201006809 六、發明說明： 【發明所屬之技術領域】 本發明提供製備5,6-二甲基_9_側氧基-9H-咕噸_4_基-乙 酸（DMAXX)的高效方法。 【先前技術】 5,6-二曱基-9-側氧基-9H-咕噸_4-基-乙酸顯示一系列生 物活性。在Rewcastle 等人.，j Med Chem，卷 34, ^了頁 (1991)中描述一種以六個步驟合成5,6_二甲基側氡基_ ^ 9H-咕噸-4-基-乙酸的方法，其總產率為約12%。開發製備 5,6-二曱基-9-側氧基-9H-咕噸·4-基-乙酸之有效方法仍面 臨重要挑戰。 【發明内容】 本發明提供一種有效製備具有以下結構式⑴之5,6二甲 基-9-側氧基_9Η-咕β镇-4-基-乙酸：201006809 VI. Description of the Invention: [Technical Field to Which the Invention Is Affected] The present invention provides an efficient method for preparing 5,6-dimethyl-9-sideoxy-9H-xanthene-4-yl-acetic acid (DMAXX). [Prior Art] 5,6-Dimercapto-9-sideoxy-9H-xanthene-4-yl-acetic acid shows a series of biological activities. A synthesis of 5,6-dimethyl fluorenyl _ ^ 9H-xanthene-4-yl-acetic acid in six steps is described in Rewcastle et al., j Med Chem, Vol. 34, pp. (1991). The method has a total yield of about 12%. An effective method for the development of 5,6-dimercapto-9-sideoxy-9H-xanthene-4-yl-acetic acid still faces important challenges. SUMMARY OF THE INVENTION The present invention provides an efficient preparation of 5,6-dimethyl-9-oxyl-9 Η-咕β--4-yl-acetic acid having the following structural formula (1):
或該化合物之鹽的方法。 合成5,6-二甲基_9_側氧基-9Η-咕噸-4-基-乙酸的方法產 生純淨及無色的產物，且適於大規模生產。另外，該方法 避免自硫酸水溶液中單離5,6-二甲基-9-侧氧基-9Η-咕噸-4-基-乙酸’其過濾時間長且沖洗殘留硫酸之過程繁雜。 該方法顯示若干關於安全性及生態的改良處。粗產物2- 140539.doc 201006809 [2-(羧甲基）苯氧基>34_二 土本罗酸（稱為化合物4)可藉 由兩個可選擇的步驟而純化， ）了藉 Λ ^生成最終產物5,6-二甲基_ 9-側氧基-9Η-咕噸基- 酸。粗產物2-[2-(羧f基）苯氧 基]二甲基苯甲酸可藉由再結晶而純化或粗產物叫 (叛甲基）苯氧基]二甲基苯甲酸可環化生成5 6二甲基_ 9-側氧基-9H-咕噸-4-基-乙酸。 本發明係針對5,6-二甲其q # ΛΤΤ Τ丞-9-侧氧基_9Η-咕嘲-4-基-乙酸 的合成法。但是，該純化步驟可用於其它需呈其鹽型方可 溶解於水中之難溶性化合物。 【實施方式】 如上述，本發明提供一種製造5,6_二曱基_9_側氧基_9η_ 咕噸-4-基-乙酸的方法。 一種方法如下列流程圖1所示： 流程圖1 〇Or a method of salt of the compound. The process for the synthesis of 5,6-dimethyl-9-oxo-oxime-xanthene-4-yl-acetic acid produces a pure and colorless product and is suitable for large scale production. Further, this method avoids the problem that the separation time of 5,6-dimethyl-9-sideoxy-9Η-xanthene-4-yl-acetic acid from the aqueous sulfuric acid solution is long and the process of washing residual sulfuric acid is complicated. This method shows several improvements in safety and ecology. Crude product 2-140539.doc 201006809 [2-(Carboxymethyl)phenoxy]34_di-boruric acid (referred to as Compound 4) can be purified by two optional steps, ^ The final product, 5,6-dimethyl-9-sideoxy-9Η-xanthene-acid, was formed. The crude product 2-[2-(carboxyl-yl)phenoxy]dimethylbenzoic acid can be purified by recrystallization or the crude product can be cyclized by (demethyl)phenoxy]dimethylbenzoic acid. 5 6 dimethyl_9-sideoxy-9H-xanthene-4-yl-acetic acid. The present invention is directed to a synthesis method of 5,6-dimethyl q# ΛΤΤ -9-sideoxy_9Η-咕 -4--4-yl-acetic acid. However, this purification step can be applied to other poorly soluble compounds which need to be in their salt form to be soluble in water. [Embodiment] As described above, the present invention provides a process for producing 5,6-dimercapto-9-sideoxy_9η_咕t-4-yl-acetic acid. One method is shown in Flowchart 1 below: Flowchart 1 〇
(2-羥基-笨基)-乙酸 2- (2-羧亨基-笨氣10-3.4-二甲基笨1»酰 (5, 6-二曱基-9-側氧基-咕嘈-4-基）乙酸 140539.doc -4- 201006809 a: NaN02/H2S04, I2/KI/H20 AcOEt, b: NaOMe/MeOH, AcOEt; c: KOtBu/DMF, CuCl; d: NaOH, H20, AcOEt, AcOH; e: H2S04(或 MeS03H，AcOH, Ac20); f: NaOH, THF, AcOH，H2〇 〇 . 流程圖1中描述的方法不需要單離5,6_二甲基_9_側氡基_ 9H-咕噸-4-基-乙酸。 i 上述流程圖1中的化合物2(稱為2-蛾-3，4-二曱氧基苯甲 . 酸鈉鹽）藉由將副產物（二甲基水楊酸）減至最少而產生高純 度及高產率。該副產物藉由在乙酸乙酯中使鈉鹽結晶而有 效去除。另外，加入庚烷有助於保持反應中的碘及避免於 冷凝器裝置上昇華。 以控制的方法’將化合物2(稱為2-破-3，4-二曱氧基苯甲 酸鈉鹽）緩慢加入含化合物3(稱為2_羥基苯基乙酸）及第三· 丁醇鉀之於1 〇/〇氯化銅（I)之存在下之二甲基甲醯胺衆物 中。反應完成之後’在經連二亞硫酸鈉還原後藉由過遽而 φ 去除銅催化劑。粗產物2-[2-(羧甲基）苯氧基]_3,4_二曱基苯 曱酸（稱為化合物4)在添加硫酸時會結晶，且經由相對應的 鈉鹽’自水/乙酸乙酯/乙酸中再結晶。 2-[2-(羧甲基）苯氧基]_3,4_二甲基苯甲酸（稱為化合物4) 在高溫下，於硫酸中經歷環化製程’之後其經由相對應的 納鹽，於四氫呋喃/水/乙酸中結晶，生成5,6_二曱基·9_側 氧基-9Η-。占噸-4-基-乙酸（在流程圖1中稱為化合物5)。 另一種替代的方法係在曱烧續酸之存在下，於乙酸中環 化叛甲基）苯氧基]_3,4_二甲基苯甲酸（稱為化合物 140539.doc 201006809 4)，以生成5,6-二甲基_9_側氧基_9H-咕噸-4-基-乙酸（在流 程圖1中稱為化合物5)。 与·兩種方法均很容易單離5,6_二曱基_9_側氧基_9H_咕噸_ 基乙酸（在/;,L程圖1中稱為化合物5 )，其以純淨無色的型 式結晶成粗晶體。 上述純化步驟不僅限於合成5,6_二曱基_9_側氧基_9H咕 嘲-4-基-乙酸。該等純化步驟可用於其它需呈其鹽型方可 溶於水中的難溶性化合物。 另一步驟可形成5,6-二甲基-9-側氧基-9H-咕噸-4-基-乙 酸之鈉鹽。舉例而言，5,6•二甲基_9_側氧基_9H咕噸-4_ 基-乙酸之鈉鹽可藉由下列反應而製備： 流程圖2 0(2-hydroxy-phenyl)-acetic acid 2-(2-carboxy-henry-stupid 10-3.4-dimethylphenyl 1) acyl (5,6-dimercapto-9- oxo-oxime- 4-yl)acetic acid 140539.doc -4- 201006809 a: NaN02/H2S04, I2/KI/H20 AcOEt, b: NaOMe/MeOH, AcOEt; c: KOtBu/DMF, CuCl; d: NaOH, H20, AcOEt, AcOH e: H2S04 (or MeS03H, AcOH, Ac20); f: NaOH, THF, AcOH, H2〇〇. The method described in Scheme 1 does not require isolation of 5,6-dimethyl_9_ side fluorenyl _ 9H-xanthene-4-yl-acetic acid. i Compound 2 in the above Scheme 1 (referred to as 2-moth-3,4-dimethoxybenzophenone. Sodium salt) by by-product (dimethyl The salicylic acid is minimized to produce high purity and high yield. The by-product is effectively removed by crystallizing the sodium salt in ethyl acetate. In addition, the addition of heptane helps to maintain the iodine in the reaction and avoids it. The condenser device is ascended. In a controlled manner, compound 2 (referred to as 2-bromo-3,4-dimethoxyoxybenzoate sodium salt) is slowly added to the compound 3 (referred to as 2-hydroxyphenylacetic acid) and 3. Potassium butoxide is dissolved in dimethylformamide in the presence of 1 〇/〇 copper chloride (I). After the reduction of sodium sulfite, the copper catalyst was removed by φ 。. The crude product 2-[2-(carboxymethyl)phenoxy]_3,4-dimercaptobenzoic acid (called compound 4) It crystallizes when sulfuric acid is added and is recrystallized from the corresponding sodium salt 'from water/ethyl acetate/acetic acid. 2-[2-(Carboxymethyl)phenoxy]_3,4-dimethylbenzene Formic acid (referred to as compound 4) crystallizes in tetrahydrofuran/water/acetic acid via a corresponding sodium salt at a high temperature and undergoes a cyclization process in sulfuric acid to form 5,6-dimercapto- 9-side oxygen. Base-9Η-. ton-4-yl-acetic acid (referred to as compound 5 in Scheme 1). An alternative method is to cyclize the methylidene phenoxylate in acetic acid in the presence of hydrazine-burning acid. Base]_3,4_dimethylbenzoic acid (referred to as compound 140539.doc 201006809 4) to form 5,6-dimethyl-9-hydroxyl-9H-xanthene-4-yl-acetic acid (at It is referred to as Compound 5) in Scheme 1. And both methods are easy to separate 5,6_dimercapto_9_sideoxy_9H_咕 tons_yl acetic acid (in /;, L process 1 is called compound 5), which is pure The colorless form crystallizes into a coarse crystal. The above purification step is not limited to the synthesis of 5,6-didecyl-9-oxyl-9H-oxime-4-yl-acetic acid. These purification steps can be applied to other poorly soluble compounds which require a salt form to be soluble in water. In another step, a sodium salt of 5,6-dimethyl-9-o-oxo-9H-nonton-4-yl-acetic acid can be formed. For example, the sodium salt of 5,6•dimethyl_9_sideoxy_9H咕t-4_yl-acetic acid can be prepared by the following reaction: Flowchart 2 0
(5, 6-二曱基-9-側氧基—咕噸-4-基）乙酸 a : NaOH、水/丙酮 0(5,6-dimercapto-9-sideoxy-xanthene-4-yl)acetic acid a : NaOH, water/acetone 0
[Η,Ο ON a (5, 6-二曱基-9-¾彳氧基-咕嘲-4-基）乙酸納鹽 製備5,6-二甲基_9·側氧基-9H-咕噸_4_基_乙酸鈉鹽的方 法產生幾乎無色的溶液。鑒定該溶液顏色的方法闡述於歐 洲樂典（European pharmacopoeia)中。 以下實例意為闡述本發明且不應視為其限制。如果未另 外提及，文中描述的方法在惰性氛圍下實施，較佳在氮氛 圍下。所有蒸發法都在減壓下進行，較佳在約5至600 140539.doc 201006809 mbar之間。產物及初始材料的結構藉由標準分析法確定， 例如，熔點（mp)及光譜特性（例如，MS、NMR)。使用的縮 寫係其專此項技術中所慣用者。 實例1 2-碘-3,4-二甲氧基苯甲酸納里製法（化合物2) 將30%氫氧化鈉（70 g)加至3,4_二甲基鄰胺基苯甲酸 (1)(82.5 g)於水（300 ml)中的懸浮液中。大部分固體在加入 期間於20_40 C下快速溶解。當於3〇_4〇。〇下攪拌約j小時而 ❿ 形成應經纖維素過濾的黑褐色溶液時，即完全溶解。然後 添加透明的過濾液至濃硫酸（2〇〇 g)及水（3〇〇 ml)中，其添 加方式應保持溫度於5(TC以下。在添加期間，3,4_二甲基 鄰胺基苯曱酸硫酸鹽結晶形成黏稠但可攪拌的漿物，其冷 部至-5 C (外套溫度-i〇°C )。在此溫度下，慢慢添加亞硝酸 鈉水溶液，其添加方式應保持溫度於_5。〇至〇c>c以下。在 此階段形成表面具有泡沫的的褐色溶液。在75_8〇。匸迴流 下，將該溶液於2-3小時内緩慢加入水（2〇〇 ml)、濃硫酸 • (2〇 g)、碘化鉀（3〇0 g)、碘（5〇 g)及庚烷（1〇〇 ml)的熱混合 物中。加入後，維持攪拌10_20min直至再無氣體釋放。然 後冷卻至40-50。〇且加入亞硫酸氫鈉溶液4〇%(55 g)，其 添加方式應保持溫度於40_5(rc之間。然後加入氫氧化鈉 30%(約420 g)，其添加方式應保持溫度於4〇_5(Γ(：之間（以 達pH於2-3之間）。然後加入乙酸乙酯（5〇〇 ml);攪拌3〇分 知，然後分離各層及去除低層的水相。若需要，經纖維素 過濾界面。用鹽水（20% NaCl溶液，1〇〇 ml)沖洗剩餘的有 機相，且再次分離低層的水相。然後在真空下濃縮該有機 140539.doc 201006809 相及加人甲醇（25G ml)，且經纖維素㈣溶液。稱重該過 滤液及取樣用於滴定。然:後加人曱醇鈉3()%(約84 g，依先 前進行的分析法決定）。然後加入乙酸乙醋（讓ml)及在 真空下（外套溫度60°C，約3〇〇 mbar)藉由蒸館去除甲醇， 及以此方式持續用乙酸乙酿置換，以維持悝定體積（以新 鮮乙酸乙0旨置換約画ml館出物）。在此階段所需產物 會結晶析出。在3〇-5(TC下攪拌約3〇分鐘。然後冷卻至〇 C，且授拌約2小日夺。然後藉由過據收集固體及用乙酸乙 醋（4〇〇如）沖洗。在6(rc真空下乾燥該固體。產量：ιΐ3 7 g化合物（2)。 實例2 2-【2-(叛甲基）苯氧基】_34二甲基苯甲致製法（化合 物4) 將第一 丁知鉀（207.2 g，1792 mm〇ie)加至含2_經基_苯基 乙酸（3)(m.4 g，880 mm〇i)之無水二甲基甲醯胺（i2〇〇mi) 溶液中。加熱該溶液至8〇它且添加相對應的2羥基苯基乙 酸二鉀鹽作為晶種❶攪拌3〇分鐘後，得到2_羥基-苯基乙酸 二鉀鹽的懸浮液。在此階段，添加含氣化銅（I)(〇 8 g，8 mmole)之二甲基甲醯胺（38 ml)漿物。之後滴加含2碘_34_ 甲氧基本甲納鹽（238.4 g，800 mmole)之二甲基甲醯 胺（800 ml)溶液。添加後，在85〇c下攪拌反應混合物2小 時。在減壓下藉由蒸餾去除大部分二甲基甲醯胺溶劑。於 殘留物中加水（152〇 mI)，及連二亞硫酸鈉（57.0 g，228 mmole)❶加熱所形成的水溶液至ι〇〇()(：且保持迴流i 5小 時。然後’冷卻均勻懸浮液至20-25。(：且加入木炭（8 g)。 140539.doc 201006809 搜拌30分鐘後，經短徑纖維素渡出後者。然後用濃硫酸 (約96 g)酸化透明的濾液至pH2_3。收集沉澱的固體用水 (1200 ml)沖洗且進行以下純化步驟：取待純化之固體（約 3〇〇 g)懸浮於水中（600 ml)，添加氫氧化納3〇%溶液（i39 g) • 使溶液達PH7-8。然後將形成的溶液緩慢滴加至含乙酸 (16〇g)之乙酸乙醋（16〇〇ml)熱溶液中，滴加過程應維持温 和迴机。一旦添加半數該水溶液後，即添加純2_[2_(羧甲 ❿ 基）苯氧基]_3,4-二曱基苯甲酸⑷作為晶種。加入後，在迴 流下攪拌形成的漿物1小時。然後冷卻至〇艺且保持該温度 1小時。然後藉由過濾分離純固體，用乙酸乙酯（6〇〇 ml)及 水（400 ml)沖洗，且在減壓及6(rc下乾燥，產生純化合物 (4)(192.3 g) 〇 實例3 5,6-二甲基-9-側氧基-9H-咕嘩-4-基-乙酸製法（化合 物5) 加熱化合物（4)(15 g)、甲烷磺酸（15 g)及乙酸（12〇 ml)至 Φ 迴流（118 C )。以10-20分鐘時間，將乙酸酐（15 g)滴加至形 成的溶液中。加入後，立即同時發生結晶。攪拌30分鐘 後，冷卻漿物至15-20°c。藉由過濾收集晶體，用乙睃（15 ml)沖洗後再用水（60 ml)沖洗且在真空及6〇〇c下乾燥約12 小時。產量：13.3 g。以此方法得到的化合物在用氫氧 化納水溶液稀釋及加入含四氫η夫喃的乙酸後，可藉由上述 相同方法純化。 實例4 5,6-二甲基-9-側氧基-9Η-咕嗜-4-基-乙酸製法（化合 物5) 140539.doc 201006809 將純化合物（4)(150 g’ 500 mmol)分批加至l〇〇°C下之濃 硫酸（460 g，96%濃度）攪拌溶液中。加入後，持續攪拌！ 小時’然後降低溫度至80。(：且添加水（500 ml)，添加之方 式應保持溫度於80-100°C之間。在此階段可過濾形成的懸 浮液’以單離粗化合物（7)或依下列方式處理該化合物：添 加氫氧化鈉（1284 g ’ 9.6 mmol)至所形成的懸浮液中，添 加之方式應保持溫度於40-60°C之間及使ρΗ>11。然後，添 加四氫咬喃（600 ml)，且讓形成的乳液靜置在6〇°c下不攪 拌’以便分離相。去除較低的水相後，添加純水（4〇〇 ml) ’之後在65 t：下（迴流下）緩慢添加乙酸（6〇 g，1 mole)。一旦加入1 〇%的乙酸後，即添加懸浮於水（3 mi)中 的晶種（1 00 mg)。加入後’在迴流下維持攪拌1小時。然 後於2小時内將懸浮液冷卻至15_25。〇，熟化1小時及過濾 收集純5,6-二甲基_9_側氧基_9H_咕噸_4_基_乙酸的粗晶體 ((5) : DMXAA，124.3 g)。 實例5 5,6_二甲基_9_側氧基_91!_咕領_4_基乙酸餉鹽製法 (化合物6) 在結晶前，製備30%濃度的NaOH，其係添加45 ““至 105 g水中（保持溫度於玎50。(：以下）。以氮氣沖刷燒瓶，以 防止形成碳酸鈉。 在雙護套玻璃反應器中，將236.4 g5,6_二甲基_9_側氧 基-9H十镇_4_基_乙酸加至625 2 g水與72〇 g act的混合物 中。加熱懸浮液至IT5(TC及添加約112§製備好的氫氧化鈉 溶液。目標PH應於9至10之間。然後再攪拌淡黃色溶液％ 140539.doc 201006809 min。若需要更多NaOH，則加入NaOH以達到所需pH範圍 内。將該溶液過濾（IT45°C至50。〇至JT 40。(：之第二反應器 中。用154 ml 1 : 1重量比的ACT/水混合物沖洗過濾器及 過濾器管道。將透明溶液冷卻至IT 35 X：且以0.32 g 5,卜二 曱基-9-側氧基-9H-咕噸-4-基·乙酸作為晶種，分散於〇4 g 水與4.8 g ACT的混合物中。於4小時内將稀懸浮液進一步 冷卻至IT25°C。在此溫度下，於4小時内添加780 g ACT。 於8小時内冷卻至IT (TC後，在此溫度下攪拌懸浮液至少一 小時。過濾該懸浮液且以360 g ACT/48 g水混合物分兩份 沖洗。在700 mbar及45。(：下乾燥濕濾餅直至達到溶劑規格 (PAKs)。 實例6分析最终產物5,6-二甲基_9_側氧基_9H-咕領_4_基_ 乙酸鈉鹽之顏色的方法 在歐洲藥典中，將溶液的顏色與顏色強度遞減之標準溶 液的等級相比較’例如Y1-Y7系列（黃色）、byi-BY7系列 (棕黃色）或B1-B9系列（棕色）。將來自六組5,6_二甲基_9_側 氧基-9H-咕噸-4-基-乙酸鈉鹽與歐洲藥典相比較，且所有 六組均相當於BY5或BY6等級。 140539.doc[Η,ΟON a (5,6-dimercapto-9-3⁄4彳oxy-indolyl-4-yl)acetic acid sodium salt to prepare 5,6-dimethyl-9·sideoxy-9H-咕The method of ton of _4_yl-acetic acid sodium salt produces an almost colorless solution. The method of identifying the color of the solution is described in European pharmacopoeia. The following examples are intended to illustrate the invention and should not be construed as limiting thereof. If not mentioned otherwise, the process described herein is carried out under an inert atmosphere, preferably under a nitrogen atmosphere. All evaporation methods are carried out under reduced pressure, preferably between about 5 and 600 140539.doc 201006809 mbar. The structure of the product and starting material is determined by standard analytical methods, for example, melting point (mp) and spectral properties (eg, MS, NMR). The abbreviations used are those that are commonly used in this technology. Example 1 2-Iodo-3,4-dimethoxybenzoic acid Nari process (Compound 2) 30% sodium hydroxide (70 g) was added to 3,4-dimethyl-o-aminobenzoic acid (1) (82.5 g) in a suspension in water (300 ml). Most of the solids dissolved rapidly at 20-40 C during the addition. When at 3〇_4〇. Stir for about j hours under the armpit and 完全 to form a dark brown solution that should be filtered through cellulose, that is, completely dissolved. Then add a transparent filtrate to concentrated sulfuric acid (2 〇〇g) and water (3 〇〇 ml), the way of addition should be kept at a temperature below 5 (TC or less. During the addition, 3,4-dimethyl-orthoamine The phenyl phthalic acid sulfate crystallizes to form a viscous but stirrable slurry with a cold portion to -5 C (coating temperature - i 〇 ° C). At this temperature, an aqueous solution of sodium nitrite is slowly added, and the manner of addition should be Keep the temperature at _5. 〇 to 〇c>c. At this stage, a brown solution with foam on the surface is formed. At 75_8 Torr. Under reflux, the solution is slowly added to water within 2-3 hours (2〇〇 Ml), concentrated sulfuric acid • (2〇g), potassium iodide (3〇0 g), iodine (5〇g) and heptane (1〇〇ml) in a hot mixture. After the addition, maintain stirring for 10-20 minutes until no more gas Release. Then cool to 40-50. Add 4% (55 g) of sodium bisulfite solution in a manner to maintain the temperature between 40_5 (rc. Then add 30% sodium hydroxide (about 420 g) It should be added in such a way that the temperature is maintained at 4 〇 5 (between : (: between pH and 2-3). Then add ethyl acetate (5 〇〇 ml); stir 3 〇 Then separate the layers and remove the lower aqueous phase. If necessary, filter the cellulose through the interface. Rinse the remaining organic phase with brine (20% NaCl solution, 1 〇〇ml) and separate the lower aqueous phase again. Concentrate the organic 140539.doc 201006809 phase and add methanol (25G ml), and pass the cellulose (tetra) solution. Weigh the filtrate and sample for titration. Then: add human sodium sterol 3 ()% (about 84 g, determined according to the previous analysis). Then add ethyl acetate (let ml) and under vacuum (coating temperature 60 ° C, about 3 mbar) to remove methanol by steaming, and continue in this way Replace with acetic acid to maintain the volume (replaced with fresh acetic acid). The desired product will crystallize at this stage. Stir at 3 〇-5 (TC for about 3 minutes) Then cool to 〇C and mix for about 2 days. Then collect the solids and rinse with ethyl acetate (4). Dry the solid at 6 (rc vacuum). Yield: ιΐ3 7 g compound (2). Example 2 2-[2-(between methyl)phenoxy]_34 dimethylbenzine production method (Compound 4) The first potassium (207.2 g, 1792 mm 〇ie) was added to anhydrous dimethyl group containing 2-hydroxyl-phenylacetic acid (3) (m. 4 g, 880 mm〇i). In a solution of guanamine (i2〇〇mi), the solution is heated to 8 Torr and the corresponding dipotassium salt of 2 hydroxyphenylacetate is added as a seed crystal. After stirring for 3 minutes, 2-hydroxy-phenylacetic acid is obtained. A suspension of potassium salt. At this stage, a slurry of dimethylformamide (38 ml) containing vaporized copper (I) (〇8 g, 8 mmole) was added. Then, a solution of 2 iodine-34-methoxybenzamide (238.4 g, 800 mmole) in dimethylformamide (800 ml) was added dropwise. After the addition, the reaction mixture was stirred at 85 ° C for 2 hours. Most of the dimethylformamide solvent was removed by distillation under reduced pressure. Water (152 〇mI) and sodium dithionite (57.0 g, 228 mmole) were added to the residue to heat the resulting aqueous solution to ι () (: and kept at reflux for 5 hours. Then 'cool the homogeneous suspension to 20-25. (: and adding charcoal (8 g). 140539.doc 201006809 After 30 minutes of mixing, the latter was passed through the short-path cellulose. The clear filtrate was then acidified to pH 2_3 with concentrated sulfuric acid (about 96 g). The precipitated solid was washed with water (1200 ml) and subjected to the following purification steps: the solid to be purified (about 3 〇〇g) was suspended in water (600 ml), and sodium hydride solution (i39 g) was added. Up to pH 7-8. The formed solution is then slowly added dropwise to a hot solution of acetic acid (16 〇g) in ethyl acetate (16 〇〇ml), and the dropwise addition process should be maintained gently. Once half of the aqueous solution is added That is, pure 2_[2_(carboxymethylsulfonyl)phenoxy]_3,4-dimercaptobenzoic acid (4) was added as a seed crystal. After the addition, the formed slurry was stirred under reflux for 1 hour, and then cooled to a sputum. And maintaining the temperature for 1 hour, then separating the pure solid by filtration, using ethyl acetate (6 〇〇ml) and (400 ml) rinse, and dry under reduced pressure and 6 (rc) to give pure compound (4) (192.3 g) 〇 Example 3 5,6-dimethyl-9- s s s s s -Base-Acetic Acid Process (Compound 5) Heat compound (4) (15 g), methanesulfonic acid (15 g) and acetic acid (12 〇ml) to Φ reflux (118 C). For 10-20 minutes, B Anhydride (15 g) was added dropwise to the formed solution. Immediately after the addition, crystallization occurred. After stirring for 30 minutes, the slurry was cooled to 15-20 ° C. The crystals were collected by filtration and rinsed with acetonitrile (15 ml). It was then rinsed with water (60 ml) and dried under vacuum at 6 ° C for about 12 hours. Yield: 13.3 g. The compound obtained in this way was diluted with aqueous sodium hydroxide and added to the acetic acid containing tetrahydronaphthol. Thereafter, it can be purified by the same method as above. Example 4 5,6-Dimethyl-9-oxooxy-9-indole-4-yl-acetic acid (Compound 5) 140539.doc 201006809 Pure compound (4) (150 g' 500 mmol) was added in portions to a concentrated solution of concentrated sulfuric acid (460 g, 96% concentration) at 10 ° C. After the addition, stirring was continued for an hour' and then the temperature was lowered to 80. (: and add Water (500 ml) should be added in a manner to maintain a temperature between 80 and 100 ° C. The formed suspension can be filtered at this stage by treating the compound separately from the crude compound (7) or by adding hydroxide Sodium (1284 g '9.6 mmol) was added to the resulting suspension in such a manner that the temperature was maintained between 40-60 °C and ρΗ>11. Then, tetrahydrocyanate (600 ml) was added, and the resulting emulsion was allowed to stand at 6 ° C without stirring to separate the phases. After removing the lower aqueous phase, pure water (4 〇〇 ml) was added followed by slow addition of acetic acid (6 〇 g, 1 mole) at 65 t: (under reflux). Once 1% acetic acid was added, seed crystals (100 mg) suspended in water (3 mi) were added. After the addition, the stirring was maintained under reflux for 1 hour. The suspension was then cooled to 15-25 in 2 hours. 〇, aging for 1 hour and filtration. The crude crystals of pure 5,6-dimethyl_9_sideoxy_9H_咕t_4_yl-acetic acid were collected ((5): DMXAA, 124.3 g). Example 5 5,6-Dimethyl_9_sideoxy_91!_咕 collar_4_based acetic acid sulfonium salt preparation (Compound 6) Before crystallization, a 30% concentration of NaOH was prepared, which was added 45" To 105 g of water (keep the temperature at 玎50. (below). Wash the flask with nitrogen to prevent the formation of sodium carbonate. In a double-sheathed glass reactor, 236.4 g of 5,6-dimethyl_9_side oxygen Base-9H ten towns_4_base_acetic acid is added to a mixture of 625 2 g water and 72 〇g act. Heat the suspension to IT5 (TC and add about 112 § prepared sodium hydroxide solution. Target pH should be Between 9 and 10. Then stir the light yellow solution % 140539.doc 201006809 min. If more NaOH is needed, add NaOH to reach the desired pH range. Filter the solution (IT 45 ° C to 50. 〇 to JT 40. (In the second reactor. Rinse the filter and filter tubing with 154 ml 1:1 ratio of ACT/water mixture. Cool the clear solution to IT 35 X: and 0.32 g 5, Base-9-sideoxy-9H-xanthene-4-yl-acetic acid as seed crystal, dispersed in a mixture of 〇4 g water and 4.8 g ACT. The dilute suspension was further cooled to IT25 °C in 4 hours. At this temperature, add 780 g of ACT in 4 hours. Cool to IT within 8 hours (after TC, stir the suspension for at least one hour at this temperature. Filter the suspension and mix with 360 g ACT/48 g water) Rinse in two portions at 700 mbar and 45. (: Dry the wet cake until the solvent size (PAKs) is reached. Example 6 Analysis of the final product 5,6-dimethyl_9_sideoxy_9H-咕 collar_ 4_Base_ Method of coloring sodium acetate In the European Pharmacopoeia, the color of the solution is compared to the grade of the standard solution with decreasing color intensity 'eg Y1-Y7 series (yellow), byi-BY7 series (brown) or B1-B9 series (brown). Comparison of six groups of 5,6-dimethyl_9_sideoxy-9H-xanthene-4-yl-acetate sodium salt compared to the European Pharmacopoeia, and all six groups are equivalent On the BY5 or BY6 rating. 140539.doc