JPH09227416A - Production of optically active beta-blocker - Google Patents
Production of optically active beta-blockerInfo
- Publication number
- JPH09227416A JPH09227416A JP8029436A JP2943696A JPH09227416A JP H09227416 A JPH09227416 A JP H09227416A JP 8029436 A JP8029436 A JP 8029436A JP 2943696 A JP2943696 A JP 2943696A JP H09227416 A JPH09227416 A JP H09227416A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- blocker
- dimethylpinanylsilylnorbornadiene
- film
- optically
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 239000002876 beta blocker Substances 0.000 title claims abstract description 29
- 229940097320 beta blocking agent Drugs 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- -1 poly(dimethylpinanylsilylnorbornadiene) Polymers 0.000 claims abstract description 24
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical group C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 9
- 229960003712 propranolol Drugs 0.000 claims description 6
- 239000000203 mixture Substances 0.000 abstract description 10
- 239000013543 active substance Substances 0.000 abstract description 4
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 abstract description 3
- 125000005842 heteroatom Chemical group 0.000 abstract description 3
- 239000012528 membrane Substances 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 230000003287 optical effect Effects 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000005540 biological transmission Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000012466 permeate Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- SCUIDIWYHKOZPE-UHFFFAOYSA-N chloro-dimethyl-(4,6,6-trimethyl-5-bicyclo[3.1.1]heptanyl)silane Chemical compound CC1CCC2C(C)(C)C1([Si](C)(C)Cl)C2 SCUIDIWYHKOZPE-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- WTARULDDTDQWMU-RKDXNWHRSA-N (+)-β-pinene Chemical compound C1[C@H]2C(C)(C)[C@@H]1CCC2=C WTARULDDTDQWMU-RKDXNWHRSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-Nopinene Natural products C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 description 3
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 description 3
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 3
- 229930006722 beta-pinene Natural products 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- LCWMKIHBLJLORW-UHFFFAOYSA-N gamma-carene Natural products C1CC(=C)CC2C(C)(C)C21 LCWMKIHBLJLORW-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- AQHHHDLHHXJYJD-CQSZACIVSA-N (R)-(+)-propranolol Chemical compound C1=CC=C2C(OC[C@H](O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-CQSZACIVSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000004687 hexahydrates Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002685 polymerization catalyst Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010066001 Cardiac autonomic neuropathy Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000807 solvent casting Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、光学活性β−ブロ
ッカーの製造法に関するものであり、詳しくは、β−ブ
ロッカーの光学異性体混合物を光学活性ポリ（ジメチル
ピナニルシリルノルボルナジエン）膜を用いて光学分割
し、光学活性β−ブロッカーを製造する方法に関するも
のである。TECHNICAL FIELD The present invention relates to a method for producing an optically active β-blocker, and more specifically, to a mixture of optical isomers of β-blocker using an optically active poly (dimethylpinanylsilylnorbornadiene) film. The present invention relates to a method for producing an optically active β-blocker by optical resolution.
【０００２】[0002]
【従来の技術及び発明が解決しようとする課題】生体に
作用を及ぼす種々の化学物質が知られているが、その中
でもカテコールアミンは、平滑筋や心臓循環器系に種々
の作用を及ぼすことが知られている。これらの作用のう
ち、β−受容体を介して起こる作用を特異的に抑制する
薬物がβ−ブロッカーと称されている。そして、β−ブ
ロッカーは、狭心症や不整脈の治療を初めとして、高血
圧症、甲状線機能亢進症、褐色細胞腫、心臓神経症から
精神神経科領域、麻酔科領域に至るまで、広範囲な治療
薬として使用されている。このようなβ−ブロッカーと
しては、式（１）BACKGROUND OF THE INVENTION Various chemical substances that act on the living body are known, and among them, catecholamines are known to exert various actions on smooth muscle and cardiac circulatory system. Has been. Of these actions, a drug that specifically suppresses the action that occurs via the β-receptor is called a β-blocker. And β-blockers are a wide range of treatments, including treatment of angina and arrhythmia, from hypertension, hyperthyroidism, pheochromocytoma, cardioneuropathy to neuropsychiatric and anesthesiology areas. Used as a medicine. Such a β-blocker is represented by the formula (1)
【０００３】[0003]
【化１】 Embedded image
【０００４】（式中、R1はヘテロ原子を含んでもよい芳
香族炭化水素基を示し、R2は水素原子またはメチル基を
示す。）で表される化合物が大部分であり、β炭素が不
斉炭素であるため、光学異性体が存在する。一般的に、
薬効は、ラセミ体よりも光学活性体の方が大きいことが
知られている。そして、従来から、公知の方法では、β
−ブロッカーのラセミ体を光学活性体に分割するのは、
極めて困難であったが、最近、クロマトグラフィー法に
よる光学分割法が提案されている（例えば、特開昭61−
161226号、特開昭62−135450号公報参照）。しかしなが
ら、このようなクロマトグラフィー法では、工業的規模
の大量生産には適さず、製造コストも高いという問題が
あった。Most of the compounds represented by the formula (wherein R 1 represents an aromatic hydrocarbon group which may contain a hetero atom and R 2 represents a hydrogen atom or a methyl group), and β carbon is Since it is an asymmetric carbon, optical isomers exist. Typically,
It is known that the optically active substance has a greater efficacy than the racemic substance. Then, conventionally, in the known method, β
-The resolution of the racemate of the blocker into the optically active form is
Although it was extremely difficult, recently, an optical resolution method by a chromatographic method has been proposed (for example, JP-A-61-1
161226, JP-A-62-135450). However, such a chromatography method has a problem that it is not suitable for mass production on an industrial scale and the manufacturing cost is high.
【０００５】また、一方、β−ブロッカーの光学活性体
を光学活性な原料を用いて製造する方法が提案されてい
る（例えば、特開昭53−119824号、特開昭55−11543
号、特開昭57−9781号、特開昭57−32254 号公報参
照）。しかしながら、これらの方法は、困難な反応操作
を伴い、製造コストも高いという問題があった。On the other hand, a method for producing an optically active substance of β-blocker using an optically active raw material has been proposed (for example, JP-A-53-119824 and JP-A-55-11543).
(See Japanese Patent Application Laid-Open No. 57-9781 and Japanese Patent Application Laid-Open No. 57-32254). However, these methods have problems in that they involve difficult reaction operations and are expensive to manufacture.
【０００６】このような背景の下に、本発明が解決しよ
うとする課題は、簡単な操作で、工業的規模の大量生産
に適した、製造コストの低いβ−ブロッカーの光学活性
体を製造する方法を提供することである。Against this background, the problem to be solved by the present invention is to produce a β-blocker optically active substance which is suitable for mass production on an industrial scale and has a low production cost by a simple operation. Is to provide a method.
【０００７】[0007]
【課題を解決するための手段】本発明者らは、上記の課
題を解決するため、鋭意研究を重ねた結果、光学活性ポ
リ（ジメチルピナニルシリルノルボルナジエン）膜が、
β−ブロッカーの光学異性体の一方を選択的に透過する
ことを見いだし、本発明を完成するに至った。Means for Solving the Problems The inventors of the present invention have conducted extensive studies in order to solve the above problems, and as a result, have found that an optically active poly (dimethylpinanylsilylnorbornadiene) film has
It was found that one of the optical isomers of the β-blocker is selectively transmitted, and the present invention has been completed.
【０００８】すなわち、本発明は、β−ブロッカーの光
学異性体混合物を光学活性ポリ（ジメチルピナニルシリ
ルノルボルナジエン）膜を用いて光学分割し、光学活性
β−ブロッカーを得ることを特徴とする光学活性β−ブ
ロッカーの製造法である。That is, according to the present invention, an optically active β-blocker is obtained by optically resolving an optical isomer mixture of β-blockers using an optically active poly (dimethylpinanylsilylnorbornadiene) film. This is a method for producing a β-blocker.
【０００９】[0009]
【発明の実施の形態】以下、本発明の実施の形態につい
て詳細に説明する。Embodiments of the present invention will be described below in detail.
【００１０】本発明におけるβ−ブロッカーとしては、
上記の式（１）で表される化合物が代表的なものであ
る。式（１）において、R1はヘテロ原子を含んでもよい
芳香族炭化水素基を示すが、このR1の具体例としては、
置換フェニル基、１−ナフチル基、下記の式（２）〜
（５）で表される基を挙げることができる。As the β-blocker in the present invention,
The compound represented by the above formula (1) is typical. In the formula (1), R 1 represents an aromatic hydrocarbon group which may contain a hetero atom. Specific examples of R 1 include
Substituted phenyl group, 1-naphthyl group, the following formula (2)-
The group represented by (5) can be mentioned.
【００１１】[0011]
【化２】 Embedded image
【００１２】本発明におけるβ−ブロッカーの具体例と
しては、例えば以下の化合物を挙げることができる。Specific examples of the β-blocker in the present invention include the following compounds.
【００１３】[0013]
【化３】 Embedded image
【００１４】[0014]
【化４】 Embedded image
【００１５】[0015]
【化５】 Embedded image
【００１６】これらの中では特にプロプラノロールが好
ましい。Of these, propranolol is particularly preferable.
【００１７】本発明における光学活性ポリ（ジメチルピ
ナニルシリルノルボルナジエン）は、下記式（６）で表
される。The optically active poly (dimethylpinanylsilylnorbornadiene) in the present invention is represented by the following formula (6).
【００１８】[0018]
【化６】 [Chemical 6]
【００１９】光学活性ポリ（ジメチルピナニルシリルノ
ルボルナジエン）を合成するには、下記の反応スキーム
による。The following reaction scheme is used to synthesize optically active poly (dimethylpinanylsilyl norbornadiene).
【００２０】[0020]
【化７】 Embedded image
【００２１】以下、この反応スキームを詳細に説明す
る。 (1) ジメチルピナニルクロロシランの合成 光学活性なβ−ピネン(i) とジメチルクロロシラン(ii)
とを、トルエン中、触媒に塩化白金酸六水和物を用い、
80℃で、24時間反応させて、ジメチルピナニルクロロシ
ラン(iii) を得る。The reaction scheme will be described in detail below. (1) Synthesis of dimethylpinanylchlorosilane Optically active β-pinene (i) and dimethylchlorosilane (ii)
And, in toluene, using chloroplatinic acid hexahydrate as a catalyst,
The reaction is carried out at 80 ° C. for 24 hours to obtain dimethylpinanylchlorosilane (iii).
【００２２】(2) ジメチルピナニルシリルノルボルナジ
エンの合成 ｎ−ブチルリチウム（ｎ−ＢｕＬｉ）の存在下、テトラ
ヒドロフラン（ＴＨＦ）中、ノルボルナジエン(iv)とナ
トリウムtert−ブトキシド（ｔ−ＢｕＯＮａ）とを、−
50 ℃で、15時間反応させて得られた生成物(v) に、前
記のジメチルピナニルクロロシラン(iii) を反応させ
て、ジメチルピナニルシリルノルボルナジエン(vi)を得
る。(2) Synthesis of dimethylpinanylsilyl norbornadiene In the presence of n-butyllithium (n-BuLi), norbornadiene (iv) and sodium tert-butoxide (t-BuONa) are added in tetrahydrofuran (THF) to give
The product (v) obtained by reacting at 50 ° C. for 15 hours is reacted with the above-mentioned dimethylpinanylchlorosilane (iii) to obtain dimethylpinanylsilylnorbornadiene (vi).
【００２３】(3) ジメチルピナニルシリルノルボルナジ
エンの重合 ジメチルピナニルシリルノルボルナジエン(vi)を、重合
触媒としてＷＣｌ6と（ＣＨ3 ）4 Ｓｎを用い、トルエ
ン中で、室温、４時間重合反応させて光学活性ポリ（ジ
メチルピナニルシリルノルボルナジエン）（６）を得
る。(3) Polymerization of dimethylpinanylsilylnorbornadiene Dimethylpinanylsilylnorbornadiene (vi) was subjected to polymerization reaction in toluene at room temperature for 4 hours using WCl 6 and (CH 3 ) 4 Sn as a polymerization catalyst. An optically active poly (dimethylpinanylsilyl norbornadiene) (6) is obtained.
【００２４】本発明で用いられる光学活性ポリ（ジメチ
ルピナニルシリルノルボルナジエン）の分子量は、製膜
性及び膜強度の上から、好ましくは10,000〜1,000,000
であり、より好ましくは50,000〜800,000 である。光学
活性ポリ（ジメチルピナニルシリルノルボルナジエン）
は白色固体で、ＴＨＦやクロロホルムなどの有機溶媒に
可溶である。The molecular weight of the optically active poly (dimethylpinanylsilylnorbornadiene) used in the present invention is preferably 10,000 to 1,000,000 from the viewpoint of film forming property and film strength.
And more preferably 50,000 to 800,000. Optically active poly (dimethylpinanylsilyl norbornadiene)
Is a white solid and is soluble in organic solvents such as THF and chloroform.
【００２５】光学活性ポリ（ジメチルピナニルシリルノ
ルボルナジエン）を製膜するには、ソルベントキャスト
法による。具体的には、先ず、このポリマーをＴＨＦに
溶解させて、水平なテフロンシート上にキャストし、次
いで、溶媒を蒸発させた後、さらに減圧乾燥する。To form a film of optically active poly (dimethylpinanylsilyl norbornadiene), a solvent casting method is used. Specifically, first, this polymer is dissolved in THF and cast on a horizontal Teflon sheet, and then the solvent is evaporated, followed by further drying under reduced pressure.
【００２６】本発明においては、このようにして得られ
た光学活性ポリ（ジメチルピナニルシリルノルボルナジ
エン）膜を用い、β−ブロッカーの光学異性体混合物を
光学分割する。光学分割の方法は特に限定されず、通常
の膜を用いた光学分割方法と同様に行えばよい。具体的
には例えば、β−ブロッカーの光学異性体混合物をメタ
ノール、水等の溶媒に溶解し、光学活性ポリ（ジメチル
ピナニルシリルノルボルナジエン）膜を透過させること
により、β−ブロッカーの光学異性体の一方が選択的に
透過し、光学活性なβ−ブロッカーが得られる。In the present invention, the optically active poly (dimethylpinanylsilylnorbornadiene) film thus obtained is used to optically resolve a mixture of optical isomers of a β-blocker. The method of optical division is not particularly limited and may be the same as the ordinary optical division method using a film. Specifically, for example, a mixture of optical isomers of β-blocker is dissolved in a solvent such as methanol and water, and the mixture is passed through an optically active poly (dimethylpinanylsilylnorbornadiene) film to give a mixture of optical isomers of β-blocker. One of them is selectively transmitted, and an optically active β-blocker is obtained.
【００２７】尚、本発明における透過実験は、ガラスセ
ルの供給側をβ−ブロッカーのラセミ体メタノール溶
液、透過側を純メタノールで満たし、濃度勾配を推進力
として透過させた。透過液の％eeを光学分割カラムを備
えたＨＰＬＣで決定し、透過物の質量から累積透過量Ｑ
（ｇ）を求め、これと膜厚、膜面積、透過時間より、下
記式により透過速度Ｐ（ｇ・ｍ／ｍ2・ｈｒ）を決定し
た。In the permeation experiment of the present invention, the supply side of the glass cell was filled with a racemic methanol solution of β-blocker and the permeation side was filled with pure methanol, and the concentration gradient was used as a driving force. The% ee of the permeate was determined by HPLC equipped with an optical resolution column, and the cumulative amount of permeation Q
(G) was determined, and the permeation rate P (g · m / m 2 · hr) was determined by the following equation from this, the film thickness, the membrane area, and the permeation time.
【００２８】Ｐ＝（Ｑ・Ｌ）／（Ａ・Ｔ） Ｌ＝膜厚（ｍ） Ａ＝膜面積（ｍ2 ） Ｔ＝透過時間（ｈｒ）P = (Q · L) / (A · T) L = film thickness (m) A = film area (m 2 ) T = transmission time (hr)
【００２９】[0029]
【実施例】以下、実施例によって本発明を具体的に説明
するが、本発明がこれらの実施例に限定されるものでな
いことは言うまでもない。EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.
【００３０】実施例１ (1) ジメチルピナニルクロロシランの合成 乾燥窒素雰囲気下において、すべての操作を行った。10
0ml の三つ口フラスコへ触媒の塩化白金酸六水和物(100
μmol)をとり、トルエン（30ml）を加え、80℃にて攪拌
した。溶解後、40℃にてジメチルクロロシラン(160mmo
l）を加え、徐々に80℃まで加熱し、そこへβ−ピネン
（80mmol）を滴下した。24時間後、ガスクロマトグラフ
ィー分析を行い、β−ピネンの 100％消費を確認した
後、過剰に加えたジメチルクロロシラン、および溶媒を
留去し、減圧蒸留にて精製した。Example 1 (1) Synthesis of dimethylpinanylchlorosilane All operations were carried out under a dry nitrogen atmosphere. Ten
Catalytic chloroplatinic acid hexahydrate (100 ml
μmol) was taken, toluene (30 ml) was added, and the mixture was stirred at 80 ° C. After dissolution, dimethylchlorosilane (160mmo
l) was added, the mixture was gradually heated to 80 ° C., and β-pinene (80 mmol) was added dropwise thereto. After 24 hours, gas chromatography analysis was performed to confirm 100% consumption of β-pinene, and then excess dimethylchlorosilane and the solvent were distilled off, and the residue was purified by vacuum distillation.
【００３１】収量：17.9ｇ（77.6mmol） 収率：97.1％ 沸点：52〜60℃／0.25mmHg (2) ジメチルピナニルシリルノルボルナジエンの合成 乾燥窒素雰囲気下において、すべての操作を行った。 1
00mlの三つ口フラスコへｎ−ＢｕＬｉのｎ−ヘキサン溶
液(1.63mol／リットル）(30.0mmol)をとり、ヘキサンを
留去し、−90℃まで冷却した。冷却後、ＴＨＦ（20ml）
を加え、ｔ−ＢｕＯＮａ（29.9mmol) 、ノルボルナジエ
ン（28.8mmol) を徐々に加え、−50℃に保つ。15時間
後、ジメチルピナニルクロロシラン（42.1mmol）を加え
室温に戻した。水洗後、エーテル相を抽出し、無水硫酸
ナトリウムを加え、乾燥した。減圧蒸留にて精製した。Yield: 17.9 g (77.6 mmol) Yield: 97.1% Boiling point: 52-60 ° C./0.25 mmHg (2) Synthesis of dimethylpinanylsilyl norbornadiene All operations were carried out under a dry nitrogen atmosphere. 1
A n-hexane solution (1.63 mol / liter) (30.0 mmol) of n-BuLi was placed in a 3-neck flask of 00 ml, hexane was distilled off, and the mixture was cooled to -90 ° C. After cooling, THF (20 ml)
Is added, and t-BuONa (29.9 mmol) and norbornadiene (28.8 mmol) are gradually added, and the temperature is kept at -50 ° C. After 15 hours, dimethylpinanylchlorosilane (42.1 mmol) was added and the temperature was returned to room temperature. After washing with water, the ether phase was extracted, anhydrous sodium sulfate was added and dried. Purified by vacuum distillation.
【００３２】収量：2.75ｇ（9.61mmol） 収率：33.4％ 沸点：95〜96℃／0.20mmHg (3) ジメチルピナニルシリルノルボルナジエンの重合 乾燥窒素雰囲気下において、すべての操作を行った。50
mlのナスフラスコへ、重合触媒のＷＣｌ6(53.1μmol)を
とり、トルエン(20ml)と共触媒の(ＣＨ3)4Ｓｎ(144μmo
l)を加え、３分間攪拌した。そこへ、ジメチルピナニル
シリルノルボルナジエン（2.13mmol) をシリンジを使っ
て注入した。室温下、４時間攪拌した後、メタノールを
加え反応を停止させた。得られたポリマーをＴＨＦに溶
解し、再沈澱により、精製を３回行った。その後、室温
下、24時間真空乾燥させ、目的物を得た。Yield: 2.75 g (9.61 mmol) Yield: 33.4% Boiling point: 95-96 ° C./0.20 mmHg (3) Polymerization of dimethylpinanylsilyl norbornadiene All operations were carried out under a dry nitrogen atmosphere. 50
WCl 6 (53.1 μmol) as a polymerization catalyst was placed in an eggplant flask of ml, and toluene (20 ml) and (CH 3 ) 4 Sn (144 μmo) as a cocatalyst were used.
l) was added and stirred for 3 minutes. Dimethyl pinanyl silyl norbornadiene (2.13 mmol) was injected there using a syringe. After stirring at room temperature for 4 hours, methanol was added to stop the reaction. The obtained polymer was dissolved in THF and reprecipitated to carry out purification three times. Then, the product was vacuum dried at room temperature for 24 hours to obtain the desired product.
【００３３】収量：0.600 ｇ 収率：98.3％ Ｍｗ：3.32×105 （ＧＰＣにより測定） Ｍｗ／Ｍｎ：5.36 旋光度： [α]20 D＝＋5.75（ｃ 1.095ｇ／dl、CCl4) ガラス転移点（Ｔｇ）：42℃（ＤＳＣにより測定） (4) 光学活性ポリ（ジメチルピナニルシリルノルボルナ
ジエン）膜の製造 得られた光学活性ポリ（ジメチルピナニルシリルノルボ
ルナジエン）の粉末２ｇをＴＨＦ５mlに溶解させ、これ
をガラス板上に貼り付けたテフロンシート上にキャスト
した。常圧下、25℃で、10時間ＴＨＦを蒸発させた後、
さらに、0.10mmHg下、25℃で、24時間乾燥させた。得ら
れた膜の厚みは、20μm であった。Yield: 0.600 g Yield: 98.3% Mw: 3.32 × 10 5 (measured by GPC) Mw / Mn: 5.36 Optical rotation: [α] 20 D = + 5.75 (c 1.095 g / dl, CCl 4 ). Glass transition point (Tg): 42 ° C. (measured by DSC) (4) Production of optically active poly (dimethylpinanylsilylnorbornadiene) film 2 g of the obtained optically active poly (dimethylpinanylsilylnorbornadiene) powder was dissolved in 5 ml of THF. Then, it was cast on a Teflon sheet attached on a glass plate. After evaporating THF under normal pressure at 25 ° C. for 10 hours,
Further, it was dried at 25 ° C. under 0.10 mmHg for 24 hours. The thickness of the obtained film was 20 μm.
【００３４】(5) 透過実験 光学分割対象物としてプロプラノロールのラセミ体を用
いた。ガラス製の透過実験装置に、上記で得られた光学
活性ポリ（ジメチルピナニルシリルノルボルナジエン）
膜を挟み、供給側に透過物であるプロプラノロールのラ
セミ体メタノール溶液、透過側に純メタノールを満た
し、スターラーで攪拌させながら、濃度勾配を推進力と
した透過実験を行った。所定時間（200 時間程度）ごと
に透過側の溶液をすべてサンプリングして、透過液と
し、空になった透過側には再び純メタノールを満たし
た。透過液は蒸発乾固した後、秤量して、透過量Ｑ
(ｇ）を決定し、透過速度Ｐ（ｇ・ｍ／ｍ2・ｈｒ）を算
出した。また、光学分割カラム（ダイセル化学工業株式
会社製 ＣＨＩＲＡＬＣＥＬ ＯＤ）を備えたＨＰＬＣ
により分析して、光学純度を決定した。透過時間2000時
間におけるＰ及び光学純度は次のとおりであった。(5) Transmission Experiment A racemic propranolol was used as an object for optical resolution. The optically active poly (dimethylpinanylsilyl norbornadiene) obtained above was added to a glass transmission experiment device.
A permeation experiment was carried out with the concentration gradient as a driving force while the racemic methanol solution of propranolol as a permeate was filled on the feed side and pure methanol was filled on the permeate side with the membrane sandwiched. All of the solution on the permeate side was sampled at every predetermined time (about 200 hours) to make a permeate, and the empty permeate side was filled with pure methanol again. The permeated liquid is evaporated to dryness and then weighed to determine the permeation amount Q
(g) was determined, and the transmission rate P (g · m / m 2 · hr) was calculated. In addition, an HPLC equipped with an optical resolution column (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd.)
And analyzed to determine the optical purity. The P and optical purities at a transmission time of 2000 hours were as follows.
【００３５】Ｐ＝1.40×10-6（ｇ・ｍ／ｍ2・ｈｒ） 光学純度 54.6％ee（Ｒ体優先） また、透過時間（ｈｒ）と透過量Ｑ（mg）との関係は図
１に示す通りであった。図１において、○はＳ−（−）
−プロプラノロールの透過量、●はＲ−（＋）−プロプ
ラノロールの透過量を示す。図１から明らかなように、
Ｒ−（＋）−プロプラノロール優位の透過を示し、分解
能は2000時間継続していた。P = 1.40 × 10 −6 (g · m / m 2 · hr) Optical purity 54.6% ee (R body priority) Further, the relationship between the transmission time (hr) and the transmission amount Q (mg) is shown in FIG. It was as shown in. In FIG. 1, ○ indicates S-(−).
-Propranolol permeation amount, ● indicates the R-(+)-propranolol permeation amount. As is clear from FIG.
R-(+)-propranolol dominant transmission was shown, and the resolution was continued for 2000 hours.
【００３６】[0036]
【発明の効果】本発明における光学活性ポリ（ジメチル
ピナニルシリルノルボルナジエン）膜は、製膜性、強
度、耐久性がよく、光学分割能を有し、β−ブロッカー
の一方の光学異性体を選択的に透過する。本発明によ
り、簡単な操作で、工業的規模の大量生産に適した、製
造コストの低い光学活性β−ブロッカーの製造法を提供
できた。INDUSTRIAL APPLICABILITY The optically active poly (dimethylpinanylsilylnorbornadiene) film of the present invention has good film-forming properties, strength and durability, has optical resolution, and selects one optical isomer of β-blocker. Transparently. According to the present invention, it is possible to provide a method for producing an optically active β-blocker, which is suitable for mass production on an industrial scale and has a low production cost, with a simple operation.
【図１】 実施例１の透過実験における、透過時間（ｈ
ｒ）とプロプラノロールの透過量Ｑ（mg）との関係を示
す図である。FIG. 1 is a permeation time (h) in a permeation experiment of Example 1.
It is a figure which shows the relationship between r) and the permeation | transmission amount Q (mg) of propranolol.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｆ 7/12 Ｃ０７Ｆ 7/12 Ｌ // Ｃ０８Ｇ 61/08 ＮＬＧ Ｃ０８Ｇ 61/08 ＮＬＧ Ｃ０７Ｍ 7:00 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location C07F 7/12 C07F 7/12 L // C08G 61/08 NLG C08G 61/08 NLG C07M 7:00
Claims (2)
学活性ポリ（ジメチルピナニルシリルノルボルナジエ
ン）膜を用いて光学分割し、光学活性β−ブロッカーを
得ることを特徴とする光学活性β−ブロッカーの製造
法。1. An optically active β-blocker characterized in that an optically active β-blocker is optically resolved by using an optically active poly (dimethylpinanylsilylnorbornadiene) film. Manufacturing method.
る請求項１記載の光学活性β−ブロッカーの製造法。2. The method for producing an optically active β-blocker according to claim 1, wherein the β-blocker is propranolol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8029436A JPH09227416A (en) | 1996-02-16 | 1996-02-16 | Production of optically active beta-blocker |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8029436A JPH09227416A (en) | 1996-02-16 | 1996-02-16 | Production of optically active beta-blocker |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09227416A true JPH09227416A (en) | 1997-09-02 |
Family
ID=12276093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8029436A Ceased JPH09227416A (en) | 1996-02-16 | 1996-02-16 | Production of optically active beta-blocker |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH09227416A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008273898A (en) * | 2007-05-02 | 2008-11-13 | Niigata Univ | Optical resolution method |
-
1996
- 1996-02-16 JP JP8029436A patent/JPH09227416A/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008273898A (en) * | 2007-05-02 | 2008-11-13 | Niigata Univ | Optical resolution method |
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