Synthesis method for constructing 4-substituted isocoumarin and analogues thereof through ring opening of oxetane

Abstract

The invention relates to the technical field of medicine preparation, discloses a synthesis method for constructing 4-substituted isocoumarin and analogues thereof through ring opening of oxetane, and synthesizes a series of isocoumarin derivatives. Comprising isocoumarin derivatives with 4-position hydroxymethyl substitution and 4-position amidomethyl substitution, and isocoumarin series compounds composed of five-membered heteroaromatic rings and dihydropyrone, and the synthesized isocoumarin series compounds have a plurality of functionalization sites, can be used as common intermediates in pharmaceutical chemistry research to rapidly provide series derivatives, and can be used for preparing the isocoumarin series compounds. Reaction raw materials and reagents used are convenient and easy to obtain and low in price, reaction conditions in the reaction process are mild, the process is simple, harsh conditions such as high temperature and high pressure are not needed, and the generated product does not contain metal ions, is convenient to separate and purify and is suitable for large-scale production in factories.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, in particular to a synthesis method for constructing 4-substituted isocoumarin and its analogs through 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 and are a variety of natural components in many plants. Isocoumarins and their derivatives have a variety of biological activities, not only have physiological and biological activities such as antibacterial, anti-inflammatory, anticancer, inhibition of protease activity and antioxidant properties, but also are key intermediates in the synthesis of heterocyclic compounds. In particular, their obvious anticancer activity has attracted widespread attention.

[0003] The prior art can conveniently and quickly synthesize 3-substituted isocoumarins and their derivatives, but there are few reports on the synthesis of 4-hydroxymethyl-substituted isocoumarins and the synthesis of isocoumarins composed of 5-membered aromatic heterocycles and dihydropyrone. In the existing synthesis method, it is impossible to synthesize isocoumarins without substitution at the 3rd position and substituted at the 4th position starting from the benzene ring substituted by alkynyl under non-metal catalysis conditions. Unlike the synthesis of 3-substituted isocoumarins, after the dihydropyrone ring of isocoumarins is cyclized by 6-endo using a metal catalyst starting from the alkynyl group, the intermediate metal cannot be replaced by hydroxymethyl to form the final product of 4-hydroxymethyl-substituted isocoumarins, and the 5-membered aromatic heterocycle substituted by the alkynyl group cannot be used as a substrate to cyclize to form tetrahydropyrone. There is currently no report on the isocoumarins composed of 5-membered aromatic heterocycles and dihydropyrone, and a new method is needed to synthesize them. In addition to the 4-hydroxymethyl substitution, the derivatives of isocoumarins such as the 4-amidomethyl substitution cannot be synthesized and prepared by the current synthesis means.

[0004] Oxetanes are a class of four-membered heterocyclic compounds containing oxygen atoms. They have unique chemical properties and broad application potential and are widely used in organic synthesis, medicinal chemistry, and materials science. The construction of 4-substituted isocoumarins and their analogs through the ring opening of oxetanes is conducive to exploring new structure-activity relationships and has broad application prospects. In the existing synthetic methods or processes, the synthesis and method routes of this compound and its analogs have not been reported. Summary of the invention

[0005] 1. Technical issues to be resolved In order to solve the above technical problems, the present invention provides a synthesis method for constructing 4-substituted isocoumarins and their analogs through ring opening of oxetane. The synthesis and method routes of the compounds and analogs have not been reported, and a new synthesis method is provided, which is conducive to exploring new structure-activity relationships and has broad application prospects.

[0006] (II) Technical solution In order to achieve the above object, the present invention discloses a synthesis method for constructing 4-substituted isocoumarin and its analogs by ring opening of oxetane, wherein the 4-substituted isocoumarin and its analogs have the following general structural formula: Formula 1 .

[0007] Preferably, in Formula 1, R1 is independently selected from one of methoxy OMe and amide NHCOR3.

[0008] Preferably, in Formula 1, 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.

[0009] Preferably, in Formula 1, R3 is independently selected from one of C1-C6 alkanes or C1-C6 halogenated alkanes.

[0010] Preferably, the aromatic ring in Formula 1 includes a benzene ring and a five-membered heteroaromatic ring.

[0011] Preferably, the five-membered heteroaromatic ring in Formula 1 is represented by Formula 2: Formula 2 .

[0012] Preferably, the formula 2 can be selected from the following groups: , , , , , , In Formula 2, R4 is independently selected from one of halogen, C1-C3 alkane or hydrogen; In Formula 2, X, Y, and Z are independently selected from one of carbon, oxygen, nitrogen, or sulfur; In Formula 2, R5 is independently selected from any electron-donating group, a neutral group, a C1-C6 alkane, a methoxy group, an amine group, a substituted amine group, a sulfide group, a silane group, a halogen, hydrogen or deuterium; these substituents may form a mono-substitution, a di-substitution or a tri-substitution; In Formula 2, R6 is independently selected from one of C1-C3 alkanes or hydrogen.

[0013] Furthermore, the formula 1 The compounds may be selected from but not limited to the following: .

[0014] Furthermore, the formula 2 Can be selected from but not limited to the following groups: , , , , , , , , , , .

[0015] Preferably, the synthetic route of the 4-substituted isocoumarins and their analogs is as follows: .

[0016] Furthermore, the preferred synthetic route of the 4-substituted isocoumarins and their analogs is as follows: .

[0017] The method disclosed in the present invention prepares 21 4-substituted isocoumarin derivatives, and the corresponding structural formulas are shown below:

[0018] 3. Beneficial technical effects (1) In the present invention, lithium diisopropylamide or n-butyl lithium is used to convert aromatic carboxylic acid or aromatic carboxylic acid with bromination at the leading position into a nucleophilic intermediate through hydrogen extraction reaction or lithium bromide exchange reaction, and then 3-oxetanone is subjected to SN2 reaction. The generated arylated 3-oxetanol is subjected to lactonization ring opening in a suitable protic acid environment to form a dihydroxy dihydropyrone intermediate, and a protic acid-mediated dehydration reaction is performed to obtain a 2-hydroxymethyl isocoumarin derivative. In a solvent containing a nitrile group, this product can be further converted to an amide through a Ritter reaction in the presence of a high concentration of protic acid, thereby generating a 4-amidomethyl isocoumarin compound. This conversion process can start not only from a phenyl substrate, but also from a 5-membered aromatic heterocyclic substrate, thereby synthesizing a series of isocoumarin compounds composed of a 5-membered aromatic heterocyclic and a dihydropyrone that have never been reported.

[0019] (2) The present invention uses a new method to synthesize a series of isocoumarin derivatives, especially isocoumarin with no substitution at the 3rd position and substitution at the 4th position. The new method obtains isocoumarin derivatives with hydroxymethyl substitution at the 4th position and amidomethyl substitution at the 4th position, respectively. The new method prepares a series of isocoumarin compounds composed of a 5-membered aromatic heterocycle and a dihydropyrone. The series of compounds synthesized by the new method fills many gaps in the series of 4-substituted isocoumarins in medicinal chemistry research. The synthesized isocoumarin series compounds have multiple functionalization sites and can be used as common intermediates in medicinal chemistry research to quickly provide a series of derivatives, which is very helpful for exploring new structure-activity relationships.

[0020] (3) The present invention does not use precious metal catalysts, and the reaction raw materials and reagents used are easy to obtain and inexpensive. In addition, the reaction conditions during the reaction are mild, the process is simple, and harsh conditions such as high temperature and high pressure are not required. The generated product does not contain metal ions, and is easy to separate and purify, which is suitable for factory scale-up production. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0022] The synthesis methods of 21 isocoumarin derivatives in the present invention are as follows.

[0023] Example 1 Synthesis of 2-bromo-5-(3-hydroxyoxetane)thiazole 4-carboxylic acid (III):

[0024] Under nitrogen protection at -78 °C, lithium diisopropylamide (2 M tetrahydrofuran solution, 30.0 mL, 60.1 mmol) was added dropwise to a solution of 2-bromo-4-carboxythiazole I (5.0 g, 24.0 mmol) dissolved in anhydrous tetrahydrofuran (50 mL) within 15 min. After the reaction was carried out for 0.5 h, a solution of 3-oxetanone II (3.46 g, 48.1 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) was added dropwise to the mixture within 20 min under nitrogen protection at -78 °C. After 2 h, 10 mL of H2O was slowly added to the reaction solution at 0 °C, and the pH value of the mixture 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 the solvent was evaporated by rotary evaporation. The crude product was pulped, filtered, and then freeze-dried to obtain product III (5.2 g, 17.7 mmol, 73.8% yield, 95.5% purity).

[0025] LCMS (ESI) m / z [M + H] + calcd. for C7H7BrNO4S 279.9; found: 280.0. 1 HNMR (400 MHz, DMSO-d6) δ 4.94 (d,J=7.2 Hz,2H),4.64 (d,J=7.2 Hz,2H). 13C NMR (100 MHz, DMSO-d6) δ 161.8,153.3,142.0,133.3,83.6,71.5. HRMS (ESI) m / z [M + H] + calcd. for C7H7BrNO4S 279.9274; found: 279.9276..

[0026] Example 2 Synthesis of 2-bromo-7-hydroxy-7-hydroxymethyl-6,7-dihydropyrone-3,4-thiazole (IV):

[0027] Toluenesulfonic acid monohydrate (204 mg, 1.1 mmol) was added to a solution of intermediate III (100 mg, 0.4 mmol) dissolved in 5 mL of 1,2-dichloroethane. The mixture was stirred at room temperature for 2 h and then dried by spin drying. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 0-10% dichloromethane / methanol gradient chromatography at a rate of 15 mL / min) to obtain product IV (80 mg, 71% yield).

[0028] LCMS (ESI) m / z [M + H] + calcd. for C7H7BrNO4S 279.9; found: 279.9. 1 HNMR (400 MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ 157.3,152.2,140.9,138.9,74.0,69.6,64.7. HRMS (ESI) m / z [M + H] + calcd. for C7H7BrNO4S 279.9279; found: 279.9269..

[0029] Example 3 Synthesis of 2-bromo-7-hydroxymethylpyrone thiazole (V):

[0030] 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 dried by spin drying. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 0-10% dichloromethane / methanol gradient chromatography at a rate of 15 mL / min) to give product V (100 mg, 85% yield).

[0031] LCMS (ESI) m / z [M + H] + calcd. for C7H5BrNO3S 261.9; found: 261.9. 1 HNMR (400 MHz, DMSO-d6) 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-d6) δ 154.9,148.9,144.6,139.4,137.8,115.8,57.1.HRMS (ESI) m / z [M + H] + calcd. for C7H5BrNO3S 261.9168; found: 261.9164..

[0032] Example 4 Synthesis of 2-bromo-7-hydroxymethylpyrone thiazole (V):

[0033] 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 dried by rotary evaporation. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 0-10% dichloromethane / methanol gradient chromatography at a rate of 15 mL / min) to obtain product V (67 mg, 64% yield).

[0034] The spectral data are the same as those in Example 3.

[0035] Example 5 Synthesis of N-(2-bromo-4-pyronethiazole)-methylacetamide (VI):

[0036] Sulfuric acid (1.4 g, 761.2 mL) was added to a solution of intermediate III (200 mg, 0.72 mmol) in 10 mL of acetonitrile. The mixture was stirred at 60 °C for 6 h, and then 30 mL of water was slowly added at 0 °C to quench the mixture. The reaction solution was extracted with ethyl acetate and dehydrated with anhydrous sodium sulfate. The solvent was then evaporated by rotary evaporation. The crude product was slurried, filtered and dried to obtain product VI (98 mg, 42.7% yield).

[0037] LCMS (ESI) m / z [M + H] + calcd. for C9H8BrN2O3S 302.9; found: 303.0. 1 HNMR (400 MHz, DMSO-d6) δ 8.43 – 8.30 (m,1H),7.90 – 7.80 (m,1H),4.19 (d,J=5.6Hz,2H),1.87 (s,3H). 13 C NMR (100 MHz, DMSO-d6) 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 C9H8BrN2O3S 302.9434; found: 302.9438.

[0038] Example 6 Synthesis of 2-(3-hydroxyoxetane)-4,5-bismethoxybenzoic acid (S2):

[0039] 2-Bromo-4,5-bismethoxy-benzoic acid S1 (1.0 g, 3.8 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and n-butyl lithium (2.5 M hexane solution 3.2 mL, 8.0 mmol) was dripped into the above solution under nitrogen protection at -78 °C. After stirring for 30 min, a solution of 3-oxetanone (552 mg, 7.7 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was dripped into the 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 dehydrated with anhydrous sodium sulfate, and the solvent was evaporated. 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).

[0040] LCMS (ESI) m / z [M – H2O + H] + calcd. for C 12 H 13 O5 237.1; found: 237.0. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 – H2O +H] + calcd. for C 12 H 13 O5 237.0757; found: 237.0756.

[0041] Example 7 Synthesis of 4-(3-hydroxyoxetane)-2-methylpyrazole-3-carboxylic acid (S4):

[0042] The reactants were 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid S3 (1.0 g, 4.9 mmol), n-butyl lithium (2.5 Min hexane, 4.1 mL, 10.2 mmol) and 3-oxetanone (703 mg, 9.8 mmol), and the other conditions were the same as in Example 6 to obtain the product S4 (405 mg, 1.96 mmol, 40.1% yield, 95.8% purity).

[0043] LCMS (ESI) m / z [M + H] + calcd. for C8H 11 N2O4 199.1; found: 199.0. 1 HNMR (400 MHz, DMSO-d6) 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-d6) δ 161.4,136.5,130.8,128.9,84.2,70.4. HRMS (ESI) m / z [M + H] + calcd. for C8H 11 N2O4 199.0713; found: 199.0694.

[0044] Example 8 Synthesis of 2-(3-hydroxyoxetane)thiophene-3-carboxylic acid (S6):

[0045] The reactants were 2-bromothiophene-3-carboxylic acid S5 (1.0 g, 4.8 mmol), n-butyl lithium (2.5 M in hexane, 4.1 mL, 10.1 mmol), 3-oxetanone (696 mg, 9.7 mmol), and the mobile phase of the chromatographic column was petroleum ether / ethyl acetate = 100 / 1 to 10 / 1. Other conditions were the same as those in Example 6 to obtain the product S6 (780 mg, 3.80 mmol, 78.7% yield, 97.5% purity).

[0046] LCMS (ESI) m / z [M + H] + calcd. for C8H9O4S 201.0; found: 201.1 1H NMR (400 MHz, DMSO-d6) 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-d6) δ 164.1,153.0,130.4,129.7,123.3,83.9,72.1. HRMS (ESI) m / z [M - H] - calcd. for C8H7O4S 199.0071; found: 199.0063.

[0047] Example 9 Synthesis of 4-(3-hydroxyoxetane)thiophene-3-carboxylic acid (S8):

[0048] The reactants were 4-bromothiophene-3-carboxylic acid S7 (500 mg, 2.4 mmol), n-butyl lithium (2.5 Minhexane, 2.0 mL, 5.1 mmol), and 3-oxetanone (348 mg, 4.8 mmol). Other conditions were the same as in Example 6 to obtain product S8 (350 mg, 1.7 mmol, 68.8% yield, 95% purity).

[0049] LCMS (ESI) m / z [M + H] + calcd. for C8H9O4S 201.0; found: 201.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d,J=5.2 Hz,1H),7.38 (d,J=5.2 Hz,1H),4.91 (d,J=7.2Hz,2H),4.72 (d,J=7.2 Hz,2H). 13 C NMR (100 MHz, DMSO-d6) 164.1,153.1,130.4,129.6,123.3,83.9,72.1. HRMS (ESI) m / z [M + H] + calcd. for C8H9O4S 201.0216; found: 201.0213.

[0050] Example 10 Synthesis of 2-bromo-7-(hydroxymethyl)-4H-pyrone thiazole (V):

[0051] 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 at 60 °C overnight and then dried by rotation. The crude product was subjected to flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 0-10% dichloromethane / methanol gradient chromatography at a rate of 15 mL / min) to obtain product V (74 mg, 71% yield). The spectral data were the same as those in Example 3. Condition B used 0.5 equivalents of sulfuric acid instead of p-toluenesulfonic acid monohydrate. The rest was the same as Condition A. The yield of Condition B was 71%. The spectral data were the same as those in Example 3.

[0052] Embodiment 11 Synthesis of 4-(Hydroxymethyl)-6,7-dimethoxyisocoumarin (VII):

[0053] The reactant was S2 (100 mg, 393.3 μmol), the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1, and the other conditions were the same as those of Example 10 Condition B to obtain product VII (60 mg, 251.13 μmol, 63.9% yield, 98.9% purity).

[0054] LCMS (ESI) m / z [M + H] + calcd. for C 12 H 13 O5 237.1; found: 237.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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] + calcd. for C 12 H 13 O5 237.0757; found: 237.0757.

[0055] Example 12 Synthesis of 4-(Hydroxymethyl)-1-methylpyrazolopyrone (VIII):

[0056] The reactant was S4 (100 mg, 504.6 μmol) and the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1. The other conditions were the same as condition B of Example 10 to obtain product VIII (81 mg, 427.1 μmol, 84.7% yield, 95% purity).

[0057] LCMS (ESI) m / z [M + H] + calcd. for C8H9N2O3 181.1; found: 181.3. 1 H NMR(400 MHz, DMSO-d6) 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-d6) δ 154.4,140.3,132.4,124.9,115.5,57.1,38.3. HRMS (ESI) m / z [M + H] + calcd. for C8H9N2O3 181.0608; found:181.0607..

[0058] Example 13 Synthesis of 7-(Hydroxymethyl)-[2,3]pyronethiophene (IX):

[0059] The reactant was S6 (100 mg, 499.5 μmol), the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1, and the other conditions were the same as condition B of Example 10 to obtain product IX (76 mg, 404.6 μmol, 81% yield, 96.8% purity).

[0060] LCMS (ESI) m / z [M + H] + calcd. for C8H7O3S 183.0; found: 183.1. 1H NMR (400 MHz, DMSO-d6) 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-d6) δ157.9,149.2,142.9,128.4,124.8,124.0,116.7,57.7. HRMS (ESI) m / z [M + H] + calcd. for C8H7O3S 183.0110; found: 183.0107..

[0061] Embodiment 14 Synthesis of 7-(Hydroxymethyl)-[3,4]pyronethiophene (X):

[0062] The reactant was S8 (100 mg, 499.5 μmol), the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1, and the other conditions were the same as those in Example 10. When p-toluenesulfonic acid monohydrate (285 mg, 1.50 mmol, condition A) was used, the product X (81 mg, 431.2 μmol, 86.3% yield, 97% purity) was obtained.

[0063] LCMS (ESI) m / z [M + H] + calcd. for C8H7O3S 183.0; found: 183.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) δ 157.9,149.2,142.9,128.4,124.8,124.0,116.7,57.8. HRMS (ESI) m / z [M + H] + calcd. forC8H7O3S 183.0110; found: 183.0108. The yield was 69% when sulfuric acid was used (condition B).

[0064] Embodiment 15 Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methoxyisochromone (XI):

[0065] The reactant was 2-bromo-5-methoxy-benzoic acid S9 (1.0 g, 4.3 mmol), the mobile phase of the chromatographic column was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, and the other conditions were the same as those in Example 6 to obtain the product XI (580 mg, 2.56 mmol, 60% yield, 99% purity).

[0066] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O5 225.1; found: 225.2. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 O5 225.0757; found: 225.0751.

[0067] Example 16 Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methoxy-6-methylisochromone (XII):

[0068] The reactant was 2-bromo-5-methoxy-4-methylbenzoic acid S10 (200 mg, 816.1 μmol), and the other conditions were the same as in Example 6 to obtain product XII (79.3 mg, 327.3 μmol, 40.1% yield, 98.4% purity).

[0069] LCMS (ESI) m / z [M + H] + calcd. for C 12 H 15 O5 239.1; found: 239.2. 1 H NMR(400 MHz, DMSO-d6) 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-d6) 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 O5239.0914; found: 239.0909.

[0070] Embodiment 17 Synthesis of 4-hydroxy-4-(hydroxymethyl)-7-methylisochromone (XIII):

[0071] The reactant was 2-bromo-5-methylbenzoic acid S11 (1.0 g, 4.7 mmol). Other conditions were the same as in Example 6 to obtain product XIII (507 mg, 2.4 mmol, 52.2% yield, 95% purity).

[0072] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O4 209.1; found: 209.1. 1H NMR (400 MHz, DMSO-d6) 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-d6) 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.forC 11 H 13 O4 209.0808; found: 209.0802.

[0073] Embodiment 18 Synthesis of 4-hydroxy-4-(hydroxymethyl)isochromanone (XIV):

[0074] The reactant was 2-bromobenzoic acid S12 (1.0 g, 5.0 mmol, 1 equiv), the chromatographic column mobile phase was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, and the other conditions were the same as in Example 6 to obtain the product XIV (390 mg, 2.0 mmol, 39.3% yield, 97.3% purity).

[0075] LCMS (ESI) m / z [M + H] + calcd. for C 10 H 11 O4 195.1; found: 195.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 O4 195.0506; found:193.0500..

[0076] Embodiment 19 Synthesis of 4-hydroxy-4-(hydroxymethyl)-6-methylisochromone (XV):

[0077] The reactant was 2-bromo-4-benzoic acid S13 (1.0 g, 4.7 mmol), and the other conditions were the same as in Example 6 to obtain product XV (460 mg, 2.1 mmol, 45.1% yield, 95% purity).

[0078] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O8 209.1; found: 209.2. 1 H NMR (400 MHz, DMSO-d6) 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-d6) δ163.9,144.3,144.2,129.3,128.9,125.4,123.5,70.7,68.8,65.4,21.5. HRMS (ESI) m / z[M + H] + calcd. for C 11 H 13 O8 209.0808; found: 209.0806.

[0079] Embodiment 20 Synthesis of 4-hydroxy-4-(hydroxymethyl)-6-methoxyisochromone (XVI):

[0080] The reactant was 2-bromo-4-methoxybenzoic acid (1.0 g, 4.3 mmol), the mobile phase of the chromatographic column was petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, and the other conditions were the same as those in Example 6 to obtain the product XVI (540 mg, 2.4 mmol, 54.7% yield, 98.4% purity).

[0081] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 13 O5 225.1; found: 225.2. 1 H NMR (400 MHz, CD3CN) 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, CD3CN) 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 O5 225.0757; found: 225.0752.

[0082] Embodiment 21 Synthesis of 4-(Hydroxymethyl)-7-methoxy-isocoumarin (XVII):

[0083] The reactant was 4-hydroxy-4-hydroxymethyl-7-methoxyisocoumarin XI (100 mg, 446.0 μmol). Condition B used sulfuric acid (21.9 mg, 223.0 μmol, 11.9 μL), and the reaction conditions were the same as those in Example 3 to obtain product XVII (78 mg, 376.73 μmol, 84.5% yield, 99.6% purity).

[0084] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O4 207.1; found: 207.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 O4 207.0652; found:207.0653.

[0085] Embodiment 22 Synthesis of 4-(Hydroxymethyl)-7-methoxy-6-methylisocoumarin (XVIII):

[0086] The reaction conditions were the same as those in Example 3, and the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1, to obtain the product XVIII (36.4 mg, 165.6 μmol, 73.2% yield, 98% purity).

[0087] LCMS (ESI) m / z [M + H] + calcd. for C 12 H 13 O4 221.1; found: 221.2. 1H NMR (400 MHz, DMSO-d6) 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-d6) 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 O4 221.0808; found: 221.0804.

[0088] Embodiment 23 Synthesis of 4-(Hydroxymethyl)-7-methylisocoumarin (XIX):

[0089] The reactant was XI (100 mg, 480.3 μmol), the reaction conditions were the same as in Example 3, the mobile phase of the chromatographic column 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.

[0090] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O3 191.1; found: 191.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 H11 O3 191.0703; found: 191.0702.

[0091] Embodiment 24 Synthesis of 4-hydroxymethylisocoumarin (XX):

[0092] The reactant was XIV (100 mg, 514.9 μmol), the reaction conditions were the same as in Example 3, the mobile phase of the chromatographic column was dichloromethane / methanol = 100 / 1 to 10 / 1, and the product XX (32 mg, 179.8 μmol, 34.92% yield, 99% purity) was obtained.

[0093] LCMS (ESI) m / z [M + H] + calcd. for C 11 H9O3 177.0; found: 177.1. 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 H9O3 177.0546; found:177.0545.

[0094] Embodiment 25 Synthesis of 4-(Hydroxymethyl)-6-methylisocoumarin (XXI):

[0095] The reactant was XV (100 mg, 480.3 μmol, 1 equiv), the reaction conditions were the same as in Example 3, the mobile phase of the chromatographic column 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.

[0096] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O3 191.1; found: 191.1. 1 H NMR(400 MHz,DMSO-d6) 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-d6) 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 O3 191.0703; found:191.0705.

[0097] Embodiment 26 Synthesis of 4-(Hydroxymethyl)-6-methoxyisocoumarin (XXII):

[0098] The reactant was XVI (100 mg, 446.0 μmol), the reaction conditions were the same as in Example 3, the mobile phase of the chromatographic column 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.

[0099] LCMS (ESI) m / z [M + H] + calcd. for C 11 H 11 O4 207.1; found: 207.1 1 H NMR (400 MHz, DMSO-d6) 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). 13C NMR (100 MHz, DMSO-d6) δ164.3,161.2,143.5,138.2,131.5,116.9,116.4,113.5,106.6,57.1,55.8. HRMS (ESI)m / z [M + H] + calcd. for C 11 H 11 O4 207.0652; found: 207.0647.

[0100] Embodiment 27 Synthesis of N-((2-bromo-4-oxo-4H-[3,4]pyranothiazolyl)methyl)-2,2,2-trichloroacetamide (XXIII):

[0101] 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 dehydrated with anhydrous sodium sulfate, and then the solvent was evaporated by rotary evaporation, the crude product was pulped and filtered and dried to obtain a crude product, which was purified by column chromatography (mobile phase was 0-20% ethyl acetate / petroleum ether gradient solvent) to obtain product XXIII (62 mg, 149.5 μmol, 20.9% yield, 98% purity).

[0102] LCMS (ESI) m / z [M + H] + calcd. for C9H5BrCl3N2O3S 404.8; found: 404.8. 1 H NMR (400 MHz, CD3CN) δ 7.93 (s,1H),7.63 (s,1H),4.37 (d,J=6.0 Hz,2H). 13 C NMR(100 MHz,CD3CN) 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 C9H5BrCl3N2O3S 404.8264; found: 404.8265..

[0103] Although the embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that all equivalent changes and improvements made within the scope of the present invention should still fall within the scope of 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 methoxy OMe 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 independently selected from one of hydrogen, C1-C6 alkane or C1-C6 halogenated alkane; The synthetic route of the 4-substituted isocoumarins and their analogs is as follows: 。 2. A method for synthesizing 4-substituted isocoumarins and their analogs by ring opening of oxetane according to claim 1, characterized in that: The aromatic ring in Formula 1 includes a benzene ring and a five-membered heteroaromatic ring.

3. A method for synthesizing 4-substituted isocoumarins and their analogs by ring opening of oxetane according to claim 2, characterized in that: The five-membered heteroaromatic ring in Formula 1 is represented by Formula 2: Formula 2 ; Includes the following groups: ， ， ， ， ， ， Wherein R4 is independently selected from one of halogen, C1-C3 alkane or hydrogen; X, Y, Z are independently selected from one of carbon, oxygen, nitrogen or sulfur; R5 is independently selected from any electron donating group, a neutral group, a C1-C6 alkane, a methoxy group, an amine group, a substituted amine group, a sulfide group, a silane group, a halogen group, hydrogen or deuterium; these substituents include mono-, di- or tri-substitutions; R6 is independently selected from one of C1-C3 alkanes or hydrogen.

4. 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: 。

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