JP2711728B2 - Novel quinoline derivative and method for producing the same - Google Patents
Novel quinoline derivative and method for producing the sameInfo
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- JP2711728B2 JP2711728B2 JP22035289A JP22035289A JP2711728B2 JP 2711728 B2 JP2711728 B2 JP 2711728B2 JP 22035289 A JP22035289 A JP 22035289A JP 22035289 A JP22035289 A JP 22035289A JP 2711728 B2 JP2711728 B2 JP 2711728B2
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は新規キノリン誘導体に関し、更に詳細には抗
癌剤として有用なカンプトテシン誘導体の合成中間体と
して有用な新規キノリン誘導体およびその製造法に関す
る。Description: TECHNICAL FIELD The present invention relates to a novel quinoline derivative, and more particularly to a novel quinoline derivative useful as a synthetic intermediate of a camptothecin derivative useful as an anticancer agent, and a method for producing the same.
カンプトテカ・アクミナタ(Camptotheca acuminat
a)の樹皮、根、果実及び葉などから単離されたカンプ
トテシンは5環性のアルカロイドで、核酸合成を阻害す
ることによって抗腫瘍活性を示すことが知られている。
そして該カンプトテシンの全合成については、G.Stork
ら〔J.Am.Chem.Soc.,93,4074(1971)〕の報告をはじめ
として数多くの報告がある。Camptotheca acuminat
Camptothecin isolated from bark, roots, fruits, leaves and the like in a) is a pentacyclic alkaloid and is known to exhibit antitumor activity by inhibiting nucleic acid synthesis.
And for the total synthesis of the camptothecin, see G. Stork
[J. Am. Chem. Soc., 93 , 4074 (1971)].
一方、より優れた抗腫瘍活性を有する化合物を求めて
種々研究がなされており、下記式 で示される化合物は優れた抗腫瘍活性を有し、かつ安全
性も高く抗癌剤として有用であることが知られている
〔特開昭58-39683号;Jpn.J.Cancer Chemother.,14,Part
-II,850(1985)〕。On the other hand, various studies have been made in search of compounds having better antitumor activity, and the following formula The compound represented by has excellent antitumor activity, and is known to be highly safe and useful as an anticancer agent (JP-A-58-39683; Jpn.J. Cancer Chemother., 14 , Part
-II, 850 (1985)].
しかしながら、従来の上記カンプトテシン誘導体の製
造法は工程数が長く、工業的に有利な方法とは言い難か
った。従って、上記カンプトテシン誘導体の工業的に有
利な製造法及び合成中間体の提供が望まれていた。However, the conventional method for producing the camptothecin derivative has a long number of steps, and is not industrially advantageous. Therefore, it has been desired to provide an industrially advantageous production method of the camptothecin derivative and a synthetic intermediate.
かかる実情において、本発明者は上記課題を解決すべ
く鋭意研究してきたところ、p−アニシジンを原料とし
て短い工程で合成される新規なキノリン誘導体が、上記
抗癌剤として優れたカンプトテシン誘導体の合成中間体
として有用であることを見出し本発明を完成した。Under such circumstances, the present inventors have intensively studied to solve the above-mentioned problems, and as a result, a novel quinoline derivative synthesized in a short process using p-anisidine as a raw material has been proposed as a synthetic intermediate of a camptothecin derivative excellent as the anticancer agent. The present invention was found to be useful, and the present invention was completed.
すなわち、本発明は次の一般式(I) 〔式中、AはC=O又はCHOHを示し、R1は水素原
子、アラルキル基又は低級アルキル基を示す〕 で表わされる新規キノリン誘導体およびその製造法を提
供するものである。That is, the present invention provides the following general formula (I) [Wherein A represents C = O or CHOH, and R 1 represents a hydrogen atom, an aralkyl group or a lower alkyl group] and a method for producing the same.
上記一般式(I)中、R1で示されるアラルキル基と
してはベンゼン基が好ましく;低級アルキル基としては
炭素数1〜6の直鎖若しくは分岐鎖のアルキル基が、特
にt−ブチル基が好ましい。In the above general formula (I), the aralkyl group represented by R 1 is preferably a benzene group; the lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, particularly preferably a t-butyl group. .
本発明の新規キノリン誘導体(I)は、例えば次の反
応式に従って製造される。The novel quinoline derivative (I) of the present invention is produced, for example, according to the following reaction formula.
〔反応式中、R2、R3、R4、R6及びR7はそれぞれ低
級アルキル基を示し、R5はアラルキル基を示し、Xは
ハロゲン原子を示す〕 以下、上記反応式の各工程について説明する。 [In the reaction formula, R 2 , R 3 , R 4 , R 6 and R 7 each represent a lower alkyl group, R 5 represents an aralkyl group, and X represents a halogen atom.] Will be described.
(1) p−アニシジン(II)とプロピオニトリルを塩
化ホウ素及び塩化アルミニウムの存在下に反応させれ
ば、2−アミノ−5−メトキシプロピオフェノン(II
I)が得られる。この反応は菅沢らの方法〔J.Am.Chem.S
oc.,100,4842(1978)〕に従って実施することができ
る。(1) By reacting p-anisidine (II) with propionitrile in the presence of boron chloride and aluminum chloride, 2-amino-5-methoxypropiophenone (II)
I) is obtained. This reaction is performed according to the method of Sugasawa et al. [J. Am. Chem. S.
oc., 100 , 4842 (1978)].
(2) 2−アミノ−5−メトキシプロピオフェノン
(III)にピロリジン誘導体(IV)を反応させて、化合
物(V)を得る。この反応は、例えばトルエン等の芳香
族炭化水素類溶媒中、加熱還流することにより行われ
る。(2) The compound (V) is obtained by reacting 2-amino-5-methoxypropiophenone (III) with a pyrrolidine derivative (IV). This reaction is carried out by heating and refluxing in an aromatic hydrocarbon solvent such as toluene.
(3) 化合物(V)を水酸化カリウム等の塩基の存在
下に加熱すれば化合物(VI)が得られる。この反応は、
エタノール、水などの溶媒中で加熱還流するのが好まし
い。(3) Compound (VI) is obtained by heating compound (V) in the presence of a base such as potassium hydroxide. This reaction is
It is preferable to heat and reflux in a solvent such as ethanol or water.
(4) 化合物(VI)にアルキルマロニルハライド(VI
I)を反応させれば、化合物(VIII)が得られる。この
反応は、炭酸水素ナトリウム、水酸化ナトリウム、炭酸
ナトリウムなどの塩基の存在下に実施するのが好まし
い。(4) Compound (VI) is substituted with alkylmalonyl halide (VI
By reacting I), compound (VIII) is obtained. This reaction is preferably carried out in the presence of a base such as sodium hydrogen carbonate, sodium hydroxide, sodium carbonate and the like.
(5) 化合物(VIII)に塩基を反応させれば、化合物
(IX)が得られる。塩基としては、ナトリウムエトキシ
ドなどの金属アルコラートが好ましい。(5) Compound (IX) is obtained by reacting compound (VIII) with a base. As the base, a metal alcoholate such as sodium ethoxide is preferable.
(6) 化合物(IX)を酸の存在下に加熱すれば、化合
物(X)が得られる。用いられる酸としては、酢酸など
が挙げられる。(6) Compound (IX) is obtained by heating compound (IX) in the presence of an acid. Examples of the acid used include acetic acid.
(7) 化合物(X)を還元して化合物(XI)を得る。
還元は水素化ホウ素ナトリウムを用いて行うのが好まし
い。(7) Compound (X) is reduced to obtain compound (XI).
The reduction is preferably carried out using sodium borohydride.
(8) 化合物(XI)を酸の存在下に加熱せしめれば、
化合物(XII)が得られる。用いられる酸としては、酢
酸ナトリウム及び無水酢酸の混合物が好ましい。(8) If compound (XI) is heated in the presence of an acid,
Compound (XII) is obtained. As the acid used, a mixture of sodium acetate and acetic anhydride is preferred.
(9) 次いで、化合物(XII)に酪酸誘導体(XIII)
を反応せしめれば、化合物(Ia)が製造される。この反
応は、n−ブチルリチウムなどの存在下に−80〜0℃の
低温下に行われる。反応溶媒はテトラヒドロフランなど
のエーテル類、n−ヘキサンなどの炭化水素類が好まし
い。(9) Then, butyric acid derivative (XIII) is added to compound (XII).
Is reacted to produce compound (Ia). This reaction is carried out at a low temperature of -80 to 0 ° C in the presence of n-butyllithium or the like. The reaction solvent is preferably an ether such as tetrahydrofuran or a hydrocarbon such as n-hexane.
(10) 化合物(Ia)を加水素分解すれば、化合物(I
b)が製造される。反応は、パラジウム炭素などの触媒
の存在下、メタノールなどのアルコール溶媒中で水素を
添加することにより実施される。(10) By subjecting compound (Ia) to hydrogenolysis, compound (Ia)
b) is manufactured. The reaction is carried out by adding hydrogen in an alcohol solvent such as methanol in the presence of a catalyst such as palladium carbon.
(11) 次に化合物(Ib)又はその反応性誘導体に低級
アルコール又はアルキル化剤を作用させればエステル誘
導体(Ic)が製造される。(11) Next, an ester derivative (Ic) is produced by reacting a lower alcohol or an alkylating agent on the compound (Ib) or its reactive derivative.
(12) 更に(Ic)をテトラヒドロフラン等のエーテル
系溶媒中で水素化リチウムアルミニウム等の還元剤を用
いて還元することにより化合物(Id)を製造することが
できる。(12) Further, compound (Id) can be produced by reducing (Ic) in an ether solvent such as tetrahydrofuran using a reducing agent such as lithium aluminum hydride.
本発明の新規キノリン誘導体(I)を利用すれば抗癌
剤として有用なカンプトテシン誘導体が短い工程で効率
よく製造できる。従って、本発明化合物はカンプトテシ
ン誘導体の製造中間体として有用である。By using the novel quinoline derivative (I) of the present invention, a camptothecin derivative useful as an anticancer agent can be efficiently produced in a short process. Therefore, the compound of the present invention is useful as an intermediate for producing a camptothecin derivative.
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) 2−アミノ−5−メトキシプロピオフェノン
(III)の合成: アニシジン615mg(5mmol)をベンゼン5mlに溶かし、
氷冷で冷却したBCl3の2.22molのベンゼン溶液2.47ml
(5.5mmol)に加えた。アニシジン−BCl3の白色付加物
が析出する。次にプロピオニトリル500.8mg(10mmol)
とAlCl3 733mg(5.5mmol)を加え、室温下BCl3−アニシ
ジン付加物及びAlCl3を攪拌溶解後、6時間加熱還流さ
せた。冷却後、2NHC10mlを加え、70〜80℃で20分間加
熱し、反応生成物を加水分解した。反応液を10%NaOHで
中和した後、酢酸エチルで抽出、水で洗浄し、無水硫酸
ナトリウムで乾燥した。酢酸エチルを減圧で留去した
後、残渣をシリカゲルカラムクロマト(塩化メチレン)
で精製し、(III)の黄色結晶420mg(47%)を得た。Example 1 (1) Synthesis of 2-amino-5-methoxypropiophenone (III): 615 mg (5 mmol) of anisidine was dissolved in 5 ml of benzene,
2.47 ml of a 2.22 mol benzene solution of BCl 3 cooled on ice
(5.5 mmol). A white adduct of anisidine-BCl 3 precipitates. Next, 500.8 mg (10 mmol) of propionitrile
And AlCl 3 733 mg of (5.5 mmol) was added, at room temperature BCl 3 - After stirring dissolved anisidine adduct and AlCl 3, was heated under reflux for 6 hours. After cooling, 10 ml of 2N HCl was added, and the mixture was heated at 70 to 80 ° C. for 20 minutes to hydrolyze the reaction product. The reaction solution was neutralized with 10% NaOH, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride).
Then, 420 mg (47%) of yellow crystals of (III) were obtained.
黄色針状晶:mp 58℃(塩化メチレン−n−ヘキサン1 H−NMR(CDCl3)δ:1.21(3H,t,J=7.3Hz),2.96(2
H,q,J=7.3Hz),3.78(3H,s),6.63(1H,d,J=9.0Hz),
6,96(1H,dd.,J=9.0,2.9Hz),7.23(1H,d,J=2.9Hz) IR(CHCl3):3500,1650cm-1 MS m/z:179(M+) 元素分析(C16H13NO2として) 計算値:C 67.04;H 7.26;N 7.82 実測値:C 66.95;H 7.54;N 7.83 (2) 化合物(V)〔式(V)中、R2=R3=C2H5〕
の合成: 2−アミノ−5−メトキシプロピオフェノン358mg(2
0mmol)と1−エキシカルボニル−3−オキソプロリジ
ン−2−酢酸エチルエステル486mg(20mmol)をトルエ
ン20mlに溶かし、トシル酸34mg(2mmol)を加え、ディ
ーン−スターク(Dean-Stark)装置を用いて8時間加熱
還流させた。反応後トルエンを減圧で留去した後、残渣
をシリカゲルカラムクロマト(塩化メチレン)で精製
し、目的物(V)の無色結晶726mg(94%)を得た。Yellow needles: mp 58 ° C. (methylene chloride-n-hexane 1 H-NMR (CDCl 3 ) δ: 1.21 (3H, t, J = 7.3 Hz), 2.96 (2
H, q, J = 7.3Hz), 3.78 (3H, s), 6.63 (1H, d, J = 9.0Hz),
6,96 (1H, dd., J = 9.0,2.9Hz), 7.23 (1H, d, J = 2.9Hz) IR (CHCl 3 ): 3500,1650cm -1 MS m / z: 179 (M + ) Element Analysis (as C 16 H 13 NO 2 ) Calculated: C 67.04; H 7.26; N 7.82 Found: C 66.95; H 7.54; N 7.83 (2) Compound (V) [in formula (V), R 2 = R 3 = C 2 H 5]
Synthesis of 2-amino-5-methoxypropiophenone 358 mg (2
0 mmol) and 486 mg (20 mmol) of 1-ethoxycarbonyl-3-oxoprolidine-2-acetic acid ethyl ester are dissolved in 20 ml of toluene, 34 mg (2 mmol) of tosylic acid is added, and the mixture is added using a Dean-Stark apparatus. The mixture was heated under reflux for 8 hours. After the reaction, toluene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) to obtain 726 mg (94%) of the target compound (V) as colorless crystals.
無色針状晶:mp 85℃(エーテル−n−ヘキサン)1 H−NMR(CDCl3)δ:1.09(3H,t,J=7.1Hz),1.33(3
H,t,J=7.6Hz),1.35(3H,t,J=7.1Hz),2.95(2H,m),
3.21(2H,m),3.95(3H,s),4.06(2H,m),4.27(2H,
m),4.82(2H,m),5.32(1H,m),7.26(1H,d,J=2.7H
z),7.34(1H,dd.,J=9.1,2.7Hz),7.96(1H,d,J=9.1H
z) IR(CHCl3):1730,1690,1620cm-1 MS m/z:386(M+) 元素分析(C21H26N2O5として) 計算値:C 65.28;H 6.74;N 7.25 実測値:C 65.09;H 6.91;N 7.24 (3) 化合物(VI〔式(VI)中、R3=C2H5〕の合
成: 化合物(V)2g(5.2mmol)をエタノール20mlに溶か
し、10%KOH溶液10mlを加え、8時間加熱還流した。エ
タノールを減圧で留去した後、10%HCl溶液で中和する
と沈澱が析出し、これを濾取した。沈澱物を真空下乾燥
した後、エタノール20mlに溶かし、HClガスを通し、3
時間加熱還流した。エタノールを減圧で留去した後、10
%KOH溶液でアルカリ性にすると沈澱が析出し、これを
濾取した。沈澱をエーテル−n−ヘキサンから再結晶
し、目的物(VI)を1.1g(67%)を得た。Colorless needles: mp 85 ° C. (ether-n-hexane) 1 H-NMR (CDCl 3 ) δ: 1.09 (3H, t, J = 7.1 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.35 (3H, t, J = 7.1Hz), 2.95 (2H, m),
3.21 (2H, m), 3.95 (3H, s), 4.06 (2H, m), 4.27 (2H,
m), 4.82 (2H, m), 5.32 (1H, m), 7.26 (1H, d, J = 2.7H
z), 7.34 (1H, dd., J = 9.1,2.7Hz), 7.96 (1H, d, J = 9.1H)
z) IR (CHCl 3 ): 1730, 1690, 1620 cm −1 MS m / z: 386 (M + ) Elemental analysis (as C 21 H 26 N 2 O 5 ) Calculated: C 65.28; H 6.74; N 7.25 Value: C 65.09; H 6.91; N 7.24 (3) Synthesis of compound (VI [R 3 = C 2 H 5 in formula (VI)]: 2 g (5.2 mmol) of compound (V) was dissolved in 20 ml of ethanol, and The ethanol was distilled off under reduced pressure and neutralized with a 10% HCl solution to precipitate a precipitate, which was collected by filtration and dried under vacuum. Dissolve in ethanol (20 ml) and pass HCl gas through.
Heated to reflux for an hour. After distilling off ethanol under reduced pressure, 10
When the solution was made alkaline with a% KOH solution, a precipitate was deposited and collected by filtration. The precipitate was recrystallized from ether-n-hexane to obtain 1.1 g (67%) of the desired product (VI).
無色粉末:mp 86〜87℃(エーテル−n−ヘキサン)1 H−NMR(CDCl3)δ:1.27(3H,t,J=7.3Hz),1.30(3
H,t,J=7.3Hz),2.64(1H,dd.,J=16.4,10.0Hz),2.96
(2H,q,J=7.3Hz),3.29(1H,dd.,J=16.4,2.9HZ),3.9
5(3H,s),4.20(2H,q,J=7.3Hz),4.40(2H,s),4.88
(2H,dd.,J=10.0,2.9Hz),7.26(1H,d,J=2.5HZ),7.3
2(1H,dd.,J=9.0,2.5Hz),7.96(1H,d,J=9.0Hz) IR(CHCl3):3350,1720,1630cm-1 MS m/z:314(M+) 元素分析(C18H2203N2として) 計算値:C 68.79;H 7.01;N 8.92 実測値:C 68.56;H 7.18;N 9.00 (4) 化合物(VIII)〔式(VIII)中、R3=R4=C2
H5〕の合成: 化合物(VI)942mg(3mmol)をベンゼン5mlに溶か
し、10%NaHCO3溶液3.3mlを加えた。反応液を攪拌しな
がらエチルマロニルクロライド541.8mg(3.6mmol)のベ
ンゼン溶液3mlを滴下した。反応液を1時間室温で攪拌
した後、ベンゼン層を分取し、水洗、乾燥した。ベンゼ
ンを減圧で留去し、残渣をメタノールから再結晶して目
的物(VIII)1.1g(86%)を得た。Colorless powder: mp 86-87 ° C. (ether-n-hexane) 1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.30 (3
H, t, J = 7.3Hz), 2.64 (1H, dd., J = 16.4,10.0Hz), 2.96
(2H, q, J = 7.3Hz), 3.29 (1H, dd., J = 16.4, 2.9HZ), 3.9
5 (3H, s), 4.20 (2H, q, J = 7.3Hz), 4.40 (2H, s), 4.88
(2H, dd., J = 10.0,2.9Hz), 7.26 (1H, d, J = 2.5HZ), 7.3
2 (1H, dd., J = 9.0, 2.5 Hz), 7.96 (1H, d, J = 9.0 Hz) IR (CHCl 3 ): 3350, 1720, 1630 cm −1 MS m / z: 314 (M + ) Element analysis (C 18 H 22 0 3 as N 2) calculated: C 68.79; H 7.01; N 8.92 Found: C 68.56; H 7.18; N 9.00 (4) in the compound (VIII) [formula (VIII), R 3 = R 4 = C 2
Synthesis of H 5 ]: 942 mg (3 mmol) of the compound (VI) was dissolved in 5 ml of benzene, and 3.3 ml of a 10% NaHCO 3 solution was added. While stirring the reaction solution, 3 ml of a benzene solution of 541.8 mg (3.6 mmol) of ethylmalonyl chloride was added dropwise. After stirring the reaction solution for 1 hour at room temperature, the benzene layer was separated, washed with water and dried. Benzene was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 1.1 g (86%) of the target compound (VIII).
無色粉末:mp 105〜106℃(メタノール)1 H−NMR(CDCl3)δ:1.07(3H,t,J=7.3Hz),1.30(6
H,t,J=7.3Hz),2.98(2H,m),3.22(1H,dd.,J=17.1,
3.4Hz),3.53,3.61(each 1H,d,J=15.1Hz),3.63(1H,
m),3.90(2H,m),3.95(3H,s),4.25(2H,q,J=7.3H
z),4.94,5.04(each 1H,d,J=13.3Hz),5.48(1H,m),
7.25(1H,d,J=2.7Hz),7.35(1H,dd.,J=9.3,2.7Hz),
7.98(1H,d,J=9.3Hz) IR(CHCl3):1730,1650,1632cm-1 MS m/z:428(M+) 元素分析(C23H2806N2として) 計算値:C 64.49;H 6.54;N 6.54 実測値:C 64.22;H 6.71;N 6.56 (5) 化合物(IX)〔式(IX)中、R4=C2H5〕の合
成: 化合物(VIII)428mg(1mmol)に1%NaOEt溶液10ml
を加え、1時間加熱還流した。反応後エタノールを減圧
で留去し、水を加え、10%HCl溶液で中和すると沈澱を
生じた。沈澱を濾取しクロロホルム−メタノールから再
結晶して目的物(IX)290mg(76%)を得た。Colorless powder: mp 105-106 ° C. (methanol) 1 H-NMR (CDCl 3 ) δ: 1.07 (3H, t, J = 7.3 Hz), 1.30 (6
H, t, J = 7.3Hz), 2.98 (2H, m), 3.22 (1H, dd., J = 17.1,
3.4Hz), 3.53, 3.61 (each 1H, d, J = 15.1Hz), 3.63 (1H,
m), 3.90 (2H, m), 3.95 (3H, s), 4.25 (2H, q, J = 7.3H
z), 4.94,5.04 (each 1H, d, J = 13.3Hz), 5.48 (1H, m),
7.25 (1H, d, J = 2.7Hz), 7.35 (1H, dd., J = 9.3,2.7Hz),
7.98 (1H, d, J = 9.3Hz) IR (CHCl 3): 1730,1650,1632cm -1 MS m / z: 428 (M +) Elemental analysis (C 23 H 28 0 as 6 N 2) Calculated: C 64.49; H 6.54; N 6.54 Found: C 64.22; H 6.71; N 6.56 (5) Synthesis of compound (IX) [in the formula (IX), R 4 = C 2 H 5 ]: Compound (VIII) 428 mg ( 1mmol) 10% 1% NaOEt solution
Was added and heated under reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, water was added, and the mixture was neutralized with a 10% HCl solution to produce a precipitate. The precipitate was collected by filtration and recrystallized from chloroform-methanol to obtain 290 mg (76%) of the desired product (IX).
無色粉末:mp 165℃(クロロホルム−メタノール)1 H−NMR(CDCl3)δ:1.34(3H,t,J=7.8Hz),1.44(3
H,t,J=7.3Hz),2.84(1H,dd.,J=17.1,3.4Hz),3.02
(2H,q,J=7.8Hz),3.32(1H,dd.,J=17.1,4.4Hz),3.9
7(3H,s),4.43(2H,m),4.76(1H,d.J=16.1Hz),5.13
(1H,d,J=16.1Hz),5.17(1H,m),7.28(1H,d,J=2.4H
z),7.38(1H,dd.,J=9.3,2.4Hz),7.98(1H,d,J=9.3H
z) IR(CHCl3):1650,1590cm-1 MS m/z:382(M+) (6) 化合物(X)の合成: 化合物(IX)1g(2.6mmol)に10%酢酸溶液10mlを加
え、30分間加熱する。反応液をクロロホルムで抽出し、
水洗、乾燥後、クロロホルムを減圧で留去した。残渣を
シリカゲルカムクロマト(クロロホルム)で精製し、n
−ヘキサン−クロロホルムから再結晶して目的物(IX)
543mg(67%)を得た。Colorless powder: mp 165 ° C. (chloroform-methanol) 1 H-NMR (CDCl 3 ) δ: 1.34 (3H, t, J = 7.8 Hz), 1.44 (3
H, t, J = 7.3Hz), 2.84 (1H, dd., J = 17.1,3.4Hz), 3.02
(2H, q, J = 7.8Hz), 3.32 (1H, dd., J = 17.1,4.4Hz), 3.9
7 (3H, s), 4.43 (2H, m), 4.76 (1H, dJ = 16.1Hz), 5.13
(1H, d, J = 16.1Hz), 5.17 (1H, m), 7.28 (1H, d, J = 2.4H
z), 7.38 (1H, dd., J = 9.3,2.4Hz), 7.98 (1H, d, J = 9.3H)
z) IR (CHCl 3 ): 1650, 1590 cm −1 MS m / z: 382 (M + ) (6) Synthesis of compound (X): 10 g of a 10% acetic acid solution was added to 1 g (2.6 mmol) of compound (IX). Heat for 30 minutes. The reaction solution was extracted with chloroform,
After washing with water and drying, chloroform was distilled off under reduced pressure. The residue is purified by silica gel cam chromatography (chloroform).
-Recrystallized from hexane-chloroform to give the desired product (IX)
543 mg (67%) were obtained.
無色粉末mp 183〜184℃(n−ヘキサン−クロロホル
ム)1 H−NMR(CDCl3)δ:1.35(1H,t,J=7.8Hz),2.57(1
H,dd.,J=17.6,12.0Hz),3.02(2H,q,J=7.8Hz),3.42
(1H,d,J=19.0Hz),3.47(1H,dd.,J=17.6,3.9Hz),3.
60(1H,d,J=19.0Hz),3.97(3H,s),4.83(1H,d,J=1
6.1Hz),5.21(1H,d,J=16.1Hz),5.32(1H,d,J=12.0,
3.9Hz),7.28(1H,d.J=2.7Hz),7.40(1H,dd.,J=9.3,
2.7Hz),7.98(1H,d,J=9.3Hz) IR(CHCl3):1730,1660,1620cm-1 MS m/z:310(M+) (7) 化合物(XI)の合成: 化合物(X)310mg(1mmol)をエタノール10mlに溶か
し、攪拌しながら、NaBH418.9mg(0.5mmol)を少しずつ
加える。1時間室温で攪拌した後エタノールを減圧で留
去し、水を加え、10%HCl溶液で中和すると沈澱が生じ
る。沈澱を濾取し、クロロホルム−n−ヘキサンから再
結晶して目的物(XI)250mg(80%)を得た。Colorless powder mp 183-184 ° C (n-hexane-chloroform) 1 H-NMR (CDCl 3 ) δ: 1.35 (1H, t, J = 7.8 Hz), 2.57 (1
H, dd., J = 17.6,12.0Hz), 3.02 (2H, q, J = 7.8Hz), 3.42
(1H, d, J = 19.0Hz), 3.47 (1H, dd., J = 17.6,3.9Hz), 3.
60 (1H, d, J = 19.0Hz), 3.97 (3H, s), 4.83 (1H, d, J = 1
6.1Hz), 5.21 (1H, d, J = 16.1Hz), 5.32 (1H, d, J = 12.0,
3.9Hz), 7.28 (1H, dJ = 2.7Hz), 7.40 (1H, dd., J = 9.3,
2.7 Hz), 7.98 (1H, d, J = 9.3 Hz) IR (CHCl 3 ): 1730, 1660, 1620 cm −1 MS m / z: 310 (M + ) (7) Synthesis of compound (XI): compound (XI) X) 310 mg (1 mmol) are dissolved in 10 ml of ethanol and, while stirring, 18.9 mg (0.5 mmol) of NaBH 4 are added in small portions. After stirring for 1 hour at room temperature, ethanol is distilled off under reduced pressure, water is added, and neutralization with a 10% HCl solution causes precipitation. The precipitate was collected by filtration and recrystallized from chloroform-n-hexane to obtain 250 mg (80%) of the desired product (XI).
無色粉末:mp 105〜108℃(クロロホルム−n−ヘキサ
ン)1 H−NMR(CDCl3)δ:1.33(3H,t,J=7.6Hz),1.79(1
H,m),2.47(1H,m),3.02(4H,m),3.97(3H,s),4.45
(1H,m),4.60(1H,d,J=16.1Hz),4.86(1H,m),5,25
(1H,d,J=16.1Hz),7.27(1H,d,J=2.9Hz),7.37(1H,
dd.,J=9.0,2.9Hz),7.99(1H,d,J=9.0Hz) IR(CHCl3):3400,1620cm-1 MS m/z:312(M+) (8) 化合物(XII)の合成: 化合物(XI)312mg(1mmol)に無水酢酸ナトリウム82
mg(1mmol)と無水酢酸1mlを加え、窒素気流下1時間加
熱する。反応液を氷水中にあけると沈澱が析出する。沈
澱を濾取した後、クロロホルム−n−ヘキサンから再結
晶し、黄色結晶の目的物(XII)250mg(85%)を得た。Colorless powder: mp 105-108 ° C (chloroform-n-hexane) 1 H-NMR (CDCl 3 ) δ: 1.33 (3H, t, J = 7.6 Hz), 1.79 (1
H, m), 2.47 (1H, m), 3.02 (4H, m), 3.97 (3H, s), 4.45
(1H, m), 4.60 (1H, d, J = 16.1Hz), 4.86 (1H, m), 5,25
(1H, d, J = 16.1Hz), 7.27 (1H, d, J = 2.9Hz), 7.37 (1H,
dd., J = 9.0, 2.9 Hz), 7.99 (1H, d, J = 9.0 Hz) IR (CHCl 3 ): 3400, 1620 cm −1 MS m / z: 312 (M + ) (8) Compound (XII) Synthesis of Compound (XI) 312 mg (1 mmol) to anhydrous sodium acetate 82
mg (1 mmol) and 1 ml of acetic anhydride are added, and the mixture is heated under a nitrogen stream for 1 hour. When the reaction solution is poured into ice water, a precipitate is formed. The precipitate was collected by filtration and recrystallized from chloroform-n-hexane to obtain 250 mg (85%) of the target compound (XII) as yellow crystals.
mp:73〜75℃(n−ヘキサン−酢酸エチル)1 H−NMR(CDCl3)δ:1.34(3H,t,J=7.6Hz),2.51(1
H,m),3.01(2H,q,J=7.6Hz),3.15(1H,m),3.97(3H,
s),5.14(1H,d,J=16.1Hz),4.77(1H,d,J=16.1Hz),
5.21(1H,m),6.12(1H,m),6.74(1H,m),7.28(1H,d,
J=2.7Hz),7.38(1H,dd.,J=9.3,2.7Hz),7.99(1H,d,
J=9.3Hz) IR(CHCl3):1660,1620,1600cm-1 MS m/z:294(M+) (9) 化合物(Ia)〔式(Ia)中、R5=ベンジル〕
の合成: 窒素気流下0℃でテトラヒドロフラン15ml中にジイソ
プロピルアミン1.09ml(15mmol)を加える。次にn−ブ
チルリチウムの1.62mol/lのn−ヘキサン溶液9.26ml(1
5mmol)を攪拌下滴下する。20分後、ドライアイス−ア
セトン浴で−78℃としα−エトキシカルボニルオキシ酪
酸ベンジル3.99g(15mmol)のテトラヒドロフラン溶液2
0mlを滴下する。1時間後化合物(XII)882mg(3mmol)
のテトラヒドロフラン溶液20mlを滴下する。−78℃で2
時間攪拌後、徐々に室温に挙げる。mp: 73-75 ° C. (n-hexane-ethyl acetate) 1 H-NMR (CDCl 3 ) δ: 1.34 (3H, t, J = 7.6 Hz), 2.51 (1
H, m), 3.01 (2H, q, J = 7.6Hz), 3.15 (1H, m), 3.97 (3H,
s), 5.14 (1H, d, J = 16.1Hz), 4.77 (1H, d, J = 16.1Hz),
5.21 (1H, m), 6.12 (1H, m), 6.74 (1H, m), 7.28 (1H, d,
J = 2.7Hz), 7.38 (1H, dd., J = 9.3,2.7Hz), 7.99 (1H, d,
J = 9.3 Hz) IR (CHCl 3 ): 1660,1620,1600 cm −1 MS m / z: 294 (M + ) (9) Compound (Ia) [in the formula (Ia), R 5 = benzyl]
Synthesis of 1.09 ml (15 mmol) of diisopropylamine in 15 ml of tetrahydrofuran at 0 ° C. under a stream of nitrogen. Next, 9.26 ml of a 1.62 mol / l n-hexane solution of n-butyllithium (1
5 mmol) are added dropwise with stirring. 20 minutes later, the solution was cooled to −78 ° C. in a dry ice-acetone bath and a solution of 3.99 g (15 mmol) of benzyl α-ethoxycarbonyloxybutyrate in tetrahydrofuran 2 was added.
0 ml is added dropwise. One hour later, 882 mg (3 mmol) of compound (XII)
20 ml of a tetrahydrofuran solution is added dropwise. 2 at -78 ° C
After stirring for an hour, the temperature is gradually raised to room temperature.
反応後、反応液を氷水中に注ぎ10%HCl溶液で、弱酸
性にしてクロロホルムで抽出する。水洗、乾燥した後、
溶媒を留去してシリカゲルカラムクロマト(クロロホル
ム)に付し、精製すると目的物(Ia)740mg(48%)を
得た。After the reaction, the reaction solution is poured into ice water, made weakly acidic with a 10% HCl solution, and extracted with chloroform. After washing and drying,
The solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform), and purification yielded 740 mg (48%) of the desired product (Ia).
無色粉末:mp 197℃(酢酸エチル−n−ヘキサン)1 H−NMR(CDCl3)δ:0.99(3H,t,J=7.3Hz),1.32(3
H,t,J=7.6Hz),1.62(1H,m),1.97(1H,m),2.16(1H,
m),2.97(3H,m),3.28(1H,m),3.60(1H,d,J=7.6H
z),3.96(3H,s),4.63(1H,d.J=16.1HZ),4.84(1H,d
d.,J=11.5,2.9Hz),5.28(2H,s),5.28(1H,d,J=16.1
Hz),7.26(1H,d,J=2.4Hz),7.39(6H,br.s),7.95(1
H,d,J=9.0Hz) IR(CHCl3):1790,1740,1660,1620cm-1 MS m/z:514(M+) (10) 化合物(Ib)の合成: 化合物(Ia)514mg(1mmol)をメタノール50mlに溶解
し、触媒として10%パラジウムカーボン50mgを用い常圧
で水素添加した。反応後触媒を濾去し、濾液を減圧下乾
固し、残留物をクロロホルムより結晶化することにより
目的物(Ib)402mg(95%)を得た。Colorless powder: mp 197 ° C. (ethyl acetate-n-hexane) 1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.3 Hz), 1.32 (3
H, t, J = 7.6Hz), 1.62 (1H, m), 1.97 (1H, m), 2.16 (1H, m
m), 2.97 (3H, m), 3.28 (1H, m), 3.60 (1H, d, J = 7.6H)
z), 3.96 (3H, s), 4.63 (1H, dJ = 16.1HZ), 4.84 (1H, d
d., J = 11.5,2.9Hz), 5.28 (2H, s), 5.28 (1H, d, J = 16.1)
Hz), 7.26 (1H, d, J = 2.4 Hz), 7.39 (6H, br.s), 7.95 (1
H, d, J = 9.0 Hz) IR (CHCl 3 ): 1790,1740,1660,1620 cm −1 MS m / z: 514 (M + ) (10) Synthesis of compound (Ib): 514 mg of compound (Ia) ( 1 mmol) was dissolved in 50 ml of methanol, and hydrogenated at normal pressure using 50 mg of 10% palladium carbon as a catalyst. After the reaction, the catalyst was removed by filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was crystallized from chloroform to obtain 402 mg (95%) of the desired product (Ib).
無色粉末:mp 231〜232℃(クロロホルム)1 H−NMR(CD3OD)δ:1.07(3H,t,J=7.3Hz),1.33(3
H,t,J=7.6Hz),1.62(1H,m),1.96(1H,m),2.20(1H,
m),2.93(1H,m),3.09(2H,q,J=7.6Hz),3.47(1H,
m),3.97(3H,s),4.68(1H,d,J=16.1Hz),4.98(1H,d
d.,J=11.5,2.9Hz),5.19(1H,d,J=16.1Hz),7.43(2
H,m),7.94(1H,d,J=10.0Hz) IR(KBr):3500-3100(br,OH),1790,1710,1640,1620cm
-1 MS m/z:424(M+) (11) 化合物(Ic)〔式(Ic)中、R7=−C(CH3)3〕
の合成: 化合物(Ib)424mgを塩化メチレン50mlに懸濁し、こ
れに濃硫酸0.5mlを加え、次いで−15℃でイソブテン
(ガス)を30分間通じ、反応させ、更に室温で一夜攪拌
する。Colorless powder: mp 231 to 232 ° C. (chloroform) 1 H-NMR (CD 3 OD) δ: 1.07 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.62 (1H, m), 1.96 (1H, m), 2.20 (1H, m
m), 2.93 (1H, m), 3.09 (2H, q, J = 7.6Hz), 3.47 (1H,
m), 3.97 (3H, s), 4.68 (1H, d, J = 16.1Hz), 4.98 (1H, d
d., J = 11.5,2.9Hz), 5.19 (1H, d, J = 16.1Hz), 7.43 (2
H, m), 7.94 (1H, d, J = 10.0Hz) IR (KBr): 3500-3100 (br, OH), 1790,1710,1640,1620cm
-1 MS m / z: 424 ( M +) (11) Compound (Ic) wherein (Ic), R 7 = -C (CH 3) 3 ]
The compound (Ib) (424 mg) is suspended in methylene chloride (50 ml), concentrated sulfuric acid (0.5 ml) is added thereto, and isobutene (gas) is passed through the mixture at -15 ° C for 30 minutes, and the mixture is further stirred at room temperature overnight.
反応混合物を、氷水に注ぎ中和後、クロロホルム抽出
する。有機層を取り、無水硫酸マグネシウムで乾燥後、
減圧下濃縮する。残留物を、シリカゲルカラムクロマト
(クロロホルム)に付し精製することにより、目的物
(Ic)422mg(88%)を得た。The reaction mixture is poured into ice water, neutralized and extracted with chloroform. After removing the organic layer and drying over anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 422 mg (88%) of the desired product (Ic).
無色粉末:mp 225℃(酢酸エチル)1 H−NMR(CDCl3)δ:1.06(3H,t,J=7.3Hz),1.33(3
H,t,J=7.6Hz),1.53(10H,br.s),1.95(1H,m),2.11
(1H,m),2.95(3H,m),3.30(1H,m),3.67(1H,d,J=
7.1Hz),3.97(3H,s),4.66(1H,d,J=16.1Hz),4.88
(1H,dd.,J=11.5,2.7Hz),5.30(1H,d,J=16.1Hz),7.
27(1H,d,J=2.4Hz),7.38(1H,dd.,J=9.3,2.4Hz),7.
96(1H,d,J=9.3HZ) IR(CHCl3):1790,1730,1650,1620cm-1 MS m/z:480(M+) (12) 化合物(Id)〔式(Id)中、R7=C(CH3)3〕の
合成: テトラヒドロフラン10mlに水素化リチウムホウ素22m
を加え、氷冷下(11)で得られた化合物(Ic)480mg(1
mmol)テトラヒドロフラン溶液30mlを滴下した。10分後
10%HCl溶液で反応を止めた。Colorless powder: mp 225 ° C. (ethyl acetate) 1 H-NMR (CDCl 3 ) δ: 1.06 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.53 (10H, br.s), 1.95 (1H, m), 2.11
(1H, m), 2.95 (3H, m), 3.30 (1H, m), 3.67 (1H, d, J =
7.1Hz), 3.97 (3H, s), 4.66 (1H, d, J = 16.1Hz), 4.88
(1H, dd., J = 11.5,2.7Hz), 5.30 (1H, d, J = 16.1Hz), 7.
27 (1H, d, J = 2.4 Hz), 7.38 (1H, dd., J = 9.3, 2.4 Hz), 7.
96 (1H, d, J = 9.3 HZ) IR (CHCl 3 ): 1790, 1730, 1650, 1620 cm -1 MS m / z: 480 (M + ) (12) Compound (Id) [in the formula (Id) Synthesis of R 7 CC (CH 3 ) 3 ]: 22 ml of lithium boron hydride in 10 ml of tetrahydrofuran
And 480 mg (1%) of the compound (Ic) obtained in (11) under ice cooling.
30 mmol) of a tetrahydrofuran solution was added dropwise. 10 minutes later
The reaction was stopped with a 10% HCl solution.
テトラヒドロフランを留去した後、クロロホルムで抽
出し、水洗、乾燥後、クロロホルムを留去した。残渣を
シリカゲルカラムクロマト(酢酸エチル)に付し、精製
すると目的物(Id)290mg(60%)を得た。After distilling off tetrahydrofuran, the mixture was extracted with chloroform, washed with water and dried, and then chloroform was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate) and purified to obtain 290 mg (60%) of the desired product (Id).
無色粉末:mp 238℃(n−ヘキサン−酢酸エチル)1 H−NMR(CDCl3)δ:0.99(3H,t,J=7.3Hz),1.33(3
H,t,J=7.6Hz),1.53(9H,br.s),1.78(1H,m),1.93
(1H,m),2.76(1H,m),3.00(2H,q,J=7.6Hz),3.12
(2H,m),3.96(3H,s),4.65(1H,d,J=16.2Hz),4.86
(1H,dd.,J=11.5,2.9Hz),5.29(1H,d,J=16.2Hz),5.
55(1H,m),7.27(1H,d,J=2.8Hz),7.37(1H,dd.,J=
9.0,2.8Hz),7.97(1H,d,J=9.0Hz) IR(CHCl3):3350(OH),1720,1640,1620cm-1 MS m/z:482(M+)Colorless powder: mp 238 ° C. (n-hexane-ethyl acetate) 1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.53 (9H, br.s), 1.78 (1H, m), 1.93
(1H, m), 2.76 (1H, m), 3.00 (2H, q, J = 7.6Hz), 3.12
(2H, m), 3.96 (3H, s), 4.65 (1H, d, J = 16.2Hz), 4.86
(1H, dd., J = 11.5,2.9Hz), 5.29 (1H, d, J = 16.2Hz), 5.
55 (1H, m), 7.27 (1H, d, J = 2.8Hz), 7.37 (1H, dd., J =
9.0, 2.8 Hz), 7.97 (1 H, d, J = 9.0 Hz) IR (CHCl 3 ): 3350 (OH), 1720, 1640, 1620 cm −1 MS m / z: 482 (M + )
Claims (3)
子、アラルキル基又は低級アルキル基を示す〕 で表わされる新規キノリン誘導体。1. The following general formula (I) [Wherein, A represents C = O or CHOH, and R 1 represents a hydrogen atom, an aralkyl group or a lower alkyl group].
基を示す〕 で表わされる酪酸誘導体を反応させることを特徴とする
次の一般式(Ia) 〔式中、R5は前記と同じ〕 で表わされる新規キノリン誘導体の製造法。3. The following formula (XII) The compound represented by the following general formula (XIII) Wherein R 5 represents an aralkyl group and R 6 represents a lower alkyl group. A butyric acid derivative represented by the following general formula (Ia): [Wherein R 5 is the same as defined above].
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-
1989
- 1989-08-29 JP JP22035289A patent/JP2711728B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH0383986A (en) | 1991-04-09 |
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