JP2003212874A - Method for producing isoquinuclidine derivative - Google Patents
Method for producing isoquinuclidine derivativeInfo
- Publication number
- JP2003212874A JP2003212874A JP2002006947A JP2002006947A JP2003212874A JP 2003212874 A JP2003212874 A JP 2003212874A JP 2002006947 A JP2002006947 A JP 2002006947A JP 2002006947 A JP2002006947 A JP 2002006947A JP 2003212874 A JP2003212874 A JP 2003212874A
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- JP
- Japan
- Prior art keywords
- producing
- compound
- isoquinuclidine
- structural formula
- isoquinuclidine 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.)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は血糖降下作用を有
し、糖尿病の治療剤として有用なイソキヌクリジン誘導
体の新規な製造方法に関する。TECHNICAL FIELD The present invention relates to a novel method for producing an isoquinuclidine derivative having a hypoglycemic effect and useful as a therapeutic agent for diabetes.
【０００２】[0002]
【従来技術】本発明者らは、イソキヌクリジン誘導体を
合成し、その薬理作用の研究を行った。そして血糖降下
作用を有しており、糖尿病治療剤として極めて有用であ
る構造式（II）で示される新規なイソキヌクリジン誘導
体及びその製造方法を提案した（特願２００１−８８６
５３）。先に提案したイソキヌクリジン誘導体の製法は
下記の化学式で示すように不斉補助基Ｒ1を用いた不斉
アルキル化により行っている。The present inventors have synthesized an isoquinuclidine derivative and studied its pharmacological action. Then, a novel isoquinuclidine derivative represented by the structural formula (II), which has a hypoglycemic effect and is extremely useful as a therapeutic agent for diabetes, and a method for producing the same have been proposed (Japanese Patent Application No. 2001-886).
53). The previously proposed method for producing an isoquinuclidine derivative is carried out by asymmetric alkylation using an asymmetric auxiliary group R 1 as shown in the following chemical formula.
【０００３】[0003]
【化３】 [Chemical 3]
【０００４】上記の不斉補助基Ｒ1としては、（４Ｒ）
−ベンジル−２−オキサゾリジノン、（１Ｓ）−（−）
−２，１０−カンファースルタムなどが用いられ、この
製造方法によると、比較的高価な不斉補助基を用いる必
要があり、また不斉アルキル化は低温下行うなど大量合
成においては問題となる点を有している。The asymmetric auxiliary group R 1 is (4R)
-Benzyl-2-oxazolidinone, (1S)-(-)
-2,10-camphorsultam is used, and according to this production method, it is necessary to use a relatively expensive asymmetric auxiliary group, and asymmetric alkylation is a problem in large-scale synthesis such as performed at low temperature. Have a point.
【０００５】[0005]
【発明が解決しようとする課題】本発明は上記の事情に
鑑みなされたもので、簡単な操作でしかも収率よく安価
にイソキヌクリジン誘導体を合成し得る方法を提供する
ことを目的とする。The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method capable of synthesizing an isoquinuclidine derivative at a low cost with a simple operation.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、前記のイ
ソキヌクリジン誘導体の合成方法について鋭意研究を行
った結果、不斉還元反応を用いるイソキヌクリジン誘導
体の合成方法を見出して、本発明を完成した。すなわ
ち、本発明は、次式の構造式（Ｉ）：Means for Solving the Problems As a result of intensive studies on the above-mentioned method for synthesizing an isoquinuclidine derivative, the present inventors have found a method for synthesizing an isoquinuclidine derivative using an asymmetric reduction reaction, and completed the present invention. . That is, the present invention provides the following structural formula (I):
【０００７】[0007]
【化４】 [Chemical 4]
【０００８】で示される化合物の二重結合を不斉還元す
ることを特徴とする次式の構造式（II）：A structural formula (II) of the following formula characterized by asymmetrically reducing the double bond of the compound represented by:
【０００９】[0009]
【化５】 [Chemical 5]
【００１０】で示されるイソキヌクリジン誘導体の製造
方法である。また、本発明は、上記出発化合物の構造式
（Ｉ）で示される化合物である。A method for producing an isoquinuclidine derivative represented by: The present invention is also the compound represented by the structural formula (I) of the above-mentioned starting compound.
【００１１】[0011]
【発明の実施の形態】以下に、本発明の製造方法を更に
詳しく説明する。本発明の出発原料である構造式（Ｉ）
で示される化合物（化合物（Ｉ）と称することがある）
は新規な化合物であり、Yamaguchiらの方法(T.Yamaguch
i et al.,Chem.Pharm.Bull. 1997,45(9),1518-1520)に
したがい合成できる。すなわち、ベンズアルデヒド（II
I）とコハク酸ジエチルエステル（IV）とを塩基存在下
反応させ、次いで加水分解してジカルボン酸（Ｖ）とす
る。更に化合物（Ｖ）を酸無水物（VI）に変換後、イソ
キヌクリジンを反応させ、目的とする化合物（Ｉ）を得
る。BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described in more detail below. Structural formula (I) which is a starting material of the present invention
A compound represented by (may be referred to as compound (I))
Is a novel compound, and the method of Yamaguchi et al. (T. Yamaguch
i et al., Chem. Pharm. Bull. 1997, 45 (9), 1518-1520). That is, benzaldehyde (II
I) and succinic acid diethyl ester (IV) are reacted in the presence of a base, and then hydrolyzed to give dicarboxylic acid (V). Furthermore, after converting the compound (V) into an acid anhydride (VI), it is reacted with isoquinuclidine to obtain the target compound (I).
【００１２】[0012]
【化６】 [Chemical 6]
【００１３】また、ベンズアルデヒド（III）とコハク
酸ジエチルエステル（IV）を反応させ、ジカルボン酸
（Ｖ）とした後、塩化チオニルと反応させ、次いでイソ
キヌクリジン塩酸塩と反応させることにより、目的とす
る化合物（Ｉ）を得ることもできる(J.Org.Chem.,1990,
55,1679)。Further, benzaldehyde (III) is reacted with succinic acid diethyl ester (IV) to give dicarboxylic acid (V), which is then reacted with thionyl chloride and then with isoquinuclidine hydrochloride to give the desired compound. (I) can also be obtained (J.Org.Chem., 1990,
55 , 1679).
【００１４】[0014]
【化７】 [Chemical 7]
【００１５】上記の如くして得られる化合物（Ｉ）の二
重結合を不斉還元することにより構造式（II）で示され
る化合物を得る。この不斉還元反応は、触媒の存在下、
水素雰囲気下にて行う。この触媒としては、次に示す如
き中心金属にＲｕ、Ｒｈ等を有する、不斉水素化反応に
通常用いられる光学活性触媒が使用できる。
（１）RuCl2[(R)-binap]：ジクロロ〔(Ｒ)−(＋)−２，
２’−ビス（ジフェニルホスフィノ）−１，１’−ビナ
フチル〕ルテニウム(II) （A.S.C.Chan et al.,U.S.Pa
tent 5,198,561）
（２）[Rh(COD)((R,R)-Et-DUPHOS)]+ClO4 -：（−)−
１，２−ビス〔(２Ｒ，５Ｒ)−２，５−ジエチルホスホ
ラノ〕ベンゼン（シクロオクタジエン）ロジウム（Ｉ）
過塩素酸塩 （J.Am.Chem.Soc.,1993,115,10125）
（３）[Rh(COD)((R,R)-DIPAMP)]+BF4 -：（Ｒ，Ｒ)−
(−)−１，２−ビス〔(Ｏ−メトキシフェニル)（フェニ
ル）ホスフィノ〕エタン（１，５−シクロオクタジエ
ン）ロジウム（Ｉ）テトラフルオロボレート （J.R.Ko
sak and T.A.Johnson,Eds.,Chem.Ind.(Marcel Dekker,I
nc.,New York,1994)Vol.53,81）
（４）[Rh(COD)((S)-binap)]+ClO4 -：〔（Ｓ）−（−）
−２，２’−ビス（ジフェニルホスフィノ）−１，１’
−ビナフチル〕(シクロオクタジエン）ロジウム（Ｉ）
過塩素酸塩 （J.Am.Chem.Soc.,1988,110,629）
溶媒としてはメタノール、ＴＨＦ、塩化メチレン等を単
独又は混合して使用する。水素は常圧又は加圧下とし、
反応は室温又は加熱して行う。The compound represented by the structural formula (II) is obtained by asymmetrically reducing the double bond of the compound (I) obtained as described above. This asymmetric reduction reaction, in the presence of a catalyst,
Perform in a hydrogen atmosphere. As this catalyst, an optically active catalyst which has Ru, Rh, etc. in the central metal as shown below and which is usually used in an asymmetric hydrogenation reaction can be used. (1) RuCl 2 [(R) -binap]: dichloro [(R)-(+)-2,
2'-bis (diphenylphosphino) -1,1'-binaphthyl] ruthenium (II) (ASCChan et al., USPa
tent 5,198,561) (2) [Rh (COD) ((R, R) -Et-DUPHOS)] + ClO 4 -: (-) -
1,2-bis [(2R, 5R) -2,5-diethylphosphorano] benzene (cyclooctadiene) rhodium (I)
Perchlorate (J.Am.Chem.Soc, 1993,115,10125.) (3 ) [Rh (COD) ((R, R) -DIPAMP)] + BF 4 -: (R, R) -
(−)-1,2-bis [(O-methoxyphenyl) (phenyl) phosphino] ethane (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate (JRKo
sak and TAJohnson, Eds., Chem.Ind. (Marcel Dekker, I
. nc, New York, 1994) Vol.53,81) (4) [Rh (COD) ((S) -binap)] + ClO 4 -: [(S) - (-)
-2,2'-bis (diphenylphosphino) -1,1 '
-Binaphtyl] (cyclooctadiene) rhodium (I)
Perchlorate (J. Am. Chem. Soc., 1988, 110, 629) As a solvent, methanol, THF, methylene chloride, etc. may be used alone or in combination. Hydrogen is at normal pressure or under pressure,
The reaction is performed at room temperature or by heating.
【００１６】[0016]
【実施例】以下、実施例及び参考例により本発明を更に
詳しく説明するが、本発明はこれらの実施例により何ら
限定されるものではない。
参考例１
２−ベンジリデン−コハク酸（化合物Ｖ）の製造方法
コハク酸ジエチルエステル（１１．２ｇ）をメタノール
（３０ｍＬ）に溶解し、ナトリウムメチラート（１．５
ｇ）を加えて還流する。ベンズアルデヒド（３．５ｇ）
のメタノール溶液（３０ｍＬ）を３０分間かけて滴下
後、２時間還流し、更に２Ｎ水酸化ナトリウム水溶液
（８０ｍＬ）を加えて１時間還流する。メタノールを留
去し、水層をエーテル洗して、１０％塩酸水溶液にて中
和後、酢酸エチル抽出する。有機層を飽和食塩水で洗浄
し、芒硝で脱水後、ろ過して濃縮する。残留物を結晶化
し、ろ過して目的物３．１ｇを無色結晶として得た。
IR(cm-1):2944,2626,2530,1668,1425,1314,1299,1281,1
224,918
Mass(m/z):206(M+),188,162,131,115(BP),89,63,501
H-NMR(CD3OD):3.52(2H,s),7.44-7.47(5H,m),7.93(1H,
s)The present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples. Reference Example 1 Method for producing 2-benzylidene-succinic acid (Compound V) Diethyl succinate (11.2 g) was dissolved in methanol (30 mL), and sodium methylate (1.5 mL) was added.
g) is added and refluxed. Benzaldehyde (3.5g)
Of methanol solution (30 mL) was added dropwise over 30 minutes, then the mixture was refluxed for 2 hours, 2N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was refluxed for 1 hour. Methanol is distilled off, the aqueous layer is washed with ether, neutralized with a 10% aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dehydrated with Glauber's salt, filtered and concentrated. The residue was crystallized and filtered to obtain 3.1 g of the desired product as colorless crystals. IR (cm -1 ): 2944,2626,2530,1668,1425,1314,1299,1281,1
224,918 Mass (m / z): 206 (M + ), 188,162,131,115 (BP), 89,63,50 1 H-NMR (CD 3 OD): 3.52 (2H, s), 7.44-7.47 (5H, m), 7.93 (1H,
s)
【００１７】参考例２
２−ベンジリデン−コハク酸無水物（化合物VI）の製造
方法
参考例１で得られた化合物（１．５ｇ）と塩化メチレン
（６ｍＬ）に溶解し、無水酢酸（２．２ｇ）を加えて２
時間還流する。反応液を濃縮し、トルエン共沸して析出
結晶をろ過し、目的物１．２ｇを緑色結晶として得た。1
H-NMR(CDCl3):3.84(2H,d),7.26(1H,s),7.50(4H,s),7.8
0(1H,s)Reference Example 2 Method for producing 2-benzylidene-succinic anhydride (Compound VI) The compound (1.5 g) obtained in Reference Example 1 and methylene chloride (6 mL) were dissolved and acetic anhydride (2.2 g) was added. ) And add 2
Reflux for an hour. The reaction solution was concentrated and azeotropically distilled with toluene, and the precipitated crystals were filtered to obtain 1.2 g of the desired product as green crystals. 1 H-NMR (CDCl 3 ): 3.84 (2H, d), 7.26 (1H, s), 7.50 (4H, s), 7.8
0 (1H, s)
【００１８】実施例１
２−ベンジリデン−４−（イソキヌクリジン−２−イ
ル）−４−オキソ−ブタン酸（化合物Ｉ）の製造方法。
イソキヌクリジン塩酸塩（１２．３ｇ）をＣＨ2Ｃｌ
2（１４０ｍＬ）に溶解し、０℃にてトリエチルアミン
（１６．８ｇ）を加え、１０分間撹拌後、参考例２で得
られた化合物（１４．２ｇ）を加え、更に３０間撹拌す
る。反応液を氷水にあけ、１０％塩酸水溶液を用いてｐ
Ｈ２とした後、酢酸エチルで抽出する。有機層を水、飽
和食塩水で洗浄し、芒硝で脱水する。ろ過し、濃縮して
残留物をシリカゲルカラムクロマトグラフィー（酢酸エ
チル）で精製し、目的物１４．９ｇを無色結晶として得
た。
IR(cm-1):3388,2920,2590,1704,1587,1449,1239,1212
Mass(m/z):298[M-H]- 1
H-NMR(CDCl3):1.65-1.83(9H,m),3.29-3.64(4,5H,m),4.
57(0.5H,s),7.34-7.41(5H,m),7.79(1H,dd)Example 1 Method for producing 2-benzylidene-4- (isoquinuclidin-2-yl) -4-oxo-butanoic acid (Compound I). Isoquinuclidine hydrochloride (12.3 g) was added to CH 2 Cl
It was dissolved in 2 (140 mL), triethylamine (16.8 g) was added at 0 ° C., the mixture was stirred for 10 minutes, the compound (14.2 g) obtained in Reference Example 2 was added, and the mixture was further stirred for 30 minutes. Pour the reaction solution into ice water and use a 10% aqueous hydrochloric acid solution.
After adjusting to H2, it is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, and dehydrated with Glauber's salt. After filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 14.9 g of the desired product as colorless crystals. IR (cm -1): 3388,2920,2590,1704,1587,1449,1239,1212 Mass (m / z): 298 [MH] - 1 H-NMR (CDCl 3): 1.65-1.83 (9H, m ), 3.29-3.64 (4,5H, m), 4.
57 (0.5H, s), 7.34-7.41 (5H, m), 7.79 (1H, dd)
【００１９】実施例２
（２Ｓ）−２−ベンジル-４−（イソキヌクリジン-２−
イル）−４−オキソ−ブタン酸（化合物II）の製造方
法。
化合物（Ｉ）１００ｍｇをＭｅＯＨ／ＴＨＦ（１３：
２、７．５ｍＬ）に溶解し、[Rh(COD)((R,R)- Et-DUPHO
S)]+ClO4 -（０．５ｍｏｌ％）を加えて水素置換し、水
素５気圧下、３０℃にて６時間撹拌する。反応液を濃縮
し、残留物をシリカゲルカラムクロマトグラフィー（ク
ロロホルム：酢酸エチル＝５：１）で精製し、目的物９
３ｍｇを無色結晶として得た。
IR(cm-1):2926,2860,1725,1590,1452,1245,1176,732,69
9
Mass(m/z):301(M+),257,190,153(BP),117,97,82,571
H-NMR(CDCl3):1.54-1.85(9H,m)2.38(1H,dd),2.47(1H,
m),2.76(1H,m), 3.01(1H,m),3.11(1H,m),3.32(1H,dd),
3.41 and 4.52(total 2H, each s),7.71-7.33(5H,m),1
3.2(1H,brs)Example 2 (2S) -2-benzyl-4- (isoquinuclidine-2-
Il) -4-oxo-butanoic acid (Compound II). Compound (I) 100 mg was added to MeOH / THF (13:
2, 7.5 mL), and [Rh (COD) ((R, R)-Et-DUPHO
S)] + ClO 4 − (0.5 mol%) was added to replace the atmosphere with hydrogen, and the mixture was stirred at 5 ° C. for 5 hours at 30 ° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give the desired product 9
3 mg was obtained as colorless crystals. IR (cm -1 ): 2926,2860,1725,1590,1452,1245,1176,732,69
9 Mass (m / z): 301 (M + ), 257,190,153 (BP), 117,97,82,57 1 H-NMR (CDCl 3 ): 1.54-1.85 (9H, m) 2.38 (1H, dd), 2.47 (1H,
m), 2.76 (1H, m), 3.01 (1H, m), 3.11 (1H, m), 3.32 (1H, dd),
3.41 and 4.52 (total 2H, each s), 7.71-7.33 (5H, m), 1
3.2 (1H, brs)
【００２０】実施例３
実施例２と同様の反応を、他の触媒を用いて行った。そ
の結果を表１に示す。いずれの反応においても定量的に
還元は進行した。なお、表１中の「％ｅ．ｅ．」は、鏡
像異性体過剰率を表す。Example 3 The same reaction as in Example 2 was carried out using another catalyst. The results are shown in Table 1. The reduction proceeded quantitatively in both reactions. In addition, "% ee" in Table 1 represents an enantiomeric excess rate.
【００２１】[0021]
【表１】 [Table 1]
【００２２】[0022]
【発明の効果】本発明によると、簡便に収率よく、しか
も安価に、糖尿病の治療剤として有用なイソキヌクリジ
ン誘導体を合成することができる。INDUSTRIAL APPLICABILITY According to the present invention, an isoquinuclidine derivative useful as a therapeutic agent for diabetes can be easily synthesized at high yield and at low cost.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 冨山 剛 長野県埴科郡坂城町大字坂城1113番地 Ｆターム(参考） 4C064 AA08 CC01 DD01 EE01 FF06 GG03 HH05 HH10 4H006 AA02 AC11 AC81 BA23 BA24 BA48 4H039 CA19 CB10 ─────────────────────────────────────────────────── ─── Continued front page (72) Inventor Tsuyoshi Tomiyama 1113 Sakajo, Sakajo-cho, Hanashina-gun, Nagano Prefecture F-term (reference) 4C064 AA08 CC01 DD01 EE01 FF06 GG03 HH05 HH10 4H006 AA02 AC11 AC81 BA23 BA24 BA48 4H039 CA19 CB10
Claims (2)
とする次式の構造式（II）： 【化２】 で示されるイソキヌクリジン誘導体の製造方法。1. A structural formula (I) represented by the following formula: Structurally represented by the following structural formula (II), which is characterized by asymmetrically reducing the double bond of the compound represented by: A method for producing an isoquinuclidine derivative represented by:
合物。2. A compound represented by the structural formula (I) according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002006947A JP2003212874A (en) | 2002-01-16 | 2002-01-16 | Method for producing isoquinuclidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002006947A JP2003212874A (en) | 2002-01-16 | 2002-01-16 | Method for producing isoquinuclidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2003212874A true JP2003212874A (en) | 2003-07-30 |
Family
ID=27645570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002006947A Pending JP2003212874A (en) | 2002-01-16 | 2002-01-16 | Method for producing isoquinuclidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2003212874A (en) |
-
2002
- 2002-01-16 JP JP2002006947A patent/JP2003212874A/en active Pending
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