JP4778710B2 - Coupling reaction using a flow reactor packed with palladium catalyst - Google Patents

Description

  The present invention relates to a method for performing a coupling reaction in the presence of a palladium catalyst. Many chemical reactions using a palladium catalyst are known. In particular, the coupling reaction is an indispensable reaction for the synthesis of organic compounds as one of the methods for forming a carbon-carbon bond.

  Examples of the coupling reaction using a palladium catalyst include Mizoroki-Heck reaction, Sonogashira reaction, Suzuki-Miyaura reaction, and Stille reaction. In these coupling reactions, generally, a palladium catalyst is used as a homogeneous catalyst in which the catalyst is dissolved in the reaction solution.

  Since palladium compounds are expensive, repeated use is required. However, in a homogeneous reaction, the palladium catalyst is dissolved in the reaction solution, and a complicated operation is required to separate the palladium catalyst from the reaction solution. In recent years, therefore, studies have started to use a palladium catalyst in a solid state, that is, to use a palladium catalyst as a heterogeneous catalyst. The heterogeneous catalyst has an advantage that the reaction solution and the palladium catalyst can be separated only by filtration after completion of the reaction.

Non-Patent Document 1 reports the result of carrying out Sonogashira coupling reaction in a batch reactor using a solid palladium catalyst supported on activated carbon. However, the yield of the desired product at a reaction time of 6 hours is as low as 77%.
Non-Patent Document 2 reports the results of conducting a Mizoroki-Heck coupling reaction of bromobenzene and methyl acrylate in a batch reactor using a solid palladium catalyst supported on activated carbon. However, the yield of the desired product is only 36% at a reaction temperature of 160 ° C. and a reaction time of 12 hours. As described above, even when a solid palladium catalyst is used in a batch reactor, there is a problem that the contact efficiency between the reaction substrate in the solution and the solid catalyst is insufficient, and the yield is low.

Further, it has been proposed to use a microreactor as a method for solving the problem of the batch reactor.
For example, Non-Patent Document 3 reports a method in which palladium metal is supported on the flow path surface of a microreactor through which a substrate flows to perform a coupling reaction. However, since palladium metal is supported on the flow path, when the palladium metal loses its catalytic activity, there is a problem that the microreactor having the palladium-supported flow path must be replaced. Also, in this method, the catalyst is not in the form of particles.
Non-Patent Document 4 reports a method of performing a coupling reaction in a microflow reactor filled with particles in which a catalyst is immobilized on an ion exchange resin. However, this method has the disadvantages of low product yield and complicated catalyst immobilization.
Non-Patent Document 5 reports a coupling reaction in which a channel is filled with an ion exchange resin, and then a palladium catalyst is fixed to the surface of the ion exchange resin and this is used as a catalyst. However, there is a problem that an operation for immobilizing the palladium catalyst is required and the yield of the product is low.

R. G. Heidenreich et al., Synlett, 2002, 7, 1118-1122. M. Arai et al., Reaction Kinetics and Catalysis Letters, 2004, 81, 281-289. G. M. Greenway et al., Sensors and Actuators B, 2000, 63, 153-158. S. J. Haswell et al., Lab on a Chip, 2001, 1, 164-166. W. Solodenko et al., European Journal of Organic Chemistry, 2004, 3601-3610.

  An object of the present invention is to provide a coupling reaction using a heterogeneous solid palladium catalyst which does not require a complicated catalyst immobilization operation and gives a high yield.

  As a result of intensive studies, the present inventors have made it possible to improve the contact between the reaction substrate and the solid catalyst by using a flow-type microreactor filled with a solid palladium catalyst, and to reduce the coupling reaction. The present invention was completed by finding that the rate could be improved.

The present invention relates to a method for performing a coupling reaction in the presence of a palladium catalyst, which is characterized by using a flow-through microreactor filled with a solid palladium catalyst.
The present invention is a method of producing a coupling reaction product from a first substrate and a second substrate in the presence of a palladium catalyst in a flow-through microreactor,
It also relates to a method in which a solid particle palladium catalyst is packed in a microreactor.
The present invention further relates to a flow-through microreactor packed with solid particle palladium catalyst.

According to the present invention, the yield of the coupling product is high.
According to the present invention, contact between the reaction substrate and the solid catalyst can be improved without using vigorous physical agitation.
Compared to batch reactors, high temperature and high pressure reaction conditions can be used with high safety.

Moreover, according to this invention, the reaction heat produced in the case of a coupling reaction can be removed efficiently.
Furthermore, according to the present invention, energy and cost required for the separation step of the palladium catalyst can be omitted.
In the present invention, since the solid palladium catalyst is not fixed to the wall surface of the microreactor, the catalyst can be easily replaced. Moreover, since the solid catalyst is not pulverized by vigorous physical agitation, the catalyst can be easily recovered after the reaction. It is also possible to regenerate the recovered catalyst and use it again in the reaction.

The flow type microreactor used in the present invention is composed of a solid palladium catalyst and a reaction tube for holding it. Since the solid palladium catalyst filled in the reaction tube is in the form of fine particles, a micro channel from the micrometer to the nanometer scale (for example, 2000 μm to 2 nm) is formed inside the reaction tube. A highly efficient catalytic reaction proceeds in the process of the reaction substrate solution flowing. The reaction tube is generally a tube having a tubular shape. The upper limit of the diameter (inner diameter) of the reaction tube (the cross section is generally circular) may be 100 mm, for example 50 mm, in particular 20 mm, in particular 10 mm. Although the minimum of the diameter of a reaction tube is not specifically limited, For example, you may be 0.1 mm-3.0 mm, especially 1.0 mm.
The lower limit of the length of the reaction tube (the length of the portion filled with the granular palladium catalyst) is 1 cm, for example 5 cm, especially 10 cm, especially 15 cm, and the upper limit of the length of the microreactor is 500 cm, for example 200 cm, in particular 100 cm, especially 50 cm.
The reaction tube may be made of various materials. Examples of materials are
Resin (for example, fluororesin (for example, polytetrafluoroethylene, Tefzel (registered trademark, ethylene / tetrafluoroethylene copolymer)), peak (PEEK resin, polyphenylsulfone),
Metal (stainless steel, titanium, hastelloy (registered trademark)),
An oxide (for example, an inorganic oxide such as fused silica).

  The flow-through microreactor is packed with a granular palladium catalyst. The palladium catalyst is one in which metallic palladium is supported on a carrier (or support). The support is preferably carbon (particularly activated carbon), metal oxide, or silicon carbide. Examples of metal oxides are aluminum oxide, silicon dioxide, titanium dioxide, zirconium dioxide, zinc oxide, magnesium oxide or mixtures thereof. Other examples of the metal oxide include alumina, silica, zeolite, mesoporous molecular sieve, glass (particularly porous glass), clay and the like.

The palladium catalyst is in the form of particles. The palladium catalyst contains 0.1 to 20% by weight, for example 0.3 to 10% by weight, in particular 2.0 to 5.0% by weight of palladium, based on the total weight of the catalyst. The shape of the catalyst particles is not particularly limited, but may be a spherical shape, a columnar shape, a film shape, or the like. The average size (especially the average maximum size) of the palladium catalyst particles may generally be from 0.1 μm to 3000 μm, such as from 1.0 μm to 100 μm, in particular from 10 μm to 30 μm.
The palladium catalyst can be prepared according to a commonly known method, for example, by immersing the support in a solution of a metal compound.
A commercially available product can be used as the palladium catalyst. Examples of commercially available palladium catalysts include N.I. E. AER type, BNA type, STD type, E105CA / W type, E10N / D type, E101R / D type available from Degussa, available from Chemcat Corporation. The present invention has an advantage that a commercially available product of a palladium catalyst can be used.

The present invention can be used for any coupling reaction catalyzed by a palladium catalyst.
A coupling reaction product is obtained by a coupling reaction between the first substrate and the second substrate. The first substrate is a compound capable of oxidative addition to palladium, and the second substrate is a compound having a leaving group.
It is preferable that the first substrate, the second substrate, and the reaction product are as follows:
R−X + A−R ′ → R−R ′

  R represents an unsaturated or saturated aliphatic group (carbon number: for example, 1 to 20), an aromatic group (carbon number: for example, 6 to 40), an araliphatic group (carbon number: for example, 7 to 40). It is. R ′ may be any group, but is preferably an organic group having a carbon atom. An example of R ′ is the same as R. R and R ′ may have oxygen and / or nitrogen as a constituent atom (for example, a ring constituent atom). R and R ′ may be substituted with a substituent or may not be substituted. X is a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), triflate, diazonium salt, or sulfonate. A is a leaving group. Examples of the leaving group are a group having a hydrogen atom; a metal atom such as copper; a boron atom, a tin atom or a silicon atom.

  The oxidative addition of the first substrate to palladium cleaves the RX bond, producing the intermediate: R-Pd-X. The first substrate is preferably a halogen-containing compound. Therefore, it is preferable that the bond cleaved for oxidative addition to palladium is a halogen-carbon bond.

Specific examples of the coupling reaction are as follows.
(1) R—X + H ₂ C═CH—R ″ → R—HC═CH—R ″
(Mizoroki-Heck coupling reaction)
(2) R—X + HC≡C—R ″ → R—C≡C—R ″
(Sonogashira coupling reaction)
(3) R−X + A ¹ −R ″ → R−R ″
(Suzuki-Miyaura coupling reaction and Stille cross coupling reaction)
The Suzuki-Miyaura coupling reaction is preferably the following reaction.
^{R-X + A 1 -HC =} CH 2 → R-HC = CH 2

In the above formula,
Examples of R and R ″ include unsaturated or saturated aliphatic groups (carbon number: for example, 1 to 20), aromatic groups (carbon number: for example, 6 to 40), araliphatic groups (carbon number: for example, 7 to 40) R and R ″ may have oxygen and / or nitrogen as a constituent atom (for example, a ring constituent atom). The aliphatic group, aromatic group and araliphatic group may be either substituted or unsubstituted. Examples of the substituent are hydroxyl group, oxyalkyl group, aryl group, acyl group, alkoxy group, aryloxy group, cyano group, alkoxycarbonyl group, aryloxycarbonyl group, acyloxy group, carboxyl group, carbamoyl group, halogen atom, An imide group, an alkylthio group, an arylthio group, a sulfo group, a sulfino group, a phosphino group, a phosphinyl group, a phosphono group, or a silyl group. The number of carbon atoms of the substituent is generally 0-40. Specific examples of R and R ″ include an alkyl group (carbon number: for example, 1 to 20), an aryl group (carbon number: for example, 6 to 40), an alkenyl group (carbon number: for example, 2 to 20), and an alkynyl group. (Carbon number: for example, 2 to 20).
X is a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), triflate, diazonium salt, or sulfonate.
A ¹ is a leaving group, for example, -BL ₂ (B is a boron atom, L is a hydroxyl group, an alkyl group (the number of carbons is 1 to 8, for example)), -SnBu ₃ (Sn is a tin atom, Bu is a butyl _{group), -. SiEtX '2 (} Si tin atom, Et is an ethyl group, X' is a halogen atom) such as chlorine.

Specific examples of the first substrate are nitrobromobenzene, iodobenzene, bromoacetophene, methoxyiodobenzene, and bromopyridine.
Specific examples of the second substrate are:
As a compound having a double bond, methyl (meth) acrylate, styrene, α-methylstyrene, acrylonitrile, α-methylacrylonitrile,
Compounds having a triple bond include phenylacetylene, 1-hexyne, 1-heptin, 5-hydroxypentine,
A compound having neither a double bond nor a triple bond is 9-octyl-9-borabicyclo [3.3.1] nonane.
In the present invention, the amount of the second substrate is 0.5 to 3 mol, for example 0.8 to 2.0 mol, particularly 1 mol, relative to 1 mol of the first substrate.

In the coupling reaction, the reaction can be carried out using only the substrate, but a solvent (generally an organic solvent) may be used. The solvent is preferably inert to the coupling reaction. Examples of solvents are aliphatic hydrocarbons (eg octane and cyclohexane), aromatic hydrocarbons (eg toluene), ketones (eg acetone and methyl ethyl ketone), ethers (eg tetrahydrofuran), esters (eg ethyl acetate) Alcohol (for example, methanol, ethanol, ethylene glycol, dipropylene glycol), nitrogen-containing compound (for example, nitrile solvent such as acetonitrile, amide solvent such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, Amine solvents such as pyrrolidine and pyridine). The solvent preferably dissolves the substrate and the reaction product. The solvent may act as a base. The boiling point of the solvent at 1 atm is preferably 130 ° C. or higher, for example, 130 to 210 ° C. The amount of the solvent may be 0.1 to 100 parts by weight, for example 1 to 10 parts by weight with respect to 1 part by weight of the substrate (the total of the first substrate and the second substrate).
In the coupling reaction, a base may be present. Specific examples of the base are alkali metal salts (for example, sodium carbonate, sodium acetate), amines (for example, piperidine, pyridine, triethylamine), hydroxides (for example, potassium hydroxide). The amount of the base may be 1 equivalent or more, for example, 1.0 to 10 equivalents relative to 1 equivalent of the first substrate.

  The reaction temperature of the coupling reaction may be, for example, 10 to 300 ° C, particularly 100 to 210 ° C. The reaction time (residence time) may be, for example, 1.0 to 300 minutes, in particular 10 to 180 minutes, in particular 30 to 120 minutes. The flow rate of the substrate mixture (substrate and optionally present solvent and base) is, for example, 0.001-10 mL / h, especially 0.1-1. It may be 0 mL / h.

In the present invention, a microreactor constituted by a reaction tube having a minute flow path is used.
FIG. 1 shows an outline of a reaction apparatus used in the present invention. The reaction apparatus has a syringe pump 10 and a microreactor 20. In the microreactor 20, a particulate palladium catalyst (Pd / C, ie palladium on carbon) is packed over a distance of Xcm.
FIG. 2 is an enlarged cross-sectional view of a part of the microreactor 20. A granular palladium catalyst 22 is packed in the microreactor. The substrate 24 flows in the direction of the arrow (right direction).

In the present invention,
(1) The substrate is introduced from the inlet of the microreactor,
(2) A substrate is contacted with a catalyst in a microreactor to perform a coupling reaction to generate a reaction product,
(3) The reaction product comes out from the microreactor outlet.

  Next, the embodiment will be described in more detail. However, the present invention is not limited by these examples.

Production Example 1
A palladium-filled microreactor was manufactured by filling a stainless steel tube (length: 5 cm, 10 cm, or 15 cm) having an inner diameter of 1.0 mm with a granular palladium catalyst. A filter was attached to each of both ends of the tube, and the granular palladium catalyst was retained in the tube. The obtained palladium-filled microreactor was used for the reaction.

Example 1
Mizoroki-Heck coupling reaction E105CA / W type (Pd amount: 5% by weight, support: carbon, average particle size: 20 μm) available from Degussa was used as a palladium catalyst.
p-Bromonitrobenzene (first substrate) 0.505 g (0.0025 mol), methyl acrylate (second substrate) 0.253 g (0.0025 mol), N-methyl-2-pyrrolidone 5.0 mL, and triethylamine 0.253 g (0.0025 mol) was mixed to obtain a solution. The solution was loaded into a syringe. Palladium filled microreactor (temperature: 140 ° C., length 5 cm) at a flow rate of 0.1 mL / h from a syringe (the microreactor also has 0.004 g (0.000038 mol) of sodium carbonate ground into fine particles in a mortar. And the reaction was conducted with a residence time of 20 minutes to obtain a coupling product. The yield was 92%.

  The yield (92%) obtained in this example is the batch type Pd / C catalyst in M. Arai et al., Reaction Kinetics and Catalysis Letters, 2004, 81, 281-289. This is superior to the yield of 36% obtained by carrying out the reaction at 160 ° C. for 12 hours.

Example 2
Sonogashira coupling reaction E. The AER type available from Chemcat Co. was used.
0.51 g (0.0025 mol) of iodobenzene (first substrate) and 0.306 g (0.003 mol) of phenylacetylene (second substrate) (molar ratio of first substrate to second substrate 1: 1.2) Was mixed with 0.213 g (0.003 mol) of pyrrolidine and 5.0 mL of N, N-dimethylacetamide and charged into a syringe. The solution was injected from a syringe into a palladium-filled microreactor (temperature: 100 ° C.) at a flow rate of 0.1 mL / h, and the reaction was performed to obtain a coupling product. The following yield was obtained.

  The yield (99%) obtained in this example is 100 ° C. using a Pd / C catalyst in batch mode in RG Heidenreich et al., Synlett, 2002, 7, 1118-1122 (Non-patent Document 1). The yield is superior to 77% obtained by carrying out the reaction for 6 hours.

  ADVANTAGE OF THE INVENTION According to this invention, an organic compound useful as an industrial chemical, a pharmaceutical, an agricultural chemical, etc. or its intermediate body can be manufactured easily and with a high yield.

An outline of a reaction apparatus used in the present invention is shown. It is an expanded sectional view of a part of a microreactor.

Explanation of symbols

10 Syringe pump 20 Microreactor 22 Granular palladium catalyst 24 Substrate

Claims (10)

A method for performing a coupling reaction in the presence of a palladium catalyst,
A flow-through microreactor filled with a solid particle palladium catalyst is used. The palladium catalyst is a metal palladium supported on a carrier, and the carrier is selected from the group consisting of carbon, metal oxide and silicon carbide. A method characterized by being.   The method according to claim 1, wherein a coupling reaction product is produced from the first substrate and the second substrate by a coupling reaction.   The method according to claim 2, wherein the first substrate is a compound capable of oxidative addition to palladium, and the second substrate is a compound having a leaving group. The first substrate, the second substrate and the reaction product are represented by the following formula:
R−X + A−R ′ → R−R ′
[Wherein, R represents an unsaturated or saturated aliphatic group, aromatic group, araliphatic group,
R ′ is an organic group having a carbon atom,
X is a halogen atom, triflate, diazonium salt, or sulfonate;
A is a leaving group. ]
The method according to claim 2, wherein   The method according to claim 2, wherein the first substrate is a halogen-containing compound and has a halogen-carbon bond. The combination of substrate and reaction product is
(1) R—X + H ₂ C═CH—R ″ → R—HC═CH—R ″
(2) R—X + HC≡C—R ″ → R—C≡C—R ″
Or (3) R−X + A ¹ −R ″ → R−R ″
[R and R ″ are an unsaturated or saturated aliphatic group, aromatic group, araliphatic group,
X is a halogen atom, triflate, diazonium salt, or sulfonate;
A ¹ is a leaving group. ]
The method of claim 2, wherein A flow-through microreactor filled with a solid particle palladium catalyst used for conducting a coupling reaction in the presence of a palladium catalyst,
The flow-through microreactor in which the palladium catalyst is a metal palladium supported on a carrier, and the carrier is selected from the group consisting of carbon, metal oxide and silicon carbide.   8. The flow-through type according to claim 7, wherein the metal oxide is aluminum oxide, silicon dioxide, titanium dioxide, zirconium dioxide, zinc oxide, magnesium oxide or a mixture thereof, or zeolite, mesoporous molecular sieve, glass or clay. Microreactor.   The method according to any one of claims 1 to 6, wherein in the flow-through microreactor, the inner diameter of the reaction tube holding the palladium catalyst is 0.1 mm to 10 mm.   The flow type microreactor according to claim 7 or 8, wherein the inner diameter of the reaction tube holding the palladium catalyst is 0.1 mm to 10 mm.

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