JP4794873B2 - Method for producing organic compound using halogen-lithium exchange reaction - Google Patents

Description

  The present invention relates to a method for producing a compound useful in fields such as pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography and dyes by halogen-lithium exchange reaction using a microreactor.

  As one of synthetic methods for converting a halogen atom of a halogen-substituted organic compound into another electrophilic group, a halogen-metal exchange reaction is known (see Non-Patent Documents 1 and 2). Examples of the metalation reagent used here include Grignard reagent, lithium magnesium ate complex, lithium copper ate complex, and organic lithium reagent.

Grignard reagents generally have low reactivity. For example, when aryl chloride or aryl bromide is used, there are problems such as limited substrates that can be reacted, excessive use of reagents, and long reaction times ( Non-Patent Document 3). When an aryl iodide is used, the reactivity is high, but the introduction of an iodo group into the raw material is expensive and is not industrially preferable.
Organolithium magnesium art complexes (see Patent Document 1) and organolithium copper art complexes (see Non-Patent Document 4) are known as reagents having appropriate reactivity and stability. These can be adjusted to the reaction substrate with different reaction activity by devising the kind of alkyl chain of the substituent of art complex and the reaction temperature, and it is industrial because it does not require cryogenic conditions. Useful for. However, it is necessary to adjust the art complex for each reaction, and the production process becomes one step, which makes the production complicated.

On the other hand, the organolithium reagent has high reactivity and is highly useful because it has a wide substrate application range. However, since the lithium intermediate produced by this method is also highly reactive and low in thermal stability, it is necessary to carry out the reaction at an ultra-low temperature in order to avoid side reactions. We must take measures such as letting In addition, the halogen-lithium exchange reaction and the reaction between the generated lithium intermediate and the electrophilic reagent are both exothermic reactions and require long-time dripping at the time of preparation. In particular, on an industrial scale, there are many problems in terms of safety risks such as mass use of organometallic compounds, which are water-inhibiting dangerous substances, and runaway exothermic reactions, and in terms of costs for facility construction and maintenance (Non-Patent Document 5). reference).
Furthermore, among the above lithium intermediates, heteroaromatic lithium compounds typified by lithiopyridine are particularly unstable, and the yield of the target product is improved even when the lithiation reaction and the reaction with the electrophilic compound are carried out at -80 ° C. Very low. An in-site quench method has been reported as a method using an unstable lithium compound (see Non-Patent Documents 6 and 7). This is a method in which a lithium reagent is dropped into a solution in which a halogen compound and an electrophilic compound coexist in advance to generate a lithium intermediate, and at the same time, a capture reaction with the electrophilic compound is performed in the reaction system. However, this method is limited to the case where the reaction rate of the lithiation reaction is higher than the reaction rate of the electrophilic compound and the lithium intermediate, and has a drawback that the reaction is greatly influenced by the type of the raw material substrate and the reaction temperature setting.

Despite these various problems, the compounds obtained by the halogen-lithium exchange reaction are highly useful as synthetic intermediates in the fields of pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography and dyes. As an example, 2-lithiopyridine using 2-bromopyridine as a raw material is a synthetic intermediate of a 2,4′-bipyridine derivative useful as a pharmacore. Examples of the 2,4′-bipyridine derivative include tetrabenazine antagonist (see Non-patent Document 8), α _1A receptor antagonist (see Patent Document 2), 5-HT _1A receptor antagonist (see Patent Document 3), α _1A receptor antagonist ( Used in synthetic intermediates such as Patent Document 4).

  As a means for solving various problems of reactions using organolithium reagents, a production method using a continuous flow reaction apparatus has been reported (see Patent Documents 5 and 6). The continuous flow reactor has a small volume in the reactor and can make the concentration distribution and temperature distribution of the raw material in the reactor uniform compared to a large-capacity reactor of several thousand liters. Further, since the heat unstable lithium intermediate is continuously advanced to the next step without being stored in large quantities, the risk of yield reduction is reduced, and the merit of this method is great. However, Patent Document 5 uses a static mixer that does not have sufficient slow heating capability for the stirrer, and the problem of thermal degradation of the lithium intermediate is not solved. Further, this method is carried out under a cryogenic condition of −70 to −35 ° C. as in the batch reaction, and requires a special cooling device, so that the production cost is high. Although the specific configuration of the continuous flow reactor is not described in Patent Document 6, it is carried out under a low temperature condition of -35 ° C., and there is a problem in terms of cost when carried out on an industrial scale.

Recently, research on synthesis reactions using microreactors has been actively conducted (see Non-Patent Documents 9 and 10). The microreactor is considered to be capable of precise flow control, temperature control, and rapid mixing, and can be expected to improve yield and expand selectivity compared to the batch reaction that has been performed in the past. It is attracting attention as a method.
Some experimental examples of lithiation reactions using a microreactor have been reported. For example, a lithium intermediate by deprotonation and a method for synthesizing a boron compound via the lithium intermediate (see Patent Document 7) and a halogen-lithium exchange reaction are used. Synthesis of Tramadol (see Non-patent Document 11) Synthesis of 3-lithioanisole and its reaction with N, N-dimethylformamide (hereinafter abbreviated as DMF) (see Non-Patent Document 12). In these examples, the yield is improved in comparison with the conventional batch reaction that does not use the microreactor. However, in Patent Document 7 and Non-Patent Document 11, actually, it is still -30 ° C or -14. The reaction is carried out under low temperature conditions such as ° C. In Non-Patent Document 12, using a device in which two microreactors are connected in series, lithiation of the first reaction is performed at 0 ° C. and a residence time of 0.19 minutes, and then the reaction with DMF of the second reaction is performed. It is performed under the conditions of 0 ° C. and residence time of 0.15 minutes. This method is an epoch-making method because the target product is obtained in a high yield of 88% at a reaction temperature that is easier to handle than conventional methods. However, this condition is not particularly suitable for unstable heteroaromatic lithium compounds, and further methods are being sought.
International Publication No. 01/57046 International Publication No. 99/07695 International Publication No. 99/03847 US Pat. No. 6,159,990 JP 2000-229981 A JP 2000-239282 A JP 2003-113185 A “The Journal of Organic Chemistry”, 1982, 47, p.331 “The Journal of Organic Chemistry,” 1986, Volume 52, p.473. “Angewante Chemie International English Ed.”, 2000, 39, p.4414 “Angewante Chemie International English Ed.”, Volume 41, p.3263 “The Journal of Medicinal Chemistry”, 1999 Volume 42 p.1088 “The Journal of Organic Chemistry”, 2002 67 p.5394 “Journal of the American Chemical Society”, 1983, 105 p.1983 “The Journal of Medicinal Chemistry”, 1984, 27, p.1182. “Chimia”, 2002 Volume 56 p.636 “Tetrahedron”, 2002 Volume 58 p.4735 “Organic Process Research and Development”, 2004 Volume 8 p.455 “Organic Process Research and Development”, 2004 Volume 8 p.440

  The object of the present invention is to use a microreactor to produce an organic compound by a halogen-lithium exchange reaction of a compound useful in the fields of pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography and dyes, etc., and no special cooling device is required. Another object of the present invention is to provide a manufacturing method that is inexpensive, safe, and does not cause pollution problems.

That is, as a result of various studies, the above object of the present invention is achieved by the following method.
(1) A halogen compound and a lithium reagent are reacted using a microreactor under the conditions of a reaction temperature of −10 to 40 ° C. and a residence time of 0.001 to 0.3 seconds. The manufacturing method of the lithium compound represented by (I).

(In formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring or a hetero ring. )
(2) The method for producing a lithium compound according to (1), wherein the ring represented by A is a heterocycle.
(3) A method for producing a compound represented by the following general formula (II), wherein the lithium compound produced by the method of (1) is continuously reacted with an electrophilic compound using a microreactor. .

(In formula (II), the ring represented by A has the same meaning as described above. Y represents an electrophilic group.)

  The microreactor can be used to produce primary products that cannot be removed because the reaction proceeds while staying in the reactor in the conventional batch method, and the reaction temperature distribution and substances in the solution. It is very effective for synthesizing lithium compounds having high reaction activity and low thermal stability from the viewpoints that the concentration distribution can be precisely controlled and that a steady-state continuous reaction can be efficiently performed.

  Furthermore, it is important to prevent heat accumulation of reaction heat in reactions with high exotherm, and temperature control such as prevention of hot spots was insufficient in conventional batch production equipment and continuous synthesis equipment using existing static mixers. As a result of intensive investigations, the present inventors have synthesized lithium compounds using a microreactor and under mild temperature conditions such as room temperature by selecting an optimal combination of reaction temperature and reaction time (residence time). In a high yield.

  According to the production method of the present invention, lithium compounds that are useful intermediates in the chemical industry, particularly in the fields of pharmaceuticals, agricultural chemicals, liquid crystals, electrophotography, dyes, etc., can be efficiently obtained without using ultra-low temperature cooling equipment. It can be obtained at low cost. Furthermore, by continuously reacting the obtained lithium compound with an electrophilic compound, the target product can be obtained in a high yield, and the production method of the present invention has extremely high practical utility in terms of synthesis. is there.

Hereinafter, the present invention will be described in more detail.
In the present invention, a synthesis reaction (first reaction) of a lithium compound by a halogen-lithium exchange reaction is performed using a microreactor under conditions of a specific reaction temperature and residence time, and then a capture reaction by a lithium compound and an electrophilic compound ( This is a method of continuously performing the second reaction).
The following is an example of the present invention in which 2,6-dibromopyridine is used as the halogen compound, n-butyllithium is used as the organolithium reagent, DMF is used as the electrophilic compound, and a microreactor is used for both the first and second reactions. The present invention is not limited to this.

Next, the macro reactor used in the present invention will be described.
A microreactor is usually defined as a device having a microchannel (microchannel) having an equivalent diameter of several millimeters or less, preferably smaller than 500 μm, and performing 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. The static micromixer is a device represented by a mixer having a fine flow path for mixing, as described in, for example, WO96 / 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. Also, 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 used in the present invention may be a known one, a commercially available product, or a 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 Systems Corp. Cytos; Yamatake YM-1 and YM-2 type mixers; Shimadzu GLC's mixing tees and tees (T-shaped connectors); Micro Chemical Engineering Co., Ltd. IMT chip reactors; A mixer etc. are mentioned, All can be used by this 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.

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.

The tube 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 inner diameter of the tube in the present invention is usually 100 μm to 4 mm, preferably 250 μm to 3 mm, more preferably 300 μm to 2 mm, and particularly preferably 500 μm to 1 mm.
The material of the micromixer or tube of the present invention can be selected from metals such as stainless steel, titanium, copper, nickel, and aluminum, glass, photuran glass, various types according to the requirements of heat resistance, pressure resistance and solvent resistance, processability, etc. Ceramics, peak resin, plastic, silicon, and Teflon resins such as PFA and TFAA can be preferably 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 photolithography method using EPON SU8 (c) Mechanical micro cutting (micro drill that rotates a drill with a drill diameter of micro order at high speed Processing)
(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 flow rate of the raw material solution fed to the microreactor used in the present invention varies depending on the mixing method of the micromixer, the structure, and the equivalent diameter of the flow path and the tube. For example, mixing tee (inner diameter: Φ0.8 mm) And a tube having an inner diameter of Φ0.8 mm is usually 0.1 μl / min to 1000 ml / min, preferably 0.1 ml / min to 100 ml / min, more preferably 1 ml / min to 50 ml / min, particularly preferably Is in the range of 5 ml / min to 30 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, after the first reaction by the microreactor, the reaction between the lithium intermediate and the electrophilic compound, which is the second reaction, needs to be continuously performed. The second reaction may be a batch reaction in which the generated lithium compound is sent to a flask, a reaction vessel, or the like under conditions where the generated lithium compound does not decompose, but an electrophilic compound is added there. Preferably, a microreactor is used. It is a continuous reaction. When the second reaction is performed in a microreactor, a continuous reaction apparatus constructed by connecting two microreactors in series may be used, or the functions of two microreactors are incorporated in one microreactor chip. Microstructures may be used. A type in which two microreactors are connected in series (series two-stage microreactor) is called a micromixer / tube reactor or a mixer-and-loop reactor. Mixing of the first reaction starts in the first stage micromixer, reacts while mixing on the way to the second stage mixer, and then mixes with the electrophilic compound in the second stage micromixer, at the mixer outlet The second reaction takes place with mixing in the connected tubes. It is preferable to optimize the reactor structure and dimensions each time so as to increase the yield of the target product depending on the reactivity of the starting material, the lithium intermediate to be produced, and the electrophile.

The reaction time in the present invention is represented by the residence time from when the raw material liquid starts to be mixed with the micromixer and then exits from the outlet through the tube connected to the rear of the micromixer. When a microreactor is used for both the first reaction and the second reaction, the reaction time is a residence time until the raw material liquid starts to be mixed with the first micromixer and mixing with the electrophilic reagent is started with the second micromixer. (First reaction zone) and the sum of the residence time (second reaction zone) from the start of mixing with the second micromixer to the exit from the outlet through the tube connected to the rear of the micromixer. In the present invention, the reaction time can be adjusted by changing the flow rate of the raw material to be supplied. However, since the micromixer is often set in advance with a flow rate range suitable for mixing, the raw material solution liquid supplied to the microreactor It is preferable to set the reaction time by a method of changing the length of the tube and the equivalent diameter so that an appropriate residence time can be obtained in accordance with the flow rate. The residence time in the microreactor 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 halogen-lithium exchange reaction is an extremely fast reaction, and the lithium intermediate formed has low thermal stability, so the residence time of the first reaction is 0.001 to 0.3 seconds. The residence time of the first reaction does not necessarily need to be set to the time necessary for completion of the halogen-lithium exchange reaction, and the electrophilic reagent of the next second reaction is mixed even when the first reaction has not been achieved. May be. Since the halogen-lithium exchange reaction is a very fast reaction, the lithium reagent becomes a competitive reaction between the halogen compound and the electrophile in the presence of the electrophile. Since there is currently no means for judging the exact end point of the halogen-lithium exchange reaction, the necessary and sufficient residence time for the first reaction is evaluated by the yield of the final product subjected to the second reaction.

The reaction rate of the second reaction is slower than that of the first reaction. However, since the thermal stability of the lithium intermediate is low, the residence time is preferably set to be the same as or slightly longer than the first reaction. The residence time of the reaction between the lithium compound and the electrophilic compound is 0.001 seconds to 10 minutes, preferably 0.005 seconds to 5 minutes, more preferably 0.01 seconds to 1 minute, and particularly preferably 0.1 seconds to 30 seconds.
The residence time of the first reaction and the entire second reaction is preferably 0.002 seconds to 10 minutes, more preferably 0.005 seconds to 5 minutes, and particularly preferably 0.01 seconds to 1 minute.

The microreactor used in the present invention can be cooled and heated, and the tube connected to the rear part of the microreactor is preferably capable of cooling and heating. The temperature control method of the microreactor in the present invention is not particularly limited. For example, a method of immersing the entire microreactor in a thermostat capable of temperature control, a method of adding a classic heat exchanger to the microreactor structure, And a method using a microreactor structure having a micro heat exchanger formed of a flow channel and a micro flow channel.
In the conventional method, for example, batch production, the lithiation reaction is performed under ultra-low temperature conditions of -75 to -40 ° C, and most of the recently reported lithiation reactions using a microreactor have a low temperature of less than 0 ° C. It is done on condition. In contrast, in the present invention, by adjusting the residence time and reaction temperature, it is possible to efficiently synthesize a rethio intermediate, particularly a heteroaromatic lithio compound, even under mild conditions of about room temperature.
The reaction temperature of the 1st reaction of this invention is -10-40 degreeC, Preferably it is -10 degreeC-35 degreeC, More preferably, it is 0-35 degreeC, Most preferably, it is 5-35 degreeC. The reaction temperature of the second reaction is not particularly limited as long as the lithium compound is not decomposed, but is usually -20 to 70 ° C, preferably -10 to 50 ° C, more preferably 0 to 40 ° C, particularly preferably 0. It is the range of -35 degreeC.

  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.

Next, the compound used in the present invention will be described. Examples of the halogen compound used in the present invention include chlorine compounds, bromine compounds, iodine compounds, etc. Among them, bromine compounds and iodine compounds are preferable because of high reactivity.
In the lithium compound represented by the general formula (I) of the present invention, the ring represented by A is specifically a monocyclic or polycyclic 6 to 10 membered member such as benzene, naphthalene, anthracene, phenanthrene and the like. Aromatic ring; monocyclic or polycyclic 3- to 10-membered saturated ring such as cyclopropane, cyclobutane, cycloheptane, cyclohexane and cyclooctane; monocyclic or polycyclic such as cyclopentene, cyclohexene, cyclooctene and indane A 3- to 10-membered partially saturated ring of: thiophene, furan, pyran, pyridine, pyrrole, pyrazine, azepine, azocine, azonin, azecine, oxazole, thiazole, pyrimidine, pyridazine, triazine, triazole, tetrazole, imidazole, pyrazole, morpholine, Thiomorpholine, piperidine, piperazine, Selected from 5-10 membered monocyclic or polycyclic nitrogen, oxygen and sulfur such as Norin, isoquinoline, indole, isoindole, quinoxaline, phthalazine, quinolidine, quinazoline, quinoxaline, naphthyridine, chromene, benzofuran, benzothiophene Represents a heterocyclic ring containing 1 to 4 atoms. Preferred is a phenyl group or a heterocycle, more preferred is a heterocycle, still more preferred is a 5- or 6-membered heterocycle, and particularly preferred is pyridine, pyridazine, pyrimidine, pyrazine, furan, oxazole, thiophene or thiazole. It is.

  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, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc., linear, branched or cyclic alkyl groups having 1 to 20 carbon atoms (including alkyl substituted by cycloalkyl); vinyl, allyl, propenyl , Butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl , Octadecenyl, nonadecenyl, icocenyl, hexadienyl, dodecatrienyl, etc., straight, branched or cyclic alkenyl groups having 2 to 20 carbon atoms; ethynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, cyclooctynyl, cyclononynyl, cyclodecynyl Linear, branched or cyclic alkynyl groups having 2 to 20 carbon atoms, such as 5-10 membered monocyclic or bicyclic aryl groups such as phenyl, naphthyl, anthranyl, etc .; methoxy, ethoxy, propoxy, butoxy, pentyloxy Alkoxy groups having 1 to 20 carbon atoms such as 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, butylthio, 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, etc .; substituted oxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, n-decyloxycarbonyl, phenoxycarbonyl, etc. Groups: 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, phenyl Substituted sulfonyl groups such as sulfonyl and naphthylsulfonyl; carbamoyl groups substituted by one or two groups selected from alkyl, alkenyl and aryl such as N-methylcarbamoyl and N, N-diphenylcarbamoyl; N-phenylsulfa A sulfamoyl group substituted by one or two groups selected from alkyl, alkenyl and aryl such as moyl, N, N-diethylcarbamoyl; acetylamino, tert-butyl 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, pivaloylamino, 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 2 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 17 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 Ureido group; C1-C16 substituted sulfonylamino group; C1-C16 mono- or di-substituted amino group, nitro group, cyano group, C1-C1 6 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; a monosubstituted or divalent 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.

In addition, hydrocarbons having 1 carbon atoms such as a methyl group, a methoxy group, and a methylthio group that are directly bonded to an aryl group are liable to undergo a reaction of extracting a proton with a strong base such as butyl lithium, and a by-product may be generated. . In addition, the methoxy group tends to cause a radical reaction, and there is a possibility that a by-product such as bisaryl is generated due to the generation of a carbon radical. For this reason, when the ring represented by A is an aromatic ring and the substituent is an alkyl group, an alkoxy group, an alkylthio group, or the like, the substituent preferably has 2 or more carbon atoms.
Further, when the ring substituent represented by A is a carbonyl group, it is possible to prevent the side reaction from proceeding during the reaction with the lithium reagent, so that the bulky steric hindrance having 4 or more carbon atoms such as a tert-butyl group. It is preferable that a large group 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 lower alkyl groups such as methyl, ethyl, propyl and butyl, aryl groups such as phenyl and naphthyl, and halogen atoms such as chlorine and fluorine.

As the organolithium reagent used in the present invention, a conventionally known organolithium compound can be used. 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 Examples include alkynyl lithium such as lithium, butynyl lithium, pentynyl lithium, and hexynyl lithium; aralkyl lithium such as benzyl lithium and phenylethyl 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 used varies depending on the type of halogen compound used, but is usually 0.01 to 20 mol, preferably 0.1 to 2.0 mol, more preferably 0.5 to 1 mol per mol of the halogen compound. 1.3 mol, more preferably 0.9 to 1.1 mol.

The electrophilic compound that can be used in the present invention is not particularly limited as long as it has a functional group having electron accepting ability, but a compound that reacts with a functional group having a high electron density or an unshared electron pair is preferable. The compounds include all electrophilic compounds used in halogen-metal exchange reactions using known organolithium reagents.
Specifically, the electrophilic compound used in the present invention includes halogen molecules such as chlorine, bromine and iodine molecules; inorganic substances such as solid sulfur, sulfur dioxide and oxygen; carbon dioxide; acetonitrile, propionitrile and benzo Nitriles such as nitrile; Imines such as benzophenone imine and acetophenone imine; Halogenated silicon such as chlorotrimethylsilane and chlorotriethylsilane; Tin compounds such as dibutyltin dichloride and diphenyltin dibromide; Paraformaldehyde, Acetaldehyde and Propion Aldehydes such as aldehyde, butyraldehyde, acrylic aldehyde, benzaldehyde, nicotinaldehyde; acetone, 2-butanone, benzophenone, acetophenone, DMF, tert-butyl-4-oxo-1-piperidinecarboxy Ketones such as ethyl acetate; esters such as ethyl chloroformate, phenyl chloroformate, methyl formate, ethyl formate, ethyl acetate, butyl acetate, octyl acetate, phenyl acetate, methyl benzoate, ethyl benzoate, phenyl benzoate; Acid anhydrides such as acetic acid, phthalic anhydride, succinic anhydride and maleic anhydride; acyl halides such as acetyl chloride, benzoyl chloride and 2-pyridinecarbonyl chloride; oxiranes such as oxirane and 2-methyl-oxirane; Aziridines such as 6-azabicyclo [3,1,0] hexane, 7-azabicyclo [4,1,0] heptane; 3-oxo-1,3-diphenyl-1-propene, 2-methyl-3-oxo- Α, β-unsaturated ketones such as 3-diphenyl-1-propene; methyl iodide, ethyl iodide, iodine Butyl iodide, methyl bromide, ethyl bromide, hexyl bromide, octyl bromide, 1,2-diiodoethane, 1,2-dibromoethane, 1,6-diiodohexane, 1,8-dibromooctane, 1, Alkyl halides such as 2-dibromocyclopentene; acid imides such as N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and N-bromophthalimide; disulfides such as dimethyl disulfide and diphenyl disulfide; Examples include phosphines such as chlorodiphenylphosphine and chlorodimethylphosphine; and phosphine oxides such as chlorodiphenylphosphine oxide and chlorodimethylphosphine oxide. Of these, chlorotrimethylsilane, benzaldehyde, and DMF are preferable.
The amount of these electrophilic compounds used is usually 0.01 to 20 mol, preferably 0.1 to 2.0 mol, more preferably 0.5 to 1.3 mol, and still more preferably, per 1 mol of the halogen compound. Is 0.9 to 1.1 moles.

  Although the preferable specific example of a compound represented by general formula (II) obtained by the method of this invention below is shown, this invention is not limited to these.

  In the production method of the present invention, the halogen compound, organolithium reagent and electrophilic compound to be used must be in a liquid or solution state. Therefore, when these compounds are not liquid, it is necessary to dissolve in advance in a solvent inert to the reaction. As a solvent to be used, 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, DMF, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone; acetates such as methyl acetate, ethyl acetate, butyl acetate N-pentane, n-hexane, n-heptane, cyclohexane, decane, paraffin and other alkanes and perfluoroalkanes; dimethyl ether, diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyether Petroleum ether, tetrahydrofuran (abbreviated as THF), dioxane, trioxane, diglyme and other ethers; N, N-dimethylimidazolidinone and other ureas; trimethylamine, triethylamine, tributylamine, N, N, N ′, N Tertiary amines such as' -tetramethylethylenediamine; halogenated alkanes such as methylene chloride and dichloroethane can be used regardless of polar or nonpolar solvents. Preferred are THF, diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, toluene, xylene, and 1,3-dimethyl-2-imidazolidinone, and more preferred are THF, dibutyl 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 and the organolithium compound. The amount of chelating agent used is usually in the range of 0.01 to 10 mol, preferably 0.1 to 2.0 mol, more preferably 0.9 to 0.1 mol with respect to 1 mol of the organolithium reagent and the organolithium compound. 1.1 moles.

The compound represented by the general formula (II) 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.
In addition, since the conversion method of the present invention is a known method for improving a halogen-metal exchange reaction, the production conditions used in the step of the present invention are the halogen-metal exchange reaction such as an organolithium reagent and an electrophilic reagent. All the production conditions other than the reaction temperature can be employed, including the method of purifying the reaction product used in this reaction.

EXAMPLES Next, although an Example demonstrates this invention further more concretely, 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 the standard substance is marketed, the reaction rate of the target object was computed from the area ratio with a standard substance by the high performance liquid chromatography (HPLC), and quantitative analysis was performed. In the case where the standard substance is not commercially available, the yield was obtained after the target substance was obtained by separating the target product by silica gel column chromatography.
Hereinafter, Examples 5, 6, 8 to 10, 14 to 16, 19 to 21, 26 to 28, 31 to 33, 36, 40 to 43, 45, 46, 48, 49, 52 to 62, 65 to 68, Reference numerals 72, 73, and 77 to 81 are reference examples.

Example 1 <Synthesis of 2-bromo-6-formylpyridine by a microreactor>
Synthesis of 6-bromo-2-lithiopyridine with n-butyllithium and 2,6-dibromopyridine, and subsequent reaction with DMF were performed using the microreactor shown in FIG. A mixing tee (manufactured by GL Sciences, an inner diameter of 0.8 mmΦ, a cross-sectional area of 0.50 mm ² ) was used for both the micromixer M1 and the micromixer M2. Sections 5 to 9 have an inner diameter of 0.5 mm (outer diameter 1/16 inch) when the residence time is 0.1 seconds or longer, and an inner diameter of 0.25 mm and less than 0.01 seconds when the residence time is 0.02 to 0.1 seconds. In this case, stainless steel tubes having an inner diameter of 0.1 mm were used. In section 8 → 10, a stainless steel tube having an inner diameter of 1.0 mm (outer diameter of 1/16 inch) was used. The residence time of the first reaction part (5 → 8) and the second reaction part (8 → 10) was adjusted by changing the length of the stainless steel tube without changing the flow rate. Further, the entire microreactor was buried in a constant temperature bath and set to a predetermined reaction temperature.

  2,6-Dibromopyridine was diluted with THF to prepare a 0.316 mol / l solution. For n-butyllithium, a commercially available 1.58 mol / l n-hexane solution was purchased, and the content was determined by titration. DMF was diluted with THF to prepare a 3.16 mol / l solution. The 2,6-dibromopyridine solution and the n-butyllithium solution were each sucked into a stainless steel syringe, and then used with a JP-H-3 type high-pressure microfeeder manufactured by Furue Science Co., Ltd., and the N, N-dimethylformamide solution was Using a 243-13 type double plunger pump manufactured by Flume, the solution was fed to the microreactor. The feeding speeds of the 2,6-dibromopyridine solution, the n-butyllithium solution, and the DMF solution were set to 5.0 ml / min, 1.0 ml / min, and 1.0 ml / min, respectively. The mixed reaction solution was discarded for several minutes until the reaction was stabilized, and then collected in a sampling tube containing methanol. The obtained reaction solution was quantitatively analyzed by an internal standard method using a standard substance by HPLC to obtain a reaction rate.

Examples 2-36
Synthesis was performed in the same manner as in Example 1, except that the reaction temperature and residence time were changed to the conditions shown in Table 1.

Comparative Example 1 <Synthesis of 2-bromo-6-formylpyridine by batch>
A 100 ml two-necked flask substituted with argon gas was charged with 5 ml of a 0.316 mol / l THF solution of 2,6-dibromopyridine, and immersed in a dry ice-acetone bath and cooled to -78 ° C. While stirring using a magnetic stirrer, 5 ml of a 1.58 mol / ln-hexane solution of n-butyllithium was dropped at a rate of 1.0 ml / min with a microsyringe pump, and the mixture was stirred at -78 ° C for 15 minutes. Next, 5 ml of a 3.16 mol / l THF solution of DMF was added dropwise at a rate of 1.0 ml / min with a syringe pump, stirred at -78 ° C for 30 minutes, and then gradually warmed to room temperature over 30 minutes. As a result of quantitative analysis of the obtained reaction solution, the yield of the target product was 36%. A 10% aqueous acetic acid solution was added to the reaction solution at 0 ° C. and stirred for 30 minutes. Then, the separated aqueous layer was removed, the organic layer was washed with water, and the organic layer was evaporated by a rotary evaporator to obtain a crude product. . The crude product was purified by silica gel column chromatography to obtain crystals. The melting point, NMR, and IR spectrum of the crystal were consistent with the commercially available standard reagent.

Comparative Examples 2 and 3
It implemented on the same conditions as the comparative example 1 except having made reaction temperature into -40 degreeC and 0 degreeC.

Comparative Examples 4 and 5
The synthesis was carried out in the same manner as in Example 1, except that the residence time was changed to the conditions described in “Org. Process Res. Dev., 2004, Vol. 8, page 440”, and the reaction temperature was changed to the conditions described in Table 1. went.
Table 1 shows the results of Examples 1 to 36 and Comparative Examples 1 to 5.

  From the results in Table 1, the following is clear. The intermediate 6-bromo-2-lithiopyridine is a particularly heat labile compound, and the batch synthesis method provides only a yield of about 30% under a temperature condition of -78 ° C. Even in the synthesis method using a microphone reactor, when the residence time and reaction temperature are not optimized, the yield is as low as 70% or less at a temperature condition of 0 ° C. and 40% or less even at a temperature condition of 10 ° C. However, by using a microreactor and optimizing the residence time and reaction temperature, the target product can be obtained in high yield even under temperature conditions such as 20 ° C. and 35 ° C.

Example 37 <Synthesis of (3-ethoxyphenyl) trimethylsilane>
The halogen-lithium exchange reaction of 3-bromophenetole using n-butyllithium was carried out by a single mixer manufactured by Institut Für Microtechnique Mainz (IMM) (channel cross-sectional area 12,000 μm ² , nickel on copper inlay ) In a stationary microreactor using This single mixer is of a type in which a large number of substreams obtained from the divided flow channels are brought into contact with each other, and SUS316 having an outer diameter of Φ1.58 mm and an inner diameter of Φ0.8 mm is provided at the outlet of the stationary microreactor. A capillary made by HPLC was connected using an HPLC connector, and the outlet of the capillary was led through a three-way valve with a drain channel on one side to a 100 ml two-necked flask with argon gas substituted with a THF solution of chlorotrimethylsilane. . The temperature of the stationary reactor, the SUS capillary, and the two-necked flask was set to 0 ° C. in the refrigerant of the constant temperature cooling water tank.

2.64 g of 3-bromophenetole was diluted with THF to a total volume of 50 ml to prepare a solution having a concentration of 0.26 mol / l. For n-butyllithium, a commercially available 1.58 mol / ln-hexane solution was purchased and the content was determined by titration. To a 100 ml two-necked flask, 1.5 g of chlorotrimethylsilane and 9 ml of THF were added and stirred. The 3-bromophenetole solution and the n-butyllithium solution were sucked into a glass syringe, and then each of them was taken from HARVARD APPARATUS INC. Using a PHD2000 type metering pump manufactured by KK and a Model100 type metering pump manufactured by Kd Scientific, the solution was fed to a stationary microreactor using a single mixer manufactured by IMM (channel cross-sectional area 12,000 μm ² , nickel on copper inlay). The feeding speeds of the 3-bromophenetol solution and the n-butyllithium solution were set to 5.0 ml / min and 1.0 ml / min, respectively. The mixed reaction solution was discarded to the drain side for the first 1 minute, and then the three-way valve was switched to send the solution to the 100 ml two-necked flask side for 7 minutes, where it was stirred for 10 minutes. As a result of quantitative analysis of the obtained reaction liquid by an internal standard method using a standard substance by HPLC, the reaction rate of the target product was 95%.
The reaction solution was extracted with water and ethyl acetate, and further distilled under reduced pressure to obtain a colorless liquid as a target product. As a result of millimass measurement (DI-EI / MS), it was consistent with the molecular weight of the target product.

Examples 38, 39
A T-shaped mixer (manufactured by SUS316, flow path inner diameter 0.8 mm, flow path cross-sectional area 0.5 mm ² ) in which a fluid collides with a T-shape is used as a stationary microreactor. The reaction was carried out under the same conditions as in Example 37, except that the reaction temperature was changed to 5 ° C and the reaction temperature in Example 39 was changed to 20 ° C.

Examples 40-50
Synthesis of 3-lithiophenetole using n-butyllithium and 3-bromophenetole, and subsequent reaction with chlorotrimethylsilane were carried out using the microreactor shown in FIG. Mixing tee (manufactured by GL Science, inner diameter 0.8 mmΦ, cross-sectional area 0.5 mm ² ) or swedilock tee (inner diameter 1.6 mmΦ, cross-sectional area 2.0 mm ² , inner diameter 3.2 mmΦ, cross-sectional area 3. 0 mm ² ) and a mixing tee (manufactured by GL Sciences, 0.8 mmφ in inner diameter, 0.5 mm ² in cross-sectional area) were used for the micromixer M2. Sections 5 → 9 used stainless steel tubes with an inner diameter of 0.5 mm (outer diameter 1/16 inch), and sections 8 → 10 used stainless steel tubes with an inner diameter of 1.0 mm (outer diameter 1/16 inch). . The residence time of the first reaction part (5 → 8) and the second reaction part (8 → 10) was adjusted by changing the flow rate. The reaction temperature was set by immersing the entire microreactor in a constant temperature bath. Otherwise, (3-ethoxyphenyl) trimethylsilane was synthesized under the same conditions as in Example 37.

Comparative Example 6 <Synthesis of (3-Ethoxyphenyl) trimethylsilane by Batch>
A 100 ml two-necked flask replaced with argon gas was charged with 7 ml of n-butyllithium and 35 ml of THF, and immersed in a dry ice-acetone bath and cooled to -78 ° C. Under stirring, 1.85 g of 3-bromophenetole was added dropwise and stirred at -78 ° C for 30 minutes. Next, a mixed solution of 1.5 g of chlorotrimethylsilane and 9 ml of THF was added dropwise thereto, followed by stirring at −78 ° C. for 20 minutes, and then the temperature was gradually raised to room temperature over 30 minutes. As a result of quantitative analysis of the obtained reaction solution by an internal standard method using a standard substance by HPLC, the reaction rate of the target product was 90%.

Comparative Example 7 <Synthesis of (3-Ethoxyphenyl) trimethylsilane by Batch>
A 100 ml two-necked flask replaced with argon gas was charged with 1.85 g of 3-bromophenetole and 35 ml of THF, and immersed in a dry ice-acetone bath and cooled to -78 ° C. Under stirring, 7 ml of n-butyllithium was added dropwise and stirred at −78 ° C. for 30 minutes. Next, a mixed solution of 1.5 g of chlorotrimethylsilane and 9 ml of THF was added dropwise thereto, followed by stirring at −78 ° C. for 20 minutes, and then the temperature was gradually raised to room temperature over 30 minutes. As a result of quantitative analysis of the obtained reaction solution by an internal standard method using a standard substance by HPLC, the reaction rate of the target product was 88%.

Comparative Example 8
The synthesis was performed under the same conditions as in Comparative Example 1 except that the reaction temperature was 0 ° C.

Comparative Example 9
The synthesis was performed under the same conditions as in Comparative Example 2, except that the reaction temperature was 0 ° C.

Comparative Examples 10 and 11
The synthesis was carried out in the same manner as in Example 1 except that the residence time was changed to the conditions described in “Org. Process Res. Dev., 2004, Vol. 8, 440” and the reaction temperature was changed to the conditions described in Table 2. went.
Table 2 shows the results of Examples 37 to 50 and Comparative Examples 6 to 11. All reaction rates were measured by an internal standard method using a standard substance by HPLC.

  From the results in Table 2, it is clear that the yield is improved by setting the reaction temperature and residence time of the first reaction to the optimum conditions as compared with the batch synthesis method and the synthesis method using a known microreactor. Moreover, if the reaction temperature and residence time of the first reaction are optimized, the target product can be obtained efficiently even if the second reaction is a batch type. Furthermore, by using the method of the present invention, the residence time (reaction time) is shortened compared with the synthesis method in the conventional microreactor, so that productivity is improved.

Examples 51-81
The synthesis was performed under the same conditions as in Example 1 except that the halogen compounds and electrophilic compounds were changed to those described in Tables 3 and 4. The results are shown in Tables 3 and 4.

From the above results, the following is clear.
That is, in the synthesis method of a thermally unstable lithium compound and the reaction using the same, the batch process requires ultra-low temperature cooling such as −78 ° C., whereas the continuous reaction using the microreactor of the present invention has a reaction temperature. By optimizing the residence time, ultra-low temperature cooling is not required, and it is possible to carry out under mild cooling conditions of about room temperature. This production method is applicable to heterocyclic compounds such as pyridine derivatives and xylene derivatives, and is highly useful.

FIG. 1 is a schematic view of a microreactor that can be used in the present invention.

Claims (3)

A halogen compound and a lithium reagent are reacted using a microreactor under the conditions of a reaction temperature of −10 to 40 ° C. and a residence time of 0.001 to 0.3 seconds, the following general formula (I) The manufacturing method of the lithium compound represented by these.

In formula (I), the ring represented by A represents an aromatic ring, a saturated ring, a partially saturated ring or a hetero ring .   The method for producing a lithium compound according to claim 1, wherein the ring represented by A is a heterocycle. A method for producing a compound represented by the following general formula (II), wherein the lithium compound produced by the method of claim 1 is continuously reacted with an electrophilic compound using a microreactor.

In formula (II), the ring represented by A has the same meaning as described above. Y represents an electrophilic group.

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