JP5146928B2 - Method for producing Claisen rearrangement compound and synthesis apparatus thereof - Google Patents
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- 238000005821 Claisen rearrangement reaction Methods 0.000 title claims description 68
- 150000001875 compounds Chemical class 0.000 title claims description 40
- 238000003786 synthesis reaction Methods 0.000 title claims description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 230000015572 biosynthetic process Effects 0.000 title description 20
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- 238000000034 method Methods 0.000 claims description 47
- 239000003054 catalyst Substances 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000003960 organic solvent Substances 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 22
- 239000000376 reactant Substances 0.000 claims description 21
- 238000000926 separation method Methods 0.000 claims description 20
- 239000000758 substrate Substances 0.000 claims description 20
- -1 allyl ethers Chemical class 0.000 claims description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
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- 238000005265 energy consumption Methods 0.000 claims description 7
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 4
- 239000003049 inorganic solvent Substances 0.000 claims description 4
- 238000010908 decantation Methods 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
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- 239000000047 product Substances 0.000 description 18
- 125000005842 heteroatom Chemical group 0.000 description 16
- QIRNGVVZBINFMX-UHFFFAOYSA-N 2-allylphenol Chemical compound OC1=CC=CC=C1CC=C QIRNGVVZBINFMX-UHFFFAOYSA-N 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 125000004430 oxygen atom Chemical group O* 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 150000002829 nitrogen Chemical class 0.000 description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
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- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 230000007613 environmental effect Effects 0.000 description 2
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- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 2
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- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- POSICDHOUBKJKP-UHFFFAOYSA-N prop-2-enoxybenzene Chemical compound C=CCOC1=CC=CC=C1 POSICDHOUBKJKP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- RIMCPGRBTHTGDH-UHFFFAOYSA-N 2-chloro-1-(2-chloronaphthalen-1-yl)oxynaphthalene Chemical compound C1=CC=C2C(OC3=C4C=CC=CC4=CC=C3Cl)=C(Cl)C=CC2=C1 RIMCPGRBTHTGDH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UBJVUCKUDDKUJF-UHFFFAOYSA-N Diallyl sulfide Natural products C=CCSCC=C UBJVUCKUDDKUJF-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
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- SBIBMFFZSBJNJF-UHFFFAOYSA-N selenium;zinc Chemical compound [Se]=[Zn] SBIBMFFZSBJNJF-UHFFFAOYSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Description
本発明は、クライゼン転位生成物の製造方法と装置に関するものであり、更に詳しくは、高温高圧状態の亜臨界水を反応溶媒とし、無触媒かつ一段階でクライゼン転位化合物を製造する方法及びその合成装置に関するものである。本発明は、温度１００℃以上、圧力０．１ＭＰａ以上の亜臨界水を反応溶媒として、触媒無添加でクライゼン転位化合物を一段階の合成反応で、短時間、かつ連続的に合成する方法及びその装置を提供するものである。ここで、クライゼン転位におけるヘテロ原子としては、酸素、窒素、硫黄が挙げられ、それぞれアリルエーテル、アリルアミン、アリルチオエーテルに対応し、更に複数のヘテロ原子が組合わされたアリル化合物も含む。 The present invention relates to an apparatus and method for manufacturing the Claisen rearrangement product, more particularly, to a subcritical water of high temperature and high pressure conditions and reaction solvent, Claisen rearrangement compound producing method and catalyst-free and one step It relates to the device. The present invention, temperature of 10 0 ° C. or higher, pressure 0. The present invention provides a method and an apparatus for continuously synthesizing a Claisen rearrangement compound in a one-step synthesis reaction without adding a catalyst using subcritical water of 1 MPa or more as a reaction solvent. Here, examples of the hetero atom in the Claisen rearrangement include oxygen, nitrogen, and sulfur, which correspond to allyl ether, allylamine, and allyl thioether, respectively, and also include allyl compounds in which a plurality of heteroatoms are combined.
クライゼン転位は、基質・原料に対して生成物の機能性と同時に付加価値をも向上するため、香料、医薬品、食品分野において有用である。通常、クライゼン転位化合物を合成する場合、従来法では、非プロトン性有機溶媒に加えて、酸・塩基触媒が必要であり、食品、医薬品に利用される場合、残存する有機溶媒、触媒の除去は、大きな労力とエネルギーを必要とし、環境に影響を与えるのみならず生体に有害である等の問題点を有していた。本発明は、アリルエーテル類から、無触媒で、水を用いるプロセスのみでクライゼン転位化合物を合成する方法とその反応組成物及びその合成装置を提供するものであり、香料、医薬品や食品のみならず、化成品合成にも応用可能であり、クライゼン転位化合物を良好な収率で、短時間に、良好なエネルギー効率で、環境に影響を与えることなく、大量に生産し、提供することを可能にするものである。 The Claisen rearrangement is useful in the perfumery, pharmaceutical and food fields because it improves the functionality of the product as well as the added value of the product relative to the substrate / raw material. In general, when synthesizing a Claisen rearrangement compound, the conventional method requires an acid / base catalyst in addition to an aprotic organic solvent. When used in foods and pharmaceuticals, removal of the remaining organic solvent and catalyst is not necessary. However, it requires a lot of labor and energy, and has problems such as being harmful to the living body as well as affecting the environment. The present invention provides a method for synthesizing a Claisen rearrangement compound from allyl ethers without using a catalyst and using only water, a reaction composition thereof, and an apparatus for the synthesis thereof. It can also be applied to the synthesis of chemical products, making it possible to produce and provide the Claisen rearrangement compound in good yield, in a short time, with good energy efficiency, and without affecting the environment. To do.
従来、クライゼン転位を利用し、アリルエーテル類からアリルフェノール類を合成する方法が種々報告されている（例えば、非特許文献１参照）。ここで、アリルエーテル類からのアリルフェノール類を合成するクライゼン転位合成技術を完成すれば、通常は、他のヘテロ原子を有するクライゼン転位は可能となるため、特に酸素を含有する置換アリルエーテルから置換アリルフェノールを合成する技術の報告例は非常に多い（図１、図２）。 Conventionally, various methods for synthesizing allylphenols from allyl ethers using Claisen rearrangement have been reported (see, for example, Non-Patent Document 1). Here, if the Claisen rearrangement synthesis technology for synthesizing allylphenols from allyl ethers is completed, usually Claisen rearrangement having other heteroatoms becomes possible. There are numerous reports of techniques for synthesizing allylphenol (FIGS. 1 and 2).
図１のように、オルト位にクライゼン転位する場合、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は、水素又はアルキル基及びヘテロ原子を含む置換基、Ｘはヘテロ原子又は置換ヘテロ原子であり、具体的には酸素（Ｏ）、硫黄（Ｓ）、窒化水素（ＮＨ）、アルキル置換窒素（ＮＲ’）である。また、図２のように、芳香環のオルト位のＲ９，Ｒ１０がアルキル基及びヘテロ原子を含む置換基の場合、パラ位にクライゼン転位が起こる。ここで、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７は水素又はアルキル基及びヘテロ原子を含む置換基、Ｘはヘテロ原子又は置換ヘテロ原子であり、具体的には酸素（Ｏ）、硫黄（Ｓ）、窒化水素（ＮＨ）、アルキル置換窒素（ＮＲ’）である。 In the case of Claisen rearrangement to the ortho position as shown in FIG. 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen or an alkyl group and a substituent containing a hetero atom. , X is a heteroatom or a substituted heteroatom, specifically oxygen (O), sulfur (S), hydrogen nitride (NH), or alkyl-substituted nitrogen (NR ′). Further, as shown in FIG. 2, when R 9 and R 10 at the ortho position of the aromatic ring are substituents containing an alkyl group and a hetero atom, Claisen rearrangement occurs at the para position. Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are hydrogen or an alkyl group and a substituent containing a hetero atom, X is a hetero atom or a substituted hetero atom, specifically Are oxygen (O), sulfur (S), hydrogen nitride (NH), and alkyl-substituted nitrogen (NR ′).
先行技術文献によれば、無溶媒条件での加熱（非特許文献２）、無溶媒又は非プロトン性有機溶媒中でのマイクロ波加熱（非特許文献３）、あるいは有機溶媒中、ＢＣｌ３（非特許文献４、５）、Ｒ２ＡｌＣｌ（非特許文献６）、ＰｄＣｌ２（ＭｅＣＮ）２（非特許文献７）等のルイス酸が使用されてきた。 According to prior art documents, heating in a solvent-free condition (Non-Patent Document 2), microwave heating in a solvent-free or aprotic organic solvent (Non-Patent Document 3), or BCl 3 (Non-Patent Document 3) in an organic solvent. Lewis acids such as Patent Documents 4 and 5), R 2 AlCl (Non-Patent Document 6), and PdCl 2 (MeCN) 2 (Non-Patent Document 7) have been used.
ここで、上記の先行技術文献では、無溶媒条件での加熱では、フェニルアリルエーテルから温度２２０℃、反応時間６時間で収率８５％でクライゼン転位化合物であるｏ−アリルフェノールが得られる。また、マイクロ波を利用した場合には、フェニルアリルエーテルからのｏ−アリルフェノール合成は、無溶媒条件で、温度３２５−３６１℃、反応時間１０分で２１％と低収率であるが、ＤＭＦを溶媒とし、温度３００−３１５℃、反応時間６分とすることで９２％の高収率で得られる。 Here, in the above-mentioned prior art documents, o-allylphenol, which is a Claisen rearrangement compound, is obtained from phenylallyl ether in a yield of 85% at a temperature of 220 ° C. and a reaction time of 6 hours by heating under solvent-free conditions. When microwaves are used, the synthesis of o-allylphenol from phenylallyl ether is a low yield of 21% at a temperature of 325-361 ° C. and a reaction time of 10 minutes under solvent-free conditions. And a temperature of 300 to 315 ° C. and a reaction time of 6 minutes, a high yield of 92% can be obtained.
ルイス酸を用いた場合には、熱エネルギー利用の場合よりも常温でも反応が１０１０倍もの反応加速があるが、ｐ−体が増加する。例えば、通常加熱でｏ−トルイルアリルエーテルを基質とした場合、ｏ−メチルフェノールとｐ−メチルフェノールがそれぞれ収率８５％、１５％で得られるが、ＢＣｌ３のルイス酸を用いた場合、ｏ−メチルフェノールとｐ−メチルフェノールがそれぞれ６０％、３１％で得られ、結局、反応の加速がある反面、選択性が低下することが報告されている（非特許文献１）。 When a Lewis acid is used, the reaction is accelerated 10 to 10 times at room temperature as compared with the case of using thermal energy, but the p-form increases. For example, when o-toluyl allyl ether is used as a substrate by normal heating, o-methylphenol and p-methylphenol are obtained in yields of 85% and 15%, respectively, but when BCl 3 Lewis acid is used, o -Methylphenol and p-methylphenol can be obtained at 60% and 31%, respectively, and it has been reported that the selectivity is lowered while the reaction is accelerated (Non-patent Document 1).
したがって、無溶媒で熱エネルギーを利用するか、あるいはマイクロ波のような外場と有機溶媒、ルイス酸、金属錯体のような触媒に加えて、有機溶媒が、クライゼン転位にとって必要不可欠である。 Therefore, an organic solvent is indispensable for Claisen rearrangement in addition to an external field such as microwave and a catalyst such as an organic solvent, a Lewis acid, and a metal complex, utilizing heat energy without a solvent.
一方、クライゼン転位における溶媒としての水の可能性に関しては、水とクロロナフチルエーテルを常温付近２３℃で１２０時間激しく攪拌するＯｎ ｗａｔｅｒ反応（非特許文献８）で収率１００％で得られることが報告されている。しかし、多数のクライゼン転位に対する適用可能性については言及されていない（非特許文献９）。 On the other hand, regarding the possibility of water as a solvent in the Claisen rearrangement, it can be obtained in a yield of 100% by an On water reaction (Non-patent Document 8) in which water and chloronaphthyl ether are vigorously stirred at 23 ° C. for about 120 hours. It has been reported. However, no mention is made of the applicability to many Claisen rearrangements (Non-Patent Document 9).
反応後における後処理は、通常、触媒・有機溶媒中クライゼン転位では、反応混合物に中和剤を添加して中和後、抽出溶媒と水あるいは飽和食塩水を加え、分液し、溶媒層はその後、乾燥、溶媒除去、蒸留あるいは精留のプロセスを得て目的物を得るが、水層には水の他に、触媒、有機溶媒、酢酸、基質、生成物、副生成物、無機物の複雑な混合物が含有される。ここで、水層からの触媒の分離が容易である場合には、回収再生され、再使用されるが、分離が困難である場合には、そのまま廃棄・処分される（図３）。無触媒・高温高圧水中クライゼン転位のように、水層に触媒、有機溶媒が含有されず、水、生成物のみが含有されるならば、生成物をデカンテーションだけで分離が可能である。このことは、水の再生を可能にし、通常法に比べて、環境低減型のプロセスであることを意味する（図４）。 In the post-reaction after the reaction, usually, in Claisen rearrangement in a catalyst / organic solvent, a neutralizing agent is added to the reaction mixture to neutralize, and then an extraction solvent and water or a saturated saline solution are added, followed by liquid separation. After that, the desired product is obtained by the process of drying, solvent removal, distillation or rectification. In addition to water, the water layer is a complex of catalyst, organic solvent, acetic acid, substrate, product, by-product, inorganic matter. Such a mixture. Here, when the separation of the catalyst from the aqueous layer is easy, the catalyst is recovered and regenerated and reused. However, when the separation is difficult, the catalyst is discarded and disposed as it is (FIG. 3). As in the case of the Claisen rearrangement without catalyst / high temperature and high pressure water, if the water layer contains no catalyst and organic solvent but only water and product, the product can be separated only by decantation. This means that the water can be regenerated and is an environment-reducing process compared to the normal method (FIG. 4).
なお、あるプロセスが環境低減型であるかどうかは、Ｅ−ファクターで判断可能である。これは、あるプロセスにおける製品単位重量あたりの廃棄物重量の比率であり、あるプロセスのＥ−ファクターの値が小さいほど、生産に対しての廃棄物割合が少ないことから、環境低減型プロセスであると言える（非特許文献１０、１１）。 Whether or not a certain process is an environment reduction type can be determined by an E-factor. This is the ratio of the waste weight per unit weight of a product in a certain process, and the smaller the value of the E-factor of a certain process, the smaller the ratio of waste to production. (Non-Patent Documents 10 and 11).
このように、従来法では、クライゼン転位の場合、外場又は触媒及び有機溶媒が必要であるため、製品の品質上、反応後の分離操作において、触媒、有機溶媒やカルボン酸の除去が必要であり、分離操作後の水層は廃棄物となりやすく廃液の問題を生じる。更に、環境に対する影響や生体への有害性への配慮から、また、ヒトが経口する食品・医薬品の安全性から、触媒・有機溶媒のより高度分離が要求される。高度分離に必要なコストは、合成操作と同程度であり、望ましくは触媒と有機溶媒を使用しない方が良い。 As described above, in the case of Claisen rearrangement, the conventional method requires an external field or a catalyst and an organic solvent. Therefore, removal of the catalyst, organic solvent and carboxylic acid is necessary in the separation operation after the reaction in terms of product quality. In addition, the aqueous layer after the separation operation tends to become waste, causing a problem of waste liquid. Furthermore, in consideration of the influence on the environment and harmfulness to living organisms, and the safety of foods and pharmaceuticals that are orally administered by humans, higher separation of catalysts and organic solvents is required. The cost required for advanced separation is comparable to that of the synthesis operation, and preferably no catalyst and organic solvent are used.
以上のことから、当該技術分野においては、簡単、低コスト、環境低減型の合成プロセスで、分離操作が容易かつ高度分離が可能で、触媒や有機溶媒の残存しないクライゼン転位の連続的合成を可能とする合成手法が強く要請されていた。 Based on the above, in this technical field, a simple, low-cost, environmentally-reduced synthesis process allows easy separation and high-level separation, and allows continuous synthesis of Claisen rearrangement without remaining catalyst or organic solvent. There was a strong demand for a synthesis method.
このような状況の中で、本発明者らは、上記従来技術に鑑みて、低コストで、環境に優しい簡単な高速合成プロセスで、上記クライゼン転位化合物を連続的かつ選択的に合成することができる新しい合成方法を開発することを目標として鋭意研究を積み重ねた結果、亜臨界水を反応溶媒とすることで、無触媒でアリルエーテル類からクライゼン転位化合物を選択的に合成できることを見出し、本発明を完成するに至った。本発明は、アリルエーテル類からクライゼン転位化合物を無触媒で、短時間の反応条件下で連続的に合成する方法、及びその合成装置を提供することを目的とするものである。 Under such circumstances, in view of the above prior art, the present inventors can synthesize the Claisen rearrangement compound continuously and selectively by a simple high-speed synthesis process at low cost and environmentally friendly. results stacked intensive research with the goal of developing a new synthetic method that can, by the subcritical water as a reaction solvent, found to be able to selectively synthesize the Claisen rearrangement compound allyl ethers in the absence of a catalyst, the present invention It came to complete. The present invention is a non-catalytic Claisen rearrangement compound allyl ethers, process for continuously synthesized under the reaction conditions of a short time, it is an object to provide a synthesis device 及 benefactor.
上記課題を解決するための本発明は、以下の技術的手段から構成される。
（１）高温高圧状態の亜臨界水を反応溶媒として使用し、触媒を用いることなく、アリルエーテル類から一段階の合成反応でアリルフェノール類を選択的に合成し、生成物のクライゼン転位化合物を回収することを特徴とするクライゼン転位化合物の製造方法。
（２）温度１００℃以上、圧力０．１ＭＰａ以上の亜臨界水を反応溶媒として使用する、前記（１）記載の方法。
（３）亜臨界水に加えて、無機溶媒、又は有機溶媒を用いる、前記（１）記載の方法。
（４）流通式高温高圧装置に、基質及び反応溶媒を導入し、反応時間を３〜１８０秒の範囲で変化させることで合成反応を実施する、前記（１）記載の方法。
（５）エネルギー消費量、廃棄物排出量（Ｅ−ファクター）を低減しつつ高効率で一段階の合成反応で目的化合物を選択的に合成する、前記（１）記載の方法。
（６）クライゼン転位後、回収水溶液に水を注入してデカンテーションし、油／水二層溶液に分離後、クライゼン転位化合物を含む油層を分液回収する簡易な連続分離工程を含む、前記（１）記載の方法。
（７）前記（１）から（５）のいずれかに記載のクライゼン転位化合物の製造方法に使用する合成装置であって、
水を送液する水送液ポンプ、水加熱用コイル、高温高圧フローセル、基質を送液する反応物送液ポンプ、炉体、反応物を炉体に導入する反応物導入管、反応溶液を排出する排出液ライン、冷却フランジ及び圧力を設定する背圧弁を具備し、水送液ポンプから水が送液され、冷却フランジを通過後、炉体へ送液され、水加熱用コイルを通過後、高温高圧フローセルに導入され、一方、反応物が反応物送液ポンプから送液され、冷却フランジを通過後、炉体へ送液され、反応物導入管を通過後、高温高圧フローセルに導入され、該高温高圧フローセルにおいて所定の温度及び圧力条件の亜臨界水により合成反応を実施するようにしたことを特徴とするクライゼン転位化合物の合成装置。
The present invention for solving the above-described problems comprises the following technical means.
(1) Using subcritical water in a high-temperature and high-pressure state as a reaction solvent, without using a catalyst, allylphenols are selectively synthesized from allyl ethers in a one-step synthesis reaction, and the resulting Claisen rearrangement compound is obtained. A method for producing a Claisen rearrangement compound, which is recovered.
(2) The method according to (1), wherein subcritical water having a temperature of 100 ° C. or higher and a pressure of 0.1 MPa or higher is used as a reaction solvent.
(3) In addition to the sub-critical water, inorganic solvent, or an organic solvent medium, wherein (1) the method described.
(4) The method according to (1) above, wherein the synthesis reaction is carried out by introducing a substrate and a reaction solvent into a flow-type high-temperature and high-pressure apparatus and changing the reaction time in the range of 3 to 180 seconds.
(5) The method according to (1) above, wherein the target compound is selectively synthesized by a one-step synthesis reaction with high efficiency while reducing energy consumption and waste emission (E-factor).
(6) After the Claisen rearrangement, including a simple continuous separation step of injecting water into the recovered aqueous solution, decanting, separating into an oil / water bilayer solution, and separating and recovering the oil layer containing the Claisen rearrangement compound, 1) The method described.
(7) A synthesis apparatus used in the method for producing a Claisen rearrangement compound according to any one of (1) to (5),
Water feed pump for feeding water, coil for water heating, high-temperature and high-pressure flow cell, reactant feed pump for feeding substrate, furnace body, reactant introduction pipe for introducing reactant into the furnace body, discharging reaction solution A drain line, a cooling flange and a back pressure valve for setting the pressure, water is sent from the water feed pump, passed through the cooling flange, sent to the furnace body, passed through the water heating coil, Introduced into the high-temperature and high-pressure flow cell, while the reactant is fed from the reactant feed pump, passes through the cooling flange, is sent to the furnace body, passes through the reactant introduction pipe, and is introduced into the high-temperature and high-pressure flow cell, An apparatus for synthesizing a Claisen rearrangement compound, wherein the synthesis reaction is carried out with subcritical water at a predetermined temperature and pressure in the high-temperature and high-pressure flow cell.
次に、本発明について更に詳細に説明する。
本発明は、化１のアリルエーテル類から化２又は化３のクライゼン転位化合物を、一段階の反応プロセスで、触媒無添加、短時間の反応条件下で、選択的かつ連続的に合成することを特徴とするものである。本発明では、上記反応溶媒として、温度１００℃以上、圧力０．１ＭＰａ以上の亜臨界水が用いられる。また、反応条件として、好適には、温度２６５℃、圧力５ＭＰａ、反応時間は３〜１８０秒の範囲、好適には反応時間が１４２秒程度に調整される。ここで、化１、化２、化３の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は、水素又はアルキル基及びヘテロ原子を含む置換基、Ｘはヘテロ原子又は置換ヘテロ原子であり、具体的には酸素（Ｏ）、硫黄（Ｓ）、窒化水素（ＮＨ）、アルキル置換窒素（ＮＲ’）である。
Next, the present invention will be described in more detail.
In the present invention, a Claisen rearrangement compound of Chemical Formula 2 or Chemical Formula 3 is selectively and continuously synthesized from allyl ethers of Chemical Formula 1 in a one-step reaction process without adding a catalyst and in a short reaction time. It is characterized by. In the present invention, the reaction solvent is a temperature of 100 ° C. or higher and a pressure of 0.8. Subcritical water of 1 MPa or more is used. The reaction conditions are preferably adjusted to a temperature of 265 ° C., a pressure of 5 MPa, a reaction time of 3 to 180 seconds, and preferably a reaction time of about 142 seconds. Here, in the formulas of Chemical Formula 1, Chemical Formula 2, and Chemical Formula 3, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are substituted with hydrogen or an alkyl group and a hetero atom The group X is a heteroatom or a substituted heteroatom, specifically oxygen (O), sulfur (S), hydrogen nitride (NH), or alkyl-substituted nitrogen (NR ′).
また、本発明により、化４のアリルエーテル類の場合は、化５のクライゼン転位化合物を一段階の反応プロセスで、触媒無添加、短時間の反応条件下で、選択的かつ連続的に合成することも可能とするものである。Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７は水素又はアルキル基及びヘテロ原子を含む置換基、Ｘはヘテロ原子又は置換ヘテロ原子であり、具体的には酸素（Ｏ）、硫黄（Ｓ）、窒化水素（ＮＨ）、アルキル置換窒素（ＮＲ’）である。 Further, according to the present invention, in the case of the allyl ethers of the chemical formula 4, the Claisen rearrangement compound of the chemical formula 5 is selectively and continuously synthesized in a one-step reaction process without adding a catalyst and in a short reaction condition. It is also possible. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen or a substituent containing an alkyl group and a hetero atom, X is a hetero atom or a substituted hetero atom, specifically oxygen ( O), sulfur (S), hydrogen nitride (NH), and alkyl-substituted nitrogen (NR ′).
本発明においては、上記基質及び反応溶媒を反応容器に導入して所定の反応時間で合成反応を実施するものである。したがって、上記反応器としては、例えば、バッチ式の高温高圧反応容器、及び連続型の流通式高温高圧反応装置を使用することができるが、本発明は、これらの反応装置型式に特に制限されるものでない。 In the present invention, the substrate and the reaction solvent are introduced into a reaction vessel and a synthesis reaction is carried out in a predetermined reaction time. Thus, as the reactor, for example, high-temperature high-pressure reactor batch, and the continuous flow through type high-temperature high-pressure reactor can be used, the present invention is especially in these reactors type restrictions It is not what is done.
本発明の方法では、反応溶媒として、高温高圧状態にある亜臨界水が用いられるが、具体的には、亜臨界水（１００℃以上、０．１ＭＰａ以上）、同じ状態の混合溶媒が例示され、好適には、亜臨界水（２００−２５０℃、５ＭＰａ以上）が用いられる。反応溶媒としては、上記以外の有機溶媒や無機溶媒を任意の割合で含むことができ、具体的には、有機溶媒として、アセトン、アセトニトリル、テトラヒドロフラン等、無機溶媒として酢酸、アンモニア等を含む反応溶液に代替することも可能である。 In the method of the present invention, as the reaction solvent, although sub-critical water is used in the Atsushi Ko high pressure, specifically, subcritical water (100 ° C. or higher, 0.1 MPa), a mixed solvent of the same state It is illustrated and subcritical water (200-250 degreeC, 5 Mpa or more) is used suitably. As a reaction solvent, an organic solvent or an inorganic solvent other than those described above can be contained in any ratio. Specifically, a reaction solution containing acetone, acetonitrile, tetrahydrofuran, etc. as an organic solvent, and acetic acid, ammonia, etc. as an inorganic solvent. It is also possible to substitute.
本発明では、上記亜臨界水の反応溶媒の組成、温度及び圧力条件、基質の種類及びその使用量、反応時間を調整することにより、短時間で、効率良く、反応生成物を合成することができる。また、本発明では、例えば、基質及び反応溶媒を流通式高温高圧装置に導入し、それらの反応時間を３〜１８０秒の範囲で変えることにより、所定の反応生成物を合成することができる。上記反応条件は、使用する出発原料、目的とする反応生成物の種類等により適宜設定することができる。 In the present invention, the composition of the reaction solvent of the upper Kia critical water, the temperature and pressure conditions, the type and amount of the substrate, by adjusting the reaction time, the short time, efficiently, to synthesize a reaction product Can do. In the present invention, for example, a predetermined reaction product can be synthesized by introducing a substrate and a reaction solvent into a flow-type high temperature and high pressure apparatus and changing the reaction time within a range of 3 to 180 seconds. The reaction conditions can be appropriately set depending on the starting material used, the type of the desired reaction product, and the like.
本発明の方法では、従来、触媒存在下で行われていた、クライゼン転位化合物の合成を、高速で連続的に、しかも、無触媒で実施できるため、長時間を要するプロセスを効率化することができる。また、本発明の方法では、従来用いられた触媒を全く使用しないので、反応後の溶液の中和処理、無害化処理等の後処理・処分の必要がなく、環境負荷低減を達成可能である。更に、反応後は静置分離操作のみであるため、触媒や有機溶媒の分離回収の必要性はなく、生成物分離が容易になる。本発明によれば、触媒無添加で、１４２秒程度の短時間で、転化率９８％以上、選択率１００％以上で合成反応を行い、対応するクライゼン転位化合物を合成可能である。本発明の合成方法は、香料、医薬品、食品に利用可能な、クライゼン転位化合物を効率良く、大量に高速で連続的に生産することを可能にするものとして有用である。 In the method of the present invention, the synthesis of the Claisen rearrangement compound, which has been conventionally carried out in the presence of a catalyst, can be carried out continuously at high speed and without a catalyst, so that a process requiring a long time can be made efficient. it can. Further, in the method of the present invention, since a conventionally used catalyst is not used at all, there is no need for post-treatment / disposal such as neutralization treatment and detoxification treatment of the solution after the reaction, and environmental load reduction can be achieved. . Furthermore, since only the static separation operation is performed after the reaction, there is no need to separate and recover the catalyst and the organic solvent, and the product separation becomes easy. According to the present invention, a corresponding Claisen rearrangement compound can be synthesized by adding a catalyst and performing a synthesis reaction at a conversion rate of 98% or more and a selectivity of 100% or more in a short time of about 142 seconds. The synthesis method of the present invention is useful as one that enables efficient and continuous production of a Claisen rearrangement compound that can be used in perfumery, pharmaceuticals, and foods in a large amount at high speed.
従来、クライゼン転位化合物をエネルギー消費量、廃棄物量（Ｅ−ファクター）を低減しつつ選択的に合成することを実証した例はなく、本発明の対象とするクライゼン転位化合物の省エネ、環境負荷低減型選択的合成反応法は、本発明者らによって初めてその有効性が実証されたものである。しかも、従来法ではアリルエーテル類から合成されるクライゼン転位化合物は、触媒及び有機溶媒の残存が問題とされていたが、本発明でアリルエーテル類から合成される反応組成物は、触媒及び有機溶媒の残存がなく、本発明のクライゼン転位化合物組成物は、従来製品にない利点を有している。 Conventionally, there has been no example of demonstrating selective synthesis of Claisen rearrangement compounds while reducing energy consumption and waste amount (E-factor). The selective synthesis reaction method has been demonstrated for the first time by the present inventors. Moreover, in the conventional method, the Claisen rearrangement compound synthesized from allyl ethers had a problem of remaining catalyst and organic solvent, but the reaction composition synthesized from allyl ethers in the present invention is a catalyst and organic solvent. The Claisen rearrangement compound composition of the present invention has advantages that are not found in conventional products.
本発明では、無触媒条件で無水カルボン酸とポリヘテロ水素化物の合成反応を実現するために、例えば、基質をあらかじめ溶媒に溶解した溶液を送液し、亜臨界水中の反応経過を高温高圧赤外フローセル（図５）により赤外分光分析によって観察する流通型高温高圧赤外分光その場測定装置（図６）を用いることも可能である。しかしながら、高温高圧赤外フローセルを窓なし高温高圧フローセル（図７）に交換し、亜臨界水の流れに対して直接反応物の流れを接触反応するように配管配置した方が、高温高圧赤外フローセルにおけるセル窓付近におけるリーク等の問題が発生せず、より高流量で短時間に合成を実施することが可能である。これらのことから、この窓なし高温高圧フローセルを装着した装置を後述する実施例で用いた。 In the present invention, in order to realize a synthesis reaction of a carboxylic anhydride and polyheteroaromatic hydride uncatalyzed conditions, for example, a solution of a substrate beforehand solvent was fed, high-temperature high-pressure red reaction course of subcritical water It is also possible to use a flow-type high-temperature high-pressure infrared spectroscopic in-situ measuring device (FIG. 6) that is observed by infrared spectroscopic analysis with an outer flow cell (FIG. 5). However, the high temperature and high pressure infrared flow cell and replaced with no window high temperature and high pressure flow cell (Fig. 7), who piping placed in contact reactions flow directly reactant to the flow of the sub-critical water, high temperature and high pressure infrared There is no problem such as leakage near the cell window in the flow cell, and the synthesis can be performed in a short time at a higher flow rate. For these reasons, an apparatus equipped with this windowless high-temperature and high-pressure flow cell was used in Examples described later.
ここで、窓なし高温高圧フローセル本体（図７）は、例えば、市販のＳＵＳ３１６製のクロス１にネジを切り、次に説明する温度センサーシース（図７の１２）に固定できるようにする。炉体雰囲気の温度を測定せずに、セル温度を示すように温度センサー位置を調節し、シース固定ネジとオネジ３でネジ止めする。ＳＵＳ３１６の配管４はクロス１にワンリングフェラル付きのテーパーネジ２でクロス１に接続される。もちろん、クロス１は、エンドネジで一つの流路を塞ぐことによってティーとしても使用可能である。 Here, the windowless high-temperature and high-pressure flow cell main body (FIG. 7) can be fixed to a temperature sensor sheath (12 in FIG. 7) to be described next by, for example, threading a commercially available SUS316 cloth 1. Without measuring the temperature of the furnace body atmosphere, the position of the temperature sensor is adjusted so as to indicate the cell temperature, and screwed with the sheath fixing screw and the male screw 3. The pipe 4 of SUS316 is connected to the cross 1 with a taper screw 2 with a one-ring ferrule on the cross 1. Of course, the cloth 1 can also be used as a tee by closing one flow path with an end screw.
図８は、窓なし高温高圧フローセルを装着した流通式高温高圧反応装置の炉体部分であり、反応装置本体である。これを、図６の流通型高温高圧流体その場赤外分光測定装置の斜線位置に設置すれば、赤外分光は測定できないものの、温度、圧力、流量が可変な亜臨界流体接触型の合成反応装置として利用可能となる。なお、この場合における反応観察は、排出後の水溶液を採取し、ＧＣ−ＦＩＤにより、生成物の純品を用いた検量線から定量を実施し、ＧＣ／ＭＳにより定性分析を実施した。また、ＮＭＲにより定量・定性分析を実施した。 FIG. 8 shows a reactor body portion of a flow-type high temperature / high pressure reactor equipped with a windowless high temperature / high pressure flow cell, which is a reactor main body. This, if placed in the hatched position of the flow-through high-temperature high-pressure fluid in situ infrared spectrometry device of Figure 6, although infrared spectroscopy can not be measured, the temperature, pressure, flow rate variable A臨Sakairyu body contact type It can be used as a synthesis reactor. In this case, the observation of the reaction was performed by collecting the aqueous solution after discharge, quantifying from a calibration curve using a pure product by GC-FID, and qualitatively analyzing by GC / MS. In addition, quantitative and qualitative analysis was performed by NMR.
以下、図８について説明すると、水送液ポンプ５から水が送液され、冷却フランジ８を通過後、炉体１３へ送液される。水加熱コイル（管コイル）９を通過後、高温高圧状態で温度センサー１１が挿入された温度センサーシース１２に支持固定された高温高圧フローセル１４に導入される。一方、反応物が反応物送液ポンプ６から送液され、冷却フランジ８を通過後、炉体１３へ送液される。コイル状の反応物導入管１０を通過後、温度センサーシース１２に固定された高温高圧フローセル１４に導入される。また、洗浄水が洗浄水送液ポンプ７により送液され、溶媒導入管１６を通過後、ティー１８に導入され、洗浄用に用いられる。 Hereinafter, with reference to FIG. 8, water is fed from the water feed pump 5, passes through the cooling flange 8, and then sent to the furnace body 13. After passing through the water heating coil (tube coil) 9, it is introduced into a high temperature / high pressure flow cell 14 supported and fixed to a temperature sensor sheath 12 in which a temperature sensor 11 is inserted in a high temperature / high pressure state. On the other hand, the reactant is fed from the reactant feed pump 6, passes through the cooling flange 8, and then sent to the furnace body 13. After passing through the coiled reactant introduction tube 10, it is introduced into a high-temperature and high-pressure flow cell 14 fixed to the temperature sensor sheath 12. Further, the washing water is fed by the washing water feeding pump 7, passes through the solvent introduction pipe 16, is introduced into the tee 18, and is used for washing.
高温高圧フローセルを通過した溶液は、排出配管１７を通過後、冷却フランジ８を通過して、炉体外を空冷されながら通過する。その後、圧力を設定している背圧弁１９からの排出液を採取し、サンプルとする。ここで、反応物や生成物を含む排出液の加熱による影響を排除する場合には、急速昇温を実施し、反応物導入管１０と排出配管１７の配管をできるだけ短く、水加熱コイル９をできるだけ長くすることが望ましい。本発明は、これらに限らず、これらと同効の反応装置であれば同様に使用することができる。 The solution that has passed through the high-temperature and high-pressure flow cell passes through the discharge pipe 17, passes through the cooling flange 8, and passes outside the furnace body while being air-cooled. Thereafter, the discharged liquid from the back pressure valve 19 that has set the pressure is collected and used as a sample. Here, in order to eliminate the influence of heating of the effluent containing the reactants and products, rapid heating is performed, the pipes of the reactant introduction pipe 10 and the discharge pipe 17 are made as short as possible, and the water heating coil 9 is installed. It is desirable to make it as long as possible. The present invention is not limited to these, and any reaction apparatus having the same effect as these can be used in the same manner.
本発明により、次のような効果が奏される。
（１）アリルエーテル類から高速で連続的にクライゼン転位化合物を合成することができる。
（２）クライゼン転位化合物をエネルギー消費量、廃棄物量（Ｅ−ファクター）を低減しつつ高効率で選択的に合成することができる。
（３）触媒及び有機溶媒を用いない合成プロセスを実現できる。
（４）そのため、触媒及び有機溶媒の残存がなく、生体に対して有害性のない安全性の高いクライゼン転位反応組成物を提供できる。
（５）生成物が水に溶解しない場合には、排出された油水分散水溶液に対して更に水を注入することで、洗浄しつつ油水二層に分液し、高純度の生成物を容易に回収できる。
（６）香料、医薬品、食品として有用なクライゼン転位反応組成物の新しい大量生産プロセスとして、既存の生産プロセスに代替し得る新しい生産技術を提供できる。
The present invention has the following effects.
(1) A Claisen rearrangement compound can be synthesized from allyl ethers continuously at high speed.
(2) The Claisen rearrangement compound can be selectively synthesized with high efficiency while reducing energy consumption and waste amount (E-factor).
(3) A synthesis process without using a catalyst and an organic solvent can be realized.
(4) Therefore, it is possible to provide a Claisen rearrangement reaction composition that does not have a catalyst and an organic solvent and that is not harmful to a living body and has high safety.
(5) When the product does not dissolve in water, water is injected into the discharged oil-water dispersion aqueous solution to separate the oil and water into two layers while washing, and a high-purity product can be easily obtained. Can be recovered.
(6) As a new mass production process of the Claisen rearrangement reaction composition useful as a fragrance, a medicine, and a food, a new production technique that can replace the existing production process can be provided.
次に、実施例に基づいて本発明を具体的に説明するが、本発明は、以下の実施例によって何ら限定されるものではない。 EXAMPLES Next, although this invention is demonstrated concretely based on an Example, this invention is not limited at all by the following Examples.
まず、本発明の実施方法を示した後、実施例を示す。
（実施方法）
本実施例では、図８の流通式高温高圧反応装置を用いて、合成条件を、無触媒、温度２００〜３００℃、圧力５ＭＰａ、滞留時間３６〜１４２秒で実施した。図８の流通式高温高圧反応装置の本体（主要部分）を、図６の流通型高温高圧流体その場赤外分光測定装置に設置した装置に、まず、温度２６５℃、圧力５ＭＰａに設定し、窓なしセル（ティー１）の水加熱コイル（配管コイル）９との接続穴をエンドで塞ぎ、水送液ポンプ５により配管コイル９への流路を塞ぎ、純水は、流量５．０ｍｌ／ｍｉｎで、炉体外のティー１８へ送液した。
First, after showing the implementation method of this invention, an Example is shown.
(Implementation method)
In this example, using the flow-type high temperature and high pressure reactor of FIG. 8, the synthesis conditions were as follows: no catalyst, temperature 200 to 300 ° C., pressure 5 MPa, residence time 36 to 142 seconds. The main body (main part) of the flow-type high-temperature and high-pressure reactor shown in FIG. 8 is first set to a temperature of 265 ° C. and a pressure of 5 MPa in the apparatus installed in the flow-type high-temperature and high-pressure fluid in-situ infrared spectrometer shown in FIG. The connection hole with the water heating coil (piping coil) 9 of the windowless cell (tee 1) is closed at the end, the flow path to the piping coil 9 is closed by the water feed pump 5, and the pure water has a flow rate of 5.0 ml / In min, the liquid was fed to the tee 18 outside the furnace body.
その後、トルエンを内標準として添加した（基質の５ｍｏｌ％）、アリルフェノール混合溶液０．５ｍｌ／ｍｉｎをポンプで送液した（混合後の水溶液濃度：０．２８ｍｏｌ／ｋｇ）。基質送液後、４０分後の背圧弁からの排出水溶液を１ｍｌ採取した。加熱炉から背圧弁出口までの配管内容積を反応体積とした場合、反応時間は７２秒であった。 Thereafter, toluene was added as an internal standard (5 mol% of the substrate), and 0.5 ml / min of the allylphenol mixed solution was pumped (concentration of aqueous solution after mixing: 0.28 mol / kg). 1 ml of the aqueous solution discharged from the back pressure valve 40 minutes after the substrate feeding was collected. When the internal volume of the pipe from the heating furnace to the back pressure valve outlet was the reaction volume, the reaction time was 72 seconds.
回収された１ｍｌの水溶液に１ｍｌのアセトンを加え、振とうし、組成をＧＣ／ＭＳ分析計（Ｈｅｗｌｅｔｔ Ｐａｃｋａｒｄ社製ＨＰ６８９０、カラムＨＰ−５、注入口温度１５０℃、初期カラム温度６０℃（保持時間２分）、昇温速度１０℃／分、最終カラム温度２５０℃（保持時間２分））で実施し、得られたマススペクトルは、Ｗｉｌｌｅｙ データベースで一致度９０％以上で確認した。また、定量及び市販試薬がある場合の定性は、トルエンを内標準としてＧＣ−ＦＩＤ（Ａｇｉｌｅｎｔ社製ＧＣ６８９０，カラムＤＢ−ＷＡＸ、注入口温度２３０℃、スプリット比５．６１、初期カラム温度５０℃（保持時間０．５分）、昇温速度２０℃／分、最終カラム温度２３０℃（保持時間３分））で実施した。 1 ml of acetone was added to 1 ml of the collected aqueous solution, shaken, and the composition was determined by GC / MS analyzer (HP 6890, Hewlett Packard, column HP-5, inlet temperature 150 ° C., initial column temperature 60 ° C. (retention time) 2 minutes), the heating rate was 10 ° C./min, and the final column temperature was 250 ° C. (holding time 2 minutes)), and the obtained mass spectrum was confirmed by the Willy database with a coincidence of 90% or more. In addition, quantification and qualitativeness in the presence of commercially available reagents are GC-FID (GC 6890, Agilent DB DB-WAX, inlet temperature 230 ° C., split ratio 5.61, initial column temperature 50 ° C. with toluene as an internal standard ( Holding time 0.5 minutes), temperature rising rate 20 ° C./min, final column temperature 230 ° C. (holding time 3 minutes)).
また、得られた生成物水溶液が油水分散状態で白濁している場合には、水を２０ｍｌ／ｍｉｎで３分注入し、デカンテーションすると油水２層溶液となり、下（上）層の油層にクライゼン転位化合物を、上（下）層の水相に水を得た（ＧＣにより確認）。このことは、生成物が水に溶解しない場合、反応終了後の油水分散水溶液に、水を更に注入することで、油水二層に変化してクライゼン転位化合物と酢酸水溶液を分液することができる。したがって、分離精製に高度な手法や膨大なエネルギーを必要とする精留は必要ない。 In addition, when the obtained aqueous product solution is clouded in an oil-water dispersion state, water is injected at 20 ml / min for 3 minutes and decanted to form an oil-water two-layer solution. Water was obtained from the rearrangement compound in the upper (lower) aqueous phase (confirmed by GC). This means that when the product does not dissolve in water, water can be further injected into the aqueous oil-dispersed aqueous solution after completion of the reaction to change the oil-water bilayer to separate the Claisen rearrangement compound and the aqueous acetic acid solution. . Therefore, an advanced technique for separation and purification and rectification that requires enormous energy are not required.
（実施例）
実施例１〜６
アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を圧力５ＭＰａ、滞留時間７２秒で温度を２００℃〜３００℃で温度依存性を検討したところ、図９のようになり、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃で、転化率９９％、選択率７４％、収率７３％で得た。このことから、２６５℃を最適温度とした。
(Example)
Examples 1-6
Allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom), pressure is 5 MPa, residence time is 72 seconds When the temperature dependence was examined at 200 ° C. to 300 ° C., as shown in FIG. 9, allylphenol (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 in the formula 2) was obtained . , R 7 and R 8 are hydrogen and X is an oxygen atom) at a temperature of 265 ° C., a conversion of 99%, a selectivity of 74%, and a yield of 73%. For this reason, 265 ° C. was set as the optimum temperature.
実施例７〜１３
アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃、滞留時間７２秒で、圧力を０．１〜２０ＭＰａで圧力依存性を検討したところ、図１０のようになり、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を圧力５ＭＰａで、転化率９９％、選択率７４％、収率７３％で得、圧力１０ＭＰａで、転化率９９．６％、選択率７６％、収率７６％で得た。圧力５ＭＰａと１０ＭＰａの結果は誤差範囲と考え、圧力５ＭＰａを採用した。
Examples 7-13
Allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) at a temperature of 265 ° C. and a residence time of 72 When the pressure dependence was examined at a pressure of 0.1 to 20 MPa in seconds, as shown in FIG. 10, allylphenol (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen, and X is an oxygen atom) at a pressure of 5 MPa, a conversion rate of 99%, a selectivity of 74%, and a yield of 73%, and a pressure of 10 MPa and a conversion rate of 99.6%. The selectivity was 76% and the yield was 76%. The results of the pressures of 5 MPa and 10 MPa were considered as error ranges, and the pressure of 5 MPa was adopted.
実施例１４〜１７
アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃、圧力５ＭＰａ、基質流量を変化させ、滞留時間を０〜１４３秒で滞留時間依存性を検討したところ、図１１のようになり、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を滞留時間１４３秒で、転化率９９．４％、選択率８５％、収率８４％で得た。このことから、滞留時間１４３秒を最適滞留時間とした。
Examples 14-17
Allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) at a temperature of 265 ° C., a pressure of 5 MPa, When the substrate flow rate was changed and the residence time dependency was examined at 0 to 143 seconds, the dependence on residence time was as shown in FIG. 11. As shown in FIG. 11, allylphenol (R 1 , R 2 , R 3 , R 4 in the formula 2) , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) at a residence time of 143 seconds, a conversion of 99.4%, a selectivity of 85%, and a yield of 84%. Therefore, the residence time of 143 seconds was set as the optimum residence time.
実施例１８〜２０
アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃、圧力５ＭＰａ、水流量を変化させ、滞留時間を０〜７２．８秒で滞留時間依存性を検討したところ、図１２のようになり、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を滞留時間７１．６秒で、転化率９９．６％、選択率９３％、収率９２％で得た。このことから、滞留時間１４３秒を最適滞留時間とした。
Examples 18-20
Allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) at a temperature of 265 ° C., a pressure of 5 MPa, When the water flow rate was changed and the residence time was examined at a residence time of 0 to 72.8 seconds, the dependence on residence time was as shown in FIG. 12, and allylphenol (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen and X is an oxygen atom) with a residence time of 71.6 seconds, a conversion of 99.6%, a selectivity of 93% and a yield of 92%. Obtained. Therefore, the residence time of 143 seconds was set as the optimum residence time.
実施例２１
実施例２０までの結果から、総合的に判断して、アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃、圧力５ＭＰａ、滞留時間１４２秒（水流量７ｍｌ／ｍｉｎ、基質流量０．２５ｍｌ／ｍｉｎ、基質濃度０．１１ｍｏｌ／ｋｇ）で反応させたところ、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を転化率９９．８％、選択率９８％、収率９８％で得た。
Example 21
From the results up to Example 20, it was judged comprehensively that allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogens) Yes, X is an oxygen atom) at a temperature of 265 ° C., a pressure of 5 MPa, a residence time of 142 seconds (water flow rate 7 ml / min, substrate flow rate 0.25 ml / min, substrate concentration 0.11 mol / kg). (Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are hydrogen and X is an oxygen atom), the conversion is 99.8% and the selectivity 98%, yield 98%.
参考実施例２２（参考例）
他方、亜臨界水の効果を調べるために、水を流さない無溶媒条件で同じ装置を用いて行った。アリルフェノール（化１の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を温度２６５℃、圧力５ＭＰａ、滞留時間１６５秒（水流量０ｍｌ／ｍｉｎ、基質流量０．２５ｍｌ／ｍｉｎ、基質濃度０．３８ｍｏｌ／ｋｇ）で反応させたところ、アリルフェノール（化２の式中、Ｒ１，Ｒ２，Ｒ３，Ｒ４，Ｒ５，Ｒ６，Ｒ７，Ｒ８は水素であり、Ｘは酸素原子）を転化率５５％、選択率６８％、収率３７％で得られ、亜臨界水により反応が促進することが明らかとなった。
Reference Example 22 (Reference Example)
On the other hand, in order to investigate the effect of subcritical water, the same apparatus was used in a solvent-free condition where no water was allowed to flow. Allylphenol (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) at a temperature of 265 ° C., a pressure of 5 MPa, When the reaction was carried out at a residence time of 165 seconds (water flow rate 0 ml / min, substrate flow rate 0.25 ml / min, substrate concentration 0.38 mol / kg), allylphenol (in the formula of R 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are hydrogen and X is an oxygen atom) with a conversion of 55%, a selectivity of 68%, and a yield of 37%. It became clear to promote.
以上の本発明の実施例２１（μ亜臨界水と略記），参考実施例２２（μ無溶媒と略記）の結果と、無溶媒マイクロ波加熱（マイクロ波−無溶媒と略記、非特許文献３）、ＤＭＦ添加マイクロ波加熱（マイクロ波−ＤＭＦと略記、非特許文献３）、通常加熱無溶媒（通常加熱−無溶媒と略記、非特許文献２）の結果を、収率、エネルギー原単位、Ｅ−ファクターで比較した結果が、図１３、図１４、図１５である。良好な収率を示し、高効率であるのが、μ亜臨界水（９８％）、マイクロ波−ＤＭＦ（９２％）、通常加熱−無溶媒（８５％）であり、その中で、エネルギー原単位とＥ−ファクターを同時に低い値を有するのが、本発明のμ亜臨界水である。したがって、本発明は、エネルギー消費量と廃棄物量（Ｅ−ファクター）を低減しつつ高効率を達成していることが分かる。 The results of Example 21 (abbreviated as μ subcritical water) and Reference Example 22 (abbreviated as μ solvent-free) and solvent-free microwave heating (abbreviated as microwave-solvent-free, Non-Patent Document 3) ), DMF-added microwave heating (abbreviated as microwave-DMF, non-patent document 3), and normal heating without solvent (abbreviated as normal heating-no solvent, non-patent document 2), yield, energy intensity, The results of comparison by E-factor are FIG. 13, FIG. 14, and FIG. It is μ subcritical water (98%), microwave-DMF (92%), usually heating-solvent-free (85%), which shows a good yield and high efficiency. It is the mu subcritical water of the present invention that has a low unit and E-factor simultaneously. Therefore, it can be seen that the present invention achieves high efficiency while reducing energy consumption and waste amount (E-factor).
以上の実施例及び参考例から、高温高圧水を反応溶媒として、無触媒でクライゼン転位化合物がエネルギー消費量、廃棄物量を低減しつつ高収率で合成可能であることが明らかとなった。また、クライゼン転位化後、回収水溶液に水を注入してデカンテーションし、油／水二層溶液に分離後、クライゼン転位化合物を含む油層を分液回収する一方、水層からは水を分離し、回収する簡易な連続分離法も明らかとなった。 From the above Examples and Reference Examples , it has been clarified that the Claisen rearrangement compound can be synthesized in a high yield while reducing the energy consumption and the amount of waste without using a catalyst with high-temperature and high-pressure water as a reaction solvent. After the Claisen rearrangement, water is injected into the recovered aqueous solution and decanted, and after separation into an oil / water bilayer solution, the oil layer containing the Claisen rearrangement compound is separated and recovered, while water is separated from the aqueous layer. A simple continuous separation method for recovery was also revealed.
以上詳述したように、本発明は、アリルフェノール類から有機溶媒を用いることなく、高温高圧流体を反応溶媒として、無触媒でクライゼン転位化合物を合成する方法及びその装置に係るものであり、従来法では、アリルフェノール類からクライゼン転位化合物の合成は、無溶媒の加熱では省エネ・高効率合成が達成不可能であり、有機溶媒中のマイクロ波加熱では、有機溶媒を除去した環境低減プロセスの実現ができず、有機溶媒に触媒を添加した数時間の反応でも、有機溶媒・触媒を除去した環境低減型プロセスが実現できなかったが、本発明で示した亜臨界水を用いることにより、触媒無添加で、有機溶媒を使用することなく、エネルギー消費量及び廃棄物量を低減しつつ高速で連続的に選択的にクライゼン転位化合物を合成することが可能となった。 As described above in detail, the present invention relates to a method and an apparatus for synthesizing a Claisen rearrangement compound without catalyst using a high-temperature and high-pressure fluid as a reaction solvent without using an organic solvent from allylphenols. According to the method, the synthesis of Claisen rearrangement compounds from allylphenols cannot achieve energy-saving and high-efficiency synthesis by solvent-free heating, and microwave heating in organic solvents realizes an environmental reduction process that removes organic solvents can not, even in the reaction for several hours with the addition of catalyst to organic solvents, although environmental-reducing process to remove the organic solvent-catalyst can not be achieved, by using a subcritical water described in the present invention, the catalyst Mu Addition to synthesize Claisen rearrangement compounds selectively and continuously at high speed while reducing energy consumption and waste without using organic solvents It has become possible.
このことは、香料、医薬品、食品として有用なクライゼン転位化合物を短時間で、大量に連続的に生産できるというメリットをもたらす。また、クライゼン転位後、回収水溶液に水を注入してデカンテーションし、油／水二層溶液に分離後、クライゼン転位化合物を含む油層を分液回収する一方、水層からは水を回収し、水をリサイクルすることが可能である。これらのことから、合成・分離プロセスを単純化させることで、プロセスの初期コスト及びランニングコストを圧縮することが可能である。更に、中和処理の後処理も不必要であり、環境調和型生産が可能となる。本発明は、香料、医薬品、食品として有用なクライゼン転位化合物の新しい大量生産プロセスとして、既存の生産プロセスに代替し得るものである。 This brings about the merit that the Claisen rearrangement compound useful as a fragrance, a medicine and a food can be produced continuously in a large amount in a short time. After the Claisen rearrangement, water is injected into the recovered aqueous solution and decanted, and after separation into an oil / water bilayer solution, the oil layer containing the Claisen rearrangement compound is separated and recovered, while water is recovered from the aqueous layer, It is possible to recycle water. From these facts, it is possible to compress the initial cost and running cost of the process by simplifying the synthesis / separation process. Furthermore, post-treatment of the neutralization treatment is unnecessary, and environmentally conscious production becomes possible. INDUSTRIAL APPLICABILITY The present invention can replace existing production processes as a new mass production process for Claisen rearrangement compounds useful as perfumes, pharmaceuticals and foods.
１ ティー又はクロス（片側口φ４ｍｍネジ切り）
２ φ４ｍｍ×５．０ｍｍＬ六角ネジ
３ ワンリングフェラル付オネジ
４ ＳＵＳ３１６チューブ
５ 水送液ポンプ
６ 反応物送液ポンプ
７ 洗浄水送液ポンプ
８ 冷却フランジ（冷却水が循環する）
９ 水加熱コイル
１０ 反応物導入管
１１ 温度センサー
１２ 温度センサーシース
１３ 炉体
１４ 高温高圧フローセル（通常昇温ではティー型、急速昇温ではクロス型）
１５ ＺｎＳｅ窓
１６ 溶媒導入管
１７ 排出配管
１８ ティー
１９ 背圧弁
２１ 水溶液
２２ 洗浄水
２３ 水溶液ポンプ
２４ 洗浄用純水送液ポンプ
２５ 炉体加熱システム
２６ 炉体
２７ 高温高圧赤外フローセル
２８ 冷却水（入口）
２９ 冷却水（出口）
３０ 背圧弁
３１ 排出水溶液受器
３２ 可動鏡
３３ 可動鏡
３４ 干渉計
３５ 光源
３６ 赤外レーザー
３７ ＭＣＴ受光器
３８ ＴＧＳ受光器
３９ 解析モニター
４０ 反応物送液ポンプ
４１ 基質送液ポンプ
４２ 水送液ポンプ
４３ 反応ティー
４４ 配管
４５ 混合ティー
４６ 排出配管
４７ 冷却器
４８ 背圧弁
４９ 回収容器
５０ 温度センサー
５１ 温度センサー
1 Tee or cloth (one side opening φ4mm threaded)
2 φ4mm × 5.0mmL hexagon screw 3 Male screw with one ring ferrule 4 SUS316 tube 5 Water feed pump 6 Reactant feed pump 7 Washing water feed pump 8 Cooling flange (cooling water circulates)
9 Water heating coil 10 Reactant introduction pipe 11 Temperature sensor 12 Temperature sensor sheath 13 Furnace body 14 High-temperature high-pressure flow cell (Tee type for normal temperature rise, cross-type for rapid temperature rise)
15 ZnSe window 16 Solvent introduction pipe 17 Discharge pipe 18 Tee 19 Back pressure valve 21 Aqueous solution 22 Washing water 23 Aqueous solution pump 24 Cleaning pure water feed pump 25 Furnace heating system 26 Furnace 27 High-temperature high-pressure infrared flow cell 28 Cooling water (inlet) )
29 Cooling water (exit)
30 Back pressure valve 31 Discharged aqueous solution receiver 32 Movable mirror 33 Movable mirror 34 Interferometer 35 Light source 36 Infrared laser 37 MCT light receiver 38 TGS light receiver 39 Analysis monitor 40 Reactant liquid feed pump 41 Substrate liquid feed pump 42 Water liquid feed pump 43 Reaction tee 44 Piping 45 Mixing tee 46 Discharge piping 47 Cooler 48 Back pressure valve 49 Collection container 50 Temperature sensor 51 Temperature sensor
Claims (7)
水を送液する水送液ポンプ、水加熱用コイル、高温高圧フローセル、基質を送液する反応物送液ポンプ、炉体、反応物を炉体に導入する反応物導入管、反応溶液を排出する排出液ライン、冷却フランジ及び圧力を設定する背圧弁を具備し、水送液ポンプから水が送液され、冷却フランジを通過後、炉体へ送液され、水加熱用コイルを通過後、高温高圧フローセルに導入され、一方、反応物が反応物送液ポンプから送液され、冷却フランジを通過後、炉体へ送液され、反応物導入管を通過後、高温高圧フローセルに導入され、該高温高圧フローセルにおいて所定の温度及び圧力条件の亜臨界水により合成反応を実施するようにしたことを特徴とするクライゼン転位化合物の合成装置。 A synthesizer used in the method for producing a Claisen rearrangement compound using subcritical water according to any one of claims 1 to 5,
Water feed pump for feeding water, coil for water heating, high-temperature and high-pressure flow cell, reactant feed pump for feeding substrate, furnace body, reactant introduction pipe for introducing reactant into the furnace body, discharging reaction solution A drain line, a cooling flange and a back pressure valve for setting the pressure, water is sent from the water feed pump, passed through the cooling flange, sent to the furnace body, passed through the water heating coil, Introduced into the high-temperature and high-pressure flow cell, while the reactant is fed from the reactant feed pump, passes through the cooling flange, is sent to the furnace body, passes through the reactant introduction pipe, and is introduced into the high-temperature and high-pressure flow cell, An apparatus for synthesizing a Claisen rearrangement compound, wherein the synthesis reaction is carried out with subcritical water at a predetermined temperature and pressure in the high-temperature and high-pressure flow cell.
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