JPH083115A - Isocarbacyclin derivative and its production - Google Patents
Isocarbacyclin derivative and its productionInfo
- Publication number
- JPH083115A JPH083115A JP6136787A JP13678794A JPH083115A JP H083115 A JPH083115 A JP H083115A JP 6136787 A JP6136787 A JP 6136787A JP 13678794 A JP13678794 A JP 13678794A JP H083115 A JPH083115 A JP H083115A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ene
- formula
- carbonyl
- bicyclic
- 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
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、イソカルバサイクリン
誘導体の新規な製造方法に関し、詳しくは、双環性エン
化合物又はオレフィン化合物と親エン体とを、光学活性
ビナフト−ル−チタン錯体を触媒として、不斉触媒的に
カルボニル−エン反応させることにより、抗血栓治療薬
として有用なイソカルバサイクリン誘導体を安価に供給
する新規な製造方法に関する。また、本発明は、この新
規な製造方法を利用して得られる、イソカルバサイクリ
ンの新規な誘導体に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing an isocarbacycline derivative, and more specifically, a bicyclic ene compound or olefin compound and a parent ene, and an optically active binaphthol-titanium complex as a catalyst. The present invention also relates to a novel method for inexpensively supplying an isocarbacycline derivative useful as an antithrombotic therapeutic agent by asymmetrically carrying out a carbonyl-ene reaction. The present invention also relates to a novel derivative of isocarbacycline obtained by utilizing this novel production method.
【０００２】[0002]
【従来の技術】イソカルバサイクリン誘導体は、優れた
血栓抑制作用を有し、しかも安定で、医薬品、特に抗血
栓治療剤として期待されている化合物であって、同じく
血栓抑制作用を示すプロスタサイクリン（別名プロスタ
グランジンＩ2）の安定性を改善する研究により見出さ
れた化合物である。このイソカルバサイクリン誘導体
は、従来、原料のプロスタグランジンを直接イソカルバ
サイクリンに誘導していた。しかしながら、原料プロス
タグランジン自体が生物活性を有する高価な物質である
ため、得られる物質が高価になることは避けられず、し
たがって、安価な原料から低コストでイソカルバサイク
リンを製造する方法が求められていた。2. Description of the Related Art Isocarbacycline derivatives are compounds that have an excellent thrombus-inhibiting action and are stable, and are expected as pharmaceuticals, especially as antithrombotic therapeutic agents. It is a compound found by research that improves the stability of synonymous with prostaglandin I 2 ). Conventionally, this isocarbacycline derivative directly induces the raw material prostaglandin into isocarbacycline. However, since the raw material prostaglandin itself is an expensive substance having biological activity, it is inevitable that the obtained substance will be expensive. Therefore, a method for producing isocarbacycline from an inexpensive raw material at low cost is sought. It was being done.
【０００３】一方、本発明者らはすでに、下記の一般式
（７）On the other hand, the present inventors have already described the following general formula (7):
【０００４】[0004]
【化４】 [Chemical 4]
【０００５】（式中Ｘはハロゲン、アルコキシ、アシル
オキシ配位子を表す）で表される光学活性ビナフト−ル
−チタン錯体を触媒として使用することにより、グリオ
キシラ−トを親エン体とするカルボニル−エン反応の不
斉触媒化、すなわち特定の光学異性体を選択的に生成さ
せることに成功している（J.Am.Chem.Soc.,1989,pp194
0:1990,pp3449）。そこで、この触媒を使用する不斉触
媒的カルボニル−エン反応により、安価な原料からイソ
カルバサイクリンを低コストで合成することができない
かと考えるに至った。By using an optically active binaphthol-titanium complex represented by the formula (wherein X represents a halogen, an alkoxy or an acyloxy ligand) as a catalyst, a carbonyl group having glyoxylate as a parent ene-form is used. We have succeeded in asymmetric catalysis of ene reaction, that is, selective generation of specific optical isomers (J. Am. Chem. Soc., 1989, pp194.
0: 1990, pp3449). Therefore, it has been wondered whether isocarbacycline can be synthesized at low cost from an inexpensive raw material by an asymmetric catalytic carbonyl-ene reaction using this catalyst.
【０００６】[0006]
【発明が解決しようとする課題】したがって、本発明の
目的は、既に２個の環を持つ双環性エン化合物又はオレ
フィン化合物を原料として使用する不斉触媒的カルボニ
ル−エン反応により、高価なプロスタグランジンを原料
として使用することなく、イソカルバサイクリンを低コ
ストで提供することであり、また、この方法を利用して
従来知られていなかった新規なイソカルバサイクリン誘
導体を提供することである。SUMMARY OF THE INVENTION Therefore, the object of the present invention is to obtain an expensive prostaglandin by an asymmetric catalytic carbonyl-ene reaction using a bicyclic ene compound or an olefin compound already having two rings as a raw material. It is to provide isocarbacycline at a low cost without using glandin as a raw material, and to provide a novel isocarbacycline derivative which has not been heretofore known by using this method.
【０００７】[0007]
【課題を解決するための手段】本発明は、一般式（１）The present invention is based on the general formula (1)
【０００８】[0008]
【化５】 Embedded image
【０００９】（式中、ＯＲ1は保護された水酸基であ
り、Ｒωはω側鎖である）で表される双環性エン化合物
又はオレフィン化合物と親エン体とを、光学活性ビナフ
ト−ル−チタン錯体を触媒として、不斉触媒的にカルボ
ニル−エン反応させることにより、一般式（２）The bicyclic ene compound or olefin compound represented by the formula (wherein OR 1 is a protected hydroxyl group and Rω is a ω side chain) and the parent ene compound are optically active binaphthol- By using a titanium complex as a catalyst and carrying out an asymmetric catalytic carbonyl-ene reaction, a compound of the general formula (2)
【００１０】[0010]
【化６】 [Chemical 6]
【００１１】（式中、ＯＲ1は水酸基又は保護された水
酸基であり、Ｒ2は親エン体に対応する側鎖であり、Ｒ
ωはω側鎖である）で表されるイソカルバサイクリン誘
導体を製造する、新規な製造方法の発明である。また、
本発明は、この新規な製造方法を利用して得られる、一
般式（２）において、ＯＲ1は水酸基又は保護された水
酸基であり、Ｒ2は下記（３）〜（６）の式で表される
基であり、Ｒωはω側鎖である、抗血栓治療剤として有
用なイソカルバサイクリンの新規な誘導体の発明であ
る。(In the formula, OR 1 is a hydroxyl group or a protected hydroxyl group, R 2 is a side chain corresponding to the parent ene, and R 2 is
ω is an ω side chain) is an invention of a novel production method for producing an isocarbacycline derivative. Also,
In the general formula (2) obtained by utilizing this novel production method, OR 1 is a hydroxyl group or a protected hydroxyl group, and R 2 is represented by the following formulas (3) to (6). And Rω is a ω side chain, which is an invention of a novel derivative of isocarbacycline useful as an antithrombotic therapeutic agent.
【００１２】[0012]
【化７】 [Chemical 7]
【００１３】本発明の原料双環性エン化合物において、
ＯＲ1は、保護された水酸基であり、保護基としてはシ
リル基などが用いられ、特にＴＢＤＭＳ（ｔｅｒｔ−ブ
チルジメチルシリル基）が好ましい。また、Ｒωとして
は次の基が好ましい。In the raw material bicyclic ene compound of the present invention,
OR 1 is a protected hydroxyl group, and a silyl group or the like is used as the protective group, and TBDMS (tert-butyldimethylsilyl group) is particularly preferable. The following groups are preferable as Rω.
【００１４】[0014]
【化８】 Embedded image
【００１５】本発明において親エン体として用いるカル
ボニル化合物は、ホルムアルデヒド、共役イナ−ル化合
物、共役エナ−ル化合物等である。共役イナ−ル化合物
及び共役エナ−ル化合物は、β−位がカルボキシル基、
又はメトキシカルボニル基及びエトキシカルボニル基の
ようなアルコキシカルボニル基等で置換されていてもよ
い。具体的には、例えばβ−メトキシカルボニルイナ−
ル、β−エトキシカルボニルイナ−ル、β−メトキシカ
ルボニルエナ−ル、β−エトキシカルボニルエナ−ル等
が挙げられる。本発明において触媒として使用する光学
活性ビナフト−ル−チタン錯体は、式（７）において、
Ｘがハロゲン原子、特に塩素または臭素であるものが好
ましい。また、光学活性ビナフト−ルとしては、Ｒ体が
使用される。The carbonyl compound used as the parent ene compound in the present invention is formaldehyde, a conjugated ionic compound, a conjugated eneal compound or the like. The conjugated ionic compound and conjugated ionic compound have a carboxyl group at the β-position,
Alternatively, it may be substituted with an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group. Specifically, for example, β-methoxycarbonyliner
And β-ethoxycarbonylenal, β-methoxycarbonylenal, β-ethoxycarbonylenal and the like. The optically active binaphthol-titanium complex used as a catalyst in the present invention has the following formula (7):
Those in which X is a halogen atom, especially chlorine or bromine, are preferred. Further, the R form is used as the optically active binaphthol.
【００１６】本発明において、双環性エン化合物と親エ
ン体とを光学活性ビナフト−ル−チタン錯体触媒の存在
下にカルボニル−エン反応させるに当たっては、一般に
適当な溶媒中に錯体触媒、エン化合物及び親エン体を加
えて攪拌することにより行われる。溶媒としては、反応
に悪影響を与えないものであれば使用可能であるが、好
ましいものは、ハロアルカン、芳香族炭化水素、特にジ
クロロメタン、或いはトルエン等である。好適な反応温
度は、反応させる物質によるが、一般的には室温以下の
温度が好ましい。触媒の使用量は、約１〜２０モル％程
度である。In the present invention, the carbonyl-ene reaction between the bicyclic ene compound and the parent ene compound in the presence of the optically active binaphthol-titanium complex catalyst is generally carried out in a suitable solvent. Then, the parent ene is added and the mixture is stirred. As the solvent, any solvent which does not adversely influence the reaction can be used, but preferable ones are haloalkane, aromatic hydrocarbon, particularly dichloromethane, toluene and the like. A suitable reaction temperature depends on the substance to be reacted, but generally a temperature of room temperature or lower is preferable. The amount of the catalyst used is about 1 to 20 mol%.
【００１７】本発明の方法によれば、特定の立体異性体
を選択的に生成させることができる。以下この点につい
てさらに詳しく説明する。まず、原料双環性エン化合物
としてＲω−鎖を持たない対称な化合物を用い、ホルム
アルデヒドを親エン体とし、Ｒ体のビナフト−ル−チタ
ン錯体を触媒とする不斉触媒的カルボニル−エン反応に
よる不斉非対称化について検討したところ、エナンチオ
選択的に（７６％）１１Ｓ体が得られることが分かっ
た。反応式を下記に示す。According to the method of the present invention, a specific stereoisomer can be selectively produced. This point will be described in more detail below. First, a symmetric compound having no Rω-chain is used as a raw material bicyclic ene compound, formaldehyde is used as a parent ene compound, and an asymmetric catalytic carbonyl-ene reaction is performed using an R-form binaphthol-titanium complex as a catalyst. When the asymmetric asymmetry was examined, it was found that the 11S isomer was obtained enantioselectively (76%). The reaction formula is shown below.
【００１８】[0018]
【化９】 [Chemical 9]
【００１９】次に、Ｒω−鎖を有する光学的に純粋なエ
ン化合物を用いて同様に不斉触媒的ホルムアルデヒド−
エン反応を行ない、重複不斉誘導について検討したとこ
ろ、二重結合を位置選択的に（９０％）６，９α位に導
入できることが分かった。その結果（３−オキサ）イソ
カルバサイクリン合成の鍵となる中間体が得られた。原
料としたＲω−鎖を有するキラル双環性エン化合物は、
光学分割した双環性β−ヒドロキシカルボン酸にＲω−
鎖を形成する工程を含む複数の工程によって得られる。
これらの反応工程をまとめて以下に示す。式中Ｒωはω
側鎖である。Next, using an optically pure ene compound having an Rω-chain, similarly asymmetric catalytic formaldehyde-
When the ene reaction was carried out and double asymmetric induction was examined, it was found that a double bond could be regioselectively (90%) introduced at the 6,9α position. As a result, a key intermediate for the synthesis of (3-oxa) isocarbacycline was obtained. The chiral bicyclic ene compound having an Rω-chain as a raw material is
Optically resolved bicyclic β-hydroxycarboxylic acid with Rω-
Obtained by multiple steps, including the step of forming chains.
These reaction steps are summarized below. Where Rω is ω
It is a side chain.
【００２０】[0020]
【化１０】 [Chemical 10]
【００２１】さらに、種々のα−鎖を有するイソカルバ
サイクリン誘導体の不斉合成を目指して、ホルムアルデ
ヒドに代えて共役イナ−ル化合物を親エン体とするカル
ボニル−エン反応の不斉触媒化を検討した。まず、Ｒω
−鎖を持たない対称な双環性エン化合物を用い、β−メ
トキシカルボニルイナ−ルとのエン反応について検討し
たところ、このアルデヒドも十分なエン反応性を有し、
対応するα−鎖を有する生成物を収率よく生成すること
が分かった。しかもその６，９α位置選択性（９１％）
及び４Ｒ選択性（８８％）が極めて高いことが分かっ
た。反応式を以下に示す。Further, aiming at the asymmetric synthesis of isocarbacycline derivatives having various α-chains, the asymmetric catalysis of carbonyl-ene reaction using a conjugated eneal compound as a parent ene body instead of formaldehyde was examined. did. First, Rω
Using a symmetric bicyclic ene compound having no chain, the ene reaction with β-methoxycarbonylinal was examined, and this aldehyde also had sufficient ene reactivity.
It was found that the product having the corresponding α-chain was produced in good yield. Moreover, its 6,9α position selectivity (91%)
And 4R selectivity (88%) was found to be very high. The reaction formula is shown below.
【００２２】[0022]
【化１１】 [Chemical 11]
【００２３】そこで、同様にしてＲω−鎖を有する双環
性エン化合物とのエン反応を行なったところ、対応する
エン生成物が、極めて高い６，９α位置選択性（９８
％）及び４Ｒ選択性（９６％）で、かつ、高収率で得ら
れた。そして、得られたエン生成物は、さらに種々の誘
導体へと変換された。これらの工程をまとめて以下に示
す。式中Ｒωは前記したとおりである。Then, when an ene reaction with a bicyclic ene compound having an Rω-chain was carried out in the same manner, the corresponding ene product showed extremely high 6,9α regioselectivity (98).
%) And 4R selectivity (96%), and a high yield was obtained. Then, the obtained ene product was further converted into various derivatives. These steps are summarized below. In the formula, Rω is as described above.
【００２４】[0024]
【化１２】 [Chemical 12]
【００２５】同様にホルムアルデヒドに代えて共役エナ
−ル化合物を親エン体とするカルボニル−エン反応の不
斉触媒化についても検討した。Similarly, the asymmetric catalysis of carbonyl-ene reaction using a conjugated eneal compound as a parent ene body instead of formaldehyde was also investigated.
【００２６】[0026]
【実施例】次に実施例をもって本発明を説明する。 実施例 アルゴン雰囲気下、モレキュラ−シ−ブス３Ａ（ＭＳ３
Ａ，１００ｍｇ）の塩化メチレン懸濁液に光学活性ビナ
フト−ル−チタン錯体（７）（０．１ミリモル，２０モ
ル％）及び、エン体（１）（０．５ミリモル）を加え、
更にホルムアルデヒド（１〜５ミリモル）を加え、−３
０℃で終夜撹拌した。反応液をジエチルエ−テルで稀釈
後、飽和ＮａＨＣＯ3水溶液にあけた。ＭＳ３Ａを瀘別
し、ジエチルエ−テル及び酢酸エチルで抽出、飽和食塩
水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減
圧下留去し、シリカゲルカラムクロマトグラフィ−（ヘ
キサン／酢酸エチル＝４：１）で精製し、エン反応生成
物（２，Ｒ2＝ＣＨ2ＣＨ2ＯＨ）を収率６１％で得た。
（原料回収３９％） この方法によって得られたイソカルバサイクリン誘導体
（ビスシリルエ−テル）は次の通りである。EXAMPLES The present invention will be described below with reference to examples. Example Under an argon atmosphere, molecular sieves 3A (MS3
A, 100 mg) in a methylene chloride suspension was added with an optically active binaphthol-titanium complex (7) (0.1 mmol, 20 mol%) and an ene body (1) (0.5 mmol),
Further add formaldehyde (1-5 mmol), -3
Stirred overnight at 0 ° C. The reaction solution was diluted with diethyl ether and then poured into a saturated NaHCO 3 aqueous solution. MS3A was filtered off, extracted with diethyl ether and ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1) to obtain an ene reaction product (2, R 2 ═CH 2 CH 2 OH) in a yield of 61%. .
(Raw material recovery 39%) The isocarbacycline derivative (bissilyl ether) obtained by this method is as follows.
【００２７】[0027]
【化１３】 [Chemical 13]
【００２８】[0028]
【発明の効果】新規誘導体を含めたイソカルバサイクリ
ン誘導体を安価に製造することができる。INDUSTRIAL APPLICABILITY Isocarbacycline derivatives including novel derivatives can be manufactured at low cost.
Claims (2)
鎖である）で表される双環性エン化合物と親エン体と
を、光学活性ビナフト−ル−チタン錯体を触媒として、
不斉触媒的にカルボニル−エン反応させることを特徴と
する、一般式（２） 【化２】 （式中、ＯＲ1は水酸基又は保護された水酸基であり、
Ｒ2は親エン体に対応する側鎖であり、Ｒωはω側鎖で
ある）で表されるイソカルバサイクリン誘導体の製造方
法。1. A compound represented by the general formula (1): (In the formula, OR 1 is a protected hydroxyl group, and Rω is a ω side chain), a bicyclic ene compound and a parent ene compound are prepared using an optically active binaphthol-titanium complex as a catalyst.
A compound represented by the general formula (2): (In the formula, OR 1 is a hydroxyl group or a protected hydroxyl group,
R 2 is a side chain corresponding to the parent ene, and Rω is a ω side chain).
が下記（３）〜（６）の基であることを特徴とするイソ
カルバサイクリン誘導体。 【化３】 2. In the general formula (2) of claim 1, R 2
Is the group of the following (3) to (6), an isocarbacycline derivative. Embedded image
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13678794A JP3632135B2 (en) | 1994-06-20 | 1994-06-20 | Isocarbacycline derivative and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13678794A JP3632135B2 (en) | 1994-06-20 | 1994-06-20 | Isocarbacycline derivative and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH083115A true JPH083115A (en) | 1996-01-09 |
| JP3632135B2 JP3632135B2 (en) | 2005-03-23 |
Family
ID=15183514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13678794A Expired - Fee Related JP3632135B2 (en) | 1994-06-20 | 1994-06-20 | Isocarbacycline derivative and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3632135B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130107A (en) * | 2014-08-06 | 2014-11-05 | 浙江新和成股份有限公司 | Preparation method for synthesizing 3-methyl-3-butene-1-ol by using formaldehyde hemiacetal |
-
1994
- 1994-06-20 JP JP13678794A patent/JP3632135B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130107A (en) * | 2014-08-06 | 2014-11-05 | 浙江新和成股份有限公司 | Preparation method for synthesizing 3-methyl-3-butene-1-ol by using formaldehyde hemiacetal |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3632135B2 (en) | 2005-03-23 |
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