A preparation method of butylphthalide
By adjusting the pH value and optimizing the ring-closure reaction of crude 2-(α-hydroxypentyl)benzoic acid, the problems of low yield, low purity and high energy consumption in the existing preparation of butylphthalide were solved, and the preparation of butylphthalide with high yield, high purity and low energy consumption was realized.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 河北广祥制药有限公司
- Filing Date
- 2026-04-07
- Publication Date
- 2026-06-26
AI Technical Summary
Existing butylphthalide preparation processes suffer from low yield, low purity, high energy consumption, and large emissions of waste, making it difficult to meet the high purity standards for high-end formulation production and export. Furthermore, solvent recovery costs are relatively high.
By adjusting the pH of crude 2-(α-hydroxypentyl)benzoic acid, 2-(α-hydroxypentyl)benzoic acid and o-formylbenzoic acid were separated and purified. The latter can be recycled. By combining the closed-ring reaction with optimized solvent and conditions, the yield and purity were improved.
This method achieves high yield and high purity preparation of butylphthalide, reduces energy consumption and solvent recovery costs, simplifies the process, and improves the overall yield.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a method for preparing butylphthalide. Background Technology
[0002] The existing process for preparing butylphthalide is as follows: Grignard addition with phthalic anhydride as the starting material, followed by acid hydrolysis, dehydration and ring closure, and purification by distillation and recrystallization. This route abandons the low-selectivity scheme of early laboratory phthalide alkylation. It achieves high-selectivity introduction of the 3-position n-butyl side chain through low-temperature Grignard addition of n-butylmagnesium bromide with phthalic anhydride. After acid hydrolysis with dilute hydrochloric acid quenching, it yields 2-n-butyl-2-hydroxyphenylpropionic acid. Then, it undergoes mild dehydration and ring closure with concentrated sulfuric acid as a catalyst to generate crude butylphthalide. Finally, it is purified by vacuum distillation combined with ethanol recrystallization. This process solves the core problems of side chain positional isomerism and intermediate oxidation. The process steps are standardized, the equipment is of general chemical industry type, and the raw materials are all readily available chemical products. It can achieve industrial scale-up to the thousand-ton level, with a total yield of approximately 55-65% and small batch-to-batch fluctuations. It is currently the mainstream butylphthalide process recognized and widely used in the industry.
[0003] Although this process is widely used, the yield and purity of butylphthalide prepared under these conditions are low, and the process has several shortcomings: First, the dehydration and ring-closing step is prone to incomplete reaction, generating o-valerylbenzoic acid ring-opening impurities. These impurities are highly similar in structure to butylphthalide, and the existing purification methods using vacuum distillation combined with ethanol recrystallization are difficult to completely separate them, resulting in a finished product purity that is difficult to exceed 99.5%, failing to meet the high purity standards for high-end formulation production and export. Second, the vacuum distillation in the purification stage requires precise temperature and pressure control equipment, which not only results in high energy consumption but also causes yield loss due to distillation residue, limiting further improvement in the overall yield. Third, the tetrahydrofuran solvent used in the process needs to be dehydrated by distillation and recycled, resulting in high solvent recovery costs and relatively large overall waste emissions. In addition, concentrated sulfuric acid, as a ring-closing catalyst, poses a potential risk of benzene ring carbonization, which is inconsistent with the current green chemical production concept. Coupled with the low overall yield, this further increases production costs. Therefore, how to provide a preparation method that improves the yield and purity of butylphthalide, is simple in process, and has low energy consumption has become an urgent technical problem to be solved in the industrial production of butylphthalide. Summary of the Invention
[0004] To address the shortcomings of traditional butylphthalide preparation processes, this invention provides a method for preparing butylphthalide with high yield, high purity, low energy consumption, and simple process.
[0005] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted: This invention provides a method for preparing butylphthalide, comprising the following steps: S1. Under solvent conditions, o-formylbenzoic acid and organometallic reagent undergo a condensation reaction to obtain crude 2-(α-hydroxypentyl)benzoic acid; S2. Add an alkaline solution to the crude 2-(α-hydroxypentyl)benzoic acid for the first treatment, wash, recover the aqueous phase, adjust the pH of the aqueous phase to 3.8~4, perform the second treatment, filter, and obtain 2-(α-hydroxypentyl)benzoic acid and filtrate; S3. Adjust the pH of the filtrate from S2 to 1.8-2, perform a third treatment, filter, and obtain o-formylbenzoic acid, which is then used in S1. S4. Under solvent conditions, the 2-(α-hydroxypentyl)benzoic acid described in S2 is subjected to a ring-closing reaction to obtain butylphthalide.
[0006] The method for preparing butylphthalide provided by this invention involves adjusting the pH of crude 2-(α-hydroxypentyl)benzoic acid to separate and purify 2-(α-hydroxypentyl)benzoic acid and a filtrate; then adjusting the pH of the filtrate to separate and purify o-formylbenzoic acid, which can be used as a raw material in the condensation reaction in step S1. This preparation method improves the yield of butylphthalide while avoiding o-formylbenzoic acid as an impurity that reduces the purity and yield of subsequent butylphthalide preparations. In step S2 of the butylphthalide preparation method provided by this invention, adjusting the pH to a specific range allows 2-(α-hydroxypentyl)benzoic acid to be purified. Reaching the isoelectric point of the acid facilitates the crystallization and purification of 2-(α-hydroxypentyl)benzoic acid. Simultaneously, because the isoelectric point of o-formylbenzoic acid has not been reached, o-formylbenzoic acid remains stably dissolved in the filtrate. This step effectively separates 2-(α-hydroxypentyl)benzoic acid from o-formylbenzoic acid in the crude 2-(α-hydroxypentyl)benzoic acid. In step S3, further lowering the pH of the filtrate system allows o-formylbenzoic acid to reach its isoelectric point, which is beneficial for its crystallization and purification. Reusing o-formylbenzoic acid in step S1 further improves the overall yield in the preparation of butylphthalide. The butylphthalide preparation method provided by this invention has low energy consumption, a simple process, and effectively improves the yield of butylphthalide.
[0007] Preferably, in S1, the temperature of the condensation reaction is -15 to -5°C, and the time is 1 to 2 hours.
[0008] Preferably, in S1, the solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, or cyclohexane.
[0009] More preferably, in S1, the solvent is tetrahydrofuran.
[0010] Preferably, in S1, the organometallic reagent is at least one of n-butyllithium, n-butylmagnesium chloride, or n-butylmagnesium bromide.
[0011] More preferably, in S1, the organometallic reagent is n-butyllithium.
[0012] Preferably, in S1, the molar ratio of o-formylbenzoic acid to organometallic reagent is 1:1.5 to 1:2.0.
[0013] More preferably, in S1, the molar ratio of o-formylbenzoic acid to the organometallic reagent is 1:1.5.
[0014] Preferably, in S1, the ratio of o-formylbenzoic acid to solvent is 40g:(1200~1250)mL.
[0015] Preferably, in S1, the o-formylbenzoic acid includes o-formylbenzoic acid obtained by hydrolysis of 3-bromophthalamide and the unreacted o-formylbenzoic acid in S3 above.
[0016] For example, in S1, the preparation of o-formylbenzoic acid specifically includes the following steps: 3-bromophthalide and water were mixed and hydrolyzed. Activated carbon was added, the mixture was filtered, cooled to 0-10°C, crystals were precipitated, filtered, washed, and dried to obtain o-formylbenzoic acid.
[0017] Preferably, the mass ratio of 3-bromophthalide to water is 1:4 to 1:5.
[0018] Specifically, the hydrolysis reaction is carried out at a temperature of 95-100℃ for 30-60 minutes.
[0019] Specifically, the crystallization temperature is 0~10℃ and the time is 1~2h.
[0020] Specifically, the drying temperature is 50°C and the time is 8-12 hours.
[0021] Preferably, in S1, after the condensation reaction is completed, the reaction system is quenched with an alkaline solution, concentrated under reduced pressure, washed with dichloromethane, and the pH of the aqueous phase is adjusted to 3.0-3.3 before stirring and filtration to obtain the crude 2-(α-hydroxypentyl)benzoic acid.
[0022] Specifically, the alkaline solution is a sodium hydroxide solution with a mass content of 2%.
[0023] More preferably, the temperature for vacuum concentration is 30~45℃.
[0024] Further preferably, the pH of the aqueous phase is adjusted to 3.0-3.3 using a 4 mol / L hydrochloric acid aqueous solution.
[0025] Preferably, in S2, the alkaline solution is at least one of a sodium hydroxide solution or a potassium hydroxide solution.
[0026] Preferably, the mass-to-volume ratio of o-formylbenzoic acid to alkaline solution is 1 g: (7~10) mL, and the mass concentration of alkaline solution is 2.5%~3.0%.
[0027] In this invention, adding an alkaline solution to crude 2-(α-hydroxypentyl)benzoic acid can effectively dissolve impurities in the reaction system and remove them.
[0028] Preferably, in S2, the pH of the aqueous phase is adjusted to 3.8-4 using a 4 mol / L hydrochloric acid aqueous solution.
[0029] The preferred pH range in this invention allows 2-(α-hydroxypentyl)benzoic acid to reach its isoelectric point, which is beneficial for the crystallization and purification of 2-(α-hydroxypentyl)benzoic acid. Under this pH condition, o-formylbenzoic acid is stably present in the filtrate.
[0030] Preferably, in S2, the solvent used for washing is dichloromethane.
[0031] Preferably, in S2, the first treatment also requires stirring, with the stirring temperature being 28~32℃ and the time being 2~3h.
[0032] Preferably, in S2, the temperature of the aqueous phase is 10~14℃.
[0033] In this invention, the stirring during the first processing step is to fully dissolve the crude 2-(α-hydroxypentyl)benzoic acid under alkaline conditions. After washing with dichloromethane, a large number of impurities dissolve in the dichloromethane, effectively removing the impurities from the crude 2-(α-hydroxypentyl)benzoic acid. Then, the crude 2-(α-hydroxypentyl)benzoic acid is cooled and the pH value is adjusted, which is conducive to the crystallization of 2-(α-hydroxypentyl)benzoic acid. After filtration, high-purity 2-(α-hydroxypentyl)benzoic acid is obtained.
[0034] Preferably, in S2, the second treatment also requires stirring, with the stirring temperature being 10~14℃ and the time being 10~15min.
[0035] Preferably, in S3, the pH of the aqueous phase is adjusted to 1.8-2 using a 4 mol / L hydrochloric acid aqueous solution.
[0036] Preferably, in S3, the third process also requires stirring, with the stirring temperature being 0~10℃ and the stirring time being 10~15min.
[0037] Preferably, in S4, the closed-loop reaction is carried out at a temperature of 38~42℃ for 6~7 hours.
[0038] Preferably, in S4, the solvent is at least one of dichloromethane, chloroform, or ethyl acetate.
[0039] More preferably, in S4, the solvent is dichloromethane.
[0040] Preferably, in S4, the amount of solvent used can be the same as that used in conventional operations known to those skilled in the art.
[0041] Specifically, in S4, the post-processing of the closed-loop reaction further includes the following steps: The reaction system after the ring-closing reaction was completed was washed, then activated carbon was added to the organic phase, stirred, filtered, the filtrate was dried, and concentrated under reduced pressure to obtain the butylphthalide.
[0042] Further preferably, the washing process specifically includes the following steps: adding a saturated sodium bicarbonate aqueous solution to the reaction system for washing, stirring for 10-20 min, letting stand for 10-20 min, separating the liquids, and collecting the organic phase; washing the organic phase again with a saturated sodium bicarbonate aqueous solution, stirring for 10-20 min, letting stand for 10-20 min, separating the liquids, and collecting the organic phase; adding purified water to the organic phase, stirring for 10-20 min, letting stand for 10-20 min, separating the liquids, and collecting the organic phase; and adding a saturated sodium chloride aqueous solution to the organic phase for washing, stirring for 10-20 min, letting stand for 10-20 min, separating the liquids, and collecting the organic phase.
[0043] Preferably, the activated carbon is stirred for 30-40 minutes at a temperature of 20-30°C.
[0044] Preferably, the vacuum concentration is carried out at a temperature of 30~38℃ for 6~8 hours. Detailed Implementation
[0045] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0046] The 3-bromophthalide used in the following examples was purchased from Shanghai Bangcheng Chemical Co., Ltd., with a purity of ≥99.0%; all other compounds or related reagents used were available from the market.
[0047] Example 1 This embodiment provides a method for preparing butylphthalide, the details of which are as follows: Step 1: Add 280g of water and 70g of 3-bromophthalide to a 2L glass flask. Maintain the temperature at 95℃ and stir for 60min. Add 0.7g of activated carbon and continue stirring for 30min. Filter immediately. After filtration, cool the reaction solution to 0℃ to allow crystals to crystallize for 2h. Filter again, wash the filter cake with 100g of purified water, and dry at 50℃ for 12h to obtain o-formylbenzoic acid. The yield of o-formylbenzoic acid is 44.98g, with a yield of 91.2% and a purity of 99.78%. Step 2: Add 44.5g of o-benzoic acid, 10g of recovered o-benzoic acid, and 1.635L of tetrahydrofuran to a 2L glass flask. Stir and cool. When the liquid temperature is -20℃, start adding 340mL of 1.6mol / L (0.552mol) n-butyllithium dropwise, controlling the dropwise temperature of n-butyllithium at -15℃. After the dropwise addition is complete, react at -15℃ for 2 hours, stirring is required during the reaction. After the reaction is complete, add 400mL of 2% sodium hydroxide solution to the above reaction solution to quench it. Stirring is required during the quenching process for 15 minutes. Concentrate the reaction system under reduced pressure at 30℃. After no more droplets are distilled off, 2-(α-hydroxypentyl)benzoic acid mother liquor is obtained. 400 mL of dichloromethane was added to the mother liquor of 2-(α-hydroxypentyl)benzoic acid for washing, and the aqueous phase was recovered. The aqueous phase was cooled to 14 °C, and 4 mol / L hydrochloric acid was added to the aqueous phase to adjust the pH to 3.3. The mixture was stirred for 15 min and filtered to obtain crude 2-(α-hydroxypentyl)benzoic acid. Step 3: Prepare a 2.5% sodium hydroxide aqueous solution. Add 400 mL of the 2.5% sodium hydroxide aqueous solution to the crude 2-(α-hydroxypentyl)benzoic acid, control the temperature at 28℃, stir and react for 3 h, add 400 mL of dichloromethane to wash, and recover the aqueous phase; cool the aqueous phase to 10℃, add 4 mol / L hydrochloric acid, adjust the pH to 4.0, control the temperature at 10℃, stir for 15 min, filter, and obtain 2-(α-hydroxypentyl)benzoic acid; Step 4: Collect the filtrate, add 4 mol / L hydrochloric acid to adjust the pH to 1.8, control the temperature at 0℃, stir for 10 min, filter, and dry the filter cake to obtain the recovered o-formylbenzoic acid. The recovered amount of o-formylbenzoic acid is 10 g, which can be used in the preparation of the next batch of 2-(α-hydroxypentyl)benzoic acid. Step 5: Add filtered 2-(α-hydroxypentyl)benzoic acid and 400 mL of dichloromethane to a 2 L glass flask. Maintain the temperature at 42 °C and stir for 6 h. After the reaction is complete, wash once with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 10 min, let stand for 20 min, separate the liquids, and collect the organic phase. Wash the organic phase again with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 15 min, let stand for 20 min, separate the liquids, and collect the organic phase. Add 400 mL of purified water to the organic phase, stir for 10 min, let stand for 20 min, separate the liquids, and collect the organic phase. Add 400 mL of saturated sodium chloride aqueous solution to the organic phase, stir for 10 min, let stand for 20 min, separate the liquids, and collect the organic phase. Add 1 g of activated carbon to the organic phase, stir at 20 °C for 40 min, and filter. Add 20 g of anhydrous sodium sulfate to the filtrate to dry the organic phase, filter off the anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure at 38 °C for 8 h to obtain butylphthalide.
[0048] Example 2 This embodiment provides a method for preparing butylphthalide, the details of which are as follows: Step 1: Add 280g of water and 70g of 3-bromophthalide to a 2L glass flask. Maintain the temperature at 100℃ and stir for 30min. Add 0.7g of activated carbon and continue stirring for another 30min. Filter immediately. After filtration, cool the reaction solution to 10℃ to allow crystals to precipitate for 1h. Filter again, wash the filter cake with 100g of purified water, and dry at 50℃ for 8h to obtain o-formylbenzoic acid. The yield of o-formylbenzoic acid is 44.58g, with a yield of 90.37% and a purity of 99.68%. Step 2: Add 44.5g of o-benzoic acid, 10.5g of recovered o-benzoic acid, and 1.65L of 2-methyltetrahydrofuran to a 2L glass flask. Stir and cool. When the liquid temperature is -15℃, start adding 458mL of 1.6mol / L (0.733mol) n-butylmagnesium chloride dropwise, controlling the dropwise temperature of n-butylmagnesium chloride at -5℃. After the dropwise addition is complete, react at -5℃ for 2h, stirring is required during the reaction. After the reaction is complete, add 400mL of 2% sodium hydroxide solution to the above reaction solution to quench it. Stirring is required during the quenching process for 15min. Concentrate the reaction system under reduced pressure at 45℃. After no more droplets are distilled off, 2-(α-hydroxypentyl)benzoic acid mother liquor is obtained. 400 mL of dichloromethane was added to the mother liquor of 2-(α-hydroxypentyl)benzoic acid for washing, and the aqueous phase was recovered. The aqueous phase was cooled to 10 °C, and 4 mol / L hydrochloric acid was added to the aqueous phase to adjust the pH to 3. The mixture was stirred for 10 min and filtered to obtain crude 2-(α-hydroxypentyl)benzoic acid. Step 3: Prepare a 2.5% sodium hydroxide aqueous solution. Add 540 mL of the 2.5% sodium hydroxide aqueous solution to the crude 2-(α-hydroxypentyl)benzoic acid, control the temperature at 32℃, stir and react for 2 h, add 400 mL of dichloromethane to wash, and recover the aqueous phase; cool the aqueous phase to 14℃, add 4 mol / L hydrochloric acid, adjust the pH to 3.8, control the temperature at 14℃, stir for 10 min, filter, and obtain 2-(α-hydroxypentyl)benzoic acid.
[0049] Step 4: Collect the filtrate, add 4 mol / L hydrochloric acid to adjust the pH to 2, control the temperature at 10℃, stir for 15 min, filter, and dry the filter cake to obtain the recovered o-formylbenzoic acid. The recovered amount of o-formylbenzoic acid is 10.5 g, which can be used in the preparation of the next batch of 2-(α-hydroxypentyl)benzoic acid. Step 5: Add filtered 2-(α-hydroxypentyl)benzoic acid and 400 mL of chloroform to a 2 L glass flask. Maintain the temperature at 38 °C and stir for 7 h. After the reaction is complete, wash once with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 20 min, let stand for 10 min, separate the liquid and collect the organic phase. Wash the organic phase again with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 10 min, let stand for 15 min, separate the liquid and collect the organic phase. Add 400 mL of purified water to the organic phase, stir for 20 min, let stand for 10 min, separate the liquid and collect the organic phase. Add 400 mL of saturated sodium chloride aqueous solution to the organic phase, stir for 20 min, let stand for 10 min, separate the liquid and collect the organic phase. Add 1 g of activated carbon to the organic phase, stir at 30 °C for 30 min, and filter. Add 30 g of anhydrous sodium sulfate to the filtrate, dry the organic phase, filter off the anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure at 30 °C for 6 h to obtain butylphthalide.
[0050] Example 3 This embodiment provides a method for preparing butylphthalide, the details of which are as follows: Step 1: Add 280g of water and 70g of 3-bromophthalide to a 2L glass flask. Maintain the temperature at 97℃ and stir for 50min. Add 0.7g of activated carbon and continue stirring for 30min. Filter immediately. After filtration, cool the reaction solution to 5℃ and allow crystals to precipitate for 1.5h. Filter again, wash the filter cake with 100g of purified water, and dry at 50℃ for 10h to obtain o-formylbenzoic acid. The yield of o-formylbenzoic acid is 45.12g, with a yield of 91.46% and a purity of 99.82%. Step 2: Add 44.5g of o-benzoic acid, 10.4g of recovered o-benzoic acid, and 1.647L of n-hexane to a 2L glass flask. Stir and cool. When the liquid temperature reaches -18℃, begin adding 388mL of 1.6mol / L (0.62mol) n-butylmagnesium bromide dropwise, controlling the dropwise temperature of n-butylmagnesium bromide at -10℃. After the dropwise addition is complete, react at -10℃ for 2 hours, stirring continuously during the reaction. After the reaction is complete, add 400mL of [unspecified substance] to the above reaction solution. The reaction was quenched with a 2% sodium hydroxide solution (L in mass), and stirring was required during the quenching process for 15 minutes. The reaction system was concentrated under reduced pressure at 40°C until no more droplets were distilled off to obtain a mother liquor of 2-(α-hydroxypentyl)benzoic acid. 400 mL of dichloromethane was added to the mother liquor of 2-(α-hydroxypentyl)benzoic acid for washing, and the aqueous phase was recovered. The aqueous phase was cooled to 12°C, and 4 mol / L hydrochloric acid was added to the aqueous phase to adjust the pH to 3.2. The mixture was stirred for 12 minutes and then filtered to obtain crude 2-(α-hydroxypentyl)benzoic acid. Step 3: Prepare a 3% sodium hydroxide aqueous solution. Add 450 mL of the 3% sodium hydroxide aqueous solution to the crude 2-(α-hydroxypentyl)benzoic acid, control the temperature at 30℃, stir for 2.5 h, add 400 mL of dichloromethane to wash, and recover the aqueous phase; cool the aqueous phase to 12℃, add 4 mol / L hydrochloric acid, adjust the pH to 3.9, control the temperature at 12℃, stir for 13 min, filter, and obtain 2-(α-hydroxypentyl)benzoic acid; Step 4: Collect the filtrate, add 4 mol / L hydrochloric acid to adjust the pH to 1.9, control the temperature at 5℃, stir for 12 min, filter, and dry the filter cake to obtain the recovered o-formylbenzoic acid. The recovered amount of o-formylbenzoic acid is 10.4 g, which will be used in the preparation of the next batch of 2-(α-hydroxypentyl)benzoic acid. Step 5: Add filtered 2-(α-hydroxypentyl)benzoic acid and 400 mL of ethyl acetate to a 2 L glass flask. Maintain the temperature at 40 °C and stir for 6.5 h. After the reaction is complete, wash once with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 15 min, let stand for 15 min, separate the liquids, and collect the organic phase. Wash the organic phase again with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 20 min, let stand for 10 min, separate the liquids, and collect the organic phase. Add 400 mL of purified water to the organic phase, stir for 15 min, let stand for 15 min, separate the liquids, and collect the organic phase. Add 400 mL of saturated sodium chloride aqueous solution to the organic phase, stir for 15 min, let stand for 15 min, separate the liquids, and collect the organic phase. Add 1 g of activated carbon to the organic phase, stir at 25 °C for 35 min, and filter. Add 25 g of anhydrous sodium sulfate to the filtrate, dry the organic phase, filter off the anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure at 35 °C for 7 h to obtain butylphthalide.
[0051] Comparative Example 1 This comparative example provides a method for preparing butylphthalide, which is based on Example 1 with adjustments. The difference is that the filtrate after crystallization of 2-(α-hydroxypentyl)benzoic acid was not collected and pH adjusted, and o-formylbenzoic acid was not separated and applied to the preparation step of 2-(α-hydroxypentyl)benzoic acid. The specific implementation includes the following steps: Step 1: Add 280g of water and 70g of 3-bromophthalide to a 2L glass flask. Maintain the temperature at 95℃ and stir for 60min. Add 0.7g of activated carbon and continue stirring for 30min. Filter immediately. After filtration, cool the reaction solution to 0℃ to allow crystals to crystallize for 2h. Filter again, wash the filter cake with 100g of purified water, and dry at 50℃ for 12h to obtain o-formylbenzoic acid. The yield of o-formylbenzoic acid is 44.48g, with a yield of 90.16% and a purity of 99.75%. Step 2: Add 44.5g of o-benzoic acid and 1.335L of tetrahydrofuran to a 2L glass flask, stir and cool. When the liquid temperature reaches -20℃, begin adding 278mL of 1.6mol / L (0.444mol) n-butyllithium dropwise, controlling the dropwise temperature of n-butyllithium at -15℃. After the dropwise addition is complete, react at -15℃ for 2 hours, stirring is required during the reaction. After the reaction is complete, add 400mL of 2% hydrogen peroxide solution to the above reaction solution. The reaction was quenched with sodium oxide solution, and stirring was required during the quenching process. The stirring was carried out for 15 minutes. The reaction system was concentrated under reduced pressure at 30°C until no more droplets were distilled off to obtain the mother liquor of 2-(α-hydroxypentyl)benzoic acid. 400 mL of dichloromethane was added to the mother liquor of 2-(α-hydroxypentyl)benzoic acid for washing, and the aqueous phase was recovered. The aqueous phase was cooled to 14°C, and 4 mol / L hydrochloric acid was added to the aqueous phase to adjust the pH to 3.3. The mixture was stirred for 15 minutes and then filtered to obtain crude 2-(α-hydroxypentyl)benzoic acid. Step 3: Prepare a 2.5% sodium hydroxide aqueous solution. Add 400 mL of the 2.5% sodium hydroxide aqueous solution to the crude 2-(α-hydroxypentyl)benzoic acid. Control the temperature at 28℃ and stir for 3 hours. Add 400 mL of dichloromethane to wash and recover the aqueous phase. Cool the aqueous phase to 10℃, add 4 mol / L hydrochloric acid, adjust the pH to 4.0, control the temperature at 10℃, stir for 15 minutes, and filter to obtain 2-(α-hydroxypentyl)benzoic acid. Step 4: Add filtered 2-(α-hydroxypentyl)benzoic acid and 400 mL of dichloromethane to a 2 L glass flask. Maintain the temperature at 42 °C and stir for 6 h. After the reaction is complete, wash once with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 10 min, let stand for 20 min, separate the liquid and collect the organic phase. Wash the organic phase again with 400 mL of saturated sodium bicarbonate aqueous solution, stir for 15 min, let stand for 20 min, separate the liquid and collect the organic phase. Add 400 mL of purified water to the organic phase, stir for 10 min, let stand for 20 min, separate the liquid and collect the organic phase. Add 400 mL of saturated sodium chloride aqueous solution to the organic phase, stir for 10 min, let stand for 20 min, separate the liquid and collect the organic phase. Add 1 g of activated carbon to the organic phase, stir at 20 °C for 40 min, and filter. Add 20 g of anhydrous sodium sulfate to the filtrate to dry the organic phase, filter off the anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure at 38 °C for 8 h to obtain butylphthalide.
[0052] Example of effect The yields of butylphthalide provided in Examples 1-3 and Comparative Example 1 were calculated. The overall yield of butylphthalide synthesized via this route was calculated according to the formula relating 3-bromophthalide to butylphthalide. The specific calculation formula is as follows:
[0053] Where m1 is the finished product mass of butylphthalide, M1 is the molar mass of butylphthalide; C1 is the finished product purity of butylphthalide; m2 is the finished product mass of 3-bromophthalide, M2 is the molar mass of 3-bromophthalide, and C2 is the purity of 3-bromophthalide.
[0054]
[0055] In this effective example, the yields of butylphthalide prepared in Examples 1-3 were 78.3%, 77.6%, and 78.7%, respectively, while the yield of the comparative example was only 62.2%. The yield of butylphthalide prepared in the examples of this invention is significantly higher than that of the comparative example. Compared with comparative example 1, the yield of example 3 increased by 16.5%, and the purity of example 1 increased by 0.24%. The experimental results show that the preparation method of butylphthalide provided by this invention is simple, energy-efficient, highly pure, and has a high yield, demonstrating significant technological advancement and industrial application value.
[0056] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing butylphthalide, characterized in that, Includes the following steps: S1. Under solvent conditions, o-formylbenzoic acid and organometallic reagent undergo a condensation reaction to obtain crude 2-(α-hydroxypentyl)benzoic acid; S2. Add an alkaline solution to the crude 2-(α-hydroxypentyl)benzoic acid for the first treatment, wash, recover the aqueous phase, adjust the pH of the aqueous phase to 3.8~4, perform the second treatment, filter, and obtain 2-(α-hydroxypentyl)benzoic acid and filtrate; S3. Adjust the pH of the filtrate from S2 to 1.8-2, perform a third treatment, filter, and obtain o-formylbenzoic acid, which is then used in S1. S4. Under solvent conditions, the 2-(α-hydroxypentyl)benzoic acid described in S2 is subjected to a ring-closing reaction to obtain butylphthalide.
2. The method for preparing butylphthalide as described in claim 1, characterized in that, In S1, the temperature of the condensation reaction is -15 to -5°C, and the time is 1 to 2 hours.
3. The method for preparing butylphthalide as described in claim 1, characterized in that, In S1, the solvent is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, or cyclohexane; and / or In S1, the organometallic reagent is at least one of n-butyllithium, n-butylmagnesium chloride, or n-butylmagnesium bromide.
4. The method for preparing butylphthalide as described in claim 1, characterized in that, In S1, the molar ratio of o-formylbenzoic acid to organometallic reagent is 1:1.5 to 1:2.
0.
5. The method for preparing butylphthalide as described in claim 1, characterized in that, In S2, the alkaline solution is at least one of sodium hydroxide solution or potassium hydroxide solution; and / or The mass-to-volume ratio of o-formylbenzoic acid to alkaline solution is 1 g: (7~10) mL, and the mass concentration of alkaline solution is 2.5%~3.0%.
6. The method for preparing butylphthalide as described in claim 1, characterized in that, In S2, the first treatment also requires stirring, with the stirring temperature at 28~32℃ and the time at 2~3h.
7. The method for preparing butylphthalide as described in claim 1, characterized in that, In S2, the temperature of the aqueous phase is 10~14℃.
8. The method for preparing butylphthalide as described in claim 1, characterized in that, In S4, the closed-loop reaction is carried out at a temperature of 38~42℃ for 6~7 hours.
9. The method for preparing butylphthalide as described in claim 1, characterized in that, In S4, the solvent for the ring-closing reaction is at least one of dichloromethane, trichloromethane, or ethyl acetate.
10. The method for preparing butylphthalide according to claim 1, characterized in that, In S4, the solvent for the ring-closing reaction is dichloromethane.