JPH0625124B2 - Process for producing (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline - Google Patents
Process for producing (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinolineInfo
- Publication number
- JPH0625124B2 JPH0625124B2 JP62190770A JP19077087A JPH0625124B2 JP H0625124 B2 JPH0625124 B2 JP H0625124B2 JP 62190770 A JP62190770 A JP 62190770A JP 19077087 A JP19077087 A JP 19077087A JP H0625124 B2 JPH0625124 B2 JP H0625124B2
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- JP
- Japan
- Prior art keywords
- group
- formula
- binap
- methoxyphenylmethyl
- lower alkyl
- Prior art date
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Classifications
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- 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
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は医薬品として有用な光学活性３−メトキシ−Ｎ
−メチルモルフイナン〔(+)−デキストロメトルフア
ン〕の製造に有用な中間体を不斉触媒反応により光学活
性体を純粋に、効率よく製造する方法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is an optically active 3-methoxy-N useful as a medicine.
TECHNICAL FIELD The present invention relates to a method for producing an optically active substance purely and efficiently by an asymmetric catalytic reaction of an intermediate useful for the production of -methylmorphinan [(+)-dextromethorphan].
生理活性のある天然有機化合物は、その光学異性体の形
により生理活性が大きく異なり、時には目的と全く逆の
作用、または有害な作用を示す場合も多い。従つてその
ような天然有機化合物の誘導体もまた光学異性体の形に
よつてその生理活性が大きく異なる場合が多い。事実、
(+)−デキストロメトルフアンは、次式(VIII) で表わされるアヘンアルカロイドの人工誘導体であり、
右旋性モルフイナン構造を有し、鎮咳剤として有用な化
合物であるにもかかわらず、その左旋性化合物は鎮痛作
用を有する。The physiologically active natural organic compound has a great difference in physiological activity depending on the form of its optical isomer, and in many cases, it exhibits a completely opposite action or a harmful action. Therefore, the derivatives of such natural organic compounds also often differ greatly in their physiological activities depending on the forms of optical isomers. fact,
(+)-Dextromethorphan has the following formula (VIII) Is an artificial derivative of opium alkaloid represented by
Despite having a dextrorotatory morphinan structure and being a compound useful as an antitussive, the levorotatory compound has an analgesic effect.
従来、(+)−デキストロメトルフアンはまず３−ヒドロ
キシ−Ｎ−メチルモルフイナンのラセミ体を合成し、こ
れを何らかの方法で光学分割して右旋性３−ヒドロキシ
−Ｎ−メチルモルフイナンを得た後、メチル化すること
により製造されていた。Conventionally, (+)-dextromethorphan has first synthesized a racemic form of 3-hydroxy-N-methylmorphinan and optically resolved it by some method to obtain dextrorotatory 3-hydroxy-N-methylmorphinan. After being obtained, it was produced by methylation.
しかしながら、ラセミ体の光学分割によつて光学異性体
を製造する方法は、目的の光学異性体を取得するにあた
り、逆の立体配置をもつ鏡像体は不用となり、経済性に
乏しいものであつた。However, the method for producing an optical isomer by optical resolution of a racemic body is not economical because the enantiomer having the opposite configuration is not necessary for obtaining the target optical isomer.
従つて(+)−デキストロメトルフアンのみを純粋に、効
率よく製造する方法の開発が望まれていた。Therefore, it has been desired to develop a method for producing only (+)-dextromethorphan purely and efficiently.
そこで本発明者は、かかる問題点を解決すべく種々検討
してきた結果、ルテニウム−ホスフイン錯体を使用する
不斉水素化反応によつて、(+)−デキストロメトルフア
ンの重要な中間体の光学異性体が高い光学純度で得られ
ることを見い出し、本発明を完成した。Therefore, the present inventor has conducted various studies to solve such problems, and as a result, an asymmetric hydrogenation reaction using a ruthenium-phosphine complex showed that the optical properties of an important intermediate of (+)-dextromethorphan. The present invention has been completed by finding that isomers can be obtained with high optical purity.
すなわち、本発明は次式(I) 〔式中、Ｒ1は水素原子または低級アルキル基を示す〕 で表わされる(Z)−Ｎ−アシル−１−（４−メトキシフ
エニルメチレン）−３，４，５，６，７，８−ヘキサヒ
ドロイソキノリンを、光学活性なルテニウム−ホスフイ
ン錯体触媒の存在下に水素添加することを特徴とする、
次式(II) 〔式中、Ｒ1は前記と同じ〕 で表わされる(+)−Ｎ−アシル−１−（４−メトキシフ
エニルメチル）−１，２，３，４，５，６，７，８−オ
クタヒドロイソキノリンの製造法を提供するものであ
る。That is, the present invention has the following formula (I) [In the formula, R 1 represents a hydrogen atom or a lower alkyl group] (Z) -N-acyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8- Hexahydroisoquinoline is hydrogenated in the presence of an optically active ruthenium-phosphine complex catalyst,
Formula (II) [Wherein R 1 is the same as above] (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octa A method for producing hydroisoquinoline is provided.
〔式中、Ｒ1は前記と同じ〕 本発明の原料化合物(I)は、新規化合物であり、次式に
従つて製造される。 [Wherein R 1 is the same as above] The starting compound (I) of the present invention is a novel compound and is produced according to the following formula.
〔式中、Ｒ1は前記と同じ、Ｒ4は水素原子又は低級アル
キル基を示す〕すなわち、１−（４−メトキシフエニル
メチル）−３，４，５，６，７，８−ヘキサヒドロイソ
キノリン(III)をアシル化することにより、(Z)−Ｎ−ア
シル−１−（４−メトキシフエニルメチレン）−３，
４，５，６，７，８−ヘキサヒドロイソキノリンが製造
される。アシル化剤としては、蟻酸、酢酸、プロピオン
酸、酪酸等の酸無水物、他の酸との混合酸無水物等が挙
げられる。反応は、ピリジン、トリエチルアミン、ジイ
ソプロピルエチルアミン、Ｎ，Ｎ−ジメチルアミノピリ
ジン等の塩基の存在下、塩化メチレン、エーテル類等の
不活性溶媒中で行なうのが好ましい。 [In the formula, R 1 is the same as above, R 4 represents a hydrogen atom or a lower alkyl group] That is, 1- (4-methoxyphenylmethyl) -3,4,5,6,7,8-hexahydro By acylating isoquinoline (III), (Z) -N-acyl-1- (4-methoxyphenylmethylene) -3,
4,5,6,7,8-hexahydroisoquinoline is produced. Examples of the acylating agent include acid anhydrides such as formic acid, acetic acid, propionic acid and butyric acid, and mixed acid anhydrides with other acids. The reaction is preferably carried out in the presence of a base such as pyridine, triethylamine, diisopropylethylamine and N, N-dimethylaminopyridine in an inert solvent such as methylene chloride and ethers.
なお、１−（４−メトキシベンジル）−３，４，５，
６，７，８−ヘキサヒドロイソキノリン(III)は、Ｏ．
Ｓchniderらの方法〔Hev.Chim.Acta.,33,1437(195
0)〕またはM.Onodaらの方法〔Chem.Pharm.Bu.,21,2
359(1973)〕により高収率で製造することができる。In addition, 1- (4-methoxybenzyl) -3,4,5,5
6,7,8-Hexahydroisoquinoline (III) was prepared from O.
The method of Schnider et al. [Hev. Chim. Acta., 33 , 1437 (195
0)] or the method of M. Onoda et al. [Chem. Pharm. Bu., 21 , 2
359 (1973)], it can be produced in high yield.
本発明において触媒として使用される光学活性なルテニ
ウム−ホスフイン錯体としては、例えば次式(IV)〜(VI)
で表わされるルテニウム金属に光学活性なホスフイン誘
導体が配位した化合物が挙げられる。Examples of the optically active ruthenium-phosphine complex used as a catalyst in the present invention include, for example, the following formulas (IV) to (VI).
A compound in which an optically active phosphine derivative is coordinated with the ruthenium metal represented by
〔式中、Ｘはハロゲン原子を示し、Ｙは水素原子、アミ
ノ基、アセチルアミノ基またはスルホン基を示し、Ｒ2
は水素原子または直鎖もしくは分岐鎖の低級アルキル基
を示し、Ａ及びＺはＣＯ4、PF6、BF4、R3COO（ここで
Ｒ3はアルキル基、ハロゲン化低級アルキル基、低級ア
ルキル置換基を有していてもよいフエニル基、α−アミ
ノアルキル基またはα−アミノフエニルアルキル基を示
すか、あるいはＡとＺが一緒になつてアルキレンジカル
ボキシ基を形成する）を示し、ｎは１または２を示す〕 式(IV)の錯体の代表的なものを次に例示する。 [In the formula, X represents a halogen atom, Y represents a hydrogen atom, an amino group, an acetylamino group or a sulfone group, and R 2
Is a hydrogen atom or a linear or branched lower alkyl group, A and Z are CO 4 , PF 6 , BF 4 , and R 3 COO (wherein R 3 is an alkyl group, a halogenated lower alkyl group, a lower alkyl-substituted group). A phenyl group which may have a group, an α-aminoalkyl group or an α-aminophenylalkyl group, or A and Z together form an alkylenedicarboxy group), and n is 1 or 2] Representative examples of the complex of the formula (IV) are shown below.
Ru2C４(BINAP)2N(C2H5)3 Ru2C４(p-To BINAP)2N(C2H5)3 （(p-To BINAPは、２，２′−ビス（ジ−ｐ−トリル
ホスフイノ）１，１′−ビナフチルをあらわす） Ru2C４(p-t-Bu BINAP)2N(C2H5)3 (p-t-Bu BINAPは、２，２′−ビス（ジ−ｐ−ターシヤ
リ−ブチルフエニルホスフイノ）−１，１′−ビナフチ
ルをあらわす） Ru2C４(5−アセチルアミノBINAP)2N(C2H5)3 （５−アセチルアミノBINAPは、２，２′−ビス（ジフ
エニルホスフイノ）−５，５′−ジアセチルアミノ−
１，１′−ビナフチルをあらわす） 式(V)の錯体の代表的なものを次に例示する。 Ru 2 C 4 (BINAP) 2 N (C 2 H 5) 3 Ru 2 C 4 (p-To BINAP) 2 N (C 2 H 5) 3 ((p-To BINAP is 2,2'-bis ( Di-p-tolylphosphino) 1,1'-binaphthyl) Ru 2 C 4 (pt-Bu BINAP) 2 N (C 2 H 5 ) 3 (pt-Bu BINAP is 2,2'-bis (di- p- Tashiyari - butyl phenylpropyl phosphine Ino) -1,1' represents the binaphthyl) Ru 2 C 4 (5-acetylamino BINAP) 2 N (C 2 H 5) 3 (5- acetylamino BINAP is 2, 2'-bis (diphenylphosphino) -5,5'-diacetylamino-
Representing 1,1'-binaphthyl) Representative examples of the complex of formula (V) are shown below.
RuHC(BINAP)2 〔RuH(BINAP)2〕PF6 式(VI)の錯体の代表的なものを次に例示する。RuHC (BINAP) 2 [RuH (BINAP) 2 ] PF 6 Representative examples of the complex of formula (VI) are shown below.
Ru(BINAP)(O2CCH3)2 Ru(p-To BINAP)2(O2CCH3)2 Ru(BINAP)(O2C-t-Bu)2 （t-Buは、ターシヤリ−ブチル基をあらわす） Ru(p-To BINAP)(O2CCH3)2 Ru(p-To BINAP)(O2CCF3)2 Ru(p-t-Bu BINAP)(O2CCH3)2 Ru（５−アセチルアミノ BINAP）(O2CCH3)2 （i-Prは、イソプロピル基をあらわす） 〔Ru(p-To BINAP)〕(CO4)2 〔Ru(p-To BINAP)〕(PF6)2 Ru(p-To BINAP)2(O2CCF3)2 式(IV)および(V)の錯体は、例えば特開昭６１−６３６
９０号に開示された方法によつて得ることができる。ま
た式(VI)の錯体は、例えば式(IV)の錯体とカルボン酸塩
をターシヤリ−ブタノール等のアルコール溶媒中で、約
１２時間加熱還流し反応せしめた後、溶媒を留去し、エ
ーテル、エタノール等の溶媒で抽出して、乾固して、錯
体をうる。カルボキシル基は、用いるカルボン酸の種類
を変えることにより所望のものを得ることが出来る。ま
た、トリフロロ酢酸基を有する錯体を製造する場合は、
上記の如くして得たジアセテート錯体にトリフロロ酢酸
を塩化メチレンを溶媒として約２５℃で約１２時間反応
せしめて得ることが出来る。また、ルテニウム金属に２
当量のリガンドの配位した錯体を製造するときは、式
(V)の錯体を原料として、これとカルボン酸塩を塩化メ
チレン等の溶媒中で反応せしめてつくることができる。Ru (BINAP) (O 2 CCH 3 ) 2 Ru (p-To BINAP) 2 (O 2 CCH 3 ) 2 Ru (BINAP) (O 2 Ct-Bu) 2 (t-Bu represents a tert-butyl group. ) Ru (p-To BINAP) (O 2 CCH 3 ) 2 Ru (p-To BINAP) (O 2 CCF 3 ) 2 Ru (pt-Bu BINAP) (O 2 CCH 3 ) 2 Ru (5-acetylamino BINAP) (O 2 CCH 3 ) 2 (I-Pr represents an isopropyl group) [Ru (p-To BINAP)] (CO 4 ) 2 [Ru (p-To BINAP)] (PF 6 ) 2 Ru (p-To BINAP) 2 (O 2 CCF 3 ) 2 Formulas (IV) and (V) complexes are described, for example, in JP-A-61-636.
It can be obtained by the method disclosed in No. 90. Further, the complex of the formula (VI) is obtained by reacting the complex of the formula (IV) and the carboxylic acid salt in an alcohol solvent such as tert-butanol by heating under reflux for about 12 hours and then distilling the solvent to remove ether, Extract with a solvent such as ethanol and dry to obtain a complex. The desired carboxyl group can be obtained by changing the type of carboxylic acid used. When producing a complex having a trifluoroacetic acid group,
It can be obtained by reacting the diacetate complex obtained as described above with trifluoroacetic acid in a solvent of methylene chloride at about 25 ° C. for about 12 hours. In addition, ruthenium metal 2
When preparing a complex in which an equivalent amount of a ligand is coordinated,
It can be prepared by reacting the complex of (V) as a raw material with a carboxylate in a solvent such as methylene chloride.
本発明の反応は、化合物(I)に上記ルテニウム−ホスフ
イン錯体を添加し、これに水素を通じることにより実施
される。好ましい実施態様としては、例えばまず化合物
(I)を塩化メチレン等の溶媒に溶解して原料の溶液を調
製しておく。一方、ルテニウム−ホスフイン錯体をメタ
ノール等の溶媒に溶解し、触媒の溶液を調製する。両溶
液を混合し、オートクレーブ中にて水素を通じることに
よつて行なわれる。The reaction of the present invention is carried out by adding the above ruthenium-phosphine complex to compound (I) and passing hydrogen through this. In a preferred embodiment, for example, the compound
A raw material solution is prepared by dissolving (I) in a solvent such as methylene chloride. On the other hand, the ruthenium-phosphine complex is dissolved in a solvent such as methanol to prepare a catalyst solution. This is done by mixing both solutions and passing hydrogen in an autoclave.
反応条件、すなわち、水素圧、反応温度、反応時間、使
用する触媒の量は、化合物(I)および触媒の種類によつ
て適宜決定される。一般に水素圧は４〜１００kg／c
m2、反応温度は２５〜７５℃、反応時間は２４〜１００
時間が好ましい。The reaction conditions, that is, the hydrogen pressure, the reaction temperature, the reaction time, and the amount of the catalyst used are appropriately determined depending on the compound (I) and the type of the catalyst. Generally, hydrogen pressure is 4-100kg / c
m 2 , reaction temperature is 25 to 75 ° C., reaction time is 24 to 100
Time is preferred.
反応終了後、溶媒を留去し、自体公知の精製手段、例え
ばカラムクロマトグラフイー等を行なえば、目的化合物
(II)が９６〜９８％eeの極めて高い光学純度で、かつ高
収率で得られる。After completion of the reaction, the solvent is distilled off, and the target compound is obtained by performing a purification means known per se, such as column chromatography.
(II) can be obtained with an extremely high optical purity of 96 to 98% ee and a high yield.
斯くして得られる(+)−Ｎ−アシル−１−（４−メトキ
シフエニルメチル）−１，２，３，４，５，６，７，８
−オクタヒドロイソキノリン(II)は、鎮咳剤として有用
な(+)−デキストロメトルフアン(VIII)の合成中間体と
して有用である。例えば化合物(II)から次の反応式に従
つて(+)−デキストロメトルフアンが製造される。(+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8 thus obtained
-Octahydroisoquinoline (II) is useful as a synthetic intermediate for (+)-dextromethorphan (VIII), which is useful as an antitussive. For example, (+)-dextromethorphan is produced from compound (II) according to the following reaction formula.
〔式中、Ｒ1は前記と同じ〕 すなわち、化合物(II)を既知の酸触媒を用いるGrewe型
環化反応に付して式(VII)の化合物を得、次いでこれを
脱アシル化、メチル化することにより、(+)−デキスト
ロメトルフアンが高収率で製造される。 [Wherein R 1 is the same as above] That is, the compound (II) is subjected to a Grewe-type cyclization reaction using a known acid catalyst to obtain a compound of the formula (VII), which is then deacylated and methylated. To produce (+)-dextromethorphan in a high yield.
Grewe型環化反応は、R.Grewe et a.,Naturwiss.33,33
3(1946)に記載の方法に準じて、リン酸、塩酸、ポリリ
ン酸等の酸触媒を用いて行なわれる。Ｒ1が水素原子ま
たはメチル基である場合、この環化反応が９０％以上の
収率であることから特に好ましい。The Grewe-type cyclization reaction is described by R. Grewe et a., Naturwiss. 33 , 33
3 (1946), using an acid catalyst such as phosphoric acid, hydrochloric acid or polyphosphoric acid. When R 1 is a hydrogen atom or a methyl group, this cyclization reaction is particularly preferable because the yield is 90% or more.
脱アシル化反応は、特公昭４６−１９１号公報に準じ
て、アルコール中の水酸化アルカリまたはアルコール中
の酸により処理することにより行なわれる。The deacylation reaction is carried out according to JP-B-46-191 by treating with an alkali hydroxide in alcohol or an acid in alcohol.
このように本発明方法を利用すれば、その製造工程中に
何ら光学分割等の経済的に不利な工程を経ることなく、
(+)−デキストロメトルフアンを純粋に効率よく製造す
ることができる。Thus, by using the method of the present invention, without undergoing any economically disadvantageous step such as optical resolution during the manufacturing process,
(+)-Dextromethorphan can be produced purely and efficiently.
次に実施例を挙げて本発明を詳細に説明する。 Next, the present invention will be described in detail with reference to examples.
実施例１ １−（４−メトキシベンジル）−３，４，５，６，７，
８−ヘキサヒドロイソキノリンの合成 Ｎ−（１−シクロヘキセニル）エチル−４−メトキシフ
エニルアセトアミド（２５．０ｇ，９１．４ｍｍｏ）
の無水ベンゼン溶液中に、窒素気流下、オキシ塩化リン
（４９．８ｍ、503.0ｍｍｏ）を滴下した。この反
応溶液を３時間還流した後、０℃まで冷却した。水５０
０ｍを加え、更に１晩攪拌した後、エーテルで洗浄後
０℃で３０％水酸化ナトリウムでpH＝１０にした。エー
テル（２５０ｍ）で３回抽出した後、このエーテル抽
出液を水で洗浄後、無水硫酸ナトリウムで乾燥した。溶
媒を減圧下濃縮すると９０％の収率で、粗１−（４−メ
トキシベンジル）−３，４，５，６，７，８−ヘキサヒ
ドロイソキノリンを得た。このものは、酸素に不安定で
あるため、ただちに次の反応に使用する。Example 1 1- (4-methoxybenzyl) -3,4,5,6,7,
Synthesis of 8-hexahydroisoquinoline N- (1-cyclohexenyl) ethyl-4-methoxyphenylacetamide (25.0 g, 91.4 mmo)
Phosphorus oxychloride (49.8 m, 503.0 mmo) was added dropwise to the anhydrous benzene solution of (1) under a nitrogen stream. The reaction solution was refluxed for 3 hours and then cooled to 0 ° C. Water 50
0 m was added, and the mixture was further stirred overnight, washed with ether, and adjusted to pH = 10 with 30% sodium hydroxide at 0 ° C. After extraction with ether (250 m) three times, the ether extract was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give crude 1- (4-methoxybenzyl) -3,4,5,6,7,8-hexahydroisoquinoline in 90% yield. This substance is unstable to oxygen and is used immediately in the next reaction.
実施例２ (Z)−Ｎ−ホルミル−１−（４−メトキシフエニルメチ
レン）−３，４，５，６，７，８−ヘキサヒドロイソキ
ノリンの合成 実施例１で得られた粗１−（４−メトキシフエニルメチ
ル）−３，４，５，６，７，８−ヘキサヒドロイソキノ
リン（２３．３ｇ，９１．９ｍｍｏ）の無水ＴＨＦ
（２５０ｍ）溶液に、窒素気流下、０℃、トリエチル
アミン（７０．０ｍ，５４８ｍｍｏ）を加えた後、
無水ホルミルピバリン酸〔Edward J.Viestra et ａ.,
Recuei，Ｊ．Roya Netherands Chem.Soc.,101(1
2),460(1982)に記載の方法で製造〕（２９ｇ，２４７ｍ
ｍｏ）をゆつくり滴下した。この反応溶液を、室温で
２４時間攪拌した。析出した塩を別した後、減圧下濃
縮すると、粗(Z)−Ｎ−ホルミル−１−（４−メトキシ
フエニルメチレン）−３，４，５，６，７，８−ヘキサ
ヒドロイソキノリンが得られた。Ｅ／Ｚの比は１／6.6
である。Example 2 Synthesis of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline Crude 1- (obtained in Example 1 4-Methoxyphenylmethyl) -3,4,5,6,7,8-hexahydroisoquinoline (23.3 g, 91.9 mmo) in anhydrous THF
After adding triethylamine (70.0 m, 548 mmo) to the (250 m) solution at 0 ° C. under a nitrogen stream,
Formyl pivalic anhydride (Edward J. Viestra et a.,
Recuei, J. Roya Netherands Chem. Soc., 101 (1
2), manufactured by the method described in 460 (1982)] (29 g, 247 m
mo) was slowly added dropwise. The reaction solution was stirred at room temperature for 24 hours. After separating the precipitated salt, it was concentrated under reduced pressure to obtain crude (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline. Was given. E / Z ratio is 1 / 6.6
Is.
このものをカラムクロマトグラフで精製し、メタノール
で再結晶すると、純粋な白色結晶の(Z)−Ｎ−ホルミル
−１−（４−メトキシフエニルメチレン）−３，４，
５，６，７，８−ヘキサヒドロイソキノリン（１９．８
ｇ，収率７６％）を得た。融点は１０３−１０４℃であ
る。This was purified by column chromatography and recrystallized from methanol to give pure white crystals of (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4.
5,6,7,8-Hexahydroisoquinoline (19.8
g, yield 76%). The melting point is 103-104 ° C.
スペクトルデータは次の通りである。１ Ｈ NMR(400MHz,ＣＤＣ３)δppm：1.69(m,4H),2.09
(m,2H),2.20(m,2H),2.29(m,2H),3.78(s,3H),3.85(t,J＝
6.0Hz,1H),6.16(s,1H),6.83(m,2H),7.23(m,2H),8.01(s,
1H)13C NMR(100MHz,ＣＤＣ３)δppm：22.19,22.80,3
0.60,31.22,37.72,55.19,113.32,114.27,125.55,128.0
0,129.98,134.42,134.48,158.30,162.77 UV(CH3OH)：225,247,297nm MS：m/e 283 実施例３ (Z)−Ｎ−ホルミル−１−（４−メトキシフエニルメチ
レン）−３，４，５，６，７，８−ヘキサヒドロイソキ
ノリンの合成 実施例２と同様な方法により、トリエチルアミンの代わ
りにジイソプロピルエチルアミンを使用すると、収率６
５％，Ｅ／Ｚの比は１／8.4で、(Z)−Ｎ−ホルミル−１
−（４−メトキシフエニルメチレン）−３，４，５，
６，７，８−ヘキサヒドロイソキノリンを得た。The spectrum data are as follows. 1 H NMR (400 MHz, CDC 3 ) δppm: 1.69 (m, 4H), 2.09
(m, 2H), 2.20 (m, 2H), 2.29 (m, 2H), 3.78 (s, 3H), 3.85 (t, J =
6.0Hz, 1H), 6.16 (s, 1H), 6.83 (m, 2H), 7.23 (m, 2H), 8.01 (s,
1H) 13 C NMR (100 MHz, CDC 3 ) δppm: 22.19,22.80,3
0.60,31.22,37.72,55.19,113.32,114.27,125.55,128.0
0,129.98,134.42,134.48,158.30,162.77 UV (CH 3 OH): 225,247,297nm MS: m / e 283 Example 3 (Z)-N-formyl-1- (4-methoxyphenyl-methylene) -3,4, Synthesis of 5,6,7,8-hexahydroisoquinoline By the same method as in Example 2, using diisopropylethylamine instead of triethylamine, a yield of 6 was obtained.
5%, E / Z ratio is 1 / 8.4, (Z) -N-formyl-1
-(4-Methoxyphenylmethylene) -3,4,5,
6,7,8-Hexahydroisoquinoline was obtained.
実施例４ (Z)−Ｎ−アセチル−１−（４−メトキシフエニルメチ
レン）−３，４，５，６，７，８−ヘキサヒドロイソキ
ノリンの合成 粗１−（４−メトキシベンジル）−３，４，５，６，
７，８−ヘキサヒドロイソキノリン（１．７４ｇ，６．
８０ｍｍｏ）の無水塩化メチレン（４０ｍ）溶液
に、窒素気流下、０℃、Ｎ，Ｎ−ジメチルアミノピリジ
ン（４０mg，０．３３ｍｍｏ）を加えた後、無水酢酸
（１．９２ｍ，２０．４ｍｍｏ）をゆつくり滴下し
た。この反応溶液を一晩攪拌した後、飽和重ソウ水に加
え、酢酸エチル（５０ｍ×３）で抽出、次いで飽和食
塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧
濃縮すると粗(Z)−Ｎ−アセチル−１−（４−メトキシ
フエニルメチレン）−３，４，５，６，７，８−ヘキサ
ヒドロイソキノリンが得られた。Ｅ／Ｚの比は１／３で
ある。Example 4 Synthesis of (Z) -N-acetyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline Crude 1- (4-methoxybenzyl) -3 , 4, 5, 6,
7,8-Hexahydroisoquinoline (1.74 g, 6.
To a solution of 80 mmo) in anhydrous methylene chloride (40 m) was added N, N-dimethylaminopyridine (40 mg, 0.33 mmo) under a nitrogen stream at 0 ° C., and then acetic anhydride (1.92 m, 20.4 mmo) was added. I dropped it gently. The reaction solution was stirred overnight, added to saturated sodium bicarbonate water, extracted with ethyl acetate (50 m × 3), washed with saturated brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crude (Z) -N-acetyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline. The E / Z ratio is 1/3.
このものをカラムクロマトグラフで精製すると、(Z)−
Ｎ−アセチル−１−（４−メトキシフエニルメチレン）
−３，４，５，６，７，８−ヘキサヒドロイソキノリン
（１．０５ｇ，５２％を得た）。When this product was purified by column chromatography, (Z)-
N-acetyl-1- (4-methoxyphenylmethylene)
-3,4,5,6,7,8-Hexahydroisoquinoline (1.05 g, yield 52%).
各スペクトルデータを示す。１ Ｈ NMR(400MHz,ＣＤＣ３)δppm：1.70(m,4H),2.11
(m,2H),2.20(m,2H),2.14(s,3H),2.29(m,2H),3.78(s,3
H),3.85(t,J＝6.0Hz,1H),6.16(s,1H),6.83(m,2H),7.23
(m,2H) MS：m/e 297 実施例５ あらかじめ乾燥し、アルゴン置換したシユレンク管に触
媒として、〔Ru(p-Ｔｏ-BINAP)〕(ＣO4)2（２１m
g，0.021ｍｍｏ）を計りとり、脱気した無水メタノー
ル（１０ｍ）を加えた溶液を調製しておく。Each spectrum data is shown. 1 H NMR (400 MHz, CDC 3 ) δppm: 1.70 (m, 4H), 2.11
(m, 2H), 2.20 (m, 2H), 2.14 (s, 3H), 2.29 (m, 2H), 3.78 (s, 3
H), 3.85 (t, J = 6.0Hz, 1H), 6.16 (s, 1H), 6.83 (m, 2H), 7.23
(m, 2H) MS: m / e 297 Example 5 [Ru (p-To-BINAP)] (CO 4 ) 2 (21 m
g, 0.021 mmo) is weighed, and degassed anhydrous methanol (10 m) is added to prepare a solution.
一方、(Z)−Ｎ−ホルミル−１−（４−メトキシフエニ
ルメチレン）−３，４，５，６，７，８−ヘキサヒドロ
イソキノリン（480.4mg，１．６９ｍｍｏ）を脱気し
た無水メタノール（１５ｍ）を加えた溶液を調製して
おく。基質溶液を触媒溶液に混ぜ、オートクレーブに移
し、水素気圧５０kg／cm2、５５℃で２８時間攪拌終了
後、減圧濃縮し、シリカゲルカラムクロマトグラフイー
で精製することにより、(+)−Ｎ−ホルミル−１−（４
−メトキシフエニルメチル）−１，２，３，４，５，
６，７，８−オクタヒドロイソキノリン（４６３mg，９
６％）を得た。On the other hand, anhydrous methanol degassed from (Z) -N-formyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8-hexahydroisoquinoline (480.4 mg, 1.69 mmo) Prepare a solution containing (15 m). The substrate solution was mixed with the catalyst solution, transferred to an autoclave, and stirred under hydrogen pressure of 50 kg / cm 2 and 55 ° C. for 28 hours, then concentrated under reduced pressure and purified by silica gel column chromatography to obtain (+)-N-formyl. -1- (4
-Methoxyphenylmethyl) -1,2,3,4,5,
6,7,8-Octahydroisoquinoline (463 mg, 9
6%) was obtained.
このものの旋光度は〔α〕25 D＝22.4゜(C＝1.60，メタノ
ール)であつた。The optical rotation of this product was [α] 25 D = 22.4 ° (C = 1.60, methanol).
光学純度はホルミル化後、生成物を２，３，４，５−テ
トラ−Ｏ−アセチル−β−Ｄ−グルコピラノシルイソチ
オシアネートと反応させ、逆相HPLC分析を行つて不斉収
率を決定した結果、９７．８％eeであつた。The optical purity was determined after formylation by reacting the product with 2,3,4,5-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate and performing reverse phase HPLC analysis to obtain an asymmetric yield. As a result of the determination, it was 97.8% ee.
各スペクトルデータを示した。１ Ｈ NMR(400MHz,ＣＤＣ３)δppm：1.68(m,4H),1.90
(m,4H),2.20(m,2H),2.64(dd,J＝10.4,13.9Hz,0.6H),2.9
0(m,2.4H),3.31(dd,J＝6.6,12.9Hz,0.4H),3.58(broadd,
J＝9.9Hz,0.6H),3.77(s,3H),4.37(dd,J＝6.7,12.9Hz,0.
6H),4.68(broads,0.4H),6.80(m,2H),6.99(m,0.6H),7.05
(m,0.4H),7.39(s,0.6H),7.92(s,0.4H)１３ Ｃ NMR(100MHz,ＣＤＣ３)δppm：22.7,22.8,22.
9,27.7,29.7,30.0,30.8,33.4,36.3,37.6,40.4,53.2,55.
2,60.4,60.8,113.6,114.1,127.8,128.9,129.8,130.0,13
0.2,130.4,158.2,158.4,160.8,161.1 UV(MeOH)：220,277,284nm MS:m/e 285 実施例６ 実施例５において、触媒としてRu(p-Ｔｏ-BINAP)(CF3
CO2)2を用いた他は、他の条件を実施例１と同様にして
反応を行つた結果、収率９４％、不斉収率９６．５％ee
で、(+)−Ｎ−ホルミル−１−（４−メトキシフエニル
メチル）−１，２，３，４，５，６，７，８−オクタヒ
ドロイソキノリンを得た。Each spectrum data is shown. 1 H NMR (400 MHz, CDC 3 ) δppm: 1.68 (m, 4H), 1.90
(m, 4H), 2.20 (m, 2H), 2.64 (dd, J = 10.4,13.9Hz, 0.6H), 2.9
0 (m, 2.4H), 3.31 (dd, J = 6.6,12.9Hz, 0.4H), 3.58 (broadd,
J = 9.9Hz, 0.6H), 3.77 (s, 3H), 4.37 (dd, J = 6.7,12.9Hz, 0.
6H), 4.68 (broads, 0.4H), 6.80 (m, 2H), 6.99 (m, 0.6H), 7.05
(m, 0.4H), 7.39 (s, 0.6H), 7.92 (s, 0.4H) 13 C NMR (100MHz, CDC 3 ) δppm: 22.7, 22.8, 22.
9,27.7,29.7,30.0,30.8,33.4,36.3,37.6,40.4,53.2,55.
2,60.4,60.8,113.6,114.1,127.8,128.9,129.8,130.0,13
0.2,130.4,158.2,158.4,160.8,161.1 UV (M e OH): 220,277,284 nm MS: m / e 285 Example 6 In Example 5, Ru (p-To-BINAP) (CF 3 ) was used as a catalyst.
The reaction was carried out under the same conditions as in Example 1 except that CO 2 ) 2 was used. As a result, the yield was 94% and the asymmetric yield was 96.5% ee.
Thus, (+)-N-formyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline was obtained.
実施例７ あらかじめ乾燥し、アルゴン置換したシユレンク管に、
〔Ru2Ｃ４(p-Ｔｏ-BINAP)2〕NEt3（２７mg，0.0294
ｍｍｏ）を計りとり、脱気した無水メタノール（３０
ｍ）を加えた溶液を調製しておく。Example 7 In a Schlenk tube previously dried and replaced with argon,
[Ru 2 C 4 (p-To-BINAP) 2 ] NEt 3 (27 mg, 0.0294
mmo) was weighed and degassed anhydrous methanol (30
Prepare a solution containing m).
一方、(Z)−Ｎ−ホルミル−１−（４−メトキシフエニ
ルメチル）−３，４，５，６，７，８−ヘキサヒドロイ
ソキノリン（５４３．１mg，２．００ｍｍｏ）を脱気
した無水塩化メチレン（２ｍ）を加えた溶液を調製し
ておく。基質溶液に触媒溶液を混ぜ、オートクレーブに
移し、水素気圧５０kg／cm2、３５℃で１００時間攪拌
後、減圧濃縮し、シリカゲルカラムクロマトグラフイー
で精製することにより、(+)−Ｎ−ホルミル−１−（４
−メトキシフエニルメチル）−１，２，３，４，５，
６，７，８−オクタヒドロイソキノリン５１４mg（不斉
収率９７．０％ee，収率８９％）を得た。On the other hand, (Z) -N-formyl-1- (4-methoxyphenylmethyl) -3,4,5,6,7,8-hexahydroisoquinoline (543.1 mg, 2.00 mmo) was degassed anhydrous Prepare a solution in which methylene chloride (2 m) is added. The catalyst solution was mixed with the substrate solution, transferred to an autoclave, stirred at hydrogen pressure of 50 kg / cm 2 and 35 ° C. for 100 hours, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (+)-N-formyl- 1- (4
-Methoxyphenylmethyl) -1,2,3,4,5,
514 mg of 6,7,8-octahydroisoquinoline (asymmetric yield 97.0% ee, yield 89%) were obtained.
実施例８ 実施例５において、触媒として〔Ru(p-Ｔｏ-BINAP)〕
(PF6)2を用い、反応温度を４５℃、反応時間を６０時間
にした他は、他の条件を実施例５と同様にして反応を行
つた結果、収率９３％、不斉収率９６．６％eeで、(+)
−Ｎ−ホルミル−１−（４−メトキシフエニルメチル）
−１，２，３，４，５，６，７，８−オクタヒドロイソ
キノリンを得た。Example 8 In Example 5, as a catalyst [Ru (p-To-BINAP)]
(PF 6 ) 2 was used, the reaction temperature was 45 ° C., and the reaction time was 60 hours, except that the reaction was carried out in the same manner as in Example 5, with the result that the yield was 93% and the asymmetric yield was 93%. With 96.6% ee, (+)
-N-formyl-1- (4-methoxyphenylmethyl)
-1,2,3,4,5,6,7,8-octahydroisoquinoline was obtained.
実施例９ 実施例７において、触媒として、Ru(OAc)2〔BINAP〕を
用いた他は、他の条件を実施例７と同様にして反応を行
つた結果、収率９１％、不斉収率９６．９％eeで、(+)
−Ｎ−ホルミル−１−（４−メトキシフエニルメチル）
−１，２，３，４，５，６，７，８−オクタヒドロイソ
キノリンを得た。Example 9 The reaction was carried out in the same manner as in Example 7 except that Ru (OAc) 2 [BINAP] was used as the catalyst in Example 7, resulting in a yield of 91% and an asymmetric yield. With a rate of 96.9% ee, (+)
-N-formyl-1- (4-methoxyphenylmethyl)
-1,2,3,4,5,6,7,8-octahydroisoquinoline was obtained.
Claims (2)
エニルメチレン）−３，４，５，６，７，８−ヘキサヒ
ドロイソキノリンを、光学活性なルテニウム−ホスフイ
ン錯体触媒の存在下に水素添加することを特徴とする、
次式(II) 〔式中、Ｒ1は前記と同じ〕 で表わされる(+)−Ｎ−アシル−１−（４−メトキシフ
エニルメチル）−１，２，３，４，５，６，７，８−オ
クタヒドロイソキノリンの製造法。1. The following formula (I) [In the formula, R 1 represents a hydrogen atom or a lower alkyl group] (Z) -N-acyl-1- (4-methoxyphenylmethylene) -3,4,5,6,7,8- Hexahydroisoquinoline is hydrogenated in the presence of an optically active ruthenium-phosphine complex catalyst,
Formula (II) [Wherein R 1 is the same as above] (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octa Method for producing hydroisoquinoline.
が、次式(IV)〜(VI) 〔式中、Ｘはハロゲン原子を示し、Ｙは水素原子、アミ
ノ基、アセチルアミノ基またはスルホン基を示し、Ｒ2
は水素原子または直鎖もしくは分岐鎖の低級アルキル基
を示し、Ａ及びＺはＣＯ4、PF6、BF4、R3COO（ここで
Ｒ3はアルキル基、ハロゲン化低級アルキル基、低級ア
ルキル置換基を有していてもよいフエニル基、α−アミ
ノアルキル基またはα−アミノフエニルアルキル基を示
すか、あるいはＡとＺが一緒になつてアルキレンジカル
ボキシ基を形成する）を示し、ｎは１または２を示す〕 で表わされる化合物から選ばれるものである特許請求の
範囲第１項記載の製造法。2. An optically active ruthenium-phosphine complex having the following formulas (IV) to (VI): [In the formula, X represents a halogen atom, Y represents a hydrogen atom, an amino group, an acetylamino group or a sulfone group, and R 2
Is a hydrogen atom or a linear or branched lower alkyl group, A and Z are CO 4 , PF 6 , BF 4 , and R 3 COO (wherein R 3 is an alkyl group, a halogenated lower alkyl group, a lower alkyl-substituted group). A phenyl group which may have a group, an α-aminoalkyl group or an α-aminophenylalkyl group, or A and Z together form an alkylenedicarboxy group), and n is The method according to claim 1, which is selected from the compounds represented by the formulas 1 or 2].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62190770A JPH0625124B2 (en) | 1987-07-30 | 1987-07-30 | Process for producing (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62190770A JPH0625124B2 (en) | 1987-07-30 | 1987-07-30 | Process for producing (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6434964A JPS6434964A (en) | 1989-02-06 |
| JPH0625124B2 true JPH0625124B2 (en) | 1994-04-06 |
Family
ID=16263434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62190770A Expired - Lifetime JPH0625124B2 (en) | 1987-07-30 | 1987-07-30 | Process for producing (+)-N-acyl-1- (4-methoxyphenylmethyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0625124B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0397042B1 (en) * | 1989-05-10 | 1995-08-16 | F. Hoffmann-La Roche Ag | Process for the preparation of isoquinoline derivatives |
-
1987
- 1987-07-30 JP JP62190770A patent/JPH0625124B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6434964A (en) | 1989-02-06 |
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