JP2018140954A - Method of manufacturing ylide compound and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop a novel synthetic route making it possible to manufacture amino acid, such as 5-aminolevulinic acid, with high safety.SOLUTION: A method of manufacturing an ylide compound includes reacting cyclic acid anhydride with sulfur methylide.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an ylide compound and use thereof. More specifically, the present invention relates to a method for producing an ylide compound, a method for producing a halomethyl compound and a method for producing an amino acid using the method for producing the ylide compound, and an ylide compound.

  Conventionally, the production method of 5-aminolevulinic acid is roughly classified into a method using a photosynthetic bacterium and a chemical synthesis method.

  Patent Document 1 discloses the production of 5-aminolevulinic acid characterized by reacting succinic anhydride with a metal cyanide salt, passing through 4-cyano-4-oxobutanoic acid or a salt thereof, and then undergoing a reduction step. A method is described.

  Prior art document 2 discloses that δ-aminolevulinic acid or a salt thereof is obtained by reacting succinic anhydride with nitromethane in the presence of a base to obtain 5-nitro-4-oxopentanoic acid or a salt thereof, and then reducing. The manufacturing method of is described.

JP 2005-272360 A (released on October 6, 2005) Japanese Patent Laid-Open No. 9-316041 (released on December 9, 1997)

  However, the conventional method for producing 5-aminolevulinic acid has a drawback that it is necessary to use a highly dangerous compound such as metal cyanide or nitromethane. Therefore, development of a new synthesis route of 5-aminolevulinic acid with improved safety is required.

  As a result of intensive studies by the present inventors in order to solve the above problems, an ylide compound is produced by reacting a cyclic acid anhydride such as succinic anhydride with a sulfur methylide that is safer than metal cyanide and nitromethane. A new synthetic route for amino acids such as 5-aminolevulinic acid was found, and the present invention was completed.

  Therefore, the manufacturing method of the ylide compound which concerns on one Embodiment of this invention is a manufacturing method of the ylide compound characterized by making a cyclic acid anhydride and sulfur methylide react.

（式（１）中、ｎは１〜３の整数である） In the manufacturing method of the ylide compound which concerns on one Embodiment of this invention, it is preferable that the said cyclic acid anhydride is represented by Formula (1).

(In formula (1), n is an integer of 1 to 3)

  In the method for producing an ylide compound according to an embodiment of the present invention, the cyclic acid anhydride is preferably succinic anhydride.

  In the manufacturing method of the ylide compound which concerns on one Embodiment of this invention, it is preferable that the said sulfur methylide produces | generates from reaction of trimethylsulfoxonium halide or a trimethylsulfonium halide, and a base.

  In the method for producing an ylide compound according to an embodiment of the present invention, it is more preferable that the sulfur methylide is generated from a reaction between trimethylsulfoxonium bromide or trimethylsulfonium bromide and a base.

In the method for producing an ylide compound according to an embodiment of the present invention, the ylide compound is preferably an ylide compound represented by formula (2-1) or formula (2-2).

  In the method for producing a halomethyl compound according to an embodiment of the present invention, it is preferable that a portion derived from sulfur methylide of the ylide compound obtained by the above-described method for producing an ylide compound is methylated with hydrogen halide.

  In the method for producing an amino acid according to one embodiment of the present invention, it is preferable that the halogen of the halomethyl compound obtained by the above-described method for producing a halomethyl compound is substituted with an amino group.

（式（３−１）中、Ｒ^１は水素原子、アルカリ金属、および炭素数１〜６のアルキル基からなる群から選ばれる一つである）

（式（３−２）中、Ｒ^２は水素原子、アルカリ金属、および炭素数１〜６のアルキル基からなる群から選ばれる一つである） The ylide compound according to one embodiment of the present invention is preferably represented by Formula (3-1) or Formula (3-2).

(In Formula (3-1), R ¹ is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)

(In Formula (3-2), R ² is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)

  If the method for producing an ylide compound according to an embodiment of the present invention is used, an amino acid such as 5-aminolevulinic acid can be produced with high safety.

  Hereinafter, the manufacturing method of the ylide compound based on this invention and one Embodiment of its utilization are demonstrated in detail.

[1] Details of Production Method of Ylide Compound Here, the production method of the ylide compound according to this embodiment will be described below with reference to the following reaction scheme 1. In addition, each compound described in Reaction Scheme 1 is a preferable example, and the present embodiment is not limited thereto.

上記反応スキーム１において、ｎは１以上の整数（好ましくは１〜３の整数）を表す。Ｘは、ハロゲン原子を表す。

In the above reaction scheme 1, n represents an integer of 1 or more (preferably an integer of 1 to 3). X represents a halogen atom.

  The method for producing an ylide compound according to this embodiment includes step 1 of obtaining an ylide compound by reacting a cyclic acid anhydride with sulfur methylide. Thereafter, the produced ylide compound may be reacted with a hydrogen halide in Step 2 to produce a halomethyl compound. Furthermore, after that, the operation of Step 3 is performed on the produced halomethyl compound to replace the halogen of the halomethyl compound with an amino group to produce an amino acid.

(1-1) Step 1: Production of an ylide compound In Step 1, by reacting a cyclic acid anhydride with sulfur methylide, the cyclic acid anhydride is opened to produce an ylide compound.

  Although a specific reaction method is not particularly limited, in a preferred example, sulfur methylide and cyclic acid anhydride are reacted in a solvent.

(Cyclic acid anhydride)
The cyclic acid anhydride is not particularly limited as long as it is a compound having a structure in which a carboxyl group of a divalent or higher carboxylic acid is dehydrated in the molecule to form a ring. Examples of the cyclic acid anhydride include succinic anhydride, glutaric anhydride, and adipic anhydride. The cyclic acid anhydride is preferably a compound having a structure in which the carboxyl group of a divalent carboxylic acid is cyclically dehydrated.

  When a non-cyclic carboxylic acid having two or more carboxyl groups (a non-anhydride carboxylic acid) is used in the production of an ylide compound, the carboxylic acid is first protected by removing one of them. To do. Next, after activating only one remaining carboxyl group and reacting with sulfur methylide, the number of steps is required. On the other hand, in this embodiment, since the step of protecting the carboxyl group and the step of activating the carboxyl group are unnecessary by using the cyclic acid anhydride, the number of necessary steps is small. Since the number of necessary steps is small, there are advantages in terms of cost such as few by-products and easy post-processing.

  In a preferred example, a compound represented by the formula (1) in the above reaction scheme 1 is used as the cyclic anhydrous compound. The compound represented by the formula (1) is a compound having a structure in which water molecules are eliminated from two carboxyl groups in the molecule to form a ring.

  The cyclic acid anhydride is preferably succinic anhydride. Succinic anhydride is inexpensive. Therefore, industrially useful 5-aminolevulinic acid (hereinafter also referred to as ALA) can be produced at low cost by using succinic anhydride as the cyclic acid anhydride.

(Sulfur methylide)
The kind of sulfur methylide is not particularly limited, and examples thereof include dimethylsulfoxomethylide and dimethylsulfomethylide. Sulfur methylide can be prepared, for example, by reacting trimethylsulfoxonium halide or trimethylsulfonium halide with a base.

  Examples of the trimethylsulfoxonium halide include trimethylsulfoxonium bromide, trimethylsulfoxonium chloride, and trimethylsulfoxonium iodide. Among these, trimethylsulfoxonium bromide is particularly preferably used. This is because trimethylsulfoxonium bromide is inexpensive and easy to handle, and the target ylide compound can be produced in a high yield.

  Examples of the trimethylsulfonium halide include trimethylsulfonium bromide, trimethylsulfonium chloride, and trimethylsulfonium iodide. Among these, trimethylsulfonium bromide is particularly preferably used because of easy handling.

  The base draws a proton from the trimethylsulfoxonium halide to produce dimethylsulfoxomethylide. The base also extracts protons from the trimethylsulfonium halide to produce dimethylsulfomethylide. Examples of the base include sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Among them, the base is preferably sodium tert-butoxide because the reaction yield is good and the operability is excellent.

(First solvent)
Hereinafter, the solvent used for reacting trimethylsulfoxonium halide or trimethylsulfonium halide or the like with a base and reacting sulfur methylide and cyclic acid anhydride in Step 1 is referred to as a first solvent. The kind of 1st solvent is not specifically limited. For example, tetrahydrofuran, tert-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 2-methylpyrrolidone, toluene, dioxane and the like can be mentioned. A solvent may be used independently and may be used in combination of two or more. Among them, the first solvent is preferably tetrahydrofuran because the reaction yield is good and the operability is excellent. The first solvent may further contain water.

  As a specific method of reacting a cyclic acid anhydride and sulfur methylide, for example, in a first solvent, sulfur methylide is converted into a first solvent by reaction of trimethylsulfoxonium halide or trimethylsulfonium halide with a base. Make the solution formed inside. The method of dripping the solution which melt | dissolved the cyclic acid anhydride in the 1st solvent with respect to the solution of sulfur methylide is mentioned. Further, a method of dropping a sulfur methylide solution into a dissolved cyclic acid anhydride solution is also conceivable. Hereinafter, a method of dropping the dissolved cyclic acid anhydride solution into the dissolved sulfur methylide solution will be specifically described.

  First, using a first solvent, a solution of sulfur methylide and a cyclic acid anhydride is prepared.

  The method for preparing sulfur methylide using the first solvent is not particularly limited. For example, after adding a base to a solvent, it is dissolved or suspended by a known method, and trimethylsulfoxonium halide or a solution in which trimethylsulfonium halide is dissolved is added thereto. Thereafter, the obtained mixed solution is reacted to produce sulfur methylide.

  In the first solvent, the amount of the base relative to the cyclic acid anhydride is preferably 0.01-fold mol to 50-fold mol, more preferably 0.1-fold mol to 10-fold mol, and even more preferably 0. .5 moles to 5 moles. When the amount of the base is within the above range, the side reaction can be suppressed and the yield can be improved.

  The temperature of the first solvent during the reaction is, for example, 5 ° C to 150 ° C, preferably 20 ° C to 100 ° C. When the temperature of the solvent is within the above range, there is an effect that sulfur methylide can be produced with high yield. The stirring time is, for example, 10 minutes to 20 hours, preferably 30 minutes to 10 hours. When the stirring time is within the above range, there is an effect that sulfur methylide can be produced with high yield.

  The amount of trimethylsulfoxonium halide or trimethylsulfonium halide in the first solvent is not particularly limited. The amount of trimethylsulfoxonium halide or trimethylsulfonium halide in the first solvent is preferably 0.01 mM to 10000 mM, more preferably 0.1 mM to 1000 mM, still more preferably 1 mM to 500 mM. is there. When the amount of trimethylsulfoxonium halide or trimethylsulfonium halide in the first solvent is within the above range, sulfur methylide can be produced in a high yield and the operability is excellent.

  The method for dissolving the cyclic acid anhydride in the first solvent is not particularly limited. For example, after adding a cyclic acid anhydride to a 1st solvent, what is necessary is just to stir until it melt | dissolves by a well-known method. During stirring, the temperature of the solvent to which the cyclic acid anhydride is added is, for example, 5 ° C to 150 ° C, preferably 20 ° C to 100 ° C. When the temperature of the solvent is within the above range, there is an effect of low cost without using a large incidental facility. The stirring time is, for example, 10 minutes to 20 hours, preferably 30 minutes to 10 hours. When the stirring time is within the above range, a more uniform solution can be prepared.

  The amount of the cyclic acid anhydride in the first solvent is not particularly limited. The amount of the cyclic acid anhydride in the first solvent is preferably 0.01 mM to 10000 mM, more preferably 0.1 mM to 1000 mM, and further preferably 1 mM to 500 mM. When the cyclic acid anhydride in the first solvent is within the above range, the operability during dropping is excellent.

  The method of dropping the cyclic acid anhydride solution into the sulfur methylide solution is not particularly limited, and may be dropped by a known method.

  Further, the amount of trimethylsulfoxonium halide or trimethylsulfonium halide is, for example, 0.01 times to 100 times mol, and preferably 0.5 times to 50 times mol with respect to the cyclic acid anhydride. More preferably, it is 0.1-fold mole to 10-fold mole, more preferably 0.5-fold mole to 5-fold mole.

  The dropping is performed, for example, for 1 minute to 24 hours, preferably 10 minutes to 10 hours. By performing the dropwise addition within the above time range, side reactions can be reduced and the reaction yield can be improved. In addition, the temperature of the first solvent at the time of dropping is preferably −70 ° C. to 100 ° C., more preferably −50 ° C. to 70 ° C., and further preferably −20 ° C. to 40 ° C. When the temperature of the first solvent at the time of dropping is within the above range, heat generation at the time of dropping can be suppressed.

  After dripping, the obtained reaction liquid is well stirred. Stirring may be performed by a known method. The conditions for stirring are not particularly limited, and may be set as appropriate depending on the type and amount of cyclic acid anhydride, sulfur methylide, first solvent and the like. Stirring is carried out at a temperature of the reaction solution obtained by dropping, preferably −70 ° C. to 100 ° C., more preferably −50 ° C. to 70 ° C., and still more preferably −20 ° C. to 40 ° C. By stirring the reaction solution obtained by dropping within the above range, the reaction can proceed efficiently. Moreover, the rapid progress of reaction can be suppressed by stirring the temperature of the reaction solution obtained by dropping within the above range.

  The stirring is preferably performed over 10 minutes to 20 hours, more preferably over 20 minutes to 10 hours, and even more preferably over 30 minutes to 5 hours.

  After dropping, the precipitated ylide compound may be recovered by a known method. For example, the reaction solution after the dropping is centrifuged to precipitate and recover the ylide compound. If necessary, the obtained precipitate may be washed and dried to obtain a solid of an ylide compound.

（式（Ｉ−２）中、ｎは１以上の整数（好ましくは１〜３の整数）を表す。）

[2] Ylide Compound The structure of the produced ylide compound depends on the type of cyclic acid anhydride and sulfur methylide used. In a preferred example, the ylide compound is a novel compound represented by the formula (I-1) in the above reaction scheme 1 or the following formula (I-2), for example, the following formulas (2-1) and (2- 2) The novel compound represented by 2) is included.

(In formula (I-2), n represents an integer of 1 or more (preferably an integer of 1 to 3).)

  The compound represented by the formula (2-1) is obtained by reacting succinic anhydride and dimethylsulfoxomethylide (for example, prepared from trimethylsulfoxonium halide). The compound represented by the formula (2-2) is obtained by reacting succinic anhydride and dimethylsulfomethylide (for example, prepared from trimethylsulfonium halide).

  The compounds represented by the above formulas (2-1) and (2-2) can be used, for example, for the production of 5-aminolevulinic acid.

[3] Production of halomethyl compound and the like from ylide compound As shown in Steps 2 and 3 of Reaction Scheme 1, other substances may be produced from the ylide compound produced in Step 1 above.

(3-1) Step 2: Production of halomethyl compound In Step 2, the ylide compound is treated with hydrogen halide to methylate a portion derived from sulfur methylide of the ylide compound to produce a halomethyl compound. The “part derived from sulfur methylide” means, for example, a structural part represented by the following formula (2-α) when dimethylsulfoxomethylide is used as the sulfur methylide. When dimethylsulfomethylide is used as the sulfur methylide, it indicates a structural portion represented by the following formula (2-β).

  The method for treating the ylide compound with hydrogen halide is not particularly limited. For example, an ylide compound and a hydrogen halide may coexist in the presence of a solvent. Hereinafter, this method will be specifically described.

  Examples of the hydrogen halide include hydrofluoric acid, hydrogen fluoride, hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, hydrogen iodide, and the like. As the hydrogen halide, hydrogen bromide is preferably used from the viewpoints of cost and yield. In step 2, the amount of hydrogen halide relative to the ylide compound is, for example, 0.1 to 50 times mole, preferably 0.5 to 20 times mole, and preferably 1 to 10 times mole. More preferably.

  Hereinafter, the solvent used for reacting the ylide compound and the hydrogen halide in Step 2 is referred to as a second solvent. The type of the second solvent is not particularly limited. Examples include tetrahydrofuran, ethyl acetate, dichloroethane, toluene, xylene, and diethyl ether. These solvents may be used alone or in combination. Among these, the second solvent is preferably tetrahydrofuran because the reaction yield is good and the operability is excellent.

  Hydrogen halide is added to the solution of the ylide compound and reacted. The temperature of the reaction is not particularly limited and is, for example, -50 ° C to 200 ° C, preferably -20 ° C to 100 ° C. If the temperature of reaction is in said range, there exists an effect that the reaction yield is good. The reaction time is not particularly limited, and for example, the reaction is performed for 10 minutes to 24 hours, preferably 30 minutes to 10 hours. When the reaction time is within the above range, side reactions can be suppressed and the operability is excellent. Thereby, a halomethyl compound can be obtained.

（式（ＩＩＩ）中、Ｘはハロゲン原子を表す。） (Halomethyl compounds)
The type of halomethyl compound produced is determined depending on the type of ylide compound, hydrogen halide, etc. to be used. For example, the compound represented by the formula (II) in the above reaction scheme 1 can be produced. Examples of the compound represented by the formula (II) include a compound represented by the following formula (III).

(In formula (III), X represents a halogen atom.)

  Preferably, the halomethyl compound is a compound represented by formula (III). If formula (III) is used as a starting material, ALA which is an industrially useful substance can be produced.

(3-2) Step 3: Introduction of an amino group into a halomethyl compound In Step 3, an amino group is produced by substituting the halogen of the halomethyl compound with an amino group. The amino acid may be obtained in the form of a salt. Although the specific method of the process 3 is not specifically limited, For example, operation of process 3-1 to 3-3 can be performed in order.

  Hereinafter, a method of substituting halogen in the halomethyl compound with an amino group will be described with reference to the following reaction scheme 2.

In the above reaction scheme 2, n represents an integer of 1 or more (preferably an integer of 1 to 3). X represents a halogen atom. R ³ represents an alkyl having 1 to 6 carbon atoms.

(3-2-1) Step 3-1
In Step 3-1, the halomethyl compound obtained in Step 2 is treated with an alcohol (R ³ OH) (R ³ is alkyl having 1 to 6 carbon atoms), and the hydroxyl group of the halomethyl compound is converted to —OR ³ (R ³ is substituted with alkyl having 1 to 6 carbon atoms. The specific reaction method is not particularly limited. In a preferred example, the reaction is performed according to the method described in the literature Moumne, R .; Lavielle, S .; Karoyan, PJ Org. Chem. 2006, 71, 3332. Do.

（式（Ｖ）において、Ｘはハロゲン原子を表す。Ｒ^３は炭素数１〜６のアルキルを表す。） The compound obtained in step 3-1 is, for example, a compound represented by the formula (IV) in the above reaction scheme 2. Examples of the compound represented by the formula (IV) include a compound represented by the following formula (V).

(In the formula (V), X represents a halogen atom. R ³ represents an alkyl having 1 to 6 carbon atoms.)

(3-2-2) Step 3-2
In Step 3-2, phthalimide is allowed to act on the compound obtained in Step 3-1, and the halogen atom of the compound obtained in Step 3-1 is substituted with a phthalimide group. The specific reaction method is not particularly limited. In a preferred example, the reaction is performed according to the method described in the document Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85. (Review). .

  Although the kind of phthalimide used at the process 3-2 is not specifically limited, For example, potassium phthalimide, sodium phthalimide, etc. can be used.

（式（ＶＩＩＩ）において、Ｒ^３は炭素数１〜６のアルキルを表す。） The compound obtained in Step 3-2 is, for example, a compound represented by Formula (VI) in Reaction Scheme 2 above. The compound represented by the formula (VI) includes a compound represented by the following formula (VII).

(In Formula (VIII), R ³ represents an alkyl having 1 to 6 carbon atoms.)

(3-2-3) Step 3-3
In Step 3-3, the phthalimide group of the compound obtained in Step 3-2 is changed to an amino group. The specific reaction method is not particularly limited. In a preferred example, the reaction is performed according to the method described in the document Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85. (Review). .

The compound obtained in Step 3-3 is, for example, a compound represented by Formula (VIII) in Reaction Scheme 2 above. The compound represented by the formula (VIII) includes 5-aminolevulinic acid represented by the following formula (IX). The amino acid may be obtained in the form of a salt (for example, hydrochloride, phosphate, sulfonate, nitrate, etc.).

(3-3) Other methods In this embodiment, a halomethyl compound is produced in step 2, and then the steps 3-1 to 3-3 are sequentially performed to introduce an amino group into the halomethyl compound. However, the method for introducing an amino group into the ylide compound according to this embodiment is not limited to this. An amino group may be introduced into the ylide compound with reference to a known method.

[4] Example of Production Scheme for 5-Aminolevulinic Acid According to one embodiment of the present invention, 5-aminolevulinic acid can be synthesized according to Reaction Scheme 3 below.

上記反応スキーム３において、ｎは１以上の整数（好ましくは１〜３の整数）を表す。Ｘは、ハロゲン原子を表す。Ｒ^３は、炭素数１〜６のアルキルを表す。ＴＭＳＯＢは、トリメチルスルホキソニウムブロマイドの略である。

In the above reaction scheme 3, n represents an integer of 1 or more (preferably an integer of 1 to 3). X represents a halogen atom. R ³ represents an alkyl having 1 to 6 carbon atoms. TMSOB is an abbreviation for trimethylsulfoxonium bromide.

  In step 1, sulfur methylide is allowed to act on succinic acid represented by formula (X). In Reaction Scheme 3, an example in which trimethylsulfoxonium bromide is used as a raw material for sulfur methylide is shown, but the sulfur methylide used is not particularly limited. Steps 2 to 3-3 can be performed according to the method described above.

（式（３−１）中、Ｒ^１は水素原子、アルカリ金属、および炭素数１〜６のアルキル基からなる群から選ばれる一つである）

（式（３−２）中、Ｒ^２は水素原子、アルカリ金属、および炭素数１〜６のアルキル基からなる群から選ばれる一つである） [5] Ylide Compound The present invention also provides compounds represented by the following formulas (3-1) and (3-2).

(In Formula (3-1), R ¹ is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)

(In Formula (3-2), R ² is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)

The compounds represented by formulas (3-1) and (3-2) can be produced by the method described above when R ¹ and R ² are hydrogen. When R ¹ and R ² are alkali metals, the compounds represented by formulas (3-1) and (3-2) are produced by a method of adding an alkali metal to the ylide compound produced by the above-described method. be able to. When R ¹ and R ² are alkyl groups having 1 to 6 carbon atoms, the compounds represented by formulas (3-1) and (3-2) are obtained by using alcohols from the ylide compounds produced by the above-described method. And can be produced by a method of esterification.

  The compounds represented by formulas (3-1) and (3-2) can be used, for example, as an intermediate for producing aminolevulinic acid.

  Examples will be shown below, and the embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail. Further, the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. Moreover, all the literatures described in this specification are used as reference.

  This example was performed according to the following reaction scheme 4. In this example, as an example of the present embodiment, a compound represented by the formula (2-1) from succinic anhydride and dimethylsulfoxomethylide prepared from trimethylsulfoxonium bromide, and a formula (XI) The specific example which manufactured the halomethyl compound represented by this is demonstrated.

  T-BuONa is an abbreviation for sodium tert-butoxide.

<Production of Compound Represented by Formula (2-1)>
A stirrer and a platinum thermometer were set in a 200 mL four-necked flask, and 40 mL of dry tetrahydrofuran (hereinafter also referred to as THF), 3.81 g of sodium tert-butoxide (hereinafter also referred to as t-BuONa) (39.7 mM, 2. 1 eq) was added. Next, 6.87 g (39.7 mM, 2.1 eq) of trimethylsulfoxonium bromide (hereinafter also referred to as TMSOB) was added at room temperature, and 42 mL of dry THF was added. The temperature in the flask was 50 ° C., and the mixture was stirred for 3 hours to react t-BuONa with TMSOB to obtain a solution of dimethylsulfoxomethylide. Further, 1.89 g of succinic anhydride was dissolved in 50 mL of dried THF to obtain a solution of succinic anhydride (18.89 mM, 1 eq). A solution of succinic anhydride was added dropwise to the solution of dimethylsulfoxomethylide cooled to 2 ° C. over 30 minutes, and the resulting reaction solution was stirred at 2 ° C. for 1 hour and further at room temperature for 1 hour. . The reaction solution was centrifuged, and the precipitate was washed with THF and then with toluene. The obtained precipitate was vacuum-dried to obtain 8.53 g of a white solid of the compound represented by the formula (2-1).

<Production of halomethyl compound represented by formula (XI)>
The white solid was suspended in 160 mL of THF, 4.70 g (27.8 mM) of 48% hydrogen bromide was added, and the mixture was heated at 60 ° C. for 3 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.03 g of a brown low-viscosity oil. This oil was purified by silica gel chromatography. In silica gel chromatography, CHCl ₃ was first used as a developing solvent, and then a mixed solvent in which CHCl ₃ and CH ₃ OH were mixed at a volume ratio of 10: 1 was used. 0.222 g of a fraction containing the compound represented by Formula 3 was obtained. ^From the integral ratio of ¹ H-NMR, the content of the compound represented by the formula (XI) in this fraction was estimated to be 63%. The yield of the compound represented by the formula (XI) determined from this content was 0.140 g (0.718 mM, yield 3.8%).

The details of the NMR conditions and the results were as follows.
¹ H-NMR (400 MHz, CDCl ₃ , δ ppm):
2.66 (t-like, 2H, J = 6.7 Hz), 2.94 (t-like, 2H, J = 6.7 Hz), 4.00 (s, 2H)
¹³ C-NMR (400 MHz, CDCl ₃ , δ ppm):
27.97, 34.17, 34.34, 174.53, 201.00

  INDUSTRIAL APPLICATION This invention can be utilized for manufacture of 5-aminolevulinic acid which can be utilized for a pharmaceutical, an agrochemical, livestock fisheries feed, a functional display food, health food, cosmetics, etc.

Claims (9)

  A process for producing an ylide compound, comprising reacting a cyclic acid anhydride with sulfur methylide. The said cyclic acid anhydride is represented by Formula (1), The manufacturing method of the ylide compound of Claim 1 characterized by the above-mentioned.

(In formula (1), n is an integer of 1 to 3)   The method for producing an ylide compound according to claim 2, wherein the cyclic acid anhydride is succinic anhydride.   The method for producing an ylide compound according to any one of claims 1 to 3, wherein the sulfur methylide is generated from a reaction between trimethylsulfoxonium halide or trimethylsulfonium halide and a base.   The method for producing an ylide compound according to claim 4, wherein the sulfur methylide is produced from a reaction between trimethylsulfoxonium bromide or trimethylsulfonium bromide and a base. The said ylide compound is an ylide compound represented by Formula (2-1) or Formula (2-2), The manufacturing method of the ylide compound of any one of Claim 1 to 5 characterized by the above-mentioned.

  A process for producing a halomethyl compound, wherein a portion derived from sulfur methylide of an ylide compound obtained by the process for producing an ylide compound according to any one of claims 1 to 6 is methylated with hydrogen halide. Method.   A method for producing an amino acid, wherein the halogen of the halomethyl compound obtained by the method for producing a halomethyl compound according to claim 7 is substituted with an amino group. An ylide compound represented by formula (3-1) or formula (3-2).

(In Formula (3-1), R ¹ is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)

(In Formula (3-2), R ² is one selected from the group consisting of a hydrogen atom, an alkali metal, and an alkyl group having 1 to 6 carbon atoms)