JP2005336120A - Method for producing high-purity 2-keto acid ester - Google Patents
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- JP2005336120A JP2005336120A JP2004158777A JP2004158777A JP2005336120A JP 2005336120 A JP2005336120 A JP 2005336120A JP 2004158777 A JP2004158777 A JP 2004158777A JP 2004158777 A JP2004158777 A JP 2004158777A JP 2005336120 A JP2005336120 A JP 2005336120A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 150000002085 enols Chemical group 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000004821 distillation Methods 0.000 claims abstract description 14
- 239000005011 phenolic resin Substances 0.000 claims abstract description 9
- 239000003822 epoxy resin Substances 0.000 claims abstract description 5
- 229920000647 polyepoxide Polymers 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- -1 keto acid ester Chemical class 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 abstract description 52
- 239000000203 mixture Substances 0.000 abstract description 9
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 229930194542 Keto Natural products 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000012535 impurity Substances 0.000 description 8
- XPIWVCAMONZQCP-UHFFFAOYSA-N methyl 2-oxobutanoate Chemical compound CCC(=O)C(=O)OC XPIWVCAMONZQCP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000000539 dimer Substances 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000005708 Sodium hypochlorite Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 4
- DDMCDMDOHABRHD-UHFFFAOYSA-N methyl 2-hydroxybutanoate Chemical compound CCC(O)C(=O)OC DDMCDMDOHABRHD-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- XITRBUPOXXBIJN-UHFFFAOYSA-N bis(2,2,6,6-tetramethylpiperidin-4-yl) decanedioate Chemical compound C1C(C)(C)NC(C)(C)CC1OC(=O)CCCCCCCCC(=O)OC1CC(C)(C)NC(C)(C)C1 XITRBUPOXXBIJN-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005837 enolization reaction Methods 0.000 description 2
- FJAKCEHATXBFJT-UHFFFAOYSA-N ethyl 2-oxobutanoate Chemical compound CCOC(=O)C(=O)CC FJAKCEHATXBFJT-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001577 simple distillation Methods 0.000 description 2
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- MRVXVYYFOMRRLK-UHFFFAOYSA-N C(C(=O)C)(=O)OCCC.C(C(=O)C)(=O)OC Chemical compound C(C(=O)C)(=O)OCCC.C(C(=O)C)(=O)OC MRVXVYYFOMRRLK-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MBNLVYPIKSWXCT-UHFFFAOYSA-N methyl 2-oxopentanoate Chemical compound CCCC(=O)C(=O)OC MBNLVYPIKSWXCT-UHFFFAOYSA-N 0.000 description 1
- AAJSMPDVABPJTE-UHFFFAOYSA-N methyl 3-chloro-2-oxobutanoate Chemical compound COC(=O)C(=O)C(C)Cl AAJSMPDVABPJTE-UHFFFAOYSA-N 0.000 description 1
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- ILPVOWZUBFRIAX-UHFFFAOYSA-N propyl 2-oxopropanoate Chemical compound CCCOC(=O)C(C)=O ILPVOWZUBFRIAX-UHFFFAOYSA-N 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、医薬や農薬などの合成原料として重要な化合物である２−ケト酸エステルを製造する方法に関する。 The present invention relates to a method for producing a 2-keto acid ester which is an important compound as a synthetic raw material for pharmaceuticals and agricultural chemicals.
一般式（２） General formula (2)
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ 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、一般式（１） 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. The 2-keto acid ester represented by the general formula (1 )
で表されるケト−エノールの平衡組成を持つ混合物であり、一定の条件を満たせば、ケト体とエノール体を分離できることが知られている。（非特許文献１） It is known that the keto body and the enol body can be separated if they satisfy a certain condition. (Non-Patent Document 1)
また、２−ケト酸エステルは不安定な化合物であり、一般式（３）、（４）、（５）で示されるような２量化物等の不純物が生成する。 Moreover, 2-keto acid ester is an unstable compound, and impurities such as dimers as represented by the general formulas (3), (4), and (5) are generated.
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。）
前記一般式（３）、（４）、（５）で示される不純物はエノール体を経由して生成することから、２−ケト酸エステル中のケト体含有率が高いほど保存安定性が高いことから、ケト体含有率の高い高純度２−ケト酸エステルを製造する工業的に有利な方法が望まれていた。 Since the impurities represented by the general formulas (3), (4) and (5) are generated via enol bodies, the higher the keto body content in the 2-keto acid ester, the higher the storage stability. Therefore, an industrially advantageous method for producing a high-purity 2-keto acid ester having a high keto content is desired.
本発明者らは課題を解決する方法について鋭意検討した結果、ケト体含有率の高い、高純度２−ケト酸エステルを製造する方法を見出し、本発明に到達した。 As a result of intensive studies on a method for solving the problems, the present inventors have found a method for producing a high-purity 2-keto acid ester having a high keto content, and have reached the present invention.
すなわち、本発明は、一般式（１） That is, the present invention relates to the general formula (1)
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。）で表されるケト体とエノール体の混合物である２−ケト酸エステルを蒸留する際に、エノール体含有率の高い前留分をｐＨ１．５〜５に調製してから加熱処理した後、蒸留工程にリサイクルすることを特徴とするケト体含有率の高い高純度２−ケト酸エステルを製造方法である。 Where 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. When the keto acid ester is distilled, the pre-fraction having a high enol content is adjusted to pH 1.5 to 5 and then heat-treated, and then recycled to the distillation step. This is a method for producing a high purity 2-keto acid ester.
本発明の方法で蒸留を行うことで、ケト体含有率が高く、安定な高純度２−ケト酸エステルを高収率で得ることができる。 By carrying out distillation by the method of the present invention, a keto body content rate is high, and a stable high-purity 2-keto acid ester can be obtained in a high yield.
本発明における一般式（２） General formula (2) in the present invention
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。）で表される２−ケト酸エステルとは、ピルビン酸メチル、ピルビン酸プロピル、２−ケトブタン酸メチル、２−ケトブタン酸エチル、２−ケトペンタン酸メチル等の２−ケト酸エステル等の２−ケト低級アルキルカルボン酸エステル類が挙げられるが、好ましくはピルビン酸メチル、ピルビン酸プロピル、２−ケト酪酸メチル、２−ケト酪酸エチルである。 (Here, 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.) The 2-keto acid ester represented by methyl pyruvate 2-keto lower alkyl carboxylic acid esters such as 2-keto acid esters such as propyl pyruvate, methyl 2-ketobutanoate, ethyl 2-ketobutanoate and methyl 2-ketopentanoate, preferably methyl pyruvate Propyl pyruvate, methyl 2-ketobutyrate, ethyl 2-ketobutyrate.
２−ケト酸エステルに含有されるケト体とエノール体の量は、それぞれの化合物に適したガスクロマトグラフィー条件で測定することが出来る。本発明でケト体含有率またはエノール体含有率と言う場合は、それぞれ、２−ケト酸エステル（ケト体とエノール体の合計量）に対する含有率を言う。 The amount of keto and enol contained in the 2-keto acid ester can be measured under gas chromatography conditions suitable for each compound. In the present invention, the term “keto body content” or “enol body content” refers to the content of 2-keto acid ester (total amount of keto body and enol body).
２−ケト酸エステルに含有されるケト体とエノール体の量は、化合物の種類によって平衡組成が異なるので一概には言えないが、例えば２−ケト酪酸メチルであれば平衡組成はケト体／エノール体が約９７／３である。また、ケト体が鉄等の金属イオンと接触すると分解が促進されて２量体等の不純物が生成するが、これは一般式（６）に示したようにケト体が金属イオンによりエノール構造に誘導されるために、もう１分子のケト体と反応し易くなり、２量体等の不純物が生成する。 The amount of keto and enol contained in the 2-keto acid ester cannot be generally specified because the equilibrium composition differs depending on the type of compound. For example, if methyl 2-ketobutyrate is used, the equilibrium composition is keto / enol. The body is about 97/3. In addition, when the keto body comes into contact with a metal ion such as iron, decomposition is promoted and impurities such as a dimer are generated. This is because the keto body is converted into an enol structure by the metal ion as shown in the general formula (6). Since it is induced, it easily reacts with another molecule of keto, and an impurity such as a dimer is generated.
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。） (Here, 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.)
また、金属が存在しなくても、ハロゲンイオン等でも同様にエノール化が促進されて不純物の増加が促進される。エノール化を促進する物質が共存しなくとも、長期に保存する場合には２−ケト酸エステル中に含有されるエノール体が分解を促進するために、エノール体の含有量をできるだけ低減させることが２−ケト酸エステル純度の低下を抑制するためには必要である。従ってエノール体含有率の低い、高純度ケト酸エステルの製造法が重要となる。 Even if no metal is present, enolization is similarly promoted by halogen ions and the like, and the increase in impurities is promoted. Even if a substance that promotes enolization does not coexist, the enol form contained in the 2-keto acid ester promotes decomposition when stored for a long period of time, so that the content of the enol form can be reduced as much as possible. It is necessary to suppress a decrease in 2-keto acid ester purity. Therefore, a method for producing a high-purity keto acid ester having a low enol content is important.
一般にケト体とエノール体は沸点が異なり、エノール体の方が低沸点である。これはエノール体が一般式（７） In general, keto bodies and enol bodies have different boiling points, and enol bodies have lower boiling points. The enol form is represented by the general formula (7)
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。）に示したように、５員環構造を形成することによる。従って、精留すればエノール体とケト体を分離することができる。 (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). As shown in FIG. . Therefore, enol and keto bodies can be separated by rectification.
例えば２−ケト酪酸メチルの場合、平衡組成（ケト体／エノール体＝９７／３）の混合物を２０〜３０段の精留塔で蒸留すると、ケト体含有率が約９９％の高純度２−ケト酪酸メチルが約８０％の収率で得られるが、約２０％の前留分に約１８％のケト体が含まれる。従って、高純度２−ケト酪酸メチルの精製回収率を向上させるためには、前留分（組成比 ケト体／エノール体＝９０／１０）を加熱処理して精留仕込み時の組成比（９７／３）まで戻してから蒸留すればよい。 For example, in the case of methyl 2-ketobutyrate, when a mixture having an equilibrium composition (keto form / enol form = 97/3) is distilled in a rectification column having 20 to 30 stages, a high purity 2- Methyl ketobutyrate is obtained in a yield of about 80%, but about 20% of the pre-distillate contains about 18% keto form. Therefore, in order to improve the purification and recovery of high-purity methyl 2-ketobutyrate, the pre-fraction (composition ratio keto body / enol body = 90/10) is heat-treated and the composition ratio (97 / 3) and then distilled.
エノール体含有率の高い留分はｐＨを１．５〜５に調製してから加熱処理して蒸留することが重要である。ここで、ｐＨを調整してから加熱処理する留分とは、エノール含有率の高い留分をいうが、好ましくは、エノール体含有率が２−ケト酸エステルに対して３％以上の留分が好ましい。 It is important that the fraction having a high enol content is distilled after heat treatment after adjusting the pH to 1.5 to 5. Here, the fraction to be heat-treated after adjusting the pH refers to a fraction having a high enol content, preferably a fraction having an enol content of 3% or more with respect to the 2-keto acid ester. Is preferred.
エノール体含有率の高い留分は、ｐＨ１．５〜５に調製するが、好ましくはｐＨ２〜４、更に好ましくは２〜３に調製する。この範囲であれば留分に含まれるエノール体の一部はケト体に変換されると同時に、大部分は分解されるが、ケト体の分解は抑制されて、全体としてケト体の回収率が向上する。 The fraction having a high enol content is adjusted to pH 1.5 to 5, preferably pH 2 to 4, more preferably 2 to 3. Within this range, a part of the enol body contained in the fraction is converted into a keto body and at the same time, most of it is decomposed, but the decomposition of the keto body is suppressed, and the recovery rate of the keto body as a whole is increased. improves.
ｐＨを１．５〜５に調製する方法は、ハロゲンイオンを含まない有機酸や無機酸、あるいはそれらの塩を添加する方法が挙げられるが、好ましくは炭酸ナトリウム、炭酸水素ナトリウム等の弱塩基性のアルカリ金属塩であり、炭酸水素ナトリウムが特に好ましい。アルカリ金属塩の添加量は仕込み前留分に対して０．０１〜０．００１重量倍が好ましく、さらに好ましくは０．００８〜０．００５重量倍である。これら弱塩基性のアルカリ金属塩を前留分に添加して所定のｐＨに調製することもできるが、硫酸水素ナトリウム、あるいはその水和物等の弱酸性のアルカリ金属塩と組み合わせる方法も採用できる。具体的には、一定量の弱塩基性アルカリ金属塩を添加した後、所定のｐＨになるまで弱酸性のアルカリ金属塩を添加する方法が好ましい。 Examples of the method for adjusting the pH to 1.5 to 5 include a method of adding an organic acid or an inorganic acid not containing a halogen ion, or a salt thereof, but preferably a weakly basic such as sodium carbonate or sodium bicarbonate. An alkali metal salt of sodium hydrogen carbonate is particularly preferable. The addition amount of the alkali metal salt is preferably 0.01 to 0.001 times by weight, more preferably 0.008 to 0.005 times by weight with respect to the fraction before charging. These weakly basic alkali metal salts can be adjusted to a predetermined pH by adding them to the pre-fraction, but a method of combining with weakly acidic alkali metal salts such as sodium hydrogen sulfate or hydrates thereof can also be adopted. . Specifically, it is preferable to add a weakly acidic alkali metal salt until a predetermined pH is reached after adding a certain amount of the weakly basic alkali metal salt.
加熱温度は室温から８０℃であり、好ましくは３０〜６０℃、特に好ましくは３５〜４５℃である。この範囲であれば、ケト体の回収率は高い。 The heating temperature is from room temperature to 80 ° C, preferably 30 to 60 ° C, particularly preferably 35 to 45 ° C. Within this range, the keto body recovery rate is high.
加熱時間は条件によって異なるが、通常は２〜１０時間である。 Although heating time changes with conditions, it is 2 to 10 hours normally.
このように、ｐＨを調製してから加熱処理を行うと、留分に含まれるエノール体の一部はケト体に変換され、大部分のエノール体は分解する。こうして、留分のエノール体含有率を低くしたあとで、蒸留する。 Thus, when the heat treatment is performed after adjusting the pH, a part of the enol body contained in the fraction is converted into a keto body, and the majority of the enol body is decomposed. Thus, after reducing the enol content of the fraction, it is distilled.
かくして得られた留分の加熱処理液はそのまま、あるいは析出しているアルカリ金属塩を濾過で除去してから、または酢酸エチル等の有機溶媒で希釈した後に水洗し、有機層の溶媒を濃縮除去してから蒸留することもできる。このようにして、エノール体含有率の高い留分をｐＨ調整後加熱処理を行って蒸留をすると、主留分としてケト体含有率の高い高純度２−ケト酸エステルを、高収率で得ることができる。 The heat treatment solution of the fraction thus obtained is left as it is or after removing the precipitated alkali metal salt by filtration or diluted with an organic solvent such as ethyl acetate and then washed with water, and the organic layer solvent is concentrated and removed. Then, it can be distilled. In this way, when a fraction having a high enol content is subjected to heat treatment after pH adjustment and distilled, a high-purity 2-keto acid ester having a high keto content is obtained in a high yield as the main fraction. be able to.
蒸留は連続で行っても、バッチ式で行っても良いが、エノール体含有率の高い留分を加熱処理し、蒸留工程にリサイクルして、連続的に行うのが好ましい。 Although distillation may be performed continuously or batchwise, it is preferable that the fraction having a high enol content is heat-treated and recycled to the distillation step to be continuously performed.
本発明の方法によれば、通常、エノール体の含有量が２−ケト酸エステルに対して２％以下の高純度の２−ケト酸エステルを得ることができる。 According to the method of the present invention, a highly pure 2-keto acid ester having an enol content of 2% or less with respect to the 2-keto acid ester can be usually obtained.
ここで、蒸留原料に使用する２−ケト酸エステルは一般式（８） Here, the 2-keto acid ester used for the distillation raw material is represented by the general formula (8).
（ここで、Ｒ１ は水素、炭素数１〜４のアルキル基であり、Ｒ２ は炭素数１〜４のアルキル基を示す。）で表される２−ヒドロキシ酸エステルを酸化して製造する事ができる。 Where 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. I can do things.
酸化法は何れの方法でも採用できるが、例えば次亜塩素酸ナトリウム水溶液で酸化する方法が採用できる。 Any method can be employed as the oxidation method. For example, a method of oxidizing with an aqueous sodium hypochlorite solution can be employed.
また、エノール体含有率の高い留分をｐＨ１．５〜５に調製して加熱処理して得た溶液中に酸化反応の原料である２−ヒドロキシ酸エステルが蓄積してきた場合には、留分の加熱処理液を酸化してから蒸留にリサイクルすることで、効率よく２−ケト酸エステルのケト体が回収できる。 Moreover, when 2-hydroxy acid ester which is a raw material of the oxidation reaction has accumulated in a solution obtained by preparing a fraction having a high enol content ratio to pH 1.5 to 5 and heat treatment, The keto body of the 2-keto acid ester can be efficiently recovered by oxidizing the heat treatment solution and recycling it to distillation.
留分の加熱処理液の酸化法は何れの方法でも採用できるが、前記した次亜塩素酸ナトリウム水溶液で酸化する方法などをあげることができる。 Any method can be used as the oxidation method of the heat treatment solution of the fraction, and examples thereof include a method of oxidizing with the above-mentioned sodium hypochlorite aqueous solution.
酸化処理後、通常の方法で回収した溶液を蒸留することで、主留分としてケト体含有率の高い高純度２−ケト酸エステルが得られる。 After the oxidation treatment, the solution collected by a usual method is distilled to obtain a high-purity 2-keto acid ester having a high keto content as the main fraction.
得られたケト体含有率の高い高純度２−ケト酸エステルは、窒素雰囲気下でフェノール樹脂、またはフェノール・エポキシ樹脂と接触させた状態で保存すれば、長期間安定に保管する事ができる。窒素雰囲気下でフェノール樹脂、またはフェノール・エポキシ樹脂と接触させた状態で保存する方法としては、これらの樹脂でライニングされた容器に保管する方法などがあげられる。 The obtained high-purity 2-keto acid ester having a high keto content can be stably stored for a long period of time if it is stored in a nitrogen atmosphere in contact with a phenol resin or a phenol / epoxy resin. Examples of the method of storing in a nitrogen atmosphere in contact with a phenol resin or a phenol / epoxy resin include a method of storing in a container lined with these resins.
以下、実施例で本発明を詳細に説明するが、本発明はこれらに限定されるものではない。なお、２−ケト酸エステルの定量分析は化合物によりＧＣ分析条件は異なるが、代表例として２−ケト酪酸メチルの分析条件を下記する。 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分析条件
カラム ：TC-17 ＜GL Sciences製＞
I.D. 0.32mmφ × 60 m , 0.25μm
温度 50℃(10min)→20℃/min→250℃（10min）
注入口、検出器温度 ：200℃
流量 ：全流量 60ml/min、カラム流量 2.26ml/min
Split ratio ：1/19
ＲＴ :エノール体 9.1min
ケト体 11.5min
GC analysis conditions Column: TC-17 <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
参考例１ ２−ケト酪酸メチルの合成法 （２−ケト酪酸メチルをＫＢＭと略す）
０〜５℃の水で冷却できるコンデンサー、温度計、ｐＨメーターの端子、次亜塩素酸ソーダ水溶液が定量的に供給できる供給口を装着した２ｌの４つ口フラスコに２−ヒドロキシ酪酸メチル１１８ｇ（１モル）、酢酸エチル４７２ｇ、酢酸３０ｇ（５００ミリモル）、三共株式会社のＳａｎｏｌＬＳ−７７０（ビス（２，２，６，６−テトラメチル−４−ピペリジル）セバケート）９．６ｇ（２０ミリモル）、及び硫酸水素ナトリウム２１ｇ（１５０ミリモル）を仕込み、強力マグネチックスターラーで撹拌した。フラスコ外部をアルミホイルで覆い遮光状態にし、内温を２５℃に保ちながら有効塩素１３．０％，遊離アルカリ０．７％、ＮａＣｌ１１．２％の次亜塩素酸ソーダ水溶液６３０ｇを１０時間かけて定量ポンプで仕込み、さらに２時間反応を継続した。反応終了後、酢酸エチル層を分液して水洗した後、単蒸留して粗ＫＢＭ１０２．５ｇを得た。ＧＣ分析した結果、ＫＢＭ中のケト体は９４．０ｇ、エノール体は３．２ｇであった。（エノール体／ケト体＝９６．７／３．３）
Reference Example 1 Synthesis of methyl 2-ketobutyrate (methyl 2-ketobutyrate is abbreviated as KBM)
A 2-liter four-necked flask equipped with a condenser that can be cooled with water at 0 to 5 ° C., a thermometer, a pH meter terminal, and a supply port capable of quantitatively supplying sodium hypochlorite aqueous solution, 118 g of methyl 2-hydroxybutyrate ( 1 mol), 472 g of ethyl acetate, 30 g (500 mmol) of acetic acid, Sanol LS-770 (bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate) from Sankyo Corporation, 9.6 g (20 mmol), And 21 g (150 mmol) of sodium hydrogen sulfate were charged and stirred with a strong magnetic stirrer. Cover the outside of the flask with aluminum foil in a light-shielded state, and maintain 630 g of sodium hypochlorite aqueous solution of 13.0% effective chlorine, 0.7% free alkali and 11.2% NaCl over 10 hours while keeping the internal temperature at 25 ° C. Charged with a metering pump, the reaction was continued for another 2 hours. After completion of the reaction, the ethyl acetate layer was separated and washed with water, followed by simple distillation to obtain 102.5 g of crude KBM. As a result of GC analysis, the keto body in KBM was 94.0 g, and the enol body was 3.2 g. (Enol body / keto body = 96.7 / 3.3)
実施例１
参考例１と同様にして合成した粗ＫＢＭ１ｋｇ（ＫＢＭ含有量９２５．０ｇ、ケト体／エノール体＝９６．８／３．２）を、ヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留し、前留分として１７０．６ｇ（ＫＢＭ含有量１６６．６ｇ、ケト体／エノール体＝８８．４／１１．６）、８０〜９０℃／３．３ｋＰａの主留分として精ＫＢＭを７４４．０ｇ得た（ＫＢＭ含有量７４１．８ｇ、ケト体／エノール体＝９８．９／１．１）。ケト体の回収率は８１．９％であった。得られた前留分に炭酸水素ナトリウム０．８５ｇを添加し、硫酸水素ナトリウム・１水和物でｐＨを２〜３に調製し、３５〜４５℃で６時間攪拌した。反応終了後、室温まで冷却してから析出結晶を濾過し、母液をヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留し、８０〜９０℃／３．３ｋＰａの主留分として、精ＫＢＭを１１８．５ｇ得た（ＫＢＭ含有量１１８．０ｇ、ケト体／エノール体＝９８．８／１．２）。粗ＫＢＭからの合計収量８５９．８ｇであり、精ＫＢＭ収率は９３．２％であった。また、更にリサイクルが可能な前留分は２８ｇであった。
Example 1
A crude KBM 1 kg (KBM content 925.0 g, keto body / enol body = 96.8 / 3.2) synthesized in the same manner as in Reference Example 1 was equipped with a 25-30 stage rectification column packed with helipack. Distilled under reduced pressure using a rectifying apparatus, the previous fraction was 170.6 g (KBM content 166.6 g, keto / enol = 88.4 / 11.6), 80 to 90 ° C./3.3 kPa. As the main fraction, 744.0 g of purified KBM was obtained (KBM content 741.8 g, keto / enol = 98.9 / 1.1). The keto body recovery was 81.9%. Sodium hydrogencarbonate 0.85g was added to the obtained front fraction, pH was adjusted to 2-3 with sodium hydrogensulfate monohydrate, and it stirred at 35-45 degreeC for 6 hours. After completion of the reaction, after cooling to room temperature, the precipitated crystals are filtered, and the mother liquor is distilled under reduced pressure using a rectification apparatus equipped with a 25-30 stage rectification column packed with helipack, 80-90 ° C / 3 As a main fraction of 3 kPa, 118.5 g of purified KBM was obtained (KBM content 118.0 g, keto / enol = 98.8 / 1.2). The total yield from the crude KBM was 859.8 g, and the refined KBM yield was 93.2%. Further, the previous fraction that could be further recycled was 28 g.
比較例１
実施例１で得られた前留分１００ｇを処理せずに、そのままヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留した結果、精ＫＢＭは僅かに５５．２ｇしか回収できなかった。
Comparative Example 1
As a result of distillation under reduced pressure using a rectification apparatus equipped with a rectification tower of 25 to 30 stages packed with Helipak without processing 100 g of the previous fraction obtained in Example 1, the purified KBM was slightly Only 55.2 g could be recovered.
実施例２〜４
実施例１と同様にして得た前留分（ＫＢＭ純度 ９７．６％、ケト体／エノール体＝８８．４／１１．６）２０ｇを５０ｍｌのガラスアンプルに仕込み、炭酸水素ナトリウム０．１ｇを添加し、スターラーで攪拌しながら硫酸水素ナトリウムで所定のｐＨに調製し、所定温度、所定時間攪拌した。得られた加熱処理液のエノール体、ケト体含有量を分析し、結果を表１に示した。
Examples 2-4
20 g of the fore fraction (KBM purity 97.6%, keto / enol = 88.4 / 11.6) obtained in the same manner as in Example 1 was charged into a 50 ml glass ampoule, and 0.1 g of sodium bicarbonate was added. The mixture was added, adjusted to a predetermined pH with sodium hydrogen sulfate while stirring with a stirrer, and stirred at a predetermined temperature for a predetermined time. The enol body and keto body contents of the obtained heat treatment liquid were analyzed, and the results are shown in Table 1.
実施例５
参考例１と同様にして合成した際、酸化反応の転化率が９８％と低いまま単離処理し、単蒸留して得た粗ＫＢＭ１ｋｇ（ＫＢＭ含有量９１１．３ｇ、ケト体／エノール体＝９６．９／３．１、 ２−ヒドロキシ酪酸メチル含有量 １８．５ｇ）を実施例１と同様にしてヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留し、前留分として１８６．９ｇ（ＫＢＭ含有量１６４．６ｇ、ケト体／エノール体＝８７．９／１２．１、２−ヒドロキシ酪酸メチル含有量 １７．２ｇ）を得た。また、８５〜９０℃／３．３ｋＰａの主留分として精ＫＢＭを７０９．８ｇ得た（ＫＢＭ含有量７０６．３ｇ、ケト体／エノール体＝９８．９／１．１）。精ＫＢＭ回収率は７７．５％であった。得られた前留物に炭酸水素ナトリウム０．８５ｇを添加し、硫酸水素ナトリウム・１水和物でｐＨを２〜３に調製し、３５〜４５℃で６時間攪拌した。反応終了後、参考例と同様にして酸化して２−ヒドロキシ酪酸メチルをＫＢＭに変換した後、酢酸エチル層を濃縮してから、ヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留し、８０〜９０℃／３．３ｋＰａの主留分として精ＫＢＭを１４１．８ｇ得た（ＫＢＭ含有量１４１．１ｇ、ケト体／エノール体＝９８．８／１．２）。粗ＫＢＭからの合計収量は８５１．６ｇであり、収率は９１．６％であった。
Example 5
When synthesized in the same manner as in Reference Example 1, 1 kg of crude KBM (KBM content 911.3 g, keto / enol = 96) obtained by isolation treatment with a low conversion rate of the oxidation reaction of 98% and simple distillation. 0.9 / 3.1, methyl 2-hydroxybutyrate 18.5 g) in the same manner as in Example 1, using a rectifying apparatus equipped with a 25-30 stage rectification column packed with helipack. As a fraction, 186.9 g (KBM content 164.6 g, keto / enol = 87.9 / 12.1, methyl 2-hydroxybutyrate 17.2 g) was obtained. Moreover, 709.8g of refined KBM was obtained as a main fraction of 85-90 degreeC / 3.3kPa (KBM content 706.3g, keto body / enol body = 98.9 / 1.1). The purified KBM recovery rate was 77.5%. Sodium hydrogencarbonate 0.85g was added to the obtained forerate, pH was adjusted to 2-3 with sodium hydrogensulfate monohydrate, and it stirred at 35-45 degreeC for 6 hours. After completion of the reaction, oxidation was carried out in the same manner as in the Reference Example to convert methyl 2-hydroxybutyrate to KBM, and after concentrating the ethyl acetate layer, a precision column equipped with a 25-30 rectification column packed with helipack was installed. Distillation under reduced pressure using a distillation apparatus gave 141.8 g of purified KBM as a main fraction of 80 to 90 ° C./3.3 kPa (KBM content 141.1 g, keto / enol = 98.8 / 1). .2). The total yield from the crude KBM was 851.6 g, and the yield was 91.6%.
比較例２
実施例５で得られた前留分を処理せずに、そのままヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留した結果、精ＫＢＭは僅かに３１．９ｇしか回収できなかった。
Comparative Example 2
As a result of performing distillation under reduced pressure using a rectification apparatus equipped with a rectification tower of 25 to 30 stages packed with Helipak without processing the previous fraction obtained in Example 5, the purified KBM was only 31. Only .9 g could be recovered.
比較例３
実施例５と同様にして前留分を処理するが、処理の順序を入れ替え、先に前留分を次亜塩素酸ナトリウム水溶液で酸化した後、次いでｐＨ２〜３に調製してから加熱処理した後、ヘリパックを充填した２５〜３０段の精留塔を装着した精留装置を使用して減圧蒸留した結果、精ＫＢＭは僅かに６９．５ｇしか得られなかった。また、不純物として、３−クロロ−２−ケト酪酸メチルが約０．７％検出された。
Comparative Example 3
The previous fraction was treated in the same manner as in Example 5. However, the order of the treatment was changed, and after the previous fraction was oxidized with an aqueous sodium hypochlorite solution, the pH was adjusted to 2-3 and then heat-treated. Then, as a result of distillation under reduced pressure using a rectification apparatus equipped with a 25-30 stage rectification column packed with helipack, only 69.5 g of purified KBM was obtained. Further, about 0.7% of methyl 3-chloro-2-ketobutyrate was detected as an impurity.
実施例６
実施例１と同様にして得た前留分（ＫＢＭ純度 ９７．６％、ケト体／エノール体＝８８．４／１１．６）２０ｇを５０ｍｌのガラスアンプルに仕込み、前留分に対し０．０１０の炭酸水素ナトリウムを添加し、スターラーで攪拌しながら硫酸水素ナトリウムでｐＨ４．９に調製し、３０℃、７時間反応したところ、ケト体／エノール体は９６．５／３．５になり、ケト体としての回収率は１００％であった。
Example 6
20 g of the fore fraction (KBM purity 97.6%, keto body / enol body = 88.4 / 11.6) obtained in the same manner as in Example 1 was charged into a 50 ml glass ampoule, and the amount of the pre-fraction was adjusted to 0. 010 sodium bicarbonate was added, pH 4.9 was adjusted with sodium hydrogen sulfate while stirring with a stirrer, and reacted at 30 ° C. for 7 hours. The keto / enol form was 96.5 / 3.5, The recovery rate as a keto body was 100%.
実施例７
実施例１で得た精ＫＢＭ（化学純度９９．６％、ケト体純度９８．４％、エノール体純度１．２％）をフェノール４Ａでライニングした容器（日鐵ドラム（株）製）にて４０℃、４２日間保管したところ、ケト体は９８．４％で全く変化しなかった。また、エノール体は０．２％に低下しており、２量体等のその他不純物が０．４％から１．４％に増加していた。
Example 7
In a container (manufactured by Nippon Steel Drum Co., Ltd.) lined with the purified KBM obtained in Example 1 (chemical purity 99.6%, keto purity 98.4%, enol purity 1.2%) with phenol 4A When stored at 40 ° C. for 42 days, the keto body was 98.4% and did not change at all. Further, the enol form decreased to 0.2%, and other impurities such as a dimer increased from 0.4% to 1.4%.
比較例４
実施例７と同様にして、実施例１で得た精ＫＢＭをＳＵＳ３１６容器に仕込み、４０℃で２８日間保管したところ、ケト体は９０．３％に減少した。また、エノール体は１．５％であり、明らかにケト体からエノール体に変換されていた。また、メタノールも０．５％検出されており、脱メタノール２量体成分や、付加タイプの２量体が増加していた。
Comparative Example 4
In the same manner as in Example 7, when the purified KBM obtained in Example 1 was charged into a SUS316 container and stored at 40 ° C. for 28 days, the keto body decreased to 90.3%. In addition, the enol form was 1.5%, which was clearly converted from the keto form to the enol form. Further, 0.5% of methanol was detected, and the demethanol dimer component and the addition type dimer were increased.
比較例５
実施例１で得た精ＫＢＭに、クロルイオンが２０〜３０ｐｐｍになるよう塩酸を添加し、パイレックス（登録商標）ガラス容器に４０℃で２８日間保管したところ、ケト体は９２％に減少した。また、エノール体は１．７％に増加し、その他不純物が多数検出された。
Comparative Example 5
Hydrochloric acid was added to the purified KBM obtained in Example 1 so that the chloro ion was 20 to 30 ppm, and stored in a Pyrex (registered trademark) glass container for 28 days at 40 ° C., the keto body decreased to 92%. In addition, the enol form increased to 1.7%, and many other impurities were detected.
本発明によれば、２−ケト酸エステルのケト体とエノール体の混合物から蒸留精製してケト体含有率の高い高純度２−ケト酸エステルが高収率で製造できる。更に、フェノール樹脂、またはフェノール・エポキシ樹脂と接触させて保管することで、長期間に渡って２−ケト酸エステルを安定に保管できる。 According to the present invention, a high-purity 2-keto acid ester having a high keto body content can be produced in high yield by distillation purification from a mixture of keto body and enol body of 2-keto acid ester. Furthermore, 2-keto acid ester can be stably stored over a long period of time by storing it in contact with a phenol resin or a phenol / epoxy resin.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6078936A (en) * | 1983-10-06 | 1985-05-04 | Kuraray Co Ltd | Stabilization of aqueous solution of pyruvic acid salt |
| JPH08100285A (en) * | 1994-09-22 | 1996-04-16 | Huels Ag | Preparation of keto compound |
| JPH1036312A (en) * | 1996-07-25 | 1998-02-10 | Toray Ind Inc | Ph adjustment of pyruvic acid-containing liquid |
| JPH10330318A (en) * | 1997-06-02 | 1998-12-15 | Toray Ind Inc | Production and storage of high grade pyruvic acid ester |
| JPH1180087A (en) * | 1997-09-05 | 1999-03-23 | Toray Ind Inc | Production of high-purity lower alkyl ester of pyruvic acid |
| JPH11315052A (en) * | 1998-03-05 | 1999-11-16 | Toray Ind Inc | Production of alpha-ketocarboxylic acid ester |
| JP2005325050A (en) * | 2004-05-14 | 2005-11-24 | Toray Fine Chemicals Co Ltd | Method for storing 2-keto acid ester |
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- 2004-05-28 JP JP2004158777A patent/JP4775785B2/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6078936A (en) * | 1983-10-06 | 1985-05-04 | Kuraray Co Ltd | Stabilization of aqueous solution of pyruvic acid salt |
| JPH08100285A (en) * | 1994-09-22 | 1996-04-16 | Huels Ag | Preparation of keto compound |
| JPH1036312A (en) * | 1996-07-25 | 1998-02-10 | Toray Ind Inc | Ph adjustment of pyruvic acid-containing liquid |
| JPH10330318A (en) * | 1997-06-02 | 1998-12-15 | Toray Ind Inc | Production and storage of high grade pyruvic acid ester |
| JPH1180087A (en) * | 1997-09-05 | 1999-03-23 | Toray Ind Inc | Production of high-purity lower alkyl ester of pyruvic acid |
| JPH11315052A (en) * | 1998-03-05 | 1999-11-16 | Toray Ind Inc | Production of alpha-ketocarboxylic acid ester |
| JP2005325050A (en) * | 2004-05-14 | 2005-11-24 | Toray Fine Chemicals Co Ltd | Method for storing 2-keto acid ester |
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