TW201204706A

TW201204706A - Process for the preparation of 2-chloro-6-fluorobenzoxazole

Info

Publication number: TW201204706A
Application number: TW100119336A
Authority: TW
Inventors: Yoshiyuki Takeuchi; Shunsuke Ochi; Yuki Fukui; Takaharu Matsuura
Original assignee: Shionogi & Amp Co Ltd
Priority date: 2010-06-03
Filing date: 2011-06-02
Publication date: 2012-02-01
Also published as: WO2011152442A1

Abstract

The present invention provides a novel method for producing a compound represented by formula (II), which is characterized by reacting a compound represented by formula (I) with a chlorinating agent.

Description

201204706 六、發明說明：【發明所屬之技術領域】本發明係關於2-氯-6-氟苯并噚唑制言之造方法王·^ 1造方法。# ，係關於具有NPY Y5受體拮抗作 ^ νψ 几邗用之化合物之製【先前技術】專利文獻1〜3記載以下式表示的化a私*201204706 VI. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for producing 2-chloro-6-fluorobenzoxazole. #, relates to a compound having a compound for NPY Y5 receptor antagonism. [Prior Art] Patent Documents 1 to 3 describe the following formula:

σ切為具有]p Vσ cut to have ]p V

Y5受體拮抗作用之化合物，並記载兌製造 Y (R^=x w 法：、R3 (式中，R各自獨立而為鹵素、Ci_c6、b«· ' Cl-Cfi 炫·氧基、C1-C6鹵烧基、C1-C6鹵烧童其十p 叛一 … -一一 —1 “叫…汉―马Cl-C6烷基. C3-C8環烧基；或也可經選自函素、C1_C6燒基、cic6 烷氧基' C1-C6鹵烷基及C1-C6鹵烷氧基當中' 取代的苯基）。田以上 f利文獻4中，記載以下列所示的製造方法。 XX>。 ^ XXV-c 亦即记載2,6-二氯苯并噚唑之製造方法，其特徵於使6_氣笨并嘮唑酮於由氣、三氯化磷及氣化磷醯構成的混合物中或由五氣化磷及氣化磷醯構成的混合物中，於150 i 17〇t的溫度在加壓下反應，此時氣及三氯化鱗相對於氣化鱗酿的會晉& $ g I ;曰，4 扪垔里比或五虱化磷相對於氯化磷醯的重罝比為o.15:uG.6G:卜又，產率為例1:5〇%、例 3 . 5 5%。疋礼丞或C1-C6烷其基，η為0〜2之整數，X為S或〇，r3 土 -C8環烧基；或也可經選自鹵素、Γι ’ -4- 201204706 先前技術文獻專利文獻專利文獻1 專利文獻2 專利文獻3 專利文獻4 【發明内容】國際公開國際公開國際公開曰本特開第2007/125952號小冊第2009/054434號小冊第2008/134228號小冊昭 60-193974 [發明所欲解決之課題] 本發明所欲解抗作用之化合物即的課題為找出具有NPY Y5受體拮體即2-氣-6-氟笨1式（VI)表示的化合物的有用的中間 [用以解決課題之大噚唑的新賴製造方法。 <方式] 本案發明人發银、， m „ ，現以下的發明。 (1)一種以式（1 ., 、）表不之化合物之製造方法，其特徵為使以式（I)表示的 ^ (1). 化s物與氣化劑反應，a compound that antagonizes the Y5 receptor, and describes the production of Y (R^=xw method: R3 (wherein R is independently halogen, Ci_c6, b«· ' Cl-Cfi methoxy, C1- C6 halogenated group, C1-C6 halogen burning child, its ten p rebellion... -1 -1 "called ... Han - horse Cl-C6 alkyl. C3-C8 cycloalkyl; or can also be selected from the element, C1_C6 alkyl group, cic6 alkoxy 'C1-C6 haloalkyl group and '1-substituted phenyl group' among C1-C6 haloalkoxy groups.) The above-mentioned production method is described in the above document. XX> ^ XXV-c is also a method for producing 2,6-dichlorobenzoxazole, which is characterized in that 6_gas and oxazolone are composed of gas, phosphorus trichloride and gasified phosphonium. In the mixture or in a mixture of five gasified phosphorus and gasified phosphonium, the reaction is carried out under pressure at a temperature of 150 i 17 〇t, at which time the gas and the trichlorinated scale are compared with the gasification scale. ; g g; 曰, 4 扪垔比 or 虱虱相对相对相对相对相对相对 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o 3 . 5 5%. 疋礼丞 or C1-C6 alkane, η is an integer of 0~2, X is S or 〇, r3 soil-C8 ring Or the like, or may be selected from the group consisting of halogen, Γι ' -4- 201204706, prior art document, patent document, patent document 1, patent document 2, patent document 3, patent document 4 [invention content] International Public International Publication International Publication 曰本开开2007 /125952 Booklet No. 2009/054434, Book No. 2008/134228, Booklet No. 60-193974 [Problems to be Solved by the Invention] The problem of the compound to be solved by the present invention is to find out that it has NPY Y5 A useful intermediate of a compound represented by the formula (VI) of 2-gas-6-fluorophenyl 1 (VI) [a new method for producing big oxazole for solving the problem. <Method] The inventor of the present invention issued silver, m „ , the following invention. (1) A method for producing a compound represented by the formula (1., . ), characterized in that the compound (1) represented by the formula (I) is vaporized. Agent reaction,

式（II):Formula (II):

(II) (2) 如上述（1)之製造方法，其係不加壓而進行。 (3) 如上述（1)或（2)之製造方法，其係於1〇〇度以下的溫度進行。 -5- 201204706 (4) 如上述（1)〜（3)中任一項之製造方法，其係於聚磷酸存在下進行。 (5) 如上述（1)〜（4)中任一項之製造方法，其係使用五氯化磷、氧氣化磷或此等的混合物當做氯化劑。 (6) 如上述（1)〜（5)中任一項之製法方法，其係使用非極性有機溶劑、氧氣化磷或此等的混合溶劑當做溶劑。 (7) —種以式（VI)表示之化合物、其鹽或此等的溶劑合物之製造方法，其特徵為包含如上述（1)〜（6)中任一項之方法。式（VI): j^^Y^NHSOrtert-Bu (vi) 又，本說明書中，使化合物與化合物反應，係包含使其鹽或此等的溶劑合物反應。「鹽」，例如鹽酸、硫酸、硝酸或磷酸等無機酸的鹽；乙酸、曱酸、對曱苯磺酸、曱烧績酸、草酸或檸檬酸等有機酸的鹽等。「溶劑合物」，係例如化合物或其鹽的水合物、醇合物等。例如，化合物或其鹽的1水合物、2水合物、1醇合物、2醇合物等。 [發明之效果] 藉由使6-氟苯并嘮唑酮與氣化劑反應，可於不加壓、以良好產率製造2-氣-6-氟苯并噚唑。亦即，本發明具有可不使用加壓設備進行的效果。又，發現：上述反應於聚磷酸存在下進行，或使用五氣化磷、氧氣化磷或此等的混合物當做氣化劑較佳。2-氯-6-氟苯并噚唑，為具有NPY Y5受體拮抗作用之化合物即以式（VI)表示之 201204706 化合物之有用中間體。能將2_氯_6_說苯并噚唑於不使用加壓設備而於10〇度以下的溫度以良好產率製造，於安全性確保方面等，對於商用生產較佳。【實施方式】 [用以實施發明之形態] 以下說明本發明。 -Cl (Π) (I) 使以式⑴表示的化合物與氯化劑反應，❿製造以式表不之化合物之步驟。製造以式⑴表示之化合物，可依照本說明書的參考例i t劑：可使用五氣化鱗、氡氣化峨、五氣化•與 ^. —氣化磷、三氣化磷與氧氣化磷之作δ物荨磷糸氣化劑，& 劑。較佳靡的氣化硫醯氯等硫系氯化或此等之混合物。尤‘為五氣化磷、氧氣化磷氯化劑，可相對於，τ、* _ , 、乂式（1)表示之化合物過量使用。例如，可使用1〜10當量里使用。當量。田里1父佳為1〜5當量，尤佳為2〜4 本步驟可於聚礙酸存在下進行。添加聚磷醆時，相f 用1 η 〇疮曰。十於以式⑴表示之化合物，可估 :。重”。，較佳為W重量％，尤丄；使重量。/〇。里里/。兀佳為30〜60 201204706 ΛΊ，係可使用非極性有機溶劑、***、聚磷 -夂胃119氫呋喃或此等之混合溶劑。較佳為非極性有機溶劑、***或此等之混合溶劑。相對於以式⑴ 表不之化合物之重4，可使用約〇倍量之體積(相對於公克’ 4毫升；相對於公斤，為公升)的溶劑。尤佳為使用2〜5倍量之體積的溶劑。非極性溶劑，係可使用甲苯、二甲苯、苯、氯仿、一氣曱烷、_*** '己&、庚烷、日氯乙烯、二氣乙烷等。反應可於室溫〜加熱下進行。例如，可於1〇〜2〇〇亡進行。又，本步驟可於l〇〇〇c以下進行。尤佳為2〇〜1〇〇 °c。例如’可於7 0〜9 0 °c進行。反應時間視規模或使用之溶劑量而有變動。例如為 3〜10小時，較佳為4〜8.5小時。本步驟係於不加麼而進行反應。亦即，可不利用加壓設備進行加壓而實施。因此，可於大氣壓或常壓進行。專利文獻4中’係從6_氯苯并噚唑酮製造2,6_二氣苯并嘮唑’但是係於丨5〇至n〇°c的溫度於加壓（例1 : 8 氣壓、例3 : 12氣壓）環境進行反應。相對於此，本步驟係不加壓而進行反應。例如，可於2氣壓以下的壓力下進行。而且，可於1 〇〇。匸以下的溫度進行。也可於常壓進行。FYYVci(II) (2) The production method according to the above (1), which is carried out without pressurization. (3) The production method according to (1) or (2) above, which is carried out at a temperature of 1 degree or less. (5) The production method according to any one of the above (1) to (3), which is carried out in the presence of a polyphosphoric acid. (5) The production method according to any one of the above (1) to (4), which uses phosphorus pentachloride, phosphorus oxide or a mixture thereof as a chlorinating agent. (6) A process according to any one of the above (1) to (5), which uses a nonpolar organic solvent, phosphorus oxide or a mixed solvent thereof as a solvent. (7) A method of producing a compound represented by the formula (VI), a salt thereof or a solvate thereof, which comprises the method according to any one of the above (1) to (6). Formula (VI): j^^Y^NHSOrtert-Bu (vi) In the present specification, the reaction of the compound with the compound involves the reaction of a salt thereof or a solvate thereof. "Salt", for example, a salt of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; a salt of an organic acid such as acetic acid, citric acid, p-toluenesulfonic acid, hydrazine-based acid, oxalic acid or citric acid. The "solvate" is, for example, a hydrate or an alcoholate of a compound or a salt thereof. For example, a compound of a compound or a salt thereof, a monohydrate, a dihydrate, a 1 alcoholate, a 2 alcoholate or the like. [Effect of the Invention] By reacting 6-fluorobenzoxazolone with a gasifying agent, 2-gas-6-fluorobenzoxazole can be produced without any pressure and in good yield. That is, the present invention has an effect that it can be carried out without using a pressurizing device. Further, it has been found that the above reaction is carried out in the presence of polyphosphoric acid, or that five gasified phosphorus, oxygenated phosphorus or a mixture thereof is preferred as the gasifying agent. 2-Chloro-6-fluorobenzoxazole, which is a useful intermediate of the compound having the NPY Y5 receptor antagonistic activity, is a compound of the formula (VI) 201204706. It is possible to produce 2_chloro_6_ benzoxazole in a good yield at a temperature of 10 Torr or less without using a pressurizing device, and it is preferable for commercial production in terms of safety assurance and the like. [Embodiment] [Mode for Carrying Out the Invention] Hereinafter, the present invention will be described. -Cl (Π) (I) A step of reacting a compound represented by the formula (1) with a chlorinating agent to produce a compound of the formula. The compound represented by the formula (1) can be produced according to the reference example of the present specification: five gasification scales, helium gasification ruthenium, five gasifications, and gasification phosphorus, three gasification phosphorus and oxygenated phosphorus can be used. δ 荨荨荨荨糸 gasification agent, & Preferably, the sulfurized sulphuric acid such as sulphur, sulphur, or the like is chlorinated or a mixture thereof. In particular, it is a five-gas phosphorus and oxygenated phosphorus chlorinating agent, which can be used in excess with respect to the compound represented by the formula (τ), τ, * _ , and ( (1). For example, it can be used in 1 to 10 equivalents. equivalent. The field 1 parent is preferably 1 to 5 equivalents, and more preferably 2 to 4. This step can be carried out in the presence of a hindrance acid. When polyphosphorus is added, phase f is treated with 1 η acne. The compound represented by the formula (1) can be estimated: Weight", preferably W% by weight, especially 丄; make the weight. / 〇. 里里.. 兀佳 is 30~60 201204706 ΛΊ, can use non-polar organic solvents, phosphorus oxychloride, polyphosphorus-夂Stomach 119 hydrogen furan or a mixed solvent thereof. It is preferably a nonpolar organic solvent, phosphorus oxychloride or a mixed solvent of the above. It can be used in an amount of about 〇 with respect to the weight of the compound represented by the formula (1) a solvent (in relation to gm '4 ml; liters per liter), especially preferably a solvent in a volume of 2 to 5 times. Non-polar solvent, toluene, xylene, benzene, chloroform, one gas曱、, _ ether 'hex &, heptane, chloroethylene, dioxane, etc. The reaction can be carried out at room temperature to heating. For example, it can be carried out at 1 〇 2 to 2 。. It can be carried out below l〇〇〇c. It is preferably 2〇~1〇〇°c. For example, 'can be carried out at 70 to 90 ° C. The reaction time varies depending on the scale or the amount of solvent used. For example 3 to 10 hours, preferably 4 to 8.5 hours. This step is carried out without any reaction, that is, without using The pressure equipment is pressurized and is carried out. Therefore, it can be carried out at atmospheric pressure or normal pressure. In Patent Document 4, '2,6-di-benzopyrazole is produced from 6-chlorobenzoxazolone but is based on 丨5. The reaction is carried out in the environment of pressurization (Example 1: 8 atmosphere, Example 3: 12 atmosphere). In contrast, this step is carried out without pressurization. For example, it can be at least 2 atmospheres. It can be carried out under pressure and can be carried out at a temperature of 1 〇〇. 也. It can also be carried out at atmospheric pressure. FYYVci

^\^C02Et^\^C02Et

-8 - (II) 201204706 使化酯於鹼存鹼只制。可使有機驗。雜雙環十 N-甲基咪驗，莫耳當量溶劑制。可從二曱基甲二曱基-2 基曱醚、腈、丙腈層溶劑或極性氧基乙烷曱基吡咯丙酯、環基亞$風、曱氧基乙 N-甲基吡酸丙S旨、曱基亞石風甲基甲醯合物（II)於溶劑中與反式-4-胺基-環己烷羧酸乙在下反應，獲得化合物（III)之步驟。要是可以良好效率進行上述步驟者即不特別限用有機驗或無機碳酸鹽等無機驗。較佳為使用例如’三乙胺、吡啶、二曱基胺基吡啶、二氮一烯、1,8-雙（二甲基胺基）萘、二異丙基乙胺、唑、N-曱基味啉等。尤佳為三乙胺。係相對於反式-4-胺基-環己烷羧酸乙酯使用1 〜5莫耳當量進行反應即可。只要是可以良好效率進行上述步驟即不特別限甲醇、乙醇、異丙醇、i，二甲氧基乙&、ν，ν· 醯胺、Ν，Ν-二甲基乙醯胺、Ν_甲基吡咯酮、I，％ -咪唑啶酮、乙酸乙酯、乙酸丙酯、甲笨、環戊四氫呋喃、2_甲基四氫呋喃、二甲基亞砜、、乙等選用1種以上。溶劑可視需I，以與水的2 含水溶劑的形式使用。較佳為例如極溶劑，係可從甲醇、乙醇、異丙醇、二、Ν，Ν-二曱基曱醯胺、Ν，Ν-二甲基乙醯胺、酮、1，3-一曱基_2_咪唑啶酮、〔酸乙酯戊基甲醚、四氫呋喃、2-甲基四氫呋喃、二甲乙腈、丙腈等選用1種以上。較佳為從！ 2_ _ :、Ν，Ν-一曱基甲醯胺、Ν，Ν_二甲基乙醯嘻酮、U3-二甲基姊坐。定酮、乙酸乙環戊基甲醚、四氫吱。南、2-甲基四氫咳喃、乙腈、丙腈等選用i種以上。尤：胺。 q — -9- 201204706 反應溫度無特別限制，通常為約 0〜100°c，較佳為於室溫〜70°c進行。反應時間無特別限制，通常為0.5小時〜20小時，較佳為1〜1 0小時。-8 - (II) 201204706 The ester is made only in alkali. Can be tested organically. Heterobicyclic ten N-methyl azo, molar equivalent solvent. Available from dimercaptomethyldidecyl-2-yl oxime ether, nitrile, propionitrile layer solvent or polar oxy ethane sulfopyryl propyl ester, cyclic phenyl group, wind, methoxyethyl N-methylpyrrolidine The step of obtaining a compound (III) by reacting with a trans-4-amino-cyclohexanecarboxylic acid B in a solvent. If the above steps can be carried out with good efficiency, inorganic tests such as organic tests or inorganic carbonates are not particularly limited. It is preferred to use, for example, 'triethylamine, pyridine, dinonylaminopyridine, diazide, 1,8-bis(dimethylamino)naphthalene, diisopropylethylamine, azole, N-oxime Basin and the like. Especially preferred is triethylamine. The reaction may be carried out using 1 to 5 molar equivalents of trans-4-amino-cyclohexanecarboxylic acid ethyl ester. As long as the above steps can be carried out with good efficiency, not particularly limited to methanol, ethanol, isopropanol, i, dimethoxyethane & ν, ν·decylamine, hydrazine, hydrazine-dimethylacetamide, Ν_ One or more selected from the group consisting of methylpyrrolidone, I, %-imidazolidinone, ethyl acetate, propyl acetate, methyl bromide, cyclopentahydrotetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, and B. The solvent may be used as I, in the form of a water-containing solvent with water. Preferably, for example, a polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, di-, hydrazine, decyl-dimethyl decylamine, hydrazine, hydrazine-dimethylacetamide, ketone, 1,3-anthracene. One or more selected from the group consisting of 2 -imidazolidinone, [ethyl ester pentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl acetonitrile, and propionitrile. Better from! 2_ _ :, Ν, Ν--mercaptomethylamine, hydrazine, hydrazine _ dimethyl hydrazine fluorenone, U3-dimethyl hydrazine. Ketone, ethylcyclopentyl methyl acetate, tetrahydroanthracene. South, 2-methyltetrahydrocethane, acetonitrile, propionitrile, etc., more than one type. Especially: amine. q — -9- 201204706 The reaction temperature is not particularly limited and is usually from about 0 to 100 ° C, preferably from room temperature to 70 ° C. The reaction time is not particularly limited and is usually from 0.5 to 20 hours, preferably from 1 to 10 hours.

將化合物（III)還原，並獲得以式（IV)表示之化合物之步驟。還原劑只要是可以良好效率進行上述步驟者即不特別限制。例如氫化鋁鋰、硼氫化鈉、硼氫化鋰、硼烷等。較佳為硼氫化鋰或硼氫化鈉。更佳為硼氫化鋰。還原劑，係相對於化合物（III)使用1莫耳當量〜5莫耳當量反應即可。溶劑只要是可以良好效率進行上述步驟即不特別限制。可從曱醇、乙醇、異丙醇、正丙醇、第三丁醇、正丁醇、1,2-二甲氧基乙烷、N，N-二甲基甲醯胺、Ν,Ν-二曱基乙醯胺、Ν 曱基吡咯酮、1,3 -二曱基-2 -咪唑啶酮、甲苯、環戊基甲醚、四氫呋喃、2-曱基四氫呋喃、二曱基亞砜等選用1種以上。溶劑可視需要以與水的2層溶劑或含水溶劑的形式使用。較佳為例如極性溶劑。極性溶劑，可從甲醇、乙醇、異丙醇、正丙醇、第三丁醇、正丁醇、1,2-二曱氧基乙烷、Ν，Ν-二甲基曱醯胺、Ν,Ν-二甲基乙醯胺、Ν-曱基吡咯酮、1，3-二曱基-2-咪唑啶酮、環戊基甲醚、四氫呋喃、2 -曱基四氫呋喃、 -10- 201204706 二甲基亞砜等選用1 、以上0尤ϋ或 >tr 混合溶劑。為四風呋喃及甲醇之通常為約〇〜1 〇〇亡較佳為反應溫度益牲2丨丨& 又…付別限制於室溫〜80°C進行。 .反應時間無特別限制佳為1〜1 0小時。通常為0.5小時〜20小時較The step of reducing the compound (III) and obtaining a compound represented by the formula (IV). The reducing agent is not particularly limited as long as it can perform the above steps with good efficiency. For example, lithium aluminum hydride, sodium borohydride, lithium borohydride, borane, and the like. Preferred is lithium borohydride or sodium borohydride. More preferably, it is lithium borohydride. The reducing agent may be used in an amount of 1 mole equivalent to 5 mole equivalents based on the compound (III). The solvent is not particularly limited as long as it can carry out the above steps with good efficiency. Can be derived from decyl alcohol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, 1,2-dimethoxyethane, N,N-dimethylformamide, hydrazine, hydrazine- Dimercaptoacetamide, indolinylpyrrolidone, 1,3 -dimercapto-2-imidazolidinone, toluene, cyclopentyl methyl ether, tetrahydrofuran, 2-mercaptotetrahydrofuran, dimercaptosulfoxide, etc. More than one type. The solvent may be used in the form of a two-layer solvent or aqueous solvent with water as needed. It is preferably, for example, a polar solvent. a polar solvent, which may be derived from methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, 1,2-dimethoxyethane, hydrazine, hydrazine-dimethyl decylamine, hydrazine, Ν-dimethylacetamide, fluorenyl-hydrazinopyrrolidone, 1,3-dioxan-2-imidazolidinone, cyclopentyl methyl ether, tetrahydrofuran, 2-indenyltetrahydrofuran, -10- 201204706 The sulfoxide or the like is selected from a mixed solvent of 1 or more and 0 or trtr. It is usually about 〇~1 〇〇较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳较佳The reaction time is not particularly limited. It is preferably from 1 to 10 hours. Usually 0.5 hours to 20 hours

(IV)(IV)

(VI) 最初的步驟，係使以^ 主- M甘上/ 使式（IV)表不之化合物與甲泸戊酿基齒化物於鹼存在下反庫坑石哭物之步驟。 < 化合蛻只要使上述步驟 μ & π双進仃者吖个付别限 °使用有機驗或無機碳酸鹽等無機鹼。較播鹼。例如，三乙胺…比啶、-甲m ρ 有機(VI) The initial step is a step of anti-cold stone crying in the presence of a base with a compound represented by the formula (IV) and a compound of the formula (IV). < Combination 蜕 As long as the above steps μ & π double-introduction are limited to ° ° use organic tests or inorganic bases such as inorganic carbonates. More soda. For example, triethylamine...bipyridine,-a m ρ organic

Tffi 疋一甲基胺基吡啶、二氮雜雙Tffi 疋monomethylaminopyridine, diazapine

畏十一稀、M-雙（二甲基胺基）萘、二異丙基乙胺、I 曱基咪唑、N-曱基咪啉等。更佳為三乙胺、二曱基胺基比啶、二氮雜雙環十一烯、二異丙基乙胺、N_f基咪唑或N -甲基味啉。尤佳為三乙胺。驗’相對於化合物（IV)使用1莫耳當量〜5蕈耳卷θ 、六了田| 進行反應即可。尤其，相對於化合物（ϊν)使用1 5莫耳备置以上較佳，更佳為使用2莫耳當量以上。 201204706 曱烷磺醯基鹵化物，相對於化合物（IV)使用1莫耳當量〜5莫耳當,量使反應即可。尤其，相對於化合物（IV) 使用1 · 5莫耳當量以卫較佳，更佳為使用2莫耳當量以上。溶劑只要可使上述步驟以良好效率進行者即不特別限定。可從1，2-二曱氧基乙烷、N，N-二甲基曱醯胺、Ν,Ν-二曱基乙醯胺、Ν -曱基吡咯酮、1,3 -二曱基-2 -咪唑啶酮、乙酸乙酯、乙酸丙酯、甲苯、環戊基甲醚、四氫呋喃、 2-甲基四氫呋喃、二甲基亞颯、乙腈、丙腈、二氣曱烷等選用1種以上。溶劑可視需要以與水之2層溶劑或含水溶劑的形式使用。較佳為從極性溶劑、甲苯及二氣甲烧選用1種以上。極性溶劑，係可從1,2-二甲氧基乙烷、Ν，Ν-二曱基曱醯胺、Ν,Ν-二曱基乙醯胺、Ν-曱基吡咯酮、1，3 -二曱基-2 -咪唑啶酮、乙酸乙酯、乙酸丙酯、環戊基曱醚、四氫吱喃、2 -甲基四氫吱喃、二甲基亞硬、乙腈、丙腈等選用1種以上。較佳為Ν，Ν-二曱基甲醯胺、Ν，Ν-二曱基乙醯胺、Ν -甲基吡咯酮、1，3 -二甲基-2 -咪唑啶酮、乙酸乙酯、乙酸丙酯、環戊基曱醚、四氫呋喃、2-甲基四氫呋喃、二曱基亞颯、乙腈或丙腈。尤佳為四氫呋喃或Ν，Ν-二曱基乙醯胺。反應溫度無特別限制，通常為約0〜1 00°C，較佳為於室溫〜60度進行。反應時間無特別限制，通常為0.5小時〜20小時，較佳為1〜1 0小時。 -12- 201204706 反應結束後’可將以式（)志-> " 式（v)表不之化合物單離而用在次一步驟。又，也可不將衣个村u式（V)表示之化合物單離精製’而使用濾取的化合物，進 j久―步驟。也可不滤取以式（V)表示之化合物，而以、，普始& , Α 、而以m蝻物（例如濃縮液、漿體、泡狀化合物等）的形式使用而進行次一步驟。第二步驟，係使以式（v)表示之化合物盥^三° 醢胺於驗存在下反應，而獲得以式⑽表；之：合：：其鹽或此專的溶劑合物的步驟。驗只要是能使上述步驟以良好效哪良灯双進仃者即不特別限制。例如弟三丁醇鉀、第三丁醇鈉、甲醇鈉、乙醇納、戌酵納：紛鈉、碳酸鈉、碳酸鉀、碳酸約、碳酸鉋'碳酸鎂、碳酸鈹、齑負各& S, η 虱氧化鈉、氫氧化鉀、氫氧化鈣、烷基裡（例如正丁基鐘笼、 , 烧基鎮、链酿胺系強驗（例如二里丙基酿胺鐘等）、丄审且_ 八甲基一石夕氮烧系強驗（例如六甲兵二石夕氮烧鐘、六甲其-货友〒基一矽虱烷鈉、六甲基二矽氮烷鉀等）、產化烧^鎮（例如漠化環己基鎭、漠化異丙基鎂、漠化乙基4美、乳化里％且技土鎂專）寺。較佳為驗金屬醇鹽或無機碳酸鹽。驗金屬醇Μ 畔風’較佳為第三丁醇鉀、第三丁醇鈉、甲醇納、乙醇叙J & 戍醇鈉、紛納等。更佳為第三丁醇钾、第三丁醇鋼、甲醇納、乙醇納或戊醇納。尤佳為第三丁醇鉀。知無機妷酸鹽’其較佳為碳酸鈉、碳酸鉀、碳酸鈣、石反酼铯、妷睃鎂、碳酸鈹等。更佳為碳酸鈉、碳酸鉀、碳酸辑或碳酴·^ ώ t 人^絶。又較佳為碳酸鉀或碳酸铯。尤佳為碳酸铯。 201204706 上述步驟中，尤佳的鹼為第三丁醇鉀或碳酸鉋鹼，係相對於化合物（V)使用1莫耳當量〜10莫量反應即可。較佳為使用1莫耳當量〜8莫耳當量，為使用1莫耳當量〜5莫耳當量。溶劑只要可使上述步驟以良好效率進行者即不限制。可從甲醇、乙醇、異丙醇、正丙醇、第三丁正丁醇、N，N-二甲基曱醯胺、N，N-二曱基乙醯胺、基吡咯酮、1，3 -二甲基-2 -咪唑啶酮、乙酸、乙酸乙乙酸丙酯、甲苯、環戊基甲醚、四氫呋喃、2-曱基呋喃、二甲基亞颯、乙腈、丙腈、丙酮、曱乙酮等 1種以上。溶劑可視需要，以與水之2層溶劑或含劑的形式使用。較佳為例如極性溶劑。極性溶劑，係可從曱醇、乙醇、異丙醇、正丙第三丁醇、正丁醇、N，N-二曱基曱醯胺、Ν,Ν-二曱醯胺、Ν-曱基吡咯酮、1,3-二甲基-2-咪唑啶酮、乙乙酸乙酯、乙酸丙酯、環戊基曱醚、四氫呋喃、2-四氫呋喃、二曱基亞颯、乙腈、丙腈、丙酮、甲乙選用1種以上。較佳為可從曱醇、乙醇、異丙醇、醇、第三丁醇、正丁醇、Ν，Ν-二甲基曱醯胺、Ν，Ν-基乙醯胺、Ν-曱基吡咯酮、1,3 -二曱基-2 -咪唑啶酮酸乙醋、乙酸丙醋、四氫°夫喃、2 -甲基四氫°夫π南、基亞砜、乙腈、丙腈、丙酮及曱乙酮選用1種以上佳為從異丙醇、Ν，Ν-二甲基曱醯胺、Ν，Ν-二曱基乙及Ν-曱基吡咯酮選用1種以上。尤佳為從異丙醇、二甲基曱醯胺及Ν，Ν-二曱基乙醯胺選用1種以上。耳當更佳特別醇、 Ν-甲酯、四氫選用水溶醇、基乙酸、甲基酮等正丙二甲、乙二甲。更醯胺 Ν,Ν- -14- 201204706 溶劑使用曱苯或環戊基甲醚時，可以曱苯-氫氧化鈉水溶液、環戊基曱醚-氫氧化鈉水溶液等的形式使用。視需要，也可添加相間轉移觸媒（例如四丁基銨鹽、三辛基曱基銨鹽、苄基二甲基十八基銨鹽等）。反應溫度不特別限制，通常為約 0〜1 50°C，較佳為於室溫〜100度進行。反應時間不特別限制，通常為0.5小時〜20小時，較佳為1 ~ 1 0小時。反應結束後，進行濃縮及/或冷卻，濾取析出的固體，可獲得以式（VI)表示之化合物、其鹽或此等的溶劑合物。以式（VI)表示之化合物之鹽，例如：鹽酸、硫酸、硝酸或磷酸等無機酸之鹽；乙酸、甲酸、對甲苯磺酸、曱烷磺酸、草酸或檸檬酸等有機酸的鹽等。例如以式（VI) 表示之化合物之鹽酸鹽、以式（VI)表示之化合物之硫酸鹽等。以式（VI)表示之化合物之溶劑合物，例如以式（VI) 表示之化合物之水合物、醇合物等。具體而言，例如以式（VI)表示之化合物之1水合物、以式（VI)表示之化合物之2水合物、以式（VI)表示之化合物之1醇合物、以式 (VI)表示之化合物之2醇合物等。以式（VI)表示之化合物、其鹽或此等的溶劑合物，顯示NPY Y5受體拮抗作用，對於當做醫藥品，尤其是與NPY Y5相關的疾病例如攝食障礙、肥胖、神經性食慾亢進症、性障礙、生殖障礙、憂鬱症、癲癇發作、高 -15- 201204706 如壓、腦溢血、奋岛兄血心臟农竭或睡眠障礙等防用的醫藥非堂古田 ^•丨早礙寺的冶療或預的疾病，例如糖尿病…r 胖疋風險因子各性冠狀广，间壓、咼脂血症、動脈硬化、总性；ti狀症候群莖从、A #丄專的/α療或預防用的醫藥非常有用。以下記载實施例加以説明。以下营…有/ 發明。又，V代ρ曰μ 下貫轭例並非限定本代表今置比，W代表重量比。 (參考例1)Dilute eleven, M-bis(dimethylamino)naphthalene, diisopropylethylamine, I mercapthylimid, N-decyl morpholine and the like. More preferred is triethylamine, dinonylaminopyridinium, diazabicycloundecene, diisopropylethylamine, N_f-imidazole or N-methyl-salt. Especially preferred is triethylamine. The test can be carried out by using 1 molar equivalent to 5 ounces of θ and hexazone relative to the compound (IV). In particular, it is preferably used in an amount of 15 moles or more with respect to the compound (??), more preferably 2 moles or more. 201204706 decanesulfonyl halide, using 1 mole equivalent to 5 moles per mole of compound (IV). In particular, it is preferred to use 1.5 moles of the equivalent of the compound (IV), more preferably 2 moles or more. The solvent is not particularly limited as long as the above steps can be carried out with good efficiency. It can be derived from 1,2-dimethoxyethane, N,N-dimethyl decylamine, hydrazine, hydrazine-dimercaptoacetamide, fluorenyl-hydrazinopyrrolidone, 1,3 -didecyl- 2 -imidazole ketone, ethyl acetate, propyl acetate, toluene, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl hydrazine, acetonitrile, propionitrile, dioxane, etc. . The solvent may be used in the form of a solvent or a water-containing solvent with water as needed. It is preferred to use one or more kinds of polar solvents, toluene and dioxane. A polar solvent which can be derived from 1,2-dimethoxyethane, hydrazine, hydrazine-dimercaptoamine, hydrazine, hydrazine-dimercaptoacetamide, fluorenyl-mercaptopyrrolone, 1,3- Dimercapto-2-imidazolidinone, ethyl acetate, propyl acetate, cyclopentyl oxime ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfite, acetonitrile, propionitrile, etc. More than one type. Preferred are hydrazine, hydrazine-dimercaptomethylamine, hydrazine, hydrazine-dimercaptoacetamide, hydrazine-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, ethyl acetate, Propyl acetate, cyclopentyl oxime ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimercaptoarylene, acetonitrile or propionitrile. It is especially preferred to be tetrahydrofuran or hydrazine, hydrazine-dimercaptoacetamide. The reaction temperature is not particularly limited and is usually from about 0 to 100 ° C, preferably from room temperature to 60 ° C. The reaction time is not particularly limited and is usually from 0.5 to 20 hours, preferably from 1 to 10 hours. -12- 201204706 After the reaction is completed, the compound represented by formula ()-> >" (v) can be used in the next step. Further, the compound represented by the formula (V) in the village may not be purified, and the compound to be filtered may be used. It is also possible to carry out the next step by using the compound represented by the formula (V) without using the compound of the formula (V), and using the compound of the formula (V), and the m-product (for example, a concentrate, a slurry, a blister compound, etc.). . In the second step, the compound represented by the formula (v) is reacted in the presence of the test compound to obtain a step of the formula (10): a combination: a salt thereof or a specific solvate. As long as the test can make the above steps work well, it is not particularly limited. For example, potassium tributoxide, sodium butoxide, sodium methoxide, sodium ethoxide, sodium sulphate: sodium, sodium carbonate, potassium carbonate, carbonic acid, carbonic acid, magnesium carbonate, barium carbonate, barium, & , η 虱虱、、, 氢氧化氢氧化、、、 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( And _ octamethyl-one-stone-nitrogen-burning system (such as Liujia Bingshi Shishi Nitrogen Burning Clock, Rokko-Cargo-Sodium-Sodium Sulfonate, Hexamethyl-Diazane Alkane, etc.) ^ Town (such as desertification cyclohexyl hydrazine, desertified isopropyl magnesium, desertified ethyl 4 US, emulsified % and technical magnesium special) temple. It is better to test metal alkoxide or inorganic carbonate. Μ 风 ' ' is preferably potassium third butanolate, sodium butoxide, sodium methoxide, ethanol, J & sodium steroxide, arsenic, etc. More preferably potassium third butanol, third butanol steel, Methanol, sodium ethoxide or sodium pentaerythritol. More preferably potassium butoxide. Know inorganic strontium 'which is preferably sodium carbonate, potassium carbonate, calcium carbonate, stone ruthenium, strontium magnesium, carbonic acid Preferably, it is sodium carbonate, potassium carbonate, carbonic acid or carbon 酴·^ ώ t. It is preferably potassium carbonate or cesium carbonate. More preferably cesium carbonate. 201204706 In the above steps, a particularly good base It is a potassium butoxide or a carbonate base, and a reaction of 1 mole equivalent to 10 moles is used with respect to the compound (V). It is preferred to use 1 mole equivalent to 8 molar equivalents for 1 mole. Equivalent to 5 molar equivalents. The solvent is not limited as long as the above steps can be carried out with good efficiency. It can be obtained from methanol, ethanol, isopropanol, n-propanol, tributyl n-butanol, N, N-dimethyl Indoleamine, N,N-dimercaptoacetamide, pyrrolidone, 1,3 -dimethyl-2-imidazolidinone, acetic acid, propyl acetate, toluene, cyclopentyl methyl ether, tetrahydrofuran One or more kinds of 2-mercaptofuran, dimethyl hydrazine, acetonitrile, propionitrile, acetone, acetophenone, etc. The solvent may be used in the form of a solvent or a mixture of two layers of water, as needed. Polar solvent. Polar solvent, which can be derived from decyl alcohol, ethanol, isopropanol, n-butanol, n-butanol, N,N-dimercaptopurine , hydrazine, hydrazine-diamine, hydrazine-hydrazinopyrrolidone, 1,3-dimethyl-2-imidazolidinone, ethyl acetate, propyl acetate, cyclopentyl oxime ether, tetrahydrofuran, 2- One or more selected from the group consisting of tetrahydrofuran, dimercaptoarylene, acetonitrile, propionitrile, acetone, and methyl b. Preferably, it can be derived from decyl alcohol, ethanol, isopropanol, alcohol, tert-butanol, n-butanol, hydrazine, hydrazine- Dimethyl decylamine, hydrazine, hydrazinyl hydrazide, fluorenyl-hydrazinopyrrolidone, 1,3 -didecyl-2-imidazolidinone ethyl acetate, propylene acetate, tetrahydrofuran, 2 -Methyltetrahydro sulphate π, sulfoxide, acetonitrile, propionitrile, acetone and acetophenone are preferably selected from the group consisting of isopropanol, hydrazine, hydrazine-dimethyl decylamine, hydrazine, hydrazine. One or more selected from the group consisting of dimercaptoethyl and fluorenyl-pyridylpyrrolidone, and more preferably one or more selected from the group consisting of isopropyl alcohol, dimethyl decylamine and hydrazine and hydrazine-dimercaptoacetamide. Better ear, special alcohol, Ν-methyl ester, tetrahydrogen, such as water-soluble alcohol, acetyl acetate, methyl ketone, etc. Further, amidoxime Ν, Ν- -14- 201204706 When a solvent is used, the benzene or a cyclopentyl methyl ether may be used in the form of a hydrazine-sodium hydroxide aqueous solution, a cyclopentyl oxime ether-sodium hydroxide aqueous solution or the like. An interphase transfer catalyst (e.g., tetrabutylammonium salt, trioctyldecyl ammonium salt, benzyldimethyloctadecyl ammonium salt, etc.) may also be added as needed. The reaction temperature is not particularly limited and is usually from about 0 to 1 50 ° C, preferably from room temperature to 100 ° C. The reaction time is not particularly limited and is usually from 0.5 to 20 hours, preferably from 1 to 10 hours. After completion of the reaction, the mixture is concentrated and/or cooled, and the precipitated solid is collected by filtration to obtain a compound represented by the formula (VI), a salt thereof or a solvate thereof. a salt of a compound represented by the formula (VI), for example, a salt of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; a salt of an organic acid such as acetic acid, formic acid, p-toluenesulfonic acid, decanesulfonic acid, oxalic acid or citric acid; . For example, a hydrochloride of a compound represented by the formula (VI), a sulfate of a compound represented by the formula (VI), and the like. A solvate of a compound represented by the formula (VI), for example, a hydrate of a compound represented by the formula (VI), an alcoholate or the like. Specifically, for example, a monohydrate of the compound represented by the formula (VI), a dihydrate of the compound represented by the formula (VI), an alcoholic compound of the compound represented by the formula (VI), and a formula (VI) An alcohol compound or the like of the compound shown. A compound represented by the formula (VI), a salt thereof or a solvate thereof exhibits NPY Y5 receptor antagonism, and is useful as a medicine, particularly a disease associated with NPY Y5 such as eating disorder, obesity, and neuropathic appetite. Symptoms, sexual disorders, reproductive disorders, depression, seizures, high -15- 201204706 such as pressure, cerebral hemorrhage, Fen Island brothers blood heart abdomen or sleep disorders, such as medicine, non-tang Gutian ^• 丨碍寺的Treatment or pre-disease, such as diabetes...r fat 疋 risk factors, various coronary coronations, interstitial pressure, dyslipidemia, arteriosclerosis, total; tiy syndrome stems, A #丄specific / alpha therapy or prevention The medicine is very useful. The examples are described below. The following camps... have / invented. Further, the V generation ρ 曰 μ lower yoke example is not limited to the present representative ratio, and W represents the weight ratio. (Reference example 1)

^ FO：v Η^ FO:v Η

CH3CN (Υ) ⑴ 於裝有機械攪拌子的1000mL 4徑燒瓶中，加入2_ 胺基-5-氟苯紛（Y)(50.〇〇g，〇 393m〇i)、及乙腈（25〇社， 5 V)以冰浴冷卻後，緩慢加χ ji羰基二咪唑(9 5 . ”呂， 0.590mo卜1 _5eq)(約12分鐘）。添加完成後，拿出冰浴，一面以HPLC確認反應的進展，一面於室温攪拌。約25 小時後，於反應液加入乙酸乙酯（1〇〇〇mL)、3m〇1/L鹽酸 (500mL)、及食鹽（5〇g)並進行分液。將水層以甲苯〇 5〇mL) 萃取’並將有機層分別以10%食鹽水（5〇〇inL)、及5%碳酸氫鈉溶液（250mL)洗滌。合併有機層，以硫酸鈉（i〇〇g) 乾燥後、過濾、濃縮。於固體出現前加入活性碳（1.25g)，並於室溫攪拌3 0分鐘。將活性碳過濾後，將濾液濃縮至約80g，加入乙酸乙酯（50mL)、甲笨（420mL)。再度濃縮至約1 30g，過遽析出的固體。將獲得的固體以甲苯250mL 洗蘇後，進行通氣乾燥及減壓乾燥，獲得目的物6 -氟苯并喝°坐_(1)(57.20芭’0.374111〇卜產率：95%)黃褐色固體。 -16- 201204706 HPLC 純度：99.0pa% NMR (CDC13) 6.90(dt, J = 9.2, 2.4 Ηζ,ΙΗ) 6.98-7.05(m, 2H) , 9.05(brs, 1H) [實施例1]CH3CN (Υ) (1) In a 1000 mL 4-well flask equipped with a mechanical stirrer, add 2-amino-5-fluorobenzene (Y) (50.〇〇g, 〇393m〇i), and acetonitrile (25〇社) , 5 V) After cooling in an ice bath, slowly add ji carbonyl carbonyl diimidazole (9 5 . 吕, 0.590 mo 1 _5 eq) (about 12 minutes). After the addition is completed, take out the ice bath and confirm the reaction by HPLC. The progress was stirred at room temperature. After about 25 hours, ethyl acetate (1 mL), 3 ml of 1/L hydrochloric acid (500 mL), and salt (5 〇g) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with toluene (5 〇 mL) and the organic layer was washed with 10% brine (5 〇〇inL) and 5% sodium hydrogen carbonate solution (250 mL). 〇〇g) After drying, filtration, concentration, adding activated carbon (1.25 g) before solid appearance, and stirring at room temperature for 30 minutes. After filtering the activated carbon, the filtrate was concentrated to about 80 g, and ethyl acetate was added. 50 mL), methyl benzene (420 mL), and concentrated again to about 1 30 g, and the solid precipitated out. The obtained solid was washed with 250 mL of toluene, and then air-dried and dried under reduced pressure to obtain Target 6-Fluorobenzophene ～(1)(57.20 芭 '0.374111 〇 yield: 95%) Tawny solid. -16- 201204706 HPLC Purity: 99.0pa% NMR (CDC13) 6.90 (dt, J = 9.2, 2.4 Ηζ, ΙΗ) 6.98-7.05(m, 2H) , 9.05(brs, 1H) [Example 1]

PC15 聚磷酸甲苯於25mL的試管中加入6_氟苯并噚唑酮（][)(〇 800g， 5_23mmol)、五氣化磷（3 26g，i5.7mmo卜 3eq)、及曱苯 (3.20mL，4V)後，加入聚磷酸（〇401g，0.5W)(全量： 7.1 9g) ’於80°C的油浴進行加熱攪拌。一面以HPLC確認反應的進展，於8 · 5小時後停止加熱（約8小時後之 HPLC之結果：6-氟苯并噚唑酮⑴：2_氣-6_氟苯并嘮唑 (11) = 3 : 94(面積比））。將反應液全量（6 5〇g)溶於乙腈（約 8〇〇mL)、四氫吱喃（約10mL)、及蒸餾水（約200mL)並進行定量，結果可知以94%的產率獲得目的物2氣_6_氟苯并噚唑（II)。 [實施例2]PC15 polyphosphoric acid toluene In a 25 mL tube, 6-fluorobenzoxazolone (] [) (〇 800 g, 5-23 mmol), phosphorus pentoxide (3 26 g, i5.7 mmo 3 eq), and toluene (3.20 mL) were added. After 4V), polyphosphoric acid (〇401g, 0.5W) (total amount: 7.1 9g) was added and heated and stirred in an oil bath of 80 °C. On one side, the progress of the reaction was confirmed by HPLC, and the heating was stopped after 8.5 hours (the result of HPLC after about 8 hours: 6-fluorobenzoxazolone (1): 2_gas-6-fluorobenzoxazole (11) = 3 : 94 (area ratio)). The whole amount of the reaction solution (65 〇g) was dissolved in acetonitrile (about 8 〇〇mL), tetrahydrofuran (about 10 mL), and distilled water (about 200 mL) and quantified, and it was found that the objective was obtained in a yield of 94%. 2 gas _6_fluorobenzoxazole (II). [Embodiment 2]

於50mL的4徑燒瓶中加入6-氟苯并唑酮 (I)(2.50g ’ 16.3mm〇1)、五氯化鱗（1〇 2〇g，49 〇mm〇1， 3叫）及甲苯（1〇.〇mL，4V)後，加入聚磷酸（i.〇3g， 0.4W)。一面以機械攪拌子攪拌，一面於油浴中緩慢加熱 201204706 (約15分鐘）至80°C。一面以HPLC確認反應的進展，於反應開始2小時後追加聚磷酸（0.52g，0.2W)。再一面以 HPLC確認反應的進展，於反應開始後6小時後停止加熱 (約6小時後的HPLC的結果：6-氟苯并噚唑酮（I) : 2-氣 -6-氟苯并嘮唑（11)= 1〇 : 86(面積比））。於以冰浴冷卻的 500mL的燒杯中，加入飽和碳酸氫鈉水溶液（約200mL) 及甲苯（6OmL)，於該混液之中緩慢加入反應液。再加入甲苯（150mL)及水（l〇〇mL)並進行分液。於有機層令加水 (150mL)，結果pH為 2.7，加入飽和碳酸氫鈉水溶液 50mL，結果pH成為7.8，進行分液。將有機層以硫酸鈉乾燥後，進行過濾、濃縮，獲得粗產物（2.20g)。將獲得的粗產物於減壓下於油浴進行蒸餾（1 2Torr、 90 °C )，獲得目的物 2-氣-6-氟苯并噚唑（11)(1.42g， 8.30mmol，產率：51%)。 HPLC 純度：98.4pa% NMR (CDC13) 7.07-7.15(m, 1H) , 7.24(dd, J = 7.5, 2.7, 1H) , 7.61(dd, J = 8.9, 5.0, 1H) [實施例3]Add 6-fluorobenzoxazolone (I) (2.50g ' 16.3mm〇1), pentachlorinated scale (1〇2〇g, 49 〇mm〇1, 3) and toluene in a 50mL 4-well flask. After (1 〇.〇mL, 4V), polyphosphoric acid (i.〇3g, 0.4W) was added. While stirring with a mechanical stirrer, slowly heat 201204706 (about 15 minutes) to 80 °C in an oil bath. The progress of the reaction was confirmed by HPLC, and polyphosphoric acid (0.52 g, 0.2 W) was added 2 hours after the start of the reaction. Further, the progress of the reaction was confirmed by HPLC, and the heating was stopped 6 hours after the start of the reaction (the result of HPLC after about 6 hours: 6-fluorobenzoxazolone (I): 2-gas-6-fluorobenzindole Azole (11) = 1 〇: 86 (area ratio)). To a 500 mL beaker cooled in an ice bath, a saturated aqueous solution of sodium hydrogencarbonate (about 200 mL) and toluene (6OmL) were added, and the mixture was slowly added to the mixture. Further, toluene (150 mL) and water (10 mL) were added and liquid separation was carried out. When water (150 mL) was added to the organic layer, the pH was 2.7, and 50 mL of a saturated aqueous sodium hydrogencarbonate solution was added, and the pH was 7.8. The organic layer was dried over sodium sulfate, filtered, and evaporated The obtained crude product was subjected to distillation in an oil bath under reduced pressure (1 2 Torr, 90 ° C) to obtain the objective compound 2- gas-6-fluorobenzoxazole (11) (1.42 g, 8.30 mmol, yield: 51%). HPLC purity: 98.4 pa% NMR (CDC13) 7.07-7.15 (m, 1H), 7.24 (dd, J = 7.5, 2.7, 1H), 7.61 (dd, J = 8.9, 5.0, 1H) [Example 3]

於試管中加入 6-氟苯并嘮唑酮（〇.3982g， 2.60mmol)(I)、五氣化填（1.6247g，7.80mmol，3eq)、及氧氣化磷（1.6mL，4V)後，加熱至80°C。一面以HPLC 確認反應的進展，於4小時後停止加熱（約3.5小時後之 -18- 201204706 HPLC : 6-氟苯并嘮唑酮（I) : 2-氯-6-氟笨并0f唑（11) = 1 : 9 4 (面積比））。將反應液溶於溶劑，以1 L的量瓶進行定量，可知以95%(HPLC之結果：6-氟苯并0f唑酮：2-氣-6-氟苯并嘮唑= 0:96(面積比））的產率獲得目的物2-氣-6-氟苯并脅吐（Π)。 P /^\^C〇2Et (參考例2) (III) I /V~ci (II) 於N，N-二曱基甲醯胺（10 mL)加入反式-4-胺基-環己烷羧酸乙酯（2.08 g, 1〇 mmol)及三乙胺（5.0 mL，36 mmol)。在5°C以下於冷卻攪拌下，於該懸浮液中滴加2_ 氣-6-氟本并坐（11)(2.23 g，13 mmol)之 N，N-二曱基曱醯胺（4 mL)溶液，並於室溫攪拌2小時。於反應液中加入乙酸乙酯（25 mL)及5%-檸檬酸水（25 mL)，將有機層分液，並將水層再度以乙酸乙酯（25 mL)萃取。合併有機層，以5 °/❶-食鹽水洗滌，並以無水硫酸鎂乾燥。將溶劑德去，將獲得的殘渣以矽膠管柱層析（正己烷-乙酸乙酯 100 : 0— 50 : 50(Wv))精製，獲得化合物（III)(3 〇4 g，.產率98%)無色固體。 H-NMR (CDC13) δ ： 1.26 (t，J = 7.10 Ηζ，3Η)， 1.27-1.38 (m, 2H), 1.58-1.68 (m, 2H), 2.04-2.13 (m, 2H), 2.23-2.34 (m，2H)，3.63-3.79 (m, 1H), 4.14 (q，j = 7.10After adding 6-fluorobenzoxazolone (〇.3982g, 2.60mmol) (I), five gasification (1.6247g, 7.80mmol, 3eq), and phosphorus oxychloride (1.6mL, 4V), Heat to 80 ° C. One side was confirmed by HPLC to confirm the progress of the reaction, and heating was stopped after 4 hours (about -35 hours after -18-201204706 HPLC: 6-fluorobenzoxazolone (I): 2-chloro-6-fluoro benzoxoxazole ( 11) = 1 : 9 4 (area ratio)). The reaction solution was dissolved in a solvent and quantified in a 1 L flask, and it was found to be 95% (HPLC result: 6-fluorobenzoxaconazole: 2-gas-6-fluorobenzoxazole = 0:96 ( The yield of the area ratio)) was obtained as the target 2-gas-6-fluorobenzosin (胁). P /^\^C〇2Et (Reference Example 2) (III) I /V~ci (II) Addition of trans-4-amino-cyclohexane to N,N-dimercaptocaramine (10 mL) Ethyl alkanoate (2.08 g, 1 mmol) and triethylamine (5.0 mL, 36 mmol). Add 2-gas-6-fluorobens and sit (11) (2.23 g, 13 mmol) of N,N-didecylguanamine (4 mL) below 5 °C with cooling and stirring. The solution was stirred at room temperature for 2 hours. Ethyl acetate (25 mL) and 5% aqueous citric acid (25 mL) were added to the mixture, and the organic layer was partitioned. The organic layer was combined, washed with brine and brine and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 100 : 0 - 50 : 50 (Wv)) to obtain compound (III) (3 〇 4 g, yield 98). %) colorless solid. H-NMR (CDC13) δ : 1.26 (t, J = 7.10 Ηζ, 3Η), 1.27-1.38 (m, 2H), 1.58-1.68 (m, 2H), 2.04-2.13 (m, 2H), 2.23-2.34 (m, 2H), 3.63 - 3.79 (m, 1H), 4.14 (q, j = 7.10

Hz, 2H), 5.31 (s, 1H), 6.86-6.93 (m, 1H), 7.00 (dd, J = 8.24, 2.53 Hz, 1H), 7.23 (dd, J = 8.24, 4.82 Hz, 1H) 201204706 MS : [Μ + Η]+ m/z 307.1Hz, 2H), 5.31 (s, 1H), 6.86-6.93 (m, 1H), 7.00 (dd, J = 8.24, 2.53 Hz, 1H), 7.23 (dd, J = 8.24, 4.82 Hz, 1H) 201204706 MS : [Μ + Η]+ m/z 307.1

(III)(III)

使化合物（111)( 1_23 g，4.0 mmol)溶解於四氫呋喊-甲醇（6_0 mL-5.0 mL)之混合溶劑，於熱攪拌。於其中花費2小時滴加硼氫化鋰(2.0m〇1/L·四氫呋喃溶液，* 〇 1^，8.〇111«1〇1)之後，於70。〇攪拌1小時。再加入甲醇（12 mL)及四氫吱喊（1·2 mL)後，花f 2小時滴加删氫化链 (2.〇111〇1/[-四氫吱喃溶液，4.〇111]1，8.〇111111〇1)，於7〇。(：搜拌1小時。將反應液冷卻至，依序加入2m〇l/L鹽酸 (32 mL)、2mol/L-氫氧化鈉水溶液（24 mL)、5%碳酸氫鈉水溶液（12 mL)，以乙酸乙酯（15 mL)萃取。將水層以乙酸乙酯（15 mL)萃取，合併有機層並以飽和食鹽水（7 5 m L)洗滌，以無水硫酸鈉乾燥。將溶劑德去，並將獲得的殘渣以正己烷及異丙醚洗滌，獲得化合物（IV)(〇 95g，產率91%)淡褐色固體。 'H-NMR (DMS〇-d6) <5 ： 0.91-1.06 (m, 2H), 1.19-1.40 (m, 3H), 1.79 (d, J = 11.66 Hz, 2H), 2.00-2.08 (m, 2H), 3.20-3.26 (m5 2H), 3.43-3.52 (m, 1H), 4.41-4.49 (m, 1H), 6.92-6.97 (m, 1H), 7.19 (dd, J = 8.49, 4.82 Hz, 1H), 7.3 2 (dd, J = 8.49, 2.53 Hz, 1H), 7.8 7 (d, J = 8.11 Hz, 1H) MS : [M + H]+ m/z 265.0 -20- 201204706 (參考例4)Compound (111) (1 - 23 g, 4.0 mmol) was dissolved in a mixed solvent of tetrahydrofuran-methanol (6_0 mL - 5.0 mL) and stirred with stirring. After charging lithium borohydride (2.0 m 〇 1 / L · tetrahydrofuran solution, * 〇 1 ^, 8. 〇 111 «1 〇 1) dropwise for 2 hours, at 70. Stir for 1 hour. After adding methanol (12 mL) and tetrahydro hydrazine (1. 2 mL), the hydrogenation chain was added dropwise over 2 hours (2. 〇111〇1/[-tetrahydrofuran solution, 4.〇111] 1,8.〇111111〇1), at 7〇. (: Mix for 1 hour. Cool the reaction solution to 2 m〇l/L hydrochloric acid (32 mL), 2 mol/L-aqueous sodium hydroxide solution (24 mL), 5% aqueous sodium hydrogencarbonate solution (12 mL). The extract was extracted with ethyl acetate (15 mL). EtOAc (EtOAc m. The residue obtained was washed with n-hexane and isopropyl ether to give compound (IV) (95 g, yield 91%) as a pale brown solid. 'H-NMR (DMS 〇-d6) <5: 0.91-1.06 (m, 2H), 1.19-1.40 (m, 3H), 1.79 (d, J = 11.66 Hz, 2H), 2.00-2.08 (m, 2H), 3.20-3.26 (m5 2H), 3.43-3.52 (m, 1H), 4.41-4.49 (m, 1H), 6.92-6.97 (m, 1H), 7.19 (dd, J = 8.49, 4.82 Hz, 1H), 7.3 2 (dd, J = 8.49, 2.53 Hz, 1H), 7.8 7 (d, J = 8.11 Hz, 1H) MS : [M + H]+ m/z 265.0 -20- 201204706 (Reference Example 4)

Η (IV)Η (IV)

第一步驟使化合物（IV)(794 mg, 3.0 mmol)溶於Ν，Ν-二甲基乙醯胺（6 mL)，於冰冷下依序加入三乙胺（1.00 mL，7.2 mmol)、曱烷磺醯氯（0.47 mL，6.0 mmol)，之後於室溫攪拌2小時。將反應液浸於冰水（25 mL)中，以乙酸乙酯萃取（20 mLx2)。將有機層以冷水（20 mLx2)洗滌，並以無水硫酸鈉乾燥。將溶劑餾去，獲得粗產物（V)( 1.2 1 5 g)。 'H-NMR (300MHz, DMSO-d6) 5 ： 1.05-1.22 (m, 2H), 1.22-1.40 (m, 2H), 1.60-1.76 (m, 1H), 1.76-1.86 (m, 2H), 2.02-2.12 (m, 2H), 3.18 (s, 3H), 3.38-3.56 (m, 1H), 4.05 (d, 2H, J = 6.3 Hz), 6.92-7.00 (m, 1H), 7.20 (dd, 1H, J =8,4, 5.1 Hz), 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 8.00 (d, 1H, J = 7.5 Hz) 第二步驟將粗產物（V)(304 mg)加入至第三丁基磺醯胺（186 mg, 1.35 mmol)、及碳酸铯（326 mg，1.00 mm〇l)之 N，N- 二曱基乙醯胺（2 mL)、及乙酸乙酯（〇 5 mL)之混合溶液 201204706 中’於80°C攪拌約1 5小時。將反應液浸於冰水（25 mL)In the first step, compound (IV) (794 mg, 3.0 mmol) was dissolved in hydrazine, hydrazine-dimethylacetamide (6 mL), and triethylamine (1.00 mL, 7.2 mmol) Alkylsulfonium chloride (0.47 mL, 6.0 mmol) was stirred at room temperature for 2 h. The reaction solution was immersed in ice water (25 mL) and extracted with ethyl acetate (20 mL×2). The organic layer was washed with cold water (20 mL×2) and dried over anhydrous sodium sulfate. The solvent was distilled off to give a crude product (V) (1.21 g). 'H-NMR (300MHz, DMSO-d6) 5 : 1.05-1.22 (m, 2H), 1.22-1.40 (m, 2H), 1.60-1.76 (m, 1H), 1.76-1.86 (m, 2H), 2.02 -2.12 (m, 2H), 3.18 (s, 3H), 3.38-3.56 (m, 1H), 4.05 (d, 2H, J = 6.3 Hz), 6.92-7.00 (m, 1H), 7.20 (dd, 1H , J = 8, 4, 5.1 Hz), 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 8.00 (d, 1H, J = 7.5 Hz) The second step adds the crude product (V) (304 mg) To N-butyl sulfonamide (186 mg, 1.35 mmol), and cesium carbonate (326 mg, 1.00 mm 〇l) of N,N-dimercaptoacetamide (2 mL), and ethyl acetate (〇) 5 mL) of the mixed solution 201204706 was stirred at 80 ° C for about 15 hours. Immerse the reaction solution in ice water (25 mL)

中’以乙酸乙酯萃取（2〇 mLx2)。將有機層以冷水（20 mL X2)洗滌，並以無水硫酸鈉乾燥。將溶劑餾去，將殘渣以石夕膠層析（氯仿-甲醇10:0至10:1 一化合物（VDUO^mg，產率70%)白/田梯度）精製，獲得 7 1=1巴固體。Medium 'extracted with ethyl acetate (2 〇 mL x 2). The organic layer was washed with cold water (20 mL EtOAc) and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by chromatography on silica gel chromatography (chloroform-methanol: 10:0 to 10:1 compound (VDUO^mg, yield 70%) white/field gradient) to obtain 7 1 = 1 bar solid. .

ci8H26FN3〇3S之分析計算值：c 4.95，N 10.96，S 8.36 38’ Η 6.83，FAnalytical calculated value of ci8H26FN3〇3S: c 4.95, N 10.96, S 8.36 38’ Η 6.83, F

Found : C 56.35, Η 6.92, F 5 15 'H-NMR (DMSO-de) δ : 〇 9 ^ 1〇-82> s 8·57 ^6-1.46 (m，3H)，1.27 (s, 9H)，丨 7?1.08 (m，2H)， ^98-2.10 (m, 2H), 2.89 (t, 2H, J = 6 〇 ^ 1-87 2H), ·7, 2·7 Hz), 7.88 1H)，6.88 (t，1H，J = 5.7 Hz)，δ·%'。。Z)’ 3.38~3.54 (m， 1H，J = 8.7, 5.1 Hz)，7.34 (dd，1H，j = % 1H)，7.19 (⑸， (d，1H，J = 7.5 Hz) 【圖式簡單說明】 jfe ο 【主要元件符號說明】無。 22-Found : C 56.35, Η 6.92, F 5 15 'H-NMR (DMSO-de) δ : 〇9 ^ 1〇-82> s 8·57 ^6-1.46 (m,3H), 1.27 (s, 9H) , 丨7?1.08 (m, 2H), ^98-2.10 (m, 2H), 2.89 (t, 2H, J = 6 〇^ 1-87 2H), ·7, 2·7 Hz), 7.88 1H) , 6.88 (t, 1H, J = 5.7 Hz), δ·%'. . Z)' 3.38~3.54 (m, 1H, J = 8.7, 5.1 Hz), 7.34 (dd, 1H, j = % 1H), 7.19 ((5), (d, 1H, J = 7.5 Hz) 】 jfe ο [Main component symbol description] None. 22-

Claims

201204706 七、申請專利範圍： 1 · 一種以式（II)表示之化合物之製造方法，其特徵為使以式（I)表示之化合物與氣化劑反應：式（I):201204706 VII. Patent application scope: 1 . A method for producing a compound represented by the formula (II), which is characterized in that a compound represented by the formula (I) is reacted with a gasifying agent: Formula (I):

式（II):Formula (II):

2 ·如申請專利範圍第1項之製造方法，其係不加壓而進行。 3. 如申請專利範圍第1或2項之製造方法，其係於1 00 度以下的溫度進行。 4. 如申請專利範圍第1至3項中任一項之製造方法，其係於聚磷酸存在下進行。 5. 如申請專利範圍第1至4項中任一項之製造方法，其係使用五氣化磷、氧氣化磷或此等之混合物當做氯化劑。 6 ·如申請專利範圍第1至5項中任一項之製造方法，其係使用非極性有機溶劑、***或此等之混合溶劑當做溶劑。 7 · —種以式（VI)表示之化合物、其鹽或此等的溶劑合物之製造方法，其特徵為包含如申請專利範圍第1至6項中任一項之製造方法， -23- 201204706 式（νι): FO：} NHS02-tert-Bu 丨、、、、、' Η (VI) -24- 201204706 四、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：無。五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：2. The manufacturing method of claim 1 of the patent application is carried out without pressurization. 3. The manufacturing method of claim 1 or 2 is carried out at a temperature of 100 ° or less. 4. The production method according to any one of claims 1 to 3, which is carried out in the presence of polyphosphoric acid. 5. The manufacturing method according to any one of claims 1 to 4, wherein five gasified phosphorus, phosphorus oxide or a mixture thereof is used as the chlorinating agent. The manufacturing method according to any one of claims 1 to 5, which uses a nonpolar organic solvent, phosphorus oxychloride or a mixed solvent thereof as a solvent. A method for producing a compound represented by the formula (VI), a salt thereof or a solvate thereof, which comprises the production method according to any one of claims 1 to 6, -23- 201204706 Formula (νι): FO:} NHS02-tert-Bu 丨,,,,,, Η (VI) -24- 201204706 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the component symbols of this representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: