JP2010195754A - Phthalimide derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a phthalimide derivative and a method for producing the same. <P>SOLUTION: In the method for producing the phthalimide derivative represented by formula (2), a phthalimide derivative represented by formula (1) is reacted with water in the presence of a palladium catalyst and an oxidizing agent. In formulas (1) and (2), X is a methylene group or an oxygen atom; Y is a hydrogen or halogen atom or a 1-10C alkyl group; m is an integer of 1-4; and n is an integer of 0-10. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to phthalimide derivatives that can be used as intermediates for the synthesis of medical pesticides and functional materials, and methods for producing them.

  Wacker oxidation reaction has long been known as a method for producing ketones by adding water to a terminal alkene compound using a catalytic amount of palladium chloride in the presence of an oxidizing agent such as copper (II) chloride in an oxygen atmosphere. ing. However, N-alkenylphthalimide or N-alkenyloxyphthalimides having a double bond at the end according to the present invention are subjected to Wacker oxidation to produce N-{(ω-1) oxoalkyl} phthalimide derivatives or N-{( There are no reported examples of methods for producing ω-1) oxoalkyloxy} phthalimide derivatives. On the other hand, Non-Patent Document 1 discloses a method for producing an N-{(ω-1) oxoalkyl} phthalimide derivative, which is obtained by reacting ω-bromoalkylphthalimide and acetoacetate in the presence of a base. A method of hydrolysis of phthalimidoalkyl) acetoacetate followed by decarboxylation is disclosed. Non-Patent Document 2 describes a method for producing N- (5-oxohexane-1-yl) phthalimide by reacting 1-bromohexane-5-one with phthalimide in the presence of a base. . Furthermore, Non-Patent Document 3 describes that N- (2-oxopropyloxy) phthalimide can be synthesized by reacting N-hydroxyphthalimide and chloroacetone in the presence of a base. However, there is no description relating to the production of the N-{(ω-1) oxoalkyloxy} phthalimide derivative represented by the general formula (3) of the present invention.

  In a known production method of an N-{(ω-1) oxoalkyl} phthalimide derivative or N-{(ω-1) oxoalkyloxy} phthalimide derivative, the method of Non-Patent Document 1 has a long reaction step, especially an alkyl group. Depending on the carbon chain length of the group, several reaction steps are required. Further, the decarboxylation step is a waste of carbon resources, and is not necessarily an industrially advantageous method. In the methods of Non-Patent Documents 2 and 3, haloketones that are unstable to bases are used as raw materials while the reaction is performed under basic conditions, and side reactions such as aldol condensation are suppressed to improve the yield. It is important and control of reaction conditions is not always easy. Further, only N- (2-oxopropyloxy) phthalimide is shown as a synthesis example, and the N-{(ω-1) oxoalkyloxy} phthalimide derivative represented by the general formula (3) of the present invention is shown. It is not clear whether the method of the said nonpatent literature is applicable to a synthesis | combination.

Journal of Medicinal Chemistry, 30 (5), 894-899 (1987) Journal of Organic Chemistry, 70 (6), 2067-2074 (2005). Ultrasonics Sonochemistry, 15 (1), 33-36 (2008)

  An object of the present invention is to provide a phthalimide derivative that can be used as a production intermediate for the synthesis of medical pesticides and functional materials, and a simple production method thereof.

  As a result of intensive studies to solve the above problems, the present inventors have found a simple method for producing a phthalimide derivative represented by the following general formula (2) of the present invention, and have completed the present invention.

  That is, the present invention relates to the general formula (1)

（式中、Ｘはメチレン基または酸素原子を表し、Ｙは水素原子、ハロゲン原子または炭素数１から１０のアルキル基を表し、ｍは１から４の整数を表す。ｎはＸがメチレン基の場合は０から１０の整数を表し、Ｘが酸素原子の場合はｎは１から１０の整数を表す。）で表されるフタルイミド誘導体を酸素雰囲気中、パラジウム触媒及び酸化剤存在下にて水と反応させて、一般式（２）

(In the formula, X represents a methylene group or an oxygen atom, Y represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 10 carbon atoms, m represents an integer of 1 to 4, and n represents that the X is a methylene group. In the case where X represents an oxygen atom, n represents an integer of 1 to 10.) In the oxygen atmosphere, the phthalimide derivative represented by By reacting, general formula (2)

（式中、Ｘ、Ｙ、ｍ及びｎは前記と同じ意味を表す。）で示されるフタルイミド誘導体を製造する方法に関するものである。

(Wherein, X, Y, m and n represent the same meaning as described above).

  In addition, the present invention provides a general formula (3)

（式中、Ｙ及びｍは前記と同じ意味を表し、ｐは２から１０の整数を表す。）で示される（ω−１）オキソアルコキシフタルイミド誘導体に関するものである。

(Wherein Y and m represent the same meaning as described above, p represents an integer of 2 to 10), and relates to the (ω-1) oxoalkoxyphthalimide derivative.

  Hereinafter, the present invention will be described in more detail.

（式中、Ｘ、Ｙ、ｍ及びｎは前記と同じ意味を表す。）
一般式（１）、（２）及び（３）で示されるフタルイミド誘導体において、Ｙで示されるハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子があげられる。Ｙで示される炭素数１から１０のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、オクチル基、デシル基等をあげることができる。

(Wherein X, Y, m and n represent the same meaning as described above.)
In the phthalimide derivatives represented by the general formulas (1), (2) and (3), examples of the halogen atom represented by Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkyl group having 1 to 10 carbon atoms represented by Y include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, octyl group and decyl group. I can give you.

  In the production method of the present invention, it is essential to carry out the reaction in the presence of a palladium catalyst. The palladium catalyst is not particularly limited as long as it is a palladium catalyst that can be used for the so-called Wacker oxidation reaction. For example, palladium chloride, palladium acetate, palladium sulfate, and the like can be used, but the yield of the target product is good. In this respect, palladium chloride is preferable. The amount of the palladium catalyst used is not particularly limited as long as it is a so-called catalyst amount, but is preferably 0.01 to 30 mol% relative to the raw material phthalimide derivative (1) in terms of a good yield, and is preferably 1 to 20 mol. % Is more preferable.

  In the production method of the present invention, it is essential to carry out the reaction in the presence of an oxidizing agent. As oxidizing agents, copper compounds such as copper (I) chloride and copper (II), iron compounds such as iron (III) chloride, manganese dioxide, heteropolyacid, hydrogen peroxide, organic peroxide, alkyl nitrite, etc. However, copper chloride is preferable because the yield of the target product is good. There is no restriction | limiting in particular in the usage-amount of an oxidizing agent, 1-10 equivalent is preferable with respect to the phthalimide derivative (1) which is a raw material, and 2-5 equivalent is further more preferable.

  In the production method of the present invention, it is essential to carry out the reaction in the presence of oxygen. There is no particular limitation on the method of adding oxygen, and the target product can be obtained by carrying out the reaction under atmospheric pressure or pressurized oxygen atmosphere, but oxygen gas is bubbled into the reaction solution in terms of good yield. It is preferable to carry out the reaction.

  In the production method of the present invention, it is essential to carry out the reaction in the presence of water. There is no restriction | limiting in particular in the usage-amount of water, It is preferable to use 1-50 equivalent with respect to the phthalimide derivative (1) which is a raw material, and 2-20 equivalent is further used by the point with the yield of a target object being good. preferable.

  Furthermore, the production method of the present invention is preferably carried out in a solvent. For example, aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene, diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like. Ether solvents, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate, ethyl propionate, ethyl butyrate, dimethyl carbonate and diethyl carbonate, N, N-dimethylformamide (DMF), amides such as N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used. Among these, it is preferable to carry out the reaction using DMF in terms of a good yield.

  The production method of the present invention can be carried out at a reaction temperature appropriately selected from the range of −40 ° C. to the reflux temperature of the reaction solvent, but is carried out at a reaction temperature appropriately selected from the range of 0 ° C. to the solvent reflux temperature. It is preferable in terms of good yield. After completion of the reaction, the desired product can be obtained by ordinary post-treatment operations, but can be purified by column chromatography or recrystallization if necessary.

  The phthalimide derivative (2) produced in the above process can synthesize thiazole derivatives useful as ligands for purifying proteins, particularly immunoglobulin G, by the methods shown in Reference Examples 1 and 2, for example. Furthermore, by immobilizing the thiazole derivative on a matrix having an activating group that can be immobilized, the thiazole derivative can be used as a purification and separation agent for proteins, particularly immunoglobulin G. Examples of the activating group include succinimideoxycarbonyl group, formyl group, carboxyl group, 2,2,2-trifluoroethylsulfonyloxy group (tresyl group), sulfonyl chloride group, tosyl group, vinylsulfonyl group, and epoxy group. be able to. The material of the matrix to which the thiazole derivative can be immobilized is not particularly limited. For example, a polypeptide or protein such as cross-linked albumin, agarose, alginate, carrageenan, chitin, cellulose, dextrin, dextran, starch or other polysaccharides, Synthetic polymers such as acrylamide, polystyrene, polyacrolein, polyvinyl alcohol, polymethacrylate, poly (2-hydroxyethyl methacrylate), polyurethane, silica, glass, porous diatomaceous earth, alumina, zirconia, iron oxide or other metal oxides, etc. And a matrix such as a copolymer formed by arbitrarily combining two or more of the above-described inorganic compounds. In addition, they contain compounds such as dextran, polyethylene glycol, polyvinyl alcohol or hydrolyzed polymers such as hydrolyzed starch used in liquid phase partitioning, or compounds such as perfluorodecalin used to form emulsions. An included matrix is also included. Further, the matrix may be granular or non-particulate, soluble or insoluble in an aqueous solvent, porous or non-porous.

  The phthalimide derivative obtained by the production method of the present invention is useful as a production intermediate for the synthesis of medical pesticides and functional materials. In particular, the phthalimide derivatives of the present invention are useful intermediates for producing ligands for affinity chromatography effective for analysis / purification of various useful proteins (particularly immunoglobulin G).

The protein chromatography result using the agarose gel which fix | immobilized the thiazole derivative synthesize | combined in the reference example 2. FIG.

  EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated further in detail, this invention is not limited to these.

  Example 1

塩化パラジウム（ＩＩ）（８２３ｍｇ，４．６４ｍｍｏｌ）のＤＭＦ（５０ｍＬ）溶液に、水（７ｍＬ）及び塩化銅（Ｉ）（２．９９ｇ，３０．２ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−（４−ペンテニル）フタルイミド（５．００ｇ，２３．２ｍｍｏｌ）のＤＭＦ溶液（５ｍＬ）をゆっくりと加え、更に酸素ガスをバブリングしながら５時間攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で２回抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液から溶媒を減圧留去することにより油状物を得た。油状物を自動設定中圧カラムクロマトグラフィーシステム（山善）で精製し、Ｎ−（４−オキソペンチル）フタルイミドの白色固体（４．４４ｇ，８３％）を得た。ｍ．ｐ．：６２から６４℃；^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．９１から２．０１（ｍ，２Ｈ），２．１４（ｓ，３Ｈ），２．５１（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．７１（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．７０から７．８７（ｍ，４Ｈ）。

Water (7 mL) and copper (I) chloride (2.99 g, 30.2 mmol) were added to a solution of palladium (II) chloride (823 mg, 4.64 mmol) in DMF (50 mL), and the reaction was carried out while bubbling oxygen gas. The solution was stirred for 2 hours until the color changed from black to green. A DMF solution (5 mL) of N- (4-pentenyl) phthalimide (5.00 g, 23.2 mmol) was slowly added to the reaction solution, and further stirred for 5 hours while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with water and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain an oil. The oil was purified by an automatic medium pressure column chromatography system (Yamazen) to obtain a white solid (4.44 g, 83%) of N- (4-oxopentyl) phthalimide. m. p. : 62 to 64 ° C .; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.91 to 2.01 (m, 2H), 2.14 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H), 3.71 (t, J = 7.5 Hz, 2H), 7.70 to 7.87 (m, 4H).

  Example 2

塩化パラジウム（ＩＩ）（５７６ｍｇ，３．２４ｍｍｏｌ）のＤＭＦ（６３ｍＬ）溶液に、水（９ｍＬ）、塩化銅（Ｉ）（３．２３ｇ，３２．６ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−（５−ヘキセニル）フタルイミド（７．８０ｇ，３２．５ｍｍｏｌ）のＤＭＦ溶液（５ｍＬ）をゆっくりと加え、更に酸素ガスをバブリングしながら５時間攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で２回抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液から溶媒を減圧留去することにより油状物を得た。油状物を自動設定中圧カラムクロマトグラフィーシステム（山善）で精製し、Ｎ−（５−オキソヘキシル）フタルイミドの白色固体（８．０６ｇ）を定量的に得た。ｍ．ｐ．：５９から６２℃；^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．１６から１．６８（ｍ，４Ｈ），２．１３（ｓ，３Ｈ），２．４９（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．６９（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．６９から７．８６（ｍ，４Ｈ）。

Water (9 mL) and copper (I) chloride (3.23 g, 32.6 mmol) were added to a solution of palladium (II) chloride (576 mg, 3.24 mmol) in DMF (63 mL), and the reaction was carried out while bubbling oxygen gas. The solution was stirred for 2 hours until the color changed from black to green. A DMF solution (5 mL) of N- (5-hexenyl) phthalimide (7.80 g, 32.5 mmol) was slowly added to the reaction solution, and the mixture was further stirred for 5 hours while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (100 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with water and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain an oil. The oil was purified by an automatic medium pressure column chromatography system (Yamazen) to quantitatively obtain a white solid (8.06 g) of N- (5-oxohexyl) phthalimide. m. p. : 59 to 62 ° C .; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.16 to 1.68 (m, 4H), 2.13 (s, 3H), 2.49 (t, J = 7.5 Hz, 2H), 3.69 (t, J = 7.5 Hz, 2H), 7.69 to 7.86 (m, 4H).

  Example 3

塩化パラジウム（ＩＩ）（０．４９ｇ，２．７６ｍｍｏｌ）のＤＭＦ（６３ｍＬ）溶液に、水（９ｍＬ）、塩化銅（Ｉ）（３．２３ｇ，３２．６ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−（７−オクテニル）フタルイミド（８．８６ｇ，３２．４ｍｍｏｌ）のＤＭＦ溶液（５ｍＬ）をゆっくりと加え、更に酸素ガスをバブリングしながら５時間攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で２回抽出した。有機層を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液から溶媒を減圧留去することにより油状物を得た。油状物を自動設定中圧カラムクロマトグラフィーシステム（山善）で精製し、Ｎ−（７−オキソオクチル）フタルイミドの白色固体（４．３８ｇ，６８％）を得た。ｍ．ｐ．：４４から４６℃；^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．２９から１．３８（ｍ，４Ｈ），１．５３から１．７６（ｍ，４Ｈ），２．１３（ｓ，３Ｈ），２．４２（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．６８（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．６９から７．８６（ｍ，４Ｈ）。

To a solution of palladium (II) chloride (0.49 g, 2.76 mmol) in DMF (63 mL), water (9 mL) and copper (I) chloride (3.23 g, 32.6 mmol) were added, and oxygen gas was bubbled. The reaction solution was stirred for 2 hours until it changed from black to green. A DMF solution (5 mL) of N- (7-octenyl) phthalimide (8.86 g, 32.4 mmol) was slowly added to the reaction solution, and further stirred for 5 hours while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain an oil. The oil was purified by an automatic medium pressure column chromatography system (Yamazen) to obtain a white solid (4.38 g, 68%) of N- (7-oxooctyl) phthalimide. m. p. : 44 to 46 ° C .; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.29 to 1.38 (m, 4H), 1.53 to 1.76 (m, 4H), 2.13 ( s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 3.68 (t, J = 7.5 Hz, 2H), 7.69 to 7.86 (m, 4H).

  Example 4

塩化パラジウム（ＩＩ）（１．３４ｇ，７．７２ｍｍｏｌ）のＤＭＦ（３００ｍＬ）溶液に、水（６３ｍＬ）、塩化銅（Ｉ）（３１．０ｇ，３１３ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−［（４−ペンテニル）オキシ］フタルイミド（３５．９ｇ，１５６ｍｍｏｌ）のＤＭＦ（１００ｍＬ）溶液を滴下し、更に酸素ガスをバブリングしながら一晩攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（９００ｍＬ）を加え、酢酸エチル（４００ｍＬ）で３回抽出した。有機層を水（８００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液から溶媒を減圧留去することにより茶色液体のＮ−（４−オキソペンチルオキシ）フタルイミド（２５．５ｇ，６６．４％）を得た。^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．９７から２．０７（ｍ，２Ｈ），２．２２（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），２．２３（ｓ，３Ｈ），４．２３（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．７３から７．８５（ｍ，４Ｈ）。

Water (63 mL) and copper (I) chloride (31.0 g, 313 mmol) were added to a solution of palladium (II) chloride (1.34 g, 7.72 mmol) in DMF (300 mL), and the reaction was carried out while bubbling oxygen gas. The solution was stirred for 2 hours until the color changed from black to green. A solution of N-[(4-pentenyl) oxy] phthalimide (35.9 g, 156 mmol) in DMF (100 mL) was added dropwise to the reaction solution, and the mixture was further stirred overnight while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (900 mL) was added, and the mixture was extracted 3 times with ethyl acetate (400 mL). The organic layer was washed with water (800 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give a brown liquid N- (4-oxopentyloxy) phthalimide ( 25.5 g, 66.4%). ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.97 to 2.07 (m, 2H), 2.22 (t, J = 7.5 Hz, 2H), 2.23 (s, 3H) 4.23 (t, J = 7.5 Hz, 2H), 7.73 to 7.85 (m, 4H).

  Example 5

塩化パラジウム（ＩＩ）（１．３４ｇ，１５１ｍｍｏｌ）のＤＭＦ（３００ｍＬ）溶液に、水（６３ｍＬ）、塩化銅（Ｉ）（３０．０ｇ，３０３ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−（５−ヘキセニルオキシ）フタルイミド（３７．１ｇ，１５１ｍｍｏｌ）のＤＭＦ（１００ｍＬ）溶液を滴下し、更に酸素ガスをバブリングしながら一晩攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（８００ｍＬ）を加え、酢酸エチル（８００ｍＬ）で２回抽出した。有機層を更に１Ｍ塩酸（８００ｍＬ×２）と飽和食塩水（８００ｍＬ）で順次洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液から溶媒を減圧留去することにより茶色液体のＮ−（５−オキソヘキシルオキシ）フタルイミド（３６．５ｇ，９３％）を得た。^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．７８から１．８４（ｍ，４Ｈ），２．１７（ｓ，３Ｈ），２．５７（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．６９（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．６９から７．８６（ｍ，４Ｈ）。

Water (63 mL) and copper (I) chloride (30.0 g, 303 mmol) were added to a solution of palladium (II) chloride (1.34 g, 151 mmol) in DMF (300 mL), and oxygen gas was bubbled into the reaction solution. The mixture was stirred for 2 hours until the color changed from black to green. A solution of N- (5-hexenyloxy) phthalimide (37.1 g, 151 mmol) in DMF (100 mL) was added dropwise to the reaction solution, and the mixture was further stirred overnight while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (800 mL) was added, and the mixture was extracted twice with ethyl acetate (800 mL). The organic layer was further washed successively with 1M hydrochloric acid (800 mL × 2) and saturated brine (800 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to give a brown liquid. Of N- (5-oxohexyloxy) phthalimide (36.5 g, 93%). ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.78 to 1.84 (m, 4H), 2.17 (s, 3H), 2.57 (t, J = 7.5 Hz, 2H) 3.69 (t, J = 7.5 Hz, 2H), 7.69 to 7.86 (m, 4H).

  Example 6

塩化パラジウム（ＩＩ）（２６８ｍｇ，１．５１ｍｍｏｌ）のＤＭＦ（５０ｍＬ）溶液に、水（１１ｍＬ）、塩化銅（Ｉ）（６．００ｇ，６１ｍｍｏｌ）を加え、酸素ガスをバブリングしながら、反応液が黒色から緑色に変化するまで２時間撹拌した。反応液にＮ−（９−デセニルオキシ）フタルイミド（１１．２ｇ，３０．４ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液を滴下し、更に酸素ガスをバブリングしながら一晩攪拌した。反応終了後、反応液を減圧濃縮し、１Ｍ塩酸（２００ｍＬ）を加え、酢酸エチル（３００ｍＬ）で２回抽出した。有機層を１Ｍ塩酸（２００ｍＬ×２）と飽和食塩水（３００ｍＬ）で順次洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液から溶媒を減圧留去した。得られた粗生成物を自動設定中圧カラムクロマトグラフィーシステム（山善）で精製することにより淡黄色液体のＮ−（９−オキソデシルオキシ）フタルイミド（３．１８ｇ，３５％）を得た。^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．３３から１．６３（ｍ，１０Ｈ），１．７３から１．８２（ｍ，２Ｈ），２．１４（ｓ，３Ｈ），２．４２（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），４．２０（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．７３から７．８６（ｍ，４Ｈ）。

To a solution of palladium (II) chloride (268 mg, 1.51 mmol) in DMF (50 mL), water (11 mL) and copper (I) chloride (6.00 g, 61 mmol) were added, and the reaction solution was stirred while bubbling oxygen gas. The mixture was stirred for 2 hours until the color changed from black to green. A solution of N- (9-decenyloxy) phthalimide (11.2 g, 30.4 mmol) in DMF (10 mL) was added dropwise to the reaction solution, and the mixture was further stirred overnight while bubbling oxygen gas. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid (200 mL) was added, and the mixture was extracted twice with ethyl acetate (300 mL). The organic layer was washed successively with 1M hydrochloric acid (200 mL × 2) and saturated brine (300 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off from the filtrate under reduced pressure. The obtained crude product was purified by an automatic medium pressure column chromatography system (Yamazen) to obtain N- (9-oxodecyloxy) phthalimide (3.18 g, 35%) as a pale yellow liquid. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.33 to 1.63 (m, 10H), 1.73 to 1.82 (m, 2H), 2.14 (s, 3H), 2 .42 (t, J = 7.5 Hz, 2H), 4.20 (t, J = 7.5 Hz, 2H), 7.73 to 7.86 (m, 4H).

  Reference example 1

Ｎ−（５−オキソヘキシル）フタルイミド（１．０ｇ，３．８３ｍｍｏｌ）のＴＨＦ（１５ｍＬ）溶液に臭化銅（ＩＩ）（１．７１ｇ，７．６６ｍｍｏｌ）を加え、２時間加熱還流した。反応液をセライト濾過により固体を瀘別し、濾液から溶媒を減圧留去して油状物を得た。得られた油状物をＤＭＦ（２０ｍＬ）に溶解し、４−メチルベンゾイルチオウレア（０．７９ｇ，４．０７ｍｍｏｌ）を加え、８０℃で８時間反応させた。反応終了後、溶媒を減圧留去して得られた粗生成物に１Ｍ塩酸（３０ｍＬ）と酢酸エチル（３０ｍＬ）を加え固体を析出させた。固体を瀘別し、酢酸エチルとエーテルによって充分洗浄し、Ｎ−［４−メチル−５−｛３−（フタルイミド）プロピル｝チアゾ−ル−２−イル］−４−メチルベンズアミド（０．６８４ｇ，収率：４０％）を得た。白色固体：ｍ．ｐ．１７８から１８０℃；^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ １．８９から１．９８（ｍ，２Ｈ），２．２１（ｓ，３Ｈ），２．３９（ｓ，３Ｈ），２．７４（ｔ，Ｊ＝５．０Ｈｚ，２Ｈ），３．６５（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．３４（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ），７．６９（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ），７．８０から７．８９（ｍ，４Ｈ），１２．３（ｂｒ ｓ，１Ｈ）。

Copper (II) bromide (1.71 g, 7.66 mmol) was added to a THF (15 mL) solution of N- (5-oxohexyl) phthalimide (1.0 g, 3.83 mmol), and the mixture was heated to reflux for 2 hours. The reaction solution was filtered through Celite to separate the solid, and the solvent was distilled off from the filtrate under reduced pressure to obtain an oily substance. The obtained oil was dissolved in DMF (20 mL), 4-methylbenzoylthiourea (0.79 g, 4.07 mmol) was added, and the mixture was reacted at 80 ° C. for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 1M hydrochloric acid (30 mL) and ethyl acetate (30 mL) were added to the crude product to precipitate a solid. The solid was filtered off and washed thoroughly with ethyl acetate and ether to give N- [4-methyl-5- {3- (phthalimido) propyl} thiazol-2-yl] -4-methylbenzamide (0.684 g, Yield: 40%). White solid: m. p. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.89 to 1.98 (m, 2H), 2.21 (s, 3H), 2.39 (s, 3H), 178 to 180 ° C. 2.74 (t, J = 5.0 Hz, 2H), 3.65 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H), 7.69 (d , J = 7.5 Hz, 2H), 7.80 to 7.89 (m, 4H), 12.3 (br s, 1H).

  Reference example 2

４−メチル−Ｎ−［４−メチル−５-｛３−（フタルイミド）プロピル｝チアゾール−２−イル］ベンズアミド（０．６９ｇ，１．６３ｍｍｏｌ）に０．５Ｍヒドラジン一水和物含有エタノール溶液（１６ｍＬ）を加え３時間した。反応終了後、反応溶液を留去し、残渣に１Ｍ塩酸（５ｍＬ）を加え、撹拌した。析出した固体を濾別し、濾液を減圧留去した。得られた固体を熱エタノール及びアセトンを用いて洗浄することにより３−｛２−（４−メチルベンゾイルアミノ）−４−メチルチアゾ−ル−５−イル｝プロピルアミン塩酸塩の白色固体（０．２０ｇ，収率：３８％）を得た。白色固体：^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６，ＤＭＳＯ，ｐｐｍ）：δ １．８１から１．８７（ｍ，２Ｈ），２．２４（ｓ，３Ｈ），２．３９（ｓ，３Ｈ），２．７５から２．８３（ｍ，４Ｈ），７．３４（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ），７．８６（ｂｒ ｓ，３Ｈ），７．９７（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ）。アミドのプロトンは帰属できなかった。

Ethanol solution containing 0.5 M hydrazine monohydrate in 4-methyl-N- [4-methyl-5- {3- (phthalimido) propyl} thiazol-2-yl] benzamide (0.69 g, 1.63 mmol) 16 mL) and added for 3 hours. After completion of the reaction, the reaction solution was distilled off, and 1M hydrochloric acid (5 mL) was added to the residue and stirred. The precipitated solid was filtered off and the filtrate was distilled off under reduced pressure. The obtained solid was washed with hot ethanol and acetone to give 3- {2- (4-methylbenzoylamino) -4-methylthiazol-5-yl} propylamine hydrochloride as a white solid (0.20 g). Yield: 38%). White solid: ¹ H-NMR (DMSO-d ₆ , DMSO, ppm): δ 1.81 to 1.87 (m, 2H), 2.24 (s, 3H), 2.39 (s, 3H), 2.75 to 2.83 (m, 4H), 7.34 (d, J = 7.5 Hz, 2H), 7.86 (brs, 3H), 7.97 (d, J = 7.5 Hz, 2H). The proton of the amide could not be assigned.

  Reference example 3

Ｎ−（５−オキソヘキシルオキシ）フタルイミド（１．０ｇ，３．８３ｍｍｏｌ）のＴＨＦ（１５ｍＬ）溶液に臭化銅（ＩＩ）（１．７１ｇ，７．６６ｍｍｏｌ）を加え、２時間加熱還流した。反応液からセライト濾過により固体を瀘別し、濾液から溶媒を減圧留去して油状物を得た。得られた油状物をＤＭＦ（２０ｍＬ）に溶解し、３，４−ジメトキシベンゾイルチオウレア（０．９２ｇ，３．８３ｍｍｏｌ）を加え、８０℃で８時間反応させた。反応終了後、溶媒を減圧留去して得られた粗生成物に１Ｍ塩酸（３０ｍＬ）と酢酸エチル（３０ｍＬ）を加え固体を析出させた。固体を瀘別し、酢酸エチルとエーテルによって充分洗浄し、灰色固体の３，４−ジメトキシ−Ｎ−［４−メチル−５−｛３−（フタルイミドオキシ）プロピル｝チアゾール−２−イル］ベンズアミド（０．５７ｇ，３１％）を得た。ｍ．ｐ．：２１１から２１５℃；^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ＴＭＳ，ｐｐｍ）：δ２．１０（ｍ，２Ｈ），２．５１（ｓ，３Ｈ），３．１３（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．９７（ｓ，３Ｈ），４．０４（ｓ，３Ｈ），４．２６（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．０２（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ），７．７６から７．８８（ｍ，５Ｈ），７．９９（ｄｄ，Ｊ＝２．５Ｈｚ ａｎｄ ７．５Ｈｚ，１Ｈ）。アミドのプロトンは帰属できなかった。

Copper (II) bromide (1.71 g, 7.66 mmol) was added to a THF (15 mL) solution of N- (5-oxohexyloxy) phthalimide (1.0 g, 3.83 mmol), and the mixture was heated to reflux for 2 hours. The solid was filtered off from the reaction solution by Celite filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain an oil. The obtained oil was dissolved in DMF (20 mL), 3,4-dimethoxybenzoylthiourea (0.92 g, 3.83 mmol) was added, and the mixture was reacted at 80 ° C. for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 1M hydrochloric acid (30 mL) and ethyl acetate (30 mL) were added to the crude product to precipitate a solid. The solid was filtered off and washed thoroughly with ethyl acetate and ether to give 3,4-dimethoxy-N- [4-methyl-5- {3- (phthalimidooxy) propyl} thiazol-2-yl] benzamide ( 0.57 g, 31%). m. p. : 211 to 215 ° C .; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 2.10 (m, 2H), 2.51 (s, 3H), 3.13 (t, J = 7.5 Hz, 2H ), 3.97 (s, 3H), 4.04 (s, 3H), 4.26 (t, J = 7.5 Hz, 2H), 7.02 (d, J = 7.5 Hz, 1H), 7.76 to 7.88 (m, 5H), 799 (dd, J = 2.5 Hz and 7.5 Hz, 1H). The proton of the amide could not be assigned.

Reference Example 4 Immobilization of thiazole derivative on agarose gel (Part 1)
The thiazole derivative synthesized by the method of Reference Example 2 was dissolved in DMSO to 40 μmol / mL, and 0.2 M sodium bicarbonate buffer (pH 8.3) containing an equal amount of 0.5 M NaCl was added thereto. A thiazole derivative solution having a concentration of 20 μmol / mL was prepared. Pass 2 mL of the thiazole derivative solution through 1 mL of agarose gel (HiTrap NHS-activated HP (trade name, GE Healthcare Bioscience) activated with N-hydroxysuccinimide (NHS); hereinafter abbreviated as HiTrap column). The immobilization was performed. Unreacted succinimideoxycarbonyl group was blocked according to the method described in non-patent literature (First Ligand Coupling Handbook, published by Amersham Biosciences, 2005).

Reference Example 5 Immobilization of thiazole derivative on agarose gel (Part 2)
A DMSO solution containing 20 μmol / mL of the thiazole derivative synthesized by the method of Reference Example 2 and 40 μmol / mL of triethylamine was prepared. After replacing the HiTrap column with DMSO, 2 mL of the above-mentioned thiazole derivative-triethylamine in DMSO was passed through it. After being left for 1 hour, 3 mL of DMSO was passed through a HiTrap column, and further, 5 mL of 0.2 M sodium hydrogen carbonate buffer (pH 8.3) containing 0.5 M NaCl was passed through to fix the column. Unreacted succinimideoxycarbonyl group was blocked according to the method described in non-patent literature (First Ligand Coupling Handbook, published by Amersham Biosciences, 2005).

Reference Example 6 Protein adsorption / desorption using thiazole derivative-immobilized agarose gel (Part 1)
The Thiazole derivative-immobilized HiTrap column prepared by the method described in Reference Example 4 or 5 is attached to a chromatography apparatus (AKTAprime plus (trade name), GE Healthcare Bioscience), and 10 mM phosphoric acid containing 0.7 M sodium sulfate. 20 mL of sodium-10 mM sodium citrate buffer (pH 7.5) (hereinafter referred to as equilibration buffer) was passed through to equilibrate. AKTAprime plus is automatically operated at a flow rate of 1 mL / min, 10 mL of equilibration buffer is passed through, and human plasma-derived immunoglobulin preparation dissolved in the same buffer (Kakekenken, the immunoglobulin of this preparation is immunoglobulin G) ) 0.5 mg (OD ₂₈₀ = 0.7) was added and passed through the column. Further, after passing 10 mL of the equilibration buffer, linear concentration gradient chromatography on sodium sulfate from the equilibration buffer to 10 mM sodium phosphate-10 mM sodium citrate buffer (pH 7.5) was performed. Elution of the immunoglobulin from the column was detected by monitoring the absorbance at 280 nm. The eluate was fractionated by 1 mL, and the absorbance of each fraction at 280 nm was measured with a U-2900 spectrophotometer (Hitachi). The results of chromatography performed using a HiTrap column with a thiazole derivative immobilized thereon are shown in FIG.

Reference Example 7 Adsorption / desorption of protein using agarose gel immobilized with thiazole derivative (Part 2)
A Thiazole derivative-immobilized HiTrap column prepared by the method described in Reference Example 4 or 5 is attached to a chromatography apparatus (AKTAprime plus (trade name), GE Healthcare Bioscience), and 20 mL of the equilibration buffer is passed therethrough. Equilibrated. AKTA prime plus is automatically operated at a flow rate of 1 mL / min, 10 mL of equilibration buffer is passed, 0.5 mg (OD ₂₈₀ = 0.3) of bovine serum albumin (SIGMA) dissolved in the same buffer is added, and the column is added. The liquid was passed through. Further, after 10 mL of the equilibration buffer was passed, linear concentration gradient chromatography on sodium sulfate from the equilibration buffer to 10 mM sodium phosphate-10 mM sodium citrate buffer (pH 7.5) was performed. The elution of bovine serum albumin from the column was detected by monitoring the absorbance at 280 nm. The eluate was fractionated by 1 mL, and the absorbance at 280 nm of each fraction was measured with a U-2900 spectrophotometer (Hitachi). FIG. 1 shows the results of chromatography performed using a HiTrap column on which various thiazole derivatives are immobilized. Bovine serum albumin was eluted by the 10th fraction, and almost no adsorption to the column was observed.

Claims (3)

General formula (1)

(In the formula, X represents a methylene group or an oxygen atom, Y represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 10 carbon atoms, m represents an integer of 1 to 4, and n represents that the X is a methylene group. In the case where X represents an oxygen atom, n represents an integer of 1 to 10.) In the oxygen atmosphere, the phthalimide derivative represented by General formula (2) characterized by reacting

(Wherein, X, Y, m and n represent the same meaning as described above). The process according to claim 1, wherein the palladium catalyst is palladium chloride and the oxidizing agent is copper chloride. General formula (3)

(Wherein Y and m represent the same meaning as described above, and p represents an integer of 2 to 10).

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