1364282 九、發明說明： 【發明所屬之技術領域】 本發明爲有關哂吩卡配特戊醯氧基（Cefcapene Pivoxil) 之甲磺酸鹽》詳言之，經由該甲磺酸鹽之哂吩卡配特戊醯 氧基鹽酸鹽之製法。 ‘【先前技術】 如下式化合物（I):1364282 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a methanesulfonate of a Cefcapene Pivoxil, which is described in detail by the methanesulfonate A method for preparing a quinone oxime hydrochloride. ‘[Prior Art] Compound (I) of the following formula:
(俗名：哂吩卡配特戊醯氧基；化學名：7)3 -[(Ζ)·2-(2-胺基噻 唑-4-基）-2-丁烯醯基]胺基-3-胺甲醯氧甲基-3-哂吩-4-羧酸 特戊醯氧甲酯）爲哂吩系抗菌劑（參照：專利文獻1)。以其 1鹽酸鹽1水合物（俗名：鹽酸哂吩卡配特戊醯氧基，參照： 專利文獻2)爲有效成分之抗菌劑乃以氟魯莫克斯錠 (Flomox，商品名，鹽野義公司製造）等市售。在專利文獻 1，由哂吩卡配特戊醯氧基之7位胺基之保護體經由自由 體（哂吩卡配特戊醯氧基）合成三氟乙酸鹽（實施例6)。在專 利文獻2，同樣由7位胺基之保護體經由自由體而單離鹽 酸鹽結晶（製造例3)。但在任何文獻均記載無哂吩卡配特 戊醯氧基之甲磺酸鹽。 -【專利文獻1】 特開昭62-89號公報 【專利文獻2】 1364282 .· *» 特開平4-295485號公報 . 【發明內容】 【發明欲解決之課題】 « 在專利文獻2之製造例3’將哂吩卡配特戊醯氧基之7 位胺基保護體之脫保護反應後之萃取液濃縮後’滴下在乙 醇、甲基異丁基酮及鹽酸之混液中使粗鹽酸鹽晶析，以甲 基異丁基酮等有機溶劑洗淨而得鹽酸鹽。但本發明者追試 該方法之結果，得知結晶之單離工程中過濾及洗淨後之分 # 離液（以下將各分離液稱「母液」及「洗液」，將合倂液 稱「母洗液」）中也有哂吩卡配特戊醯氧基鹽酸鹽以數％程 度殘存，作爲大量生産之精製法有改善之必要。 故殷望確立哂吩卡配特戊醯氧基1鹽酸鹽水合物之更適 宜之製法。 【解決課題之手段】 於是本發明者就由上述母洗液中之哂吩卡配特戊醯氧基 鹽酸鹽之回收予以種種檢討之結果，發現將母洗液中之該 ^ 鹽酸鹽一旦變換爲甲磺酸鹽而單離後，再度變換爲鹽酸鹽 ，則可有效回收，終於完成以下之發明。 (1)一種如下式哂吩卡配特戊醯氧基之甲磺酸鹽，(common name: 哂 卡 配 配 ; ;; 化学 ; ;;; chemical name: 7) 3 -[(Ζ)·2-(2-aminothiazol-4-yl)-2-butenyl]amino-3 -Aminomethane oxymethyl-3- phenan-4-carboxylic acid tetrapentamethoxymethyl ester) is a porphin-based antibacterial agent (refer to Patent Document 1). The antibacterial agent which is an active ingredient of the monohydrochloride salt 1 hydrate (common name: guanidine hydrochloride with a pentamidine, reference: Patent Document 2) is a Fluomox ingot (Flomox, trade name, salt) It is commercially available from Noah Co., Ltd.). In Patent Document 1, a trifluoroacetate salt is synthesized from a protective agent of an amine group at the 7-position of a quinone-substituted quinoneoxy group via a free form (porphine-incorporated with a pentamidine group) (Example 6). In Patent Document 2, the hydrochloride of the 7-position amine group was also crystallized by a free body (manufacturing Example 3). However, in any literature, the methanesulfonate of the pentyloxy group is described. [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Example 3 'concentration of the extract after the deprotection reaction of the 7-position amine protecting group of the phenanthrene group with the pentyloxy group, and then dropping the crude hydrochloric acid in a mixture of ethanol, methyl isobutyl ketone and hydrochloric acid The salt is crystallized and washed with an organic solvent such as methyl isobutyl ketone to obtain a hydrochloride. However, the inventors of the present invention pursued the results of the method, and learned that the crystallization of the single separation from the engineering and the separation of the liquid after the # #液 (hereinafter, each separation liquid is called "mother liquor" and "washing liquid", the sputum is called " In the mother lotion, there is also a case where the phenanthrene card and the pentamidine hydrochloride are present in a certain amount of %, and it is necessary to improve the purification method for mass production. Therefore, Yinwang has established a more suitable method for the preparation of the phenoxy card with the pentyloxy 1 hydrochloride hydrate. [Means for Solving the Problem] The inventors of the present invention have conducted various reviews on the recovery of the porphin card in the above-mentioned mother lotion, and found that the hydrochloride in the mother lotion Once converted to the mesylate salt and then converted to the hydrochloride salt, it can be effectively recovered, and finally the following invention is completed. (1) A methanesulfonate of the following formula:
(2) 其係結晶之上述1記載之甲磺酸鹽。 (3) 在含有哂吩卡配特戊醯氧基之鹽酸鹽之有機溶劑溶液中 1364282 加甲磺酸爲特徵之上述1或2記載之哂吩卡配特戊醯氧基 . 之甲磺酸鹽之製法。 (4) —種哂吩卡配特戊醯氧基之鹽酸鹽水合物之製法，其包 括將上述1或2記載之甲磺酸鹽變換爲哂吩卡配特戊醯氧 基後，與鹽酸反應之工程。 (5) 如上述4記載之哂吩卡配特戊醯氧基之鹽酸鹽水合物之 製法，其包括以下之工程： (第1工程） # 在含有哂吩卡配特戊醯氧基之鹽酸鹽之有機溶劑溶液中 加甲磺酸而使哂吩卡配特戊醯氧基之甲磺酸鹽晶析之工程； 及 (第2工程） 將該甲磺酸鹽變換爲哂吩卡配特戊醯氧基後，與鹽酸反 應之工程。 (6) 有機溶劑爲乙醇與甲基異丁基酮之混合溶劑之上述5記 載之製法。 • (7)有機溶劑中之乙醇與甲基異丁基酮之比率爲1:0〜 l:100(Wv)之上述5記載之製法》 (8) 有機溶劑溶液中之哂吩卡配特戊醯氧基之鹽酸鹽之濃度 爲0.05〜10%之上述5記載之製法》 (9) 對哂吩卡配特戊醯氧基之鹽酸鹽加甲磺酸1〜100莫耳 當量之上述5記載之製法。 【發明之效果】 本發明提供哂吩卡配特戊醯氧基之甲磺酸鹽，宜其結晶 1364282 。哂吩卡配特戊醯氧基鹽酸鹽之精製工程中，從母洗淨液 等晶析該甲磺酸鹽後，變換爲鹽酸鹽，則可有效率地回收 哂吩卡配特戊醯氧基鹽酸鹽。故本發明也提供溶劑中混在 之哂吩卡配特戊醯氧基鹽酸鹽之回收方法及包含它之新穎 製法。 【實施發明之最佳形態】 (1)甲磺酸鹽之調製 本發明之甲磺酸鹽宜爲結晶。該結晶可爲溶劑合物，宜 非溶劑合物。溶劑合物時，溶劑可爲水、醇（例如甲醇、 乙醇）、酮類（例如甲基異丁基酮）等。 該結晶用粉末X線繞射宜呈如下主峰。 20 =17.93,18.61，19.63,20.17,20.93,22.39,24.79,25.71(單位 :度） 該甲磺酸鹽之製法無特限，宜由對應之鹽酸鹽製造。例 如在含有哂吩卡配特戊醯氧基之鹽酸鹽之溶劑（宜有機溶 劑）之溶液中添加甲磺酸，使甲磺酸鹽或其溶劑合物，宜 追些之結晶析出。 甲磺酸可爲純品，也可爲工業上販售之70%甲磺酸等。 有機溶劑只要能溶解哂吩卡配特戊醯氧基之鹽酸鹽之溶 劑即可’例如甲醇、乙醇、2-丙醇、2-甲氧基乙醇、乙二 醇、甲氧基乙醇、甘油、丙二醇等醇類，二噚烷、四氫呋 喃、二甲氧基乙烷、二乙二醇二甲醚等醚類，丙酮、丁酮 '甲基異丁基酮等嗣類，甲酸甲酯 '甲酸乙酯、甲酸丙酯 、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸丁酯、丙酸甲酯 1364282(2) The mesylate salt described in the above 1, which is a crystal. (3) In the organic solvent solution containing the hydrochloride of the porphin card with the pentamidine hydrochloride, 1364282 is added with methanesulfonic acid, and the methane sulfonate of the above-mentioned 1 or 2 is described. The method of preparing the acid salt. (4) A method for producing a hydrochloric acid salt hydrate of a quinone-substituted quinone oxime group, which comprises converting the mesylate salt described in the above 1 or 2 into a porphinyl group and a pentamidine group, and a hydrochloric acid Reaction engineering. (5) The method for producing a hydrochloric acid salt hydrate of a porphinyloxy group as described in the above 4, which comprises the following works: (first project) # salt containing a quinone cardinyl group a process in which a methanesulfonic acid salt is added to a solution of an acid salt in an organic solvent solution to form a methanesulfonate salt of a phenanthrene group; and (second work) converting the mesylate salt into a porphin card The reaction with hydrochloric acid after the p-pentyloxy group. (6) The organic solvent is a preparation method of the above five records of a mixed solvent of ethanol and methyl isobutyl ketone. • (7) The ratio of ethanol to methyl isobutyl ketone in the organic solvent is 1:0~l:100 (Wv). The method described in the above 5 (8) The porphin card in the organic solvent solution The concentration of the decyloxyl hydrochloride is 0.05 to 10%, and the above-mentioned preparation method of the above 5 (9) is the above-mentioned hydrochloride of the phenanthrene carboxylic acid and the methyl sulfonic acid of 1 to 100 molar equivalents. 5 records of the system. [Effects of the Invention] The present invention provides a mesylate salt of a porphin card with a pentamidine group, which is preferably crystallized 1364282. In the refining process of the porphyrin card with the pentamidine hydrochloride, the methanesulfonate is crystallized from the mother washing solution, and then converted to the hydrochloride to efficiently recover the porphin Acetone hydrochloride. Therefore, the present invention also provides a method for recovering a porphin card with a pentamidine oxyhydrochloride mixed in a solvent and a novel process comprising the same. [Best Mode for Carrying Out the Invention] (1) Preparation of Mesylate Salt The mesylate salt of the present invention is preferably a crystal. The crystal may be a solvate, preferably a non-solvate. In the case of a solvate, the solvent may be water, an alcohol (for example, methanol or ethanol), a ketone (for example, methyl isobutyl ketone), or the like. The crystallization of the crystal by powder X-ray diffraction preferably has the following main peak. 20 = 17.93, 18.61, 19.63, 20.17, 20.93, 22.39, 24.79, 25.71 (unit: degree) The methanesulfonate is produced without limitation and is preferably produced from the corresponding hydrochloride. For example, methanesulfonic acid is added to a solution containing a solvent (preferably an organic solvent) of a hydrochloride of a phenanthrene group and a pentamidine group, and a mesylate salt or a solvate thereof is preferably precipitated. The methanesulfonic acid may be a pure product or a commercially available 70% methanesulfonic acid or the like. The organic solvent can be dissolved in a solvent such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, or glycerin as long as it dissolves the solvent of the hydrochloride of the phenothrane with the pentamidine. , alcohols such as propylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether, anthracene such as acetone and methyl ethyl ketone 'methyl isobutyl ketone, methyl formate 'formic acid Ethyl ester, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate 1364282
、丙酸乙酯等酯類，二氯甲烷 '氯仿、四氯化碳， 氯乙烷、三氯乙烷、氯苯、二氯苯等有機鹵化烴類 、丙腈等腈類，二甲基甲醯胺、二甲亞颯、二甲基 、N-甲基吡咯啶酮、喹啉、吡啶類，及三乙胺等， 混合溶劑，也可含少量水。更宜比對哂吩卡配特戊 之甲磺酸鹽，對鹽酸鹽之溶解性較高之有機溶劑， 醇，甲基異丁基酮或彼等混合溶劑。乙醇與甲基異 之混合比率通常爲1:0〜1:100&~)，宜1:0.5~1:1丨 1 : 1 〜1 :5，特宜 1 :1 〜1 :3。 有機溶劑中之哂吩卡配特戊醯氧基鹽酸鹽之濃度 0 · 0 1 〜2 0 %，宜 0.0 5 〜1 0 %，更宜 0 · 1 〜5 %。 甲磺酸之添加量對哂吩卡配特戊醯氧基鹽酸鹽， 1〜100莫耳當量，宜5〜50莫耳當量，更宜20〜 當量。 甲磺酸添加後，依所望反應液調節溫度。宜0°C ，更宜冷却爲〇°C〜10°c，靜置數十分〜數小時。 所望添加甲磺酸鹽之種晶。所得結晶次以通常之分 (例如過濾，離心等）由溶劑分離，依所望乾燥而可〗 若上述有機溶劑之溶液爲含哂吩卡配特戊醯氧基 之反應液、其萃取液、或母洗液等時，也有可能原 應副生物等不純物混入，但也可以甲磺酸鹽，宜其 離來除去該不純物。尤其由乙醇與甲基異丁基酮之 劑中回收哂吩卡配特戊醯氧基時，即使以哂吩卡配 氧基之自由體單離，也因溶解度過高而産率低。5 ‘ 1，2-二 ，乙腈 :乙醯胺 或彼等 1酸氧基 例如乙 丁基酮 〇，更宜 通常爲 通常爲 30莫耳 〜室溫 也可依 -離手段 單離。 :鹽酸鹽 :料或反 ;結晶單 :混合溶 丨特戊醯 :將哂吩 1364282 卡配特戊醯氧基就以鹽酸鹽直接單離，也因不純牧 效果低’又有凝膠化之危險性，故作爲工業製法不宜。相 對於這些方法，本發明之依甲磺酸鹽之回收方法，不純物 之除去效果闻，産率也高（例如約70%以上）。故作爲哂吩 卡配特戊醯氧基或其鹽酸鹽之工業回收法，精製法，或製 造法有用》 (2)甲磺酸鹽變換爲鹽酸鹽 本發明更提供哂吩卡配特戊醯氧基之甲磺酸鹽變換爲鹽 酸鹽之方法。宜將哂吩卡配特戊醯氧基之甲磺酸鹽，其溶 劑合物或彼等結晶溶解或懸浮在有機溶劑A，次加含鹼之 水溶液來中和溶解後，除去水層，以哂吩卡配特戊醯氧基 爲自由體在有機溶劑中萃取。更宜將該水層以有機溶劑B 反萃取’與先前所得有機溶劑之萃取液合倂。將該萃取液 仿特開平4-295485號之方法處理而得鹽酸鹽水合物，宜 其結晶。具體而言，將該萃取液濃縮而蒸除二氯甲烷等後 ’依所望以有機溶劑C稀釋，將此滴下在有機溶劑D及鹽 酸之混合液中，而使哂吩卡配特戊醯氧基之鹽酸鹽或其水 合物結晶析出後，依常法乾燥（産率例如：90%以上）。所得 鹽酸鹽水合物可就此當作醫藥活性成分，也可依所望再度 當作精製工程中原料或種晶再利用。 有機溶劑A，B，C可由前述有機溶劑適宜選擇，宜有機 溶劑A及B爲二氯甲烷、醇（例如：乙醇）或其混合溶劑’ 有機溶劑C及D爲醇（例如：乙醇）、甲基異丁基酮或其混 合溶劑。 -10- 1364282 中和用之鹼可爲氫氧化鹼金屬（例如：NaOH，KOH)或碳酸 ' 氫鹼金屬（例如：NaHC03，KHC03)等。例如氫氧化鈉水溶 i 液時，宜約15〜25%，碳酸氫鈉水溶液時，宜5〜1〇%。 鹽酸之濃度通常爲10〜5〇%，宜3〇〜40%，對甲磺酸鹽 通常使用1〜50莫耳當量，宜1〜1〇莫耳當量。 施行上述（1)及（2)之方法，將哂吩卡配特戊醯氧基之鹽酸 鹽更有效率地回收。即本發明包含以下工程爲特徴，也提 供哂吩卡配特戊醯氧基之鹽酸鹽水合物之製法。 (第1工程） 在含有哂吩卡配特戊醯氧基之鹽酸鹽之有機溶劑溶液中 加甲磺酸來使哂吩卡配特戊醯氧基之甲磺酸鹽晶析之工程 〇 (第2工程） 將該甲磺酸鹽變換爲哂吩卡配特戊醯氧基後，與鹽酸反 應之工程。 上述各工程可仿前述（1)及（2)之方法施行。由採用包括上 述2工程之精製法，可將反應萃取後之母洗液中所殘存之 鹽酸哂吩卡配特戊醯氧基以例如60%以上之産率回收。故 大量生産上非常有利。 如上所述，本發明之哂吩卡配特戊醯氧基甲磺酸鹽（宜其 結晶）可當作抗菌劑（例如：哂吩卡配特戊醯氧基鹽酸鹽）之 中間體。該甲磺酸鹽本身也可當作醫藥活性成分。 【實施方式】 以下列示實施例。 實施例1(由母洗液回收甲磺酸鹽） 仿專利第2960790號公報（對應公開編號：特開平4· 2 9548 5號）之製造例3記載之方法，以哂吩卡配特戊醯氧 基之7位胺基保護體（7；3-[(Ζ)-2-(2·第三丁氧羰胺基噻唑-4-基）-2-丁烯醯基]胺基-3-胺甲醯氧甲基-3-哂吩-4-羧酸特 戊醯氧甲酯）1 03 9g爲原料，溶劑及試藥類乃依原料之使用 量之比率增加之條件，施行同様之脫保護反應，使哂吩卡 配特戊醯氧基之鹽酸鹽晶析，濾取結晶。所得結晶以甲基 異丁基酮及二氯甲烷順次洗淨。 將上述過濾之過程分離之濾液（母液）6.9L及由甲基異丁 基酮洗淨後分離之洗淨液（洗液）3.1L混合之母洗液（內在量 :依哂吩卡配特戊醯氧基鹽酸鹽38.7g，含有溶劑比乙醇： 甲基異丁基酮=1:2.6)在8 °C溫度調節後，添加甲磺酸 15 5.6g(25當量），攪拌熟成8小時。濾取所得結晶，結晶 以95%乙醇200mL洗淨後，風乾而得目的之哂吩卡配特戊 醯氧基甲磺酸鹽結晶32.1 g(由母洗液中之産率：73.1 %)。 1 H-NMR (d6-DMSO) l_02(t，3H) 1.17(s，9H) 2.26(t-d，2H，）2.50(s，3H) 3.61(br- s，2H) 4,73(q，2H) 5.24(d，lH) 5.7 5 - 5.9 7 (m, 3 H, 7 - H) 6.5 5(m-t，2H) 9.47(d，lH) 元素分析 C23H29N508S2 · CH3S03H 理論値 C 43.20，Η 5.04, N 10.49, S 14.41 測定値 C 43.32，Η 5.06, N 10.47，S 14.53 1364282 (X線繞射測定條件：管球CuKiZ線，管電壓30Κν，管電流 15mA，dsin0=nA(n爲整數，0爲繞射角）） 實施例2(甲磺酸鹽之鹽酸鹽化）, esters such as ethyl propionate, organic halogenated hydrocarbons such as dichloromethane 'chloroform, carbon tetrachloride, ethyl chloride, trichloroethane, chlorobenzene, dichlorobenzene, nitriles such as propionitrile, dimethyl Formamide, dimethyl hydrazine, dimethyl, N-methylpyrrolidone, quinoline, pyridine, triethylamine, etc., mixed solvent, may also contain a small amount of water. It is more preferable to compare the methanesulfonate of the phenanthrene card with the methanesulfonate, the organic solvent having high solubility to the hydrochloride, the alcohol, the methyl isobutyl ketone or a mixed solvent thereof. The mixing ratio of ethanol to methyl is usually 1:0~1:100&~), preferably 1:0.5~1:1丨 1 :1~1:5, especially 1 :1 ~1 :3. The concentration of the porphin card in the organic solvent with the pentamidine hydrochloride is 0 · 0 1 〜 2 0 %, preferably 0.0 5 〜1 0 %, more preferably 0 · 1 〜 5 %. The amount of methanesulfonic acid added is preferably from 1 to 100 mole equivalents, preferably from 5 to 50 mole equivalents, more preferably from 20 to equivalents. After the methanesulfonic acid is added, the temperature is adjusted depending on the desired reaction solution. It should be 0 ° C, more preferably cooled to 〇 ° C ~ 10 ° C, and the number of standing is very ~ ~ hours. It is expected that the seed crystal of the mesylate salt is added. The obtained crystallization is separated from the solvent by a usual amount (for example, filtration, centrifugation, etc.), and is dried as desired. If the solution of the above organic solvent is a reaction liquid containing a quinone-containing p-pentyloxy group, an extract thereof, or In the case of a mother lotion or the like, it may be mixed with an impurity such as a by-product, but a mesylate salt may be used to remove the impurity. In particular, when the porphin card is bonded with the p-pentyloxy group in the solvent of ethanol and methyl isobutyl ketone, the yield is low because the solubility is too high even if the free form of the phenoxy card is liberated. 5 ‘ 1,2-di, acetonitrile: acetamide or their 1 acid oxy group such as butyl ketone oxime, more usually usually 30 moles to room temperature can also be separated by means. : hydrochloride: material or reverse; crystal single: mixed solution 丨 丨 醯 醯 哂 哂 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 136 The danger of chemicalization is not suitable as an industrial method. With respect to these methods, the method for recovering the mesylate salt of the present invention has an effect of removing impurities, and the yield is also high (e.g., about 70% or more). Therefore, it is useful as an industrial recovery method, a purification method, or a production method for the use of a p-amyloxy group or a hydrochloride thereof. (2) Conversion of a methanesulfonate to a hydrochloride salt. A method in which a mesylate salt of a pentyloxy group is converted to a hydrochloride. It is preferred to use a sulfonium salt of a quinone oxime group, a solvate or a crystal of the same, dissolved or suspended in the organic solvent A, followed by an aqueous solution containing a base to neutralize and dissolve, and then remove the water layer to remove The porphyrin card is prepared by extracting a pentamidineoxy group as a free body in an organic solvent. More preferably, the aqueous layer is back-extracted with an organic solvent B to be combined with an extract of the previously obtained organic solvent. The extract is treated by the method of No. 4-295485 to obtain a salt hydrate hydrochloride, which is preferably crystallized. Specifically, after concentrating the extract and distilling off methylene chloride or the like, it is diluted with an organic solvent C as it is desired, and this is dripped in a mixed solution of an organic solvent D and hydrochloric acid to form a quinone with a pentylene oxide. After the salt of the hydrochloride or the hydrate thereof is crystallized, it is dried by a usual method (yield, for example, 90% or more). The obtained hydrochloride salt hydrate can be used as a pharmaceutically active ingredient, and can be reused as a raw material or seed crystal in a refining process as desired. The organic solvents A, B, and C may be appropriately selected from the above organic solvents, and the organic solvents A and B are preferably dichloromethane, alcohol (for example, ethanol) or a mixed solvent thereof. 'Organic solvents C and D are alcohols (for example, ethanol), A Isobutyl ketone or a mixed solvent thereof. -10- 1364282 The base used for neutralization may be an alkali metal hydroxide (for example: NaOH, KOH) or a carbonic acid alkali metal (for example, NaHC03, KHC03). For example, when sodium hydroxide is dissolved in water, it is preferably about 15 to 25%, and when sodium bicarbonate is used, it is preferably 5 to 1%. The concentration of hydrochloric acid is usually 10 to 5 %, preferably 3 to 40%, and the methanesulfonate is usually 1 to 50 mole equivalents, preferably 1 to 1 mole equivalent. The above methods (1) and (2) are carried out to recover the hydrochloride of the porphin card with the pentyloxy group more efficiently. That is, the present invention includes the following features, and also provides a method for producing a hydrochloride salt of a quinone card with a pentamidine. (1st project) The addition of methanesulfonic acid to an organic solvent solution containing a hydrochloride of a phenanthrene group and a salt of a pentamethoxy group to crystallize a sulfonium salt of a sulfonium group with a methanesulfonate. (Second Project) A process in which the methanesulfonate is converted into a quinone-substituted pentamidine group and reacted with hydrochloric acid. Each of the above items can be carried out in the same manner as the above methods (1) and (2). By using the purification method including the above two processes, the hydrochloric acid quinone card remaining in the mother lotion after the reaction extraction can be recovered in a yield of, for example, 60% or more. Therefore, it is very advantageous in mass production. As described above, the porphin card of the present invention may be used as an intermediate of an antibacterial agent (e.g., porphin-doped pivalate oxychloride). The mesylate salt itself can also be used as a pharmaceutically active ingredient. [Embodiment] The following examples are shown. Example 1 (Recovery of the mesylate salt from the mother lotion) The method described in the production example 3 of the patent publication No. 2960790 (corresponding to the publication number: JP-A No. 4/2 9548 5) Amino protecting group at position 7 of the oxy group (7; 3-[(Ζ)-2-(2·t-butoxycarbonylaminothiazol-4-yl)-2-butenyl]amino-3- Aminomethyl methoxymethyl-3- phenan-4-carboxylic acid, p-pentyloxymethyl ester) 1 03 9g is used as a raw material, and the solvent and the reagents are deprotected according to the conditions of increasing the ratio of the amount of the raw materials used. The reaction is carried out to crystallize the porphin card with a salt of a pentamidine group, and the crystals are collected by filtration. The obtained crystals were washed successively with methyl isobutyl ketone and dichloromethane. The filtrate (mother liquor) separated by the above filtration process is 6.9 L and the washing liquid (washing liquid) separated by methyl isobutyl ketone is mixed with 3.1 L of the mother liquid (intrinsic amount: 哂 卡 卡 卡38.7 g of pentamidine hydrochloride, containing solvent: ethanol: methyl isobutyl ketone = 1:2.6) After adjusting at 8 ° C, 15 5.6 g (25 equivalents) of methanesulfonic acid was added and stirred for 8 hours. . The crystals obtained were collected by filtration, washed with 200 mL of ethyl alcohol (200 mL), and then air-dried to obtain 32.1 g (yield: 73.1% from the mother lotion) of the desired phenanthene card. 1 H-NMR (d6-DMSO) l_02(t,3H) 1.17(s,9H) 2.26(td,2H,) 2.50(s,3H) 3.61(br-s,2H) 4,73(q,2H) 5.24(d,lH) 5.7 5 - 5.9 7 (m, 3 H, 7 - H) 6.5 5(mt,2H) 9.47(d,lH) Elemental analysis C23H29N508S2 · CH3S03H Theory 値C 43.20,Η 5.04, N 10.49, S 14.41 Determination of 値C 43.32, Η 5.06, N 10.47, S 14.53 1364282 (X-ray diffraction measurement conditions: tube CuKiZ line, tube voltage 30 Κ ν, tube current 15 mA, dsin0 = nA (n is an integer, 0 is the diffraction angle) )) Example 2 (hydrochlorination of mesylate)
將實施例1所得哂吩卡配特戊醯氧基甲磺酸鹽20.0 g在 二氯甲烷140 mL予以料漿化，加預先調節成60.5%濃度 之乙醇水140 mL來攪拌混合。於此加20%之氫氧化鈉水 溶液5.9 g，中和溶解後，萃取而除去水層。更以2.5%氯 化鈉水溶液6 0 mL萃取洗淨2回，而得萃取液。萃取中所 得水層以二氯甲烷60 mL反萃取，所得反萃取二氯甲烷層 與萃取液合併。將合倂之萃取液減壓濃縮，蒸除二氯甲烷20.0 g of the porphin card obtained in Example 1 and 20 parts of p-pentyloxy methanesulfonate were slurried in 140 mL of dichloromethane, and 140 mL of ethanol water previously adjusted to a concentration of 60.5% was added thereto, followed by stirring and mixing. 5.9 g of a 20% sodium hydroxide aqueous solution was added thereto, and after neutralization and dissolution, extraction was carried out to remove the aqueous layer. The extract was further washed with 25% of a 2.5% sodium chloride aqueous solution to obtain an extract. The aqueous layer obtained in the extraction was back-extracted with 60 mL of dichloromethane, and the obtained back-extracted dichloromethane layer was combined with the extract. The combined extracts were concentrated under reduced pressure, and dichloromethane was evaporated.
，得哂吩卡配特戊醯氧基之乙醇溶液約48 g。所得液以甲 基異丁基酮60mL稀釋，以5分滴下在調節爲20±2°C之乙 醇8 mL、甲基異丁基酮32 mL及3 5%鹽酸3.4 g之混液中 來使生成物晶析。在同溫攪拌30分，在5±2°C攪拌2小時 後，濾取析出之結晶。結晶以冷甲基異丁基酮60 mL及冷 二氯甲烷78 mL順次洗淨後，風乾而得目的之哂吩卡配特 戊醯氧基1鹽酸鹽水合物16.2 g(産率 91.9%)。化合物之 鑑定乃依液體層析法施行。 【圖式簡單說明】 【第1圖】乃示實施例1所得哂吩卡配特戊醯氧基之甲磺 酸鹽結晶之粉末X線繞射圖形。縱軸爲峰強度，橫軸爲繞 射角度。 【第2圖】將實施例1所得哂吩卡配特戊醯氧基之甲磺酸 鹽結晶之粉末X線繞射圖形予以數據處理之圖。縱軸爲峰 強度，横軸爲繞射角度。 -13 -Approximately 48 g of an ethanol solution of a pentyloxy group. The obtained solution was diluted with 60 mL of methyl isobutyl ketone, and a mixture of 8 mL of ethanol adjusted to 20 ± 2 ° C, 32 mL of methyl isobutyl ketone and 3.4 g of 35% hydrochloric acid was added dropwise at 5 minutes to form a mixture. Crystallization. After stirring at the same temperature for 30 minutes and stirring at 5 ± 2 ° C for 2 hours, the precipitated crystals were collected by filtration. The crystals were washed successively with 60 mL of cold methyl isobutyl ketone and 78 mL of cold dichloromethane, and then air-dried to obtain 16.2 g (yield 91.9%) of the desired quinone card with pentyloxy 1 hydrochloride hydrate. . Identification of the compounds was carried out by liquid chromatography. BRIEF DESCRIPTION OF THE DRAWINGS [Fig. 1] Fig. 1 is a powder X-ray diffraction pattern of a methanesulfonate crystal of a porphin card group obtained in Example 1. The vertical axis is the peak intensity and the horizontal axis is the diffraction angle. [Fig. 2] The X-ray diffraction pattern of the powder of the methanesulfonate crystal of the porphin card group obtained in Example 1 was subjected to data processing. The vertical axis is the peak intensity and the horizontal axis is the diffraction angle. -13 -