TW200827357A - Improved process for the manufacture of mirtazapine - Google Patents

Abstract

lmproved process for manufacturing mirtazapine. A process is described for preparing mirtazapine starting from a compound of formula (II), which is subjected to a ring cyclization, obtaining mirtazapine for pharmaceutical use in crystalline and anhydrous form.

Description

200827357 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種用於製備米氮平（mirtazapine)之方 法。 【先前技術】 米氮平（商標Remeron®) ’亦即具有式⑴之ι，2,3,41〇, 14b-六氫-2-甲基-吡嗪並[2，l-a]吡啶幷[2,3_c][2]·苯幷氮 口平：200827357 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing mirtazapine. [Prior Art] Mirtazapine (trademark Remeron®) 'is also of the formula (1), i, 2, 3, 41, 14b-hexahydro-2-methyl-pyrazine [2, la] pyridinium [2] , 3_c][2]·benzoquinone nitrogen mouth:

已由美國食品及藥品管理局（u s F〇〇d and Dmg Administration)批准用於治療抑鬱症。 米氮平可由美國專利第4,062,848號（Akzona Incorporated)中所述之方法製得。美國專利第4,〇62,848號 之實例1明確揭示一種藉由在室溫下將濃硫酸添加至式（π) 之1-(3-羥甲基吡啶基-2)-2-苯基-4-甲基哌嗪來製備米氮平 的方法。It has been approved by the US Food and Drug Administration (U s F〇〇d and Dmg Administration) for the treatment of depression. Mirtazapine can be prepared by the method described in U.S. Patent No. 4,062,848 (Akzona Incorporated). Example 1 of U.S. Patent No. 4, No. 62,848, which expressly discloses the addition of concentrated sulfuric acid to 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4 of the formula (π) at room temperature. -Methylpiperazine to prepare mirtazapine.

(II) 然而’此方法存在一些缺點，而使得此方法無法令人滿 117490.doc 200827357 思地用於工業實施。部分缺點描述如下·· •室溫下將濃硫酸逐滴添加至固體化合物，使得無法有效 ' 攪拌混合物且難以控制反應。 •以氯仿萃取反應混合物，從而亦會萃取雜質。 •藉由添加醚使米氮平結晶，而醚在大規模生產中極難處 * 理。 •由石油醚40-60重結晶米氮平，而石油醚4〇_6〇在大規模 生產中極難處理。 ' ’ 在W〇 00/62782之實例2及3中，已揭示可藉由將式（π)之 1 -(3-經甲基η比咬基-2)·2-苯基-4-甲基旅嗓添加至濃硫酸中 來進行相同反應。在實例2中，反應係在室溫下進行4小 時，隨後加熱至約50°C至60°C歷經1小時。在實例3中，反 應係在35°C下進行6小時。 在EP 1 209 159 A2之製備實例1及製備實例2中，已揭示 在5°C至30°C下將式（II)之化合物分成數份添加至濃硫酸 中，且在30°C至40°C下攪拌混合物8小時。此外，由甲苯 i . 及庚烷之混合物獲得米氮平。 根據專利申請案EP 1 209 159 A2之"實施方式”： * •需要濃硫酸之溫度（當將吡啶甲醇化合物添加至濃硫酸中 時）為〇°C至40°C，較佳為5°C至35°C，以便抑制熱量產生及 柏油狀雜質之產生。（參看[0017]第3行）。 •在將吼咬甲醇化合物添加至硫酸中之情況下，較佳將ϋ比 σ定曱醇化合物分成數份添加至濃硫酸中，以便使反應有效 進行。舉例而言，較佳將吡啶曱醇化合物分成5至20份添 117490.doc 200827357 加至浪硫酸中。（參看[0018]第3行）。 二考慮之處在於吡咬甲醇化合物係以固體形式添加至 石爪馱中，就工業角度而言此為不利之處。 已知方法因較為複雜而具有多種缺點’需要觀察特定反 應條件且並非每次均產生足夠品質用於醫藥用途之米氮 :之需要一種可用於在工業規模上製備高品質米氮 【發明内容】 =發明之-目標係提供—種用於製備米氮平且避免先前 =方法之缺點的方法。本發明之另—目標係提供一種獲 得尚純度米氮平之方法。 根據本發明，提供—種用於製備米氮平之方法，其包含 以下步驟： 、 (a)將式（II)之化合物 ch2〇(II) However, this method has some shortcomings that make this method unsatisfactory. 117490.doc 200827357 Thoughts on industrial implementation. Some of the disadvantages are described below. • Concentrated sulfuric acid is added dropwise to the solid compound at room temperature, making it impossible to 'stir the mixture' and it is difficult to control the reaction. • The reaction mixture is extracted with chloroform, which also extracts impurities. • Crystallization of mirtazapine by the addition of ether, which is extremely difficult to produce in large-scale production. • Recrystallization of mirtazapine from petroleum ether 40-60, while petroleum ether 4〇_6〇 is extremely difficult to handle in large-scale production. ' ' In Examples 2 and 3 of W〇00/62782, it has been revealed that by the formula (π) 1 - (3-methyl η ratio 咬 base-2) · 2-phenyl-4- The base is added to concentrated sulfuric acid to carry out the same reaction. In Example 2, the reaction was carried out at room temperature for 4 hours, followed by heating to about 50 ° C to 60 ° C for 1 hour. In Example 3, the reaction was carried out at 35 ° C for 6 hours. In Preparation Example 1 and Preparation Example 2 of EP 1 209 159 A2, it has been disclosed that the compound of the formula (II) is added in several portions to concentrated sulfuric acid at 5 ° C to 30 ° C, and at 30 ° C to 40 ° The mixture was stirred at ° C for 8 hours. Further, mirtazapine was obtained from a mixture of toluene i. and heptane. According to the "embodiment of the patent application EP 1 209 159 A2: * • The temperature of the concentrated sulfuric acid (when the pyridine methanol compound is added to the concentrated sulfuric acid) is 〇 ° C to 40 ° C, preferably 5 ° C to 35 ° C in order to suppress the generation of heat and the formation of tar-like impurities (see [0017] line 3). • In the case of adding a bite methanol compound to sulfuric acid, it is preferred to set the ratio σ The alcohol compound is added in portions to concentrated sulfuric acid to effect the reaction. For example, it is preferred to divide the pyridinium compound into 5 to 20 parts of 117490.doc 200827357 and add it to the sulfuric acid. (See [0018] Line 3) The second consideration is that the butyl methoxide compound is added to the stone scorpion in a solid form, which is disadvantageous from an industrial point of view. The known method has many disadvantages due to its complexity. Conditions and not necessarily producing sufficient quality of rice nitrogen for medical use each time: a need for one can be used to prepare high quality rice nitrogen on an industrial scale [invention] = invention - target is provided - for the preparation of mirtazapine And avoid A method for the disadvantages of the former method. Another object of the present invention is to provide a method for obtaining a purified mirtazapine. According to the present invention, there is provided a method for preparing mirtazapine comprising the steps of: a compound of formula (II) ch2〇

C, (II) 溶解或懸β仍、狄恶稀釋劑中以獲得第一混合物 混 (b)將閉環試劑添加至該第一混合物中以獲得第 物； (c) 使弟一混合物中形成米氮平； (d) 自第二混合物中分離米氮平。 本發明之一較佳實施例係關於一種用於製備米氮平之之 117490.doc 200827357 法，其包含藉由自有機醋溶劑結晶來純化米氮平。 【實施方式】 本發明係關於一種由式#人从•在•丨1 l 種田式（II)之化合物製造無水米氮平之 改良方法。 产本發明亦提供-種藉由自乙酸乙gl重結晶純化粗無水米 氮平來製造純無水米氮平的新穎方法。 ^在本發明之方法中’將式（π)之化合物溶解或懸浮於液 態稀釋劑中。冑閉環試劑添加至所得混合物中，JL在所選 擇之溫度下進行反應。可藉由HPLC(高效液相層析）或薄層 層析監測反應之完成。 完成閉環所需之時間隨反應溫度而變化。較高反應溫度 一般需要較紐反應時間，而較低反應溫度一般需要較長反 應時間。 可使用之稀釋劑為水，諸如二氯甲烷之_化烴，諸如甲 苯或苯甲醚之烴。較佳之稀釋劑為二氯甲烷及水，尤其為 水。稀釋劑之量為以i重量份式（11)之化合物計使用〇.25至5 重量份，更佳為0.4至1.1重量份。 適當之閉環試劑為脫水劑。可添加至反應混合物中之脫 水劑包括酸及酸衍生物，諸如硫酸、濃硫酸、磷酸、磷醯 氯。尤其較佳之脫水劑為硫酸及濃硫酸。濃硫酸之濃度較 佳在96 wt%至99 wt%之範圍内。若閉環試劑可與稀釋劑反 應，則使用足以使米氮平形成之過量閉環試劑。閉環試劑 之較佳量為以1重量份式（Π)之化合物計使用1至6重量份， 更佳為2.5至5.0重量份。 117490.doc 200827357 尤其車乂 ^土使用水作為稀釋劑且使用濃硫酸作為閉環試 劑。而稀釋劑之尤其較佳之量為以式⑻化合物計使用04 至〇.6重量份’且閉環試劑之尤其較佳之量為以式⑽匕合 物計使用4至5重量份。C, (II) dissolving or suspending β still, dioxin diluent to obtain a first mixture mixture (b) adding a ring closure reagent to the first mixture to obtain a first product; (c) forming a mixture in the mixture Nitrogen; (d) separation of mirtazapine from the second mixture. A preferred embodiment of the invention relates to a process for the preparation of mirtazapine 117490.doc 200827357 which comprises purifying mirtazapine by crystallization from an organic vinegar solvent. [Embodiment] The present invention relates to an improved method for producing anhydrous mirtazapine from a compound of the formula (II). The present invention also provides a novel process for producing pure anhydrous mirtazapine by recrystallizing crude anhydrous mirtazapine from recrystallization of ethyl acetate gl. ^ In the process of the present invention, the compound of the formula (π) is dissolved or suspended in a liquid diluent. A rhodium ring closure reagent is added to the resulting mixture and JL is reacted at the temperature selected. The completion of the reaction can be monitored by HPLC (high performance liquid chromatography) or thin layer chromatography. The time required to complete the closed loop varies with the reaction temperature. Higher reaction temperatures generally require a longer reaction time, while lower reaction temperatures generally require longer reaction times. The diluent which can be used is water, such as a hydrocarbon of methylene chloride, a hydrocarbon such as toluene or anisole. Preferred diluents are dichloromethane and water, especially water. The amount of the diluent is from 0.25 to 5 parts by weight, more preferably from 0.4 to 1.1 parts by weight, based on 1 part by weight of the compound of the formula (11). A suitable closed loop reagent is a dehydrating agent. Dehydrating agents which may be added to the reaction mixture include acids and acid derivatives such as sulfuric acid, concentrated sulfuric acid, phosphoric acid, and phosphonium chloride. Particularly preferred dehydrating agents are sulfuric acid and concentrated sulfuric acid. The concentration of concentrated sulfuric acid is preferably in the range of 96 wt% to 99 wt%. If the ring closure reagent can be reacted with a diluent, an excess of the ring closure reagent sufficient to form the mirtazapine is used. The preferred amount of the ring closure reagent is from 1 to 6 parts by weight, more preferably from 2.5 to 5.0 parts by weight, based on 1 part by weight of the compound of the formula (?). 117490.doc 200827357 In particular, the soil uses water as a diluent and concentrated sulfuric acid as a closed loop reagent. Particularly preferred amounts of the diluent are from 04 to 0.6 parts by weight based on the compound of the formula (8) and a particularly preferred amount of the ring closure agent is from 4 to 5 parts by weight based on the compound of the formula (10).

較佳以使反應混合物之溫度保持在其回流溫度以下之速 率、，將閉環試劑以細流之形式添加至化合物（Π)與稀釋劑 之心口物中。添加閉％試劑後，較佳在約室溫至回流溫度 之:皿度下U物攪拌約1至24小時。溫度較佳低於 9〇C，尤其低於8(rc，且反應時間較佳為小時，尤其 為、勺2 "夺右將水用作稀釋劑且將濃硫酸用作閉環試 劑，則此等條件尤其較佳。 在反應進行時’閉壤試劑(例如)因將反應混合物細流添 加至水或驗性水溶液中而經稀釋或受到破壞。在添加過程 中反應此合物之溫度較佳為〇。〇至贼。當閉環試劑經 &稀釋或破壞時’則藉由添加驗性水溶液使混合物呈驗 f生車乂 U驗化過程中存在與水不混溶之溶劑以便使米氮 平始=持溶解。可使用任何驗，包括（但不限於）氫氧化 納虱氧化鉀、碳酸鋼、碳酸氣納及氣氧化錢。其中，氯 氧化納及氫氧化銨較佳。 在該方法t &佳實施例中，將反應混合物添加至水 中’且在鹼化之前添加與水不混溶之溶劑。在另一較佳實 施例中，將反應混合物添加至驗性水溶液中。在此情況 員先U不，容之溶劑添加至驗性水溶液中或反應 此口物中此外，可能將水或驗性水溶液添加至反應混合 117490.doc 200827357 物中。在此情況下，亦較佳在反應混合物與任何驗性組份 接觸之過程中存在與水不混溶之溶劑。 、刀 可使用常用之與水不混溶之溶劑，諸如甲苯或二氯甲 烧。甲苯較佳。在萃取米氮平粗產物的過程中，視需要調 整鹼性水層之pH值，使PH值不小於8，為8至1〇，較佳 8.5至 9.5。 乂土- 可視需要以乾燥劑處理經分離之含有米氮平之與水不混 溶之層以自其中移除水份。乾燥劑可為任何習知之乾燥: 劑，包括（但不限於）無水硫酸鈉、無水硫酸鎂及分子篩。 或者，可使用共沸餾移除水份。 此外，亦較佳將脫色劑添加至含有米氮平之與水不混溶 之層中’以便改良所得無水米氮平晶體之品質屬性(如顏 色)及純度。脫色劑可為任何習知之脫色劑，包括(但不限 於m化銘、活性氧化銘、二氧化石夕及木炭。脫色溫度較 佳介於室溫與80。〇之間，更佳低於4(rc。 藉由蒸餾移除與水不混溶之溶劑且添加允許結晶無水米 氮平形成之不同溶劑，而獲得粗無水米氮平。 、 可藉由任何㉟财式，較佳藉由減壓蒸料行與水不混 溶之溶劑。之蒸館。減壓係使蒸顧過程之溫度低於5(rc，更 佳低於40C之壓力。將溶劑添加至蒸德殘餘物且繼續減壓 蒸餾。接著將溶劑添加至殘餘物，並將混合物加熱至適當 溫度:適當溫度包括（例如）溶劑之回流溫度。將反應混合 物冷部至較佳]〇CS1(rc，更佳代至代後，粗無水米 氮平/儿版。冷郃後，在〇〇c至5它下將混合物攪拌至少1小 117490.doc -10- 200827357 時且至多約6小時，更佳至多约4小時以增加無水米氮平晶 體之產率。較佳可藉由過濾或離心收集無水米氮平粗產物 晶體。Preferably, the ring closure reagent is added to the core of the compound (Π) and the diluent in a fine stream at a rate such that the temperature of the reaction mixture is maintained below its reflux temperature. After the addition of the % blocking reagent, the U material is preferably stirred at about room temperature to reflux temperature for about 1 to 24 hours. The temperature is preferably lower than 9 〇C, especially lower than 8 (rc, and the reaction time is preferably hour, especially, spoon 2 " using water as a diluent and concentrated sulfuric acid as a ring closure reagent, then The conditions are particularly preferred. The blocking reagent is, for example, diluted or destroyed by the addition of a fine stream of the reaction mixture to water or an aqueous test solution during the reaction. The temperature at which the compound is reacted during the addition is preferably 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当 当Start = hold. Any test can be used, including (but not limited to) sodium bismuth hydroxide, carbon steel, carbonation and gas oxidation. Among them, sodium oxychloride and ammonium hydroxide are preferred. In a preferred embodiment, the reaction mixture is added to water' and a water immiscible solvent is added prior to alkalization. In another preferred embodiment, the reaction mixture is added to the aqueous test solution. U first, no solvent is added to In addition to or in the aqueous solution, it is possible to add water or an aqueous test solution to the reaction mixture 117490.doc 200827357. In this case, it is also preferred that the reaction mixture is in contact with any of the test components. There is a solvent which is immiscible with water. The knife can use a commonly used water-immiscible solvent such as toluene or methylene chloride. Toluene is preferred. In the process of extracting the crude product of mirtazapine, the base is adjusted as needed. The pH of the aqueous layer is such that the pH is not less than 8, and is 8 to 1 Torr, preferably 8.5 to 9.5. Bauxite - The separated water-immiscible layer containing mirtazapine may be treated with a desiccant as needed. The moisture is removed therefrom. The desiccant can be any conventional drying: agents including, but not limited to, anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves. Alternatively, azeotropic distillation can be used to remove moisture. Preferably, the decolorizing agent is added to the water-immiscible layer containing mirtazapine to improve the quality properties (such as color) and purity of the resulting anhydrous mirtazapine crystal. The decolorizing agent can be any conventional decolorizing agent, including (but not limited to m Ming, live Oxidation, dioxide, and charcoal. The decolorization temperature is preferably between room temperature and 80. Torr, more preferably less than 4 (rc. The solvent which is immiscible with water is removed by distillation and added to allow crystallized anhydrous rice Nitrogen is formed into different solvents to obtain crude anhydrous mirtazapine. It can be steamed by any of the 35 formulas, preferably by steam distillation under water and steam. The temperature of the process is below 5 (rc, more preferably below 40 C. The solvent is added to the steam residue and the distillation is continued under reduced pressure. The solvent is then added to the residue and the mixture is heated to the appropriate temperature: appropriate temperature Including, for example, the reflux temperature of the solvent. The reaction mixture is cooled to a preferred condition 〇CS1 (rc, more preferably after generation, crude anhydrous mirtazapine/children. After chilling, under 〇〇c to 5 under it The mixture is stirred at least 1 small 117490.doc -10- 200827357 and up to about 6 hours, more preferably up to about 4 hours to increase the yield of anhydrous mirtazapine crystals. Preferably, the crude product of anhydrous mirtazapine is collected by filtration or centrifugation.

1， 較佳使/朝濕粗無水米氮平晶體再重結晶。將粗無水米氮 平與新鮮溶劑混合’並將其加熱至回流溫度。溶劑量為在 回流溫度下獲得溶液所必需之量。將溶液冷卻至〇€&gt;c至5 且在此度下授拌約6小時，更佳約4小時以增加無水米氮 平晶體之產率。較佳可藉由過濾或離心收集無水米氮平晶 體。較佳在減壓下乾燥所收集之無水米氮平晶體以減少無 水米氮平晶體中之殘餘溶劑。乾燥溫度較佳為“艽至几 °c，更佳為40°C至6(rc。減壓更佳為約1〇〇 mm Hg，且在 約40。。下乾燥產物約2小時’隨後在6〇t：下乾燥約4小時以 自無水米氮平晶體移除殘餘溶劑。 使無水米氮平晶體形成之溶劑為有機酯，較佳為有機乙 酸酯，更佳為乙酸乙酯。 式（Π)之起始化合物可購得。或者，可根據美國專利第 4’〇62’848號中所述之方法製備化合物⑼且視需要藉由自 乙酸乙酯重結晶加以純化。 出於說明本發明之目的提供以下實例，且不應將該等實 例解釋為對本發明之料或精神之限制。 實例1 117490.doc • 11 - 200827357 在一適當反應器中裝载·· -3.5 kg去離子水 _7·0 kg叫羥甲基终2_基)句基_2_苯基哌嗪(亦即式 (II)之化合物）。 將反應器冷卻至io°c且伴以持續攪拌。在保持低於8〇Ό 之溫度下添加32.2 kg硫酸（96·1〇 wt%，對應於3〇94 kg HjCU)。添加後，將反應混合物保持在乃·^^下持續剀、 時。接著將反應器内容物冷卻至室溫，且保持低於25。〇之 溫度下添加至40 kg去離子水（預先冷卻至不超過15。〔)）中。 接著藉由添加57 kg甲苯及54 kg 26%氯氧化錢將pH值調 整至8.9-9.3來萃取米氮平。分離相並用13 kg甲苯再萃取水 相。 分離相並用8 kg甲苯再萃取水相。 將有機相裝載至適當反應器中並用61 kg去離子水洗 i條。 用無水硫酸鈉處理有機萃取物並過濾。接著用活性炭將 溶液脫色2次並過濾。 在真空下於不超過40°C之溫度下蒸餾去除甲苯，並自乙 酸乙酯結晶米氮平且過濾。 自乙&amp;L乙酯重結晶所獲得的潮濕固體，過濾並在不超過 約1胃〇〇 mm Hg之壓力下於40t下，且接著於6(rc下乾燥。 獲得4.7 kg(莫耳產率：72%)無水結晶米氮平。 接著，研磨固體，經500 μηι篩篩分且摻合歷經至少2小 時。 117490.doc 12· 200827357 HPLC純度為99.7%。殘餘溶劑（如藉由氣相層析所測 定）··低於100 ppm之偵測極限時使用甲苯，299 ppm之伯 測極限時使用乙酸乙酯。 實例2 此實例展示使用1份式（II)之化合物+0.5份水+4·6份脫水 劑（重量份）且將反應混合物保持於40。〇下歷經2.5 h +60。〇 下歷經1 h+80°C下歷經1 h來製備米氮平。 在24至34°C下，經15分鐘向20 g 1-(3-羥曱基吡啶_2-基&gt; 4-甲基-2-苯基哌嗪於1〇 ml去離子水中之懸浮液中逐滴添 加50 ml硫酸（96_10 wt%)。接著，將溶液加熱至4(rc並保 持2小時30分鐘，隨後加熱至6〇°C並保持1小時，且最後加 熱至80°C並保持1小時。由此獲得溶液。 在室温下，緩慢添加50 ml水。接著添加188 mi甲苯，且 接著用28%氳氧化銨將混合物之pH值調整至約9。在調整 pH值之過程中將溫度保持低於3(rc。 使此溶液分成兩層並再次用甲苯萃取水層。 接著合併有機相並用175 ml水加以洗滌。此後，用硫酸 鈉乾燥甲苯幷用〇·6 g木炭使脫色。45分鐘後過濾溶液。減 壓蒸乾溶劑。HPLC純度為99.45%。 將21 ml乙酸乙酯添加至殘餘物，加熱至回流溫度且接 著冷卻至5°C，並在相同溫度下攪拌1小時且過瀘。 用2 ml乙酸乙酯洗滌所得晶體得到潮濕粗無水米氮平。 HPLC純度為 99.94%。 用15 ml乙酸乙酯使米氮平粗產物結晶。此後將混合物 117490.doc -13- 200827357 冷卻至0-5°C，並在相同溫度下攪拌1小時。 過濾並用2 ml乙酸乙酯洗滌後，減壓下於6〇。〇下乾燥潮 濕aa體直至丨亙重以得到經純化之無水米氮平晶體。hplC 純度為99.98%。殘餘溶劑（如藉由氣相層析所測定）：低於 100 ppm之偵測極限時使用甲苯，175 ppm之偵測極限時使 用乙酸乙酯。 實例3 此實例展示使用1份式（II)之化合物+〇·5份水+4.6份脫水 片丨J (重里伤）且將反應混合物保持於6 〇 °c下歷經7 h來製備米 氮平。 在20至60°C下’經20分鐘向20 g 1-(3-經甲基π比唆基）-4-曱基-2-苯基哌嗪於,1〇 mi去離子水中之懸浮液中逐滴添 加50 ml硫酸（96.10 wt%)。接著將溶液加熱至6〇°c並保持7 小時。 由此獲得溶液，將其冷卻至〇-5°C並缓慢添加50 ml水。 接著添加188 ml甲苯，且接著用28%氫氧化銨將混合物之 pH值調整至約9。在調整pH值之過程中將溫度保持低於25 °C。 使此溶液分成兩層並再次用甲苯萃取水層。 接著合併有機相並用1 75 ml水加以洗滌。此後，用硫酸 鈉乾燥甲苯，並用0.6 g木炭使脫色。1小時15分鐘後過遽 溶液。減壓蒸乾溶劑，得到17·45 g固體殘餘物。HPLC純 度為 98.48%。 將2 1 ml乙酸乙酯添加至殘餘物，加熱至回流溫度且接 117490.doc -14- 200827357 著冷卻至5 C ’並在相同溫度下攪拌1小時且過據。用2加 乙酸乙酯洗滌所得晶體，得到16.87 g潮濕無水米氮平粗產 物。HPLC純度為99.20%。 用15 ml乙酸乙酯使米氮平粗產物結晶。此後將混合物 冷卻至0-5°C，並在相同溫度下攪拌1小時。 過;慮並用2 ml乙酸乙酯洗務後，減壓下於°c下乾燥潮 濕晶體直至恆重以得到15.05 g(莫耳產率·· 80·35%)經純化 之無水米氮平晶體。HPLC純度為99.58%。殘餘溶劑（如藉 由氣相層析所測定）：低於1 00 ppm之偵測極限時使用甲 苯，25 8 ppm之偵測極限時使用乙酸乙醋。 實例4 此貫例展示使用1份式（π)之化合物+1份水+2·76份脫水 劑（重量份）且將反應混合物保持於60。〇至1 〇〇範圍内之溫 度下歷經1 h來製備米氮，平。 在20至58C下’以15分鐘時間，在20 g 1-(3-羥甲基吡 唆-2-基）_4_甲基-2-苯基旅嗓於20 ml去離子水中之懸浮液 中逐滴添加30 ml硫酸（96.10 wt%)。接著經1小時將溶液逐 漸加熱至100°C。 由此獲得溶液，將其冷卻至22t：並緩慢添加3〇 ml水。 接著添加188 ml甲苯，且接著用28%氫氧化銨將混合物之 pH值调整至約9。在調整pH值之過程中將溫度保持低於25 °C 〇 使此溶液分成兩層並再次用甲苯萃取水層。 接著合併有機相並用175 ml水加以洗滌。此後，用硫酸 117490.doc -15- 200827357 鈉乾燥甲苯幷用0.6 g木炭使脫色。1小時15分鐘後過濾溶 液。減壓蒸乾溶劑得到16.39 g固體殘餘物。 將21 ml乙酸乙酯添加至殘餘物，加熱至回流溫度且接 著冷卻至5°C，並在相同溫度下攪拌i小時且過渡。 用2 ml乙酸乙酯洗滌所得晶體得到13·68 g潮濕粗無水米 氮平。HPLC純度為97.32%。 用15 ml乙酸乙酯使粗品結晶。此後將混合物冷卻至 °C，並在相同溫度下攪拌1小時。 過濾並用2 ml乙酸乙酯洗滌後，減壓下於6(rc下乾燥潮 濕晶體直至恆重以得到11.18 g(莫耳產率·· 59.09%)經純化 之無水米氮平晶體。HPLC純度為99.40%。殘餘溶劑（如藉 由氣相層析所測定）：低於1 00 ppm之偵測極限時使用甲 苯，3 21 ppm之偵測極限時使用乙酸乙醋。 實例5 此實例展示使用1份式（II)之化合物‘ + 1份水+2·76份脫水 劑（重量份）且將反應混合物保持於20 °C下歷經3 h 1〇 min+75-80°C下歷經1 h 30 min來製備米氮平。 在20至58°C下，經25分鐘向20 g 1-(3-經曱基η比咬基）_ 4-曱基-2-苯基哌嗪於20 ml去離子水中之懸浮液中逐滴添 加30 ml硫酸（96.10 wt%)。接著，在室溫下攪拌溶液3小時 10分鐘。接著，將溶液加熱至75-80°C歷經1 h 30 min。 由此獲得溶液，將其冷卻至室溫並緩慢添加35 ml水。 接著添加188 ml甲苯，且接著用28%氫氧化銨將混合物之 pH值調整至約9。在調整pH值之過程中將溫度保持低於25 117490.doc -16- 200827357 °c。 使此溶液分成兩層並再次用曱苯萃取水層。 接著合併有機相並用175 ml水加以洗滌。此後，用硫酸 納乾知甲苯幷用〇·6 g木炭使脫色。i小時15分鐘後過渡溶 液減壓瘵乾溶劑得到16.65 g固體殘餘物。HPLC純度為 98.26% 〇 將21 ml乙酸乙酯添加至殘餘物，加熱至回流溫度且接 者冷卻至5。。，並在相同溫度下攪拌!小時且過濾。 用2 ml乙酸乙酯洗滌所得晶體得到14·49 g潮濕粗無水米 氮平。HPLC純度為99.70%。 用18 ml乙酸乙酯使米氮平粗產物結晶。此後將混合物 冷卻至0-5°C，並在相同溫度下攪拌i小時。 過遽並用2 ml乙酸乙酯洗務後，減壓下於6〇它下乾燥潮 濕晶體直至恆重，以得到^丨g(莫耳產率· 64·6〇%)經純 化之無水米氮平晶體。HPLC純度為99.96%。殘餘溶劑（如 藉由氣相層析所測定）：低於1〇〇 ppm之偵測極限時使用甲 笨’ 229 ppm之偵測極限時使用乙酸乙酯。 實例6 此實例展示使用1份式（II)之化合物+4.64份二氯曱烧+4.6 份脫水劑（重量份）且將反應混合物保持於室溫下歷經16 h 來製備米氮平。 將10 g 1-(3-羥甲基吡啶-2-基）-4-甲基·2·苯基哌唤懸浮 於35 ml二氣甲烷中，接著經1〇分鐘添加25 ml硫酸（98.08 wt%)。將混合物保持在室溫下歷經16小時。 117490.doc -17- 200827357 保持内部溫度低於25°C，添加50…水。接著添加25如 甲苯且冷卻混合物。接著，用30%氫氧化銨將混合物之pH 值凋整至約9。此時，再添加5〇 ml甲苯且溶液分成兩層， 並用甲苯再次萃取水層。 接著合併有機相並用硫酸鈉乾燥甲苯且過濾。減壓蒸乾 &gt;谷劑得到8·76 g固體殘餘物。此米氮平殘餘物2HpLC純度 為 96.99%。 將8 g所獲得的殘餘物溶解於9 mi熱乙酸乙酯中，且接著 冷卻至5 C並在相同溫度下攪拌1小時，且過濾得到7 〇5 g 潮濕粗無水米氮平。HPLC純度為98.70%。 用5 ml乙酸乙酯使米氮平粗產物結晶。此後將混合物冷 卻至0-5°C，並在相同溫度下攪拌1小時。 過滤後，減壓下於60°C下乾燥潮濕晶體直至恆重以得到 6·4 g(莫耳產率：74.98%)經純化之無水米氮平晶體。 HPLC純度為99.73%。殘餘溶劑（如藉由氣相層析所測定）： 低於100 ppm之偵測極限時使用甲苯，低於1〇〇 ppm之偵測 極限時使用二氯甲烷，154 ppm之檢測極限時使用乙酸乙 酯0 117490.doc -18 -1. It is preferred to recrystallize the crystals of the wet and crude mirtazapine. The crude anhydrous mirtazapine is mixed with fresh solvent' and heated to reflux temperature. The amount of solvent is the amount necessary to obtain a solution at the reflux temperature. The solution is cooled to &&gt;c to 5 and mixed at this level for about 6 hours, more preferably about 4 hours, to increase the yield of anhydrous mirtazapine crystals. Preferably, the anhydrous mirtazapine crystals are collected by filtration or centrifugation. The collected anhydrous mirtazapine crystals are preferably dried under reduced pressure to reduce residual solvent in the anhydrous mirtazapine crystals. The drying temperature is preferably "艽 to a few ° C, more preferably 40 ° C to 6 (rc. More preferably, the pressure is about 1 mm Hg, and at about 40. The product is dried for about 2 hours). 6 〇 t: drying for about 4 hours to remove the residual solvent from the anhydrous mirtazapine crystal. The solvent for forming the anhydrous mirtazapine crystal is an organic ester, preferably an organic acetate, more preferably ethyl acetate. The starting compound of (Π) is commercially available. Alternatively, compound (9) can be prepared according to the method described in U.S. Patent No. 4'62', and is optionally purified by recrystallization from ethyl acetate. The following examples are provided for the purpose of the present invention and should not be construed as limiting the material or spirit of the present invention. Example 1 117490.doc • 11 - 200827357 Loading in a suitable reactor · · 3.5 kg deionization Water _7·0 kg is called hydroxymethyl terminal 2 yl) succinyl-2-phenylpiperazine (ie, a compound of formula (II)). The reactor is cooled to io °c with continuous stirring. Add 32.2 kg of sulfuric acid (96·1〇wt%, corresponding to 3〇94 kg HjCU) at a temperature below 8〇Ό. After the addition, mix the reaction The contents were kept under 乃·^^, then the reactor contents were cooled to room temperature and kept below 25. The temperature was added to 40 kg of deionized water (pre-cooled to no more than 15.) Then, extract the mirtazapine by adding 57 kg of toluene and 54 kg of 26% chlorine oxide to adjust the pH to 8.9-9.3. Separate the phase and re-extract the aqueous phase with 13 kg of toluene. Separate the phase and use 8 kg of toluene. The aqueous phase was re-extracted. The organic phase was loaded into a suitable reactor and the strip was washed with 61 kg of deionized water. The organic extract was treated with anhydrous sodium sulfate and filtered. The solution was then decolorized twice with activated carbon and filtered. Toluene was distilled off at a temperature above 40 ° C, and mirtazapine was crystallized from ethyl acetate and filtered. The wet solid obtained by recrystallization from ethyl &amp; L ethyl ester, filtered and not more than about 1 stomach 〇〇 mm Hg Under a pressure of 40 t, and then dried at 6 (rc) to obtain 4.7 kg (mole yield: 72%) anhydrous crystalline mirtazapine. Next, the solid was ground, sieved through a 500 μη sieve and blended at least 2 hours. 117490.doc 12· 200827357 HPLC purity was 99.7%. Residual solvent (as determined by gas chromatography) · Use toluene below the detection limit of 100 ppm, ethyl acetate used at the limit of 299 ppm. Example 2 This example shows the use of 1 part (II) ) compound + 0.5 parts water + 4 · 6 parts dehydrating agent (parts by weight) and the reaction mixture is maintained at 40. The underarms are subjected to 2.5 h + 60. The underarms are prepared at 1 h + 80 ° C for 1 h. Nitrogen flat. To a suspension of 20 g of 1-(3-hydroxymethylpyridine-2-yl)&gt; 4-methyl-2-phenylpiperazine in 1 mL of deionized water at 24 to 34 ° C for 15 minutes 50 ml of sulfuric acid (96_10 wt%) was added dropwise. Then, the solution was heated to 4 (rc and held for 2 hours and 30 minutes, then heated to 6 ° C for 1 hour, and finally heated to 80 ° C and kept 1 hour. The solution was thus obtained. At room temperature, 50 ml of water was slowly added, followed by the addition of 188 mi of toluene, and then the pH of the mixture was adjusted to about 9 with 28% ammonium cerium oxide. The temperature was kept below 3 (rc. The solution was separated into two layers and the aqueous layer was again extracted with toluene. The organic phase was then combined and washed with 175 ml of water. Thereafter, toluene was dried over sodium sulfate and decolorized with 〇6 g charcoal. After 45 minutes, the solution was filtered, and the solvent was evaporated to dryness <mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs The resulting crystal was washed with 2 ml of ethyl acetate to give a crude crude anhydrous mirtazapine. HPLC purity was 99.94%. The crude product of mirtazapine was crystallized from 15 ml of ethyl acetate. After that, the mixture 117490.doc -13 - 200827357 was cooled to 0-5 ° C and stirred at the same temperature for 1 hour. After filtration and washing with 2 ml of ethyl acetate, The pressure was reduced to 6 Torr. The wet aa body was dried under the crucible until it was heavier to obtain purified anhydrous mirtazapine crystals. The purity of hplC was 99.98%. Residual solvent (as determined by gas chromatography): lower than Toluene was used at the detection limit of 100 ppm, and ethyl acetate was used at the detection limit of 175 ppm. Example 3 This example shows the use of 1 part of the compound of formula (II) + 5 parts of water + 4.6 parts of dehydrated tablets J ( The mirtazapine was prepared by maintaining the reaction mixture at 6 ° C for 7 h. At 20 to 60 ° C, 20 g to 20 g of 1-(3-methylpyridylthiol) 4-Mercapto-2-phenylpiperazine 50 ml of sulfuric acid (96.10 wt%) was added dropwise to a suspension of 1 〇mi of deionized water. The solution was then heated to 6 ° C for 7 hours. The solution was thus obtained, which was cooled to 〇-5 ° C and 50 ml of water was slowly added. Then 188 ml of toluene was added, and then the mixture was mixed with 28% ammonium hydroxide. The pH was adjusted to about 9. The temperature was kept below 25 ° C during the pH adjustment. The solution was divided into two layers and the aqueous layer was again extracted with toluene. The organic phases were combined and washed with 1 75 ml of water. The toluene was dried over sodium sulfate and decolorized with 0.6 g of charcoal. After 1 hour and 15 minutes, the solution was passed through. The solvent was evaporated to dryness to give a solid residue of 17.45 g. The HPLC purity was 98.48%. 2 1 ml of ethyl acetate was added to the residue, and the mixture was heated to reflux temperature and then cooled to 5 C &apos; and then stirred at the same temperature for 1 hour. The obtained crystals were washed with 2 portions of ethyl acetate to give a crude product of 16.87 g of wet anhydrous mirtazapine. The HPLC purity was 99.20%. The crude product of mirtazapine was crystallized from 15 ml of ethyl acetate. Thereafter, the mixture was cooled to 0 to 5 ° C and stirred at the same temperature for 1 hour. After washing with 2 ml of ethyl acetate, the wet crystals were dried under reduced pressure at ° C until constant weight to obtain 15.05 g (mole yield · 80. 35%) purified anhydrous mirtazapine crystals. . The HPLC purity was 99.58%. Residual solvent (as determined by gas chromatography): Use of toluene below the detection limit of 100 ppm and ethyl acetate in the detection limit of 25 8 ppm. Example 4 This example shows the use of 1 part of a compound of the formula (π) +1 part of water + 2.76 parts of a dehydrating agent (parts by weight) and the reaction mixture was maintained at 60. The rice nitrogen was prepared and dried at a temperature within the range of 1 〇〇 for 1 h. At 20 to 58 C in a suspension of 20 g of 1-(3-hydroxymethylpyridin-2-yl)-4-methyl-2-phenyl in 20 ml of deionized water at 15 minutes 30 ml of sulfuric acid (96.10 wt%) was added dropwise. The solution was then gradually heated to 100 ° C over 1 hour. The solution was thus obtained, which was cooled to 22 t: and 3 ml of water was slowly added. Next, 188 ml of toluene was added, and then the pH of the mixture was adjusted to about 9 with 28% ammonium hydroxide. The temperature was kept below 25 °C during the pH adjustment. 此 The solution was divided into two layers and the aqueous layer was again extracted with toluene. The organic phases were then combined and washed with 175 mL water. Thereafter, toluene was dried with sulfuric acid 117490.doc -15-200827357 sodium and decolorized with 0.6 g of charcoal. The solution was filtered after 1 hour and 15 minutes. The solvent was evaporated under reduced pressure to give a crystallite. 21 ml of ethyl acetate was added to the residue, heated to reflux temperature and then cooled to 5 ° C, and stirred at the same temperature for one hour and then transferred. The obtained crystals were washed with 2 ml of ethyl acetate to give 13.68 g of crude crude anhydrous hexane. The HPLC purity was 97.32%. The crude product was crystallized from 15 ml of ethyl acetate. Thereafter, the mixture was cooled to ° C and stirred at the same temperature for 1 hour. After filtration and washing with 2 ml of ethyl acetate, the dried crystals were dried under reduced pressure at 6 rc until constant weight to obtain 11.18 g (mole yield · 59.09%) purified anhydrous mirtazapine crystals. 99.40%. Residual solvent (as determined by gas chromatography): Toluene was used below the detection limit of 100 ppm, and ethyl acetate was used at the detection limit of 3 21 ppm. Example 5 This example shows the use of 1 Part compound of formula (II) ' + 1 part water + 2. 76 parts dehydrating agent (parts by weight) and the reaction mixture is maintained at 20 ° C for 3 h 1 〇 min + 75-80 ° C for 1 h 30 Min to prepare mirtazapine. At 20 to 58 ° C, after 20 minutes to 20 g 1-(3- thiol η than butyl group) 4- 4-mercapto-2-phenylpiperazine in 20 ml 30 ml of sulfuric acid (96.10 wt%) was added dropwise to the suspension in ionic water. Then, the solution was stirred at room temperature for 3 hours and 10 minutes. Then, the solution was heated to 75-80 ° C for 1 h 30 min. The solution was obtained, it was cooled to room temperature and 35 ml of water was slowly added. Then 188 ml of toluene was added, and then the pH of the mixture was adjusted to about 9 with 28% ammonium hydroxide. The temperature was kept below 25 117490.doc -16-200827357 °c. The solution was divided into two layers and the aqueous layer was extracted again with benzene. The organic phase was then combined and washed with 175 ml of water. The toluene was decolorized with 〇6 g charcoal. After 15 hours, the transition solution was depressurized and the solvent was evaporated to give a solid residue of 16.65 g. HPLC purity 98.26% 21 21 ml of ethyl acetate was added to the residue and heated to The temperature was refluxed and the mixture was cooled to 5 ° and stirred at the same temperature for an hour and filtered. The obtained crystal was washed with 2 ml of ethyl acetate to give 14.49 g of crude crude anhydrous mirtazapine. HPLC purity was 99.70%. The crude product of mirtazapine was crystallized from 18 ml of ethyl acetate. After this time, the mixture was cooled to 0-5 ° C and stirred at the same temperature for one hour. After hydrating and washing with 2 ml of ethyl acetate, under reduced pressure at 6干燥 Dry the wet crystals until constant weight to obtain purified anhydrous mirtazapine crystals with a purity of 99.96%. Residual solvent (eg by gas phase) Determined by chromatography): used below the detection limit of 1〇〇ppm Ethyl acetate was used at the detection limit of 229 ppm. Example 6 This example shows the use of 1 part of the compound of formula (II) + 4.64 parts of dichlorohydrazine + 4.6 parts of dehydrating agent (parts by weight) and the reaction mixture was kept at Prepare mirtazapine at room temperature for 16 h. Suspend 10 g of 1-(3-hydroxymethylpyridin-2-yl)-4-methyl·2·phenyl piperazine in 35 ml of di-methane. Then 25 ml of sulfuric acid (98.08 wt%) was added over 1 minute. The mixture was kept at room temperature for 16 hours. 117490.doc -17- 200827357 Keep the internal temperature below 25 ° C and add 50...water. Next, 25 such as toluene is added and the mixture is cooled. Next, the pH of the mixture was reduced to about 9 with 30% ammonium hydroxide. At this time, 5 〇 ml of toluene was further added and the solution was separated into two layers, and the aqueous layer was again extracted with toluene. The organic phases were combined and dried with sodium sulfate and filtered. Evaporation under reduced pressure &gt; granules gave 8.76 g of a solid residue. The mirtazapine residue 2HpLC had a purity of 96.99%. 8 g of the obtained residue was dissolved in 9 mi of hot ethyl acetate, and then cooled to 5 C and stirred at the same temperature for 1 hour, and filtered to obtain 7 〇 5 g of wet crude mirtazapine. The HPLC purity was 98.70%. The crude product of mirtazapine was crystallized from 5 ml of ethyl acetate. Thereafter, the mixture was cooled to 0 to 5 ° C and stirred at the same temperature for 1 hour. After filtration, the moist crystals were dried at 60 ° C under reduced pressure until constant weight to obtain 4.6 g (mole yield: 74.98%) of purified anhydrous mirtazapine crystals. The HPLC purity was 99.73%. Residual solvent (as determined by gas chromatography): Toluene is used below the detection limit of 100 ppm, dichloromethane is used below the detection limit of 1 〇〇ppm, and acetic acid is used at the detection limit of 154 ppm Ethyl ester 0 117490.doc -18 -

Claims (1)

200827357 十、申請專利範圍： - 1 · 一種用於製備米氮平（mirtazapine)之方法，其包含以下 步驟： (a)將式（II)之化合物200827357 X. Patent application scope: - 1 · A method for preparing mirtazapine comprising the following steps: (a) a compound of formula (II) f， 溶解或懸浮於液態稀釋劑中，以獲得第一混合物； (b) 將閉環試劑添加至該第一混合物中，以獲得第二混 合物； (c) 使該第二混合物中形成米氮平； (d) 自該第二混合物中分離米氮平。 2.如請求項！之方法，其中該液態稀釋劑係選自由幽化 烴、烴及水組成之群。 月求員2之方法，其中該液態稀釋劑係選自二氯甲烷 I 及水。 4·如明求項1至3中任_項之方法，其中該閉環試劑係選自 由硫酸、濃硫酸、餐及魏氯組成之群。 5·如明求項4之方法’其中該閉環試劑為濃硫酸。 6·如睛求項1至5中任_+丄 貝之方法，其中該米氮平形成之步 驟包含將該第 二混合妨7仅^ σ物保持在低於90°c之溫度下歷經1至 4小時之時間。 7·如請求項1至6中任一 項之方法，其中該分離米氮平之步 117490.doc 200827357 :=使該第二混合物與水或與水溶液接觸，以獲得包 S水相之第三混合物。 8 ·如請求項7之方、、去，甘 / ，、中該水相之PH值經調整至不低於 〇 ° 9·如請求項7或8之方法，Α 中δ亥刀離未虱平之步驟包括添 加與水不混溶之溶劑。 1 〇 ·如清求項9之方沐 甘 其中該與水不混溶之溶劑係選自由 本及二氯甲烷組成之群。 Π·如請求項9或1〇之方法， 具甲該7刀離未虱平之步驟包括 :q有米氮平之與水不混溶相與該水相分離。 12.:::求項11之方法’其中將該水相使用與水不混溶之溶 卒取—或多次以獲得另-份與水不混溶相。 13·如請求項^或12 万忐，其中使该與水不混溶相經歷脫 色。 14 ·如請求項9至13 Φ /工 ^ 步驟另外包括移除該溶劑 中任一項之方法，其中該分離米氮平之 L 15. 如喷求項n4中任一項之方法，其另包含藉由自有 醋溶劑中，使該經分離之米氮平結晶一或多次，以進 純化之步驟。 16. 如請求項15之方法’其中該溶劑為乙酸乙酯。 曰曰 17. 如咐求項15或16之方法，其中該米氮平係以無水結 式獲得。 18. 如請求項1至17中任一項之方法，其中 (a)將該式（π)之化合物與水混合，以獲得該第一混 117490.doc 200827357 物； (b) 添加硫酸作為閉環試劑，以獲得該第二混合物； (c) 將該第二混合物保持在低於9〇£?c之溫度下歷經2小時 之時間以使該第二混合物中形成米氮平； 、 ⑷藉由使第二混合物與水接觸，添加 之PH值調整至8至10，隨後分離該 ^ 著蒸發移除該甲苯，而自 色接 平。 弟一心合物中分離米氮 乙酸乙酯中結晶來 19.如請求項18之方法’其另包含藉由 純化該所獲得之米氮平的步驟。 117490.doc 200827357 七、 指定代表圖： _ (一)本案指定代表圖為：（無） (二)本代表圖之元件符號簡單說明： 八、 本案若有化學式時，請揭示最能顯示發明特徵的化學式：f, dissolved or suspended in a liquid diluent to obtain a first mixture; (b) adding a ring closure reagent to the first mixture to obtain a second mixture; (c) forming a mirtazapine in the second mixture (d) separating mirtazapine from the second mixture. 2. As requested! The method wherein the liquid diluent is selected from the group consisting of a ghosting hydrocarbon, a hydrocarbon, and water. The method of claim 2, wherein the liquid diluent is selected from the group consisting of dichloromethane I and water. The method of any of clauses 1 to 3, wherein the ring closure reagent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, meal, and Wei chloride. 5. The method of claim 4 wherein the ring closure reagent is concentrated sulfuric acid. 6. The method of claim 1 to 5, wherein the step of forming the mirtazapine comprises maintaining the second mixture of only 7 σ at a temperature lower than 90 ° C. Up to 4 hours. The method of any one of claims 1 to 6, wherein the step of separating the mirtazapine 117490.doc 200827357 := contacting the second mixture with water or with an aqueous solution to obtain a third phase of the aqueous phase of the package S mixture. 8 · If the pH of the water phase is adjusted to not lower than 〇 ° 9 according to the side of the request item 7, and the 水 亥 亥 · · · · · · · · · · · · · · · · · · · · · · The flat step involves adding a solvent that is immiscible with water. 1 〇 · If the solvent is immiscible, the solvent which is immiscible with water is selected from the group consisting of carbon and methylene chloride. Π·If the method of claim 9 or 1 ,, the step of having the 7-knife away from the sputum includes: q having the immersion phase of mirtazapine and the water being separated from the aqueous phase. 12.::: The method of claim 11 wherein the aqueous phase is dissolved in a water-immiscible solution or a plurality of times to obtain a further water-immiscible phase. 13. If the request item ^ or 120,000 忐 is used, the water-immiscible phase is subjected to discoloration. 14. The method of claim 9, wherein the method of removing any one of the solvents, wherein the separation of the mirtazapine L 15. is as in the method of any one of the items n4, The step of purifying the separated mirtazapine by one or more times by using a solvent of its own vinegar is carried out. 16. The method of claim 15 wherein the solvent is ethyl acetate.曰曰 17. The method of claim 15 or 16, wherein the mirtazapine is obtained in an anhydrous form. 18. The method of any one of claims 1 to 17, wherein (a) mixing the compound of formula (π) with water to obtain the first mixture 117490.doc 200827357; (b) adding sulfuric acid as a closed loop Reagent to obtain the second mixture; (c) maintaining the second mixture at a temperature below 9 ?c for 2 hours to form mirtazapine in the second mixture; (4) The second mixture was contacted with water, and the pH of the addition was adjusted to 8 to 10, followed by separation to remove the toluene by evaporation, and the color was leveled. Separation of rice nitrogen from ethyl acetate in crystallization. 19. The method of claim 18, which further comprises the step of purifying the obtained mirtazapine. 117490.doc 200827357 VII. Designated representative map: _ (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula: 117490.doc -4-117490.doc -4-