JP4691629B2 - Safe and efficient method for producing cyano compounds - Google Patents
Safe and efficient method for producing cyano compounds Download PDFInfo
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Description
本発明は、有機合成反応における１炭素増炭型３成分連結反応に有用なシアノ化合物の大量合成に応用可能な効率的かつ安全な製造方法に関する。
The present invention relates to an efficient and safe production method applicable to a large-scale synthesis of a cyano compound useful for a one-carbon augmentation type three-component linking reaction in an organic synthesis reaction.
下記一般式(1)で表される化合物は一つの炭素上に求電子機能と求核機能を持たせており、穏和条件で一炭素増炭反応と続く求核付加反応を一段階で高収率に行うことができるため、医薬品・機能性材料等の有機合成において他に類を見ないきわめて重要な試薬である（根本尚夫、ＭＡＣ反応剤 -簡便な１炭素増炭型３成分連結反応- 有機合成化学協会誌, 2004,4,347）。 The compound represented by the following general formula (1) has an electrophilic function and a nucleophilic function on one carbon, and high yield is achieved in one step by a one-carbon carbonization reaction followed by a nucleophilic addition reaction under mild conditions. It is an extremely important reagent unlike any other in organic synthesis of pharmaceuticals, functional materials, etc. (Naoto Nemoto, MAC Reactor-Simple 1-Carbon Carbonate Type Three-Component Linkage Reaction- Journal of Synthetic Organic Chemistry, 2004, 4, 347).
化合物(1)の製造方法については、マロン酸ジエチルから６段階にて合成する下記の合成法が知られている（Hisao Nemoto, et. al, J. Org. Chem., 1990, 55, 4516）。 As for the production method of compound (1), the following synthesis method is known which is synthesized from diethyl malonate in 6 steps (Hisao Nemoto, et. Al, J. Org. Chem., 1990, 55, 4516). .
しかしながら、上記合成法は、６段階もの工程を必製とし、２週間以上の反応時間を必要とするを必要とする工程(５段階目)を含み、また高価な縮合剤を必要とする(６段階目)と共に、総収率も十分でない(１０%程度)という問題があり、その改善が求められていた。
However, the above synthesis method requires 6 steps, requires a reaction time of 2 weeks or more (step 5), and requires an expensive condensing agent (6 At the same time, there was a problem that the total yield was not sufficient (about 10%), and an improvement was demanded.
また化合物(1)の製造方法として、既知の化合物(2)の酸化開裂とそれに続く化合物(3)の水酸基の保護の２段階にて合成する下記の合成法が知られている。（特願2001-326484）
As a method for producing the compound (1), the following synthesis method is known in which synthesis is performed in two steps, that is, oxidative cleavage of the known compound (2) and subsequent protection of the hydroxyl group of the compound (3). (Japanese Patent Application 2001-326484)
この合成方法は化合物(2)でＲ'がメチル基の場合、安価なマロン酸ニトリルから簡便に合成できることにより比較的安価にかつ短工程で化合物(1)を合成する事ができる手法として有用ではあるが、その製造工程において爆発性の非常に高い過酢酸を含む溶液を濃縮する工程を含むため、工業プロセスに用いる際には非常に危険であることが容易に推測され、改善が求められていた。
This synthesis method is useful as a method for synthesizing compound (1) at a relatively low cost and in a short process because compound (2) can be easily synthesized from inexpensive malononitrile when R ′ is a methyl group. However, since the production process includes a step of concentrating a solution containing peracetic acid having a very high explosive property, it is easily assumed that it is extremely dangerous when used in an industrial process, and improvement is required. It was.
また、発明者らの知見では、この合成方法の酸化開裂の段階において、反応が進行するに伴い反応速度が急激に加速し反応系中の温度上昇が起こるため、グラムスケールで反応を行った際は温度上昇に伴う化合物の分解が起こるという問題点があった。
In addition, according to the knowledge of the inventors, in the oxidative cleavage stage of this synthesis method, as the reaction proceeds, the reaction rate rapidly accelerates and the temperature in the reaction system rises. However, there is a problem that the decomposition of the compound occurs with increasing temperature.
本発明は上記の製法が有していた問題を解決しようとするものであり、１炭素増炭型３成分連結反応に有用なシアノ化合物を短工程にかつ爆発危険性を回避した、安全で大量合成に応用可能な合成法を実現することを目的とするものである。
The present invention is intended to solve the problems of the above-described production method, and is a safe and large-scale cyano compound useful for a one-carbon increased carbon type ternary linking reaction in a short process and avoiding explosion hazard. The object is to realize a synthesis method applicable to synthesis.
本発明者は、上記課題を解決すべく、下記一般式（１）
の化合物の製造方法において、下記一般式（２）で示される化合物
に過酸化水素水、ＮａＩＯ４、ＮａＣｌＯ、Ｏｘｏｎｅ（登録商標）等の爆発性の危険が低いことが知られている酸化剤を用いて酸化的開裂反応を行い得られた粗生成物中の水酸基に保護試薬を加えて保護化反応させることにより、短工程かつ爆発の危険性のある工程を回避した一般式化合物（１）の製造が可能であることを見いだした。
In order to solve the above problems, the present inventor has the following general formula (1).
A compound represented by the following general formula (2):
Hydroxyl group in the crude product obtained by oxidative cleavage reaction using an oxidizing agent known to have low explosive risk such as hydrogen peroxide, NaIO 4 , NaClO, Oxone (registered trademark) It was found that a general formula compound (1) can be produced by adding a protective reagent to the compound to cause a protective reaction and avoiding a short process and a process with a risk of explosion.
本発明の化合物の製造方法は、酸化開裂反応において、爆発の危険性が低いことが知られている酸化剤を用いて反応を行うことにより、爆発の危険性のある工程を回避することができ、短工程で一般式化合物(1)を合成することが可能となる。また、酸化開裂反応の工程において酸触媒を付加することにより、反応中の急激な温度上昇に伴う化合物の分解等を防ぐ事が可能となる。従って、本発明の化合物の製造方法は、有機合成反応における１炭素増炭型３成分連結反応に有用なシアノ化合物(1)を工業スケールで大量合成する際の問題点を解決することができる点で、非常に有用である。
In the oxidative cleavage reaction, the compound production method of the present invention can avoid a step having a risk of explosion by performing a reaction using an oxidizing agent known to have a low risk of explosion. It becomes possible to synthesize the general formula compound (1) in a short process. Further, by adding an acid catalyst in the step of oxidative cleavage reaction, it becomes possible to prevent decomposition of the compound accompanying a rapid temperature increase during the reaction. Therefore, the method for producing the compound of the present invention can solve the problems in synthesizing a large amount of a cyano compound (1) useful for a one-carbon augmentation type three-component linking reaction in an organic synthesis reaction on an industrial scale. And very useful.
以下に本発明を詳細に説明する。本発明は化合物(2)を出発原料として２段階の工程により、目的とする一般式(1)で表される化合物を効率的かつ安全に大量合成に適用可能な方法にて製造することを目的とする。
The present invention is described in detail below. The object of the present invention is to produce the target compound represented by the general formula (1) by a method that can be applied to mass synthesis efficiently and safely by a two-step process using the compound (2) as a starting material. And
本発明の製造方法における反応式は以下の様に表される。
The reaction formula in the production method of the present invention is expressed as follows.
本発明の出発原料である一般式(2)において、Ｒ'は、アルキル基またはアリール基を広く用いることができるが、入手の容易さからＣＨ３基、Ｐｈ基、NO2-Phが好ましく、特にＣＨ３基が好適に使用できる。
In the general formula (2) which is the starting material of the present invention, R ′ can widely use an alkyl group or an aryl group, but is preferably a CH 3 group, a Ph group, or NO 2 —Ph because of availability. In particular, a CH 3 group can be preferably used.
一般式(2)においてＲ'がメチルである化合物(4)の合成法は、Hori et. al, Sci.Papers Inst.Phys.Chem.Res., 1962, 216やMichael et.al, J.Org.Chem.,1985, 50, 2622にその合成法が記載されており、以下、本発明ではこれを出発原料とした例につき説明する。
The synthesis method of the compound (4) in which R ′ is methyl in the general formula (2) is Hori et. Al, Sci. Papers Inst. Phys. Chem. Res., 1962, 216 and Michael et. Al, J. Org. Chem., 1985, 50, 2622 describes the synthesis method. In the present invention, an example using this as a starting material will be described below.
まず、化合物(4)に過酸化水素水もしくはＮａＩＯ４、ＮａＣｌＯ、Ｏｘｏｎｅ（登録商標）等の爆発性の低いと考えられる過酸化物を加え、攪拌を行い酸化的開裂を行う。反応後、中和剤を加え過酸化物の中和を行う。中和後、水−有機溶媒系で生成物の抽出、溶媒の留去を行い生成物(3)を得る。
First, a peroxide that is considered to have low explosive properties such as aqueous hydrogen peroxide, NaIO 4 , NaClO, or Oxone (registered trademark) is added to the compound (4), followed by stirring and oxidative cleavage. After the reaction, a neutralizer is added to neutralize the peroxide. After neutralization, the product (3) is obtained by extracting the product and distilling off the solvent in a water-organic solvent system.
この酸化的開裂の段階で用いる溶媒としては、水溶媒もしくは水溶媒とメタノール等の有機溶媒の混合溶媒を広く用いることができる。加える過酸化水素水もしくは爆発性の低いと考えられる過酸化物の量は化合物(4)に対して１モル等量〜５モル等量、好ましくは１．２モル〜２モル等量である。反応温度は特に限定される物ではないが、好ましくは１０度〜３０度の室温下で行う事が望ましい。攪拌時間は２〜１０時間、より好ましくは３〜５時間攪拌する。中和剤は硫化ジメチル等を好適に使用でき、加える量はＫＩ試験紙にて過酸消失が確認できる程度に適量加える物とする。
As a solvent used in this oxidative cleavage stage, a water solvent or a mixed solvent of a water solvent and an organic solvent such as methanol can be widely used. The amount of the hydrogen peroxide solution added or the peroxide considered to have low explosive properties is 1 to 5 mole equivalents, preferably 1.2 to 2 mole equivalents, relative to the compound (4). The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a room temperature of preferably 10 to 30 degrees. The stirring time is 2 to 10 hours, more preferably 3 to 5 hours. As the neutralizing agent, dimethyl sulfide or the like can be preferably used, and the amount added is such that an appropriate amount can be added so that the disappearance of the peracid can be confirmed with KI test paper.
また、この酸化的開裂の段階で反応の初期段階より酸触媒を付加することにより反応速度が急激に加速することに伴う反応系中の温度上昇を防ぐことができる。この酸触媒を付加していない段階での温度上昇は、反応開始当初は酸化的開裂反応は非常に遅く進行するが、酸化的開裂反応が進行するに従って反応系中に酸（Ｒ'がメチルの際は酢酸）が発生し、これが触媒となって反応が加速的に進行するため、特に大量合成においては急激な温度上昇が引き起こされるためと推測される。
In addition, by adding an acid catalyst from the initial stage of the reaction at the stage of oxidative cleavage, it is possible to prevent a temperature increase in the reaction system accompanying a rapid acceleration of the reaction rate. The temperature increase in the stage where the acid catalyst is not added proceeds at a very slow rate in the oxidative cleavage reaction at the beginning of the reaction. However, as the oxidative cleavage reaction proceeds, the acid (R ′ is methyl in the reaction system). In this case, acetic acid) is generated, which acts as a catalyst, and the reaction proceeds at an accelerated rate. This is presumably because a rapid temperature rise is caused particularly in large-scale synthesis.
酸触媒は、一般的に知られている無機酸、有機酸を広く用いることができ、好ましくは、硫酸、蟻酸、酢酸、トリフルオロ酢酸、クロロ酢酸、ジクロロ酢酸、トリクロロ酢酸、メタンスルホン酸、4-トルエンスルホン酸、カンファースルホン酸、2,4,6-トリニトロフェノール、酒石酸、クエン酸、アスコルビン酸、リン酸などを使用できる。
As the acid catalyst, generally known inorganic acids and organic acids can be widely used. Preferably, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, methanesulfonic acid, 4 -Toluenesulfonic acid, camphorsulfonic acid, 2,4,6-trinitrophenol, tartaric acid, citric acid, ascorbic acid, phosphoric acid, etc. can be used.
反応の初期段階とは、出発原料(2)と過酸化物との混合開始段階のことをいい、試薬を加える順番によらない。好ましくは酸化物の混合後１０分程度までである。
The initial stage of the reaction refers to the stage of starting the mixing of the starting material (2) and the peroxide, and does not depend on the order in which the reagents are added. Preferably, it is up to about 10 minutes after mixing the oxides.
得られた化合物(3)は蒸留に伴う熱やシリカゲルカラムの酸性条件に不安定であるため化合物の精製が行う事ができない。よって水酸基の保護を行い目的化合物(4)を得ることにより精製を行う事ができ化合物の製造が完結する。
The resulting compound (3) cannot be purified because it is unstable to the heat accompanying distillation and the acidic conditions of the silica gel column. Therefore, purification can be performed by protecting the hydroxyl group to obtain the target compound (4), and the production of the compound is completed.
本発明における「保護基」とは、水酸基を保護することが知られている保護基を広く用いることができ、好ましくはシリル系保護基、エーテル系保護基、アシル系保護基を用いることができ、より好ましくはトリメチルシリル（ＴＭＳ）基、トリエチルシリル（ＴＥＳ）基、t-ブチルジメチルシリル（ＴＢＳ）基、メトキシメチル（ＭＯＭ）基、エトキシエチル（ＥＥ）基、アセチル（Ａｃ）基、ベンゾイル基、トリデカノイル基、トリイソプロピルシリル（ＴＩＰＳ）基、t-ブチルジフェニルシリル（ＴＢＤＰＳ）基、2-テトラヒドロピラニル（ＴＨＰ）基、ベンジロキシメチル（ＢＯＭ）基、t-ブチロキシカルボニル（Boc）基、ベンジロキシカルボニル（Cbz）基、3,3,3-トリクロロプロピオニルオキシカルボニル（Tco）基、アリルオキシカルボニル（Alloc）基等を好的に使用できるが、これに限定されない。保護反応は一般的に知られている条件を広く用いることができる。
As the “protecting group” in the present invention, a protecting group known to protect a hydroxyl group can be widely used, and a silyl protecting group, an ether protecting group, and an acyl protecting group can be preferably used. More preferably, trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBS) group, methoxymethyl (MOM) group, ethoxyethyl (EE) group, acetyl (Ac) group, benzoyl group, Tridecanoyl group, triisopropylsilyl (TIPS) group, t-butyldiphenylsilyl (TBDPS) group, 2-tetrahydropyranyl (THP) group, benzyloxymethyl (BOM) group, t-butyroxycarbonyl (Boc) group, benzi Roxycarbonyl (Cbz) group, 3,3,3-trichloropropionyloxycarbonyl (Tco) group, allyloxycar Although a nil (Alloc) group, favorable to use, but is not limited thereto. For the protection reaction, generally known conditions can be widely used.
以下に、実施例を示すことによって本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto.
実施例で用いた化合物および反応式は次である。
The compounds and reaction formulas used in the examples are as follows.
実施例１
（i）過酸化水素を用いた合成法
(4)（0.54g,5mmol）を過酸化水素水（30%水溶液0.68ml,6mmol相当）に溶かし室温で5時間撹拌した。硫化ジメチル（0.1ml,0.7mmol相当）を加えKI試験紙で過酸消失を確認後、水（10ml）を加えエーテル（10ml×３）で抽出、brine（5ml）で洗浄後、有機層を硫酸マグネシウム（0.5g）で乾燥した。硫酸マグネシウムをろ過後、溶媒を留去するとcrudeの(3)(0.41g)を得た。Rf = 0.275 (Hexane/AcOEt = 3/1)。得られた粗精製物(3)に、無水酢酸（1.5ml,15mmol）、ピリジン（0.21ml,2.5mmol相当）、ジメチルアミノピリジン（65mg,0.5mmol）の順に加え０℃で10分間撹拌した。5％KHSO4（10ml）を加えエーテル（10ml×３）で抽出し、有機層を硫酸マグネシウム（0.5g）で乾燥した。硫酸マグネシウムをろ過後、溶媒を留去し、得られた残留物を減圧下蒸留を用いて精製し、無色油状の(5)（0.30g,2.4mmol）を２段階収率４7％で得た。1H NMR(300MHz, CDC13):δ2.29(s,3H)、6.lO(s,1H); 13CNMR(75MHz, CDCl3):δ167.1, l09.2, 47.5, 19.7; IR(neat):2261.1784cm-1
Example 1
(I) Synthesis method using hydrogen peroxide
(4) (0.54 g, 5 mmol) was dissolved in aqueous hydrogen peroxide (corresponding to 30% aqueous solution 0.68 ml, 6 mmol) and stirred at room temperature for 5 hours. Dimethyl sulfide (equivalent to 0.1 ml, 0.7 mmol) was added, and after confirming the disappearance of peracid with KI test paper, water (10 ml) was added, extracted with ether (10 ml × 3), washed with brine (5 ml), and the organic layer was sulfuric acid. Dried with magnesium (0.5 g). After filtering the magnesium sulfate, the solvent was distilled off to obtain crude (3) (0.41 g). R f = 0.275 (Hexane / AcOEt = 3/1). Acetic anhydride (1.5 ml, 15 mmol), pyridine (corresponding to 0.21 ml, 2.5 mmol) and dimethylaminopyridine (65 mg, 0.5 mmol) were added in this order to the resulting crude product (3), and the mixture was stirred at 0 ° C. for 10 minutes. 5% KHSO4 (10 ml) was added and extracted with ether (10 ml × 3), and the organic layer was dried over magnesium sulfate (0.5 g). After filtering off magnesium sulfate, the solvent was distilled off, and the resulting residue was purified using distillation under reduced pressure to obtain colorless oil (5) (0.30 g, 2.4 mmol) in a two-stage yield of 47%. . 1 H NMR (300 MHz, CDC1 3 ): δ 2.29 (s, 3H), 6.lO (s, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ 167.1, l09.2, 47.5, 19.7; IR (neat): 2261.1784cm -1
実施例２
(ii)その他の酸化剤を用いた合成法
(4)（108mg,1mmol）を水６ml、過酸化物（1.2mmol相当）に溶かし室温で撹拌した。硫化ジメチル（0.1ml,0.7mmol相当）を加えKI試験紙で過酸消失を確認後、無水酢酸（0.3ml,3mmol）、ピリジン（0.04ml,0.5mmol相当）、ジメチルアミノピリジン（13mg,0.1mmol）を加え０℃で10分間撹拌した。5％KHSO4（10ml）を加えエーテル（10ml×３）で抽出し、有機層を硫酸マグネシウム（1g）で乾燥した。ろ過した後に、溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝４：１,シリカゲル8g,2cm id×12cm）を用いて精製し、無色油状の(5)を得た。
Example 2
(ii) Synthesis method using other oxidizing agents
(4) (108 mg, 1 mmol) was dissolved in 6 ml of water and peroxide (corresponding to 1.2 mmol) and stirred at room temperature. Dimethyl sulfide (0.1 ml, equivalent to 0.7 mmol) was added and the disappearance of peracid was confirmed with KI test paper. Acetic anhydride (0.3 ml, 3 mmol), pyridine (0.04 ml, equivalent to 0.5 mmol), dimethylaminopyridine (13 mg, 0.1 mmol) ) And stirred at 0 ° C. for 10 minutes. 5% KHSO4 (10 ml) was added and extracted with ether (10 ml × 3), and the organic layer was dried over magnesium sulfate (1 g). After filtration, the solvent was distilled off, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1, silica gel 8 g, 2 cm id × 12 cm) to give colorless oil (5) Got.
実施例３
（iii）酸触媒存在下、過酸化水素を用いた合成法
(4)（5.4g,50mmol）を過酸化水素水（30%水溶液6.8ml,60mmol相当）、酸触媒（0.5mol%）に溶かし室温で撹拌した。この際、発熱は見られなかった。硫化ジメチル（1ml,7mmol相当）を加えKI試験紙で過酸消失を確認後、水（100ml）を加えエーテル（100ml×３）で抽出、Brine（50ml）で洗浄後、有機層を硫酸マグネシウム（5g）で乾燥した。硫酸マグネシウムをろ過後、溶媒を留去するとcrudeの(3)を得た。(3)を無水アセトニトリル10mlに溶かし無水酢酸（15ml,150mmol）、無水塩化コバルト（0.04g,0.3mmol相当）で60℃で40時間撹拌した。セライトろ過した後に、溶媒を留去し、得られた残留物を減圧下蒸留を用いて精製し、無色油状の(5)を得た。
Example 3
(Iii) Synthesis method using hydrogen peroxide in the presence of an acid catalyst
(4) (5.4 g, 50 mmol) was dissolved in hydrogen peroxide (30% aqueous solution, 6.8 ml, equivalent to 60 mmol) and an acid catalyst (0.5 mol%) and stirred at room temperature. At this time, no exotherm was observed. Dimethyl sulfide (1 ml, equivalent to 7 mmol) was added, and after confirming the disappearance of peracid with KI test paper, water (100 ml) was added, extracted with ether (100 ml × 3), washed with Brine (50 ml), and the organic layer was washed with magnesium sulfate ( 5g) and dried. After filtering the magnesium sulfate, the solvent was distilled off to obtain crude (3). (3) was dissolved in 10 ml of anhydrous acetonitrile and stirred with acetic anhydride (15 ml, 150 mmol) and anhydrous cobalt chloride (0.04 g, equivalent to 0.3 mmol) at 60 ° C. for 40 hours. After filtration through celite, the solvent was distilled off, and the resulting residue was purified by distillation under reduced pressure to obtain colorless oil (5).
Claims (5)
の化合物の製造方法であって、下記一般式（２）で示される化合物
に過酸化水素水を加え酸化的開裂反応を行い得られた粗生成物中の水酸基に保護試薬を加えて保護化反応させることを特徴とする化合物の製造方法。 The following general formula (1)
A compound represented by the following general formula (2):
A method for producing a compound, comprising adding a protective reagent to a hydroxyl group in a crude product obtained by adding an aqueous hydrogen peroxide solution to oxidative cleavage reaction to a hydroxyl group.
の化合物の製造方法であって、下記一般式（２）で示される化合物
にＮａＩＯ4、ＮａＣｌＯ、Ｏｘｏｎｅ（登録商標）より選ばれる酸化剤を加え酸化的開裂反応を行い、得られた粗生成物中の水酸基に保護試薬を加えて保護化反応させることを特徴とする化合物の製造方法。 The following general formula (1)
A compound represented by the following general formula (2):
A compound characterized by adding an oxidizing agent selected from NaIO 4 , NaClO, and Oxone (registered trademark) to oxidative cleavage reaction and adding a protective reagent to the hydroxyl group in the resulting crude product Manufacturing method.
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