JPH07233166A - Production of optically active diazabicycloheptene derivative - Google Patents
Production of optically active diazabicycloheptene derivativeInfo
- Publication number
- JPH07233166A JPH07233166A JP27487394A JP27487394A JPH07233166A JP H07233166 A JPH07233166 A JP H07233166A JP 27487394 A JP27487394 A JP 27487394A JP 27487394 A JP27487394 A JP 27487394A JP H07233166 A JPH07233166 A JP H07233166A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- group
- hydrogen atom
- diazabicycloheptene
- derivative
- 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.)
- Granted
Links
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- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-M N-benzyloxycarbonyl-L-leucinate Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は優れたカリウムチャンネ
ル開口作用を有し、高血圧症治療剤、狭心症治療剤、喘
息治療剤等の医薬として有用なジアザビシクロヘプテン
誘導体の光学活性体を効率的に製造する方法に関する。The present invention relates to an optically active diazabicycloheptene derivative which has an excellent potassium channel opening action and is useful as a drug for treating hypertension, angina, and asthma. The present invention relates to a method of efficiently producing
【０００２】[0002]
【従来の技術】高血圧症の治療のためには抗高血圧薬の
長期間の服用が必要である。そのため抗高血圧薬には、
強い抗高血圧作用だけでなく、長期間服用によって種々
の不利益が生じないことが求められている。すなわち、
（１）抗高血圧作用が強く、かつ持続的であることが要
求され；（２）抗高血圧作用の発現が急激であると循環
器系の恒常性を著名に変化させ｛ライフ サイエンス、
４７巻，１６９３〜１７０５頁（１９９０年）｝、反射
性の頻脈が出現しやすい｛ジャパニーズ ジャーナル
オブ ファーマコロジー．５８巻（サプリメント．１
巻）３６頁（１９９２年）｝ことから、作用の発現が緩
徐であることが要求され；（３）また腎臓の血流障害は
高血圧症の維持、進展に密接に関連しており、腎血流量
の増加作用によって高血圧症の改善が期待される｛サー
キュレーション６９巻，１１４２〜１１４５頁（１９８
４年）｝ことから、腎血流量を増加させることが望まし
い。2. Description of the Related Art For the treatment of hypertension, it is necessary to take an antihypertensive drug for a long period of time. So for antihypertensive drugs,
It is required not only to have a strong antihypertensive effect, but also to prevent various disadvantages from being taken for a long time. That is,
(1) A strong and long-lasting antihypertensive effect is required; (2) A rapid onset of the antihypertensive effect markedly changes the homeostasis of the circulatory system {Life Science,
47, pp. 1693-1705 (1990)}, reflex tachycardia is likely to appear {Japanese Journal
Of Pharmacology. Volume 58 (Supplement. 1
Vol. 36 (1992)}, it is required that the onset of action is slow; (3) Moreover, impaired blood flow in the kidney is closely related to the maintenance and progress of hypertension. Improvement of hypertension is expected by the action of increasing the flow rate {circulation 69, 1142-1145 (198).
Therefore, it is desirable to increase renal blood flow.
【０００３】ところで、従来、下記式（２）By the way, conventionally, the following equation (2)
【０００４】[0004]
【化４】 [Chemical 4]
【０００５】〔式中、Ｒは水素原子、アルキル基、アリ
ール基、アラルキル基等を示す〕[In the formula, R represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, or the like]
【０００６】で表わされる化合物はカリウムチャネル開
口作用に基づく、持続的で強い抗高血圧作用を有し、抗
高血圧薬として有用なことが知られている（特開平２−
１４５５８４号公報、特開平３−２０２７５号公報、ジ
ャーナル オブ メディシナルケミストリー．，３３
巻，２７５９〜２７６７頁（１９９０年））。It is known that the compound represented by the formula (1) has a long-lasting and strong antihypertensive action based on the potassium channel opening action and is useful as an antihypertensive drug (JP-A-2-
145584, JP-A-3-20275, Journal of Medicinal Chemistry. , 33
Vol., 2759-2767 (1990)).
【０００７】しかしながら、上記式（２）の化合物は、
抗高血圧作用の強さ及び持続性ではほぼ満足しているも
のの、抗高血圧作用の発現様式及び腎血流量の増加作用
の面で満足できるものではなかった。However, the compound of the above formula (2) is
Although the strength and duration of the antihypertensive effect were almost satisfactory, the expression mode of the antihypertensive effect and the effect of increasing renal blood flow were not satisfactory.
【０００８】かかる観点から、本発明者等は種々のジア
ザビシクロアルケン誘導体を合成し、その薬理作用を検
討した結果、下記一般式（１）で表わされるジアザビシ
クロヘプテン誘導体が優れたカリウムチャネル開口作
用、及び持続的かつ強力な抗高血圧作用を有し、その作
用発現が緩徐で、かつ強い腎血流量の増加作用を有し、
高血圧症治療剤として有用であり、更に血管や気管支平
滑筋の収縮によって引き起こされる他の疾病、例えば狭
心症や喘息の治療剤としても有用であることを見出し、
先に特許出願した（特願平５−１０８４６６号）。From these viewpoints, the present inventors have synthesized various diazabicycloalkene derivatives and studied their pharmacological actions. As a result, the diazabicycloheptene derivative represented by the following general formula (1) is excellent in potassium. It has a channel opening action and a long-lasting and strong antihypertensive action, its action expression is slow, and it has a strong renal blood flow increasing action.
It is useful as a therapeutic agent for hypertension, and further found to be useful as a therapeutic agent for other diseases caused by contraction of blood vessels and bronchial smooth muscle, for example, angina and asthma,
A patent application was filed earlier (Japanese Patent Application No. 5-108466).
【０００９】[0009]
【化５】 [Chemical 5]
【００１０】〔式中、Ｒ1 は水素原子、低級アルケニル
基、低級アルキニル基、置換基を有してもよい低級アル
キル基又は置換基を有してもよいアラルキル基を示し、
Ｒ2 は、水素原子又は低級アルキル基を示す〕[Wherein R 1 represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a lower alkyl group which may have a substituent or an aralkyl group which may have a substituent,
R 2 represents a hydrogen atom or a lower alkyl group]
【００１１】しかしながら、このジアザビシクロヘプテ
ン誘導体（１）には、ベンゾピラン環の３位及び４位、
並びにジアザビシクロヘプテン環の１′位及び６′位の
４個の不斉炭素原子が存在し、またその合成法であるピ
ラン環のエポキシ基の開環反応（ジャーナル オブ メ
ディシナル ケミストリー，２６巻，１５８２〜１５８
９頁（１９８３））に基づき、ベンゾピラン環の３位と
４位はトランス配位をとることから、４種類の光学異性
体が存在する。これらの４種類の光学異性体は、ラセミ
体までは通常のカラムクロマトグラフィー等により分別
できるが、当該ラセミ体の光学活性体への分割は困難で
あった。However, the diazabicycloheptene derivative (1) contains the 3- and 4-positions of the benzopyran ring,
In addition, there are four asymmetric carbon atoms at the 1'-position and the 6'-position of the diazabicycloheptene ring, and their synthesis method is the ring opening reaction of the epoxy group of the pyran ring (Journal of Medicinal Chemistry, Vol. , 1582-158
Based on page 9 (1983)), the 3rd and 4th positions of the benzopyran ring have a trans configuration, and therefore there are four types of optical isomers. These four types of optical isomers can be separated up to the racemate by ordinary column chromatography or the like, but it was difficult to resolve the racemate into the optically active form.
【００１２】ところで、上記一般式（１）の化合物とは
異なるが、光学活性なベンゾピラン誘導体の製造法がい
くつか知られている。例えば特開昭５９−１７６２８２
号公報には、ラセミの最終体に、光学活性なイソシアネ
ートを反応させ、カルバミン酸誘導体とし、カラムクロ
マトグラフィー又は分別結晶で各ジアステレオマーを分
離する方法が開示されている。また、特開平２−１４５
５８４号公報には、（＋）−カンファースルホン酸クロ
リドを用いる方法が開示されている。また、ジャーナル
オブ メディシナル ケミストリー，３３巻、２７５
９〜２７６７頁（１９９０）には、カンファン酸クロリ
ドを用いる方法が示されている。しかし、これらの不斉
分割剤は、高価であり、工業的生産には不向きである。By the way, there are known some methods for producing an optically active benzopyran derivative, which is different from the compound represented by the general formula (1). For example, Japanese Patent Laid-Open No. 59-176282
The publication discloses a method in which a racemic final product is reacted with an optically active isocyanate to give a carbamic acid derivative, and each diastereomer is separated by column chromatography or fractional crystallization. In addition, JP-A-2-145
Japanese Patent No. 584 discloses a method using (+)-camphorsulfonic acid chloride. Also, Journal of Medicinal Chemistry, Volume 33, 275.
Pages 9-2767 (1990) show a method using camphanic acid chloride. However, these asymmetric resolving agents are expensive and unsuitable for industrial production.
【００１３】[0013]
【発明が解決しようとする課題】従って、本発明の目的
は、医薬として有用なジアザビシクロヘプテン誘導体
（１）の光学活性体を工業的に有利に製造する方法を提
供することにある。SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a method for industrially advantageously producing an optically active substance of a diazabicycloheptene derivative (1) which is useful as a medicine.
【００１４】[0014]
【課題を解決するための手段】そこで、本発明者は、鋭
意研究を重ねた結果、ラセミのジアザビシクロヘプテン
誘導体から、安価に入手できる光学活性なアミノ酸類を
用いるか、又は光学活性なカラムを用いた高速液体クロ
マトグラフィーを用いることにより、光学活性なジアザ
ビシクロヘプテン誘導体を製造する方法を見いだし、本
発明を完成するに至った。Therefore, as a result of intensive studies, the present inventor has used an optically active amino acid which is inexpensively available from a racemic diazabicycloheptene derivative, or has an optically active amino acid. The inventors have found a method for producing an optically active diazabicycloheptene derivative by using high performance liquid chromatography using a column, and completed the present invention.
【００１５】すなわち、本発明は前記一般式（１）で表
わされるジアザビシクロヘプテン誘導体のラセミ体を、
光学活性なアミノ酸類を用いるか、又は光学活性なカラ
ムによる高速液体クロマトグラフィーを用いて光学分割
することを特徴とする、一般式（１）で表わされるジア
ザビシクロヘプテン誘導体の光学活性体の製造法に係る
ものである。That is, the present invention provides a racemic diazabicycloheptene derivative represented by the general formula (1):
A diazabicycloheptene derivative represented by the general formula (1), which is characterized in that it is optically resolved using optically active amino acids or high performance liquid chromatography using an optically active column. It relates to the manufacturing method.
【００１６】上記一般式（１）において、低級アルキル
基としては、炭素数１〜６の直鎖状又は分枝状のものを
あげることができ、具体例としてはメチル基、エチル
基、プロピル基、イソプロピル基、ブチル基、第三級ブ
チル基などをあげることができる。低級アルケニル基と
しては、炭素数が２〜６の直鎖状又は分枝状のものをあ
げることができ、具体例としては、ビニル基、プロペニ
ル基などをあげることができる。低級アルキニル基とし
ては、炭素数２〜６の直鎖状又は分枝状のものをあげる
ことができ、具体例としてはエチニル基、１−プロピニ
ル基、２−プロピニル基をあげることができる。アラル
キル基としては、フェニル、ビフェニル基などのアリー
ル基に炭素１〜４のアルキレン基が結合した基をあげる
ことができ、具体例としては、ベンジル基、フェニルエ
チル基、ナフチルメチル基などが挙げられる。置換基を
有する低級アルキル基としては、ヒドロキシ低級アルキ
ル基、低級アシル低級アルキル基、低級アルコキシ低級
アルキル基、低級アシルオキシ低級アルキル基等をあげ
ることができる。置換基を有するアラルキル基として
は、アリール部分にハロゲン原子、低級アルキル基、ヒ
ドロキシ基、メトキシ基、シアノ基、ホルミル基、ニト
ロ基を有するアラルキル基が挙げられる。In the above general formula (1), the lower alkyl group may be a linear or branched one having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group and a propyl group. , Isopropyl group, butyl group, tertiary butyl group and the like. Examples of the lower alkenyl group include linear or branched ones having 2 to 6 carbon atoms, and specific examples thereof include a vinyl group and a propenyl group. Examples of the lower alkynyl group include linear or branched ones having 2 to 6 carbon atoms, and specific examples thereof include ethynyl group, 1-propynyl group and 2-propynyl group. Examples of the aralkyl group include groups in which an alkylene group having 1 to 4 carbon atoms is bonded to an aryl group such as phenyl and biphenyl groups, and specific examples thereof include a benzyl group, a phenylethyl group and a naphthylmethyl group. . Examples of the lower alkyl group having a substituent include a hydroxy lower alkyl group, a lower acyl lower alkyl group, a lower alkoxy lower alkyl group, a lower acyloxy lower alkyl group and the like. Examples of the aralkyl group having a substituent include an aralkyl group having a halogen atom, a lower alkyl group, a hydroxy group, a methoxy group, a cyano group, a formyl group or a nitro group in the aryl portion.
【００１７】これらの置換基のうち、Ｒ1 としては水素
原子又は低級アルキル基が好ましい。このうち、Ｒ1 が
水素原子又は炭素数１〜６の直鎖状若しくは分枝状のア
ルキル基であり、Ｒ2 が水素原子又は炭素数１〜６の直
鎖状若しくは分枝状のアルキル基である場合がより好ま
しい。また、Ｒ1 が水素原子又はメチル基であり、Ｒ 2
が水素原子又はメチル基である場合が更に好ましい。Of these substituents, R1As hydrogen
Atoms or lower alkyl groups are preferred. Of these, R1But
Hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms
Rukiru group, R2Is a hydrogen atom or a straight chain having 1 to 6 carbon atoms
More preferred is a chain or branched alkyl group.
Good Also, R1Is a hydrogen atom or a methyl group, and R 2
Is more preferably a hydrogen atom or a methyl group.
【００１８】本発明方法に用いらる化合物（１）のラセ
ミ体としては、鏡像関係にある２種の光学異性体の同量
混合物であれば特に制限されないが、特に下記（１ａ）
及び（１ｃ）からなるラセミ体、又は（１ｂ）及び（１
ｄ）からなるラセミ体が好ましい。The racemate of the compound (1) used in the method of the present invention is not particularly limited as long as it is a mixture of two enantiomers of the two optical isomers in the same amount, but the following (1a) is particularly preferable.
And (1c) or (1b) and (1
The racemate consisting of d) is preferred.
【００１９】[0019]
【化６】 [Chemical 6]
【００２０】〔式中、Ｒ1 及びＲ2 は前記と同じ〕[Wherein R 1 and R 2 are the same as above]
【００２１】これら４種の光学異性体のうち、（１ａ）
又は（１ｂ）の構造を有する化合物すなわち、（３Ｓ，
４Ｒ，１′Ｒ*，６′Ｓ*）−体が血圧降下作用、平滑筋
弛緩作用等の薬理作用が強いことから、特に好ましい。
従って、本発明においては原料として（１ａ）及び（１
ｃ）、又は（１ｂ）及び（１ｄ）よりなるラセミ体を光
学分割して（３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−体を得
る方法が特に好ましい。Of these four optical isomers, (1a)
Or a compound having the structure of (1b), that is, (3S,
4R, 1'R * , 6'S * )-body is particularly preferable because it has a strong pharmacological action such as a hypotensive action and a smooth muscle relaxing action.
Therefore, in the present invention, (1a) and (1
Particularly preferred is the method of obtaining the (3S, 4R, 1'R * , 6'S * )-form by optically resolving the racemic form consisting of c) or (1b) and (1d).
【００２２】本発明方法のうち、光学活性アミノ酸類を
用いて光学分割する方法（方法Ａ）について説明する。Among the methods of the present invention, a method for optically resolving using optically active amino acids (method A) will be described.
【００２３】[0023]
【化７】 [Chemical 7]
【００２４】〔式中、Ｒ3 はアミノ酸の窒素の保護基を
示し、Ａはアミノ酸残基を示し、Ｒ1及びＲ2 は前記と
同じ〕[In the formula, R 3 represents a nitrogen-protecting group of amino acid, A represents an amino acid residue, and R 1 and R 2 are the same as above]
【００２５】すなわち、この方法Ａは、ジアザビシクロ
ヘプテン誘導体（１）のラセミ体に光学活性なアミノ酸
類（Ｒ3−Ａ−ＯＨ）を反応させ、生成するジアステレ
オマーエステル混合物（３）を各ジアステレオマーエス
テルに分離した後加水分解することにより実施される。That is, this method A is a diastereomeric ester mixture (3) produced by reacting a racemic diazabicycloheptene derivative (1) with an optically active amino acid (R 3 -A-OH). Is separated into each diastereomeric ester and then hydrolyzed.
【００２６】ここで用いられるアミノ酸類（Ａ−ＯＨ）
としては、例えばＬ−アラニン、Ｌ−バリン、Ｌ−ロイ
シン、Ｌ−イソロイシン、Ｌ−フェニルアラニン、Ｌ−
メチオニン、Ｌ−チロシン、Ｌ−プロリン、Ｌ−トリプ
トファン等が挙げられる。そして、かかるアミノ酸の窒
素原子上の保護基（Ｒ3 ）としては、通常のアミノ酸の
エステル合成に用いられる保護基、例えばベンジルオキ
シカルボニル基、ｔ−ブトキシカルボニル基、９−フル
オレニルメチルオキシカルボニル基、トリチル基等が挙
げられる。また、光学活性なアミノ酸類（Ｒ3−Ａ−Ｏ
Ｈ）の具体例としては、Ｎ−ベンジルオキシカルボニル
−Ｌ−アラニン、Ｎ−ベンジルオキシカルボニル−Ｌ−
バリン、Ｎ−ベンジルオキシカルボニル−Ｌ−ロイシ
ン、Ｎ−ベンジルオキシカルボニル−Ｌ−イソロイシ
ン、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラ
ニン、Ｎ−ベンジルオキシカルボニル−Ｌ−メチオニ
ン、Ｎ−ベンジルオキシカルボニル−Ｌ−チロシン、Ｎ
−ベンジルオキシカルボニル−Ｌ−プロリン、Ｎ−ベン
ジルオキシカルボニル−Ｌ−トリプトファン、Ｎ−ｔ−
ブトキシカルボニル−Ｌ−アラニン、Ｎ−ｔ−ブトキシ
カルボニル−Ｌ−バリン、Ｎ−ｔ−ブトキシカルボニル
−Ｌ−ロイシン、Ｎ−ｔ−ブトキシカルボニル−Ｌ−イ
ソロイシン、Ｎ−ｔ−ブトキシカルボニル−Ｌ−フェニ
ルアラニン、Ｎ−ｔ−ブトキシカルボニル−Ｌ−メチオ
ニン、Ｎ−ｔ−ブトキシカルボニル−Ｌ−チロシン、Ｎ
−ｔ−ブトキシカルボニル−Ｌ−プロリン、Ｎ−ｔ−ブ
トキシカルボニル−Ｌ−トリプトファン、Ｎ−９−フル
オレニルメチルオキシカルボニル−Ｌ−アラニン、Ｎ−
９−フルオレニルメチルオキシカルボニル−Ｌ−バリ
ン、Ｎ−９−フルオレニルメチルオキシカルボニル−Ｌ
−ロイシン、Ｎ−９−フルオレニルメチルオキシカルボ
ニル−Ｌ−イソロイシン、Ｎ−９−フルオレニルメチル
オキシカルボニル−Ｌ−フェニルアラニン、Ｎ−９−フ
ルオレニルメチルオキシカルボニル−Ｌ−メチオニン、
Ｎ−９−フルオレニルメチルオキシカルボニル−Ｌ−チ
ロシン、Ｎ−９−フルオレニルメチルオキシカルボニル
−Ｌ−プロリン、Ｎ−９−フルオレニルメチルオキシカ
ルボニル−Ｌ−トリプトファン、Ｎ−トリチル−Ｌ−ア
ラニン、Ｎ−トリチル−Ｌ−バリン、Ｎ−トリチル−Ｌ
−ロイシン、Ｎ−トリチル−Ｌ−イソロイシン、Ｎ−ト
リチル−Ｌ−フェニルアラニン、Ｎ−トリチル−Ｎ−メ
チオニン、Ｎ−トリチル−Ｌ−チロシン、Ｎ−トリチル
−Ｌ−プロリン、Ｎ−トリチル−Ｌ−トリプトファン等
が挙げられる。このうち、Ｎ−ベンジルオキシカルボニ
ル保護のアミノ酸、Ｎ−ｔ−ブトキシカルボニル保護の
アミノ酸やＮ−９−フレオレニルメチルオキシカルボニ
ル保護のアミノ酸が好ましく、特にＮ−ベンジルオキシ
カルボニル−Ｌ−アラニン、Ｎ−ベンジルオキシカルボ
ニル−Ｌ−フェニルアラニン、Ｎ−ベンジルオキシカル
ボニル−Ｌ−バリン、Ｎ−ベンジルオキシカルボニル−
Ｌ−プロリン、Ｎ−ｔ−ブトキシカルボニル−Ｌ−アラ
ニン及びＮ−（９−フルオレニルメチルオキシカルボニ
ル）−Ｌ−アラニンが好ましい。Amino acids (A-OH) used here
Examples of L-alanine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-
Methionine, L-tyrosine, L-proline, L-tryptophan and the like can be mentioned. The protecting group (R 3 ) on the nitrogen atom of such an amino acid is a protecting group used in the usual ester synthesis of amino acids, for example, benzyloxycarbonyl group, t-butoxycarbonyl group, 9-fluorenylmethyloxycarbonyl. Group, trityl group and the like. In addition, optically active amino acids (R 3 -A-O
Specific examples of H) include N-benzyloxycarbonyl-L-alanine and N-benzyloxycarbonyl-L-.
Valine, N-benzyloxycarbonyl-L-leucine, N-benzyloxycarbonyl-L-isoleucine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-methionine, N-benzyloxycarbonyl-L- Tyrosine, N
-Benzyloxycarbonyl-L-proline, N-benzyloxycarbonyl-L-tryptophan, Nt-
Butoxycarbonyl-L-alanine, Nt-butoxycarbonyl-L-valine, Nt-butoxycarbonyl-L-leucine, Nt-butoxycarbonyl-L-isoleucine, Nt-butoxycarbonyl-L-phenylalanine , Nt-butoxycarbonyl-L-methionine, Nt-butoxycarbonyl-L-tyrosine, N
-T-butoxycarbonyl-L-proline, Nt-butoxycarbonyl-L-tryptophan, N-9-fluorenylmethyloxycarbonyl-L-alanine, N-
9-fluorenylmethyloxycarbonyl-L-valine, N-9-fluorenylmethyloxycarbonyl-L
-Leucine, N-9-fluorenylmethyloxycarbonyl-L-isoleucine, N-9-fluorenylmethyloxycarbonyl-L-phenylalanine, N-9-fluorenylmethyloxycarbonyl-L-methionine,
N-9-fluorenylmethyloxycarbonyl-L-tyrosine, N-9-fluorenylmethyloxycarbonyl-L-proline, N-9-fluorenylmethyloxycarbonyl-L-tryptophan, N-trityl-L -Alanine, N-trityl-L-valine, N-trityl-L
-Leucine, N-trityl-L-isoleucine, N-trityl-L-phenylalanine, N-trityl-N-methionine, N-trityl-L-tyrosine, N-trityl-L-proline, N-trityl-L-tryptophan Etc. Of these, N-benzyloxycarbonyl-protected amino acids, Nt-butoxycarbonyl-protected amino acids and N-9-fluorenylmethyloxycarbonyl-protected amino acids are preferable, and N-benzyloxycarbonyl-L-alanine and N-benzyloxycarbonyl-L-alanine are particularly preferable. -Benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-
L-proline, Nt-butoxycarbonyl-L-alanine and N- (9-fluorenylmethyloxycarbonyl) -L-alanine are preferred.
【００２７】化合物（１）のラセミ体と光学活性なアミ
ノ酸類との反応は、例えば不活性有機溶媒中で、脱水試
薬及び必要により塩基の存在下に脱水縮合させるのが好
ましい。ここで用いられる不活性有機溶媒としては、例
えばジクロロメタン、テトラヒドロフラン、ジメチルホ
ルムアミド等が用いられるが、ジクロロメタンが特に好
ましい。脱水試薬としては、通常エステル合成に用いら
れる脱水試薬、例えばＮ，Ｎ′−ジシクロヘキシルカル
ボジイミド、１−エチル−３−（３−ジメチルアミノプ
ロピル）カルボジイミド、カルボニルジイミダゾール、
ビルスマイヤー試薬、トシルクロリド、オキシ塩化リ
ン、塩化チオニル、ジメチルホルムアミドジエチルアセ
タールなどが挙げられるが、このうち１−エチル−３−
（３−ジメチルアミノプロピル）カルボジイミド、Ｎ，
Ｎ’−ジシクロヘキシルカルボジイミドが好ましい。ま
た塩基としては、有機塩基、例えばピリジン、４−ジメ
チルアミノピリジン、１−ヒドロキシベンゾトリアゾー
ル、トリエチルアミンなどが用いられるが、このうち４
−ジメチルアミノピリジンが特に好ましい。この反応
は、−７８℃から加熱還流の温度で、好ましくは室温か
ら５０℃の温度で行うのが好ましい。The reaction of the racemate of the compound (1) with the optically active amino acid is preferably carried out by dehydration condensation in the presence of a dehydrating reagent and optionally a base in an inert organic solvent. As the inert organic solvent used here, for example, dichloromethane, tetrahydrofuran, dimethylformamide and the like are used, and dichloromethane is particularly preferable. As the dehydrating reagent, a dehydrating reagent usually used for ester synthesis, for example, N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole,
Vilsmeier reagent, tosyl chloride, phosphorus oxychloride, thionyl chloride, dimethylformamide diethyl acetal and the like can be mentioned, among which 1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide, N,
N'-dicyclohexylcarbodiimide is preferred. As the base, organic bases such as pyridine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, triethylamine and the like can be used.
-Dimethylaminopyridine is particularly preferred. This reaction is preferably carried out at a temperature of -78 ° C to heating under reflux, preferably at a temperature of room temperature to 50 ° C.
【００２８】得られたジアステレオマーエステル混合物
（３）の各ジアステレオマーエステルへの分離は、通常
の分離手段、例えば分別結晶法、カラムクロマトグラフ
ィー等により行われる。Separation of the obtained diastereomeric ester mixture (3) into each diastereomeric ester is carried out by an ordinary separation means such as fractional crystallization or column chromatography.
【００２９】分離されたジアステレオマーエステルの加
水分解は、例えば不活性有機溶媒中、塩基の存在下に行
うのが好ましい。ここで用いられる不活性有機溶媒とし
ては、例えばエタノール、メタノール、テトラヒドロフ
ラン、ジメチルホルムアミド、ジエチルエーテル、アセ
トニトリル等が挙げられるが、このうち、メタノールが
特に好ましい。塩基としては、炭酸カリウム、水酸化ナ
トリウムなどの無機塩基、及びピリジン、トリエチルア
ミンなどの有機塩基が挙げられるが、炭酸カリウムが特
に好ましい。Hydrolysis of the separated diastereomeric ester is preferably carried out, for example, in an inert organic solvent in the presence of a base. Examples of the inert organic solvent used here include ethanol, methanol, tetrahydrofuran, dimethylformamide, diethyl ether, acetonitrile and the like. Of these, methanol is particularly preferable. Examples of the base include inorganic bases such as potassium carbonate and sodium hydroxide, and organic bases such as pyridine and triethylamine, and potassium carbonate is particularly preferable.
【００３０】次に、光学活性なカラムによる高速液体ク
ロマトグラフィーを用いる方法（方法Ｂ）について説明
する。光学活性なカラムとは、光学活性な固定相と、移
動相とが平衡状態にあって、そこへ試料が添加され、そ
の試料の各成分が両相との相互作用によって分布して平
衡に達し、移動相の移動につれてその分布平衡が繰り返
されて各成分が分離される場を意味し、普通、管柱状の
金属製又はガラス製のクロマト管に、光学活性な固定相
をシリカゲルなどの支持体に固定した充填剤を充填した
ものをいう。用いられる光学活性なカラムの充填剤とし
ては、例えば、アミロースカルバメート誘導体被覆型シ
リカゲル、セルロースエステル誘導体被覆型シリカゲ
ル、セルロースカルバメート誘導体被覆型シリカゲルが
挙げられ、好ましくは、アミロースカルバメート誘導体
被覆型シリカゲル（ＣＨＩＲＡＬＰＡＫ ＡＳ，ＣＨＩ
ＲＡＬＰＡＫ ＡＤ、ダイセル化学工業）が挙げられ
る。溶離液としては、ヘキサン、ジエチルエーテル、イ
ソプロピルエーテル、酢酸エチル、アセトニトリル、ア
セトン、酢酸、エタノール、メタノール、イソプロパノ
ール、ブタノール、水などが挙げられ、好ましくはヘキ
サンとメタノール、あるいはヘキサンとエタノールの混
合溶媒が挙げられ、その混合比は、９９対１から５０対
５０であり、好ましくは９５対５から７０対３０であ
る。流速としては、毎分０．１から１０００ミリリット
ル、好ましくは、毎分１から１００ミリリットルが好ま
しい。カラムの温度は、室温から１００℃であり、好ま
しくは室温から５０℃である。Next, a method (method B) using high performance liquid chromatography with an optically active column will be described. An optically active column is a state in which an optically active stationary phase and a mobile phase are in equilibrium, to which a sample is added, and each component of the sample is distributed by interaction with both phases to reach equilibrium. , A field in which each component is separated by repeating its distribution equilibrium as the mobile phase moves. Usually, a columnar metal or glass chromatographic tube is provided with an optically active stationary phase on a support such as silica gel. Filled with a filler fixed to. Examples of the packing material of the optically active column used include amylose carbamate derivative-coated silica gel, cellulose ester derivative-coated silica gel, and cellulose carbamate derivative-coated silica gel, preferably amylose carbamate derivative-coated silica gel (CHIRALPAK AS , CHI
RALPAK AD, Daicel Chemical Industries). Examples of the eluent include hexane, diethyl ether, isopropyl ether, ethyl acetate, acetonitrile, acetone, acetic acid, ethanol, methanol, isopropanol, butanol, water and the like, and preferably a mixed solvent of hexane and methanol, or hexane and ethanol. The mixing ratio is 99: 1 to 50:50, preferably 95: 5 to 70:30. The flow rate is preferably 0.1 to 1000 ml / min, and more preferably 1 to 100 ml / min. The temperature of the column is from room temperature to 100 ° C, preferably room temperature to 50 ° C.
【００３１】なお、本発明方法において、原料として用
いられる化合物（１）のラセミ体は、例えば次の反応式
に従って製造することができる。In the method of the present invention, the racemate of compound (1) used as a starting material can be produced, for example, according to the following reaction formula.
【００３２】[0032]
【化８】 [Chemical 8]
【００３３】〔式中、Ｒ1 及びＲ2 は前記と同じ〕[In the formula, R 1 and R 2 are the same as above]
【００３４】すなわち、化合物（４）をメタノール、エ
タノールなどの低級脂肪族アルコール、アセトニトリ
ル、酢酸などの溶媒中でヒドラジン類（５）と反応さ
せ、得られた化合物（６）に化合物（７）を反応させる
ことによって得られるジアステレオマー混合物から、通
常の分離方法、例えば分別結晶、カラムクロマトグラフ
ィーなどによって、化合物（１）のラセミ体を得ること
ができる。That is, the compound (4) is reacted with a hydrazine (5) in a solvent such as a lower aliphatic alcohol such as methanol or ethanol, acetonitrile or acetic acid, and the obtained compound (6) is converted to the compound (7). From the diastereomeric mixture obtained by the reaction, the racemate of compound (1) can be obtained by an ordinary separation method such as fractional crystallization and column chromatography.
【００３５】なお、光学活性な本発明化合物（１）は水
和物、溶媒和物として、またアモルファスとして単離さ
れることがあるが、これらはいずれも本発明に含まれ
る。The optically active compound (1) of the present invention may be isolated as a hydrate, a solvate or an amorphous, and these are all included in the present invention.
【００３６】[0036]
【実施例】以下、参考例及び実施例を挙げて本発明を更
に詳細に説明するが、本発明はこれらによって限定され
るものではない。The present invention will be described in more detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto.
【００３７】参考例１ ３，４−トランス−３，４−ジヒドロ−２，２−ジメチ
ル−３−ヒドロキシ−４−（２−オキソ−３，４−ジア
ザビシクロ［４．１．０］ヘプト−４−エン−５−イル
オキシ）−２Ｈ−１−ベンゾピラン−６−カルボニトリ
ル （ａ）（±）−３−（４−メトキシベンジル）−３，４
−ジアザビシクロ［４．１．０］ヘプタン−２，５−ジ
オン ４−メトキシベンジルヒドラジン（６７．０ｇ、０．４
４ｍｏｌ）を、アセトニトリル（３００ｍｌ）中に加
え、氷冷下にシクロプロパン−１，２−ジカルボン酸無
水物（４９．５ｇ、０．４４ｍｏｌ）のアセトニトリル
（３００ｍｌ）溶液を滴下した。滴下後、一夜加熱還流
した。冷却後、析出した結晶を濾取し、エタノ−ルで再
結晶し、標題の化合物を３６．５ｇ得た。 融点 １８０−１８３℃ NMR(DMSO-d6,TMS) δ(ppm):0.91(1H,m),1.61(1H,m),1.9
7-2.03(1H,m),2.08-2.13(1H,m),3.73(3H,s),4.48(1H,d,
J=15.1Hz),4.61(1H,d,J=15.1Hz),6.90(2H,d,J=8.3Hz),
7.18(2H,d,J=8.3Hz),10.35(1H,br s)Reference Example 1 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-4 -En-5-yloxy) -2H-1-benzopyran-6-carbonitrile (a) (±) -3- (4-methoxybenzyl) -3,4
-Diazabicyclo [4.1.0] heptane-2,5-dione 4-methoxybenzylhydrazine (67.0 g, 0.4
4 mol) was added to acetonitrile (300 ml), and a solution of cyclopropane-1,2-dicarboxylic acid anhydride (49.5 g, 0.44 mol) in acetonitrile (300 ml) was added dropwise under ice cooling. After the dropping, the mixture was heated under reflux overnight. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the title compound (36.5 g). Melting point 180-183 ° C NMR (DMSO-d 6 , TMS) δ (ppm): 0.91 (1H, m), 1.61 (1H, m), 1.9
7-2.03 (1H, m), 2.08-2.13 (1H, m), 3.73 (3H, s), 4.48 (1H, d,
J = 15.1Hz), 4.61 (1H, d, J = 15.1Hz), 6.90 (2H, d, J = 8.3Hz),
7.18 (2H, d, J = 8.3Hz), 10.35 (1H, br s)
【００３８】（ｂ）３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（３−
（４−メトキシベンジル）−２−オキソ−３，４−ジア
ザビシクロ［４．１．０］ヘプト−４−エン−５−イル
オキシ）−２Ｈ−１−ベンゾピラン−６−カルボニトリ
ル （ａ）で得た（±）−３−（４−メトキシベンジル）−
３，４−ジアザビシクロ［４．１．０］ヘプタン−２，
５−ジオン（１．２３ｇ、５．０ｍｍｏｌ）、及び
（±）−３，４−ジヒドロ−２，２−ジメチル−３，４
−エポキシ−２Ｈ−１−ベンゾピラン−６−カルボニト
リル（１．００ｇ、５．０ｍｍｏｌ）、ピリジン（０．
４ｍｌ）を、エタノール（１０ｍｌ）中に加え、８時間
加熱還流した。溶媒を減圧留去後、残渣をシリカゲルカ
ラムクロマトグラフィ−（クロロホルム−メタノール）
により各ジアステレオマーを分離し、標題の化合物の低
極性ジアステレオマー（ｉｓｏｍｅｒ Ａ）を０．６４
ｇ、高極性ジアステレオマー（ｉｓｏｍｅｒ Ｂ）を
０．６６ｇ得た。 低極性ジアステレオマー（ｉｓｏｍｅｒ Ａ） 融点 １８３−１８４℃ NMR(CDCl3,TMS)δ(ppm):0.99(1H,m),1.27(3H,s),1.50(3
H,s),1.72(1H,m),2.27(1H,m),2.37(1H,m),3.78(3H,s),
3.83(1H,dd,J=2.9 and 8.3Hz),4.49(1H,d,J=2.9Hz),4.5
2(1H,d,J=14.2Hz),4.90(1H,d,J=14.2Hz),5.46(1H,d,J=
8.3Hz),6.84(2H,d,J=8.8Hz),6.88(1H,d,J=8.3Hz),7.28
(2H,d,J=8.8Hz),7.48(1H,dd,J=2.0 and 8.3Hz),7.54(1
H,d,J=2.0Hz) 高極性ジアステレオマー（ｉｓｏｍｅｒ Ｂ） 融点２１４−２１５℃ NMR(CDCl3,TMS)δ(ppm):0.95(1H,m),1.29(3H,s),1.48(3
H,s),1.62(1H,m),2.04(1H,m),2.18(1H,m),3.66(1H,d,J=
3.9Hz),3.78(3H,s),3.81(1H,dd,J=3.9 and 7.8Hz),4.62
(1H,d,J=14.2Hz),4.78(1H,d,J=14.2Hz),5.67(1H,d,J=7.
8Hz),6.84(2H,d,J=8.8Hz),6.89(1H,d,J=8.3Hz),7.25(2
H,d,J=8.8Hz),7.48(1H,dd,J=2.0 and 8.3Hz),7.52(1H,
d,J=2.0Hz)(B) 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (3-
(4-Methoxybenzyl) -2-oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile Obtained with (a). (±) -3- (4-methoxybenzyl)-
3,4-diazabicyclo [4.1.0] heptane-2,
5-dione (1.23 g, 5.0 mmol), and (±) -3,4-dihydro-2,2-dimethyl-3,4.
-Epoxy-2H-1-benzopyran-6-carbonitrile (1.00 g, 5.0 mmol), pyridine (0.
4 ml) was added to ethanol (10 ml), and the mixture was heated under reflux for 8 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform-methanol).
The diastereomers were separated by to give 0.64 of the less polar diastereomer (isomer A) of the title compound.
g, 0.66 g of a highly polar diastereomer (isomer B) was obtained. Low polarity diastereomer (isomer A) Melting point 183-184 ° C NMR (CDCl 3 , TMS) δ (ppm): 0.99 (1H, m), 1.27 (3H, s), 1.50 (3
H, s), 1.72 (1H, m), 2.27 (1H, m), 2.37 (1H, m), 3.78 (3H, s),
3.83 (1H, dd, J = 2.9 and 8.3Hz), 4.49 (1H, d, J = 2.9Hz), 4.5
2 (1H, d, J = 14.2Hz), 4.90 (1H, d, J = 14.2Hz), 5.46 (1H, d, J =
8.3Hz), 6.84 (2H, d, J = 8.8Hz), 6.88 (1H, d, J = 8.3Hz), 7.28
(2H, d, J = 8.8Hz), 7.48 (1H, dd, J = 2.0 and 8.3Hz), 7.54 (1
H, d, J = 2.0Hz) High polarity diastereomer (isomer B) Melting point 214-215 ° C NMR (CDCl 3 , TMS) δ (ppm): 0.95 (1H, m), 1.29 (3H, s), 1.48 (3
H, s), 1.62 (1H, m), 2.04 (1H, m), 2.18 (1H, m), 3.66 (1H, d, J =
3.9Hz), 3.78 (3H, s), 3.81 (1H, dd, J = 3.9 and 7.8Hz), 4.62
(1H, d, J = 14.2Hz), 4.78 (1H, d, J = 14.2Hz), 5.67 (1H, d, J = 7.
8Hz), 6.84 (2H, d, J = 8.8Hz), 6.89 (1H, d, J = 8.3Hz), 7.25 (2
H, d, J = 8.8Hz), 7.48 (1H, dd, J = 2.0 and 8.3Hz), 7.52 (1H,
(d, J = 2.0Hz)
【００３９】（ｃ）３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル （ｂ）で得られた高極性ジアステレオマー（ｉｓｏｍｅ
ｒ Ｂ）３，４−トランス−３，４−ジヒドロ−２，２
−ジメチル−３−ヒドロキシ−４−（３−（４−メトキ
シベンジル）−２−オキソ−３，４−ジアザビシクロ
［４．１．０］ヘプト−４−エン−５−イルオキシ）−
２Ｈ−１−ベンゾピラン−６−カルボニトリル（０．５
ｇ、１．１ｍｍｏｌ）、２，３−ジクロロ−５，６−ジ
シアノ−１，４−ベンゾキノン（１．５２ｇ、６．７ｍ
ｍｏｌ）、及び水（０．０８ｍｌ）を、１，２−ジクロ
ロエタン（４０ｍｌ）中に加え、４時間加熱還流した。
減圧濃縮し、残渣にエタノールを加え、析出晶を濾取
し、エタノールで再結晶し、標題の化合物を０．１５ｇ
得た。 融点２５０−２５１℃ NMR(DMSO-d6,TMS)δ(ppm):δ1.08(1H,m),1.24(3H,s),1.
42(3H,s),1.64(1H,m),2.06(1H,m),2.16(1H,m),3.76(1H,
dd,J=5.4 and 7.3Hz),5.67(1H,d,J=7.3Hz),5.94(1H,d,J
=5.4Hz),6.97(1H,d,J=8.3Hz),7.65(1H,d,J=2.0Hz),7.67
(1H,dd,J=2.0 and 8.3Hz),10.02(1H,d,J=1.5Hz)(C) 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (b) The highly polar diastereomer (isome) obtained
r B) 3,4-trans-3,4-dihydro-2,2
-Dimethyl-3-hydroxy-4- (3- (4-methoxybenzyl) -2-oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy)-
2H-1-benzopyran-6-carbonitrile (0.5
g, 1.1 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.52 g, 6.7 m)
mol) and water (0.08 ml) were added to 1,2-dichloroethane (40 ml) and the mixture was heated under reflux for 4 hours.
After concentration under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give the title compound (0.15 g)
Obtained. Melting point 250-251 ° C NMR (DMSO-d 6 , TMS) δ (ppm): δ 1.08 (1H, m), 1.24 (3H, s), 1.
42 (3H, s), 1.64 (1H, m), 2.06 (1H, m), 2.16 (1H, m), 3.76 (1H,
dd, J = 5.4 and 7.3Hz), 5.67 (1H, d, J = 7.3Hz), 5.94 (1H, d, J
= 5.4Hz), 6.97 (1H, d, J = 8.3Hz), 7.65 (1H, d, J = 2.0Hz), 7.67
(1H, dd, J = 2.0 and 8.3Hz), 10.02 (1H, d, J = 1.5Hz)
【００４０】参考例２ （３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−３，４−ジヒドロ
−２，２−ジメチル−３−ヒドロキシ−４−（２−オキ
ソ−３，４−ジアザビシクロ［４．１．０］ヘプト−４
−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン−
６−カルボニトリル （ａ）（３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−３，４−ジ
ヒドロ−２，２−ジメチル−３−ヒドロキシ−４−（３
−（４−メトキシベンジル）−２−オキソ−３，４−ジ
アザビシクロ［４．１．０］ヘプト−４−エン−５−イ
ルオキシ）−２Ｈ−１−ベンゾピラン−６−カルボニト
リル 参考例１と同様にして、（±）−３−（４−メトキシベ
ンジル）−３，４−ジアザビシクロ［４．１．０］ヘプ
タン−２，５−ジオン及び（３Ｓ，４Ｓ）−３，４−ジ
ヒドロ−２，２−ジメチル−３，４−エポキシ−２Ｈ−
１−ベンゾピラン−６−カルボニトリルより、標題の化
合物の高極性ジアステレオマー（ｉｓｏｍｅｒ Ｂ）を
得た。 ［α］D 24＝−２０５．１゜（ｃ＝１，メタノ−ル） NMR(DMSO-d6,TMS)δ(ppm):0.91(1H,m),1.24(3H,s),1.40
(3H,s),1.66(1H,td,J=9.3 and 4.4Hz),2.22(2H,dd,J=8.
8 and 4.9Hz),3.71(3H,s),3.78(1H,dd,J=6.8 and 5.4H
z),4.54(1H,d,J=14.7Hz),4.73(1H,d,J=14.7Hz),5.63(1
H,d,J=6.8Hz),5.90(1H,d,J=5.4Hz),6.85(2H,d,J=8.8H
z),6.96(1H,d,J=8.8Hz),7.20(2H,d,J=8.8Hz),7.59(1H,
d,J=2.0Hz),7.66(1H,dd,J=2.0 and 8.8Hz)Reference Example 2 (3S, 4R, 1'R * , 6'S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo) [4.1.0] Hept-4
-En-5-yloxy) -2H-1-benzopyran-
6-Carbonitrile (a) (3S, 4R, 1'R * , 6'S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (3
-(4-Methoxybenzyl) -2-oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile Similar to Reference Example 1. And (±) -3- (4-methoxybenzyl) -3,4-diazabicyclo [4.1.0] heptane-2,5-dione and (3S, 4S) -3,4-dihydro-2, 2-dimethyl-3,4-epoxy-2H-
The highly polar diastereomer (isomer B) of the title compound was obtained from 1-benzopyran-6-carbonitrile. [Α] D 24 = −205.1 ° (c = 1, methanol) NMR (DMSO-d 6 , TMS) δ (ppm): 0.91 (1H, m), 1.24 (3H, s), 1.40
(3H, s), 1.66 (1H, td, J = 9.3 and 4.4Hz), 2.22 (2H, dd, J = 8.
8 and 4.9Hz), 3.71 (3H, s), 3.78 (1H, dd, J = 6.8 and 5.4H
z), 4.54 (1H, d, J = 14.7Hz), 4.73 (1H, d, J = 14.7Hz), 5.63 (1
H, d, J = 6.8Hz), 5.90 (1H, d, J = 5.4Hz), 6.85 (2H, d, J = 8.8H
z), 6.96 (1H, d, J = 8.8Hz), 7.20 (2H, d, J = 8.8Hz), 7.59 (1H,
d, J = 2.0Hz), 7.66 (1H, dd, J = 2.0 and 8.8Hz)
【００４１】（ｂ）（３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）
−３，４−ジヒドロ−２，２−ジメチル−３−ヒドロキ
シ−４−（２−オキソ−３，４−ジアザビシクロ［４．
１．０］ヘプト−４−エン−５−イルオキシ）−２Ｈ−
１−ベンゾピラン−６−カルボニトリル 前述の（ａ）で得られた（３Ｓ，４Ｒ，１′Ｒ*，６′
Ｓ*）−３，４−ジヒドロ−２，２−ジメチル−３−ヒ
ドロキシ−４−（３−（４−メトキシベンジル）−２−
オキソ−３，４−ジアザビシクロ［４．１．０］ヘプト
−４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラ
ン−６−カルボニトリル（ｉｓｏｍｅｒＢ）を参考例１
の（ｃ）と同様にして処理し標題の化合物を得た。 ［α］D 25＝−１６８．１°（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS)δ(ppm):1.18(1H,m),1.33(3H,s),1.52(3
H,s),1.60-2.10(1H,br s),1.81(1H,m),2.21(1H,m),3.92
(1H,d,J=7.3Hz),5.71(1H,d,J=7.3Hz),6.91(1H,d,J=8.3H
z),7.50(1H,dd,J=2.0 and 8.3Hz),7.59(1H,d,J=2.0Hz),
7.71(1H,s)(B) (3S, 4R, 1'R * , 6'S * )
-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo [4.
1.0] Hept-4-en-5-yloxy) -2H-
1-benzopyran-6-carbonitrile (3S, 4R, 1'R * , 6 'obtained in (a) above.
S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (3- (4-methoxybenzyl) -2-
Oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomerB) was used as Reference Example 1.
This was treated in the same manner as in (c) above to give the title compound. [Α] D 25 = -168.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.18 (1H, m), 1.33 (3H, s), 1.52 (3
H, s), 1.60-2.10 (1H, br s), 1.81 (1H, m), 2.21 (1H, m), 3.92
(1H, d, J = 7.3Hz), 5.71 (1H, d, J = 7.3Hz), 6.91 (1H, d, J = 8.3H
z), 7.50 (1H, dd, J = 2.0 and 8.3Hz), 7.59 (1H, d, J = 2.0Hz),
7.71 (1H, s)
【００４２】参考例３ ３，４−トランス−３，４−ジヒドロ−３−ヒドロキシ
−４−（３−メチル−２−オキソ−３，４−ジアザビシ
クロ［４．１．０］ヘプト−４−エン−５−イルオキ
シ）−２，２，３−トリメチル−２Ｈ−１−ベンゾピラ
ン−６−カルボニトリル （ａ）（±）−３−メチル−３，４−ジアザビシクロ
［４．１．０］ヘプタン−２，５−ジオン 参考例１の（ａ）と同様にして、（±）−３−メチル−
３，４−ジアザビシクロ［４．１．０］ヘプタン−２，
５−ジオンを得た。 融点１９５−１９６℃ NMR(CDCl3,TMS)δ(ppm):1.21(1H,m),1.71(1H,m),2.12(1
H,m),2.24(1H,m),3.21(3H,s) （ｂ）３，４−トランス−３，４−ジヒドロ−３−ヒド
ロキシ−４−（３−メチル−２−オキソ−３，４−ジア
ザビシクロ［４．１．０］ヘプト−４−エン−５−イル
オキシ）−２，２，３−トリメチル−２Ｈ−１−ベンゾ
ピラン−６−カルボニトリル 参考例１の（ｂ）と同様にして、（ａ）で得られた
（±）−３−メチル−３，４−ジアザビシクロ［４．
１．０］ヘプタン−２，５−ジオン及び（±）−３，４
−ジヒドロ−３，４−エポキシ−２，２，３−トリメチ
ル−２Ｈ−１−ベンゾピラン−６−カルボニトリルよ
り、標題の化合物の高極性ジアステレオマー（ｉｓｏｍ
ｅｒ Ｂ）を得た。 融点２２６−２２７℃ NMR(CDCl3,TMS)δ(ppm):1.03(1H,m),1.24(3H,s),1.42(3
H,s),1.50(3H,s),1.73(1H,m),2.22-2.31(2H,m),3.24(3
H,s),3.95(1H,s),5.83(1H,s),6.90(1H,d,J=8.3Hz),7.51
(1H,dd,J=2.0 and 8.3Hz),7.65(1H,d,J=2.0Hz)Reference Example 3 3,4-trans-3,4-dihydro-3-hydroxy-4- (3-methyl-2-oxo-3,4-diazabicyclo [4.1.0] hept-4-ene -5-yloxy) -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile (a) (±) -3-methyl-3,4-diazabicyclo [4.1.0] heptane-2 , 5-dione In the same manner as in (a) of Reference Example 1, (±) -3-methyl-
3,4-diazabicyclo [4.1.0] heptane-2,
Obtained 5-dione. Melting point 195-196 ° C NMR (CDCl 3 , TMS) δ (ppm): 1.21 (1H, m), 1.71 (1H, m), 2.12 (1
H, m), 2.24 (1H, m), 3.21 (3H, s) (b) 3,4-trans-3,4-dihydro-3-hydroxy-4- (3-methyl-2-oxo-3, 4-Diazabicyclo [4.1.0] hept-4-en-5-yloxy) -2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile In the same manner as in (b) of Reference Example 1. , (±) -3-methyl-3,4-diazabicyclo [4.
1.0] Heptane-2,5-dione and (±) -3,4
-Dihydro-3,4-epoxy-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile from the highly polar diastereomer (isom) of the title compound.
er B) was obtained. Melting point 226-227 ° C NMR (CDCl 3 , TMS) δ (ppm): 1.03 (1H, m), 1.24 (3H, s), 1.42 (3
H, s), 1.50 (3H, s), 1.73 (1H, m), 2.22-2.31 (2H, m), 3.24 (3
H, s), 3.95 (1H, s), 5.83 (1H, s), 6.90 (1H, d, J = 8.3Hz), 7.51
(1H, dd, J = 2.0 and 8.3Hz), 7.65 (1H, d, J = 2.0Hz)
【００４３】実施例１ ３，４−トランス−３−（（２Ｓ）−２−ベンジルオキ
シカルボニルアミノプロピオニルオキシ）−４−（２−
オキソ−３，４−ジアザビシクロ［４．１．０］ヘプト
−４−エン−５−イルオキシ）−３，４−ジヒドロ−
２，２−ジメチル−２Ｈ−１−ベンゾピラン−６−カル
ボニトリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（１．０
ｇ、３．０６ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニ
ル−Ｌ−アラニン（０．８９２ｇ、４．０ｍｍｏｌ）、
４−ジメチルアミノピリジン（０．１ｇ、０．８２ｍｍ
ｏｌ）及び１−エチル−３−（３−ジメチルアミノプロ
ピル）カルボジイミド塩酸塩（０．９６ｇ、５．０ｍｍ
ｏｌ）を、テトラヒドロフラン（２００ｍｌ）中に加
え、室温で３日間攪拌した。減圧濃縮し、酢酸エチルで
抽出し、水、飽和食塩水で洗浄し、硫酸ソ−ダで乾燥
し、減圧濃縮し、残渣をシリカゲルカラムクロマトグラ
フィー（クロロホルム−メタノ−ル）でジアステレオマ
ーエステルを分離し、標題の化合物の低極性ジアステレ
オマーエステルを０．５３ｇ、高極性ジアステレオマー
エステルを０．３６ｇ得た。 低極性ジアステレオマーエステル ［α］D 25＝−８３．１゜（ｃ＝１，メタノール） NMR(CDCl3,TMS)δ(ppm):1.07(1H,m),1.32(3H,s),1.41(3
H,s),1.44(1H,d,J=7.3Hz),1.66(1H,m),2.07(1H,m),2.13
(1H,m),4.37(1H,m),5.10(2H,s),5.30(1H,d,J=6.8Hz),5.
37(1H,d,J=5.9Hz),5.84(1H,d,J=6.8Hz),6.93(1H,d,J=8.
3Hz),7.34(5H,br s),7.51(1H,d,J=8,3Hz),7.61(1H,br
s),8.09(1H,br s) 高極性ジアステレオマーエステル ［α］D 25＝＋４７．０゜（ｃ＝１，メタノール） NMR(CDCl3 ,TMS)δ(ppm):1.10(1H,m),1.25(3H,s),1.36
(3H,s),1.39(3H,d,J=6.8Hz,),1.69(1H,m),2.05(1H,m),
2.18(1H,m),4.39(1H,m),5.0-5.15(2H,m),5.35(1H,m),5.
38(1H,d,J=5.9Hz),5.83(1H,d,J=5.9Hz),6.94(1H,d,J=8.
3Hz),7.34(5H,s),7.52(1H,dd,J=2.0 and 8.3Hz),7.56(1
H,br s),7.95-8.15(1H,m)Example 1 3,4-trans-3-((2S) -2-benzyloxycarbonylaminopropionyloxy) -4- (2-
Oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy) -3,4-dihydro-
2,2-Dimethyl-2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2- obtained in Reference Example 1 Oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (1.0
g, 3.06 mmol), N-benzyloxycarbonyl-L-alanine (0.892 g, 4.0 mmol),
4-dimethylaminopyridine (0.1g, 0.82mm
ol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.96 g, 5.0 mm)
ol) was added to tetrahydrofuran (200 ml), and the mixture was stirred at room temperature for 3 days. Concentrate under reduced pressure, extract with ethyl acetate, wash with water and saturated saline, dry over sodium sulfate, concentrate under reduced pressure, and diastereomer ester the residue by silica gel column chromatography (chloroform-methanol). Separation gave 0.53 g of the low polarity diastereomeric ester of the title compound and 0.36 g of the high polarity diastereomeric ester. Low-polar diastereomeric ester [α] D 25 = -83.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.07 (1H, m), 1.32 (3H, s), 1.41 (3
H, s), 1.44 (1H, d, J = 7.3Hz), 1.66 (1H, m), 2.07 (1H, m), 2.13
(1H, m), 4.37 (1H, m), 5.10 (2H, s), 5.30 (1H, d, J = 6.8Hz), 5.
37 (1H, d, J = 5.9Hz), 5.84 (1H, d, J = 6.8Hz), 6.93 (1H, d, J = 8.
3Hz), 7.34 (5H, br s), 7.51 (1H, d, J = 8,3Hz), 7.61 (1H, br
s), 8.09 (1H, br s) highly polar diastereomeric ester [α] D 25 = + 47.0 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.10 (1H, m ), 1.25 (3H, s), 1.36
(3H, s), 1.39 (3H, d, J = 6.8Hz,), 1.69 (1H, m), 2.05 (1H, m),
2.18 (1H, m), 4.39 (1H, m), 5.0-5.15 (2H, m), 5.35 (1H, m), 5.
38 (1H, d, J = 5.9Hz), 5.83 (1H, d, J = 5.9Hz), 6.94 (1H, d, J = 8.
3Hz), 7.34 (5H, s), 7.52 (1H, dd, J = 2.0 and 8.3Hz), 7.56 (1
H, br s), 7.95-8.15 (1H, m)
【００４４】実施例２ （３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−３，４−ジヒドロ
−２，２−ジメチル−３−ヒドロキシ−４−（２−オキ
ソ−３，４−ジアザビシクロ［４．１．０］ヘプト−４
−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン−
６−カルボニトリル 実施例１で得られた低極性ジアステレオマ−エステル
（０．３０ｇ、０．５６ｍｍｏｌ）を、メタノ−ル（１
０ｍｌ）中に溶解し、炭酸カリウム（０．３５ｇ、２．
５ｍｍｏｌ）を加え、室温で３時間攪拌した。不溶物を
濾去し、濾液を減圧濃縮し、酢酸エチルで抽出し、水、
飽和食塩水で洗浄し、硫酸ソ−ダで乾燥後、減圧濃縮
し、残渣をシリカゲルカラムクロマトグラフィー（クロ
ロホルム−メタノ−ル）で精製し、水−エタノールで再
結晶し、標題の化合物（０．１１４ｇ）を得た。 ［α］D 25＝−１６８．１゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS)δ(ppm):1.18(1H,m),1.33(3H,s),1.52(3
H,s),1.60-2.10(1H,br s),1,81(1H,m),2.21(1H,m),3.92
(1H,d,J=7.3Hz),5.71(1H,d,J=7.3Hz),6.91(1H,d,J=8.3H
z),7.50(1H,dd,J=2.0 and 8.3Hz),7.59(1H,d,J=2.0Hz),
7.71(1H,s) 尚、ここで得られた化合物と参考例２で得られた化合物
のＮＭＲ，旋光度のデータは一致し、同一の化合物であ
ることが確認された。Example 2 (3S, 4R, 1'R * , 6'S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo) [4.1.0] Hept-4
-En-5-yloxy) -2H-1-benzopyran-
6-Carbonitrile The low polarity diastereomer ester (0.30 g, 0.56 mmol) obtained in Example 1 was treated with methanol (1
0 ml) and potassium carbonate (0.35 g, 2.
5 mmol) was added and the mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, water,
The extract was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and recrystallized from water-ethanol to give the title compound (. 114 g) was obtained. [Α] D 25 = -168.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.18 (1H, m), 1.33 (3H, s), 1.52 (3
H, s), 1.60-2.10 (1H, br s), 1,81 (1H, m), 2.21 (1H, m), 3.92
(1H, d, J = 7.3Hz), 5.71 (1H, d, J = 7.3Hz), 6.91 (1H, d, J = 8.3H
z), 7.50 (1H, dd, J = 2.0 and 8.3Hz), 7.59 (1H, d, J = 2.0Hz),
7.71 (1H, s) The NMR and optical rotation data of the compound obtained here and the compound obtained in Reference Example 2 were in agreement, and it was confirmed that they were the same compound.
【００４５】実施例３ （３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−３，４−ジヒドロ
−２，２−ジメチル−３−ヒドロキシ−４−（２−オキ
ソ−３，４−ジアザビシクロ［４．１．０］ヘプト−４
−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン−
６−カルボニトリル 参考例１で得た３，４−トランス−３，４−ジヒドロ−
２，２−ジメチル−３−ヒドロキシ−４−（２−オキソ
−３，４−ジアザビシクロ［４．１．０］ヘプト−４−
エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン−６
−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（０．２５ｇ、
０．７６ｍｍｏｌ）を、メタノ−ルに溶解し、光学活性
カラム（ＣＨＩＲＡＬＰＡＫ ＡＳ（２ｃｍφ×２５ｃ
ｍ）、ダイセル化学工業）を用いて、高速液体クロマト
グラフィ−（溶離液：エタノール／ヘキサン＝２５／７
５；流速：６ｍｌ／ｍｉｎ）にかけ、保持時間の短い鏡
像体を８７ｍｇ、保持時間の長い鏡像体を９４ｍｇ得
た。保持時間の長い鏡像体は、実施例２で得られた化合
物とＮＭＲ及び旋光度のデ−タが一致し、同一の化合物
であることが確認された。 保持時間の長い鏡像体 ［α］D 25＝−１６８．１゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS)δ(ppm):1.18(1H,m),1.33(3H,s),1.52(3
H,s),1.60-2.10(1H,br s),1,81(1H,m),2.21(1H,m),3.92
(1H,d,J=7.3Hz),5.71(1H,d,J=7.3Hz),6.91(1H,d,J=8.3H
z),7.50(1H,dd,J=2.0 and 8.3Hz),7.59(1H,d,J=2.0Hz),
7.71(1H,s)Example 3 (3S, 4R, 1'R * , 6'S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo) [4.1.0] Hept-4
-En-5-yloxy) -2H-1-benzopyran-
6-Carbonitrile 3,4-trans-3,4-dihydro-obtained in Reference Example 1
2,2-Dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-4-
En-5-yloxy) -2H-1-benzopyran-6
-Carbonitrile (isomer B) (0.25 g,
0.76 mmol) was dissolved in methanol, and an optically active column (CHIRALPAK AS (2 cmφ × 25c
m), Daicel Chemical Industries, Ltd., using high performance liquid chromatography (eluent: ethanol / hexane = 25/7).
5; flow rate: 6 ml / min) to obtain 87 mg of an enantiomer with a short retention time and 94 mg of an enantiomer with a long retention time. It was confirmed that the enantiomers having a long retention time had the same NMR and optical rotation data as the compound obtained in Example 2 and were the same compounds. Enantiomer with long retention time [α] D 25 = -168.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.18 (1H, m), 1.33 (3H, s ), 1.52 (3
H, s), 1.60-2.10 (1H, br s), 1,81 (1H, m), 2.21 (1H, m), 3.92
(1H, d, J = 7.3Hz), 5.71 (1H, d, J = 7.3Hz), 6.91 (1H, d, J = 8.3H
z), 7.50 (1H, dd, J = 2.0 and 8.3Hz), 7.59 (1H, d, J = 2.0Hz),
7.71 (1H, s)
【００４６】実施例４ （３Ｓ，４Ｒ，１′Ｒ*，６′Ｓ*）−３，４−ジヒドロ
−３−ヒドロキシ−４−（３−メチル−２−オキソ−
３，４−ジアザビシクロ［４．１．０］ヘプト−４−エ
ン−５−イルオキシ）−２，２，３−トリメチル−２Ｈ
−１−ベンゾピラン−６−カルボニトリル 参考例３で得た３，４−トランス−３，４−ジヒドロ−
３−ヒドロキシ−４−（３−メチル−２−オキソ−３，
４−ジアザビシクロ［４．１．０］ヘプト−４−エン−
５−イルオキシ）−２，２，３−トリメチル−２Ｈ−１
−ベンゾピラン−６−カルボニトリル（ｉｓｏｍｅｒ
Ｂ）（０．３０ｇ、０．８５ｍｍｏｌ）をメタノ−ルに
溶解し、光学活性カラム（ＣＨＩＲＡＬＰＡＫ ＡＤ
（２ｃｍφ×２５ｃｍ）、ダイセル化学工業）を用い
て、高速液体クロマトグラフィ−（溶離液：エタノール
／ヘキサン＝１５／８５；流速：４ｍｌ／ｍｉｎ）にか
け、保持時間の短い鏡像体を０．１２ｇ、保持時間の長
い鏡像体を０．１１ｇ得た。 保持時間の短い鏡像体 融点１９２−１９３℃ ［α］D 25＝−１６２．２°（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.04(1H,m),1.25(3H,s),1.42
(3H,s),1.50(3H,s),1.74 (1H,m),2.22-2.35(2H,m),3.25
(3H,s),3.90(1H,s),5,83(1H,s),6.91(1H,d,J=8.3 Hz),
7.51(1H,dd,J=2.0 and 8.3Hz),7.66(1H,s) 保持時間の長い鏡像体 融点１８５−１８６℃ ［α］D 25＝＋１５３．３°（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS)δ(ppm):1.04(1H,m),1.25(3H,s),1.42(3
H,s),1.50(3H,s),1.75(1H,m),2.22-2.35(2H,m),3.25(3
H,s),3.95(1H,s),5.83(1H,s),6.91(1H,d,J=8.3Hz),7.51
(1H,dd,J=2.0 and 8.3Hz),7.67(1H,d,J=2.0Hz)Example 4 (3S, 4R, 1'R * , 6'S * )-3,4-dihydro-3-hydroxy-4- (3-methyl-2-oxo-)
3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy) -2,2,3-trimethyl-2H
-1-Benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-obtained in Reference Example 3
3-hydroxy-4- (3-methyl-2-oxo-3,
4-diazabicyclo [4.1.0] hept-4-ene-
5-yloxy) -2,2,3-trimethyl-2H-1
-Benzopyran-6-carbonitrile (isomer
B) (0.30 g, 0.85 mmol) was dissolved in methanol, and an optically active column (CHIRALPAK AD
High-performance liquid chromatography (eluent: ethanol / hexane = 15/85; flow rate: 4 ml / min) using (2 cmφ × 25 cm), Daicel Chemical Industries, Ltd. to retain 0.12 g of the enantiomer with a short retention time. 0.11 g of a long time enantiomer was obtained. Enantiomer with short retention time Melting point 192-193 ° C. [α] D 25 = -162.2 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.04 (1H, m), 1.25 (3H, s), 1.42
(3H, s), 1.50 (3H, s), 1.74 (1H, m), 2.22-2.35 (2H, m), 3.25
(3H, s), 3.90 (1H, s), 5,83 (1H, s), 6.91 (1H, d, J = 8.3 Hz),
7.51 (1H, dd, J = 2.0 and 8.3Hz), 7.66 (1H, s) Enantiomer with long retention time Melting point 185-186 ° C [α] D 25 = + 153.3 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.04 (1H, m), 1.25 (3H, s), 1.42 (3
H, s), 1.50 (3H, s), 1.75 (1H, m), 2.22-2.35 (2H, m), 3.25 (3
H, s), 3.95 (1H, s), 5.83 (1H, s), 6.91 (1H, d, J = 8.3Hz), 7.51
(1H, dd, J = 2.0 and 8.3Hz), 7.67 (1H, d, J = 2.0Hz)
【００４７】以下、実施例１と同様にして実施例５〜９
のジアステレオマ−エステルを合成した。いずれの場合
も、低極性ジアステレオマ−エステルを加水分解するこ
とにより、実施例２で得られた（３Ｓ，４Ｒ，１’
Ｒ*，６’Ｓ*）−３，４−ジヒドロ−２，２−ジメチル
−３−ヒドロキシ−４−（２−オキソ−３，４−ジアザ
ビシクロ［４．１．０］ヘプト−４−エン−５−イルオ
キシ）−２Ｈ−１−ベンゾピラン−６−カルボニトリル
を得ることができる。Hereinafter, in the same manner as in Example 1, Examples 5 to 9
The diastereomeric ester of was synthesized. In each case, the low polar diastereomeric ester was hydrolyzed to give the product of Example 2 (3S, 4R, 1 ′).
R * , 6'S * )-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-4-ene- 5-yloxy) -2H-1-benzopyran-6-carbonitrile can be obtained.
【００４８】実施例５ ３，４−トランス−３−（（２Ｓ）−２−（ベンジルオ
キシカルボニルアミノ）−３−フェニルプロピオニルオ
キシ）−３，４−ジヒドロ−２，２−ジメチル−４−
（２−オキソ−３，４−ジアザビシクロ［４．１．０］
ヘプト−４−エン−５−イルオキシ）−２Ｈ−１−ベン
ゾピラン−６−カルボニトリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（１．０
ｇ、３．０６ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニ
ル−Ｌ−フェニルアラニン（１．３７ｇ、４．５９ｍｍ
ｏｌ）、４−ジメチルアミノピリジン（０．１ｇ、０．
８２ｍｍｏｌ）、及びＮ，Ｎ’−ジシクロヘキシルカル
ボジイミド（１．０３ｇ、５．０ｍｍｏｌ）を、塩化メ
チレン（３００ｍｌ）中に加え、室温で２時間撹拌し
た。減圧濃縮し、ヘキサンを加え、不溶物を濾去し、ク
ロロホルムで洗浄し、有機層をまとめて減圧濃縮し、残
渣をシリカゲルカラムクロマトグラフィ−（クロロホル
ム）でジアステレオマ−エステルを分離し、標題の化合
物の低極性ジアステレオマ−エステルを０．７５ｇ、高
極性ジアステレオマ−エステルを０．６５ｇ得た。 低極性ジアステレオマ−エステル ［α］D 25＝−１１３．４°（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):0.88(1H,m),1.08(1H,m),1.25
(3H,s),1.35(3H,s),1.64(1H,m),2.04(1H,m),2.11(1H,
m),3.00(1H,dd,J=7.8 and 14.2Hz),3.16(1H,dd,J=5.9 a
nd 14.2Hz),4.64(1H,m),5.04(1H,d,J=12.2Hz),5.08(1H,
d,J=12.2Hz),5.09(1H,d,J=7.8Hz),5.34(1H,d,J=5.9Hz),
5.80(1H,d,J=5.9Hz),6.91(1H,d,J=8.3Hz),7.15-7.37(10
H,m),7.51(1H,d,J=8,3Hz),7.59(1H,s),7.77(1H,s) 高極性ジアステレオマ−エステル ［α］D 25＝＋８８．５゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.08(1H,m),1.30(3H,s),1.38
(3H,s),1.67(1H,m),2.01(1H,m),2.14(1H,m),3.06(2H,
m),4.64(1H,m),5.02(1H,d,J=12.2Hz),5.06(1H,d,J=12.2
Hz),5.19(1H,d,J=7.8Hz),5.35(1H,d,J=4.9Hz),5.62(1H,
d,J=4.9Hz),6.93(1H,d,J=8.3Hz),7.09-7.36(10H,m),7.5
2(1H,dd,J=2.0 and 8.3Hz),7.57(1H,s),7.78(1H,s)Example 5 3,4-trans-3-((2S) -2- (benzyloxycarbonylamino) -3-phenylpropionyloxy) -3,4-dihydro-2,2-dimethyl-4-
(2-oxo-3,4-diazabicyclo [4.1.0]
(Hept-4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-obtained in Reference Example 1 4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (1.0
g, 3.06 mmol), N-benzyloxycarbonyl-L-phenylalanine (1.37 g, 4.59 mm)
ol), 4-dimethylaminopyridine (0.1 g, 0.
82 mmol) and N, N'-dicyclohexylcarbodiimide (1.03 g, 5.0 mmol) were added to methylene chloride (300 ml), and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, hexane was added, insoluble matter was filtered off, washed with chloroform, the organic layers were combined and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform) to separate diastereomeric esters, and the title compound 0.75 g of low polarity diastereomer ester and 0.65 g of high polarity diastereomer ester were obtained. Low polarity diastereomer ester [α] D 25 = -113.4 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 0.88 (1H, m), 1.08 (1H, m) , 1.25
(3H, s), 1.35 (3H, s), 1.64 (1H, m), 2.04 (1H, m), 2.11 (1H,
m), 3.00 (1H, dd, J = 7.8 and 14.2Hz), 3.16 (1H, dd, J = 5.9 a
nd 14.2Hz), 4.64 (1H, m), 5.04 (1H, d, J = 12.2Hz), 5.08 (1H,
d, J = 12.2Hz), 5.09 (1H, d, J = 7.8Hz), 5.34 (1H, d, J = 5.9Hz),
5.80 (1H, d, J = 5.9Hz), 6.91 (1H, d, J = 8.3Hz), 7.15-7.37 (10
H, m), 7.51 (1H, d, J = 8,3Hz), 7.59 (1H, s), 7.77 (1H, s) High polarity diastereomer ester [α] D 25 = + 88.5 ° (c = 1 , Methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.08 (1H, m), 1.30 (3H, s), 1.38
(3H, s), 1.67 (1H, m), 2.01 (1H, m), 2.14 (1H, m), 3.06 (2H,
m), 4.64 (1H, m), 5.02 (1H, d, J = 12.2Hz), 5.06 (1H, d, J = 12.2
Hz), 5.19 (1H, d, J = 7.8Hz), 5.35 (1H, d, J = 4.9Hz), 5.62 (1H,
d, J = 4.9Hz), 6.93 (1H, d, J = 8.3Hz), 7.09-7.36 (10H, m), 7.5
2 (1H, dd, J = 2.0 and 8.3Hz), 7.57 (1H, s), 7.78 (1H, s)
【００４９】実施例６ ３，４−トランス−３−（（２Ｓ）−２−（ベンジルオ
キシカルボニルアミノ）−３−メチルブチリルオキシ）
−３，４−ジヒドロ−２，２−ジメチル−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（０．５
ｇ、１．５３ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニ
ル−Ｌ−バリン（０．５８ｇ、２．３０ｍｍｏｌ）、４
−ジメチルアミノピリジン（５０ｍｇ、０．４１ｍｍｏ
ｌ）、及びＮ，Ｎ’−ジシクロヘキシルカルボジイミド
（０．４９ｇ、２．４ｍｍｏｌ）を、塩化メチレン（１
５０ｍｌ）中に加え、室温で一日間撹拌した。減圧濃縮
し、ヘキサンを加え、不溶物を濾去し、クロロホルムで
洗浄し、有機層をまとめて減圧濃縮し、残渣をシリカゲ
ルカラムクロマトグラフィ−（クロロホルム−メタノー
ル）でジアステレオマ−エステルを分離し、標題の化合
物の低極性ジアステレオマ−エステルを０．２０ｇ、高
極性ジアステレオマ−エステルを０．２１ｇ得た。 低極性ジアステレオマ−エステル ［α］D 25＝−９５．６゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):0.90(3H,d,J=6.8Hz),1.02(3H,
d,J=6.4Hz),1.08(1H,m),1.33(3H,s),1.43(3H,s),1.67(1
H,m),2.05(1H,m),2.12(1H,m),2.23(1H,m),4.32(1H,m),
5.05-5.20(3H,m),5.36(1H,d,J=6.4Hz),5.82(1H,d,J=6.4
Hz),6.93(1H,d,J=8.8Hz),7.36(5H,m),7.52(1H,dd,J=2.0
and 8.8Hz),7.60(1H,s),7.69(1H,s) 高極性ジアステレオマ−エステル ［α］D 25＝＋４０．１゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):0.88(3H,d,J=6.8Hz),0.98(3H,
d,J=6.8Hz),1.13(1H,m),1.36(3H,s),1.45(3H,s),1.73(1
H,m),2.0-2.25(3H,m),4.30(1H,m),5.07(1H,d,J=12.2H
z),5.12(1H,d,J=12.2Hz),5.20(1Hd,J=8.8Hz),5.40(1H,
d,J=6.8Hz),5.85(1H,d,J=6.8Hz),6.94(1H,d,J=8.3Hz),
7.36(5H,br s),7.52(1H,dd,J=2.0 and 8.3Hz),7.57(1H,
s),7.63(1H,s)Example 6 3,4-trans-3-((2S) -2- (benzyloxycarbonylamino) -3-methylbutyryloxy)
-3,4-Dihydro-2,2-dimethyl-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-obtained in Reference Example 1 (2-oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (0.5
g, 1.53 mmol), N-benzyloxycarbonyl-L-valine (0.58 g, 2.30 mmol), 4
-Dimethylaminopyridine (50 mg, 0.41 mmo
l), and N, N′-dicyclohexylcarbodiimide (0.49 g, 2.4 mmol) were added to methylene chloride (1
50 ml) and stirred at room temperature for 1 day. After concentration under reduced pressure, hexane was added, insoluble matter was filtered off, washed with chloroform, the organic layers were combined and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol) to separate diastereomeric esters, and the title compound was isolated. 0.20 g of a low polarity diastereomer ester and 0.21 g of a high polarity diastereomer ester of the compound were obtained. Low polarity diastereomer ester [α] D 25 = -95.6 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 0.90 (3H, d, J = 6.8Hz), 1.02 (3H,
d, J = 6.4Hz), 1.08 (1H, m), 1.33 (3H, s), 1.43 (3H, s), 1.67 (1
H, m), 2.05 (1H, m), 2.12 (1H, m), 2.23 (1H, m), 4.32 (1H, m),
5.05-5.20 (3H, m), 5.36 (1H, d, J = 6.4Hz), 5.82 (1H, d, J = 6.4
Hz), 6.93 (1H, d, J = 8.8Hz), 7.36 (5H, m), 7.52 (1H, dd, J = 2.0
and 8.8Hz), 7.60 (1H, s), 7.69 (1H, s) Highly polar diastereomeric ester [α] D 25 = + 40.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 0.88 (3H, d, J = 6.8Hz), 0.98 (3H,
d, J = 6.8Hz), 1.13 (1H, m), 1.36 (3H, s), 1.45 (3H, s), 1.73 (1
H, m), 2.0-2.25 (3H, m), 4.30 (1H, m), 5.07 (1H, d, J = 12.2H
z), 5.12 (1H, d, J = 12.2Hz), 5.20 (1Hd, J = 8.8Hz), 5.40 (1H,
d, J = 6.8Hz), 5.85 (1H, d, J = 6.8Hz), 6.94 (1H, d, J = 8.3Hz),
7.36 (5H, br s), 7.52 (1H, dd, J = 2.0 and 8.3Hz), 7.57 (1H,
s), 7.63 (1H, s)
【００５０】実施例７ ３，４−トランス−３−（Ｎ−ベンジルオキシカルボニ
ル−Ｌ−プロリルオキシ）−３，４−ジヒドロ−２，２
−ジメチル−４−（２−オキソ−３，４−ジアザビシク
ロ［４．１．０］ヘプト−４−エン−５−イルオキシ）
−２Ｈ−１−ベンゾピラン−６−カルボニトリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（０．５
ｇ、１．５３ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニ
ル−Ｌ−プロリン（０．５７ｇ、２．３０ｍｍｏｌ）、
４−ジメチルアミノピリジン（５０ｍｇ、０．４１ｍｍ
ｏｌ）、及びＮ，Ｎ’−ジシクロヘキシルカルボジイミ
ド（０．８２ｇ、４．０ｍｍｏｌ）を、塩化メチレン
（１５０ｍｌ）中に加え、室温で一日間撹拌した。減圧
濃縮し、ヘキサンを加え、不溶物を濾去し、クロロホル
ムで洗浄し、有機層をまとめて減圧濃縮し、残渣をシリ
カゲルカラムクロマトグラフィ−（クロロホルム−メタ
ノール）でジアステレオマ−エステルを分離し、標題の
化合物の低極性ジアステレオマ−エステルを０．３４
ｇ、高極性ジアステレオマ−エステルを０．３３ｇ得
た。 低極性ジアステレオマ−エステル ［α］D 25＝−１０７．９゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):二種の回転異性体の混合物
（約３：１）として観測された。 1.07(1H,m),1.28(s,minor Me),1.29(s,major Me),1.34
(s,minor Me),1.40(s,major Me),1.71(1H,m),1.95(3H,
m),2.05-2.17(2H,m),2.27(1H,m),3.47-3.60(2H,m),4.41
(1H,m),5.06(d,J=12.7Hz,minor benzyl),5.14(s,major
benzyl),5.18(d,J=12.7Hz,minor benzyl),5.31(d,J=5.9
Hz,minor H-3),5.36(d,J=6.4Hz,major H-3),5.68(d,J=
5.9Hz,minor H-4),5.87(d,J=6.4Hz,major H-4),6.92(1
H,d,J=8.8Hz),7.20-7.38(5H,m),7.47(s,minor H-5),7.5
2(1H,dd,J=2.0 and 8.8Hz),7.59(s,major H-5),8.07(s,
1H) 高極性ジアステレオマ−エステル ［α］D 25＝＋１６．４゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):二種の回転異性体の混合物
（約２：１）として観測された。 1.12(1H,m),1.18(s,minor Me),1.22(s,minor Me),1.34
(s,major Me),1.49(s,major Me),1.72(1H,m),1.85-2.28
(6H,m),3.40-3.67(2H,m),4.41(1H,m),4.95-5.15(2H,m),
5.27(d,J=5.9Hz,minor H-3),5.39(d,J=7.3Hz,major H-
3),5.77(d,J=5.9Hz,minor H-4),5.85(d,J=7.3Hz,major
H-4),6.91(d,J=8.3Hz,minor H-5),6.93(d,J=8.3Hz,majo
r H-5),7.20-7.35(5H,m),7.43-7.75(3H,m)Example 7 3,4-trans-3- (N-benzyloxycarbonyl-L-prolyloxy) -3,4-dihydro-2,2
-Dimethyl-4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-4-en-5-yloxy)
-2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3,4) obtained in Reference Example 1 -Diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (0.5
g, 1.53 mmol), N-benzyloxycarbonyl-L-proline (0.57 g, 2.30 mmol),
4-Dimethylaminopyridine (50 mg, 0.41 mm
ol) and N, N′-dicyclohexylcarbodiimide (0.82 g, 4.0 mmol) were added to methylene chloride (150 ml), and the mixture was stirred at room temperature for 1 day. After concentration under reduced pressure, hexane was added, insoluble matter was filtered off, washed with chloroform, the organic layers were combined and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol) to separate diastereomeric esters, and the title compound was obtained. The low polar diastereomeric ester of the compound was 0.34
g, 0.33 g of a highly polar diastereomer ester was obtained. Low-polarity diastereomer ester [α] D 25 = -107.9 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): mixture of two rotamers (about 3: 1) ) Was observed. 1.07 (1H, m), 1.28 (s, minor Me), 1.29 (s, major Me), 1.34
(s, minor Me), 1.40 (s, major Me), 1.71 (1H, m), 1.95 (3H,
m), 2.05-2.17 (2H, m), 2.27 (1H, m), 3.47-3.60 (2H, m), 4.41
(1H, m), 5.06 (d, J = 12.7Hz, minor benzyl), 5.14 (s, major
benzyl), 5.18 (d, J = 12.7Hz, minor benzyl), 5.31 (d, J = 5.9
Hz, minor H-3), 5.36 (d, J = 6.4Hz, major H-3), 5.68 (d, J =
5.9Hz, minor H-4), 5.87 (d, J = 6.4Hz, major H-4), 6.92 (1
H, d, J = 8.8Hz), 7.20-7.38 (5H, m), 7.47 (s, minor H-5), 7.5
2 (1H, dd, J = 2.0 and 8.8Hz), 7.59 (s, major H-5), 8.07 (s,
1H) Highly polar diastereomeric ester [α] D 25 = + 16.4 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): mixture of two rotamers (about 2: It was observed as 1). 1.12 (1H, m), 1.18 (s, minor Me), 1.22 (s, minor Me), 1.34
(s, major Me), 1.49 (s, major Me), 1.72 (1H, m), 1.85-2.28
(6H, m), 3.40-3.67 (2H, m), 4.41 (1H, m), 4.95-5.15 (2H, m),
5.27 (d, J = 5.9Hz, minor H-3), 5.39 (d, J = 7.3Hz, major H-
3), 5.77 (d, J = 5.9Hz, minor H-4), 5.85 (d, J = 7.3Hz, major
H-4), 6.91 (d, J = 8.3Hz, minor H-5), 6.93 (d, J = 8.3Hz, majo
r H-5), 7.20-7.35 (5H, m), 7.43-7.75 (3H, m)
【００５１】実施例８ ３，４−トランス−３−（（２Ｓ）−２−ｔ−ブトキシ
カルボニルアミノプロピオニルオキシ）−３，４−ジヒ
ドロ−２，２−ジメチル−４−（２−オキソ−３，４−
ジアザビシクロ［４．１．０］ヘプト−４−エン−５−
イルオキシ）−２Ｈ−１−ベンゾピラン−６−カルボニ
トリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（０．５
ｇ、１．５３ｍｍｏｌ）、Ｎ−ｔ−ブトキシカルボニル
−Ｌ−アラニン（０．５１ｇ、２．７ｍｍｏｌ）、４−
ジメチルアミノピリジン（５０ｍｇ、０．４１ｍｍｏ
ｌ）、及びＮ，Ｎ’−ジシクロヘキシルカルボジイミド
（０．８２ｇ、４．０ｍｍｏｌ）を、塩化メチレン（１
００ｍｌ）中に加え、室温で５時間撹拌した。減圧濃縮
し、酢酸エチルを加え、不溶物を濾去し、クロロホルム
で洗浄し、有機層をまとめて減圧濃縮し、残渣をシリカ
ゲルカラムクロマトグラフィ−（クロロホルム−メタノ
ール）でジアステレオマ−エステルを分離し、標題の化
合物の低極性ジアステレオマ−エステルを０．３６ｇ、
高極性ジアステレオマ−エステルを０．２７ｇ得た。 低極性ジアステレオマ−エステル ［α］D 25＝−９８．３゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.11(1H,m),1.35(3H,s),1.41
(3H,d,J=7.3Hz),1.43(3H,s),1.44(9H,s),1.72(1H,m),2.
18(1H,m),4.28(1H,m),4.93(1H,d,J=7.8Hz),5.38(1H,d,J
=5.9Hz),5.81(1H,d,J=5.9Hz),6.94(1H,d,J=8.8Hz),7.52
(1H,dd,J=2.0 and 8.8Hz),7.63(1H,d,J=2.0Hz),7.92(1
H,br s) 高極性ジアステレオマ−エステル ［α］D 25＝＋３１．８゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.13(1H,m),1.35(3H,d,J=7.3H
z),1.37(3H,s),1.42(9H,s),1.46(3H,s),1.73(1H,m),2.0
8(1H,m),2.19(1H,m),4.30(1H,m),4.94(1H,d,J=6.4Hz),
5.37(1H,d,J=6.8Hz),5.85(1H,d,J=6.8Hz),6.94(1H,d,J=
8.8Hz),7.52(1H,dd,J=2.0 and 8.8Hz),7.59(1H,d,J=2.0
Hz),7.66(1H,br s)Example 8 3,4-trans-3-((2S) -2-t-butoxycarbonylaminopropionyloxy) -3,4-dihydro-2,2-dimethyl-4- (2-oxo-3) , 4-
Diazabicyclo [4.1.0] hept-4-en-5-
Iloxy) -2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (2-oxo-3) obtained in Reference Example 1 , 4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (0.5
g, 1.53 mmol), Nt-butoxycarbonyl-L-alanine (0.51 g, 2.7 mmol), 4-
Dimethylaminopyridine (50 mg, 0.41 mmo
l), and N, N′-dicyclohexylcarbodiimide (0.82 g, 4.0 mmol) were added to methylene chloride (1
(00 ml) and stirred at room temperature for 5 hours. After concentration under reduced pressure, ethyl acetate was added, insoluble materials were filtered off, washed with chloroform, the organic layers were combined and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol) to separate diastereomeric esters, 0.36 g of the low polarity diastereomeric ester of the compound of
0.27 g of highly polar diastereomeric ester was obtained. Low-polarity diastereomer ester [α] D 25 = -98.3 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.11 (1H, m), 1.35 (3H, s) , 1.41
(3H, d, J = 7.3Hz), 1.43 (3H, s), 1.44 (9H, s), 1.72 (1H, m), 2.
18 (1H, m), 4.28 (1H, m), 4.93 (1H, d, J = 7.8Hz), 5.38 (1H, d, J
= 5.9Hz), 5.81 (1H, d, J = 5.9Hz), 6.94 (1H, d, J = 8.8Hz), 7.52
(1H, dd, J = 2.0 and 8.8Hz), 7.63 (1H, d, J = 2.0Hz), 7.92 (1
H, br s) Highly polar diastereomeric ester [α] D 25 = + 31.8 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.13 (1H, m), 1.35 ( 3H, d, J = 7.3H
z), 1.37 (3H, s), 1.42 (9H, s), 1.46 (3H, s), 1.73 (1H, m), 2.0
8 (1H, m), 2.19 (1H, m), 4.30 (1H, m), 4.94 (1H, d, J = 6.4Hz),
5.37 (1H, d, J = 6.8Hz), 5.85 (1H, d, J = 6.8Hz), 6.94 (1H, d, J =
8.8Hz), 7.52 (1H, dd, J = 2.0 and 8.8Hz), 7.59 (1H, d, J = 2.0
Hz), 7.66 (1H, br s)
【００５２】実施例９ ３，４−トランス−３，４−ジヒドロ−２，２−ジメチ
ル−３−（（２Ｓ）−２−（９−フルオレニルメチルオ
キシカルボニルアミノ）プロピオニルオキシ）−４−
（２−オキソ−３，４−ジアザビシクロ［４．１．０］
ヘプト−４−エン−５−イルオキシ）−２Ｈ−１−ベン
ゾピラン−６−カルボニトリル 参考例１で得られた３，４−トランス−３，４−ジヒド
ロ−２，２−ジメチル−３−ヒドロキシ−４−（２−オ
キソ−３，４−ジアザビシクロ［４．１．０］ヘプト−
４−エン−５−イルオキシ）−２Ｈ−１−ベンゾピラン
−６−カルボニトリル（ｉｓｏｍｅｒ Ｂ）（０．５
ｇ、１．５３ｍｍｏｌ）、Ｎ−（９−フルオレニルメチ
ルオキシカルボニル）−Ｌ−アラニン １水和物（０．
７６ｇ、２．３ｍｍｏｌ）、４−ジメチルアミノピリジ
ン（５０ｍｇ、０．４１ｍｍｏｌ）、及びＮ，Ｎ’−ジ
シクロヘキシルカルボジイミド（０．８２ｇ、４．０ｍ
ｍｏｌ）を、塩化メチレン（２００ｍｌ）中に加え、室
温で一日間撹拌した。減圧濃縮し、ヘキサンを加え、不
溶物を濾去し、クロロホルムで洗浄し、有機層をまとめ
て減圧濃縮し、残渣をシリカゲルカラムクロマトグラフ
ィ−（クロロホルム−メタノール）でジアステレオマ−
エステルを分離し、標題の化合物の低極性ジアステレオ
マ−エステルを０．４４ｇ、高極性ジアステレオマ−エ
ステルを０．３３ｇ得た。 低極性ジアステレオマ−エステル ［α］D 25＝−８０．１゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.07(1H,m),1.33(3H,s),1.42
(3H,s),1.46(3H,d,J=7.3Hz),1.67(1H,m),2.05-2.17(2H,
m),4.21(1H,t,J=6.8Hz),4.37(1H,m),4.40(1H,d,J=6.8H
z),5.24(1H,d,J=7.8Hz),5.37(1H,d,J=5.9Hz),5.82(1H,
d,J=5.9Hz),6.92(1H,d,J=8.3Hz),7.31(2H,t,J=7.8Hz),
7.40(2H,t,J=7.8Hz),7.51(1H,dd,J=2.0 and 8.3Hz),7.6
1(3H,m),7.77(2H,d,J=7.3Hz),7.88(1H,s) 高極性ジアステレオマ−エステル ［α］D 25＝＋２６．６゜（ｃ＝１，メタノ−ル） NMR(CDCl3,TMS) δ(ppm):1.11(1H,m),1.36(3H,s),1.40
(3H,d,J=7.3Hz),1.45(3H,s),1.72(1H,m),2.07(1H,m),2.
19(1H,m),4.19(1H,t,J=6.8Hz),4.30-4.40(1H,m),4.38(2
H,d,J=6.8Hz),5.27(1H,d,J=7.8Hz),5.38(1H,d,J=6.4H
z),5.84(1H,d,J=6.4Hz),6.92(1H,d,J=8.3Hz),7.31(2H,
m),7.41(2H,t,J=7.3Hz),7.50(1H,dd,J=2.0 and 8.3Hz),
7.57(3H,m),7.77(2H,d,J=7.3Hz),7.82(1H,s)Example 9 3,4-trans-3,4-dihydro-2,2-dimethyl-3-((2S) -2- (9-fluorenylmethyloxycarbonylamino) propionyloxy) -4-
(2-oxo-3,4-diazabicyclo [4.1.0]
(Hept-4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile 3,4-trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-obtained in Reference Example 1 4- (2-oxo-3,4-diazabicyclo [4.1.0] hept-
4-en-5-yloxy) -2H-1-benzopyran-6-carbonitrile (isomer B) (0.5
g, 1.53 mmol), N- (9-fluorenylmethyloxycarbonyl) -L-alanine monohydrate (0.
76 g, 2.3 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol), and N, N'-dicyclohexylcarbodiimide (0.82 g, 4.0 m).
mol) was added to methylene chloride (200 ml), and the mixture was stirred at room temperature for 1 day. After concentration under reduced pressure, hexane was added, insoluble materials were filtered off, washed with chloroform, the organic layers were combined and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol) for diastereomerization.
The ester was separated to obtain 0.44 g of a low polarity diastereomer ester and 0.33 g of a high polarity diastereomer ester of the title compound. Low polarity diastereomer ester [α] D 25 = -80.1 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.07 (1H, m), 1.33 (3H, s) , 1.42
(3H, s), 1.46 (3H, d, J = 7.3Hz), 1.67 (1H, m), 2.05-2.17 (2H,
m), 4.21 (1H, t, J = 6.8Hz), 4.37 (1H, m), 4.40 (1H, d, J = 6.8H
z), 5.24 (1H, d, J = 7.8Hz), 5.37 (1H, d, J = 5.9Hz), 5.82 (1H,
d, J = 5.9Hz), 6.92 (1H, d, J = 8.3Hz), 7.31 (2H, t, J = 7.8Hz),
7.40 (2H, t, J = 7.8Hz), 7.51 (1H, dd, J = 2.0 and 8.3Hz), 7.6
1 (3H, m), 7.77 (2H, d, J = 7.3Hz), 7.88 (1H, s) High polarity diastereomer ester [α] D 25 = + 26.6 ° (c = 1, methanol) NMR (CDCl 3 , TMS) δ (ppm): 1.11 (1H, m), 1.36 (3H, s), 1.40
(3H, d, J = 7.3Hz), 1.45 (3H, s), 1.72 (1H, m), 2.07 (1H, m), 2.
19 (1H, m), 4.19 (1H, t, J = 6.8Hz), 4.30-4.40 (1H, m), 4.38 (2
H, d, J = 6.8Hz), 5.27 (1H, d, J = 7.8Hz), 5.38 (1H, d, J = 6.4H
z), 5.84 (1H, d, J = 6.4Hz), 6.92 (1H, d, J = 8.3Hz), 7.31 (2H,
m), 7.41 (2H, t, J = 7.3Hz), 7.50 (1H, dd, J = 2.0 and 8.3Hz),
7.57 (3H, m), 7.77 (2H, d, J = 7.3Hz), 7.82 (1H, s)
【００５３】[0053]
【発明の効果】本発明方法によれば、優れたカリウムチ
ャネル開口作用を有し、高血圧症治療剤等の医薬として
有用なジアザビシクロヘプテン誘導体の光学活性体を工
業的に有利に製造することができる。Industrial Applicability According to the method of the present invention, an optically active diazabicycloheptene derivative having an excellent potassium channel opening action and useful as a drug such as a therapeutic agent for hypertension is industrially advantageously produced. be able to.
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 (Ｃ０７Ｄ 405/12 237:26 311:22） Ｃ０７Ｍ 7:00 Continuation of front page (51) Int.Cl. 6 Identification number Reference number within the agency FI technical display location (C07D 405/12 237: 26 311: 22) C07M 7:00
Claims (7)
キニル基、置換基を有してもよい低級アルキル基又は置
換基を有してもよいアラルキル基を示し、Ｒ2 は、水素
原子又は低級アルキル基を示す〕で表わされるジアザビ
シクロヘプテン誘導体のラセミ体を、光学活性なアミノ
酸類を用いるか、又は光学活性なカラムによる高速液体
クロマトグラフィーを用いて光学分割することを特徴と
する、一般式（１）で表わされるジアザビシクロヘプテ
ン誘導体の光学活性体の製造法。1. A compound represented by the general formula (1): [In the formula, R 1 represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a lower alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R 2 represents a hydrogen atom or A lower alkyl group] is used to optically resolve a racemic diazabicycloheptene derivative using optically active amino acids or high performance liquid chromatography using an optically active column. A method for producing an optically active form of a diazabicycloheptene derivative represented by the general formula (1).
キニル基、置換基を有してもよい低級アルキル基又は置
換基を有してもよいアラルキル基を示し、Ｒ2 は水素原
子又は低級アルキル基を示す〕で表わされるジアザビシ
クロヘプテン誘導体のラセミ体に、光学活性なアミノ酸
類を反応させ、生成するジアステレオマーエステル混合
物を各ジアステレオマーエステルに分離した後加水分解
することを特徴とする一般式（１）で表わされるジアザ
ビシクロヘプテン誘導体の光学活性体の製造法。2. A compound represented by the general formula (1): [In the formula, R 1 represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a lower alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R 2 represents a hydrogen atom or a lower group. Alkyl group]] is reacted with a racemic diazabicycloheptene derivative represented by an optically active amino acid, and the resulting diastereomeric ester mixture is separated into diastereomeric esters and then hydrolyzed. A method for producing an optically active form of a diazabicycloheptene derivative represented by the general formula (1).
アラニン、Ｎ−保護Ｌ−バリン、Ｎ−保護Ｌ−ロイシ
ン、Ｎ−保護Ｌ−イソロイシン、Ｎ−保護Ｌ−フェニル
アラニン、Ｎ−保護Ｌ−メチオニン、Ｎ−保護Ｌ−チロ
シン、Ｎ−保護Ｌ−プロリン及びＮ−保護Ｌ−トリプト
ファンから選ばれるものである請求項２記載の製造法。3. The optically active amino acid is N-protected L-.
Alanine, N-protected L-valine, N-protected L-leucine, N-protected L-isoleucine, N-protected L-phenylalanine, N-protected L-methionine, N-protected L-tyrosine, N-protected L-proline The method according to claim 2, which is selected from N-protected L-tryptophan.
オキシカルボニル−Ｌ−アラニン、Ｎ−ベンジルオキシ
カルボニル−Ｌ−フェニルアラニン、Ｎ−ベンジルオキ
シカルボニル−Ｌ−バリン、Ｎ−ベンジルオキシカルボ
ニル−Ｌ−プロリン、Ｎ−ｔ−ブトキシカルボニル−Ｌ
−アラニン及びＮ−（９−フルオレニルメチルオキシカ
ルボニル）−Ｌ−アラニンから選ばれるものである請求
項２記載の製造法。4. The optically active amino acids are N-benzyloxycarbonyl-L-alanine, N-benzyloxycarbonyl-L-phenylalanine, N-benzyloxycarbonyl-L-valine, N-benzyloxycarbonyl-L-. Proline, Nt-butoxycarbonyl-L
The method according to claim 2, which is selected from -alanine and N- (9-fluorenylmethyloxycarbonyl) -L-alanine.
キニル基、置換基を有してもよい低級アルキル基又は置
換基を有してもよいアラルキル基を示し、Ｒ2 は、水素
原子又は低級アルキル基を示す〕で表わされるジアザビ
シクロヘプテン誘導体のラセミ体を、光学活性カラムを
用いた高速液体クロマトグラフィーにより光学分割する
ことを特徴とする一般式（１）で表わされるジアザビシ
クロヘプテン誘導体の光学活性体の製造法。5. A compound represented by the general formula (1): [In the formula, R 1 represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group, a lower alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R 2 represents a hydrogen atom or A diazabicycloheptene derivative represented by a lower alkyl group] is optically resolved by high performance liquid chromatography using an optically active column. A method for producing an optically active substance of a heptene derivative.
り、Ｒ2 が水素原子又は低級アルキル基である請求項
１、２、３、４又は５記載の製造法。6. The method according to claim 1 , wherein R 1 is a hydrogen atom or a lower alkyl group, and R 2 is a hydrogen atom or a lower alkyl group.
2 が水素原子又はメチル基である請求項１、２、３、４
又は５記載の製造法。7. R 1 is a hydrogen atom or a methyl group, and R 1
2 is a hydrogen atom or a methyl group.
Or the production method described in 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27487394A JP3706160B2 (en) | 1993-11-12 | 1994-11-09 | Process for producing optically active diazabicycloheptene derivatives |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28326893 | 1993-11-12 | ||
| JP5-332339 | 1993-12-27 | ||
| JP33233993 | 1993-12-27 | ||
| JP5-283268 | 1993-12-27 | ||
| JP27487394A JP3706160B2 (en) | 1993-11-12 | 1994-11-09 | Process for producing optically active diazabicycloheptene derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07233166A true JPH07233166A (en) | 1995-09-05 |
| JP3706160B2 JP3706160B2 (en) | 2005-10-12 |
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ID=27336214
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27487394A Expired - Fee Related JP3706160B2 (en) | 1993-11-12 | 1994-11-09 | Process for producing optically active diazabicycloheptene derivatives |
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| Country | Link |
|---|---|
| JP (1) | JP3706160B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6120361A (en) * | 1997-02-03 | 2000-09-19 | Tokyo Electron Limited | Polishing apparatus, polishing member |
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1994
- 1994-11-09 JP JP27487394A patent/JP3706160B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6120361A (en) * | 1997-02-03 | 2000-09-19 | Tokyo Electron Limited | Polishing apparatus, polishing member |
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| Publication number | Publication date |
|---|---|
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