A method for preparing dexmedetomidine hydrochloride

Abstract

This invention discloses a method for preparing dexmedetomidine hydrochloride, which constructs a chiral center through an asymmetric reduction method, avoiding the generation of non-target chiral byproducts and improving raw material utilization. Simultaneously, by optimizing the chlorination reaction system, the conversion rate of this step is improved without causing changes in chiral configuration, ensuring the subsequent preparation of the target product with high optical purity. Furthermore, post-processing is simpler, and no volatile or corrosive waste is generated. Overall, the process is simplified, the effectiveness of chiral center construction is improved, and the operation is more convenient, making it more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing dexmedetomidine hydrochloride, and more particularly to a method for preparing highly efficient dexmedetomidine hydrochloride, belonging to the pharmaceutical field. Background Technology

[0002] Dexmedetomidine hydrochloride, as a selective α2-adrenergic receptor agonist, is mainly used for sedation in surgical patients undergoing general anesthesia during endotracheal intubation and mechanical ventilation. Patent CN103694175A discloses a method for preparing dexmedetomidine hydrochloride, as follows:

[0003] .

[0004] This method uses dimethylbromobenzene as the starting material, proceeding sequentially through a Grignard reaction and a substitution reaction to obtain a racemic product. Then, using D-p-xylyltartaric acid as the resolving agent, chiral resolution, desalting, and purification are performed to finally obtain dexmedetomidine hydrochloride. This method suffers from low raw material utilization; during chiral resolution, more than half of the starting materials are non-target chiral molecules and are discarded, resulting in a calculated total molar yield of only 29.5%. Furthermore, the Grignard reaction is difficult to control, making it unsuitable for scale-up production, and it also places high demands on the reaction equipment. Summary of the Invention

[0005] Purpose of the invention: The present invention aims to provide a highly efficient method for preparing dexmedetomidine hydrochloride.

[0006] Technical solution: The preparation method of dexmedetomidine hydrochloride according to the present invention includes the following steps:

[0007] ,

[0008] (1) Compound SMA was asymmetrically reduced to give intermediate 1;

[0009] (2) Intermediate 1 is chlorinated to obtain intermediate 2;

[0010] (3) Intermediate 2 is subjected to a substitution reaction with compound SMB to obtain intermediate 3, which is then post-processed to obtain dexmedetomidine hydrochloride.

[0011] The preparation method designed in this invention constructs chiral centers through asymmetric reduction, avoiding the generation of non-target chiral byproducts and improving raw material utilization. Simultaneously, by optimizing the chlorination reaction system, the conversion rate of this step is improved without causing changes in chiral configuration. This enhances the chiral purity of the intermediates and ensures the subsequent preparation of high-purity target products. Furthermore, post-processing is simplified, and no volatile or corrosive waste is generated. Overall, the process is simplified, improving the effectiveness of chiral center construction and operational convenience, making it more suitable for industrial production.

[0012] Preferably, in step (1), a purple carrot-buffered salt system is used for asymmetric reduction.

[0013] Further preferably, the mass ratio of the purple carrot to the compound SMA is 1:5 to 1:10.

[0014] More preferably, the mass ratio of the purple carrot to the compound SMA is 1:10.

[0015] More preferably, the buffer salt is a disodium hydrogen phosphate / sodium dihydrogen phosphate buffer system or a tris(hydroxymethyl)aminomethane / hydrochloric acid buffer system.

[0016] More preferably, the buffer salt is a disodium hydrogen phosphate / sodium dihydrogen phosphate buffer system.

[0017] Further preferably, the buffer salt has a pH value of 7.5 to 8.5.

[0018] More preferably, the buffer salt has a pH value of 7.5, 8.0, or 8.5.

[0019] Further preferred, the buffer salt has a pH value of 8.5.

[0020] Further preferably, the buffer salt is a disodium hydrogen phosphate / sodium dihydrogen phosphate buffer system with a pH of 7.5-8.5 or a tris(hydroxymethyl)aminomethane / hydrochloric acid buffer system with a pH of 7.5-8.5.

[0021] More preferably, the buffer salt is a disodium hydrogen phosphate / sodium dihydrogen phosphate buffer system with a pH of 8.5.

[0022] Further preferably, the asymmetric reduction is carried out in ethanol at 10~30℃.

[0023] Preferably, the chlorination reaction system used in intermediate 1 in step (2) contains a chlorination reagent and a chlorination auxiliary agent. The chlorination reagent is selected from oxalyl chloride, and the chlorination auxiliary agent is selected from calcium fluoride, potassium fluoride or sodium fluoride.

[0024] Further optimization is made by selecting either oxalyl chloride-calcium fluoride or oxalyl chloride-sodium fluoride from the chlorination reaction system.

[0025] Further preferred, the chlorination reaction system is oxalyl chloride-calcium fluoride.

[0026] More preferably, the molar ratio between intermediate 1, chlorination reagent, and chlorination auxiliary agent is 1:1.5~3:0.1~0.3.

[0027] More preferably, the molar ratio of intermediate 1, chlorination reagent, and chlorination auxiliary agent is 1:1.5:0.1.

[0028] Further preferred, the molar ratio between intermediate 1, oxalyl chloride, and calcium fluoride is 1:1.5~3:0.1~0.3.

[0029] Even more preferably, the molar ratio between intermediate 1, oxalyl chloride, and calcium fluoride is 1:1.5:0.1.

[0030] Preferably, in the chlorination reaction, the temperature during the dropwise addition of the chlorination reagent is 0~5℃; and the temperature during the heat preservation reaction stage after the dropwise addition is 10~30℃.

[0031] Preferably, the substitution reaction catalyst used in step (3) is selected from titanium tetrachloride, aluminum trichloride, tin chloride, ferric chloride or zinc chloride.

[0032] Further preferred, the molar ratio of the substitution reaction catalyst to intermediate 2 is 1:1.5~2.

[0033] Even more preferably, the molar ratio of the substituted reaction catalyst to intermediate 2 is 1:1.5.

[0034] Further optimization involves using titanium tetrachloride as the catalyst for the substitution reaction in step (3).

[0035] Even more preferably, the molar ratio of titanium tetrachloride to intermediate 2 is 1:1.5~2.

[0036] Further optimization is achieved by using a molar ratio of titanium tetrachloride to intermediate 2 of 1:1.5.

[0037] Preferably, in the substitution reaction, the temperature of the heat preservation reaction stage is 20~25℃.

[0038] Preferably, the post-processing in step (3) includes quenching, extraction, free alkali, crystallization, hydrochloride formation, and purification steps.

[0039] Specifically, after the substitution reaction, the free base of intermediate 3 needs to be separated and purified first, and then converted into hydrochloride.

[0040] Further preferably, the pH value adjusted in the free alkali step is 10-11.

[0041] Further preferably, the crystallization method involves heating the organic phase containing the crude free alkali to reflux, then slowly and gradually cooling it to 0-5°C and maintaining the temperature for crystallization.

[0042] Further preferably, the reaction solvent for forming the hydrochloride salt is acetone.

[0043] Further optimization involved purification using a hot dissolution recrystallization method with acetone as the recrystallization solvent and a crystallization temperature of 20-25°C.

[0044] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0045] The preparation method designed in this invention employs an asymmetric reduction strategy combined with optimization of the chlorination reaction system, resulting in more efficient and stable construction of chiral centers and a significant improvement in the conversion rate at each step. The raw materials are readily available, the operation is convenient, no difficult-to-treat waste is generated, it is equipment- and environmentally friendly, and suitable for large-scale applications. Attached Figure Description

[0046] Figure 1 The chiral purity detection spectrum of dexmedetomidine hydrochloride prepared in Example 1;

[0047] Figure 2 The chiral purity detection spectrum of intermediate 1 prepared in Example 2;

[0048] Figure 3 The chiral purity detection spectrum of dexmedetomidine hydrochloride prepared in Example 2;

[0049] Figure 4 The image shows the chiral purity detection spectrum of dexmedetomidine hydrochloride prepared in Example 3. Detailed Implementation

[0050] The technical solution of the present invention will be further described below with reference to the embodiments.

[0051] Example 1

[0052]

[0053] (1) Synthesis of (S)-1-(2,3-dimethylphenyl)ethanol intermediate 1: 200 g of 2,3-dimethylacetophenone, 1400 mL of purified water, 120 mL of pH 8.5 disodium hydrogen phosphate / sodium dihydrogen phosphate buffer solution and 200 mL of ethanol were added to a reaction flask and stirred for 10 min; then 20 g (10% W / W) of purple carrot was added, and the reaction system was stirred at room temperature for 24 h. The system was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, the solid was collected by filtration, and dried under vacuum at 40 °C to obtain 164.1 g of off-white intermediate 1 with a chemical purity of 98.7% and a yield of 80.9%.

[0054] 1 H HNMR (400MHz CDCl3): 7.34 (d, 1H), 7.11 (m, 1H), 7.06 (d, 1H), 5.15 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 1.44 (d, 3H).

[0055] (2) Synthesis of (S)-1-(1-chloroethyl)-2,3-dimethylbenzene (intermediate 2): 164.1 g of intermediate 1, 8.6 g (0.1 eq) of calcium fluoride, and 1700 mL of dichloromethane were added to a reaction flask, and the temperature was lowered to 5 °C. 210.8 g (1.5 eq) of oxalyl chloride was added dropwise. After the addition was complete, the mixture was kept at 5 °C for 1 h, and then heated to room temperature for 1 h. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.1. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 167.2 g of off-white intermediate 2 with a chemical purity of 99.2% and a yield of 90.8%.

[0056] 1 H HNMR (400MHz CDCl3): 7.34 (d, 1H), 7.11 (m, 1H), 7.06 (d, 1H), 4.96 (m, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 1.53 (d, 3H).

[0057] (3) Synthesis of crude (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazolium (intermediate 3): 1300 mL of dichloromethane was added to the reaction flask, followed by 283.2 g (1.5 eq) of titanium tetrachloride. The internal temperature was controlled to ≤20℃. 418.8 g (3.0 eq) of trimethylsilylimidazolium (SMB) was added dropwise. After the addition was complete, 167.2 g of intermediate 2 was added. The reaction was carried out at 25℃ for 10 hours. The reaction system was cooled to 5℃, and 1200 mL of purified water was slowly added. After the addition was complete, the mixture was allowed to stand and separated. The organic phase was extracted twice with 400 mL of purified water, and the aqueous phases were combined. 800 mL of ethyl acetate was added to the aqueous phase, and the internal temperature was controlled to ≤30℃. 1 mol / L NaOH aqueous solution was added dropwise to adjust the pH to 10.6. The mixture was allowed to stand and separated. The organic phase was washed three times with 200 mL of purified water and anhydrous sodium sulfate. Filter, concentrate by half the volume under reduced pressure, heat to reflux and hold for 30 min, then slowly gradient-cool to an internal temperature of 5°C over 1 h, maintaining this temperature while stirring to crystallize for 6 hours. Filter, vacuum dry the filter cake for 4 hours, dissolve the resulting solid in 500 mL of acetone, slowly add 68 mL of concentrated hydrochloric acid, and adjust the pH to 3.6. Filter, concentrate the filtrate under reduced pressure, remove water with 800 mL of acetone until a white or pale yellow solid is obtained, and vacuum dry the solid at 40°C for 6 hours to obtain 178.8 g of intermediate 3, yield 76.5%.

[0058] 1H HNMR (400MHz DMSO): 14.84 (br, 2H), 9.08 (s, 1H), 7.43 (s, 1H), 7.05 (m, 1H), 7.03 (m, 1H), 6.91 (m, 1H), 4.55 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 1.61 (d, 3H).

[0059] (4) Synthesis of dexmedetomidine hydrochloride: 178.8 g of intermediate 3 and 880 mL of acetone were added to a reaction flask and the mixture was heated to reflux for 1 hour. The mixture was then cooled to 20-25 °C, filtered, and the filter cake was dried under vacuum at 45 °C to obtain 153.2 g of white powder. Yield: 85.7%, chemical purity: 99.9% (see...) Figure 1 The optical purity was 99.99%, and the total molar yield of dexmedetomidine hydrochloride was 48.2%.

[0060] Example 2

[0061] (1) Synthesis of (S)-1-(2,3-dimethylphenyl)ethanol intermediate 1: 50 g of 2,3-dimethylacetophenone, 350 mL of purified water, 30 mL of pH 7.5 disodium hydrogen phosphate / sodium dihydrogen phosphate buffer solution, and 50 mL of ethanol were added to a reaction flask and stirred for 10 min; then 10 g (20% / w / w) of purple carrot was added, and the reaction system was stirred at room temperature for 30 h. The system was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, the solid was collected by filtration, and dried under vacuum at 40 °C to obtain 40.1 g of off-white intermediate 1 with a chemical purity of 98.1% and an optical purity of 99.91% (see [link to relevant documentation]). Figure 2 The yield was 79.1%.

[0062] (2) Synthesis of (S)-1-(1-chloroethyl)-2,3-dimethylbenzene (intermediate 2): 40.1 g of intermediate 1, 6.3 g (0.3 eq) of calcium fluoride, and 400 mL of dichloromethane were added to a reaction flask, and the mixture was cooled to 0 °C. 52.7 g (1.5 eq) of oxalyl chloride was added dropwise. After the addition was complete, the mixture was kept at 0 °C for 1 h, and then heated to room temperature for 1 h. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.4. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 39.9 g of off-white intermediate 2 with a chemical purity of 98.8% and a yield of 88.6%.

[0063] (3) Synthesis of crude (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazolium (intermediate 3): 400 mL of dichloromethane was added to the reaction flask, followed by 89.7 g (2.0 eq) of titanium tetrachloride. The internal temperature was controlled to ≤20℃. 99.5 g (3.0 eq) of trimethylsilylimidazolium (SMB) was added dropwise. After the addition was complete, 39.9 g of intermediate 2 was added. The reaction was carried out at 20℃ for 10 hours. The reaction system was cooled to 0℃, and 300 mL of purified water was slowly added. After the addition was complete, the mixture was allowed to stand and separated. The organic phase was extracted twice with 100 mL of purified water, and the aqueous phases were combined. 200 mL of ethyl acetate was added to the aqueous phase, and the internal temperature was controlled to ≤30℃. 1 mol / L NaOH aqueous solution was added dropwise to adjust the pH to 10.2. The mixture was allowed to stand and separated. The organic phase was washed three times with 50 mL of purified water and anhydrous sodium sulfate. Filter, concentrate by half the volume under reduced pressure, heat to reflux and hold for 30 min, then slowly gradient-cool to 0°C over 1 h, maintaining this temperature while stirring to crystallize for 6 hours. Filter, dry the filter cake under vacuum for 4 hours, dissolve the resulting solid in 120 mL of acetone, slowly add 17 mL of concentrated hydrochloric acid, and adjust the pH to 3.9. Filter, concentrate the filtrate under reduced pressure, remove water with 200 mL of acetone until a white or pale yellow solid is obtained, and dry the solid under vacuum at 40°C for 6 hours to obtain 42.6 g of intermediate 3, yield 76.4%.

[0064] (4) Synthesis of dexmedetomidine hydrochloride: 42.6 g of intermediate 3 and 210 mL of acetone were added to the reaction flask and the mixture was heated to reflux for 1 hour. The mixture was cooled to 20-25 °C, filtered, and the filter cake was dried under vacuum at 45 °C to obtain 36.3 g of white powder. The yield was 85.2%, the chemical purity was 99.9%, the optical purity was 99.97%, and the total molar yield of dexmedetomidine hydrochloride was 45.6%.

[0065] Example 3

[0066] (1) Synthesis of (S)-1-(2,3-dimethylphenyl)ethanol intermediate 1: 50 g of 2,3-dimethylacetophenone, 350 mL of purified water, 30 mL of pH 7.5 disodium hydrogen phosphate / sodium dihydrogen phosphate buffer solution and 50 mL of ethanol were added to a reaction flask and stirred for 10 min; then 5 g (10% / w / w) of purple carrot was added, and the reaction system was stirred at room temperature for 30 h. The system was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, the solid was collected by filtration, and dried under vacuum at 40 °C to obtain 41.5 g of off-white intermediate 1 with a chemical purity of 98.8% and a yield of 81.9%.

[0067] (2) Synthesis of (S)-1-(1-chloroethyl)-2,3-dimethylbenzene (intermediate 2): 41.5 g of intermediate 1, 2.2 g (0.1 eq) of calcium fluoride, and 400 mL of dichloromethane were added to a reaction flask, and the temperature was lowered to 5 °C. 105.4 g (3.0 eq) of oxalyl chloride was added dropwise. After the addition was complete, the mixture was kept at 5 °C for 1 h, and then heated to room temperature for 1 h. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.7. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 41.7 g of off-white intermediate 2 with a chemical purity of 99.3% and a yield of 89.5%.

[0068] (3) 44.3g of intermediate 3 was obtained by following the procedure in Example 1, with a yield of 76.0%.

[0069] (4) 37.2 g of white powder was obtained according to the operation of Example 1, with a yield of 84.0%, chemical purity of 99.9%, optical purity of 99.93%, and a total molar yield of dexmedetomidine hydrochloride of 46.8%.

[0070] Comparative Example 1

[0071] (1) Synthesis of (S)-1-(2,3-dimethylphenyl)ethanol intermediate 1: Under nitrogen protection, a mixture of 580 mg NaBH4 (1.5 eq), 100 mL dichloromethane, and 5 mL ethanol was stirred at room temperature for 1 h. The dropping rate was controlled, and a 60 mL dichloromethane solution containing 150 mg of catalyst Salen-Co(II) (2.5% eq) and 1.48 g of substrate 2,3-dimethylacetophenone was slowly added dropwise through a constant pressure funnel. After reacting at 5 °C for 2 h, the reaction was quenched with 50 mL of saturated NH4Cl solution. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was separated by silica gel column chromatography to remove the metal catalyst. The eluent was ethyl acetate / petroleum ether (V:V = 1:3), yielding 1.08 g of intermediate 1 with a chemical purity of 97.8% and a yield of 72%.

[0072] (2) 1.04 g of intermediate 2 was obtained by following the procedure in Example 1, with a yield of 85.8%.

[0073] (3) 1.09 g of intermediate 3 was obtained by following the procedure in Example 1, with a yield of 75.0%.

[0074] (4) 0.91 g of white powder was obtained by following the procedure in Example 1, with a yield of 83.5%, chemical purity of 99.7%, optical purity of 98.50%, and a total molar yield of dexmedetomidine hydrochloride of 38.7%.

[0075] Comparative Example 2

[0076] (1) Synthesis of (S)-1-(2,3-dimethylphenyl)ethanol intermediate 1: 10 g of 2,3-dimethylacetophenone, 70 mL of purified water, 6 mL of pH 8.5 disodium hydrogen phosphate / sodium dihydrogen phosphate buffer solution and 10 mL of ethanol were added to a reaction flask and stirred for 10 min; then 1 g (10% W / W) of purple carrot was added, and the reaction system was stirred at room temperature for 24 h. The system was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, the solid was collected by filtration, and dried under vacuum at 40 °C to obtain 8.1 g of off-white intermediate 1 with a chemical purity of 98.7% and a yield of 79.9%.

[0077] (2) Synthesis of (S)-1-(1-chloroethyl)-2,3-dimethylbenzene (intermediate 2): 8.1 g of intermediate 1, 0.4 g (0.1 eq) of calcium fluoride, and 80 mL of dichloromethane were added to a reaction flask, and the temperature was lowered to 5 °C. 9.6 g (1.5 eq) of thionyl chloride was added dropwise. After the addition was complete, the mixture was kept at 5 °C for 1 h, and then heated to room temperature for 1 h. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.8. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 7.48 g of off-white intermediate 2 with a chemical purity of 98.7% and a yield of 82.2%.

[0078] (3) 7.79 g of intermediate 3 was obtained by following the procedure in Example 1, with a yield of 74.5%.

[0079] (4) 6.46 g of white powder was obtained by following the procedure in Example 1, with a yield of 82.9%, chemical purity of 99.5%, optical purity of 99.12%, and a total molar yield of dexmedetomidine hydrochloride of 40.6%.

Claims

1. A method for preparing dexmedetomidine hydrochloride, characterized in that, Includes the following steps: ， (1) Compound SMA was asymmetrically reduced to give intermediate 1; (2) Intermediate 1 is chlorinated to obtain intermediate 2; (3) Intermediate 2 is subjected to a substitution reaction with compound SMB to obtain intermediate 3, which is then post-processed to obtain dexmedetomidine hydrochloride.

2. The method for preparing dexmedetomidine hydrochloride according to claim 1, characterized in that, In step (1), an asymmetric reduction was carried out using a purple carrot-pH7.5~pH8.5 buffer salt system.

3. The method for preparing dexmedetomidine hydrochloride according to claim 2, characterized in that, The mass ratio of the purple carrot to the compound SMA is 1:5 to 1:

10.

4. The method for preparing dexmedetomidine hydrochloride according to claim 3, characterized in that, The mass ratio of the purple carrot to the compound SMA is 1:

10.

5. The method for preparing dexmedetomidine hydrochloride according to claim 2, characterized in that, The asymmetric reduction was carried out in ethanol at 10-30°C.

6. The method for preparing dexmedetomidine hydrochloride according to claim 1, characterized in that, The chlorination reaction system used in step (2) intermediate 1 contains a chlorination reagent and a chlorination auxiliary agent. The chlorination reagent is selected from oxalyl chloride, and the chlorination auxiliary agent is selected from calcium fluoride, potassium fluoride or sodium fluoride.

7. The method for preparing dexmedetomidine hydrochloride according to claim 6, characterized in that, The molar ratio of intermediate 1, chlorination reagent, and chlorination auxiliary agent is 1:1.5~3:0.1~0.

3.

8. The method for preparing dexmedetomidine hydrochloride according to claim 7, characterized in that, The molar ratio of intermediate 1, chlorination reagent, and chlorination auxiliary agent is 1:1.5:0.

1.

9. The method for preparing dexmedetomidine hydrochloride according to claim 1, characterized in that, The substitution reaction catalyst used in step (3) is selected from titanium tetrachloride, aluminum trichloride, tin chloride, ferric chloride or zinc chloride.

10. The method for preparing dexmedetomidine hydrochloride according to claim 9, characterized in that, The molar ratio of the substitution reaction catalyst to intermediate 2 is 1:1.5~2.

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