separated, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The ethyl acetate phases were combined, evaporated to dryness under reduced pressure, and dispersed by stirring in 30 ml of acetone. The mixture was filtered and dried to obtain 10.8 g of solid, with a yield of 89% and an HPLC purity of 99.6%.

[0062] Example 7: Preparation of dexmedetomidine-L-(+)-tartrate

[0063] 10 g (0.05 mol) of metoprimidine and 7.5 g (0.05 mol) of L-(+)-tartaric acid were added to 200 ml of anhydrous ethanol. The mixture was heated to reflux until completely dissolved, then cooled to room temperature and stirred overnight. The mixture was filtered to obtain a white solid. The solid was recrystallized once with 200 ml of ethanol to obtain 6.60 g of solid with a purity of 99.8% and a yield of 43%.

[0064] Example 8: Preparation of dexmedetomidine hydrochloride

[0065] Add 5g of dexmedetomidine-L-(+)-tartrate to 30ml of dichloromethane and 30ml of purified water. Adjust the pH to 9-10 with sodium hydroxide aqueous solution. Separate the contents, dichloromethane is evaporated under reduced pressure, and the residue is dissolved in 20ml of ethanol. Then add 8ml of 2mol / L hydrogen chloride ethanol solution, followed by 100ml of methyl ether at 5-10℃. Filter and dry to obtain 2.3g of solid, yield 81%, HPLC purity 99.9%, and levomedetomidine content 0.3%.

Claims

1. A method for preparing a compound as shown in Formula II, characterized in that, It comprises the following steps: (1) the mother liquor after the resolution of dexmedetomidine is freezed by adding alkali, extracted, concentrated, and dexmedetomidine is recovered; (2) then the compound of formula I is obtained by bromination reaction under light irradiation after dissolving in solvent and dropping bromine; (3) the compound of formula II is obtained by hydrolysis with sodium hydroxide aqueous solution; 2. The method for preparing the compound of formula II as described in claim 1, characterized in that, The alkali used in the step (1) is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably sodium hydroxide; the extraction solvent is selected from dichloromethane, chloroform, 2-methyltetrahydrofuran or ethyl acetate, preferably dichloromethane.

3. The method for preparing the compound of formula II as described in claim 1, characterized in that, The solvent used in the step (2) is selected from dichloromethane, chloroform or 2-methyltetrahydrofuran, preferably dichloromethane; the amount of bromine is 1.0-1.2 equivalents, preferably 1.05 equivalents; the light source used for irradiation is a 100W high-pressure mercury lamp.

4. The method for preparing the compound of formula II as described in claim 1, characterized in that, The concentration of sodium hydroxide aqueous solution used in the step (3) is 5%-20%, preferably 10% sodium hydroxide aqueous solution.

5. A method of racemization of a dexmedetomidine hydrochloride resolution by-product, characterized by, It comprises the following steps: (1) the mother liquor after the resolution of dexmedetomidine is freezed by adding alkali, extracted, concentrated, and dexmedetomidine is recovered; (2) then the compound of formula I is obtained by bromination reaction under light irradiation after dissolving in solvent and dropping bromine; (3) the compound of formula II is obtained by hydrolysis with sodium hydroxide aqueous solution; (4) the compound of formula III is obtained by dehydroxylation of the compound of formula II; (5) the racemic dexmedetomidine is obtained by hydrogenation reduction of the compound of formula III; (6) the dexmedetomidine hydrochloride is obtained by resolution of dexmedetomidine into salt; The compound of formula II is prepared according to the preparation method of claim 1.

6. The method of racemization of the dextromethorphan hydrochloride resolution by-product according to claim 5, wherein, The alkali used in the step (1) is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably sodium hydroxide; the extraction solvent is selected from dichloromethane, chloroform, 2-methyltetrahydrofuran or ethyl acetate, preferably dichloromethane.

7. The method of racemization of the dextromethorphan hydrochloride resolution by-product according to claim 5, wherein, The solvent used in the step (2) is selected from dichloromethane, chloroform or 2-methyltetrahydrofuran, preferably dichloromethane; the amount of bromine is 1.0-1.2 equivalents, preferably 1.05 equivalents; the light source used for irradiation is a 100W high-pressure mercury lamp.

8. The method of racemization of the dextromethorphan hydrochloride resolution by-product according to claim 5, wherein, The concentration of sodium hydroxide aqueous solution used in the step (3) is 5%-20%, preferably 10% sodium hydroxide aqueous solution.

9. The method of racemization of the dextromethorphan hydrochloride resolution by-product according to claim 5, wherein, The dehydroxylation in the step (4) is selected from trifluoroacetic acid / triethylsilane system.

10. The method of racemization of the dextromethorphan hydrochloride resolution by-product according to claim 5, wherein, The catalytic hydrogenation reduction in the step (5) is selected from Pd / C; the chiral resolution in the step (6) is selected from L-(+)-tartaric acid.

Images