A synthetic process of a butylphthalide derivative

Abstract

The application relates to the field of drug chemical synthesis, in particular to a synthesis process of a butylphthalide derivative. The synthesis method of the butylphthalide derivative comprises the following steps: butylphthalide and lithium aluminum hydride are mixed in tetrahydrofuran, reacted with tert-butyl dimethyl chlorosilane, then reacted with acid and tetrabutylammonium fluoride trihydrate, esterified with 2-morinol or a derivative thereof after oxidation, and purified to obtain the butylphthalide derivative. The synthesis method has the characteristics of mild conditions, simple operation, fewer side reactions, high selectivity, better industrial adaptability of the prepared butylphthalide derivative, and high purity of the finished product.

Description

Technical Field

[0001] This invention pertains to the field of chemical synthesis, specifically relating to the synthesis process of a butylphthalide derivative. Background Technology

[0002] Butylphthalide, also known as 3-butyl-1(3H)-isobenzofuranone (3-n-Butylphthalide, NBP), or apigenin A, is one of the more widely used drugs for treating cerebral ischemia. Pharmacodynamic studies have shown that butylphthalide can shrink the infarct foci after focal cerebral ischemia, increase cerebral blood flow in the ischemic area, and improve microcirculation in the ischemic area, exhibiting a strong anti-cerebral ischemia effect. It can significantly reduce the infarct area of ​​local cerebral ischemia in rats, alleviate cerebral edema, improve cerebral energy metabolism and microcirculation and blood flow in the ischemic area, and has anti-cerebral thrombosis and anti-platelet aggregation effects. Clinically, it is mainly used to treat mild to moderate acute ischemic stroke. Although butylphthalide can act on multiple pathological aspects of cerebral ischemia, its overall efficacy is not high, so it is often used in combination with other drugs to achieve the desired therapeutic effect. Furthermore, butylphthalide's poor water solubility is a major reason that limits its widespread use in treating conditions such as acute cerebral ischemia. Derivatizing butylphthalide to allow it to exert multiple effects with other substances with similar functions, or even forming its derivatives into salts to enhance the water solubility of the compounds, is a new approach to fully utilize the efficacy of butylphthalide-like substances, achieving a multi-pronged approach that leverages its strengths and avoids its weaknesses.

[0003] Chinese invention patent application CN109503548A discloses a butylphthalide derivative, its preparation method, and its application. The method for preparing the butylphthalide derivative involves demethylating anisoletrithium (ADT) under alkaline conditions at a certain temperature, then saponifying (S)- or (R)-NBP in a solvent via saponification and acidification to obtain a lactone ring-opening compound (S) or (R)-HPBA. This compound is then mixed with an alkyl acyl chloride, a hydrogen sulfide donor ADTOH, and a condensing agent, and esterified to obtain the target compound, the butylphthalide derivative. This butylphthalide derivative exhibits excellent antiplatelet aggregation and antithrombotic activity and can be used clinically to prepare drugs for the prevention or treatment of diseases related to platelet aggregation. Another Chinese invention patent application CN113292524A discloses a butylphthalide derivative and its application in the preparation of drugs for protecting nerve cells. This invention provides the use of butylphthalide derivatives or pharmaceutical compositions thereof in the preparation of drugs for the prevention and / or treatment of cell damage-related diseases and neurodegenerative diseases. However, the above-mentioned method for synthesizing butylphthalide derivatives involves hydrolyzing butylphthalide followed by condensation, esterification, and other reactions. Since the hydrolyzed 2-(1-hydroxypentyl)benzoic acid is unstable and easily re-rings to form butylphthalide, the yield of subsequent condensation reactions is low.

[0004] Therefore, in order to meet the needs of the pharmaceutical industry for butylphthalide derivatives, there is an urgent need to provide a synthetic process for butylphthalide derivatives with fewer side reactions and milder conditions. Summary of the Invention

[0005] To address the problems existing in the prior art, the present invention provides a synthesis process for butylphthalide derivatives.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for synthesizing a butylphthalide derivative, characterized by comprising the following steps:

[0008] (1) React butylphthalide and lithium aluminum hydride in tetrahydrofuran to obtain intermediate 1;

[0009] (2) Intermediate 1 reacts with tert-butyldimethylchlorosilane to give intermediate 2;

[0010] (3) Intermediate 2 undergoes an acid condensation reaction to obtain a condensation product, which then reacts with tetrabutylammonium fluoride trihydrate to obtain intermediate 3.

[0011] (4) Intermediate 3 reacts with an oxidizing agent to give an aldehyde compound, which is further oxidized to give intermediate 4;

[0012] (5) Intermediate 4 is esterified with 2-camphenol or a 2-camphenol derivative to obtain butylphthalide derivative.

[0013] Preferably, the ratio of butylphthalide, lithium aluminum hydride and tetrahydrofuran in step (1) is 0.5-1.5 mol: 1 mol: 8-12 mL / g, the reaction time is 0.5-1.5 h, and water is added after the reaction until the system becomes a suspension, then filtered, dried and evaporated.

[0014] Preferably, the solvent for the reaction in step (2) includes dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine, the reaction time is 10-14 h, and the reaction is followed by washing with water. The ratio of intermediate 1, tert-butyldimethylchlorosilane, dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine is 1 mol: 0.8-1.2 mol: 6-9 mL / g: 0.05-0.15 mol: 2-3 mol.

[0015] Preferably, the acid in step (3) is selected from acetic anhydride and butoxycarbonyl-L-alanine, the molar ratio of intermediate 2 to acid is 1:1.1-2, the molar ratio of condensation product to tetrabutylammonium fluoride trihydrate is 1:1-3, the reaction time of condensation product and tetrabutylammonium fluoride trihydrate is 2-5h, after the condensation reaction, water is added to the system and stirred for 20-40min, then dichloromethane is added for extraction 1-3 times, then washed with water 1-3 times, finally washed with saturated NaCl solution 1-3 times, and finally dried and purified.

[0016] Preferably, the oxidant in step (4) is selected from one or more of manganese dioxide, Dessmartin reagent, potassium permanganate and sodium hypochlorite, the reaction time of intermediate 3 with the oxidant is 8-12 h, the oxidant for further oxidation of the aldehyde compound includes glacial acetic acid, aminosulfonic acid and sodium chlorite, the further oxidation time is 0.5-1.5 h, the molar ratio of intermediate 3 to oxidant is 1:6-9, and the ratio of aldehyde compound, glacial acetic acid, aminosulfonic acid and sodium chlorite is 1 mol:8-12 mL / g:1-3 mol:1-3 mol.

[0017] Preferably, in step (5), the molar ratio of intermediate 4 to 2-camphenol is 1:1.5, the reaction time is 8-12 h, and the butylphthalide derivative has an amino group, so the butylphthalide derivative is further reacted with hydrogen chloride and / or dioxane solution. After the reaction, the product is filtered, washed, dried and purified.

[0018] Preferably, the ratio of the butylphthalide derivative to the hydrogen chloride / dioxane solution is 0.5-1.5g:1-10mL, and the concentration of the hydrogen chloride and / or dioxane solution is 3-5mol / L.

[0019] Preferably, the preparation method of the 2-camphenol derivative in step (5) includes reacting 2-camphenol, sodium hydride, potassium iodide and chloromethyl methyl sulfide in a tetrahydrofuran solution.

[0020] Preferably, potassium iodide is used as a catalyst, and the ratio of 2-camphenol, sodium hydride, chloromethyl methyl sulfide, and tetrahydrofuran is 1 mol: 1-2 mol: 0.5-1.5 mol: 8-12 mL / g. After the reaction, water is added to the system, and the mixture is stirred for 10-20 min. The mixture is then separated, and the aqueous phase is extracted with ethyl acetate 1-3 times, while the organic phase is washed with water 1-3 times for purification. The color is monitored using potassium permanganate solution.

[0021] Preferably, all reactions in each step are monitored by TLC to determine whether the reaction is complete. The developing solvent used in the TLC is a mixture of petroleum ether and ethyl acetate with a volume ratio of 3-10:1. The reaction temperature is 0-5℃ for step (4) and 20-25℃ for the other steps. The drying reagent is anhydrous sodium sulfate. The purification is carried out by column chromatography. The chromatographic column packing used for purification is 200-300 mesh silica gel. The eluent used for purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 3-30:1. The amount of eluent used is 1.2-3L.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] This invention provides a synthetic process for butylphthalide derivatives. The process is mild, simple to operate, has few side reactions, and is highly selective. It can minimize the problem of low purity of the final product caused by the cyclization of butylphthalide to 2-(1-hydroxypentyl)carboxylic acid in subsequent reactions. Attached Figure Description

[0024] Figure 1 For butylphthalide derivative A 1 H NMR spectrum.

[0025] Figure 2 It is butylphthalide derivative B 1 H NMR spectrum.

[0026] Figure 3 C is a butylphthalide derivative. 1 H NMR spectrum.

[0027] It is worth noting that the lack of clarity in the accompanying drawings does not affect the understanding of the technical solution of the present invention by those skilled in the art. Detailed Implementation

[0028] It is worth noting that the raw materials used in this invention are all commercially available products.

[0029] Example 1: Synthesis of Butylphthalide Derivative A

[0030] The chemical formula of butylphthalide derivative A is shown below:

[0031]

[0032] The synthesis route is shown in the following formula:

[0033]

[0034] Synthesis process:

[0035] Intermediate 1: Butylphthalide (1.0 eq) and anhydrous tetrahydrofuran (10.0 mL / g) were added to a reaction flask, and the system temperature was maintained at room temperature. Lithium aluminum hydride (1.0 eq) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 h, and monitored by TLC. The volume ratio of the TLC developing solvent was petroleum ether:ethyl acetate = 3:1. After the reaction was complete, the system temperature was maintained at room temperature, and water was slowly added dropwise until the system became a white suspension. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a yellow waxy intermediate 1, with a yield of 93.60%. MS (ESI) m / z: 195.4 [M+H] + .

[0036] Intermediate 2: Intermediate 1 (1.0 eq), dichloromethane (7.0 mL / g), 4-dimethylaminopyridine (0.1 eq), and diisopropylethylamine (2.5 eq) were added to a reaction flask. The system temperature was maintained at room temperature, and tert-butyldimethylchlorosilane (1.02 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC, with a petroleum ether:ethyl acetate volume ratio of 3:1. After the reaction was complete, the system was washed three times with water. A light yellow oily intermediate 2 was obtained, with a yield of 95.66%. MS (ESI) m / z: 309.8 [M+H] + .

[0037] Intermediate 3: Intermediate 2 (1.0 eq), dichloromethane (10.0 mL / g), diisopropylethylamine (3.0 eq), and 4-dimethylaminopyridine (0.3 eq) were added to a 250 mL three-necked flask, and acetic anhydride (2.0 eq) was slowly added dropwise at room temperature. The reaction was stirred at room temperature for 5 h and monitored by TLC. After the reaction was complete, water was added to the system, and the mixture was stirred for 30 min. The liquid phase was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed twice with water, once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily intermediate 3 was obtained, with a yield of 90.19%. MS (ESI) m / z: 351.4 [M+H] + .

[0038] Intermediate 4: Intermediate 3 (1.0 eq), tetrahydrofuran (10.0 ml / g), and tetrabutylammonium fluoride trihydrate (2.0 eq) were added to a 250 ml three-necked flask and stirred at room temperature for 2 h, monitored by TLC. After the reaction was complete, water was added to the system and stirred for 30 min. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed twice with water, once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by column chromatography using 200-mesh silica gel, with a petroleum ether:ethyl acetate volume ratio of 10:1 and a eluent volume of 1.2 L. The final product was a light yellow oily intermediate 4, with a yield of 42.74%.

[0039] MS(ESI) m / z: 237.6 [M+H] + ;

[0040] 1 H NMR (400MHz, CDCl3); δppm7.34-7.40(m,4H), 5.91-5.93(m,1H), 4.91-4.95( m,2H), 2.08(s,3H), 1.73-1.77(m,2H), 1.29-1.41(m,4H), 0.87-0.92(m,3H).

[0041] Intermediate 5: Intermediate 4 (1.0 eq), dichloromethane (10.0 mL / g), and MnO2 (7.0 eq) were added to a 250 mL three-necked flask and stirred overnight at room temperature under TLC monitoring. After the reaction was complete, the mixture was filtered, and the filter cake was washed with a small amount of dichloromethane. The system was evaporated to dryness to give a yellow oily intermediate 5, with a yield of 97.37%. MS (ESI) m / z: 235.2 [M+H] + .

[0042] Intermediate 6: Intermediate 5 (1.0 eq), glacial acetic acid (10.0 ml / g), and aminosulfonic acid (1.5 eq) were added to a 250 ml three-necked flask. The mixture was cooled in an ice-water bath at 0-5 °C, and sodium chlorite (2.0 eq) aqueous solution was slowly added dropwise. The mixture was stirred for 1 h while maintaining the temperature, and the reaction was monitored by TLC. After the reaction was complete, water was added to the system, and the mixture was stirred for 30 min. The mixture was extracted twice with dichloromethane, and then washed with water until the pH of the aqueous phase reached 6. Finally, the mixture was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography using 200-mesh silica gel as the packing material. The eluent volume ratio was petroleum ether:ethyl acetate = 3:1, and the eluent volume was 2.5 L. The final product was a light yellow oily intermediate 6, with a yield of 50.79%.

[0043] MS(ESI) m / z: 251.4 [M+H] + 249.2 [MH] - ;

[0044] 1 H NMR (400MHz, CDCl3); δppm 8.00-8.02(m,1H), 7.52-7.58(m,2H), 7.34-7.40(m,1H), 6.53-6.56(m,2 H), 2.10(s,3H), 1.81-1.87(m,2H), 1.41-1.48(m,4H), 0.87-0.92(m,3H).

[0045] Butylphthalide derivative A: Intermediate 6 (1.0 eq), dichloromethane (10.0 ml / g), N,N-dicyclohexylcarboimide (1.5 eq), 4-dimethylaminopyridine (0.3 eq), and 2-camphenol (1.5 eq) were added to a reaction flask and stirred overnight at room temperature. The reaction was monitored by TLC with a petroleum ether:ethyl acetate volume ratio of 3:1. After the reaction was complete, the mixture was filtered, the filtrate was diluted with dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, and purified by column chromatography using 300-mesh silica gel as the packing material. The eluent volume ratio was petroleum ether:ethyl acetate of 20:1, and the eluent volume was 2.5 L. Butylphthalide derivative A, a pale yellow solid, was obtained with a yield of 47.73%.

[0046] The purity of the synthesized butylphthalide derivative A was 98.2%, and the overall yield of the route was 8.15%. Figure 1 For butylphthalide derivative A 1 H NMR spectrum.

[0047] MS(ESI) m / z: 387.9 [M+H] + ;

[0048] 1 H NMR (400MHz, CDCl3); δppm 7.87-7.89(d,J=8,1H), 7.47-7.53(m,2H), 7.26-7.34(m,1H), 5.13-5.15(m, 1H), 2.11(s,3H),1.76-1.89(m,2H), 1.26-1.42(m,8H), 0.89-0.97(m,12H).

[0049] Example 2 Synthesis of Butylphthalide Derivative B

[0050] The chemical formula of butylphthalide derivative B is shown below:

[0051]

[0052] The synthesis route is shown in the following formula:

[0053]

[0054] Synthesis process:

[0055] Intermediate 1: Butylphthalide (0.5 eq) and anhydrous tetrahydrofuran (10.0 mL / g) were added to a reaction flask, and the system temperature was maintained at room temperature. Lithium aluminum hydride (1.0 eq) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 h, and monitored by TLC. The volume ratio of the TLC developing solvent was petroleum ether:ethyl acetate = 3:1. After the reaction was complete, the system temperature was maintained at room temperature, and water was slowly added dropwise until the system became a white suspension. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a yellow waxy intermediate 1, with a yield of 93.60%. MS (ESI) m / z: 195.4 [M+H]+.

[0056] Intermediate 2: Intermediate 1 (1.0 eq), dichloromethane (7.0 mL / g), 4-dimethylaminopyridine (0.1 eq), and diisopropylethylamine (2.5 eq) were added to a reaction flask. The system temperature was maintained at room temperature, and tert-butyldimethylchlorosilane (0.8 eq) was slowly added dropwise. After addition, the mixture was stirred at room temperature for 12 h, and monitored by TLC. The volume ratio of petroleum ether to ethyl acetate was 3:1. After the reaction was complete, the system was washed three times with water. A light yellow oily intermediate 2 was obtained, with a yield of 95.66%. MS (ESI) m / z: 309.8 [M+H]+.

[0057] Intermediate 7: Intermediate 2 (1.0 eq), N,N-dimethylformamide (10.0 ml / g), N,N-dicyclohexylcarboimide (1.5 eq), 4-dimethylaminopyridine (0.1 eq), and tert-butoxycarbonyl-L-alanine (2 eq) were added to a reaction flask and stirred at room temperature for 2 h. The reaction was monitored by TLC, with a TLC solvent ratio of petroleum ether:ethyl acetate = 10:1. After the reaction was complete, the mixture was filtered, the filtrate was diluted with dichloromethane, washed three times with water, and dried over anhydrous sodium sulfate to obtain a yellow oily intermediate 7. Based on the theoretical amount, it was directly added to the next step. MS (ESI) m / z: 481.2 [M+H] + .

[0058] Intermediate 8: Intermediate 7 (1.0 eq), tetrahydrofuran (10.0 ml / g), tetrabutylammonium fluoride trihydrate (2.0 eq), glacial acetic acid acid (2.0 eq) was added to a reaction flask and stirred at room temperature for 2 h. The reaction was monitored by TLC, with a petroleum ether:ethyl acetate volume ratio of 3:1. After the reaction was complete, the system was washed three times with water. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography using 200-mesh silica gel. The eluent volume ratio was petroleum ether:ethyl acetate = 3:1, and the eluent volume was 1.5 L. A pale yellow, oily, pure intermediate 8 was obtained, with a yield of 68.60%.

[0059] MS(ESI) m / z: 366.8 [M+H] + ;

[0060] 1 H NMR (400MHz, CDCl3); δppm 7.39-7.52(m,1H), 7.31-7.38(m,2H), 7.23-7.29(m,1H), 5.93-5.97(m,1H), 4.86-5.0 4(m,2H), 4.25-4.34(m,1H), 1.65-1.85(m,2H), 1.26-1.50(m,16H), 0.88-0.91(m,3H).

[0061] Intermediate 9: Intermediate 8 (1.0 eq), dichloromethane (10.0 mL / g), and manganese dioxide (7.5 eq) were added to a reaction flask and stirred overnight at room temperature under TLC monitoring (petroleum ether: ethyl acetate = 3:1). After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give a yellow oily product 9, with a yield of 96.58%. MS (ESI) m / z: 364.9 [M+H] + .

[0062] Intermediate 10: Intermediate 9 (1.0 eq), AcOH (5.0 ml / g), and aminosulfonic acid (1.5 eq) were added to a reaction flask, cooled to 10°C, and sodium chlorite (2.0 eq) was slowly added dropwise in an aqueous solution (1.5 ml / g). The mixture was stirred at this temperature for 1 h and monitored by TLC. The volume ratio of the TLC eluent was petroleum ether:ethyl acetate = 3:1. After the reaction was complete, the mixture was diluted with dichloromethane, and saturated sodium sulfite solution was added until the system turned pale yellow or colorless. The mixture was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined and washed twice with water and once with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography using 200-mesh silica gel. The volume ratio of the eluent was petroleum ether:ethyl acetate = 3:1, and the amount of eluent used was 3.0 L. The resulting pale yellow oily pure intermediate 10 was obtained, with a yield of 63.58%.

[0063] MS(ESI) m / z: 381.7 [M+H] + 378.1 [MH] - ;

[0064] 1H NMR (400MHz, CDCl3); δppm 7.98-8.01(m,1H), 7.50-7.53(m,1H), 7.36-7.39(m,1H), 7.27-7.32(m,1H), 5.13-5.15(m,1H), 4.09-4.1 1(m,1H), 1.70-1.73(m,2H), 1.30-1.45(m,12H), 1.23-1.25(m,2H), 1.10-1.21(m,2H), 0.86-0.91(m,3H).

[0065] Intermediate 11: Intermediate 10 (1.0 eq), tetrahydrofuran (10.0 mL / g), EDCI (1.5 eq), 4-dimethylaminopyridine (0.05 eq), and 2-camphenol (1.0 eq) were added to a reaction flask and stirred overnight at room temperature. The reaction was monitored by TLC, with a petroleum ether:ethyl acetate volume ratio of 3:1. After the reaction was complete, the mixture was filtered, the filtrate was diluted with dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, and purified by column chromatography using 200-mesh silica gel as the packing material. The eluent volume ratio was petroleum ether:ethyl acetate of 20:1, and the eluent volume was 2.0 L. A pale yellow oily pure intermediate 11 was obtained, with a yield of 59.87%.

[0066] MS(ESI) m / z: 517.0 [M+H] + ;

[0067] 1 H NMR (400MHz, CDCl3); δppm 7.90-7.92(d,J=8,1H), 7.48-7.54(m,2H), 7.30-7.35(m,1H), 6.61-6.65(m,1H), 5.11-5.15(m,2H), 2.45-2. 53(m,1H), 2.04-2.16(m,1H), 1.68-1.91(m,7H), 1.29-1.44(m,14H), 1.26-1.29(m,2H), 0.87-0.98(m,12H).

[0068] Butylphthalide derivative B: Intermediate 11 (1.0 eq), hydrogen chloride / dioxane solution (4 mol / L), and (4.0 mL / g) were added to a reaction flask and stirred at room temperature for 1 h. The reaction was monitored by TLC, with a TLC solvent ratio of petroleum ether:ethyl acetate = 10:1. After the reaction was complete, petroleum ether (10.0 mL / g) was added to the system, and the mixture was refrigerated overnight. The mixture was then filtered to obtain a white solid, butylphthalide derivative B, in 75.33% yield.

[0069] The purity of the synthesized butylphthalide derivative B was 99.9%, and the overall yield of the route was 17.01%. Figure 2 It is butylphthalide derivative B 1 H NMR spectrum.

[0070] MS(ESI) m / z: 452.3 [M+H] + .

[0071] 1 H NMR (400MHz, DMSO-d6); δppm 8.56(s,2H), 7.68-7.87(m,1H), 7.49-7.67(m,2H), 7.49-7.67(m,2H), 7.45-7.49(m,1H) ), 6.53-6.56(m,1H),, 5.07-5.09(d,1H,J=8), 4.12-4.17(m,1H), 2.39-2.47(m,1H), 1. 95-2.01(m,1H), 1.74-1.90(m,4H), 1.47-1.50(d,3H,J=12), 1.39-1.41(m,2H), 1.23-1 .35(m,4H), 1.10-1.11(d,1H,J=4), 0.95(s,3H),,0.88-0.91(m,6H), 0.84-0.86(m,3H).

[0072] Example 3 Synthesis of Butylphthalide Derivative C

[0073] The chemical formula of butylphthalide derivative C is shown below:

[0074]

[0075] The synthesis route is shown in the following formula:

[0076]

[0077] Synthesis process:

[0078] Intermediate 1: Butylphthalide (1.5 eq) and anhydrous tetrahydrofuran (10.0 mL / g) were added to a reaction flask, and the system temperature was maintained at room temperature. Lithium aluminum hydride (1.0 eq) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 h, and monitored by TLC. The volume ratio of the TLC developing solvent was petroleum ether:ethyl acetate = 3:1. After the reaction was complete, the system temperature was maintained at room temperature, and water was slowly added dropwise until the system became a white suspension. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a yellow waxy intermediate 1, with a yield of 93.60%. MS (ESI) m / z: 195.4 [M+H]+.

[0079] Intermediate 2: Intermediate 1 (1.0 eq), dichloromethane (7.0 mL / g), 4-dimethylaminopyridine (0.1 eq), and diisopropylethylamine (2.5 eq) were added to a reaction flask. The system temperature was maintained at room temperature, and tert-butyldimethylchlorosilane (1.2 eq) was slowly added dropwise. After addition, the mixture was stirred at room temperature for 12 h, and monitored by TLC. The volume ratio of petroleum ether to ethyl acetate was 3:1. After the reaction was complete, the system was washed three times with water. A light yellow oily intermediate 2 was obtained, with a yield of 95.66%. MS (ESI) m / z: 309.8 [M+H]+.

[0080] Intermediate 3: Intermediate 2 (1.0 eq), dichloromethane (10.0 mL / g), diisopropylethylamine (3.0 eq), and 4-dimethylaminopyridine (0.3 eq) were added to a 250 mL three-necked flask, and acetic anhydride (1.1 eq) was slowly added dropwise at room temperature. The reaction was stirred at room temperature for 5 h and monitored by TLC. After the reaction was complete, water was added to the system and stirred for 30 min. The mixture was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed twice with water, once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. A yellow oily intermediate 3 was obtained, with a yield of 90.19%. MS (ESI) m / z: 351.4 [M+H]+.

[0081] Intermediate 4: Intermediate 3 (1.0 eq), tetrahydrofuran (10.0 ml / g), and tetrabutylammonium fluoride trihydrate (2.5 eq) were added to a 250 ml three-necked flask and stirred at room temperature for 2 h, monitored by TLC. After the reaction was complete, water was added to the system and stirred for 30 min. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed twice with water, once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by column chromatography using 200-mesh silica gel, with a petroleum ether:ethyl acetate volume ratio of 10:1 and a eluent volume of 1.5 L. The final product was a light yellow oily intermediate 4, with a yield of 42.74%.

[0082] MS(ESI) m / z: 237.6 [M+H]+;

[0083] 1 H NMR (400MHz, CDCl3); δppm7.34-7.40(m,4H), 5.91-5.93(m,1H), 4.91-4.95( m,2H), 2.08(s,3H), 1.73-1.77(m,2H), 1.29-1.41(m,4H), 0.87-0.92(m,3H).

[0084] Intermediate 5: Intermediate 4 (1.0 eq), dichloromethane (10.0 mL / g), and manganese dioxide (7.0 eq) were added to a 250 mL three-necked flask and stirred overnight at room temperature under TLC monitoring. After the reaction was complete, the mixture was filtered, and the filter cake was washed with a small amount of dichloromethane. The system was evaporated to dryness to give a yellow oily intermediate 5, with a yield of 97.37%. MS (ESI) m / z: 235.2 [M+H]+.

[0085] Intermediate 6: Intermediate 5 (1.0 eq), glacial acetic acid (10.0 ml / g), and aminosulfonic acid (1.5 eq) were added to a 250 ml three-necked flask. The mixture was cooled in an ice-water bath at 0-5 °C, and sodium chlorite (2.0 eq) aqueous solution was slowly added dropwise. The reaction was maintained at this temperature with stirring for 1 h, and monitored by TLC. After the reaction was complete, water was added to the system, and the mixture was stirred for 30 min. The mixture was extracted twice with dichloromethane, and then washed with water until the pH of the aqueous phase reached 6. Finally, the mixture was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography using 300-mesh silica gel as the packing material. The eluent volume ratio was petroleum ether:ethyl acetate = 3:1, and the eluent volume was 3.0 L. The final product was a light yellow oily intermediate 6, with a yield of 50.79%.

[0086] MS(ESI)m / z: 251.4[M+H]+, 249.2[MH]-;

[0087] 1 H NMR (400MHz, CDCl3); δppm 8.00-8.02(m,1H), 7.52-7.58(m,2H), 7.34-7.40(m,1H), 6.53-6.56(m,2 H), 2.10(s,3H), 1.81-1.87(m,2H), 1.41-1.48(m,4H), 0.87-0.92(m,3H).

[0088] Intermediate 12: 2-Cambarol (1.0 eq), tetrahydrofuran (10.0 mL / g), and sodium hydride (1.2 eq) were added to a reaction flask and stirred at room temperature for 30 min. A catalytic amount of potassium iodide was added, followed by the slow dropwise addition of chloromethyl methyl sulfide (1.0 eq) and tetrahydrofuran solution. The mixture was stirred overnight at room temperature. TLC was monitored, with a petroleum ether:ethyl acetate volume ratio of 10:1. After the reaction was complete, a small amount of water was added to the system, and the mixture was stirred for 15 min. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed twice with a small amount of water. The crude product was purified by column chromatography, with color monitoring using potassium permanganate solution, yielding a pale yellow oily intermediate 12 in 33.45% yield.

[0089] 1H NMR (400MHz, CDCl3); δppm 4.68-4.71(m,2H), 3.91-3.97(m,1H), 2.14(s,3H), 1.91-1.99(m,1H), 1.6 2-1.77(m,2H), 1.06-1.28(m,2H), 1.02-1.05(m,2H), 0.85-0.99(m,12H).

[0090] Butylphthalide derivative C: Intermediate 12 (1.0 eq) and tetrahydrofuran (5.0 mL / g) were added to a 50 mL reaction flask, followed by a suspension of intermediate 6 (1.0 eq), N-iodosuccinimide (3.5 eq), and dichloromethane (5.0 mL / g). The mixture was stirred at room temperature for 3 h and monitored by TLC. The TLC eluent volume ratio was petroleum ether:ethyl acetate = 3:1. After the reaction was complete, the mixture was diluted with dichloromethane, washed once with saturated sodium sulfite solution, and then washed twice with saturated sodium chloride solution. The crude product was evaporated to dryness to obtain a yellow oily product. The product was purified by column chromatography using 300-mesh silica gel as the packing material and petroleum ether:ethyl acetate volume ratio of 30:1. The eluent volume was 2.0 L. The resulting pale yellow oily pure butylphthalide derivative C was obtained in 16.48% yield.

[0091] The purity of the synthesized butylphthalide derivative C was 98.0%, and the overall yield of the route was 2.81%. Figure 3 C is a butylphthalide derivative. 1 H NMR spectrum.

[0092] MS(ESI) m / z: 417.7 [M+H] + ;

[0093] 1 H NMR (400MHz, CDCl3); δppm 7.92-7.94(d, J=8,1H), 7.50-7.54(m,2H), 7.3-7.49(m,1H), 6.55-6.58(m,1H), 5.61-5.67(m,1H), 5.44 -5.49(m,1H), 3.94-3.99(m,1H), 20.9(s,3H),1.63-1.89(m,5H), 1.21-1.44(m,8H), 0.85-0.91(m,12H).

[0094] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a butylphthalide derivative, characterized in that, Includes the following steps: (1) Butylphthalide and lithium aluminum hydride were reacted in tetrahydrofuran to obtain intermediate 1; (2) Intermediate 1 reacts with tert-butyldimethylchlorosilane to give intermediate 2; (3) Intermediate 2 reacts with either acetic anhydride or tert-butoxycarbonyl-L-alanine, and the resulting product reacts with tetrabutylammonium fluoride trihydrate to obtain intermediate 3; (4) Intermediate 3 reacts with an oxidizing agent to give an aldehyde compound, which is further oxidized to give intermediate 4; (5) Intermediate 4 undergoes esterification with 2-camphenol or a 2-camphenol derivative to yield butylphthalide derivative. The preparation method of the 2-camphor derivative in step (5) includes reacting 2-camphor, sodium hydride, potassium iodide and chloromethyl methyl sulfide in a tetrahydrofuran solution; The structural formulas of intermediate 1 and intermediate 2 are as follows: 、 ； The structural formula of the butylphthalide derivative is selected from any one of the following: 、 、 。 2. The synthesis method according to claim 1, characterized in that, The ratio of butylphthalide, lithium aluminum hydride and tetrahydrofuran in step (1) is 0.5-1.5 mol: 1 mol: 8-12 mL / g, the reaction time is 0.5-1.5 h, and water is added after the reaction until the system becomes a suspension, then filtered, dried and evaporated.

3. The synthesis method according to claim 1, characterized in that, The solvent for the reaction in step (2) is dichloromethane.

4. The synthesis method according to claim 1, characterized in that, The oxidant in step (4) is selected from one or more of manganese dioxide, Dessmartin reagent, potassium permanganate and sodium hypochlorite. The reaction time of intermediate 3 with the oxidant is 8-12 h. The oxidant for further oxidation of the aldehyde compound includes aminosulfonic acid and sodium chlorite. The further oxidation time is 0.5-1.5 h. The molar ratio of intermediate 3 to oxidant is 1:6-9. The ratio of aldehyde compound, glacial acetic acid, aminosulfonic acid and sodium chlorite is 1 mol:8-12 mL / g:1-3 mol:1-3 mol.

5. The synthesis method according to claim 1, characterized in that, In step (5), the molar ratio of intermediate 4 to 2-camphenol is 1:1.5, the reaction time is 8-12 h, and when the butylphthalide derivative has an amino group, the butylphthalide derivative is further reacted with hydrogen chloride and / or dioxane solution. After the reaction, the product is filtered, washed, dried and purified.

6. The synthesis method according to claim 5, characterized in that, The ratio of the butylphthalide derivative to the hydrogen chloride / dioxane solution is 0.5-1.5g:1-10mL, and the concentration of the hydrogen chloride and / or dioxane solution is 3-5mol / L.

7. The synthesis method according to claim 1, characterized in that, The potassium iodide is used as a catalyst. The ratio of 2-camphenol, sodium hydride, chloromethyl methyl sulfide and tetrahydrofuran is 1 mol: 1-2 mol: 0.5-1.5 mol: 8-12 mL / g. After the reaction, water is added to the system, and the mixture is stirred for 10-20 min. The mixture is then separated into liquid and liquid phases. The aqueous phase is extracted with ethyl acetate 1-3 times, and the organic phase is washed with water 1-3 times. The mixture is purified, and the color is monitored by potassium permanganate solution.

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