JP4853834B2 - Optical resolution method - Google Patents
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- JP4853834B2 JP4853834B2 JP2007121411A JP2007121411A JP4853834B2 JP 4853834 B2 JP4853834 B2 JP 4853834B2 JP 2007121411 A JP2007121411 A JP 2007121411A JP 2007121411 A JP2007121411 A JP 2007121411A JP 4853834 B2 JP4853834 B2 JP 4853834B2
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- 238000000034 method Methods 0.000 title claims description 16
- 230000003287 optical effect Effects 0.000 title claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000000178 monomer Substances 0.000 description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- 101000864780 Homo sapiens Pulmonary surfactant-associated protein A1 Proteins 0.000 description 2
- 101000651017 Homo sapiens Pulmonary surfactant-associated protein A2 Proteins 0.000 description 2
- 102100027773 Pulmonary surfactant-associated protein A2 Human genes 0.000 description 2
- ARCJQKUWGAZPFX-KBPBESRZSA-N S-trans-stilbene oxide Chemical compound C1([C@H]2[C@@H](O2)C=2C=CC=CC=2)=CC=CC=C1 ARCJQKUWGAZPFX-KBPBESRZSA-N 0.000 description 2
- 150000000475 acetylene derivatives Chemical class 0.000 description 2
- 239000002156 adsorbate Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005557 chiral recognition Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960000930 hydroxyzine Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920006389 polyphenyl polymer Polymers 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229960005345 trimebutine Drugs 0.000 description 2
- BJAADAKPADTRCH-UHFFFAOYSA-N 2-methoxy-1-(2-methoxynaphthalen-1-yl)naphthalene Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3OC)=C(OC)C=CC2=C1 BJAADAKPADTRCH-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- 229960000456 carbinoxamine maleate Drugs 0.000 description 1
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002207 flavanone derivatives Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 229960003220 hydroxyzine hydrochloride Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- Epoxy Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、ラセミ体の光学分割法に関する。 The present invention relates to a method for optical resolution of a racemate.
従来のラセミ体の光学分割法としては、キラルポリマーをカラムに充填し、このカラムにラセミ体の溶液を通して保持時間の差を利用してエナンチオマーを分割する方法が最も広く用いられている。しかし、この方法はバッチ式であり、一度に大量の分離を行うことが困難であった。 As a conventional method for optical resolution of racemates, a method in which a chiral polymer is packed in a column and a solution of the racemate is passed through this column to separate enantiomers using a difference in retention time is most widely used. However, this method is a batch method, and it is difficult to perform a large amount of separation at a time.
また、ラセミ体の溶液に光学分割剤を添加して、エナンチオマー間の溶解度差を利用して再結晶する方法も知られているが、操作に時間がかかり、効率が悪かった。
そこで、本発明は、一度に大量に、効率よくエナンチオマーを分離することができる、新規の光学分割法を提供することを目的とする。 Therefore, an object of the present invention is to provide a novel optical resolution method capable of efficiently separating enantiomers in a large amount at a time.
上記課題を解決するために鋭意検討した結果、キラルらせん主鎖構造を有するポリフェニルアセチレン誘導体のテトラヒドロフラン溶液中にメタノールを添加した際に、キラルらせん主鎖構造が維持されたままポリフェニルアセチレン誘導体が沈殿することを見出した。さらに、このテトラヒドロフラン溶液に添加するメタノールにラセミ体を溶解させておくと、選択的に一方のエナンチオマーのみを吸着してポリフェニルアセチレン誘導体が沈殿することを見出し、本発明に想到した。 As a result of diligent studies to solve the above problems, when methanol was added to a tetrahydrofuran solution of a polyphenylacetylene derivative having a chiral helical main chain structure, the polyphenylacetylene derivative was maintained while the chiral helical main chain structure was maintained. Found to precipitate. Furthermore, when the racemate was dissolved in methanol added to the tetrahydrofuran solution, it was found that only one enantiomer was selectively adsorbed to precipitate a polyphenylacetylene derivative, and the present invention was conceived.
すなわち、本発明の光学分割法は、キラルらせん主鎖構造を有するポリフェニルアセチレン誘導体を第一の溶媒に溶解した第一の溶液と、ラセミ体を第二の溶媒に溶解した第二の溶液とを混合し、前記ラセミ体の一方のエナンチオマーのみ選択的に前記ポリフェニルアセチレン誘導体に吸着させて沈殿させることを特徴とする。 That is, the optical resolution method of the present invention includes a first solution in which a polyphenylacetylene derivative having a chiral helical main chain structure is dissolved in a first solvent, and a second solution in which a racemate is dissolved in a second solvent. And only one enantiomer of the racemate is selectively adsorbed on the polyphenylacetylene derivative and precipitated.
また、前記ポリフェニルアセチレン誘導体は、
さらに、前記第一の溶媒はテトラヒドロフランであり、前記第二の溶媒はメタノールであることを特徴とする。 Further, the first solvent is tetrahydrofuran, and the second solvent is methanol.
本発明によれば、一度に大量に、効率よくエナンチオマーを分離することができる。 According to the present invention, enantiomers can be efficiently separated in a large amount at a time.
本発明の光学分割法は、キラルらせん主鎖構造を有するポリフェニルアセチレン誘導体を第一の溶媒に溶解した第一の溶液と、ラセミ体を第二の溶媒に溶解した第二の溶液とを混合し、前記ラセミ体の一方のエナンチオマーのみ選択的に前記ポリフェニルアセチレン誘導体に吸着させて沈殿させるものである。 The optical resolution method of the present invention comprises mixing a first solution in which a polyphenylacetylene derivative having a chiral helical main chain structure is dissolved in a first solvent and a second solution in which a racemate is dissolved in a second solvent. Then, only one enantiomer of the racemate is selectively adsorbed on the polyphenylacetylene derivative and precipitated.
本発明で用いるキラルらせん主鎖構造を有するポリフェニルアセチレン誘導体は、フェニルアセチレン誘導体モノマーを公知のキラル触媒系で重合することで得られる。このポリフェニルアセチレン誘導体としては、例えば、
同様に、本発明で用いられるポリフェニルアセチレン誘導体の原料となるフェニルアセチレン誘導体モノマーとしては、フェニル基上に種々の置換基を有するものを用いることができる。 Similarly, as the phenylacetylene derivative monomer used as a raw material of the polyphenylacetylene derivative used in the present invention, those having various substituents on the phenyl group can be used.
本発明で用いられる第一の溶媒は、ポリフェニルアセチレン誘導体を溶解できるものであって、ポリフェニルアセチレン誘導体のモノマー換算で０．１ｍＭ以上溶解できるものが好適に用いられる。さらに好ましくは、０．５ｍＭ以上溶解できるものが用いられる。例えば、テトラヒドロフラン（ＴＨＦ）などを用いることができる。 The 1st solvent used by this invention can melt | dissolve a polyphenyl acetylene derivative, Comprising: The thing which can melt | dissolve 0.1 mM or more in conversion of the monomer of a polyphenyl acetylene derivative is used suitably. More preferably, those capable of dissolving 0.5 mM or more are used. For example, tetrahydrofuran (THF) can be used.
また、第二の溶媒としては、第一の溶媒と任意の混合比で均一に混合でき、ポリフェニルアセチレン誘導体をほとんど溶解せず、かつ、光学分割の対象となるラセミ体を溶解できるものが好適に用いられる。例えば、メタノールなどを用いることができる。 As the second solvent, a solvent that can be uniformly mixed with the first solvent at an arbitrary mixing ratio, hardly dissolves the polyphenylacetylene derivative, and can dissolve the racemate to be optically resolved is preferable. Used for. For example, methanol can be used.
そして、本発明の光学分割法によれば、第一の溶液と第二の溶液を混合したときにポリフェニルアセチレン誘導体が析出し、析出する際に選択的に一方のエナンチオマーのみを吸着して沈殿する。このように、ポリフェニルアセチレン誘導体が析出するまでは系が均一であり、ポリフェニルアセチレン誘導体が析出するまでのポリフェニルアセチレン誘導体とラセミ体は液相中で相互作用する。この相互作用は、固相−液相間での相互作用よりも強く、その結果、効率的に、かつ、高い選択性で光学分割を行うことができる。 According to the optical resolution method of the present invention, when the first solution and the second solution are mixed, the polyphenylacetylene derivative is precipitated, and only one enantiomer is selectively adsorbed during the precipitation. To do. Thus, the system is uniform until the polyphenylacetylene derivative is precipitated, and the polyphenylacetylene derivative and the racemate until the polyphenylacetylene derivative is precipitated interact in the liquid phase. This interaction is stronger than the interaction between the solid phase and the liquid phase, and as a result, optical resolution can be performed efficiently and with high selectivity.
なお、従来の光学分割剤のキラル認識能を確認するための吸着実験は、固相−液相間の相互作用を観察するものであり、上記のように本発明の光学分割法とは異なるものである。 In addition, the adsorption experiment for confirming the chiral recognition ability of the conventional optical resolution agent observes the interaction between the solid phase and the liquid phase, and is different from the optical resolution method of the present invention as described above. It is.
以下、具体的な実施例に基づいて、本発明について詳細に説明する。なお、本発明は、以下の実施例によって制限されるものではない。 Hereinafter, the present invention will be described in detail based on specific examples. In addition, this invention is not restrict | limited by a following example.
ポリフェニルアセチレン誘導体として、ポリ（ＤｏＤＨＰＡ）、又はポリ（ＰＳＰＡ）を用い、
ポリフェニルアセチレン誘導体（モノマー換算で２．６０μｍｏｌ）のＴＨＦ溶液３ｍｌ（モノマー換算で０．８６５ｍＭ）と、ラセミ体（０．１６μｍｏｌ）のメタノール溶液１ｍｌを混合した。なお、混合後のラセミ体のモル濃度は、ポリフェニルアセチレン誘導体のモノマー換算量（モノマーユニット）に対して、モノマーユニット／ラセミ体＝１６／１となっている。 3 ml (0.865 mM in terms of monomer) of a THF solution of a polyphenylacetylene derivative (monomer conversion in 2.60 μmol) and 1 ml of a methanol solution in a racemic form (0.16 μmol) were mixed. The molar concentration of the racemate after mixing is monomer unit / racemate = 16/1 with respect to the monomer equivalent amount (monomer unit) of the polyphenylacetylene derivative.
１２時間静置後、所定量（２ｍｌ又は１ｍｌ）の上澄み液を採取し、濃縮、乾燥後、高速液体クトマトグラフィー（ＨＰＬＣ）用の溶離液で溶解し、さらに濾過してからＨＰＬＣ装置を用いてエナンチオマー量を定量した。その結果を以下に示す。 After standing for 12 hours, collect a predetermined amount (2 ml or 1 ml) of the supernatant, concentrate, dry, dissolve in the eluent for high-performance liquid chromatography (HPLC), filter the solution, and then use the HPLC apparatus. The amount of enantiomer was quantified. The results are shown below.
ここで、上澄み液中のα値は、ＨＰＬＣのピーク面積から求めた２種類のエナンチオマーの比であり、ピーク面積の大きい方（主要なエナンチオマー）の値を小さい方の値で割った値である。また、吸着物のα値は、上澄み液中のα値から計算した値である。立体配置（Ｄ又はＬ、Ｒ又はＳ）、旋光性（＋又は−）、主要なエナンチオマーの溶出の順番（１ｓｔ又は２ｎｄ）を括弧内に示す。また、ポリ（ＤｏＤＨＰＡ）の比旋光度［α］Ｄ ２０＝−２１６．７°、ポリ（ＰＳＰＡ）の比旋光度［α］Ｄ ２０＝−９８．４°である。 Here, the α value in the supernatant is a ratio of two enantiomers determined from the peak area of HPLC, and is a value obtained by dividing the value of the larger peak area (major enantiomer) by the smaller value. . The α value of the adsorbate is a value calculated from the α value in the supernatant. The configuration (D or L, R or S), optical rotation (+ or −), and the order of elution of major enantiomers (1st or 2nd) are shown in parentheses. Further, specific rotation of the poly (DoDHPA) [α] D 20 = -216.7 °, a specific rotation of poly (PSPA) [α] D 20 = -98.4 °.
上澄み液中のα値の結果より、チロシンに対して最も高い選択性が見られ、カルビノキサミン、ヒドロキシジン、シクロペントレートに対しても高い選択性が確認された。吸着物のα値の結果より、チロシン、ヒドロキシジン、シクロペントレートのほかに、トリメブチン、ＢＩＮＯＭｅに対して高い選択性が確認された。 As a result of the α value in the supernatant, the highest selectivity for tyrosine was observed, and high selectivity for carbinoxamine, hydroxyzine, and cyclopentrate was also confirmed. From the result of the α value of the adsorbate, high selectivity for trimebutine and BINOME was confirmed in addition to tyrosine, hydroxyzine and cyclopentrate.
［比較例］
比較例として、従来の光学分割剤のキラル認識能を確認するための吸着実験と同様な方法により、エナンチオマーの選択性を確認した。
[Comparative example]
As a comparative example, the selectivity of the enantiomer was confirmed by the same method as the adsorption experiment for confirming the chiral recognition ability of the conventional optical resolution agent.
溶媒に溶解していないポリ（ＤｏＤＨＰＡ）（モノマー換算で２．６０μｍｏｌ）とフェニルアラニンのラセミ体（０．１６μｍｏｌ）を４ｍｌのメタノールへ加えて撹拌した。１２時間静置後、上記実施例と同様にしてエナンチオマー量を定量した。その結果を以下に示す。 Poly (DoDHPA) not dissolved in the solvent (2.60 μmol in terms of monomer) and phenylalanine racemate (0.16 μmol) were added to 4 ml of methanol and stirred. After standing for 12 hours, the amount of enantiomer was quantified in the same manner as in the above Example. The results are shown below.
実施例と比較して、上澄み液中のα値、吸着量が低く、本発明の光学分割法が優れた方法であることが確認された。 Compared with the examples, the α value in the supernatant and the adsorption amount were low, and it was confirmed that the optical resolution method of the present invention was an excellent method.
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| JP3715358B2 (en) * | 1995-11-29 | 2005-11-09 | ダイセル化学工業株式会社 | Novel optically active phenylacetylene polymer and process for producing the same |
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