JP5612977B2 - Process for producing 6-bromo-N-methyl-2-naphthamide - Google Patents
Process for producing 6-bromo-N-methyl-2-naphthamide Download PDFInfo
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６−ブロモ−２−ナフトエ酸を酸クロリド化して得られる６−ブロモ−２−ナフトエ酸クロリドをモノメチルアミンと反応させて、医薬品等の原料として有用な、６−ブロモ−Ｎ−メチル−２−ナフタミドを効率よく製造する方法に関する。 6-Bromo-2-naphthoic acid obtained by converting 6-bromo-2-naphthoic acid to acid chloride is reacted with monomethylamine to produce 6-bromo-N-methyl-2- The present invention relates to a method for efficiently producing naphthamide.
６−ブロモ−Ｎ−メチル−２−ナフタミドの製法は例えば、６−ブロモ−２−ナフトエ酸を酢酸エチル溶媒下、Ｎ，Ｎ−ジメチルホルムアミド（以下「ＤＭＦ」と略する場合もある。）触媒存在下で酸クロリド化した後、モノメチルアミンメタノール溶液と塩基としてトリエチルアミンの混合溶液を添加する方法が公知である（例えば特許文献１）。 The method for producing 6-bromo-N-methyl-2-naphthamide is, for example, N, N-dimethylformamide (hereinafter sometimes abbreviated as “DMF”) catalyst in the presence of ethyl acetate solvent of 6-bromo-2-naphthoic acid. A method of adding a monomethylamine methanol solution and a mixed solution of triethylamine as a base after acid chlorideation in the presence is known (for example, Patent Document 1).
本法は酸クロリド化反応液から酸クロリドを単離せずに、そのままアミド化する方法で、効率的ではある。しかし、触媒として使用したＤＭＦがアミド化反応において精製で除去し難い副生物を生成すること、また、モノメチルアミン溶液における溶媒であるメタノールも６−ブロモ−２−ナフトエ酸クロリドと反応して精製で除去し難い副生物を生成すること等、工業的に製造する方法としては適当でない。 This method is efficient because it is amidated as it is without isolating the acid chloride from the acid chloride reaction solution. However, DMF used as a catalyst produces a by-product that is difficult to remove by purification in the amidation reaction, and methanol as a solvent in the monomethylamine solution also reacts with 6-bromo-2-naphthoic acid chloride for purification. It is not suitable as an industrially produced method such as producing by-products that are difficult to remove.
尚、上記の反応で生成する結晶は反応釜壁にこびりつき、反応釜から分離装置への移送に難渋する。さらに乾燥品は流動性のない粉体で、乾燥機内壁への残存が無視できず、取り出しに難渋する。 In addition, the crystal | crystallization produced | generated by said reaction sticks to the reaction kettle wall, and it is difficult to transfer from a reaction kettle to a separation apparatus. Furthermore, the dry product is a non-flowable powder, and the remaining on the inner wall of the dryer cannot be ignored, making it difficult to take out.
一方、２−ナフトエ酸からＮ−メチル−２−ナフタミドを合成する方法として、ピリジン存在下に溶媒を兼ねて塩化チオニルを多量に配合して酸クロリド化反応を行い、反応後は過剰な塩化チオニルを蒸留除去した後、メチルアミン水溶液と水酸化ナトリウム水溶液中に滴下して反応し、生成物を水洗後、エタノール水から再結晶して目的物を製造する方法が知られている（非特許文献１）。この方法と同様に操作して、６−ブロモ−２−ナフトエ酸から６−ブロモ−Ｎ−メチル−２−ナフタミドを製造することは可能であるが、溶媒として使用した過剰な塩化チオニルを蒸留除去することは非効率であり、設備の観点からも工業的ではない。また、酸クロリド化反応後は精製工程が必要とされるため、この観点からも工業的ではない。 On the other hand, as a method for synthesizing N-methyl-2-naphthamide from 2-naphthoic acid, an acid chloride reaction is performed by adding a large amount of thionyl chloride in the presence of pyridine and also serving as a solvent. After the reaction, excess thionyl chloride is used. Is distilled and then dropped into a methylamine aqueous solution and a sodium hydroxide aqueous solution to react, and the product is washed with water and recrystallized from ethanol water to produce the desired product (Non-Patent Document). 1). Although it is possible to produce 6-bromo-N-methyl-2-naphthamide from 6-bromo-2-naphthoic acid by operating in the same manner as this method, excess thionyl chloride used as a solvent is distilled off. It is inefficient and not industrial from the point of view of equipment. Moreover, since a purification process is required after the acid chloride reaction, it is not industrial from this viewpoint.
本発明の目的は、より経済的で効率よく、６−ブロモ−Ｎ−メチル−２−ナフタミドを製造する方法を提供することにある。 An object of the present invention is to provide a method for producing 6-bromo-N-methyl-2-naphthamide more economically and efficiently.
本発明者らは、６−ブロモ−Ｎ−メチル−２−ナフタミドを製造する方法において、これまでに提案されている製造法の煩雑な工程、すなわち過剰な塩化チオニルを除去する工程および副生物を除去するための精製工程を必要とせず、またアミド化反応物の形状を改善し、反応スラリー液を容易に移送できる製造方法を検討した。その結果、アミド化反応において、溶媒としてＮ−メチル−２−ピロリドン、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド系溶媒を使用することによって、精製工程を必要とすることなく、不純物の極めて少ない粒状の高純度６−ブロモ−Ｎ−メチル−２−ナフタミドを製造できることが判明した。 In the method for producing 6-bromo-N-methyl-2-naphthamide, the present inventors have carried out complicated steps of production methods that have been proposed so far, that is, steps for removing excess thionyl chloride and by-products. The present inventors have studied a production method that does not require a purification step for removal, improves the shape of the amidation reaction product, and can easily transfer the reaction slurry. As a result, by using an amide solvent such as N-methyl-2-pyrrolidone or N, N-dimethylacetamide as a solvent in the amidation reaction, it is possible to obtain a granular material with very few impurities without requiring a purification step. It has been found that high purity 6-bromo-N-methyl-2-naphthamide can be produced.
以上の知見に基づき提供される本発明は次のとおりである。
（１）６−ブロモ−２−ナフトエ酸クロリドを含有する第１の液体と、モノメチルアミ
ンおよび塩化水素のトラップ剤を含有する第２の液体とを混合させて６−ブロモ−Ｎ−メ
チル−２−ナフタミドを製造する方法であって、前記第２の液体にアミド系溶媒を含有し
、前記アミド系溶媒はＮ−メチル−２−ピロリドンおよびＮ，Ｎ−ジメチルアセトアミド
からなる群から選ばれる一種または二種からなることを特徴とする方法。
The present invention provided on the basis of the above findings is as follows.
(1) A first liquid containing 6-bromo-2-naphthoic acid chloride and a second liquid containing a monomethylamine and hydrogen chloride trapping agent are mixed to produce 6-bromo-N-methyl-2. -A method for producing naphthamide, wherein the second liquid contains an amide solvent, and the amide solvent is selected from the group consisting of N-methyl-2-pyrrolidone and N, N-dimethylacetamide or A method characterized by comprising two kinds .
（２）前記塩化水素のトラップ剤はアルカリ性水溶液からなる上記（１）記載の方法。
（３）前記第１の液体と前記第２の液体とが混合してなる液体に水をさらに添加する上記（１）記載の方法。
(2) The method according to (1), wherein the hydrogen chloride trapping agent comprises an alkaline aqueous solution.
(3) The method according to (1), wherein water is further added to a liquid obtained by mixing the first liquid and the second liquid.
本発明に係るアミド系溶媒としてＮ−メチル−２−ピロリドンおよび／またはＮ，Ｎ−ジメチルアセトアミドが好ましい。また、塩化水素のトラップ剤として好適なアルカリ性水溶液として、水酸化ナトリウム水溶液、水酸化カリウム水溶液および水酸化リチウム水溶液が例示される。 N-methyl-2-pyrrolidone and / or N, N-dimethylacetamide is preferred as the amide solvent according to the present invention. Examples of the alkaline aqueous solution suitable as a hydrogen chloride trapping agent include a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution and a lithium hydroxide aqueous solution.
本発明の製造方法は、従来技術に比べてより経済的で効率よく、６−ブロモ−Ｎ−メチル−２−ナフタミドを製造する方法を提供することができる。 The production method of the present invention can provide a method for producing 6-bromo-N-methyl-2-naphthamide more economically and efficiently than the prior art.
以下、本発明に係る６−ブロモ−Ｎ−メチル−２−ナフタミドの製造方法について詳細に説明する。
（１）第１の液体
本発明に係る第１の液体は６−ブロモ−２−ナフトエ酸クロリドを含有する。試薬として入手した６−ブロモ−２−ナフトエ酸クロリドを芳香族系溶媒などで溶解することによっても第１の液体を得ることができるが、６−ブロモ−２−ナフトエ酸クロリドを試薬として入手することは困難であるから、例えば後述する方法で製造された６−ブロモ−２−ナフトエ酸クロリドを含有する液体を第１の液体としてもよい。この場合には、第１の液体は、６−ブロモ−２−ナフトエ酸クロリドがピリジンなどの触媒および副生成物とともに、トルエンなどの芳香族系溶媒に溶解した液体となる。
Hereinafter, the method for producing 6-bromo-N-methyl-2-naphthamide according to the present invention will be described in detail.
(1) First liquid The first liquid according to the present invention contains 6-bromo-2-naphthoic acid chloride. The first liquid can also be obtained by dissolving 6-bromo-2-naphthoic acid chloride obtained as a reagent with an aromatic solvent or the like, but 6-bromo-2-naphthoic acid chloride is obtained as a reagent. Since this is difficult, for example, a liquid containing 6-bromo-2-naphthoic acid chloride produced by a method described later may be used as the first liquid. In this case, the first liquid is a liquid in which 6-bromo-2-naphthoic acid chloride is dissolved in an aromatic solvent such as toluene together with a catalyst such as pyridine and a by-product.
（２）第２の液体
本発明に係る第２の液体はモノメチルアミンおよび塩化水素のトラップ剤を含有する。
モノメチルアミンは工業的には水溶液またはメタノール溶液として入手されるため、これをそのまま第２の液体として使用することが簡便である。第２の液体におけるモノメチルアミンの含有量は、第１の液体に含まれる６−ブロモ−２−ナフトエ酸クロリドの含有量との関係で設定される。モノメチルアミンの含有量は、モノメチルアミンの６−ブロモ−２−ナフトエ酸クロリドに対するモル比が０．９〜３．０とすることが好ましく、１．０〜２．７とすることがさらに好ましい。
(2) Second Liquid The second liquid according to the present invention contains a monomethylamine and hydrogen chloride trapping agent.
Since monomethylamine is industrially obtained as an aqueous solution or a methanol solution, it is convenient to use it as the second liquid as it is. The content of monomethylamine in the second liquid is set in relation to the content of 6-bromo-2-naphthoic acid chloride contained in the first liquid. The content of monomethylamine is preferably such that the molar ratio of monomethylamine to 6-bromo-2-naphthoic acid chloride is 0.9 to 3.0, and more preferably 1.0 to 2.7.
本発明に係る第２の液体が含有する「トラップ剤」とは、モノメチルアミンと６−ブロモ−２−ナフトエ酸クロリドとの反応により形成された塩化水素を捕捉するためのものであり、塩化水素を溶解し、これを中和する機能を有する。トラップ剤はアルカリ性水溶液からなることが好ましく、アルカリ性水溶液として、水酸化ナトリウム水溶液、水酸化カリウム水溶液および水酸化リチウム水溶液が例示される。トラップ剤の含有量は第１の液体に含まれる６−ブロモ−２−ナフトエ酸クロリドの含有量との関係で適宜設定すればよい。一例を挙げれば、６−ブロモ−２−ナフトエ酸に対し０．９〜３．０モル倍であり、１．０〜２．７モル倍とすれば好ましい。 The “trap agent” contained in the second liquid according to the present invention is for capturing hydrogen chloride formed by the reaction of monomethylamine and 6-bromo-2-naphthoic acid chloride. It has a function of dissolving and neutralizing this. The trapping agent is preferably composed of an alkaline aqueous solution, and examples of the alkaline aqueous solution include a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution and a lithium hydroxide aqueous solution. The content of the trapping agent may be appropriately set in relation to the content of 6-bromo-2-naphthoic acid chloride contained in the first liquid. As an example, it is 0.9 to 3.0 moles, preferably 1.0 to 2.7 moles, with respect to 6-bromo-2-naphthoic acid.
（３）アミド系溶媒
本発明に係る第２の液体はアミド系溶媒を含有する。本発明において「アミド系溶媒」とは１０〜３０℃において液体であって、一般式がＲ１−ＣＯ−Ｎ（Ｒ２）Ｒ３、（Ｒ１〜Ｒ３はそれぞれ水素および炭素数１〜３のアルキル基から選ばれ、Ｒ１およびＲ３がアルキル基である場合には連結して環状構造をなしていてもよい。）で表される溶媒であり、Ｎ−メチル−２−ピロリドン、Ｎ−メチルホルムアミド、Ｎ−メチルアセトアミド、Ｎ，Ｎ−ジメチルアセトアミドが例示される。これらの中でも、Ｎ−メチル−２−ピロリドンおよびＮ，Ｎ−ジメチルアセトアミドが好ましい。
(3) Amide solvent The second liquid according to the present invention contains an amide solvent. In the present invention, the “amide-based solvent” is liquid at 10 to 30 ° C., and has a general formula of R 1 —CO—N (R 2 ) R 3 , where R 1 to R 3 are hydrogen and carbon number 1 to 3 and a solvent represented by N-methyl-2-pyrrolidone, which may be linked to form a cyclic structure when R 1 and R 3 are alkyl groups, Examples include N-methylformamide, N-methylacetamide, N, N-dimethylacetamide. Among these, N-methyl-2-pyrrolidone and N, N-dimethylacetamide are preferable.
アミド系溶媒は、６−ブロモ−２−ナフトエ酸クロリドのアミド化反応により生成した６−ブロモ−Ｎ−メチル−２−ナフタミドの結晶性状を良好にする作用を有する。このため、得られた６−ブロモ−Ｎ−メチル−２−ナフタミドの結晶は流動性を有する顆粒状となり、反応容器からの取り出しなどの作業性に優れる。このことは全体的な収率の向上にも寄与する。また、得られた結晶における不純物含有量は特に少ない（純度は９９％程度以上になる）ため、得られた結晶に対して再結晶工程を行うことは必要とされない。このことも全体的な収率の向上に寄与する。 The amide solvent has an effect of improving the crystalline properties of 6-bromo-N-methyl-2-naphthamide produced by amidation reaction of 6-bromo-2-naphthoic acid chloride. For this reason, the obtained crystals of 6-bromo-N-methyl-2-naphthamide are in the form of granules having fluidity, and are excellent in workability such as removal from the reaction vessel. This also contributes to an improvement in overall yield. In addition, since the impurity content in the obtained crystal is particularly small (purity is about 99% or more), it is not necessary to perform a recrystallization step on the obtained crystal. This also contributes to an improvement in overall yield.
アミド系溶媒の使用量は特に限定されないが、過少の場合には上記の作用効果を得ることが困難となり、過多の場合には６−ブロモ−Ｎ−メチル−２−ナフタミドの一部が第１の液体と第２の液体との混合液体内に溶解することが懸念される。この溶解分は濾過工程で濾液とともに除去されてしまうため経済的に不利である。このため、使用量は６−ブロモ−２−ナフトエ酸に対する重量比で０．５〜５．０とすることが好ましく、２．０〜３．０とすればさらに好ましい。 The amount of the amide solvent used is not particularly limited. However, when the amount is too small, it is difficult to obtain the above-described effect. When the amount is excessive, a part of 6-bromo-N-methyl-2-naphthamide is first. There is a concern about dissolution in the mixed liquid of the second liquid and the second liquid. Since this dissolved component is removed together with the filtrate in the filtration step, it is economically disadvantageous. For this reason, the amount used is preferably 0.5 to 5.0 by weight ratio to 6-bromo-2-naphthoic acid, and more preferably 2.0 to 3.0.
ここで、本発明に係るアミド系溶媒はＤＭＦ（Ｎ，Ｎ−ジメチルホルムアミド）を含まない。ＤＭＦは６−ブロモ−２−ナフトエ酸クロリドのアミド化反応においてモノメチルアミンと競合して６−ブロモ−Ｎ−メチル−２−ナフタミドの生成反応を阻害し、６−ブロモ−Ｎ，Ｎ−ジメチル−２−ナフトアミドを生成するためである。この６−ブロモ−Ｎ，Ｎ−ジメチル−２−ナフトアミドが６−ブロモ−Ｎ−メチル−２−ナフタミドとともに生成すると、６−ブロモ−Ｎ，Ｎ−ジメチル−２−ナフトアミドの除去はきわめて困難であり、再結晶などの精製工程を経ても６−ブロモ−Ｎ−メチル−２−ナフタミド中に残存し、精製品の純度低下をもたらす。なお、ＤＭＦはカルボン酸のクロライド化反応において触媒的に作用し、その反応条件を温和にすることが知られている。このため、第１の液体に含有される６−ブロモ−２−ナフトエ酸クロリドを製造する際にも含有される場合もある。この場合においても、ＤＭＦ由来の６−ブロモ−Ｎ，Ｎ−ジメチル−２−ナフトアミドが生成する。 Here, the amide solvent according to the present invention does not contain DMF (N, N-dimethylformamide). DMF competes with monomethylamine in the amidation reaction of 6-bromo-2-naphthoic acid chloride to inhibit the formation reaction of 6-bromo-N-methyl-2-naphthamide, and 6-bromo-N, N-dimethyl- This is to produce 2-naphthamide. When this 6-bromo-N, N-dimethyl-2-naphthamide is produced together with 6-bromo-N-methyl-2-naphthamide, removal of 6-bromo-N, N-dimethyl-2-naphthamide is extremely difficult. Even after purification steps such as recrystallization, it remains in 6-bromo-N-methyl-2-naphthamide, resulting in a decrease in purity of the purified product. DMF is known to act catalytically in the chlorination reaction of carboxylic acid to moderate the reaction conditions. For this reason, it may be contained when producing 6-bromo-2-naphthoic acid chloride contained in the first liquid. Even in this case, DMF-derived 6-bromo-N, N-dimethyl-2-naphthamide is produced.
（４）混合方法およびその後の製造方法
第１の液体と第２の液体との混合方法は特に限定されないが、反応の安定的な進行を実現する観点から、滴下法を用いることが好ましい。滴下法を用いる場合には、第１の液体を第２の液体に滴下する。滴下中の混合液の温度は１０〜３０℃とすることが好ましい。滴下に要する時間は任意であるが、反応の安定性確保の観点から滴下中の温度が保時できる速度が好ましい。滴下とともに反応生成物としての固形物が析出するが、滴下終了後の混合液は１０〜３０℃で１〜３時間程度保持して反応を十分に完了させることが好ましい。
(4) Mixing Method and Subsequent Manufacturing Method The mixing method of the first liquid and the second liquid is not particularly limited, but it is preferable to use a dropping method from the viewpoint of realizing a stable progress of the reaction. When the dropping method is used, the first liquid is dropped onto the second liquid. It is preferable that the temperature of the liquid mixture during dripping shall be 10-30 degreeC. Although the time required for dropping is arbitrary, a speed at which the temperature during dropping can be maintained is preferable from the viewpoint of ensuring the stability of the reaction. A solid product as a reaction product is precipitated with the dropwise addition, but the mixed solution after the dropwise addition is preferably maintained at 10 to 30 ° C. for about 1 to 3 hours to complete the reaction sufficiently.
こうして得られた混合液にさらに水を添加することもできる。水を添加することにより、副生する塩化水素とトラップ剤との反応生成物（例えば塩化ナトリウム等の無機塩）が容易に溶解される。水の添加量はその目的を達成できる範囲で任意である。水を添加したのち、混合液をさらに３０分を目安に保持して析出した固形物を完全に沈殿させる。本発明に係る方法によれば反応容器上に析出する固形物は極めて少ないため、反応生成物はほぼ全量沈殿する。 Water can also be added to the mixed solution thus obtained. By adding water, a reaction product (for example, an inorganic salt such as sodium chloride) of hydrogen chloride produced as a by-product and a trapping agent is easily dissolved. The amount of water added is arbitrary as long as the purpose can be achieved. After adding water, the mixed liquid is kept for about 30 minutes as a guide to completely precipitate the precipitated solid. According to the method of the present invention, since the amount of solids deposited on the reaction vessel is extremely small, almost all of the reaction product is precipitated.
これを濾過することによって副生成物は濾液とともに除去され、６−ブロモ−Ｎ−メチル−２−ナフタミドのケーキが得られる。得られたケーキを例えば５ｍｍＨｇの減圧下、５０℃で恒量になるまで乾燥することで高純度の６−ブロモ−Ｎ−メチル−２−ナフタミドが顆粒状の結晶として得られる。本発明に係る方法によればこの段階で９９％程度の純度を十分に確保できるため、さらに再結晶工程を行うことは必要とされない。 By filtration, the by-product is removed along with the filtrate, and a 6-bromo-N-methyl-2-naphthamide cake is obtained. The obtained cake is dried to a constant weight at 50 ° C. under a reduced pressure of, for example, 5 mmHg to obtain high-purity 6-bromo-N-methyl-2-naphthamide as granular crystals. According to the method of the present invention, a purity of about 99% can be sufficiently secured at this stage, so that it is not necessary to perform a further recrystallization step.
（５）第１の液体の調製方法
ここで、反応生成物としての６−ブロモ−２−ナフトエ酸クロリドを含む第１の液体の調製方法の一例を以下に説明する。
(5) Method for Preparing First Liquid Here, an example of a method for preparing a first liquid containing 6-bromo-2-naphthoic acid chloride as a reaction product will be described below.
６−ブロモ−２−ナフトエ酸、塩化チオニルおよびピリジンを溶媒に溶解させ、加熱しながら攪拌して酸クロライド化反応を進行させることにより、６−ブロモ−２−ナフトエ酸クロリドを含む第１の液体を得ることができる。 A first liquid containing 6-bromo-2-naphthoic acid chloride is prepared by dissolving 6-bromo-2-naphthoic acid, thionyl chloride and pyridine in a solvent and stirring while heating to proceed with the acid chloride reaction. Can be obtained.
塩化チオニルの使用量は６−ブロモ−２−ナフトエ酸の使用量と関係で設定される。６−ブロモ−２−ナフトエ酸の使用量に対するモル比率で、１．０〜１．７とすることが好ましく、1．1〜1．５とすればさらに好ましい。 The amount of thionyl chloride used is set in relation to the amount of 6-bromo-2-naphthoic acid used. The molar ratio with respect to the amount of 6-bromo-2-naphthoic acid used is preferably 1.0 to 1.7, and more preferably 1.1 to 1.5.
ピリジンの使用量は、６−ブロモ−２−ナフトエ酸に対する比率で、モル比として０．０３〜０．３とすることが好ましい。これよりも少ないと反応に時間を要し、多ければ経済的に不利である。 The amount of pyridine used is preferably a ratio with respect to 6-bromo-2-naphthoic acid, and a molar ratio of 0.03 to 0.3. If it is less than this, the reaction takes time, and if it is more, it is economically disadvantageous.
溶媒は特に限定されず、トルエンなどの芳香族炭化水素を用いればよい。また、溶媒の使用量は、反応物を溶解できること、反応で充分攪拌できること、および生成する６−ブロモ−２−ナフトエ酸クロリドを溶解することを満足できる量であればよい。通常、６−ブロモ−２−ナフトエ酸仕込み重量の１．０〜１０倍、好ましくは３．０〜７．５倍である。 The solvent is not particularly limited, and an aromatic hydrocarbon such as toluene may be used. Further, the amount of the solvent used may be an amount that can satisfy the ability to dissolve the reaction product, the ability to sufficiently stir the reaction, and the dissolution of the produced 6-bromo-2-naphthoic acid chloride. Usually, it is 1.0 to 10 times, preferably 3.0 to 7.5 times the charged weight of 6-bromo-2-naphthoic acid.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されない。
分析は、下記条件の高速液体クロマトグラフィー（ＨＰＬＣ）で行った。尚、実施例において濃度は面積％を示し、収率はモル％を示す。
測定条件
カラム：ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ ＵＧ１２０ ５μｍ
長さ２５０ｍｍ、内径４．６ｍｍ（ジーエルサイエンス株式会社製）
移動相：０．１％酢酸水／メタノール １ｍｌ／ｍｉｎ
（混合容積比３：２を２５分で９：１とし４０分まで保時するグラジェント）
検出器：ＵＶ（２５４ｎｍ）
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
The analysis was performed by high performance liquid chromatography (HPLC) under the following conditions. In the examples, the concentration indicates area%, and the yield indicates mol%.
Measurement condition
Column: CAPCELL PAK C18 UG120 5 μm
Length 250mm, inner diameter 4.6mm (manufactured by GL Sciences Inc.)
Mobile phase: 0.1% aqueous acetic acid / methanol 1 ml / min
(Gradient with mixing volume ratio 3: 2 in 9 minutes in 25 minutes and holding for 40 minutes)
Detector: UV (254 nm)
（実施例１）
還流冷却器、温度測定管および電磁攪拌機を備えた２００ｍｌのガラス製反応容器に、窒素雰囲気下、６−ブロモ−２−ナフトエ酸１０．０ｇ（３９．８ｍｍｏｌ）、トルエン７３．０ｇおよびピリジン０．３１ｇを仕込んだ。次いで塩化チオニル６．９４ｇ（５８．３ｍｍｏｌ）を添加し、内温を６５℃に昇温した。その後、この温度で１．５時間反応させた。反応後、冷却し酸クロリド化反応溶液を得た。
Example 1
In a 200 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer, 10.0 g (39.8 mmol) of 6-bromo-2-naphthoic acid, 73.0 g of toluene and 0. 31 g was charged. Next, 6.94 g (58.3 mmol) of thionyl chloride was added, and the internal temperature was raised to 65 ° C. Then, it was made to react at this temperature for 1.5 hours. After the reaction, it was cooled to obtain an acid chloride reaction solution.
次に、還流冷却器、温度測定管および電磁攪拌機を備えた３００ｍｌのガラス製反応容器に、４０％モノメチルアミン水溶液８．１５ｇと２０％水酸化ナトリウム水溶液２０．５ｇ及びＮ−メチル−２−ピロリドン２７．７ｇを仕込んだ。２０℃に冷却し、この温度を保持しながら前述の操作で得た酸クロリド化反応溶液を滴下した。滴下とともに固形物が析出した。滴下後、この温度で１．５時間反応させた。反応後５０．０ｇの水を添加し、濾過器にデカントした。デカント後反応容器壁に固形物は無かった。 Next, in a 300 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and an electromagnetic stirrer, 8.15 g of 40% monomethylamine aqueous solution, 20.5 g of 20% sodium hydroxide aqueous solution and N-methyl-2-pyrrolidone were added. 27.7 g was charged. The solution was cooled to 20 ° C., and the acid chloride reaction solution obtained by the above operation was added dropwise while maintaining this temperature. A solid substance precipitated with the dropwise addition. After dropping, the reaction was carried out at this temperature for 1.5 hours. After the reaction, 50.0 g of water was added and decanted into a filter. There was no solid on the reaction vessel wall after decanting.
濾過物を５ｍｍＨｇの減圧下、５０℃で恒量になるまで乾燥し、白色で流動性を有する顆粒状の６−ブロモ−Ｎ−メチル−２−ナフタミド１０．５ｇ（純度９９．９％）を得た。こうして得られた６−ブロモ−Ｎ−メチル−２−ナフタミド乾燥品の光学顕微鏡観察画像を図１に示す。６−ブロモ−Ｎ−メチル−２−ナフタミド乾燥品の６−ブロモ−２−ナフトエ酸基準の収率は９９．８％であった。 The filtrated product was dried under reduced pressure of 5 mmHg to a constant weight at 50 ° C. to obtain 10.5 g (purity 99.9%) of granular 6-bromo-N-methyl-2-naphthamide having white fluidity. It was. An optical microscope image of the dried 6-bromo-N-methyl-2-naphthamide thus obtained is shown in FIG. The yield of 6-bromo-N-methyl-2-naphthamide dry product based on 6-bromo-2-naphthoic acid was 99.8%.
（実施例２）
還流冷却器、温度測定管および電磁攪拌機を備えた５０ｍｌのガラス製反応容器に、窒素雰囲気下、６−ブロモ−２−ナフトエ酸２．５１ｇ（１０．０ｍｍｏｌ）、トルエン１８．１ｇおよびピリジン０．０７３ｇを仕込み、次いで塩化チオニル１．８１ｇ（１５．２ｍｍｏｌ）を添加し、内温を６５℃に昇温した。その後、この温度で１．５時間反応させた。反応後、冷却し酸クロリド化反応溶液を得た。
(Example 2)
In a 50 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer, 2.51 g (10.0 mmol) of 6-bromo-2-naphthoic acid, 18.1 g of toluene, and 0. 073 g was charged, and then 1.81 g (15.2 mmol) of thionyl chloride was added, and the internal temperature was raised to 65 ° C. Then, it was made to react at this temperature for 1.5 hours. After the reaction, it was cooled to obtain an acid chloride reaction solution.
次に、還流冷却器、温度測定管および電磁攪拌機を備えた１００ｍｌのガラス製反応容器に、４０％モノメチルアミン水溶液２．１０ｇと２０％水酸化ナトリウム水溶液５．２３ｇ及びＮ，Ｎ−ジメチルアセトアミド７．１ｇを仕込んだ。２０℃に冷却し、この温度を保持しながら前述の操作で得た酸クロリド化反応溶液を滴下した。滴下とともに固形物が析出した。滴下後、この温度で１．５時間反応させた。反応後１２．５ｇの水を添加し、濾過器にデカントした。デカント後反応容器壁に固形物は無かった。 Next, in a 100 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and an electromagnetic stirrer, 2.10 g of 40% monomethylamine aqueous solution, 5.23 g of 20% sodium hydroxide aqueous solution and N, N-dimethylacetamide 7 .1 g was charged. The solution was cooled to 20 ° C., and the acid chloride reaction solution obtained by the above operation was added dropwise while maintaining this temperature. A solid substance precipitated with the dropwise addition. After dropping, the reaction was carried out at this temperature for 1.5 hours. After the reaction, 12.5 g of water was added and decanted into a filter. There was no solid on the reaction vessel wall after decanting.
濾過物を５ｍｍＨｇの減圧下、５０℃で恒量になるまで乾燥し、白色で流動性を有する顆粒状の６−ブロモ−Ｎ−メチル−２−ナフタミド２．４５ｇ（純度９９．０％）を得た。６−ブロモ−２−ナフトエ酸基準の収率は９１．８％であった。 The filtrate was dried under reduced pressure of 5 mmHg to a constant weight at 50 ° C. to obtain 2.45 g (purity 99.0%) of granular 6-bromo-N-methyl-2-naphthamide having white fluidity. It was. The yield based on 6-bromo-2-naphthoic acid was 91.8%.
（比較例１）
還流冷却器、温度測定管および電磁攪拌機を備えた２００ｍｌのガラス製反応容器に、６−ブロモ−２−ナフトエ酸１０．０ｇ（３９．８ｍｍｏｌ）、酢酸エチル７１．７ｇとＤＭＦ０．４８ｇを仕込み、次いで塩化チオニル６．２０ｇ（５２．１ｍｍｏｌ）を滴下し、内温を６５℃に昇温した。その後、この温度で０．５時間反応させた。反応後、２０℃まで冷却した。冷却後、４０％モノメチルアミンメタノール溶液６．２４ｇとトリエチルアミン８．１８ｇの混合液を２０℃で滴下した。滴下と共に固形物が析出した。滴下後２０℃で３時間攪拌した。その後２０℃で水５０．３ｇを滴下し、濾過器にデカントした。固形物は流出したが反応容器壁に付着して残存していたためスパチュラで掻き出した。
(Comparative Example 1)
A 200 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer was charged with 10.0 g (39.8 mmol) of 6-bromo-2-naphthoic acid, 71.7 g of ethyl acetate and 0.48 g of DMF, Next, 6.20 g (52.1 mmol) of thionyl chloride was added dropwise, and the internal temperature was raised to 65 ° C. Then, it was made to react at this temperature for 0.5 hour. After the reaction, it was cooled to 20 ° C. After cooling, a mixture of 6.24 g of 40% monomethylamine methanol solution and 8.18 g of triethylamine was added dropwise at 20 ° C. A solid substance precipitated with the dropwise addition. After dropping, the mixture was stirred at 20 ° C. for 3 hours. Thereafter, 50.3 g of water was added dropwise at 20 ° C. and decanted into a filter. Although the solid substance flowed out but remained attached to the reaction vessel wall, it was scraped out with a spatula.
濾過分離した固形物を、メタノール／水（１／４）の混合液２１．０ｇで洗浄し、５ｍｍＨｇ減圧下、５０℃で恒量になるまで乾燥した。その結果、淡黄白色で流動性のない粉末の６−ブロモ−Ｎ−メチル−２−ナフタミド８．７２ｇ（純度９５．７％）を得た。６−ブロモ−２−ナフトエ酸基準の収率は７９．４％であった。 The solid substance separated by filtration was washed with 21.0 g of a methanol / water (1/4) mixed solution and dried under reduced pressure of 5 mmHg to a constant weight at 50 ° C. As a result, 8.72 g (purity 95.7%) of 6-bromo-N-methyl-2-naphthamide as a pale yellowish white and non-flowable powder was obtained. The yield based on 6-bromo-2-naphthoic acid was 79.4%.
（比較例２）
還流冷却器、温度測定管および電磁攪拌機を備えた５０ｍｌのガラス製反応容器に、窒素雰囲気下、６−ブロモ−２−ナフトエ酸２．５１ｇ（１０．０ｍｍｏｌ）、トルエン１８．３ｇおよびピリジン０．０８１ｇを仕込んだ。次いで塩化チオニル１．７７ｇ（１４．９ｍｍｏｌ）を添加し、内温を６５℃に昇温した。その後、この温度で１．５時間反応させた。反応後、冷却し酸クロリド化反応溶液を得た。
(Comparative Example 2)
In a 50 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer, 2.51 g (10.0 mmol) of 6-bromo-2-naphthoic acid, 18.3 g of toluene and 0. 081 g was charged. Next, 1.77 g (14.9 mmol) of thionyl chloride was added, and the internal temperature was raised to 65 ° C. Then, it was made to react at this temperature for 1.5 hours. After the reaction, it was cooled to obtain an acid chloride reaction solution.
次に、還流冷却器、温度測定管および電磁攪拌機を備えた１００ｍｌのガラス製反応容器に、４０％モノメチルアミン水溶液２．０２ｇと２０％水酸化ナトリウム水溶液５．２５ｇを仕込んだ。２０℃に冷却し、この温度を保持しながら、前述の操作で得た酸クロリド化反応溶液を滴下した。滴下と共に固形物が析出した。滴下後２０℃で１．５時間反応させた。その後２０℃で水１２．２ｇを滴下し、濾過器にデカントした。デカントで流出した固形物を濾過分離し、５ｍｍＨｇ減圧下、５０℃で恒量になるまで乾燥し、淡黄白色で流動性のない粉末の６−ブロモ−Ｎ−メチル−２−ナフタミド０．８６ｇ（純度９８．７％）を得た。６−ブロモ−２−ナフトエ酸基準の収率は３２％であった。尚、デカントで固形物は殆ど流出せず大半は反応容器壁付着していたためスパチュラで掻き落とし濾液で濾過器に洗い流して濾過した。濾過分離した固形物を５ｍｍＨｇ減圧下、５０℃で恒量になるまで乾燥し、淡黄白色で流動性のない粉末の６−ブロモ−Ｎ−メチル−２−ナフタミド１．７３ｇ（純度９８．７％）を得た。こうして得られた６−ブロモ−Ｎ−メチル−２−ナフタミド乾燥品の光学顕微鏡観察画像を図２に示す。６−ブロモ−Ｎ−メチル−２−ナフタミド乾燥品の６−ブロモ−２−ナフトエ酸基準の収率は６４．６％であった。 Next, a 100% glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and an electromagnetic stirrer was charged with 2.02 g of 40% monomethylamine aqueous solution and 5.25 g of 20% sodium hydroxide aqueous solution. The solution was cooled to 20 ° C., and the acid chloride reaction solution obtained by the above-described operation was added dropwise while maintaining this temperature. A solid substance precipitated with the dropwise addition. After dropping, the reaction was carried out at 20 ° C. for 1.5 hours. Thereafter, 12.2 g of water was added dropwise at 20 ° C. and decanted into a filter. The solid substance flowing out by decant was separated by filtration, dried to a constant weight at 50 ° C. under reduced pressure of 5 mmHg, and 0.86 g of a pale yellowish white, non-flowable powder of 6-bromo-N-methyl-2-naphthamide ( Purity 98.7%). The yield based on 6-bromo-2-naphthoic acid was 32%. In addition, since most of the solid matter did not flow out by decanting and most of the solid matter adhered to the reaction vessel wall, it was scraped off with a spatula, washed into the filter with the filtrate, and filtered. The solid separated by filtration was dried to a constant weight at 50 ° C. under reduced pressure of 5 mmHg, and 1.73 g of 6-bromo-N-methyl-2-naphthamide (pure 98.7%) as a pale yellowish white non-flowable powder. ) The optical microscope observation image of the 6-bromo-N-methyl-2-naphthamide dried product thus obtained is shown in FIG. The yield of 6-bromo-N-methyl-2-naphthamide dry product based on 6-bromo-2-naphthoic acid was 64.6%.
（比較例３）
還流冷却器、温度測定管および電磁攪拌機を備えた５０ｍｌのガラス製反応容器に、窒素雰囲気下、６−ブロモ−２−ナフトエ酸２．５０ｇ（１０．０ｍｍｏｌ）、トルエン１８．１ｇおよびピリジン０．０７８ｇを仕込んだ。次いで塩化チオニル１．８２ｇ（１５．３ｍｍｏｌ）を添加し、内温を６５℃に昇温した。その後、この温度で１．５時間反応させた。反応後、冷却し酸クロリド化反応溶液を得た。
(Comparative Example 3)
In a 50 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer, 2.50 g (10.0 mmol) of 6-bromo-2-naphthoic acid, 18.1 g of toluene, and 0. 078 g was charged. Subsequently, 1.82 g (15.3 mmol) of thionyl chloride was added, and the internal temperature was raised to 65 ° C. Then, it was made to react at this temperature for 1.5 hours. After the reaction, it was cooled to obtain an acid chloride reaction solution.
次に、還流冷却器、温度測定管および電磁攪拌機を備えた１００ｍｌのガラス製反応容器に、４０％モノメチルアミン水溶液２．１２ｇと２０％水酸化ナトリウム水溶液５．４４ｇ及びトルエン７．０６ｇを仕込んだ。２０℃に冷却し、この温度を保持しながら、前述の操作で得た酸クロリド化反応溶液を滴下した。滴下と共に固形物が析出した。滴下後２０℃で１．５時間反応させた。その後２０℃で水１２．７ｇを滴下し、濾過器にデカントした。デカントで流出した固形物を濾過分離し、５ｍｍＨｇ減圧下、５０℃で恒量になるまで乾燥し、淡黄白色で流動性のない粉末の６−ブロモ−Ｎ−メチル−２−ナフタミド０．８８ｇ（純度９８．５％）を得た。６−ブロモ−２−ナフトエ酸基準の収率は３２．８％であった。尚、デカントで固形物は殆ど流出せず大半は反応容器壁付着していたためスパチュラで掻き落とし濾液で濾過器に洗い流して濾過した。濾過分離した固形物を５ｍｍＨｇ減圧下、５０℃で恒量になるまで乾燥し、淡黄白色で流動性のない粉末の６−ブロモ−Ｎ−メチル−２−ナフタミド１．７６ｇ（純度９８．５％）を得た。６−ブロモ−２−ナフトエ酸基準の収率は６５．６％であった。 Next, a 100 ml glass reaction vessel equipped with a reflux condenser, a temperature measuring tube and a magnetic stirrer was charged with 2.12 g of 40% monomethylamine aqueous solution, 5.44 g of 20% sodium hydroxide aqueous solution and 7.06 g of toluene. . The solution was cooled to 20 ° C., and the acid chloride reaction solution obtained by the above-described operation was added dropwise while maintaining this temperature. A solid substance precipitated with the dropwise addition. After dropping, the reaction was carried out at 20 ° C. for 1.5 hours. Thereafter, 12.7 g of water was added dropwise at 20 ° C. and decanted into a filter. The solid substance flowing out by decant was separated by filtration, dried to a constant weight at 50 ° C. under reduced pressure of 5 mmHg, and 0.88 g of 6-bromo-N-methyl-2-naphthamide as a pale yellowish white non-flowable powder ( Purity 98.5%). The yield based on 6-bromo-2-naphthoic acid was 32.8%. In addition, since most of the solid matter did not flow out by decanting and most of the solid matter adhered to the reaction vessel wall, it was scraped off with a spatula, washed into the filter with the filtrate, and filtered. The solid separated by filtration was dried to a constant weight at 50 ° C. under reduced pressure of 5 mmHg, and 1.76 g of 6-bromo-N-methyl-2-naphthamide (pure 98.5%) as a pale yellowish white non-flowable powder. ) The yield based on 6-bromo-2-naphthoic acid was 65.6%.
Claims (3)
前記第２の液体はアミド系溶媒を含有し、該アミド系溶媒はＮ−メチル−２−ピロリド
ンおよびＮ，Ｎ−ジメチルアセトアミドからなる群から選ばれる一種または二種からなること
を特徴とする方法。 A first liquid containing 6-bromo-2-naphthoic acid chloride is mixed with a second liquid containing monomethylamine and hydrogen chloride trapping agent to give 6-bromo-N-methyl-2-naphthamide. A method of manufacturing comprising:
The second liquid contains an amide solvent, and the amide solvent is one or two selected from the group consisting of N-methyl-2-pyrrolidone and N, N-dimethylacetamide. .
Priority Applications (1)
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