WO2011136231A1 - Novel process for producing bisaminophenylalkylurea - Google Patents

Novel process for producing bisaminophenylalkylurea Download PDF

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WO2011136231A1
WO2011136231A1 PCT/JP2011/060182 JP2011060182W WO2011136231A1 WO 2011136231 A1 WO2011136231 A1 WO 2011136231A1 JP 2011060182 W JP2011060182 W JP 2011060182W WO 2011136231 A1 WO2011136231 A1 WO 2011136231A1
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bisaminophenylalkylurea
producing
reaction
formula
nitro compound
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PCT/JP2011/060182
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French (fr)
Japanese (ja)
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顕司 高瀬
健一 徳永
裕一 後藤
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日産化学工業株式会社
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Priority to JP2012512863A priority Critical patent/JP5790645B2/en
Priority to CN201180032682.9A priority patent/CN102971288B/en
Publication of WO2011136231A1 publication Critical patent/WO2011136231A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings

Definitions

  • the present invention relates to a novel method for producing bisaminophenylalkylurea, which is a diamine compound useful as a raw material for a polymer for producing a liquid crystal alignment film.
  • Some of the bisaminophenylalkylureas produced in the present invention are novel compounds, and therefore the present invention also relates to a process for producing such novel diamine compounds.
  • a polyimide film is often used as a liquid crystal alignment film used in a liquid crystal display element.
  • the liquid crystal alignment film of this polyimide film is a solution of a polyamic acid that is a precursor of polyimide or a solvent-soluble polyimide.
  • the solution is applied to a substrate, fired, and the resulting film is produced by a method of orientation treatment such as rubbing treatment.
  • the polyamic acid and the solvent-soluble polyimide are generally produced by a polycondensation reaction between a tetracarboxylic acid derivative such as tetracarboxylic acid dihydrate and a diamine compound (see Patent Documents 1 and 2).
  • the diamine compound which is a raw material such as polyamic acid and polyimide, is important because it affects the characteristics of the liquid crystal alignment film obtained therefrom, and thus the characteristics of the liquid crystal display element, and various amine compounds have been used conventionally. Proposed.
  • a bisaminophenylalkylurea represented by the following formula (1) has been proposed as International Publication WO2010 / 053128.
  • R 11 and R 21 are each independently an alkylene group having 1 to 3 carbon atoms.
  • Some of such bisaminophenylalkylureas are novel compounds not yet described in the literature prior to the filing of the present application.
  • a nitrophenylalkylamine halide salt and a carbonyl compound such as bis (4-nitro-substituted or unsubstituted phenyl) carbonate are subjected to a condensation reaction in a reaction solvent. It is conceivable to produce a target compound by producing a nitro compound and reducing the nitro compound in a reaction solvent.
  • Another object of the present invention is to provide a production method for obtaining a novel substance that has not been known so far in bisaminophenylalkylurea with high purity and high yield.
  • the present inventor has intensively studied to achieve the above object.
  • the starting material, nitrophenylalkylamine halogenate, and a specific carbonyl compound are subjected to a condensation reaction to produce a nitro compound.
  • a specific organic solvent is used as the reaction solvent and the reaction solvent in the case of producing the desired bisaminophenylurea by reducing the obtained nitro compound, and the above nitro compound is crystallized out.
  • the above object can be achieved by using a specific solvent as a solvent used for crystallization.
  • the present invention has the following gist.
  • a (nitrophenyl) alkylamine halide represented by the following formula (1) and a carbonyl compound represented by the following formula (2) are subjected to a condensation reaction in the presence of a base in an amide solvent.
  • R is an alkylene group having 1 to 3 carbon atoms
  • Y is a phenoxy group or 1-imidazolyl group in which a nitro group may be substituted on any carbon atom.
  • a (nitrophenyl) alkylamine halide represented by the formula (1) and a carbonyl compound represented by the formula (2) are subjected to a condensation reaction in the presence of a base in an amide solvent, A method for producing a nitro compound represented by the above formula (3), wherein lower alcohol is added to the obtained reaction mixture containing the nitro compound represented by the above formula (3) for crystallization.
  • the reaction rate is high, the volumetric efficiency is high, the by-products are low, the purity is high, and the yield is high, as will be apparent from the examples shown in contrast to the comparative examples described later.
  • the target product bisaminophenylalkylurea.
  • bisaminophenylalkylureas bis (4-aminophenylethyl) urea which is a novel compound can be obtained with high purity and high yield.
  • the starting material nitrophenylalkylamineamine halogenate
  • R is an alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group.
  • X is a halogen atom, preferably a chlorine atom or a bromine atom.
  • nitrophenyl alkylamine halide include 2- (4-nitrophenyl) ethylamine (also referred to as 4-nitrophenethylamine) hydrochloride or bromate, and (4-nitrophenyl) methylamine hydrochloride.
  • a salt hydrochloride or bromate may be mentioned.
  • Examples of the carbonyl compound represented by the above formula (2) include bis (4-nitro-substituted or unsubstituted phenyl) carbonate (also referred to as bis (4-nitro-substituted or unsubstituted phenyl) carbonate), carbonyldiimidazole, and the like.
  • the bis (4-nitro-substituted or unsubstituted phenyl) carbonate is preferably bis (4-nitrophenyl) carbonate or bis (4-phenyl) carbonate.
  • the condensation reaction rate is higher than that of a solvent such as tetrahydrofuran, ketone, or alcohol, and therefore the volumetric efficiency is extremely high.
  • the volumetric efficiency of Example 1 reaches 3.5 to 4 times that of Comparative Example 1 using tetrahydrofuran as the reaction solvent.
  • examples of the amide solvent include dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, hexamethylphosphoric triamide, and dimethylformamide is particularly preferable.
  • the nitrophenylalkylamine halide salt and the carbonyl compound are preferably used in an amount of 0.4 to 0.6 mol, particularly preferably 0.45 to 0.5 mol, with respect to 1 mol of the former. .
  • the amide solvent is preferably used in an amount of 0.5 to 10 times, more preferably 5.5 to 6.5 times the weight of the nitrophenylalkylamine halide.
  • various bases are preferably used as a catalyst.
  • Preferred examples of such a base include trialkylamines such as triethylamine, trimethylamine and tripropylamine; 4-NN-dimethylaminopyridine and the like. These bases are preferably used in an amount of 1.5 to 6 mol, particularly preferably 1.8 to 2.2 mol, per mol of the nitrophenylalkylamine halide.
  • the reaction temperature in the above condensation reaction is preferably in the range of 30 to 100 ° C., more preferably 55 to 65 ° C.
  • the specific condensation reaction is preferably carried out as follows. That is, in an inert atmosphere such as nitrogen, the nitrophenylalkylamine halide salt and the carbonyl compound are dissolved in dimethylformamide as a reaction solvent to form a solution, and preferably 30 to 100 with respect to the solution. At 35 ° C., particularly preferably 55 to 65 ° C., triethylamine as a catalyst is preferably added gradually over 5 minutes to 10 hours, preferably with stirring. If necessary, stirring is continued while maintaining the above temperature. Thus, the condensation reaction proceeds, and the nitro compound, which is the target product represented by the above formula (3), is produced.
  • a lower alcohol which is a poor solvent for the nitro compound is added to the obtained reaction mixture containing the nitro compound.
  • the lower alcohol an alcohol having 1 to 3 carbon atoms, more preferably methanol or ethanol, is used.
  • the lower alcohol is preferably added gradually at 30 to 100 ° C., particularly preferably at 55 to 65 ° C., preferably over 5 minutes to 10 hours.
  • the lower alcohol solution of the obtained nitro compound is preferably crystallized by cooling to 0 to 10 ° C.
  • the nitro compound obtained by crystallization is preferably washed with a lower alcohol and dried as necessary.
  • a nitro compound is obtained from a lower alcohol solution of the nitro compound obtained above. Without being crystallized and isolated, it can be used as it is in the next step.
  • the nitro compound represented by the formula (3) is reduced to produce the target bisaminoalkylphenylurea represented by the formula (4).
  • Such a reduction reaction is also carried out in a solvent.
  • the reaction solvent greatly affects the rate of the reduction reaction and greatly affects the volumetric efficiency of the reaction.
  • reaction by-products with the solvent may be generated.
  • a lower alcohol is used as a reaction solvent.
  • tetrahydrofuran or the like which is a common organic solvent, is used as a reaction solvent, volume efficiency is low and a by-product that is an adduct is generated.
  • a catalyst is preferably used.
  • a metal catalyst generally used for catalytic reduction for example, nickel, palladium, platinum, rhodium, ruthenium, cobalt, copper and the like can be used.
  • a palladium catalyst it is preferable to use a palladium catalyst.
  • These catalysts can be used even in a metal state, but usually they are used by being supported on a carrier surface such as carbon, barium sulfate, silica gel, alumina, celite, etc., and nickel, cobalt, copper, etc. are used in Raney.
  • the amount of the catalyst used is not particularly limited, but is preferably 0.01 to 10% by mass with respect to the nitro compound represented by the formula (3). The amount is 8% by mass, and preferably 0.1 to 5% by mass when supported on a carrier.
  • the reducing agent is particularly preferable.
  • the reducing agent is preferably used in an amount of 1 to 15 mol, more preferably 2 to 10 mol, relative to 1 mol of the nitro compound represented by the formula (3).
  • the amount of the reaction solvent to be used is preferably 4 to 30 times by mass, preferably 7.5 to 8.5 times by mass with respect to the nitro compound.
  • the reaction temperature is preferably 40 to 60 ° C, particularly preferably 45 to 55 ° C.
  • the reaction pressure is preferably 0 to 1 MPa-G (gauge pressure), more preferably 0.1 to 0.4 MPa-G.
  • the specific reduction reaction is preferably carried out as follows.
  • a nitro compound as a starting material, a reduction catalyst, and a lower alcohol as a reaction solvent are charged into a reactor such as an autoclave, and hydrogen as a reducing agent is introduced with stirring at preferably 40 to 60 ° C. And preferably stirred for 1 to 20 hours.
  • the end point of the reaction can be determined by the amount of hydrogen absorption or by thin layer chromatography or high performance liquid chromatography.
  • the nitro compound represented by formula (3) is reduced to produce bisaminophenylalkylurea.
  • the produced bisaminophenylalkylurea may be recovered as it is, but can be preferably treated with hydrazine in order to further increase the purity.
  • Hydrazine preferably maintains a lower alcohol solution containing bisaminophenylalkylurea at 4.5 to 5.5 ° C., preferably 0 to 0.3 mol, more preferably 1 mol of bisaminophenylalkylurea. Is carried out by adding 0.15 to 0.25 mol, preferably stirring for 1 minute to 1 hour.
  • the target bisaminophenylalkylurea is recovered from the thus obtained lower alcohol solution containing the bisaminophenylalkylurea represented by the formula (4).
  • This recovery is performed by an existing method. be able to. That is, the lower alcohol solution containing bisaminophenylalkylurea is filtered and washed to remove the used catalyst and the like. A poor solvent is added to crystallize the target product from the filtrate, and bisaminophenylalkylurea is recovered by crystallization. In this case, as the poor solvent, isopropanol, butanol or the like is used.
  • various bisaminophenylalkylureas are produced as described above, and examples thereof include those represented by the following formulas (1-4) to (1-10).
  • those represented by formula (1-6), formula (1-7) and formula (1-8) are novel compounds and are provided for the first time by the present invention. is there.
  • DMF Dimethylformamide
  • DMAP 4-N, N-dimethylaminopyridine
  • THF Tetrahydrofuran
  • BNPU 1,3-bis (4-nitrophenylethyl) urea
  • BAPU 1,3-bis (4-aminophenylethyl) urea
  • Example 1 Synthesis of BNPU A 500 mL four-necked flask was charged with 13.98 g (69.0 mmol) of 4-nitrophenethylamine hydrochloride, 10.00 g (32.9 mmol) of bisnitrophenyl carbonate and 60 g of DMF, and stirred with a blade. The temperature was raised to 60 ° C., and 13.34 g (131.5 mmol) of triethylamine was appropriately reduced at 59 to 63 ° C. over 3 to 5 minutes, followed by stirring at 58 to 62 ° C. for 2 hours. The reaction yield was 94%. Subsequently, 100 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution.
  • Example 1 The reaction in Example 1 is as follows.
  • Comparative Example 1 A 2000 mL jacketed separable flask was charged with 31.50 g (155.4 mmol) of 4-nitrophenethylamine hydrochloride, 1.81 g (14.8 mmol) of DMAP, 89.88 g (888.3 mmol) of triethylamine, and 338 g of THF. While stirring, the temperature was raised to 60 ° C., and a solution obtained by dissolving 22.51 g (74.02 mmol) of bisnitrophenyl carbonate in 225 g of THF was added dropwise at 57 to 63 ° C. over 42 minutes. Subsequently, the mixture was stirred at 58 to 62 ° C. for 4 hours.
  • Example 2 A 120 mL autoclave was charged with 6.01 g (16.8 mmol) of BNPU, 0.076 g of 10% Pd / C (50% wet), 0.60 g of activated carbon and 48 g of methanol, and the temperature was raised to 50 ° C. while stirring with a magnetic stirrer. The mixture was warmed and stirred at 50 to 55 ° C. for 11 hours under a hydrogen gas atmosphere of 0.3 MPa-G. Next, 0.17 g of hydrazine monohydrate was added to the reaction solution, filtered at 50 ° C., and then washed with 12 g of methanol to remove the catalyst and activated carbon.
  • the precipitated crystals were filtered, washed with 6 g of isopropanol, and dried under reduced pressure to obtain 2.18 g of BAPU white crystals (purity 99.2%) (yield 86.5%). It was.
  • the activated carbon was used to prevent coloring of the product, and the ion exchange resin was used to remove contained metals.
  • Comparative Example 2 A 2000 mL autoclave was charged with 18.06 g (50.3 mmol) of BNPU, 0.90 g of 5% Pd / c (50% wet), 1.80 g of activated carbon and 540 g of THF, and the temperature was raised to 40 ° C. while stirring with a blade. The mixture was stirred at 40 to 46 ° C. for 2 hours under a hydrogen gas atmosphere of 0.3 MPa-G. Next, the reaction solution was filtered at 40 ° C. and then washed with 54 g of THF to remove the catalyst and activated carbon.
  • the reaction solution was transferred to a 1000 mL four-necked flask, and 180 g of heptane was added dropwise over 10 to 15 minutes while stirring with a blade. Subsequently, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered, washed with a mixed solvent of 25.2 g of THF and 10.8 g of heptane, and dried under reduced pressure to give 19.38 g of BAPU white crystals (purity 99.3%) ( Yield 85.2%) was obtained. In the metal analysis of the crystal, it was confirmed that Na, K, Al, Ca, Cr, Cu, Mg, Mn, Ni, Fe, Pd, and Zn were all less than 1 ppm.
  • Example 3 A 500 mL four-necked flask was charged with 21.07 g (104 mmol) of 4-nitrophenethylamine hydrochloride, 8.02 g (49.3 mmol) of carbonyldiimidazole and 90 g of DMF. (197.2 mmol) was added dropwise at 57-63 ° C. over 3-5 minutes. Subsequently, 1.21 g (6.6 mmol) of DMAP was added, and the mixture was stirred at 58 to 62 ° C. for 5 hours. Next, 150 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution.
  • Example 4 In a 500 mL four-necked flask, charged with 14.08 g (69.5 mmol) of 4-nitrophenethylamine hydrochloride, 7.07 g (33.0 mmol) of diphenyl carbonate and 60 g of DMF, heated to 60 ° C. while stirring with a blade, 40.03 g of triethylamine (395.6 mmol) was added dropwise at 59-68 ° C. over 3-5 minutes. Subsequently, 0.80 g (6.6 mmol) of DMAP was added, and the mixture was stirred at 58 to 62 ° C. for 5 hours. Next, 100 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution.
  • the bisaminophenylalkylurea produced according to the present invention can be used for various applications.
  • polyamic acid obtained by polycondensation reaction with a tetracarboxylic acid derivative such as tetracarboxylic acid dihydrate, and the polyamic acid can be used.
  • a polyimide obtained by imidizing is useful as a raw material for a polymer for producing a liquid crystal alignment film used in a liquid crystal display element. It should be noted that the entire contents of the specification, claims, drawings and abstract of Japanese Patent Application 2010-105935 filed on April 30, 2010 are cited herein as disclosure of the specification of the present invention. Incorporated.

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Abstract

Disclosed is a process for producing a high-purity bisaminophenylalkylurea as the desired compound in high yield while attaining a high volumetric efficiency and generating little by-product. A (nitrophenyl)alkylamine hydrohalogenide represented by formula (1) and a carbonyl compound represented by formula (2) are subjected to condensation reaction in an amide solvent in the presence of a base to produce a nitro compound represented by formula (3). Subsequently, the obtained nitro compound is reduced in a lower alcohol solvent to thereby produce a bisaminophenylalkylurea represented by formula (4).

Description

ビスアミノフェニルアルキルウレアの新規な製造方法Novel process for producing bisaminophenylalkylurea
　本発明は、液晶配向膜を作製するための重合体の原料などとして有用であるジアミン化合物であるビスアミノフェニルアルキルウレアの新規な製造方法に関する。本発明で製造されるビスアミノフェニルアルキルウレアの一部のものは新規化合物であり、従って、本発明は、かかる新規なジアミン化合物の製造方法にも関する。 The present invention relates to a novel method for producing bisaminophenylalkylurea, which is a diamine compound useful as a raw material for a polymer for producing a liquid crystal alignment film. Some of the bisaminophenylalkylureas produced in the present invention are novel compounds, and therefore the present invention also relates to a process for producing such novel diamine compounds.
　現在、液晶表示素子に用いられる液晶配向膜には、多くの場合、ポリイミド膜が使用されており、このポリイミド膜の液晶配向膜は、ポリイミドの前駆体であるポリアミック酸の溶液又は溶媒可溶性ポリイミドの溶液を基板に塗布し、焼成して、得られる膜をラビング処理などの配向処理する方法により作製されている。（特許文献１、２を参照）、このポリアミック酸や溶媒可溶性ポリイミドは、一般的に、テトラカルボン酸二水物などのテトラカルボン酸誘導体と、ジアミン化合物との縮重合反応によって製造されている。 Currently, a polyimide film is often used as a liquid crystal alignment film used in a liquid crystal display element. The liquid crystal alignment film of this polyimide film is a solution of a polyamic acid that is a precursor of polyimide or a solvent-soluble polyimide. The solution is applied to a substrate, fired, and the resulting film is produced by a method of orientation treatment such as rubbing treatment. The polyamic acid and the solvent-soluble polyimide are generally produced by a polycondensation reaction between a tetracarboxylic acid derivative such as tetracarboxylic acid dihydrate and a diamine compound (see Patent Documents 1 and 2).
　かかるポリアミック酸やポリイミドなどの原料であるジアミン化合物は、これから得られる液晶配向膜の特性、ひいては、液晶表示素子の特性に影響するので重要であり、従来から種々のアミン化合物が使用されており、提案されている。 The diamine compound, which is a raw material such as polyamic acid and polyimide, is important because it affects the characteristics of the liquid crystal alignment film obtained therefrom, and thus the characteristics of the liquid crystal display element, and various amine compounds have been used conventionally. Proposed.
特開平７－１２０７６９号公報JP-A-7-120769 特開平９－１４６１００号公報JP-A-9-146100
　出願人は、先に、かかるジアミン化合物として、ラビング処理時の膜表面への傷や削れが少ない機械的強度が大きく、液晶配向性が良好な液晶配向膜を得られるポリアミック酸やポリイミドの原料として、下記の式（１）で表わされるビスアミノフェニルアルキルウレアを国際公開ＷＯ２０１０／０５３１２８号として提案した。 The applicant previously mentioned, as such a diamine compound, as a raw material for polyamic acid and polyimide, which can obtain a liquid crystal alignment film having a large mechanical strength and a good liquid crystal alignment property with little scratches and scratches on the film surface during rubbing treatment. A bisaminophenylalkylurea represented by the following formula (1) has been proposed as International Publication WO2010 / 053128.
Figure JPOXMLDOC01-appb-C000002
（式中、Ｒ１１及びＲ２１は、相互に独立して、炭素数１～３のアルキレン基である。）
　かかるビスアミノフェニルアルキルウレアの一部のものは、本願出願前の文献未載の新規化合物である。
　一方、かかるビスアミノフェニルアルキルウレアの製造方法としては、ニトロフェニルアルキルアミンハロゲン酸塩と、ビス（４－ニトロ置換又は無置換フェニル）カーボネートなどのカルボニル化合物とを反応溶媒中にて縮合反応させてニトロ化合物を製造し、該ニトロ化合物を反応溶媒中で還元して目的物を製造することが考えられる。
Figure JPOXMLDOC01-appb-C000002
(In the formula, R 11 and R 21 are each independently an alkylene group having 1 to 3 carbon atoms.)
Some of such bisaminophenylalkylureas are novel compounds not yet described in the literature prior to the filing of the present application.
On the other hand, as a method for producing such bisaminophenylalkylurea, a nitrophenylalkylamine halide salt and a carbonyl compound such as bis (4-nitro-substituted or unsubstituted phenyl) carbonate are subjected to a condensation reaction in a reaction solvent. It is conceivable to produce a target compound by producing a nitro compound and reducing the nitro compound in a reaction solvent.
　しかし、この場合、テトラヒドロフラン、ケトン、アルコールなどの通常使用される溶媒中にてビスアミノフェニルアルキルウレアを製造しようとする場合、反応速度が小さく、容積効率が低いため大きな装置が必要とされ、また、ある場合には、溶媒との反応による副生物が生じたり、生成物が着色するなど高純度のものが得られない。
　本発明は、上記の反応により上記ビスアミノフェニルアルキルウレアを製造する場合において、反応速度が高く、容積効率が高く、副生物が少なく、高純度で、かつ高収率にて目的物が得られる方法を提供することを目的とする。
　また、本発明は、ビスアミノフェニルアルキルウレアのうちでもこれまで知られていない新規物質を、高純度で、かつ高収率で得る製造方法を提供することを目的とする。 However, in this case, when bisaminophenylalkylurea is to be produced in a commonly used solvent such as tetrahydrofuran, ketone, alcohol, etc., a large apparatus is required because the reaction rate is low and the volumetric efficiency is low. In some cases, a high-purity product such as a by-product due to reaction with a solvent or a colored product cannot be obtained.
In the present invention, when the bisaminophenylalkylurea is produced by the above reaction, the target product can be obtained with high reaction rate, high volumetric efficiency, few by-products, high purity and high yield. It aims to provide a method.
Another object of the present invention is to provide a production method for obtaining a novel substance that has not been known so far in bisaminophenylalkylurea with high purity and high yield.
　本発明者は、上記の目的を達成するべく鋭意研究を進めたところ、出発原料である、ニトロフェニルアルキルアミンハロゲン酸塩と、特定のカルボニル化合物とを縮合反応させてニトロ化合物を製造する場合の反応溶媒、及び得られたニトロ化合物を還元して目的とするビスアミノフェニルウレアを製造する場合の反応溶媒として、それぞれ、特定の有機溶媒を使用し、また、上記のニトロ化合物を晶析して反応を進める場合には、晶析に使用する溶媒として、特定の溶媒を使用することにより、上記の目的を達成し得ることを見出した。 The present inventor has intensively studied to achieve the above object. As a result, the starting material, nitrophenylalkylamine halogenate, and a specific carbonyl compound are subjected to a condensation reaction to produce a nitro compound. A specific organic solvent is used as the reaction solvent and the reaction solvent in the case of producing the desired bisaminophenylurea by reducing the obtained nitro compound, and the above nitro compound is crystallized out. In the case of advancing the reaction, it has been found that the above object can be achieved by using a specific solvent as a solvent used for crystallization.
　本発明は以下の要旨を有する。
〔１〕下式（１）で表わされる（ニトロフェニル）アルキルアミンハロゲン酸塩と、下式（２）で表わされるカルボニル化合物と、をアミド系溶媒中にて塩基の存在下に縮合反応せしめて下式（３）で表わされるニトロ化合物を製造し、
　次いで、得られる前記ニトロ化合物を低級アルコール溶媒中にて還元反応せしめることを特徴とする、下式（４）で表わされるビスアミノフェニルアルキルウレアの製造方法。 The present invention has the following gist.
[1] A (nitrophenyl) alkylamine halide represented by the following formula (1) and a carbonyl compound represented by the following formula (2) are subjected to a condensation reaction in the presence of a base in an amide solvent. Producing a nitro compound represented by the following formula (3):
Next, the method for producing a bisaminophenylalkylurea represented by the following formula (4), wherein the obtained nitro compound is subjected to a reduction reaction in a lower alcohol solvent.
Figure JPOXMLDOC01-appb-C000003
（式中、Ｒは炭素数１～３のアルキレン基であり、Ｙは、任意の炭素原子上にニトロ基が置換されていてもよいフェノキシ基又は１－イミダゾリル基である。）
Figure JPOXMLDOC01-appb-C000003
(In the formula, R is an alkylene group having 1 to 3 carbon atoms, and Y is a phenoxy group or 1-imidazolyl group in which a nitro group may be substituted on any carbon atom.)
〔２〕前記縮合反応せしめて得られるニトロ化合物を含む反応混合物に対し低級アルコールを添加して晶析せしめて該ニトロ化合物を単離する上記〔１〕記載のビスアミノフェニルアルキルウレアの製造方法。
〔３〕前記縮合反応せしめて得られるニトロ化合物を含む反応混合物に対し低級アルコールを添加して該ニトロ化合物を単離せしめることなく、還元反応せしめる上記〔１〕記載のビスアミノフェニルアルキルウレアの製造方法。
〔４〕前記還元反応せしめて得られるビスアミノフェニルアルキルウレアをヒドラジン処理する上記〔１〕～〔３〕のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。
〔５〕前記（ニトロフェニル）アルキルアミンハロゲン酸塩が、２－（４－ニトロフェニル）エチルアミン塩酸塩若しくは（４－ニトロフェニル）メチルアミン塩酸塩である上記〔１〕～〔４〕のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。
〔６〕前記カルボニル化合物が、ビス（４－ニトロ置換又は無置換フェニル）カーボネート、又はカルボニルジイミダゾールである上記〔１〕～〔５〕のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。
〔７〕前記ビスアミノフェニルアルキルウレアが、ビス（４－アミノフェニルメチル）ウレアである上記〔１〕～〔６〕のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。
〔８〕前記ビスアミノフェニルアルキルウレアが、ビス（４－アミノフェニルエチル）ウレアである上記〔１〕～〔６〕のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。
〔９〕前記式（１）で表わされる（ニトロフェニル）アルキルアミンハロゲン酸塩と、前記式（２）で表わされるカルボニル化合物と、をアミド系溶媒中にて塩基の存在下に縮合反応せしめ、得られる前記式（３）で表わされるニトロ化合物を含む反応混合物に対して低級アルコールを添加して晶析することを特徴とする前記式（３）で表わされるニトロ化合物の製造方法。 [2] The process for producing a bisaminophenylalkylurea according to the above [1], wherein a lower alcohol is added to the reaction mixture containing the nitro compound obtained by the condensation reaction and crystallized to isolate the nitro compound.
[3] Production of bisaminophenylalkylurea as described in [1] above, wherein the reaction mixture containing the nitro compound obtained by the condensation reaction is reduced without adding a lower alcohol to isolate the nitro compound. Method.
[4] The method for producing a bisaminophenylalkylurea according to any one of the above [1] to [3], wherein the bisaminophenylalkylurea obtained by the reduction reaction is treated with hydrazine.
[5] Any of the above [1] to [4], wherein the (nitrophenyl) alkylamine halide is 2- (4-nitrophenyl) ethylamine hydrochloride or (4-nitrophenyl) methylamine hydrochloride A process for producing a bisaminophenylalkylurea as described in 1.
[6] The process for producing a bisaminophenylalkylurea according to any one of the above [1] to [5], wherein the carbonyl compound is bis (4-nitro-substituted or unsubstituted phenyl) carbonate or carbonyldiimidazole.
[7] The process for producing a bisaminophenylalkylurea according to any one of [1] to [6] above, wherein the bisaminophenylalkylurea is bis (4-aminophenylmethyl) urea.
[8] The method for producing a bisaminophenylalkylurea according to any one of [1] to [6], wherein the bisaminophenylalkylurea is bis (4-aminophenylethyl) urea.
[9] A (nitrophenyl) alkylamine halide represented by the formula (1) and a carbonyl compound represented by the formula (2) are subjected to a condensation reaction in the presence of a base in an amide solvent, A method for producing a nitro compound represented by the above formula (3), wherein lower alcohol is added to the obtained reaction mixture containing the nitro compound represented by the above formula (3) for crystallization.
　本発明によれば、後記する比較例と対比して示される実施例から明らかにされるように、反応速度が高く、容積効率が高く、副生物が少なく、高純度で、高収率にて目的物であるビスアミノフェニルアルキルウレアが製造される。
　本発明の製造方法によれば、ビスアミノフェニルアルキルウレアのうちでも、新規化合物であるビス（４－アミノフェニルエチル）ウレアが高純度で、高収率で得られる。 According to the present invention, the reaction rate is high, the volumetric efficiency is high, the by-products are low, the purity is high, and the yield is high, as will be apparent from the examples shown in contrast to the comparative examples described later. The target product, bisaminophenylalkylurea, is produced.
According to the production method of the present invention, among bisaminophenylalkylureas, bis (4-aminophenylethyl) urea which is a novel compound can be obtained with high purity and high yield.
Ａ：ニトロフェニルアルキルアミンハロゲン酸塩と、カルボニル化合物とを縮合反応させてニトロ化合物を製造する工程
　かかる工程は、下記の反応式によって表わされる。
Figure JPOXMLDOC01-appb-C000004
 A: A step of producing a nitro compound by a condensation reaction of a nitrophenylalkylamine halide and a carbonyl compound. This step is represented by the following reaction formula.
Figure JPOXMLDOC01-appb-C000004
　出発物質であるニトロフェニルアルキルアミンアミンハロゲン酸塩は、上記の式（１）で表わされる化合物である。式（１）中、Ｒは、炭素数1～３のアルキレン基であり、好ましくはメチレン基又はエチレン基である。Ｘは、ハロゲン原子であり、好ましくは、塩素原子又は臭素原子である。
　ニトロフェニルアルキルアミンハロゲン酸塩の好ましい具体例としては、２－（４－ニトロフェニル）エチルアミン（４－ニトロフェネチルアミンともいう。）の塩酸塩若しくは臭素酸塩、（４－ニトロフェニル）メチルアミンの塩酸塩の塩酸塩若しくは臭素酸塩が挙げられる。 The starting material, nitrophenylalkylamineamine halogenate, is a compound represented by the above formula (1). In the formula (1), R is an alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group. X is a halogen atom, preferably a chlorine atom or a bromine atom.
Preferable specific examples of the nitrophenyl alkylamine halide include 2- (4-nitrophenyl) ethylamine (also referred to as 4-nitrophenethylamine) hydrochloride or bromate, and (4-nitrophenyl) methylamine hydrochloride. A salt hydrochloride or bromate may be mentioned.
　上記式（２）で表わされるカルボニル化合物としては、ビス（４－ニトロ置換又は無置換フェニル）カーボネート（炭酸ビス（４－ニトロ置換又は無置換フェニル）ともいう）、カルボニルジイミダゾールなどが挙げられる。ビス（４－ニトロ置換又は無置換フェニル）カーボネートとしては、好ましくはビス（４－ニトロフェニル）カーボネート、又はビス（４－フェニル）カーボネートが挙げられる。
　上記の縮合反応は、有機溶媒中で行われるが、本発明者の知見によると、かかる反応溶媒は、縮合反応の速度に大きく影響し、その結果、反応の容積効率に大きく影響することが見出された。すなわち、反応溶媒として、アミド系溶媒を使用した場合には、テトラヒドロフラン、ケトン、アルコールなどの溶媒に比べて、縮合反応速度が大きく、従って、容積効率が極めて大きいことが判明した。この結果、例えば、反応溶媒としてテトラヒドロフランを使用する比較例１の容積効率と比べて、実施例１の容積効率は３．５～４倍にも達する。 Examples of the carbonyl compound represented by the above formula (2) include bis (4-nitro-substituted or unsubstituted phenyl) carbonate (also referred to as bis (4-nitro-substituted or unsubstituted phenyl) carbonate), carbonyldiimidazole, and the like. The bis (4-nitro-substituted or unsubstituted phenyl) carbonate is preferably bis (4-nitrophenyl) carbonate or bis (4-phenyl) carbonate.
Although the above condensation reaction is carried out in an organic solvent, according to the knowledge of the present inventor, such a reaction solvent greatly affects the rate of the condensation reaction, and as a result, greatly affects the volumetric efficiency of the reaction. It was issued. That is, it was found that when an amide solvent is used as the reaction solvent, the condensation reaction rate is higher than that of a solvent such as tetrahydrofuran, ketone, or alcohol, and therefore the volumetric efficiency is extremely high. As a result, for example, the volumetric efficiency of Example 1 reaches 3.5 to 4 times that of Comparative Example 1 using tetrahydrofuran as the reaction solvent.
　本発明において、上記アミド系溶媒としては、ジメチルホルムアミド（ＤＭＦ）、Ｎ,Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、Ｎ－エチルピロリドン、へキサメチルリン酸トリアミドなどが挙げられるが、特にジメチルホルムアミドが好ましい。
　ニトロフェニルアルキルアミンハロゲン酸塩とカルボニル化合物とは、前者の１モルに対して、後者は、好ましくは０．４～０．６モル、特に好ましくは０．４５～０．５モルが使用される。
　上記アミド系溶媒は、ニトロフェニルアルキルアミンハロゲン酸塩に対して、好ましくは０．５～１０質量倍、より好ましくは５．５～６．５質量倍使用される。
　上記縮合反応においては、好ましくは　触媒として、各種の塩基が使用される。かかる塩基の好ましい例としてしては、トリエチルアミン、トリメチルアミン、トリプロピルアミンなどのトリアルキルアミン；　　４－ＮＮ－ジメチルアミノピリジンなどが使用される。これらの塩基は、ニトロフェニルアルキルアミンハロゲン酸塩の１モルに対して、後者は、好ましくは１．５～６モル、特に好ましくは１．８～２．２モルが使用される。 In the present invention, examples of the amide solvent include dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, hexamethylphosphoric triamide, and dimethylformamide is particularly preferable.
The nitrophenylalkylamine halide salt and the carbonyl compound are preferably used in an amount of 0.4 to 0.6 mol, particularly preferably 0.45 to 0.5 mol, with respect to 1 mol of the former. .
The amide solvent is preferably used in an amount of 0.5 to 10 times, more preferably 5.5 to 6.5 times the weight of the nitrophenylalkylamine halide.
In the condensation reaction, various bases are preferably used as a catalyst. Preferred examples of such a base include trialkylamines such as triethylamine, trimethylamine and tripropylamine; 4-NN-dimethylaminopyridine and the like. These bases are preferably used in an amount of 1.5 to 6 mol, particularly preferably 1.8 to 2.2 mol, per mol of the nitrophenylalkylamine halide.
　上記の縮合反応における反応温度は、好ましくは３０～１００℃の範囲、より好ましくは５５～６５℃である。
　具体的な縮合反応は、好ましくは下記のようにして実施される。すなわち、窒素などの不活性雰囲気中にて、ニトロフェニルアルキルアミンハロゲン酸塩、及び上記カルボニル化合物を反応溶媒であるジメチルホルムアミド中に溶解して溶液とし、該溶液に対して、好ましくは３０～１００℃、特に好ましくは５５～６５℃にて、触媒であるトリエチルアミンが好ましくは撹拌しながら好ましくは５分～１０時間かけて徐々に添加される。必要に応じて、さらに上記の温度を維持しながら撹拌を続ける。かくして、縮合反応は進行し、上記式（３）で表わされる目的物であるニトロ化合物が製造される。 The reaction temperature in the above condensation reaction is preferably in the range of 30 to 100 ° C., more preferably 55 to 65 ° C.
The specific condensation reaction is preferably carried out as follows. That is, in an inert atmosphere such as nitrogen, the nitrophenylalkylamine halide salt and the carbonyl compound are dissolved in dimethylformamide as a reaction solvent to form a solution, and preferably 30 to 100 with respect to the solution. At 35 ° C., particularly preferably 55 to 65 ° C., triethylamine as a catalyst is preferably added gradually over 5 minutes to 10 hours, preferably with stirring. If necessary, stirring is continued while maintaining the above temperature. Thus, the condensation reaction proceeds, and the nitro compound, which is the target product represented by the above formula (3), is produced.
　得られたニトロ化合物を含む反応混合物に対して、該ニトロ化合物に対する貧溶媒である低級アルコールが添加される。低級アルコールとしては、炭素数が好ましくは１～３のアルコール、より好ましくはメタノール、エタノールが使用される。低級アルコールは、好ましくは３０～１００℃、特に好ましくは５５～６５℃にて、好ましくは５分～１０時間かけて徐々に添加される。
　次いで、得られるニトロ化合物の低級アルコール溶液は、好ましくは０～１０℃に冷却することにより晶析される。晶析により得られたニトロ化合物は、必要に応じて、好ましくは低級アルコールにより洗浄し、乾燥せしめられる。 A lower alcohol which is a poor solvent for the nitro compound is added to the obtained reaction mixture containing the nitro compound. As the lower alcohol, an alcohol having 1 to 3 carbon atoms, more preferably methanol or ethanol, is used. The lower alcohol is preferably added gradually at 30 to 100 ° C., particularly preferably at 55 to 65 ° C., preferably over 5 minutes to 10 hours.
Next, the lower alcohol solution of the obtained nitro compound is preferably crystallized by cooling to 0 to 10 ° C. The nitro compound obtained by crystallization is preferably washed with a lower alcohol and dried as necessary.
　なお、得られたニトロ化合物からビスアミノアルキルフェニルウレアを製造する場合は、本発明では、反応溶媒として、低級アルコールが使用されるので、上記で得られたニトロ化合物の低級アルコール溶液から、ニトロ化合物を晶析して単離することなく、そのまま、次工程において使用することが可能である。 In the case of producing bisaminoalkylphenylurea from the obtained nitro compound, since a lower alcohol is used as a reaction solvent in the present invention, a nitro compound is obtained from a lower alcohol solution of the nitro compound obtained above. Without being crystallized and isolated, it can be used as it is in the next step.
Ｂ：ニトロ化合物を還元してビスアミノフェニルウレアを製造する工程
　かかる工程は、下記の反応式によって表わされる。
Figure JPOXMLDOC01-appb-C000005
 B: Step of producing bisaminophenylurea by reducing a nitro compound This step is represented by the following reaction formula.
Figure JPOXMLDOC01-appb-C000005
　上記のように、式（３）で表わされるニトロ化合物は、還元されて目的物である式（４）で表わされるビスアミノアルキルフェニルウレアが製造される。かかる還元反応も、溶媒中で行われるが、その場合の反応溶媒も、還元反応の速度に大きく影響し、反応の容積効率に大きく影響する。同時に、使用する溶媒によっては溶媒との反応副生物が生じる場合がある。
　本発明では、反応溶媒として、低級アルコールが使用され、その結果、大きい容積効率が得られるとともに、溶媒との反応副生物が生じることはない。例えば、反応溶媒として一般的な有機溶媒である、テトラヒドロフランなどを使用した場合には、容積効率が小さいとともに、付加物である副生物が生じてしまう。 As described above, the nitro compound represented by the formula (3) is reduced to produce the target bisaminoalkylphenylurea represented by the formula (4). Such a reduction reaction is also carried out in a solvent. In this case, the reaction solvent greatly affects the rate of the reduction reaction and greatly affects the volumetric efficiency of the reaction. At the same time, depending on the solvent used, reaction by-products with the solvent may be generated.
In the present invention, a lower alcohol is used as a reaction solvent. As a result, a large volumetric efficiency is obtained and no reaction by-product with the solvent is generated. For example, when tetrahydrofuran or the like, which is a common organic solvent, is used as a reaction solvent, volume efficiency is low and a by-product that is an adduct is generated.
　上記の還元反応では好ましくは触媒が使用される。かかる触媒としては、一般に接触還元に用いられている金属触媒、例えばニッケル、パラジウム、白金、ロジウム、ルテニウム、コバルト、銅などを使用することができる。工業的にはパラジウム触媒を使用するのが好ましい。これらの触媒は、金属の状態でも使用することができるが、通常は、カーボン、硫酸バリウム、シリカゲル、アルミナ、セライトなどの担体表面に担持させて用いたり、また、ニッケル、コバルト、銅などはラネー触媒としても用いられる。
　触媒の使用量は特に制限はないが、式（３）で表されるニトロ化合物に対して好ましくは０．０１～１０質量％であり、通常、金属の状態で使用する場合は好ましくは２～８質量％であり、担体に担持させた場合では好ましくは０．１～５質量％である。 In the above reduction reaction, a catalyst is preferably used. As such a catalyst, a metal catalyst generally used for catalytic reduction, for example, nickel, palladium, platinum, rhodium, ruthenium, cobalt, copper and the like can be used. Industrially, it is preferable to use a palladium catalyst. These catalysts can be used even in a metal state, but usually they are used by being supported on a carrier surface such as carbon, barium sulfate, silica gel, alumina, celite, etc., and nickel, cobalt, copper, etc. are used in Raney. Also used as a catalyst.
The amount of the catalyst used is not particularly limited, but is preferably 0.01 to 10% by mass with respect to the nitro compound represented by the formula (3). The amount is 8% by mass, and preferably 0.1 to 5% by mass when supported on a carrier.
　還元剤としては、特に水素が好ましい。還元剤は、式（３）で表されるニトロ化合物の１モルに対して好ましくは１～１５モル、より好ましくは２～１０モル使用される。
　反応溶媒の使用量は、ニトロ化合物に対して好ましくは４～３０質量倍、好ましくは７．５～８．５質量倍である。反応温度は、好ましくは４０～６０℃、特に４５～５５℃が好ましい。また反応圧力は、好ましくは０～１ＭＰa‐Ｇ（ゲージ圧）、より好ましくは０．１～０．４ＭＰa‐Ｇである。具体的な還元反応は、好ましくは下記のようにして実施される。すなわち、オートクレーブなどの反応器中に、出発原料であるニトロ化合物、還元触媒、及び反応溶媒である低級アルコールを仕込み、好ましくは４０～６０℃にて、撹拌下に、還元剤である水素が導入され、好ましくは１～２０時間、撹拌される。反応の終点は水素吸収量によっても、あるいは薄層クロマトグラフィーや高速液体クロマトグラフィーなどによっても決定できる。 As the reducing agent, hydrogen is particularly preferable. The reducing agent is preferably used in an amount of 1 to 15 mol, more preferably 2 to 10 mol, relative to 1 mol of the nitro compound represented by the formula (3).
The amount of the reaction solvent to be used is preferably 4 to 30 times by mass, preferably 7.5 to 8.5 times by mass with respect to the nitro compound. The reaction temperature is preferably 40 to 60 ° C, particularly preferably 45 to 55 ° C. The reaction pressure is preferably 0 to 1 MPa-G (gauge pressure), more preferably 0.1 to 0.4 MPa-G. The specific reduction reaction is preferably carried out as follows. That is, a nitro compound as a starting material, a reduction catalyst, and a lower alcohol as a reaction solvent are charged into a reactor such as an autoclave, and hydrogen as a reducing agent is introduced with stirring at preferably 40 to 60 ° C. And preferably stirred for 1 to 20 hours. The end point of the reaction can be determined by the amount of hydrogen absorption or by thin layer chromatography or high performance liquid chromatography.
　かくして式（３）で表されるニトロ化合物は還元され、ビスアミノフェニルアルキルウレアが製造される。生成したビスアミノフェニルアルキルウレアはそのまま回収してもよいが、より純度を高めるために、好ましくは、ヒドラジンで処理することができる。ヒドラジンは、ビスアミノフェニルアルキルウレアを含む低級アルコール溶液を好ましくは４．５～５．５℃に保持し、ビスアミノフェニルアルキルウレアの１モルに対して好ましくは０～０．３モル、より好ましくは、０．１５～０．２５モル添加し、好ましくは１分～１時間撹拌することにより行われる。 Thus, the nitro compound represented by formula (3) is reduced to produce bisaminophenylalkylurea. The produced bisaminophenylalkylurea may be recovered as it is, but can be preferably treated with hydrazine in order to further increase the purity. Hydrazine preferably maintains a lower alcohol solution containing bisaminophenylalkylurea at 4.5 to 5.5 ° C., preferably 0 to 0.3 mol, more preferably 1 mol of bisaminophenylalkylurea. Is carried out by adding 0.15 to 0.25 mol, preferably stirring for 1 minute to 1 hour.
　このようにして得られた式（４）で表わされるビスアミノフェニルアルキルウレアを含む低級アルコール溶液から、目的であるビスアミノフェニルアルキルウレアが回収されるが、この回収は、既存の方法にておこなうことができる。すなわち、ビスアミノフェニルアルキルウレアを含む低級アルコール溶液を濾過し洗浄し、使用した触媒などを除去する。濾液から目的物を晶析するために貧溶媒を添加し、晶析によりビスアミノフェニルアルキルウレアが回収される。この場合の貧溶媒としては、イソプロパノール、ブタノールなどが使用される。 The target bisaminophenylalkylurea is recovered from the thus obtained lower alcohol solution containing the bisaminophenylalkylurea represented by the formula (4). This recovery is performed by an existing method. be able to. That is, the lower alcohol solution containing bisaminophenylalkylurea is filtered and washed to remove the used catalyst and the like. A poor solvent is added to crystallize the target product from the filtrate, and bisaminophenylalkylurea is recovered by crystallization. In this case, as the poor solvent, isopropanol, butanol or the like is used.
　本発明によれば上記のようにして種々のビスアミノフェニルアルキルウレアが製造されるが、その例としては下記の式（１－４）～式（１－１０）で表わされるものが挙げられる。かかるビスアミノフェニルアルキルウレアのうち、式（１－６）、式（１－７）及び式（１－８）で表わされるものは、新規な化合物であり、本発明により初めて提供されるものである。 According to the present invention, various bisaminophenylalkylureas are produced as described above, and examples thereof include those represented by the following formulas (1-4) to (1-10). Among such bisaminophenylalkylureas, those represented by formula (1-6), formula (1-7) and formula (1-8) are novel compounds and are provided for the first time by the present invention. is there.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　以下に実施例を挙げ、本発明を更に詳しく説明するが、本発明はこれらに限定して解釈されるものではない。
　ＤＭＦ：ジメチルホルムアミド
　ＤＭＡＰ： ４－Ｎ，Ｎ－ジメチルアミノピリジン
　ＴＨＦ：テトラヒドロフラン
　ＢＮＰＵ： １，３－ビス（４－ニトロフェニルエチル）ウレア
　ＢＡＰＵ：１，３－ビス（４－アミノフェニルエチル）ウレア The present invention will be described in more detail with reference to the following examples, but the present invention should not be construed as being limited thereto.
DMF: Dimethylformamide DMAP: 4-N, N-dimethylaminopyridine THF: Tetrahydrofuran BNPU: 1,3-bis (4-nitrophenylethyl) urea BAPU: 1,3-bis (4-aminophenylethyl) urea
実施例１：ＢＮＰＵの合成
　５００ｍＬの四つ口フラスコに、4-ニトロフェネチルアミン塩酸塩 １３．９８ｇ （６９．０ｍｍｏｌ）、ビスニトロフェニルカーボネート１０．００ｇ （３２．９ｍｍｏｌ）及びＤＭＦ ６０ｇを仕込み、羽根攪拌下に、６０℃に昇温し、トリエチルアミン １３．３４ｇ （１３１．５ｍｍｏｌ）を５９～６３℃で３～５分かけて適下し、５８～６２℃で２時間撹拌した。反応収率は９４％であった。
　次いで、メタノール １００ｇを１０～１５分かけて滴下し、反応液を全溶させた。続いて、５℃まで冷却し、析出した結晶をろ過後、メタノール８０ｇで洗浄し、減圧乾燥すると白色結晶 １０．０１ｇ (純度９９．７％) （収率８６．０％)が得られた。 Example 1: Synthesis of BNPU A 500 mL four-necked flask was charged with 13.98 g (69.0 mmol) of 4-nitrophenethylamine hydrochloride, 10.00 g (32.9 mmol) of bisnitrophenyl carbonate and 60 g of DMF, and stirred with a blade. The temperature was raised to 60 ° C., and 13.34 g (131.5 mmol) of triethylamine was appropriately reduced at 59 to 63 ° C. over 3 to 5 minutes, followed by stirring at 58 to 62 ° C. for 2 hours. The reaction yield was 94%.
Subsequently, 100 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution. Subsequently, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered, washed with 80 g of methanol, and dried under reduced pressure to obtain 10.01 g (purity 99.7%) of white crystals (yield 86.0%).
　この結晶は、１Ｈ ＮＭＲ分析結果より、ＢＮＰＵであることを確認した。
　1H NMR (DMSO-d6, δppm) : 8.2 (d, J=8.6Hz, 4H), 7.5 (d, J=8.8Hz, 4H), 5.9 (t, J=5.6Hz, 2H), 3.3 (dt, J=6.8, 6.1Hz 4H), 2.8 (t, J=6.8Hz, 4H) This crystal was confirmed to be BNPU from 1H NMR analysis results.
1H NMR (DMSO-d6, δppm): 8.2 (d, J = 8.6Hz, 4H), 7.5 (d, J = 8.8Hz, 4H), 5.9 (t, J = 5.6Hz, 2H), 3.3 (dt, J = 6.8, 6.1Hz 4H), 2.8 (t, J = 6.8Hz, 4H)
　上記実施例１における反応は、以下のとおりである。
Figure JPOXMLDOC01-appb-C000007
 The reaction in Example 1 is as follows.
Figure JPOXMLDOC01-appb-C000007
比較例１
　２０００ｍＬのジャケット付セパラブルフラスコに、4-ニトロフェネチルアミン塩酸塩 ３１．５０ｇ （１５５．４ｍｍｏｌ）、ＤＭＡＰ １．８１ｇ （１４．８ｍｍｏｌ）、トリエチルアミン ８９．８８ｇ (８８８．３ｍｍｏｌ) 及びＴＨＦ ３３８ｇを仕込み、羽根攪拌下に、６０℃に昇温し、ビスニトロフェニルカーボネート２２．５１ｇ （７４．０２ｍｍｏｌ）をＴＨＦ２２５ｇに溶解した溶液を、５７～６３℃で４２分かけて滴下した。続いて、５８～６２℃で４時間攪拌した。 Comparative Example 1
A 2000 mL jacketed separable flask was charged with 31.50 g (155.4 mmol) of 4-nitrophenethylamine hydrochloride, 1.81 g (14.8 mmol) of DMAP, 89.88 g (888.3 mmol) of triethylamine, and 338 g of THF. While stirring, the temperature was raised to 60 ° C., and a solution obtained by dissolving 22.51 g (74.02 mmol) of bisnitrophenyl carbonate in 225 g of THF was added dropwise at 57 to 63 ° C. over 42 minutes. Subsequently, the mixture was stirred at 58 to 62 ° C. for 4 hours.
　次いで、メチルイソブチルケトン １１３ｇ、水酸化ナトリウム ４７．３７ｇ （１１８４ｍｍｏｌ） を溶解した純水 ４５０ｇを添加し、６０℃にて攪拌後、水層を除去した。続いて、有機層を純水 ４５０ｇを用いて洗浄し水層を除去する工程を、２回繰り返した。続いて、ヘプタン ２２５ｇを１０～１５分かけて滴下した。２０℃まで冷却し、析出した結晶をろ過後、メタノール１１３ｇで洗浄し、減圧乾燥するとＢＮＰＵの淡黄色結晶 ２２．７０ｇ (純度９９．８％) (収率８５．６％)が得られた。 Next, 450 g of pure water solution in which 113 g of methyl isobutyl ketone and 47.37 g of sodium hydroxide (1184 mmol) were dissolved was added and stirred at 60 ° C., and then the aqueous layer was removed. Subsequently, the process of washing the organic layer with 450 g of pure water tank and removing the aqueous layer was repeated twice. Subsequently, 225 g of heptane cake was added dropwise over 10 to 15 minutes. After cooling to 20 ° C., the precipitated crystals were filtered, washed with 113 g of methanol, and dried under reduced pressure to obtain 22.70 g 淡 (purity 99.8%) (yield 85.6%) of BNPU.
参考例
　４－ニトロフェネチルアミン塩酸塩６０g （３９６mmol）及びＯＤＢ（オルトジクロロベンゼン）７２０gを仕込み、１２０℃でホスゲンガス（１．５～２．２mol）を５～６時間吹き込んだ。また、４－ニトロフェネチルアミン塩酸塩３０g（１４８mmol）を水に溶解し、４８％水酸化ナトリウム溶液を添加することによりフリー化し、ＯＤＢ３００mLで抽出したものを、先の溶液に添加した。
　析出した結晶を濾化後、固体をジメチルホルムアミド８００mlで再溶解し、水５００gを添加した。再度析出した結晶を濾化後、減圧乾燥するとＢＮＰＵのクリム色結晶 ４８．７ｇ (純度９９．３％) (収率９２％)が得られた。 Reference Example 4-Nitrophenethylamine hydrochloride 60 g (396 mmol) and ODB (orthodichlorobenzene) 720 g were charged, and phosgene gas (1.5 to 2.2 mol) was blown at 120 ° C. for 5 to 6 hours. Also, 30 g (148 mmol) of 4-nitrophenethylamine hydrochloride was dissolved in water, made free by adding a 48% sodium hydroxide solution, and extracted with 300 mL of ODB was added to the previous solution.
After the precipitated crystals were filtered, the solid was redissolved with 800 ml of dimethylformamide, and 500 g of water was added. The precipitated crystals were filtered again and dried under reduced pressure to obtain 48.7 g (purity 99.3%) (yield 92%) of BNPU-crime crystals.
実施例２：
　１２０ｍＬのオートクレーブに、ＢＮＰＵ ６．０１ｇ （１６．８ｍｍｏｌ）、１０%Pd/C(５０％wet) ０．０７６ｇ、活性炭 ０．６０ｇ 及びメタノール ４８ｇを仕込み、マグネチックスターラー攪拌下に、５０℃に昇温し、０．３ＭＰａ－Ｇの水素ガス雰囲気下、５０～５５℃で１１時間攪拌した。
　次いで、反応液にヒドラジン一水和物 ０．１７ｇを加え、５０℃でろ過後、メタノール １２ｇで洗浄し、触媒と活性炭を除去した。反応液の３/４を、１００ｍＬ四つ口フラスコに移し、強酸性Ｈ＋型イオン交換樹脂１．４ｇを添加し、５０℃で1時間攪拌し、ろ過後、メタノール ９ｇで洗浄した。この反応液の２/３を、イソプロパノール １２ｇを添加した後に、１２０～１５０Ｔｏｒｒ,４０℃で１５ｇまで濃縮し、イソプロパノール １５ｇを滴下した。続いて、５℃まで冷却し、析出した結晶をろ過後、イソプロパノール６ｇで洗浄し、減圧乾燥するとＢＡＰＵの白色結晶 ２．１８ｇ (純度９９．２％) (収率８６．５％)が得られた。なお、上記活性炭は、生成物の着色を防ぐため、また、イオン交換樹脂は、含有金属を除去するために使用した。 Example 2:
A 120 mL autoclave was charged with 6.01 g (16.8 mmol) of BNPU, 0.076 g of 10% Pd / C (50% wet), 0.60 g of activated carbon and 48 g of methanol, and the temperature was raised to 50 ° C. while stirring with a magnetic stirrer. The mixture was warmed and stirred at 50 to 55 ° C. for 11 hours under a hydrogen gas atmosphere of 0.3 MPa-G.
Next, 0.17 g of hydrazine monohydrate was added to the reaction solution, filtered at 50 ° C., and then washed with 12 g of methanol to remove the catalyst and activated carbon. 3/4 of the reaction solution was transferred to a 100 mL four-necked flask, 1.4 g of strongly acidic H + -type ion exchange resin was added, stirred at 50 ° C. for 1 hour, filtered, and washed with 9 g of methanol. After adding 12 g of isopropanol, 2/3 of this reaction solution was concentrated to 15 g at 120 to 150 Torr and 40 ° C., and 15 g of isopropanol was added dropwise. Subsequently, after cooling to 5 ° C., the precipitated crystals were filtered, washed with 6 g of isopropanol, and dried under reduced pressure to obtain 2.18 g of BAPU white crystals (purity 99.2%) (yield 86.5%). It was. The activated carbon was used to prevent coloring of the product, and the ion exchange resin was used to remove contained metals.
　この結晶は、１Ｈ ＮＭＲ分析結果より、ＢＡＰＵであることを確認した。
　1H NMR (DMSO-d6, δppm) : 6.8 (d, J=7.8Hz, 4H), 6.5 (d, J=7.6Hz, 4H), 5.8 (t, J=5.4Hz, 2H), 3.8 (dt, J=6.6, 6.4Hz 4H), 2.5 (t, J=6.9Hz, 4H)
　尚、結晶の金属分析では、Ｎａ、Ｋ、Ａｌ、Ｃａ、Ｃｒ、Ｃｕ、Ｍｇ、Ｍｎ、Ｎｉ、Ｆｅ、Ｐｄ、Ｚｎはいずれも１ｐｐｍ未満であることを確認した。 This crystal was confirmed to be BAPU from 1H NMR analysis results.
1H NMR (DMSO-d6, δppm): 6.8 (d, J = 7.8Hz, 4H), 6.5 (d, J = 7.6Hz, 4H), 5.8 (t, J = 5.4Hz, 2H), 3.8 (dt, J = 6.6, 6.4Hz 4H), 2.5 (t, J = 6.9Hz, 4H)
In the metal analysis of the crystal, it was confirmed that all of Na, K, Al, Ca, Cr, Cu, Mg, Mn, Ni, Fe, Pd, and Zn were less than 1 ppm.
　上記実施例における反応は、以下のとおりである。
Figure JPOXMLDOC01-appb-C000008
 The reactions in the above examples are as follows.
Figure JPOXMLDOC01-appb-C000008
比較例２
　２０００ｍＬのオートクレーブに、ＢＮＰＵ １８．０６ｇ （５０．３ｍｍｏｌ）、５％Ｐｄ/ｃ（５０％ｗｅｔ） ０．９０ｇ、活性炭 １．８０ｇ 及びＴＨＦ ５４０ｇを仕込み、羽根攪拌下に、４０℃に昇温し、０．３ＭＰａ－Ｇの水素ガス雰囲気下、４０～４６℃で2時間攪拌した。
　次いで、反応液を４０℃でろ過後、ＴＨＦ ５４ｇで洗浄し、触媒と活性炭を除去した。反応液を、１０００ｍＬの四つ口フラスコに移し、羽根攪拌下に、ヘプタン １８０ｇを１０～１５分かけて滴下した。続いて、５℃まで冷却し、析出した結晶をろ過後、ＴＨＦ ２５．２ｇ とヘプタン１０．８ｇの混合溶媒で洗浄し、減圧乾燥するとＢＡＰＵの白色結晶 １９．３８ｇ (純度９９．３％) (収率８５．２％)が得られた。
　なお、結晶の金属分析では、Na,K,Al,Ca,Cr,Cu,Mg,Mn,Ni,Fe,Pd,Znいずれも1ppm未満であることを確認した。 Comparative Example 2
A 2000 mL autoclave was charged with 18.06 g (50.3 mmol) of BNPU, 0.90 g of 5% Pd / c (50% wet), 1.80 g of activated carbon and 540 g of THF, and the temperature was raised to 40 ° C. while stirring with a blade. The mixture was stirred at 40 to 46 ° C. for 2 hours under a hydrogen gas atmosphere of 0.3 MPa-G.
Next, the reaction solution was filtered at 40 ° C. and then washed with 54 g of THF to remove the catalyst and activated carbon. The reaction solution was transferred to a 1000 mL four-necked flask, and 180 g of heptane was added dropwise over 10 to 15 minutes while stirring with a blade. Subsequently, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered, washed with a mixed solvent of 25.2 g of THF and 10.8 g of heptane, and dried under reduced pressure to give 19.38 g of BAPU white crystals (purity 99.3%) ( Yield 85.2%) was obtained.
In the metal analysis of the crystal, it was confirmed that Na, K, Al, Ca, Cr, Cu, Mg, Mn, Ni, Fe, Pd, and Zn were all less than 1 ppm.
実施例３
　500mLの四つ口フラスコに、4-ニトロフェネチルアミン塩酸塩 21.07g （104mmol）、カルボニルジイミダゾール8.02g （49.3 mmol）及びDMF 90gを仕込み、羽根攪拌下に、60℃に昇温し、トリエチルアミン 19.97g (197.2mmol)を57～63℃で3～5分かけて滴下した。続いて、DMAP 1.21g （6.6mmol）を添加し、58～62℃で5時間攪拌した。
　次いで、メタノール 150gを10～15分かけて滴下し、反応液を全溶させた。続いて、5℃まで冷却し、析出した結晶をろ過後、メタノール120gで洗浄し、減圧乾燥するとBNPU白色結晶 14.8g (純度100%) (収率84.2%)が得られた。 Example 3
A 500 mL four-necked flask was charged with 21.07 g (104 mmol) of 4-nitrophenethylamine hydrochloride, 8.02 g (49.3 mmol) of carbonyldiimidazole and 90 g of DMF. (197.2 mmol) was added dropwise at 57-63 ° C. over 3-5 minutes. Subsequently, 1.21 g (6.6 mmol) of DMAP was added, and the mixture was stirred at 58 to 62 ° C. for 5 hours.
Next, 150 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution. Subsequently, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered, washed with 120 g of methanol, and dried under reduced pressure to obtain 14.8 g of BNPU white crystals (purity 100%) (yield 84.2%).
実施例４
　500mLの四つ口フラスコに、4-ニトロフェネチルアミン塩酸塩 14.08g （69.5mmol）、ジフェニルカーボネート7.07g （33.0mmol）及びDMF 60gを仕込み、羽根攪拌下に、60℃に昇温し、トリエチルアミン 40.03g (395.6mmol)を59～68℃で3～5分かけて滴下した。続いて、DMAP 0.80g （6.6mmol）を添加し、58～62℃で5時間攪拌した。
　次いで、メタノール 100gを10～15分かけて滴下し、反応液を全溶させた。続いて、5℃まで冷却し、析出した結晶をろ過後、メタノール80gで洗浄し、減圧乾燥するとBNPUの極薄い淡黄色結晶 9.80g (純度100%) (収率82.9%)が得られた。 Example 4
In a 500 mL four-necked flask, charged with 14.08 g (69.5 mmol) of 4-nitrophenethylamine hydrochloride, 7.07 g (33.0 mmol) of diphenyl carbonate and 60 g of DMF, heated to 60 ° C. while stirring with a blade, 40.03 g of triethylamine (395.6 mmol) was added dropwise at 59-68 ° C. over 3-5 minutes. Subsequently, 0.80 g (6.6 mmol) of DMAP was added, and the mixture was stirred at 58 to 62 ° C. for 5 hours.
Next, 100 g of methanol was added dropwise over 10 to 15 minutes to completely dissolve the reaction solution. Subsequently, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered, washed with 80 g of methanol, and dried under reduced pressure to obtain 9.80 g (purity: 100%) (yield: 82.9%) of BNPU.
　本発明により製造されたビスアミノフェニルアルキルウレアは、種々の用途に使用できるが、なかでも、テトラカルボン酸二水物などのテトラカルボン酸誘導体と縮重合反応させて得られるポリアミック酸や該ポリアミック酸をイミド化したポリイミドなどは、液晶表示素子に用いられる液晶配向膜を作製するための重合体の原料として有用である。
　なお、２０１０年４月３０日に出願された日本特許出願２０１０－１０５９３５号の明細書、特許請求の範囲、図面及び要約書の全内容をここに引用し、本発明の明細書の開示として、取り入れるものである。 The bisaminophenylalkylurea produced according to the present invention can be used for various applications. Among them, polyamic acid obtained by polycondensation reaction with a tetracarboxylic acid derivative such as tetracarboxylic acid dihydrate, and the polyamic acid can be used. A polyimide obtained by imidizing is useful as a raw material for a polymer for producing a liquid crystal alignment film used in a liquid crystal display element.
It should be noted that the entire contents of the specification, claims, drawings and abstract of Japanese Patent Application 2010-105935 filed on April 30, 2010 are cited herein as disclosure of the specification of the present invention. Incorporated.

Claims (9)

  1. 　下式（１）で表わされる（ニトロフェニル）アルキルアミンハロゲン酸塩と、下式（２）で表わされるカルボニル化合物と、をアミド系溶媒中にて塩基の存在下に縮合反応せしめて下式（３）で表わされるニトロ化合物を製造し、
    　次いで、得られる前記ニトロ化合物を低級アルコール溶媒中にて還元反応せしめることを特徴とする、下式（４）で表わされるビスアミノフェニルアルキルウレアの製造方法。
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ｒは炭素数１～３のアルキレン基であり、Ｙは、任意の炭素原子上にニトロ基が置換されていてもよいフェノキシ基又は１－イミダゾリル基である。）     A (nitrophenyl) alkylamine halide salt represented by the following formula (1) and a carbonyl compound represented by the following formula (2) are subjected to a condensation reaction in the presence of a base in an amide solvent to obtain the following formula ( 3) producing a nitro compound represented by
    Next, the method for producing a bisaminophenylalkylurea represented by the following formula (4), wherein the obtained nitro compound is subjected to a reduction reaction in a lower alcohol solvent.
    Figure JPOXMLDOC01-appb-C000001
    (In the formula, R is an alkylene group having 1 to 3 carbon atoms, and Y is a phenoxy group or 1-imidazolyl group in which a nitro group may be substituted on any carbon atom.)
  2. 　前記縮合反応せしめて得られるニトロ化合物を含む反応混合物に対し低級アルコールを添加して晶析せしめて該ニトロ化合物を単離する請求項１に記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing a bisaminophenylalkylurea according to claim 1, wherein a lower alcohol is added to the reaction mixture containing the nitro compound obtained by the condensation reaction and crystallized to isolate the nitro compound.
  3. 　前記縮合反応せしめて得られるニトロ化合物を含む反応混合物に対し低級アルコールを添加して該ニトロ化合物を単離せしめることなく、還元反応せしめる請求項１に記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing a bisaminophenylalkylurea according to claim 1, wherein a reduction reaction is carried out without adding a lower alcohol to the reaction mixture containing the nitro compound obtained by the condensation reaction and isolating the nitro compound.
  4. 　前記還元反応せしめて得られるビスアミノフェニルアルキルウレアをヒドラジン処理する請求項１～３のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing bisaminophenylalkylurea according to any one of claims 1 to 3, wherein the bisaminophenylalkylurea obtained by the reduction reaction is treated with hydrazine.
  5. 　前記（ニトロフェニル）アルキルアミンのハロゲン酸塩が、２－（４－ニトロフェニル）エチルアミンの塩酸塩若しくは（４－ニトロフェニル）メチルアミンの塩酸塩である請求項１～４のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。 The halogen salt of (nitrophenyl) alkylamine is 2- (4-nitrophenyl) ethylamine hydrochloride or (4-nitrophenyl) methylamine hydrochloride, according to any one of claims 1 to 4. A method for producing bisaminophenylalkylurea.
  6. 　前記カルボニル化合物が、ビス（４－ニトロ置換又は無置換フェニル）カーボネート、又はカルボニルジイミダゾールである請求項１～５のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing a bisaminophenylalkylurea according to any one of claims 1 to 5, wherein the carbonyl compound is bis (4-nitro-substituted or unsubstituted phenyl) carbonate or carbonyldiimidazole.
  7. 　前記ビスアミノフェニルアルキルウレアが、ビス（４－アミノフェニルメチル）ウレアである請求項１～６のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing bisaminophenylalkylurea according to any one of claims 1 to 6, wherein the bisaminophenylalkylurea is bis (4-aminophenylmethyl) urea.
  8. 　前記ビスアミノフェニルアルキルウレアが、ビス（４－アミノフェニルエチル）ウレアである請求項１～６のいずれかに記載のビスアミノフェニルアルキルウレアの製造方法。 The method for producing bisaminophenylalkylurea according to any one of claims 1 to 6, wherein the bisaminophenylalkylurea is bis (4-aminophenylethyl) urea.
  9. 　前記式（１）で表わされる（ニトロフェニル）アルキルアミンハロゲン酸塩と、式（２）で表わされるカルボニル化合物と、をアミド系溶媒中にて塩基の存在下に縮合反応せしめ、得られる前記式（３）で表わされるニトロ化合物を含む反応混合物に対して低級アルコールを添加して晶析することを特徴とする前記式（３）で表わされるニトロ化合物の製造方法。 The above formula obtained by subjecting the (nitrophenyl) alkylamine halide represented by the formula (1) and the carbonyl compound represented by the formula (2) to a condensation reaction in the presence of a base in an amide solvent. A method for producing a nitro compound represented by the above formula (3), wherein the reaction mixture containing the nitro compound represented by (3) is crystallized by adding a lower alcohol.
PCT/JP2011/060182 2010-04-30 2011-04-26 Novel process for producing bisaminophenylalkylurea WO2011136231A1 (en)

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