JP2005255577A - Method of continuous production using tubular reactor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial method for producing a compound expressed by general formula (1). <P>SOLUTION: The method for producing the compound expressed by general formula (1) is to severely control reaction temperature by using a tubular reactor and react a compound expressed by general formula (2) with a compound expressed by general formula (3) in the same molar equivalent. The method for producing a compound expressed by general formula (4) is to hydrolyze the compound expressed by general formula (1). The hydrolysis is continuously carried out by using the tubular reactor. In the formulae, R and R<SB>1</SB>express each H, an alkyl or the like; R<SB>2</SB>expresses H or F; Y expresses a protection group of a carboxylic acid; X<SB>1</SB>and X<SB>2</SB>express each a halogen atom. <P>COPYRIGHT: (C)2005,JPO&amp;NCIPI

Description

  The present invention relates to a novel production method using a tubular reactor for a compound represented by the general formula (1). Furthermore, this invention relates to the method of manufacturing continuously to the compound represented by General formula (4) represented by flurbiprofen, ibuprofen, etc. which are useful as an active ingredient of a pharmaceutical.

  General formula (4)

［式中、Ｒは、水素原子、Ｃ1〜Ｃ4アルキル基またはアラルキル基、Ｒ¹は、水素原子、Ｃ1〜Ｃ6アルキル基、アリール基、アラルキル基、フッ素化アリール基またはアリールオキシ基、Ｒ²は、水素原子またはフッ素原子である］
で表される化合物は、人間や動物に対して消炎、鎮痛、解熱等の薬効を示す。中でもＲがメチル基、Ｒ¹がイソブチル基、Ｒ²が水素原子である化合物（イブプロフェン）、Ｒがメチル基、Ｒ¹がフェニル基、Ｒ²がＲ¹に対してオルト位に位置するフッ素原子である化合物（フルルビプロフェン）及びこれらの塩は、特に優れた消炎、鎮痛、解熱の薬理効果を示すことが知られている。

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is A hydrogen atom or a fluorine atom]
The compounds represented by the formula show medicinal effects such as anti-inflammatory, analgesic and antipyretic effects on humans and animals. Among them, a compound in which R is a methyl group, R ¹ is an isobutyl group and R ² is a hydrogen atom (ibuprofen), R is a methyl group, R ¹ is a phenyl group, and R ² is in a position ortho to R ¹ It is known that the compound (flurbiprofen) and salts thereof exhibit particularly excellent anti-inflammatory, analgesic and antipyretic pharmacological effects.

  Examples of conventionally known methods for producing these compounds or salts thereof include, for example, Patent Documents 1 to 10. Each of these production methods is a skillful combination of well-known chemical reactions, but is generally not satisfactory because of the long process and low yield. In addition, the production methods described in Patent Documents 11 and 12 have a short production process and a high yield, but each uses a very expensive raw material that is not industrially common, such as manganese iodide or hexamethylphosphoric triamide. Therefore, it is not suitable as an industrial manufacturing method. Furthermore, in patent documents 13 and 14, since expensive catalysts, such as platinum, are used, there exists a subject that recovery operation of a catalyst takes time. And although the manufacturing method described in patent document 15 is a method with a short process and advantageous, it still leaves the subject of a low yield.

JP-A-56-97247 Japanese Examined Patent Publication No. 2-37335 JP-A-2-223542 Japanese Unexamined Patent Publication No. 57-9757 Japanese Examined Patent Publication No. 62-24419 JP-A-55-157523 JP-A-55-157530 JP 54-9249 A JP 60-243040 A Japanese Examined Patent Publication No. 62-20175 JP 60-11439 A Japanese Patent Publication No. 3-19216 JP 51-127042 A JP 56-95147 A JP 58-35145 A

  The present invention provides a compound useful as an active ingredient of a pharmaceutical represented by the general formula (4) and a novel industrial production method of the compound represented by the general formula (1) which is a useful intermediate thereof. This is the issue.

  As a result of intensive studies to solve the above problems, the inventors of the present invention have produced a tubular reactor in the production method of the compound represented by the general formula (1) as compared with a conventionally known production method. The yield is greatly improved by using the reaction temperature strictly and / or reacting the compounds represented by the general formulas (2) and (3) with the same molar equivalent. The headline has led to the present invention. Further, the inventors have found that the yield is further improved by adding a catalyst ligand and / or a reducing agent, etc., and have led to the present invention. Furthermore, as a method for producing the compound represented by the general formula (4), the step of hydrolyzing the compound represented by the general formula (1) to obtain the compound represented by the general formula (4) is also a tubular reaction. It has been found that a continuous and high performance can be obtained by using a vessel, and the present invention has been made.

That is, the present invention
(1) General formula (1)

［式中、Ｒは、水素原子、Ｃ1〜Ｃ4アルキル基またはアラルキル基、Ｒ¹は、水素原子、Ｃ1〜Ｃ6アルキル基、アリール基、アラルキル基、フッ素化アリール基またはアリールオキシ基、Ｒ²は、水素原子またはフッ素原子であり、Ｙは、カルボン酸の保護基］
で表される化合物の製造方法であって、

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is A hydrogen atom or a fluorine atom, and Y is a protecting group for carboxylic acid]
A process for producing a compound represented by

Process 1: General formula (2)

［式中、Ｘ¹は、ハロゲン原子であり、Ｒ¹、Ｒ²は、前記と同じ意味を示す］
で表される化合物を溶解した第一の溶液と、一般式（３）

[Wherein, X ¹ is a halogen atom, and R ¹ and R ² have the same meaning as described above]
A first solution in which a compound represented by formula (3) is dissolved;

［式中、Ｘ²は、ハロゲン原子であり、Ｒ、Ｙは、前記と同じ意味を示す］
で表される化合物にニッケル、ニッケル化合物、パラジウム及びパラジウム化合物の中から選ばれる1種以上からなる触媒を添加した第ニの混合液を、それぞれ別の容器に準備する工程。

[Wherein X ² is a halogen atom, and R and Y have the same meaning as described above]
Preparing a second mixed solution obtained by adding a catalyst composed of one or more selected from nickel, nickel compounds, palladium and palladium compounds to separate compounds.

Step 2: A step of reacting at a constant temperature while mixing and flowing the first solution and the second mixed solution into the tubular reactor.
A process for producing a compound represented by the general formula (1), characterized by comprising:
(2) General formula (1)

［式中、Ｒは、水素原子、Ｃ1〜Ｃ4アルキル基またはアラルキル基、Ｒ¹は、水素原子、Ｃ1〜Ｃ6アルキル基、アリール基、アラルキル基、フッ素化アリール基またはアリールオキシ基、Ｒ²は、水素原子またはフッ素原子であり、Ｙは、カルボン酸の保護基］
で表される化合物の製造方法であって、
工程１：一般式（２）

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is A hydrogen atom or a fluorine atom, and Y is a protecting group for carboxylic acid]
A process for producing a compound represented by
Process 1: General formula (2)

［式中、Ｘ¹は、ハロゲン原子であり、Ｒ¹、Ｒ²は、前記と同じ意味を示す］
で表される化合物を溶解した第一の溶液と、一般式（３）

[Wherein, X ¹ is a halogen atom, and R ¹ and R ² have the same meaning as described above]
A first solution in which a compound represented by formula (3) is dissolved;

［式中、Ｘ²は、ハロゲン原子であり、Ｒ、Ｙは、前記と同じ意味を示す］
で表される化合物にニッケル、ニッケル化合物、パラジウム及びパラジウム化合物の中から選ばれる1種以上からなる触媒、更に、還元剤又は錯体形成量を超える量の触媒配位子を添加した第二の混合液を、それぞれ別の容器に準備する工程。
工程２：第一の溶液と第二の混合液を管型反応器内に混合流通させながら反応させる工程。
からなることを特長とする一般式（１）で表される化合物の製造方法；
（３） 前記（１）又は（２）に記載の一般式（１）で表される化合物を製造する工程を第一工程、
一般式（１）で表される化合物を加水分解して得られる一般式（４）

[Wherein X ² is a halogen atom, and R and Y have the same meaning as described above]
A second mixture in which a catalyst comprising at least one selected from nickel, nickel compounds, palladium and palladium compounds, and a catalyst ligand in an amount exceeding the amount of reducing agent or complex formation are added to the compound represented by The step of preparing the liquid in separate containers.
Step 2: A step of reacting the first solution and the second mixed liquid while mixing and flowing in the tubular reactor.
A process for producing a compound represented by the general formula (1), characterized by comprising:
(3) A step of producing a compound represented by the general formula (1) described in (1) or (2) is a first step,
General formula (4) obtained by hydrolyzing the compound represented by general formula (1)

［式中、Ｒは、水素原子、Ｃ1〜Ｃ4アルキル基またはアラルキル基、Ｒ¹は、水素原子、Ｃ1〜Ｃ6アルキル基、アリール基、アラルキル基、フッ素化アリール基またはアリールオキシ基、Ｒ²は、水素原子またはフッ素原子］
で表される化合物を製造する工程を第二工程とし、第一工程と第二工程を連続的におこなうことを特長する一般式（４）で表される化合物の製造方法；

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is , Hydrogen atom or fluorine atom]
A process for producing a compound represented by formula (2), wherein the first process and the second process are carried out continuously;

(4) In the above (1) or (2), the temperature of the first solution and the second mixed solution is adjusted to −20 ° C. or higher and lower than 0 ° C., and the reaction tube temperature is set to −20 ° C. or higher and lower than 0 ° C. A method for producing a compound represented by the general formula (1), characterized in that the temperature is controlled within ± 5 ° C. at a certain temperature;
(5) In the above (4), the tube volume and the flow rate of both liquids are adjusted so that the reaction tube volume and the flow rate of both liquids can pass through the tube for 7 minutes or more and 25 minutes or less from the time when both liquids are mixed. The manufacturing method of the compound represented by General formula (1) characterized by these.

(6) In the method (5), a method for producing a compound represented by the general formula (1), wherein a plug flow type reaction tube having a tube length / diameter of 2 or more is used;
(7) Obtained at a constant rate in the step of producing the compound represented by the general formula (1) according to any one of (1), (2), (4), (5) or (6). A solution of the compound (1)
(A) A step of continuously supplying liquid to a thin film distiller and performing solvent distillation until the solvent remaining in the thin film distiller reaches a certain concentration:
(B) A step of continuously extracting and washing with an aqueous ammonium chloride solution:
(C) A step of continuously hydrolyzing the compound represented by the general formula (1) by passing the solution into a reaction tube under basic conditions:
A continuous process for producing a compound represented by the general formula (4), characterized by combining the steps comprising:
(8) In the mixing flow of the first solution and the second mixed solution in the tubular reactor, the product of the molar concentration of the first solution and the flow rate of the first solution and the mole of the second mixed solution The method for producing a compound according to any one of (1) to (7) above, wherein the product of the concentration and the flow rate of the second liquid mixture is equal;

(9) The method for producing a compound according to the above (8), wherein the first solution and the second mixed solution having the same molar concentration are mixed at the same flow rate;
(10) In the compound represented by the general formula (1), R ¹ is a phenyl group, R ² is a fluorine atom, the substitution position of R ² is the ortho position of R ¹ , and R is a methyl group A method for producing the compound according to any one of (1) to (9) above;
About.

  The production method of the present invention can obtain the compound represented by the general formula (1) with high yield. Furthermore, the compound represented by the general formula (4) can be obtained simply and with high production capacity.

  First, general formula (1), which is an object of the production method of the present invention, will be described.

  In the present specification, unless otherwise specified, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkyl group include saturated hydrocarbon groups composed of linear, cyclic, branched, or combinations thereof. Accordingly, specific examples of the C1-C4 alkyl group include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, cyclopropyl group, n-butyl group, i-butyl group, and s-butyl. Group, t-butyl group, cyclobutyl group, or cyclopropylmethyl group. Specific examples of the C1 to C6 alkyl group include, for example, n-pentyl in addition to the specific examples of the C1 to C4 alkyl group. Group, cyclopentyl group, cyclobutylmethyl group, cyclopropylethyl group, n-hexyl group, cyclohexyl group, cyclopentylmethyl group, cyclobutylethyl group, cyclopropylpropyl group, etc., and specific examples of C1-C7 alkyl group Examples include, in addition to the specific examples of the C1-C6 alkyl group, for example, n-heptyl group, cycloheptyl group, cyclohexyl group. Rumechiru group, and cyclopentylethyl group.

  Examples of the aryl group include a monocyclic aromatic hydrocarbon group, a monocyclic aromatic heterocyclic group, a condensed aromatic hydrocarbon group, a condensed aromatic heterocyclic group, and the like, and a monocyclic aromatic hydrocarbon Group and a condensed aromatic hydrocarbon group are preferable, and a monocyclic aromatic hydrocarbon group is more preferable. The monocyclic aromatic hydrocarbon group is preferably a phenyl group, and the condensed aromatic hydrocarbon group is preferably a 1-naphthyl group, a 2-naphthyl group, a 2-anthryl group, or the like. The monocyclic aromatic heterocyclic group is preferably a 2- or 3-thienyl group, 2-, 3- or 4-pyridyl group, and the condensed aromatic heterocyclic group is 2-, 3-, 4 -, 5- or 8-quinolyl group, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group, 1-, 2-, 3-, 4-, 5-, 6- Or 7-indolyl group etc. are preferable.

  Examples of the fluorinated aryl group include aryl groups in which 1 to 3, preferably 1 to 2, more preferably 1 arbitrary hydrogen atom is substituted with a fluorine atom in the above aryl group. Specific examples include fluorinated monocyclic aromatic hydrocarbon groups, fluorinated monocyclic aromatic heterocyclic groups, fluorinated condensed aromatic hydrocarbon groups, fluorinated condensed aromatic heterocyclic groups, and the like. A fluorinated monocyclic aromatic hydrocarbon group and a fluorinated condensed aromatic hydrocarbon group are preferred, and a fluorinated monocyclic aromatic hydrocarbon group is more preferred. Preferable examples of the fluorinated aryl group include a 2-, 3- or 4-fluorophenyl group.

  Aryloxy groups include monocyclic aromatic hydrocarbon ether groups, monocyclic aromatic heterocyclic ether groups, fluorinated condensed aromatic hydrocarbon ether groups, fluorinated condensed aromatic heterocyclic ether groups, etc. A monocyclic aromatic hydrocarbon ether group and a condensed aromatic hydrocarbon ether group are preferred, and a monocyclic aromatic hydrocarbon ether group is more preferred. Preferable examples of the aryloxy group include a phenoxy group, a 2- or 3-thienyloxy group, a 2-, 3- or 4-pyridyloxy group, and the phenoxy group is particularly preferable.

  Examples of the aralkyl group include a hydrocarbon group in which one or more, preferably 1 to 3, more preferably 1 arbitrary hydrogen atom of a linear or branched saturated hydrocarbon group is substituted with an aromatic ring. Usually, a C7-19 aralkyl group is preferred. Specifically, a benzyl group, a phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group and the like are preferable, a benzyl group and a phenethyl group are more preferable, and a benzyl group is particularly preferable.

  R is a hydrogen atom, a C1-C4 alkyl group or an aralkyl group. R is preferably a hydrogen atom, a C1-C4 alkyl group, or a benzyl group, and more preferably a hydrogen atom, a methyl group, or a benzyl group. Further, a C1-C4 alkyl group and a benzyl group are more preferable, and a methyl group and a benzyl group are more preferable. Furthermore, a C1-C4 alkyl group is particularly preferable, and a methyl group is particularly preferable.

R ¹ is a hydrogen atom, a C ¹ -C 6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group or an aryloxy group. R ¹ includes a hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, phenyl group, benzyl group, 2-, 3- Or a 4-fluorophenyl group or a phenoxy group, a hydrogen atom, a methyl group, an ethyl group, an i-butyl group, an s-butyl group, a phenyl group or a benzyl group is more preferable, and an i-butyl group or a phenyl group is particularly preferable. .

R ² is a hydrogen atom or a fluorine atom. As R ² , a hydrogen atom is preferable, and a fluorine atom is also very preferable. The substitution position in the case of a fluorine atom includes an ortho position or a meta position with respect to R ¹ , but an ortho position and a meta position are preferable, and an ortho position is particularly preferable.

  Y is a protecting group for carboxylic acid. Any protecting group for carboxylic acid may be used as long as it is a known protecting group for carboxylic acid. For example, a C1 to C7 alkyl group, an aryl group or an aralkyl group is preferred. Y is preferably a methyl group, an ethyl group, a t-butyl group, a phenyl group or a benzyl group, more preferably a methyl group, an ethyl group, a t-butyl group or a benzyl group, a methyl group, an ethyl group or a t-butyl group. The group is particularly preferred.

In compound (1), preferred combinations of the substituents are not particularly limited.
(1) A compound wherein R is a hydrogen atom, a methyl group or a benzyl group;
(2) The compound in which R is a C1-C4 alkyl group (3) The compound in which R is a methyl group;
(4) R ¹ is a hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, phenyl group, benzyl group, 2-, A compound which is a 3- or 4-fluorophenyl group or a phenoxy group;
(5) A compound in which R ¹ is an i-butyl group or a phenyl group;
(6) The compound wherein R ¹ is a phenyl group;
(7) A compound in which Y is a methyl group, an ethyl group, a t-butyl group, a phenyl group, or a benzyl group;
(8) A compound in which Y is a methyl group, an ethyl group, or a t-butyl group;
(9) R is a hydrogen atom, a methyl group or a benzyl group, and R ¹ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, A compound in which t-butyl group, phenyl group, benzyl group, 2-, 3- or 4-fluorophenyl group or phenoxy group, and Y is methyl group, ethyl group, t-butyl group, phenyl group or benzyl group ;
(10) A compound in which R is a methyl group, R ¹ is an i-butyl group or a phenyl group, and Y is a methyl group, an ethyl group, or a t-butyl group;
(11) The compound wherein R is a methyl group and R ¹ is a phenyl group;
(12) The compound according to (11) above, wherein Y is a methyl group, an ethyl group, or a t-butyl group;
(13) The compound according to any one of (1) to (12), wherein R ² is a fluorine atom;
(14) The compound according to any one of (1) to (13) above, wherein R ² is substituted at the ortho position of R ¹ ; (15) R is a methyl group, and R ¹ is an i-butyl group. Compound;
(16) The compound according to (15) above, wherein Y is a methyl group, an ethyl group, or a t-butyl group;
(17) The compound according to the above (1) to (10), (15) or (16), wherein R ² is a hydrogen atom;
Is more preferable.

Next, general formula (2) and general formula (3), and each term will be described.
X ¹ is a halogen atom. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are preferable, a chlorine atom, a bromine atom and an iodine atom are more preferable, and a bromine atom and an iodine atom are particularly preferable.

X ² is a halogen atom. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are preferable, a chlorine atom, a bromine atom and an iodine atom are more preferable, and a bromine atom and an iodine atom are particularly preferable.

The catalyst comprising one or more selected from nickel, nickel compounds, palladium and palladium compounds is a simple metal catalyst such as nickel or palladium, or a compound such as an inorganic acid salt or an organic acid salt, or any of them. However, inorganic acid salts and organic acid salts such as nickel or palladium are preferable. A simple metal phosphine complex such as nickel or palladium is also preferable. As the inorganic acid salt, for example, a halide is preferable. As the halide, chloride, bromide, iodide and the like are preferable, and a phosphine complex of the halide is also preferable. For example, nickel chloride (NiCl ₂ ), nickel bromide (NiBr ₂ ), nickel iodide (NiI ₂ ), palladium chloride (PdCl ₂ ), or phosphine complexes thereof are preferable, of which nickel chloride (NiCl ₂ ), Nickel bromide (NiBr ₂ ), nickel iodide (NiI ₂ ), phosphine complexes thereof, phosphine complexes of simple metals such as nickel or palladium, or phosphine complexes of palladium chloride (PdCl ₂ ) are particularly preferred. Further, as the inorganic acid salt, for example, sulfate and nitrate are preferable, and as the organic acid salt, for example, carbonate, formate, acetate, acetylacetonate and the like are preferable. As the nickel compound and / or palladium compound, nickel chloride (NiCl ₂ ), nickel bromide (NiBr ₂ ), nickel iodide (NiI ₂ ), palladium chloride (PdCl ₂ ), or a phosphine complex thereof is preferable. More preferred are nickel (NiCl ₂ ), nickel bromide (NiBr ₂ ), nickel iodide (NiI ₂ ), phosphine complexes thereof, or phosphine complexes of palladium chloride (PdCl ₂ ). Specific examples of the catalyst comprising one or more selected from nickel, nickel compounds, palladium and palladium compounds include NiCl ₂ , NiBr ₂ , NiI ₂ , PdCl ₂ , NiCl ₂ [P (C ₆ H ₅ ) ₃ ]. ₂ , Ni [P (C ₆ H ₅ ) ₃ ] ₄ , NiCl ₂ [(C ₆ H ₅ ) ₂ PCH ₂ CH ₂ P (C ₆ H ₅ ) ₂ ], NiCl ₂ [(C ₆ H ₅ ) ₂ PFeP (C ₆ H ₅ ) ₂ ], NiCl ₂ [(C ₆ H ₅ ) ₂ PCH ₂ CH ₂ CH ₂ P (C ₆ H ₅ ) ₂ ], PdCl ₂ [(C ₆ H ₅ ) ₂ PFeP (C ₆ H ₅ ) ₂ ] and other catalysts selected from, for example, NiCl ₂ , NiBr ₂ , NiCl ₂ [P (C ₆ H ₅ ) ₃ ] ₂ , Ni [P (C ₆ H ₅ ) ₃ ] ₄ , NiCl ₂ [(C ₆ H ₅ ) ₂ PCH ₂ CH ₂ P (C ₆ H ₅ ) ₂ ], NiCl ₂ [(C ₆ H ₅ ) ₂ PFeP (C ₆ H ₅ ) ₂ ], NiCl ₂ [(C ₆ H ₅ ) ₂ PCH ₂ CH ₂ CH ₂ P (C ₆ H ₅ ) ₂ ], PdCl ₂ [(C ₆ H ₅ ) ₂ PFeP (C ₆ H ₅ ) ₂ ], etc. More preferred is a catalyst comprising NiCl ₂ [P (C ₆ H ₅ ) ₃ ] ₂ , Ni [P (C ₆ H ₅ ) ₃ ] ₄ , NiCl ₂ [(C ₆ H ₅ ) ₂ PCH ₂ CH ₂ P (C ₆ A catalyst comprising one or more selected from H ₅ ) ₂ ], etc. is particularly preferred, and NiCl ₂ [P (C ₆ H ₅ ) ₃ ] ₂ is most preferred. In addition, a catalyst in which these catalysts are supported on some kind of support such as carbon powder is also preferable.

  The catalyst ligand to be added in an amount exceeding the complex formation amount is preferably a phosphine series, for example, triphenylphosphine, 1,2-diphenylphosphinoethane (DPPE), 1,2-diphenylphosphinoferrocene (DPPF). Among them, triphenylphosphine is particularly preferable. Usually, when a halide such as nickel or palladium or a phosphine complex thereof is used as a catalyst comprising a nickel compound or a palladium compound, it is preferable to use a catalyst ligand of these phosphine complexes. The combination of the catalyst and the catalyst ligand is not limited in any way. In particular, when a phosphine complex of a halide such as nickel or palladium is used as the nickel compound and / or palladium compound, the phosphine complex. It is preferable to select a catalyst ligand of the same type as the above.

  As the reducing agent, for example, diisobutylaluminum hydride (DIBAL), lithium aluminum hydride (LAH) and the like are preferable, and DIBAL is more preferable.

  The Grignard reagent prepared from the halogenated benzene represented by the compound represented by the general formula (2) and metal magnesium in the present invention is reacted with the α-haloalkanecarboxylic acid ester represented by the compound represented by the general formula (3). The amount of nickel compound and / or palladium compound used sometimes is preferably 0.01 mol% to 10 mol%, more preferably 0.05 mol% to 0.5 mol%, based on the Grignard reagent. The amount of the α-haloalkanecarboxylic acid ester represented by the general formula (3) is preferably 0.8-fold mol to about 2-fold mol of the halogenated benzene represented by the general formula (2) used in preparing the Grignard reagent, 1.0-fold mole to 1.5-fold mole is more preferable.

  In the present invention, when a catalyst ligand is used, the amount used exceeds the amount necessary for the catalyst and the catalyst ligand to form a complex when the catalyst is other than a phosphine complex. It is preferred to add an amount of catalyst ligand. Specifically, when the catalyst is a single metal catalyst of nickel and / or palladium, the lower limit is preferably an amount exceeding 4 times mol, more preferably 4.5 times mol or more, and 5.5 times mol or more. Further preferred. At this time, the upper limit is preferably 9 times mol or less, and more preferably 6.5 times mol or less.

Further, when the catalyst is a divalent nickel and / or palladium compound and other than a phosphine complex, for example, NiCl ₂ , the lower limit of the amount of the catalyst ligand to be added is 2 times mole. Is more preferably 2.5 times mol or more, more preferably 3.5 times mol or more. At this time, the upper limit is preferably 7 times mole or less, and more preferably 4.5 times mole or less.

When the catalyst is a phosphine complex, for example, NiCl ₂ [P (C ₆ H ₅ ) ₃ ] ₂ , Ni [P (C ₆ H ₅ ) ₃ ] _4, etc. As a minimum of quantity, the quantity exceeding 0.1 times mole is preferred, 0.5 times mole or more is more preferred, and 1.5 times mole or more is still more preferred. At this time, the upper limit is preferably 5 times mol or less, and more preferably 2.5 times mol or less.

  As the solvent that can be used for the first solution and the solvent that can be used for the second mixed solution, any solvent can be used as long as it is an inert solvent, but an ether solvent is preferable, for example, tetrahydrofuran. , Tetrahydropyran, diethyl ether and the like are preferable. Moreover, you may use the mixed solvent of arbitrary ratios of these solvents. Furthermore, you may use the solvent which mixed hydrocarbon solvent etc. in these solvents in the appropriate ratio. Examples of the hydrocarbon solvent include saturated hydrocarbon solvents and aromatic hydrocarbon solvents. Examples of the saturated hydrocarbon solvent include a C5-C10 linear alkane solvent, a C5-C10 branched alkane solvent, or a carbon number that may have a linear and / or branched alkyl substituent. Specific examples include 6 to 10 cyclic alkane solvents, and specific examples include pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. It is done. Examples of the aromatic hydrocarbon solvent include benzene, toluene, xylene, ethylbenzene, and the like.

  As the concentration of the first solution and / or the second mixed solution, the product of the molar concentration of the first solution and the flow rate of the first solution and the second mixing in the relationship with the mixing flow rate described later. The product of the molar concentration of the liquid and the flow rate of the second liquid mixture may be made equal, but it is preferable to unify the concentration of the compound dissolved in the solvent at the same molar concentration. Specifically, the molar ratio of the first solution to the second mixed solution is (number of moles of the compound represented by the general formula (2) in the first solution) / (second mixed solution). The number of moles of the compound represented by the general formula (3) is preferably 0.5 to 2.0, more preferably 0.67 to 1.5, still more preferably 0.8 to 1.2, 0 .9 to 1.1 are very preferred and 1 is most preferred. The lower limit of the specific concentration is preferably 0.01M or more, more preferably 0.1M or more, further preferably 0.5M or more, and most preferably 1M or more. The upper limit of the specific concentration is preferably 10M or less, more preferably 5M or less, further preferably 2M or less, and most preferably 1M or less.

Next, a specific tubular reactor for carrying out the present invention will be described.
In FIG. 1, containers A and B for storing the first solution and the second mixed liquid are containers that can be temperature-controlled at −30 ° C. or higher and 80 ° C. or lower, and are usually pharmaceuticals and / or Any container may be used as long as it is used for the production of pharmaceutical intermediates. For example, a glass or stainless steel container that can be filled with nitrogen is preferable. As the temperature control capability, it is preferable that the temperature of the solution can be controlled within ± 5 ° C of the set temperature, more preferably within ± 3 ° C, particularly preferably within ± 2 ° C, and within ± 1 ° C. It is highly preferred that it can be controlled.

  As the liquid feeding pump, any liquid feeding system that accurately discharges the set flow rate and does not cause pulsation may be used. For example, a rotary pump may be mentioned. Examples of the tubular reactor that can be used in the present invention include a tubular reactor having a temperature control ability sufficient to control the heat of reaction described later. As a kind of reactor, although a plug flow type reaction tube etc. are mentioned as a suitable example, for example, it is not limited to this in particular.

  As the material of the tubular reactor, any reactor can be used as long as it is usually used for the production of pharmaceuticals and / or pharmaceutical intermediates. For example, a glass or stainless steel container that can be filled with nitrogen is preferable. Take as an example.

  The shape of the tubular reactor is preferably a shape having a tube length / tube diameter value of 2 or more.

  The reaction of the compound represented by the general formula (2) and the compound represented by the general formula (3) is strictly controlled by the reaction temperature. The reaction temperature accurately refers to the temperature of the reaction solution, but when a tubular reactor having a temperature control capability sufficient to control the heat of reaction is used, the temperature of each solution before mixing, that is, If the set temperature of the container for storing the first solution, the set temperature of the container for storing the second mixed solution, and the set temperature of the tubular reactor are the same, the set temperature of the tubular reactor is as close as possible. It becomes. In this reaction, the set temperature of the container for storing the first solution, the set temperature of the container for storing the second mixed solution, and the set temperature of the tubular reactor are the same, and the reaction temperature is around the set temperature. It is preferable to manage at a constant temperature.

  The temperature control ability sufficient to control the heat of reaction means that the heat of reaction generated when the first solution and the second liquid mixture are mixed and reacted in the tubular reactor can be sufficiently cooled, and is not satisfactory. The ability to not lower the temperature of the reaction solution below the set temperature as necessary. Specifically, the ability to control the temperature of the reaction solution within ± 5 ° C. of the set temperature is preferable, the ability to control within ± 3 ° C. is more preferable, the ability to control within ± 2 ° C. is more preferable, and ± 1 The ability to control within degrees Celsius is highly preferred.

  When auxiliary materials such as a catalyst ligand or a reducing agent are not added, the set temperature of the container storing the first solution, the set temperature of the container storing the second mixed solution, and the set temperature of the tubular reactor The lower limit is preferably −30 ° C. or higher, more preferably −20 ° C. or higher, further preferably −10 ° C. or higher, and the upper limit is preferably 25 ° C. or lower, and more preferably 0 ° C. or lower.

  On the other hand, when an auxiliary material such as a catalyst ligand or a reducing agent is added, the set temperature of the container storing the first solution, the set temperature of the container storing the second mixed solution, and the set temperature of the tubular reactor Is preferably −20 ° C. or higher, more preferably −10 ° C. or higher, further preferably 0 ° C. or higher, and the upper limit is preferably less than 80 ° C., more preferably 25 ° C. or lower, and even more preferably 0 ° C. or lower. .

Next, a mixing flow method in the reaction of the compound represented by the general formula (2) and the compound represented by the general formula (3) will be described. The speed at which the first solution and the second mixed liquid are mixed is defined as a mixing flow rate. As described above, the mixed flow rate is equal to the product of the molar concentration of the first solution and the flow rate of the first solution, and the product of the molar concentration of the second mixed solution and the flow rate of the second mixed solution. What should I do. As a preferred embodiment, the first solution and the second mixed solution having the same molar concentration are mixed at the same flow rate, and the compound represented by the general formula (2) and the compound represented by the general formula (3) are mixed. Are mixed at the same molar concentration. Specifically, the same flow rate is, as a ratio of the flow rate of the first solution and the second mixed solution, (flow rate of the first solution) / (flow rate of the second mixed solution), 0.5 to 2.0 is preferable, 0.67 to 1.5 is more preferable, 0.8 to 1.2 is more preferable, 0.9 to 1.1 is very preferable, and 1 is most preferable.
In addition, each flow rate when the first solution and the second mixed solution are flowed into the tubular reactor controls the heat of reaction described later depending on the reaction conditions such as the size of the reaction equipment and the reaction temperature. It may be determined so as to have sufficient temperature control capability. As an example, when the reaction tube volume is 15 ml (tube length L: 300 mm, diameter D: 8 mm (H / D = 37.5)) and the reaction set temperature is −10 ° C., the passage time in the tube is 7 min or more and 25 minutes or less. However, the present invention is not limited to this. However, the present invention is not limited to this.

Next, a method for continuously producing up to the compound represented by the general formula (4) using the reaction solution containing the compound represented by the general formula (1) eluted from FIG. .
In FIG. 2, the process of producing the compound represented by the general formula (4)
(A) Concentrated solvent recovery step in which the solvent is continuously fed to the thin film still and the solvent remaining in the thin film still is distilled to a certain concentration:
(B) Extraction / separation process for continuous extraction and washing with aqueous ammonium chloride solution:
(C) Hydrolysis reaction step of continuously hydrolyzing the compound represented by the general formula (1) by passing the solution into a reaction tube under basic conditions:
Consists of The order of performing the steps is not limited, but the order shown above is preferable from the viewpoint of solvent recovery and removal of by-products.

  In the concentrated solvent recovery step, a thin-film distiller having an ability to concentrate the reaction solution eluted from the tubular reactor shown in FIG. 1 to a specified concentration is preferable. The concentration temperature is preferably 40 to 80 ° C., more preferably 50 to 70 ° C. The specified concentration is a concentration that is suitably separated when mixed with ammonium chloride in the extraction / separation process described later, and may be anything as long as the viscosity is so high that it is difficult to handle.

  In the extraction / separation step, the mixing ratio between the aqueous ammonium chloride solution and the concentrated solution (ammonium chloride aqueous solution amount / concentrated liquid amount) is preferably 0.5 to 5, and more preferably 1 to 2. Although the mixing and extracting method is not particularly limited, for example, it is sufficient to mix the inside of the piping in a turbulent flow region. As the liquid separation standing time, it is preferable to leave it for 10 minutes or more.

In the hydrolysis reaction step, anything may be used as long as it is hydrolyzed with a basic solvent. As the basic solvent, for example, a sodium hydroxide solution is preferable. The concentration of sodium hydroxide is preferably 1M to 5M, and more preferably 2M. As for the usage-amount of sodium hydroxide, 1-10 are preferable, and, as for the mixing ratio (sodium hydroxide / extract) with an extract, More preferably, it is 3-6. The reaction temperature is preferably 20 to 200 ° C, more preferably 100 to 150 ° C. The material of the tubular reactor may be any container that is usually used for the production of pharmaceuticals and / or pharmaceutical intermediates, and preferred examples include stainless steel containers.
In the tubular reactor according to this reaction, the flow through the pipe is preferably a turbulent region, and more preferably a static mixer or the like.

Next, the manufacturing method of this invention is demonstrated.
The production method of the present invention has the general formula (2)

［式中、Ｒ¹は、水素原子、Ｃ1〜Ｃ6アルキル基、アリール基、アラルキル基、フッ素化アリール基またはアリールオキシ基、Ｒ²は水素原子またはフッ素原子、Ｘ¹はハロゲン原子である］
で表される化合物、即ちグリニャール試薬と、一般式（３）

[Wherein R ¹ is a hydrogen atom, a C ¹ -C 6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group or an aryloxy group, R ² is a hydrogen atom or a fluorine atom, and X ¹ is a halogen atom]
A compound represented by general formula (3): Grignard reagent

［式中、Ｒは、水素原子、Ｃ1〜Ｃ4アルキル基またはアラルキル基、Ｘ²はハロゲン原子であり、Ｙはカルボン酸の保護基である。］
で示されるα−ハロアルカンカルボン酸エステルを、ニッケル化合物又はパラジウム化合物に代表される触媒の存在下、特に、反応温度を−２０℃以上０℃未満のある一定温度において、温度管理幅を±５℃以内で温度管理に制御して反応させること、若しくは上記の混合物にさらにトリフェニルホスフィンに代表される金属配位子、または水素化ジイソブチルアルミニウムリチウムに代表される還元剤を加えて、管型反応器を反応容器として用いることを特徴として、反応熱を充分に制御しながら連続的に反応させることにより、一般式（１）で表される化合物を収率よく得る工程を特徴とする。

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, X ² is a halogen atom, Y is a protecting group of a carboxylic acid. ]
In the presence of a catalyst typified by a nickel compound or a palladium compound, the α-haloalkanecarboxylic acid ester represented by the formula is a temperature control range of ± 5 ° C., particularly at a certain temperature of −20 ° C. or more and less than 0 ° C. Within a tubular reactor by adding a metal ligand typified by triphenylphosphine or a reducing agent typified by diisobutylaluminum hydride to the above mixture. Is used as a reaction vessel, and is characterized in that the compound represented by the general formula (1) is obtained in a high yield by continuously reacting while sufficiently controlling the heat of reaction.

An embodiment of the method for producing the compound represented by the general formula (1) by the method of the present invention, that is, the compound represented by the general formula (2) and the compound represented by the general formula (3) is described below. Detailed description.
(Method 1)
As a first solution, a tetrahydrofuran solution (2M solution) of the compound represented by the general formula (2) is prepared in a separate container under an inert gas atmosphere such as nitrogen, and a temperature of −20 ° C. or more and 80 ° C. or less, Here, the temperature is controlled at −10 ° C.

  Separately, as a second mixed liquid, an ether solvent solution or suspension of tetrahydrofuran, etc., of a compound represented by the general formula (3) and a nickel compound or a palladium compound catalyst in an inert gas atmosphere such as nitrogen, The concentration of the compound of the general formula (3) is adjusted to 2M, and the temperature is controlled at a temperature of −20 ° C. or more and 80 ° C. or less, here, −10 ° C.

  A plug flow type reaction tube is selected as the tubular reactor, and the temperature of the cooling medium is previously controlled at a temperature between −20 ° C. and 80 ° C., in this case −10 ° C.

The first solution and the second mixed solution are reacted while being sent and mixed in a plug flow type reaction tube. The mixing speed is set so that the heat of reaction is within ± 5 ° C. Specifically, it is preferable to control the flow rate so that the reaction time, that is, the residence time in the reaction tube is 7 min to 25 min. Is controlled to be 7 minutes or more and 15 minutes or less.
(Method 2)
As a first solution, a tetrahydrofuran solution (2M solution) of the compound represented by the general formula (2) is prepared in a separate container under an inert gas atmosphere such as nitrogen, and a temperature of −20 ° C. or more and 80 ° C. or less, Here, the temperature is controlled at −10 ° C.

Separately, as the second mixed liquid, a catalyst ligand such as triphenylphosphine or hydrogen is added to an ether solvent solution or suspension of tetrahydrofuran or the like in which the compound represented by the general formula (3) and the nickel compound or palladium compound catalyst. A compound added with a reducing agent such as diisobutylaluminum fluoride is prepared as M as the concentration of the compound of general formula (3) under an inert gas atmosphere such as nitrogen, and a temperature of −20 ° C. to 80 ° C. Then, the temperature is controlled at −10 ° C.
A plug flow type reaction tube is selected as the tubular reactor, and the temperature of the cooling medium is previously controlled at a temperature between −20 ° C. and 80 ° C., in this case −10 ° C.
The first solution and the second mixed solution are reacted while being sent and mixed in a plug flow type reaction tube. The mixing speed is set so that the heat of reaction is within ± 5 ° C. Specifically, the flow rate is controlled so that the reaction time, that is, the residence time in the reaction tube is 7 min or more, but preferably 15 min or less. It is mentioned to control to become.

In the method 1 and method 2, when isolating the compound represented by the general formula (1), the reaction solution after the reaction is added to an aqueous ammonium chloride solution, and the compound represented by the general formula (1) After the organic layer containing the crude product is recovered, operations such as dehydration and concentration can be performed, and purification and acquisition can be performed by a process such as silica gel column chromatography, vacuum distillation or crystallization. However, the compound represented by the general formula (1) is represented by the general formula (4) having an analgesic anti-inflammatory action by performing a deprotection reaction of the protecting group of the carboxylic acid such as hydrolysis without isolation. It may be continually derived into a compound which is α-substituted phenyl-alkanecarboxylic acid. In that case, the reaction liquid containing the compound represented by the general formula (1) obtained in the method 1 or 2 is recovered by a concentration operation under normal pressure and reduced pressure. It is preferable to use it. Next, continuous extraction is performed with an aqueous ammonium chloride solution. The order of post-treatment is not particularly limited, but extraction after solvent recovery is preferable from the viewpoint of reuse of the recovered solvent. The extracted organic layer can be obtained by mixing and hydrolyzing with an aqueous sodium hydroxide solution in a tube using a tube reactor and efficiently obtaining the compound represented by the general formula (4).
In addition, it is preferable to use a racemate as a compound represented by General formula (3), and when using an optically active substance, the hydrolysis conditions for obtaining the compound represented by General formula (4) As acid conditions are preferred.

  In the compound represented by the general formula (1), the carbon atom substituted by the substituent R is an asymmetric carbon when R is other than a hydrogen atom. The configuration of this asymmetric carbon is not particularly limited and may be either S configuration or R configuration, and may be any mixture or racemate of an optically active pair in a pure form based on this asymmetric carbon. Although it is good, a racemic body is preferable as an object of the production method of the present invention.

  In addition, the compound represented by the general formula (1) may have one or more asymmetric carbons depending on the type of the substituent, but the configuration other than the specific asymmetric carbon is as follows. It is not specifically limited, Arbitrary three-dimensional configuration may be sufficient. A pure form of an optically active pair based on one or more asymmetric carbons or a stereoisomer such as a diastereoisomer, an arbitrary mixture of stereoisomers, a racemate and the like are all objects of the production method of the present invention. Are included in the general formula (1).

  The obtained compound represented by the general formula (1) is continuously subjected to post-treatment, that is, distillation of the solvent by thin-film distillation, followed by liquid-liquid extraction, followed by hydrolysis to give the general formula ( 4)

［式中、Ｒ、Ｒ¹及びＲ²は、前記と同じ意味を示す］
で表されるα−置換フェニル−アルカンカルボン酸にまで、連続的に変換し得る。

[Wherein R, R ¹ and R ² have the same meaning as described above]
Can be continuously converted to an α-substituted phenyl-alkanecarboxylic acid represented by:

  In practicing the present invention, the compound represented by the general formula (2) used as a starting material can be produced as follows. General formula (5)

［式中、Ｒ¹、Ｒ²及びＸ¹は、前記と同じ意味を示す］
で表されるハロゲン化ベンゼンと金属マグネシウムを、無水エーテル系溶媒中で窒素等不活性ガス雰囲気下にて反応させる、通常のグリニャール試薬を得る反応に準じて行えばよい。反応に用いる溶媒としては、エーテル系溶媒が好ましく、例えば、テトラヒドロフラン、テトラヒドロピラン、ジエチルエーテル等が好ましい例として挙げられる。

[Wherein R ¹ , R ² and X ¹ have the same meaning as described above]
The reaction may be carried out in accordance with the usual reaction for obtaining a Grignard reagent in which a halogenated benzene represented by the formula (I) is reacted with magnesium metal in an anhydrous ether solvent in an inert gas atmosphere such as nitrogen. The solvent used for the reaction is preferably an ether solvent, and preferred examples include tetrahydrofuran, tetrahydropyran, diethyl ether and the like.

  The compound represented by the general formula (5) can be obtained as a commercially available compound or can be obtained by a known method, for example, Patent Documents “DE 2241913”, “FR 2231393”, “DE 2426160”, or “Synth. 32, 2, 279-286 (2002) ”.

  In addition, the compound represented by the general formula (3) can be obtained as a commercially available compound, or can be obtained by a known method such as literatures “Helv. Chim. Acta, 66 (4), 1028-1030 (1983)”, “ J. Indian Chem. Soc., 10, 592, (1933) ”and“ Chem. Zentralbl., 105 (I), 2105 (1934) ”. In the compound represented by the general formula (3), the carbon atom substituted by the substituent R is an asymmetric carbon atom when R is other than a hydrogen atom. As the compound represented by the general formula (3), the steric configuration of this asymmetric carbon is not particularly limited, and may be either S configuration or R configuration, and a pure form of optical system based on this asymmetric carbon. Although any mixture or racemic mixture of active pairs may be used, it is usually preferable to use a racemate in the present invention.

Next, an Example is shown and this invention is demonstrated concretely.
[Device preparation]
As shown in Fig. 3, the container, piping, and reaction tube are fully dried and then replaced with dehydrated THF (Wako Pure Chemical Industries, Ltd.). Control the temperature to perform.

[Example 1] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester 4-bromo-2-fluorobiphenyl (4.37 g (0.18 mol) of metal magnesium piece and 90 ml of tetrahydrofuran in a nitrogen atmosphere Aldrich Chem. Co .; 45.2 g, 0.18 mol) dissolved in 90 ml of tetrahydrofuran was added dropwise at room temperature, stirred for 3 hours, adjusted to Grignard reagent, and filled into container A as the first solution. And cooled to −10 ° C. ± 1 ° C.

  On the other hand, 2-bromopropionic acid methyl ester (manufactured by Tokyo Chemical Industry Co., Ltd .; 31 g, 0.18 mol) was dissolved in 180 ml of tetrahydrofuran under a nitrogen atmosphere in a separate container in advance, and nickel (II) chloride / bis ( Triphenylphosphine) complex (Tokyo Chemical Industry Co., Ltd .; 1.17 g, 1.8 mmol) was added and filled into the container B in the apparatus, and filled into the container B as the second mixed solution at −10 ° C. ± 1 Cooled to ° C.

The temperature in the 15 ml reaction tube was controlled at −10 ° C. ± 2 ° C., and the pump flow rates of both solutions were added at 0.5 ml / min. The eluted reaction solution was added to an aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried, concentrated and purified by silica gel column chromatography to obtain 33.5 g of 2- (2-fluoro-4-biphenyl) propionic acid methyl ester (yield 72%). It was.
¹ H-NMR (CDCl ₃ , δ ppm)
7.1-7.6 (8H, m), 3.8 (1H, q, J = 7Hz), 3.7 (3H, s), 1.5 (3H, d, J = 7Hz)
[Example 2] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester The temperature in the reaction tube of Example 1 is controlled to -20 ° C ± 2 ° C, and the vessel A and the vessel B are filled. 2- (2-fluoro-4-biphenyl) propionic acid methyl ester in the same manner as in Example 1 except that the cooling temperature of the first solution and the second mixed solution was set to −20 ° C. ± 1 ° C. 28.8 g (62% yield) was obtained.

Example 3 Method for Producing 2- (2-Fluoro-4-biphenyl) propionic acid methyl ester The temperature in the reaction tube of Example 1 was controlled at 0 ° C. ± 2 ° C., and filled in containers A and B. 3- (2-Fluoro-4-biphenyl) propionic acid methyl ester 30.7 g in the same manner as in Example 1 except that the cooling temperature of the first solution and the second mixed solution was set to 0 ° C. ± 1 ° C. (Yield 66%) was obtained.

[Example 4] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester In the same manner as in Example 1 except that the amount of both liquids used in Example 1 was changed to 0.3 ml / min, 2- 30.7 g (yield 66%) of (2-fluoro-4-biphenyl) propionic acid methyl ester was obtained.

[Example 5] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester In the same manner as in Example 1, except that the amount of both liquids used in Example 1 was 1.0 ml / min, 2- 32.5 g (yield 70%) of (2-fluoro-4-biphenyl) propionic acid methyl ester was obtained.

[Example 6] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester 4-bromo-2-fluorobiphenyl (4.37 g (0.18 mol) of metal magnesium piece and 90 ml of tetrahydrofuran in a nitrogen atmosphere A solution prepared by dissolving Aldrich Chem. Co. (45.2 g, 0.18 mol) in 90 ml of tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred for 3 hours to adjust the Grignard reagent and charged into the container A in the apparatus.

  On the other hand, 2-bromopropionic acid methyl ester (manufactured by Tokyo Chemical Industry Co., Ltd .; 31 g, 0.18 mol) was dissolved in 180 ml of tetrahydrofuran under a nitrogen atmosphere in a separate container in advance, and nickel (II) chloride / bis ( Triphenylphosphine) complex (manufactured by Tokyo Chemical Industry Co., Ltd .; 1.17 g, 1.8 mmol) and triphenylphosphine (manufactured by Wako Pure Chemical Industries, Ltd .; 0.94 g, 3.6 mmol) are added and filled into the container B in the apparatus. Cooled to -10 ° C.

  The temperature in the reaction tube was controlled at −10 ° C. ± 2 ° C., and the pump flow rates of both solutions were added at 0.5 ml / min. The eluted reaction solution was added to an aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried, concentrated, and purified by silica gel column chromatography to obtain 38.1 g (82% yield) of 2- (2-fluoro-4-biphenyl) propionic acid methyl ester. It was.

[Example 7] Method for producing 2- (2-fluoro-4-biphenyl) propionic acid methyl ester Instead of 0.94 g of triphenylphosphine used in Example 6, n-hexane solution of diisobutylaluminum hydride (Wako Pure Chemical Industries, Ltd.) (1 mol / L); 3.6 ml, 3.6 mmol) was used, and 36.7 g (yield 79) of 2- (2-fluoro-4-biphenyl) propionic acid methyl ester was obtained in the same manner as in Example 6. %).

[Comparative Example 1]
Under a nitrogen atmosphere, a solution of 4-bromo-2-fluorobiphenyl (Aldrich Chem. Co .; 4.52 g, 18 mmol) dissolved in 18 ml of tetrahydrofuran in 437 mg (18 mmol) of metal magnesium piece and 18 ml of tetrahydrofuran was added dropwise at room temperature. Thereafter, the mixture was stirred for 3 hours to adjust the Grignard reagent.

  On the other hand, 2-bromopropionic acid methyl ester (manufactured by Tokyo Chemical Industry Co., Ltd .; 3.1 g, 18 mmol) was previously dissolved in 18 ml of tetrahydrofuran under a nitrogen atmosphere in a separate container, and nickel (II) chloride / bis ( Triphenylphosphine) complex (manufactured by Tokyo Chemical Industry Co., Ltd .; 117 mg, 0.18 mmol) was added and cooled to 0 ° C. To this was added dropwise the 4-bromo-2-fluorobiphenyl Grignard reagent tetrahydrofuran solution obtained by the above method while controlling the reaction start temperature at 0 ° C. and controlling the temperature throughout the reaction at 1-2 ° C. Added. After stirring for 10 minutes, an aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The ethyl acetate extract was washed with brine, dried, concentrated, and purified by silica gel column chromatography to obtain 2.8 g (yield 32%) of 2- (2-fluoro-4-biphenyl) propionic acid methyl ester. It was.

Next, a method of continuously producing up to the compound represented by the general formula (4) using the reaction solution containing the compound represented by the general formula (1) eluted from the apparatus 1 in Example 1. Will be described in detail.
[Device preparation]
The apparatus is assembled as shown in FIG.
(1) In the concentrated solvent recovery step, the pipe / thin film distiller is sufficiently dried and then replaced with dehydrated THF (manufactured by Wako Pure Chemical Industries, Ltd.), and the thin film distiller jacket is previously controlled at the concentration temperature. Keep it.
(2) In the extraction / separation step, the piping, extraction mixing tube, and separator are replaced with an aqueous ammonium chloride solution (prepared by Wako Pure Chemical Industries, Ltd.).
(3) In the hydrolysis reaction step, the piping and the reaction tube are replaced with an aqueous sodium hydroxide solution (manufactured by Wako Pure Chemical Industries, Ltd.), and the reaction tube is controlled in advance to the reaction temperature [Example 8] 2 -(2-Fluoro-4-biphenyl) propionic acid production method As in Example 1, the reaction solution eluted from the 45 ml reaction tube in FIG. The reaction solution was introduced into the vessel (conditions: temperature; 40 ° C., pressure; normal pressure), and the reaction solution concentrated to one third of the amount of the introduced solution was received in the container B at a constant flow rate. Then, extract and mix at a flow rate of 1 ml / min at a mixing ratio of 1.5% 10% ammonium chloride aqueous solution with respect to the concentrate 1 (condition: tube diameter: 1 mm, tube length: 500 mm, temperature: 40 ° C.). The liquid was separated using a separator. In the final hydrolysis reaction step, the organic layer of the separator is mixed at a flow rate of 1 ml / min, and the hydrolysis reaction is performed at a ratio of 2N aqueous sodium hydroxide solution 5 times that of the concentrate 1 (condition: tube diameter; 1 mm, tube length; 10 m, temperature; 140 ° C.).

After the above operation is continued for 1 hour, the treatment liquid received in the container F is crystallized at room temperature to obtain crude crystals. To the crude crystals, 568 ml of water was added and dissolved by heating at 50 ° C., followed by extraction with 352 ml of toluene. Thereafter, the extracted aqueous layer was adjusted to pH 2 with aqueous hydrochloric acid, and the precipitated crystals were separated and dried to obtain 28.4 g of 2- (2-fluoro-4-biphenyl) propionic acid (yield 71%). (Yield 99% after thin film distillation)
¹ H-NMR (CDCl ₃ , δ ppm)
11.2-10.8 (1H, broad S), 7.1-7.6 (8H, m), 3.8 (1H, q, J = 7Hz), 1.5 (3H, d, J = 7Hz)

  The present invention can continuously produce from a compound represented by the general formula (1) to a compound represented by the general formula (4) showing pharmacological effects of anti-inflammatory, analgesic and antipyretic using a tubular reactor. Therefore, it is useful as a simple and highly productive production method.

It is the schematic of the reactor which makes the compound represented by General formula (2) and General formula (3) react. It is the schematic of the apparatus which manufactures from the reaction completion liquid of the compound represented by General formula (1) to the compound represented by General formula (4). It is the schematic of the reactor which makes the compound represented by General formula (2) and General formula (3) react. It is the schematic of the apparatus which manufactures from the reaction completion liquid of the compound represented by General formula (1) to the compound represented by General formula (4).

Claims (10)

General formula (1)

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is A hydrogen atom or a fluorine atom, and Y is a protecting group for carboxylic acid]
A process for producing a compound represented by
Process 1: General formula (2)

[Wherein, X ¹ is a halogen atom, and R ¹ and R ² have the same meaning as described above]
A first solution in which a compound represented by formula (3) is dissolved;

[Wherein X ² is a halogen atom, and R and Y have the same meaning as described above]
Preparing a second mixed solution obtained by adding a catalyst composed of one or more selected from nickel, nickel compounds, palladium and palladium compounds to separate compounds.
Step 2: A step of reacting at a constant temperature while mixing and flowing the first solution and the second mixed solution into the tubular reactor.
The manufacturing method of the compound represented by General formula (1) characterized by consisting of. General formula (1)

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is A hydrogen atom or a fluorine atom, and Y is a protecting group for carboxylic acid]
A process for producing a compound represented by
Process 1: General formula (2)

[Wherein, X ¹ is a halogen atom, and R ¹ and R ² have the same meaning as described above]
A first solution in which a compound represented by formula (3) is dissolved;

[Wherein X ² is a halogen atom, and R and Y have the same meaning as described above]
A second mixture in which a catalyst comprising at least one selected from nickel, nickel compounds, palladium and palladium compounds, and a catalyst ligand in an amount exceeding the amount of reducing agent or complex formation are added to the compound represented by The step of preparing the liquid in separate containers.
Step 2: A step of reacting the first solution and the second mixed liquid while mixing and flowing in the tubular reactor.
The manufacturing method of the compound represented by General formula (1) characterized by consisting of. The step of producing the compound represented by the general formula (1) according to claim 1 or 2 is a first step, and the general formula (4) obtained by hydrolyzing the compound represented by the general formula (1) )

[Wherein, R represents a hydrogen atom, C1 -C4 alkyl or aralkyl group, R ¹ is a hydrogen atom, C1 -C6 alkyl group, an aryl group, an aralkyl group, a fluorinated aryl group, or an aryloxy group, R ² is , Hydrogen atom or fluorine atom]
A method for producing a compound represented by the general formula (4), wherein the step of producing the compound represented by formula (2) is a second step, and the first step and the second step are carried out continuously.   In Claim 1 or 2, the temperature of a 1st solution and a 2nd liquid mixture is adjusted to -20 degreeC or more and less than 0 degreeC, and the temperature in reaction tube is temperature at a certain fixed temperature of -20 degreeC or more and less than 0 degreeC. A method for producing a compound represented by the general formula (1), characterized in that the temperature is controlled within ± 5 ° C.   In claim 4, the reaction tube volume and the both liquid flow rates are adjusted such that the tube passage time and the both liquid flow rates are within 7 minutes or more and 25 minutes or less from the time when both liquids are mixed. The manufacturing method of the compound represented by General formula (1).   6. The method for producing a compound represented by the general formula (1) according to claim 5, wherein a plug flow type reaction tube having a tube length / diameter of 2 or more is used. In the step of producing a compound represented by the general formula (1) according to any one of claims 1, 2, 4, 5 or 6, a solution of the compound (1) obtained at a constant rate,
(A) A step of continuously supplying liquid to a thin film distiller and performing solvent distillation until the solvent remaining in the thin film distiller reaches a certain concentration:
(B) A step of continuously extracting and washing with an aqueous ammonium chloride solution:
(C) A step of continuously hydrolyzing the compound represented by the general formula (1) by passing the solution into a reaction tube under basic conditions:
A continuous process for producing a compound represented by the general formula (4), characterized by combining the steps consisting of:   In the mixing flow of the first solution and the second mixed solution in the tubular reactor, the product of the molar concentration of the first solution and the flow rate of the first solution, the molar concentration of the second mixed solution, and the first The method for producing a compound according to claim 1, wherein the products of the flow rates of the two mixed liquids are equal.   The method for producing a compound according to claim 8, wherein the first solution and the second mixed solution having a uniform molar concentration are mixed at the same flow rate. In the compound represented by the general formula (1), R ¹ is a phenyl group, R ² is a fluorine atom, the substitution position of R ² is the ortho position of R ¹ , and R is a methyl group. Item 10. A method for producing a compound according to Item 1-9.

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