200307676 玫、發明說明： 【發明所屬之技術領域】 本發明涉及一種製造酮基泛解酸内酯的氧化反應方法， 特別涉及一種在微波場中將泛解酸内酯氧化為酮基泛解酸 内酯之方法。 【先前技術】 酮基泛解酸内酯係製造泛解酸的關鍵中間物，而泛解酸 係複合維他命B的成貝之一且為輔酶的構成成分。酮基泛解 酸内酯之非對稱氫化作用生成了（D)_(-)-泛解酸内酯，隨後 即由此化合物製得泛解酸。 由泛解酸内酯（其係具有下列分子式之化合物）200307676 Rose and description of the invention: [Technical field to which the invention belongs] The present invention relates to an oxidation reaction method for producing ketopantolactone, in particular to an oxidation reaction of pantolactone to ketopantoate in a microwave field Method of lactone. [Previous Technology] Keto-pantolactone is a key intermediate in the production of pantothenic acid, while pantothenic acid is one of the shellfish of vitamin B complex and is a constituent of coenzyme. The asymmetric hydrogenation of keto-pantoic acid lactones yields (D) _ (-)-pantoic acid lactones. Pantoic acids are then prepared from this compound. By pantolactone (which is a compound having the following formula)
氧化成下列分子式之酮基泛解酸内酯之反應Reaction of oxidation to ketopantolactone of the following formula
已在各種公開案中有所描述，例如：日本未審查專利公開 案 Kokai 04/095087 A2 (CA117 ’ 69720m):使用二氧化錳之 氧化反應；日本未審查專利公開案Kokai 04/095086 A2 rCA117 ’ 69719t)及日本未審查專利公開案Kokai 05/306276 A2 rCA120 ’ 163965d):使用二甲基亞颯之氧化反應；日本 未審查專利公開案Kokai 61/242586 A2〔CA107，5783v)及 200307676It has been described in various publications, for example: Japanese Unexamined Patent Publication Kokai 04/095087 A2 (CA117 '69720m): Oxidation reaction using manganese dioxide; Japanese Unexamined Patent Publication Kokai 04/095086 A2 rCA117' 69719t) and Japanese Unexamined Patent Publication Kokai 05/306276 A2 rCA120'163163d): Oxidation reaction using dimethyl sulfene; Japanese Unexamined Patent Publication Kokai 61/242586 A2 [CA107,5783v) and 200307676
Reel. Trav· Chim· Pays-Bas，110(5)，155_7(1991):微生物 氧化反應；Synth· Commun· 14(7)，第 697-700 頁（1984):釕 催化之需氧氧化反應；及「應用化學」（Angew. Chem.) 96(7) ’第519-520頁（1984):使用第三丁基過氧化氫以釘催化脫 氫反應。 迄今為止，現有之方法對於將酮基泛解酸内酯用於商用 規模生產之產率、選擇性及反應時間方面尚不盡如人意。 【發明内容】 頃發現在水性溶劑系統及微波場中，於釕系催化劑存在 下，藉由泛解酸内酯與過碘酸鹽（1〇4·，亦稱為"偏過碘酸 鹽；下文所提及之"過碘酸鹽"）之氧化反應，可在較短之反 應時間内製得具有良好選擇性、轉換性之酮基泛解酸内 酯。因而，本發明提供一種用於將泛解酸内酯之方法，該 方法包括在水性溶劑系統及微波場中，於釕系催化劑存在 下，與過碘酸鹽進行氧化反應。 本發明所述之方法中所使用之過琪酸鹽宜為鹼金屬過酸 鹽，譬如：過碘酸鈉或過碘酸鉀[Na+I04·或ΚΊΟ^]。釕系催 化劑可為氧化方法中常用且應易溶解於本發明方法所使用 之水性溶劑系統中之任何釕系催化劑。該等催化劑之實例 為釕（皿）鹽，譬如釕（瓜）鹵化物，特定言之為氣化釕 (瓜）[RuCl3]及溴化釕（皿）[RuBr3];及釕氧化物，特定言之為 三氧化二釕（瓜）[Ru2〇3]及其水合物、氧化釕（IV)[Ru〇2]及其 水合物。較佳之催化劑為氯化釕（瓜）。 本文中所使用之術語，，水性溶劑系統"意指包括由水及可 84740 200307676 溶於水之有機溶劑組成之混合物之溶劑系統，且泛解酸内 酯及酮基泛解酸内酯應可溶於其中。該有機溶劑必須至少 部分可溶於水；依所使用之有機溶劑而定，該系統通常為 雙相系統。例如以乙酸乙酯作為該有機溶劑即屬此狀況。 該等適合之有機溶劑之實例為脂系酯，例如乙酸乙酯及乙 酸異丙酯；環狀酯，例如r-丁内酯；及碳酸酯，例如碳酸 乙烯酯及碳酸丙婦酯。較佳為雙相水性溶劑系統。該水性 溶劑系統中水與該有機溶劑之體積比以約丨5:1至約1〇:1為 適且，以約3:1至約5:1為較佳。溶劑系統中水之用量相對於 初始物質泛解酸内酯之用量以每毫莫耳泛解酸内酯使用約 1毫升至約5毫升水為適宜，以每毫莫耳泛解酸内酯使用約 1·5笔升至約2.5毫升水為較佳。較佳之有機溶劑係乙酸乙 酯，含乙酸乙酯作為有機溶劑之較佳水性溶劑系統係由約2 個體積之水對1個體積之乙酸乙酯之比例組成之混合物。 不論其特性如何，本發明之方法中，過碘酸鹽之用量相 對於初始物質泛解酸内酯之用量以每1克泛解酸内酯使用 約4克至約10克過琪酸鹽為適宜，以每j克泛解酸内酯使用 約4·5克至約6.5克過碘酸鹽為較佳。 在釕系催化劑之相對用量方面，適宜用量係每丨克泛解酸 内酯使用約0·001克至約〇.〇5克釕系催化劑，較佳為每i克泛 解酸内酯使用約0.01克至約〇·〇15克該催化劑。 該微波場可藉由任一習知使用之微波發射設備提供。本 文所用之術語’’微波"指頻率為3〇〇 MHz至30 GHz之電磁波 譜區域’因此相應波長為1 m至1 cm。為了不干擾雷達之波 84740 -8 - 200307676 長（1 cm至25 cm)，依據國際規範，工業用微波發射器之操 作波長應為 12.2 cm (2.45 GHz)或 33 ·3 cm (900 MHz)。此方 面可參閱「化學學會综述」（Chem· Soc. Rev·)逆，第1-47 頁（1991年）。因此，在本發明之較佳具體實施例中，施加之 微波場具有約12.2 cm或約33.3 cm之波長。通常，該微波場 係用於促進為時約1分鐘至約60分鐘（以約5分鐘至約40分 鐘較佳，約10分鐘至約30分鐘尤佳）之氧化作用。 本發明之方法中適宜使用之微波反應器為諸如該等處於 ’•Ethos”範圍之内之反應器，如MLS GmbH公司（Auenweg 37, D-88299 Leutkirch im Allgau，德國）所提供之Ethos 1600 反應器（德國以外之供應商為如Milestone S.r.l·，Via Fatebenefratelli，1/5，I_24010 Sorisole (BG)，義大利及 Milestone Inc.，160 B Shelton Road，Monroe，CT 06468， 美國）。本發明之方法中的輻照宜採用約400瓦特至約1000 瓦特之照射率進行，以約500瓦特至約800瓦特為更佳。 依據本發明所述之氧化方法，所施加之微波場最好使得 該氧化作用可在所使用之水性溶劑系統之沸點溫度下進 行。 在本發明方法之較佳具體實施例中，該微波場係施加至 含在適當水性溶劑系統中的泛解酸内酯及釕系催化劑之溶 液，直至該反應混合物之溫度達到其沸點，亦即回流溫度 為止，此時可添加過碘酸鹽氧化劑。該反應適宜藉由如氣 相層析法監控，以確定由泛解酸内酯形成所期望之酮基泛 解酸内酯之最佳轉化點。藉此方法可避免若因反應時間不 84740 -9- 200307676 必要地延長而可能形成非預期之產物及因此有可能降低最 終獲得之酮基泛解酸内酯之產率之問題。一旦達到解酸内 酯形成酮基泛解酸内酯之最隹轉化點時，典型的在初始之 泛解酸内酯完成80%之轉化後’即冷卻反應溶液，並適當 地藉由過滤去除固態物質之後’分離兩個溶劑相及蒸發非 水相，單離出期望之產物-酮基泛解酸内酯。該水相通常包 含未反應之物質，若須要，可再循環，特別回收其中未反 應之泛解酸内酯。 【實施方式】 以下實例對本發明進行了闡述。 實例 取由29.5克之泛解酸内酯、300毫克之氣化釕（in)、400 毫升水及200毫升之乙酸乙酯組成之混合物，藉由具有700 瓦特之輸出功率之微波反應器（Ethos 1600，可自德國MLS GmbH公司，D-88299 Leutkirch im Allgau獲得）產生之微波 場攪拌加熱至回流溫度。在十分鐘内，添加145.5克之（偏） 過碘酸鈉至該沸騰之混合物中。接著再攪拌該反應混合物 20分鐘，然後快速冷卻。自該水相中分離有機相，抽吸過 濾有機相中之碘酸鈉沉澱，以20毫升之乙酸乙酯沖洗5次。 分離雙相混合物，且該水相以50毫升之乙酸乙酯萃取2次。 合併之有機相以無水硫酸鎂脫水，過濾及減壓蒸發。所得 之酮基泛解内酿之純度為98%，按初始泛解酸内酿計，產 率為60%。可再自該水相中單離出12%產物。未反應之泛解 酸内酯可自該水相中收回。 84740 • 10 · 200307676 遵循此製程，80%之初始泛解酸内酯可轉化為酮基泛解 酸内酯，並可達到0.95之選擇性。 84740 •11-Reel. Trav · Chim · Pays-Bas, 110 (5), 155_7 (1991): Microbial oxidation reaction; Synth · Commun · 14 (7), pp. 697-700 (1984): Aerobic oxidation reaction catalyzed by ruthenium; And "Angew. Chem." 96 (7) pp. 519-520 (1984): the use of a third butyl hydrogen peroxide to catalyze the dehydrogenation reaction. To date, existing methods have been unsatisfactory in terms of yield, selectivity, and reaction time for the use of ketopantolactones for commercial scale production. [Summary of the invention] It is found that in an aqueous solvent system and a microwave field, in the presence of a ruthenium-based catalyst, pantolactone and periodate (104 ··, also known as " metaperiodate) The oxidation reaction of " periodate " mentioned below can produce ketopantolactone with good selectivity and conversion in a short reaction time. Accordingly, the present invention provides a method for pantolactone, which method comprises performing an oxidation reaction with periodate in the presence of a ruthenium-based catalyst in an aqueous solvent system and a microwave field. The perchlorate used in the method of the present invention is preferably an alkali metal peracid, such as sodium periodate or potassium periodate [Na + I04 · or ΚΊΟ ^]. The ruthenium-based catalyst may be any ruthenium-based catalyst which is commonly used in oxidation methods and should be easily soluble in the aqueous solvent system used in the method of the present invention. Examples of such catalysts are ruthenium (dish) salts, such as ruthenium (melon) halides, specifically gaseous ruthenium (melon) [RuCl3] and ruthenium bromide (dish) [RuBr3]; and ruthenium oxides, specifically These are ruthenium trioxide (melon) [Ru203] and its hydrate, and ruthenium (IV) oxide [Ru〇2] and its hydrate. The preferred catalyst is ruthenium chloride (melon). As used herein, the term "aqueous solvent system" means a solvent system including a mixture of water and an organic solvent that is soluble in water from 84740 200307676. The pantolactone and ketopantolactone should be Soluble in it. The organic solvent must be at least partially soluble in water; depending on the organic solvent used, the system is usually a two-phase system. This is the case, for example, with ethyl acetate as the organic solvent. Examples of such suitable organic solvents are aliphatic esters such as ethyl acetate and isopropyl acetate; cyclic esters such as r-butyrolactone; and carbonates such as ethylene carbonate and propyl carbonate. A two-phase aqueous solvent system is preferred. The volume ratio of water to the organic solvent in the aqueous solvent system is suitably about 5: 1 to about 10: 1, and more preferably about 3: 1 to about 5: 1. The amount of water in the solvent system is relative to the amount of pantolactone in the starting material. It is suitable to use about 1 ml to about 5 ml of water per millimolar pantolactone, and to use per millimolar pantolide About 1.5 pens to about 2.5 milliliters of water is more preferred. The preferred organic solvent is ethyl acetate, and the preferred aqueous solvent system containing ethyl acetate as the organic solvent is a mixture consisting of a ratio of about 2 volumes of water to 1 volume of ethyl acetate. Regardless of its characteristics, in the method of the present invention, the amount of periodate relative to the amount of the starting material pantolactone is about 4 to about 10 grams of perkidate per gram of pantolactone. Conveniently, from about 4.5 grams to about 6.5 grams of periodate per j grams of pantolactone is preferred. In terms of the relative amount of ruthenium-based catalyst, a suitable amount is about 0.001 to about 0.05 g of ruthenium-based catalyst per gram of pantolactone, preferably about 1 to 1 gram of pantolactone. 0.01 g to about 0.015 g of the catalyst. The microwave field can be provided by any conventionally used microwave transmitting device. The term '' microwave 'as used herein refers to the electromagnetic spectrum region having a frequency of 300 MHz to 30 GHz and therefore a corresponding wavelength of 1 m to 1 cm. In order not to interfere with radar waves 84740 -8-200307676 long (1 cm to 25 cm), according to international regulations, the operating wavelength of industrial microwave transmitters should be 12.2 cm (2.45 GHz) or 33.3 cm (900 MHz). In this regard, see "Review of the Chemical Society" (Chem. Soc. Rev.), page 1-47 (1991). Therefore, in a preferred embodiment of the present invention, the applied microwave field has a wavelength of about 12.2 cm or about 33.3 cm. Generally, the microwave field is used to promote oxidation for about 1 minute to about 60 minutes (preferably about 5 minutes to about 40 minutes, and particularly preferably about 10 minutes to about 30 minutes). Suitable microwave reactors for use in the method of the present invention are such reactors within the scope of '• Ethos', such as the Ethos 1600 reaction provided by MLS GmbH (Auenweg 37, D-88299 Leutkirch im Allgau, Germany). (Suppliers outside Germany such as Milestone Srl ·, Via Fatebenefratelli, 1/5, I_24010 Sorisole (BG), Italy and Milestone Inc., 160 B Shelton Road, Monroe, CT 06468, USA). Method of the invention The irradiation in the medium should preferably be performed with an irradiation rate of about 400 watts to about 1,000 watts, and more preferably about 500 watts to about 800 watts. According to the oxidation method of the present invention, the applied microwave field preferably makes the oxidation effect It can be carried out at the boiling temperature of the aqueous solvent system used. In a preferred embodiment of the method of the present invention, the microwave field is applied to a pantolactone and a ruthenium-based catalyst contained in a suitable aqueous solvent system. Solution until the temperature of the reaction mixture reaches its boiling point, that is, the reflux temperature, at which time periodate oxidant can be added. The reaction is suitably carried out by, for example, a gas phase layer Monitoring to determine the optimal conversion point for the formation of the desired ketopantolactone from pantolactone. This method can avoid the possibility of non-prone formation if the reaction time is unnecessarily extended 84740 -9- 200307676 The expected product and therefore the possibility of lowering the yield of the ketopantolactone finally obtained. Once the maximum conversion point to form the ketopantolactone is reached, typically at the initial After 80% conversion of pantolactone is completed, the reaction solution is cooled, and the solid phase is appropriately removed by filtration. The two solvent phases are separated and the non-aqueous phase is evaporated to separate the desired product, keto-pantolysis. Acid lactones. The water phase usually contains unreacted materials. If necessary, they can be recycled, and the unreacted pantoic acid lactones can be recovered in particular. [Embodiments] The following examples illustrate the invention. The examples are based on 29.5 grams A mixture of pantolactone, 300 mg of ruthenium (in) vaporized, 400 ml of water and 200 ml of ethyl acetate, using a microwave reactor (Ethos 1600, 700 Mw, available from MLS, Germany) GmbH, obtained from D-88299 Leutkirch im Allgau) and heated to reflux temperature with stirring. Within ten minutes, 145.5 grams of (meta) sodium periodate was added to the boiling mixture. The reaction mixture was then stirred again 20 Minutes, then rapid cooling. The organic phase was separated from the aqueous phase, the sodium iodate precipitate in the organic phase was filtered with suction, and washed 5 times with 20 ml of ethyl acetate. The biphasic mixture was separated, and the aqueous phase was separated with 50 ml It was extracted twice with ethyl acetate. The combined organic phases were dehydrated with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The purity of the obtained keto-based hydrolyzed internal fermentation was 98%, and the yield was 60% based on the initial pan-hydrolyzed internal fermentation. A further 12% of the product can be isolated from this aqueous phase. Unreacted pantolides can be recovered from the aqueous phase. 84740 • 10 · 200307676 Following this process, 80% of the initial pantolactone can be converted to ketopantolactone with a selectivity of 0.95. 8474011-