WO2005073239A1 - Method for purifying quinolinecarboxylic acid derivative - Google Patents
Method for purifying quinolinecarboxylic acid derivative Download PDFInfo
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- WO2005073239A1 WO2005073239A1 PCT/JP2005/001318 JP2005001318W WO2005073239A1 WO 2005073239 A1 WO2005073239 A1 WO 2005073239A1 JP 2005001318 W JP2005001318 W JP 2005001318W WO 2005073239 A1 WO2005073239 A1 WO 2005073239A1
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- methyl
- oxo
- compound
- quinoline
- fluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to 6-fluoro-1-methyl-7- [4_ (5-methyl-2-oxo-1,3-dioxolen-41-yl) methyl-1-piperajur] -14-year-old xo 4H- [
- the present invention relates to a method for purifying [1,3] thiazeto [3,2-a] quinoline-l--3-carboxylic acid (hereinafter, compounds A and V).
- Compound A has excellent antibacterial activity (see, for example, Patent Document 1), and has been mentioned as a synthetic antibacterial agent.
- the powerful compound A is synthesized as follows.
- the final process power The purity of the obtained compound A is in the range of 80-90%, so that it can be provided as a raw drug substance. Requires higher purity. Therefore, recrystallization may be considered to increase the purity, but the compound A cannot be sufficiently purified even if recrystallized as it is. For this reason, conventionally, a method has been adopted in which the extraction treatment is repeated three times with methylene chloride to increase the purity to 93% or more, and then recrystallized with acetonitrile.
- methylene chloride used as a solvent in the extraction process requires a high level of environmental control, and its total amount is 50 times the volume (mL) of the weight of Compound A (g). Is also necessary.
- the above-mentioned conventional method has a problem that a long time is required for the treatment operation, and a simple and inexpensive method for purifying Compound A with little adverse effect on the environment is required.
- Patent Document 1 Japanese Patent Application Laid-Open No. 1-294680
- An object of the present invention is to provide a simple and inexpensive purification method for Compound A having excellent medicinal properties, which has a small adverse effect on the environment.
- the inventors of the present invention have conducted intensive studies on the method of purifying Compound A. After heating and stirring the crude Compound A in a predetermined solvent, the suspension was cooled, and the precipitated crystals were collected by filtration. The present inventors have found that a novel purification method of drying achieves the above object, and have completed the present invention.
- Compound A is converted into N, N-dimethylformamide (hereinafter, referred to as DMF), N-methylformamide (hereinafter, referred to as NMF), formamide (hereinafter, referred to as FA), dimethylacetamide (hereinafter, referred to as DMA), A group consisting of dimethylimidazole (hereinafter, referred to as DMI) and dimethylsulfoxide (hereinafter, referred to as DMSO). Heating and stirring in a selected solvent. After cooling the suspension, precipitate crystals are collected by filtration. A method for purifying Compound A, comprising a step of drying.
- purity refers to a value measured and calculated under the following conditions.
- Detector UV absorption spectrophotometer (275 nm) SPD-6A (Shimadzu Corporation) Sample Dissolve about 10 mg of measurement sample in 10 ml of acetonitrile and inject 2.0 ⁇ l of it, or dissolve about 25 mg of measurement sample in 2 ml of DMF and dissolve Inject 4 1
- Measurement range / Solution force of solvent peak is also 10 times the retention time of compound A Purity calculation method Calculated by Z area percentage
- one time volume (mL) with respect to the weight (g) of Compound A means the volume (mL) of the solvent with respect to the weight (g) of Compound A as a solute.
- double volume (mL) means that the solvent amount is 20 mL for 10 g of Compound A.
- the “cooling temperature” refers to the temperature of the suspension at the time of filtering the precipitated crystals from the suspension after heating and stirring.
- cooling holding time refers to the time during which the suspension after heating and stirring is cooled to a predetermined cooling temperature, and then left or stirred while maintaining the cooling temperature.
- Examples of the solvent used in the present invention include amide solvents such as DMF, NMF, and FA, DMI, and DMSO. Of these, DMF is more preferred. The suitability of these solvents is detailed in Test Example 1.
- the amount of the solvent used in the present invention is suitably in the range of 0.5 to 5 times volume (mL) with respect to the weight (g) of the compound A, and in the range of 0.9 to 2.5 times volume. 1 volume is particularly preferred. The appropriate amount of the solvent in this range will be described in detail in Test Example 2.
- the heating temperature should be different depending on the solvent used. One 100 ° C is more preferable.
- the heating and stirring time varies depending on the solvent and the stirring device used, but is suitably in the range of 0.5 to 5 hours, more preferably 1 hour. Suitability of the heating temperature and the stirring time in this range will be described in detail in Test Example 3.
- the cooling rate after heating and stirring hardly affects the purity.
- the cooling hold time after reaching the specified cooling temperature does not affect the purity, but the recovery rate is poor if the set temperature is high and the time is short, so the cooling temperature is 30 or less, and the cooling hold time is 30 minutes.
- the above is preferable. Suitability of the cooling temperature and the cooling holding time in this range will be described in detail in Test Example 4.
- Compound A used in this purification may be one produced by the above method.However, if water is contained in Compound A, it will affect the degree of purification and the recovery rate, so it must be washed and dried in advance with isopropanol. It is preferable to remove the water by performing a treatment such as drying.
- the purified compound A can be recrystallized using, for example, acetonitrile as a recrystallization solvent. This can increase the purity of compound A to 99% or more.
- the recrystallization can be performed by a conventional method.
- Test Example 4 Cooling conditions and purification effect One-fold volume of DMF was added to Compound A, and the mixture was heated and stirred at 80 ° C for 1.2 hours, cooled to a predetermined temperature at a predetermined cooling rate, stirred as it was for a predetermined time, and the precipitated crystals were collected by filtration and dried. The results are shown in Table 4.
- the purification method by the heating and stirring treatment has a purification effect equal to or higher than the purification method by the extraction treatment.
- the purification method according to the present invention is a simple and inexpensive purification method with less adverse effect on the environment as compared with the conventional purification method by extraction treatment. Very useful.
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Abstract
Disclosed is a method for purifying 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl) methyl-1-piperazinyl]-4-oxo-4H-[1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (compound A) which has an excellent medicinal effect. This purifying method is characterized by comprising a step wherein the compound A is heated and stirred in a solvent selected from the group consisting of N,N-dimethylformamide, N-methylformamide, formamide, dimethylacetoamide, dimethylimidazole and dimethylsulfoxide, then the resulting suspension is cooled, and precipitated crystals are filtered out and dried. This method is very useful as a purifying method of the compound A.
Description
キノリンカルボン酸誘導体の精製方法 Purification method of quinoline carboxylic acid derivative
技術分野 Technical field
[0001] 本発明は、 6—フルオロー 1ーメチルー 7— [4_(5—メチルー 2—ォキソ—1, 3—ジォキソレ ンー 4一ィル)メチルー 1ーピぺラジュル]一 4一才キソー 4H—[1, 3]チアゼト [3, 2—a]キノ リン一 3 -力ルボン酸 (以下、化合物 Aと V、う）の精製方法に関するものである。 [0001] The present invention relates to 6-fluoro-1-methyl-7- [4_ (5-methyl-2-oxo-1,3-dioxolen-41-yl) methyl-1-piperajur] -14-year-old xo 4H- [ The present invention relates to a method for purifying [1,3] thiazeto [3,2-a] quinoline-l--3-carboxylic acid (hereinafter, compounds A and V).
背景技術 明 Background art
[0002] 化合物 Aは優れた抗菌活性を有し (例えば、特許文献 1参照。 )、合成抗菌剤として 上巿されて V、る。力かる化合物 Aは次のよ書うに合成されて V、る。 [0002] Compound A has excellent antibacterial activity (see, for example, Patent Document 1), and has been mentioned as a synthetic antibacterial agent. The powerful compound A is synthesized as follows.
[化 1] [Chemical 1]
(上記反応式中、 Etはェチル基、 Meはメチル基を表す。） 上記最終工程力 得られる化合物 Aの純度は 80— 90%の範囲内であるので、医 薬品の原末として提供するためには純度を上げる必要がある。そこで、純度を上げる ために再結晶することが考えられるが、該化合物 Aは、そのまま再結晶しても十分に 精製することができない。そのため従来は、塩化メチレンにより抽出処理を 3回繰り返 し、純度を 93%以上に高めた後、ァセトニトリルで再結晶を行うといった方法が採ら れていた。 (In the above reaction formula, Et represents an ethyl group and Me represents a methyl group.) The final process power The purity of the obtained compound A is in the range of 80-90%, so that it can be provided as a raw drug substance. Requires higher purity. Therefore, recrystallization may be considered to increase the purity, but the compound A cannot be sufficiently purified even if recrystallized as it is. For this reason, conventionally, a method has been adopted in which the extraction treatment is repeated three times with methylene chloride to increase the purity to 93% or more, and then recrystallized with acetonitrile.
し力しながら、抽出処理の溶媒として用いる塩化メチレンは、高いレベルの環境規 制を求められる上に、その全使用量は、化合物 Aの重量 (g)に対し 50倍容量 (mL)
も必要である。更に、上記従来方法では、処理操作に時間を要する等の問題点を有 していること力ら、環境に対する悪影響が少なぐ簡便で、安価な化合物 Aの精製方 法が求められている。 However, methylene chloride used as a solvent in the extraction process requires a high level of environmental control, and its total amount is 50 times the volume (mL) of the weight of Compound A (g). Is also necessary. In addition, the above-mentioned conventional method has a problem that a long time is required for the treatment operation, and a simple and inexpensive method for purifying Compound A with little adverse effect on the environment is required.
[0003] 特許文献 1：特開平 1-294680号公報 [0003] Patent Document 1: Japanese Patent Application Laid-Open No. 1-294680
発明の開示 Disclosure of the invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0004] 本発明の目的は、優れた薬効を有する化合物 Aにつ V、て、環境に対する悪影響が 少なぐ簡便で、安価な精製方法を提供することにある。 [0004] An object of the present invention is to provide a simple and inexpensive purification method for Compound A having excellent medicinal properties, which has a small adverse effect on the environment.
課題を解決するための手段 Means for solving the problem
[0005] 本発明者は、化合物 Aの精製方法につ V、て鋭意検討したところ、粗化合物 Aを所 定の溶媒中で加熱攪拌後、懸濁液を冷却し、析出晶をろ取、乾燥するという、新規な 精製方法が上記目的を達成することを見出し、本発明を完成した。 [0005] The inventors of the present invention have conducted intensive studies on the method of purifying Compound A. After heating and stirring the crude Compound A in a predetermined solvent, the suspension was cooled, and the precipitated crystals were collected by filtration. The present inventors have found that a novel purification method of drying achieves the above object, and have completed the present invention.
本発明としては、例えば、 As the present invention, for example,
(1)化合物 Aを、 N, N—ジメチルホルムアミド（以下、 DMFという）、 N メチルホルム アミド（以下、 NMFという）、ホルムアミド（以下、 FAという）、ジメチルァセトアミド (以 下、 DMAという）、ジメチルイミダゾール（以下、 DMIという）及びジメチルスルホキシ ド (以下、 DMSOという）からなる群力 選択される溶媒中で加熱攪拌する工程、及 び、懸濁液を冷却後、析出晶をろ取し、乾燥する工程を有することを特徴とする、化 合物 Aの精製方法、 (1) Compound A is converted into N, N-dimethylformamide (hereinafter, referred to as DMF), N-methylformamide (hereinafter, referred to as NMF), formamide (hereinafter, referred to as FA), dimethylacetamide (hereinafter, referred to as DMA), A group consisting of dimethylimidazole (hereinafter, referred to as DMI) and dimethylsulfoxide (hereinafter, referred to as DMSO). Heating and stirring in a selected solvent. After cooling the suspension, precipitate crystals are collected by filtration. A method for purifying Compound A, comprising a step of drying.
(2)精製されるべき化合物 Aの純度が 80— 90%の範囲内である、上記（1)の精製方 法、 (2) The purification method according to (1) above, wherein the purity of the compound A to be purified is within a range of 80 to 90%.
(3)溶媒が DMFである、上記（1)の精製方法、 (3) the purification method of the above (1), wherein the solvent is DMF,
(4)溶媒量力化合物 Aの重量 (g)に対し 0. 5— 5倍容量 (mL)である、上記（1)の精 製方法、 (4) The purification method of the above (1), wherein the solvent is 0.5 to 5 times the volume (mL) with respect to the weight (g) of the compound A,
(5)加熱攪拌時の温度が 65— 120 の範囲內である、上記（1)の精製方法、 (5) The purification method of (1) above, wherein the temperature during heating and stirring is in the range of 65-120.
(6)冷却温度が 6—30°Cの範囲内である、上記（1)の精製方法、 (6) the purification method of (1) above, wherein the cooling temperature is within a range of 6-30 ° C;
を挙げ、ることができる。 Can be mentioned.
[0006] 本発明中「純度」とは、以下の条件で測定，算出した値をいう。
HPLC装置/ LC (島津製作所） [0006] In the present invention, "purity" refers to a value measured and calculated under the following conditions. HPLC / LC (Shimadzu Corporation)
カラム ZCosmosil 5C 一 AR 4. 6mm φ X 15cm (ナカライテスタ株式会 Column ZCosmosil 5C-I AR 4.6 mm φ X 15 cm (Nakarai Testa Co., Ltd.)
18 18
社） Company)
移動相 /薄めたリン酸水溶液（1→1000)にトリェチルァミンを加え pH3. 0 に調整した溶液：ァセトュトリル = 3： 2 Mobile phase / Dilute phosphoric acid aqueous solution (1 → 1000) with Triethylamine added to adjust the pH to 3.0: Acetutril = 3: 2
流速 Z 0. 8ml/ min. Flow rate Z 0.8 ml / min.
カラム温度 Z40°C Column temperature Z40 ° C
検出器 紫外吸光光度計 (275nm) SPD - 6A (島津製作所） 試料 測定サンプル約 10mgをァセトニトリル 10mlに溶解しその 2· 0 μ 1を 注入、又は、測定サンプル約 25mgを DMF2mlに溶解し、その 0. 4 1を注入 Detector UV absorption spectrophotometer (275 nm) SPD-6A (Shimadzu Corporation) Sample Dissolve about 10 mg of measurement sample in 10 ml of acetonitrile and inject 2.0 μl of it, or dissolve about 25 mg of measurement sample in 2 ml of DMF and dissolve Inject 4 1
測定範囲 /溶媒ピークの後力も化合物 Aの保持時間の 10倍の範囲 純度計算方法 Z面積百分率で算出 Measurement range / Solution force of solvent peak is also 10 times the retention time of compound A Purity calculation method Calculated by Z area percentage
本発明中「化合物 Aの重量 (g)に対し一倍容量 (mL)」とは、溶質である化合物 Aの 重量 (g)に対する溶媒の容量 (mL)を意味する。例えば「2倍容量 (mL)」とは、化合 物 A 10gに対し溶媒量は 20mLを表す。 In the present invention, “one time volume (mL) with respect to the weight (g) of Compound A” means the volume (mL) of the solvent with respect to the weight (g) of Compound A as a solute. For example, “double volume (mL)” means that the solvent amount is 20 mL for 10 g of Compound A.
本発明中「冷却温度」とは、加熱攪拌後の懸濁液から析出晶をろ取する時の懸濁 液の温度をいう。 In the present invention, the “cooling temperature” refers to the temperature of the suspension at the time of filtering the precipitated crystals from the suspension after heating and stirring.
本発明中「冷却保持時間」とは、加熱攪拌後の懸濁液を所定の冷却温度まで冷却 した後、該冷却温度を保ったまま放置又は攪拌する時間を!ヽぅ。 In the present invention, the term "cooling holding time" refers to the time during which the suspension after heating and stirring is cooled to a predetermined cooling temperature, and then left or stirred while maintaining the cooling temperature.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 以下に本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
[0008] 本発明に用いる溶媒としては、 DMF、 NMF、 FA等のアミド系溶媒、 DMI、 DMS Oを挙げることができる。このうち DMFがより好ましい。これらの溶媒が適当であると いうことは、試験例 1で詳述する。 [0008] Examples of the solvent used in the present invention include amide solvents such as DMF, NMF, and FA, DMI, and DMSO. Of these, DMF is more preferred. The suitability of these solvents is detailed in Test Example 1.
本発明に用いる溶媒量としては、ィ匕合物 Aの重量 (g)に対し 0. 5— 5倍容量 (mL) の範囲内が適当であり、 0. 9-2. 5倍容量の範囲内がより好ましぐ 1倍容量が特に 好ましい。この範囲の溶媒量が適当であるということは、試験例 2で詳述する。 The amount of the solvent used in the present invention is suitably in the range of 0.5 to 5 times volume (mL) with respect to the weight (g) of the compound A, and in the range of 0.9 to 2.5 times volume. 1 volume is particularly preferred. The appropriate amount of the solvent in this range will be described in detail in Test Example 2.
加熱温度は、用いる溶媒により異なる力 65— 120°Cの範囲內が適当であり、 80
一 100°Cがより好ましい。加熱攪拌時間は、用いる溶媒や攪拌装置により異なるが、 0. 5— 5時間の範囲内が適当であり、 1時間がより好ましい。この範囲の加熱温度及 び攪拌時間が適当であるということは、試験例 3で詳述する。 The heating temperature should be different depending on the solvent used. One 100 ° C is more preferable. The heating and stirring time varies depending on the solvent and the stirring device used, but is suitably in the range of 0.5 to 5 hours, more preferably 1 hour. Suitability of the heating temperature and the stirring time in this range will be described in detail in Test Example 3.
加熱攪拌後の冷却速度は純度にほとんど影響しない。また、所定の冷却温度に達 した後の冷却保持時間は、純度に影響しないが、設定温度が高く短時間だと回収率 が悪くなるため、冷却温度は 30で以下、冷却保持時間は 30分以上が好ましい。この 範囲の冷却温度及び冷却保持時間が適当であるということは、試験例 4で詳述する。 なお、本精製に用いる化合物 Aは、上記の方法により製造したものを用いればよい が、化合物 Aに水分が含まれていると精製の度合いや回収率に影響するため、予め イソプロパノールで洗浄、乾燥する等の処理を行うことにより、水分を除去しておくこと が好ましい。 The cooling rate after heating and stirring hardly affects the purity. The cooling hold time after reaching the specified cooling temperature does not affect the purity, but the recovery rate is poor if the set temperature is high and the time is short, so the cooling temperature is 30 or less, and the cooling hold time is 30 minutes. The above is preferable. Suitability of the cooling temperature and the cooling holding time in this range will be described in detail in Test Example 4. Compound A used in this purification may be one produced by the above method.However, if water is contained in Compound A, it will affect the degree of purification and the recovery rate, so it must be washed and dried in advance with isopropanol. It is preferable to remove the water by performing a treatment such as drying.
[0009] 精製した化合物 Aは、例えばァセトニトリルを再結晶溶媒として再結晶することがで きる。これにより化合物 Aの純度を 99%以上に高めることができる。該再結晶は、常 法により行うことができる。 [0009] The purified compound A can be recrystallized using, for example, acetonitrile as a recrystallization solvent. This can increase the purity of compound A to 99% or more. The recrystallization can be performed by a conventional method.
実施例 Example
[0010] 以下に参考例、実施例及び試験例を掲げて本発明を更に詳しく説明するが、本発 明はこれらのみに限定されるものではない。 [0010] Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.
[0011] 参考例 1 6—フルオロー 1ーメチルー 7_「4ー（5—メチルー 2—ォキソ一 1. 3—ジォキソレン 一 4一ィル）メチルー 1—ピペラジニル Ί一 4一ォキソ一 4H_「1, 31チアゼト「3. 2— alキノリ ンー 3—力ルボン酸 (化合物 A)の合成 Reference Example 1 6-Fluoro-1-methyl-7_ “4- (5-methyl-2-oxo-1.3-dioxolen-14-yl) methyl-1-piperazinyl Ί4-oxo-1 4H_“ 1,31 thiazet “3.2—Al quinoline-3-sulfuric acid (Compound A) Synthesis
工程 1 4ーブロモメチルー 5—メチルー 1， 3—ジォキソレン一 2—オンの合成 Step 1 Synthesis of 4-bromomethyl-5-methyl-1,3-dioxolen-1-one
4一クロロメチルー 5—メチルー 1, 3—ジォキソレン一 2—オン 177. 8g、臭化ナトリウム 2 4-Chloromethyl-5-methyl-1,3-dioxolen-1 2-one 177.8 g, sodium bromide 2
29. 2g、 DMF330mLを室温で 2. 5時間攪拌した。反応液にアセトン l lOmLを添 加し、さらに 1. 4時間攪拌した後、反応液をろ過した。 目的化合物は単離することな ぐ溶液のまま次の反応に用いた。 29.2 g and 330 mL of DMF were stirred at room temperature for 2.5 hours. To the reaction solution, 110 mL of acetone was added, and the mixture was further stirred for 1.4 hours, and then filtered. The target compound was used for the next reaction without isolation as a solution.
工程 2 化合物 Aの合成 Step 2 Synthesis of Compound A
工程 1で得られたろ液に炭酸水素カリウム 191. 8gを加え攪拌しながら、文献記載 ( Add 191.8 g of potassium bicarbonate to the filtrate obtained in Step 1 and stir the mixture as described in the literature (
J. Heterocyclic Chem. , 1997, 34, 1773)の方法に準じて合成した 6-フル
オロー 1ーメチルー 7—1—ピぺラジュルー 4一ォキソ一 4H— [1, 3]チアゼト [3, 2— a]キノリ ンー 3—力ルボン酸 362. 7gの DMF930ml懸濁液を加え、 3時間攪拌した。酢酸 86. 3g及び水 90mLを添カ卩し、更に水 4. 2L、氷 4. 2kgをカ卩え、攪拌し、析出晶をろ取し 、 630. 6gの目的物（水分含量 34%、水分を除く純度 89. 9%)を得た。 J. Heterocyclic Chem., 1997, 34, 1773). Olor 1-Methyl-7-1-Piradulou 4-oxo-1H- [1,3] thiazeto [3,2-a] quinolin-3-Capillonic acid 362.7 g of DMF in 930 ml was added and stirred for 3 hours did. 86.3 g of acetic acid and 90 mL of water were added to the mixture, and 4.2 L of water and 4.2 kg of ice were added. The mixture was stirred, and the precipitated crystals were collected by filtration. 630.6 g of the desired product (water content 34%, The purity excluding water was 89.9%).
[0012] 参考例 2 塩化メチレンを用 1、た柚出処理による化合物 Aの精製 Reference Example 2 Purification of Compound A by Mizukude Treatment
参考例 1で得られた化合物 A209. 87g、塩化メチレン 6Lを室温で 1時間攪拌し、 一晩放置した。翌日、分液ロートにて抽出液を分離した。分液した上層に塩化メチレ ン 0. 8Lを加え、 1時間攪拌し分液ロートにて抽出液を分離した。分液した上層に塩 ィ匕メチレン 0. 4Lを加え、 1時間攪拌し分液ロートにて抽出液を分離した。全抽出液 に無水硫酸マグネシウム 75. Ogを加え、攪拌した後ろ過した。ろ液を液量が 180mL になるまで常圧濃縮し、ァセトニトリル 125mLを加え攪拌し、冷却し、結晶を析出さ せた。析出晶をろ取、乾燥し、精製ィ匕合物 A120. 8g (純度 97. 6%)を得た。 87 g of the compound A obtained in Reference Example 1 and 6 L of methylene chloride were stirred at room temperature for 1 hour and left overnight. The next day, the extract was separated using a separating funnel. 0.8 L of methylene chloride was added to the separated upper layer, the mixture was stirred for 1 hour, and the extract was separated with a separating funnel. 0.4 L of Shiridani methylene was added to the separated upper layer, the mixture was stirred for 1 hour, and the extract was separated with a separating funnel. 75. Og of anhydrous magnesium sulfate was added to all the extracts, and the mixture was stirred and filtered. The filtrate was concentrated under normal pressure until the liquid volume became 180 mL, 125 mL of acetonitrile was added, the mixture was stirred, cooled, and crystals were precipitated. Precipitated crystals were collected by filtration and dried to obtain 120.8 g (purity 97.6%) of Purified Dani-drug A12.
[0013] 実施例 1 DMFを用いた加熱懵枠処理による化合物 Aの精製 Example 1 Purification of Compound A by Heating and Flame Treatment Using DMF
参考例 1で得られた化合物 A419. lgを 300mLのイソプロパノール中で攪拌、ろ 取後、乾燥し、化合物 Aの洗浄晶 295. 5gを得た。該洗浄晶 262. 9g、 DMF237ml を 100°Cで 1時間加熱攪拌後、空冷し、一晩放置した。翌日、水冷攪拌 (室温)し析 出晶をろ取後、イソプロパノールで洗浄、乾燥し、精製化合物 A206. lg (純度 97. 8 %)を得た。 Compound A419.lg obtained in Reference Example 1 was stirred in 300 mL of isopropanol, filtered, and dried to obtain 295.5 g of a washed crystal of Compound A. 262.9 g of the washed crystals and 237 ml of DMF were heated and stirred at 100 ° C for 1 hour, air-cooled, and left overnight. The next day, the mixture was stirred with water cooling (room temperature), and the precipitated crystals were collected by filtration, washed with isopropanol and dried to obtain a purified compound A206.lg (purity: 97.8%).
[0014] 試験例 1 による 力奥 [0014] Power depth according to Test Example 1
純度 88. 37%の化合物 Αに各種溶媒を所定量加え、所定温度で所定時間加熱攪 拌後、 15— 20°Cまで冷却し、そのまま約 40分間攪拌した後、析出晶をろ取、乾燥し た。その結果を表 1に示す。 Predetermined amounts of various solvents were added to compound 88 with a purity of 88.37%, and the mixture was heated and stirred at the specified temperature for the specified time, cooled to 15-20 ° C, stirred for about 40 minutes, and the precipitated crystals were collected by filtration and dried. did. The results are shown in Table 1.
[表 1] [table 1]
[0015] 試験例 2 m ^ [0015] Test example 2 m ^
化合物 Aに DMFを所定量加え、所定温度で所定時間加熱攪拌後、 15— 20°Cま で冷却し、そのまま約 40分間攪拌した後、析出晶をろ取、乾燥した。その結果を表 2 に示す。 A predetermined amount of DMF was added to Compound A, and the mixture was heated with stirring at a predetermined temperature for a predetermined time, cooled to 15 to 20 ° C, stirred for about 40 minutes as it was, and the precipitated crystals were collected by filtration and dried. The results are shown in Table 2.
[表 2] [Table 2]
[0016] 試験例 3 カロ薩拌 謹 [0016] Test Example 3
純度 89. 2%の化合物 Aに DMFを 1倍容量カ卩え、所定温度で所定時間加熱攪拌 後、 15— 20°Cまで冷却し、そのまま約 40分間攪拌した後、析出晶をろ取、乾燥した 。その結果を表 3に示す。 Add 1 volume of DMF to Compound A having a purity of 89.2%, heat and stir at a predetermined temperature for a predetermined time, cool to 15-20 ° C, stir as it is for about 40 minutes, and collect the precipitated crystals by filtration. Dried. The results are shown in Table 3.
[表 3] [Table 3]
[0017] 試験例 4 冷却条件と精製効果
化合物 Aに DMFを 1倍容量加え、 80°Cで 1. 2時間加熱攪拌後、所定の冷却速度 で所定温度まで冷却し、そのまま所定時間攪拌後、析出晶をろ取、乾燥した。その結 果を表 4に示す。 Test Example 4 Cooling conditions and purification effect One-fold volume of DMF was added to Compound A, and the mixture was heated and stirred at 80 ° C for 1.2 hours, cooled to a predetermined temperature at a predetermined cooling rate, stirred as it was for a predetermined time, and the precipitated crystals were collected by filtration and dried. The results are shown in Table 4.
[表 4] [Table 4]
[0018] 試験例 5 抽出処理と加熱攪拌処理の対比 Test Example 5 Comparison between extraction treatment and heating and stirring treatment
塩化メチレンを用いた抽出処理による精製は、参考例 2に準じて行った。本処理に は塩化メチレンを 50倍容量使用した。加熱攪拌処理による精製は、実施例 1に準じ て行った。溶媒量は 0. 9倍量、加熱攪拌は 100°Cで lhr、冷却温度は 23°C、冷却保 持時間は 5時間で行った。 Purification by extraction using methylene chloride was performed according to Reference Example 2. For this treatment, 50 times the volume of methylene chloride was used. Purification by heating and stirring was performed according to Example 1. The amount of the solvent was 0.9 times, the heating and stirring were performed at 100 ° C for lhr, the cooling temperature was 23 ° C, and the cooling holding time was 5 hours.
また、それぞれの精製方法により得られたィ匕合物 Aを用いて、ァセトニトリル力も再 結晶した。その結果を表 5に示す。 In addition, the acetonitrile power was recrystallized using the compound A obtained by each purification method. Table 5 shows the results.
[表 5]
上記表 5に示す通り、加熱攪拌処理による精製方法は、抽出処理による精製方法と 同等以上の精製効果がある。 [Table 5] As shown in Table 5 above, the purification method by the heating and stirring treatment has a purification effect equal to or higher than the purification method by the extraction treatment.
産業上の利用可能性 Industrial applicability
[0019] 以上に示したように、本発明に係る精製方法は、従来の抽出処理による精製方法 に比べ、環境に対する悪影響が少なぐ簡便で、安価な精製方法であり、化合物 Aの 精製方法として非常に有用である。
[0019] As described above, the purification method according to the present invention is a simple and inexpensive purification method with less adverse effect on the environment as compared with the conventional purification method by extraction treatment. Very useful.
Claims
[1] 6_フルオロー 1ーメチルー 7— [4— (5—メチルー 2—ォキソ—1, 3—ジォキソレン一 4一ィル） メチルー 1ーピぺラジュル]一 4ーォキソー 4H—[1, 3]チアゼト [3, 2— a]キノリン一 3—力 ルボン酸を、 N, N—ジメチルホルムアミド、 N—メチルホルムアミド、ホルムアミド、ジメ チルァセトアミド、ジメチルイミダゾール及びジメチルスルホキシド力 なる群力 選択 される溶媒中で加熱攪拌する工程、及び、懸濁液を冷却後、析出晶をろ取し、乾燥 する工程を有することを特徴とする、 6—フルオロー 1ーメチルー 7— [4_ (5—メチルー 2— ォキソ一 1 , 3—ジォキソレン一 4一ィル）メチルー 1ーピぺラジュル]一 4一ォキソ一 4H— [ 1 , 3]チアゼト [3, 2— a]キノリン一 3—力ルボン酸の精製方法。 [1] 6_Fluoro-1-methyl-7- [4- (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazur] -1-oxo-4H- [1,3] thiazet [3,2-a] quinoline 1-3-force Rubonic acid is heated in a selected solvent under the group power of N, N-dimethylformamide, N-methylformamide, formamide, dimethylacetamide, dimethylimidazole and dimethylsulfoxide. 6-fluoro-1-methyl-7- [4_ (5-methyl-2-oxo-1,3), which comprises the steps of: —Dioxolen-41-yl) methyl-1-piperazur] -1-4-oxo-4H— [1,3] thiazeto [3,2-a] quinoline-a 3-quinoline—A method for purifying rubonic acid.
[2] 精製されるべき 6-フルォロ— 1一メチル -7— [4— (5-メチルー 2—ォキソ一 1, 3-ジォキ ソレン一 4一ィル）メチルー 1—ピぺラジュル]一 4一ォキソ一 4H_[1, 3]チアゼト [3, 2— a] キノリン- 3-カルボン酸の純度が 80 90%の範囲内である、請求項 1記載の精製方 法。 [2] 6-Fluoro-1-methyl-7 to be purified [4- (5-Methyl-2-oxo-1,3-dioxolen-41-yl) methyl-1-pirazur] -1-41 The purification method according to claim 1, wherein the purity of oxo mono 4H_ [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid is in the range of 80 to 90%.
[3] 溶媒が N, N-ジメチルホルムアミドである、請求項 1記載の精製方法。 [3] The purification method according to claim 1, wherein the solvent is N, N-dimethylformamide.
[4] 溶媒量が 6—フルオロー 1ーメチルー 7_ [4— (5—メチルー 2—ォキソ—1, 3—ジォキソレン 一 4一ィル)メチルー 1ーピぺラジュル]一 4一才キソー 4H_[1， 3]チアゼト [3， 2— a]キノリ ン— 3—力ルボン酸の重量 (g)に対し 0. 5— 5倍容量 (mL)の範囲内である、請求項 1 記載の精製方法。 [4] Solvent amount is 6-fluoro-1-methyl-7_ [4- (5-methyl-2-oxo-1,3-dioxolen-14-yl) methyl-1-piperazur] 1-4 3. The purification method according to claim 1, wherein the amount is within a range of 0.5 to 5 times the volume (mL) of the weight (g) of 3] thiazeto [3,2-a] quinolin-3-3-carboxylic acid.
[5] 加熱攪拌時の温度が 65— 120°Cの範囲内である、請求項 1記載の精製方法。 [5] The purification method according to claim 1, wherein the temperature during heating and stirring is in the range of 65 to 120 ° C.
[6] 冷却温度が一 6— 30°Cの範囲内である、請求項 1記載の精製方法。 [6] The purification method according to claim 1, wherein the cooling temperature is in the range of 16 to 30 ° C.
[7] 精製されるべき 6—フルォロ— 1ーメチルー 7— [4— (5—メチルー 2—ォキソ一 1， 3—ジォキ ソレン一 4一ィル）メチルー 1—ピペラジニル]一 4ーォキソー 4H_[1, 3]チアゼト [3, 2— a] キノリン一 3—力ルボン酸の純度が 80 90%の範囲内であり、溶媒が N, N—ジメチル ホルムアミドであり、カかる溶媒量力 S6—フルォロ— 1ーメチルー 7_[4— (5—メチルー 2— ォキソ一 1 , 3—ジォキソレン一 4一ィル)メチルー 1ーピペラジニル]一 4一ォキソ一 4H— [ 1 , 3]チアゼト [3, 2— a]キノリン一 3—力ルボン酸の重量 (g)に対し 0. 5— 5倍容量 (mL) の範囲内であり、加熱攪拌時の温度が 65 120°Cの範囲内であり、かつ、冷却温度 が- 6— 30°Cの範囲内である、請求項 1記載の精製方法。
請求項 1一 7のいずれかに記載の精製方法により精製した 6 -フルオロー 1ーメチルー 7 - [4— (5—メチルー 2—ォキソ _1 , 3—ジォキソレン一 4一ィル）メチルー 1ーピぺラジュル] 一 4一才キソー 4H— [1, 3]チアゼト [3, 2— a]キノリン一 3—力ルボン酸をさらに再結晶す ることを特徴とする、 6—フルオロー 1ーメチルー 7— [4— (5—メチルー 2—ォキソ一 1， 3—ジ ォキソレン一 4一ィル)メチルー 1ーピぺラジュル]一 4一才キソー 4H—[1， 3]チアゼト [3， 2-a]キノリン一 3—力ルボン酸の精製方法。
[7] 6-Fluoro-1-methyl-7- [4- (5-methyl-2-oxo-1, 3-dioxolen-1 4-yl) methyl-1-piperazinyl] 1-4-oxo 4H_ [1, 3] Thiazeto [3, 2-a] quinoline- 1- 3-Rubonic acid has a purity of 80-90%, solvent is N, N-dimethylformamide, and the solvent capacity is S6-fluoro-1-methyl- 7_ [4— (5-Methyl-2-oxo-1, 3-dioxolen-1 41-yl) methyl-1-piperazinyl] -1 4-oxo-1 4H— [1,3] thiazeto [3,2-a] quinoline-1 3 —The amount is 0.5 to 5 times the volume (mL) of the weight (g) of the carboxylic acid, the temperature during heating and stirring is within the range of 65 to 120 ° C, and the cooling temperature is −6. — The purification method according to claim 1, wherein the temperature is in the range of 30 ° C. A 6-fluoro-1-methyl-7- [4- (5-methyl-2-oxo_1,3-dioxolen-141-yl) methyl-1-pidrajur purified by the purification method according to claim 17. ] 14-year-old xo 4H- [1, 3] thiazeto [3, 2-a] quinoline 13- carboxylic acid characterized by further recrystallization, 6-fluoro-1-methyl-7- [4- (5-Methyl-2-oxo-1,3-dioxolene 41-yl) methyl-1-piperazur] -1 4-year-old xo 4H— [1,3] thiazeto [3,2-a] quinoline-1 3 —Method of purifying rubonic acid.
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