JP4775784B2 - Storage method of 2-keto acid ester - Google Patents

Description

  The present invention relates to a method for stably storing a 2-keto acid ester which is an important compound as a synthetic raw material for pharmaceuticals and agricultural chemicals.

  Conventionally, general formula (1)

（ここで、Ｒ^１は水素、炭素数１〜４のアルキル基であり、Ｒ^２は炭素数１〜４のアルキル基を示す。）で表される２−ケト酸エステルはケトーエノールの平衡があり（非特許文献１）、不安定な化合物である事は知られているが、医薬品製造の原料として使用するに当たり、長期間安定に保管するという視点に立った保管方法は全く知られていない。

(Wherein R ¹ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms.) The 2-keto acid ester represented by the formula has an equilibrium of ketoeenol. (Non-patent Document 1) Although known to be an unstable compound, there is no known storage method from the viewpoint of stable storage for a long period of time when used as a raw material for pharmaceutical production.

Translation of Kaori Nakanishi, Feather Organic Chemistry, Vol. 289-290 (Maruzen Co., Ltd.)

  Therefore, an industrially advantageous method for stably storing a high-purity 2-keto acid ester for a long time in an easily available storage container has been desired.

  As a result of intensive studies on a method for solving the above problems, the present inventors have elucidated the cause of deterioration of 2-keto acid esters and have reached the present invention. That is, the general formula (1)

（ここで、Ｒ^１は水素、炭素数１〜４のアルキル基であり、Ｒ^２は炭素数１〜４のアルキル基を示す。）で表される２−ケト酸エステルは下式に示されるようにケト−エノール平衡があるが、不純化はエノール体から進行することが判った。更に、ケト−エノール平衡を詳細に調べた結果、平衡は熱、アルカリ、金属、ハロゲンイオン等が触媒する事を見出した。

Here, R ¹ is hydrogen, an alkyl group having 1 to 4 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms. Thus, it was found that there is a keto-enol equilibrium, but the impure progresses from the enol form. Furthermore, as a result of examining keto-enol equilibrium in detail, it was found that the equilibrium is catalyzed by heat, alkali, metal, halogen ion and the like.

また、エノール体の分解は酸素により加速される事も見出した。従って、ケト−エノール平衡が促進されない条件下であれば２−ケト酸エステルを安定に保存できることを見出し、本発明に到達した。すなわち、窒素雰囲気下、フェノール樹脂、またはフェノール・エポキシ樹脂共存下で保管することによる２−ケト酸エステルを長期間、安定に保管する方法である。

It was also found that the decomposition of the enol body is accelerated by oxygen. Therefore, the present inventors have found that 2-keto acid esters can be stably stored under conditions where the keto-enol equilibrium is not promoted, and the present invention has been achieved. That is, it is a method of stably storing 2-keto acid esters for a long period of time by storing them in the presence of phenol resin or phenol / epoxy resin in a nitrogen atmosphere.

  According to the present invention, 2-keto acid ester, which is an important compound as a synthetic raw material for pharmaceuticals and agricultural chemicals, is stored in a readily available phenol resin, phenol-epoxy resin, or a container lined with these resins. Then, it can be stably stored for a long time.

  The 2-keto acid ester represented by the general formula (1) in the present invention is 2-keto such as methyl pyruvate, propyl pyruvate, methyl 2-ketobutanoate, ethyl 2-ketobutanoate and methyl 2-ketopentanoate. Examples include 2-keto lower alkyl carboxylic acid esters such as acid esters, preferably methyl pyruvate, propyl pyruvate, methyl 2-ketobutanoate, and ethyl 2-ketobutanoate.

  The phenol resin or phenol / epoxy resin of the present invention is any of those obtained by solidifying these resins in the form of beads or chips, those lined on metal pieces, or those lined on metal drums. A resin in the form can also be used. In consideration of long-term storage and transportation, it is preferable to use a metal container lined with these resins. In view of economic efficiency, a commercially available metal container lined with these resins is preferable, and a phenolic resin or drum epoxy resin lined drum can manufactured by any manufacturer can be used. Moreover, if it is a container which cannot be lined, what solidified the said resin and what lined to the metal piece can also coexist. Specifically, those obtained by lining phenol-based 4A or epoxy-based 519S (both made by Toyo Ink) are available, and drums lined with these resins are commercially available. (For example, Toho Seat Frame Co., Ltd., Nippon Steel Drum Co., Ltd.)

  When in contact with these resins, the equilibrium of ketoeenol is suppressed, and even when stored for a long period of time, the recovery rate of keto bodies is extremely high, and only decomposition of the enol bodies that coexist proceeds, and dimers, etc. The decomposition product increases.

  In the present invention, the nitrogen atmosphere means that oxygen is substantially absent in the gas phase portion, and the oxygen concentration in the gas phase portion is 1.0% or less, preferably 0.1% or less.

  Halogen ions are chlorine ions, bromine ions, iodine ions, and the like, and are preferably suppressed to 5 ppm or less with respect to the 2-keto acid ester. Here, the concentration of halogen ions contained in the 2-keto acid ester can be determined by potentiometric titration or the like.

  The 2-keto acid ester used in the present invention can be produced by any method. In addition, the keto-enol equilibrium composition varies depending on the type of compound, but generally the boiling point of the enol body is lower than that of the keto body due to hydrogen bonding in the molecule. A 2-keto acid ester can be obtained. Further, since the impure is often progressed from the enol form, the 2-keto acid ester having a low enol form content is preferred for stable storage of the 2-keto acid ester for a long period of time.

  The storage temperature is preferably a low temperature, but if it is 40 ° C. or lower, the keto body is hardly reduced in two months.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these. In addition, although the GC analysis conditions differ according to the compound for quantitative analysis of 2-keto acid ester, the analysis conditions for methyl 2-ketobutyrate are shown below as a representative example.

GC analysis conditions
Column: TC-17 <made by GL Sciences>
ID 0.32mmφ × 60 m, 0.25μm
Temperature 50 ℃ (10min) → 20 ℃ / min → 250 ℃ (10min)
Inlet and detector temperature: 200 ° C
Flow rate: Total flow rate 60ml / min, column flow rate 2.26ml / min
Split ratio: 1/19
RT: Enol body 9.1min
Keto body 11.5min

Reference Example 2-Synthesis Method of Methyl Ketobutyrate A 200 ml four-necked flask equipped with a condenser that can be cooled with water at 0 to 5 ° C., a thermometer, a pH sensor, and a supply port that can quantitatively supply sodium hypochlorite aqueous solution 2-methylbutyrate 11.8 g (100 mmol), ethyl acetate 47.2 g, acetic acid 3.0 g (50 mmol), Sanol LS-770 (bis (2,2,6,6-tetramethyl-4-piperidyl)) 0.96 g (2 mmol) manufactured by Sebacate Sankyo Co., Ltd. and 2.1 g (15 mmol) of sodium hydrogen sulfate were charged and stirred with a magnetic stirrer. Next, the outside of the flask was covered with aluminum foil to provide a light-shielded state, and while maintaining the internal temperature at 25 ° C., 63.0 g of sodium hypochlorite aqueous solution containing 13.0% effective chlorine, 0.7% free alkali and 11.2% NaCl was added. The mixture was charged with a metering pump over 5 hours, and the reaction was further continued for 2 hours. After completion of the reaction, the ethyl acetate layer was separated and washed with water, followed by simple distillation to obtain crude methyl 2-ketobutyrate. As a result of GC analysis, the keto form in methyl 2-ketobutyrate was about 97%, and the enol form was 3%. The obtained crude product was rectified to obtain 6.7 g of purified 2-ketobutyrate as a fraction of 80 to 90 ° C./3.3 kPa. As a result of GC analysis, it was 98.6% keto body and 1.2% enol body. In addition, the enol body contained in the crude body was recovered as a pre-fraction.

Example 1
Pyrex (registered trademark) glass container (manufactured by Shibata Hario Glass) was charged with 50 g of methyl 2-ketobutyrate (GC analysis value 1.2% enol, 98.6% keto, 5 ppm or less chloroion), and phenol / epoxy A metal test piece (manufactured by Toho Seat Frame Co., Ltd., 1.5 mm × 4.5 mm × 1.0 mm) lined with a system 519S was placed, and the air at the top of the container was replaced with nitrogen and sealed. After this container was stored at 40 ° C. for 1 month, methyl 2-ketobutyrate was analyzed. As a result, the enol form was 0.3% and the keto form was 98.6%.

Examples 2-5
The abundances of enol form and keto form after storage under the storage conditions shown in Table 1 in the same manner as in Example 1 are shown.

Examples 6-7
After the metal test piece was stored under the storage conditions shown in Table 2 in the same manner as in Example 1 except that the phenolic test piece was changed to phenol 4A (manufactured by Toho Seat Frame Co., Ltd., 1.5 mm × 4.5 mm × 1.0 mm). The abundance of enol form and keto form is shown.

Comparative Example 1 (no resin test piece)
As a result of storing for 42 days in the same manner as in Example 1 without using a resin test piece, the keto body decreased to 97.6% and the enol body increased to 1.9%. Furthermore, when stored for 140 days, the keto form decreased to 96.2%, the enol form increased to 2.5%, and the dimer increased to 1.2%.

Comparative Example 2 (in the presence of SUS)
Put 50 g of methyl 2-ketobutyrate (1.2% enol, 98.6% keto) and SUS304, 1.5 mm x 4.5 mm x 3.0 mm test piece in a glass container, and nitrogen the air at the top of the container. Sealed after replacement. As a result of storing this container at 40 ° C. for 1 month, methyl 2-ketobutyrate was colored, the enol form increased to 1.5%, and the keto form decreased to 90.3%.

Comparative Examples 3 to 4 (high density polyethylene)
The test piece is replaced with high-density polyethylene (1.5 mm × 4.5 mm × 1.0 mm, manufactured by Toho Seat Frame Co., Ltd.), and the enol body and keto after being stored under the storage conditions shown in Table 2 in the same manner as in Comparative Example 1. Indicates the abundance of the body.

  The enol form of the preservation solution increased and the keto form decreased. Since the equilibrium composition at 40 ° C. is about 3/97 of the enol / keto body, the high-density polyethylene promoted the keto-enol equilibrium, so that the enol body increased more than that when charged.

Comparative Example 4 (chlorine ion)
A glass container was charged with 50 g of methyl 2-ketobutyrate having a concentration of 1.2% enol, 98.6% keto, and 10 ppm chloride ion, and the air at the top of the container was replaced with nitrogen and sealed. When this container was stored at 40 ° C. for 2 months and analyzed by GC, the enol form increased to 2.0% and the keto form decreased to 96.5%. -Degradation of methyl ketobutyrate was accelerated.

Comparative Example 5 (in air)
A glass container was charged with 50 g of methyl 2-ketobutyrate having a concentration of 1.2% enol and 98.6% keto, and the container was sealed without replacing the air with nitrogen. When this container was stored at 40 ° C. for 2 months and analyzed by GC, the enol form increased to 2.1% and the keto form decreased to 97.8%.

Example 8
Put 200 kg of 2-ketobutyrate (GC analysis value: enol body: 1.8%, keto body: 97.9%) into a 200L drum can (Toho Seat Frame Co., Ltd.) lined with phenol / epoxy system 519S, and air in the upper part of the container Was replaced with nitrogen and then sealed. After this container was stored at 20-30 ° C. for 2 months, methyl 2-ketobutyrate was analyzed. As a result, the enol form was 0.8% and the keto form was 97.9%, and no decomposition of the keto form was observed. .

According to the present invention, a 2-keto acid ester, which is an important compound as a synthetic raw material for pharmaceuticals and agricultural chemicals, is brought into contact with a readily available phenol resin or phenol-epoxy resin, or is lined with these resins. If stored in a separate container, the 2-keto acid ester can be stably stored for a long period of time.

Claims (4)

General formula (1)

(Wherein R ¹ is hydrogen, an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms). A method for storing a 2-keto acid ester characterized by storing in the presence of a resin or a phenol / epoxy resin.
The method for storing a 2-keto acid ester according to claim 1 , wherein the phenol resin or the phenol-epoxy resin is a molded container.
Phenolic resins or phenol-epoxy resins, storage method of claim 1 Symbol placement No 2-keto acid esters, characterized in that lined with a phenolic resin or a phenol-epoxy resins, a metal container.
The method for storing a 2-keto acid ester according to any one of claims 1 to 3, wherein the halogen ion coexisting in the 2-keto acid ester is 5 ppm or less.