JP2006169158A - Method for producing optically active amino acids - Google Patents
Method for producing optically active amino acids Download PDFInfo
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- JP2006169158A JP2006169158A JP2004363270A JP2004363270A JP2006169158A JP 2006169158 A JP2006169158 A JP 2006169158A JP 2004363270 A JP2004363270 A JP 2004363270A JP 2004363270 A JP2004363270 A JP 2004363270A JP 2006169158 A JP2006169158 A JP 2006169158A
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- optically active
- valine
- acid
- diastereomer
- phenoxypropionic
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 150000001413 amino acids Chemical class 0.000 title description 35
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 claims abstract description 88
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 50
- SXERGJJQSKIUIC-UHFFFAOYSA-N 2-Phenoxypropionic acid Chemical class OC(=O)C(C)OC1=CC=CC=C1 SXERGJJQSKIUIC-UHFFFAOYSA-N 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000004474 valine Substances 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012452 mother liquor Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 2
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 claims 1
- 150000005599 propionic acid derivatives Chemical class 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 48
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 239000007787 solid Substances 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 34
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 239000008367 deionised water Substances 0.000 description 11
- 229910021641 deionized water Inorganic materials 0.000 description 11
- SXERGJJQSKIUIC-SSDOTTSWSA-N (2r)-2-phenoxypropanoic acid Chemical class OC(=O)[C@@H](C)OC1=CC=CC=C1 SXERGJJQSKIUIC-SSDOTTSWSA-N 0.000 description 10
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- SXERGJJQSKIUIC-ZETCQYMHSA-N (2s)-2-phenoxypropanoic acid Chemical class OC(=O)[C@H](C)OC1=CC=CC=C1 SXERGJJQSKIUIC-ZETCQYMHSA-N 0.000 description 7
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 4
- 229930182831 D-valine Natural products 0.000 description 4
- DKHJWWRYTONYHB-ZCFIWIBFSA-N (2r)-2-(4-chlorophenoxy)propanoic acid Chemical compound OC(=O)[C@@H](C)OC1=CC=C(Cl)C=C1 DKHJWWRYTONYHB-ZCFIWIBFSA-N 0.000 description 3
- BTQZPXFENISXER-MRVPVSSYSA-N (2r)-2-(4-methylphenoxy)propanoic acid Chemical compound OC(=O)[C@@H](C)OC1=CC=C(C)C=C1 BTQZPXFENISXER-MRVPVSSYSA-N 0.000 description 3
- DKHJWWRYTONYHB-LURJTMIESA-N (2s)-2-(4-chlorophenoxy)propanoic acid Chemical compound OC(=O)[C@H](C)OC1=CC=C(Cl)C=C1 DKHJWWRYTONYHB-LURJTMIESA-N 0.000 description 3
- BTQZPXFENISXER-QMMMGPOBSA-N (2s)-2-(4-methylphenoxy)propanoic acid Chemical compound OC(=O)[C@H](C)OC1=CC=C(C)C=C1 BTQZPXFENISXER-QMMMGPOBSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003905 agrochemical Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- -1 racemic-amino Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BTQZPXFENISXER-UHFFFAOYSA-N 2-(4-methylphenoxy)propanoic acid Chemical compound OC(=O)C(C)OC1=CC=C(C)C=C1 BTQZPXFENISXER-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- DKHJWWRYTONYHB-UHFFFAOYSA-N CPP Chemical compound OC(=O)C(C)OC1=CC=C(Cl)C=C1 DKHJWWRYTONYHB-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、光学分離剤を使用した光学活性バリン又は光学活性２−アミノブタン酸の製造方法及び光学分離の工程で得られるジアステレオマーに関する。 The present invention relates to a method for producing optically active valine or optically active 2-aminobutanoic acid using an optical separating agent, and a diastereomer obtained in the step of optical separation.
光学活性アミノ酸類は医薬、農薬のキラルプールとして幅広い利用が期待されており、例えば２−アミノブタン酸は、抗てんかん薬（特許文献１）、血圧降下薬（特許文献２）等の利用例が報告されている。 Optically active amino acids are expected to be widely used as chiral pools for pharmaceuticals and agricultural chemicals. For example, 2-aminobutanoic acid is reported to be used as an antiepileptic drug (Patent Document 1), an antihypertensive drug (Patent Document 2), etc. Has been.
光学活性アミノ酸の製造法には下記（ａ〜ｃ）のような方法があるが、製造時に特別な装置が不要で、工業的規模まで比較的容易にスケールアップできる等の理由からｃの光学分割法が注目されている。
ａ．生体触媒法
ｂ．不斉合成法
ｃ．光学分割法
There are the following methods (a to c) for producing optically active amino acids, but no special equipment is required during production, and c is an optical resolution because it can be scaled up relatively easily to an industrial scale. The law is drawing attention.
a. Biocatalytic method b. Asymmetric synthesis c. Optical resolution method
アミノ酸類の光学分割においては、アミノ基あるいはカルボキシ基のどちらかに官能基保護を行うのが一般的である。官能基保護を不要とするアミノ酸分割例として、例えば２−アミノブタン酸では、下記のような化合物を用いた光学分割が発表されている。
１．光学活性スルホン酸を用いる光学分割（非特許文献１）。
２．光学活性マンデル酸を用いる光学分割（特許文献３）。
しかし、１は分割剤の入手が困難であるうえ、回収が難しい難点がある。２についてはアミノ酸−マンデル酸複合体からアミノ酸の単離についての記載がないうえ、アミノ酸の光学純度も記述されていないため実用性に乏しい。
In optical resolution of amino acids, functional group protection is generally performed on either an amino group or a carboxy group. As an example of amino acid resolution that does not require functional group protection, for example, in 2-aminobutanoic acid, optical resolution using the following compounds has been announced.
1. Optical resolution using optically active sulfonic acid (Non-patent Document 1).
2. Optical resolution using optically active mandelic acid (Patent Document 3).
However, 1 is difficult to obtain a resolving agent and difficult to recover. As for No. 2, there is no description about the isolation of an amino acid from an amino acid-mandelic acid complex, and the optical purity of the amino acid is not described.
本発明者らは、先に光学活性２−フェノキシプロピオン酸を用いた、光学活性ピペコリン酸の光学分割による製法を確立した（特許文献４）。 The present inventors previously established a production method by optical resolution of optically active pipecolic acid using optically active 2-phenoxypropionic acid (Patent Document 4).
本発明は製造時に特別な装置が不要で、工業的規模まで比較的容易にスケールアップできる光学分割法により、官能基保護を必要とすることなく、ラセミ−バリン又はラセミ−２−アミノブタン酸から効率的に光学活性バリン又は光学活性２−アミノブタン酸を分離、製造する方法を提供することを目的とする。 The present invention eliminates the need for special equipment at the time of manufacture, and is effective from racemic-valine or racemic-2-aminobutanoic acid without the need for functional group protection by an optical resolution method that can be scaled up relatively easily to an industrial scale. It is another object of the present invention to provide a method for separating and producing optically active valine or optically active 2-aminobutanoic acid.
本発明は前記課題を解決する手段として次の（１）〜（４）の構成を採る。
（１）ラセミ−バリン又はラセミ−２−アミノブタン酸を、水、低級アルコール又はそれらの混合物からなる媒体中で、一般式（１）で表される光学活性２−フェノキシプロピオン酸誘導体と反応させ、光学活性バリンと光学活性２−フェノキシプロピオン酸誘導体又は光学活性２−アミノブタン酸と光学活性２−フェノキシプロピオン酸誘導体で構成される複合体である難溶性のジアステレオマーを生成させ、固液分離することを特徴とする光学活性バリン又は光学活性２−アミノブタン酸のジアステレオマーの製造方法。
(1) reacting racemic-valine or racemic-2-aminobutanoic acid with an optically active 2-phenoxypropionic acid derivative represented by the general formula (1) in a medium comprising water, a lower alcohol or a mixture thereof; A hardly soluble diastereomer that is a complex composed of an optically active valine and an optically active 2-phenoxypropionic acid derivative or an optically active 2-aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative is generated and separated into solid and liquid. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid.
（２）前記（１）の方法において固液分離した後の母液から光学活性２−フェノキシプロピオン酸誘導体を分離したのち、使用した光学活性２−フェノキシプロピオン酸誘導体と反対の対掌体である光学活性２−フェノキシプロピオン酸誘導体を添加して反応させ、光学活性バリンと光学活性２−フェノキシプロピオン酸誘導体又は光学活性２−アミノブタン酸と光学活性２−フェノキシプロピオン酸誘導体で構成される複合体である難溶性のジアステレオマーを生成させ、固液分離することを特徴とする光学活性バリン又は光学活性２−アミノブタン酸のジアステレオマーの製造方法。 (2) The optically active 2-phenoxypropionic acid derivative is separated from the mother liquor after the solid-liquid separation in the method of (1) above, and then the optical opposite to the optically active 2-phenoxypropionic acid derivative used It is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative by adding and reacting active 2-phenoxypropionic acid derivative. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid, wherein a hardly soluble diastereomer is produced and separated into solid and liquid.
（３）光学活性バリンと光学活性２−フェノキシプロピオン酸誘導体又は光学活性２−アミノブタン酸と光学活性２−フェノキシプロピオン酸誘導体で構成される複合体である光学活性バリン又は光学活性２−アミノブタン酸のジアステレオマーを、水と水に難溶性の有機溶媒との混合液に溶解又は懸濁させて攪拌してジアステレオマーを分解させ、水層から光学活性バリン又は光学活性２−アミノブタン酸を、有機溶媒層から光学活性２−フェノキシプロピオン酸誘導体をそれぞれ回収することを特徴とする光学活性バリン又は光学活性２−アミノブタン酸の製造方法。 (3) optically active valine or optically active 2-aminobutanoic acid which is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative The diastereomer is dissolved or suspended in a mixed solution of water and a water-insoluble organic solvent, and stirred to decompose the diastereomer, and optically active valine or optically active 2-aminobutanoic acid is separated from the aqueous layer. A method for producing optically active valine or optically active 2-aminobutanoic acid, wherein an optically active 2-phenoxypropionic acid derivative is respectively recovered from an organic solvent layer.
（４）光学活性バリンと一般式（１）で表される光学活性２−フェノキシプロピオン酸誘導体又は光学活性２−アミノブタン酸と一般式（１）で表される光学活性２−フェノキシプロピオン酸誘導体で構成される複合体である光学活性バリン又は光学活性２−アミノブタン酸のジアステレオマー。
本発明によれば、光学活性２−フェノキシプロピオン酸誘導体を光学分割剤として、ラセミ体のバリン又は２−アミノブタン酸に作用させることにより、溶解度差により分離が可能な光学活性バリン又は光学活性２−アミノブタン酸と光学活性２−フェノキシプロピオン酸誘導体とで構成される複合体であるジアステレオマーを製造し、これを分離した後に分解させることにより、農薬や医薬品などの合成用中間体として有用な光学活性バリン又は光学活性２−アミノブタン酸を効率的に製造することができる。 According to the present invention, an optically active 2-phenoxypropionic acid derivative as an optical resolving agent is allowed to act on racemic valine or 2-aminobutanoic acid, whereby the optically active valine or optically active 2- A diastereomer that is a complex composed of aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative is produced, separated and then decomposed to provide an optical useful as an intermediate for the synthesis of agricultural chemicals and pharmaceuticals. Active valine or optically active 2-aminobutanoic acid can be produced efficiently.
本発明は、光学活性２−フェノキシプロピオン酸誘導体を光学分割剤として用い、ラセミ−バリン又はラセミ−２−アミノブタン酸（両者を合わせてラセミ−アミノ酸と略称）から、それぞれ光学活性バリン又は光学活性２−アミノブタン酸（両者を合わせて光学活性−アミノ酸と略称）を製造するものである。具体的な製造工程は次のとおりである。
１）適当な溶媒にラセミ‐アミノ酸と、光学分割剤として光学活性２−フェノキシプロピオン酸誘導体を加え加熱溶解する。
２）この溶液を冷却後、生じた難溶性のジアステレオマー（光学活性−アミノ酸と光学活性２−フェノキシプロピオン酸誘導体とで構成される複合体）を分離し、適当な溶媒で光学精製後、分離、乾燥する。
The present invention uses an optically active 2-phenoxypropionic acid derivative as an optical resolving agent, and from optically active valine or optically active 2 from racemic-valine or racemic-2-aminobutanoic acid (both are abbreviated as racemic-amino acid), respectively. -Aminobutanoic acid (a combination of the two and optical activity-abbreviated as amino acid) is produced. The specific manufacturing process is as follows.
1) A racemic amino acid and an optically active 2-phenoxypropionic acid derivative as an optical resolution agent are added to an appropriate solvent and dissolved by heating.
2) After cooling this solution, the resulting poorly soluble diastereomer (a complex composed of an optically active amino acid and an optically active 2-phenoxypropionic acid derivative) was separated and optically purified with an appropriate solvent, Separate and dry.
３）このジアステレオマーを水に難溶性の有機溶媒と水の混合液に溶解又は懸濁させ、攪拌して光学活性−アミノ酸と光学活性２−フェノキシプロピオン酸誘導体とに分離させた後、静置して水層と有機溶媒層とに分離する。
４）水層から減圧留去などにより水を除去して光学活性アミノ酸、有機溶媒層から減圧留去などにより有機溶媒を除去して光学活性２−フェノキシプロピオン酸誘導体をそれぞれ単離する。
3) This diastereomer is dissolved or suspended in a mixture of a water-insoluble organic solvent and water, and stirred to separate into optically active amino acid and optically active 2-phenoxypropionic acid derivative. And separating into an aqueous layer and an organic solvent layer.
4) Water is removed from the aqueous layer by distillation under reduced pressure and the like, and the optically active amino acid is removed. The organic solvent is removed from the organic solvent layer by distillation under reduced pressure and the optically active 2-phenoxypropionic acid derivative is isolated.
５）前記２）でジアステレオマーを分離し、必要により１）で使用した光学活性２−フェノキシプロピオン酸誘導体を分離した後の母液に、１）の操作で用いたものとは逆の対掌体である光学活性２−フェノキシプロピオン酸誘導体を加えて加熱したのち、２）と同様の操作を行い、２）で得られたものとは逆のアミノ酸対掌体のジアステレオマーを単離する。
６）５）の操作により得られたジアステレオマーに３）、４）の操作を行い、４）で得られたアミノ酸とは逆のアミノ酸対掌体である光学活性アミノ酸を得る。
5) The diastereomer was separated in 2) above, and if necessary, the optically active 2-phenoxypropionic acid derivative used in 1) was separated into the mother liquor opposite to that used in 1). After adding and heating the optically active 2-phenoxypropionic acid derivative which is the isomer, the same operation as 2) is performed, and the diastereomer of the amino acid enantiomer opposite to that obtained in 2) is isolated. .
6) The diastereomer obtained by the operation of 5) is subjected to the operations of 3) and 4) to obtain an optically active amino acid which is the opposite enantiomer of the amino acid obtained in 4).
本発明においては、光学分割剤として一般式（１）で表される光学活性２−フェノキシプロピオン酸誘導体を使用する。特に光学活性の２−フェノキシプロピオン酸、２−（４′−メチルフェノキシ）プロピオン酸、２−（４′−クロロフェノキシ）プロピオン酸が好ましい。
ラセミ−アミノ酸に対して光学分割剤として（Ｓ）−２−フェノキシプロピオン酸誘導体を使用した場合にはそれぞれの組合せに対応して（Ｓ）−アミノ酸又は（Ｒ）−アミノ酸とのジアステレオマーが生成し、（Ｒ）−２−フェノキシプロピオン酸誘導体を使用した場合にはそれぞれの組合せに対応して（Ｒ）−アミノ酸又は（Ｓ）−アミノ酸とのジアステレオマーが生成する。ここでラセミ−アミノ酸の光学分割の中間生成物として得られるジアステレオマーは光学活性−アミノ酸と光学活性２−フェノキシプロピオン酸誘導体とで構成される複合体であり、従来、合成された報告はなく、全て新規物質である。 When an (S) -2-phenoxypropionic acid derivative is used as an optical resolving agent for racemic amino acids, diastereomers with (S) -amino acids or (R) -amino acids correspond to the respective combinations. When the (R) -2-phenoxypropionic acid derivative is used, a diastereomer with (R) -amino acid or (S) -amino acid is generated corresponding to each combination. Here, the diastereomer obtained as an intermediate product of the optical resolution of racemic amino acid is a complex composed of optically active amino acid and optically active 2-phenoxypropionic acid derivative. , All new substances.
前記１）、２）によるジアステレオマーの調製は無溶媒の条件でも可能ではあるが、通常は溶媒を用いるのが好ましい。溶媒は光学活性２−フェノキシプロピオン酸誘導体及びラセミ−アミノ酸を溶解させると同時に、光学活性２−フェノキシプロピオン酸誘導体と光学活性アミノ酸から成るジアステレオマーを難溶性のジアステレオマーとして析出させ、ジアステレオマーを形成していないもう一方の光学異性体のアミノ酸を溶解しうる溶媒が、操作上好ましい。ここでは水と親和性のある溶媒が好ましく、具体的には水、メタノール、エタノールなどのアルコール系溶媒、アセトン、１，４−ジオキサン又はそれらの混合物が使用できる。製造コストや環境への配慮などから好ましくは水又はメタノール、エタノールなどの低級アルコール若しくはそれらの混合物である。 Although preparation of the diastereomers according to the above 1) and 2) is possible even under solvent-free conditions, it is usually preferable to use a solvent. The solvent dissolves the optically active 2-phenoxypropionic acid derivative and the racemic-amino acid, and simultaneously precipitates a diastereomer composed of the optically active 2-phenoxypropionic acid derivative and the optically active amino acid as a hardly soluble diastereomer. A solvent capable of dissolving the amino acid of the other optical isomer that does not form a mer is preferred in terms of operation. Here, a solvent having an affinity for water is preferable. Specifically, water, alcohol solvents such as methanol and ethanol, acetone, 1,4-dioxane or a mixture thereof can be used. From the viewpoint of production costs and environmental considerations, water, lower alcohols such as methanol and ethanol, or mixtures thereof are preferable.
溶媒の使用量は、２−フェノキシプロピオン酸誘導体及びラセミ−アミノ酸が溶解し、ジアステレオマーが析出し、ジアステレオマーを形成していないもう一方の光学異性体のアミノ酸は溶解している範囲が望ましく、通常ラセミ−アミノ酸に対して１〜５０重量倍の範囲である。 The amount of the solvent used is such that the 2-phenoxypropionic acid derivative and the racemic amino acid are dissolved, the diastereomer is precipitated, and the amino acid of the other optical isomer not forming the diastereomer is dissolved. Desirably, it is usually in the range of 1 to 50 times the weight of the racemic amino acid.
２−フェノキシプロピオン酸誘導体とラセミ−アミノ酸の反応温度は溶媒の融点から沸点の範囲である。例えば、水を使用した場合には、混合物を６０−９０℃で加熱溶解後、１０−３０℃まで冷却して、析出した結晶を固液分離することによりジアステレオマーが得られる。分離したジアステレオマー中の目的とする光学活性アミノ酸の光学純度が低い場合は、ジアステレオマーを１回〜数回再結晶することにより精製可能である。
ラセミ−アミノ酸と光学活性２−フェノキシプロピオン酸の混合比は１０：１〜１：１０で、好ましくは２：０．８〜１．２である。
The reaction temperature of the 2-phenoxypropionic acid derivative and the racemic amino acid ranges from the melting point to the boiling point of the solvent. For example, when water is used, the mixture is heated and dissolved at 60 to 90 ° C., cooled to 10 to 30 ° C., and the precipitated crystals are solid-liquid separated to obtain a diastereomer. When the optical purity of the target optically active amino acid in the separated diastereomer is low, it can be purified by recrystallizing the diastereomer once to several times.
The mixing ratio of racemic amino acid and optically active 2-phenoxypropionic acid is 10: 1 to 1:10, preferably 2: 0.8 to 1.2.
前記３）、４）の工程においては、ジアステレオマーからの光学活性アミノ酸単離時の有機溶媒は水に難溶で、アミノ酸及び２−フェノキシプロピオン酸誘導体に対して不活性ならばどのような溶媒でも使用可能である。すなわち、１−ブタノールなどのアルコール系溶媒、酢酸エチル、酢酸ブチルなどの酢酸エステル系溶媒、４−メチル−２−ペンタノンなどのケトン類、クロロホルム、ジクロロメタン、１，２−ジクロロエタンなどのハロゲン化アルキル類、トルエン、ヘキサンなど炭化水素類、ｔ−ブチルメチルエーテルなどのエーテル系溶媒が利用できる。経済性及び安全性から酢酸エチル又はｔ−ブチルメチルエーテル、４−メチル―２−ペンタノンが好ましい。有機溶媒の使用量は実用的にはジアステレオマーに対し２〜１０倍量である。また、ジアステレオマー結晶の溶解に使用される水の使用量は、実用的にはジアステレオマーに対し２〜１０倍量である。 In the steps 3) and 4), the organic solvent used for isolating the optically active amino acid from the diastereomer is hardly soluble in water and is inert to the amino acid and 2-phenoxypropionic acid derivative. Solvents can also be used. That is, alcohol solvents such as 1-butanol, acetate solvents such as ethyl acetate and butyl acetate, ketones such as 4-methyl-2-pentanone, alkyl halides such as chloroform, dichloromethane and 1,2-dichloroethane , Hydrocarbons such as toluene and hexane, and ether solvents such as t-butyl methyl ether can be used. In view of economy and safety, ethyl acetate, t-butyl methyl ether, and 4-methyl-2-pentanone are preferable. The amount of organic solvent used is practically 2 to 10 times the amount of diastereomer. Moreover, the usage-amount of the water used for melt | dissolution of a diastereomeric crystal | crystallization is 2-10 times amount with respect to a diastereomer practically.
以下実施例により本発明をさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
〔実施例１〕
ラセミ−バリン１００ｇ（０．８５ｍｏｌ）、（Ｓ）−２−フェノキシプロピオン酸７１．０ｇ（０．４２７ｍｏｌ）、脱イオン水８５５ｇを混合し、８５〜９５℃で１時間撹拌した。溶液の温度を一夜かけて２０〜３０℃まで冷却し、生じた結晶を分離乾燥し粗ジアステレオマー９８ｇを得た。得られたジアステレオマー結晶中の（Ｒ）−バリンの光学純度は旋光度から４０％ｅｅであった。
この粗ジアステレオマー結晶９７．５ｇをジアステレオマー結晶に対し５倍量の脱イオン水４８７ｇに溶解させる再結晶を実施して６８．３ｇの精製ジアステレオマー結晶を得た。このジアステレオマーは（Ｒ）−バリンと（Ｓ）−２−フェノキシプロピオン酸からなる複合体（Ｒ−Ｖａｌ／Ｓ−ＡＰＰ）である。
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
[Example 1]
Racemic-valine 100 g (0.85 mol), (S) -2-phenoxypropionic acid 71.0 g (0.427 mol), and deionized water 855 g were mixed and stirred at 85 to 95 ° C. for 1 hour. The temperature of the solution was cooled to 20-30 ° C. overnight, and the resulting crystals were separated and dried to obtain 98 g of a crude diastereomer. The optical purity of (R) -valine in the obtained diastereomeric crystals was 40% ee from the optical rotation.
Recrystallization was carried out by dissolving 97.5 g of this crude diastereomeric crystal in 487 g of deionized water in an amount five times that of the diastereomeric crystal to obtain 68.3 g of purified diastereomeric crystal. This diastereomer is a complex (R-Val / S-APP) composed of (R) -valine and (S) -2-phenoxypropionic acid.
得られた精製ジアステレオマー結晶１０ｇにｔ−ブチルメチルエーテル１００ｍｌ、水１００ｍｌを加え、２０〜３０℃で３０分攪拌した。その後、分液し水層から水を減圧留去して定量的に（Ｒ）−バリンを得た。得られた（Ｒ）−バリンの旋光度は−２３．４°（温度：２６℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
一方、ｔ−ブチルメチルエーテル層を濃縮して、（Ｓ）−２−フェノキシプロピオン酸を定量的に回収することができた。
To 10 g of the purified diastereomeric crystals obtained, 100 ml of t-butyl methyl ether and 100 ml of water were added and stirred at 20-30 ° C. for 30 minutes. Thereafter, liquid separation was performed, and water was distilled off from the aqueous layer under reduced pressure to quantitatively obtain (R) -valine. The optical rotation of the obtained (R) -valine was −23.4 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v).
On the other hand, the t-butyl methyl ether layer was concentrated and (S) -2-phenoxypropionic acid could be recovered quantitatively.
〔実施例２〕
実施例１で得られた粗ジアステレオマー分離母液に、ｔ−ブチルメチルエーテル１００ｍｌを加えて撹拌後分液する操作を３回繰り返した。この操作で得られた水層に（Ｒ）−２−フェノキシプロピオン酸７１．０ｇ（０．４２７ｍｏｌ）を加え８５〜９５℃で１時間撹拌した。その後一夜かけて溶液の温度を２０〜３０℃まで冷却し、生じた結晶を分離乾燥して９５ｇの粗ジアステレオマー（このジアステレオマーの一部からアミノ酸を単離して、旋光度を測定した結果、光学純度は５０％ｅｅであった）を得た。
この粗ジアステレオマー結晶９４．５ｇをジアステレオマー結晶に対し５倍量の脱イオン水４７２ｇに溶解後、再結晶して６６．０ｇの精製ジアステレオマー結晶を得た。このジアステレオマーは（Ｓ）−バリンと（Ｒ）−２−フェノキシプロピオン酸からなる複合体（Ｓ−Ｖａｌ／Ｒ−ＡＰＰ）である。
[Example 2]
The operation of adding 100 ml of t-butyl methyl ether to the crude diastereomer separation mother liquor obtained in Example 1 and separating the solution after stirring was repeated three times. 71.0 g (0.427 mol) of (R) -2-phenoxypropionic acid was added to the aqueous layer obtained by this operation, and the mixture was stirred at 85 to 95 ° C. for 1 hour. Thereafter, the temperature of the solution was cooled to 20 to 30 ° C. overnight, and the resulting crystals were separated and dried to isolate 95 g of a crude diastereomer (an amino acid was isolated from a part of this diastereomer and the optical rotation was measured. As a result, the optical purity was 50% ee).
94.5 g of this crude diastereomeric crystal was dissolved in 472 g of deionized water 5 times the amount of the diastereomeric crystal, and then recrystallized to obtain 66.0 g of purified diastereomeric crystal. This diastereomer is a complex (S-Val / R-APP) composed of (S) -valine and (R) -2-phenoxypropionic acid.
得られた精製ジアステレオマー結晶１０ｇにｔ−ブチルメチルエーテル１００ｍｌ、水１００ｍｌを加え、２０〜３０℃で３０分攪拌した。その後、分液し水層から水を減圧留去して定量的に（Ｓ）−バリンを得た。得られた（Ｓ）−バリンの旋光度は＋２３．７°（温度：２６℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
また、ｔ−ブチルメチルエーテル層を濃縮して、（Ｒ）−２−フェノキシプロピオン酸を定量的に回収することができた。
To 10 g of the purified diastereomeric crystals obtained, 100 ml of t-butyl methyl ether and 100 ml of water were added and stirred at 20-30 ° C. for 30 minutes. Thereafter, liquid separation was performed, and water was distilled off from the aqueous layer under reduced pressure to quantitatively obtain (S) -valine. The optical rotation of the obtained (S) -valine was + 23.7 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v).
Further, the t-butyl methyl ether layer was concentrated, and (R) -2-phenoxypropionic acid could be recovered quantitatively.
〔実施例３〕
ラセミ−バリン１００ｇ（０．８５４ｍｏｌ）、（Ｒ）−２−フェノキシプロピオン酸７１．０ｇ（０．４２７ｍｏｌ）、脱イオン水８５５ｇを混合し、８５〜９５℃で１時間した。溶液の温度を一夜かけて２０〜３０℃まで冷却し、生じた結晶を分離乾燥し粗ジアステレオマー９４ｇ（得られたジアステレオマー結晶中のアミノ酸の光学純度：４０％ｅｅ）を得た。
この粗ジアステレオマー結晶９４ｇを脱イオン水で再結晶し精製ジアステレオマー結晶６６．０ｇを得た。このジアステレオマーは（Ｓ）−バリンと（Ｒ）−２−フェノキシプロピオン酸からなる複合体（Ｓ−Ｖａｌ／Ｒ−ＡＰＰ）である。
Example 3
100 g (0.854 mol) of racemic-valine, 71.0 g (0.427 mol) of (R) -2-phenoxypropionic acid, and 855 g of deionized water were mixed, and the mixture was stirred at 85 to 95 ° C. for 1 hour. The temperature of the solution was cooled to 20-30 ° C. overnight, and the resulting crystals were separated and dried to obtain 94 g of crude diastereomers (optical purity of amino acids in the obtained diastereomeric crystals: 40% ee).
94 g of the crude diastereomeric crystals were recrystallized with deionized water to obtain 66.0 g of purified diastereomeric crystals. This diastereomer is a complex (S-Val / R-APP) composed of (S) -valine and (R) -2-phenoxypropionic acid.
得られた精製ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｓ）−バリンを得た。得られた（Ｓ）−バリンの旋光度は＋２３．８°（温度：２５℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。また、実施例１と同様にｔ−ブチルメチルエーテル層から（Ｒ）−２−フェノキシプロピオン酸を定量的に回収することができた。 10 g of the obtained purified diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -valine. The optical rotation of the obtained (S) -valine was + 23.8 ° (temperature: 25 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). Further, (R) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer as in Example 1.
〔実施例４〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｓ）−２−フェノキシプロピオン酸８０．６ｇ（０．４８５ｍｏｌ）、脱イオン水９０３ｇを混合して実施例１と同様な操作を実施し、１１５ｇの粗ジアステレオマー結晶を得た。ＨＰＬＣ（高速液体クロマトグラフィー）にて分析した含有アミノ酸光学純度は９５％ｅｅであった。
この粗ジアステレオマー結晶１１４．５ｇを実施例１と同様な操作で再結晶して精製ジアステレオマー結晶７０．０ｇを得た。このジアステレオマーは（Ｒ）−２−アミノブタン酸と（Ｓ）−２−フェノキシプロピオン酸からなる複合体（Ｒ−２−ＡＢＡ／Ｓ−ＡＰＰ）である。
Example 4
100 g (0.970 mol) of racemic-2-aminobutanoic acid, 80.6 g (0.485 mol) of (S) -2-phenoxypropionic acid, and 903 g of deionized water were mixed, and the same operation as in Example 1 was performed. 115 g of crude diastereomeric crystals were obtained. The optical purity of the contained amino acid analyzed by HPLC (high performance liquid chromatography) was 95% ee.
114.5 g of this crude diastereomeric crystal was recrystallized in the same manner as in Example 1 to obtain 70.0 g of purified diastereomeric crystal. This diastereomer is a complex (R-2-ABA / S-APP) composed of (R) -2-aminobutanoic acid and (S) -2-phenoxypropionic acid.
得られた精製ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｒ）−２−アミノブタン酸を得た。得られた（Ｒ）−２−アミノブタン酸の旋光度は−２０．６°（温度：２８℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であり、ＨＰＬＣで分析した光学純度は９９％ｅｅ以上であった。
また、ｔ−ブチルメチルエーテル層から（Ｓ）−２−フェノキシプロピオン酸を定量的に回収することができた。
10 g of the obtained purified diastereomer crystal was operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water, to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid is −20.6 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). The optical purity analyzed by HPLC was 99% ee or higher.
Further, (S) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
〔実施例５〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｒ）−２−フェノキシプロピオン酸７１．０ｇ（０．４２７ｍｏｌ）、脱イオン水９０３ｇを混合して実施例１と同様な操作を実施し、１０６ｇの粗ジアステレオマー結晶（ＨＰＬＣにて分析した含有アミノ酸光学純度は９５％ｅｅ）を得た。
この粗ジアステレオマー結晶１０５ｇを実施例１と同様な操作で再結晶して精製ジアステレオマー結晶６９．０ｇを得た。このジアステレオマーは（Ｓ）−２−アミノブタン酸と（Ｒ）−２−フェノキシプロピオン酸からなる複合体（Ｓ−２−ＡＢＡ／Ｒ−ＡＰＰ）である。
Example 5
Racemic-2-aminobutanoic acid 100 g (0.970 mol), (R) -2-phenoxypropionic acid 71.0 g (0.427 mol), and deionized water 903 g were mixed and the same operation as in Example 1 was performed. 106 g of crude diastereomeric crystals (optical amino acid purity analyzed by HPLC is 95% ee) was obtained.
105 g of this crude diastereomeric crystal was recrystallized in the same manner as in Example 1 to obtain 69.0 g of purified diastereomeric crystal. This diastereomer is a complex (S-2-ABA / R-APP) composed of (S) -2-aminobutanoic acid and (R) -2-phenoxypropionic acid.
得られた精製ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｓ）−２−アミノブタン酸を得た。得られた（Ｓ）−２−アミノブタン酸の旋光度は＋２０．１°（温度：２８℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であり、ＨＰＬＣで分析した光学純度は９９％ｅｅ以上であった。
また、ｔ−ブチルメチルエーテル層から（Ｒ）−２−フェノキシプロピオン酸を定量的に回収することができた。
10 g of the obtained purified diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water, to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid is + 20.1 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v), The optical purity analyzed by HPLC was 99% ee or higher.
In addition, (R) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
〔実施例６〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｓ）−２−（４′−メチルフェノキシ）プロピオン酸８７．４ｇ（０．４８５ｍｏｌ）、脱イオン水９３７ｇを混合して実施例１と同様な操作を実施し、８５ｇの粗ジアステレオマー結晶（ＨＰＬＣにて分析した含有アミノ酸光学純度は７０％ｅｅ）を得た。このジアステレオマーはＳ−２−アミノブタン酸と（Ｓ）−２−（４′−メチルフェノキシ）プロピオン酸からなる複合体（Ｓ−２−ＡＢＡ／Ｓ−４−Ｍｅ−ＡＰＰ）である。
得られた粗ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｓ）−２−アミノブタン酸を得た。得られた（Ｓ）−２−アミノブタン酸の旋光度は＋１４．４°（温度：２５℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
また、ｔ−ブチルメチルエーテル層から（Ｓ）−２−（４′−メチルフェノキシ）プロピオン酸を定量的に回収することができた。
Example 6
The same as in Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 87.4 g (0.485 mol) of (S) -2- (4′-methylphenoxy) propionic acid, and 937 g of deionized water were mixed. Then, 85 g of crude diastereomeric crystals (containing amino acid optical purity analyzed by HPLC is 70% ee) was obtained. This diastereomer is a complex (S-2-ABA / S-4-Me-APP) composed of S-2-aminobutanoic acid and (S) -2- (4′-methylphenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid was + 14.4 ° (temperature: 25 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). .
In addition, (S) -2- (4′-methylphenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
〔実施例７〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｒ）−２−（４′−メチルフェノキシ）プロピオン酸８７．４ｇ（０．４８５ｍｏｌ）、脱イオン水９３７ｇを混合して実施例１と同様な操作を実施し、８８ｇの粗ジアステレオマー結晶（ＨＰＬＣにて分析した含有アミノ酸光学純度は６５％ｅｅ）を得た。このジアステレオマーはＲ−２−アミノブタン酸と（Ｒ）−２−（４′−メチルフェノキシ）プロピオン酸からなる複合体（Ｒ−２−ＡＢＡ／Ｒ−４−Ｍｅ−ＡＰＰ）である。
得られた粗ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｒ）−２−アミノブタン酸を得た。得られた（Ｒ）−２−アミノブタン酸の旋光度は−１３．７°（温度：２７℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
また、ｔ−ブチルメチルエーテル層から（Ｒ）−２−（４′−メチルフェノキシ）プロピオン酸を定量的に回収することができた。
Example 7
The same as in Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 87.4 g (0.485 mol) of (R) -2- (4′-methylphenoxy) propionic acid, and 937 g of deionized water were mixed. Thus, 88 g of crude diastereomer crystals (containing amino acid optical purity analyzed by HPLC: 65% ee) was obtained. This diastereomer is a complex (R-2-ABA / R-4-Me-APP) composed of R-2-aminobutanoic acid and (R) -2- (4′-methylphenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid was −13.7 ° (temperature: 27 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). It was.
In addition, (R) -2- (4′-methylphenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
〔実施例８〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｒ）−２−（４′−クロロフェノキシ）プロピオン酸９７．３ｇ（０．４８５ｍｏｌ）、脱イオン水１０００ｇを混合して実施例１と同様な操作を実施し、１００ｇの粗ジアステレオマー結晶（ＨＰＬＣにて分析した含有アミノ酸光学純度は６３％ｅｅ）を得た。このジアステレオマーはＲ−２−アミノブタン酸と（Ｒ）−２−（４′−クロロフェノキシ）プロピオン酸からなる複合体（Ｒ−２−ＡＢＡ／Ｒ−４−Ｃｌ−ＡＰＰ）である。
得られた粗ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｒ）−２−アミノブタン酸を得た。得られた（Ｒ）−２−アミノブタン酸の旋光度は−１２．９°（温度：２６℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
また、ｔ−ブチルメチルエーテル層から（Ｒ）−２−（４′−クロロフェノキシ）プロピオン酸を定量的に回収することができた。
Example 8
Same as Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 97.3 g (0.485 mol) of (R) -2- (4′-chlorophenoxy) propionic acid and 1000 g of deionized water were mixed. Thus, 100 g of crude diastereomeric crystals (containing optical purity of 63% ee analyzed by HPLC) was obtained. This diastereomer is a complex (R-2-ABA / R-4-Cl-APP) composed of R-2-aminobutanoic acid and (R) -2- (4′-chlorophenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid was −12.9 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). It was.
In addition, (R) -2- (4′-chlorophenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
〔実施例９〕
ラセミ−２−アミノブタン酸１００ｇ（０．９７０ｍｏｌ）、（Ｓ）−２−（４′−クロロフェノキシ）プロピオン酸９７．３ｇ（０．４８５ｍｏｌ）、脱イオン水１０００ｇを混合して実施例１と同様な操作を実施し、１０３ｇの粗ジアステレオマー結晶を得た。このジアステレオマーはＳ−２−アミノブタン酸と（Ｓ）−２−（４′−クロロフェノキシ）プロピオン酸からなる複合体（Ｓ−２−ＡＢＡ／Ｓ−４−Ｃｌ−ＡＰＰ）である。
得られた粗ジアステレオマー結晶１０ｇを、ｔ−ブチルメチルエーテルと水との混合溶媒を用いて実施例１と同様に操作し、定量的に（Ｓ）−２−アミノブタン酸を得た。得られた（Ｓ）−２−アミノブタン酸の旋光度は＋１２．３°（温度：２８℃、溶媒：１．０Ｍ ＨＣｌ、光源：Ｎａ Ｌａｍｐ、濃度：１．０％ｗ／ｖ）であった。
また、ｔ−ブチルメチルエーテル層から（Ｓ）−２−（４′−クロロフェノキシ）プロピオン酸を定量的に回収することができた。
Example 9
Same as Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 97.3 g (0.485 mol) of (S) -2- (4′-chlorophenoxy) propionic acid and 1000 g of deionized water were mixed. Thus, 103 g of crude diastereomeric crystals were obtained. This diastereomer is a complex (S-2-ABA / S-4-Cl-APP) composed of S-2-aminobutanoic acid and (S) -2- (4′-chlorophenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid was + 12.3 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). .
In addition, (S) -2- (4′-chlorophenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.
実施例１〜５で得られた精製ジアステレオマー及び実施例６〜９で得られた粗ジアステレオマーについて測定したＮＭＲ分析結果を表１に示す。また、これらの試料（実施例３の物は除く）について旋光度及び融点を測定した結果を表２に示す。なお、表２の旋光度の測定条件は次のとおりである。
温度：２８℃
溶媒：酢酸（実施例１〜５）、メタノール（実施例６〜９）
光源：Ｎａ Ｌａｍｐ
濃度：１．０％ｗ／ｖ
The NMR analysis results measured for the purified diastereomers obtained in Examples 1 to 5 and the crude diastereomers obtained in Examples 6 to 9 are shown in Table 1. Table 2 shows the results of measuring the optical rotation and melting point of these samples (excluding those of Example 3). In addition, the measurement conditions of the optical rotation in Table 2 are as follows.
Temperature: 28 ° C
Solvent: acetic acid (Examples 1-5), methanol (Examples 6-9)
Light source: Na Lamp
Concentration: 1.0% w / v
本発明の製造方法によって得られる光学活性のバリン及び２−アミノブタン酸は、医薬、農薬などの化学品の分野において、キラルプールとして幅広い利用が期待されている。また、光学活性バリン又は光学活性２−アミノブタン酸と光学活性２−フェノキシプロピオン酸誘導体とで構成される複合体であるジアステレオマーはラセミ−アミノ酸の光学分割の中間生成物として利用価値の高いものである。 Optically active valine and 2-aminobutanoic acid obtained by the production method of the present invention are expected to be widely used as chiral pools in the field of chemicals such as pharmaceuticals and agricultural chemicals. In addition, diastereomers, which are complexes composed of optically active valine or optically active 2-aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative, have high utility as intermediate products of optical resolution of racemic amino acids. It is.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011001889A1 (en) | 2009-06-29 | 2011-01-06 | 三菱瓦斯化学株式会社 | METHOD FOR RACEMIZING OPTICALLY ACTIVE α-AMINO ACIDS |
| JP2011024572A (en) * | 2009-06-29 | 2011-02-10 | Mitsubishi Gas Chemical Co Inc | Method for producing optically active amino acid |
| JP5576791B2 (en) * | 2008-06-03 | 2014-08-20 | 株式会社カネカ | Method for producing optically active amino acid derivative |
| JP5683273B2 (en) * | 2008-12-12 | 2015-03-11 | 第一三共株式会社 | Process for producing optically active carboxylic acid |
| US9120722B1 (en) | 2014-08-14 | 2015-09-01 | Wellman Biosciences Co. Ltd. | Optically active valine complex and a method for producing the same |
| CN105385621A (en) * | 2015-11-20 | 2016-03-09 | 浙江昌明药业有限公司 | Acinetobacter junii zjutfet-1 and application thereof |
| JP2016168014A (en) * | 2015-03-13 | 2016-09-23 | 三井化学株式会社 | Method for producing 2-aminobutanoic acid, 2-aminobutanoic acid, decarboxylase, method for using decarboxylase, method for producing decarboxylase, gene, vector or transformant |
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| JP5576791B2 (en) * | 2008-06-03 | 2014-08-20 | 株式会社カネカ | Method for producing optically active amino acid derivative |
| JP5683273B2 (en) * | 2008-12-12 | 2015-03-11 | 第一三共株式会社 | Process for producing optically active carboxylic acid |
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| CN105385621A (en) * | 2015-11-20 | 2016-03-09 | 浙江昌明药业有限公司 | Acinetobacter junii zjutfet-1 and application thereof |
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