JP2005527484A5

JP2005527484A5 -

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Publication number: JP2005527484A5
Application number: JP2003546834A
Authority: JP
Filing date: 2002-11-27
Publication date: 2006-06-22

Description

レボフロキサシンは対掌性フッ素化カルボキシキノロンである。その化学名は（Ｓ）−９−フルオロ−２，３−ジヒドロ−３−メチル−１０−（４−メチル−１−ピペラジニル）−７−オキソ−７Ｈ−ピリド〔１，２，３−ｄｅ〕−１，４−ベンゾキサジン−６−カルボン酸（ＣＡＳ登録番号１００９８６−８５−４）である。レボフロキサシンの化学構造を式Ｉとして示す。

Levofloxacin is a chiral fluorinated carboxyquinolone. Its chemical name is (S) -9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3- de ]. -1,4-benzoxazine-6-carboxylic acid (CAS Registry Number 100986-85-4). The chemical structure of levofloxacin is shown as Formula I.

米国特許第４，３８２，８９２号はピリド〔１，２，３−ｄｅ〕〔１，４〕ベンゾキサジン誘導体とその製法に係わる。 U.S. Pat. No. 4,382,892 relates to pyrido [1,2,3- de ] [1,4] benzoxazine derivatives and their preparation.

発明の詳細な説明
粗製及び半精製のレボフロキサシンなら、公知の方法で製造することができる。また、例えば下記の方法でも低純度のレボフロキサシンを製造することができる：機械的攪拌器、凝縮器及び温度計を装備し、８０℃に加熱された１リットル反応装置に８７．５ｇ（０．３１モル）の（Ｓ）−（−）−９，１０−ジフルオロ−３−メチル−７−オキソ−２，３−ジヒドロ−７Ｈ−ピリド〔１，２，３−ｄｅ〕〔１，４〕ベンゾキサジン−６−カルボン酸、６１．３ｍＬのＤＭＳＯ及び８６．３ｍＬ（０．７７モル）のＮ−メチルピペラジンを注入する。（ＨＰＬＣによってモニターしながら）反応が完了するまで８０℃、チッソ雰囲気下で２５０ｒｐｍの速度でスラリーを攪拌する。次いで、スラリーを７５℃に冷却し、イソプロパノール（６７５ｍＬ）と水（２５ｍＬ）の混合物を２時間かけてこの温度において１滴ずつ添加する。次いで、４時間かけて５℃にまで冷却し、この温度を２時間維持し、この温度において真空下で濾過する。固形物を１７５ｍＬのイソプロパノールで洗浄（２度のリンス）し、真空乾燥して低純度レボフロキサシンを得る。 DETAILED DESCRIPTION OF THE INVENTION Crude and semi-purified levofloxacin can be produced by known methods. Also, for example, low purity levofloxacin can also be produced by the following method: 87.5 g (0.31) in a 1 liter reactor equipped with a mechanical stirrer, condenser and thermometer and heated to 80 ° C. Mol) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3- de ] [1,4] benzoxazine- 6-carboxylic acid, 61.3 mL DMSO and 86.3 mL (0.77 mol) N-methylpiperazine are injected. The slurry is stirred at a rate of 250 rpm in a nitrogen atmosphere at 80 ° C. until the reaction is complete (monitoring by HPLC). The slurry is then cooled to 75 ° C. and a mixture of isopropanol (675 mL) and water (25 mL) is added dropwise at this temperature over 2 hours. It is then cooled to 5 ° C. over 4 hours, this temperature is maintained for 2 hours and filtered under vacuum at this temperature. The solid is washed with 175 mL isopropanol (2 rinses) and vacuum dried to obtain low purity levofloxacin.

酸化防止剤を使用するなら、精製工程中の種々の段階で添加することができる。例えば、一態様では、晶析工程の前または晶析工程中にまたは溶解段階中に酸化防止剤をレボフロキサシンと混合する。好ましい態様は、晶析工程の前に酸化防止剤を添加するため、精製前のレボフロキサシンがＨＰＬＣによって検出可能な量のN-オキシドレボフロキサシンを含有しているかどうかを判定するステップを含む。他の実施例では、高温においてレボフロキサシンに変換する前に、酸化防止剤を（Ｓ）−（−）−９，１０−ジフルオロ−３−メチル−７−オキソ−２，３−ジヒドロ−７Ｈ−ピリド〔１，２，３−ｄｅ〕〔１，４〕ベンゾキサジン−６−カルボン酸と混合する。 If an antioxidant is used, it can be added at various stages during the purification process. For example, in one embodiment, an antioxidant is mixed with levofloxacin before, during or during the crystallization process. A preferred embodiment includes the step of determining whether the pre-purification levofloxacin contains an amount of N-oxide levofloxacin detectable by HPLC, because an antioxidant is added prior to the crystallization step. In another example, the antioxidant is converted to (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido prior to conversion to levofloxacin at elevated temperatures. [1,2,3- de ] [1,4] Benzoxazine-6-carboxylic acid is mixed.

下に掲げる表１は下記の例に関する実験結果をまとめたものである。表１におけるそれぞれの成分の％はオフロキサシン中の関連物質のためのヨーロッパ薬局方に基づく方法を採用してＨＰＬＣにより測定された。
表１：晶析の過程における純度

Table 1 below summarizes the experimental results for the following examples. The percentage of each component in Table 1 was measured by HPLC employing a method based on the European Pharmacopoeia for related substances in ofloxacin.
Table 1: Purity in the crystallization process

例１０：ACN:H₂O（９：１）/メタ重亜硫酸塩
１．５ｇのレボフロキサシン粗製物と８ｍｇのメタ重亜硫酸ナトリウムを、チッソ雰囲気下で１０．５ｍｌの混合物ＡＣＮ：Ｈ₂Ｏ（９：１）中に懸濁させた。材料が完全に溶解するまで、混合物を還流温度に加熱した。次いで、３０分間かけて溶液をＲＴまで冷却した。真空下で沈殿物を濾過し、混合物ＡＣＮ：Ｈ₂Ｏ（９：１）（４ｍｌ）で洗浄し、真空オーブン中で６０℃で乾燥させることにより、１．１６ｇ（７７％）の純粋なレボフロキサシンを得た。 Example 10: AC N: H ₂ O (9: 1) / metabisulfite 1.5 g of levofloxacin crude and 8 mg of sodium metabisulfite are mixed with 10.5 ml of mixture ACN: H ₂ O (in a nitrogen atmosphere). 9: 1). The mixture was heated to reflux temperature until the material was completely dissolved. The solution was then cooled to RT over 30 minutes. 1.16 g (77%) of pure levofloxacin by filtering the precipitate under vacuum, washing with the mixture ACN: H ₂ O (9: 1) (4 ml) and drying in a vacuum oven at 60 ° C. Got.

例１１：ACN:H₂O（９５：５）/メタ重亜硫酸塩（８ｍｇ）
１．５ｇのレボフロキサシン粗製物と８ｍｇのメタ重亜硫酸ナトリウムを、チッソ雰囲気下で１０．５ｍｌの混合物ＡＣＮ：Ｈ₂Ｏ（９５：５）中に懸濁させた。混合物を還流温度に加熱し、熱濾過した。溶液を再び還流温度まで加熱してから、３０分間かけて３℃にまで冷却した。真空下で沈殿物を濾過し、真空オーブン中で６０℃で乾燥させることにより、５００ｍｇ（３３％）の純粋なレボフロキサシンを得た。 Example 11: AC N: H ₂ O (95: 5) / metabisulfite (8 mg)
1.5 g crude levofloxacin and 8 mg sodium metabisulfite were suspended in 10.5 ml of mixture ACN: H ₂ O (95: 5) under a nitrogen atmosphere. The mixture was heated to reflux temperature and filtered hot. The solution was again heated to reflux and then cooled to 3 ° C. over 30 minutes. The precipitate was filtered under vacuum and dried in a vacuum oven at 60 ° C. to give 500 mg (33%) of pure levofloxacin.

例１３：ＤＭＳＯ/アスコルビン酸
凝縮器を装備した三つ首フラスコ中で、５ｇ（１７．８ミリモル）の（Ｓ）−（−）−９，１０−ジフルオロ−３−メチル−７−オキソ−２，３−ジヒドロ−７Ｈ−ピリド〔１，２，３−ｄｅ〕〔１，４〕ベンゾキサジン−６−カルボン酸と、４．４６ｇ（４４．６ミリモル）、３１ｍｇ（０．１７ミリモル）のアスコルビン酸とを、チッソ雰囲気下、８０℃において３．５ｍｌのＤＭＳＯ中に懸濁させた。反応完了までこの反応混合物をこの温度で加熱した（４ｈ３０）。次いで、溶液を７０℃まで冷却し、ＩＰＡ（４０ｍｌ）を滴加した。１時間かけて混合物を０℃にまで冷却し、この温度で３０分間攪拌した。真空下で沈殿物を濾過し、ＩＰＡ（１０ｍｌ）で洗浄し、真空オーブン中で６０℃で乾燥させることにより、５．６３ｇ（８７．６％）の純粋なレボフロキサシンを得た。 Example 13: DMSO / ascorbic acid 5 g (17.8 mmol) (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2 in a three-necked flask equipped with a condenser , 3-Dihydro-7H-pyrido [1,2,3- de ] [1,4] benzoxazine-6-carboxylic acid and 4.46 g (44.6 mmol), 31 mg (0.17 mmol) ascorbic acid Were suspended in 3.5 ml DMSO at 80 ° C. under a nitrogen atmosphere. The reaction mixture was heated at this temperature until the reaction was complete (4h30). The solution was then cooled to 70 ° C. and IPA (40 ml) was added dropwise. The mixture was cooled to 0 ° C. over 1 hour and stirred at this temperature for 30 minutes. The precipitate was filtered under vacuum, washed with IPA (10 ml) and dried in a vacuum oven at 60 ° C. to give 5.63 g (87.6%) of pure levofloxacin.

例１４：ＤＭＳＯ/メタ重亜硫酸塩
凝縮器を装備した三つ首フラスコ中で、１０ｇ（３５．５ミリモル）の（Ｓ）−（−）−９，１０−ジフルオロ−３−メチル−７−オキソ−２，３−ジヒドロ−７Ｈ−ピリド〔１，２，３−ｄｅ〕〔１，４〕ベンゾキサジン−６−カルボン酸と、９．０ｇ（９０ミリモル）、３４ｍｇ（０．１７ミリモル）メタ重亜硫酸ナトリウムとを、チッソ雰囲気下、８０℃において７ｍｌのＤＭＳＯ中に懸濁させた。反応完了までこの反応混合物をこの温度で加熱した（５時間３０分）。次いで、溶液を７０℃まで冷却し、ＩＰＡ（４０ｍｌ）を滴加した。１時間かけて混合物を０℃にまで冷却し、この温度で３０分間攪拌した。真空下で沈殿物を濾過し、ＩＰＡ（１０ｍｌ）で洗浄し、真空オーブン中で６０℃で乾燥させることにより、１１．８ｇ（９２．４％）の純粋なレボフロキサシンを得た。 Example 14: DMSO / Metabisulfite 10 g (35.5 mmol) (S)-(−)-9,10-difluoro-3-methyl-7-oxo in a three-necked flask equipped with a condenser -2,3-dihydro-7H-pyrido [1,2,3- de ] [1,4] benzoxazine-6-carboxylic acid, 9.0 g (90 mmol), 34 mg (0.17 mmol) metabisulfite Sodium was suspended in 7 ml DMSO at 80 ° C. under a nitrogen atmosphere. The reaction mixture was heated at this temperature until the reaction was complete (5 hours 30 minutes). The solution was then cooled to 70 ° C. and IPA (40 ml) was added dropwise. The mixture was cooled to 0 ° C. over 1 hour and stirred at this temperature for 30 minutes. The precipitate was filtered under vacuum, washed with IPA (10 ml) and dried in a vacuum oven at 60 ° C. to give 11.8 g (92.4%) of pure levofloxacin.

Claims

A process for producing levofloxacin having a purity of 99 % or more,
Levofloxacin is dissolved in a polar solvent at a temperature of 80 ° C. to 110 ° C . ; and purified levofloxacin crystallizes out;
The process wherein the polar solvent is selected from the group consisting of dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, butanol, mixtures thereof, and mixtures thereof with water.

The method according to claim 1, wherein the purity of the purified levofloxacin is 99.5 wt% or more.

The process according to claim 1, wherein the high temperature is the reflux temperature of the solution.

The process according to claim 1, wherein the solvent is acetonitrile.

The method according to claim 1, wherein the solvent is a mixture of acetonitrile and water, and the amount of water in the solvent is 10 % or less.

The method according to claim 1, wherein the amount of desmethyllevofloxacin in levofloxacin after purification is at least 1/3 less than the amount contained in levofloxacin before purification.

The method according to claim 1, further comprising an antioxidant addition step before the crystallization step.

As an antioxidant, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6 -Of di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, tocopherol, and pharmaceutically acceptable salts and mixtures thereof Either method is used, The manufacturing method of Claim 7 characterized by the above-mentioned.

The process according to claim 7, wherein the antioxidant is sodium metabisulfite.

The process according to claim 7, wherein the antioxidant is ascorbic acid.

8. The process according to claim 7, wherein the amount of N-oxide levofloxacin contained in levofloxacin after purification is at least 1/3 less than that in levofloxacin before purification.

The amount of N-oxide levofloxacin contained in the purified levofloxacin is 0 . The method according to claim 7, wherein the content is 1% or less.

The method according to claim 7, wherein the purity of the purified levofloxacin is 99.5% by weight or more.

The method according to claim 7, further comprising the step of determining whether the levofloxacin before purification contains an amount of N-oxide levofloxacin detectable by HPLC.

8. The process according to claim 7, wherein the solvent is acetonitrile and the purified levofloxacin is almost pure levofloxacin hemihydrate.

The process according to claim 1, wherein the purified levofloxacin is a substantially pure levofloxacin hemihydrate.

A levofloxacin hemihydrate process having a 99% purity or greater,
Levofloxacin is dissolved in a polar solvent at a temperature of 80 ° C to 110 ° C ;
Crystallize levofloxacin hemihydrate;
The process according to claim 1, wherein the polar solvent is selected from the group consisting of dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, butanol, mixtures thereof, and mixtures thereof with water.

The process according to claim 17, wherein the high temperature is the reflux temperature of the solution.

The process according to claim 17, wherein the solvent is a mixed solvent of dimethyl sulfoxide and H ₂ O mixed at a ratio of 1 : 5.

The process according to claim 17, wherein the solvent is methyl ethyl ketone.

The process according to claim 17, wherein the solvent is n-butanol.

The process according to claim 17, wherein the solvent is acetonitrile.

A levofloxacin-containing preparation having a purity of 99% or more according to the process of claim 1.

A levofloxacin-containing preparation having a purity of 99% or more in the process according to claim 7.

A preparation containing levofloxacin hemihydrate having a purity of 99% or more according to the process of claim 17.

The antioxidant is levofloxacin 0 . The process according to claim 7, characterized in that it ranges from 2 to 5 % by weight.

A process according to claim 7, characterized in that the addition of the antioxidant prior to the dissolution step to levofloxacin.

A process according to claim 1, characterized in that further comprising adding an antioxidant during the crystallization step.

A process for the preparation of levofloxacin hemihydrate comprising:
Levofloxacin at a temperature of 80 to 110 ° C. , acetonitrile, mixed solvent of acetonitrile and H ₂ O, mixed solvent of dimethyl sulfoxide and H ₂ O , methyl ethyl ketone, butanol, mixed solvent of butanol and H ₂ O and mixtures thereof A process comprising dissolving in a solvent selected from the group consisting of and crystallizing levofloxacin hemihydrate.

Wherein the solvent is 9: 1 ratio of butanol and H ₂ mixture of O solvent or 9 9: consisting essentially of a mixed solvent of acetonitrile and H ₂ O in a ratio of 1, method according to claim 29, wherein.

Wherein the solvent is 9 9: 1 consisting essentially of a mixture of acetonitrile and of H ₂ O ratio claim 30 procedure described.

30. The process of claim 29, wherein the mixture of levofloxacin and the solvent is filtered at a temperature of 80 to 110 [deg.] C. before the crystallization step.

30. The process of claim 29, wherein the dissolving step comprises refluxing the solvent.

Comprising drying with further to 6 0 ° C. The crystallized levofloxacin hemihydrate, method according to claim 29, wherein.

Wherein the solvent is 9: 1 consisting essentially of a mixed solvent of butanol and of H ₂ O ratio claim 30 procedure described.

30. A process according to claim 29, wherein the yield of the levofloxacin hemihydrate produced ranges from 56% to 84%.

The method according to claim 17, wherein the mixture of levofloxacin and the solvent is filtered at a temperature of 80 to 110 ° C before the crystallization step.

The polar solvent is selected from the group consisting of acetonitrile, a mixed solvent of acetonitrile and H ₂ O, a mixed solvent of dimethyl sulfoxide and H ₂ O , methyl ethyl ketone, a mixed solvent of methyl ethyl ketone and H ₂ O , butanol, and a mixture thereof. The method according to claim 17.

The process according to claim 17, further comprising an antioxidant addition step before the crystallization step.

The polar solvent is selected from the group consisting of acetonitrile, a mixed solvent of acetonitrile and H ₂ O, a mixed solvent of dimethyl sulfoxide and H ₂ O , methyl ethyl ketone, a mixed solvent of methyl ethyl ketone and H ₂ O , butanol, and a mixture thereof. The method according to claim 18.

A preparation containing levofloxacin having a purity of 99% or more .

A preparation containing levofloxacin hemihydrate having a purity of 99% or more .