CN117229144A - Synthesis process of butylphthalide derivative - Google Patents

Synthesis process of butylphthalide derivative Download PDF

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CN117229144A
CN117229144A CN202311203421.XA CN202311203421A CN117229144A CN 117229144 A CN117229144 A CN 117229144A CN 202311203421 A CN202311203421 A CN 202311203421A CN 117229144 A CN117229144 A CN 117229144A
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butylphthalide
derivative
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程增江
赵京华
王颢卓
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Corbeille Park Beijing Medical Technology Co ltd
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Corbeille Park Beijing Medical Technology Co ltd
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Abstract

The invention relates to the field of pharmaceutical chemical synthesis, in particular to a synthesis process of a butylphthalide derivative. The synthesis method of the butylphthalide derivative comprises the steps of mixing butylphthalide and lithium aluminum hydride in tetrahydrofuran, reacting with tert-butyl dimethyl chlorosilane, reacting with acid and tetrabutylammonium fluoride trihydrate, esterifying with 2-camphol or the derivative thereof after oxidation, and purifying to obtain the butylphthalide derivative. The synthesis method has the characteristics of mild condition, simple operation, less side reaction, strong selectivity, better industrial adaptability of the prepared butylphthalide derivative and high purity of the finished product.

Description

Synthesis process of butylphthalide derivative
Technical Field
The invention belongs to the field of chemical synthesis, and in particular relates to a synthesis process of a butylphthalide derivative.
Background
Butylphthalide, also known as 3-butyl-1 (3H) -isobenzofuranone (NBP), also known as apigenin, is one of the more widely used drugs for treating cerebral ischemia. Pharmacodynamic researches show that butylphthalide can reduce infarct focus after focal cerebral ischemia, increase cerebral blood flow in ischemic areas and improve microcirculation in cerebral ischemic areas, has strong cerebral ischemia resisting effect, can obviously reduce cerebral ischemia infarct area of rats, lighten cerebral edema, improve cerebral energy metabolism and cerebral ischemia microcirculation and blood flow, has the effects of resisting cerebral thrombosis and platelet aggregation, and is mainly used for treating light and medium acute ischemic cerebral apoplexy clinically. Although butylphthalide can act on a plurality of pathological links of cerebral ischemia, the overall curative effect is not high, so that the butylphthalide is often combined with other medicines to achieve the curative effect. In addition, the poor water solubility of the butylphthalide is also an important reason for limiting the wide application of the butylphthalide in treating acute cerebral ischemia and other diseases, derivatization of the butylphthalide, multiple functions with other substances with related effects are realized, and even the derivative is salified to enhance the water solubility of the compound, so that the butylphthalide is a new idea for fully exerting the effects of butylphthalide substances, and the effects of prolonging the advantages, avoiding the disadvantages and reducing the dosage are achieved.
The invention discloses a butylphthalide derivative and a preparation method and application thereof, and the invention provides a preparation method of the butylphthalide derivative, which comprises the following steps: the invention relates to a method for preparing a target compound butylphthalide derivative, which comprises the steps of demethylating anethol trithione (ADT) under alkaline condition with a certain temperature, then saponifying (S) -or (R) -NBP in a solvent, acidifying to prepare a lactone ring-opening compound (S) or (R) -HPBA, then mixing with alkyl chloride, hydrogen sulfide donor ADTOH and a condensing agent, and esterifying to obtain the target compound butylphthalide derivative. Another chinese patent application CN113292524a discloses a butylphthalide derivative and its application in preparing a medicament for protecting nerve cells, and the invention provides an application of butylphthalide derivative or a pharmaceutical composition comprising the same in preparing a medicament for preventing and/or treating diseases related to cell injury and neurodegenerative diseases. However, the synthesis method of the butylphthalide derivative is that the butylphthalide is hydrolyzed and then subjected to condensation, esterification and other reactions, and the hydrolyzed 2- (1-hydroxypentyl) benzoic acid is unstable and is easy to re-cyclize to generate the butylphthalide, so that the subsequent condensation reaction yield is lower.
Therefore, in order to meet the requirements of the pharmaceutical industry of butylphthalide derivatives, there is an urgent need to provide a synthesis process of butylphthalide derivatives with less side reactions and mild conditions.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a synthesis process of a butylphthalide derivative.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a synthesis method of a butylphthalide derivative, which is characterized by comprising the following steps:
(1) Reacting butylphthalide and lithium aluminum hydride in tetrahydrofuran to obtain an intermediate 1;
(2) Intermediate 1 reacts with tert-butyldimethylchlorosilane to form intermediate 2;
(3) The intermediate 2 is subjected to condensation reaction with acid to obtain a condensation product, and the condensation product is subjected to reaction with tetrabutylammonium fluoride trihydrate to obtain an intermediate 3;
(4) Reacting the intermediate 3 with an oxidant to obtain an aldehyde compound, and further oxidizing the aldehyde compound to obtain an intermediate 4;
(5) And the intermediate 4 and 2-camphene or 2-camphene derivative are subjected to esterification reaction to obtain butylphthalide derivative.
Preferably, in the step (1), the ratio of the butylphthalide to the lithium aluminum hydride to the tetrahydrofuran is 0.5-1.5mol:1mol:8-12mL/g, the reaction time is 0.5-1.5h, water is also required to be added until the system becomes suspension after the reaction, and then the suspension is filtered, dried and spun-dried.
Preferably, the solvent for the reaction in the step (2) comprises dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine, the reaction time is 10-14h, water washing is further carried out after the reaction, and the ratio of the intermediate 1, tertiary butyl dimethylchlorosilane, dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine is 1mol:0.8-1.2mol:6-9mL/g:0.05-0.15mol:2-3mol.
Preferably, in the step (3), the acid is selected from any one of acetic anhydride and butoxycarbonyl-L-alanine, the molar ratio of the intermediate 2 to the acid is 1:1.1-2, the molar ratio of the condensation product to tetrabutylammonium fluoride trihydrate is 1:1-3, the reaction time of the condensation product and tetrabutylammonium fluoride trihydrate is 2-5h, water is further added into the system for stirring for 20-40min after the condensation reaction, dichloromethane is added for extraction for 1-3 times, water is used for washing for 1-3 times, saturated NaCl solution is used for washing for 1-3 times, and finally drying and purification are carried out.
Preferably, in the step (4), the oxidizing agent is selected from one or more of manganese dioxide, dess-martin reagent, potassium permanganate and sodium hypochlorite, the reaction time of the intermediate 3 and the oxidizing agent is 8-12h, the oxidizing agent for further oxidation of the aldehyde compound comprises glacial acetic acid, sulfamic acid and sodium chlorite, the further oxidation time is 0.5-1.5h, the molar ratio of the intermediate 3 to the oxidizing agent is 1:6-9, and the ratio of the aldehyde compound, glacial acetic acid, sulfamic acid and sodium chlorite is 1mol:8-12mL/g and 1-3mol.
Preferably, in the step (5), the molar ratio of the intermediate 4 to the 2-camphene is 1:1.5, the reaction time is 8-12 hours, the butylphthalide derivative has an amino group, and the butylphthalide derivative is further reacted with hydrogen chloride and/or dioxane solution, and the reaction is followed by filtration, washing, drying and purification.
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.
Preferably, the preparation method of the 2-camphene derivative in the step (5) comprises the step of reacting 2-camphene, sodium hydride, potassium iodide and chloromethyl methyl sulfide in tetrahydrofuran solution.
Preferably, the potassium iodide is used as a catalyst, the proportion of the 2-camphol, the sodium hydride, the chloromethyl methyl sulfide and the tetrahydrofuran is 1mol:1-2mol:0.5-1.5mol:8-12mL/g, water is added into the system after the reaction, stirring is carried out for 10-20min, the solution is separated, the aqueous phase is extracted for 1-3 times by ethyl acetate, the organic phase is washed for 1-3 times by water, and the solution is purified and monitored by color development of the potassium permanganate solution.
Preferably, all reactions in each step are monitored by TLC, the developing agent adopted by TLC is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3-10:1, the reaction temperature is 0-5 ℃ except for the reaction temperature in the step (4), the reaction temperature in the rest step is 20-25 ℃, the dried reagent is anhydrous sodium sulfate, the purification is column chromatography purification, the chromatographic column packing adopted by the purification is 200-300 meshes of silica gel, the eluent adopted by the purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3-30:1, and the using amount of the eluent is 1.2-3L.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthesis process of butylphthalide derivative, which has mild process conditions, simple operation, less side reaction and strong selectivity, and can avoid the problem of lower purity of the final product caused by re-cyclization of butylphthalide in the subsequent reaction after the butylphthalide is hydrolyzed into 2- (1-hydroxypentyl) formic acid.
Drawings
FIG. 1 shows a butylphthalide derivative A 1 H NMR chart.
FIG. 2 shows a butylphthalide derivative B 1 H NMR chart.
FIG. 3 shows a butylphthalide derivative C 1 H NMR chart.
It is noted that the clarity of the drawings does not affect the understanding of the technical solution of the invention by a person skilled in the art.
Detailed Description
It is worth noting that the raw materials used in the invention are all common commercial products.
EXAMPLE 1 Synthesis of Butylphthalide derivative A
The chemical formula of the butylphthalide derivative A is shown as follows:
the synthetic route is shown in the following formula:
the synthesis process comprises the following steps:
intermediate products1: butylphthalide (1.0 eq), anhydrous tetrahydrofuran (10.0 ml/g) was charged into a reaction flask, the system temperature was kept at room temperature, and lithium aluminum hydride (1.0 eq) was slowly charged. After the addition, stirring for 1h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction, keeping the temperature of the system at room temperature, and slowly dripping water until the system becomes white suspension. Suction filtration, drying of the filtrate over anhydrous sodium sulfate, spin drying gave yellow waxy intermediate 1 in 93.60% yield. MS (ESI) m/z:195.4[ M+H ]] + 。
Intermediate 2: intermediate 1 (1.0 eq), methylene chloride (7.0 ml/g), 4-dimethylaminopyridine (0.1 eq), diisopropylethylamine (2.5 eq) were charged into a reaction flask, the temperature of the system was kept at room temperature, and tert-butyldimethylchlorosilane (1.02 eq) was slowly added dropwise. After the addition, stirring for 12h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction was completed, the system was washed three times with water. Intermediate 2 was obtained as a pale yellow oil in 95.66% yield. MS (ESI) m/z:309.8[ M+H ]] + 。
Intermediate 3: intermediate 2 (1.0 eq), dichloromethane (10.0 ml/g), diisopropylethylamine (3.0 eq), 4-dimethylaminopyridine (0.3 eq) were placed in a 250ml three-necked flask and acetic anhydride (2.0 eq) was slowly added dropwise at room temperature. The reaction was stirred at room temperature for 5h and monitored by tlc. After the reaction, water was added to the system and stirred for 30min. The solution was separated and the aqueous phase was extracted 1 time with dichloromethane. The organic phases were combined, washed with water 2 times, saturated NaCl solution 1 time, dried over anhydrous sodium sulfate, and spun-dried. Intermediate 3 was obtained as a yellow oil in 90.19% yield. MS (ESI) m/z:351.4[ M+H ]] + 。
Intermediate 4: intermediate 3 (1.0 eq), tetrahydrofuran (10.0 ml/g), tetrabutylammonium fluoride trihydrate (2.0 eq) were placed in a 250ml three-necked flask and stirred at room temperature for 2h, monitored by TLC. After the reaction, water was added to the system and stirred for 30min. The solution was separated and the aqueous phase was extracted 2 times with dichloromethane. The organic phases were combined, washed with water 2 times, saturated NaCl solution 1 time, dried over anhydrous sodium sulfate, and spun-dried. Purifying by column chromatography, wherein the adopted chromatographic column filler is 200 meshes of silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 10:1, eluent was used in an amount of 1.2L, finally obtaining intermediate 4 as a pale yellow oil in a yield of 42.74%.
MS(ESI)m/z：237.6[M+H] + ；
1 H NMR(400MHz,CDCl 3 )；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)。
Intermediate 5: intermediate 4 (1.0 eq), methylene chloride (10.0 ml/g), mnO 2 (7.0 eq) was placed in a 250ml three-necked flask and the reaction was stirred overnight at room temperature, monitored by TLC. After the reaction was completed, the mixture was filtered, and the cake was rinsed with a small amount of dichloromethane. The system was dried by spin to give intermediate 5 as a yellow oil in 97.37% yield. MS (ESI) m/z:235.2[ M+H ]] + 。
Intermediate 6: intermediate 5 (1.0 eq), glacial acetic acid (10.0 ml/g), sulfamic acid (1.5 eq) were put into a 250ml three-necked flask, the temperature was reduced by 0-5 ℃ in an ice-water bath, an aqueous solution of sodium chlorite (2.0 eq) was slowly added dropwise, the temperature was maintained and the reaction was stirred for 1h, monitored by tlc. After the reaction, water was added to the system and stirred for 30min. Dichloromethane was added to extract twice, the organic phase was washed with water to ph=6, finally with saturated NaCl solution for 1 time, dried over anhydrous sodium sulfate and spun dry. Purifying by column chromatography, wherein the adopted chromatographic column filler is 200 meshes of silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 3:1, eluent was used in an amount of 2.5L, finally obtaining intermediate 6 as a pale yellow oil in a yield of 50.79%.
MS(ESI)m/z：251.4[M+H] + ，249.2[M-H] - ；
1 H NMR(400MHz,CDCl 3 )；δppm 8.00-8.02(m,1H)，7.52-7.58(m,2H)，7.34-7.40(m,1H)，6.53-6.56(m,2H)，2.10(s,3H)，1.81-1.87(m,2H)，1.41-1.48(m,4H)，0.87-0.92(m,3H)。
Butylphthalide derivative a: intermediate 6 (1.0 eq), dichloromethane (10.0 ml/g), N, N-dicyclohexylcarbodiimide (1.5 eq), 4-dimethylaminopyridine (0.3 eq), 2-camphol (1.5 eq) were put into a reaction flask, stirred overnight at room temperature, monitored by TLC, the volume ratio of TLC developing agent was petroleum ether: ethyl acetate=3:1. After the reaction is finished, filtering, diluting filtrate with dichloromethane, washing with water for three times, drying with anhydrous sodium sulfate, purifying by column chromatography, wherein the adopted chromatographic column filler is 300-mesh silica gel, and the volume ratio of eluent is petroleum ether: ethyl acetate = 20:1, the dosage of the eluent is 2.5L, and the pale yellow solid butylphthalide derivative A is obtained, and the yield is 47.73%.
The purity of the synthesized butylphthalide derivative A is 98.2%, the total route yield is 8.15%, wherein the butylphthalide derivative A is shown in figure 1 1 H NMR chart.
MS(ESI)m/z：387.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )；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)。
EXAMPLE 2 Synthesis of Butylphthalide derivative B
The chemical formula of the butylphthalide derivative B is shown as follows:
the synthetic route is shown in the following formula:
the synthesis process comprises the following steps:
intermediate 1: butylphthalide (0.5 eq), anhydrous tetrahydrofuran (10.0 ml/g) was charged into a reaction flask, the system temperature was kept at room temperature, and lithium aluminum hydride (1.0 eq) was slowly charged. After the addition, stirring for 1h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction, keeping the temperature of the system at room temperature, and slowly dripping water until the system becomes white suspension. Suction filtration, drying of the filtrate over anhydrous sodium sulfate, spin drying gave yellow waxy intermediate 1 in 93.60% yield. MS (ESI) m/z:195.4[ M+H ] +.
Intermediate 2: intermediate 1 (1.0 eq), methylene chloride (7.0 ml/g), 4-dimethylaminopyridine (0.1 eq), diisopropylethylamine (2.5 eq) were charged into a reaction flask, the temperature of the system was kept at room temperature, and tert-butyldimethylchlorosilane (0.8 eq) was slowly added dropwise. After the addition, stirring for 12h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction was completed, the system was washed three times with water. Intermediate 2 was obtained as a pale yellow oil in 95.66% yield. MS (ESI) m/z:309.8[ M+H ] +.
Intermediate 7: intermediate 2 (1.0 eq), N, N-dimethylformamide (10.0 ml/g), N, N-dicyclohexylcarbodiimide (1.5 eq), 4-dimethylaminopyridine (0.1 eq), t-butoxycarbonyl-L-alanine (2 eq) were put into a reaction flask, stirred at room temperature for 2h, monitored by TLC, the volume ratio of TLC developing agent being petroleum ether: ethyl acetate=10:1. After the reaction, the mixture was filtered, the filtrate was diluted with dichloromethane, washed three times with water and dried over anhydrous sodium sulfate to give intermediate 7 as a yellow oil, which was calculated on a theoretical basis and taken directly to the next step. MS (ESI) m/z:481.2[ M+H ]] + 。
Intermediate 8: intermediate 7 (1.0 eq), tetrahydrofuran (10.0 ml/g), tetrabutylammonium fluoride trihydrate (2.0 eq), glacial acetic acidAcid(s)(2.0 eq) was placed in a reaction flask, stirred at room temperature for 2h, monitored by TLC, the volume ratio of TLC developing agent was petroleum ether: ethyl acetate=3:1. After the reaction was completed, the system was washed three times with water. The organic phase is dried by anhydrous sodium sulfate, and is purified by column chromatography, wherein the adopted chromatographic column filler is 200-mesh silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 3:1, eluent was used in an amount of 1.5L to give intermediate 8 as a pale yellow oily pure product in a yield of 68.60%.
MS(ESI)m/z：366.8[M+H] + ；
1 H NMR(400MHz,CDCl 3 )；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)，4.86-5.04(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)。
Intermediate 9: intermediate 8 (1.0 eq), methylene chloride (10.0 ml/g), manganese dioxide (7.5 eq) were put into a reaction flask and stirred overnight at room temperature, monitored by TLC (petroleum ether: ethyl acetate=3:1). After the reaction, suction filtration is carried out, and the filtrate is dried by spin to obtain the yellow oily product 9 with the yield of 96.58 percent. MS (ESI) m/z:364.9[ M+H ]] + 。
Intermediate 10: intermediate 9 (1.0 eq), acOH (5.0 ml/g), sulfamic acid (1.5 eq) were placed in a reaction flask, cooled to 10℃and slowly added dropwise with a solution of sodium chlorite (2.0 eq) in water (1.5 ml/g). Stirring for 1h under heat preservation, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction, the mixture was diluted with methylene chloride, and a saturated sodium sulfite solution was added until the system became pale yellow or colorless. Separating, extracting the aqueous phase with dichloromethane once, combining the organic phases, washing with water twice, washing with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, purifying by column chromatography, wherein the adopted chromatographic column packing is 200-mesh silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 3:1, eluent was used in an amount of 3.0L to give intermediate 10 as a pale yellow oily pure product in 63.58% yield.
MS(ESI)m/z：381.7[M+H] + ，378.1[M-H] - ；
1 H NMR(400MHz,CDCl 3 )；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)，4.09-4.11(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)。
Intermediate 11: intermediate 10 (1.0 eq), tetrahydrofuran (10.0 ml/g), EDCI (1.5 eq), 4-dimethylaminopyridine (0.05 eq), 2-camphol (1.0 eq) were put into a reaction flask, stirred overnight at room temperature, monitored by TLC, the volume ratio of TLC developing solvent was petroleum ether: ethyl acetate=3:1. After the reaction is finished, filtering, diluting filtrate with dichloromethane, washing with water for three times, drying with anhydrous sodium sulfate, purifying by column chromatography, wherein the adopted chromatographic column filler is 200-mesh silica gel, and the volume ratio of eluent is petroleum ether: ethyl acetate = 20:1, eluent was used in an amount of 2.0L to give intermediate 11 as a pale yellow oily pure product in 59.87% yield.
MS(ESI)m/z：517.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )；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)。
Butylphthalide derivative B: intermediate 11 (1.0 eq), hydrogen chloride/dioxane solution (4 mol/L), (4.0 ml/g) was put into a reaction flask and stirred for 1h at room temperature, monitored by TLC, the volume ratio of TLC developing agent being petroleum ether: ethyl acetate=10:1. Petroleum ether (10.0 ml/g) was added to the system after the reaction was completed, and the mixture was refrigerated overnight. Suction filtration to obtain white solid butylphthalide derivative B with a yield of 75.33%.
The purity of the synthesized butylphthalide derivative B is 99.9%, the total route yield is 17.01%, and the butylphthalide derivative B is shown in figure 2 1 H NMR chart.
MS(ESI)m/z：452.3[M+H] + 。
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)。
EXAMPLE 3 Synthesis of Butylphthalide derivative C
The chemical formula of the butylphthalide derivative C is shown as follows:
the synthetic route is shown in the following formula:
the synthesis process comprises the following steps:
intermediate 1: butylphthalide (1.5 eq), anhydrous tetrahydrofuran (10.0 ml/g) was charged into a reaction flask, the system temperature was kept at room temperature, and lithium aluminum hydride (1.0 eq) was slowly charged. After the addition, stirring for 1h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction, keeping the temperature of the system at room temperature, and slowly dripping water until the system becomes white suspension. Suction filtration, drying of the filtrate over anhydrous sodium sulfate, spin drying gave yellow waxy intermediate 1 in 93.60% yield. MS (ESI) m/z:195.4[ M+H ] +.
Intermediate 2: intermediate 1 (1.0 eq), methylene chloride (7.0 ml/g), 4-dimethylaminopyridine (0.1 eq): diisopropylethylamine (2.5 eq) was charged into a reaction flask, the temperature of the system was kept at room temperature, and t-butyldimethylchlorosilane (1.2 eq) was slowly added dropwise. After the addition, stirring for 12h at room temperature, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction was completed, the system was washed three times with water. Intermediate 2 was obtained as a pale yellow oil in 95.66% yield. MS (ESI) m/z:309.8[ M+H ] +.
Intermediate 3: intermediate 2 (1.0 eq), dichloromethane (10.0 ml/g), diisopropylethylamine (3.0 eq), 4-dimethylaminopyridine (0.3 eq) were placed in a 250ml three-necked flask and acetic anhydride (1.1 eq) was slowly added dropwise at room temperature. The reaction was stirred at room temperature for 5h and monitored by tlc. After the reaction, water was added to the system and stirred for 30min. The solution was separated and the aqueous phase was extracted 1 time with dichloromethane. The organic phases were combined, washed with water 2 times, saturated NaCl solution 1 time, dried over anhydrous sodium sulfate, and spun-dried. Intermediate 3 was obtained as a yellow oil in 90.19% yield. MS (ESI) m/z:351.4[ M+H ] +.
Intermediate 4: intermediate 3 (1.0 eq), tetrahydrofuran (10.0 ml/g), tetrabutylammonium fluoride trihydrate (2.5 eq) were placed in a 250ml three-necked flask and stirred at room temperature for 2h, monitored by TLC. After the reaction, water was added to the system and stirred for 30min. The solution was separated and the aqueous phase was extracted 2 times with dichloromethane. The organic phases were combined, washed with water 2 times, saturated NaCl solution 1 time, dried over anhydrous sodium sulfate, and spun-dried. Purifying by column chromatography, wherein the adopted chromatographic column filler is 200 meshes of silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 10:1, eluent in an amount of 1.5L, to finally give intermediate 4 as a pale yellow oil in a yield of 42.74%.
MS(ESI)m/z：237.6[M+H]+；
1 H NMR(400MHz,CDCl 3 )；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)。
Intermediate 5: intermediate 4 (1.0 eq), methylene chloride (10.0 ml/g), manganese dioxide (7.0 eq) were put into a 250ml three-necked flask and reacted overnight with stirring at room temperature, monitored by TLC. After the reaction was completed, the mixture was filtered, and the cake was rinsed with a small amount of dichloromethane. The system was dried by spin to give intermediate 5 as a yellow oil in 97.37% yield. MS (ESI) m/z:235.2[ M+H ] +.
Intermediate 6: intermediate 5 (1.0 eq), glacial acetic acid (10.0 ml/g), sulfamic acid (1.5 eq) were put into a 250ml three-necked flask, the temperature was reduced by 0-5 ℃ in an ice-water bath, an aqueous solution of sodium chlorite (2.0 eq) was slowly added dropwise, the temperature was maintained and the reaction was stirred for 1h, monitored by tlc. After the reaction, water was added to the system and stirred for 30min. Dichloromethane was added to extract twice, the organic phase was washed with water to ph=6, finally with saturated NaCl solution for 1 time, dried over anhydrous sodium sulfate and spun dry. Purifying by column chromatography, wherein the adopted chromatographic column filler is 300 mesh silica gel, and the volume ratio of the eluent is petroleum ether: ethyl acetate = 3:1, eluent was used in an amount of 3.0L, finally obtaining intermediate 6 as a pale yellow oil in a yield of 50.79%.
MS(ESI)m/z：251.4[M+H]+，249.2[M-H]-；
1 H NMR(400MHz,CDCl 3 )；δppm 8.00-8.02(m,1H)，7.52-7.58(m,2H)，7.34-7.40(m,1H)，6.53-6.56(m,2H)，2.10(s,3H)，1.81-1.87(m,2H)，1.41-1.48(m,4H)，0.87-0.92(m,3H)。
Intermediate 12: 2-camphol (1.0 eq), tetrahydrofuran (10.0 ml/g) and sodium hydride (1.2 eq) were put into a reaction flask, stirred at room temperature for 30min, a catalytic amount of potassium iodide was added, chloromethyl methyl sulfide (1.0 eq) and tetrahydrofuran solution were slowly added dropwise, and stirred at room temperature overnight. TLC monitoring, the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=10:1. After the reaction, a small amount of water was added to the system and stirred for 15min. The mixture was separated, and the aqueous phase was extracted with ethyl acetate 2 times. The organic phases were combined and washed with a small amount of water 2 more times. The crude product was purified by column chromatography and monitored for color development in potassium permanganate solution to give intermediate 12 as a pale yellow oil in 33.45% yield.
1 H NMR(400MHz,CDCl 3 )；δppm 4.68-4.71(m,2H)，3.91-3.97(m,1H)，2.14(s,3H)，1.91-1.99(m,1H)，1.62-1.77(m,2H)，1.06-1.28(m,2H)，1.02-1.05(m,2H)，0.85-0.99(m,12H)。
Butylphthalide derivative C: intermediate 12 (1.0 eq), tetrahydrofuran (5.0 ml/g) were placed in a 50ml reaction flask, and a suspension of intermediate 6 (1.0 eq), N-iodosuccinimide (3.5 eq) and dichloromethane (5.0 ml/g) was placed in the flask. Stirring at room temperature for 3h, monitoring by TLC, wherein the volume ratio of the TLC developing agent is petroleum ether: ethyl acetate=3:1. After the reaction, methylene chloride was added to dilute the mixture, and the mixture was washed once with a saturated sodium sulfite solution and then with a saturated sodium chloride solution for 2 times. Spin-drying to obtain yellow oily crude product, purifying by column chromatography, wherein the adopted chromatographic column filler is 300 mesh silica gel, and the volume ratio of eluent is petroleum ether: ethyl acetate = 30:1, the dosage of the eluent is 2.0L, and the pale yellow oily pure butylphthalide derivative C is obtained, and the yield is 16.48%.
The purity of the synthesized butylphthalide derivative C is 98.0%, the total route yield is 2.81%, wherein, figure 3 shows the butylphthalide derivative C 1 H NMR chart.
MS(ESI)m/z：417.7[M+H] + ；
1 H NMR(400MHz,CDCl 3 )；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)。
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. A synthesis method of a butylphthalide derivative, which is characterized by comprising the following steps:
(1) Reacting butylphthalide and lithium aluminum hydride in tetrahydrofuran to obtain an intermediate 1;
(2) Intermediate 1 reacts with tert-butyldimethylchlorosilane to form intermediate 2;
(3) The intermediate 2 is subjected to condensation reaction with acid to obtain a condensation product, and the condensation product is subjected to reaction with tetrabutylammonium fluoride trihydrate to obtain an intermediate 3;
(4) Reacting the intermediate 3 with an oxidant to obtain an aldehyde compound, and further oxidizing the aldehyde compound to obtain an intermediate 4;
(5) And the intermediate 4 and 2-camphene or 2-camphene derivative are subjected to esterification reaction to obtain butylphthalide derivative.
2. The synthesis method according to claim 1, wherein the ratio of butylphthalide, lithium aluminum hydride and tetrahydrofuran in the step (1) is 0.5-1.5mol:1mol:8-12mL/g, the reaction time is 0.5-1.5h, and water is added after the reaction until the system becomes suspension, and then the suspension is filtered, dried and spun-dried.
3. The synthetic method according to claim 1, wherein the solvent for the reaction in the step (2) comprises dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine, the reaction time is 10-14 hours, water washing is further performed after the reaction, and the ratio of the intermediate 1, t-butyldimethylchlorosilane, dichloromethane, 4-dimethylaminopyridine and diisopropylethylamine is 1mol:0.8-1.2mol:6-9mL/g:0.05-0.15mol:2-3mol.
4. The method according to claim 1, wherein in the step (3), the acid is selected from any one of acetic anhydride and butoxycarbonyl-L-alanine, the molar ratio of the intermediate 2 to the acid is 1:1.1-2, the molar ratio of the condensation product to tetrabutylammonium fluoride trihydrate is 1:1-3, the reaction time of the condensation product and tetrabutylammonium fluoride trihydrate is 2-5 hours, water is added into the system for stirring for 20-40min after the condensation reaction, dichloromethane is added for extraction 1-3 times, water is used for washing 1-3 times, saturated NaCl solution is used for washing 1-3 times, and finally drying and purifying are carried out.
5. The synthetic method according to claim 1, wherein the oxidizing agent in the step (4) is selected from one or more of manganese dioxide, dess-martin reagent, potassium permanganate and sodium hypochlorite, the intermediate 3 is reacted with the oxidizing agent for 8 to 12 hours, the oxidizing agent for further oxidation of the aldehyde compound comprises glacial acetic acid, sulfamic acid and sodium chlorite, the further oxidation time is 0.5 to 1.5 hours, the molar ratio of the intermediate 3 to the oxidizing agent is 1:6 to 9, and the ratio of the aldehyde compound, glacial acetic acid, sulfamic acid and sodium chlorite is 1mol:8 to 12mL/g:1 to 3mol.
6. The synthesis method according to claim 1, wherein the molar ratio of the intermediate 4 to 2-borneol in the step (5) is 1:1.5, the reaction time is 8-12h, the butylphthalide derivative has an amine group, the butylphthalide derivative is further reacted with hydrogen chloride and/or dioxane solution, and the reaction is followed by filtration, washing, drying and purification.
7. The method according to claim 6, wherein the ratio of the butylphthalide derivative to the hydrogen chloride/dioxane solution is 0.5-1.5 g/1-10 mL, and the concentration of the hydrogen chloride and/or dioxane solution is 3-5mol/L.
8. The synthesis method according to claim 1, wherein the preparation method of the 2-borneol derivative in the step (5) comprises the step of reacting 2-borneol, sodium hydride, potassium iodide and chloromethyl methyl sulfide in tetrahydrofuran solution.
9. The synthesis method according to claim 8, wherein the potassium iodide is used as a catalyst, the ratio of 2-camphol, sodium hydride, chloromethyl methyl sulfide and tetrahydrofuran is 1mol:1-2mol:0.5-1.5mol:8-12mL/g, water is further added into the system after the reaction, stirring is carried out for 10-20min, liquid separation is carried out, the aqueous phase is extracted for 1-3 times by ethyl acetate, the organic phase is washed for 1-3 times by water, purification is carried out, and the color development of the potassium permanganate solution is monitored.
10. The method according to any one of claims 1 to 9, wherein all reactions in each step are monitored by TLC using a mixture of petroleum ether and ethyl acetate in a volume ratio of 3 to 10:1 as developing agent, the reaction temperature is 20 to 25 ℃ except for the reaction temperature in step (4), the dried reagent is anhydrous sodium sulfate, the purification is column chromatography purification, the chromatographic column packing used in the purification is 200 to 300 mesh silica gel, the eluent used in the purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3 to 30:1, and the eluent is used in an amount of 1.2 to 3.0L.
CN202311203421.XA 2023-09-18 2023-09-18 Synthesis process of butylphthalide derivative Pending CN117229144A (en)

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