568913 A7 B7 五、發明說明（/) 〔技術領域〕 本發明為關於下式一般式U )所示之米貝黴素類之 5-_基衍生物之製法。568913 A7 B7 V. Description of the Invention (/) [Technical Field] The present invention relates to a method for producing a 5-base derivative of mbemycins represented by the following general formula U).
(請先閱讀背面之注意事項再填寫本頁) ;» 〔式中，R1為甲基、乙基、異丙基或第二丁基〕。 「背景技術」 --線_ 於第13位具有酯基之米貝徽素衍生物為具有殺蟲活性 和驅蟲作用，乃例如於日本特開平（Π- 1 04078號公報、 日本特開平05-255343號公報及日本特開平08-259570號 公報等中掲示。 經濟部智慧財產局員工消費合作社印製 關於此類5 -酮基-13 -酯衍生物之製法已知可大致分成 下述所示的（A )及（B )之方法。 (A)令13 -羥基-5-酮基米貝徽素類，與羧酸類或其反 應性衍生物反應酯化之方法：該製法例如於日本特開平 01_104078號公報及日本特開平05-255 343號公報中掲示。 該製法之起始原料為1 3 -羥基-5 -酮基米貝徽素類。於特 一 3 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 568913 A7 _B7 五、發明說明（2 ) 開 6卜1 0 3884號公報中，記載該起始原料之製法。該公昭 報記載之方法具有第一：産率為50%以下，第二：於廢 棄物中含有具毒性的二氣化硒，第三：起始原料之13-羥基_5_酮基米貝徽素類為難以一般性取得等之問題點。 (B)令^13,14-15 -羥基-5 -酮基米貝徽素類，於酸觸 媒存在下，與羧酸反應而酯化之方法。 該製法例如於日本特開平05-255343號公報及日本特 開平08-259570號公報中掲示，該製法之起始原料為Λ13 ,14-15 -羥基-5- _基米貝徽素類。於特開昭60-158191 號公報中，記載該起始原料之製法。該公報記載之方法 具有第一：産生二値反應産物、無法僅選擇性地生成化 合物，第二：産率為約50%以下，第三：反應試藥因使 用毒性及***性強的吖阱化氫酸故伴隨箸危險，第四： 起始原料之^13,14-15 -羥基-5-酮基米貝徽素類為難以 取得等之問題點。 因為以上之理由，故追求確立出不伴隨上述問題點之 米貝徽素類之5 -酮基-1 3 -酯中間體的新穎製法。 本發明為以提供上述一般式（I)所示之米貝徽素類之 -ϋ ϋ -ϋ ϋ H Γ ϋ I I I ϋ I · ϋ I (請先閱讀背面之注意事項再填寫本頁) . 經濟部智慧財產局員工消費合作社印製 的 巨 其 為 法 0 S3 之 佳 率 效 且 全 安 的 物 生 衍 J 酯示 3-掲 -1之 基明 _ 發 式 般 1 述 下 令 於 關 為 明 發 本 物 合 化 素 徽 貝 米 基 酮 4 之 示 所 基 氧 環 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 568913 A7 _B7 五、發明說明（J )(Please read the notes on the back before filling this page); »[wherein R1 is methyl, ethyl, isopropyl or second butyl]. "Background technology"-line_ Rice shellin derivative having an ester group at the 13th position has an insecticidal activity and an insect repellent effect, for example, in Japanese Patent Application Laid-Open No. 1- 04078, Japanese Patent Application Laid-Open No. 05 -255343 and Japanese Unexamined Patent Publication No. 08-259570, etc. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs on the production of such 5-keto-13-ester derivatives is known to be roughly divided into the following: (A) and (B). (A) A method of esterifying 13-hydroxy-5-ketomibetin with a carboxylic acid or a reactive derivative thereof: The production method is, for example, in Japan It is shown in JP-A 01-104078 and JP-A 05-255 343. The starting material of this method is 1 3 -hydroxy-5 -ketomibetin. It is applicable to China in the paper size of 1-3 National Standard (CNS) A4 Specification (210 X 297 mm) 568913 A7 _B7 V. Description of the Invention (2) Publication No. 6B 10 3884 describes the method of making the starting material. The method described in the Gazette has the first 1: Yield is below 50%, Second: Toxic two gases are contained in waste Selenium, the third: 13-hydroxy_5_ketomibetins of the starting material are difficult to obtain in general, etc. (B) Order ^ 13,14-15 -hydroxy-5 -ketomi Shellfishes are esterified by reacting with a carboxylic acid in the presence of an acid catalyst. This production method is shown, for example, in Japanese Patent Application Laid-Open No. 05-255343 and Japanese Patent Application Laid-Open No. 08-259570. The starting material is Λ13,14-15 -hydroxy-5- _ Kimibeilin. In Japanese Patent Application Laid-Open No. 60-158191, the production method of the starting material is described. The method described in the publication has the first: production The reaction product of Erbium does not produce compounds only selectively. Second: Yield is less than about 50%. Third: Reaction reagents are associated with Erbium danger due to the use of toxic and explosive acryl hydrogen acid. Fourth: ^ 13,14-15-Hydroxy-5-ketomibebaxins as starting materials are difficult to obtain, etc. Because of the above reasons, we have sought to establish mibebamins that do not accompany the above problems. A novel method for producing 5-keto-1 3 -ester intermediates. The present invention is to provide -mibexil-like compounds represented by the general formula (I) above. ϋ -ϋ ϋ H Γ ϋ III ϋ I · ϋ I (Please read the precautions on the back before filling out this page). The printed by the Intellectual Property Bureau Employee Consumer Cooperatives of the Ministry of Economic Affairs is the most effective and comprehensive method 0 S3 Ann's Wushengyan J Ester Shows 3- 掲 -1's base Ming _ hair style like 1 stated the order Yu Guan Wei Mingfa's combination of chemical emblem bemyl ketone 4 base oxygen ring paper size applicable to Chinese national standards ( CNS) A4 specification (210 X 297 mm) 568913 A7 _B7 V. Description of the invention (J)
(請先閱讀背面之注意事項再填寫本頁) -,¾ (式中，R1為甲基、乙基、異丙基或第二丁基，R2為 氫原子或三甲基甲矽烷基〕 訂： 與甲矽烷基化劑反應取得下述一般式（III)所示之中間 體化合物後(Please read the notes on the back before filling out this page)-, ¾ (where R1 is methyl, ethyl, isopropyl or second butyl, R2 is hydrogen atom or trimethylsilyl group) Order : After reacting with a silylating agent to obtain an intermediate compound represented by the following general formula (III)
本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --線· 568913 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（车） (式中，R4、R5及R6分別獨立表示Ci至C6烷基）所 示之基〕，令該中間體化合物未單離或精製，於酸存在 下與2 -甲氧基亞胺基-2 -苯基醋酸反應所形成之下述一般 式（I)所示之米貝徽素類之5 -酮基-13 -酯衍生物的製法。This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)-line · 568913 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (car) (where R4, R5 And R6 each independently represent a group represented by Ci to C6 alkyl)], so that the intermediate compound is not isolated or purified, and is formed by reacting with 2-methoxyimino-2-phenylacetic acid in the presence of an acid The following is a method for producing a 5-keto-13-ester derivative of musselin represented by the following general formula (I).
又，本發明為關於上述製法中，一般式（I I I)所示化 合物之R3為三甲基甲矽烷基之製法。 本發明之製法為由使用米貝徽素類之14,15-環氣基體 (參照日本特開平06-220068號公報）作為起始物質，由 前述一般式（II)所示之化合物導出前述一般式（III)所 示中間體化合物之第一工程，及由前述一般式（III)所 示之中間體化合物導出前述一般式（I)所示化合物之第 二工程所組成。 於前述一般式（I)所示之化合物、前述一般式（II)所 示之化合物及前述一般式（III)所示之中間體化合物中 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) .. 線· 568913 A7 經濟部智慧財產局員工消費合作社印製 B7_五、發明說明（，） ，R1為甲基、乙基，異丙基或第二丁基，適當為甲基 或乙基，更適當為乙基。 前逑一般式（III)所示之化合物（式中，R1為甲基、 乙基、異丙基或第二丁基，R2為氫原子或三甲基甲矽 烷基，R3為氫原子或式：SiR4RsR6 (式中，R4、Rs 及R6分別獨立表示Ci至（：6烷基）所示之基）為日本特 開平G6-220068號公報中所掲示的米貝徽素衍生物。 於前述一般式（I I I )所示化合物中之R 3取代基之一所 列舉的式：S i R 4 R 5 R 6 (式中，R 4、R 5及R 6分別獨 立表示（^至（：6烷基）中，所以「（：1至（：6烷基」為指 甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二 丁基或第三丁基，較佳為甲基。 (第一工程） 第一工程為令前述一般式（II)所示之化合物的環氣基 ，於甲矽烷基化劑及鹸存在下開環，變換成前逑一般式 (III)所示烯丙醇衍生物之工程。 反應所使用之甲矽烷基化劑可列舉經三烷基取代之甲 矽烷基三氟甲烷磺酸酯[CF3 S02 OSiR4 Rs R6 (式中， R 4、R 5及R 6分別獨立表示C i至C e烷基）]等，例如 ，三甲基甲矽烷基三氟甲烷磺酸酯、三乙基甲矽烷基三 氟甲烷磺酸酯、三異丙基甲矽烷基三氟甲烷磺酸酯或第 三丁基二甲基甲矽烷基三氟甲烷磺酸酯等，較佳為三甲 基甲矽烷基三氟甲烷磺酸海或第三丁基二甲基三氟甲烷 磺酸酯，更佳為三甲基甲矽烷基三氟甲烷磺酸酯。 (請先閱讀背面之注意事項再填寫本頁) % --線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 經濟部智慧財產局員工消費合作社印製 568913 A7 B7 五、發明說明（7 ) ' 酯、醋酸丙酯之酯類；N，N-二甲基甲醯胺、N，N_二甲基 乙醯胺之醯胺類；二甲基亞碘之亞礁類；乙腈、丙腈之 腈類、或由其中選出二種以上之混合物，旦較佳為甲基 環己烷、甲苯等之鹵化羥類般之烴類·，二氯甲烷般之鹵 化烴類、或由其中選出二種以上之混合物，更佳為甲基 環己烷、二氣甲烷或其混合物。 反應溫度範圍之下限為-50〜-30 °C,上限為50〜100 °C ，較佳範圍為-3 0〜5 0 °C。‘ 反應時間為根據反應溫度，反應所使用之甲矽烷基化 劑、鹼及溶劑等而定，其範圍之下限為1小時，上限為 2〜1 2小時，較佳範圍為1〜2小時。 反應終了後，可依據常法，由反應混合物中，採集前 述一般式（I I I )所示之中間體化合物。例如，反應終了後 ，將反應液以1當量鹽酸，水、磺酸氫銷水溶液及水之 順序，使用分液漏斗經由液-液分配進行洗淨，並且經由 濃縮蒸除溶劑而取得。濃縮法若為通常濃縮液體之方法 則無特別限定，例如為風乾、常壓濃縮、減壓濃縮及蒸 餾等，較佳為減壓濃縮。減壓濃縮為將泵、旋轉蒸發器 、該蒸發器用燃瓶及水浴式恆溫槽等予以組合進行，可 令化合物於該燃燒瓶中呈現乾固狀態。所得之中間體化 合物可未被單離或精製地使用於下一工程。 (第二工程） 第二工程為令第一工程所得之前逑一般式（III)所示 之中間體化合物，於酸存在下，與2 -甲氣基亞胺基- 2-苯基醋酸反應，製造前述一般式（I)所示之米貝徽素類 之5-酮基-13-酯衍生物之工程。 _- Q 一_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --r--—--------- (請先閱讀背面之注意事項再填寫本頁) ·- 線· 568913 經濟部智慧財產局員工消費合作社印製 A7 B7_ 五、發明說明（ί ) 反應所使用之2-甲氯基亞胺基-2-苯基醋酸之份量範 圍之下限為1〜1 . 5莫耳當量，上限為2〜20莫耳當量， 較佳範圍為1.5〜2莫耳當量。 反應所使用之酸，若為通常化學反應中所使用之酸則 無特別限定，可列舉例如硫酸、鹽酸般之無機酸、或三 氟醋酸、三氟甲烷磺酸、苯磺酸、對氯苯磺酸般之有機 酸，較佳為三氟醋酸、三氟甲烷磺酸、苯磺酸，對氣苯 磺酸般之有機酸，更佳為三氟甲烷磺酸。 反應所使用之酸份量為根據酸之種類等而定，其範圍 之下限為0.01〜0.1莫耳當量，上限為0.8〜0.9莫耳當量 ，較佳範圍為0.1〜8莫耳當量。 若於反應条中，添加無機化合物之粉末，則可促進反 應^>於本發明之製法中，亦可視需要，添加此類無機化 合物之粉末。無機化合物若為用以促進通常反應所添加 之無機化合物，則無特別限定，可列舉例如三氟甲烷磺 酸銅、碘化銅、碘化鋅、碘化鈷、碘化鎳般之金屬鹽， Celite化，矽驂、氣化鋁等，較佳為三氟甲烷磺酸銅、 碘化銅般之銅鹽，更佳為碘化銅。 反應所使用之溶劑，若為可令反應物及産物安定地溶 解&不阻礙反應之溶劑則無特別限定，例如正己烷、石 油醚、環己烷、甲基環己烷、苯、甲苯、二甲苯之羥 類；氣仿、二氯甲烷、1，2-二氣乙烷之鹵化烴類；醋 酸乙酯、醋酸丙酯之酯類·，二***、四氳呋喃、二鸣 烷、二甲氧基乙烷之醚類，二甲基甲醯胺，N，N-二甲 基乙醯胺之醯胺類；二甲基亞SJ8之亞硪類；乙腈、丙 -10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） #丨丨 (請先閱讀背面之注意事項再填寫本頁) 訂： -1線· 568913 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明（？） 腈之腈類、或由其中選出二種以上之混合物，且較佳為 石油醚、璟己烷、甲基璟己烷、甲苯等之鹵化烴類；二 氯甲烷1,2 -二氛乙烷般之鹵化烴類，或由其中選出二種 以上之混合物，更佳為甲基環己烷、二氛甲烷或其混合 物。 反應溫度範圍之下限為-10〜01，上限為50〜100¾ ，較佳範圍為0〜5〇υ。 反應時間為根據反應溫度，反應所使用之酸，溶劑及 無機添加物等，其範圍之下限為5至10分鐘，上限為5 至10小時，較佳為10分鐘至5小時。 反應終了後，可依據常法，由反應混合物中，採集前 述一般式（I)所示之中間體化合物。例如，反應終了後， 將反應液以水、磺酸氫鈉水溶液及水之順序，使用分 液漏斗經由液-液分配進行洗淨，並且經由濃縮蒸除溶 劑而取得。濃縮法若為通常濃縮液體之方法則無持別限 定，例如為風乾、常壓濃縮、減壓濃縮及蒸餾等，較佳 為減壓濃縮。經由減壓濃縮為如前述，取得乾固狀態之 化合物。 經由反應所取得之前述一般式（I)所示之目的化合物 視需要，可使用柱層析等之手段再進行精製。 柱層析用之柱中所充瑱之載體若為通常精製有機化合 物所用之載體，則無特別限定，可列舉例如矽膠、C 1S 逆相膠、氧化鋁、活性炭等，較佳為矽膠。 目的化合物之舉動可根據高速液體層析法之定量分析 -11 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 11---'---------- (請先閱讀背面之注意事項再填寫本頁) . -I線· 568913 A7The present invention also relates to a production method in which R3 of the compound represented by general formula (I I I) is trimethylsilyl in the above production method. The production method of the present invention is based on the use of a 14,15-ring gas matrix (refer to Japanese Patent Application Laid-Open No. 06-220068) as a starting material, and the aforementioned general formula is derived from the compound represented by the aforementioned general formula (II). The first process of the intermediate compound represented by the formula (III) and the second process of deriving the compound represented by the aforementioned general formula (I) from the intermediate compound represented by the aforementioned general formula (III). Among the compounds represented by the aforementioned general formula (I), the compounds represented by the aforementioned general formula (II), and the intermediate compounds represented by the aforementioned general formula (III), the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) .. Line 568913 A7 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs B7_V. Invention Description (,), R1 is methyl, B Group, isopropyl or second butyl, suitably methyl or ethyl, more preferably ethyl. The compound represented by the foregoing general formula (III) (where R1 is methyl, ethyl, isopropyl or second butyl, R2 is a hydrogen atom or trimethylsilyl group, and R3 is a hydrogen atom or formula : SiR4RsR6 (wherein R4, Rs, and R6 each independently represent a group represented by Ci to (: 6 alkyl)) is a mibevinin derivative shown in Japanese Patent Application Laid-Open No. G6-220068. In the foregoing general One of the R 3 substituents in the compound represented by the formula (III): S i R 4 R 5 R 6 (wherein R 4, R 5 and R 6 each independently represent (^ to (: 6 alkane) Group, so "(: 1 to (: 6 alkyl)" means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, or third butyl, Methyl is preferred. (First process) In the first process, the ring gas group of the compound represented by the general formula (II) is opened in the presence of a silylating agent and fluorene, and converted into the general formula (III) Engineering of an allyl alcohol derivative. The silylating agent used in the reaction may be a trialkyl-substituted silyltrifluoromethanesulfonate [CF3 S02 OSiR4 Rs R6 (where, R4. R 5 and R 6 each independently represent C i to C e alkyl)] etc., for example, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tris Isopropylsilyl trifluoromethanesulfonate or third butyldimethylsilyl trifluoromethanesulfonate, etc., preferably trimethylsilyl trifluoromethanesulfonate or third butyl Dimethyl trifluoromethane sulfonate, more preferably trimethylsilyl trifluoromethane sulfonate. (Please read the precautions on the back before filling this page)% --line-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 568913 A7 B7 V. Description of the Invention (7) 'Ester, Ester of Acetate; N, N-Dimethyl Methylamine, N, N-dimethylacetamide, amines; dimethyl iodide, reefs; acetonitrile, propionitrile, nitriles, or a mixture of two or more selected from them. Preferred are halogenated hydroxy-like hydrocarbons such as methylcyclohexane and toluene; halogenated hydrocarbons such as dichloromethane; or a mixture of two or more kinds selected therefrom. More preferred is methylcyclohexane, digas methane or a mixture thereof. The lower limit of the reaction temperature range is -50 to -30 ° C, the upper limit is 50 to 100 ° C, and the preferred range is -3 0 to 50 ° C. The reaction time is based on the reaction temperature, the silylating agent, the base, and the solvent used in the reaction, and the lower limit is 1 hour, the upper limit is 2 to 12 hours, and the preferred range is 1 to 2 hours. After the reaction is completed, the intermediate compound represented by the general formula (III) can be collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the reaction solution is sold with 1 equivalent of hydrochloric acid, water, and hydrogen sulfonate. In the order of water and water, washing was performed by liquid-liquid distribution using a separatory funnel, and the solvent was obtained by concentration and evaporation of the solvent. The concentration method is not particularly limited as long as it is a method of generally condensing a liquid, and examples thereof include air-drying, normal-pressure concentration, reduced-pressure concentration, and distillation, and more preferably concentrated under reduced pressure. The concentration under reduced pressure is carried out by combining a pump, a rotary evaporator, a burner for the evaporator, and a water bath-type thermostatic bath, etc., so that the compound can be rendered dry and solid in the burner. The obtained intermediate compound can be used in the next process without isolation or purification. (Second process) The second process is to make the intermediate compound shown by the general formula (III) obtained before the first process react with 2-methylaminoimino-2-phenylacetic acid in the presence of an acid, A process for producing a 5-keto-13-ester derivative of rice shellin represented by the aforementioned general formula (I). _- Q 一 _ This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) --r ------------ (Please read the notes on the back before filling in this (Page) ·-Line · 568913 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7_ 5. Description of the Invention (ί) The lower limit of the amount of 2-methylchloroimino-2-phenylacetic acid used in the reaction is 1 to 1.5 mole equivalents, the upper limit is 2 to 20 mole equivalents, and a preferred range is 1.5 to 2 mole equivalents. The acid used in the reaction is not particularly limited as long as it is an acid used in a general chemical reaction, and examples thereof include sulfuric acid, an inorganic acid such as hydrochloric acid, or trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-chlorobenzene. The sulfonic acid-like organic acid is preferably trifluoroacetic acid, trifluoromethanesulfonic acid, and benzenesulfonic acid, and the p-benzenebenzenesulfonic acid-like organic acid is more preferably trifluoromethanesulfonic acid. The amount of acid used in the reaction depends on the type of acid and the like, and the lower limit is 0.01 to 0.1 mol equivalent, the upper limit is 0.8 to 0.9 mol equivalent, and the preferred range is 0.1 to 8 mol equivalent. If a powder of an inorganic compound is added to the reaction bar, the reaction can be promoted. In the production method of the present invention, if necessary, a powder of such an inorganic compound can be added. The inorganic compound is not particularly limited as long as it is an inorganic compound added to promote ordinary reactions, and examples thereof include metal salts such as copper trifluoromethanesulfonate, copper iodide, zinc iodide, cobalt iodide, and nickel iodide, Celite, silicon rhenium, aluminum vaporized, etc., preferably copper trifluoromethanesulfonate, copper iodide-like copper salt, and more preferably copper iodide. The solvent used in the reaction is not particularly limited as long as it is a solvent that can stably dissolve the reactants and products & does not hinder the reaction, such as n-hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, Hydroxyls of xylene; Halogenated hydrocarbons of gas-form, dichloromethane, 1,2-digasethane; esters of ethyl acetate, propyl acetate, diethyl ether, tetramethylfuran, dioxane, dioxane Ethers of methoxyethane, dimethylformamide, N, N-dimethylacetamide, amines; dimethylmethylene SJ8, fluorenes; acetonitrile, propyl-10- paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) # 丨 丨 (Please read the precautions on the back before filling out this page) Order: -1 line · 568913 Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed clothing A7 B7 V. Description of the invention (?) Nitriles, nitriles, or mixtures of two or more selected from them, and preferably halogenated hydrocarbons such as petroleum ether, hexane, methyl hexane, toluene, etc .; Methane 1, 2-dioxane-like halogenated hydrocarbons, or a mixture of two or more selected from them, more preferably A Cyclohexane, bis atmosphere methane or mixtures thereof. The lower limit of the reaction temperature range is -10 ~ 01, the upper limit is 50 ~ 100¾, and the preferred range is 0 ~ 5〇υ. The reaction time is based on the reaction temperature, acids, solvents and inorganic additives used in the reaction. The lower limit of the range is 5 to 10 minutes, the upper limit is 5 to 10 hours, and preferably 10 minutes to 5 hours. After completion of the reaction, the intermediate compound represented by the aforementioned general formula (I) can be collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the reaction solution is washed in the order of water, aqueous sodium hydrogen sulfonate solution, and water using a separatory funnel through liquid-liquid distribution, and the solvent is obtained by concentration and evaporation of the solvent. The concentration method is not limited as long as it is a conventional method for concentrating liquids, such as air-drying, normal-pressure concentration, reduced-pressure concentration, and distillation, and more preferably reduced-pressure concentration. The compound was obtained by concentration under reduced pressure as described above to obtain a dry solid. The target compound represented by the aforementioned general formula (I) obtained through the reaction can be further purified by means such as column chromatography if necessary. The carrier charged in the column for column chromatography is not particularly limited as long as it is a carrier used for purifying organic compounds in general, and examples thereof include silicon gel, C 1S reverse phase gel, alumina, and activated carbon. Silicon gel is preferred. The behavior of the target compound can be quantitatively analyzed by high-speed liquid chromatography. -11-This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 11 ---'--------- -(Please read the notes on the back before filling this page). -I line · 568913 A7
五、發明說明（〇 ) 之混合溶劑中，於氮氣流下〇至5°C下，加入2,6 -甲基 _啶20.0毫升（1?1.4毫莫耳），並且攪拌1小時〇於其 中加入三甲基甲矽烷基三氟甲烷磺酸酯11.0毫升（57.1 毫獒耳），並於〇至5T!下攪拌1小時。再者，加入三甲 »甲矽烷基三氟甲烷磺酸酯2<3毫升Π1.9毫莫耳），並 於〇至5°C下攪拌1小時。令反應液以水、10%硫酸水溶 液、水、5 %磺酸氫鈉水溶液、水之順序，依據液-液分配 法進行洗淨，並使用蒸發器進行減壓濃縮，取得中間體 化合物之粗製産物19·7克。將此粗製産物未精製地使用 於下之第二工程。 (第二工程） 令中間體化合物之粗製産物19.7克和甲氣基亞胺苯 基醋酸9. 14克（51.1毫其耳）溶解於二氯甲烷1〇5毫升和 甲基環己烷2 4 5毫升之混合溶劑中，並將三氟甲烷磺酸 1-31毫升（12.8毫莫耳）於氬氣流下〇至5°0中滴下，並 非0至5。0下攪拌3小時30分鐘，反應液以水、5%磺酸 氫鈉水溶液、水之順序，依據液-液分配法進行洗淨， 並以硫酸鎂乾燥後，令使用蒸發器之減壓濃縮將溶劑蒸 (請先閱讀背面之注意事項再填寫本頁) 訂---------線 « 經濟部智慧財產局員工消費合作社印製 液液 溶溶 合 合 混混 酯酯 乙乙 酸酸 醋醋 I 隹 烷烷 己己 正正 於經 解至 溶加 物添 留且 殘並 。令 ， 除中 ί 醋 A 衡-以 平烷中 中 7 止 合 tt ^ ^ 膠rl% 矽 之 化 溶 合 混 酯 乙 酸 柱酸 該醋加 至令增0 ^ Μ 吸«段 梯 物"pi L逐ο 彳之1Φ 二 己烷 正己 以正 並於 & * ϋϋ 中乙 ΠΠ 有 含 將 出 溶 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）V. Description of the invention (0) In a mixed solvent of (0), add 20.0 ml (1 to 1.4 mmol) of 2,6-methyl-pyridine under nitrogen flow at 0 to 5 ° C, and stir for 1 hour. Trimethylsilyl trifluoromethanesulfonate is 11.0 ml (57.1 millitorr) and stirred at 0 to 5 T! For 1 hour. Further, trimethyl »silyl trifluoromethanesulfonate 2 (3 ml (1.9 mM)) was added and stirred at 0 to 5 ° C for 1 hour. The reaction solution was washed in the order of water, 10% sulfuric acid aqueous solution, water, 5% sodium hydrogensulfonate aqueous solution, and water in accordance with the liquid-liquid distribution method, and concentrated under reduced pressure using an evaporator to obtain a crude intermediate compound. The product was 19.7 grams. This crude product was used in the next process without purification. (Second process) Dissolve 19.7 g of the crude product of the intermediate compound and 9.14 g (51.1 mil) of methylaminoiminophenylacetic acid in 105 ml of dichloromethane and methylcyclohexane 2 4 In 5 ml of the mixed solvent, 1-31 ml (12.8 mmol) of trifluoromethanesulfonic acid was dropped under a stream of argon at 0 to 5 ° 0, instead of stirring at 0 to 5.0 for 3 hours and 30 minutes. The reaction The liquid was washed in the order of water, 5% sodium hydrogen sulfonate aqueous solution, and water according to the liquid-liquid distribution method. After drying with magnesium sulfate, the solvent was concentrated under reduced pressure using an evaporator to evaporate the solvent. Please fill in this page again) Order --------- Line «Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Cooperatives, printed liquid-liquid-melt-mixed mixed esters of ethyl acetate, acetic acid, vinegar, acetane, hexane Add to the solution and remain in the solution. Let ’s remove the vinegar, A, and acetone in the middle of 7 and tt ^ ^ ^ gel rl% silicon melted mixed ester acetic acid column acid. The vinegar is added to the increase of 0 ^ Μ suction «step ladder " pi L 逐 ο 彳 的 1Φ dihexane is added to & * ϋϋ Chinese B ΠΠ contains the content of the paper will be dissolved and the size of the paper applies the Chinese National Standard (CNS) A4 (210 X 297 mm)