JP4014329B2 - Purification method of quinoline derivatives - Google Patents
Purification method of quinoline derivatives Download PDFInfo
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- JP4014329B2 JP4014329B2 JP08511599A JP8511599A JP4014329B2 JP 4014329 B2 JP4014329 B2 JP 4014329B2 JP 08511599 A JP08511599 A JP 08511599A JP 8511599 A JP8511599 A JP 8511599A JP 4014329 B2 JP4014329 B2 JP 4014329B2
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- quinoline
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Description
【0001】
【発明の属する技術分野】
本発明は医薬品中間体として有用な式(1)[化2]
【化2】
で表されるキノリン誘導体を精製する方法に関する。
【0002】
【従来の技術及び発明が解決しようとする課題】
癌の治療に対する制ガン剤の研究開発は従来から活発に行われており、臨床的にも種々の制ガン剤が癌の治療に用いられている。その効果は年々着実に改善されつつあるが、多くの場合、癌の増殖を完全に抑制し、癌患者の生存を長期にわたり維持せしめるには必ずしも満足のできる効果は得られていない。
【0003】
このような事情において、近年、既存制ガン剤の効果増強作用を持つ薬物としてキノリン環を有する化合物が見いだされている(特開平3−101662号公報)。
【0004】
このようなキノリン誘導体の製造方法としては、特開平3−101662号公報に記載されている方法を利用し、製造することが出来る。しかしながら、これらの方法では、精製方法がシリカゲルカラムクロマトグラフィーを用いる等煩雑であり、反応収率、品質、コストの面で問題があった。
【0005】
【発明が解決しようとする課題】
本発明者等は上記課題を解決するため鋭意検討した結果、式(1)で表されるキノリン誘導体を酸で造塩し、塩を分取後、塩基で脱塩することで、キノリン誘導体を収率よく、簡便で効率的に精製する方法を見いだし、本発明を完成するに至った。
【0006】
すなわち、本発明は、式(1)[化3]
【化3】
で表されるキノリン誘導体を酸で造塩し、塩を分取後、塩基で脱塩する精製方法である。
【0007】
【発明の実施の形態】
以下、本発明を詳細に説明する。
本発明において、式(1)で表されるキノリン誘導体の製造方法としては、特開平3−101662号公報に記載されている方法を利用し、製造することが出来る。すなわち、5−ヒドロキシキノリンを乾燥ジメチルホルムアミド(以下DMFと略す)に溶解し、塩基存在下、エピクロルヒドリンと反応させる事で式(1)で表されるキノリン誘導体を製造出来る。この様にして得られたキノリン誘導体は酸で造塩し、塩を晶析分取後、塩基で脱塩し、晶析することで収率よく、簡便で効率的に精製できる。
【0008】
造塩で用いられる酸としては塩酸、硫酸、硝酸、リン酸等の無機酸またはフマル酸、フタル酸、コハク酸、シュウ酸、マロン酸、酒石酸、クエン酸、ギ酸、酢酸、プロピオン酸、乳酸、安息香酸、トシル酸等の有機酸が挙げられる。
【0009】
造塩反応の溶媒としては水、メタノール、エタノール等のプロトン性溶媒、テトラヒドロフラン、ジオキサン、ジグリム等のエーテル類、酢酸エチル等のエステル類、塩化メチレン、クロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、ヘキサン、石油エーテル等の炭化水素類が挙げられ、これらは単独または混合して用いられる。
【0010】
造塩温度としては通常0℃〜溶媒の沸点の範囲であり、造塩時間は1〜48時間の範囲で反応すれば十分である。
このようにして得られた塩を有機溶媒または有機溶媒−水混合溶媒中で晶析する。
【0011】
ここで挙げられる有機溶媒とはメタノール、エタノール等のプロトン性溶媒、テトラヒドロフラン、ジオキサン、ジグリム等のエーテル類、酢酸エチル等のエステル類、塩化メチレン、クロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、ヘキサン、石油エーテル等の炭化水素類が挙げられる。
【0012】
脱塩で用いられる塩基としては水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、水酸化マグネシウム、炭酸水素ナトリウム、炭酸ナトリウム、アンモニア等の無機塩基またはトリエチルアミン、DBU、ピロール、ピリジン、ピラジン、ピリダジン、ピリミジン、ピロリジン、ピペリジン、ピペラジン等の有機塩基が挙げられる。
【0013】
脱塩反応の溶媒としては水、メタノール、エタノール等のプロトン性溶媒、テトラヒドロフラン、ジオキサン、ジグリム等のエーテル類等が挙げられ、これらは単独または混合して用いられる。
【0014】
脱塩温度としては通常0℃〜溶媒の沸点の範囲であり、脱塩時間は1〜48時間の範囲で反応すれば十分である。
【0015】
このようにして得られたキノリン誘導体を有機溶媒または有機溶媒−水混合溶媒中で晶析することで精製することが出来る。
【0016】
ここで挙げられる有機溶媒とはメタノール、エタノール等のプロトン性溶媒、テトラヒドロフラン、ジオキサン、ジグリム等のエーテル類が挙げられる。
【0017】
【実施例】
以下に実施例を挙げて本発明を説明するが、本発明はこれらによって限定されるものではない。
【0018】
HPLC分析条件
カラム: YMC A−514
カラム温度: 40℃
溶離液:水3750mlにKH2PO4 10.3gを溶解し、H2PO4でpHを3.5に調整する。アセトニトリル1250mlを追加後脱気して溶離液とする。
波長: 225nm
流量: 1.2ml/min
内部標準品(IS): o−クロロフェノール
試料の調整:IS20mg、サンプル20mgを秤採り溶離液で20mlとして3μlを注入、測定する。
【0019】
実施例1
a)5−ヒドロキシキノリン4.85gをアセトン40.6gに溶解し、炭酸セシウム13.6gを添加した後、58℃で30分間加熱攪拌した。反応液にグリシジルトシレート6.56gを加え、50℃で10時間加熱攪拌した後、濾過により塩を除去した。
反応液にN−(2,2−ジフェニルアセチル)ピペラジン7.65gを加え、溶媒を減圧下留去した。残留物に水を加え、40℃で6時間加熱攪拌し、メタノールを加えて活性炭で精製した。
b)a)で得られた反応液にフマル酸9.5gを加え、63℃で1時間加熱攪拌し、塩を結晶化させた後、塩を濾取した。この塩をメタノール51.2gに懸濁させ、10%水酸化ナトリウム水溶液を加え、60℃で1時間半加熱攪拌した。反応液に水を加えて晶析後、濾取し乾燥させると、5−[3−{4−(2,2−ジフェニルアセチル)ピペラジン−1−イル}−2−ヒドロキシプロポキシ]キノリンが9g得られた。
NMR(CDCl3):2.1−2.3(m,1H),2.3−2.75(m,5H),3.3−3.6(m,3H),3.6−3.8(m,2H),4.05−4.25(m,3H),5.18(s,1H),6.83(d,1H), 7.1−7.45(m,11H),7.57(t,1H),7.69(d, 1H),8.4−8.55(m,1H)
【0020】
比較例1
a)5−ヒドロキシキノリン1gを乾燥DMF20mlに溶解し、水素化ナトリウム(60%含有)0.28gを添加した後、50℃で30分間加熱攪拌した。反応液にエピクロルヒドリン1.92gを加え、90℃で3時間加熱攪拌した後、溶媒を減圧下留去した。残留物に水を加え、クロロホルムで抽出した。クロロホルム抽出液は、活性炭で脱色精製後、無水芒硝で乾燥した後、留去した。残渣をシリカゲルカラムクロマトを用い精製した。クロロホルム:メタノール=100:1で流出させると、目的である、5−(2,3−エポキシ−プロポキシ)キノリンが油状物として0.88g得られた。
b)上記で得られたエポキシ体0.85gと、N−(2,2−ジフェニルアセチル)ピペラジン1.12gとをエタノール20mlに溶解し、3時間加熱環流した。反応後、エタノールを留去して、残渣をシリカゲルカラムクロマトグラフィーにて精製した。クロロホルム:メタノール=50:1で流出し、目的物画分を合わせ、溶媒を留去した後、残渣に少量のエーテルを加え結晶化させた後、濾取し乾燥させると、5−[3−{4−(2,2−ジフェニルアセチル)ピペラジン−1−イル}−2−ヒドロキシプロポキシ]キノリンが1.2g得られた。
【0021】
比較例2
比較例1−a)によって合成されたエポキシ体0.85gとN−(2,2−ジフェニルアセチル)ピペラジン1.12gとをエタノール20mlに溶解し、3時間加熱環流した。反応後、エタノールを留去して、残渣に少量のエーテルを加え結晶化させた後、濾取し乾燥させると、5−[3−{4−(2,2−ジフェニルアセチル)ピペラジン−1−イル}−2−ヒドロキシプロポキシ]キノリンが2.7g得られた。
【0022】
比較例3
5−ヒドロキシキノリン4.85gをアセトン40.6gに溶解し、炭酸セシウム13.6gを添加した後、58℃で30分間加熱攪拌した。反応液にグリシジルトシレート6.56gを加え、50℃で10時間加熱攪拌した後、濾過により塩を除去した。反応液にN−(2,2−ジフェニルアセチル)ピペラジン7.65gを加え、溶媒を減圧下留去した。残留物に水を加え、40℃で6時間加熱攪拌し、イソプロピルアルコールを加え結晶化させた後、濾取し乾燥させると、5−[3−{4−(2,2−ジフェニルアセチル)ピペラジン−1−イル}−2−ヒドロキシプロポキシ]キノリンが6.8g得られた。
【表1】
【0023】
【発明の効果】
本発明は上記の実施例、比較例の結果からも明らかなように、キノリン誘導体を酸により造塩し、脱塩することにより、純度および収率が改善され、簡便かつ効率よくキノリン誘導体を精製する方法を提供するものである。[0001]
BACKGROUND OF THE INVENTION
The present invention is useful as a pharmaceutical intermediate of formula (1) [Formula 2]
[Chemical 2]
It is related with the method of purifying the quinoline derivative represented by these.
[0002]
[Prior art and problems to be solved by the invention]
Research and development of anticancer drugs for the treatment of cancer has been actively conducted, and various anticancer drugs are clinically used for the treatment of cancer. Although the effect is steadily improving year by year, in many cases, a satisfactory effect is not necessarily obtained in order to completely suppress the growth of cancer and maintain the survival of cancer patients over a long period of time.
[0003]
Under such circumstances, in recent years, a compound having a quinoline ring has been found as a drug having an effect of enhancing the effects of existing anticancer drugs (Japanese Patent Laid-Open No. 3-101661).
[0004]
As a method for producing such a quinoline derivative, it can be produced by utilizing the method described in JP-A-3-101661. However, in these methods, the purification method is complicated such as using silica gel column chromatography, and there are problems in terms of reaction yield, quality, and cost.
[0005]
[Problems to be solved by the invention]
As a result of intensive studies to solve the above-mentioned problems, the present inventors salted the quinoline derivative represented by the formula (1) with an acid, separated the salt, and then desalted with a base to obtain the quinoline derivative. The inventors have found a simple and efficient purification method with good yield, and have completed the present invention.
[0006]
That is, the present invention relates to the formula (1) [Formula 3].
[Chemical 3]
In the purification method, a salt of the quinoline derivative represented by the formula is formed with an acid, the salt is separated, and desalted with a base.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
In the present invention, as a method for producing the quinoline derivative represented by the formula (1), it can be produced by utilizing the method described in JP-A-3-101626. That is, a quinoline derivative represented by the formula (1) can be produced by dissolving 5-hydroxyquinoline in dry dimethylformamide (hereinafter abbreviated as DMF) and reacting with epichlorohydrin in the presence of a base. The quinoline derivative thus obtained is salted with an acid, and after the salt is crystallized, the salt is desalted with a base and crystallized, so that the quinoline derivative can be purified simply and efficiently with good yield.
[0008]
Acids used in salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or fumaric acid, phthalic acid, succinic acid, oxalic acid, malonic acid, tartaric acid, citric acid, formic acid, acetic acid, propionic acid, lactic acid, Examples include organic acids such as benzoic acid and tosylic acid.
[0009]
Solvents for salt-forming reactions include water, protic solvents such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and diglyme, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride and chloroform, benzene and toluene , Hydrocarbons such as hexane, petroleum ether and the like, and these may be used alone or in combination.
[0010]
The salt-forming temperature is usually in the range of 0 ° C. to the boiling point of the solvent, and the salt-forming time is sufficient to react in the range of 1 to 48 hours.
The salt thus obtained is crystallized in an organic solvent or an organic solvent-water mixed solvent.
[0011]
Organic solvents mentioned here are protic solvents such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and diglyme, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride and chloroform, benzene, toluene, Examples include hydrocarbons such as hexane and petroleum ether.
[0012]
Bases used for desalting include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, ammonia, or triethylamine, DBU, pyrrole, pyridine, pyrazine And organic bases such as pyridazine, pyrimidine, pyrrolidine, piperidine and piperazine.
[0013]
Examples of the solvent for the desalting reaction include water, protic solvents such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and diglyme, and these are used alone or in combination.
[0014]
The desalting temperature is usually in the range of 0 ° C. to the boiling point of the solvent, and the desalting time is sufficient in the range of 1 to 48 hours.
[0015]
The quinoline derivative thus obtained can be purified by crystallization in an organic solvent or an organic solvent-water mixed solvent.
[0016]
Examples of the organic solvent mentioned here include protic solvents such as methanol and ethanol, and ethers such as tetrahydrofuran, dioxane and diglyme.
[0017]
【Example】
Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.
[0018]
HPLC analysis condition column: YMC A-514
Column temperature: 40 ° C
Eluent: 10.3 g of KH 2 PO 4 is dissolved in 3750 ml of water, and the pH is adjusted to 3.5 with H 2 PO 4 . Add 1250 ml of acetonitrile and deaerate to make the eluent.
Wavelength: 225nm
Flow rate: 1.2ml / min
Internal standard (IS): Preparation of o-chlorophenol sample: IS 20 mg, 20 mg of sample are weighed and 20 ml is injected with eluent, and 3 μl is injected and measured.
[0019]
Example 1
a) 4.85 g of 5-hydroxyquinoline was dissolved in 40.6 g of acetone, 13.6 g of cesium carbonate was added, and the mixture was heated and stirred at 58 ° C. for 30 minutes. To the reaction solution was added 6.56 g of glycidyl tosylate, and the mixture was stirred with heating at 50 ° C. for 10 hours, and then the salt was removed by filtration.
To the reaction solution, 7.65 g of N- (2,2-diphenylacetyl) piperazine was added, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was heated and stirred at 40 ° C. for 6 hours. Methanol was added and the residue was purified with activated carbon.
b) 9.5 g of fumaric acid was added to the reaction solution obtained in a), and the mixture was heated and stirred at 63 ° C. for 1 hour to crystallize the salt, and then the salt was collected by filtration. This salt was suspended in 51.2 g of methanol, a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred with heating at 60 ° C. for 1.5 hours. Water was added to the reaction solution for crystallization, followed by filtration and drying to obtain 9 g of 5- [3- {4- (2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline. It was.
NMR (CDCl 3 ): 2.1-2.3 (m, 1H), 2.3-2.75 (m, 5H), 3.3-3.6 (m, 3H), 3.6-3 .8 (m, 2H), 4.05-4.25 (m, 3H), 5.18 (s, 1H), 6.83 (d, 1H), 7.1-7.45 (m, 11H) ), 7.57 (t, 1H), 7.69 (d, 1H), 8.4-8.55 (m, 1H)
[0020]
Comparative Example 1
a) 1 g of 5-hydroxyquinoline was dissolved in 20 ml of dry DMF, 0.28 g of sodium hydride (containing 60%) was added, and the mixture was heated and stirred at 50 ° C. for 30 minutes. After adding 1.92 g of epichlorohydrin to the reaction solution and heating and stirring at 90 ° C. for 3 hours, the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with chloroform. The chloroform extract was decolorized and purified with activated carbon, dried over anhydrous sodium sulfate, and then distilled off. The residue was purified using silica gel column chromatography. Elution with chloroform: methanol = 100: 1 gave 0.88 g of the desired 5- (2,3-epoxy-propoxy) quinoline as an oil.
b) 0.85 g of the epoxy compound obtained above and 1.12 g of N- (2,2-diphenylacetyl) piperazine were dissolved in 20 ml of ethanol and heated to reflux for 3 hours. After the reaction, ethanol was distilled off and the residue was purified by silica gel column chromatography. After eluting with chloroform: methanol = 50: 1, the target fractions were combined, the solvent was distilled off, the residue was crystallized with a small amount of ether, filtered and dried to give 5- [3- 1.2 g of {4- (2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline was obtained.
[0021]
Comparative Example 2
0.85 g of the epoxy compound synthesized by Comparative Example 1-a) and 1.12 g of N- (2,2-diphenylacetyl) piperazine were dissolved in 20 ml of ethanol and heated to reflux for 3 hours. After the reaction, ethanol was distilled off, and a small amount of ether was added to the residue for crystallization, followed by filtration and drying to give 5- [3- {4- (2,2-diphenylacetyl) piperazine-1- Yl} -2-hydroxypropoxy] quinoline was obtained.
[0022]
Comparative Example 3
After dissolving 4.85 g of 5-hydroxyquinoline in 40.6 g of acetone and adding 13.6 g of cesium carbonate, the mixture was heated and stirred at 58 ° C. for 30 minutes. To the reaction solution was added 6.56 g of glycidyl tosylate, and the mixture was stirred with heating at 50 ° C. for 10 hours, and then the salt was removed by filtration. To the reaction solution, 7.65 g of N- (2,2-diphenylacetyl) piperazine was added, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was stirred with heating at 40 ° C. for 6 hours. After adding isopropyl alcohol to crystallize, it was collected by filtration and dried to give 5- [3- {4- (2,2-diphenylacetyl) piperazine. 6.8 g of -1-yl} -2-hydroxypropoxy] quinoline was obtained.
[Table 1]
[0023]
【The invention's effect】
As is clear from the results of the above Examples and Comparative Examples, the present invention improves purity and yield by salting a quinoline derivative with an acid and desalting it, and purifies the quinoline derivative simply and efficiently. It provides a way to
Claims (2)
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JP08511599A JP4014329B2 (en) | 1999-03-29 | 1999-03-29 | Purification method of quinoline derivatives |
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JP08511599A JP4014329B2 (en) | 1999-03-29 | 1999-03-29 | Purification method of quinoline derivatives |
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JP4014329B2 true JP4014329B2 (en) | 2007-11-28 |
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DE10321255B4 (en) * | 2003-05-06 | 2006-09-28 | Schering Ag | Process for the preparation of purest rac-1 {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethane-1-one fumarate and purest rac-1 {4 - [2-hydroxy-3- (5-quinolyloxy) propyl] piperazine-1-yl} -2,2 |
US7462718B2 (en) | 2003-05-06 | 2008-12-09 | Schering Ag | Process for the production of high-purity rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and high-purity rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate |
US8071656B2 (en) | 2009-03-03 | 2011-12-06 | Dynasep Llc | Nylon extraction from commingled materials |
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