JP4143163B2 - Method for producing amide derivative - Google Patents

Description

【０００８】
〔式中、Ｒ¹ 及びＲ² は同一又は異なって水素原子又は炭素数１〜６の直鎖アルキル基を示し、Ｒ³ は炭素数２以上の一価アルコール由来の基を示し、ＣＯＲ⁴ＣＯはジカルボン酸ジハライド由来の基を示し、Ｘはハロゲン原子を示し、ｎは１〜１６の数を示す〕
【０００９】
すなわち、本発明は一般式（１）で表されるアミノカルボン酸又は一般式（２）で表される環状ラクタムに、無機酸の存在下、炭素数２以上の一価アルコールを反応させ、未反応のアルコールを留去し、続いて三級アミンの存在下にジカルボン酸ジハライドを反応させることを特徴とする一般式（３）で表されるアミド誘導体の製造法を提供するものである。
【００１０】
【発明の実施の形態】
以下、各工程毎に本発明を説明する。
【００１１】
（工程１）
本工程は、アミノカルボン酸（１）又は、環状ラクタム（２）に、無機酸の存在下、Ｒ³ＯＨで表される一価アルコールを反応せしめる工程である。
【００１２】
式（１）又は式（２）中、Ｒ¹ 又はＲ² としては、所望のアミド誘導体（３）に対応するものを用いればよいが、反応性及び収率の点からＲ¹ 、Ｒ² は水素原子、メチル基、エチル基が好ましい。また、ｎ個のＲ¹ 及びＲ² は同一又は異なっていてもよい。
【００１３】
また、ｎは１〜１６であり、所望のアミド誘導体（３）に対応する値のものを用いればよいが、反応性及び収率の点から、２〜１２が好ましく、５〜１２が特に好ましい。
【００１４】
本発明製造法で用いられるアミノカルボン酸（１）の好ましい具体例としては、６−アミノヘキサン酸、１１−アミノウンデカン酸、１２−アミノドデカン酸等が挙げられる。
【００１５】
また、本発明製造法で用いられる環状ラクタム（２）の好ましい具体例としては、ε−カプロラクタム、ウンデカラクタム、ラウリンラクタム等が挙げられる。
【００１６】
Ｒ³ＯＨは、炭素数２以上の一価アルコールを示し、好ましいＲ³ は炭素数２〜４０までの直鎖、分岐鎖又は環状のアルキル基である。本発明においては、かかるアルコールは上記範囲内のものであれば、所望のアミド誘導体（３）に対応するものを用いればよいが、得られるアミノカルボン酸エステルが液状又は溶媒にとけやすくなる点、反応性、収率及び反応終了後の除去のしやすさの点から炭素数２〜１２の直鎖、分岐鎖又は環状のアルコールを用いるのが好ましく、炭素数２〜８の直鎖、分岐鎖又は環状のアルコールを用いるのがさらに好ましく、エタノール、ｎ−プロパノール、ｉ−プロパノール、ｉ−ブタノール、２−エチルヘキサノールが特に好ましく、エタノール、ｉ−ブタノールが最も好ましい。
【００１７】
また、ここで用いられる無機酸としては、特に制限はないが、特に二価又は三価の無機酸が好ましい。具体的には、硫酸、リン酸が挙げられ、中でも生成するアミノカルボン酸エステルを溶液状又は液状に保つことができることから硫酸が好ましい。
【００１８】
反応は無溶媒下で行ってもよく、また不活性溶媒中で行ってもよい。
ここで用いられる不活性溶媒としては、ヘキサン等の炭化水素系溶媒；ベンゼン、トルエン、キシレン等の芳香族系溶媒；ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒等が挙げられる。
【００１９】
この工程は、反応液を常圧下又は減圧下、必要に応じて加熱や脱水することにより行われる。ここで反応温度としては室温〜２００℃、好ましくは５０℃〜その気圧下における用いた一価アルコールの沸点の範囲である。
【００２０】
（工程２）
この工程は、工程１で得られた反応液中の過剰のアルコールを留去する工程である。かかる留去は常圧下又は減圧下、必要に応じて加熱下又は冷却下で行われる。ここで反応温度としては０〜２００℃、好ましくは２０℃〜その気圧下における用いた一価アルコールの沸点の範囲である。
【００２１】
（工程３）
この反応は、工程２で得られた反応液を無溶媒又は不活性溶媒中、三級アミンの存在下、ジカルボン酸ジハライド（ＸＣＯＲ⁴ＣＯＸ）と反応せしめる工程である。
【００２２】
ここで用いられるジカルボン酸ジハライドにおいて、Ｒ⁴ は好ましくは炭素数１〜４０の二価の炭化水素基を示し、さらに好ましくは炭素数１〜２２の直鎖、分岐鎖又は環状の二価の炭化水素基を示し、特に好ましくは炭素数１〜２２の直鎖又は分岐鎖のアルキレン基を示す。また、Ｘは塩素、臭素、ヨウ素等のハロゲン原子を示す。かかるジカルボン酸ジハライドの具体例としては、マロン酸ジクロリド、コハク酸ジクロリド、グルタル酸ジクロリド、アジピン酸ジクロリド、ピメリン酸ジクロリド、スベリン酸ジクロリド、アゼライン酸ジクロリド、セバシン酸ジクロリド、ドデカンジカルボン酸ジクロリド、１，１８−オクタデカンジカルボン酸ジクロリド、エイコサンジカルボン酸ジクロリド、２−メチルコハク酸ジクロリド、２，２−ジメチルコハク酸ジクロリド、３，３−ジエチルグルタル酸ジクロリド、ヘキサヒドロフタル酸ジクロリド、フタル酸ジクロリド、マレイン酸ジクロリド、アセチレンジカルボン酸ジクロリド、フタル酸ジクロリド等が挙げられる。
【００２３】
ここで用いられる不活性溶媒としては、ヘキサン、トルエン、キシレン、ベンゼン、ジエチルエーテル、テトラヒドロフラン、塩化メチレン、クロロホルム等が挙げられる。
【００２４】
ここで用いられる三級アミンとしては、トリメチルアミン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ピリジン、ジメチルピリジン等が挙げられる。
【００２５】
この工程は、０〜２００℃の範囲内で行われ、１０〜１００℃の範囲内で行うのが好ましい。
【００２６】
反応終了後、反応混合物から生成した三級アミン塩を水洗等により除去し、溶媒を留去すれば、容易に目的のアミド誘導体が得られる。
【００２７】
【発明の効果】
本発明のアミド誘導体の製造法は、中間に生成するアミノカルボン酸エステル塩が液状又は溶媒に溶けやすいため、固体化合物を経由せず、工業的に極めて製造が容易で、アシル化工程全体が工業的に有利な方法である。
【００２８】
【実施例】
次に実施例を挙げて本発明を詳細に説明するが、本発明はこれに何ら限定されるものではない。
【００２９】
実施例１
Ｒ¹ 〜Ｒ⁴ 及びｎが次に示すものであるアミド誘導体（３−ａ）の製造：
【００３０】
【化５】

【００３１】
１２−アミノドデカン酸１００ｇを１リットルフラスコに仕込み、イソブタノール３４４ｇを加えて攪拌を開始した。次いで、５０℃に加熱して、硫酸５０ｇを滴下した。滴下終了後加熱還流させ、５時間後７０℃に冷却し、未反応のイソブタノールを減圧留去すると液状の化合物が得られた。これにトルエン２６０ｇを加えて溶解させた。次いで、５０℃にてトリエチルアミン１５５ｇを１０分かけて滴下した。これに、５０℃にてセバシン酸ジクロリド５６ｇを１時間かけて滴下し、さらに７０℃で３時間反応させた。反応終了後、生成した塩を水洗により除去し、溶媒を減圧留去して標記化合物（３−ａ）３１９ｇを得た。
【００３２】
実施例２
Ｒ¹ 〜Ｒ⁴ 及びｎが次に示すものであるアミド誘導体（３−ｂ）の製造：
【００３３】
【化６】

【００３４】
実施例１において、イソブタノールの代りにエタノールを、またセバシン酸５６ｇの代りにアジピン酸ジクロリド４３ｇを１時間かけて滴下し、さらに６０℃で２時間反応させた以外は実施例１と同様にして、標記化合物（３−ｂ）２６５ｇを得た。
【００３５】
実施例３
Ｒ¹ 〜Ｒ⁴ 及びｎが次に示すものであるアミド誘導体（３−ｃ）の製造：
【００３６】
【化７】

【００３７】
ε−カプロラクタム１１３ｇを２リットルフラスコに仕込み、イソブタノール７４１ｇを加えて攪拌を開始した。次いで、５０℃に加熱して、硫酸１０８ｇを滴下した。滴下終了後加熱還流させ、２２時間後７０℃に冷却し、未反応のイソブタノールを減圧留去すると液状の化合物が得られた。これにトルエン２５０ｇを加えて溶解させた。次いで、５０℃にてトリエチルアミン３３４ｇを３０分かけて滴下した。これに、５０℃にてセバシン酸ジクロリド１２０ｇを１時間かけて滴下し、さらに７０℃で５時間反応させた。反応終了後、生成した塩を水洗により除去し、溶媒を減圧留去して標記化合物（３−ｃ）５０９ｇを得た。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing a bisamide carboxylic acid ester using aminocarboxylic acid or cyclic lactam and dicarboxylic acid dihalide as starting materials.
[0002]
[Prior art and problems to be solved by the invention]
Conventionally, bisamide carboxylic acid esters have been used as raw materials in the production of various useful compounds. As these production methods, a method using an aminocarboxylic acid as a starting material is used. Specifically, (1) the aminocarboxylic acid in the presence of sodium hydroxide or the like in water or a water-alcohol solvent. In the method of acylating with dicarboxylic acid dihalide (Schotten-Baumann method) and then esterifying, (2) once esterifying aminocarboxylic acid with acid catalyst, neutralizing acid catalyst and free aminocarboxylic acid A method (Polymer Bulletin, 8, 109-116 (1982)) in which an ester is taken out and acylated with dicarboxylic acid dihalide is used.
[0003]
However, although the production method (1) is useful as a production method using a highly water-soluble aminocarboxylic acid such as an amino acid, it has a low water-soluble aminocarboxylic acid such as an ω-aminoalkylcarboxylic acid having a large number of carbon atoms. As a production method using an acid, there is a problem that a large amount of a reaction solvent is required to dissolve an aminocarboxylic acid or the product is precipitated in the reaction system, which makes the operation complicated. Has a point. In addition, the production method (2) has a problem that a high yield cannot be expected because the produced free aminocarboxylic acid ester has a property of being extremely easily polymerized. Thus, the method of manufacturing bisamide carboxylic acid ester industrially cheaply and simply has not been known yet.
[0004]
Accordingly, an object of the present invention is to provide a method for easily and conveniently producing an amide derivative from an aminocarboxylic acid or the like on an industrial scale.
[0005]
[Means for Solving the Problems]
The present inventors esterify an aminocarboxylic acid or a cyclic lactam with a specific alcohol in the presence of a specific acid catalyst, and then distill off excess alcohol as it is, followed by an acylation reaction using dicarboxylic acid dihalide. By doing so, there is no problem that a large amount of reaction solvent is required or the intermediate product is polymerized, and there is no problem that the production process is complicated because the intermediate product is obtained in liquid form. Was found to be inexpensive and easy to produce, and the present invention was completed.
[0006]
The method of the present invention can be represented by the following reaction process formula.
[0007]
[Formula 4]

[0008]
[Wherein, R ¹ and R ² are the same or different and represent a hydrogen atom or a linear alkyl group having 1 to 6 carbon atoms, R ³ represents a group derived from a monohydric alcohol having 2 or more carbon atoms, COR ⁴ CO Represents a group derived from dicarboxylic acid dihalide, X represents a halogen atom, and n represents a number of 1 to 16.
[0009]
That is, in the present invention, an aminocarboxylic acid represented by the general formula (1) or a cyclic lactam represented by the general formula (2) is reacted with a monohydric alcohol having 2 or more carbon atoms in the presence of an inorganic acid. The present invention provides a method for producing an amide derivative represented by the general formula (3), wherein the alcohol in the reaction is distilled off, followed by reaction with a dicarboxylic acid dihalide in the presence of a tertiary amine.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described for each step.
[0011]
(Process 1)
This step is a step of reacting the monocarboxylic alcohol represented by R ³ OH with the aminocarboxylic acid (1) or the cyclic lactam (2) in the presence of an inorganic acid.
[0012]
In formula (1) or formula (2), as R ¹ or R ² , those corresponding to the desired amide derivative (3) may be used. From the viewpoint of reactivity and yield, R ¹ and R ² are A hydrogen atom, a methyl group, and an ethyl group are preferable. Further, n R ¹ and R ² may be the same or different.
[0013]
Moreover, n is 1-16, What is necessary is just to use the thing of the value corresponding to a desired amide derivative (3), but 2-12 are preferable from the point of reactivity and a yield, and 5-12 are especially preferable. .
[0014]
Preferable specific examples of aminocarboxylic acid (1) used in the production method of the present invention include 6-aminohexanoic acid, 11-aminoundecanoic acid, 12-aminododecanoic acid and the like.
[0015]
Further, preferred specific examples of the cyclic lactam (2) used in the production method of the present invention include ε-caprolactam, undecalactam, laurin lactam and the like.
[0016]
R ³ OH represents a monohydric alcohol having 2 or more carbon atoms, and preferred R ³ is a linear, branched or cyclic alkyl group having 2 to 40 carbon atoms. In the present invention, as long as the alcohol is within the above range, the alcohol corresponding to the desired amide derivative (3) may be used, but the obtained aminocarboxylic acid ester is easily dissolved in a liquid or solvent, From the viewpoint of reactivity, yield, and ease of removal after completion of the reaction, it is preferable to use a linear, branched or cyclic alcohol having 2 to 12 carbon atoms, and a linear or branched chain having 2 to 8 carbon atoms. Alternatively, it is more preferable to use a cyclic alcohol, ethanol, n-propanol, i-propanol, i-butanol and 2-ethylhexanol are particularly preferable, and ethanol and i-butanol are most preferable.
[0017]
In addition, the inorganic acid used here is not particularly limited, but a divalent or trivalent inorganic acid is particularly preferable. Specific examples include sulfuric acid and phosphoric acid, and sulfuric acid is preferred because the aminocarboxylic acid ester produced can be kept in solution or in liquid form.
[0018]
The reaction may be performed in the absence of a solvent or in an inert solvent.
Examples of the inert solvent used here include hydrocarbon solvents such as hexane; aromatic solvents such as benzene, toluene and xylene; ether solvents such as diethyl ether and tetrahydrofuran.
[0019]
This step is performed by heating or dehydrating the reaction solution under normal pressure or reduced pressure as necessary. Here, the reaction temperature ranges from room temperature to 200 ° C., preferably from 50 ° C. to the boiling point of the monohydric alcohol used under the atmospheric pressure.
[0020]
(Process 2)
This step is a step of distilling off excess alcohol in the reaction solution obtained in step 1. Such distillation is carried out under normal pressure or reduced pressure and, if necessary, under heating or cooling. Here, the reaction temperature ranges from 0 to 200 ° C., preferably from 20 ° C. to the boiling point of the monohydric alcohol used under the atmospheric pressure.
[0021]
(Process 3)
This reaction is a step of reacting the reaction solution obtained in Step 2 with dicarboxylic acid dihalide (XCOR ⁴ COX) in the presence of a tertiary amine in a solvent-free or inert solvent.
[0022]
In the dicarboxylic acid dihalide used here, R ⁴ preferably represents a divalent hydrocarbon group having 1 to 40 carbon atoms, more preferably a linear, branched or cyclic divalent carbon group having 1 to 22 carbon atoms. A hydrogen group is particularly preferable, and a linear or branched alkylene group having 1 to 22 carbon atoms is particularly preferable. X represents a halogen atom such as chlorine, bromine or iodine. Specific examples of such dicarboxylic acid dihalides include malonic acid dichloride, succinic acid dichloride, glutaric acid dichloride, adipic acid dichloride, pimelic acid dichloride, suberic acid dichloride, azelaic acid dichloride, sebacic acid dichloride, dodecanedicarboxylic acid dichloride, 1,18. -Octadecanedicarboxylic acid dichloride, eicosanedicarboxylic acid dichloride, 2-methylsuccinic acid dichloride, 2,2-dimethylsuccinic acid dichloride, 3,3-diethylglutaric acid dichloride, hexahydrophthalic acid dichloride, phthalic acid dichloride, maleic acid dichloride, Acetylenedicarboxylic acid dichloride, phthalic acid dichloride and the like can be mentioned.
[0023]
Examples of the inert solvent used here include hexane, toluene, xylene, benzene, diethyl ether, tetrahydrofuran, methylene chloride, chloroform and the like.
[0024]
Examples of the tertiary amine used here include trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, dimethylpyridine, and the like.
[0025]
This step is performed within a range of 0 to 200 ° C, and preferably performed within a range of 10 to 100 ° C.
[0026]
After completion of the reaction, the tertiary amide salt produced from the reaction mixture is removed by washing with water and the solvent is distilled off to easily obtain the desired amide derivative.
[0027]
【The invention's effect】
In the method for producing the amide derivative of the present invention, since the aminocarboxylic acid ester salt formed in the middle is easily dissolved in a liquid or solvent, it is extremely easy to produce industrially without passing through a solid compound, and the entire acylation process is industrial. This is an advantageous method.
[0028]
【Example】
EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this at all.
[0029]
Example 1
Production of amide derivative (3-a) wherein R ^{1 to} R ⁴ and n are as follows:
[0030]
[Chemical formula 5]

[0031]
100 g of 12-aminododecanoic acid was charged into a 1 liter flask, and 344 g of isobutanol was added to start stirring. Subsequently, it heated at 50 degreeC and 50 g of sulfuric acid was dripped. After completion of dropping, the mixture was heated to reflux, and after 5 hours, cooled to 70 ° C., and unreacted isobutanol was distilled off under reduced pressure to obtain a liquid compound. To this, 260 g of toluene was added and dissolved. Next, 155 g of triethylamine was added dropwise at 50 ° C. over 10 minutes. To this, 56 g of sebacic acid dichloride was added dropwise at 50 ° C. over 1 hour, and further reacted at 70 ° C. for 3 hours. After completion of the reaction, the produced salt was removed by washing with water, and the solvent was distilled off under reduced pressure to obtain 319 g of the title compound (3-a).
[0032]
Example 2
Production of amide derivative (3-b) in which R ^{1 to} R ⁴ and n are as follows:
[0033]
[Chemical 6]

[0034]
In Example 1, ethanol was used instead of isobutanol, and 43 g of adipic acid dichloride was added dropwise over 1 hour instead of 56 g of sebacic acid, and the reaction was further continued at 60 ° C. for 2 hours. To 265 g of the title compound (3-b).
[0035]
Example 3
Production of amide derivative (3-c) wherein R ^{1 to} R ⁴ and n are as follows:
[0036]
[Chemical 7]

[0037]
113 g of ε-caprolactam was charged into a 2 liter flask, and 741 g of isobutanol was added to start stirring. Subsequently, it heated at 50 degreeC and 108 g of sulfuric acid was dripped. After completion of the dropwise addition, the mixture was heated to reflux, then cooled to 70 ° C. after 22 hours, and unreacted isobutanol was distilled off under reduced pressure to obtain a liquid compound. To this, 250 g of toluene was added and dissolved. Next, 334 g of triethylamine was added dropwise at 50 ° C. over 30 minutes. To this, 120 g of sebacic acid dichloride was added dropwise at 50 ° C. over 1 hour, and further reacted at 70 ° C. for 5 hours. After completion of the reaction, the produced salt was removed by washing with water, and the solvent was distilled off under reduced pressure to obtain 509 g of the title compound (3-c).

Claims (5)

The following general formula (1)

[Wherein R ¹ and R ² are the same or different and represent a hydrogen atom or a linear alkyl group having 1 to 6 carbon atoms, and n represents a number of 1 to 16] or General formula (2)

[Wherein R ¹ , R ² and n are as defined above] , in the presence of a divalent or trivalent inorganic acid, in the absence of a solvent or in a hydrocarbon solvent, an aromatic solvent and In one or more inert solvents selected from ether solvents, a monohydric alcohol (R ³ OH) having 2 or more carbon atoms is reacted to distill off unreacted alcohol, followed by the presence of a tertiary amine. Dicarboxylic acid dihalide (XCOR ⁴ COX) [X represents a halogen atom] is reacted, and the following general formula (3)

[Wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined above] . The process according to claim 1, wherein R ³ in the monohydric alcohol (R ³ OH) having 2 or more carbon atoms is a linear, branched or cyclic alkyl group having 2 to 8 carbon atoms.   The process according to claim 1 or 2, wherein the aminocarboxylic acid represented by the general formula (1) is 12-aminododecanoic acid, 11-aminoundecanoic acid or 6-aminohexanoic acid.   The method according to any one of claims 1 to 3, wherein the cyclic lactam represented by the general formula (2) is ε-caprolactam, undecaractam, or laurin lactam. The production method according to any one of claims 1 to 4, wherein R ⁴ in the dicarboxylic acid dihalide (XCOR ⁴ COX) is a divalent hydrocarbon group having 1 to 40 carbon atoms.