JP5629080B2 - Method for producing polycyclic compound - Google Patents

Description

  The present invention relates to a method for producing polycyclic compounds such as biaryls and bipyridines useful in the fields of pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography, dyes, organic EL, and the like using a microreactor.

  A compound having a biaryl structure is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, liquid crystals, organic EL, and the like. Various compounds having a biaryl skeleton are used as liquid crystal display compounds used in TN, STN, and TFT which are liquid crystal display systems. There are many physiologically active substances having a biaryl skeleton in pharmaceuticals and agricultural chemicals. In addition, there are many compounds having a biaryl structure such as bipyridine in the molecular structure of a light emitting display element used such as organic EL which is an IT material.

  A conventionally used method for synthesizing biaryls is the Ullmann reaction, which is used as a method for synthesizing a symmetrical biaryl structure.

  A method for synthesizing asymmetric biaryls having structures in which different aryl groups are bonded to each other includes a cross-coupling reaction between a metal reagent, an aryl halide and a transition metal catalyst, and the metal reagent is relatively stable. Compounds such as boron, magnesium, zinc, tin, silicon, and art complexes thereof are used (see Non-Patent Document 1).

Recently, the synthesis of aromatic boronic acids and organic halogen compounds by a cross-coupling reaction is called Suzuki coupling, and many reports have been made. In this method, a palladium-based catalyst and a ligand are used as a transition metal catalyst, and a cross-coupling product is selectively obtained with a relatively high yield, so that it is often used in sample development. However, since the implementation of the Suzuki coupling reaction is very costly, it is desired to establish a more efficient and economical production method industrially.
One reason for this is that although palladium-based catalysts are used in this reaction, palladium metal and zero-valent palladium catalysts and ligands are very expensive raw materials, so even if they are used in catalytic amounts. However, there is an economic problem in using it for industrial production of kilograms or tons of general-purpose products, and the product becomes very expensive. Therefore, the amount of palladium catalyst used is reduced, the ligand structure is improved, inexpensive nickel-based catalysts and iron-based catalysts are used instead of palladium catalysts, and the catalyst is supported on a solid support. Research on improved methods, such as repeated collection and reuse, has been actively conducted. However, problems still remain in the limitations of applicable compound structures and selectivity.

The second reason for increasing the production cost by the cross-coupling reaction is that the yield of the target compound obtained is limited even when an expensive metal reagent is used.
The third reason is a safety problem when handling the metal reactant. Metal reactants such as boron, magnesium, zinc, tin, and silicon are usually synthesized by metal exchange reactions from organolithium and Grignard reagents, but scale-up production of organolithium and Grignard reagents is highly reactive. Is not easy.

  That is, since organic lithium has high reactivity and is unstable at room temperature, the production usually requires ultra-low temperature conditions of −80 ° C. and −100 ° C., and mass production with batch equipment is difficult. On the other hand, a Grignard reagent is synthesized at a temperature of about 0 ° C. to 80 ° C., but it cannot be said that all compounds of Grignard reagent can be produced. Organolithium and Grignard reagents are both water-inhibiting substances, and there is a great risk of reaction runaway in mass production. For this reason, special equipment for ensuring safety is required, and the equipment cost also increases. In addition, the synthesis reaction of an organic boric acid compound from organolithium or a Grignard reagent is generally difficult to scale up, resulting in decreased selectivity and yield.

  As a method for producing biaryls at low cost, a cross-coupling reaction in which an organolithium compound or a Grignard reagent is directly used in the reaction without using expensive metal reactants such as boron, magnesium, zinc, tin, and silicon is considered. It is done.

  The reaction using this Grignard reagent as a metal reagent is known as the Tamao-Kumada reaction. In the method using this reaction, a relatively expensive nickel catalyst is used as the transition metal catalyst. In addition, the reaction is limited to a substrate capable of synthesizing a Grignard reagent, and there remain problems such as a large amount of catalyst used, and aryl iodide must be used as a substrate to obtain sufficient conversion efficiency. (See Non-Patent Document 2).

With respect to reactions using organolithium as a metal reactant, a method has been reported in which a stable aromatic organolithium is dropped over a long period of time in a solution of an aromatic halogen compound in the presence of a transition metal catalyst. Murahashi et al. Showed that biphenyl was synthesized by reaction with iodobenzene using a catalyst solution prepared from palladium chloride-triphenylphosphine-methyllithium (see Non-Patent Document 3).
In addition, an example using a nickel catalyst as a coupling catalyst is described in a patent issued by Rhodia (see Patent Document 1). However, all of the organolithium compounds that can be used in the above two reports need to be lithium compounds that are stable at room temperature, but in general, organolithium is unstable at room temperature and can be used in the above methods. Is limited.

  The present inventors have proposed a production method in which a halogen compound and a lithium reagent are reacted using a microreactor to synthesize a lithium compound, and an electrophilic compound is reacted therewith. In this method, the reaction temperature is -10 to 40 ° C., which is extremely high compared to the temperature of the conventional batch process, and it can be applied to reactions of lithium compounds that are unstable at room temperature and heterocyclic lithium compounds. This is a feature. However, this patent document does not describe performing a cross-coupling reaction. (See Patent Document 2 and Patent Document 3)

Special table 2003-522744 gazette Publication 2005-104871 Publication No. 2006-241065 Chem. Rev. 95, 2457 (1995), Chem. Lett. , 301 (1977), J.A. Amer. Chem. Soc. , 101 (17), 4992 (1979), J. MoI. Org. Chem. 42 (10) 1821 (1977), J. MoI. Organomet. Chem. , 118, 349 (1976), Tetrahedron Lett. , 845 (1980) Bull. Chem. Soc. Jpn. , 49 (7), 1958 (1976) J. et al. Org. Chem. , 44 (14), 2408 (1979), J. Am. Organomet. Chem. 653, 27 (2002), Org. Synth. , 7, 172 (1990)

  The object of the present invention is to eliminate polycyclic compounds such as biaryls that are useful in the fields of pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography, dyes, etc. It is to provide a manufacturing method that does not cause a problem.

  As a result of intensive studies, the present inventors conducted a cross-coupling reaction using an organolithium compound, a halogen compound, and a transition metal catalyst in a flow path using a microreactor, whereby a polycyclic compound such as biaryl can be easily and easily obtained. It discovered that it could manufacture with sufficient purity. The present inventors also used a front and rear multistage type microreactor to synthesize an organolithium compound from an aromatic halogen compound in the front stage microreactor (step 1), and then continuously removed the product without taking it out to the outside. It has been found that polycyclic compounds such as biaryls can be continuously produced with good yield by performing a cross-coupling reaction between an organolithium compound, a halogen compound and a transition metal catalyst in a microreactor (Step 2). . The present invention has been completed based on these findings.

Ａ環およびＢ環は、各々独立に、芳香環またはヘテロ芳香環を表し、Ｒ _１ およびＲ _２ は各々独立に水素原子または置換基を表し、Ｘ _１ およびＸ _２ は各々独立にハロゲン原子を表す。Ｒ _３ はアルキル基、アルケニル基、アルキニル基またはアラルキル基を表す。ここで、Ａ環にＲ _１ が、Ｂ環にＲ _２ が複数置換していてもよい。
（２）前後多段型のマイクロリアクターを用いて、第１段のマイクロリアクターで［工程１］を行い、下記芳香族ハロゲン化合物（１）と下記有機リチウム試薬（２）と反応させて下記芳香族有機リチウム化合物（３）を流路中で製造し、引き続き第２段のマイクロリアクターで［工程２］を行い、下記ハロゲン化環状化合物（５）と前記［工程１］で得られた芳香族有機リチウム化合物（３）を有効量のパラジウム触媒（４）の存在下で流路中で反応させ、下記多環式化合物（６）を製造することを特徴とする多環式化合物の製造方法。

Ａ環およびＢ環は、各々独立に、芳香環またはヘテロ芳香環を表し、Ｒ _１ およびＲ _２ は各々独立に水素原子または置換基を表し、Ｘ _１ およびＸ _２ は各々独立にハロゲン原子を表す。Ｒ _３ はアルキル基、アルケニル基、アルキニル基またはアラルキル基を表す。ここで、Ａ環にＲ _１ が、Ｂ環にＲ _２ が複数置換していてもよい。
（３）前記芳香族ハロゲン化合物（１）と前記有機リチウム試薬（２）とを、反応温度が−１０〜４０℃かつ滞留時間が０．００１〜１０秒の条件下でマイクロリアクターを用いて流路中で反応させ前記芳香族有機リチウム化合物（３）を得ることを特徴とする（２）に記載の製造方法。
（４）第２段のマイクロリアクターの流路内の反応温度が、０〜８０℃であることを特徴とする（１）または（２）に記載の多環式化合物の製造方法。
（５）第２段のマイクロリアクターの流路内の滞留時間が、０．００１秒〜１０分であることを特徴とする（４）に記載の多環式化合物の製造方法。
（６）前記パラジウム触媒（４）が、アリル［１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾル−２−イリデン］パラジウム（ＩＩ）クロライド、アリル［１，３−ビス（メシチル）イミダゾル−２−イリデン］パラジウム（ＩＩ）クロライド、１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾル−２−イリデン］（３−クロロピリジル）パラジウム（ＩＩ）クロライド、［１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾル−２−イリデン］（３−クロロピリジル）パラジウム（ＩＩ）クロライド：銅（Ｉ）ヨージド、１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾリデン）（３−クロロピリジル）パラジウム（ＩＩ）ジクロライドから選択されることを特徴とする（１）〜（５）のいずれか１項に記載の多環式化合物の製造方法。
（７）前記パラジウム触媒（４）が、（１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾリデン）（３−クロロピリジル）パラジウム（ＩＩ）ジクロライド，または（１，３−ビス（２，６−ジイソプロピルフェニル）イミダゾル−２−イリデン）（３−クロロピリジル）パラジウム（ＩＩ）クロライドであることを特徴とする（１）〜（６）のいずれか１項に記載の多環式化合物の製造方法。
（８）前記ハロゲン化環状化合物（５）と前記芳香族有機リチウム化合物（３）と前記パラジウム触媒（４）との混合反応を、等価直径が１０μｍ〜１ｍｍ以下の流路内で互いに接触させて行うことを特徴とする（１）〜（７）のいずれか１項に記載の多環式化合物の製造方法。
（９）前記の流路中での反応の際に前記パラジウム触媒（４）とともにアミン化合物を存在させることを特徴とする（１）〜（８）のいずれか１項に記載の多環式化合物の製造方法。
The object of the present invention has been achieved by the following means.
(1) A process for producing a polycyclic compound comprising [Step 1] and [Step 2], wherein at least [Step 2] is reacted using a microreactor ,
In the [Step 1], the following aromatic organolithium compound (3) is produced by reacting the following aromatic halogen compound (1) with the following organolithium reagent (2):
In [Step 2], the following halogenated cyclic compound (5) and the aromatic organolithium compound (3) obtained in [Step 1] are reacted in the channel of the microreactor in the presence of a palladium catalyst (4). is allowed, the manufacturing method of the polycyclic compound characterized that you produce the following polycyclic compound (6).

A ring and B ring each independently represent an aromatic ring or a heteroaromatic ring, R ₁ and R ₂ each independently represent a hydrogen atom or a substituent, and X ₁ and X ₂ each independently represent a halogen atom. . R ₃ represents an alkyl group, an alkenyl group, an alkynyl group or an aralkyl group. Here, R ₁ may be substituted on the A ring and R ₂ may be substituted on the B ring .
(2) [Step 1] is performed in the first-stage microreactor using front and rear multistage microreactors, and the following aromatic halogen compound (1) and the following organolithium reagent (2) are reacted to produce the following aromatic The organolithium compound (3) is produced in the flow path, and then [Step 2] is carried out in the second stage microreactor. The halogenated cyclic compound (5) and the aromatic organic compound obtained in the above [Step 1] are obtained. lithium compound (3) are reacted in the flow path in the presence of an effective amount of a palladium catalyst (4) a method for producing a polycyclic compound characterized that you produce the following polycyclic compound (6).

A ring and B ring each independently represent an aromatic ring or a heteroaromatic ring, R ₁ and R ₂ each independently represent a hydrogen atom or a substituent, and X ₁ and X ₂ each independently represent a halogen atom. . R ₃ represents an alkyl group, an alkenyl group, an alkynyl group or an aralkyl group. Here, R ₁ may be substituted on the A ring and R ₂ may be substituted on the B ring .
(3) flow using microreactor under the conditions of the aromatic halogen compound (1) and said organic lithium reagent (2), the reaction temperature is -10 to 40 ° C. and the residence time is 0.001 seconds the process according to you, wherein (2) to obtain reacted in the road the aromatic organolithium compound (3).
(4) reaction temperature in the flow channel of the second stage of the microreactor, method for producing a polycyclic compound according to you being a 0 to 80 ° C. (1) or (2).
(5) The method for producing a polycyclic compound according to (4), wherein the residence time in the flow path of the second stage microreactor is 0.001 second to 10 minutes.
(6) The palladium catalyst (4) is allyl [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] palladium (II) chloride, allyl [1,3-bis (mesityl) imidazole- 2-Ilidene] palladium (II) chloride, 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride, [1,3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride: copper (I) iodide, 1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) Any one of (1) to (5), characterized in that it is selected from palladium (II) dichloride Method for producing a polycyclic compound according to item 1.
( 7 ) The palladium catalyst (4) is (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride, or (1,3-bis (2, 6-Diisopropylphenyl) imidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride , The production of the polycyclic compound according to any one of (1) to ( 6 ) Method.
(8) The mixed reaction between the halogenated cyclic compound (5) with the aromatic organolithium compound (3) and the palladium catalyst (4), the equivalent diameter is brought into contact with each other in the following flow channel 10μm~1mm The manufacturing method of the polycyclic compound of any one of (1)-( 7 ) characterized by performing.
( 9 ) The polycyclic compound according to any one of (1) to ( 8 ), wherein an amine compound is present together with the palladium catalyst (4) during the reaction in the flow path. Manufacturing method.

  According to the production method of the present invention, a polycyclic compound such as biaryl can be produced easily and with good yield in a good yield by a cross-coupling reaction using an aromatic organolithium compound, a halogenated cyclic compound and a transition metal catalyst. Can do.

  Further, according to the production method of the present invention, a microreactor for the synthesis of an aromatic organolithium compound from an aromatic halogen compound (Step 1), and a cross using an aromatic organolithium compound, a halogenated cyclic compound, and a transition metal catalyst The microreactor of the coupling reaction (step 2) can be connected by a flow path and can be performed as one continuous step. This makes it possible to produce a biaryl polycyclic compound efficiently, safely and stably. That is, even in a reaction using an unstable aromatic organolithium compound as a raw material, which could not be handled at room temperature by a conventional method, an aromatic organolithium compound can be produced without using ultra-low temperature conditions. Therefore, it is possible to produce a polycyclic compound such as biaryl safely, simply and with high purity without storing (taking out) a large amount of a highly dangerous aromatic organolithium compound.

It is the schematic of the microreactor which can be used by this invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention. FIG. 3 is a schematic diagram of still another microreactor that can be used in the present invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention. FIG. 2 is a schematic diagram of another microreactor that can be used in the present invention.

  The production method of the polycyclic compound of the present invention is shown by the following scheme.

In the formula, the ring represented by A is an aromatic ring or a heteroaromatic ring, the ring represented by B is an aromatic ring or a heteroaromatic ring, and the A ring or B ring may have a substituent. In addition, it may be a condensed ring with another ring, and A ring and B ring may be different or the same. R ₁ and R ₂ represent a hydrogen atom or a substituent described later, and X ₁ and X ₂ represent a halogen atom. R ₃ represents an alkyl group or the like as described later. In the scheme, an example in which R ₁ and R ₂ are one is shown, but there may be a plurality of these substituents.

  As one specific example of the above scheme, 4-bromoanisole is used as the aromatic halogen compound in Step 1, n-butyllithium is used as the organolithium reagent, bromobenzene is used as the halogenated cyclic compound in Step 2, and a transition metal catalyst. (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride, and a microreactor continuous in both steps 1 and 2 is used. Although an example is given, this invention is not limited to this.

Next, the compound used for the production method of the present invention will be described.
The aromatic halogen compound (1) used in the production method of Step 1 of the present invention is an aromatic compound substituted with at least one halogen atom (X ₁ ) (fluorine atom, chlorine atom, bromine atom, iodine atom). is there. Examples of the halogen atom substituted for the aromatic halide include chlorine, bromine and iodine. Among them, bromine and iodine are preferable because of high reactivity. An aromatic compound represents an unsaturated cyclic compound having (4n + 2) electrons (integers such as n = 0, 1, 2, 3, etc.) contained in a π-electron system on the ring. Alternatively, it may be a condensed ring. In the production method of the present invention, in addition to carbocyclic compounds such as benzene ring, naphthalene ring and anthracene ring, pyridine ring, furan ring, thiophene ring, thiazole ring, pyrrole containing hetero atoms such as nitrogen atom, oxygen atom and sulfur atom Any of heterocyclic compounds such as a ring, an imidazole ring, an indole ring, and benzothiadiazole can be used.

  The aromatic ring represented by A of the aromatic halogen compound in Step 1 is specifically a monocyclic or polycyclic 6 to 10 membered aromatic ring such as benzene, naphthalene, anthracene, phenanthrene, etc .; thiophene, furan , Pyran, pyridine, pyrrole, pyrazine, azepine, azocine, azonin, azecine, oxazole, thiazole, birimidine, biridazine, triazine, triazole, tetrazole, imidazole, pyrazole, morpholine, thiomorpholine, piperidine, piperazine, quinoline, isoquinoline, indole , Isoindole, quinoxaline, phthalazine, quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene, etc., selected from 5-10 membered monocyclic or polycyclic nitrogen, oxygen and sulfur It is an aromatic heterocyclic ring containing 1 to 4 atoms. Preferred are benzene rings and heteroaromatic rings, more preferred are benzene rings, 5- or 6-membered heterocycles, and further preferred are benzene, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, thiazole, and thiadiazole. Particularly preferred are benzene, pyridine and thiophene.

  The ring represented by A may further have a substituent, and the number and type of substituents are not particularly limited. Specific examples of the substituent include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, cyclo Linear, branched or cyclic alkyl groups having 1 to 20 carbon atoms such as propyl, cycloptyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl (including alkyl substituted by cycloalkyl); vinyl, allyl, Propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, hebutadecenyl , Octadecenyl, nonadecenyl, icocenyl, hexagenyl, dodecatrienyl, etc., straight, branched or cyclic alkenyl groups having 2 to 20 carbon atoms; ethynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, cyclooctynyl, cyclononynyl, Linear, branched or cyclic C2-C20 alkynyl groups such as cyclodecynyl; 5- to 10-membered monocyclic or bicyclic aryl groups such as phenyl, naphthyl, anthranyl; methoxy, ethoxy, propoxy, butoxy, pentyl Alkoxy groups having 1 to 20 carbon atoms such as oxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, dodecyloxy, hexadecyloxy, octadecyloxy; aryloxy groups such as phenoxy, naphthyloxy; Alkylthio groups having 1 to 20 carbon atoms such as tilthio, ethylthio, propylthio, ptylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, dodecylthio, hexadecylthio, octadecylthio; arylthio groups such as phenylthio, naphthylthio; acetyl, propanoyl, butanoyl , Pentanoyl, hexanoyl, heptanoyl, etc., acyl having 2 to 20 carbon atoms, and substituted carbonyl groups such as benzoyl, naphthoyl; methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, n-decyloxycarbonyl, phenoxycarbonyl, etc. Oxycarbonyl group; acetyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy C2-C20 acyloxy such as xy and substituted carbonyloxy groups such as benzoyloxy and naphthoyloxy; methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, A substituted sulfonyl group such as phenylsulfonyl and naphthylsulfonyl; a carbamoyl group substituted by one or two groups selected from alkyl, alkenyl and aryl such as N-methylcarbamoyl and N, N-diphenylcarbamoyl; A sulfamoyl group substituted by one or two groups selected from alkyl, alkenyl and aryl such as famoyl, N, N-diethylcarbamoyl; acetylamino, tert-petite C2-C20 acylamino such as carbonylamino and n-hexylcarbonylamino, and substituted carbonylamino groups such as benzoylamino and naphthoylamino; alkyl such as N-methylureido and N, N-diethylureido, alkenyl and aryl A ureido group substituted by one or two groups selected from: sulfonylamino having 1 to 20 carbon atoms such as methylsulfonylamino, tert-butylsulfonylamino, n-octylsulfonylamino, and phenylsulfonylamino, naphthylsulfonyl Substituted sulfonylamino groups such as amino; methylamino, phenylamino, tert-butoxycarbonylamino, bivaloylamino, benzylamino, phthaloylamino, N, N-dimethylamino group, N, N-diethylamino , N, N-diphenylamino group, mono- or di-substituted amino group such as N-methyl-N-phenylamino group; nitro group; cyano group; substituted silyl group such as trimethylsilyl, triethylsilyl; fluorine, bromine, chlorine, Halogen atoms such as iodine; thiophene, furan, pyran, pyridine, pyrrole, pyrazine, azepine, azocine, azonin, azecine, oxazole, thiazole, pyrimidine, pyridazine, triazine, triazole, tetrazole, imidazole, pyrazole, morpholine, thiomorpholine, piperidine , Piperazine, quinoline, isoquinoline, indole, isoindole, quinoxaline, phthalazine, quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene, etc. And heterocyclic residues containing 1 to 4 atoms selected from cyclic or polycyclic nitrogen, oxygen and sulfur.

  Preferably, it is an alkyl group having 1 to 16 carbon atoms, an alkenyl group having 2 to 16 carbon atoms, an alkynyl group having 2 to 16 carbon atoms, an aryl group, an alkoxy group having 2 to 16 carbon atoms, an aryloxy group, or 2 to 2 carbon atoms. 16 alkylthio groups, arylthio groups, substituted carbonyl groups having 2 to 17 carbon atoms, substituted oxycarbonyl groups having 2 to 16 carbon atoms, substituted carbonyloxy groups having 2 to 17 carbon atoms, substituted sulfonyl groups having 1 to 16 carbon atoms, C2-C17 monosubstituted or disubstituted carbamoyl group, C1-C16 monosubstituted or disubstituted sulfamoyl group, C2-C17 substituted carbonylamino group; C2-C17 monosubstituted or disubstituted A ureido group; a substituted sulfonylamino group having 1 to 16 carbon atoms; a mono- or disubstituted amino group having 1 to 161 carbon atoms, a nitro group, a cyano group, Prime 1 to 16 substituted silyl group, a halogen atom, a heterocyclic residue. More preferably, an alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an aryl group, an alkoxy group having 2 to 8 carbon atoms, an aryloxy group, and 2 carbon atoms. -8 alkylthio group, arylthio group, substituted carbonyl group having 2 to 9 carbon atoms, substituted oxycarbonyl group having 2 to 9 carbon atoms, substituted carbonyloxy group having 2 to 9 carbon atoms, substituted sulfonyl group having 1 to 8 carbon atoms A monosubstituted or disubstituted carbamoyl group having 2 to 9 carbon atoms, a monosubstituted or disubstituted sulfamoyl group having 1 to 8 carbon atoms, a substituted carbonylamino group having 2 to 9 carbon atoms, a monosubstituted or divalent group having 2 to 9 carbon atoms; Substituted ureido group, substituted sulfonylamino group having 1 to 8 carbon atoms, mono- or disubstituted amino group having 1 to 8 carbon atoms, nitro group, cyano group, substituted silyl group having 1 to 8 carbon atoms, halogen Child, a heterocyclic residue, and the like. Particularly preferably, the alkyl group having 2 to 8 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the alkynyl group having 2 to 8 carbon atoms, the aryl group, the alkoxy group having 2 to 8 carbon atoms, the aryloxy group, and 2 carbon atoms. -8 alkylthio group, arylthio group, substituted carbonyl group having 5 to 9 carbon atoms, substituted oxycarbonyl group having 5 to 9 carbon atoms, substituted carbonyloxy group having 5 to 9 carbon atoms, substituted sulfonyl group having 4 to 8 carbon atoms A monosubstituted or disubstituted carbamoyl group having 5 to 9 carbon atoms, a monosubstituted or disubstituted sulfamoyl group having 4 to 8 carbon atoms, a substituted carbonylamino group having 5 to 9 carbon atoms; Substituted ureido group, substituted sulfonylamino group having 4 to 8 carbon atoms, mono- or disubstituted amino group having 4 to 8 carbon atoms, nitro group, cyano group, substituted silyl group having 1 to 8 carbon atoms, halogen Child, a heterocyclic residue.

  Moreover, when the substituent of the aromatic ring represented by A is a carbonyl group, it is possible to prevent the side reaction from proceeding during the reaction with the organolithium reagent (2), so that the number of carbon atoms is 4 or more such as a tert-butyl group. It is preferable that a bulky group having a large steric hindrance is substituted. These substituents may further have a substituent and are not particularly limited as long as they do not participate in the reaction. Further substituents include halogen atoms (eg fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl groups (eg methyl, ethyl), aryl groups (eg phenyl, naphthyl), cyano group, carboxyl group, alkoxycarbonyl Groups (eg methoxycarbonyl), aryloxycarbonyl groups (eg phenoxycarbonyl), substituted or unsubstituted carbamoyl groups (eg carbamoyl, N-phenylcarbamoyl, N, N-dimethylcarbamoyl), alkylcarbonyl groups (eg acetyl), aryl Carbonyl group (eg benzoyl), nitro group, substituted or unsubstituted amino group (eg amino, dimethylamino, anilino), acylamino group (eg acetamido, ethoxycarbonylamino), sulfonamide group (eg methane) Sulfoneimide), imide groups (eg succinimide, phthalimide), imino groups (eg benzylideneamino), hydroxy groups, alkoxy groups (eg methoxy), aryloxy groups (eg phenoxy), acyloxy groups (eg acetoxy), alkylsulfonyloxy groups ( For example, methanesulfonyloxy), arylsulfonyloxy group (for example, benzenesulfonyloxy), sulfo group, substituted or unsubstituted sulfamoyl group (for example, sulfamoyl, N-phenylsulfamoyl), alkylthio group (for example, methylthio), arylthio group (for example, A phenylthio) alkylsulfonyl group (for example, methanesulfonyl), an arylsulfonyl group (for example, benzenesulfonyl), a heterocyclic ring, etc. can be mentioned. Further, the substituent may be further substituted, and when there are a plurality of substituents, they may be the same or different. The substituent may form a condensed ring with an aromatic ring to which a halogen atom is bonded.

A conventionally well-known organolithium compound can be used for the organolithium reagent (2) (R < ₃ > -Li) used for the manufacturing method of the process 1 of this invention. For example, alkyl lithium such as methyl lithium, ethyl lithium, propyl lithium, butyl lithium, pentyl lithium, hexyl lithium, methoxymethyl lithium, ethoxymethyl lithium; alkenyl lithium such as vinyl lithium, allyl lithium, propenyl lithium, butenyl lithium; ethynyl lithium, butynyl lithium, pentenyl lithium, Al key alkenyl lithium such as hexenyl lithium; benzyl lithium, saturated aliphatic hydrocarbon aralkyl lithium, etc. the number of carbon atoms, such as phenyl ethyl lithium to 18, from 2 to 18 carbon atoms not Saturated hydrocarbons, alicyclic hydrocarbons having 3 to 18 carbon atoms, aromatic hydrocarbon groups having 6 to 18 carbon atoms, and the like can be mentioned, but they are organic groups and can give the above lithium compound (3). Especially if it is a thing Not. In the present invention, using an alkyl lithium, alkenyl lithium, an alkynyl lithium or aralkyl lithium. Of these, alkyl lithium, alkenyl lithium, and alkynyl lithium are preferable. Among them, methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, sec-butyl lithium, iso-butyl lithium, tert-butyl lithium, and n-hexyl are preferable. Lithium, n-octyllithium, n-decyllithium, vinyllithium, allyllithium, methoxymethyllithium, benzyllithium, phenyllithium, 2-thienyllithium, tri (n-butyl) magnesiumlithium are preferable, and n-butyllithium is more preferable. Is preferred.

  The amount of the organolithium reagent (2) used varies depending on the type of the aromatic halogen compound (1) to be used, but is usually 0.01 to 10 mol, preferably 0.1 to 2. mol per mol of the aromatic halogen compound. The amount is 0 mol, more preferably 0.5 to 1.3 mol, still more preferably 0.9 to 1.1 mol.

The halogenated cyclic compound (5) used in Step 2 of the production method of the present invention is a cyclic compound substituted with at least one halogen atom (X ₂ ) (fluorine atom, chlorine atom, bromine atom, iodine atom). . Examples of the halogen atom substituted on the ring include chlorine, bromine and iodine. Among them, bromine and iodine are preferable because of high reactivity.

The ring represented by B of the halogenated cyclic compound (5) in Step 2 is specifically a monocyclic or polycyclic 6 to 10 membered aromatic ring such as benzene, naphthalene, anthracene, phenanthrene; thiophene, Furan, pyran, viridine, pyrrole, pyrazine, azepine, azocine, azonin, azesin, oxazole, thiazole, birimidine, biridazine, triazine, triazole, tetrazole, imidazole, pyrazole, morpholine, thiomorpholine, piperidine, piperazine, quinoline, isoquinoline, indole , Isoindole, quinoxaline, phthalazine, quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene, etc., selected from 5-10 membered monocyclic or polycyclic nitrogen, oxygen and sulfur Aromatic heterocycles containing 1 to 4 atoms; saturated carbocycles such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, partially unsaturated carbocycles such as cyclopropene, cyclobutene, cyclopentene, cyclohexene; pyrrole, morpholine, etc. A saturated heterocycle , preferably a benzene ring, a heterocycle, a saturated carbocycle, and a partially unsaturated carbocycle, more preferably a benzene ring, a heterocycle, and a saturated carbocycle, and even more preferably benzene, pyridine, Pyridazine, pyrimidine, pyrazine, furan, thiophene, thiazole, thiadiazole, 5 or 6 saturated carbocyclic ring, particularly preferably benzene, pyridine, thiophene, and cyclohexane . In the present invention, it is an aromatic ring or a heteroaromatic ring .

  The usage-amount of a halogenated cyclic compound (5) is 0.01-20 mol normally with respect to 1 mol of aromatic organolithium compounds (3), Preferably it is 0.1-2.0 mol, More preferably, it is 0.00. It is 5-1.5 mol, More preferably, it is 0.9-1.1 mol.

Transition metal catalysts used in the production process of Engineering about 2 uses a palladium catalyst (4) in the present invention. Palladium catalyst (4) is a catalyst containing palladium as the transition metal, it is possible to use a palladium compound, such as zero-valent palladium and divalent palladium, and salts and complexes containing palladium.
Although transition metal catalysts may be used by dissolving in a solution of pre halogenated cyclic compound (5), as a solution of a transition metal catalyst, it has a 3 liquid supply port of the mixed microreactor (three liquids, at the same time Alternatively, the reaction may be performed by supplying an organolithium reagent solution, a transition metal catalyst, and a halogen compound solution to a microreactor having a flow channel structure for sequentially mixing fluids.

The transition metal catalysts used in the production method of Step 2 of the present invention is a solid catalyst may also be used. The solid catalyst may be in the form of adsorbed and supported on the solid surface pores of particles such as activated carbon, silica gel, apatite, aluminosilicate, metallosilicate, zeolite, etc. It may be in a form in which the surface of the carrier solid is chemically bonded to particles chemically modified with linker molecules. The shape of the transition metal catalyst may be spherical or crushed particles, and may be a monolith or element structure having a three-dimensional structure. Although it is not limited to the particle size of the transition metal catalyst, the smaller the particle size, the larger the surface area per volume and the more the reaction activity.

Transition metal catalysts used in the production method of Step 2 of the present invention, specifically, palladium (0) / carbon, tetrakis (triphenylphosphine) palladium (0), bis (acetylacetonato) palladium (II) , Dichlorobis (acetonitrile) palladium (II), bisbenzonitrile dichloropalladium (II), bis (benzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichloro [1,1′-bis ( Diphenylphosphino) ferrocene] palladium (II), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tricyclohexylphosphine) palladium (II), bis (triphenylphosphine) palladium (II) diacetate, dichloro (1, 5-siku Looctadiene) palladium (II), dichloro [1,2-bis (diphenylphosphino) ethane] palladium (II), dichloro [1,3-bis (diphenylphosphino) propane] palladium (II), dichloro [1,4 -Bis (diphenylphosphino) butane] palladium (II), allyl [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] palladium (II) chloride, allyl [1,3-bis (mesityl) ) Imidazol-2-ylidene] palladium (II) chloride, 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride, [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloro Pyridyl) palladium (II) chloride: copper (I) iodide, [1,2,3,4-tetrakis (methoxycarbonyl) -1,3-butadiene-1,4-diyl] palladium (II), 1,3- Bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride can be used, but the above substances are not all. Preferably, allyl [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] palladium (II) chloride, allyl [1,3-bis (mesityl) imidazol-2-ylidene] palladium (II) Chloride, 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride, [1,3-bis (2,6-diisopropylphenyl) imidazol-2 -Ilidene] (3-chloropyridyl) palladium (II) chloride: copper (I) iodide, 1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride . Particularly preferred is 1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride. In the present invention, the organolithium compound is more reactive than the organoboron compound, but since there are many thermally unstable compounds, a reaction system for performing a cross-coupling reaction within a short time within the lifetime of the organolithium compound. Design, ie catalyst selection, is important.
The reaction mechanism of the palladium-catalyzed reaction starts with an oxidative addition reaction between a palladium (zero valent) catalyst and a halogen compound, followed by transmetalation with an organolithium compound, followed by a reductive elimination reaction. Thus, it is estimated that a polycyclic compound and a palladium (zero-valent) catalyst are produced, and the catalyst cycle is rotated. In selecting a catalyst in the present invention, it is important to control the activation of the above three reactions in a well-balanced manner.
The catalyst is preferably a compound in which palladium metal and ligand are bound, but a bulky ligand promotes the reductive elimination reaction, and the strong σ electron donating ability of the ligand strongly binds to palladium metal. Thus, dissociation of the palladium metal is prevented, and the catalytic activity is increased. From this viewpoint, in the present invention, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride, and (1,3-bis (2,6-diisopropyl) are used. The use of (phenyl) imidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride is particularly preferred, and a cross-coupling reaction system using an organolithium compound can be designed in a short time.

Transition metal catalysts may be used as a commercial product, but also may be used a catalyst solution prepared the desired catalyst in situ (in situ). Depending on the structure of the catalyst, it may be unstable to air or poor in thermal stability, and these unstable catalysts may be produced continuously using microreactors and used continuously without storage. Is preferably constructed.

In the present invention, the catalyst is dissolved in a reaction solvent, or the catalyst is supported on a carrier and used, for example, as a flow-type catalytic reactor. A method of dissolving the catalyst in a reaction solvent is preferably used.
Transition metals are very expensive, and the setting of the amount of transition metal catalyst used is very important in manufacturing process design. Stoichiometrically, the amount of transition metal catalyst required per mole of the halogen compound is 1 mole, but since the catalyst is regenerated after the reaction, the transition metal catalyst can be reacted in an amount of less than 1 mole. It becomes possible. However, if the amount of the transition metal catalyst is too small, the reaction rate decreases, so the reaction time becomes longer in order to increase the conversion rate, and problems such as product deterioration, excessive reaction progress, catalyst deterioration due to prolonged heating. Occurs. When the amount of the transition metal catalyst is excessively large, the reaction is not hindered. However, a large amount of the expensive transition metal catalyst increases the production cost and is not adopted as an industrial process. When a flow-through catalytic reactor filled with a solid catalyst is used, the catalyst can be continuously reused without being discarded, so that the catalyst cost is only the initial introduction cost. Even if there is an excessive amount of catalyst in the reactor, there will be no problem in the reaction, but rather it will be possible to use a catalyst of equimolar or more stoichiometrically, increasing the reaction rate, shortening the reaction time, etc. Benefits arise.
In the present invention, even if the amount of transition metal catalyst used is excessive, the reaction is not affected, but from the viewpoint of cost, it is desirable that the amount of catalyst used is small. The yield of the compound can be increased. Usually, the amount of the catalyst used may be at least 0.0001 mol, preferably 0.001 mol or more, more preferably 0.01 mol or more, and still more preferably 0 with respect to 1 mol of the halogenated cyclic compound (5). 0.02 mol or more. The upper limit is 10 mol or less in any case.
When the catalyst is dissolved in the reaction solvent, it is preferable to select a catalyst that can be dissolved in the reaction solvent among those exemplified above.

Further, the transition metal catalysts used in the production method of Step 2 of the present invention, the reaction can also be carried out by adding a ligand. Examples of the ligand include triphenylphosphine (PPh ₃ ), methyldiphenylphosphine (Ph ₂ PCH ₃ ), trifurylphosphine (P (2-furyl) ₃ ), tri (o-tolyl) phosphine (P (o-tol). ₃ ), tri (cyclohexyl) phosphine (PCy ₃ ), dicyclohexylphenylphosphine (PhPCy ₂ ), tri (t-butyl) phosphine (P (t-Bu) ₃ ), 2,2′-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 2,2'-bis [(diphenylphosphino) diphenyl] ether (DPEphos) (Tatrahedron Letters, 39, 5327 (1998)) Reference), diphenylphosphinoferrocene (DPPF), 1, '-Bis (di-tert-butylphosphino) ferrocene (DtBPF), N, N-dimethyl-1- [2- (diphenylphosphino) ferrocenyl] ethylamine, 1- [2- (diphenylphosphino) ferrocenyl] ethyl Methyl ether, 2-dicyclohexylphosphino-2′-dimethylamino-1,1′-biphenyl (Journal of the American Chemical Society, Volume 120, page 9722 (1998) Spiro-type phosphonium salts (see Angewante Chemie International Edition, 37, 481 (1998)) Sphine ligands, 1,3-bis (2,6-diisopropylphenyl) imidazolinium chloride, 1,3-bis (2,6-diisopropylphenyl) imidazolium chloride, 1,3-bis (2, 4,6-trimethylphenyl) imidazolinium chloride, 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride, 1- (2,6-diisopropylphenyl) -3- (2,4,6) Phosphine mimic ligands such as -trimethylphenyl) -imidazolinium chloride, 1,3-bis (2,6-diisopropylphenyl) -1,3-dihydro-2H-imidazol-2-ylidene (Angevante Chemie International・ Edition in English (Angewandte Chemie Int (editional edition in English) 36, 2163 (1997)). Reaction of palladium with a substituent on the ligand to produce palladacycle (Angewandte Chemie International Edition in English, Vol. 34, p. 1844 (1995)) It may be formed.
Preferably, trifurylphosphine, tri (o-tolyl) phosphine (which may form a palladacycle), tri (cyclohexyl) phosphine, tri (t-butyl) phosphine, dicyclohexylphenylphosphine, 1,1′-bis ( Di-t-butylphosphino) ferrocene, 2-dicyclohexylphosphino-2′-dimethylamino-1,1′-biphenyl, 1,3-bis (2,6-diisopropylphenyl) imidazolinium chloride, 1,3 -Bis (2,6-diisopropylphenyl) imidazolium chloride, 1,3-bis (2,4,6-trimethylphenyl) imidazolinium chloride, 1,3-bis (2,4,6-trimethylphenyl) imidazo Rium chloride, 1- (2,6-diisopropylphenyl) -3- (2, , 6-trimethylphenyl) -imidazolinium chloride, 1,3-bis (2,6-diisopropylphenyl) -1,3-dihydro-2H-imidazol-2-ylidene, and other phosphine mimic ligands, Preferably, 1,3-bis (2,6-diisopropylphenyl) imidazolinium chloride, 1,3-bis (2,6-diisopropylphenyl) imidazolium chloride, 1,3-bis (2,4,6- Trimethylphenyl) imidazolinium chloride, 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride, 1- (2,6-diisopropylphenyl) -3- (2,4,6-trimethylphenyl) -Imidazolinium chloride, 1,3-bis (2,6-diisopropylphenyl) -1,3-di A phosphine mimic ligand such as dro-2H-imidazol-2-ylidene, particularly preferably 1,3-bis (2,6-diisopropylphenyl) imidazolinium chloride, 1,3-bis (2,6 -Diisopropylphenyl) imidazolium chloride.

  Even if the amount of the ligand used is excessive, the reaction is not affected, but the amount of the catalyst used is preferably small from the viewpoint of process cost design. Usually, the amount of the ligand used is 1 mol of the halogenated cyclic compound (5). Although 0.0001-10 mol is used, Preferably it is 0.001 mol or more, More preferably, it is 0.01 mol or more, More preferably, it is 0.02 mol or more.

Next, the macro reactor used in the present invention will be described.
The microreactor (microflow reactor) in the present invention is a micro flow reactor comprising a mixing part (micromixer) for mixing a plurality of substances and a flow path (reactor) for causing a desired reaction subsequent thereto. Typically, the minimum length of the cross section of the flow path of the reaction part and the reaction part is several μm to several thousand μm. Depending on the purpose, the minimum length of the channel cross section and other lengths can be appropriately selected. There is no restriction | limiting in particular as a shape of the flow-path cross section of the said microreactor, According to the objective, it can select suitably. For example, a circle, a rectangle, a semicircle, a triangle, etc. are mentioned. Further, the liquid can be divided and circulated in a plurality of flow paths inside. The length and shape of the reaction flow path of the microreactor are not particularly limited and can be appropriately selected according to the type of reaction, reaction time, and the like.
A method of installing the whole or a part of the microreactor in a thermostat, a method of circulating a heat medium (refrigerant) in another channel installed near the channel, and a cooler or heater near the channel The reaction temperature can be controlled by the installation method or the like.
A multi-stage reaction can be performed by a method using a plurality of the microreactors connected together and a method using an apparatus incorporating a plurality of microreactors.
A microreactor is usually defined as a device that has a microchannel (microchannel) with an equivalent diameter of several mm or less, preferably smaller than 1000 μm, and performs a reaction in the microchannel. It is a reaction apparatus for carrying out the reaction in a steady state using a micromixer (static micromixer). Here, the equivalent diameter is a diameter when the cross section of the flow path is converted into a circle. A static micromixer is a device represented by a mixer having a fine flow path for mixing, as described in, for example, WO 96/30113, 3. Mixer described in Chapter 3, W. Ehrfeld, V. Hessel, H. Lowe, published by Wiley-VCH.

In the world of microreactors where the microchannels are microscales, both the size and the flow velocity are small, the Reynolds number is 200 or less, and the flow is dominated by laminar flow. While the fluids that perform the reaction flow in a laminar state in the flow path, they react while diffusing only by the spontaneous behavior of the molecules. In a microreactor, the reaction is carried out in a flow, so that the reaction time can be easily controlled by the residence time in the microreactor, and the specific surface area (surface area per unit volume of the fluid involved in the reaction) is large, so the heat balance is efficient. Temperature control during the reaction can be precisely and efficiently performed. Therefore, the selectivity of the reaction, particularly the high-speed reaction can be greatly improved. Further, according to the diffusion theory, the heat exchange (heat transfer) time (t) is proportional to d ² / α (d: microchannel width, α: thermal diffusivity of liquid), so if the microchannel width is reduced. The more the heat exchange efficiency is improved.

  The microreactor itself used in the present invention can be selected from known ones, commercially available products, or those newly designed and prototyped for the intended reaction. Commercially available microreactors include, for example, a microreactor having an interdigital channel structure, a single mixer and a caterpillar mixer manufactured by Institute, Fleet, Microtechnique Mainz (IMM); a microglass reactor manufactured by Microglass; CPC Cytos manufactured by Systems Co., Ltd .; YM-1 and YM-2 mixers manufactured by Yamatake Corporation; mixing tees and tees manufactured by Shimadzu GLC (T-shaped connector, Y-shaped connector); IMT chip reactor manufactured by Micro Chemical Engineering Co., Ltd .; Toray Engineering The developed product is a micro-high mixer; a center collision type mixer (KM type) and the like, and any of them can be used in the present invention.

  The minimum structural unit of the microreactor used in the present invention is a micromixer and a tube reactor. Also, a multi-reaction microreactor can be constructed by connecting a plurality of micromixers and tube reactors. In the synthesis reaction, it is necessary to construct a flow reaction apparatus incorporating a microreactor. In that case, the apparatus configuration includes a micromixer, a tube reactor, a supply pump for supplying a raw chemical solution to the microreactor, a thermostat, and a circulation circulator. A heat exchanger for temperature adjustment, a temperature sensor, a flow sensor, a pressure sensor for measuring the pressure in the pipe, a product tank for storing the product solution, and the like.

In the present invention, a plurality of reaction raw materials (including a catalyst) in Step 2 are mixed or introduced while mixing with the product flow in the microreactor in Step 1 shown in the above-mentioned scheme using a micromixer. And reacting with the product of Step 1 above.
The micromixer used in the present invention preferably has a small channel that mixes liquid or solution compounds with each other, and even if a simple T-shaped channel tee that mixes two substreams is used, the micromixer is compressed. Adequate mixing and reaction performance can be obtained by using flow effects and flow turbulence at high flow rates. Inside the micromixer, the reaction is started by mixing, and at the same time, heat is generated by the reaction. Conventional size Kenic static mixers with a large channel cross-sectional area do not provide sufficient mixing performance in the mixing reaction due to the large channel size, and the ability to gradually heat the heat generated during the reaction is insufficient. It is distinguished from the micromixer used in the present invention. When the reaction is carried out by mixing two substreams, the cross-sectional area of the substream is usually determined by the cross-sectional area of the flow path of the mixer used. The flow path of the micro-mixer of the present invention is usually 100μm ² ~16mm ^2, preferably 1000μm ² ~4.0mm ^2, more preferably 10000μm ² ~2.1mm ^2, particularly preferably the cross-sectional area of 190000μm ² ~1mm ² Have. The cross-sectional shape of the flow path is not particularly limited, and may be circular, rectangular, semicircular, or triangular.

  A tube as a reactor connected to the rear part of the micromixer has functions of diffusion mixing of raw materials, mixing reaction, and reaction heat removal. The smaller the tube inner diameter is, the shorter the diffusion distance becomes, so that the reaction rate increases, which is advantageous for shortening the reaction time. Also, the smaller the tube inner diameter, the greater the heat exchange capacity, and it is also effective for reactions involving a large exotherm. However, the smaller the inner diameter of the tube, the higher the pressure loss when the liquid flows. Therefore, the pump to be used must have a special high pressure resistance specification, and the flow rate of the liquid is limited. Will also be inconvenient. The minimum length of the flow path cross section of the tube in the present invention is 10 μm to 5000 μm in the first reaction, preferably 200 μm to 3000 μm, more preferably 250 μm to 2000 μm, particularly preferably 500 μm to 1000 μm, and 10 μm to 10,000 μm in the second reaction, preferably Has a thickness of 10 μm to 8000 μm, more preferably 10 μm to 6000 μm, and particularly preferably 10 μm to 5000 μm.

  The material of the micromixer or tube reactor (hereinafter sometimes simply referred to as a tube) of the present invention is made of stainless steel, titanium, copper, nickel, depending on requirements such as heat resistance, pressure resistance and solvent resistance, and processability. Metals such as aluminum, glass, photocuran glass, various ceramics, peak resins, polyimide resins, edge plastics, silicon, and Teflon (registered trademark) resins such as PFA and TFAA can be suitably used.

A microreactor is manufactured by a microfabrication technique, and there are the following microfabrication techniques suitable for a microreactor.
(A) LIGA technology combining X-ray lithography and electroplating (b) High aspect ratio photolithographic method using EPON-SU8 (c) Mechanical micro cutting (micro that rotates a drill with a drill diameter of micro order at high speed) Drilling etc.)
(D) High aspect ratio processing method of silicon by Deep RIE (e) Hot Emboss processing method (f) Stereolithography method (g) Laser processing method (h) Ion beam method The microreactor used in the present invention is one of the above-mentioned micro processings A technique may be used and is not particularly limited.

  The schematic diagram of the microreactor apparatus used by this invention is shown in FIGS.

Each figure will be described below.
In FIG. 1, each symbol has the following meaning.
Sections 1-3: Temperature control section of Solution A Sections 2-4: Temperature control section of Solution B Point 1, 2: Raw material supply port to microreactor Point 3, 4: Raw material supply port to micromixer Point 5: Solution Mixing start point of A and solution B Sections 5 to 6: Reaction section of solution A and solution B Point 6: Reactor outlet

In FIG. 2, each symbol has the following meaning.
Sections 21 to 24: Temperature control section of Solution A Sections 22 to 25: Temperature control section of Solution B Sections 23 to 26: Temperature control section of Solution C Points 21, 22, and 23: Feed port to the microreactor Point 24, 25, 26: Raw material supply port to micromixer Point 27: Mixing start point of solution A, solution B, and solution C Sections 27 to 28: Reaction section of solution A, solution B, and solution C Point 28: Reactor outlet

In FIG. 3, each symbol has the following meaning.
Sections 31-33: Temperature control section of solution A Sections 32-34: Temperature control section of solution B Points 31, 32: Raw material supply port to microreactor Points 33, 34: Raw material supply port to micromixer Point 35: Solution Mixing start point of A and solution B Sections 35-36: catalytic reactor with transition metal catalyst
(Reaction section of solution A and solution B)
Point 36: Reactor outlet FIG. 1 is a schematic diagram of a microreactor (MR) that can be used in step 2 of the present invention, which is composed of a micromixer (M) and a microtube (R). The microreactor (MR) has two raw material supply ports (points 1 and 2) and one product outlet (point 6). An organic lithium compound solution (solution A) is provided at one of the raw material supply ports. The other supply port is supplied with a solution (solution B) in which the halogenated cyclic compound and the transition metal catalyst are dissolved. The solution A and the solution B are contacted and mixed at the point 5 of the micromixer M, and the reaction is completed in the section from the point 5 to the point 6 to obtain a product.
FIG. 2 is also a schematic diagram of a microreactor (MR) that can be used in step 2 of the present invention, and is composed of a micromixer (M) and a microtube (R). The difference from the microreactor (MR) shown in FIG. 1 is that the micromixer (M) can mix three liquids simultaneously. The microreactor (MR) has three raw material supply ports (point 21, point 22, and point 23) and one product outlet (point 28), and one of the supply ports (point 21) has an aromatic organolithium compound. Solution (solution A) is supplied, a solution (solution B) in which the halogenated cyclic compound is dissolved is supplied to the other supply port (point 22), and a transition metal is supplied to another supply port (point 23). A solution in which the catalyst is dissolved (solution C) is supplied, and the solutions A, B, and C are brought into contact with and mixed at a point 27 inside the mixer, and the reaction is completed in a region from the point 27 to the point 28. can get.
FIG. 3 is a schematic view of a microreactor (MR) that can be used in step 2 of the present invention, and is composed of a micromixer (M) and a catalytic reactor (R3). The difference from the microreactor (MR) shown in FIGS. 1 and 2 is that a transition metal catalyst is used in a solid state. The microreactor (MR) has two raw material supply ports (points 31 and 32) and one product outlet (point 36). One of the raw material supply ports has a solution of an aromatic organolithium compound (solution A). ) And a solution (solution B) in which the halogenated cyclic compound is dissolved is supplied to the other supply port. The solution A and the solution B are brought into contact with and mixed at the point 35 of the micromixer M, and the reaction is completed on the catalyst surface supported in the section from the point 35 to the point 36 to obtain a product.

Next, FIGS. 4 to 8 will be described. First, in FIG. 4, each symbol has the following meaning.
Sections 41 to 43: Temperature control section of Solution A Sections 42 to 44: Temperature control section of Solution B Sections 47 to 48: Temperature control section of Solution C Points 41, 42, 47: Raw material supply port to the microreactor Point 43, 44, 46, 48: Raw material supply port to micromixer Point 45: Mixing start point of mixing of solution A and solution B Point 49: Mixing start point of reaction with solution C Sections 45 to 46: Mixing of solutions A and B Section Section 49-40: Reaction section with Solution C Point 40: Reactor outlet

In FIG. 5, each symbol has the following meaning.
Sections 51-53: Temperature control section of solution A Sections 52-54: Temperature control section of solution B Sections 57-58: Temperature control section of solution C Points 51, 52, 57: Raw material supply port to microreactor Point 53, 54, 56, 58: Raw material supply port to micromixer Point 55: Mixing start point of mixing of solution A and solution B Point 59: Mixing start point of reaction with solution C Sections 55-56: Mixing of solutions A and B Section Section 59-50: Reaction section with Solution C Point 50: Reactor outlet

In FIG. 6, each symbol has the following meaning.
Zones 61-63: Temperature control zone for solution A Zones 62-64: Temperature control zone for solution B Zones 67-68: Temperature control zone for solution C Points 61, 62, 67: Feed port for feed to microreactor Point 63, 64, 66, 68: Raw material supply port to the micromixer Point 65: Mixing start point of the first step (reaction of solutions A and B) Point 69: Mixing start point of the second step (reaction with solution C) Section 65 ~ 66: Reaction section of step 1 Section 69-60: Reaction section of step 2 Point 60: Reactor outlet

In FIG. 7, each symbol has the following meaning.
Zones 71-73: Temperature control zone for solution A Zones 72-74: Temperature control zone for solution B Zones 77-78: Temperature control zone for solution C Points 71, 72, 77: Feed port for the microreactor Point 73, 74, 76, 78: Raw material supply port to micro mixer Point 75: Mixing start point of first step (reaction of solutions A and B) Point 79: Mixing start point of second step (reaction with solution C) Section 75 ~ 76: Reaction section of step 1 Section 79 to 70: Reaction section of step 2 Point 70: Reactor outlet

In FIG. 8, each symbol has the following meaning.
Sections 81-83: Temperature control section of solution A Sections 82-84: Temperature control section of solution B Sections 87-88: Temperature control section of solution C Points 81, 82, 87: Feed port for feed to microreactor Point 83, 84, 86, 88: Raw material supply port to micromixer Point 85: Mixing start point of first step (reaction of solutions A and B) Point 89: Mixing start point of second step (reaction with solution C) Section 85 ~ 86: Reaction section of Step 1 Section 89 ~ 80: Reaction section of Step 2 Point 90: Micromixer outlet Section 90-80: Reaction temperature variable section of Step 2 Point 80: Reactor outlet

FIG. 4 is also a schematic diagram of a microreactor (MR) that can be used in step 2 of the present invention, and is composed of a micromixer (M1, M2) and a microtube (R1, R2). The difference from the microreactor (MR) shown in FIG. 1 is that the transition metal catalyst solution (solution A) and the halogenated cyclic compound solution (solution B) are continuously mixed by the micromixer M1, and then the micromixer is continued. (M2) is supplied to react with the organolithium compound (solution C).
FIG. 5 is also a schematic diagram of a microreactor (MR) that can be used in step 2 of the present invention, and is composed of a micromixer (M1, M2) and a microtube (R1, R2). The difference from the microreactor (MR) shown in FIG. 1 is that the transition metal catalyst solution (solution A) and the organolithium compound solution (solution B) are continuously mixed by the micromixer M1 to activate the catalyst. Then, it is supplied to the micromixer (M2) and reacted with the halogenated cyclic compound (solution C).
FIG. 6 is a schematic view of a microreactor (MR) that can be used in a continuous process from step 1 to step 2 of the present invention, and is composed of a micromixer (M1, M2) and a microtube (R1, R2).
FIG. 7 is also a schematic diagram of a microreactor (MR) that can be used in the continuous process from step 1 to step 2 of the present invention, and is composed of a micromixer (M1, M2) and a microtube (R1, R2). The A difference from the microreactor (MR) shown in FIG. 6 is that a transition metal catalyst having a fixed state is used.
FIG. 8 is also a schematic diagram of a microreactor (MR) that can be used in a continuous process from step 1 to step 2 of the present invention, and is composed of a micromixer (M1, M2) and a microtube (R1, R2). The A difference from the microreactor (MR) shown in FIG. 6 is that a reaction temperature variable section in step 2 is provided.

  The flow rate of the raw material solution supplied to the microreactor used in the present invention varies depending on the mixing method, structure, and flow path of the micromixer and the equivalent diameter of the tube. For example, when using a mixing tee having an inner diameter of Φ0.5 mm (hereinafter, simply referred to as “Tee”) and a tube having an inner diameter of Φ500 μm, it is usually 0.1 μl / min to 1000 ml / min, preferably 0. The range is from 1 ml / min to 100 ml / min, more preferably from 1 ml / min to 70 ml / min, particularly preferably from 5 ml / min to 50 ml / min. Further, the flow rates of a plurality of raw materials supplied to the microreactor may be the same flow rate or different flow rates. Any pump for industrial use can be used as the pump for liquid feeding, but it is desirable that the pump does not cause pulsation during liquid feeding as much as possible. A plunger pump, a gear pump, a rotary pump, a diaphragm pump, etc. are preferable.

  In the microreactor, a liquid or solution-like compound is mixed and reacted by the kinetic energy of the flowing liquid and the solution, but if necessary, energy for promoting mixing such as vibration energy may be added from the outside of the microreactor. Mixing can be performed from static mixing (laminar flow) to dynamic mixing (turbulence) depending on the flow rate / flow rate and the shape of the reactor (three-dimensional shape of the wetted part, bend of the flow path, wall roughness, etc.). And may be mixed by turbulent flow or laminar flow.

  In the present invention, the aromatic organolithium compound (3) used in Step 2 may be the one produced in Step 1, or a commercially available aromatic organolithium compound. In the case of performing the reaction in steps 1 and 2 in succession using a microreactor, in step 1, it is not necessary to cool at -100 ° C, and the reaction can be carried out under mild cooling conditions at -10 to 40 ° C. Therefore, there is a great merit in equipment cost and energy cost. In addition, since the reaction is completed within a few minutes including Step 1 to Step 2, the production amount per hour can be increased.

  The microreactor that can be used in the present invention is a structure in which a micromixer alone, a microtube alone, or a micromixer and a microtube (tube reactor) are connected. In this case, a structure in which a plurality of the above-described micromixers and microtubes are combined as necessary is used, and a plurality of microreactors may be connected by tubes. The shape and dimensions of the micromixer and the microtube can be optimized so as to increase the yield of the target product.

  The microreactor used in the second step of the present invention is a structure having a solid catalyst for coupling inside the reactor, for example, a catalyst on a support chemically or physically or a powder-filled type, a wall-supported type, a wall-surface chemical bond It may have the function of a catalytic reactor represented by a mold structure or the like, and is not limited to the utilization form of the catalyst. The transition metal catalyst is expensive, and the structure having the coupling solid catalyst in the reactor can easily separate the catalyst from the reaction solution, and the process cost can be reduced.

  The microreactor used in the present invention can be cooled or heated, but the method for adjusting the temperature of the microreactor in the present invention is not particularly limited. Reaction temperature control is performed by heat exchange with the heat medium from the channel wall surface of the microreactor, but the raw material chemical solution to be introduced into the microreactor may be supplied at a desired temperature by a heat exchanger in advance, for example, When the reaction is exothermic, the raw material chemical solution supplied to the microreactor may be cooled.

  In the present invention, when the first step and the second step are continuously performed using a microreactor, the halogen lithium exchange reaction between the aromatic halogen compound and the organolithium reagent in the first microreactor is performed in the first step. The reaction temperature is set so that the yield of the target aromatic organolithium compound is maximized, and is usually -10 to 40 ° C, preferably -10 to 35 ° C, particularly preferably 0 to 35 ° C. is there. If this temperature is too low, it is necessary to lengthen the reaction time. If the temperature is too high, side reactions such as deterioration and disproportionation of the produced aromatic organolithium compound proceed. The deterioration and side reactions of organolithium are greatly affected by temperature, and the higher the temperature, the more prominent the deterioration is.

  On the other hand, in the second step of the present invention, the reaction temperature in the second microreactor is such that the aromatic lithium compound does not decompose within the residence time in the microreactor and the coupling reaction with the target halogen compound is performed. It is necessary to be within a temperature range that can be performed at a sufficient reaction rate, and the reaction temperature in the second microreactor is usually −30 to 100 ° C., preferably −20 to 90 ° C., more preferably −10. It is -80 degreeC, Most preferably, it is 0-80 degreeC.

  The reaction time in the present invention is represented by the residence time from when the raw material liquid is introduced into the micromixer inlet to the outside through the tube reactor connected to the micromixer outlet. The residence time in the microreactor in each step varies depending on parameters such as the reactivity of the halogen compound and the organolithium reagent, the reagent concentration, the reaction temperature, and the stability of the lithium compound. The residence time in each process is set by changing the feed rate of the raw chemical solution according to the internal space volume of the microreactor to be used, but if the feed time of the raw chemical solution is fixed, the internal space of the microreactor It may be set by changing the volume, and is set by adjusting the cross-sectional area and length of the microtube.

  In the present invention, when the first step and the second step are continuously performed using a microreactor, the residence time of the halogen-lithium exchange reaction performed in the microreactor of the first step is 0.001 to 10 seconds, preferably It is 0.001 second to 5 seconds, more preferably 0.001 second to 4 seconds, and particularly preferably 0.01 to 3 seconds. The halogen-lithium exchange reaction is an extremely fast reaction, but if the residence time in the first step is too short, the reaction will not be completed completely, and the raw material aromatic halogen compound and organolithium reagent remain, and the reaction in the second step. Affects yield. On the other hand, if the residence time is too long, the resulting lithium intermediate has low thermal stability, which causes degradation and side reactions of the produced aromatic organolithium compound (3), affecting the reaction yield in the second step. Is undesirable.

  The residence time of the coupling reaction using the catalyst of the aromatic organolithium compound (3) and the halogenated cyclic compound (5) performed in the microreactor of the second step is 0.001 seconds to 10 minutes, preferably 0.005 seconds. -5 minutes, more preferably 0.01 seconds to 3 minutes, and particularly preferably 0.1 seconds to 2 minutes. If the residence time in the second step is too short, the reaction will not be completed completely. Conversely, if the residence time is too long, side reactions from the product occur, which is not preferable.

  In the present invention, the progress of the reaction can be monitored using various known analytical instruments. The reaction rate can be confirmed by, for example, high performance liquid chromatography, capillary gas chromatography or the like. It is also possible to monitor the reaction online by tracking changes in absorbance using an online FT-IR spectrometer or an online NIR spectrometer.

  In the method of the present invention, the aromatic halogen compound (1), the organolithium reagent (2), and the halogenated cyclic compound (3) can be reacted in a liquid or solution state. When the above raw materials are not liquid, it is necessary to dissolve them in a solvent inert to the reaction and use them in the reaction. As the solvent that can be used in Step 1 and Step 2 of the present invention, any of the solvents used in known halogen-metal exchange reactions can be used. Specifically, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, durene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, diphenylmethane, chlorobenzene, 1,2-dichlorobenzene, 1,2,4-trichlorobenzene, etc. Compounds; polar solvents such as pyridine, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone; methyl acetate, ethyl acetate, butyl acetate Acetic esters such as n-pentane, n-hexane, n-heptane, cyclohexane, decane, paraffin and other alkanes and perfluoroalkanes; dimethyl ether, diethyl ether, diisopropyl ether, dibutyl Ethers such as ether, 1,2-dimethoxyethane (abbreviated as DME), petroleum ether, tetrahydrofuran (abbreviated as THF), cyclopentyl methyl ether, dioxane, trioxane, diglyme; N, N-dimethylimidazolidinone, etc. Ureas; tertiary amines such as trimethylamine, triethylamine, tributylamine, N, N, N ′, N′-tetramethylethylenediamine; halogenated alkanes such as methylene chloride and dichloroethane, regardless of polar or nonpolar solvents Either can be used. Preferably, THF, diethyl ether, cyclopentyl methyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, toluene, xylene, 1,3-dimethyl-2-imidazolidinone, more preferably THF, diethyl ether, dibutyl ether, Cyclopentyl methyl ether, dimethoxyethane, and toluene. These solvents can be used alone or in admixture of two or more kinds, and the mixing ratio at the time of mixing and use can be arbitrarily determined. The amount of the solvent used is usually in the range of 1 to 10,000 ml, preferably 300 to 6000 ml, more preferably 600 to 3000 ml, with respect to 1 mol of each compound as a substrate.

In the production method of the present invention, a chelating agent such as a tertiary amine can be added to activate the organolithium reagent (2) and the aromatic organolithium compound (3). The amount of chelating agent used is usually in the range of 0.01 to 10 moles, preferably 0.05 to 5 moles, more preferably 0.1 to 0.1 moles per mole of the organolithium reagent and aromatic organolithium compound. 2.0 moles.
As a chelating agent, N, N, N ′, N′-tetramethylethylenediamine (TMEDA), N, N, N ′, N ″, N ″ -pentamethyldiethylenetriamine (PMDTA), N, N, N Tertiary amines such as', N ″, N ′ ″, N ′ ″-hexamethyltriethylenetetramine (HMTTA) can be used.

Although the preferable specific example of the polycyclic compound (6) represented by the said general formula obtained by the method of this invention is shown below, this invention is not limited to these.
Abbreviations in the following compounds are as follows (the same applies hereinafter).
Me: methyl Ph: phenyl Bu: butyl Et: ethyl Pr: propyl

  The polycyclic compound (6) represented in the scheme obtained by the method of the present invention can be isolated by a known method. For example, an extraction method using an organic solvent, a distillation method, a reprecipitation method using an organic solvent, water, or a mixture of an organic solvent and water, or column chromatography is used alone or in combination as appropriate. It is possible to purify.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these.

  The structure of the product was identified by NMR, IR, and millimass measurement. Moreover, about the thing with which a standard substance is marketed, the reaction rate of the target object was computed from the area ratio with a standard substance by gas chromatography (GC), and was computed by the quantitative analysis method. For those for which standard substances are not commercially available, the isolation yield was determined by silica gel column chromatography.

An example of the coupling reaction of the aromatic organolithium compound (3) and the halogenated cyclic compound (5) in the presence of a transition metal catalyst will be described.
Example 1 <Synthesis of 4-methoxybiphenyl by microreactor>
Using the reaction raw materials shown in Table 1, step 2 was performed as follows.
Phenyl lithium as the aromatic organolithium compound, 4-bromoanisole as the halogenated cyclic compound, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) as the transition metal catalyst A cross coupling reaction was carried out using each dichloride and the microreactor apparatus shown in FIG.
The microreactor is composed of a micromixer and a microtube. The micromixer uses a mixing tee (manufactured by GL Sciences Co., Ltd., cross-sectional area 0.20 mm ² ) with an inner diameter of Φ0.5 mm, and the microtube has an inner diameter of 0.5 mm and an outer diameter. A SUS316 tube (manufactured by GL Science) having a length of 1/16 inch and a length of 40 mm was used, and a SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch was manufactured. The microreactor section 1 to section 6 and section 2 to section 6 were buried in a thermostatic water bath and set to 50 ° C.
Aromatic organolithium compound solution (liquid A) was synthesized by halogen-lithium exchange reaction from -reaction of bromobenzene and 1.60 mol / l n-butyllithium / hexane solution in dehydrated THF solvent at -78 ° C. The obtained phenyllithium solution was diluted with dehydrated THF and adjusted to a concentration of 0.310 mol / l. The halogenated cyclic compound (5) and the transition metal catalyst solution (Liquid B) were prepared by diluting 4-bromoanisole with dehydrated THF to prepare a solution having a concentration of 0.517 mol / l. -Bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (10 mol% with respect to 4-bromoanisole) was added and dissolved. Liquid A and liquid B were each sucked into a stainless steel syringe and then sent to the microreactor using a PHD-4400 high-pressure syringe pump manufactured by Harvard. The supply flow rate of the A liquid microreactor is 7.5 ml / min, and the supply flow rate of the B liquid is 3.0 ml / min. At this time, the residence time between the sections 5 to 6 in FIG. 1 is 16.4 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. The yield of the target compound was 79%.

Examples 2-4
The test was carried out under the same conditions as in Example 1 except that the catalyst amount, reaction temperature, and residence time were changed to the conditions shown in Table 2.

Comparative Example 1 <Synthesis of 4-methoxybiphenyl by Batch Formula>
A 100 mL Schlenk tube containing a magnetic stirrer was replaced with dehydrated argon gas, 7.5 ml of a dehydrated THF solution of 0.310 mol / l bromobenzene was added, and the mixture was stirred using a magnetic stirrer while being in a dry ice-acetone bath. And cooled to -78 ° C. Next, 1.55 mol / l of n-butyllithium in n-hexane was sucked into the microsyringe, and 1.5 ml was added dropwise at a rate of 0.3 ml / min over 5 minutes. The mixture was stirred at 0 ° C. for 10 minutes to prepare a phenyl lithium solution (solution A).
In a solution prepared by diluting 4-bromoanisole with dehydrated THF to a solution of 0.517 mol / l concentration, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) ) A Schlenk tube containing solution A in which palladium (II) dichloride was dissolved by adding 10 mol% of 4-bromoanisole and dissolved (liquid B) into a microsyringe and cooled to −78 ° C. 3 ml was added dropwise at a rate of 3 ml / min over 1 minute. After completion of dropping, the mixture was stirred at -78 ° C for 2 hours. After completion of the reaction, methanol was added at −78 ° C. to stop the reaction. The obtained solution was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. As a result, the yield of the target product was 0%.

Comparative Examples 2 and 3
The reaction was performed under the same conditions as in Comparative Example 1 except that the reaction temperature was changed to the conditions shown in Table 2.

  From the results in Table 2, in the batch synthesis method in which a halogen compound and a transition metal catalyst are dropped into a THF solution of phenyllithium and reacted, the yield of the target product is low due to the progress of decomposition and deterioration of phenyllithium. It takes a long time to make it happen. However, since the continuous synthesis method using a microreactor can complete the reaction at a high temperature in a short time, side reactions are suppressed and the yield of the target compound is remarkably high.

Examples 5-7
The halogenated cyclic compounds were changed to those described in Table 3, and synthesis was performed under the reaction conditions shown in Table 4. The results are shown in Table 4.

Example 8 <Synthesis of 4-methoxybiphenyl by microreactor>
4-methoxyphenyllithium is synthesized by reaction with 4-bromoanisole as the aromatic halogen compound and n-butyllithium as the organolithium reagent in the first step, and bromobenzene as the halogenated cyclic compound in the subsequent second step. A cross-coupling reaction using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a metal catalyst is carried out using the microreactor apparatus shown in FIG. did.
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee (manufactured by GL Sciences, cross-sectional area 0.20 mm) with an inner diameter of 0.5 mm. ² ), the micro tube R1 is an SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences Inc., cross-sectional area 0). 20 mm ² ), and the micro tube R2 has an inner diameter of 0.5 mm, an outer diameter of 1/16 inch, a 40 mm long SUS316 tube (manufactured by GL Sciences Inc.), and an inner diameter of 1.0 mm, an outer diameter of 1/16. Made using inch SUS316 tube (GL Sciences Inc.) It was. The section 61 to section 66 and the section 62 to section 66 of the microreactor are cooled by immersing them in a constant temperature water bath having a liquid temperature of 0 ° C., and the sections 67 to 60 are immersed in a constant temperature water bath having a liquid temperature of −20 ° C. Cooled down.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 4-bromoanisole with dehydrated THF to a concentration of 0.292 mol / l was used. The organolithium reagent (solution B) was an n-hexane solution of n-butyllithium having a concentration of 1.45 mol / l. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting bromobenzene with dehydrated THF to adjust the concentration to 0.487 mol / l (1,3-bis (2,6- Diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% with respect to bromobenzene) was added and dissolved. Liquid A, Liquid B, and Liquid C were each sucked into a stainless steel syringe and then sent to the microreactor using a Harvard PHD-4400 type high pressure syringe pump. The supply flow rate of the microreactor of A liquid is 7.5 ml / min, the supply flow rate of B liquid is 1.5 ml / min, and the supply speed of C liquid is 3.0 ml / min. The residence time of 2.6 is 2.6 seconds, and the residence time between sections 69 to 60 is 16.4 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. The yield of the target compound was 53%.

Examples 9-13
Synthesis was performed in the same manner as in Example 8, except that the reaction temperature, residence time, and catalyst amount were changed to the conditions shown in Table 6.

Example 14
4-methoxyphenyllithium is synthesized by reaction with 4-bromoanisole as an aromatic halogen compound and n-butyllithium as an organolithium reagent in the first step, and bromobenzene as a halogenated cyclic compound in the subsequent second step. A cross-coupling reaction using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a transition metal catalyst is performed using a microreactor apparatus shown in FIG. Carried out.
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee (manufactured by GL Sciences, cross-sectional area 0.20 mm) with an inner diameter of 0.5 mm. ² ), the micro tube R1 is an SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences Inc., cross-sectional area 0). 20 mm ² ), and the micro tube R2 has an inner diameter of 0.5 mm, an outer diameter of 1/16 inch, a 40 mm long SUS316 tube (manufactured by GL Sciences Inc.), and an inner diameter of 1.0 mm, an outer diameter of 1/16. Made using inch SUS316 tube (GL Sciences Inc.) It was. The section 61 to section 66 and the section 62 to section 66 of the microreactor are cooled by immersing them in a constant temperature water bath having a liquid temperature of 0 ° C., and the sections 67 to 60 are immersed in a constant temperature water bath having a liquid temperature of 50 ° C. for heating. did.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 4-bromoanisole with dehydrated THF to a concentration of 0.292 mol / l was used. The organolithium reagent (solution B) was an n-hexane solution of n-butyllithium having a concentration of 1.45 mol / l. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting bromobenzene with dehydrated THF to adjust the concentration to 0.487 mol / l (1,3-bis (2,6- Diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% with respect to bromobenzene) was added and dissolved. Liquid A, Liquid B, and Liquid C were each sucked into a stainless steel syringe and then sent to the microreactor using a Harvard PHD-4400 type high pressure syringe pump. The supply flow rate of the microreactor of A liquid is 7.5 ml / min, the supply flow rate of B liquid is 1.5 ml / min, and the supply speed of C liquid is 3.0 ml / min. The residence time of 2.6 is 2.6 seconds, and the residence time between sections 69 to 60 is 16.4 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. The yield of the target compound was 80%.

Examples 15-18
In Example 14, the synthesis was performed in the same manner as in Example 14, except that the reaction raw materials were changed to the compounds shown in Table 5 and the reaction temperature, residence time and catalyst amount were changed to the conditions shown in Table 6.

Example 19
In Example 14, the reaction raw materials were set to the compounds shown in Table 5, the reaction conditions were set to the conditions shown in Table 6, and the transition metal catalyst of liquid C was changed to (1,3-bis (2,6-diisopropylphenyl) imidazo Other than changing from (Ridene) (3-chloropyridyl) palladium (II) dichloride to 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride, Synthesis was performed in the same manner as in Example 14.

Example 20
Example 14 is the same as Example 14 except that the reaction raw materials were set to the compounds shown in Table 5, the reaction conditions were set to the conditions shown in Table 6, and the solvent of solution C was changed from THF to 1,2-dimethoxyethane. The synthesis was performed in the same manner.

Comparative Example 4
The 100 mL Schlenk tube containing the magnetic stirrer was replaced with dehydrated argon gas, and 7.5 ml of 0.292 mol / l of dehydrated THF solution of 4-bromoanisole was charged and stirred with a magnetic stirrer while using dry ice It was immersed in an acetone bath and cooled to -78 ° C. Next, 1.45 mol / l of n-butyllithium in n-hexane was sucked into the microsyringe, and 1.5 ml was added dropwise at a rate of 0.3 ml / min over 5 minutes. Stir at 10 ° C. for 10 minutes to prepare a 4-methoxyphenyllithium solution.
In a solution prepared by diluting bromobenzene with dehydrated THF to a concentration of 0.487 mol / l, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium ( II) A Schlenk tube containing 4-methoxyphenyllithium solution, in which a solution (liquid B) in which dichloride was added and dissolved in an amount of 10 mol% with respect to bromobenzene was sucked into a microsyringe and cooled to −78 ° C. 3 ml was added dropwise at a rate of 3 ml / min over 1 minute. After completion of dropping, the mixture was stirred at -78 ° C for 2 hours. After completion of the reaction, methanol was added at −78 ° C. to stop the reaction. The obtained solution was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. As a result, the yield of the target product was 0%.

Comparative Examples 5 and 6
Synthesis was performed in the same manner as in Comparative Example 1, except that the reaction temperature was changed to the conditions shown in Table 6 in Comparative Example 1.

Example 21
In Example 14, the synthesis was performed in the same manner as in Example 14, except that the reaction temperature in the first step was changed to 20 ° C. and the residence time was changed to 1 second.

Example 22
In Example 14, the synthesis was performed in the same manner as in Example 18 except that the reaction raw materials were as shown in Table 5 and the amount of catalyst was reduced under the reaction conditions shown in Table 6.
Table 6 shows the results of Examples 8 to 22 and Comparative Examples 4 to 6.

  From the results of Table 2, Table 4, and Table 6, the following is clear. Since the product of the first step, phenyllithium and 4-methoxyphenyllithium, which are aromatic organolithium compounds, are thermally unstable at room temperature, it is necessary to carry out the synthesis at an ultra-low temperature of −78 ° C. in the batch synthesis method. On the other hand, since the aromatic organolithium compound has a short lifetime under the high temperature conditions necessary for the reaction in the second step, the yield of the target product is low. However, in the continuous synthesis method using a microphone reactor, the aromatic organolithium compound synthesized in the first step is used for the reaction under the high temperature conditions in the second step without time loss, so that the thermally unstable aromatic organolithium is used. Even a production process in which a compound is used as an intermediate can be carried out in high yield. As a result of effective rapid mixing reaction, reaction temperature control, and residence time control using a microreactor, the target product was obtained in high yield. Furthermore, since an ultra-low temperature condition is not required in the synthesis of the aromatic organolithium compound, it is possible to construct a process that is inexpensive in terms of energy.

Examples 23-31
In Example 21, n-butyllithium having a concentration of 1.6 mol / l was used. Table 7 shows the inner diameters and inner diameters of the mixer M1, the mixer M2, the microtube R1, the microtube R2, and the second reaction mixer. The synthesis was performed in the same manner as in Example 21 except that the conditions were changed. Table 7 shows the results of Examples 23 to 31.

Examples 32-39
In Example 14, the experiment was performed in the same manner as in Example 14 except that the aromatic halogen compound and the halogenated cyclic compound were changed to those shown in Table 8 and the synthesis was performed under the reaction conditions shown in Table 9. It was. Table 9 shows the results of Examples 32-39.

Example 40 <Synthesis of 4-methoxybiphenyl by microreactor>
In the first step, 4-bromoanisole is synthesized as an aromatic halogen compound and n-butyllithium is used as an organolithium reagent, and then 4-methoxyphenyllithium is synthesized in the second step. Using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a catalyst, a cross-coupling reaction was carried out using the microreactor apparatus shown in FIG. .
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences, cross-sectional area of 0.20 mm2). ), SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 0.5 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.25 mm (manufactured by GL Sciences Inc., cross-sectional area of 0.05 mm2). The microtube R2 was manufactured using a SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch. The microreactor section 81 to section 90, section 82 to section 90, and section 87 to section 90 are cooled by being immersed in a constant temperature water bath having a liquid temperature of 0 ° C., and the temperature from section 90 to section 80 is controlled to a constant temperature of 30 ° C. It was buried in the aquarium.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 4-bromoanisole with dehydrated THF to a concentration of 0.33 mol / l was used. As the organic lithium reagent (solution B), an n-hexane solution of n-butyllithium having a concentration of 1.65 mol / l was used. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting bromobenzene with dehydrated THF to adjust the concentration to 0.55 mol / l, (1,3-bis (2,6- Diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% with respect to bromobenzene) was added and dissolved. Liquid A, liquid B, and liquid C were each sent to the microreactor using an LC-20AT plunger pump manufactured by Shimadzu Corporation. The supply flow rate of the A liquid microreactor is 7.5 ml / min, the supply flow rate of the B liquid is 1.5 ml / min, and the supply speed of the C liquid is 3.0 ml / min. The residence time is 2.6 seconds, and the residence time between sections 89 to 80 is 15.7 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. As a result, the yield of the target compound was 84%.

Examples 41-43
It implemented on the same conditions as Example 40 except having set the residence time in the sections 89-80 in Example 40 to the value of Table 10.

Example 44
It implemented on the same conditions as Example 40 except having set the constant temperature water tank of the sections 90-80 in Example 40 to liquid temperature 50 degreeC.

Examples 45-47
It implemented on the same conditions as Example 44 except having set the residence time between the areas 89-80 in Example 44 to the value of Table 10.

Example 48
It implemented on the same conditions as Example 40 except having set the constant temperature water tank of the sections 90-80 in Example 40 to liquid temperature 70 degreeC.

Examples 49-51
It implemented on the same conditions as Example 48 except having set the residence time between the areas 89-80 in Example 48 to the value of Table 10. Table 10 shows the results of Examples 40 to 51.

Example 52 <Synthesis of 2-phenylthiophene by microreactor>
In the first step, 2-bromothiophene is synthesized as an aromatic halogen compound and n-butyllithium is used as an organolithium reagent, and then 2-thienyllithium is synthesized in the second step. Using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a catalyst, a cross-coupling reaction was carried out using the microreactor apparatus shown in FIG. .
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences, cross-sectional area of 0.20 mm2). ), SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 0.5 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.25 mm (manufactured by GL Sciences Inc., cross-sectional area of 0.05 mm2). The microtube R2 was manufactured using a SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch. The microreactor section 81 to section 90, section 82 to section 90, and section 87 to section 90 are cooled by being immersed in a constant temperature water bath having a liquid temperature of 0 ° C., and the temperature from section 90 to section 80 is a constant temperature of 50 ° C. It was buried in the aquarium.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 2-bromothiophene with dehydrated THF to a concentration of 0.33 mol / l was used. As the organic lithium reagent (solution B), an n-hexane solution of n-butyllithium having a concentration of 1.65 mol / l was used. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting bromobenzene with dehydrated THF to adjust the concentration to 0.55 mol / l, (1,3-bis (2,6- Diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% with respect to bromobenzene) was added and dissolved. Liquid A, liquid B and liquid C were each sent to the microreactor using an LC-20AT plunger pump manufactured by Shimadzu Corporation. The supply flow rate of the A liquid microreactor is 7.5 ml / min, the supply flow rate of the B liquid is 1.5 ml / min, and the supply speed of the C liquid is 3.0 ml / min. The residence time is 2.6 seconds, and the residence time between sections 89 to 80 is 31.4 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. The yield of the target compound was 55%.

Examples 53 and 54
It implemented on the same conditions as Example 52 except having set the residence time in the area 89-80 in Example 52 to the value of Table 11.

Examples 55-58
The constant temperature water bath in the sections 90 to 80 in Example 52 was set to a liquid temperature of 70 ° C., and the residence time in the sections 89 to 80 was set to the values described in Table 11 and was performed under the same conditions as in Example 52. . The results of Examples 52 to 58 are shown in Table 11.

Example 59 <2-phenylthiophene synthesis by microreactor>
In the first step, 2-bromothiophene is synthesized as an aromatic halogen compound and n-butyllithium is used as an organolithium reagent, and then 2-thienyllithium is synthesized in the second step. Using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a catalyst, a cross-coupling reaction was carried out using the microreactor apparatus shown in FIG. .
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences, cross-sectional area of 0.20 mm2). ), SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 0.5 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.25 mm (manufactured by GL Sciences Inc., cross-sectional area of 0.05 mm2). The microtube R2 was manufactured using a SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch. The microreactor section 81 to section 90, section 82 to section 90, and section 87 to section 90 are cooled by being immersed in a constant temperature water bath having a liquid temperature of 0 ° C., and the temperature from section 90 to section 80 is a constant temperature of 70 ° C. It was buried in the aquarium.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 2-bromothiophene with dehydrated CPME and adjusting the concentration to 0.33 mol / l was used. As the organic lithium reagent (solution B), an n-hexane solution of n-butyllithium having a concentration of 1.65 mol / l was used. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting bromobenzene with dehydrated CPME to adjust the concentration to 0.55 mol / l (1,3-bis (2,6- Diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% relative to bromobenzene), N, N, N ′, N′-tetramethylethylenediamine (TMEDA) (2-bromothiophene and The same mol) was added and dissolved. Liquid A, liquid B, and liquid C were each sent to the microreactor using an LC-20AT plunger pump manufactured by Shimadzu Corporation. The supply flow rate of the A liquid microreactor is 7.5 ml / min, the supply flow rate of the B liquid is 1.5 ml / min, and the supply speed of the C liquid is 3.0 ml / min. The residence time is 2.6 seconds, and the residence time between sections 89 to 80 is 94.2 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. As a result, the yield of the target compound was 80%.

Example 60 <Synthesis of 2- (2-thienyl) pyridine by a microreactor>
In the first step, 2-bromothiophene is synthesized as an aromatic halogen compound and n-butyllithium is used as an organolithium reagent, and then 2-thienyl lithium is synthesized. Then, in the second step, 2-bromopyridine is transitioned as a halogenated cyclic compound. Using (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride as a metal catalyst, a cross-coupling reaction was carried out using the microreactor apparatus shown in FIG. did.
The microreactor is composed of two micromixers (M1, M2) and two microtubes (R1, R2). The micromixer M1 is a mixing tee having an inner diameter of 0.5 mm (manufactured by GL Sciences, cross-sectional area of 0.20 mm2). ), SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 0.5 mm and an outer diameter of 1/16 inch, and the micromixer M2 is a mixing tee having an inner diameter of 0.25 mm (manufactured by GL Sciences Inc., cross-sectional area of 0.05 mm2). The microtube R2 was manufactured using a SUS316 tube (manufactured by GL Sciences Inc.) having an inner diameter of 1.0 mm and an outer diameter of 1/16 inch. The microreactor section 81 to section 90, section 82 to section 90, and section 87 to section 90 are cooled by being immersed in a constant temperature water bath having a liquid temperature of 0 ° C., and the temperature from section 90 to section 80 is a constant temperature of 50 ° C. It was buried in the aquarium.
As the aromatic halogen compound (liquid A), a solution prepared by diluting 2-bromothiophene with dehydrated CPME and adjusting the concentration to 0.33 mol / l was used. As the organic lithium reagent (solution B), an n-hexane solution of n-butyllithium having a concentration of 1.65 mol / l was used. The halogenated cyclic compound and the transition metal catalyst solution (solution C) were prepared by diluting 2-bromopyridine with dehydrated CPME to adjust the concentration to 0.55 mol / l, (1,3-bis (2, 6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride (5 mol% relative to bromobenzene), N, N, N ′, N′-tetramethylethylenediamine (TMEDA) (2-bromo What was dissolved by adding 2 times the mole of thiophene) was used. Liquid A, liquid B, and liquid C were each sent to the microreactor using an LC-20AT plunger pump manufactured by Shimadzu Corporation. The supply flow rate of the A liquid microreactor is 7.5 ml / min, the supply flow rate of the B liquid is 1.5 ml / min, and the supply speed of the C liquid is 3.0 ml / min. The residence time is 2.6 seconds, and the residence time between sections 89 to 80 is 94.2 seconds. The reaction solution flowing out from the reactor outlet was sampled for 60 seconds in a sampling tube containing 5 ml of methanol after a waiting period of 3 minutes, and stirred at 25 ° C. for 10 minutes. The solution after the reaction was analyzed using GC, and quantitative analysis was performed by an internal standard method using a standard substance. The yield of the target compound was 87%.

From the above results, the following is clear.
That is, in the cross-coupling reaction using a thermally unstable organolithium compound, it is necessary to synthesize and store the organolithium compound under an ultra-low temperature condition such as -80 ° C in a batch process, and the yield of the cross-coupling reaction is Very low. However, in the continuous reaction using the microreactor of the present invention, it is possible to synthesize the target product with high yield by high-temperature and short-time reaction by controlling the reaction temperature and residence time of the cross-coupling reaction. . This production method can be applied to a heterocyclic compound such as a pyridine derivative and is highly useful.

MR: Microreactor M: Micromixer R: Microtube

Claims (9)

A process for producing a polycyclic compound comprising [Step 1] and [Step 2], wherein at least [Step 2] is reacted using a microreactor ,
In the [Step 1], the following aromatic organolithium compound (3) is produced by reacting the following aromatic halogen compound (1) with the following organolithium reagent (2):
In [Step 2], the following halogenated cyclic compound (5) and the aromatic organolithium compound (3) obtained in [Step 1] are reacted in the channel of the microreactor in the presence of a palladium catalyst (4). is allowed, the manufacturing method of the polycyclic compound characterized that you produce the following polycyclic compound (6).

A ring and B ring each independently represent an aromatic ring or a heteroaromatic ring, R ₁ and R ₂ each independently represent a hydrogen atom or a substituent, and X ₁ and X ₂ each independently represent a halogen atom. . R ₃ represents an alkyl group, an alkenyl group, an alkynyl group or an aralkyl group. Here, R ₁ may be substituted on the A ring and R ₂ may be substituted on the B ring . [Step 1] is performed in the first stage microreactor using a front and rear multistage type microreactor and reacted with the following aromatic halogen compound (1) and the following organic lithium reagent (2) to obtain the following aromatic organic lithium compound: (3) is produced in the flow path, and then [Step 2] is carried out in the second stage microreactor, and the following halogenated cyclic compound (5) and the aromatic organolithium compound obtained in [Step 1] ( 3) reacting the flow path in the presence of an effective amount of a palladium catalyst (4) a method for producing a polycyclic compound characterized that you produce the following polycyclic compound (6).

A ring and B ring each independently represent an aromatic ring or a heteroaromatic ring, R ₁ and R ₂ each independently represent a hydrogen atom or a substituent, and X ₁ and X ₂ each independently represent a halogen atom. . R ₃ represents an alkyl group, an alkenyl group, an alkynyl group or an aralkyl group. Here, R ₁ may be substituted on the A ring and R ₂ may be substituted on the B ring . And said aromatic halogen compound (1) and the organic lithium reagent (2), the flow path by using a microreactor under the conditions of the reaction temperature is -10 to 40 ° C. and the residence time is 0.001 seconds the method according to 請 Motomeko 2 it and obtaining the aromatic organolithium compound (3) is reacted. Manufacturing method of the reaction temperature in the flow path of the two-stage microreactor, polycyclic compound according to 請 Motomeko 1 or 2 you being a 0 to 80 ° C.. The method for producing a polycyclic compound according to claim 4, wherein the residence time in the flow path of the second-stage microreactor is 0.001 second to 10 minutes. The palladium catalyst (4) is allyl [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] palladium (II) chloride, allyl [1,3-bis (mesityl) imidazol-2-ylidene. ] Palladium (II) chloride, 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride, [1,3-bis (2,6-diisopropyl) Phenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) chloride: copper (I) iodide, 1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium ( II) selected from dichlorides, according to any one of claims 1 to 5 Method for producing a polycyclic compound of the mounting. The palladium catalyst (4) is (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride, or (1,3-bis (2,6-diisopropyl). The method for producing a polycyclic compound according to any one of claims 1 to 6 , which is phenyl) imidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride. The mixing reaction between the halogenated cyclic compound (5) with the aromatic organolithium compound (3) and the palladium catalyst (4), the equivalent diameter is to be performed by contacting each other in the following flow channel 10μm~1mm method for producing a polycyclic compound according to any one of claims 1 to 7, characterized. The method for producing a polycyclic compound according to any one of claims 1 to 8 , wherein an amine compound is present together with the palladium catalyst (4) during the reaction in the flow path.

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