An allylphthalide compound, its preparation method and application

Abstract

This invention discloses an allylphthalide compound and its preparation method. 3-hydroxyisobenzofuran-1(3H)-one and allyl borate pinacol ester are added to water, stirred, and reacted to obtain a reaction solution. This solution is then separated and purified to obtain the final product. Compared with existing technologies, the preparation method of this invention is carried out in an aqueous phase, requiring no metal catalyst. Furthermore, the reaction conditions are mild, and the substrate is highly versatile. Various 3-hydroxyisobenzofuran-1(3H)-ones with different functional group modifications can be rapidly allylated in high yields. In addition, the aqueous phase synthesis method greatly simplifies the chemical synthesis steps, improves the synthesis efficiency, and contributes to the sustainable development of chemistry in the future, possessing potential application value for fine chemistry and industrial production. The allylphthalide compounds of this invention can utilize their allyl and phthalide moieties as building blocks for various derivatizations in organic synthesis, showing great application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to an allylphthalide compound, its preparation method, and its application. Background Technology

[0002] The phthalide molecular skeleton is widely found in nature and is also the core skeleton of many clinical drugs. For example, mycophenolic acid (MPA) is an immunosuppressant used to treat autoimmune diseases and prevent organ transplant rejection. Furthermore, modifications at the C3 position, such as spirolaxine, can be used for the antibacterial treatment of Helicobacter pylori. Even simple methyl or n-butyl substitutions at the C3 position, such as n-butylphthalide (NBP), can inhibit platelet aggregation, improve microcirculation, and reduce ischemic brain injury, making it a drug for treating ischemic stroke and already approved in my country as an anti-ischemic stroke treatment.

[0003] The introduction of allyl functional groups can provide diverse transformation pathways for the phthalide skeleton, which is beneficial for its further development. Over the past few decades, researchers have been dedicated to developing more efficient, green, and sustainable methods for synthesizing 3-substituted phthalide compounds, including biocatalysis, metal-catalyzed transfer hydrogenation, aldol reactions, ketone hydrogenation and acylation, addition reactions, and cyclization reactions. These methods have greatly promoted the rapid construction of 3-allyl phthalides. Currently, 3-allyl phthalides are generally synthesized using o-formylbenzoate or o-carboxybenzaldehyde and allylating agents. However, these methods generally suffer from harsh reaction conditions and are mostly designed for single target compounds, lacking applicability. Furthermore, the pre-modification steps in these methods cause additional waste and environmental pollution.

[0004] Compared to traditional reaction solvents (organic solvents), water has natural advantages as a reaction solvent. Firstly, water itself is very safe, inexpensive, and pollution-free, aligning with the development philosophy of modern green chemistry. Aqueous synthesis methods greatly simplify chemical synthesis steps, improve synthesis efficiency, and contribute to the sustainable development of chemistry in the future. Therefore, the most ideal way to construct 3-allylphthalene is to use water as a solvent, utilizing 3-hydroxyisobenzofuran-1(3H)-one and allyl borate pinacol ester. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide an allylphthalide compound and its preparation method.

[0006] Another objective of this invention is to provide applications of the above-mentioned allylphthalide compounds.

[0007] Technical solution

[0008] An allylphthalide compound, the structural formula of which is shown in formula (I):

[0009]

[0010] Among them, R 1 Selected from C1-C15 alkyl, fused-ring aryl, heteroaryl or n-aryl groups with methyl, methoxy, cyano, nitro, tert-butyl, fluoro, trifluoromethyl, chloro, bromo, ferrocene, ethynyl or trimethylsilaneethynyl groups on the benzene ring;

[0011] R 2 Selected from C1-C15 alkyl, fused-ring aryl, heteroaryl or n-aryl groups with methyl, methoxy, cyano, nitro, tert-butyl, fluoro, trifluoromethyl, chloro, bromo, ferrocene, ethynyl or trimethylsilaneethynyl groups on the benzene ring;

[0012] R 3 It is a C1-C15 alkyl group or hydrogen;

[0013] R 4 Alkyl or hydrogen selected from C1-C15.

[0014] The preparation method of the above-mentioned allylphthalide compounds includes the following steps:

[0015] (1) Add 3-hydroxyisobenzofuran-1(3H)-one and allyl borate pinacol ester to water, stir and react to obtain a reaction solution;

[0016] (2) The reaction solution was separated and purified to obtain allylphthalide compounds.

[0017] In step (1), the structural formula of the 3-hydroxyisobenzofuran-1(3H)-one is shown in formula (II):

[0018]

[0019] In equation (II), R 1 In the same formula (I), R 1 The correspondence is consistent.

[0020] In step (1), the structural formula of the allyl borate pinacol ester is shown in formula (III):

[0021]

[0022] In equation (III), R 2 R 3 and R 4 In the same formula (I), R 2 R 3 and R 4The correspondence is consistent.

[0023] Furthermore, in step (1), the reaction temperature is 25-60℃ and the reaction time is 5-96h.

[0024] Furthermore, in step (1), the molar ratio of 3-hydroxyisobenzofuran-1(3H)-one and allylboronic acid pinacol ester is 1:(1.1-1.3).

[0025] Further, in step (1), the 3-hydroxyisobenzofuran-1(3H)-one is selected from 3-hydroxyisobenzofuran-1(3H)-one, 5-fluoro-3-hydroxyisobenzofuran-1(3H)-one, 5-chloro-3-hydroxyisobenzofuran-1(3H)-one, 3-hydroxy-5-methoxyisobenzofuran-1(3H)-one, 5-(tert-butyl)-3-hydroxyisobenzofuran-1(3H)-one, 3-hydroxy-5-phenylisobenzofuran-1(3H)-one, methyl 3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboxylate, 6-fluoro-3-hydroxyisobenzofuran-1(3H)-one, 3-hydroxy-7-methoxyisobenzofuran-1(3H)-one, etc. The following is a list of furan-1(3H)-one, 3-hydroxy-5,6-dimethoxyisobenzofuran-1(3H)-one, 3-hydroxynaphtho[1,2-c]furan-1(3H)-one, 3-hydroxynaphtho[2,3-c]furan-1(3H)-one, 7-hydroxyfuran[3,4-b]pyridin-5(7H)-one, (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid, and (1S,2S,5R)-2-isopropyl-5-methylcyclohexyl-3-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid ester.

[0026] Further, in step (1), the allyl borate pinacol ester is selected from allyl borate pinacol ester, 4,4,5,5-tetramethyl-2-(2-methylallyl)-1,3,2-dioxoborane, 4,4,5,5-tetramethyl-2-(2-methylene-3-en-1-yl)-1,3,2-dioxoborane, 4,4,5,5-tetramethyl-2-(3-methyl-2-methylenebut-3-en-1-yl)-1,3,2-dioxoborane, 4,5,5-tetramethyl-2-(2-methylbut-3-en-) 2-yl)-1,3,2-dioxborane, 2-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl)acrylate, 2-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl)acrylate, 2-(but-3-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, 4,4,5,5-tetramethyl-2-(2-methyl-3-en-2-yl)-1,3,2-dioxaborane, any one of them.

[0027] Further, in step (2), the separation and purification method is as follows: first, the reaction solution is extracted with diethyl ether to separate the organic phase, then the organic phase is dried with anhydrous Na2SO4, then filtered to remove diethyl ether, and finally purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent.

[0028] The application of the above-mentioned allylphthalide compounds in the synthesis of drug molecules with an allylphthalide structure.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) This invention discloses a method for the direct allylation modification of 3-hydroxyisobenzofuran-1(3H)-one with allyl borate pinacol ester. The reaction is carried out in an aqueous phase, without the need for a metal catalyst, and the reaction conditions are mild with high substrate versatility. Various 3-hydroxyisobenzofuran-1(3H)-ones modified with different functional groups can be rapidly allylated in high yields. Furthermore, the aqueous phase synthesis method greatly simplifies the chemical synthesis steps, improves the synthesis efficiency, and contributes to the sustainable development of chemistry in the future, possessing potential application value for fine chemistry and industrial production.

[0031] (2) The allylphthalide compounds of the present invention can be used as building blocks for various derivatizations in organic synthesis, utilizing their allyl and phthalide moieties. They are important skeletons widely found in natural products, biological and pharmaceutical molecules, and have potential biological and pharmaceutical activities. Therefore, research and development on 3-allylphthalide compounds are increasing. Attached Figure Description

[0032] Figure 1 This is the 1H NMR spectrum of compound 3 prepared in Example 1;

[0033] Figure 2 This is the carbon NMR spectrum of compound 3 prepared in Example 1;

[0034] Figure 3 This is the 1H NMR spectrum of compound 5 prepared in Example 2;

[0035] Figure 4 This is the carbon NMR spectrum of compound 5 prepared in Example 2;

[0036] Figure 5 This is the 1H NMR spectrum of compound 7 prepared in Example 3;

[0037] Figure 6 This is the carbon NMR spectrum of compound 7 prepared in Example 3;

[0038] Figure 7 This is the 1H NMR spectrum of compound 9 prepared in Example 4;

[0039] Figure 8 This is the carbon NMR spectrum of compound 9 prepared in Example 4;

[0040] Figure 9 This is the 1H NMR spectrum of compound 11 prepared in Example 5;

[0041] Figure 10 This is the carbon NMR spectrum of compound 11 prepared in Example 5. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0043] Example 1

[0044] A method for preparing an allylphthalide compound includes the following steps:

[0045] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 5 h to obtain the reaction solution.

[0046] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain colorless liquid compound 3 with a yield of 99%.

[0047] The reaction equation is:

[0048]

[0049] Compound 3 was characterized. Figure 1 This is the 1H NMR spectrum of compound 3 prepared in Example 1; Figure 2 This is the carbon NMR spectrum of compound 3 prepared in Example 1. The data characterization is as follows:

[0050] 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=7.7Hz,1H),7.71–7.66(m,1H),7.57–7.46(m ,2H),5.84–5.69(m,1H),5.54(t,J=6.0Hz,1H),5.23–5.12(m,2H),2.81–2.61(m,2H).

[0051] 13 C NMR(101MHz,Chloroform-d)δ170.4,149.3,134.0,131.2,129.2,126.2,125.7,122.0, 119.8,80.3,38.7.IR(KBr):3445,3005,1758,1639,1384,1275,1260,1063,764,750cm -1 .

[0052] HRMS(ESI)m / z:[M+H] + Calcd.for C 11 H 11 O2:175.0759; found 175.0751.

[0053] Characterization results indicate that compound 3 is (S)-3-allylisobenzofuran-1(3H)-one.

[0054] Example 2

[0055] A method for preparing an allylphthalide compound includes the following steps:

[0056] (1) In a 10 mL Shrek tube, 0.2 mmol of 5-chloro-3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 24 h to obtain the reaction solution.

[0057] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain colorless liquid compound 5 with a yield of 74%.

[0058] The reaction equation is:

[0059]

[0060] Compound 5 was characterized. Figure 3 This is the 1H NMR spectrum of compound 5 prepared in Example 2; Figure 4 This is the carbon NMR spectrum of compound 5 prepared in Example 2. The data characterization is as follows:

[0061] 1 H NMR (400MHz, Chloroform-d) δ7.83(d,J=8.1Hz,1H),7.56–7.43(m,2H),5.84–5.67(m,1H),5.50(t,J=5.9Hz,1H),5.27–5.11(m,2H),2.79–2.61(m,2H).

[0062] 13 C NMR(101MHz,Chloroform-d)δ169.2,150.9,140.7,130.7,130.0,126.9,124.8,122.5,120.2,79.6 ,38.6.IR(KBr):3435,2921,1762,1611,1339,1275,1261,1210,1072,985,764,750,592,551,472cm -1 .

[0063] HRMS(ESI)m / z:[M+H] + Calcd.for C 11 H 10 O2Cl:209.0369; found 209.0364.

[0064] Characterization results indicate that compound 5 is 3-allyl-5-chloroisobenzofuran-1(3H)-one.

[0065] Example 3

[0066] A method for preparing an allylphthalide compound includes the following steps:

[0067] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of 2-(but-3-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane were added to 6 mL of water and stirred at 30 °C for 12 h to obtain the reaction solution;

[0068] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain colorless liquid compound 7 with a yield of 93%.

[0069] The reaction equation is:

[0070]

[0071] Compound 7 was characterized. Figure 5 This is the 1H NMR spectrum of compound 7 prepared in Example 3; Figure 6 This is the carbon NMR spectrum of compound 7 prepared in Example 3. The data characterization is as follows:

[0072] 1 H NMR(400MHz,Chloroform-d)δ7.85–7.77(m,2H),7.64–7.55(m,2H),7.49–7.34(m,4H),5.62–5.48(m,2H),5.45(t,J=6.0Hz ,1H),5.40(t,J=6.0Hz,1H),5.36–5.24(m,2H),2.78–2.66(m,1H),2.64–2.46(m,3H),1.60–1.55(m,3H),1.55–1.50(m,3H).

[0073] 13C NMR(101MHz,Chloroform-d)δ170.65,170.60,149.68,149.65,134.00,133.96,130.6,129.23,129.18,128.9,126.4,126.3,123.7,12 2.6,122.1,122.0,80.9,80.6,37.7,32.0,18.1,13.2.IR(KBr):3446,2919,1760,1660,1384,1276,1071,984,890,764,749,695,630cm -1 .

[0074] HRMS(ESI)m / z:[M+H] + Calcd.for C 12 H 13 O2:189.0916;found 189.0908..

[0075] Characterization results indicate that compound 7 is 3-(but-2-en-1-yl)isobenzofuran-1(3H)-one.

[0076] Example 4

[0077] A method for preparing an allylphthalide compound includes the following steps:

[0078] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxynaphtho[2,3-c]furan-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 24 h to obtain the reaction solution;

[0079] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain colorless liquid compound 9 with a yield of 67%.

[0080] The reaction equation is:

[0081]

[0082] Compound 9 was characterized. Figure 7 This is the 1H NMR spectrum of compound 9 prepared in Example 4; Figure 8 This is the carbon NMR spectrum of compound 9 prepared in Example 4. The data characterization is as follows:

[0083] 1H NMR(401MHz,Chloroform-d)δ8.46(s,1H),8.03(d,J=8.2Hz,1H),7.95(d,J=8.2Hz,1H),7.88(s,1 H),7.72–7.51(m,2H),5.92–5.75(m,1H),5.72–5.66(m,1H),5.28–5.13(m,2H),2.91–2.67(m,2H).

[0084] 13 C NMR(101MHz,Chloroform-d)δ170.4,143.1,136.3,133.3,131.4,130.0,129.1,128.4,127.1,127.1,124.1,121.0,119. 9,80.4,39.4.IR(KBr):3502,2921,1761,1682,1641,1610,1508,1424,1320,1261,1169,1057,923,764,749,591,475cm -1 .

[0085] HRMS(ESI)m / z:[M+H] + Calcd.for C 15 H 13 O2: 225.0916; found 225.0925.

[0086] Characterization results showed that compound 9 is 3-enylnaphtho[2,3-c]furan-1(3H)-one.

[0087] Example 5

[0088] A method for preparing an allylphthalide compound includes the following steps:

[0089] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of 4,4,5,5-tetramethyl-2-(2-methyl-3-en-2-yl)-1,3,2-dioxorane were added to 6 mL of water and stirred at 30 °C for 36 h to obtain the reaction solution;

[0090] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain colorless liquid compound 11 with a yield of 90%.

[0091] The reaction equation is:

[0092]

[0093] Compound 11 was characterized. Figure 9 This is the 1H NMR spectrum of compound 11 prepared in Example 5; Figure 10 This is the carbon NMR spectrum of compound 11 prepared in Example 5. The data characterization is as follows:

[0094] 1H NMR(400MHz,Chloroform-d)δ7.91(d,J=7.6Hz,1H),7.69–7.64(m,1H),7.54(t,J=7.5Hz,1H),7.47(d ,J=7.6Hz,1H),5.48(t,J=6.2Hz,1H),5.21–5.08(m,1H),2.78–2.52(m,2H),1.71(s,3H),1.61(s,3H).

[0095] 13C NMR(101MHz,Chloroform-d)δ170.6,149.8,136.6,133.8,129.1,126.3,125.6,122.0,116.8,80.9,33.3, 25.8,18.1.IR(KBr):3444,2972,2916,1760,1614,1466,1384,1276,1261,1067,984,764,750,708,693cm -1 .

[0096] HRMS(ESI)m / z:[M+H]+Calcd.for C13H15O2:203.1072; found 203.1067.

[0097] Characterization results showed that compound 11 is 3-(3-methyl-2-en-1-yl)isobenzofuran-1(3H)-one.

[0098] Example 6

[0099] A method for preparing an allylphthalide compound includes the following steps:

[0100] (1) In a 500 mL flask, 8 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 9.6 mmol of allyl borate pinacol ester were added to 240 mL of water and stirred at 30 °C for 7 h to obtain the reaction solution.

[0101] (2) After the reaction solution is allowed to stand for 2 hours, the target compound 3 is directly aspirated.

[0102] The NMR purity is above 95%, and the product yield is 99%. No further extraction or column chromatography is required, which greatly increases the practical applicability of this reaction.

[0103] Example 7

[0104] The amount of water used in step (1) was changed to 4 mL, the stirring reaction time was 10 h, and the rest was the same as in Example 1.

[0105] The yield of compound 3 was 99%.

[0106] Example 8

[0107] The amount of water used in step (1) was changed to 5 mL, the stirring reaction time was 8 h, and the rest was the same as in Example 1.

[0108] The yield of compound 3 was 99%.

[0109] Comparative Example 1

[0110] The reaction solvent in step (1) was changed from water to PBS buffer with a pH of 7, and the reaction time was 12 hours. The rest was the same as in Example 1.

[0111] The yield of compound 3 was 28%.

[0112] Comparative Example 2

[0113] The reaction solvent in step (1) was changed from water to PBS buffer with a pH of 7.4, and the reaction time was 12 hours. The rest was the same as in Example 1.

[0114] The yield of compound 3 was 20%.

[0115] Comparative Example 3

[0116] The reaction solvent in step (1) was changed from water to PBS buffer with a pH of 6.5, and the reaction time was 12 hours. The rest was the same as in Example 1.

[0117] The yield of compound 3 was 27%.

[0118] Comparative Example 4

[0119] A method for preparing an allylphthalide compound includes the following steps:

[0120] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of toluene and stirred at 30 °C for 20 h to obtain the reaction solution.

[0121] (2) The solvent (toluene) was removed from the reaction solution, and the product was purified by thin-layer chromatography. The developing solvent was petroleum ether and ethyl acetate in a volume ratio of 10:1, to obtain colorless liquid compound 3 with a yield of 99%.

[0122] Comparative Example 5

[0123] A method for preparing an allylphthalide compound includes the following steps:

[0124] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of dichloromethane and stirred at 30 °C for 20 h to obtain the reaction solution.

[0125] (2) The solvent (dichloromethane) was removed from the reaction solution, and the product was purified by thin-layer chromatography. The developing solvent was petroleum ether and ethyl acetate in a volume ratio of 10:1, to obtain colorless liquid compound 3 with a yield of 99%.

[0126] Example 9

[0127] A method for preparing an allylphthalide compound includes the following steps:

[0128] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxynaphtho[1,2-c]furan-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 5 h to obtain the reaction solution;

[0129] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain 3-enylnaphtho[1,2-c]furan-1(3H)-one with a yield of 37%.

[0130] Example 10

[0131] A method for preparing an allylphthalide compound includes the following steps:

[0132] (1) In a 10 mL Shrek tube, 0.2 mmol of 7-hydroxyfuran[3,4-b]pyridine-5(7H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 5 h to obtain the reaction solution;

[0133] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain 7-allylfuran[3,4-b]pyridin-5(7H)-one with a yield of 46%.

[0134] Example 11

[0135] A method for preparing an allylphthalide compound includes the following steps:

[0136] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of 2-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl)acrylate were added to 6 mL of water and stirred at 30 °C for 64 h to obtain the reaction solution;

[0137] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain methyl 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)methacrylate, with a yield of 67%.

[0138] Example 12

[0139] A method for preparing an allylphthalide compound includes the following steps:

[0140] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxyisobenzofuran-1(3H)-one and 0.24 mmol of 2-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)meth)acrylate were added to 6 mL of water and stirred at 30 °C for 64 h to obtain the reaction solution;

[0141] (2) The reaction solution was extracted three times with diethyl ether (3×15mL), the organic phases were combined, dried with anhydrous Na2SO4, filtered to remove the solvent (diethyl ether), and the product was purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain ethyl 2-((3-oxo-1,3-dihydroisobenzofuran-1-yl)meth)acrylate, with a yield of 99%.

[0142] Application Example 1

[0143] Compound 3 prepared in Example 1 was used to prepare compound 13:

[0144] (1) Add Pd2(dba)3 (8.24 mg, 0.009 mmol) and 3 mL DMA to a 10 mL flask dried in an oven to obtain a solution of Pd2(dba)3; add compound 3 (52.2 mg, 0.3 mmol) and 2 mL DMA to a 10 mL flask dried in an oven to obtain a solution of compound 3; add the solution of compound 3 to a flask containing compound 12 (214 mg, 0.33 mmol), and then quickly add the solution of Pd2(dba)3 and react for 80 minutes.

[0145] (2) After the reaction was complete as monitored by TLC, the mixture was diluted with 20 mL of ethyl acetate, washed with water, then washed with brine, dried with anhydrous sodium sulfate, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin-layer chromatography with petroleum ether / ethyl acetate system (10 / 1) as the developing solvent. The product was a colorless liquid compound 13 with a yield of 65%.

[0146] The chemical equation is:

[0147]

[0148] This application example transforms the allylated product (compound 3) into a structure containing vitamin E and tocopherol, which is a high-performance antioxidant and nutrient with high bioactivity and food safety. It is widely used in the fields of medicine, health products, food, and cosmetics.

[0149] Application Example 2

[0150] Compound 7, prepared in Example 2, was used to prepare n-butylphthalide (NBP):

[0151] (1) Add compound 7 (38 mg, 0.2 mmol), ethyl acetate (4 ml) and 10% Pd / C (4 mg) to a 25 mL flask, rinse with hydrogen, and then place under a hydrogen balloon for 2 hours.

[0152] (2) After the reaction was complete as monitored by TLC, the product was extracted with ethyl acetate (EA), the organic layers were combined, dried with anhydrous sodium sulfate, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin-layer chromatography with petroleum ether / ethyl acetate system (10 / 1) as the developing solvent. The product was a colorless liquid compound butylphthalide (14) (NBP, used to treat mild to moderate acute ischemic stroke), with a yield of 99%.

[0153] The reaction equation is:

[0154]

[0155] Application Example 3

[0156] Preparation of compound 16:

[0157] (1) In a 10 mL Shrek tube, 0.2 mmol of 3-hydroxy-5,7-dimethyloxyisophenylfuran-1(3H)-one and 0.24 mmol of allyl borate pinacol ester were added to 6 mL of water and stirred at 30 °C for 24 h to obtain the reaction solution.

[0158] (2) The reaction solution was extracted with diethyl ether, the organic layers were combined and dried with anhydrous sodium sulfate, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin-layer chromatography with petroleum ether / ethyl acetate system (10 / 1) as the developing solvent. The product was a white solid compound 16 with a yield of 81%.

[0159] The reaction equation is:

[0160]

[0161] Compound 16 is a key intermediate in the preparation of Herbaric Acids and Spirolaxine (J. Org. Chem. 2010, 75, 7388; Tetrahedron Lett. 2016, 57, 25.).

[0162] 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, and 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 an allylphthalide compound, characterized in that, Includes the following steps: (1) 3-hydroxyisobenzofuran-1(3H)-one compounds and allyl borate pinacol ester compounds were added to water and stirred under the condition of no metal catalyst to obtain a reaction solution; (2) The reaction solution was separated and purified to obtain allylphthalide compounds; The structural formula of the allylphthalide compounds is shown in formula (I): （I） Among them, R 1 Selected from C1-C15 alkyl, fused-ring aryl, or heteroaryl groups; R 2 Selected from C1-C15 alkyl, fused-ring aryl, or heteroaryl groups; R 3 It is a C1-C15 alkyl group or hydrogen; R 4 Selected from C1-C15 alkyl or hydrogen; In step (1), the structural formula of the 3-hydroxyisobenzofuran-1(3H)-ketone compound is shown in formula (II): (II) In equation (II), R 1 In the same formula (I), R 1 Consistent correspondence; In step (1), the structural formula of the allyl borate pinacol ester compound is shown in formula (III): (III) In equation (III), R 2 R 3 and R 4 In the same formula (I), R 2 R 3 and R 4 The correspondence is consistent.

2. The method for preparing allylphthalide compounds as described in claim 1, characterized in that, In step (1), the reaction temperature is 25-60℃ and the reaction time is 5-96h.

3. The method for preparing allylphthalide compounds as described in claim 1, characterized in that, In step (1), the molar ratio of the 3-hydroxyisobenzofuran-1(3H)-one compound and the allylboronic acid pinacol ester compound is 1:(1.1-1.3).

4. The method for preparing allylphthalide compounds according to any one of claims 1 to 3, characterized in that, In step (2), the separation and purification method is as follows: first, the reaction solution is extracted with diethyl ether to separate the organic phase, then the organic phase is dried with anhydrous Na2SO4, then filtered to remove diethyl ether, and finally purified by thin-layer chromatography with petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent.

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