JP2022130903A - Method for producing acid anhydride compound, and flow-type reaction system for producing acid anhydride compound - Google Patents

Abstract

To provide a method for producing an acid anhydride compound that makes it possible to produce an acid anhydride compound of interest in high purity, and a flow-type reaction system suitable for the production method.SOLUTION: The present invention discloses a method for producing an acid anhydride compound by causing a flow-type reaction to occur between an amine compound represented by formula (1a) and a metalhydroxide in the presence of an onium salt compound, in a state where an organic phase is separated from an aqueous phase, thereby producing a compound of formula (1b). (R is an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or H; L is a single bond, O, S, NRA or CRB2; RA is an alkyl group, an aryl group or H; RB is an alkyl group, an aryl group, a halogen atom or H; Hal is a halogen atom).SELECTED DRAWING: Figure 1

Description

The present invention relates to a method for producing an acid anhydride compound. The present invention also relates to a flow reaction system for producing acid anhydride compounds.

It has been proposed to apply a flow-type reaction system capable of continuously synthesizing a target compound and precisely controlling mixing efficiency, reaction time, reaction temperature, etc., to a chemical synthesis reaction.
For example, in Patent Document 1, a liquid A containing an anionic polymerizable monomer, a liquid B containing an anionic polymerization initiator, and a polymerization terminator are introduced into different flow paths, and each liquid is circulated in each flow path, and the liquid A and liquid B are combined using a multi-layer cylindrical mixer, the combined liquid anionically polymerizes the anionically polymerizable monomer while flowing downstream in the reaction channel, and the polymerization reaction liquid flowing in the reaction channel. A method for producing a polymer is described, which includes merging with a polymerization terminator to terminate the polymerization reaction. According to the technique described in Patent Document 1, it is said that a monodispersed polymer with a constant degree of dispersion can be stably supplied without precisely controlling the flow rate.
Further, Patent Document 2 describes a method for producing cupric oxide microparticles by a flow reaction. According to Patent Document 2, at the junction where the copper (II) salt solution flowing in the first channel and the basic compound solution flowing in the second channel meet, basicity with respect to the copper (II) salt It is said that the shape of the resulting cupric oxide particles can be adjusted to be spherical, rod-like or plate-like by controlling the reaction molar ratio of the compounds.

Acid anhydride compounds are highly reactive and are widely used as intermediates for organic synthesis reactions, raw materials for synthetic resins, curing agents for epoxy resins, and the like. Since the acid anhydride compound is easily hydrolyzed by the action of water, it is necessary to avoid contact with water as much as possible during the synthesis reaction process and stable storage.
For example, a dicarbonic acid diester compound, which is a type of acid anhydride compound, is easily hydrolyzed in the presence of a base to produce an alcohol and carbon dioxide. In order to suppress this decomposition, the synthesis of dicarbonic acid diester compounds is generally carried out by adding the base (metal hydroxide) necessary for the production of the reaction intermediate (metal salt of monoester carbonate) to the aqueous phase (layer). , is carried out by a two-phase (layer) reaction in which the desired product dicarbonic acid diester compound separates into an organic phase (layer). This two-phase reaction is usually carried out in the presence of an onium salt compound, and the reaction intermediates produced in the aqueous phase can be efficiently transferred to the organic phase by the action of the onium salt compound, and the desired dicarbonic acid is produced in the organic phase. A diester compound is produced. The two-phase reaction itself is a reaction system that has been known for a long time in organic synthesis reactions (for example, Patent Document 3).

WO2019/065709 JP 2016-160124 A JP-A-2002-302480

The present inventors have investigated the preparation of acid anhydride compounds by a two-phase reaction. As a result, in the conventional batch-type two-phase reaction system, decomposition of the target acid anhydride compound cannot be sufficiently suppressed, and improvement in the purity of the target acid anhydride compound recovered in the organic phase is limited. I have come to understand that there is
Accordingly, an object of the present invention is to provide a method for producing an acid anhydride compound capable of obtaining a desired acid anhydride compound with high purity, and a reaction system suitable for this production method.

式中、Ｒはアルキル基、脂肪族環状炭化水素基、アリール基、複素環基、アルケニル基、ハロゲン原子又は水素原子を示す。Ｌは単結合、Ｏ、Ｓ、ＮＲ^Ａ又はＣＲ^Ｂ _２を示し、Ｒ^Ａはアルキル基、アリール基又は水素原子を示し、Ｒ^Ｂはアルキル基、アリール基、ハロゲン原子又は水素原子を示す。Ｈａｌはハロゲン原子を示す。
〔２〕
上記フロー式反応における反応溶媒として有機溶媒と水との混合溶媒を用いる、〔１〕に記載の酸無水物化合物の製造方法。
〔３〕
上記フロー式反応における反応溶媒として有機溶媒と水とを用いて、有機相と水相とが相分離した状態でフロー式反応により反応させて上記の一般式（１ｂ）で表される酸無水物化合物を有機相中に得る、〔１〕に記載の酸無水物化合物の製造方法。
〔４〕
上記の一般式（１ａ）で表される化合物を含有する有機溶液と、上記アミン化合物と上記金属水酸化物と上記オニウム塩化合物とを含有する水溶液とを、それぞれ異なる流路に導入して各溶液を各流路内に流通させ、
上記有機溶液と上記水溶液とを合流し、この合流液が有機相と水相とが相分離した状態で下流へ流通中に、上記アミン化合物と上記金属水酸化物とが上記の一般式（１ａ）で表される化合物に作用する
ことを含む、〔３〕に記載の酸無水物化合物の製造方法。
〔５〕
上記の一般式（１ａ）で表される化合物を含有する有機溶液と、上記金属水酸化物と上記オニウム塩化合物とを含有する水溶液（ＡＬ）と、上記アミン化合物を含有する水溶液（ＢＬ）とを、それぞれ異なる流路に導入して各溶液を各流路内に流通させ、
上記有機溶液と上記水溶液（ＡＬ）とを合流し、この合流液（ＣＬ）が有機相と水相とが相分離した状態で下流へ流通中に、上記金属水酸化物が上記の一般式（１ａ）で表される化合物に作用し、
次いで上記合流液（ＣＬ）と上記水溶液（ＢＬ）とを合流し、この合流液（ＤＬ）が有機相と水相とが相分離した状態で下流へ流通中に、上記アミン化合物が上記の一般式（１ａ）で表される化合物に作用する
ことを含む、〔３〕に記載の酸無水物化合物の製造方法。
〔６〕
上記の一般式（１ａ）で表される化合物を含有する有機溶液（ＥＬ）と、上記の一般式（１ａ）で表される化合物を含有する有機溶液（ＦＬ）と、上記金属水酸化物と上記オニウム塩化合物とを含有する水溶液（ＧＬ）と、上記アミン化合物を含有する水溶液（ＨＬ）とを、それぞれ異なる流路に導入して各溶液を各流路内に流通させ、
上記有機溶液（ＥＬ）と上記水溶液（ＧＬ）とを合流し、この合流液（ＩＬ）が有機相と水相とが相分離した状態で下流へ流通中に、上記金属水酸化物が上記の一般式（１ａ）で表される化合物に作用し、
次いで上記合流液（ＩＬ）と上記有機溶液（ＦＬ）とを合流し、この合流液（ＪＬ）が有機相と水相とが相分離した状態で下流へ流通中に、上記金属水酸化物が上記の一般式（１ａ）で表される化合物に作用し、
次いで上記合流液（ＪＬ）と上記水溶液（ＨＬ）とを合流し、この合流液（ＫＬ）が有機相と水相とが相分離した状態で下流へ流通中に、上記アミン化合物が上記の一般式（１ａ）で表される化合物に作用する
ことを含む、〔３〕に記載の酸無水物化合物の製造方法。
〔７〕
上記フロー式反応における合流部の少なくとも１つに二層筒型ミキサーを用いる、〔４〕～〔６〕のいずれかに記載の酸無水物化合物の製造方法。
〔８〕
上記オニウム塩化合物として下記一般式（２）で表される化合物を用いる、〔１〕～〔７〕のいずれかに記載の酸無水物化合物の製造方法。

式中、Ｚは窒素原子又はリン原子を示す。Ｙは対イオンを示す。Ｒ^１～Ｒ^４はアルキル基又は芳香族性基を示す。但し、Ｒ^１～Ｒ^４の少なくとも１つは芳香族性基及び炭素数６以上のアルキル基の少なくとも１種を有する。
〔９〕
上記一般式（２）で表される化合物が第四級アンモニウム塩である、〔８〕に記載の酸無水物化合物の製造方法。
〔１０〕
上記アミン化合物として、環構成原子として窒素原子を含む複素環式化合物を用いる、〔１〕～〔９〕のいずれかに記載の酸無水物化合物の製造方法。
〔１１〕
上記複素環式化合物がピリジン化合物を含む、〔１０〕に記載の酸無水物化合物の製造方法。
〔１２〕
反応停止液を合流して反応を終了させる、〔１〕～〔１１〕のいずれかに記載の酸無水物化合物の製造方法。
〔１３〕
下記一般式（１ａ）で表される化合物を含有する有機溶液を導入する第１流路と、
アミン化合物と金属水酸化物とオニウム塩化合物とを含有する水溶液を導入する第２流路と、
第１流路と第２流路とが合流する第１合流部と、
第１合流部の下流に接続された第３流路と
を有し、
第３流路内を流通する合流液は有機相と水相とが相分離した状態にあり、
上記オニウム塩化合物として、芳香族性基及び炭素数６以上のアルキル基の少なくとも１種を有するオニウム塩化合物を用いる、下記一般式（１ｂ）で表される酸無水物化合物を製造する酸無水物化合物を製造するフロー式反応システム。

式中、Ｒはアルキル基、脂肪族環状炭化水素基、アリール基、複素環基、アルケニル基、ハロゲン原子又は水素原子を示す。Ｌは単結合、Ｏ、Ｓ、ＮＲ^Ａ又はＣＲ^Ｂ _２を示し、Ｒ^Ａはアルキル基、アリール基又は水素原子を示し、Ｒ^Ｂはアルキル基、アリール基、ハロゲン原子又は水素原子を示す。Ｈａｌはハロゲン原子を示す。
〔１４〕
下記一般式（１ａ）で表される化合物を含有する有機溶液を導入する第１流路と、
金属水酸化物とオニウム塩化合物とを含有する水溶液を導入する第２流路と、
第１流路と第２流路とが合流する第１合流部と、
第１合流部の下流に接続された第３流路と、
アミン化合物を含有する水溶液を導入する第４流路と、
第３流路と第４流路とが合流する第２合流部と、
第２合流部の下流に接続された第５流路と
を有し、
第３流路内及び第５流路内を流通する各合流液は有機相と水相とが相分離した状態にあり、
上記オニウム塩化合物として、芳香族性基及び炭素数６以上のアルキル基の少なくとも１種を有するオニウム塩化合物を用いる、下記一般式（１ｂ）で表される酸無水物化合物を製造するフロー式反応システム。

式中、Ｒはアルキル基、脂肪族環状炭化水素基、アリール基、複素環基、アルケニル基、ハロゲン原子又は水素原子を示す。Ｌは単結合、Ｏ、Ｓ、ＮＲ^Ａ又はＣＲ^Ｂ _２を示し、Ｒ^Ａはアルキル基、アリール基又は水素原子を示し、Ｒ^Ｂはアルキル基、アリール基、ハロゲン原子又は水素原子を示す。Ｈａｌはハロゲン原子を示す。
〔１５〕
下記一般式（１ａ）で表される化合物を含有する有機溶液を導入する第１流路と、
金属水酸化物とオニウム塩化合物とを含有する水溶液を導入する第２流路と、
第１流路と第２流路とが合流する第１合流部と、
第１合流部の下流に接続された第３流路と、
上記一般式（１ａ）で表される化合物を含有する有機溶液を導入する第４流路と、
第３流路と第４流路とが合流する第２合流部と、
第２合流部の下流に接続された第５流路と、
アミン化合物を含有する水溶液を導入する第６流路と、
第５流路と第６流路とが合流する第３合流部と、
第３合流部の下流に接続された第７流路と
を有し、
第３流路内、第５流路内及び第７流路内を流通する各合流液は有機相と水相とが相分離した状態にあり、
上記オニウム塩化合物として、芳香族性基及び炭素数６以上のアルキル基の少なくとも１種を有するオニウム塩化合物を用いる、下記一般式（１ｂ）で表される酸無水物化合物を製造するフロー式反応システム。

式中、Ｒはアルキル基、脂肪族環状炭化水素基、アリール基、複素環基、アルケニル基、ハロゲン原子又は水素原子を示す。Ｌは単結合、Ｏ、Ｓ、ＮＲ^Ａ又はＣＲ^Ｂ _２を示し、Ｒ^Ａはアルキル基、アリール基又は水素原子を示し、Ｒ^Ｂはアルキル基、アリール基、ハロゲン原子又は水素原子を示す。Ｈａｌはハロゲン原子を示す。 In view of the above problems, the present inventors have made extensive studies and attempted to apply a flow-type reaction system to the preparation of acid anhydride compounds. It was found that decomposition can be effectively suppressed. The present invention has been completed through further studies based on such findings.
The problems of the present invention have been solved by the following means.
[1]
An acid anhydride compound represented by the following general formula (1b) by reacting a compound represented by the following general formula (1a), an amine compound and a metal hydroxide in the presence of an onium salt compound by a flow reaction. including obtaining
A method for producing an acid anhydride compound, wherein an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms is used as the onium salt compound.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.
[2]
The method for producing an acid anhydride compound according to [1], wherein a mixed solvent of an organic solvent and water is used as a reaction solvent in the flow reaction.
[3]
Using an organic solvent and water as a reaction solvent in the flow reaction, the acid anhydride represented by the above general formula (1b) is reacted by a flow reaction in a state where the organic phase and the aqueous phase are phase-separated. The method for producing an acid anhydride compound according to [1], wherein the compound is obtained in an organic phase.
[4]
An organic solution containing the compound represented by the general formula (1a) and an aqueous solution containing the amine compound, the metal hydroxide, and the onium salt compound are introduced into different flow paths, respectively. circulating the solution in each channel,
The organic solution and the aqueous solution are combined, and the combined solution is distributed downstream in a state where the organic phase and the aqueous phase are phase-separated. The method for producing an acid anhydride compound according to [3], which comprises acting on the compound represented by ).
[5]
An organic solution containing the compound represented by the general formula (1a), an aqueous solution (AL) containing the metal hydroxide and the onium salt compound, and an aqueous solution (BL) containing the amine compound. are introduced into different channels, and each solution is circulated in each channel,
The organic solution and the aqueous solution (AL) are combined, and the combined solution (CL) is phase-separated into an organic phase and an aqueous phase while flowing downstream. acting on the compound represented by 1a),
Next, the combined liquid (CL) and the aqueous solution (BL) are combined, and the combined liquid (DL) is phase-separated into an organic phase and an aqueous phase while flowing downstream. A method for producing an acid anhydride compound according to [3], which comprises acting on a compound represented by formula (1a).
[6]
An organic solution (EL) containing the compound represented by the general formula (1a), an organic solution (FL) containing the compound represented by the general formula (1a), and the metal hydroxide An aqueous solution (GL) containing the onium salt compound and an aqueous solution (HL) containing the amine compound are introduced into different channels, respectively, and each solution is circulated in each channel,
The organic solution (EL) and the aqueous solution (GL) are combined, and the combined liquid (IL) is phase-separated into an organic phase and an aqueous phase, and during the flow downstream, the metal hydroxide becomes the above acting on the compound represented by the general formula (1a),
Next, the combined liquid (IL) and the organic solution (FL) are combined, and the metal hydroxide is generated while the combined liquid (JL) is flowing downstream in a state where the organic phase and the aqueous phase are phase-separated. Acting on the compound represented by the general formula (1a) above,
Next, the combined liquid (JL) and the aqueous solution (HL) are combined, and the combined liquid (KL) is separated into an organic phase and an aqueous phase while flowing downstream. A method for producing an acid anhydride compound according to [3], which comprises acting on a compound represented by formula (1a).
[7]
The method for producing an acid anhydride compound according to any one of [4] to [6], wherein a two-layer cylindrical mixer is used in at least one of the confluences in the flow reaction.
[8]
The method for producing an acid anhydride compound according to any one of [1] to [7], wherein a compound represented by the following general formula (2) is used as the onium salt compound.

In the formula, Z represents a nitrogen atom or a phosphorus atom. Y represents a counterion. R ¹ to R ⁴ represent an alkyl group or an aromatic group. However, at least one of R ¹ to R ⁴ has at least one of an aromatic group and an alkyl group having 6 or more carbon atoms.
[9]
The method for producing an acid anhydride compound according to [8], wherein the compound represented by the general formula (2) is a quaternary ammonium salt.
[10]
The method for producing an acid anhydride compound according to any one of [1] to [9], wherein a heterocyclic compound containing a nitrogen atom as a ring-constituting atom is used as the amine compound.
[11]
The method for producing an acid anhydride compound according to [10], wherein the heterocyclic compound contains a pyridine compound.
[12]
The method for producing an acid anhydride compound according to any one of [1] to [11], wherein the reaction stop solution is added to terminate the reaction.
[13]
a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing an amine compound, a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first confluence,
The combined liquid flowing through the third channel is in a phase-separated state of the organic phase and the aqueous phase,
An acid anhydride for producing an acid anhydride compound represented by the following general formula (1b), using an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms as the onium salt compound A flow-type reaction system for manufacturing compounds.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.
[14]
a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an aqueous solution containing an amine compound;
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence,
Each combined liquid flowing through the third channel and the fifth channel is in a state where the organic phase and the aqueous phase are phase-separated,
Flow-type reaction for producing an acid anhydride compound represented by the following general formula (1b), using an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms as the onium salt compound system.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.
[15]
a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence;
a sixth channel for introducing an aqueous solution containing an amine compound;
a third junction where the fifth flow path and the sixth flow path join;
a seventh flow path connected downstream of the third confluence,
The combined liquids flowing through the third channel, the fifth channel, and the seventh channel are in a phase-separated state of an organic phase and an aqueous phase,
Flow-type reaction for producing an acid anhydride compound represented by the following general formula (1b), using an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms as the onium salt compound system.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.

In the present invention or in the specification, a numerical range represented by "-" means a range including the numerical values before and after "-" as lower and upper limits.
In the present invention or the specification, when explaining the pipe internal cross-sectional size (equivalent diameter) of a flow path, a confluence section, a mixer, etc., the connecting portion between the flow paths, the connecting portion between the flow path and the confluence section, the flow path and the mixer The size does not include the connecting portion. That is, the size of each connecting portion is appropriately adjusted using a connecting tube or the like so that the fluid flows through the connecting portion from upstream to downstream.
In the present invention or the specification, when specifying the carbon number of a certain group, this carbon number means the carbon number of the group as a whole. In other words, when this group is in the form of further having a substituent, it means the total number of carbon atoms including this substituent.
As used herein, the terms "upstream" and "downstream" are used with respect to the direction in which the fluid flows, the side to which the fluid is introduced (the side from which the fluid flows) is upstream, and the fluid flows out. side is downstream.

According to the method for producing an acid anhydride compound of the present invention, the desired acid anhydride compound can be obtained with high purity. In addition, the flow reaction system of the present invention can be used to carry out the above production method to obtain the desired acid anhydride compound with high purity.

BRIEF DESCRIPTION OF THE DRAWINGS It is explanatory drawing which shows the outline of mass transfer in a two-phase reaction. BRIEF DESCRIPTION OF THE DRAWINGS It is explanatory drawing which shows the outline of one Embodiment of the flow-type reaction system of this invention. It is an explanatory view showing the structure of a two-layer cylindrical mixer. It is an explanatory view showing the structure of a two-layer cylindrical mixer. FIG. 2 is an explanatory diagram showing an outline of another embodiment of the flow reaction system of the present invention; FIG. 2 is an explanatory diagram showing an outline of still another embodiment of the flow reaction system of the present invention; FIG. 2 is an explanatory diagram showing an outline of still another embodiment of the flow reaction system of the present invention;

[Production of acid anhydride compound by flow reaction]
The method for producing an acid anhydride compound of the present invention (hereinafter also referred to as "the production method of the present invention") employs a flow reaction. In this flow-type reaction, a compound represented by the following general formula (1a), an amine compound, and a metal hydroxide are each reacted in the presence of an onium salt compound having a specific structure, which will be described later, while flowing through a channel. . As a result, the acid anhydride compound represented by the following general formula (1b) can be obtained with high purity.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.

The compound represented by formula (1a) may be one kind, or two or more kinds. The acid anhydride compound represented by formula (1b) is obtained using the compound represented by formula (1a) as a starting material. Therefore, the corresponding L and R are the same between the acid anhydride compound represented by formula (1b) and the compound represented by formula (1a) from which it is derived.
In Formula (1b), two L's may be the same or different, and two R's may be the same or different. Preferably, two L's in formula (1b) are the same. Moreover, it is preferable that two R's in the formula (1b) are the same.

The alkyl group that can be used as R may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1-20, more preferably 1-10, still more preferably 1-8, and also preferably 1-6. Preferred specific examples of alkyl groups include methyl, ethyl, propyl and butyl, with methyl, ethyl or t-butyl being preferred, and ethyl or t-butyl being more preferred.

The aliphatic cyclic hydrocarbon group that can be used as R may be a saturated aliphatic cyclic hydrocarbon group or an unsaturated aliphatic cyclic hydrocarbon group, preferably a saturated aliphatic cyclic hydrocarbon group. The aliphatic cyclic hydrocarbon group includes a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aliphatic cyclic hydrocarbon group having a bridge structure (adamantyl group, etc.), and a cycloalkyl group or a saturated hydrocarbon group having a bridge structure. Aliphatic cyclic hydrocarbon groups are preferred. The number of carbon atoms in the aliphatic cyclic hydrocarbon group is preferably 3-20, more preferably 3-15, even more preferably 3-12. Preferred specific examples of the aliphatic cyclic hydrocarbon group that can be used as R include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.

The aryl group that can be used as R preferably has 6 to 20 carbon atoms, more preferably 6 to 15 carbon atoms, still more preferably 6 to 12 carbon atoms, and even more preferably 6 to 10 carbon atoms. Preferred examples of aryl groups include phenyl and naphthyl, with phenyl being more preferred.

The heterocyclic group that can be used as R is a cyclic group having at least one heteroatom (an atom other than a carbon atom such as a nitrogen atom, an oxygen atom, a sulfur atom) as a ring-constituting atom, and may be aliphatic. It may be aromatic. The number of ring-constituting atoms of the heterocyclic group is preferably 3-20, more preferably 4-15, even more preferably 5-12. Preferable examples of heterocyclic groups include pyrrole, pyrrolidine, piperidine, piperazine, pyridine, pyrazine, triazine, tetrahydrofuran, morpholine, thiomorpholine, imidazole, thiophene, furan, thiazole, indole, benzofuran, quinoline, isoquinoline, benzothiophene, and benzothiazole. , benzoxazole, carbazole, dibenzofuran, acridine, phenazine, dibenzothiophene and the like.

The alkenyl group that can be used as R may be linear or branched. The alkenyl group preferably has 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, still more preferably 2 to 8 carbon atoms, and also preferably 2 to 6 carbon atoms. Preferred specific examples of alkenyl groups include vinyl, allyl, butenyl, styryl and the like.

Halogen atoms that can be used as R include, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

L represents a _single bond, O, S, NR ^A or CR ^B2 . L is preferably O or CR ^B ₂ , more preferably O. When L is O, R is preferably an alkyl group or an aryl group. That is, the compound represented by the general formula (1a) is preferably a halogenoformate compound (preferably a chloroformate compound), and the acid anhydride compound represented by the general formula (1b) is a dicarbonic acid diester compound. Preferably.
Examples of the alkyl group that can be used as ^RA include the above alkyl groups that can be used as R. Among them, the alkyl group that can be used as ^RA is preferably methyl, ethyl or t-butyl.
Examples of the aryl group that can be used as ^RA include the above aryl groups that can be used as R. Among them, the aryl group that can be used as ^RA is preferably phenyl.
Examples of the alkyl group that can be used as ^RB include the above alkyl groups that can be used as R. Among them, the alkyl group that can be used as R 2 ^B is preferably methyl, ethyl or t-butyl.
As the aryl group that can be used as RB, the above aryl groups that can be used as ^R can be mentioned. Among them, the aryl group that can be used as ^RB is preferably phenyl.
Examples of the halogen atom that can be used as ^RB include the above halogen atoms that can be used as R. A halogen atom that can be used as R 2 ^B is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.
CR ^B ₂ may be a ring structure formed by linking two R ^B s, or may be a halogen-substituted alkyl group.

When -LR is -CR ^B ₂ -R, -CR ^B ₂ -R is trifluoromethyl, chloromethyl, bromomethyl, benzyl, cyclopropyl, t-butyl, t-amyl, cyclopentyl, cyclohexyl, thiopheneacetyl , 2-ethylhexyl, adamantyl, adamantylmethyl, or heptafluoropropyl.

Halogen atoms that can be used as Hal include the above halogen atoms that can be used as R. Hal is preferably a chlorine atom.

Preferred specific examples of the compound represented by formula (1a) include methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, methacryloyl chloride, acryloyl chloride, isobutyryl chloride, pivaloyl chloride, and cyclohexane. Carbonyl chloride, phenylacetyl chloride, adamantane carbonyl chloride and the like can be mentioned.

The production method of the present invention applies a flow reaction system to the synthesis reaction for obtaining the acid anhydride compound represented by the general formula (1b) from the compound represented by the general formula (1a). By applying a flow reaction system, decomposition of the target acid anhydride compound can be effectively suppressed even in a one-phase reaction. The reason for this is not clear, but by conducting a flow reaction at a constant speed in the closed space of the flow channel, the raw materials in the reaction solution are mixed and stirred moderately, not too vigorously, and not too gently. One of the factors is that the presence of the onium salt compound effectively improves the solubility and diffusibility of the raw material or intermediate in the solution and suppresses the decomposition of the target product. it is conceivable that.

In the production method of the present invention, only an organic solvent can be used as a reaction solvent for the one-phase reaction in the above-described flow-type reaction.
Further, in the above-described flow-type reaction, it is also preferable to use a mixed solvent of an organic solvent and water as a reaction solvent for the one-phase reaction. In the present invention, the "mixed solvent" means that the organic solvent and water are compatible with each other without phase separation. In this case, the flow reaction is a one-phase reaction. By using a mixed solvent of an organic solvent and water, the salt dissolves in water, which is preferable in that clogging of the flow path is less likely to occur. In the present invention, the reaction solvent means a solvent in a process in which all components contributing to the reaction, such as raw materials and catalysts, are mixed. For example, in FIG. 2 it is the solvent flowing through the channel (IV), and in FIGS. 6 and 7 it is the solvent flowing through the channel (IV-2).

Among them, in the production method of the present invention, an organic solvent and water are used as reaction solvents in the flow reaction, and the organic phase and the aqueous phase are phase-separated. A form in which the acid anhydride compound represented by (1b) is obtained in the organic phase is preferred.
That is, each of the compound represented by the general formula (1a), the amine compound, and the metal hydroxide is dissolved in either water or an organic solvent, and an organic It is preferable that the phase and the aqueous phase are reacted while flowing through the channel in a phase-separated state (hereinafter, this reaction is also referred to as "flow-type two-phase reaction" or simply "two-phase reaction"). As a result, an acid anhydride compound represented by the following general formula (1b) can be finally obtained in the organic phase.
By carrying out the two-phase reaction system in a flow system as described above, during the flow in the flow channel of the flow reaction system in a state where the organic phase and the aqueous phase are phase-separated, the action of the onium salt compound with a specific structure , the compound represented by the above general formula (1a) and the amine compound or the reaction intermediate are thought to be able to move more efficiently between the aqueous phase and the organic phase. In addition, the amine compound itself acts like an onium salt compound and can promote phase transfer of the compound represented by the general formula (1a). As a result, in the aqueous phase, the compound represented by general formula (1a) is activated by the action of the metal hydroxide (base), and in the organic phase, the compound represented by general formula (1a) is activated by the action of the amine compound. , both of the activators react in the organic phase to obtain the acid anhydride compound represented by the general formula (1b) in the organic phase.
Using ethyl chloroformate as the compound represented by the general formula (1a), pyridine as the amine compound, and sodium hydroxide as the metal hydroxide, a two-phase reaction produces dicarbonic acid in the organic phase. An outline of a series of mass transfers and accompanying reactions to obtain diethyl is shown in FIG. In FIG. 1, "PTC" indicates an onium salt compound and "Et" indicates ethyl. For the purpose of understanding the present invention, FIG. 1 shows presumed mass transfer and accompanying reaction forms, and does not exhaustively show all mass transfers. The present invention is not limited to the configuration of FIG. 1 except as specified in the present invention.
Hereinafter, the production method of the present invention may be described assuming a two-phase reaction system, but unless otherwise specified, the following description also applies to a one-phase reaction system.

The amine compound used in the production method of the present invention is not particularly limited as long as it can react with the compound represented by formula (1a) to form a quaternary ammonium salt. The anion in this quaternary ammonium salt is usually a halogen ion derived from Hal of general formula (1a). The amine compound may be aliphatic or aromatic. The molecular weight of the amine compound is preferably 50-600, more preferably 60-300. The amine compound is preferably a compound having one or two amino groups.
A tertiary amine compound is preferably used as the amine compound in the production method of the present invention. In this case, all of the amine compounds may be tertiary amine compounds, or an amine compound other than the tertiary amine compound may be used in combination with the tertiary amine compound. More preferably all of the amine compounds are tertiary amine compounds. In the present invention, the tertiary amine compound also includes an aromatic compound having a nitrogen atom as a ring-constituting atom such as pyridine.
In the production method of the present invention, it is preferable to use a heterocyclic compound containing a nitrogen atom as a ring-constituting atom (hereinafter also referred to as a nitrogen-containing heterocyclic compound) as the amine compound. In this case, all of the amine compounds may be nitrogen-containing heterocyclic compounds, or an amine compound other than the nitrogen-containing heterocyclic compounds may be used in combination with the nitrogen-containing heterocyclic compounds. More preferably, all of the amine compounds are nitrogen-containing heterocyclic compounds.
The nitrogen-containing heterocyclic compound preferably has a 5- or 6-membered ring structure. The nitrogen-containing heterocyclic compound preferably contains an aromatic compound, more preferably an aromatic compound. In addition, the nitrogen-containing heterocyclic compound preferably contains a pyridine compound (a compound having a pyridine ring), more preferably a pyridine compound. The nitrogen-containing heterocyclic compound preferably contains pyridine, more preferably pyridine.

Preferable specific examples of the amine compound that can be used in the production method of the present invention are shown below, but the present invention is not limited to the form using these.

The metal hydroxide used in the production method of the present invention acts on the compound represented by general formula (1a) to produce a metal salt compound (activated form). Due to their high hydrophilicity, metal hydroxides are practically unable to migrate into the organic phase, so the reaction proceeds in the aqueous phase.
The metal hydroxide is not particularly limited as long as it can act on the compound represented by the general formula (1a) in the aqueous phase to form a metal salt compound. One or more metal hydroxides can be used in the production method of the present invention. As the metal hydroxide, an alkali metal hydroxide and/or an alkaline earth metal hydroxide can be preferably used, and an alkali metal hydroxide is more preferably used. When alkali metal hydroxides are used, all of the metal hydroxides may be alkali metal hydroxides, or a combination of metal hydroxides other than alkali metals and alkali metal hydroxides may be used. can. More preferably, all of the metal hydroxides are alkali metal hydroxides. At least one of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide is preferably used as the metal hydroxide, and sodium hydroxide or potassium hydroxide is more preferably used.
Examples of the alkaline earth metal hydroxides include magnesium hydroxide, calcium hydroxide, barium hydroxide, and strontium hydroxide.

The onium salt compound used in the production method of the present invention itself can travel between the aqueous phase and the organic phase, and can be widely applied to compounds used to promote the transfer of substances between the aqueous phase and the organic phase. . From the viewpoint of more efficient mass transfer, the onium salt compound used in the production method of the present invention has at least one of an aromatic group and an alkyl group having 6 or more carbon atoms. All of the onium salt compounds may be onium salt compounds having at least one of an aromatic group and an alkyl group of 6 or more carbon atoms, and an onium salt having at least one of an aromatic group and an alkyl group of 6 or more carbon atoms. A combination form of the compound and other onium salt compounds can also be used. In particular, all of the onium salt compounds are preferably onium salt compounds having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms. In the present invention, when the onium salt compound has an alkyl group having an aromatic group as a substituent, and the alkyl group as a whole including the aromatic group as the substituent has 6 or more carbon atoms, Since this onium salt compound has the above-mentioned alkyl group having an aromatic group as a substituent, it is understood that it has an aromatic group and an alkyl group having 6 or more carbon atoms.
The aromatic group is preferably a group having a 5- or 6-membered ring structure, and may be a condensed ring group in which these ring structures are condensed. A ring structure constituting the aromatic group is preferably a benzene ring or a pyridine ring, more preferably a benzene ring. The above aromatic group preferably has a monocyclic structure. The aromatic group in the onium salt compound preferably has 6 to 20 carbon atoms, more preferably 6 to 15 carbon atoms, still more preferably 6 to 12 carbon atoms, and particularly preferably 6 to 10 carbon atoms.
The above alkyl group having 6 or more carbon atoms may be linear or branched. In addition, the above alkyl group having 6 or more carbon atoms preferably has 6 to 30 carbon atoms, more preferably 6 to 20 carbon atoms.
As the onium salt compound used in the present invention, it is preferable to use a compound represented by the following general formula (2). In this case, all of the onium salt compounds may be compounds represented by the following general formula (2), and an onium salt compound other than the compound represented by the following general formula (2) and the following general formula (2). A combination form with a compound is also possible.

In the formula, Z represents a nitrogen atom or a phosphorus atom. Y represents a counterion. R ¹ to R ⁴ represent an alkyl group or an aromatic group. However, at least one of R ¹ to R ⁴ has at least one of an aromatic group and an alkyl group having 6 or more carbon atoms. Preferred forms of the aromatic group and the alkyl group having 6 or more carbon atoms are as explained in the structure of the onium salt compound above. In addition, when R ¹ to R ⁴ include an alkyl group having 5 or less carbon atoms, the alkyl group preferably has 1 to 3 carbon atoms, more preferably methyl or ethyl. That is, in the compound represented by the general formula (2), at least one of R ¹ to R ⁴ is a group having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms, and the remaining group is preferably an alkyl group having 5 or less carbon atoms (preferably an alkyl group having 1 to 3 carbon atoms, more preferably methyl or ethyl).
Z is preferably a nitrogen atom. That is, it is preferable that the compound represented by the general formula (2) is a quaternary ammonium salt.
The counter ion of Y is not particularly limited, and examples thereof include halogen ion, hexafluorophosphate ion, hexafluoroarsenate ion, tetrafluoroborate ion, tetraphenylborate ion, trifluoromethanesulfonate ion, acyloxy ion, methanesulfone acid ions, p-toluenesulfonate ions, dibenzenesulfonate ions, bis(trifluoromethanesulfonic acid)imide ions, nitrate ions, and the like.

Preferable specific examples of the onium salt compound that can be used in the production method of the present invention are shown below, but the present invention is not limited to the form using these. OAc represents an acetyloxy ion and OTf represents a trifluoromethanesulfonate ion.

In the production method of the present invention, the compound represented by the general formula (1a), the amine compound, the metal hydroxide, and the onium salt compound are each used alone or in combination of two or more, in the form of an aqueous solution or It is introduced into the flow reaction system in the state of an organic solution. Whether an aqueous solution or an organic solution is introduced into the flow reaction system depends on the purpose, taking into consideration the solubility in water, the solubility in the organic solvent or organic solution used, the phase transfer efficiency, etc. is determined by
Since the compound represented by the general formula (1a) is generally gradually decomposed in water, it is preferable to supply the compound dissolved in an organic solvent to the flow reaction system.
The amine compound may be supplied to the flow reaction system in a state of being dissolved in either water or an organic solvent. If the amine compound is mixed with the compound represented by the above general formula (1a) in an organic solvent, there is concern that an exothermic acylammation reaction may proceed outside the flow apparatus. It is preferable to supply to the flow reaction system in the state of
Metal hydroxides are usually water-soluble and have low solubility in organic solvents or organic solutions that are immiscible with aqueous solutions. Therefore, it is preferred that it is supplied as an aqueous solution to the flow-type reaction system and essentially stays in the aqueous phase from the beginning to the end of the flow. In addition, the production method of the present invention also includes a form in which a metal hydroxide is mixed in an organic solvent and supplied. In this case, the metal hydroxide is likely to precipitate, and it may be necessary to deal with clogging of the flow path.
The onium salt compound may be dissolved in water and supplied to the flow reaction system, or may be dissolved in an organic solvent or organic solution before being supplied to the flow reaction system. From the viewpoint of solubility, it is preferable to supply to the flow reaction system in the form of an aqueous solution.

Examples of the organic solvent used as a medium for the organic solution include ketone solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, ether solvents, alcohol solvents, amide solvents, sulfoxide solvents, and the like. be done.
Ketone solvents include, for example, acetone, 2-butanone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, and methyl isobutyl ketone.
Examples of hydrocarbon solvents include hexane, cyclohexane, toluene, xylene, and trimethylbenzene.
Examples of halogenated hydrocarbon solvents include dichloromethane (methylene chloride), chloroform, dichloroethane, trichlorethylene, tetrachloroethylene, chlorobenzene, dichlorobenzene, chlorotoluene and the like.
Examples of ester solvents include methyl acetate, ethyl acetate, butyl acetate, 2-methoxy-1-methylethyl acetate and the like.
Ether solvents include tetrahydrofuran, cyclopentylmethyl ether, 1,2-dimethoxyethane, t-butyl methyl ether and the like.
Examples of alcohol solvents include ethanol, isopropanol, butanol, cyclohexanol, 1-methoxy-2-propanol and the like.
Examples of amide solvents include dimethylformamide and dimethylacetamide.
Examples of sulfoxide solvents include dimethylsulfoxide.
The above organic solvents may be used alone, or two or more of them may be used in a mixed state. When two or more kinds of organic solvents are used, those which are compatible with each other are used.
Among them, it is preferable to use at least one of acetone, methylene chloride, toluene, cyclopentyl methyl ether, methyl ethyl ketone, cyclohexanone, xylene, ethyl acetate, tetrahydrofuran, cyclopentyl methyl ether, and t-butyl methyl ether, and acetone, methylene chloride, toluene. , cyclopentyl methyl ether, methyl ethyl ketone, tetrahydrofuran, and ethyl acetate, and more preferably at least one of acetone, methylene chloride, toluene, and tetrahydrofuran.
When the organic solvent contains a large amount of water, the water can be removed by contacting the organic solvent with a commercially available dehydrating agent (molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.).

The concentration and flow rate of each solution supplied to the flow reaction system are appropriately adjusted in consideration of stoichiometry and the like. An example is described below.
When the compound represented by the general formula (1a) is dissolved in an organic solvent and supplied, the content of the compound represented by the general formula (1a) in the organic solvent can be 1 to 90% by mass. , preferably 20 to 70% by mass, more preferably 40 to 70% by mass.
In addition, the amine compound and the onium salt compound are not consumed by the reaction, and the amount thereof used may be appropriately adjusted. For example, when supplying the amine compound as an aqueous solution (this aqueous solution may dissolve other components such as metal hydroxides and onium salt compounds), the content of the amine compound in the aqueous solution is 0.01. It can be up to 30% by mass, preferably 0.1 to 10% by mass, and more preferably 0.2 to 5% by mass. When the onium salt compound is supplied as an aqueous solution (this aqueous solution may dissolve other components such as metal hydroxides and amine compounds), the content of the onium salt compound in the aqueous solution is 0.5. 01 to 30% by mass, preferably 1 to 20% by mass, and more preferably 2 to 10% by mass.
Further, in an aqueous solution obtained by dissolving a metal hydroxide (this aqueous solution may dissolve other components such as an amine compound and an onium salt compound), the content of the metal hydroxide in the aqueous solution is It can be 0.1 to 60% by mass, preferably 2 to 30% by mass, and more preferably 4 to 20% by mass.
The mass % of the solute in the solution is calculated assuming that the density of the solution is 1 g/cm ³ .
In the production method of the present invention, it is also preferable to supply (quench) the reaction stop liquid to the two-phase reaction liquid flowing through the channel in order to terminate the reaction. The reaction terminating solution is not particularly limited, and examples of reaction terminating agents include inorganic or organic acids such as sodium hydrogensulfate, potassium hydrogensulfate, ammonium chloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, and oxalic acid. An aqueous solution obtained by dissolving one or more of acid, formic acid, phosphoric acid, boric acid and the like can be mentioned. The reaction termination liquid is preferably recovered as an aqueous phase at the end, and therefore preferably supplied as an aqueous solution. The concentration of the reaction terminator in this aqueous solution is not particularly limited, and can be, for example, 0.2 to 30% by mass, preferably 1 to 15% by mass, and also 2 to 10% by mass. preferable.

In the present invention, "a state in which the organic phase and the aqueous phase are phase-separated" means that the relationship between the organic phase and the aqueous phase is such that 10 mL of the organic phase and 20 mL of the aqueous phase are mixed in a glass container using a magnetic stirrer. It means that the state of phase separation into the organic phase and the aqueous phase can be visually confirmed when the mixture is stirred and mixed (20° C., rotation speed of 300 rpm, 10 minutes) and then allowed to stand at 20° C. for 15 minutes. The phase separation state is not particularly limited, and the interface between the organic phase and the aqueous phase may be planar (ie separated into two layers) or spherical (ie emulsified). Phase separation into an organic phase and an aqueous phase can be achieved by employing mutually immiscible solvents as solvents constituting each phase (for example, water and ethyl acetate). In addition, although the solvents that make up each phase are compatible with each other, it is also possible to increase the ionic strength by dissolving raw materials and salts to create a mutually incompatible state as a whole solution (for example, water and acetone). . In the present invention, the terms "solution" and "phase" mean that each component is dissolved in a solvent. good too.
In the two-phase liquid flowing through the channel, the volume ratio of the aqueous phase and the organic phase can be from 1/10 to 10/1, and the aqueous phase/organic phase is 3. /7 to 9/1, more preferably aqueous phase/organic phase = 5/5 to 8/2.

One embodiment of the flow reaction system used in the production method of the present invention will be described with reference to the drawings. Each drawing is an explanatory view for facilitating understanding of the present invention, and the size of each member or relative size relationship may be changed for convenience of explanation, and the actual relationship is left as it is. not shown. In addition, the outer shape and shape shown in these drawings are not limited to matters other than those specified in the present invention. The explanation of the flow reaction system below assumes a two-phase reaction system. A one-phase reaction system can also be used, and such a form is also preferable as an embodiment of the present invention.

FIG. 2 is a schematic diagram showing an example of a flow reaction system used in the production method of the present invention. The flow-type reaction system (100) shown in FIG. It has a channel (II) provided with an inlet (iB) for introducing an aqueous solution obtained by dissolving a metal hydroxide and an onium salt compound. The embodiment of FIG. 2 further has a flow path (III) having an inlet (iC) for introducing a reaction stop liquid, and separates the aqueous phase and the organic phase after joining the reaction stop liquid (SE ) to obtain the desired acid anhydride compound in the organic phase (O). This liquid separation operation may be an operation of simply separating the aqueous phase (W) and the organic phase (O), or may be performed by adding an organic solvent, an aqueous solution, or the like. In any case, the desired acid anhydride compound can be obtained in the organic phase (O).
The flow path (I) and the flow path (II) merge at the junction (M1), and the flow path (IV) is connected to the downstream end of the junction (M1). The flow path (IV) and the flow path (III) merge at a junction (M2), and a pipe (V) is connected to the downstream end of the junction (M2).

In the embodiment of FIG. 2, a two-layer cylindrical mixer is used in the junction (M1). This two-layer cylindrical mixer can combine the organic phase and the aqueous phase while controlling the mixing efficiency to be low, and can further suppress decomposition of the target product due to the action of the aqueous phase. The structure of this two-layer cylindrical mixer is shown in FIGS.
FIG. 3 is a cross-sectional view showing the state of liquid confluence using a two-layer cylindrical mixer applied to the confluence portion (M1) of FIG. In addition, in FIG. 3, in the junction part (M1) shown in FIG. 2, the side which the flow path (II) connects is shown as upper side. The channel (I) is connected to the opening (MA) of the inner tube (T1) penetrating through the two-layer cylindrical mixer (M1), or the channel (I) itself is integrated with the inner tube (T1). As a result, the organic solution flowing through the channel (I) flows through the inner tube (T1) from the opening (MB) toward the discharge side (outflow side, MO).
On the other hand, the channel (II) is connected to the opening (MB) of the two-layer cylindrical mixer (M1). As a result, the aqueous solution flowing through the channel (II) flows into the channel adjacent to the inner tube (T1) of the two-layer cylindrical mixer (M1) (that is, the inner tube (T1) and the inner tube (T1) ) and the adjacent tube (T2, outer tube)), and flows toward the discharge side (MO).
The organic solution flowing through the inner tube (T1) toward the discharge side (MO) flows through the flow path adjacent to the inner tube (T1) at the discharge side (MO) end (junction J) of the inner tube (T1). It joins with the aqueous solution flowing toward the discharge side (MO) inside, and is introduced into the channel (IV) connected downstream.
FIG. 4 shows a cross section of the junction J in FIG. 3 as viewed from the discharge side (MO). In FIG. 4, the organic solution flows in the inner tube (T1), and the aqueous solution flows between the inner tube (T1) and the tube (T2) adjacent to the inner tube (T1).

The organic solution and the aqueous solution are combined by the two-layer cylindrical mixer (M1), and each reaction proceeds while the combined liquid is flowing through the channel (IV) to produce the desired acid anhydride represented by the general formula (1b). compounds are formed in the organic phase.
The value of the ratio of the linear velocity r2 of the aqueous solution flowing through the channel adjacent to the inner tube of the two-layer cylindrical mixer (M1) to the linear velocity r1 of the organic solution flowing through the inner tube (r2/r1 ) is preferably 1/100 to 1/2 or 100/1 to 2/1, more preferably 1/30 to 1/3 or 30/1 to 3/1. By controlling the linear velocities of both solutions in this manner, the mixing efficiency can be suppressed to some extent, and a two-phase reaction system can be constructed more reliably. As a result, decomposition of the desired acid anhydride compound produced in the organic phase can be effectively suppressed, and the purity of the obtained desired acid anhydride compound can be further increased.
In the present invention, the unit of "linear velocity" is, for example ^, cm/min. The linear velocity is calculated by dividing by the area (cm ² ).

In the above embodiment, an organic solution obtained by dissolving the compound represented by the general formula (1a) is circulated through the inner tube, and an aqueous solution obtained by dissolving the amine compound, the metal hydroxide and the onium salt compound is supplied. Although the form in which the liquid is circulated in the channel adjacent to the inner tube has been described, the liquid to be circulated may be reversed. In other words, it is also preferable as an embodiment of the production method of the present invention to circulate the aqueous solution through the inner tube and circulate the organic solution through the channel adjacent to the inner tube. Also in this case, the relationship between the linear velocity of the aqueous solution flowing through the inner tube and the linear velocity of the organic solution flowing through the channel adjacent to the inner tube is preferably within the range of the ratio described above.

Each of the introduction ports (iA), (iB), and (iC) is usually connected to a liquid-feeding pump (not shown) such as a syringe pump, and by operating these pumps, each solution is transferred to each It can be circulated in the channel at a desired flow rate.

Each configuration of the embodiment shown in FIG. 2 will be described in more detail.

<Flow path (I)>
The channel (I) is a channel that supplies the organic solution introduced from the inlet (iA) to the junction (M1).
The channel (I) preferably has an equivalent diameter of 0.2 to 50 mm. By setting the equivalent diameter of the channel (I) to 0.2 mm or more, it is possible to suppress the pressure increase during liquid transfer, and to suppress clogging of the channel even when insoluble matter is generated. Further, by setting the equivalent diameter of the flow path (I) to 50 mm or less, it is possible to appropriately control the temperature of the liquid when it is introduced into the junction (M1). The equivalent diameter of the channel (I) is more preferably 0.5 to 30 mm, still more preferably 1 to 20 mm.
The above "equivalent diameter" is also called an equivalent (diameter) diameter, and is a term used in the field of mechanical engineering. When a circular pipe is assumed to be equivalent to a pipe or flow path with an arbitrary internal cross-sectional shape, the diameter of the internal cross-section of the equivalent circular pipe is called the equivalent diameter. The equivalent diameter (deq) is defined as deq=4A/p, where A is the cross-sectional area of the pipe, and p is the wet edge length (inner circumference) of the pipe. When applied to a circular pipe, this equivalent diameter corresponds to the diameter of the internal cross-section of the circular pipe. Equivalent diameter is used to estimate the flow or heat transfer properties of a pipe based on equivalent circular pipe data and represents the spatial scale (typical length) of the phenomenon. The equivalent diameter is deq = 4a ² /4a = a for a regular square pipe with a side a, and deq = a/3 ^1/2 for an equilateral triangular pipe with a side a. Then, deq=2h (see, for example, Japan Society of Mechanical Engineers, "Encyclopedia of Mechanical Engineering", 1997, Maruzen Co., Ltd.).

The length of the channel (I) is not particularly limited, and for example, it can be composed of a tube with a length of about 10 cm to 15 m (preferably 30 cm to 10 m).
The material of the tube is not particularly limited. Examples include quartz glass and lime soda glass. From the viewpoint of flexibility and chemical resistance, the material of the tube is preferably PFA, Teflon (registered trademark), stainless steel, nickel alloy or titanium.

The flow rate for introducing the organic solution from the inlet (iA) is not particularly limited. can be set as appropriate. For example, 0.1 to 5000 mL (cm ³ )/min (min) is preferable, 0.5 to 3000 mL/min is more preferable, and 1 to 3000 mL/min is even more preferable.

The temperature of the channel (I) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Flow path (II)>
The channel (II) is a channel that supplies the aqueous solution introduced from the inlet (iB) to the junction (M1). The channel (II) preferably has an equivalent diameter of 0.1 to 50 mm. By setting the equivalent diameter of the channel (II) to 0.1 mm or more, it is possible to suppress the pressure increase during liquid transfer, and to suppress the clogging of the channel even when insoluble matter is generated. Further, by setting the equivalent diameter of the flow path (II) to 50 mm or less, the liquid temperature at the time of introduction into the confluence portion (M1) can be appropriately controlled. The equivalent diameter of the channel (II) is more preferably 0.5 to 30 mm, still more preferably 1 to 20 mm.

There is no particular limitation on the length of the channel (II), and for example, it can be composed of a tube with a length of about 10 cm to 15 m (preferably 30 cm to 10 m).
There is no particular limitation on the material of the tube, and tubes made of the materials exemplified for the channel (I) can be used.

There is no particular limitation on the flow rate for introducing the aqueous solution from the inlet (iB), and the equivalent diameter of the flow channel, the concentration of the organic solution, the concentration of the aqueous solution, the introduction flow rate of the organic solution, etc., can be taken into account. can be set as appropriate. For example, 0.1 to 5000 mL/min (min) is preferable, 0.5 to 3000 mL/min is more preferable, and 1 to 3000 mL/min is even more preferable.
In addition, the relationship between the flow rate rB at which the aqueous solution is introduced from the inlet (iB) and the flow rate rA at which the organic solution is introduced from the inlet (iA) is not particularly limited. It can be set as appropriate in consideration of the change in efficiency and the like. For example, [flow rate rA]/[flow rate rB]=10/1 to 1/10, preferably [flow rate rA]/[flow rate rB]=5/1 to 1/5. In this specification, the units of flow rates rA and rB are both mL (cm ³ )/min.
The temperature of the channel (II) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Joining section (M1)>
In the embodiment shown in FIG. 2, the flow path (I) through which the organic solution flows and the flow path (II) through which the aqueous solution flows are merged at a junction (M1), and the merged liquid is an organic phase and an aqueous phase. While flowing downstream in the channel (IV) in a state where the phases are separated, the flow-type two-phase reaction accompanied by the mass transfer between the two phases described above causes the acid represented by the general formula (1b) in the organic phase An anhydride compound is obtained.
In the form of FIG. 2, the two-layer cylindrical mixer is applied to the connection between the flow path (I) and the flow path (II) (the form of the junction (M1)) as described above. Materials for the two-layer cylindrical mixer include, for example, perfluoroalkoxyalkane (PFA), Teflon (registered trademark), aromatic polyetherketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, Quartz glass, lime soda glass and the like are preferred.
The equivalent diameter of the inner tube of the two-layer cylindrical mixer (M1) is preferably 0.1 to 10 mm. Also, the equivalent diameter of the outer tube of the two-layer cylindrical mixer (M1) is preferably 2 to 50 mm.

The temperature of the junction (M1) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Flow path (IV)>
The flow path (IV) is a flow path that supplies the combined liquid of the organic solution and the aqueous solution that have merged in the confluence section (M1) to the confluence section (M2) while causing the two-phase reaction. The channel (IV) preferably has an equivalent diameter of 0.1 to 50 mm. By setting the equivalent diameter of the channel (IV) to 0.1 mm or more, it is possible to suppress the pressure increase during liquid transfer, and to suppress clogging of the channel even when insoluble matter is generated. Further, by setting the equivalent diameter of the channel (IV) to 50 mm or less, the liquid temperature in the channel can be appropriately controlled. The equivalent diameter of the channel (IV) is more preferably 0.5 to 30 mm, still more preferably 1 to 20 mm.

The length of the channel (IV) is not particularly limited, and for example, it can be composed of a tube with a length of about 10 cm to 15 m (preferably 30 cm to 10 m).
There is no particular limitation on the material of the tube, and tubes made of the materials exemplified for the channel (I) can be used.
The reaction time for producing the compound represented by the general formula (1b) in the organic phase by the flow-type two-phase reaction is determined by the equivalent diameter and length of the channel (IV), the flow rate setting of the liquid feed pump, etc. It can be adjusted as appropriate. For example, the flow time of the converged liquid converged at the confluence portion (M1) can be 3 to 600 seconds, preferably 5 to 200 seconds. This circulation time is also applied as a preferable circulation time in the channel (IV-2) in each embodiment shown in FIGS. 6 and 7, which will be described later.

The temperature of the channel (IV) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Flow path (III)>
The flow path (III) is a flow path that supplies the above-described reaction stop liquid introduced from the inlet (iC) to the junction (M2). The channel (III) preferably has an equivalent diameter of 0.1 to 50 mm. By setting the equivalent diameter of the channel (III) to 0.1 mm or more, it is possible to suppress the pressure increase during liquid transfer, and to suppress clogging of the channel even when insoluble matter is generated. Further, by setting the equivalent diameter of the flow path (III) to 50 mm or less, the temperature of the liquid when introduced into the confluence portion (M2) can be appropriately controlled. The equivalent diameter of the channel (III) is more preferably 0.5 to 30 mm, still more preferably 1 to 20 mm.

There is no particular limitation on the length of the channel (III), and for example, it can be composed of a tube with a length of about 10 cm to 15 m (preferably 30 cm to 10 m).
There is no particular limitation on the material of the tube, and tubes made of the materials exemplified for the channel (I) can be used.

There is no particular limitation on the flow rate for introducing the reaction stopping solution from the inlet (iC), the equivalent diameter of the channel, the concentration of the reaction stopping solution, the concentration of the organic solution flowing through the channel (I), the channel ( II) can be appropriately set according to the purpose, taking into consideration the concentration of the aqueous solution flowing through the inside. For example, 0.1 to 5000 mL/min (min) is preferable, 0.5 to 3000 mL/min is more preferable, and 1 to 3000 mL/min is even more preferable.
In addition, the relationship between the flow rate rC of the reaction stop solution introduced from the inlet (iC) and the flow rate rD of the combined liquid flowing through the channel (IV) is not particularly limited, and the concentration of each solution, etc., can be considered. It can be set as appropriate. For example, [flow rate rC]/[flow rate rD]=10/1 to 1/10, preferably [flow rate rC]/[flow rate rD]=5/1 to 1/5.

The temperature of the channel (III) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Joining section (M2)>
The combined liquid (two-phase reaction liquid) flowing through the channel (IV) and the reaction stop liquid flowing through the channel (III) join together at the junction (M2). The confluence portion (M2) has a role of a mixer, and the pipe ( There is no particular limitation as long as the solution converged to V) can be sent out. For example, a T-shaped or Y-shaped (the configuration in FIG. 2 is a T-shaped) connector can be used as a mixer. In addition, the two-layer cylindrical mixer mentioned above can also be used for the junction (M2).
Materials for the above T-shaped mixer and Y-shaped mixer are, for example, perfluoroalkoxyalkane (PFA), Teflon (registered trademark), aromatic polyetherketone resin, stainless steel, copper or copper alloy, nickel or nickel Alloys, titanium or titanium alloys, quartz glass, lime soda glass and the like are preferred.
Examples of commercially available mixers include Microglass Reactor manufactured by Microglass; Cytos manufactured by CPC Systems; YM-1 and YM-2 type mixers manufactured by Yamatake; GL Sciences mixing tees and tees (T connector); Upchurch mixing tees and tees (T connector); Upchurch mixing tees and tees (T connector); Valco mixing tees and tees (T connector); a T-shaped connector manufactured by Swagelok, a SUST type mixer manufactured by IDEX, and the like, and any of them can be used in the present invention.
The equivalent diameter of the channel in the confluence (M2) is preferably 0.1 to 30 mm from the viewpoint of better mixing performance.

The temperature of the junction (M1) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

<Piping (V)>
The combined liquid that joins at the confluence portion (M2) flows into the pipe (V) while maintaining a two-phase state, and during downstream circulation in the pipe (V), the reaction terminator and the metal hydroxide or amine compound reacts in the aqueous phase to terminate the formation reaction of general formula (1b). In addition, in this specification, piping (V) may be called flow path (V).
The form of the pipe (V) is not particularly limited, and a tube is usually used. Preferred materials for the pipe (V) are the same as those for the channel (I) described above. Also, the reaction time can be adjusted by the equivalent diameter and length of the pipe (V), the flow rate setting of the liquid transfer pump, and the like. Usually, the equivalent diameter of the pipe (V) is preferably 0.1 to 50 mm, more preferably 0.2 to 20 mm, still more preferably 0.4 to 15 mm, still more preferably 0.7 ~12 mm, more preferably 1 to 10 mm. Also, the length of the pipe (V) is preferably 0.5 to 50 m, more preferably 1 to 30 m.

The temperature of the pipe (V) can be, for example, -30 to 40°C, preferably -10 to 20°C, more preferably 0 to 10°C.

Finally, the organic phase and the aqueous phase flowing through the pipe (V) are separated to obtain an organic solution containing the acid anhydride compound represented by the general formula (1b).

Another embodiment of a flow reaction system for carrying out the production method of the present invention is shown in FIG.
The flow reaction system (200) shown in FIG. 5 is the same as the embodiment of FIG. 2 except that a T-shaped mixer is used in place of the two-layer cylindrical mixer in the confluence section (M1). In addition, it is also preferable to use a Y-shaped mixer as the confluence section (M1). As the mixer used in the confluence section (M1), the mixer described in the confluence section (M2) of the embodiment of FIG. 2 can be used.

Regarding the embodiment shown in FIGS. 2 and 5, the present invention provides the following manufacturing method as one embodiment.

An organic solution containing the compound represented by the general formula (1a) and an aqueous solution containing the amine compound, the metal hydroxide, and the onium salt compound are introduced into different flow paths, respectively. circulating the solution in each channel,
The organic solution and the aqueous solution are combined, and the combined solution is distributed downstream in a state where the organic phase and the aqueous phase are phase-separated. ) to obtain an acid anhydride compound represented by the general formula (1b) in an organic phase.
This method for producing an acid anhydride compound includes a step of joining the two-phase combined liquid and the reaction stop liquid to stop the production reaction of the acid anhydride compound represented by the general formula (1b) (quenching step).
It is also preferable to include a step of purifying the acid anhydride compound represented by the general formula (1b) generated in the organic phase by a liquid separation operation.

Moreover, the present invention provides the following flow-type reaction system with respect to the embodiments shown in FIGS.

a first channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second channel for introducing an aqueous solution containing the amine compound, the metal hydroxide, and the onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first confluence,
A flow-type reaction system for producing an acid anhydride compound represented by the general formula (1b), wherein the combined liquid flowing through the third channel is in a phase-separated state of an organic phase and an aqueous phase.
This flow-type reaction system includes a fourth flow path for introducing an aqueous solution containing the reaction stopping liquid, a second junction where the third flow path and the fourth flow path join, and downstream of the second junction. It is also preferred to have a connected fifth channel.

Still another embodiment of a flow reaction system for carrying out the production method of the present invention is shown in FIG.
The flow reaction system (300) shown in FIG. 6 supplies an aqueous solution in which a metal hydroxide, an onium salt compound, and an amine compound are dissolved in the embodiment of FIG. and the onium salt compound are separately supplied from the inlet (iB-1), and the aqueous solution in which the amine compound is dissolved is separately supplied from the inlet (iB-2). Different from the form.
That is, in the embodiment of FIG. 6, an organic solution obtained by dissolving the compound represented by the general formula (1a) is supplied into the channel (I), and the metal hydroxide and the onium salt compound are dissolved. An aqueous solution is supplied into the channel (II-1), the two solutions are merged at the confluence portion (M1-1), and the combined liquid is phase-separated into an organic phase and an aqueous phase, and the channel (IV-1) ) to the downstream. Next, this combined liquid and an aqueous solution containing an amine compound dissolved in the channel (II-2) are combined at the confluence section (M1-2), and the combined liquid is divided into an organic phase and an aqueous phase. The separated state is allowed to flow downstream in the channel (IV-2) to produce the target acid anhydride compound represented by the general formula (1b) in the organic phase. The two-phase converged liquid flowing in the channel (IV-2) is combined with the reaction stop liquid flowing in the channel (III) at the confluence section (M2) to obtain the reaction represented by the general formula (1b). stop the formation reaction of the acid anhydride compound. Finally, the organic phase (O) and the aqueous phase (W) are separated (SE) to obtain an organic solution (O) containing the acid anhydride compound represented by the general formula (1b).
For each flow path, the concentration of the solution flowing through the flow path, the mixer, etc., those of the embodiments already described can be appropriately applied.

Regarding the embodiment shown in FIG. 6, the present invention provides the following manufacturing method as one embodiment.

An organic solution containing the compound represented by the general formula (1a), an aqueous solution (AL) containing the metal hydroxide and the onium salt compound, and an aqueous solution (BL) containing the amine compound. are introduced into different channels, and each solution is circulated in each channel,
The organic solution and the aqueous solution (AL) are combined, and the combined solution (CL) is phase-separated into an organic phase and an aqueous phase while flowing downstream. acting on the compound represented by 1a),
Next, the combined liquid (CL) and the aqueous solution (BL) are combined, and the combined liquid (DL) is phase-separated into an organic phase and an aqueous phase while flowing downstream. A method for producing an acid anhydride compound, comprising reacting a compound represented by formula (1a) to obtain an acid anhydride compound represented by general formula (1b) in an organic phase.
This method for producing an acid anhydride compound preferably includes a step of combining a combined liquid (DL) and a reaction stopping liquid to stop the production reaction of the acid anhydride compound represented by the general formula (1b). .
It is also preferable to include a step of purifying the acid anhydride compound represented by the general formula (1b) generated in the organic phase by a liquid separation operation.

Moreover, regarding the embodiment shown in FIG. 6, the present invention provides the following flow reaction system.

a first channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second channel for introducing an aqueous solution containing the metal hydroxide and the onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an aqueous solution containing the amine compound;
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence,
A flow for producing an acid anhydride compound represented by the above general formula (1b), wherein the combined liquids flowing in the third channel and the fifth channel are in a phase-separated state into an organic phase and an aqueous phase. formula reaction system.
This flow-type reaction system includes a sixth flow path for introducing an aqueous solution containing the reaction stop liquid, a third junction where the fifth and sixth flow paths join, and downstream of the third junction. It is also preferred to have a connected seventh channel.

Yet another embodiment of a flow reaction system for carrying out the production method of the present invention is shown in FIG.
In the embodiment of FIG. 6, the flow reaction system (400) shown in FIG. 7 divides the organic solution obtained by dissolving the compound represented by the general formula (1a) into two, and the introduction port (iA-1 ) and inlet (iA-2) to the flow reaction system, the embodiment is the same as the embodiment of FIG.
That is, in the embodiment of FIG. 7, an organic solution obtained by dissolving the compound represented by the general formula (1a) is supplied into the channel (I-1) to dissolve the metal hydroxide and the onium salt compound. An aqueous solution consisting of the following is supplied into the channel (II-1), the two solutions are merged at the confluence portion (M1-1a), and the combined liquid is phase-separated into an organic phase and an aqueous phase, and the channel (IV - 1a) to flow downstream. Next, this combined liquid and the organic solution in which the compound represented by the general formula (1a) is dissolved, which flows through the channel (I-2), are combined at the confluence section (M1-1b) to merge. The liquid is allowed to flow downstream through the flow path (IV-1b) while being phase-separated into an organic phase and an aqueous phase. Next, this combined liquid and an aqueous solution containing an amine compound dissolved in the channel (II-2) are combined at the confluence section (M1-2), and the combined liquid is divided into an organic phase and an aqueous phase. The separated state is allowed to flow downstream in the channel (IV-2) to produce the target acid anhydride compound represented by the general formula (1b) in the organic phase. The two-phase converged liquid flowing in the channel (IV-2) is combined with the reaction stop liquid flowing in the channel (III) at the confluence section (M2) to obtain the reaction represented by the general formula (1b). stop the formation reaction of the acid anhydride compound. Finally, the organic phase (O) and the aqueous phase (W) are separated (SE) to obtain an organic solution (O) containing the acid anhydride compound represented by the general formula (1b).
For each channel, the concentration of the solution flowing through each channel, the mixer, etc., those of the embodiments already described can be appropriately applied.

Regarding the embodiment shown in FIG. 7, the present invention provides the following manufacturing method as one embodiment.

An organic solution (EL) containing the compound represented by the general formula (1a), an organic solution (FL) containing the compound represented by the general formula (1a), and the metal hydroxide An aqueous solution (GL) containing the onium salt compound and an aqueous solution (HL) containing the amine compound are introduced into different channels, respectively, and each solution is circulated in each channel,
The organic solution (EL) and the aqueous solution (GL) are combined, and the combined liquid (IL) is phase-separated into an organic phase and an aqueous phase, and during the flow downstream, the metal hydroxide becomes the above acting on the compound represented by the general formula (1a),
Next, the combined liquid (IL) and the organic solution (FL) are combined, and the metal hydroxide is generated while the combined liquid (JL) is flowing downstream in a state where the organic phase and the aqueous phase are phase-separated. Acting on the compound represented by the general formula (1a) above,
Next, the combined liquid (JL) and the aqueous solution (HL) are combined, and the combined liquid (KL) is separated into an organic phase and an aqueous phase while flowing downstream. A method for producing an acid anhydride compound, comprising reacting a compound represented by formula (1a) to obtain an acid anhydride compound represented by general formula (1b) in an organic phase.
This method for producing an acid anhydride compound preferably includes a step of combining the combined liquid (KL) and the reaction stop liquid to stop the reaction for producing the acid anhydride compound represented by the general formula (1b). .
It is also preferable to include a step of purifying the acid anhydride compound represented by the general formula (1b) generated in the organic phase by a liquid separation operation.

Moreover, the present invention provides the following flow reaction system with respect to the embodiment shown in FIG.

a first channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second channel for introducing an aqueous solution containing the metal hydroxide and the onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence;
a sixth channel for introducing an aqueous solution containing an amine compound;
a third junction where the fifth flow path and the sixth flow path join;
a seventh flow path connected downstream of the third confluence,
The acid anhydride represented by the above general formula (1b), wherein the combined liquids flowing through the third channel, the fifth channel, and the seventh channel are in a state where the organic phase and the aqueous phase are separated. A flow-type reaction system that manufactures chemical compounds.
This flow-type reaction system includes an eighth channel for introducing an aqueous solution containing the reaction stop liquid, a fourth junction where the seventh channel and the eighth channel join, and downstream of the fourth junction. It is also preferred to have a connected ninth channel.

In each embodiment described above, it is preferable to use a two-layer cylindrical mixer in at least one of the confluences in the flow reaction. In particular, it is preferable to use a two-layer cylindrical mixer for at least one of the merging portions other than the merging portion for merging the reaction stop liquid.

According to the production method of the present invention, decomposition of the target compound, the acid anhydride compound represented by the general formula (1b), can be effectively suppressed. The acid anhydride compound represented by the general formula (1b) can be obtained with high purity only by carrying out the liquid operation. For example, the acid anhydride compound represented by the general formula (1b) can be obtained with a high purity of 50% by mass or more, preferably 60% by mass or more, more preferably 70% by mass or more, and still more preferably 80% by mass. It can be obtained with a purity of 85% by mass or more, more preferably 85% by mass or more.

Although the present invention has been described in conjunction with its preferred embodiments, the present invention is in no way limited to the above embodiments, except as specified in the present invention.

The present invention will be described in more detail based on examples, but the present invention is not limited by these examples.

[Example 1]
Diethyl dicarbonate, which is an acid anhydride compound, was synthesized using the flow reaction system 100 configured as shown in FIG. Specific reaction conditions are as follows.

<Liquid sending pump (not shown)>
All PU716B and PU718 manufactured by GL Science Co., Ltd. were used, and a pulse damper HPD-1, a back pressure valve (44-2361-24) manufactured by Tescom, and a relief valve RHA (4 MPa) manufactured by IBS Co., Ltd. were sequentially installed on the flow outlet side. .

<Temperature control>
All of the channels (I) to (V) and the junctions M1 and M2 were immersed in water set at 5°C.

<Flow path (I) to (V)>
In both cases, a SUS316 tube with an outer diameter of 1/16 inch and an inner diameter of 1.0 mm was used. The length of each channel was as follows.
Flow path (I): 0.5m
Flow path (II): 0.5m
Flow path (III): 0.5m
Channel (IV): 1.0m
Flow path (V): 0.5m
The reaction time of the two-phase reaction (circulation time in channel (IV)) was 9 seconds.

<Joining section (M1)>
As the concentric cylindrical two-layer cylindrical mixer (M1) shown in FIGS. 3 and 4, Union Tee (SS-400-3) manufactured by Swagelok Co., Ltd. was used. Channel (I) was connected to opening (MA) and channel (II) was connected to opening (MB). The mixer channel uses a SUS316 straight pipe with an outer diameter of 1/4 inch, an inner diameter of 4.35 mm, and a length of 50 mm for the outer pipe T2, and an SUS316 straight pipe with an outer diameter of 1/8 inch and an inner diameter of 2.17 mm for the inner pipe T1. It was used. The end of the inner tube (J) through which the liquid is discharged was set at a position 80 mm from the end of the outer tube.

<Confluence section (M2) (T-shaped mixer)>
As a T-shaped mixer (M2), a SUST type mixer manufactured by IDEX with an inner diameter of 0.5 mm was used.

<Organic solution obtained by dissolving the compound represented by the general formula (1a)>
200 mL of an organic solution was obtained by dissolving 108.52 g of ethyl chloroformate as a compound represented by the general formula (1a) in dehydrated acetone (concentration of ethyl chloroformate: 54.26% by mass (the density of the organic solution was 1 g/ Calculated as mL, same below)).

<Aqueous solution obtained by dissolving an amine compound, a metal hydroxide and an onium salt compound>
2.00 g of pyridine as an amine compound, 20.22 g of sodium hydroxide as a metal hydroxide, and 19.78 g of benzyloctyldimethylammonium chloride as an onium salt compound (trade name: QBA-811, 50% by mass aqueous solution, manufactured by Takemoto Yushi Co., Ltd.) was dissolved in ion-exchanged water to obtain 200 mL of an aqueous solution (pyridine concentration: 1% by mass, sodium hydroxide concentration: 10.11% by mass, benzyloctyldimethylammonium chloride concentration: 4.95% by mass).

<Reaction stop solution>
250 mL of an aqueous solution obtained by dissolving 10.20 g of potassium hydrogen sulfate in ion-exchanged water was obtained (potassium hydrogen sulfate concentration: 4.1% by mass).

<Liquid sending conditions>
Organic solution obtained by dissolving the compound represented by general formula (1a): 1.0 mL/min
Aqueous solution obtained by dissolving amine compound, metal hydroxide and onium salt compound: 1.0 mL/min
Reaction stop solution: 1.0 mL/min
The linear velocity ratio of the organic solution (inner tube) and aqueous solution (outer tube) in the two-layer cylindrical mixer (M1) is [linear velocity of organic solution]/[linear velocity of aqueous solution]=3/1.

<Purity of reaction product (acid anhydride compound)>
The reaction liquid was sampled from the outlet (most downstream, before SE) of the flow path (V), liquid separation operation (SE) was performed using ethyl acetate, and the organic phase (O) was extracted. Further, this organic phase (O) was subjected to liquid separation washing using a 0.3 mol/L potassium hydrogensulfate aqueous solution. Thereafter, the organic solvent in the organic phase was distilled off using a rotary evaporator, and the purity of the obtained diethyl dicarbonate was analyzed by gas chromatography under the following conditions to measure the purity (% by mass). The results are shown in the table below. In the table below, ">97" means a purity greater than 97% by mass, and "<10" means a purity less than 10% by mass.
-Analysis conditions-
Measuring instrument: GC-2010 (manufactured by Shimadzu Corporation)
Column: DB-624 (30 m × 0.25 mm × 1.4 μm) manufactured by Agilent)
Column temperature: 65→200°C
Vaporization chamber temperature: 95°C
Detector temperature: 250°C
Carrier gas: Nitrogen Injection volume: 1 μL
The results are shown in the table below.

Assessment of flow path blockage:
A pressure gauge is installed in the middle of the flow path between the tertiary amine solution inlet (iB) and the confluence (M1) (that is, in the flow path (II)) to ensure that the liquid supply is stable and the reaction is in a steady state. Evaluation "A" when the pressure after 1 hour has elapsed is less than 0.05 MPa, evaluation "B" when 0.05 MPa or more and less than 0.1 MPa, evaluation "C" when 0.1 MPa or more did. The results are shown in the table below.

[Examples 2 to 19 and 22 to 24, Comparative Examples 1 to 5]
Reaction system (flow reaction system shown in FIG. 2, FIG. 5, FIG. 6 or FIG. 7, or batch reaction system), onium salt compound (PTC1 to 11 above and PTC101 below), metal hydroxide, amine compound (above amines 1 to 3, 5 to 9) and the solvent were as shown in the table below, the synthesis reaction was carried out in the same manner as in Example 1. Details are given below.

In any flow reaction system, the concentration of each component in the introduced organic solution and aqueous solution was the same as in Example 1. For example, in the flow-type reaction system shown in FIG. 6, the concentration of the aqueous amine solution flowing through the channel (II-2) was set to 1% by mass, the same as the aqueous solution flowing through the channel (II) in Example 1. . Further, for example, in the flow-type reaction system shown in FIG. It was made 54.26% by mass, the same as the organic solution circulating in the path (I).

In Example 19, since tetrahydrofuran and water are in a compatible state, the reaction is not a two-phase reaction but a one-phase reaction.
In Example 23 the medium was all acetone (acetone was used instead of water), and in Example 24 the medium was all methylene chloride (only methylene chloride was used without water). Thus, Examples 23 and 24 are not two-phase reactions, but one-phase reactions with organic solutions only.

In Comparative Examples 2 and 3, a batch type reaction was performed instead of a flow type reaction. This batch-type reaction consists of an organic solution (the concentration is the same as in Example 1) in which ethyl chloroformate is dissolved, and an aqueous solution (the concentration is the same as in Example 1) in which an amine compound, a metal hydroxide, and an onium salt compound are dissolved. 1) is a two-phase reaction. 20 mL of the above aqueous solution was put into a 200 mL eggplant-shaped flask and stirred at 5° C. at a stirring speed of 300 rpm using a magnetic stirrer. Next, 10 mL of the above organic solution was added and stirred for 10 minutes in a two-phase state. After that, 60 mL of a reaction stopping solution was added to terminate the reaction.
In Comparative Example 4, tetrahydrofuran was used as the medium of the organic solution, and in Comparative Example 5, acetone was used instead of water. . Comparative Examples 4 and 5 are both one-phase reactions.

In the flow reaction system (200) of FIG. 5, a SUST type mixer manufactured by IDEX with an inner diameter of 0.5 mm was used in the confluence (M1). In the flow reaction system (200) of FIG. 5, the reaction time of the two-phase reaction (circulation time in channel (IV)) is 9 seconds.

In the flow reaction system (300) shown in FIG. 6, the flow paths (II-1), (IV-1), (II-2) and (IV-2) are A 1.0 mm SUS316 tube was used with a channel length of 0.5 m. Other flow paths are the same as those of the flow reaction system (200) of FIG. 5 (for example, Example 4). In addition, in the flow-type reaction system (300) shown in FIG. 6, a SUST type mixer manufactured by IDEX and having an inner diameter of 0.5 mm was used in each confluence section. In the flow-type reaction system (300) of FIG. 6, the reaction time of the two-phase reaction (circulation time in channel (IV-2)) is 9 seconds.

In the flow reaction system (400) shown in FIG. 7, the flow paths (I-1), (I-2), (IV-1a) and (IV-1b) are A 1.0 mm SUS316 tube was used with a channel length of 0.5 m. Other flow paths are the same as those of the flow reaction system (300) of FIG. 6 (for example, Example 5). In addition, in the flow-type reaction system (400) shown in FIG. 7, a SUST type mixer manufactured by IDEX and having an inner diameter of 0.5 mm was used in each confluence section. In the flow reaction system (400) of FIG. 7, the reaction time of the two-phase reaction (flow time in channel (IV-2)) is 9 seconds.

[Example 20]
In Example 1, as the organic solution obtained by dissolving the compound represented by the general formula (1a), 68.29% by mass of t-butyl chloroformate was used instead of the 54.26% by mass organic solution of ethyl chloroformate. Di-t-butyl dicarbonate was obtained in the organic phase in the same manner as in Example 1, except that an organic solution was used.

[Example 21]
In Example 1, as the organic solution obtained by dissolving the compound represented by the general formula (1a), 46.26 wt. Propionic anhydride was obtained in the organic phase in the same manner as in Example 1, except that a wt % organic solution was used.

As shown in the table above, when the onium salt compound did not have the structure specified in the present invention, the intended acid anhydride compound was inferior in purity (Comparative Example 1).
Further, when a batch type reaction was performed instead of the flow type reaction, even if the reaction time was controlled to some extent in a two-phase reaction system, the acid anhydride compound obtained was a low-purity product (Comparative Examples 2 to 5).
In contrast, when the method for producing an acid anhydride compound of the present invention was applied, it was found that a highly pure acid anhydride compound was obtained in the organic phase (Examples 1 to 24). In the case of a one-phase reaction using only an organic solution without using an aqueous solution, blockages tended to occur due to precipitation of metal hydroxides or reaction intermediates. It can be seen that the compound is obtained.

100, 200, 300, 400 Flow type reaction system iA, iA-1, iA-2 Organic solution inlet iB, iB-1, iB-2 Aqueous solution inlet iC Reaction stop liquid inlet I Stream equipped with inlet iA Channel I-1 Channel with inlet iA-1 I-2 Channel with inlet iA-2
II Flow path with inlet iB
II-1 Flow path with inlet iB-1
II-2 Flow path with inlet iB-2
III Channel with inlet iC
IV, IV-1, IV-2, IV-1a, IV-1b Channel through which liquid in two-phase state flows V Channel through which liquid in two-phase state flows (stop reaction channel)
M1, M1-1, M1-1a, M1-1b, M1-2, M2 Merging part SE Liquid separation operation W Aqueous phase (aqueous solution, waste liquid)
O organic phase (acid anhydride compound-containing solution)

Claims (15)

An acid anhydride compound represented by the following general formula (1b) by reacting a compound represented by the following general formula (1a), an amine compound and a metal hydroxide in the presence of an onium salt compound by a flow reaction. including obtaining
A method for producing an acid anhydride compound, wherein an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms is used as the onium salt compound.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom. 2. The method for producing an acid anhydride compound according to claim 1, wherein a mixed solvent of an organic solvent and water is used as a reaction solvent in the flow reaction. Using an organic solvent and water as a reaction solvent in the flow reaction, the acid anhydride represented by the general formula (1b) is reacted by a flow reaction in a state where the organic phase and the aqueous phase are phase-separated. 2. A method for producing an acid anhydride compound according to claim 1, wherein the compound is obtained in an organic phase. An organic solution containing the compound represented by the general formula (1a) and an aqueous solution containing the amine compound, the metal hydroxide, and the onium salt compound are introduced into different flow paths, respectively. circulating the solution in each channel,
The organic solution and the aqueous solution are merged, and the amine compound and the metal hydroxide are combined with the above general formula (1a 4. The method for producing an acid anhydride compound according to claim 3, comprising acting on a compound represented by ). An organic solution containing the compound represented by the general formula (1a), an aqueous solution (AL) containing the metal hydroxide and the onium salt compound, and an aqueous solution (BL) containing the amine compound are introduced into different channels, and each solution is circulated in each channel,
The organic solution and the aqueous solution (AL) are combined, and the combined liquid (CL) is phase-separated into an organic phase and an aqueous phase while flowing downstream, and the metal hydroxide is added by the general formula ( acting on the compound represented by 1a),
Next, the combined liquid (CL) and the aqueous solution (BL) are combined, and the combined liquid (DL) is phase-separated into an organic phase and an aqueous phase while flowing downstream. 4. The method for producing an acid anhydride compound according to claim 3, comprising acting on the compound represented by formula (1a). An organic solution (EL) containing the compound represented by the general formula (1a), an organic solution (FL) containing the compound represented by the general formula (1a), and the metal hydroxide An aqueous solution (GL) containing the onium salt compound and an aqueous solution (HL) containing the amine compound are introduced into different channels, respectively, and each solution is circulated in each channel,
When the organic solution (EL) and the aqueous solution (GL) are combined, and the combined solution (IL) is distributed downstream in a state where the organic phase and the aqueous phase are phase-separated, the metal hydroxide is acting on the compound represented by the general formula (1a),
Next, the combined liquid (IL) and the organic solution (FL) are combined, and the combined liquid (JL) is separated into an organic phase and an aqueous phase while flowing downstream, and the metal hydroxide is Acting on the compound represented by the general formula (1a),
Next, the combined liquid (JL) and the aqueous solution (HL) are combined, and the combined liquid (KL) is separated into an organic phase and an aqueous phase while flowing downstream. 4. The method for producing an acid anhydride compound according to claim 3, comprising acting on the compound represented by formula (1a). The method for producing an acid anhydride compound according to any one of claims 4 to 6, wherein a two-layer cylindrical mixer is used in at least one of the confluences in the flow reaction. The method for producing an acid anhydride compound according to any one of claims 1 to 7, wherein a compound represented by the following general formula (2) is used as the onium salt compound.

In the formula, Z represents a nitrogen atom or a phosphorus atom. Y represents a counterion. R ¹ to R ⁴ represent an alkyl group or an aromatic group. However, at least one of R ¹ to R ⁴ has at least one of an aromatic group and an alkyl group having 6 or more carbon atoms. 9. The method for producing an acid anhydride compound according to claim 8, wherein the compound represented by formula (2) is a quaternary ammonium salt. The method for producing an acid anhydride compound according to any one of claims 1 to 9, wherein a heterocyclic compound containing a nitrogen atom as a ring-constituting atom is used as the amine compound. 11. The method for producing an acid anhydride compound according to claim 10, wherein said heterocyclic compound comprises a pyridine compound. 12. The method for producing an acid anhydride compound according to any one of claims 1 to 11, wherein a reaction stopping solution is added to terminate the reaction. a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing an amine compound, a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first confluence,
The combined liquid flowing through the third channel is in a phase-separated state of the organic phase and the aqueous phase,
An acid anhydride for producing an acid anhydride compound represented by the following general formula (1b), wherein an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms is used as the onium salt compound. A flow-type reaction system for manufacturing compounds.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom. a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an aqueous solution containing an amine compound;
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence,
Each combined liquid flowing through the third channel and the fifth channel is in a state where the organic phase and the aqueous phase are phase-separated,
Flow-type reaction for producing an acid anhydride compound represented by the following general formula (1b), wherein an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms is used as the onium salt compound. system.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom. a first channel for introducing an organic solution containing a compound represented by the following general formula (1a);
a second channel for introducing an aqueous solution containing a metal hydroxide and an onium salt compound;
a first junction where the first flow path and the second flow path join;
a third flow path connected downstream of the first junction;
a fourth channel for introducing an organic solution containing the compound represented by the general formula (1a);
a second junction where the third flow path and the fourth flow path join;
a fifth flow path connected downstream of the second confluence;
a sixth channel for introducing an aqueous solution containing an amine compound;
a third junction where the fifth flow path and the sixth flow path join;
a seventh flow path connected downstream of the third confluence,
The combined liquids flowing through the third channel, the fifth channel, and the seventh channel are in a phase-separated state of an organic phase and an aqueous phase,
Flow-type reaction for producing an acid anhydride compound represented by the following general formula (1b), wherein an onium salt compound having at least one of an aromatic group and an alkyl group having 6 or more carbon atoms is used as the onium salt compound. system.

In the formula, R represents an alkyl group, an aliphatic cyclic hydrocarbon group, an aryl group, a heterocyclic group, an alkenyl group, a halogen atom or a hydrogen atom. L represents a _single bond, O, S, ^NRA or ^CRB2 , ^RA represents an alkyl group, an aryl group or a hydrogen atom, and ^RB represents an alkyl group, an aryl group, a halogen atom or a hydrogen atom. Hal represents a halogen atom.

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