A synthetic method for constructing 4-substituted isocoumarins and their analogues by ring-opening of oxetane

Abstract

The present invention relates to the technical field of drug preparation, and discloses a synthetic method for constructing 4-substituted isocoumarins and their analogs by oxetane ring opening. A series of isocoumarin derivatives have been synthesized, including isocoumarin derivatives substituted with hydroxymethyl at the 4-position and amide-methyl at the 4-position, and isocoumarin series compounds composed of 5-membered aromatic heterocycles and dihydropyranones. The synthesized isocoumarin series compounds have multiple functionalized sites, can rapidly provide a series of derivatives as common intermediates in medicinal chemistry research, are extremely beneficial to exploring new structure-activity relationships. The reaction raw materials and reagents used are convenient to obtain, inexpensive, the reaction conditions during the reaction are mild, the process is simple, and no harsh conditions such as high temperature and high pressure are required. The generated products do not contain metal ions, are convenient for separation and purification, and are suitable for large-scale production in factories.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and specifically to a synthesis method for constructing 4-substituted isocoumarins and their analogs by ring-opening of oxetane. Background Art

[0002] Isocoumarins are a class of lactone compounds with a benzochromenone skeleton structure. Isocoumarins and their derivatives are widely distributed in nature, with a large variety and being natural components in many plants. Isocoumarins and their derivatives have various biological activities, not only having physiological and biological activities such as antibacterial, anti-inflammatory, anticancer, protease activity inhibition, and antioxidant properties, but also being key intermediates in the process of synthesizing heterocyclic compounds. In particular, their obvious anticancer activity has attracted wide attention.

[0003] The prior art can conveniently and rapidly synthesize 3-substituted isocoumarins and their derivatives, but there are few reports on the synthesis of 4-hydroxymethyl-substituted isocoumarins and isocoumarins composed of a 5-membered aromatic heterocycle and dihydropyranone. In the existing synthesis methods, under non-metal catalytic conditions, it is impossible to synthesize isocoumarins with no substitution at the 3-position and substitution at the 4-position starting from an alkynyl-substituted benzene ring. Different from the synthesis of 3-substituted isocoumarins, after cyclizing the dihydropyranone ring of isocoumarin in a 6-endo manner using a metal catalyst starting from an alkynyl group, it is impossible to replace the metal in the intermediate state with a hydroxymethyl group to form a 4-hydroxymethyl-substituted isocoumarin end product, and an alkynyl-substituted 5-membered aromatic heterocycle cannot be used as a substrate to cyclize to form a tetrahydropyranone. There is currently no report on isocoumarins composed of a 5-membered aromatic heterocycle and dihydropyranone, and new methods are needed for synthesis. In addition to 4-hydroxymethyl substitution, derivatives of isocoumarins such as 4-aminomethyl substitution cannot be synthesized by the current synthesis means.

[0004] Oxetane is a class of four-membered heterocyclic compounds containing an oxygen atom, with unique chemical properties and broad application potential, and has extensive applications in the fields of organic synthesis, medicinal chemistry, and materials science. Constructing 4-substituted isocoumarins and their analogs by ring-opening of oxetane is beneficial to exploring new structure-activity relationships and has broad application prospects. In the existing synthesis methods or processes, there is no report on the synthesis and method routes of this compound and its analogs. Summary of the Invention

[0005] (I) Technical Problems to be Solved

[0006] In order to solve the above technical problems, the present invention provides a synthesis method for constructing 4-substituted isocoumarins and their analogs by ring-opening of oxetane. There is no report on the synthesis and method routes of this compound and its analogs. A new synthesis method is provided, which is beneficial to exploring new structure-activity relationships and has broad application prospects.

[0007] (II) Technical Solution

[0008] To achieve the above object, the present invention discloses a synthesis method for constructing 4-substituted isocoumarins and their analogs by oxetane ring opening. The 4-substituted isocoumarins and their analogs have the following general structural formula:

[0009] Formula 1 .

[0010] Preferably, in Formula 1, R 1 independently selects one from methoxy OMe or amide group NHCOR 3 .

[0011] Preferably, in Formula 1, R 2 independently selects one from hydrogen or hydroxyl. When R 2 is hydroxyl, the double bond on the pyranone ring is reduced. When R 2 is hydrogen, the double bond on the pyranone ring is not reduced.

[0012] Preferably, in Formula 1, R 3 independently selects one from C 1 -C 6 alkane or C 1 -C 6 haloalkane.

[0013] Preferably, the aromatic ring in Formula 1 includes one of benzene ring and five-membered heteroaromatic ring.

[0014] Preferably, the five-membered heteroaromatic ring in Formula 1 is represented by Formula 2:

[0015] Formula 2 .

[0016] Preferably, Formula 2 can be selected from the following groups:

[0017] , , ,

[0018] , , ,

[0019] In Formula 2, R 4 independently selects one from halogen, C 1 -C 3 alkane or hydrogen;

[0020] In Formula 2, X, Y, Z independently select one from carbon, oxygen, nitrogen or sulfur;

[0021] In Formula 2, R 5Independently selected from any electron-donating group, neutral group, C 1 -C 6 alkane, methoxy group, amino group, substituted amino group, sulfhydryl group, silyl group, halogen, hydrogen or deuterium; these substituents can form mono-substitution, di-substitution or tri-substitution;

[0022] In the formula 2, R 6 is independently selected from one of C 1 -C 3 alkane or hydrogen.

[0023] Furthermore, the formula 1 can be selected from, but not limited to, the following compounds:

[0024] .

[0025] Furthermore, the formula 2 can be selected from, but not limited to, the following groups:

[0026] , , , , , , , , , , .

[0027] Preferably, the synthetic route of the 4-substituted isocoumarin and its analogs is as follows:

[0028] .

[0029] Furthermore, the preferred synthetic route of the 4-substituted isocoumarin and its analogs is as follows:

[0030] .

[0031] 21 4-substituted isocoumarin derivatives are prepared by the method disclosed in the present invention, and the corresponding structural formulas are shown as follows:

[0032]

[0033] (III) Beneficial technical effects

[0034] (1) In the present invention, lithium diisopropylamide or n-butyllithium is used to convert aryl carboxylic acid or ortho-bromo aromatic carboxylic acid into a nucleophilic intermediate through a deprotonation reaction or a bromine-lithium exchange reaction, and then an SN2 reaction is carried out on 3-oxetone. The resulting arylated 3-oxetanol forms a dihydroxydihydropyranone intermediate through lactone ring opening in a suitable protonic acid environment, and a 2-hydroxymethylisocoumarin derivative is obtained through a dehydration reaction mediated by a protonic acid. In a solvent containing a nitrile group, this product can further convert the terminal hydroxyl group into an amide through a Ritter reaction in the presence of a high-concentration protonic acid, thereby generating a 4-aminomethylisocoumarin compound. This conversion process can not only start from a benzene substrate but also from a 5-membered heteroaromatic substrate, and thus a series of isocoumarin compounds composed of a 5-membered aromatic heterocycle and dihydropyranone that have not been reported can be synthesized.

[0035] (2) In the present invention, a series of isocoumarin derivatives are synthesized by a new method, especially isocoumarin with no substitution at the 3-position and substitution at the 4-position. The new method respectively obtains isocoumarin derivatives with a hydroxymethyl substitution at the 4-position and an aminomethyl substitution at the 4-position, and the new method prepares a series of isocoumarin compounds composed of a 5-membered aromatic heterocycle and dihydropyranone. The series of compounds synthesized by the new method fills many blanks in the series of 4-substituted isocoumarin in pharmaceutical chemistry research. The synthesized series of isocoumarin compounds have multiple functionalization sites and can quickly provide a series of derivatives as common intermediates in pharmaceutical chemistry research, which is extremely beneficial for exploring new structure-activity relationships.

[0036] (3) The present invention does not use noble metal catalysts, and the reaction raw materials and reagents used are all convenient to obtain and inexpensive. Moreover, the reaction conditions during the reaction process are mild and the process is simple, without requiring harsh conditions such as high temperature and high pressure. The generated product does not contain metal ions, is convenient for separation and purification, and is suitable for large-scale production in factories. Detailed implementation mode

[0037] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0038] The synthesis methods of 21 isocoumarin derivatives in the present invention are as follows.

[0039] Example 1

[0040] Synthesize 2-bromo-5-(3-hydroxyoxetane)thiazole-4-carboxylic acid (III):

[0041]

[0042] Under nitrogen protection at -78 °C, lithium diisopropylamide (2 M solution in tetrahydrofuran, 30.0 mL, 60.1 mmol) was added dropwise within 15 min to a solution formed by dissolving 2-bromo-4-thiazolecarboxylic acid I (5.0 g, 24.0 mmol) in anhydrous tetrahydrofuran (50 mL). After the reaction proceeded for 0.5 h, under nitrogen protection at -78 °C, a solution of 3-oxetanone II (3.46 g, 48.1 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to this mixture within 20 min. After 2 h, 10 mL of H 2 O was slowly mixed into the reaction solution at 0 °C, and then the pH value of the mixed solution was adjusted to about 3 using 1N hydrochloric acid solution. The reaction solution was extracted with ethyl acetate and dehydrated with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The crude product was slurried, filtered, dried by rotary evaporation, and then freeze-dried to obtain product III (5.2 g, 17.7 mmol, 73.8% yield, 95.5% purity).

[0043] LCMS (ESI) m / z [M + H] + calcd. for C 7 H 7 BrNO 4 S 279.9; found: 280.0. 1 HNMR (400 MHz, DMSO-d 6 ) δ 4.94 (d, J = 7.2 Hz, 2H), 4.64 (d, J = 7.2 Hz, 2H). 13 C NMR(100 MHz, DMSO-d 6 ) δ 161.8, 153.3, 142.0, 133.3, 83.6, 71.5. HRMS (ESI) m / z [M + H] + calcd. for C 7 H 7 BrNO 4 S 279.9274; found: 279.9276.。

[0044] Example 2

[0045] Synthesis of 2-bromo-7-hydroxy-7-hydroxymethyl-6,7-dihydropyranone-3,4-thiazole (IV):

[0046]

[0047] p -Toluenesulfonic acid monohydrate (204 mg, 1.1 mmol) was added to a solution of Intermediate III (100 mg, 0.4 mmol) in 5 mL of 1,2-dichloroethane. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, eluting with a gradient of 0 - 10% dichloromethane / methanol at a flow rate of 15 mL / min) to give Product IV (80 mg, 71% yield).

[0048] LCMS (ESI) m / z [M + H] + calcd. for C 7 H 7 BrNO 4 S 279.9; found: 279.9. 1 HNMR (400 MHz, DMSO-d 6 ) δ 6.44 (s, 1H), 5.64 (t, J = 5.2 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 3.66 – 3.59 (m, 1H), 3.54 – 3.47 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 157.3, 152.2, 140.9, 138.9, 74.0, 69.6, 64.7. HRMS (ESI) m / z [M + H] + calcd. for C 7 H 7 BrNO 4 S 279.9279; found: 279.9269.

[0049] Example 3

[0050] Synthesis of 2-Bromo-7-hydroxymethylpyran-4-one Thiazole (V):

[0051]

[0052] Sulfuric acid (21.9 mg, 0.223 mmol) was added to a solution of Intermediate Ⅳ (126 mg, 0.45 mmol) in 1,2-dichloroethane (6 mL). The mixture was stirred at 60 °C for 1 h and then concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, gradient elution with 0 - 10% dichloromethane / methanol at a flow rate of 15 mL / min) to give Product Ⅴ (100 mg, 85% yield).

[0053] LCMS (ESI) m / z [M + H] + calcd. for C 7 H 5 BrNO 3 S 261.9; found: 261.9. 1 HNMR (400 MHz, DMSO-d 6 ) δ 7.84 (s,1H), 5.71 (t, J = 5.2 Hz, 1H), 4.42 (dd, J = 5.2, 1.2Hz, 2H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 154.9, 148.9, 144.6, 139.4, 137.8, 115.8, 57.1. HRMS (ESI) m / z [M + H] + calcd. for C 7 H 5 BrNO 3 S 261.9168; found: 261.9164.

[0054] Example 4

[0055] Synthesis of 2-bromo-7-hydroxymethylpyran-4-one thiazole (V):

[0056]

[0057] p-Toluenesulfonic acid monohydrate (75 mg, 0.4 mmol) was added to a solution of Intermediate Ⅲ (100 mg, 0.4 mmol) in 5 mL of 1,2-dichloroethane. The mixture was stirred at 60 °C overnight and then concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, gradient elution with 0 - 10% dichloromethane / methanol at a flow rate of 15 mL / min) to give Product Ⅴ (67 mg, 64% yield).

[0058] The spectral data was the same as that in Example 3.

[0059] Example 5

[0060] Synthesis of N-(2-bromo-4-pyranone thiazole)-methylacetamide (VI):

[0061]

[0062] Sulfuric acid (1.4 g, 761.2 mL) was added to a solution of intermediate III (200 mg, 0.72 mmol) dissolved in 10 mL of acetonitrile. The mixture was stirred at 60 °C for 6 h, then slowly mixed with 30 mL of water at 0 °C to quench. The reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The crude product was slurried, filtered, and dried by rotary evaporation to obtain product VI (98 mg, 42.7% yield).

[0063] LCMS (ESI) m / z [M + H] + calcd. for C 9 H 8 BrN 2 O 3 S 302.9; found: 303.0. 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.43 – 8.30 (m, 1H), 7.90 – 7.80 (m, 1H), 4.19 (d, J = 5.6 Hz, 2H), 1.87 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 169.9, 154.5, 149.3, 146.4, 138.5, 137.6, 113.0, 36.5, 22.4. HRMS (ESI) m / z [M + H] + calcd. for C 9 H 8 BrN 2 O 3 S 302.9434; found: 302.9438.

[0064] Example 6

[0065] Synthesis of 2-(3-hydroxyoxetane)-4,5-dimethoxybenzoic acid (S2):

[0066]

[0067] 2-Bromo-4,5-dimethoxy-benzoic acid S1 (1.0 g, 3.8 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). n-Butyllithium (3.2 mL of 2.5 M hexane solution, 8.0 mmol) was added dropwise to the above solution under nitrogen protection at -78 °C. After stirring for 30 min, a solution of 3-oxetanone (552 mg, 7.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to this mixture at -78 °C under nitrogen protection. After 2 h, the reaction was warmed to 0 °C. 10 mL of water was slowly added to quench the reaction, and the pH was adjusted to 3 with 1 M hydrochloric acid solution. The reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The crude product was separated and purified by column chromatography (mobile phase gradient dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain S2 (460 mg, 1.77 mmol, 46.29% yield, 98% purity).

[0068] LCMS (ESI) m / z [M – H 2 O + H] + calcd. for C 12 H 13 O 5 237.1; found: 237.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.63 (s, 1H), 7.25 (s, 1H), 5.03 – 4.99 (m, 2H), 4.98 – 4.94 (m, 2H), 3.98 (s, 3H), 3.84 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 173.5, 160.5, 156.0, 147.0, 121.4, 110.7, 109.6, 89.0, 84.7, 61.6, 61.3. HRMS (ESI) m / z [M – H 2 O +H] + calcd. for C 12 H 13 O 5 237.0757; found: 237.0756.。

[0069] Example 7

[0070] Synthesis of 4-(3-hydroxyoxetane)-2-methylpyrazole-3-carboxylic acid (S4):

[0071]

[0072] The reactants were 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid S3 (1.0 g, 4.9 mmol), n-butyllithium (2.5 M in hexane, 4.1 mL, 10.2 mmol), and 3-oxetanone (703 mg, 9.8 mmol). Under the same conditions as in Example 6, the product S4 (405 mg, 1.96 mmol, 40.1% yield, 95.8% purity) was obtained.

[0073] LCMS (ESI) m / z [M + H] + calcd. for C 8 H 11 N 2 O 4 199.1; found: 199.0. 1 HNMR (400 MHz, DMSO-d 6 ) δ 7.62 (s, 1H), 4.85 (d, J = 6.8 Hz, 2H), 4.63 (d, J = 6.8 Hz, 2H), 4.04 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 161.4, 136.5, 130.8, 128.9, 84.2, 70.4. HRMS (ESI) m / z [M + H] + calcd. for C 8 H 11 N 2 O 4 199.0713; found: 199.0694.

[0074] Example 8

[0075] Synthesis of 2-(3-hydroxyoxetane)thiophene-3-carboxylic acid (S6):

[0076]

[0077] The reactants were 2-bromothiophene-3-carboxylic acid S5 (1.0 g, 4.8 mmol), n-butyllithium (2.5 M in hexane, 4.1 mL, 10.1 mmol), 3-oxetanone (696 mg, 9.7 mmol). The mobile phase for column chromatography was petroleum ether / ethyl acetate = 100 / 1 to 10 / 1. Under the same conditions as in Example 6, the product S6 (780 mg, 3.80 mmol, 78.7% yield, 97.5% purity) was obtained.

[0078] LCMS (ESI) m / z [M + H] + calcd. for C 8 H 9 O 4 S 201.0; found: 201.1 1 H NMR(400 MHz,DMSO-d 6 ) δ 7.49 (d,J=5.2 Hz,1H),7.38 (d,J=5.2 Hz,1H),4.91 (d,J=6.8Hz,2H),4.72 (d,J=6.8 Hz,2H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 164.1,153.0,130.4,129.7,123.3,83.9,72.1. HRMS (ESI) m / z [M - H] - calcd. for C 8 H 7 O 4 S 199.0071;found: 199.0063.

[0079] Example 9

[0080] Synthesis of 4-(3-hydroxyoxetane)thiophene-3-carboxylic acid (S8):

[0081]

[0082] The reactants were 4-bromothiophene-3-carboxylic acid S7 (500 mg, 2.4 mmol), n-butyllithium (2.5 M in hexane, 2.0 mL, 5.1 mmol), and 3-oxetanone (348 mg, 4.8 mmol). Other conditions were the same as in Example 6, and the product S8 (350 mg, 1.7 mmol, 68.8% yield, 95% purity) was obtained.

[0083] LCMS (ESI) m / z [M + H] + calcd. for C 8 H 9 O 4 S 201.0; found: 201.1. 1 H NMR(400 MHz,DMSO-d 6) δ 7.50 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 4.91 (d, J = 7.2 Hz, 2H), 4.72 (d, J = 7.2 Hz, 2H). 13 C NMR (100 MHz, DMSO-d 6 ) 164.1, 153.1, 130.4, 129.6, 123.3, 83.9, 72.1. HRMS (ESI) m / z [M + H] + calcd. for C 8 H 9 O 4 S 201.0216; found: 201.0213.。

[0084] Example 10

[0085] Synthesis of 2-bromo-7-(hydroxymethyl)-4H-pyranone thiazole (V):

[0086]

[0087] Condition A: p-Toluenesulfonic acid monohydrate (222 mg, 1.2 mmol) was added to a solution of intermediate III (100 mg, 0.4 mmol) dissolved in 6 mL of 1,2-dichloroethane. The mixture was stirred overnight at 60 °C and then concentrated in vacuo. The resulting crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, gradient elution with 0 - 10% dichloromethane / methanol at a flow rate of 15 mL / min) to give product V (74 mg, 71% yield). The spectral data was the same as in Example 3. Condition B: 0.5 equivalent of sulfuric acid was used instead of p-toluenesulfonic acid monohydrate, and the other conditions were the same as in Condition A. The yield of Condition B was 71%. The spectral data was the same as in Example 3.

[0088] Example 11

[0089] Synthesis of 4-(hydroxymethyl)-6,7-dimethoxyisocoumarin (VII):

[0090]

[0091] The reactant was S2 (100 mg, 393.3 μmol). The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1. Using the same other conditions as in Condition B of Example 10, product VII (60 mg, 251.13 μmol, 63.9% yield, 98.9% purity) was obtained.

[0092] LCMS (ESI) m / z [M + H]+ Calculated for C 12 H 13 O 5 237.1; found: 237.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.54 (s, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 8.0 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ161.3, 154.8, 149.3, 141.9, 131.5, 117.0, 113.5, 109.2, 105.0, 57.2, 56.1, 55.7. HRMS(ESI) m / z [M + H] + Calculated for C 12 H 13 O 5 237.0757; found: 237.0757.。

[0093] Example 12

[0094] Synthesis of 4-(hydroxymethyl)-1-methylpyrazolopyranone (VIII):

[0095]

[0096] The reactant was S4 (100 mg, 504.6 μmol). The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1. Other conditions were the same as those in Example 10, Condition B, to obtain product VIII (81 mg, 427.1 μmol, 84.7% yield, 95% purity).

[0097] LCMS (ESI) m / z [M + H] + Calculated for C 8 H 9 N 2 O 3 181.1; found: 181.3. 1 H NMR (400 MHz, DMSO-d 6) δ 7.95 (s,1H),7.35 (s,1H),5.31 (t,J=5.6 Hz,1H),4.45 – 4.42(m,2H),4.20 (s,3H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 154.4,140.3,132.4,124.9,115.5,57.1,38.3. HRMS (ESI) m / z [M + H] + calcd. for C 8 H 9 N 2 O 3 181.0608; found:181.0607.。

[0098] Example 13

[0099] Synthesis of 7-(hydroxymethyl)-[2,3]pyranothiophene (IX):

[0100]

[0101] The reactant was S6 (100 mg, 499.5 μmol). The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1. Other conditions were the same as those in Condition B of Example 10, and the product IX (76 mg, 404.6 μmol, 81% yield, 96.8% purity) was obtained.

[0102] LCMS (ESI) m / z [M + H] + calcd. for C 8 H 7 O 3 S 183.0; found: 183.1. 1 H NMR(400 MHz,DMSO-d 6 ) δ 7.81 (d,J=5.2 Hz,1H),7.69 (s,1H),7.56 (d,J=5.2 Hz,1H),5.44 (t,J=5.2 Hz,1H),4.45 (dd,J=5.2,0.8 Hz,2H). 13 C NMR (100 MHz,DMSO-d 6 ) δ157.9,149.2,142.9,128.4,124.8,124.0,116.7,57.7. HRMS (ESI) m / z [M + H] + calcd. for C8 H 7 O 3 S 183.0110; found: 183.0107.

[0103] Example 14

[0104] Synthesis of 7-(hydroxymethyl)-[3,4]pyranothiophene (X):

[0105]

[0106] The reactant was S8 (100 mg, 499.5 μmol). The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1. Other conditions were the same as in Example 10. When using p-toluenesulfonic acid monohydrate (285 mg, 1.50 mmol, Condition A), product X (81 mg, 431.2 μmol, 86.3% yield, 97% purity) was obtained.

[0107] LCMS (ESI) m / z [M + H] + calcd. for C 8 H 7 O 3 S 183.0; found: 183.1. 1 H NMR(400 MHz,DMSO-d 6 ) δ 7.81 (d,J=5.2 Hz,1H),7.68 (s,1H),7.56 (d,J=5.2 Hz,1H),5.44 (t,J=5.2 Hz,1H),4.45 (d,J=4.8 Hz,2H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 157.9,149.2,142.9,128.4,124.8,124.0,116.7,57.8. HRMS (ESI) m / z [M + H] + calcd. forC 8 H 7 O 3 S 183.0110; found: 183.0108. The yield was 69% when using sulfuric acid (Condition B).

[0108] Example 15

[0109] Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methoxyisochromanone (XI):

[0110]

[0111] The reactant was 2-bromo-5-methoxy-benzoic acid S9 (1.0 g, 4.3 mmol). The mobile phase for column chromatography was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1. Other conditions were the same as in Example 6, and the product XI (580 mg, 2.56 mmol, 60% yield, 99% purity) was obtained.

[0112] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 5 225.1; found: 225.2. 1 H NMR(400 MHz, DMSO-d 6 ) δ 7.53 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H), 7.29 (dd, J = 8.4, 2.8 Hz, 1H), 5.70 – 5.58 (m, 1H), 5.19 – 5.02 (m, 1H), 4.44 (d, J = 10.8 Hz, 1H), 4.18(d, J = 10.8 Hz, 1H), 3.81 (s, 3H), 3.56 – 3.50 (m, 1H), 3.48 – 3.43 (m, 1H). 13 C NMR(100 MHz, DMSO-d 6 ) δ 163.9, 158.9, 136.4, 126.7, 124.6, 120.8, 112.4, 71.2, 68.5, 65.3, 55.5. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 5 225.0757; found: 225.0751.

[0113] Example 16

[0114] Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methoxy-6-methylisochromanone (XII):

[0115]

[0116] The reactant was 2-bromo-5-methoxy-4-methylbenzoic acid S10 (200 mg, 816.1 μmol). Other conditions were the same as in Example 6, and the product XII (79.3 mg, 327.3 μmol, 40.1% yield, 98.4% purity) was obtained.

[0117] LCMS (ESI) m / z [M + H] + calcd. for C 12 H 15 O 5 239.1; found: 239.2. 1 H NMR(400 MHz,DMSO-d 6 ) δ 7.39 (s,1H),7.33 (s,1H),5.91 – 5.44 (m,1H),5.37 – 4.72(m,1H),4.43 (d,J=10.8 Hz,1H),4.15 (d,J=10.8 Hz,1H),3.84 (s,3H),3.51 (s,2H),2.24 (s,3H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 164.0,157.0,136.4,132.9,127.2,122.2,109.3,71.1,68.5,65.3,55.6,16.6. HRMS (ESI) m / z [M + H] + calcd. for C 12 H 15 O 5 239.0914; found: 239.0909.

[0118] Example 17

[0119] Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methylisochromanone (XIII):

[0120]

[0121] The reactant was 2-bromo-5-methylbenzoic acid S11 (1.0 g, 4.7 mmol). Other conditions were the same as in Example 6, and the product XIII (507 mg, 2.4 mmol, 52.2% yield, 95% purity) was obtained.

[0122] LCMS (ESI) m / z [M + H] + calcd. for C 11 H13 O 4 209.1; found: 209.1. 1 H NMR(400 MHz, DMSO-d 6 ) δ 7.71 (s, 1H), 7.56 – 7.48 (m, 2H), 5.67 (s, 1H), 5.13 (t, J = 5.8Hz, 1H), 4.44 (d, J = 10.8 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.56 – 3.49 (m, 1H), 3.49 – 3.42 (m, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.0, 141.3, 137.7, 134.6, 129.2, 125.0, 123.3, 70.8, 68.6, 65.3, 20.5. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 4 209.0808; found: 209.0802.

[0123] Example 18

[0124] Synthesis of 4-hydroxy-4-(hydroxymethyl)isochromanone (XIV):

[0125]

[0126] The reactant was 2-bromobenzoic acid S12 (1.0 g, 5.0 mmol, 1 equiv). The mobile phase for column chromatography was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1. Other conditions were the same as in Example 6, and the product XIV (390 mg, 2.0 mmol, 39.3% yield, 97.3% purity) was obtained.

[0127] LCMS (ESI) m / z [M + H] + calcd. for C 10 H 11 O 4 195.1; found: 195.1. 1 H NMR(400 MHz, DMSO-d 6) δ 7.90 (dd, J = 8.0, 1.2 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.62 (dd, J = 7.6, 0.8 Hz, 1H), 7.50 (dd, J = 7.6, 1.2 Hz, 1H), 5.73 (s, 1H), 5.15 (t, J = 5.6 Hz, 1H), 4.46 (d, J = 10.8 Hz, 1H), 4.22 (d, J = 10.8 Hz, 1H), 3.59 – 3.53 (m, 1H), 3.64 – 3.46 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 163.8, 144.2, 133.9, 129.1, 128.2, 125.0, 123.5, 70.8, 68.8, 65.4. HRMS (ESI) m / z [M + H] + calcd. for C 10 H 11 O 4 195.0506; found: 193.0500.

[0128] Example 19

[0129] Synthesis of 4-hydroxy-4-(hydroxymethyl)-6-methylisochromanone (XV):

[0130]

[0131] The reactant was 2-bromo-4-benzoic acid S13 (1.0 g, 4.7 mmol). Other conditions were the same as in Example 6, and the product XV (460 mg, 2.1 mmol, 45.1% yield, 95% purity) was obtained.

[0132] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 8 209.1; found: 209.2. 1 H NMR (400 MHz, DMSO-d 6) δ 7.79 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.70 (s, 1H), 5.15 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 10.8 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.57 – 3.50 (m, 1H), 3.49 – 3.43 (m, 1H), 2.41 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 163.9, 144.3, 144.2, 129.3, 128.9, 125.4, 123.5, 70.7, 68.8, 65.4, 21.5. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 8 209.0808; found: 209.0806.。

[0133] Example 20

[0134] Synthesis of 4-hydroxy-4-(hydroxymethyl)-6-methoxyisochromanone (XVI):

[0135]

[0136] The reactant was 2-bromo-4-methoxybenzoic acid (1.0 g, 4.3 mmol). The mobile phase for column chromatography was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1. Other conditions were the same as in Example 6, and the product XVI (540 mg, 2.4 mmol, 54.7% yield, 98.4% purity) was obtained.

[0137] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 5 225.1; found: 225.2. 1 H NMR(400 MHz, CD 3CN) δ 7.92 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 4.44 (d, J = 10.8 Hz, 1H), 4.23 – 4.17 (m, 1H), 3.89 (s, 3H), 3.86 (s, 1H), 3.69 (dd, J = 11.8, 5.6 Hz, 1H), 3.53 (dd, J = 11.6, 4.4 Hz, 1H), 3.36 (t, J = 5.6 Hz, 1H). 13 C NMR (100 MHz, CD 3 CN) δ 165.3, 165.0, 146.9, 133.1, 115.6, 110.4, 71.1, 70.7, 66.3, 56.6. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O 5 225.0757; found: 225.0752.。

[0138] Example 21

[0139] Synthesis of 4-(hydroxymethyl)-7-methoxy-isocoumarin (XVII):

[0140]

[0141] The reactant was 4-hydroxy-4-hydroxymethyl-7-methoxyisocoumarin XI (100 mg, 446.0 μmol). Sulfuric acid (21.9 mg, 223.0 μmol, 11.9 μL) was used under Condition B, and the reaction conditions were the same as in Example 3 to obtain product XVII (78 mg, 376.73 μmol, 84.5% yield, 99.6% purity).

[0142] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 4 207.1; found: 207.1. 1 H NMR(400 MHz, DMSO-d 6) δ 7.75 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (s, 1H), 5.23 (t, J = 5.2 Hz, 1H), 4.49 (d, J = 5.2 Hz, 2H), 3.89 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 161.5, 159.1, 140.8, 129.4, 125.6, 123.6, 121.9, 116.9, 110.3, 57.1, 55.6. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 4 207.0652; found: 207.0653.。

[0143] Example 22

[0144] Synthesis of 4-(hydroxymethyl)-7-methoxy-6-methylisocoumarin (XVIII):

[0145]

[0146] The reaction conditions were the same as in Example 3, and the mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1, to obtain product XVIII (36.4 mg, 165.6 μmol, 73.2% yield, 98% purity).

[0147] LCMS (ESI) m / z [M + H] + calcd. for C 12 H 13 O 4 221.1; found: 221.2. 1 H NMR(400 MHz, DMSO-d 6 ) δ 7.61 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 5.21 (t, J = 5.6 Hz, 1H), 4.48 (dd, J = 5.6, 0.8 Hz, 2H), 3.92 (s, 3H), 2.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6) δ161.6,157.5,141.1,135.3,129.4,125.6,119.7,116.9,107.7,57.01,55.7,16.8. HRMS(ESI) m / z [M + H] + calcd. for C 12 H 13 O 4 221.0808; found: 221.0804.。

[0148] Example 23

[0149] Synthesis of 4-(hydroxymethyl)-7-methylisocoumarin (XIX):

[0150]

[0151] The reactant was XI (100 mg, 480.3 μmol), and the reaction conditions were the same as those in Example 3. The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1, and the product XIX (63 mg, 318.8 μmol, 66.4% yield, 96.2% purity) was obtained.

[0152] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 3 191.1; found: 191.1. 1 H NMR(400 MHz,DMSO-d 6 ) δ 8.00 (s,1H),7.75 – 7.68 (m,2H),7.51 (s,1H),5.22 (t,J=5.2Hz,1H),4.50 (d,J=5.2 Hz,2H),2.45 (s,3H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 161.7,142.1,138.5,136.2,133.5,128.7,123.8,120.5,117.0,57.1,20.8. HRMS (ESI) m / z [M+ H] + calcd. for C 11 H 11 O 3 191.0703; found: 191.0702.。

[0153] Example 24

[0154] Synthesis of 4-hydroxymethylisocoumarin (XX):

[0155]

[0156] The reactant was XIV (100 mg, 514.9 μmol), and the reaction conditions were the same as those in Example 3. The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1, and the product XX (32 mg, 179.8 μmol, 34.92% yield, 99% purity) was obtained.

[0157] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 9 O 3 177.0; found: 177.1. 1 H NMR(400 MHz,DMSO-d 6 ) δ 8.19 (d,J=8.0 Hz,1H),7.94 – 7.87 (m,1H),7.79 (d,J=8.0 Hz,1H),7.69 – 7.60 (m,1H),7.56 (s,1H),5.26 (t,J=5.2 Hz,1H),4.52 (d,J=5.2 Hz,2H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 161.7,143.0,136.0,135.2,129.2,128.8,123.9,120.6,117.1,57.1. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 9 O 3 177.0546; found:177.0545.

[0158] Example 25

[0159] Synthesis of 4-(hydroxymethyl)-6-methylisocoumarin (XXI):

[0160]

[0161] The reactant was XV (100 mg, 480.3 μmol, 1 equiv). The reaction conditions were the same as those in Example 3. The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1, and the product XXI (59.0 mg, 308.7 μmol, 65% yield, 99.5% purity) was obtained.

[0162] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 3 191.1; found: 191.1. 1 H NMR(400 MHz, DMSO-d 6 ) δ 8.08 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.48 – 7.43(m, 1H), 5.23 (t, J = 5.2 Hz, 1H), 4.50 (dd, J = 5.2, 0.8 Hz, 2H), 2.48 (s, 3H). 13 C NMR(100 MHz, DMSO-d 6 ) δ 161.5, 145.8, 143.0, 135.9, 129.8, 129.1, 123.6, 118.1, 116.9, 57.0, 21.7. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 3 191.0703; found: 191.0705.

[0163] Example 26

[0164] Synthesis of 4-(hydroxymethyl)-6-methoxyisocoumarin (XXII):

[0165]

[0166] The reactant was XVI (100 mg, 446.0 μmol). The reaction conditions were the same as those in Example 3. The mobile phase for column chromatography was dichloromethane / methanol = 100 / 1 to 10 / 1, and the product XXII (28.2 mg, 135.6 μmol, 30.41% yield, 99% purity) was obtained.

[0167] LCMS (ESI) m / z [M + H] + calcd. for C11 H 11 O 4 207.1; found: 207.1 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.24 – 7.13 (m, 2H), 5.27 (t, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H). 13 13C NMR (100 MHz, DMSO-d 6 ) δ 164.3, 161.2, 143.5, 138.2, 131.5, 116.9, 116.4, 113.5, 106.6, 57.1, 55.8. HRMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O 4 207.0652; found: 207.0647.

[0168] Example 27

[0169] Synthesis of N-((2-bromo-4-oxo-4H-[3,4]pyranothiazolyl)methyl)-2,2,2-trichloroacetamide (XXIII):

[0170]

[0171] Sulfuric acid (700.3 mg, 7.1 mmol, 380.6 μL) was added to a solution of compound IV (200 mg, 714.0 μmol) dissolved in 2,2,2-trichloroacetonitrile (5 mL). The mixture was stirred at 60 °C for 6 h, then slowly mixed with 30 mL of water at 0 °C to quench. The reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The crude product was obtained by filtration after pulping and then dried by rotary evaporation. The crude product was purified by column chromatography (mobile phase: 0 - 20% ethyl acetate / petroleum ether gradient solvent) to obtain product XXIII (62 mg, 149.5 μmol, 20.9% yield, 98% purity).

[0172] LCMS (ESI) m / z [M + H] + calcd. for C 9 H 5 BrCl 3 N2 O 3 S 404.8; found: 404.8. 1 H NMR (400 MHz, CD 3 CN) δ 7.93 (s, 1H), 7.63 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H). 13 C NMR(100 MHz, CD 3 CN) δ 163.4, 155.8, 150.6, 148.4, 139.4, 138.8, 112.4, 93.1, 40.3. HRMS(ESI) m / z [M + H] + calcd. for C 9 H 5 BrCl 3 N 2 O 3 S 404.8264; found: 404.8265.。

[0173] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. All equivalent changes and improvements made in accordance with the scope of the present invention application shall still fall within the scope covered by the present invention.

Claims

1. A method for synthesizing 4-substituted isocoumarins and their analogs by ring opening of oxetane, characterized in that: The 4-substituted isocoumarins and their analogs have the following general structural formula: Formula 1 ; in, R1 is independently selected from one of hydroxyl or amide NHCOR3; R2 is independently selected from one of hydrogen and hydroxyl, when R2 is hydroxyl, the double bond on the pyrone ring is reduced, and when R2 is hydrogen, the double bond on the pyrone ring is not reduced; R3 is one of C1-C6 alkanes; The synthetic route of the 4-substituted isocoumarins and their analogs is as follows: ； In the synthetic route of the 4-substituted isocoumarin and its analogs, the alkyl in the chemical formula E is R3; Ar in Formula 1 is selected from a benzene ring and a five-membered heteroaromatic ring.

2. A method for synthesizing 4-substituted isocoumarins and their analogs by ring opening of oxetane according to claim 1, characterized in that: The synthesis method is as follows: 。 3. A method for synthesizing 4-substituted isocoumarins and their analogs by ring opening of oxetane, characterized in that: The 4-substituted isocoumarins and their analogs have the following general structural formula: Formula 1 ; in, R1 is independently selected from one of hydroxyl or amide NHCOR3; R2 is independently selected from one of hydrogen and hydroxyl, when R2 is hydroxyl, the double bond on the pyrone ring is reduced, and when R2 is hydrogen, the double bond on the pyrone ring is not reduced; R3 is one of C1-C6 alkanes; The general formula of Ar in Formula 1 is as follows: Formula 2 ; Ar in Formula 2 is selected from the following groups: ， ， ， ， ， ， Wherein R4 is independently selected from one of halogen, C1-C3 alkane or hydrogen; R5 is independently selected from one of C1-C6 alkane, methoxy, thiol, halogen, hydrogen or deuterium; these substituents include mono-, di- or tri-substitution; R6 is independently selected from one of C1-C3 alkanes or hydrogen; X is independently selected from one of carbon and nitrogen; Y, Z are independently selected from one of carbon, oxygen, nitrogen or sulfur; The synthetic route of the 4-substituted isocoumarins and their analogs is as follows: 。

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