Isochromanone derivative and synthesis method thereof

Abstract

The present invention discloses an isochromanone derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. The present invention is a method for synthesizing an isochromanone derivative by reacting an α-ketoester with phthalic anhydride or 3-alkylene isobenzofuran-1(3 H )-ketone compounds react under the promotion of a phosphorus reagent to obtain isochroman-1-one or isochroman-1,4-dione derivatives; the raw materials used in the present invention are simple and easy to obtain, have good stability, and are simple to operate; the reaction conditions of the present invention are mild, easy to scale up, have good substrate universality and functional group compatibility, and can be used for the later modification of natural product molecules; the present invention provides candidate compounds for the design, synthesis, and development of new drug molecules containing isochromanone structures.

Description

Technical Field

[0001] The invention relates to an isochromanone derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. Background Art

[0002] Isochromanone structures are commonly found in natural products and pharmaceutical molecules, such as hydrangea phenol, ochratoxin A, and melotoxin (Rizzacasa, MA et al. Org. Lett. 2024, 26, 1062). This class of compounds exhibits a wide range of biological activities, including antifungal and potassium channel inhibition (Muller, R. et al. Angew. Chem. Int. Ed. 2012, 51, 1256), and can be used as hepatitis C virus inhibitors (Rizzacasa, MA et al. Org. Lett. 2024, 26, 1062) and aldosterone synthase inhibitors (Adams, C. et al. Patent WO / 2007 / 117982, 2007). Therefore, the development of efficient synthesis methods for these compounds has long been a focus of organic synthesis researchers.

[0003] Constructing cyclic structures through intramolecular nucleophilic substitution, electrophilic addition, and oxidative coupling is an effective method for synthesizing isochromanones (Xu, M.-H. et al. Chem. Eur. J. 2013, 19, 865; Jiang, X. et al. Syn Open 2018, 2, 293; Wirth, T. et al. Synthesis 2019, 51, 276; Maddani, R. et al. Org. Biomol. Chem. 2023, 21, 2504), but the substrate structure is usually complex and involves multi-step reactions. Compounds with a 1,3-indanedione skeleton can be converted into isochromanone molecules through the Baeyer-Villiger oxidation reaction (Deepthi, A. et al. J. Heterocycl. Chem. 2019, 56, 2333; Xu, S. et al. J. Org. Chem. 2022, 87, 6362; Liu, J. et al. Eur. J. Org. Chem. 2023, 26, e202300499; Fan, X. et al. Chin. J. Chem. 2024, 42, 363). However, this type of reaction is not suitable for substrates that are sensitive to oxidants and has poor functional group compatibility. The [5+1] cyclization reaction of free carbene and phthalic anhydride provides a mild route for the synthesis of isochromanone derivatives (Warkentin, J. et al. Liebigs Ann. 1995, 1907; Shevchenko, I. et al. Eur. J. Org. Chem. 2007, 2055), but the reported reactions are limited to the use of relatively stable oxa- or nitrogen-containing carbenes as substrates, and the product substitution pattern is relatively fixed, making the reaction less practical.

[0004] Therefore, developing methods that are mild, require cheap and readily available raw materials, and can synthesize isochromanone derivatives with different substitution patterns remains a worthy and challenging topic in organic synthesis. Summary of the Invention

[0005] The present invention aims to provide an isochromanone derivative and a synthesis method thereof. Isochroman-1-one or isochroman-1,4-dione derivatives are obtained by reacting an α-ketoester with phthalic anhydride or a 3-alkylene isobenzofuran-1(3H)-one compound derived therefrom under the promotion of a phosphorus reagent. The synthesis conditions are mild, the raw materials are cheap and readily available, and the derivatives have different substitution patterns.

[0006] Taking the reaction of phthalic anhydride derivatives with α-ketoesters as an example, the mechanism of the present invention is as follows: a phosphorus reagent reacts with the α-ketoester to form a Kukhtin-Ramirez adduct A. A, acting as a resonance form of A, then undergoes a nucleophilic attack on the phthalic anhydride compound, forming an intermediate D through an addition-elimination process. D then undergoes an intramolecular nucleophilic substitution reaction, simultaneously removing the phosphine oxide and forming an isochromanone product. The specific process is shown in the following formula:

[0007]

[0008] Isochromanone derivatives are phthalic anhydride derivatives (III) or 3-alkylene isobenzofuran-1(3H)-one compounds (IV) derived therefrom.

[0009]

[0010] With α-keto ester V

[0011]

[0012] The reaction is obtained under the promotion of phosphorus reagent.

[0013] The general reaction formula is:

[0014]

[0015] In the above structural formula, R1 is selected from hydrogen, alkyl, halogen or alkoxy; R2 is selected from alkyl, aryl or heteroaryl; R3 is selected from alkyl or aryl; R4 and R5 are selected from alkyl or aryl.

[0016] The present invention provides a method for synthesizing an isochromanone derivative, comprising the following steps:

[0017] An α-ketoester and phthalic anhydride or a 3-alkylene isobenzofuran-1(3H)-one compound derived therefrom are dissolved in an organic solvent, and the resulting reaction mixture is stirred at low temperature. A diluted phosphorus reagent is then added dropwise to the reaction mixture over 5 to 15 minutes, wherein the molar ratio of the α-ketoester, phthalic anhydride or 3-alkylene isobenzofuran-1(3H)-one compound, and the phosphorus reagent is 1 to 2:1:1 to 1.5. After the dropwise addition is complete, the reaction mixture is naturally warmed to room temperature and stirred for 2 to 3 hours. After the reaction is completed, the solvent is removed by rotary evaporation, and the crude product is purified by 200 to 300 mesh silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 6:1 to 8:1 as the eluent. The yield of the obtained product is calculated to be 36 to 99%, depending on the target compound.

[0018] In the above synthesis method, the organic solvent includes a non-polar solvent or a polar solvent, the non-polar solvent is toluene; the polar solvent includes one of tetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate, and the amount of the organic solvent used is 5-20 mL / mmol of α-keto ester.

[0019] In the above synthesis method, the low temperature is -78°C to -40°C.

[0020] In the above synthesis method, the phosphorus reagent is hexamethylphosphoramidite P(NMe2)3.

[0021] In the above synthesis method, the phosphorus reagent is diluted with an organic solvent and then added to the reaction system (the solvent used is the same as the above organic solvent); the concentration of the diluted phosphorus reagent is 0.5 to 1 mol / L.

[0022] Beneficial effects of the present invention:

[0023] (1) The raw materials used in the present invention are simple and easy to obtain, have good stability, and are simple to operate;

[0024] (2) The reaction conditions of the present invention are mild, easy to scale up, and have good substrate universality and functional group compatibility, and can be used for the later modification of natural product molecules;

[0025] (3) The present invention provides candidate compounds for the design, synthesis and development of new drug molecules containing isochromanone structures. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is described in detail below through specific embodiments. The examples listed are intended to illustrate the technical solution of the present invention in detail rather than to limit the protection scope of the present invention.

[0027] The phthalic anhydride used in the following examples was purchased from the market, and the 3-alkylidene isobenzofuran-1(3H)-one compound derived therefrom was prepared from phthalic anhydride and ethyl 2-chloroacetoacetate according to a known synthesis method (see Valadbeigi, Y. et al. J. Mol. Struct. 2020, 1200, 127105), and its general structural formula is shown in III and IV:

[0028]

[0029] The α-ketoester compound used was purchased from the market or prepared by referring to known synthesis methods, from ethyl oxalyl chloride and substituted benzene through Friedel-Crafts acylation reaction or from bromobenzene and diethyl oxalate through nucleophilic substitution reaction (see Zhang, Z. et al. J. Org. Chem. 2008, 73, 3842-3847; Ashfeld, BL et al. Chem. Commun. 2014, 50, 10853), and its general structural formula is V:

[0030]

[0031] The general structural formula of the synthesized isochromanone derivative is I or II:

[0032]

[0033] In the above general structural formula: R1 is selected from hydrogen, alkyl, halogen, alkoxy; R2 is selected from alkyl, aryl or heteroaryl; R3 is selected from alkyl, aryl; R4 and R5 are selected from alkyl, aryl.

[0034] Example 1

[0035] Synthesis of isochroman-1,4-dione derivatives, with the general structural formula R1=H, R2=Ph, R3=Et.

[0036]

[0037] To a 25 mL Schlenk flask equipped with a magnetic stirrer, 1.5 mL of acetonitrile, 29.6 mg (0.20 mmol) of phthalic anhydride (R1 = H), and 42.8 mg (0.24 mmol) of an α-ketoester (R2 = Ph, R3 = Et) were added sequentially; the resulting reaction mixture was stirred at -40°C, and a solution of 55.0 μL (0.30 mmol) of hexamethylphosphoramidite in 0.5 mL of acetonitrile was slowly added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 2 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the crude product was purified by chromatography on a 200-300 mesh silica gel column to obtain an isochromatic an-1,4-dione derivative using petroleum ether (boiling range 60-90°C):ethyl acetate in a volume ratio of 6:1 to 8:1, using a gradient elution method; 58.3 mg of the product was obtained as a colorless oily liquid in a yield of 94%.

[0038] 1H NMR (400MHz, CDCl3) δ8.27–8.22(m,1H,ArH),8.05(dd,J1=7.5Hz,J2=1.6Hz,1H,ArH),7.87–7.79(m,2H,ArH), 7.65(dd,J1=7.9Hz,J2=1.9Hz,2H,ArH),7.43–7.35(m,3H),4.31–4.23(m,2H,OEt),1.22(t,J=7.1Hz,3H,OEt);

[0039] 13 C NMR (101MHz, CDCl3) δ187.0,165.9,161.1,136.0,135.2,133.2,131.1,130.7,129.6,128.7,127.6,127.1,126.8,90.7,63.7,14.0ppm;

[0040] HRMS-ESI([M+H] + )Calcd for C 18 H 15 O5 + 311.0914; found 311.0894.

[0041] Example 2

[0042] Synthesis of isochroman-1,4-dione derivatives, with the general structural formula R1=5-Br, R2=Ph, R3=Et.

[0043]

[0044] The synthesis steps are basically the same as those in Example 1, except that the differences are listed below:

[0045] The phthalic anhydride R1 used was 5-Br, and the amount used was 45.4 mg (0.20 mmol), and 76.4 mg of a light yellow solid was obtained with a yield of 98% and a melting point of 105-107°C.

[0046] 1 H NMR(400MHz, CDCl3)δ8.20(d,J=7.7Hz,1H,ArH),7.99(d,J=8.0Hz,1H,ArH),7.64–7.56 (m,3H,ArH),7.45–7.38(m,3H,ArH),4.30–4.20(m,2H,OEt),1.19(t,J=7.1Hz,3H,OEt);

[0047] 13C NMR (101MHz, CDCl3) δ185.0,166.0,160.3,141.2,135.2,132.1,130.4,130.2,130.1,129.8,128.8,126.8,121.8,89.6,63.7,14.0ppm.

[0048] HRMS-ESI([M+H] + )Calcd for C 18 H 14 BrO5 + 389.0019; found 389.0013.

[0049] The product structure was determined by X-ray single crystal diffraction:

[0050]

[0051] Example 3

[0052] Synthesis of isochroman-1,4-dione derivatives, with the general structural formula R1=5-CH3, R2=Ph, R3=Et.

[0053]

[0054] The synthesis steps are basically the same as those in Example 1, except that the differences are listed below:

[0055] The amount of phthalic anhydride R1 = 5-Me used was 32.4 mg (0.20 mmol), and 59.7 mg of a white solid mixed product was obtained. The ratio of regioisomers was 93:7, and the yield was 92%.

[0056] 1 H NMR (400MHz, CDCl3) δ8.11 (d, J=7.1Hz, 0.99H, ArH), 7.69–7.56 (m, 4.41H, ArH), 7.44–7.37 (m, 3.35H, ArH), 4.25(q,J=7.1Hz,2.21H,OEt),2.79(s,0.23H,Ar-CH3),2.67(s,3H,Ar-CH3),1.19(t,J=7.1Hz,3.26H,OEt);

[0057] 13C NMR (101MHz, CDCl3) δ188.1,187.5,166.4,166.2,161.7,160.6,144.2,141.2,139.3,138.3,134.8,134.3,133.0,132.9,132.4,131. 1,129.5,129.4,129.1,128.6,128.6,128.5,127.9,127.7,126.7,125.5,125.2,90.0,89.8,63.54,63.47,22.5,21.4,14.2,14.0ppm.

[0058] HRMS-ESI([M+H] + )Calcd for:C 19 H 17 O5 + 325.1071; found 325.1060.

[0059] Example 4

[0060] Synthesis of isochroman-1,4-dione derivatives, with the general structural formula R1=H, R2=Me, R3=Et.

[0061]

[0062] The synthesis steps are basically the same as those in Example 1, except that the differences are listed below:

[0063] The α-ketoester R2=Me, R3=Et was used in an amount of 27.9 mg (0.24 mmol) to obtain 30.5 mg of a colorless oily liquid with a yield of 62%.

[0064] 1 H NMR (400MHz, CDCl3) δ8.26 (dd, J1=7.8Hz, J2=1.3Hz, 1H, ArH), 8.02 (dd, J1=7.8, J2=1.3Hz, 1H, A rH),7.90–7.77(m,2H,ArH),4.21–4.10(m,2H,OEt),1.92(s,3H,Me),1.15(t,J=7.1Hz,3H,OEt);

[0065] 13 C NMR (101MHz, CDCl3) δ188.5,167.4,161.6,136.1,134.8,130.7,130.6,128.9,126.7,88.8,63.7,20.6,14.0ppm

[0066] HRMS-ESI([M+Na] + )Calcd for C 13 H 12 NaO5 + 271.0577; found 271.0556.

[0067] Example 5

[0068] Synthesis of isochroman-1-one derivatives, wherein R1=H, R2=Ph, R3=Et, R4=R5=Et.

[0069]

[0070] In a 25 mL Schlenk flask equipped with a magnetic stirrer, 1.5 mL of acetonitrile, 58.1 mg (0.20 mmol) of a phthalic anhydride-derived 3-alkylidene isobenzofuran-1(3H)-one compound (R1 = H, R4 = R5 = Et), and 42.8 mg (0.24 mmol) of an α-ketoester (R2 = Ph, R3 = Et) were added in sequence; the resulting reaction mixture was stirred at -78°C, and 55.0 μL (0.30 mmol) of hexamethylphosphoramide in acetonitrile (0 .5mL) solution was slowly added dropwise to the above reaction mixture over 10 minutes; after the addition was complete, the temperature was slowly raised to room temperature and stirred for 3 hours; after the reaction was complete, the solvent was removed by rotary evaporation, and the crude product was purified by 200-300 mesh silica gel column chromatography to obtain an isochromatic an-1,4-dione derivative, the eluent being petroleum ether (boiling range 60-90°C): ethyl acetate in a volume ratio of 6:1-8:1, and gradient washing; 83.0 mg of a white solid product was obtained, with a yield of 92% and a melting point of 92-94°C.

[0071] 1 H NMR (400MHz, CDCl3) δ8.03 (dd, J1=6.8Hz, J2=1.3Hz, 1H, ArH), 7.57–7.42 (m, 5H, ArH), 7.34–7.27 (m, 3H, ArH),4.23–4.08(m,4H,OEt),3.98–3.84(m,2H,OEt),1.19(t,J=7.1Hz,3H,OEt),1.16–1.09(m,6H,OEt);

[0072] 13C NMR (101MHz, CDCl3) δ166.9,165.9,163.7,162.2,140.9,135.3,134.9,134.0,131.4,1 30.8,130.0,129.5,128.3,128.2,128.1,124.9,89.3,63.1,62.6,62.4,13.9,13.8ppm.

[0073] HRMS-ESI([M+H] + )Calcd forC 25 H 25 O8 + 453.1544; found 453.1538.

[0074] A parallel experiment was conducted on the above example by changing the solvent: only the type of solvent was changed, and other conditions remained unchanged. The results are as follows: when tetrahydrofuran, toluene, 1,4-dioxane, ethyl acetate and dichloromethane were used as solvents to carry out the above reaction, the yields obtained were 84% (75.8 mg), 83% (74.9 mg), 81% (73.1 mg), 65% (58.6 mg) and 91% (82.1), respectively.

[0075] A parallel experiment was conducted on the above example, varying only the reaction temperature while keeping all other conditions constant. The results are as follows: At -40°C, the reaction yield reached 95% (85.7 mg). A scale-up experiment was also conducted under these conditions: increasing the amounts of the α-ketoester-derived 3-alkylideneisobenzofuran-1(3H)-one compound to 3.6 mmol and 3 mmol, respectively, resulted in a gram-scale synthesis of an isochroman-1-one derivative (1.27 g, 94% yield).

[0076] Example 6

[0077] Synthesis of isochroman-1-one derivatives, with the general structural formula R1=6,7-di-Chloro, R2=Ph, R3=Et, R4=R5=Et.

[0078]

[0079] In a 25 mL Schlenk flask equipped with a magnetic stirrer, 1.5 mL of acetonitrile, 71.8 mg (0.20 mmol) of a phthalic anhydride-derived 3-alkylideneisobenzofuran-1(3H)-one compound (R1 = 6,7-di-Chloro, R4 = R5 = Et), and 42.8 mg (0.24 mmol) of an α-ketoester (R2 = Ph, R3 = Et) were added in sequence. The resulting reaction mixture was stirred at -40°C, and 55.0 μL (0.30 mmol) of hexamethylphosphoramide was added. A solution of acetonitrile (0.5 mL) was slowly added dropwise to the reaction mixture over 10 minutes; after the addition was complete, the temperature was slowly raised to room temperature and stirred for 3 hours; after the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was purified by 200-300 mesh silica gel column chromatography to obtain an isochromatic an-1,4-dione derivative, the eluent being petroleum ether (boiling range 60-90°C): ethyl acetate in a volume ratio of 6:1-8:1, and gradient washing; 77.1 mg of a white solid product was obtained with a yield of 74% and a melting point of 172-175°C.

[0080] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H,ArH),7.53(s,1H,ArH),7.51(dd,J1=6.6Hz,J2=3.1Hz,2H,ArH),7.37–7.28 (m,3H,ArH),4.33–4.22(m,2H,OEt),4.21–4.08(m,2H,OEt),4.00–3.87(m,2H,OEt),1.25–1.14(m,9H,OEt);

[0081] 13 C NMR (101MHz, CDCl3) δ166.4,165.1,163.2,160.5,138.9,138.3,136.1,134.39,134.35,13 1.9,131.6,129.9,129.7,128.5,127.9,124.2,89.4,63.3,63.0,62.6,13.9,13.8,13.8ppm

[0082] HRMS-ESI([M+H] + )Calcd for C 25 H 23 Cl2O8 + 521.0764; found 521.0770.

[0083] Example 7

[0084] Synthesis of isochroman-1-one derivatives, wherein the general structural formula is R1=8-I, R2=Ph, R3=Et, R4=R5=Et.

[0085]

[0086] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0087] The 3-alkylidene isobenzofuran-1(3H)-one compound R1=8-I, R4=R5=Et derived from phthalic anhydride used was 83.2 mg (0.20 mmol) to obtain 41.2 mg of colorless oily liquid product with a yield of 36%.

[0088] 1 H NMR (400MHz, CDCl3) δ8.09 (dd, J1=8.0Hz, J2=1.1Hz, 1H, ArH), 7.58–7.52 (m, 2H), 7.40 (dd, J1=7.8Hz, J2=1.1Hz, 1H, ArH), 7.35–7.30 (m, 3H, A rH),7.09(dd,J1=J2=7.9Hz,1H,ArH),4.18–4.07(m,4H,OEt),3.87–3.70(m,2H,OEt),1.16(t,J=7.1Hz,3H,OEt),1.13–1.08(m,6H,OEt)ppm;

[0089] 13 C NMR (101MHz, CDCl3) δ167.1,165.2,163.2,159.9,144.9,140.8,137.7,133.7,133.6,13 0.9,129.7,128.8,128.4,128.1,126.5,96.3,88.4,63.1,62.7,62.4,13.9,13.84,13.78

[0090] HRMS(ESI)m / z:[M+Na] + Calcd for C 25 H 23 INaO8 + 601.0330;found 601.0338.

[0091] Example 8

[0092] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1 = 8-Cl, R2 = Ph, R3 = Et, R4 = R5 = Et.

[0093]

[0094] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0095] The 3-alkylidene isobenzofuran-1(3H)-one compound R1=8-Cl, R4=R5=Et derived from phthalic anhydride used was 64.9 mg (0.20 mmol) to obtain 48.4 mg of colorless oily liquid product with a yield of 50%.

[0096] 1 H NMR (400MHz, CDCl3) δ7.59–7.53(m,2H,ArH),7.51(d,J=8.0Hz,1H,ArH),7.41–7.30(m,5H,ArH),4. 19–4.07(m,4H,OEt),3.90–3.70(m,2H,OEt),1.17(t,J=7.1Hz,3H,OEt),1.15–1.07(m,6H,OEt)ppm;

[0097] 13 C NMR (101MHz, CDCl3) δ167.0,165.2,163.2,158.7,140.8,138.3,136.5,134.1,133.9,13 3.6,131.1,129.7,128.4,128.1,127.3,122.4,88.5,63.1,62.7,62.4,13.83,13.78ppm;

[0098] HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 24 ClO8 + 487.1154; found 487.1161.

[0099] Example 9

[0100] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-MeOC6H4, R3=Et, R4=R5=Et.

[0101]

[0102] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0103] The 3-alkylidene isobenzofuran-1(3H)-one compound derived from phthalic anhydride used, R1=H, R4=R5=Et, was used in an amount of 58.1 mg (0.20 mmol), and the α-ketoester used, R2=4-MeOC6H4, R3=Et, was used in an amount of 50.0 mg (0.24 mmol). The reaction time at room temperature was 12 hours, and 87.6 mg of a white solid product was obtained with a yield of 91% and a melting point of 120-122°C.

[0104] 1 H NMR(400MHz, CDCl3) δ8.01(d,J=8.2Hz,1H,ArH),7.53–7.40(m,5H,ArH),6.79(d,J=8.8Hz,2H),ArH,4.21–4. 05(m,4H,OEt),3.97–3.85(m,2H,OEt),3.73(s,3H,OMe),1.18(t,J=7.1Hz,3H,OEt),1.15–1.07(m,6H,OEt);

[0105] 13 C NMR (101MHz, CDCl3) δ167.0,165.8,163.6,162.3,160.2,141.1,135.2,133.9,131.3,130.5,1 29.9,129.6,128.2,126.6,124.8,113.6,89.1,62.9,62.5,62.3,55.4,13.79,13.76,13.7ppm.

[0106] HRMS-ESI([M+Na] + )Calcd for C 26 H 26 NaO9 + 505.1469; found 505.1466.

[0107] Example 10

[0108] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-CNC6H4, R3=Et, R4=R5=Et.

[0109]

[0110] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0111] The α-ketoester R2=4-CNC6H4, R3=Et was used in an amount of 48.8 mg (0.24 mmol) to obtain 69.7 mg of a white solid product with a yield of 73% and a melting point of 112-114°C.

[0112] 1 H NMR (400MHz, CDCl3) δ8.04–7.97(m,1H,ArH),7.71–7.66(m,2H,ArH),7.61–7.54(m,2H,ArH),7.54–7.46(m,2H,ArH),7.46– 7.39(m,1H,ArH),4.26–4.05(m,6H,OEt),1.25(t,J=7.1Hz,3H,OEt),1.17(t,J=5.6Hz,3H,OEt),1.14(t,J=5.6Hz,3H,OEt);

[0113] 13 C NMR (101MHz, CDCl3) δ165.6,163.9,161.3,140.6,139.9,134.42,134.37,132.2,131.8,131 .1,130.2,128.6,128.2,124.3,118.3,113.2,88.5,63.4,62.8,62.7,13.9,13.8,13.7ppm;

[0114] HRMS-ESI([M+H] + )Calcd for C 26 H 24 NO8 + 478.1496; found 478.1498.

[0115] Example 11

[0116] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-BrC6H4, R3=Et, R4=R5=Et.

[0117]

[0118] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0119] The α-ketoester R2=4-BrC6H4, R3=Et was used in an amount of 61.7 mg (0.24 mmol) to obtain 79.1 mg of colorless oily liquid product with a yield of 75%.

[0120] 1H NMR (400MHz, CDCl3) δ8.05–7.97(m,1H,ArH),7.49–7.32(m,7H,ArH),4.18–3.89(m,6H,OEt),1.25–1.19(m,3H,OEt),1.19–1.09(m,6H,OEt)ppm;

[0121] 13 C NMR (101MHz, CDCl3) δ166.3,165.7,163.8,161.8,140.5,134.9,134.3,134.2,131.6,1 31.5,130.8,130.1,129.7,128.2,124.6,123.8,88.8,63.2,62.7,62.5,13.9,13.8ppm;

[0122] HRMS-ESI([M+H] + )Calcd for:C 25 H 24 BrO8 + 531.0649;found 531.0649.

[0123] Example 12

[0124] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-ClC6H4, R3=Et, R4=R5=Et.

[0125]

[0126] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0127] The α-ketoester R2=4-ClC6H4, R3=Et was used in an amount of 51.0 mg (0.24 mmol) to obtain 71.7 mg of colorless oily liquid product with a yield of 74%.

[0128] 1 H NMR (400MHz, CDCl3) δ8.00–7.90(m,1H,ArH),7.53–7.34(m,5H,ArH),7.19(d,J=8.6Hz,2H,ArH),4.18–3.89(m,6H,OEt),1.20–1.03(m,9H,OEt);

[0129] 13C NMR (101MHz, CDCl3) δ166.4,165.8,163.8,161.8,140.5,135.4,134.9,134.2,133.7,13 1.6,130.8,130.1,129.5,128.6,128.2,124.6,88.8,63.2,62.7,62.5,13.83,13.79ppm;

[0130] HRMS-ESI([M+H] + )Calcd for:C 25 H 24 ClO8 + 487.1154; found 487.1168.

[0131] Example 13

[0132] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-PhC6H4, R3=Et, R4=R5=Et.

[0133]

[0134] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0135] The α-ketoester R2=4-PhC6H4, R3=Et was used in an amount of 61.0 mg (0.24 mmol) to obtain 104.2 mg of colorless oily liquid product with a yield of 99%.

[0136] 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.1Hz,1H,ArH),7.63(d,J=8.3Hz,2H,ArH),7.56–7.46(m,7H,ArH),7.41(dd,J1=J2=7.5 Hz,2H,ArH),7.33(dd,J1=J2=7.3Hz,1H,ArH),4.25–4.11(m,4H,OEt),4.00–3.88(m,2H,OEt),1.23–1.12(m,9H,OEt)ppm;

[0137] 13C NMR (101MHz, CDCl3) δ166.81,165.79,163.6,162.1,142.1,140.8,140.2,135.2,134.0,133.7,131.4, 130.7,130.0,129.0,128.6,128.2,127.8,127.1,126.9,124.8,89.2,63.0,62.6,62.3,13.8,13.7ppm;

[0138] HRMS-ESI([M+H] + )Calcd forC 31 H 29 O8 + 529.1857; found 529.1907.

[0139] Example 14

[0140] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=3-MeOC6H4, R3=Et, R4=R5=Et.

[0141]

[0142] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0143] The α-ketoester R2=3-MeOC6H4, R3=Et was used in an amount of 50.0 mg (0.24 mmol) to obtain 37.8 mg of a white solid product with a yield of 39% and a melting point of 113-115°C.

[0144] 1 H NMR (400MHz, CDCl3) δ8.10–7.98(m,1H,ArH),7.53–7.41(m,3H,ArH),7.20(dd,J1=J2=7.2Hz,1H,ArH),7.16–7.07(m,2H,ArH),6.87–6 .78(m,1H,ArH),4.23–4.08(m,4H,OEt),4.00–3.90(m,2H,OEt),3.76(s,3H,OMe),1.21(t,J=7.2Hz,3H,OEt),1.17–1.10(m,6H,OEt);

[0145] 13C NMR (101MHz, CDCl3) δ166.8,165.9,163.7,162.3,159.5,140.9,136.3,135.3,134.0,131.4,130.7,1 30.0,129.4,128.3,124.9,120.3,115.2,113.8,89.1,63.1,62.6,62.4,55.5,13.9,13.83,13.81ppm;

[0146] HRMS-ESI[M+Na] + Calcd for:C 26 H 26 NaO9 + 505.1469; found 505.1465.

[0147] Example 15

[0148] Synthesis of isochroman-1-one derivatives, where R1=H, R2=4- n BuC6H4, R3=Et, R4=R5=Et.

[0149]

[0150] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0151] α-ketoester R2=4- n BuC6H4, R3=Et, the dosage was 56.2 mg (0.24 mmol), and 97.3 mg of colorless oily liquid product was obtained, with a yield of 96%.

[0152] 1 H NMR (400MHz, CDCl3) δ8.07–7.96(m,1H,ArH),7.54–7.38(m,5H,ArH),7.09(d,J=8. 4Hz,2H,ArH),4.20–4.05(m,4H,OEt),3.90–3.76(m,2H,OEt),2.53(t,J=7.7Hz,2H, n Bu), 1.56–1.47 (m, 2H, n Bu), 1.33–1.25(m,2H, n Bu), 1.16(t, J=7.2Hz,3H, n Bu),1.10(t,J=7.1Hz,6H,OEt),0.86(t,J=7.3Hz,3H, n Bu)ppm;

[0153] 13 C NMR (101MHz, CDCl3) δ167.1,165.8,163.5,162.3,144.3,141.0,135.3,133.8,131.7,131.3,130.6 ,129.9,128.2,128.2,128.1,124.9,89.2,62.9,62.5,62.1,35.4,33.4,22.4,14.0,13.8,13.7ppm;

[0154] HRMS-ESI[M+Na] + Calcd for C 29 H 32 NaO8 + 531.1989;found 531.1990.

[0155] Example 16

[0156] Synthesis of isochroman-1-one derivatives, with the general structural formula wherein R1=H, R2=4-MeC6H4, R3=Et, R4=R5=Et.

[0157]

[0158] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0159] The α-ketoester R2=4-MeC6H4, R3=Et was used in an amount of 46.1 mg (0.24 mmol) to obtain 91.1 mg of a colorless oily liquid product with a yield of 98%.

[0160] 1 H NMR (400MHz, CDCl3) δ8.05–7.98(m,1H,ArH),7.53–7.38(m,5H,ArH),7.08(d,J=8.1Hz,2H,ArH),4.22–4.05 (m,4H,OEt),3.97–3.82(m,2H,OEt),2.26(s,3H,Et),1.18(t,J=7.2Hz,3H,OEt),1.15–1.07(m,6H,OEt)ppm;

[0161] 13C NMR (101MHz, CDCl3) δ166.9,165.8,163.5,162.2,141.0,139.3,135.2,133.9,131.8,131.3,13 0.5,129.8,128.9,128.1,127.9,124.8,89.2,62.9,62.5,62.2,21.2,13.73,13.70,13.69ppm;

[0162] HRMS-ESI([M+H] + )Calcd forC 26 H 27 O8 + 467.1700; found 467.1703.

[0163] Example 17

[0164] Synthesis of isochroman-1-one derivatives, wherein the general structural formula is R1 = H, R2 = 2-pyridyl, R3 = Et, R4 = R5 = Et.

[0165]

[0166] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0167] The α-ketoester R2 = 2-pyridyl, R3 = Et was used in an amount of 43.0 mg (0.24 mmol) to obtain 70.5 mg of a white solid product with a yield of 78% and a melting point of 111-113°C.

[0168] 1 H NMR (400MHz, CDCl3) δ8.43 (d, J=5.0Hz, 1H, ArH), 8.03 (dd, J1=6.0Hz, J2=3.2Hz, 1H, ArH ),7.76(d,J=8.0Hz,1H,ArH),7.71–7.62(m,1H,ArH),7.51–7.44(m,2H,ArH),7.38(dd, J1=5.8Hz,J2=3.2Hz,1H,ArH),7.18(dd,J1=7.1Hz,J2=5.2Hz,1H,ArH),4.24–4.08(m,4 H,OEt),3.92–3.75(m,2H,OEt),1.17(t,J=7.1Hz,3H,OEt),1.10(t,J=7.1Hz,6H,OEt);

[0169] 13C NMR (101MHz, CDCl3) δ166.5,165.9,163.5,162.2,154.4,148.6,140.9,136.5,134.8,133.8,13 1.4,130.2,129.8,128.2,124.9,124.1,124.0,89.6,62.9,62.5,62.2,13.8,13.74,13.71ppm;

[0170] HRMS-ESI([M+H] + )Calcd for C 24 H 24 NO8 + 454.1496; found 454.1506.

[0171] Example 18

[0172] Synthesis of isochroman-1-one derivatives, wherein the general structural formula is R1 = H, R2 = 2-thienyl, R3 = Et, R4 = R5 = Et.

[0173]

[0174] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0175] The α-ketoester R2 = 2-thienyl, R3 = Et was used in an amount of 44.2 mg (0.24 mmol) to obtain 64.2 mg of a yellow oily liquid product with a yield of 70%.

[0176] 1 H NMR (400MHz, CDCl3) δ8.09–8.02(m,1H,ArH),7.57–7.43(m,3H,ArH),7.31(dd,J1=5.1Hz,J2=1.3Hz,1H,ArH),7.19(dd,J1=3.7Hz,J2=1.3Hz,1H, ArH),6.90(dd,J1=5.1Hz,J2=3.7Hz,1H,ArH),4.23–4.10(m,4H,OEt),4.08–3.93(m,2H,OEt),1.21(t,J=7.1Hz,3H,OEt),1.18–1.09(m,6H,OEt);

[0177] 13C NMR (101MHz, CDCl3) δ166.1,165.6,163.5,161.6,140.2,137.4,134.6,134.0,131.5,1 30.2,130.0,129.4,128.3,127.9,126.5,124.8,86.7,63.3,62.6,62.4,13.8,13.7ppm;

[0178] HRMS-ESI[M+Na] + Calcd for C 23 H 22 NaO8S + 481.0928; found 481.0936.

[0179] Example 19

[0180] Synthesis of isochroman-1-one derivatives, wherein the general structural formula is R1 = H, R2 = Ph, R3 = (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl, and R4 = R5 = Et.

[0181]

[0182] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0183] The α-ketoester R2 = Ph, R3 = (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl was used in an amount of 69.2 mg (0.24 mmol) to obtain 86.6 mg of a colorless oily liquid product with a yield of 77% and a diastereoisomer ratio of 91:9.

[0184] 1 H NMR (400MHz, CDCl3) δ8.14–8.02(m,1H,ArH),7.64–7.49(m,4H,ArH),7.48–7.30(m,4H,ArH),4.64–4.53(m,1H,OCH),4.21–4.08(m,2 H,ArH,OEt),3.71–3.48(m,2H,OEt),1.78–1.21(m,7H),1.16–1.03(m,6H),0.97–0.77(m,6H),0.66(d,J=6.8Hz,2H),0.47(m,3H)ppm;

[0185] 13C NMR (101MHz, CDCl3) δ167.6,167.2,165.7,165.6,163.1,163.0,162.74,162.69,140.64,140.56,136. 0,135.5,134.1,133.8,133.8,133.7,131.2,131.12,131.08,129.98,129.96,129.7,129.6,128.8,128 .7,128.5,128.3,128.2,128.1,125.1,125.0,89.5,89.2,77.9,77.9,62.5,62.1,62.0,46.8,46.5,40. 2,39.8,34.0,31.5,31.4,25.49,25.45,23.0,22.6,22.1,22.0,21.0,20.9,15.9,15.5,13.8,13.7ppm;

[0186] HRMS-ESI([M+H] + )Calcd for C 33 H 39 O8 + 563.2639; found 563.2659.

[0187] Example 20

[0188] Synthesis of isochroman-1-one derivatives, where R1=H, R2=Ph, R3= t Bu, R4=R5=Et.

[0189]

[0190] The synthesis steps are basically the same as those in Example 6, except that the differences are listed below:

[0191] The α-ketoester used R2=Ph, R3= t Bu was used in an amount of 49.5 mg (0.24 mmol) to obtain 84.5 mg of a colorless oily liquid product with a yield of 88%.

[0192] 1H NMR(400MHz,CDCl3)δ8.11–8.03(m,1H,ArH),7.62–7.56(m,2H,ArH),7.56–7.49(m,2H,ArH),7.47–7.42(m,1H,ArH),7.37–7.30(m,3H),ArH,4.13(q,J=7.1Hz,2H,OEt),3.60(qd,J1=7.1Hz,J2=3.9Hz,2H,OEt),1.25(s,9H,O t Bu),1.09(dt,J1=9.2Hz,J2=7.2Hz,6H,OEt)ppm;

[0193] 13 C NMR(101MHz,CDCl3)δ166.4,165.7,163.1,162.9,141.4,135.7,134.1,133.7,131.3,130.6,129.8,129.6,128.8,128.3,128.2,125.3,89.4,84.7,62.5,62.0,27.6,13.72,13.70ppm;

[0194] HRMS(ESI)m / z:[M+H] + Calcd forC 27 H 29 O8 + 481.1857;found 481.1862。

Claims

1. A method for synthesizing an isochromanone derivative, characterized in that: The isochromanone derivatives have the structural formula shown in I or II: ， ， In the above structural formula, R1 is selected from hydrogen, alkyl, halogen or alkoxy; R2 is selected from alkyl, aryl or heteroaryl; R3 is selected from alkyl or aryl; R4 and R5 are selected from alkyl or aryl; The synthesis method of the isochromanone derivative is to prepare a phthalic anhydride derivative III or a 3-alkylene isobenzofuran-1(3 H )-Ketone Compound IV ， ， With α-keto ester V ， The reaction is carried out under the promotion of a phosphorus reagent to obtain; in the above structural formula, R1 is selected from hydrogen, alkyl, halogen or alkoxy; R2 is selected from alkyl, aryl or heteroaryl; R3 is selected from alkyl or aryl; R4 and R5 are selected from alkyl or aryl; The phosphorus reagent is hexamethylphosphoramidite P(NMe2)3.

2. The method for synthesizing an isochromanone derivative according to claim 1, wherein The synthesis steps include: α-ketoester and phthalic anhydride derivative or 3-alkylene isobenzofuran-1(3 H )-ketone compounds are dissolved in an organic solvent, and the resulting reaction mixture is stirred at -78°C to -40°C, and then the diluted phosphorus reagent is added dropwise to the above reaction mixture within 5 to 15 minutes, α-ketoester, phthalic anhydride derivative or 3-alkylene isobenzofuran-1(3 H The molar feed ratio of the )-ketone compound and the phosphorus reagent is 1-2:1:1-1.

5. After the dropwise addition is completed, the reaction is naturally warmed to room temperature and stirred for 2-3 hours. After the reaction is completed, the solvent is removed by rotary evaporation. The crude product is purified by 200-300 mesh silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 6:1-8:1 as the eluent. The yield of the obtained product is calculated to be 36-99%, depending on the target compound.

3. The method for synthesizing an isochromanone derivative according to claim 2, wherein: The organic solvent includes a non-polar solvent or a polar solvent, the non-polar solvent is toluene; the polar solvent includes one of tetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate, and the amount of the organic solvent used per mmol of α-ketoester is 5-20 mL.

4. The method for synthesizing an isochromanone derivative according to claim 1, wherein: The phosphorus reagent is diluted with an organic solvent and then added to the reaction system; the concentration of the diluted phosphorus reagent is 0.5~1 mol / L.

5. The method for synthesizing an isochromanone derivative according to claim 4, wherein: The organic solvent includes a non-polar solvent or a polar solvent, and the non-polar solvent is toluene; the polar solvent includes one of tetrahydrofuran, dichloromethane, acetonitrile, and ethyl acetate; and the organic solvent used to dilute the phosphorus reagent is the same as the organic solvent in the reaction system.

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