Preparation method of ropivacaine hydrochloride
The method of protecting the amino group with acetic anhydride and splitting and recovering the by-products solves the problem of high purity and high yield in the preparation of ropivacaine hydrochloride, and realizes environmentally friendly and economical industrial production.
Patent Information
- Application Number
- CN202510794779.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-14
- Publication Date
- 2025-09-23
AI Technical Summary
The existing preparation methods of ropivacaine hydrochloride have the problems of using expensive chiral raw materials, causing environmental pollution and low yield, making it difficult to achieve industrial production.
Acetic anhydride is used for acetylation reaction to protect the amino group, and the by-product R-ropivacaine is recovered by splitting and racemized. High-purity ropivacaine hydrochloride is synthesized through multiple steps, including amidation, deprotection, splitting, racemization and substitution reactions.
The purity and yield of ropivacaine hydrochloride are improved, environmental pollution is reduced, production costs are lowered, and the method is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to a preparation method of ropivacaine hydrochloride, and belongs to the field of pharmaceutical chemical synthesis. Background Art
[0002] Ropivacaine hydrochloride is a white or off-white crystalline powder chemical. Its chemical name is (S)-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinamide hydrochloride monohydrate, and its structural formula is shown in Formula I below. Ropivacaine hydrochloride is a new, long-acting amide local anesthetic that reversibly blocks impulse conduction along nerve fibers by inhibiting sodium ion channels in nerve cells, blocking the influx of sodium ions into nerve fiber membranes. It is primarily used for epidural anesthesia in surgical procedures, including cesarean sections, and regional blockade for acute pain control, either by continuous epidural infusion or intermittent single-dose administration, such as for postoperative or labor pain.
[0003]
[0004] At present, the preparation methods of ropivacaine hydrochloride reported in the existing literature mainly include: (1) using L-type 2-piperidinic acid as the starting material, undergoing acylation reaction with triphosgene, phosphorus pentachloride or thionyl chloride to obtain 2-piperidinic acid chloride, which is then condensed with 2,6-dimethylaniline, and finally alkylated with bromopropane to obtain ropivacaine hydrochloride. However, this method uses chiral raw materials, which are expensive and have limited commercial availability. The use of acylation reagents such as triphosgene, phosphorus pentachloride or thionyl chloride produces a lot of waste gas and waste liquid. , there is an environmental pollution problem. In addition, the use and storage of triphosgene are very dangerous and it is not suitable for industrial production. (2) Using racemized 2-piperidinic acid as a raw material, the target product is finally prepared through acylation reaction, condensation, alkylation, splitting, salt formation and other reactions. The total yield of the product of this method is low and the preparation cost is too high, so it is not conducive to industrial production. In addition, the above method will produce self-condensation impurities due to incomplete protection of piperidine carboxylic acid in the preparation of N-(2',6'-xylyl)-2-piperidinamide.
[0005] Therefore, how to provide a method for preparing mepivacaine hydrochloride with high purity and high yield has become a technical problem to be solved urgently. To this end, the present invention is proposed. Summary of the Invention
[0006] In response to the shortcomings of the prior art, the present invention provides a method for preparing ropivacaine hydrochloride. The method of the present invention utilizes readily available raw materials, is simple to prepare, has a high yield and purity of the target product, can recycle by-products, has a high overall process conversion rate, and is market competitive.
[0007] Terminology Notes:
[0008] Compound of formula I: Ropivacaine hydrochloride
[0009] Compound of formula II: 2-piperidinic acid
[0010] Compound of formula III: 2-(acetylpiperidinyl)acetic anhydride
[0011] Compound of formula IV: 2,6-dimethylaniline;
[0012] Compound of formula V: N-(2',6'-dimethylphenyl)-2-(acetylpiperidinyl)carboxamide
[0013] Compound of formula VI: Roperamide
[0014] Formula VII compound: L-(-)-dibenzoyltartaric acid (monohydrate)
[0015] Compound of formula VIII: R-ropiperamide
[0016] Compound of formula IX: L-ropiperamide tartrate
[0017] Compound of formula X: L-ropepamide
[0018] The compound numbers of the present invention have the same reference relationship as the structural formula numbers, and are based on the structural formula.
[0019] The technical solutions of the present invention are as follows:
[0020] A method for preparing ropivacaine hydrochloride comprises the following steps:
[0021] (1) the compound of formula II is acetylated with acetic anhydride to prepare the compound of formula III, and the compound of formula III is amidated with the compound of formula IV to prepare the compound of formula V;
[0022]
[0023] (2) the compound of formula V obtained in step (1) is subjected to a deprotection reaction to obtain a compound of formula VI;
[0024]
[0025] (3) The compound of formula VI obtained in step (2) is subjected to a resolution reaction with the compound of formula VII to prepare a compound of formula IX and a resolution mother liquor containing the compound of formula VIII;
[0026]
[0027] (4) The mother liquor containing the compound of formula VIII obtained in step (3) is subjected to reduced pressure distillation to remove the solvent, and then is freed in an aqueous sodium hydroxide solution, and then subjected to a racemization reaction to obtain the compound of formula VI, which is recovered and the operation of step (3) is repeated;
[0028] (5) The compound of formula IX obtained in step (3) and step (4) is freed by sodium hydroxide to obtain a compound of formula X, and the compound of formula X undergoes a substitution reaction with bromopropane, and the salt is formed and recrystallized to obtain ropivacaine hydrochloride;
[0029]
[0030] According to the preferred embodiment of the present invention, the molar ratio of acetic anhydride to the compound of formula II in step (1) is 8-10:1; the temperature of the acetylation reaction is 90-100° C., and the acetylation reaction time is 6-8 h.
[0031] According to a preferred embodiment of the present invention, in step (1), the post-treatment method of the reaction solution obtained by the acetylation reaction is as follows: the obtained reaction solution of the compound of formula III is subjected to reduced pressure distillation to remove acetic anhydride, and the temperature of the reduced pressure distillation is 90-100°C.
[0032] Preferably, according to the present invention, the solvent for the amidation reaction in step (1) is toluene, the mass ratio of toluene to the compound of formula II is 8-12:1; the molar ratio of the compound of formula IV to the compound of formula II is 2-3:1; the temperature of the amidation reaction is 70-80°C, and the amidation reaction time is 6-8h.
[0033] Preferably, in step (1), the post-treatment step of the reaction solution obtained by the amidation reaction is as follows: the obtained reaction solution of the compound of formula V is washed with a 1 mol / L hydrochloric acid solution and purified water in sequence, and the organic phase obtained by washing is concentrated under reduced pressure to remove the solvent to obtain the compound of formula V.
[0034] According to the preferred embodiment of the present invention, the deprotection step in step (2) is as follows: methanol and piperidine are sequentially added to the compound of formula V obtained in step (1) to carry out deprotection; the mass ratio of methanol to the compound of formula II is 4-6:1; the molar ratio of piperidine to the compound of formula II is 1-2:1; the temperature of the deprotection reaction is 60-70°C, and the deprotection reaction time is 3-4h; after the deprotection reaction is completed, the obtained reaction solution is cooled to -5-5°C for crystallization, grown at -5-5°C for 2-3h, filtered, washed with methanol at -5-5°C, and dried at 50-60°C to constant weight to obtain a compound of formula VI.
[0035] According to the preferred embodiment of the present invention, the molar ratio of the compound of formula VII to the compound of formula VI in step (3) is 0.3-0.5:1; the resolution reaction is carried out in a mixed solvent of acetone and water, and the mass ratio of acetone, water and the compound of formula VI is 6-8:1.5-2:1; the temperature of the resolution reaction is 30-40°C, and the resolution reaction time is 2-3h.
[0036] According to the preferred embodiment of the present invention, in step (3), the post-treatment step of the reaction solution obtained by the resolution reaction is as follows: the reaction solution is cooled to 0-5°C for crystallization, the crystals are grown at 0-5°C for 2-3 hours, filtered, washed with acetone at 0-5°C, and dried at 50-60°C to constant weight to obtain a compound of formula IX. The resolution mother liquor is used in step (4) to recover the compound of formula VI. The resolution mother liquor includes filtering the filtrate obtained and the washing liquid.
[0037] According to the present invention, preferably, the temperature of the reduced pressure distillation in step (4) is 60-70°C; after the reduced pressure distillation, purified water and a 10% by mass sodium hydroxide aqueous solution are added to the obtained product, and the reaction is carried out at 20-30°C for 1-2 hours. After the reaction is completed, the temperature is lowered to 0-5°C for crystallization for 1-2 hours, and the mixture is filtered to obtain the compound of formula VIII; the mass ratio of the purified water to the compound of formula VI is 8-10:1, and the mass ratio of the 10% by mass sodium hydroxide aqueous solution to the compound of formula VI is 2.5-3.0:1.
[0038] According to a preferred embodiment of the present invention, the racemization reaction in step (4) is as follows: mixing the free compound of formula VIII with purified water and sodium hydroxide to carry out a racemization reaction; then cooling to 0-10°C for crystallization for 1-2 hours, filtering, washing with purified water, and drying at 50-60°C to constant weight to obtain a compound of formula VI, and repeating step (3); the mass ratio of sodium hydroxide to the compound of formula VI is 0.5-1.0:1, and the mass ratio of purified water to the compound of formula VI is 5-8:1; the temperature of the racemization reaction is 90-100°C, and the reaction time is 20-25 hours.
[0039] According to a preferred embodiment of the present invention, in step (5), the sodium hydroxide freeing step comprises: adding the compound of formula IX to a mixture of methyl isobutyl ketone, purified water and sodium hydroxide, and reacting at room temperature for 0.5-1 hour; after the reaction is completed, separating the liquids, and washing the organic phase with water to obtain a methyl isobutyl ketone solution of the compound of formula X; the mass ratio of the methyl isobutyl ketone to the compound of formula IX is 3-5:1, the mass ratio of the sodium hydroxide to the compound of formula IX is 0.3-0.4:1; and the mass ratio of the purified water to the compound of formula IX is 2.5-3.5:1.
[0040] According to a preferred embodiment of the present invention, the substitution reaction in step (5) comprises the following steps: adding potassium carbonate, purified water and bromopropane to a methyl isobutyl ketone solution of the free compound of formula X, reacting at 80-90° C. for 6-8 hours, wherein the mass ratio of potassium carbonate to the compound of formula IX is 0.3-0.4:1, the mass ratio of purified water to the compound of formula IX is 1.0-1.5:1, and the molar ratio of bromopropane to the compound of formula X is 1.2-1.4:1; after the reaction, washing the reaction solution with water, adding 37% concentrated hydrochloric acid to the organic phase, forming a salt at 30-40° C. for 1-2 hours, then cooling to 0-10° C. for crystallization for 2-3 hours, filtering, washing with acetone at 0-10° C., and drying at 50-60° C. to constant weight to obtain crude ropivacaine hydrochloride; the mass ratio of concentrated hydrochloric acid to the compound of formula IX is 0.4-0.5:1.
[0041] According to the present invention, preferably, the recrystallization step in step (5) is: adding the crude ropivacaine hydrochloride to a mixed solvent of acetone and purified water, heating to 50-60°C for dissolution, cooling to 0-5°C for crystallization for 2-3h, filtering, washing with 0-10°C acetone, and drying at 50-60°C to constant weight to obtain ropivacaine hydrochloride; the mass ratio of the acetone to the crude ropivacaine hydrochloride is 4.0-5.0:1, and the mass ratio of the purified water to the crude ropivacaine hydrochloride is 1.0-1.5:1.
[0042] The reaction scheme of the present invention is as follows:
[0043]
[0044] The technical features and beneficial effects of the present invention are as follows:
[0045] 1. The present invention uses acetic anhydride to carry out acetylation reaction to protect the amino group, thereby reducing the side reaction on the piperidine ring nitrogen, that is, the acylation reaction of 2-piperidinecarbonyl chloride itself, while improving the reaction conversion rate, and the obtained ropivacaine hydrochloride has high purity and low impurity content;
[0046] 2. The by-product of the present invention, compound VIII, R-ropiperamide, is racemized and recovered for recycling, thereby improving the overall conversion rate of the process and being environmentally friendly;
[0047] 3. The raw materials of the method of the present invention are easily available, the process reaction conditions are mild, the post-processing is simple, the cost is low, and it is conducive to industrial production. DETAILED DESCRIPTION
[0048] The present invention is described in detail below with reference to the embodiments, but the present invention is not limited thereto.
[0049] The methods described in the examples are conventional methods unless otherwise specified; the reagents used are commercially available unless otherwise specified.
[0050] The yields in the examples are all molar yields.
[0051] Example 1
[0052] A method for preparing ropivacaine hydrochloride comprises the following steps:
[0053] (1) Add 20.00 g of 2-piperidinecarboxylic acid (II) and 142.27 g of acetic anhydride to a reaction flask, heat to 95 ° C and react for 7 h. After the reaction is completed, control the temperature at 95 ° C and distill under reduced pressure to remove acetic anhydride to obtain 2-(acetylpiperidinyl)acetic anhydride (III) concentrate; add 200.00 g of toluene and 46.91 g of 2,6-dimethylaniline (IV) to the obtained concentrate, heat to 75 ° C and react for 7 h; after the reaction is completed, cool the obtained reaction solution to room temperature, add 350 mL of 1 mol / L hydrochloric acid solution for washing, separate the organic phase and wash it twice with 200 mL of purified water, control the temperature of the obtained organic phase at 70-80 ° C and distill under reduced pressure to remove the solvent to obtain N-(2',6'-xylyl)-2-(acetylpiperidinyl)formamide (V) concentrate.
[0054] (2) To the concentrate of N-(2',6'-xylyl)-2-(acetylpiperidine)formamide (V) obtained in step (1) were added 100.00 g of methanol and 20.00 g of piperidine in sequence, and the temperature was raised to 65° C. for reaction for 3.5 h. TLC detected that the reaction of the raw materials was complete, and the temperature was lowered to -5-5° C. for crystallization. The crystals were grown for 2.5 h, filtered, washed with 10.0 g of -5-5° C. methanol, and dried at 55° C. to constant weight to obtain 32.50 g of lopramamide (VI) with a molar yield of 90.34% and a purity of 99.6%.
[0055] (3) 32.50 g of the above-mentioned ropiperamide (VI), 227.50 g of acetone and 57.00 g of purified water were added to a reaction flask, and the temperature was raised to 35° C. for dissolution. 21.06 g of L-(-)-dibenzoyltartaric acid (monohydrate) (VII) was added and the reaction was carried out at 35° C. for 2.5 h. After the reaction was completed, the resulting reaction solution was cooled to 0-5° C. for crystallization, grown at 0-5° C. for 2.5 h, filtered, washed with 20.00 g of 0-5° C. acetone, and dried at 55° C. to constant weight to obtain 27.52 g of L-ropiperamide tartrate (IX) and a resolution mother liquor containing the compound of formula VIII, with an L-ropiperamide (X) content of 54.3%, equivalent to 14.94 g of L-ropiperamide (X), and a molar yield of 45.99%. The resolution mother liquor includes the filtrate obtained by filtration and the washing liquid.
[0056] (4) The mother liquor was distilled under reduced pressure at a temperature of 60-70°C. 293.00 g of purified water and 90.00 g of a 10% sodium hydroxide aqueous solution were added to the resulting product, and the reaction was carried out at a temperature of 25°C for 1.5 h. After the reaction was completed, the temperature was lowered to 0-5°C for crystallization for 1.5 h, and the mixture was filtered to obtain a wet product of R-ropiperamide (VIII). The wet product of R-ropiperamide (VIII) was mixed with 211.00 g of purified water and 24.38 g of sodium hydroxide, and the temperature was raised to 95°C for racemization reaction for 24 h. The temperature was lowered to 0-10°C for crystallization for 1.5 h, and the mixture was filtered, washed with 30 mL of purified water, and dried at 55°C to constant weight to obtain 15.13 g of ropiperamide (VI) with a molar yield of 86.16% and a purity of 98.0%.
[0057] (5) 15.13 g of ropiperamide (VI) obtained in step (4) above, 105.90 g of acetone, and 26.50 g of purified water were added to a reaction flask, and the mixture was heated to 35° C. for dissolution. 9.80 g of L-(-)-dibenzoyltartaric acid (monohydrate) (VII) was added, and the mixture was reacted at 35° C. for 2.5 h. The mixture was cooled to 0-5° C. for crystallization, and grown at 0-5° C. for 2.5 h. The mixture was filtered, washed with 10.0 g of 0-5° C. acetone, and dried at 55° C. to constant weight to obtain 12.55 g of L-ropiperamide tartrate (IX), with an L-ropiperamide (X) content of 52.2%, equivalent to 6.55 g of L-ropiperamide (X), and a molar yield of 43.29%.
[0058] (6) Add 27.52 g of L-ropiperamide tartrate (IX) obtained in step (3) and 12.55 g of the tartrate obtained in step (5) to the reaction flask. L-ropiperamide tartrate (IX), 160.30g methyl isobutyl ketone, 120.00g purified water and 14.02g sodium hydroxide were reacted at room temperature for 1h; the resulting reaction solution was separated, the organic phase was washed with 120mL of water, and the methyl isobutyl ketone solution of L-ropiperamide (X) was obtained. 14.02g potassium carbonate, 50.00g purified water and 14.79g bromopropane were added to the methyl isobutyl ketone solution of L-ropiperamide (X), and the temperature was raised to 85°C for reaction for 7h. TLC detected that the reaction of the raw materials was complete; the resulting reaction solution was washed twice with 120mL of purified water, and the liquid was separated. 18.03g of concentrated hydrochloric acid with a mass fraction of 37% was added to the organic phase, the temperature was controlled at 35°C for salification for 1.5h, the temperature was lowered to 0-10°C for crystallization for 2.5h, and the mixture was filtered with suction, and 20.00g The product was washed with acetone at 0-10°C and dried at 55°C to constant weight to obtain 28.90 g of crude ropivacaine hydrochloride with a molar yield of 94.17% (calculated based on L-ropivacaine) and a purity of 99.8%.
[0059] (7) 28.90 g of crude ropivacaine hydrochloride, 130.00 g of acetone, and 36.12 g of purified water were added to a reaction flask, heated to 55°C for dissolution, cooled to 0-5°C for crystallization for 2.5 h, filtered, washed with 10.00 g of 0-10°C acetone, and dried at 55°C to constant weight to obtain 27.08 g of ropivacaine hydrochloride with a molar yield of 93.70%.
[0060] The purity of the ropivacaine hydrochloride prepared in this example was 99.96%, the dextrorotatory isomer was not detected, and the total molar yield was 53.18% (calculated based on 2-piperidinic acid (II) as the starting material).
[0061] Comparative Example 1
[0062] A method for preparing ropivacaine hydrochloride comprises the following steps:
[0063] Steps (1)-(3) are the same as steps (1)-(3) in Example 1.
[0064] (4) 27.52 g of L-ropiperamide tartrate (IX), 110.00 g of methyl isobutyl ketone, 83.00 g of purified water and 9.63 g of sodium hydroxide were added to the reaction flask and reacted at room temperature for 1 h; the obtained reaction solution was separated, the organic phase was washed with 83 mL of water, and the methyl isobutyl ketone solution of L-ropiperamide (X) was obtained. 9.63 g of potassium carbonate, 34.00 g of purified water and 10.28 g of bromopropane were added to the obtained methyl isobutyl ketone solution of L-ropiperamide (X), and the temperature was raised to 85°C for reaction for 7 h. TLC detected that the reaction of the raw materials was complete; the obtained reaction solution was washed twice with 55 mL of purified water, and the liquid was separated. 12.38 g of concentrated hydrochloric acid with a mass fraction of 37% was added to the organic phase, and the temperature was controlled at 35°C for salt formation for 1.5 h, and the temperature was lowered to 0-10°C for crystallization for 2.5 h, and the mixture was filtered and filtered with 14.00 g of methyl isobutyl ketone. The product was washed with acetone at 0-10°C and dried at 55°C to constant weight to obtain 19.90 g of crude ropivacaine hydrochloride with a molar yield of 94.10% (calculated based on L-ropivacaine).
[0065] (2) 19.90 g of crude ropivacaine hydrochloride, 89.60 g of acetone, and 24.90 g of purified water were added to a reaction flask, heated to 55° C. for dissolution, cooled to 0-5° C. for crystallization for 2.5 h, filtered, washed with 7.00 g of 0-10° C. acetone, and dried at 55° C. to constant weight to obtain 18.41 g of ropivacaine hydrochloride with a molar yield of 92.51%.
[0066] The purity of the ropivacaine hydrochloride prepared in this comparative example was 99.94%, the dextrorotatory isomer was not detected, and the total molar yield was 36.17% (calculated based on 2-piperidinic acid (II) as the starting material), which was significantly lower than that in Example 1.
[0067] Comparative Example 2
[0068] A method for preparing ropivacaine hydrochloride comprises the following steps:
[0069] (1) Add 20.00 g of 2-piperidinic acid (II) and 200 mL of dichloromethane to a reaction flask, introduce hydrogen chloride until the pH of the system is 1, stir and react for 1 hour, add 24.00 g of thionyl chloride, heat to 35-40° C. and react for 7 hours, control the temperature at 35° C. and distill under reduced pressure to obtain 2-piperidinic acid chloride concentrate; add 200.00 g of toluene and 46.91 g of 2,6-dimethylaniline (IV) to the obtained concentrate, heat to 75° C. and react for 7 hours; after the reaction is completed, cool the obtained reaction solution naturally to room temperature, add 400 mL of purified water for back extraction, separate the aqueous phase, and back extract the organic phase with 100 mL of purified water each time, back extract twice, combine the aqueous phases, add 30% by mass NaOH solution to adjust the pH to 12, cool to 0-10° C. and crystallize, grow the crystals for 2.5 hours,
[0070] The mixture was filtered, washed with 40 mL of purified water, and dried at 55° C. to constant weight to obtain 28.70 g of ropiperamide (VI) with a molar yield of 79.78% and a purity of 99.2%.
[0071] (2) 28.70 g of the above-mentioned ropiperamide (VI), 200.90 g of acetone and 50.22 g of purified water were added to a reaction flask, and the temperature was raised to 35° C. for dissolution. 18.60 g of L-(-)-dibenzoyltartaric acid (monohydrate) (VII) was added and reacted at 35° C. for 2.5 h. After the reaction was completed, the temperature was lowered to 0-5° C. for crystallization, and the crystals were grown at 0-5° C. for 2.5 h. The mixture was filtered, washed with 17.70 g of 0-5° C. acetone, and dried at 55° C. to constant weight to obtain 24.00 g of L-ropiperamide tartrate (IX), with an L-ropiperamide (X) content of 54.0%, equivalent to 12.96 g of L-ropiperamide (X), and a molar yield of 45.16%.
[0072] (3) 24.00 g of L-ropiperamide tartrate (IX), 96.00 g of methyl isobutyl ketone, 72.00 g of purified water and 8.40 g of sodium hydroxide were added to the reaction flask and reacted at room temperature for 1 h; the obtained reaction solution was separated, and the organic phase was washed with 72 mL of water to obtain a methyl isobutyl ketone solution of L-ropiperamide (X). 8.40 g of potassium carbonate, 30.00 g of purified water and 8.92 g of bromopropane were added to the obtained methyl isobutyl ketone solution of L-ropiperamide (X), and the temperature was raised to 85° C. to react for 7 h. TLC detected that the reaction of the raw materials was complete; the obtained reaction solution was washed twice with 72 mL of purified water, separated, and 10.80 g of 37% concentrated hydrochloric acid was added to the organic phase. The temperature was controlled at 35° C. to form salt for 1.5 h, and the temperature was lowered to 0-10° C. to crystallize for 2.5 h, filtered, and filtered with 12.00 g of ... The product was washed with acetone at 0-10°C and dried at 55°C to constant weight to obtain 16.95 g of crude ropivacaine hydrochloride with a molar yield of 92.39% (calculated based on L-ropivacaine) and a purity of 99.4%.
[0073] (4) 16.95 g of crude ropivacaine hydrochloride, 76.28 g of acetone, and 21.20 g of purified water were added to a reaction flask, heated to 55°C for dissolution, cooled to 0-5°C for crystallization for 2.5 h, filtered, washed with 6.00 g of 0-10°C acetone, and dried at 55°C to constant weight to obtain 15.48 g of ropivacaine hydrochloride with a molar yield of 91.32%.
[0074] The purity of the ropivacaine hydrochloride prepared in this comparative example was 99.7%, the dextrorotatory isomer was not detected, and the total molar yield was 30.40% (calculated based on 2-piperidinic acid (II) as the starting material), which was significantly lower than that in Example 1 and Comparative Example 1.
[0075] Comparative Example 3
[0076] A method for preparing ropivacaine hydrochloride comprises the following steps:
[0077] (1) 28.70 g of the above-mentioned ropiperamide (VI) prepared according to Comparative Example 2, 200.90 g of acetone and 50.22 g of purified water were added to a reaction flask, and the temperature was raised to 35° C. for dissolution. 18.60 g of L-(-)-dibenzoyltartaric acid (monohydrate) (VII) was added and reacted at 35° C. for 2.5 h. After the reaction was completed, the temperature was lowered to 0-5° C. for crystallization, and the crystals were grown at 0-5° C. for 2.5 h. The mixture was filtered, washed with 17.70 g of 0-5° C. acetone, and dried at 55° C. to constant weight to obtain 23.85 g of L-ropiperamide tartrate (IX), with an L-ropiperamide (X) content of 53.6%, equivalent to 12.78 g of L-ropiperamide (X), and a molar yield of 44.53%. The mother liquor was separated by filtering the filtrate and the washing liquid.
[0078] (2) The mother liquor was distilled under reduced pressure at a temperature of 60-70°C. 258.00 g of purified water and 78.90 g of a 10% sodium hydroxide aqueous solution were added to the resulting product, and the mixture was reacted at a temperature of 25°C for 1.5 h. After the reaction was completed, the mixture was cooled to 0-5°C for crystallization for 1.5 h, and filtered to obtain a wet product of R-ropinamide (VIII). The wet product of R-ropinamide (VIII) was mixed with 187.00 g of purified water and 21.53 g of sodium hydroxide, and the mixture was heated to 95°C for racemization reaction for 24 h. The mixture was cooled to 0-10°C for crystallization for 1.5 h, and filtered to obtain 13.70 g of ropinamide (VI) with a molar yield of 86.06% and a purity of 97.9%.
[0079] (3) 13.70 g of the above-mentioned ropiperamide (VI), 95.90 g of acetone, and 24.00 g of purified water were added to a reaction flask, and the temperature was raised to 35° C. for dissolution. 8.87 g of L-(-)-dibenzoyltartaric acid (monohydrate) (VII) was added, and the reaction was carried out at 35° C. for 2.5 h. The temperature was lowered to 0-5° C. for crystallization, and the crystals were grown at 0-5° C. for 2.5 h. The mixture was filtered, washed with 9.0 g of 0-5° C. acetone, and dried at 55° C. to constant weight to obtain 11.28 g of L-ropiperamide tartrate (IX), with an L-ropiperamide (X) content of 51.8%, equivalent to 5.84 g of L-ropiperamide (X), and a molar yield of 42.63%.
[0080] (4) Add 23.85 g of L-ropiperamide tartrate (IX) obtained in step (1) and 11.28 g of the tartrate obtained in step (3) to the reaction flask. L-ropiperamide tartrate (IX), 140.50g methyl isobutyl ketone, 105.00g purified water and 12.30g sodium hydroxide were reacted at room temperature for 1h; the resulting reaction solution was separated, the organic phase was washed with 105mL of water, and the methyl isobutyl ketone solution of L-ropiperamide (X) was obtained. 12.30g potassium carbonate, 44.00g purified water and 12.81g bromopropane were added to the methyl isobutyl ketone solution of L-ropiperamide (X), and the temperature was raised to 85°C for reaction for 7h. TLC detected that the reaction of the raw materials was complete; the resulting reaction solution was washed twice with 105mL of purified water, and the liquid was separated. 15.80g of concentrated hydrochloric acid with a mass fraction of 37% was added to the organic phase, the temperature was controlled at 35°C for salification for 1.5h, the temperature was lowered to 0-10°C for crystallization for 2.5h, and the mixture was filtered with suction, and 17.50g of 1% chloroform was added. The product was washed with acetone at 0-10°C and dried at 55°C to constant weight to obtain 24.79 g of crude ropivacaine hydrochloride with a molar yield of 94.05% (calculated based on L-ropivacaine) and a purity of 99.5%.
[0081] (5) Add 24.79 g of crude ropivacaine hydrochloride, 111.50 g of acetone, and 31.00 g of purified water to a reaction flask, heat to 55°C for dissolution, cool to 0-5°C for crystallization for 2.5 h, filter with suction, wash with 9.00 g of 0-10°C acetone, and dry at 55°C to constant weight to obtain 23.20 g of ropivacaine hydrochloride with a molar yield of 93.59%.
[0082] The purity of the ropivacaine hydrochloride prepared in this comparative example was 99.6%, the dextrorotatory isomer was not detected, and the total molar yield was 45.56% (calculated based on 2-piperidinic acid (II) as the starting material).
Claims
1. A method for preparing ropivacaine hydrochloride, characterized in that, The steps are as follows: (1) the compound of formula II is acetylated with acetic anhydride to prepare the compound of formula III, and the compound of formula III is amidated with the compound of formula IV to prepare the compound of formula V; (2) the compound of formula V obtained in step (1) is subjected to a deprotection reaction to obtain a compound of formula VI; (3) The compound of formula VI obtained in step (2) is subjected to a resolution reaction with the compound of formula VII to prepare a compound of formula IX and a resolution mother liquor containing the compound of formula VIII; (4) The mother liquor containing the compound of formula VIII obtained in step (3) is subjected to reduced pressure distillation to remove the solvent, and then is freed in an aqueous sodium hydroxide solution, and then subjected to a racemization reaction to obtain the compound of formula VI, which is recovered and the operation of step (3) is repeated; (5) The compound of formula IX obtained in step (3) and step (4) is freed by sodium hydroxide to obtain a compound of formula X, and the compound of formula X undergoes a substitution reaction with bromopropane, and the salt is formed and recrystallized to obtain ropivacaine hydrochloride; 2. The preparation method of ropivacaine hydrochloride according to claim 1, wherein The molar ratio of acetic anhydride to the compound of formula II in step (1) is 8-10:1; the temperature of the acetylation reaction is 90-100° C., and the acetylation reaction time is 6-8 hours; The post-treatment method of the reaction solution obtained by the acetylation reaction is as follows: the obtained reaction solution of the compound of formula III is subjected to reduced pressure distillation to remove acetic anhydride, and the temperature of the reduced pressure distillation is 90-100°C.
3. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The solvent for the amidation reaction in step (1) is toluene, and the mass ratio of toluene to the compound of formula II is 8-12:1; the molar ratio of the compound of formula IV to the compound of formula II is 2-3:1; the temperature of the amidation reaction is 70-80° C., and the amidation reaction time is 6-8 hours; The post-treatment steps of the reaction solution obtained by the amidation reaction are as follows: the obtained reaction solution of the compound of formula V is washed with a 1 mol / L hydrochloric acid solution and purified water in sequence, and the organic phase obtained by washing is concentrated under reduced pressure to remove the solvent to obtain the compound of formula V.
4. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The deprotection step in step (2) is as follows: methanol and piperidine are sequentially added to the compound of formula V obtained in step (1) to carry out deprotection; the mass ratio of methanol to the compound of formula II is 4-6:1; the molar ratio of piperidine to the compound of formula II is 1-2:1; the temperature of the deprotection reaction is 60-70°C, and the deprotection reaction time is 3-4h; after the deprotection reaction is completed, the resulting reaction solution is cooled to -5-5°C for crystallization, grown at -5-5°C for 2-3h, filtered, washed with methanol at -5-5°C, and dried at 50-60°C to constant weight to obtain a compound of formula VI.
5. The method for preparing ropivacaine hydrochloride according to claim 1, wherein In step (3), the molar ratio of the compound of formula VII to the compound of formula VI is 0.3-0.5:1; the resolution reaction is carried out in a mixed solvent of acetone and water, and the mass ratio of acetone, water and the compound of formula VI is 6-8:1.5-2:1; the temperature of the resolution reaction is 30-40° C., and the resolution reaction time is 2-3 hours; The post-treatment steps of the reaction solution obtained by the resolution reaction are as follows: the reaction solution is cooled to 0-5°C for crystallization, the crystals are grown at 0-5°C for 2-3 hours, filtered, washed with acetone at 0-5°C, and dried at 50-60°C to constant weight to obtain the compound of formula IX. The resolution mother liquor is used in step (4) to recover the compound of formula VI. The resolution mother liquor includes the filtrate obtained by filtration and the washing liquid.
6. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The temperature of the reduced pressure distillation in step (4) is 60-70°C; after the reduced pressure distillation, purified water and a 10% by mass sodium hydroxide aqueous solution are added to the resulting product, and the reaction is carried out at 20-30°C for 1-2 hours. After the reaction is completed, the temperature is lowered to 0-5°C for crystallization for 1-2 hours, and filtered to obtain a compound of formula VIII; the mass ratio of the purified water to the compound of formula VI is 8-10:1, and the mass ratio of the 10% by mass sodium hydroxide aqueous solution to the compound of formula VI is 2.5-3.0:
1.
7. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The racemization reaction in step (4) is as follows: mixing the free compound of formula VIII with purified water and sodium hydroxide to carry out a racemization reaction; then cooling to 0-10°C for crystallization for 1-2 hours, filtering, washing with purified water, and drying at 50-60°C to constant weight to obtain a compound of formula VI, and repeating step (3); the mass ratio of sodium hydroxide to the compound of formula VI is 0.5-1.0:1, and the mass ratio of purified water to the compound of formula VI is 5-8:1; the temperature of the racemization reaction is 90-100°C, and the reaction time is 20-25 hours.
8. The method for preparing ropivacaine hydrochloride according to claim 1, wherein In step (5), the sodium hydroxide freeing step is as follows: adding the compound of formula IX to a mixture of methyl isobutyl ketone, purified water and sodium hydroxide, and reacting at room temperature for 0.5-1h; after the reaction is completed, separating the liquids, and washing the organic phase with water to obtain a methyl isobutyl ketone solution of the compound of formula X; the mass ratio of the methyl isobutyl ketone to the compound of formula IX is 3-5:1, the mass ratio of the sodium hydroxide to the compound of formula IX is 0.3-0.4:1; and the mass ratio of the purified water to the compound of formula IX is 2.5-3.5:
1.
9. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The substitution reaction in step (5) comprises the following steps: adding potassium carbonate, purified water and bromopropane to a methyl isobutyl ketone solution of the free compound of formula X, reacting at 80-90° C. for 6-8 hours, wherein the mass ratio of potassium carbonate to the compound of formula IX is 0.3-0.4:1, the mass ratio of purified water to the compound of formula IX is 1.0-1.5:1, and the molar ratio of bromopropane to the compound of formula X is 1.2-1.4:1; after the reaction, washing the resulting reaction solution with water, adding 37% concentrated hydrochloric acid to the resulting organic phase, forming a salt at 30-40° C. for 1-2 hours, then cooling to 0-10° C. for crystallization for 2-3 hours, filtering, washing with acetone at 0-10° C., and drying at 50-60° C. to constant weight to obtain crude ropivacaine hydrochloride; the mass ratio of concentrated hydrochloric acid to the compound of formula IX is 0.4-0.5:
1.
10. The method for preparing ropivacaine hydrochloride according to claim 1, wherein The recrystallization step in step (5) comprises the following steps: adding crude ropivacaine hydrochloride to a mixed solvent of acetone and purified water, heating the mixture to 50-60° C. for dissolution, cooling the mixture to 0-5° C. for crystallization for 2-3 hours, filtering the mixture, washing the mixture with 0-10° C. acetone, and drying the mixture at 50-60° C. to a constant weight to obtain ropivacaine hydrochloride; the mass ratio of the acetone to the crude ropivacaine hydrochloride is 4.0-5.0:1, and the mass ratio of the purified water to the crude ropivacaine hydrochloride is 1.0-1.5:1.