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 五、發明説明（/ ) 【發明之應用範疇】 本發明是關於一種如下式之8-經基朱路力咬 (8-hydr〇xyjiilolidine)及其類似化合物的製造方法： 2 其中’R1及R2代表氫原子、齒素、羥基或烷基等取代基； 【發明背景】 經濟部智慧財產局員工消費合作社印製 香豆素（coumarin)因吸收和放射光譜重疊少，具有高量子 產率和高莫耳吸收常數，且有不尋常的調諧波長範圍，成為最常 用的雷射染料之一，並可作為生物檢測螢光的指標。根據美國專 利 US Patent 3,873,940，US Patent 3,932,415，US Patent 4,005,092， US Patent 4,471，041，US Patent 4,736,032 和 US Patent 4,794，184 等 所揭示的技術，以環烷化方法固定7-胺基的剛性分子，將可大幅 增加偶極距，並減少因胺基旋轉所導致的能量損失。如此可增加 香豆素雷射染料的螢光量子產率，從而大幅提高雷射染料的發光 效能。 製造8-經基朱路力唆和8，10-二輕基朱路力咬的方法卻报少。 3 本紙張尺度適用中國國家標準（CNs ) μ規格（210X297公釐） Ϊ287009 A7 B7 五、發明説明（> ) 根據 US Patent 4,005,092 ’ US Patent 4,471，041 和 Jbwrwa/ CAemiy/7 1987年52卷1465-1468頁等習知的發明及文獻記載， 都是由3-曱氧基苯胺（m-anisidine)或3,5-二甲氧基苯胺 (3,5-dimethoxyaniline )與大量的 1-溴-3-氯丙烷 (l-bromo-3-chloropropane)進行環烷化反應，再用強酸去除甲基 而製得。欲獲得3·甲氧基苯胺或3,5-二甲氧基苯胺，通常則是由 3-胺基紛(3-aminophenol)或 3,5-二輕基苯胺(3,5-dihydroxyaniline ) 與硫酸二甲S旨（dimethyl sulfate )進行甲基化反應。 上述製法有以下的缺點：（1)使用大量（7.6至15莫耳倍數） 的^溴-3-氯丙烧，不合擴量生產之效益，(2)去除甲基要使用鹽 酸、碘酸或三溴化硼等具腐蝕性的強酸。（3)先使用毒性強的硫 酸二甲酯來保護羥基，在進行環烷化反應後，又需用強酸去除甲 基’增加兩個步驟而降低總產率（<3〇〇/0)。 【發明之目的】 經濟部智慧財產局員工消費合作社印製 有鑑於此，本發明的目的乃在提供一嶄新的製造心羥基朱珞 力啶及其類似化合物的方法。只需做一步反應，無須經過保護經 基及去除甲基的步驟，即可很容易的合成所需要的環烷紛化合物。 本發明的目的也在提供一種新穎的8-羥基朱珞力啶及其類似 4 本紙張尺度適用中國國家標準（CNS ) M規格（21〇乂297公董） !287〇〇9 A7 B7 五、發明説明（今） 化合物的製造方法，可以避免使用有毒性的硫酸二甲酯試劑。 本發明的另一目的，也在提供一種新穎的8-羥基朱珞力啶及 其類似化合物的製造方法，可以減少1-溴-3-氣丙烷的使用量，並 減輕回收或廢棄之處理工作，以節省製造成本，並符合清潔製程 的要求。 本發明的再一目的，也在提供一種新穎的8-羥基朱路力啶及 其類似化合物的製造方法，可以避免使用鹽酸、碘酸或三溴化硼 等具腐蝕性的強酸。 本發明之目的也在提供一種只使用一水溶劑或一有機溶劑及 其等之組合溶劑，即可完成製備之8-羥基朱珞力啶及其類似化合 物的方法。 【發明之簡述】 經濟部智慧財產局員工消費合作社印製 本發明提供一嶄新的製造8-羥基朱珞力啶及其類似化合物的 方法。只需做一步反應，無須經過保護經基及去除甲基的步驟， 即可很容易的合成所需要的環烷酚化合物。本發明製法的化學反 應如下式所示，只要使用適當的反應條件，就可以選擇性地只在 胺基進行烷化反應，而不影響羥基。因此本發明提供了一製造^ 經基朱珞力啶及其類似化合物的簡便方法，與文獻報導的多步反 5 本紙張尺度適用中國國家標準（CMS ) A4規格（210X297公釐） 1287009 A7 B7 五、發明説明（屮） 應之總產率比較’本發明的產率相當或更高，不僅可以縮短製程 時間，亦可以節省製造成本。 本發明之方法包括如下式之化學反應：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) 1R2 H2N v, OH (Additive) 1

X(CH2)3YX(CH2)3Y

在上式中’ R1和R2代表一氫原子、齒素、經基或烧基等取代 基，X和Y代表一齒素、醯氧基或磺醯氧基等離去基。反應溶液 可以添加一有機鹼或一無機鹼或一界面活性劑。 本發明所製得之產物具有如下之化學式：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:

經 濟 部 智 慧 財 產 局 員 工 消 費 合 5 社 印 製 其中，R1及R2代表氫原子、自素、羥基或烷基等取代基； 本發明之反應溶液可以添加一有機鹼或一無機鹼或一界面活 性劑，適用之添加物包括三乙基胺、氫氧化鋰、碳酸納、碳酸氫 納、有機銨鹽及有機磺酸鹽等。 在本發明中，可以使用1，3·二醯基丙烷來替代1-溴-3-氣丙烷 進行環烷化反應。 紙張尺度適用中關家標準（CNS ) A4規格（21G X297公釐） (請先閱讀背面之注意事項再填寫本頁)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)

12870091287009

五、發明説明（f ) 本發明並提供制再結晶或使输_連續萃取，獲得高純 度8-羥基朱珞力啶的白色片狀結晶的方法。 本發明也祕了使料-_由3_絲贿錄合成8_經基 朱路力咬類似物的方法。 本發明也提供了由上述絲製轉騎化合物之方法。 【發明之詳細說明】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]

為讓本發明之上述和其他目的、特徵、和優點能更明顯易懂， 下文特舉數個實施例，作詳細的說明。 實施例1合成8-羥基朱珞力啶 訂 Φ 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 於100毫升的雙頸圓底瓶放入3-胺基酚（110毫克，丨毫莫 耳）’ 1-溴-3-氣丙烧（2.35克，1.6亳升，15毫莫耳）及無水的 碳酸鈉（212克，2毫莫耳）。於圓底瓶口接上加料漏斗，在加料 漏斗内放入分子篩（4 A，0.3克），再接上冷凝管，反應在氮氣下 進行。混合物加熱至攝氏70度攪拌3小時，然後加熱至攝氏no 度迴流15小時，反應溶液轉為紅色。冷卻至室溫，慢慢加入濃鹽 酸（15毫升）以溶解膠狀物，並加入二氣甲烷（5毫升）萃取。 水層加入40%的氫氧化鈉水溶液中和，再以二氣甲烷（50毫升X 4)萃取。合併二氣甲烷萃取液，以鹽水洗滌，再以硫酸鎮除水後 本纸張尺度適用中國國家標準（CNS ) A4規格（210 X297公釐） 1287009 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（) 濃縮。所得之粗產物經石夕膠管柱層析法分離純化，以乙酸乙酯/正 己烷（1:9)沖提，可得到化合物8-羥基朱珞力啶（72毫克，0.38 毫莫耳），38%產率。 以正己烧為溶劑做再結晶，得白色片狀結晶。溶點為攝氏128 到 130 度（文獻值：攝氏 126 到 128 度）。TLC (EtOAc/hexane，1 : 9) i?广 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 實施例2合成8-經基朱路力唆 根據實施例1的步驟，取3-胺基酚（U克，ι〇毫莫耳），μ 溴-3-氣丙烷（23.5克，16毫升，150毫莫耳）及無水的碳酸納 (4.27克，40毫莫耳）混合，加熱至攝氏7〇度攪拌3小時，然 後加熱至攝氏110度迴流15小時。經石夕膠管柱層析可以獲得8〇〇 亳克8-羥基朱珞力啶，42%產率。 實施例3合成8-經基朱路力咬 根據實施例1的步驟，取3-胺基紛（ιι·〇克，ιοί毫莫耳）， 氣丙烷（127.4克，80亳升，809毫莫耳）及無水的碳酸 鈉（42·4克’ 400毫莫耳）混合。加熱至攝氏7〇度授拌3小時， 8 (請先閱讀背面之注意事項再填寫本頁) 訂---------線一 A7 1287009 ----~--E--- i ^ ( η ) 然後加熱至攝氏no度迴流i5小時。經石夕膠管柱層析可以獲得7 3 克8-羥基朱珞力啶，38%產率。 實施例4合成8-經基朱珞力唆 根據實施例1的步驟，取3-胺基酚（5.0克，46毫莫耳），j 溴-3-氣丙烷（23.9克，15毫升，151毫莫耳）溶於二甲基 甲酿胺（15亳升）。加熱迴流5小時。經梦膠管柱層析可以獲得 5.5克8-|^基朱路力’ 62%產率。 實施例5合成8-备基朱路力咬 於100毫升的雙頸圓底瓶放入3-胺基盼（U克，10亳莫耳）， 1-漠-3-氣丙烷（屯8克，3毫升，30亳莫耳）及乙醇（1〇亳升）。 加熱迴流，並在11小時内滴入碳酸氫納（2·〇克，23毫莫耳）之 水溶液（20毫升），再加熱迴流37小時。減壓蒸餾移除溶劑後， 得到的粗產物以正己燒作固-液相重覆萃取，可得到661毫克8_經 基朱珞力啶，35%產率。 實施例6合成8-經基朱路力咬 根據實施例5的步驟，取3_胺基酚（5 〇克，45·8毫莫耳）， 1-溴-3·氣丙烷（23·9克，15毫升，15〇毫莫耳）溶於乙醇（50毫 升），加熱迴流，並慢慢滴入碳酸氫納（1〇·〇克，119毫莫耳）之 9 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱）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請先閱讀背面之注意事項再本頁) 經濟部智慧財產局員工消費合作社印製 1287009 五、發明説明（g 經濟部智慧財產局員工消費合作社印製 A7 B7 水溶液(20毫升）。迴流24小時後可得到3·40克8-羥基朱珞力啶， 39%產率。 實施例7合成8-羥基朱络力唆 根據實施例1的步驟，取3-胺基酚（11〇毫克，1亳莫耳）， 1-溴-3-氣丙烷（0.48克，〇·3毫升，3毫莫耳），二水合碟酸二氫納 (623亳克’ 4宅莫耳）和水（1〇毫升）。加熱迴流12小時，並經 矽膠管柱層析可以獲得30毫克8-羥基朱珞力啶，16%產率。 實施例8合成8-經基朱路力淀 根據實施例1的步驟，取3-胺基酚（115毫克，1亳莫耳）， 1-溴-3-氣丙烧（0.48克，〇·3亳升，3毫莫耳）和緩衝溶液（將十 二水合磷酸氫二鈉（1.50克，4亳莫耳）和二水合磷酸二氫納（〇.6〇 克，4毫莫耳）溶於水（10毫升））。加熱迴流24小時。經石夕膠 管柱層析，可以獲得40毫克8-羥基朱珞力啶，21%產率。 實施例9合成8-經基朱路力唆 根據實施例1的步驟，取3-胺基酚（116毫克，1毫莫耳）， 1-溴-3-氣丙烷（0.48克，〇·3毫升，3毫莫耳），十二烷基苯績酸納 (349毫克，1毫莫耳）和緩衝溶液（將十二水合鱗酸氫二納（15〇 克，4毫莫耳）和二水合碟酸二氫納（〇6〇克，4毫莫耳）溶於水 私紙張尺度適用中國國家標準（CNS ) Α4規格石釐f (請先閲讀背面之注意事項再填寫本頁)--------^--------- 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 Α71287009 Α7

經濟部智慧財產局員工消費合作社印製 (10毫升））。加熱迴流12小時，並經梦膠管柱層析，可以獲得 28毫克8-經基朱路力咬，15%產率。 實施例10合成8-羥基朱珞力啶 根據實施例1的步驟，取3-胺基酚（11〇亳克，1亳莫耳）， 1，3-二曱苯續醯基丙烷（3·84克，1〇毫莫耳），濕的二氧代環己烷 (l，4-di〇xane，3毫升）及無水的碳酸鈉（424亳克，4亳莫耳） 混合，加熱迴流5天，並經石夕膠管柱層析可以獲得51亳克8_羥基 朱珞力啶，27%產率。 實施例11合成8，10-二經基朱珞力唆 根據實施例1的步驟，取1，3-二羥基-5-苯胺（1·30克，1〇毫 莫耳）和1-溴-3-氣丙烷（4.77克，3毫升，30毫莫耳），溶於 二甲基甲酿胺（10毫升），加熱迴流5小時，並經石夕膠管柱層析可 以獲得617毫克8,10-二羥基朱珞力啶，30%產率。此產物不安定， 暴露在空氣中即逐漸由無色轉成紅色。 溶點:攝氏 164 到 168 度。TLC (EtOAc/hexane，1:2)外=0.34。 !H NMR (CDC13,300 MHz) : δ 1·87 (4 H，m)，2.51 (4 H，m)，2.94 (4 H，m)，5.63 (1 H，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 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁)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)

經濟部智慧財產局員工消費合作社印製 1287009 A7 一 - R7 五、發明説明（/0)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):所/:205 (MV 實施例12合成8，10-二苯甲氧基朱珞力啶及8，10_二羥基朱珞力啶 取U-苯甲氧基-5-苯胺（3·5克，11.3毫莫耳），1-溴_3_氣 丙烷（12.7克，9.2毫升，84.5毫莫耳）及三乙基胺（3·5克，4.7 亳升，33.3亳莫耳）溶於二氧代環己烷（45毫升），並在攝氏 96至100度間加熱迴流24小時。在移除揮發物後，加入二氣甲烷 (30亳升）萃取，並以飽和碳酸氫納水溶液（15毫升）洗滌。水 層再以二氣甲烷萃取（15毫升X 2)。合併二氣甲烷萃取液，濃縮 後，加入乙酸乙酯（15毫升）逼出沉殿物。過濾、掉沉藏物，渡液 濃縮後，經矽膠管柱層析，以乙酸乙酯/正己烷沖提。 再以乙酸乙酯/正己烷為溶劑做再結晶，可得到8，10-二苯甲氧 基朱珞力唆之微黃色結晶（1.2克，3.1毫莫耳），28%產率，炼點：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:

攝氏 84 到 86 度。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 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）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 (請先閲讀背面之注意事項再填寫本頁)w ·...... m i n (Please read the notes on the back and fill out this page)

訂 -Order -

經濟部智慧財產局員工消費合作社印製 1287009 A7 _________B7_ 五、發明説明（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")。 將8，10-二苯甲氧基朱珞力啶（1·2克，3.1毫莫耳）溶於乙 酸乙酯（60毫升），加入活性碳支樓的鈀金屬催化劑（i〇〇/〇Pd/C， 600亳克），並在氫氣球覆蓋下攪拌6小時。過濾，以乙酸乙酯洗 滌後，將濾液濃縮，並經石夕膠管柱層析可以獲得520毫克8，10-二 羥基朱珞力啶，81%產率。 實施例13合成8，10_二羥基-9-曱醯基朱珞力咬並與丙二酸二乙酯 進行縮合反應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

取8，10-二羥基朱珞力啶（1.00克，5亳莫耳）溶解在二 甲基甲醯胺（1毫升），加入填醯氣（790亳克，〇·5毫升，5.6毫 莫耳）的二甲基甲醯胺（5毫升）溶液，在室溫下挽拌i小 時。加入水（1毫升），過濾沈澱，可得8,10-二羥基-9-曱醯基朱珞 力啶（化合物如式3，932毫克），80%產率。iHNMR^CDCUJOO 13 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29*7公釐） (請先閱讀背面之注意事項再填寫本頁)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 五、發明説明（/}) MHz) : δ 1.82 (4 H，m)，2.47 (4 H，m)，3·16 (4 η，m)，9·7〇 (1 H，s)。 取8，10-二羥基-9-f醯基朱珞力啶（232亳克，〇·9亳莫耳）， 丙二酸二乙酯（114毫克，0.1毫升，丨毫莫耳）及六氫嘧啶 (piperidine，172毫克，0.2毫升，2毫莫耳）溶解在氰甲燒（1 毫升）和苯（3毫升）中，加熱迴流2小時，然後減壓蒸餘以移除 溶劑。粗產物以乙酸乙酯再結晶純化，可得到香豆素化合物4 ( 293 亳克），89%產率。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)。 實施例14化合物8，10-二經基朱珞力咬與3-幾基丁酸乙醋之縮合 (請先閲讀背面之注意事項再填寫本頁)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)

訂Order

反應 OHReaction OH

OH ?h3 & EtO，、 OH CH3OH ?h3 & EtO,, OH CH3

經濟部智慧財產局員工消費合作社印製 取8，10-二羥基朱珞力啶（208毫克，1毫莫耳），3-羰基丁酸 乙酯（220毫克，1.6毫莫耳），二氣化鋅（12亳克，u毫莫耳） 和乙醇（10毫升）。加熱迴流22小時，然後減壓蒸餾以移除溶劑。 14 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X 297公釐）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)

、發明説明（β) 經濟部智慧財產.¾員工消費^咋注中踅, invention description (β) Ministry of Economic Affairs intellectual property. 3⁄4 employee consumption ^ note in the middle

1287009 粗產物以乙酸乙酯再結晶純化，可得到香豆素化合物5 (225毫 克），83%產率。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 實施例15合成香豆素化合物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

取香豆素化合物4(見實施例13) (520亳克，ι·66亳莫耳）懸 浮於«二甲基甲醯胺（10毫升）’在室溫下加入3〇%氰化鈉（M3 毫克，3.32毫莫耳）水溶液（0.4亳升）。攪拌後，將此混合物之 溶液以冰浴冷卻，並小心滴入漠液（292毫克，1·83亳莫耳）。混 合液立刻由橘紅色轉成粉紅色’並有沈殿物生成。在室溫授拌16 小時後，將沈澱物過濾，以少量«二甲基甲醯胺和水洗膝。將 濾液以乙酸乙酯（60毫升X 3)萃取，萃取液濃縮後，所剩之粗 產物以乙酸乙酯/正己烷（2 : 1)再結晶純化，可得到香豆素化合 物6 (540亳克），96%產率。 熔點:攝氏 175 到 177 度。TLC (EtOAc/hexane 叫⑴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卜3·39 (4 Η，m)，4.40 (2 Η，q，7 Hz), 15 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） (請先聞讀背面之注意事項再填寫本頁)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 五、發明説明（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脆 =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. 雖然本發明已以數個實施例揭露如上，然其並非用以限定本 發明，任何熟習此技藝者，在不脫離本發明之精神和範圍内，當 可作各種之更動與潤飾，因此本發明之保護範園當視後附之申請 專利範圍所界定者為準。 (請先閱讀背面之注意事項再填寫本頁)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 經濟部智慧財產局員工消費合作社印製 16 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）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)

12870091287009 六、申請專利範圍 【申請專利範圍】 示8-羥基朱珞力啶之方法·· \y —種製備如下式所Sixth, the scope of application for patents [Scope of application] The method of showing 8-hydroxyxanthene ····· 其中，R及R2代表氫原子、C1_C4烧基或經基等取代基； 其方法包括下式之單一步驟反應： h2nWherein 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 其中，X及Y代表鹵素或醯氧基等離去基，ri&r2定義同前；且該 /'j、、加M (Additive)為一有機驗或一無機驗。 2·如申請專利範圍第1項之方法，其中該化學反應係在一溶劑中進行 者，且該溶劑係選自一水溶劑、一苯類溶劑、一醚類溶劑、一醇類溶劑、 氰燒類溶劑、一醯胺類溶劑或其等之組合溶劑。 3·如申請專利範圍第1項之之方法，其中該添加劑為一有機鹼，且該有 機鹼係選自一環狀胺類化合物或一非環狀胺類化合物者。 4·如申請專利範圍第1項之方法，其中該添加劑為一無機鹼，且該無機 驗係選自：氫氧化物、碳酸鹽、碳酸氫鹽、磷酸鹽、磷酸氫鹽或磷酸二氫 鹽者。 5·如申請專利範圍第1項之方法’其中該反應係在一界面活性劑存在下 進行者。 6·如申請專利範圍第5項之方法，其中該界面活性劑係選自一有機銨鹽 或一有機磺酸鹽者。 17 1287009 7·如申請專利範圍帛！項之方法，其中該醯氧基為一燒酿氧基或一笨酿 氧基。 8·如申請專利範圍第i項之方法，另包括將該產物以液，相連續萃取方 法或使用一溶劑再結晶，而獲得高純度產物的步驟。 9·如申請專利範圍第8項之方法，其中該再結晶溶劑係選自··烧類溶劑、 j烷類溶劑、苯類溶劑、醚類溶劑、酯類溶劑或其等之溶劑。 mA —種製備如下式香豆素化合物之方法，包括下列步驟：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: 其中，R1代表氫原子，i素、C1.C4^或經基：r3代表氫原子、醋 基、石肖基、氰基、魏或苯基等取代基，及r4代表氫原子、_素或氛基； 該方法包括下列步驟： 製備如下式所示之8-羥基朱珞力啶：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: 其中’ R|定義同前’以表氫原子、Ci_C4絲或織等取代基；及 將該8-經基朱路力從物與—自旨類化合物反應，讀得該香豆素化合 其中，該崎基朱路力錢以如下式之單__步驟反應製得：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: 其中，X及Y代表i素或醯氧基謝基，rI^r2定義同前；且該 18 1287009 〜，、加劑（Additive)為一有機鹼或一無機鹼。 U·如申請專利範圍第]〇項之方法，i 衣備8-鉍基朱珞力啶之化學反 應係在一洛劑中進行者，且該溶劑 、、六十，… W你k自水洛劑、一苯類溶劑、一醚類 /谷劑、一醇類溶劑、一素炫類、文逾丨 减n —__靖或其等之組合溶劑。 2.如申凊專利範圍第1〇項之方法，i w 八中+加劑為一有機鹼，且該有機 驗係選自-械胺類化合物或—非環狀胺類化合物者。 13.如申請專利範圍第ι〇項之方 女其中该添加劑為一無機鹼，且該無機 鹼係選自：氫氧化物、碳酸鹽、碳酸 '欠虱孤、％s欠鹽、磷酸氫鹽或磷酸二氫 鹽者。 H.如申請專利範圍第10項之方法，其中該製備8經基朱路力狀反應係 在一界面活性劑存在下進行者。 15•如申請專利範圍第14項之方法，其中該界面活性劑係選自一有機娜 或一有機續酸鹽者。 16.如申請專利範圍第H)項之方法，其中該醯氧基為一院醯氧基或一笨醯 氧基。 Π.如申請專利範圍第H)項之方法，另包括將該8_經基朱路力咬產物以液 -固相連續萃取方法或使用-溶劑再結晶，而獲得高純度產物的步驟。 18•如申請專利細第Π項之轉，其中該再結晶溶_選自：院類溶 劑、鹵炫類溶劑、苯類溶劑、_溶劑、醋類溶劑或其等之溶劑。 19Wherein, 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