[0002] 先前，由飽和醇化合物轉換為對應之硫醚化合物的方法，已知將羥基轉換為脫離基後，以硫醇(thiol)化合物進行親核取代反應之方法，或使用三苯基膦之光延反應。 [0003] 具體而言，已知許多(1)以三溴化磷溴化後，硫醚化之方法(非專利文獻1)；(2)於三乙基胺存在下，以甲基磺醯氯進行甲基磺醯化後，硫醚化之方法(非專利文獻2)等階段性地進行由飽和醇化合物轉換為對應之硫醚化合物的方法。 [0004] 然而，於該些方法中，為了在第一階段反應後進行萃取操作，而在萃取操作中使用大量有機溶劑，以及需要長時間操作等點上，以工業製造方法而言存在問題。 [0005] 並且，雖然已知使用三苯基膦與偶氮二羧酸衍生物之光延反應(非專利文獻3)，但作為工業製造方法，存在難以去除副產之大量低溶解性之氧化三苯基膦的問題。 [0006] 進而，雖然已知p-甲苯磺醯化後，以一鍋方式進行硫醚化之方法(非專利文獻4)，但起始物質僅限於羥基部分具高反應性之炔丙醇化合物，而將飽和醇化合物作為起始物質者，尚未為人所知曉。此處，所謂以一鍋方式合成，係藉由將反應物依序投入至反應容器而進行多階段之反應的合成手法。 [先前技術文獻] [非專利文獻] [0007] 非專利文獻1：Australian Journal of Chemistry, 40(2), 281-290 (1987) 非專利文獻2：Journal of Organic Chemistry, 68(11), 4215-4234 (2003) 非專利文獻3：Journal of the American Chemical Society, 137(48), 15098-15101 (2015) 非專利文獻4：Synlett, (20), 3067-3070 (2005)[0002] Previously, a method for converting a saturated alcohol compound into a corresponding thioether compound was known as a method of converting a hydroxyl group to a leaving group and then performing a nucleophilic substitution reaction with a thiol compound, or using triphenylphosphine. Light extension reaction. [0003] Specifically, many (1) methods of thioetherification after bromination with phosphorus tribromide (non-patent document 1) are known; (2) in the presence of triethylamine, methylsulfonium After the methyl sulfonation of chlorine, the method of thioetherification (non-patent document 2) and the like convert the saturated alcohol compound into the corresponding thioether compound stepwise. [0004] However, in these methods, in order to perform an extraction operation after the first-stage reaction, a large amount of organic solvent is used in the extraction operation, and a long-time operation is required, which has problems in terms of industrial manufacturing methods. [0005] In addition, although a photofinishing reaction using triphenylphosphine and an azodicarboxylic acid derivative is known (Non-Patent Document 3), as an industrial manufacturing method, there are a large number of low-solubility trioxide which is difficult to remove by-products. The problem with phenylphosphine. [0006] Furthermore, although a method of performing thioetherification in a one-pot manner after p-toluenesulfonation (Non-Patent Document 4) is known, the starting material is limited to a propargyl alcohol compound having a highly reactive hydroxyl moiety. The use of saturated alcohol compounds as starting materials has not been known. Here, the so-called one-pot synthesis is a synthesis method in which a multi-stage reaction is performed by sequentially putting reactants into a reaction vessel. [Prior Art Literature] [Non-Patent Literature] [0007] Non-Patent Literature 1: Australian Journal of Chemistry, 40 (2), 281-290 (1987) Non-Patent Literature 2: Journal of Organic Chemistry, 68 (11), 4215 -4234 (2003) Non-Patent Document 3: Journal of the American Chemical Society, 137 (48), 15098-15101 (2015) Non-Patent Document 4: Synlett, (20), 3067-3070 (2005)
[發明之概要] [發明欲解決之課題] [0008] 本發明的課題為提供一種於工業而言優良的方法，其係不使用三苯基膦等之磷化合物，而以一鍋方式進行由飽和醇化合物成為對應之硫醚化合物的2階段反應的方法。 [解決課題之手段] [0009] 本發明者們潛心研究之結果，發現將飽和醇化合物磺醯化作為第1步驟，之後不進行萃取等後處理操作，於相同反應容器加入2-巰基苯并噻唑衍生物作為第2步驟，藉由於二相系統進行反應，可有效率地製造對應之硫醚化合物。 [0010] 即，本發明為，式(1) [0011][0012] 所表示之化合物，於鹼存在下，使用R1
SO2
Cl所表示之磺醯氯化物而成為式(2) [0013][0014] 所表示之化合物的第1步驟，以及，其後，使用式(3)所表示之2-巰基苯并噻唑衍生物，使式(2)所表示之化合物成為式(4) [0015][0016][0017] 所表示之化合物的第2步驟，而以一鍋方式製造式(4)所表示之化合物之方法。 [0018] 此處，R1
表示可經1個或複數個鹵素原子所取代之C1
～C4
烷基(惟，鹵素原子的取代數限於化學之可能範圍)，或者表示可允許重覆經選自由C1
～C4
烷基、鹵素原子及硝基所組成的群組的1～2個基於任意位置取代之苯基；R2
表示氫原子(即，2-苯并噻唑基為無取代)，或者表示可允許重覆選自由C1
～C4
烷基、鹵素原子、C1
～C4
烷氧基、氰基及硝基所組成的群組的1～2個基；X表示氫原子、鋰原子、鈉原子、鉀原子或1/2鋅原子。 [發明之效果] [0019] 根據本發明，可不使用三苯基膦等之磷化合物，而以一鍋方式、且以實際的產率進行由飽和醇化合物成為對應之硫醚化合物的2階段反應。該以一鍋方式的製造方法，因為可以減少後處理之溶劑量或作業時間，而可削減廢棄物量或能源消耗量，係一種低環境負荷且低成本於工業而言優良的製造方法。[Summary of the Invention] [Problems to be Solved by the Invention] [0008] The object of the present invention is to provide an industrially superior method that does not use a phosphorus compound such as triphenylphosphine, and performs a one-pot method A saturated alcohol compound is a two-stage reaction method of a corresponding thioether compound. [Means for Solving the Problem] [0009] As a result of intensive research, the present inventors found that sulfonylation of a saturated alcohol compound as the first step, and subsequent post-processing operations such as extraction were not performed, and 2-mercaptobenzo was added to the same reaction vessel. As a second step, a thiazole derivative can react with a two-phase system to efficiently produce a corresponding thioether compound. [0010] That is, the present invention is: (1) The compound represented by the formula (2) in the presence of a base using a sulfonium chloride represented by R 1 SO 2 Cl The first step of the compound represented by the formula, and thereafter, using the 2-mercaptobenzothiazole derivative represented by the formula (3) to make the compound represented by the formula (2) into the formula (4) ] [0016] The second step of the compound represented by the method of producing the compound represented by the formula (4) in a one-pot manner. [0018] Here, R 1 represents a C 1 to C 4 alkyl group which may be substituted by one or a plurality of halogen atoms (however, the substitution number of the halogen atom is limited to the possible range of chemistry), or it is allowed to repeat the process. 1 or 2 phenyl groups substituted at any position selected from the group consisting of a C 1 to C 4 alkyl group, a halogen atom, and a nitro group; R 2 represents a hydrogen atom (that is, the 2-benzothiazolyl group is unsubstituted ), Or it is allowed to repeat 1 to 2 groups selected from the group consisting of a C 1 to C 4 alkyl group, a halogen atom, a C 1 to C 4 alkoxy group, a cyano group, and a nitro group; X represents hydrogen Atom, lithium atom, sodium atom, potassium atom or 1/2 zinc atom. [Effects of the Invention] According to the present invention, a two-stage reaction from a saturated alcohol compound to a corresponding thioether compound can be performed in a one-pot manner at a practical yield without using a phosphorus compound such as triphenylphosphine. . This one-pot manufacturing method can reduce the amount of post-treatment solvent or working time, and can reduce the amount of waste or energy consumption. It is a manufacturing method that is low in environmental load and low in cost for industrial use.
[0020] 本發明係，作為第1步驟之磺醯化，及作為第2步驟之2-巰基苯并噻唑衍生物之加成的2階段反應，於1個反應容器內連續實施者。以下，依序說明該2階段反應之適宜實施態樣。 (第1步驟) 本發明之第1步驟雖如前述般使用R1
SO2
Cl所表示之磺醯氯化物，其中較佳為使用C1
～C4
烷基磺醯氯化物或可經1～2個C1
～C4
烷基所取代之苯磺醯氯化物，更佳為使用甲基磺醯氯或p-甲苯磺醯氯，最佳為使用甲基磺醯氯。相對於基質的飽和醇，其較佳的使用量為1.0～2.0莫耳當量，更佳為1.05～1.3莫耳當量。 [0021] 作為本發明第1步驟中所使用的鹼，無特別限定，較佳為有機鹼，例如可使用三級胺。其中較佳為如三乙基胺或二異丙基乙基胺般的三烷基胺，最佳為三乙基胺。相對於基質的飽和醇，其使用量較佳為1.0～2.0莫耳當量，更佳為1.05～1.6莫耳當量。 [0022] 作為本發明第1步驟中所使用的溶劑，無特別限定，例如可列舉，四氫呋喃、乙腈、丙酮、甲苯、二氯甲烷、二甲基甲醯胺及二甲基乙醯胺。該些溶劑可單獨使用，亦可組合使用。該些中較佳為甲苯。相對於基質的飽和醇，其合適的使用量為3～10 v/w，更佳為4～8 v/w。 [0023] 本發明第1步驟之反應溫度，雖依所使用之溶劑而相異，較佳為0～45℃，較佳的反應時間為30分～2小時。 [0024] 本發明第1步驟之反應結束後可添加水，相對於基質的飽和醇，其量較佳為1～5 v/w，更佳為1～3 v/w。 (第2步驟) 於本發明的第2步驟中所使用的式(3)所表示之2-巰基苯并噻唑衍生物，取代基R2
表示氫原子，或者表示選自由C1
～C4
烷基、鹵素原子、C1
～C4
烷氧基、氰基及硝基所組成的群組的1～2個基，其中較佳為氫原子及1個鹵素原子，特佳為氫原子。又，X為氫原子、鋰原子、鈉原子、鉀原子或1/2鋅原子，其中較佳為氫原子及鈉原子，特佳為鈉原子。相對於基質的飽和醇，其使用量較佳為1.0～2.0莫耳當量，更佳為1.1～1.4莫耳當量 [0025] 本發明第2步驟之反應溫度，雖依所使用之溶劑而相異，較佳為60～90℃，較佳的反應時間為4～12小時。 [0026] 於第1步驟較佳的磺醯氯化物或鹼之使用量、溶劑之使用量、反應溫度、反應時間，及添加之水的量，於第2步驟較佳之2-巰基苯并噻唑衍生物之使用量、反應溫度及反應時間，一般而言如上所述，但所屬技術領域中具有通常知識者，可參考該些範圍或後述之實施例，因應起始物質的種類或反應裝置等個別的前提條件，而決定適當之反應條件。視需要可藉由試行而進行條件的最佳化。 [實施例] [0027] 於本實施例，使用以下之機器等進行分析。 [0028] 氣相色譜法(GC) 裝置：安捷倫科技(Agilent Technologies)公司 7890B GC system 管柱：DB-624(長度：30.0 m、內徑：0.32 mm、膜厚：1.80μm) 注入口溫度：180℃ 檢出器溫度：260℃ 初期溫度：80℃ 初期滯留時間：2分鐘 升溫速度：18℃/分 最終溫度：250℃ 最終滯留時間：30分鐘 分流(split)比：1：10 載體氣體：氦 載體氣體流量：2 mL/分 高效液相色譜法(HPLC) 裝置：安捷倫科技公司 1260 Infinity 管柱：Inertsil ODS-4(粒徑：3 μm、內徑：4.6 mm、長度：150 mm) 流速：0.6 mL/分 測定波長：226 nm 管柱溫度：35℃ 移動相 A液：0.1%磷酸水溶液 B液：甲醇 移動相A及移動相B之混合比，以如下之濃度梯度控制。 [0029]核磁共振(NMR) 裝置：布魯克(Bruker)公司 Ultra Shield(400MHz) 軟體：布魯克公司 TopSpin [實施例1] 2-((((1r, 3R, 4S)-3,4-二氟環戊基)甲基)巰基)苯[d]噻唑之合成 [0030][0031] 於氮氣流下，將甲苯(200 mL)、((1r, 3R, 4S)-3,4-二氟環戊基)甲醇(40.0 g、293.82 mmol)，及三乙基胺(61.4 mL、440.72 mmol)加入反應容器後，冷卻至2℃。甲基磺醯氯(25.01 mL、323.20 mmol)以1.7小時滴下後，於10～20℃攪拌1.3小時。反應終了後，加入水(40 mL)於室溫攪拌20分後，添加2-巰基苯并噻唑鈉(66.72 g、352.58 mmol)，於80℃攪拌6小時。反應終了後，添加水(80 mL)冷卻至40℃後，去除水層。於有機層追加甲苯(200 mL)後，依序以2 mol/L氫氧化鈉水溶液(200 mL)、水(200 mL，2回)洗淨。所得之有機層在減壓下濃縮，得到標題之化合物(79.21 g)。產率95%。1
H-NMR(400 MHz, CDCl3
)δ 1.86-1.97(m，2H)，2.22-2.34(m，2H)、2.48-2.55(m，1H)、3.47(d，J = 7.6 Hz，2H)、4.81-4.98(m，2H)、7.28-7.32(m，1H)、7.39-7.44(m，1H)、7.74-7.77(m，1H)、7.85-7.88(m，1H)。 [實施例2] 2-((((1r, 3R, 4S)-3,4-二氟環戊基)甲基)巰基)苯[d]噻唑之合成 [0032][0033] 於氮氣流下，將甲苯(50 mL)、((1r, 3R, 4S)-3,4-二氟環戊基)甲醇(10.0 g、73.45 mmol)，及三乙基胺(15.4 mL、110.18 mmol)加入反應容器後，冷卻至0℃。添加p-甲苯磺醯氯(16.80 g、88.14 mmol)後，於10～20℃攪拌6小時。反應終了後，添加水(16.7 mL)及2-巰基苯并噻唑鈉(16.68 g、88.14 mmol)，於80℃攪拌18小時。反應終了後，添加水(20 mL)冷卻至40℃後，去除水層。於有機層追加甲苯(50 mL)後，依序以2 mol/L氫氧化鈉水溶液(50 mL)、水(50 mL，2回)洗淨。所得之有機層在減壓下濃縮，得到標題之化合物(20.93 g)。產率100%。 [產業上之利用可能性] [0034] 本發明之硫醚化合物的製造方法，可利用於包含例如醫藥品製造業之化學工業。[0020] The present invention is a two-stage reaction in which the sulfonation of the first step and the addition of a 2-mercaptobenzothiazole derivative in the second step are carried out continuously in one reaction vessel. Hereinafter, suitable embodiments of the two-stage reaction will be described in order. (First Step) Although the first step of the present invention uses the sulfonium chloride represented by R 1 SO 2 Cl as described above, it is preferred to use a C 1 to C 4 alkylsulfonium chloride or to pass 1 to Methanesulfonyl chloride or p-toluenesulfonyl chloride is more preferably used as the benzenesulfonyl chloride substituted by two C 1 -C 4 alkyl groups, and most preferably, methanesulfonyl chloride is used. Relative to the base saturated alcohol, the preferred usage amount is 1.0 to 2.0 mol equivalents, and more preferably 1.05 to 1.3 mol equivalents. [0021] The base used in the first step of the present invention is not particularly limited, and is preferably an organic base. For example, a tertiary amine can be used. Among these, a trialkylamine such as triethylamine or diisopropylethylamine is preferred, and triethylamine is most preferred. The use amount of the saturated alcohol with respect to the matrix is preferably 1.0 to 2.0 mol equivalents, and more preferably 1.05 to 1.6 mol equivalents. [0022] The solvent used in the first step of the present invention is not particularly limited, and examples thereof include tetrahydrofuran, acetonitrile, acetone, toluene, dichloromethane, dimethylformamide, and dimethylacetamide. These solvents may be used alone or in combination. Among these, toluene is preferable. Relative to the substrate's saturated alcohol, its suitable amount is 3 to 10 v / w, more preferably 4 to 8 v / w. [0023] Although the reaction temperature in the first step of the present invention varies depending on the solvent used, it is preferably 0 to 45 ° C, and the preferred reaction time is 30 minutes to 2 hours. [0024] After the reaction in the first step of the present invention is completed, water may be added, and its amount is preferably 1 to 5 v / w, more preferably 1 to 3 v / w, relative to the saturated alcohol of the substrate. (Second step) The 2-mercaptobenzothiazole derivative represented by the formula (3) used in the second step of the present invention, wherein the substituent R 2 represents a hydrogen atom or is selected from the group consisting of C 1 to C 4 alkanes 1 to 2 groups of a group consisting of a hydrogen group, a halogen atom, a C 1 to C 4 alkoxy group, a cyano group, and a nitro group. Among them, a hydrogen atom and a halogen atom are preferred, and a hydrogen atom is particularly preferred. X is a hydrogen atom, a lithium atom, a sodium atom, a potassium atom, or a 1/2 zinc atom. Among these, a hydrogen atom and a sodium atom are preferred, and a sodium atom is particularly preferred. The used amount of the saturated alcohol relative to the substrate is preferably 1.0 to 2.0 mol equivalents, more preferably 1.1 to 1.4 mol equivalents. [0025] Although the reaction temperature in the second step of the present invention varies depending on the solvent used It is preferably 60 to 90 ° C, and the preferable reaction time is 4 to 12 hours. [0026] The preferred amount of sulfonium chloride or base used in the first step, the amount of solvent used, the reaction temperature, the reaction time, and the amount of water added are preferably 2-mercaptobenzothiazole in the second step. The amount of derivative, reaction temperature, and reaction time are generally as described above, but those with ordinary knowledge in the technical field can refer to these ranges or the examples described below, depending on the type of starting material or reaction device, etc. The individual preconditions determine the appropriate reaction conditions. If necessary, conditions can be optimized by trial. [Example] [0027] In this example, analysis was performed using the following equipment and the like. [0028] Gas chromatography (GC) device: Agilent Technologies 7890B GC system column: DB-624 (length: 30.0 m, inner diameter: 0.32 mm, film thickness: 1.80 μm) Note inlet temperature: 180 ° C Detector temperature: 260 ° C Initial temperature: 80 ° C Initial residence time: 2 minutes Heating rate: 18 ° C / min Final temperature: 250 ° C Final residence time: 30 minutes Split ratio: 1:10 Carrier gas: Helium carrier gas flow rate: 2 mL / min. High performance liquid chromatography (HPLC) device: Agilent Technologies 1260 Infinity column: Inertsil ODS-4 (particle size: 3 μm, inner diameter: 4.6 mm, length: 150 mm) Flow rate : 0.6 mL / min Measurement wavelength: 226 nm Column temperature: 35 ° C Mobile phase A liquid: 0.1% phosphoric acid aqueous solution B liquid: Methanol mobile phase A and mobile phase B The mixing ratio is controlled by the following concentration gradient. [0029] Nuclear magnetic resonance (NMR) device: Bruker Ultra Shield (400MHz) Software: Bruker TopSpin [Example 1] 2-((((1r, 3R, 4S) -3,4-difluorocyclopentyl)) Synthesis of methyl) mercapto) benzene [d] thiazole [0030] [0031] Under a stream of nitrogen, toluene (200 mL), ((1r, 3R, 4S) -3,4-difluorocyclopentyl) methanol (40.0 g, 293.82 mmol), and triethylamine (61.4 mL (440.72 mmol) was added to the reaction vessel, and then cooled to 2 ° C. Methanesulfonyl chloride (25.01 mL, 323.20 mmol) was dropped over 1.7 hours, and then stirred at 10 to 20 ° C for 1.3 hours. After the reaction was completed, water (40 mL) was added and the mixture was stirred at room temperature for 20 minutes, and then 2-mercaptobenzothiazole sodium (66.72 g, 352.58 mmol) was added, followed by stirring at 80 ° C for 6 hours. After the reaction was completed, water (80 mL) was added to cool to 40 ° C, and then the aqueous layer was removed. Toluene (200 mL) was added to the organic layer, and then washed with a 2 mol / L sodium hydroxide aqueous solution (200 mL) and water (200 mL, twice) in this order. The obtained organic layer was concentrated under reduced pressure to obtain the title compound (79.21 g). Yield 95%. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.86-1.97 (m, 2H), 2.22-2.34 (m, 2H), 2.48-2.55 (m, 1H), 3.47 (d, J = 7.6 Hz, 2H) 4.81-4.98 (m, 2H), 7.28-7.32 (m, 1H), 7.39-7.44 (m, 1H), 7.74-7.77 (m, 1H), 7.85-7.88 (m, 1H). [Example 2] Synthesis of 2-((((1r, 3R, 4S) -3,4-difluorocyclopentyl) methyl) mercapto) benzene [d] thiazole [0032] [0033] Under a stream of nitrogen, toluene (50 mL), ((1r, 3R, 4S) -3,4-difluorocyclopentyl) methanol (10.0 g, 73.45 mmol), and triethylamine (15.4 mL (110.18 mmol) was added to the reaction vessel, and then cooled to 0 ° C. After adding p-toluenesulfonyl chloride (16.80 g, 88.14 mmol), the mixture was stirred at 10 to 20 ° C for 6 hours. After the reaction was completed, water (16.7 mL) and sodium 2-mercaptobenzothiazole (16.68 g, 88.14 mmol) were added, and the mixture was stirred at 80 ° C. for 18 hours. After the reaction was completed, water (20 mL) was added to cool to 40 ° C, and then the aqueous layer was removed. After toluene (50 mL) was added to the organic layer, it was washed with a 2 mol / L sodium hydroxide aqueous solution (50 mL) and water (50 mL, twice) in this order. The obtained organic layer was concentrated under reduced pressure to obtain the title compound (20.93 g). Yield 100%. [Industrial Applicability] [0034] The method for producing a thioether compound of the present invention can be used in the chemical industry including, for example, pharmaceutical manufacturing.