JPH04261172A - Production of optically active benzopyran compound - Google Patents
Production of optically active benzopyran compoundInfo
- Publication number
- JPH04261172A JPH04261172A JP3042591A JP4259191A JPH04261172A JP H04261172 A JPH04261172 A JP H04261172A JP 3042591 A JP3042591 A JP 3042591A JP 4259191 A JP4259191 A JP 4259191A JP H04261172 A JPH04261172 A JP H04261172A
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- optically active
- benzopyran
- dimethyl
- hydroxy
- 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.)
- Pending
Links
- -1 benzopyran compound Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims abstract description 8
- BGRDGMRNKXEXQD-UHFFFAOYSA-N Maleic hydrazide Chemical compound OC1=CC=C(O)N=N1 BGRDGMRNKXEXQD-UHFFFAOYSA-N 0.000 claims abstract description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract 2
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000002040 relaxant effect Effects 0.000 abstract description 5
- 210000002460 smooth muscle Anatomy 0.000 abstract description 5
- HCYIWPLDKSWKGY-UHFFFAOYSA-N 2,2-dimethyl-1a,7b-dihydrooxireno[2,3-c]chromene-6-carbonitrile Chemical compound CC1(C)OC2=CC=C(C#N)C=C2C2C1O2 HCYIWPLDKSWKGY-UHFFFAOYSA-N 0.000 abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract 3
- MKSZWGXGVWPUAP-UHFFFAOYSA-N 1a,7a-dimethyl-7h-oxireno[2,3-b]chromene-7-carbonitrile Chemical compound N#CC1C2=CC=CC=C2OC2(C)C1(C)O2 MKSZWGXGVWPUAP-UHFFFAOYSA-N 0.000 abstract 1
- QUBVZXJLQLOSDC-UHFFFAOYSA-N 5-hydroxy-1,2-dihydropyridazine-3,4-dione Chemical compound OC1=CNNC(=O)C1=O QUBVZXJLQLOSDC-UHFFFAOYSA-N 0.000 abstract 1
- 230000002541 vasodepressive effect Effects 0.000 abstract 1
- 239000003071 vasodilator agent Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 150000001562 benzopyrans Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- APHWBGUCQBONMO-MNOVXSKESA-N (3s,4r)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile Chemical compound C1=C(C#N)C=C2[C@@H](N)[C@H](O)C(C)(C)OC2=C1 APHWBGUCQBONMO-MNOVXSKESA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- LGSZGTPDCMPPSO-UHFFFAOYSA-N CC1(C)Oc2ccccc2C2=C1O2 Chemical compound CC1(C)Oc2ccccc2C2=C1O2 LGSZGTPDCMPPSO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- GFBVBBRNPGPROZ-UHFFFAOYSA-N azanium;(2-bromo-4,7-dimethyl-3-oxo-7-bicyclo[2.2.1]heptanyl)methanesulfonate Chemical compound [NH4+].C1CC2(C)C(=O)C(Br)C1C2(CS([O-])(=O)=O)C GFBVBBRNPGPROZ-UHFFFAOYSA-N 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は強力な血圧降下作用、平
滑筋弛緩作用を有する光学活性なベンゾピラン化合物の
工業的に有利な製造法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an industrially advantageous method for producing optically active benzopyran compounds having strong antihypertensive and smooth muscle relaxing effects.
【０００２】0002
【従来の技術】近年、医薬としてキラルな炭素を有する
化合物が開発される際、薬理学的活性の増強、副作用の
除去、毒性の低減、吸収・代謝・分布・排泄の単純化、
溶解性の改良などの観点から、薬理作用の主体をなす光
学活性体（ｅｕｔｏｍｅｒ）の開発が重要になってきて
いる。強力な血圧降下作用、平滑筋弛緩作用を有するベ
ンゾピラン系の化合物についても種々の光学活性体が研
究されており、特に６−シアノ−３，４−ジヒドロ−２
，２−ジメチル−トランス−４−（２−オキソ−１−ピ
ロリジニル）−２Ｈ−１−ベンゾピラン−３−オール（
クロマカリム）はその副作用の問題から（−）−異性体
であるレマカリムとして開発されている。このレマカリ
ムの製造法としては、特開平２−２４００７９号公報に
（±）−トランス−４−アミノ−６−シアノ−３，４−
ジヒドロ−２，２−ジメチル−２Ｈ−１−ベンゾピラン
−３−オールを（＋）−３−ブロモ−９−カンフアース
ルホン酸アンモニウムを用いて光学分割し、所望の（＋
）−体に４−クロロ酪酸クロリドを反応させ、さらに閉
環反応に付すという極めて複雑な工程をとることが開示
されている。一方、特開昭５９−１７６２８２号および
特開平１−１５１５７１号公報には最終物をキラルなイ
ソシアネートと反応させてカルバミン酸誘導体に導いた
後、分別結晶により分割する方法が開示されている。ま
た、特開昭６３−３０３９７７号および特開平２−４２
０７４号公報には、光学活性なエポキシド体を用いて、
一工程で目的物が得られることが記載されている。[Prior Art] In recent years, when compounds with chiral carbon have been developed as pharmaceuticals, they have been developed to enhance pharmacological activity, eliminate side effects, reduce toxicity, simplify absorption, metabolism, distribution, and excretion.
From the viewpoint of improving solubility, the development of optically active substances (eutomers) that play a major role in pharmacological action has become important. Various optically active forms of benzopyran compounds, which have strong antihypertensive and smooth muscle relaxing effects, have been studied, and in particular, 6-cyano-3,4-dihydro-2
, 2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-3-ol (
Due to its side effects, the (-)-isomer, Remakarim, has been developed. The method for producing this remakarim is described in JP-A No. 2-240079 (±)-trans-4-amino-6-cyano-3,4-
Dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol was optically resolved using ammonium (+)-3-bromo-9-camphorsulfonate to obtain the desired (+
)-isomer with 4-chlorobutyric acid chloride and then subjecting it to a ring-closing reaction, which is an extremely complicated process. On the other hand, JP-A-59-176282 and JP-A-1-151571 disclose a method in which the final product is reacted with a chiral isocyanate to obtain a carbamic acid derivative, and then separated by fractional crystallization. Also, JP-A No. 63-303977 and JP-A No. 2-42
No. 074 discloses that using an optically active epoxide,
It is stated that the desired product can be obtained in one step.
【０００３】0003
【発明が解決しようとする課題】本発明は、強力な血圧
降下作用、平滑筋弛緩作用を有するベンゾピラン系化合
物の光学活体を経済的に効率よく、安価に製造する方法
を提供することを目的とする。[Problems to be Solved by the Invention] An object of the present invention is to provide an economically efficient and inexpensive method for producing optically active benzopyran compounds that have strong antihypertensive and smooth muscle relaxing effects. do.
【０００４】0004
【課題を解決するための手段】本発明者は鋭意研究をか
さねた結果、光学活性な６−シアノ−３，４−ジヒドロ
−２，２−ジメチル−３，４−エポキシ−２Ｈ−１−ベ
ンゾピランを用いて、一工程でレマカリムを始めとする
種々の有用化合物を製造する方法を見出して本発明を完
成するに至った。[Means for Solving the Problems] As a result of intensive research, the present inventors have discovered an optically active 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyrane. The present invention was completed by discovering a method for producing various useful compounds including remakarim in one step using the method.
【０００５】すなわち、本発明は光学活性な６−シアノ
−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（以下、化合物Ｉという
こともある。）と、２−オキソピロリジン、１，６−ジ
ヒドロ−３−ヒドロキシ−６−オキソピリダジン、１，
２−ジヒドロ−２−オキソピリジン（以下、あわせて化
合物ＩＩということもある。）とを反応させることを特
徴とする一般式That is, the present invention provides optically active 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (hereinafter also referred to as compound I). , 2-oxopyrrolidine, 1,6-dihydro-3-hydroxy-6-oxopyridazine, 1,
A general formula characterized by reacting with 2-dihydro-2-oxopyridine (hereinafter also referred to as compound II)
【化２】
〔式中、Ｒ１ 、Ｒ２ は一緒になって２−オキソピロ
リジニル、１，６−ジヒドロ−３−ヒドロキシ−６−オ
キソピリダジニル、１，２−ジヒドロ−２−オキソピリ
ジルを示す。〕により表される光学活性なベンゾピラン
化合物の製造法に関する。[Formula, R1 and R2 together represent 2-oxopyrrolidinyl, 1,6-dihydro-3-hydroxy-6-oxopyridazinyl, 1,2-dihydro-2-oxo Indicates pyridyl. ] This invention relates to a method for producing an optically active benzopyran compound represented by:
【０００６】本発明の方法を詳細に説明すると、化合物
Ｉと化合物ＩＩの一種を望ましくは塩基の存在下、例え
ば、水素化ナトリウム／ジメチルスルホキシド、ブチル
リチウム／ヘキサメチルホスホルアミド、カリウムｔ−
ブトキシド／ジメチルホルムアミド、ピリジンまたはト
リエチルアミン／エタノールまたはベンジルトリメチル
アンモニウムヒドロキシド／メタノールの組み合わせを
用いて、室温から加熱還流下に行われる。得られた〔化
２〕の化合物は、通常の方法により分離して単一の光学
活性体とするが、これは分別結晶によるのが実用的であ
り、酢酸エステル類（メチルエステル、エチルエステル
、ブチルエステルなど）低級アルコール類、（メタノー
ル、エタノール、プロパノールなど）、炭化水素類（石
油エーテル、ヘキサン、ベンゼン、トルエンなど）、ハ
ロアルカン類（メチレンクロライド、クロロホルム、ジ
クロロエタンなど）、エーテル類（ジエチルエーテル、
ジオキサン、テトラヒドロフランなど）、ケトン類（ア
セトン、メチルエチルケトンなど）、アミド類（ジメチ
ルホルムアミド、ジメチルアセトアミドなど）および水
ないしはこれら相互の混合溶媒を使用することができる
。本発明の合成原料である光学活性な６−シアノ−３，
４−ジヒドロ−２，２−ジメチル−３，４−エポキシ−
２Ｈ−１−ベンゾピランは、ヨーロッパ特許公開公報第
３８６６４０号に記載された大量分割可能な製造法によ
り製造されたものを使用することができる。To explain the method of the present invention in detail, one of Compound I and Compound II is preferably prepared in the presence of a base, for example, sodium hydride/dimethyl sulfoxide, butyllithium/hexamethylphosphoramide, potassium t-
It is carried out using a combination of butoxide/dimethylformamide, pyridine or triethylamine/ethanol or benzyltrimethylammonium hydroxide/methanol under heating to reflux from room temperature. The obtained compound [Chemical formula 2] is separated into a single optically active substance by a conventional method, but it is practical to use fractional crystallization to obtain a single optically active substance. (butyl ester, etc.), lower alcohols (methanol, ethanol, propanol, etc.), hydrocarbons (petroleum ether, hexane, benzene, toluene, etc.), haloalkanes (methylene chloride, chloroform, dichloroethane, etc.), ethers (diethyl ether,
Dioxane, tetrahydrofuran, etc.), ketones (acetone, methyl ethyl ketone, etc.), amides (dimethylformamide, dimethylacetamide, etc.), water, or a mixed solvent of these can be used. Optically active 6-cyano-3, which is a synthetic raw material of the present invention,
4-dihydro-2,2-dimethyl-3,4-epoxy-
As the 2H-1-benzopyran, one produced by a production method described in European Patent Publication No. 386640 that can be divided into large quantities can be used.
【０００７】[0007]
【実施例】以下、実施例により本発明を具体的に説明す
るが、本発明はこれらにより何ら限定されるもではない
。[Examples] The present invention will be specifically explained below with reference to Examples, but the present invention is not limited by these in any way.
【０００８】実施例１：（−）−トランス−（３Ｓ，４
Ｒ）−６−シアノ−３，４−ジヒドロ−２，２−ジメチ
ル−４−（２−オキソ−１−ピロリジニル）−２Ｈ−１
−ベンゾピラン−３−オール（レマカリム）ジメチルス
ルホキシド３０ｍｌを５〜１０℃の水浴上で軽く攪拌し
ながら６０％水素化ナトリウム４．０２ｇ（パラフィン
中）を加える。さらに、同温度で攪拌しながら２−オキ
ソピロリジン１０ｍｌを数回に分けて加え、５分後、室
温で３０分間攪拌を続ける。反応液に（−）−６−シア
ノ−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１４．０ｇを一度に加
え、水浴上２５〜３０℃で３時間攪拌する。浴温を４０
〜４５℃に上昇させ２時間攪拌する。室温でエタノール
６ｍｌを加えて攪拌し、次いで、氷水を加えて強く攪拌
するとスラリーを得る。不溶物を濾取しエタノールから
再結晶する。結晶を乾燥後、酢酸エチルから再結晶する
と標記化合物１１．７ｇを得る。
融点２３６．５〜２３７．５℃、旋光度：〔α〕Ｄ ２
５＝−５８．３°（クロロホルム、ｃ＝１）Example 1: (-)-trans-(3S,4
R)-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1
-Benzopyran-3-ol (remakarim) 4.02 g of 60% sodium hydride (in paraffin) are added to 30 ml of dimethyl sulfoxide with light stirring on a water bath at 5-10°C. Furthermore, 10 ml of 2-oxopyrrolidine was added in several portions while stirring at the same temperature, and after 5 minutes, stirring was continued at room temperature for 30 minutes. 14.0 g of (-)-6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran was added at once to the reaction solution, and the mixture was heated on a water bath at 25 to 30°C for 3 hours. Stir for an hour. Bath temperature 40
Raise to ~45°C and stir for 2 hours. Add 6 ml of ethanol and stir at room temperature, then add ice water and stir vigorously to obtain a slurry. Insoluble matter is filtered off and recrystallized from ethanol. After drying the crystals, they are recrystallized from ethyl acetate to obtain 11.7 g of the title compound. Melting point: 236.5-237.5°C, optical rotation: [α]D2
5=-58.3° (chloroform, c=1)
【０００９
】0009
]
【発明の効果】本発明の方法は、強力な血圧降下作用、
平滑筋弛緩作用を有する光学活性なベンゾピラン化合物
を光学活性な６−シアノ−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
から一工程で製造することができ、工業的で安価な、経
済性に優れた製造法である。[Effect of the invention] The method of the present invention has a strong blood pressure lowering effect,
An optically active benzopyran compound having a smooth muscle relaxing effect is combined with an optically active 6-cyano-3,4-dihydro-2,2-
It can be produced in one step from dimethyl-3,4-epoxy-2H-1-benzopyran, and is an industrial and inexpensive production method with excellent economic efficiency.
Claims (1)
ドロ−２，２−ジメチル−３，４−エポキシ−２Ｈ−１
−ベンゾピランと、２−オキソピロリジン、１，６−ジ
ヒドロ−３−ヒドロキシ−６−オキソピリダジンまたは
１，２−ジヒドロ−２−オキソピリジンとを反応させる
ことを特徴とする一般式 【化１】 〔式中、Ｒ１ 、Ｒ２ は一緒になって２−オキソピロ
リジニル、１，６−ジヒドロ−３−ヒドロキシ−６−オ
キソピリダジニル、１，２−ジヒドロ−２−オキソピリ
ジルを示す。〕により表される光学活性なベンゾピラン
化合物の製造法。Claim 1: Optically active 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1
General formula [Formula 1] characterized by reacting -benzopyran with 2-oxopyrrolidine, 1,6-dihydro-3-hydroxy-6-oxopyridazine or 1,2-dihydro-2-oxopyridine [Chemical formula 1] In the formula, R1 and R2 together represent 2-oxopyrrolidinyl, 1,6-dihydro-3-hydroxy-6-oxopyridazinyl, and 1,2-dihydro-2-oxopyridyl. ] A method for producing an optically active benzopyran compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3042591A JPH04261172A (en) | 1991-02-14 | 1991-02-14 | Production of optically active benzopyran compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3042591A JPH04261172A (en) | 1991-02-14 | 1991-02-14 | Production of optically active benzopyran compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04261172A true JPH04261172A (en) | 1992-09-17 |
Family
ID=12640309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3042591A Pending JPH04261172A (en) | 1991-02-14 | 1991-02-14 | Production of optically active benzopyran compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04261172A (en) |
-
1991
- 1991-02-14 JP JP3042591A patent/JPH04261172A/en active Pending
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