(8) (8)1320782 胺化步驟與環化步驟亦可，亦可於烯胺化後，進行後處理 之後一度取出烯胺體（V)後，進行環化反應完成本步驟 〇 式（V)所示化合物爲互變異構體，當然亦存在做爲 下式（V ’）所示之化合物者。(8) (8) 1320782 The amination step and the cyclization step may also be carried out after the amination, after the post-treatment, after the removal of the enamine body (V), the cyclization reaction is carried out to complete the step (V). The compound shown is a tautomer, and of course, a compound represented by the following formula (V ') is also present.
[式中，R1，R2，R3及R5與上記意義相同。] [步驟（Π )] 步驟（ii )中，首先使式（III )化合物與式（IV )化 合物進行反應後，進行烯胺化步驟。式（IV )所示化合物 之結構其R2及R3因應式（I )化合物視其目的物之式（I ) 化合物結構進行適當選定之。又，R5代表Ci.4烷基，又 以甲基或乙基爲宜。理想式（IV)化合物之具體例如：2-甲基乙醯醋酸甲酯、2-甲基乙醯醋酸乙酯、2-苄基乙醯醋 酸乙酯、2-乙基乙醯醋酸乙酯、2-異丙基乙醯醋酸乙酯、 2-烯丙基乙醯醋酸乙酯等例。式（IV)所代表之α-烷基- β-酮酯之量可依其反應條件等進行適當選定之，通常以 0.8〜2.0 當量爲宜，更佳者爲1.0~1.5 當量，最佳者爲 -12- (9) (9)1320782 1.2〜1 .3 當量》 反應係於酸性觸媒或鹽基性觸媒之存在下進行者宜， 又以酸性觸媒爲更佳使用者。酸性觸媒之例如：醋酸、三 氟醋酸、對甲苯磺酸等質子酸、三氟化硼二乙醚絡合體等 路易斯酸例者，做爲犟基性觸媒例者如六氫化吡啶例者。 使用六氫化吡啶時，以乙醇溶媒使用者宜，惟，反應時間 相較於酸性觸媒時，其較爲耗時者。 此烯胺化無溶媒亦可進行之，一般於與甲苯、二甲苯 、乙醇等之水做成共沸混合物之不活性溶媒中進行之。於 100 °c~140 °c下進行加熱後，藉由共沸作用有效促進去 除所生成水之反應者宜。又，爲有效去除經時性所生成之 水，於反應裝置中裝入丁·斯達克（Dean and Stark)阴: 裝置、分子篩、等適當之脫水劑，做成可有效去除水之反 應容器者宜。 反應以甲苯用於溶媒時，於迴流條件下，進行2小 時〜5小時攪拌之同時進行之。反應之進行係藉由高速液 體層析法等觀測原料4-烷基-2-氟苯胺衍生物之殘存率後 ’可得知。此反應爲平衡反應，其原料未完全消失，於幾 乎停止減少4 -烷基-2-氟苯胺衍生物時停止反應者宜。時 間延長不但使所生成式（V)烯胺體之再分解等不良反應 出現，亦導致收率降低。 又，取得烯胺化合物爲不安定者，矽膠中迅速分解， 因此，矽膠層析法中不易單離。於精製，單離時藉由蒸餾 後進行單離者宜。通常，未進行單離，利用以下之環化反 -13- 1320782 do) 應即可。 本發明理想之注意事項爲殘留原料4 -烷基-2 -氟苯胺 後進行環化反應時，所生成後記式（I)(惟，r4 = h )之 互變異構體之式（VI)所示喹啉酚體之4位酮部位與4·院 基-2 -氟苯胺之胺基進行反應後，生成副產物，恐大幅降 低收率。因此，理想之本發明形態係結束嫌胺化反應後， 將反應液之液性加入六氫化吡啶、三乙胺等鹽基做成鹽基 性進行安定化後，再加入無水醋酸、氯化乙醯酯等之乙醯 化劑後，進行殘存4-烷基-2-氟苯胺之胺基的乙醯化，抑 制胺基之求核性後，抑制副產物之生成。胺基之保護不限 於乙醯基，亦可以一般所使用三甲基乙醯等醯胺型保護基 、苄基氧羰基、第三-丁氧羰基等之胺基甲酸酯型保護基 進行保護之。 步驟（ii)中，持續進行式（V)化合物之環化反應 係藉由加熱進行者。反應係於適當溶媒中進行加熱之同時 ，可於溶媒之迴流溫度下進行之。理想之溶媒例如：二苯 醚、二甲苯、多磷酸、暗煤、聯苯、二甲基甲醯胺、二甲 亞碩等例。 本發明理想形態係於該烯胺反應後持續於單槽進行環 化反應時，加入二苯醚於烯胺反應液’餾去甲苯之同時進 行加熱至二苯醚沸點之250 °C後進行反應之。此反應係 使烯胺之α，β·不飽和羰基部份之新雙烯物與苯核於分子 內藉由熱可發現出現多中心反應’此係所謂康拉-林柏奇 之鸣啉酚合成之反應者。此反應亦可以二甲苯溶媒，於 -14- (11) 1320782 140 °c~迴流條件下進行之。又，依WO 00/475 77號公報 爲基準，使多磷酸做成溶媒後，加熱至160. °C，一次引 發烯胺化一環化反應後，亦可取得式（I )(惟，R4 = H ) 之喹啉酚體。 式（I )(惟，R4 = H )化合物爲互變異構體，亦可存 在下式（VI )者。 0[wherein, R1, R2, R3 and R5 have the same meanings as in the above. [Step (Π)] In the step (ii), the compound of the formula (III) is first reacted with the compound of the formula (IV), followed by an enaminelation step. The structure of the compound of the formula (IV) wherein R2 and R3 are appropriately selected depending on the structure of the compound of the formula (I) according to the object of the formula (I). Further, R5 represents a Ci.4 alkyl group, and a methyl group or an ethyl group is preferred. Specific examples of the compound of the formula (IV) are, for example, methyl 2-methylacetamacetate, ethyl 2-methylacetate acetate, ethyl 2-benzylacetate, ethyl 2-ethylacetate, Examples of ethyl 2-isopropylacetate, ethyl 2-allylacetate, and the like. The amount of the α-alkyl-β-ketoester represented by the formula (IV) can be appropriately selected depending on the reaction conditions and the like, and is usually preferably 0.8 to 2.0 equivalents, more preferably 1.0 to 1.5 equivalents, and most preferably For the -12-(9) (9)1320782 1.2~1.3 equivalents, the reaction is carried out in the presence of an acidic catalyst or a salt-based catalyst, and an acidic catalyst is preferred. Examples of the acid catalyst include a protonic acid such as acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, and a Lewis acid such as a boron trifluoride diethyl ether complex, and those which are thiol-based catalysts such as hexahydropyridine. When hexahydropyridine is used, it is preferred to use an ethanol solvent, but the reaction time is relatively time consuming compared to an acidic catalyst. This enamine can be carried out without a solvent, and is generally carried out in an inactive solvent which is made into an azeotropic mixture with water such as toluene, xylene or ethanol. After heating at 100 ° C to 140 ° C, it is preferred to promote the removal of the formed water by azeotropic action. Further, in order to effectively remove the water generated by the lapse of time, a Dean and Stark yin is placed in the reaction apparatus: a device, a molecular sieve, and the like, and a suitable dehydrating agent is used to form a reaction container capable of effectively removing water. Suitable. When the reaction is carried out using toluene as a solvent, it is carried out under reflux conditions for 2 hours to 5 hours while stirring. The progress of the reaction is observed by observing the residual ratio of the starting 4-alkyl-2-fluoroaniline derivative by high-speed liquid chromatography or the like. This reaction is an equilibrium reaction in which the starting material is not completely disappeared, and it is preferred to stop the reaction when the reduction of the 4-alkyl-2-fluoroaniline derivative is stopped a little. The prolongation of time not only causes an adverse reaction such as re-decomposition of the produced (V) alkene, but also causes a decrease in yield. Further, the obtained enamine compound is unstable, and the tannin extract rapidly decomposes, so that it is difficult to separate in the gelatin chromatography. In the case of refining, it is preferred to carry out the separation by distillation. Usually, without detachment, the following cyclization anti-13-1320782 do) should be used. An ideal precaution of the present invention is to carry out the cyclization reaction after the residual starting material 4-alkyl-2-fluoroaniline, and the formula (VI) of the tautomer of formula (I) (only, r4 = h) is formed. When the ketone moiety at the 4-position of the quinolinol body reacts with the amine group of the 4th keto-2-fluoroaniline, a by-product is formed, which may drastically reduce the yield. Therefore, in the preferred embodiment of the present invention, after the amination reaction is completed, the liquidity of the reaction liquid is added to a salt group such as hexahydropyridine or triethylamine to form a salt-based stability, and then anhydrous acetic acid and chloride B are added. After the acetalization agent such as an oxime ester, the acetylation of the amine group of the 4-alkyl-2-fluoroaniline is carried out, and the formation of by-products is suppressed after the nucleation of the amine group is suppressed. The protection of the amine group is not limited to the ethyl hydrazide group, and it may be generally protected by a urethane type protecting group such as a guanamine type protecting group such as trimethyl acetyl hydrazine, a benzyloxycarbonyl group or a tert-butoxycarbonyl group. It. In the step (ii), the cyclization reaction of the compound of the formula (V) is carried out by heating. The reaction is carried out at a reflux temperature of the solvent while heating in a suitable solvent. Preferred solvents are, for example, diphenyl ether, xylene, polyphosphoric acid, dark coal, biphenyl, dimethylformamide, and dimethyl sulfoxide. In a preferred embodiment of the present invention, after the enamine reaction is continued in a single tank for cyclization, diphenyl ether is added to the enamine reaction solution to distill off toluene while heating to 250 ° C of the boiling point of diphenyl ether. It. This reaction is based on the fact that the new diene of the α,β·unsaturated carbonyl moiety of the enamine and the benzene nucleus are found to be multi-centered by heat in the molecule, which is synthesized by the so-called Conrad-Linbach Responder. This reaction can also be carried out in a xylene solvent under reflux conditions of -14-(11) 1320782 140 °c. Further, according to WO 00/475 77, after the polyphosphoric acid is used as a solvent, the mixture is heated to 160 ° C, and once the enaminerization-cyclization reaction is initiated once, the formula (I) can also be obtained (only, R4 = H) Quinolinol body. The compound of the formula (I) (here, R4 = H) is a tautomer, and the following formula (VI) may also be present. 0
FTFT
[式中’ R1、R2及R3與上述意義相同者。] 環化反應係混合烯胺反應混合物與溶媒後，亦加加熱 反應系’又可於沸騰溶媒中滴入餾去甲苯之烯胺反應混合 物。反應之進行快速，反應液之溫度當到達245 t ~2 50 〇C 時反應爲完成者。反應溫度恢復至室溫時，通常緩慢攪拌 12小時之同時進行結晶化操作後，可取得幾乎呈單—之 式（I)化合物（惟，R4 = H)。[wherein R1, R2 and R3 have the same meanings as described above. The cyclization reaction is carried out by mixing the enamine reaction mixture with a solvent, and heating the reaction system, and dropping the enamine reaction mixture of toluene into the boiling solvent. The reaction proceeds rapidly, and the temperature of the reaction liquid reaches the completion when it reaches 245 t to 2 50 〇C. When the reaction temperature is returned to room temperature, the compound of the formula (I) which is almost mono- (i.e., R4 = H) can be obtained after the crystallization operation is carried out while stirring slowly for 12 hours.
本發明中，必要時藉由常法於4位羥基進行取得式（I )化合物（惟，R4 = H )之保護。羥基之保護基並未特別 限定’理想具體例如iCm烷基、Cu烷基羰基、d.6 院氧基羰基、Cm烷氧基Ci-6烷基羰基' d-6烷基羰基 氧基C!·6烷基羰基、C3·6環烷基羰基、或，C3-6環烷氧 -15- (12) (12)1320782 °該導入係藉由慣用於其保護基之方法進行者 宜。如：保護基爲乙醯基時，反應係加入溶於吡啶之基（1 )化合物（惟’ r4=h )與適量之無水醋酸或氯化乙醯， 於8 0 °C反應1小時後，可取得幾乎定量之目的物，2，3 ’ 6 -二烷基-8-氟-4 -乙酸基卩奎啉衍生物。 式（I)化合物於反應結束後，濃縮溶劑後，由正-己 院進行再結晶後可取得純結晶。又，爲做成碳酸酯保護型 ’使式（I)化合物（惟，r4 = H )之4位羥基以氫化鈉等適 當鹽基取出質子’再與氯蟻酸乙酯所代表之碳酸酯化試劑 反應之。另外，爲做成烷基醚保護型，使碳酸鉀等鹽基同 時與碘化甲基所代表烷化劑進行反應即可。 【實施方式】 [實施例] 以下，以實施例進行本發明之具體說明。 [實施例1] 4-第三-丁基-2-氟苯胺 加入5.50ml 36%鹽酸與攪拌子於玻璃製反應容器，進 行氯化鋅（5· 24 g，0.0383 mol)之溶解。攪拌該溶液之同 時，將2-氟苯胺（10_0ml，0.104mol)及第三-丁醇（ 9.90ml，0.104mol)依序進行加入，將此坡璃容器置入不 銹鋼製耐壓容器使內部壓力不會滲漏進行密封’加熱至 190 °C攪拌同時反應之。初期壓力約爲5氣壓。此反應持 續72小時。確定溫度充份降低後’打開壓力容器β加入 -16 - (13) (13)1320782 醋酸乙酯（200ml )，攪拌後使整體均勻後，加入水（ 200ml )，以氫氧化鈉進行中和調整pH爲9。濾別大量析 出之茶色固體，濾液進行分液後’再度水洗有機層。濃縮 取得之有機層，取得16.9g茶褐色油狀物質。此者以標的 物做爲基準以絕對檢量線法進行定量之。其結果爲收率 7 9.2%。 EI-MS; m/z 170 ( M + H ) + ： 'H NMR ( CDC13) 51.26 (9Η，s，t，Bu) ，3 · 5 6 ( br，N H2 ) ，6 · 7 4 ( 1 H，t· 1 i ke ，J = 9.3Hz，H6 ) ，6.95 ( 1H，ddd，J = 7.5，2.1，0.7Hz，In the present invention, the protection of the compound of the formula (I) (R4 = H) is carried out by a usual method at the 4-hydroxyl group. The protecting group for the hydroxy group is not particularly limited. It is desirably specifically, for example, iCm alkyl group, Cu alkylcarbonyl group, d.6 oxycarbonyl group, Cm alkoxy Ci-6 alkylcarbonyl group 'd-6 alkylcarbonyloxy group C! • 6 alkylcarbonyl, C 3 6 cycloalkylcarbonyl, or C 3-6 cycloalkoxy-15-(12) (12) 1320782 °. The introduction is carried out by a method conventionally used for its protecting group. For example, when the protecting group is an acetamidine group, the reaction is carried out by adding a compound (1 r4=h) dissolved in pyridine (only 'r4=h) with an appropriate amount of anhydrous acetic acid or acetyl chloride, and reacting at 80 ° C for 1 hour. An almost quantitative target, 2,3' 6 -dialkyl-8-fluoro-4-acetic acid quinoid quinone derivative can be obtained. After the completion of the reaction of the compound of the formula (I), the solvent is concentrated, and then recrystallized from the Orthodox Institute to obtain pure crystals. Further, in order to obtain a carbonate-protected type, a carbonic acid esterifying reagent represented by a 4-hydroxy group of the compound of the formula (I) (only, r4 = H) is taken up with a suitable salt such as sodium hydride and then with ethyl chloroformate. Reaction. Further, in order to form an alkyl ether-protected type, a salt group such as potassium carbonate may be reacted with an alkylating agent represented by methyl iodide at the same time. [Embodiment] [Examples] Hereinafter, the present invention will be specifically described by way of examples. [Example 1] 4-Terve-butyl-2-fluoroaniline A solution of 5.50 ml of 36% hydrochloric acid and a stirrer in a glass reaction vessel was added to dissolve zinc chloride (5·24 g, 0.0383 mol). While stirring the solution, 2-fluoroaniline (10_0 ml, 0.104 mol) and third-butanol (9.90 ml, 0.104 mol) were sequentially added, and the glass container was placed in a pressure vessel made of stainless steel to make internal pressure. The seal will not leak and will be heated to 190 ° C while stirring. The initial pressure is about 5 atmospheres. This reaction lasted for 72 hours. After confirming that the temperature is sufficiently reduced, 'open the pressure vessel β and add -16 - (13) (13) 1320782 ethyl acetate (200 ml), stir to make the whole uniform, add water (200 ml), and adjust the neutralization with sodium hydroxide. The pH is 9. A large amount of the precipitated brown solid was filtered, and the filtrate was subjected to liquid separation, and the organic layer was washed again. The obtained organic layer was concentrated to give 16.9 g of a brown oily material. This is quantified by the absolute calibration line method based on the subject matter. The result was a yield of 7 9.2%. EI-MS; m/z 170 ( M + H ) + : 'H NMR ( CDC13 ) 51.26 (9Η, s, t, Bu) , 3 · 5 6 ( br, N H2 ) , 6 · 7 4 ( 1 H , t· 1 i ke , J = 9.3 Hz, H6 ) , 6.95 ( 1H, ddd, J = 7.5, 2.1, 0.7 Hz,
Hs ) > 7.94 ( 1H - dd > J=13.4 > 1.9Hz * H3 )。 [實施例2] 6-第三-丁基-8·氟-2，3-二甲基-4-卩奎啉酚 將4-第三-丁基-2-氟苯胺（5.06g，30.3mmol)溶於甲 苯（120ml )，加入2-甲基乙醯醋酸乙酯（5.75ml， 40.6mmol)與對甲苯磺酸1水和物（50mg)，以具丁 .斯 達克裝置之反應裝置進行加熱迴流3小時。反應液回復 至室溫，依序加入二苯醚（50ml)，六氫化吡啶（2.0ml )及無水醋酸（1.0ml )，進行攪拌30分鐘。再進行加溫 ，之後，餾去溶媒甲苯。更使反應溫度昇溫至250 °C， 其溫度保持10分鐘，完成環化反應。室溫下放冷反應液 ，靜置1晚後，進行結晶化。濾別析出之白色結晶，以正-己烷洗淨，減壓、室溫下進行取得白色結晶乾燥3小時 後，取得4.82g之6-第三-丁基-8-氟-2，3-二甲基-4-[]奎啉酚 。收率 6 4.5 %。 -17- (14) (14)1320782Hs ) > 7.94 ( 1H - dd > J=13.4 > 1.9Hz * H3 ). [Example 2] 6-Terti-butyl-8·fluoro-2,3-dimethyl-4-oxime quinolol 4-tert-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) Dissolved in toluene (120 ml), and added 2-methylacetamidineacetate (5.75 ml, 40.6 mmol) and p-toluenesulfonic acid 1 water (50 mg) in a reaction apparatus with a butyl. Heat to reflux for 3 hours. The reaction mixture was returned to room temperature, and diphenyl ether (50 ml), hexahydropyridine (2.0 ml) and anhydrous acetic acid (1.0 ml) were added and stirred for 30 minutes. Heating was further carried out, after which the solvent toluene was distilled off. Further, the reaction temperature was raised to 250 ° C, and the temperature was maintained for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to stand at room temperature, and after standing overnight, crystallization was carried out. The precipitated white crystals were filtered, washed with n-hexane, and dried under reduced pressure at room temperature for 3 hours to obtain 4.82 g of 6-tri-butyl-8-fluoro-2,3- Dimethyl-4-[]quinolinol. Yield 6 4.5%. -17- (14) (14) 1320782
FAB-MS; m/z 248 ( M + H ) + ； 'h NMR ( CDC13 ) 51 .33 ( 9H > s > t-Bu ) > 2.13 (3Η» s> CH3) ，2.52(3H ’ s’ CH3 ) ’ 7.34 ( 1 H > dd，J = 1 2.9，2.2 Η z，H 3-aromatic) ’ 8.10 ( 1H ’ d ’ J=1.5Hz，Hs-aromatic)， 8.92 ( 1H，bs，NH )。 [實施例3] 6-第三-丁基-8·氟-2，3·二甲基-4-0奎啉酚（ EMA滴入法） 將4 -弟二-丁基-2-氣本胺（5.06g，30.3mmol)溶於甲 苯（80ml)，加入對甲苯磺酸1水合物（50mg)，以具丁 •斯達克裝置之反應裝置進行加熱迴流。於此加熱溶液中 以2個小時進行滴入溶於甲苯（20ml)之2 -甲基乙醯醋酸 乙酯（5.75ml’ 40.6mmol)。結束滴畢，更進行加熱迴流 2小時。反應液回復至室溫，依序加入二苯醚（50ml) ，六氫化吡啶（2.0ml )，及無水醋酸（1.0ml )，之後攪 拌30分鐘。再度進行加溫，餾去溶媒甲苯。更使反應溫 度昇溫至250 °C，於此溫度保持10分鐘完成環化反應。 反應液於室溫下放冷，靜置1晚進行結晶化。濾別析出之 白色結晶，以正·己烷進行洗淨，將取得白色結晶於減壓 室溫下進行乾燥3小時，取得5.17g之6-第三-丁基-8-氟-2 ，3 -二甲基·4·喧啉酚。收率69.0%。 [實施例4] 6-第三-丁基-8·氟-2，3-二甲基-4-D奎啉酚 將多磷酸（l〇.8g)加熱至160 °C，之後滴入4-第三· -18- (15) (15)1320782 丁基-2-氟苯胺（l.89g，11.3mmol)與2-甲基乙醯醋酸乙 酯（1.96g，13.5mmol )之混合物，同溫度下進行攪拌3 小時。反應液冷卻後，加入水（5 0 m 1 )，以醋酸乙酯（ 50ml )進行萃取2次。使有機層合一後進行水洗，減壓下 餾去有機層，取得油狀之濃縮殘渣。由醋酸乙酯一正-己 烷進行再結晶後，取得0.97g之6-第三·丁基-8-氟-2，3-二 甲基-4-喹啉酚白色結晶。收率34· 7%。 FAB-MS; m/z 248 ( M + H )十：'H NMR ( CDC13 ) S1.33(9H，s，t-Bu) ，2.13(3H，s，CH3) ，2·52(3Η ，s，CH3 ) ，7.33 ( 1H，dd，J = 12.9，2.2Hz，H3- aromatic ) ，8 · 1 0 ( 1 H，d，J = 1 . 5 Hz，H5 - aromat i c )， 8.93 ( 1H，bs，NH )。 [實施例5] 6-第三-丁基-8-氟·2，3-二甲基-4-卩奎啉酚 將4-第三-丁基-2-氟苯胺（5.06g，30.3mmol)溶於甲 苯（120ml)，力□入2 -甲基乙醯醋酸乙酯（5.75ml， 40_6mmol)與對甲苯磺酸1水合物（50mg)，於具有Din Stank裝置之反應裝置進行加熱迴流3 小時。放冷後， 於飽和蘇打水中投入反應液’以醋酸乙酯（50ml )進行萃 取之。以無水硫酸鎂進行乾燥有機層’濾別固形物後，濃 縮濾液後，取得5.99g之茶色油狀物。將此溶於二甲苯（ 155ml)後，於160 °C下進行加熱攪拌1小時。使反應液 冷卻後，濃縮溶媒，以矽膠柱體層析法（醋酸乙酯-正-己 院1:1)進行精製後，取得845g 6 -第二-丁基-8-氟-2’ 3 -二 •19· (16) (16)1320782 甲基-4 - D奎啉酚。收率1 1 . 3 %。FAB-MS; m/z 248 ( M + H ) + ; 'h NMR ( CDC13 ) 51 .33 ( 9H > s > t-Bu ) > 2.13 (3Η» s> CH3) , 2.52 (3H ' s' CH3 ) ' 7.34 ( 1 H > dd, J = 1 2.9, 2.2 Η z, H 3-aromatic) ' 8.10 ( 1H ' d ' J=1.5Hz, Hs-aromatic), 8.92 ( 1H, bs, NH). [Example 3] 6-tert-butyl-8·fluoro-2,3·dimethyl-4-0 quinolol (EMA instillation method) 4-di-di-butyl-2-carbonate The amine (5.06 g, 30.3 mmol) was dissolved in toluene (80 ml), p-toluenesulfonic acid monohydrate (50 mg) was added, and the mixture was heated and refluxed in a reaction apparatus equipped with a butyl Stark apparatus. Into this heated solution, 2-methylacetamidineacetate (5.75 ml' 40.6 mmol) dissolved in toluene (20 ml) was added dropwise over 2 hours. After the completion of the dropwise addition, the mixture was further heated under reflux for 2 hours. The reaction solution was returned to room temperature, and diphenyl ether (50 ml), hexahydropyridine (2.0 ml) and anhydrous acetic acid (1.0 ml) were sequentially added, followed by stirring for 30 minutes. The mixture was warmed again, and the solvent toluene was distilled off. The reaction temperature was further raised to 250 ° C, and the temperature was maintained for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to stand at room temperature and allowed to stand overnight for crystallization. The precipitated white crystals were filtered, washed with n-hexane, and the obtained white crystals were dried under reduced pressure at room temperature for 3 hours to obtain 5.17 g of 6-t-butyl-8-fluoro-2,3. - Dimethyl·4·porphyrin phenol. The yield was 69.0%. [Example 4] 6-Terti-butyl-8·fluoro-2,3-dimethyl-4-D quinolinol Polyphosphoric acid (10 g. 8 g) was heated to 160 ° C, and then dropped into 4 -Third -18- (15) (15) 1320782 a mixture of butyl-2-fluoroaniline (1.89 g, 11.3 mmol) and ethyl 2-methylacetate (1.96 g, 13.5 mmol), Stirring was carried out for 3 hours at temperature. After the reaction mixture was cooled, water (50 m 1 ) was added and extracted twice with ethyl acetate (50 ml). The organic layer was combined, washed with water, and the organic layer was evaporated under reduced pressure to give a concentrated residue. After recrystallization from ethyl acetate-n-hexane, 0.97 g of 6-t-butylbutyl-8-fluoro-2,3-dimethyl-4-quinolinol was obtained as white crystals. The yield was 34.7%. FAB-MS; m/z 248 ( M + H ) 10: 'H NMR ( CDC13 ) S1.33 (9H, s, t-Bu) , 2.13 (3H, s, CH3) , 2·52 (3Η , s , CH3), 7.33 (1H, dd, J = 12.9, 2.2Hz, H3-aromatic), 8 · 1 0 ( 1 H,d,J = 1. 5 Hz, H5 - aromat ic ), 8.93 ( 1H, bs , NH). [Example 5] 6-Terti-butyl-8-fluoro-2,3-dimethyl-4-oxime quinolol 4-tert-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) Soluble in toluene (120 ml), and distilled into 2-methylethylacetate ethyl acetate (5.75 ml, 40_6 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and heated under reflux in a reaction apparatus with a Din Stank apparatus. hour. After allowing to cool, the reaction mixture was poured into saturated soda water and extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous magnesium sulfate. After the solid matter was filtered, the filtrate was concentrated to yield 5.99 g of a brown oil. This was dissolved in xylene (155 ml), and the mixture was stirred under heating at 160 ° C for 1 hour. After cooling the reaction mixture, the solvent was concentrated, and purified by silica gel column chromatography (ethyl acetate-Jin-Jinyuan 1:1) to obtain 845 g of 6-second-butyl-8-fluoro-2'3. -2·19· (16) (16) 1320782 Methyl-4 - D quinolinol. The yield was 11.3%.
FAB-MS; m/z 248 ( M + H ) + ； *Η NMR ( CDC13 ) δΐ .33 ( 9Η > s > t-Bu ) ，2.13(3H，s，CH3) » 2.52 ( 3H ，s C H 3 ) ’ 7.33 ( 1H，dd，J=12.9，2.1Hz，H3-aromatic )，8 · 1 1 ( 1 H，d，J = 1 · 5 Η z，H 5 · ar o ma t i c ) ，8.92 ( 1H， bs，NH )。 [實施例6] 6-第三-丁基-8-氟-2，3-二甲基-4-乙酸基[]奎啉 將實施例5取得之6-第三-丁基-8-氟-2，3-二甲基-4-Q奎 啉酣（3_93g，15_9mmol)溶於 D 比陡（13ml，159mmol) 後，力□入無水醋酸（1 5ml，1 59mmol )，於80 °C下進行 加熱攪拌1小時。減壓下餾去溶媒吡啶與殘存之無水醋 酸，取得4.90g之油狀殘渣。將此溶於正-己烷（4.5ml )， 置入晶種，室溫下，緩緩進行攪拌12小時，大量取得白 色結晶。過濾結晶後，以冷正-己烷（4.5ml )快速洗淨， 室溫下使取得結晶進行乾燥12小時，取得2.53 g之6-第 三-丁基-8·氟-2，3-二甲基-4-乙酸基D奎啉白色結晶。收率 9 0.1%。 FAB-MS; m/z 290 ( M + H ) + ； 'Η NMR ( CDC13 ) δ1·38 ( 9H，s，t-Bu ) ，2‘26 ( 3H，s，Acetyl ) · 2.52 ( 3H，s，CH3 ) ，2.75 ( 3H，s，CH3 ) ，7.37 ( 1H，d， J=1.9Hz，Hs-aromatic ) ，7.43 ( 1H，dd，J = 12.9，1.9 Hz ，H7-aromatic ) ° -20- (17) (17)1320782 [實施例7] 4-第三-戊基-2-氟苯胺 於玻璃製之反應容器中加入攪拌子與5.50ml 36%鹽酸 ，溶於氯化鋅（5.24g’0.0383m〇l)。攪拌之同時，依序 加入2-氟苯胺（l〇.〇ml ’ 〇.l〇4mol )及第三-戊基醇（ 1 1,4ml * 0.104mol )，將此玻璃容器置入不銹鋼製之耐壓 容器，使內部壓力不外洩進行密封後，加熱至190 t進 行攪拌反應。初期壓力約爲5氣壓。此反應持續72個小時 。確定溫度充份降低後’打開壓力容器。加入醋酸乙酯（ 20 0ml )，攪拌後均勻整體後加入水（200ml )，以氫氧化 鈉進行中和調整pH爲9。'濾別大量析出之茶色固體之後， 使濾液進行分濾後，再度水洗有機層9濃縮取得有機層後 ，取得17.5g之茶褐色油狀物質。此油狀物質以矽膠柱體 層析法（正·己烷-醋酸乙酯1〇:1)進行精製，分離後，取 得9.22g之4-第三-戊基-2-氟苯胺。收率49.0%。又，結構 確認係做成部份採樣後，進行胺基之乙醯化做成乙醯體後 進行之。 4-第三-戊基-2-氟-N-乙醯苯胺 EI-MS; m/z 224 (M + H) +； 'H NMR(CDC13) δθ.67 (3Η，t，J = 7.3Hz，amyl-CH2CH3 ) ，1.25 ( 6H，s， amyl-CH3 ) ，1.60 ( 2H，q，J = 7.5Hz > amyl-CH2CH3 ) ’ 2.21 ( 3H，s，Acetyl-CH3 ) ，7.03 ( 1H，dd，J=17.1， 1.9Hz，H3) ，7.07 ( 1H，dd，J = 8.3，2.0Hz，H5 ) · 7.29 (1H，brs，NH) ，8 · 1 6 ( 1 H，dd，J= 8 · 5，8 · 5 Hz，H6 ) -21 - (18) (18)1320782 [實施例8] 6-第三-戊基-8-氟-2，3-二甲基-4-D奎啉酚 將4-第三.戊基-2-氟苯胺（2.00g，ll.lmmol)溶於甲 苯（15ml )，加入2-甲基乙醯醋酸乙酯（1 .56ml ’ 11 .lmmol )與三氟化硼二乙醚絡合體（5〇ml ) ’以燒瓶上 部具有塡入分子篩之迴流管反應裝置進行加熱迴流6小 時。反應液回復至室溫，依序加入二苯醚（5 0ml )’六氫 化吡啶（〇.7ml)及無水醋酸（0.3ml) ’進行攪拌30分 鐘。再度進行加溫後’餾去溶媒甲苯。更使反應溫度昇溫 至250 °C，於該溫度保持1〇分鐘，完成環化反應。將反 應液於室溫下冷卻，靜置1晚後進行結晶化。濾別析出之 褐色結晶後’以正-己烷進行洗淨’減壓’室溫下乾燥取 得褐色結晶3個小時後’取得1.18g之6-第三-戊基-8-氟-2 ，3 -二甲基-4-卩奎啉酚。收率41.0%。 FAB-MS; m/z 263 ( M + H ) + ； *H NMR ( CDC13 ) δ0 64 ( 3 Η，t，J = 7.6Ηz，amy 1 · CΗ2CΗ3 ) ’ 1.31 ( 6H ’ s ，amyl-CH3 ) ’ 1.65 ( 2H > q，J = 7.3Hz，amyl-CH2CH3 ) ，2.14 ( 3H，s，2-CH3 ) ，2.48 ( 3H，s，3-CH3 ) ，2.52 (3H，s，CH3 ) ，7.29 ( 1H，dd ’ J= 12 · 9，1 · 9 Η z，H 7- aromatic ) ，8 · 0 5 ( 1 H，d，J = 1 · 2 Η z，H 5 - ar o m a t i c )， 8.5 1 ( 1 H，bs，NH )。 [實施例9] 6-第三-戊基-8-氟-2，3-二甲基-4-乙酸基咱琳 將實施例8取得之6-第三·戊基-8·氟-2，3-二甲基-4-喹 -22- (19) (19)1320782 啉酚（1.10g，4.21mmol)溶於吡啶（3.4ml，42.1mmol) 後，加入無水醋酸（6.0ml，63.6mmol)，於80 °C下進行 加熱攪拌2小時。減壓下餾去溶媒吡啶與殘存之無水醋 酸，加入醋酸乙酯（100ml )之後，依序以飽和食鹽水， 1 0 %檸檬酸水及飽和食鹽水進行洗淨，再以無水硫酸鎂 進行乾燥有機層，過濾固形物後’減壓下濃縮濾液。以矽 膠柱體層析法（正-己烷-醋酸乙酯8:1)進行精製，分離取 得油狀濃縮殘渣後，取得1.22g之6-第三-戊基-8-氟-2，3_ 二甲基-4-乙酸基D奎啉。收率9 5.9%。 FAB-MS; m/z 3 0 4 ( M +Η ) + ; 1 Η NM R ( C D C 13 ) δ0_68 ( 3Η，t，J = 7.3Hz，amyl-CH2CH3 ) ，1.34 ( 6H，s ，amyl-CHs ) ，1.69 ( 2H，q，J = 7.6Hz * amyl-CH2CH3 ) ，2.26 ( 3H，s，Acetyl-CH3 ) ，2.52 ( 3H，s，2-CH3 ) ，2.75 ( 3H，s’ 3-CH3 ) ，7.32 ( 1H，d > J=1.7Hz，H5- aromatic ) ，7 · 3 7 ( 1 H ’ d d，J = 1 2 · 9，2.0 Η z，H 7 - ar o m at i c )。 [實施例10] 6-第三-丁基-8-氟-2’ 3-二甲基-4-甲氧基羰氧 基D奎啉 將實施例5取得之6-第三-丁基-8-氟_2，3-二甲基-4-喹 啉酚（l.OOg，4.05mmol)溶於乾燥四氫呋喃（20ml)後 ，冰冷下，氣氣氛下加入60%氫化鈉（160mg)，回復至 室溫後，進行攪拌1小時至停止產生氣體爲止。再度冰 冷後，滴入溶於乾燥四氫呋喃（5ml)之氯甲酸甲酯（ -23- (20) (20)1320782 376ml，4.86mmoI)，更於室溫下持續攪泮3小時β反應 液置於冰水，將此以醋酸乙酯（50ml)進行萃取之。以無 水硫酸鎂進行乾燥有機層，濾別固形物後，減壓下濃縮濾 液。以矽膠柱體層析法（醋酸乙酯-正·己烷3:1 )精製取得 濃縮之殘渣後，取得784mg之6-第三-丁基_8_氟·2, 3_二甲 基-4-甲氧基羰氧基D奎啉。收率63.5%。 FAB-MS; m/z 306 ( M + H ) + ； 'H NMR ( CDC13 ) δ 1 .3 8 ( 9H » s’ t-Bu ) ’ 2.32 ( 3H，s’ 2-CH3) ，2.76 ( 3H ’ s，3 -CH3 ) ，4.00 ( 3H，s’ OCH3 ) ，7.42 ( 1H，d ，J = 1.9 H z，Hs-aromatic ) ’ 7.45 ( 1 H > dd，J = 1 2.9， 1 _ 9 Η z，H 7 · ar o m at i c )。 [實施例11] 6-第三-丁基-8-氟-2，3-二甲基-4-乙氧基甲氧 基D奎啉 將實施例5取得之6-第三-丁基-8-氟-2，3-二甲基-4-B奎 啉酣（l.OOg，4.05mmol)溶於乾燥四氫咲喃（20ml)， 冰冷下，於氬氣氛中加入60%氫化鈉（320mg )，回復至 室溫後’進行攪拌1小時至停止產生氣體爲止。再度冰 冷後，滴入溶於乾燥四氫呋喃（5ml)之乙氧基甲基氯化 物（761ml，8.10mmol)，更於室溫下持續攪泮6 小時。 反應液置於冰水，將此以醋酸乙酯（50ml )進行萃取之。 以無水硫酸鎂乾燥有機層，濾別固形物後，減壓下濃縮濾 液。以矽膠柱體層析法（醋酸乙酯-正-己烷3:1)精製取得 濃縮殘渣後，取得145mg之6-第三·丁基-8·氟-2，3·二甲 -24- (21) (21)1320782 基-4-乙氧基甲氧基D奎啉。收率1 1.7%。 FAB-MS; m/z 306 ( M + H ) + ； *H NMR ( CDCI3 ) δΐ .21 ( 3H，t，J = 7.1 Hz ) * 1.36 ( 9H « s * t-Bu ) ，2.17 (3H > s> 2-CH3 ) ，2.53(3H，s，3-CH3) 3.51 ( 2H > q > J = 7.1 Hz ) ’ 5.53 (2H，s) ’ 7.37 ( 1H，dd，J=17.3， 2.4Hz，H7-aromatic ) ，8 · 2 1 ( 1 H，d，J = 2 · 4 Η z，H 5 - aromatic ) o [實施例12] 4-環己基-2-氟苯胺 於玻璃製反應容器中加入攪拌子與5.50ml之36 %鹽酸 後，溶於氯化鋅（5.24g，〇.〇383mol)。攪拌之同時依序 加入2-氟苯胺（10.0ml，0.104mol)及環己醇（10.4ml， 〇. l〇4mol )，將此玻璃容器置入不銹鋼製之耐壓容器後， 使內部壓力不會外漏後進行密封，加熱至190 °C後，進 行攪拌反應之。初期壓力約爲5氣壓。此反應持續進行72 個小時。確定溫度充份降低後，打開壓力容器。加入醋酸 乙酯（200ml)，攪拌後整體呈均勻後加入水（200ml)， 以氫氧化鈉中和後調整PH爲9。濾別大量析出之茶色固體 後，使濾液進行分液’再度水洗有機層。濃縮取得之有機 層後，取得15.1g之茶褐色油狀物質。此者以矽膠柱體層 析法（醋酸乙酯·正-己烷1:5)進行精製後，取得6.63g之 4-環己基-2-氟苯胺。收率33.0%» EI-MS; m/z 194 ( M + H) + ; NMR ( CDC13) δ1·34 (6Η，m) ，1·82 ( 4H，m) ，2.39 ( 1H，m) » 3.55 ( -25- (22) (22)1320782 2H > b s > N H2 ) ，6.73 ( 1 H 5 dd，J = 1 7. 1 > 8.1Hz ) ，6.78 (1H，dd，J = 8.0，1.9Hz ) ，6.84 ( 1H，dd，J= 12.4 - 1.7 H z )。 [實施例13] 6-環己基-8-氟-2，3-二甲基-4-ti奎啉酚 將4-環己基-2·氟苯胺（5.00g，25.9m mol)溶於甲苯 (100ml )後，力□入2·甲基乙醯醋酸乙酯（4.77ml， 33.7mmol)與對甲苯磺酸1水合物（50mg)，於具有丁· 斯達克裝置之反應裝置進行加熱迴流3小時。反應液回 復至室溫後，依序加入二苯醚（50ml )，六氫化吡啶（ 2.0ml)及無水醋酸（1.0ml)，攪拌30分鐘。再度進行 加溫後，餾去溶媒甲苯，更使反應溫度昇溫至25 0 °C， 該溫度下保持1〇分鐘，完成環化反應。將反應液於室溫 下放冷後，靜置1晚之後進行結晶化。濾別析出之白色結 晶後，以正-己烷洗淨後，將取得白色結晶於減壓，室溫 下進行乾燥3小時後，取得3.56g之6-環己基-8-氟-2’ 3-二甲基-4-£1奎啉酚。收率50.4%。 FAB-MS; m/z 274 ( M + H ) + ； NMR ( d6-DMSO) 61 .40 ( 6H > m ) ，1.60(4H，m) ，2.41(3H，s) > 7.41 (lH，d，J=12.9) ，7.68(lH，s) ，11.25 (lH，s)。 [實施例14] 6-環己基-8-氟-2，3·二甲基-4·乙酸基B奎啉 將實施例5取得之6·環己基-8·氟-2 ’ 3-二甲基-4-D奎啉 酚（3.00g，ll.Ommol)溶於 D比症（8.70ml，llOmmol)， -26- (23) 1320782 加入無水醋酸（1 1 .2ml，1 lOmmol )，於80 °C下進行加 熱攪拌2小時。減壓下餾去溶媒吡啶及殘存之之無水醋 酸，加入醋酸乙酯（l〇〇ml )後，依序以飽和食鹽水， 1 〇%檸檬酸水及飽和食鹽水進行洗淨後，以無水硫酸鎂乾 燥有機層，過濾固形物後，減壓下濃縮濾液。將取得油狀 濃縮殘渣以矽膠柱體層析法（正-己烷-醋酸乙酯8:1 )進行 精製，分離後，取得3.17g之6-環己基-8-氟·2，3-二甲基-4 -乙酸基鸣啉。收率9 1.2 %。 FAB-MS; m/z 3 17( M + H ) + ； 'H NMR ( CDC13 ) δΐ.27 ( 2H 5 m) ，1.45 ( 4H，m) ，1.90 ( 4H，m)， 2.26 ( 3H > s，Acetyl-CH3 ) ，2.25 ( 3H ’ s) ，2.52 ( 3H ，s ) ，2.75 ( 3H，s) ，2.64 ( 1H > m ) ，7.25 ( 2H，m -27-FAB-MS; m/z 248 ( M + H ) + ; *Η NMR ( CDC13 ) δΐ .33 ( 9Η > s > t-Bu ) , 2.13(3H,s,CH3) » 2.52 ( 3H ,s CH 3 ) ' 7.33 ( 1H, dd, J = 12.9, 2.1 Hz, H3-aromatic ), 8 · 1 1 ( 1 H, d, J = 1 · 5 Η z, H 5 · ar o ma tic ) , 8.92 (1H, bs, NH). [Example 6] 6-Terti-butyl-8-fluoro-2,3-dimethyl-4-acetic acid [] quinoline 6-tri-butyl-8-fluoro obtained in Example 5. -2,3-Dimethyl-4-Q-quinoline oxime (3_93 g, 15_9 mmol) was dissolved in D (thickness (13 ml, 159 mmol), and then poured into anhydrous acetic acid (15 ml, 1 59 mmol) at 80 ° C Heating and stirring were carried out for 1 hour. The solvent pyridine and the residual anhydrous acetic acid were distilled off under reduced pressure to obtain 4.90 g of an oily residue. This was dissolved in n-hexane (4.5 ml), seeded, and stirred at room temperature for a period of 12 hours to obtain a large amount of white crystals. After filtration and crystallization, it was quickly washed with cold n-hexane (4.5 ml), and the crystals were dried at room temperature for 12 hours to obtain 2.53 g of 6-t-butyl-8-fluoro-2,3-di. Methyl-4-acetoxy D-quinoline white crystals. Yield 9 0.1%. FAB-MS; m/z 290 ( M + H ) + ; 'Η NMR ( CDC13 ) δ1·38 ( 9H, s, t-Bu ) , 2'26 ( 3H, s, Acetyl ) · 2.52 ( 3H, s , CH3), 2.75 (3H, s, CH3), 7.37 (1H, d, J=1.9Hz, Hs-aromatic), 7.43 (1H, dd, J = 12.9, 1.9 Hz, H7-aromatic) ° -20- (17) (17) 1320782 [Example 7] 4-Terti-pentyl-2-fluoroaniline was added to a glass reaction vessel with a stir bar and 5.50 ml of 36% hydrochloric acid dissolved in zinc chloride (5.24 g' 0.0383m〇l). While stirring, 2-fluoroaniline (l〇.〇ml '〇.l〇4mol) and third-pentyl alcohol (1 1,4ml * 0.104mol) were sequentially added, and the glass container was placed in stainless steel. The pressure vessel is sealed so that the internal pressure is not leaked and then heated to 190 t for stirring. The initial pressure is about 5 atmospheres. This reaction lasted for 72 hours. After confirming that the temperature is sufficiently reduced, the pressure vessel is opened. Ethyl acetate (200 ml) was added, and after stirring, the whole was uniformly added, and water (200 ml) was added thereto, and the mixture was neutralized with sodium hydroxide to adjust the pH to 9. After filtering a large amount of the precipitated brown solid, the filtrate was subjected to filtration, and the organic layer 9 was again washed with water to obtain an organic layer, and then 17.5 g of a brown oily substance was obtained. This oily substance was purified by silica gel column chromatography (n-hexane-ethyl acetate 1 : 1), and after separation, 9.22 g of 4-tri-pentyl-2-fluoroaniline was obtained. The yield was 49.0%. Further, the structure confirmation was carried out after partial sampling, and the amino group was converted into an acetamidine. 4-T-pentyl-2-fluoro-N-ethylaniline EI-MS; m/z 224 (M + H) +; 'H NMR (CDC13) δ θ.67 (3 Η, t, J = 7.3 Hz ,amyl-CH2CH3),1.25 (6H,s,amyl-CH3), 1.60 ( 2H,q,J = 7.5Hz > amyl-CH2CH3 ) ' 2.21 ( 3H,s,Acetyl-CH3 ) ,7.03 ( 1H,dd , J=17.1, 1.9Hz, H3), 7.07 (1H, dd, J = 8.3, 2.0Hz, H5) · 7.29 (1H, brs, NH), 8 · 1 6 ( 1 H, dd, J = 8 · 5,8 · 5 Hz, H6 ) -21 - (18) (18) 1320782 [Example 8] 6-Terti-pentyl-8-fluoro-2,3-dimethyl-4-D quinol 4-Trisylpentyl-2-fluoroaniline (2.00 g, 11 mmol) was dissolved in toluene (15 ml), and ethyl 2-methylacetateacetate (1.56 ml '11.lmmol) and trifluorobenzene were added. The boron dicarboxylate complex (5 〇 ml ) was heated and refluxed for 6 hours with a reflux tube reactor equipped with a molecular sieve in the upper portion of the flask. The reaction solution was returned to room temperature, and diphenyl ether (50 ml) <RTI ID=0.0>> After heating again, the solvent toluene was distilled off. Further, the reaction temperature was raised to 250 ° C, and the temperature was maintained at this temperature for 1 Torr to complete the cyclization reaction. The reaction solution was cooled at room temperature, allowed to stand for 1 night, and then crystallized. After filtering out the precipitated brown crystals, 'washing with n-hexane', decompression, drying at room temperature to obtain brown crystals for 3 hours, and obtaining 1.18 g of 6-tri-pentyl-8-fluoro-2. 3-Dimethyl-4-indolyl phenol. The yield was 41.0%. FAB-MS; m/z 263 ( M + H ) + ; *H NMR ( CDC13 ) δ0 64 ( 3 Η,t,J = 7.6Ηz, amy 1 · CΗ2CΗ3 ) ' 1.31 ( 6H ' s ,amyl-CH3 ) ' 1.65 ( 2H > q, J = 7.3Hz, amyl-CH2CH3 ) , 2.14 ( 3H, s, 2-CH3 ) , 2.48 ( 3H, s, 3-CH3 ) , 2.52 (3H, s, CH3 ) , 7.29 (1H, dd ' J = 12 · 9,1 · 9 Η z, H 7- aromatic ) , 8 · 0 5 ( 1 H,d,J = 1 · 2 Η z,H 5 - ar omatic ), 8.5 1 ( 1 H, bs, NH ). [Example 9] 6-Third-pentyl-8-fluoro-2,3-dimethyl-4-acetic acid phthalocyanine 6-Third-pentyl-8·fluoro-2 obtained in Example 8. ,3-dimethyl-4-quino-22-(19) (19)1320782 phenol (1.10 g, 4.21 mmol) dissolved in pyridine (3.4 ml, 42.1 mmol), then anhydrous acetic acid (6.0 ml, 63.6 mmol) The mixture was heated and stirred at 80 ° C for 2 hours. The solvent pyridine and the residual anhydrous acetic acid were distilled off under reduced pressure, and ethyl acetate (100 ml) was added thereto, followed by washing with saturated brine, 10% citric acid water and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. Purification by gel column chromatography (n-hexane-ethyl acetate 8:1), separation of oily residue was obtained, and 1.22 g of 6-tri-pentyl-8-fluoro-2,3_ was obtained. Dimethyl-4-acetoxy D-quinoline. The yield was 9.9%. FAB-MS; m/z 3 0 4 ( M +Η ) + ; 1 Η NM R ( CDC 13 ) δ0_68 ( 3Η, t, J = 7.3Hz, amyl-CH2CH3 ) , 1.34 ( 6H, s , amyl-CHs ), 1.69 ( 2H,q,J = 7.6Hz * amyl-CH2CH3 ) , 2.26 ( 3H,s,Acetyl-CH3 ) , 2.52 ( 3H,s,2-CH3 ) , 2.75 ( 3H,s' 3-CH3 ) , 7.32 ( 1H, d > J = 1.7 Hz, H5- aromatic ) , 7 · 3 7 ( 1 H ' dd, J = 1 2 · 9, 2.0 Η z, H 7 - ar om at ic ). [Example 10] 6-Terti-butyl-8-fluoro-2' 3-dimethyl-4-methoxycarbonyloxy D-quinoline The 6-t-butyl group obtained in Example 5 After 8-fluoro-2,3-dimethyl-4-quinolinol (1.0 g, 4.05 mmol) was dissolved in dry tetrahydrofuran (20 ml), 60% sodium hydride (160 mg) was added under ice-cooling, and the mixture was recovered. After reaching room temperature, stirring was carried out for 1 hour until the gas generation ceased. After re-cooling, methyl chloroformate (-23-(20) (20) 1320782 376 ml, 4.86 mmoI) dissolved in dry tetrahydrofuran (5 ml) was added dropwise, and the reaction mixture was further stirred at room temperature for 3 hours. Ice water was extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solid was filtered. The filtrate was concentrated under reduced pressure. After purifying the residue by gel column chromatography (ethyl acetate-n-hexane 3:1), 784 mg of 6-tri-butyl-8-fluoro-2,3-dimethyl- 4-methoxycarbonyloxy D-quinoline. The yield was 63.5%. FAB-MS; m/z 306 ( M + H ) + ; 'H NMR ( CDC13 ) δ 1 .3 8 ( 9H » s' t-Bu ) ' 2.32 ( 3H,s' 2-CH3) , 2.76 ( 3H ' s,3 -CH3 ) , 4.00 ( 3H,s' OCH3 ) , 7.42 ( 1H,d ,J = 1.9 H z,Hs-aromatic ) ' 7.45 ( 1 H > dd,J = 1 2.9, 1 _ 9 Η z, H 7 · ar om at ic ). [Example 11] 6-Terti-butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxy D-quinoline The 6-t-butyl group obtained in Example 5 8-Fluoro-2,3-dimethyl-4-B quinolinium (1.00 g, 4.05 mmol) was dissolved in dry tetrahydrofuran (20 ml). Under ice cooling, 60% sodium hydride was added under argon ( 320 mg), after returning to room temperature, ' stirring for 1 hour until the gas generation ceased. After chilling again, ethoxymethyl chloride (761 ml, 8.10 mmol) dissolved in dry tetrahydrofuran (5 ml) was added dropwise, and the mixture was further stirred at room temperature for 6 hours. The reaction solution was placed in ice water and extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and then filtered and evaporated. After purifying the residue by gel column chromatography (ethyl acetate-n-hexane 3:1), 145 mg of 6-t-butylbutyl-8·fluoro-2,3·dimethyl-24- (21) (21) 1320782 -4-ethoxymethoxy D-quinoline. Yield 1 1.7%. FAB-MS; m/z 306 ( M + H ) + ; *H NMR ( CDCI3 ) δΐ .21 ( 3H,t,J = 7.1 Hz ) * 1.36 ( 9H « s * t-Bu ) , 2.17 (3H > ;s> 2-CH3), 2.53(3H,s,3-CH3) 3.51 ( 2H > q > J = 7.1 Hz ) ' 5.53 (2H,s) ' 7.37 ( 1H,dd,J=17.3, 2.4 Hz, H7-aromatic ) , 8 · 2 1 ( 1 H, d, J = 2 · 4 Η z, H 5 - aromatic ) o [Example 12] 4-cyclohexyl-2-fluoroaniline in a glass reaction vessel After adding a stir bar and 5.50 ml of 36% hydrochloric acid, it was dissolved in zinc chloride (5.24 g, 〇.〇 383 mol). 2-fluoroaniline (10.0 ml, 0.104 mol) and cyclohexanol (10.4 ml, 〇.l〇4 mol) were sequentially added while stirring, and the glass container was placed in a pressure vessel made of stainless steel to prevent internal pressure. After leaking, it was sealed, heated to 190 °C, and stirred for reaction. The initial pressure is about 5 atmospheres. This reaction lasted for 72 hours. After confirming that the temperature is sufficiently reduced, the pressure vessel is opened. Ethyl acetate (200 ml) was added, and after stirring, the whole was homogeneous, and water (200 ml) was added thereto, and the mixture was adjusted to pH 9 after neutralization with sodium hydroxide. After filtering a large amount of the precipitated brown solid, the filtrate was subjected to liquid separation to wash the organic layer again. After concentrating the obtained organic layer, 15.1 g of a brown oily substance was obtained. This was purified by a silica gel column chromatography (ethyl acetate-n-hexane 1:5) to obtain 6.63 g of 4-cyclohexyl-2-fluoroaniline. Yield 33.0%» EI-MS; m/z 194 ( M + H) + ; NMR (CDC13) δ1·34 (6Η,m) ,1·82 ( 4H,m) , 2.39 ( 1H,m) » 3.55 ( -25- (22) (22)1320782 2H > bs > N H2 ) , 6.73 ( 1 H 5 dd, J = 1 7. 1 > 8.1 Hz ) , 6.78 (1H, dd, J = 8.0, 1.9 Hz), 6.84 (1H, dd, J = 12.4 - 1.7 H z ). [Example 13] 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-tiquinolinol 4-cyclohexyl-2·fluoroaniline (5.00 g, 25.9 mmol) was dissolved in toluene ( After 100 ml), a solution of 2·methylacetamidineacetate (4.77 ml, 33.7 mmol) and p-toluenesulfonic acid monohydrate (50 mg) was heated and refluxed in a reaction apparatus having a D. Stark apparatus. hour. After the reaction mixture was returned to room temperature, diphenyl ether (50 ml), hexahydropyridine (2.0 ml) and anhydrous acetic acid (1.0 ml) were sequentially added and stirred for 30 minutes. After heating again, the solvent toluene was distilled off, and the reaction temperature was raised to 25 ° C, and the temperature was maintained for 1 minute to complete the cyclization reaction. After the reaction solution was allowed to stand at room temperature, it was allowed to stand for 1 night and then crystallized. The precipitated white crystals were filtered, washed with n-hexane, and then white crystals were obtained under reduced pressure. After drying at room temperature for 3 hours, 3.56 g of 6-cyclohexyl-8-fluoro-2' 3 was obtained. - dimethyl-4-£1 quinolinol. The yield was 50.4%. </ RTI> <RTIgt; d, J = 12.9), 7.68 (lH, s), 11.25 (lH, s). [Example 14] 6-Cyclohexyl-8-fluoro-2,3·dimethyl-4·acetic acid B-quinoline The 6·cyclohexyl-8·fluoro-2′ 3-dimethyl group obtained in Example 5 Base-4-D quinolinol (3.00 g, ll. Ommol) dissolved in D ratio (8.70 ml, 11 mmol), -26- (23) 1320782 Added anhydrous acetic acid (11.2 ml, 1 lOmmol) at 80 Heating and stirring were carried out for 2 hours at °C. The solvent pyridine and the residual anhydrous acetic acid were distilled off under reduced pressure, and ethyl acetate (10 ml) was added thereto, followed by washing with saturated brine, 1% citric acid water and saturated saline, followed by anhydrous The organic layer was dried over magnesium sulfate, and the solid was filtered. The oily concentrated residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 8:1). After separation, 3.17 g of 6-cyclohexyl-8-fluoro-2,3-di was obtained. Methyl-4-acetic acid morphine. The yield was 9 1.2%. FAB-MS; m/z 3 17( M + H ) + ; 'H NMR ( CDC13 ) δΐ.27 ( 2H 5 m) , 1.45 ( 4H,m) , 1.90 ( 4H,m), 2.26 ( 3H > s, Acetyl-CH3), 2.25 ( 3H ' s) , 2.52 ( 3H , s ) , 2.75 ( 3H, s) , 2.64 ( 1H > m ) , 7.25 ( 2H , m -27-