TWI287009B - Method for producing 8-hydroxyjulolidine and analogs thereof - Google Patents

Abstract

This invention provides a method for producing 8-hydroxyjulolidine and analog thereof. This invention utilizes 3-aminophenol or 1,3-dihydroxy-5-aniline and 1,3-dihalo-propane or analog thereof to proceed the cyclization, which only needs one step reaction to synthesize the required cycloalkane-containing phenol compound and improves the producing efficiency. The compounds produced according to this invention have following chemical structure: wherein, R1 and R2 represent substituents such as hydrogen, halogen, hydroxyl or alkyl and so on. The method of this invention comprises the following chemical reaction: wherein, X and Y represent leaving groups such as halogen, acyloxy group, sulfonyl group or phosphonyl group and so on, and the definitions of R1 and R1 are the same as the previous. This invention also provides the method of producing the coumarin compound by further proceeding the addition of 8-hydroxyjulolidine and analogs thereof. The products and intermediate products produced by each method in this invention are also provided.

Description

1287009 A7 B7 V. INSTRUCTIONS (/) [Application Fields of the Invention] The present invention relates to a method for producing 8-hydroxyindole (8-hydr〇xyjiilolidine) and the like: 2 wherein 'R1 and R2 represents a substituent such as a hydrogen atom, a dentate, a hydroxyl group or an alkyl group; [Background of the Invention] The coumarin of the Ministry of Economic Affairs, the Intellectual Property Bureau employee consumption cooperative, has a high quantum yield due to the small overlap of absorption and emission spectra. The high molar absorption constant, with an unusual tuning wavelength range, is one of the most commonly used laser dyes and can be used as an indicator of biometric fluorescence. The 7-amino based rigid molecule is immobilized by a cycloalkylation process according to the techniques disclosed in U.S. Patent No. 3,873,940, U.S. Patent No. 3,932,415, U.S. Patent No. 4,005,092, U.S. Patent No. 4,471,041, U.S. Patent No. 4,736,032, and U.S. Patent No. 4,794,184, It will greatly increase the dipole moment and reduce the energy loss caused by the rotation of the amine group. This increases the fluorescence quantum yield of the coumarin laser dye, thereby greatly improving the luminescent efficacy of the laser dye. The method of making 8-base Zhulu Lijun and 8,10-two light-based Zhululi bite is reported. 3 The paper size is applicable to the Chinese National Standard (CNs) μ specification (210X297 mm) Ϊ287009 A7 B7 V. Invention Description (>) According to US Patent 4,005,092 ' US Patent 4,471,041 and Jbwrwa/ CAemiy/7 1987 52 Volume 1465 -1468 pages and other conventional inventions and literatures, all from 3-anthoxyaniline (m-anisidine) or 3,5-dimethoxyaniline (3,5-dimethoxyaniline) with a large amount of 1-bromo- 3-chloropropane (l-bromo-3-chloropropane) is obtained by subjecting a cycloalkylation reaction to removal of a methyl group with a strong acid. To obtain 3 methoxyaniline or 3,5-dimethoxyaniline, usually by 3-aminophenol or 3,5-dihydroxyaniline (3,5-dihydroxyaniline) The methylation reaction is carried out by dimethyl sulfate. The above preparation method has the following disadvantages: (1) using a large amount (7.6 to 15 moles of multiple) of bromine-3-chloropropane, the benefit of not expanding the production, and (2) removing the methyl group by using hydrochloric acid, iodic acid or A corrosive strong acid such as boron tribromide. (3) First use toxic dimethyl sulfate to protect the hydroxyl group. After the cycloalkylation reaction, it is necessary to remove the methyl group with a strong acid. Add two steps to reduce the total yield (<3〇〇/0) . [Objective of the Invention] Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives In view of the above, it is an object of the present invention to provide a novel process for the manufacture of hydroxyquinone and similar compounds. Only one step of the reaction is required, and the desired naphthenic compound can be easily synthesized without the need to pass through the protecting group and removing the methyl group. The object of the present invention is also to provide a novel 8-hydroxyazuridine and its similar four paper scales applicable to the Chinese National Standard (CNS) M specification (21〇乂297 公董)!287〇〇9 A7 B7 V. Invention Description (Today) The method of producing a compound can avoid the use of a toxic dimethyl sulfate reagent. Another object of the present invention is to provide a novel method for producing 8-hydroxycampidine and the like, which can reduce the amount of 1-bromo-3-aeropropane used and reduce the disposal of waste or waste. Save manufacturing costs and meet the requirements of the cleaning process. Still another object of the present invention is to provide a novel method for producing 8-hydroxyl-cilicitidine and the like, which can avoid the use of a corrosive strong acid such as hydrochloric acid, iodic acid or boron tribromide. It is also an object of the present invention to provide a process for preparing 8-hydroxyculpidine and the like using only a monohydric solvent or an organic solvent and a combination thereof. [Summary of the Invention] Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives The present invention provides a novel method for producing 8-hydroxyxatilidine and the like. Only one step of the reaction is required, and the desired cycloalkanol compound can be easily synthesized without the steps of protecting the radical and removing the methyl group. The chemical reaction of the process of the present invention is as shown in the following formula, and as long as the appropriate reaction conditions are employed, it is possible to selectively carry out the alkylation reaction only on the amine group without affecting the hydroxyl group. Therefore, the present invention provides a simple method for the manufacture of hydrazinodine and the like, and the multi-step inverse paper size reported in the literature is applicable to the Chinese National Standard (CMS) A4 specification (210X297 mm) 1287009 A7 B7. DESCRIPTION OF THE INVENTION (屮) The total yield of the product should be comparable or higher than the yield of the present invention, which not only shortens the process time but also saves manufacturing costs. The method of the invention comprises a chemical reaction of the formula:

R2 H2N v, OH (Additive) 1

X(CH2)3Y

In the above formula, 'R1 and R2 represent a substituent such as a hydrogen atom, a dentate, a trans group or a decyl group, and X and Y represent a leaving group such as a dentate, a decyloxy group or a sulfonyloxy group. The reaction solution may be added with an organic base or an inorganic base or a surfactant. The product obtained by the present invention has the following chemical formula:

The Ministry of Economic Affairs, Intellectual Property Office, and the Consumers' Union, Printed by the Society, R1 and R2 represent substituents such as a hydrogen atom, a self-polymer, a hydroxyl group or an alkyl group; the reaction solution of the present invention may be added with an organic base or an inorganic base or an interfacial activity. Suitable additives include triethylamine, lithium hydroxide, sodium carbonate, sodium hydrogencarbonate, organic ammonium salts and organic sulfonates. In the present invention, 1,3·dimercaptopropane may be used in place of 1-bromo-3-aeropropane for the cycloalkylation reaction. The paper scale applies to the National Standard (CNS) A4 specification (21G X297 mm) (please read the notes on the back and fill out this page)

1287009

V. INSTRUCTION DESCRIPTION (f) The present invention provides a process for recrystallization or continuous extraction to obtain white flake crystals of high purity 8-hydroxycampidine. The present invention also discloses a method for synthesizing a material-- by a 3_ silk bribe. The present invention also provides a method of transferring a compound from the above-described silk. [Detailed Description of the Invention]

The above and other objects, features, and advantages of the present invention will become more apparent and understood. Example 1 Synthesis of 8-hydroxyxantheneidine Φ Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed in a 100 ml double neck round bottom bottle with 3-aminophenol (110 mg, 丨 millimoles)' 1-bromo 3-Acetone (2.35 g, 1.6 liters, 15 mmol) and anhydrous sodium carbonate (212 g, 2 mmol). The addition funnel was attached to the bottom of the round bottom, and molecular sieves (4 A, 0.3 g) were placed in the addition funnel, followed by a condenser, and the reaction was carried out under nitrogen. The mixture was heated to 70 ° C for 3 hours, then heated to Celsius for 15 hours, and the reaction solution turned red. After cooling to room temperature, concentrated hydrochloric acid (15 ml) was slowly added to dissolve the gum, and then extracted with di-methane (5 ml). The aqueous layer was neutralized by adding a 40% aqueous sodium hydroxide solution and extracted with di-methane (50 mL of EtOAc). Combine the two gas methane extracts, wash them with salt water, and remove the water with sulfuric acid. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X297 mm). 1287009 A7 B7 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative V. Description of the invention () Concentration. The obtained crude product was separated and purified by silica gel column chromatography, eluting with ethyl acetate / n-hexane (1:9) to give the compound 8-hydroxy-ciridine (72 mg, 0.38 mmol), 38% Yield. Recrystallization is carried out by using a solvent as a white flake to obtain a white flake crystal. The melting point is 128 to 130 degrees Celsius (literature value: 126 to 128 degrees Celsius). TLC (EtOAc/hexane, 1: 9) i? broad 0·23. 4 NMR (CDC13, 300 MHz): δ 1.94-1.99 (4 H, m), 2.62-2.70 (4 H, m), 3.04-3.12 (4 H,m),4·43 (1 H,s),6·04 (1 H,d,J=7·9 Hz),6·64 (1 H,d,7.9 Hz) 〇Example 2 Synthesis of 8-carbyl ruthenium according to the procedure of Example 1, taking 3-aminophenol (U g, ι〇m), μ bromo-3-propane (23.5 g, 16 ml, 150 mmol) It was mixed with anhydrous sodium carbonate (4.27 g, 40 mmol), heated to 7 ° C for 3 hours, and then heated to 110 ° C for 15 hours. 8 〇〇 8 8-hydroxycampidine, 42% yield, was obtained by chromatography on a Shixi gum column. Example 3 Synthesis of 8-Benyl Crude Forces According to the procedure of Example 1, 3-amino group (ιι·〇克, ιοί millimol), aeropropane (127.4 g, 80 liters, 809 mmol) was taken. Mix with anhydrous sodium carbonate (42. 4 g '400 mmol). Heat to 7 degrees Celsius for 3 hours, 8 (please read the notes on the back and fill out this page) Order---------Line A7 1287009 ----~--E--- i ^ ( η ) is then heated to Celsius at a degree of reflux for 5 hours. Seventy-three grams of 8-hydroxyxantheneidine was obtained by gas chromatography on a silica gel column, and the yield was 38%. Example 4 Synthesis of 8-Benylhydrazine. According to the procedure of Example 1, 3-aminophenol (5.0 g, 46 mmol), j bromo-3-propane (23.9 g, 15 ml, 151 mmol) was taken. Ear) dissolved in dimethyl ketoamine (15 liters). Heat to reflux for 5 hours. After a dream rubber column chromatography, 5.5 g of 8-?^-based Zhulu force '62% yield can be obtained. Example 5 Synthesis of 8-prepared Zhulu Li bite into a 100 ml double-necked round bottom bottle into 3-amino-based (U g, 10 亳 Mo Er), 1- desert-3-propane (屯 8 g, 3 ML, 30 亳 Mo) and ethanol (1 liter). The mixture was heated to reflux, and aq. sodium hydrogen sulfate (2····· After the solvent was removed by distillation under reduced pressure, the obtained crude product was purified by solid-liquid phase extraction with hexane to afford 661 mg of s. Example 6 Synthesis of 8-Carbene-based bite According to the procedure of Example 5, 3-aminophenol (5 g, 45·8 mmol), 1-bromo-3·apropane (23·9 g, 15 ml, 15 〇mol) dissolved in ethanol (50 ml), heated to reflux, and slowly dropped into sodium bicarbonate (1 〇·〇克, 119 mmol) 9 paper scales applicable to Chinese national standards ( CNS) A4 specification (210 X 297 public)

--------^--------- f Please read the notes on the back first (this page) Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 128709 V. Invention description (g Ministry of Economics wisdom The A7 B7 aqueous solution (20 ml) was printed by the property bureau employee consumption cooperative. After refluxing for 24 hours, 3·40 g of 8-hydroxyxantheneidine was obtained, 39% yield. Example 7 Synthesis of 8-hydroxyl hydrazine 唆 according to the examples Step 1, taking 3-aminophenol (11 mg, 1 mol), 1-bromo-3-aeropropane (0.48 g, 〇·3 ml, 3 mmol), dihydrogen dihydrochloride Na (623 gram '4 house Moules) and water (1 〇 ml), heated under reflux for 12 hours, and subjected to silica gel column chromatography to obtain 30 mg of 8-hydroxyxanthene, 16% yield. 8-Cymidine-based Liquor According to the procedure of Example 1, 3-aminophenol (115 mg, 1 Torr), 1-bromo-3-aluminum-burning (0.48 g, 〇·3 liters, 3 mM) Mol) and buffer solution (disodium hydrogen phosphate dodecahydrate (1.50 g, 4 Torr) and dihydrogen phosphate dihydrate (〇.6 g, 4 mmol) dissolved in water (10 ml) ). Heating reflux 24 After an hourly chromatography on silica gel column, 40 mg of 8-hydroxyxantheneidine was obtained in 21% yield. Example 9 Synthesis of 8-carbylulidine oxime According to the procedure of Example 1, 3-aminophenol (116) was taken. Mg, 1 mmol), 1-bromo-3-aeropropane (0.48 g, 〇·3 ml, 3 mmol), dodecyl benzoic acid sodium (349 mg, 1 mmol) and buffer Solution (dissolve dihydrogen sulphate dihydrate (15 gram, 4 mM) and dihydrogen sodium dihydrochloride (〇6 gram, 4 mM) in water-free paper scale for Chinese national standards (CNS) Α4 Specifications Shili f (Please read the notes on the back and fill out this page)

1287009 Α7

Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (10 ml)). The mixture was heated under reflux for 12 hours, and subjected to a dream rubber column chromatography to obtain 28 mg of 8- thiopyramine bit, 15% yield. Example 10 Synthesis of 8-Hydroxycylindole According to the procedure of Example 1, 3-aminophenol (11 g, 1 mol), 1,3-diphenylbenzene hydrazinopropane (3·84 g) was taken. , 1 〇 millimolar), wet dioxocyclohexane (1,4-di〇xane, 3 ml) and anhydrous sodium carbonate (424 g, 4 Torr) were mixed and heated to reflux for 5 days. And through the Shixi rubber column chromatography, 51 g of 8-hydroxyxanthene can be obtained, 27% yield. Example 11 Synthesis of 8,10-di-based hydrazinium According to the procedure of Example 1, 1,3-dihydroxy-5-aniline (1·30 g, 1 〇 mmol) and 1-bromo-3- Propane (4.77 g, 3 ml, 30 mmol), dissolved in dimethylamine (10 ml), heated under reflux for 5 hours, and 617 mg of 8,10-di Hydroxycylindene, 30% yield. This product is unstable and gradually changes from colorless to red when exposed to air. Melting point: 164 to 168 degrees Celsius. TLC (EtOAc/hexane, 1:2) = 0.34. !H NMR (CDC13, 300 MHz): δ 1·87 (4H, m), 2.51 (4H, m), 2.94 (4H, m), 5.63 (1H, s). 13C NMR (CDC13/CD30D, 100 MHz): δ 20·6 (2 x), 21.9 (2 x), 50.1 (2 x), 91.4, 100·8 (2 x), 144.6, 152.3 (2 x). 11 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) (please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing 1287009 A7 I - R7 V. Invention Description (/0)

IR (KBr): 2932, 2846, 1593, 1434, 1288, 1142, 1089 cm-1. MS (FAB): Institute /: 205 (MV Example 12 Synthesis of 8,10-Diphenylmethoxycampidine and 8,10-Dihydroxy-Jupidine) U-Benzyloxy-5-aniline (3·5)克, 11.3 mmol, 1-bromo-3-propane (12.7 g, 9.2 ml, 84.5 mmol) and triethylamine (3.5 g, 4.7 liters, 33.3 Torr) Dioxocyclohexane (45 ml) and heated to reflux for 24 hours between 96 and 100 ° C. After removing the volatiles, dihalo methane (30 liters) was added for extraction and saturated aqueous sodium bicarbonate ( 15 ml), the aqueous layer was extracted with di-methane (15 ml of X 2 ). The combined methane methane extracts were concentrated, and then ethyl acetate (15 ml) was added to extract the sediments. After the mixture is concentrated, it is subjected to chromatography on a ruthenium column and eluted with ethyl acetate / n-hexane. Recrystallization from ethyl acetate / n-hexane is used to obtain 8,10-diphenylmethoxy hydrazine. Yellowish crystals (1.2 g, 3.1 mmol), 28% yield, refining point:

84 to 86 degrees Celsius. TLC (EtOAc/hexane = 1:9) 〇·44. 4 NMR (CDC13, 300 MHz): δ 1.90-1.98 (4 H, quinW = 6 Hz), 2·70 (4 H, t J = 6 Hz) , 3.06 (4 H, t, "/= 6 Hz), 4.99 (4 H, s), 5.98 (1 H, s), 7·20-7·41 (10 H, m). 13C NMR (CDC13, 100 MHz): δ 21.13 (2 x), 21.91 (2 x), 50.14 (2 x), 70·04 (2 x), 87·45, 103·71 (2 x), 127.08 ( 4 x), 127.50 12 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

w ·...... m i n (Please read the notes on the back and fill out this page)

Order -

Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 1287009 A7 _________B7_ V. Invention Description (丨丨) (2 X), 128.45 (4 X), 137.87 (2 X), 144.56, 154.98 (2 X). IR (KBr): 2919, 2853, 1600, 1493, 1454, 1281, 1169 cm·1. MS: m/z 385 (Μ), 294 01-60, 91 (Bn"). 8.10-Diphenylmethoxycampidine (1.2 g, 3.1 mmol) was dissolved in ethyl acetate (60 ml), and a palladium metal catalyst (i〇〇/〇Pd/) was added to the activated carbon branch. C, 600 g) and stirred under a hydrogen balloon for 6 hours. After filtration and washing with ethyl acetate, the filtrate was concentrated, and then purified by silica gel column chromatography to obtain 520 mg of 8,10-dihydroxy-ciridine, 81% yield. Example 13 Synthesis of 8,10-Dihydroxy-9-mercapto-Jupiter and Condensation with Diethyl Malonate

Take 8,10-dihydroxyazuridine (1.00 g, 5 Torr) dissolved in dimethylformamide (1 ml) and add helium (790 g, 〇·5 ml, 5.6 mmol) A solution of dimethylformamide (5 ml) was stirred at room temperature for 1 hour. Water (1 ml) was added and the precipitate was filtered to give <RTI ID=0.0>>> iHNMR^CDCUJOO 13 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X29*7 mm) (please read the notes on the back and fill out this page)

1287009 V. INSTRUCTIONS (/}) MHz): δ 1.82 (4 H, m), 2.47 (4 H, m), 3·16 (4 η, m), 9·7〇 (1 H, s). Take 8,10-dihydroxy-9-f-decyl-jujuxidine (232 g, 〇·9 mol), diethyl malonate (114 mg, 0.1 ml, 丨mole) and hexahydropyrimidine (piperidine, 172 mg, 0.2 ml, 2 mmol) dissolved in cyanamide (1 ml) and benzene (3 ml), heated to reflux for 2 hr. The crude product was purified by recrystallization from ethyl acetate to give coumarin compound 4 (293 g). b NMR (CDC13, 300 MHz): δ 1.36 (3 H, t, 6.0 Hz), 1·93 (4 H, m), 2·61 (2 H, t, 6·4 Hz), 2·77 ( 2 H,t,6·4 Hz), 3·28 (4 H,m), 4·33 (2 H,q,/= 6·0 Hz), 8.75 (1 H, s). Example 14 Condensation of the compound 8,10-di-based carbaryl and 3-methylbutyric acid vinegar (Please read the back note first and then fill out this page)

Order

Reaction OH

OH ?h3 & EtO,, OH CH3

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, 8,10-dihydroxyazuridine (208 mg, 1 mmol), ethyl 3-carbonylbutyrate (220 mg, 1.6 mmol), zinc pentoxide (12 grams, u millimoles) and ethanol (10 ml). The mixture was heated to reflux for 22 hours, and then distilled under reduced pressure to remove solvent. 14 This paper size applies to the Chinese National Standard (CNS) Μ Specifications (210X 297 mm)

, invention description (β) Ministry of Economic Affairs intellectual property. 3⁄4 employee consumption ^ note in the middle

The crude product was purified by recrystallization from ethyl acetate to give coumarin compound 5 (225 m.). 4 NMR (CDC13, 200 MHZ) : δ ! 9〇(4 H,m), 2.49 (3 H,s),2.53 (4 H,m),3.23 (4 H,m),5·67 (1 H , s) 〇 Example 15 synthesis of coumarin compounds

The coumarin compound 4 (see Example 13) (520 gram, ι·66 亳mol) was suspended in «dimethylformamide (10 ml)' and 3 〇% sodium cyanide was added at room temperature ( M3 mg, 3.32 mmol (aqueous solution) (0.4 liters). After stirring, the solution of this mixture was cooled in an ice bath, and carefully dripped into a desert liquid (292 mg, 1.83 Torr). The mixture immediately turned from orange-red to pink' and was formed by the temple. After 16 hours of incubation at room temperature, the precipitate was filtered and the knee was washed with a small amount of «dimethylformamide and water. The filtrate was extracted with ethyl acetate (60 mL of EtOAc). EtOAc (EtOAc:EtOAc) g), 96% yield. Melting point: 175 to 177 degrees Celsius. TLC (EtOAc/hexane is called (1) 々=〇24 !H NMR (CDC13, 200 ΜΗζ): δ 1 ·39 (3 H,7 Hz), 1 ·94—1.96 (4 H, m), 2·74-2 ·84 (4 Η,m),3·3 Bu3·39 (4 Η,m), 4.40 (2 Η,q,7 Hz), 15 This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 X297 mm) (Please read the notes on the back and fill out this page)

1287009 A7 B7 V. DESCRIPTION OF THE INVENTION (丨>) 7.24 (1 H,s)· 13C NMR (CDC13, 50 ΜΗζ): δ 14.0, 19.9, 20.9, 27.4, 50.0, 50·4, 62·2, 106· 0, 106.5, 110.2, 113.2, 120.7, 124.8, 127.4, 149.2, 152.0, 157.0, 162·7· IR (ΚΒγ): 2335, 1748, 1614 cm-1· MS: m/z 338 (Μ4), 310 ( W - CO), 266 (Μ+- C02C2H5), 57 (QHtN)· UV-vis: λ-brittle = 508.8 nm (ε = 27478) in EtOH; 503.6 mn (ε = 31236) in acetone; 494.4 run (ε = 21726) in THF. Fluorescence: Xmax = 560 nm in EtOAc; 559 nm in THF; 569 nm in acetone; 575 nm in EtOH. Anal, calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.27. Found: C , 67.15; H, 5.36; N, 8.17. Although the present invention has been disclosed in the above several embodiments, it is not intended to limit the invention, and those skilled in the art, without departing from the spirit and scope of the invention, Various changes and modifications may be made, and thus the protection scope of the present invention is subject to the definition of the scope of the patent application. (Please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 16 This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm)

Claims (1)

1287009 Sixth, the scope of application for patents [Scope of application] The method of showing 8-hydroxyxanthene ····· Wherein R and R2 represent a hydrogen atom, a C1_C4 alkyl group or a substituent such as a thiol group; and the method comprises a single step reaction of the following formula: h2n Wherein X and Y represent a leaving group such as a halogen or a decyloxy group, and ri&r2 has the same meaning as defined above; and the /'j, plus M (Additive) is an organic test or an inorganic test. 2. The method of claim 1, wherein the chemical reaction is carried out in a solvent selected from the group consisting of a monohydric solvent, a benzene solvent, an ether solvent, an alcohol solvent, and cyanogen. A solvent for burning a solvent, a monoamine solvent or the like. 3. The method of claim 1, wherein the additive is an organic base, and the organic base is selected from the group consisting of a cyclic amine compound or a non-cyclic amine compound. 4. The method of claim 1, wherein the additive is an inorganic base, and the inorganic test is selected from the group consisting of: hydroxides, carbonates, hydrogencarbonates, phosphates, hydrogen phosphates or dihydrogen phosphates. By. 5. The method of claim 1, wherein the reaction is carried out in the presence of a surfactant. 6. The method of claim 5, wherein the surfactant is selected from the group consisting of an organic ammonium salt or an organic sulfonate. 17 1287009 7·If you apply for a patent scope帛! The method of the invention, wherein the methoxy group is a burnt oxy group or a stupid oxy group. 8. The method of claim i, further comprising the step of obtaining the high purity product by liquid, phase continuous extraction or recrystallization using a solvent. 9. The method of claim 8, wherein the recrystallization solvent is selected from the group consisting of: a burning solvent, a j-alkane solvent, a benzene solvent, an ether solvent, an ester solvent, or the like. mA - A method of preparing a coumarin compound of the following formula, comprising the steps of: Wherein R1 represents a hydrogen atom, i, C1.C4^ or a thiol group: r3 represents a substituent such as a hydrogen atom, a vine group, a schishyl group, a cyano group, a propyl group or a phenyl group, and r4 represents a hydrogen atom, a _ element or an aryl group. The method comprises the steps of: preparing 8-hydroxyxanthene as shown in the following formula: Wherein 'R|is defined as the same as the former' is a substituent such as a hydrogen atom, a Ci_C4 filament or a woven fabric; and the 8-basic-grain force is reacted with a self-acting compound to read the coumarin compound, the saki Ji Zhu Lu Li Qian is made by the following formula: Wherein, X and Y represent i or methoxy methoxy group, rI^r2 is as defined above; and the 18 1287009 〜, Additive is an organic base or an inorganic base. U. For example, in the method of applying for the scope of patents, the chemical reaction of 8-methylpyrrolidine is carried out in a solution, and the solvent, sixty, ... W you from the water agent , a combination of a benzene solvent, a monoether / a granule, an alcohol solvent, a genus, a text, a smear, or a combination of solvents. 2. The method of claim 1, wherein the additive is an organic base, and the organic test is selected from the group consisting of an amine-based compound or an acyclic amine compound. 13. The method of claim 1, wherein the additive is an inorganic base, and the inorganic base is selected from the group consisting of: hydroxides, carbonates, carbonates, sulphur, %s, salt, hydrogen phosphate Or dihydrogen phosphate. H. The method of claim 10, wherein the preparation 8 is carried out in the presence of a surfactant in the presence of a surfactant. 15. The method of claim 14, wherein the surfactant is selected from the group consisting of a genus or an organic lactate. 16. The method of claim H, wherein the methoxy group is a hospital oxime or a acetonyloxy group.如. The method of claim H), further comprising the step of obtaining the high purity product by the liquid-solid phase continuous extraction method or by re-crystallization using the solvent. 18• If the patent application is changed, the recrystallization solution is selected from the group consisting of: a solvent for a hospital, a halogen solvent, a benzene solvent, a solvent, a vinegar solvent or the like. 19