WO2009048086A1 - Method for purification of dibenzoxepin compound - Google Patents

Method for purification of dibenzoxepin compound Download PDF

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Publication number
WO2009048086A1
WO2009048086A1 PCT/JP2008/068325 JP2008068325W WO2009048086A1 WO 2009048086 A1 WO2009048086 A1 WO 2009048086A1 JP 2008068325 W JP2008068325 W JP 2008068325W WO 2009048086 A1 WO2009048086 A1 WO 2009048086A1
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Prior art keywords
dimethylaminopropylidene
acid
acetic acid
oxepin
addition salt
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PCT/JP2008/068325
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French (fr)
Japanese (ja)
Inventor
Tadashi Katsura
Taketo Hayashi
Kei Komatsu
Masahide Tanaka
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Sumitomo Chemical Company, Limited
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Priority to CN200880109944A priority Critical patent/CN101815708A/en
Priority to CH00491/10A priority patent/CH700068B8/en
Publication of WO2009048086A1 publication Critical patent/WO2009048086A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed

Definitions

  • the present invention relates to a method for purifying a dibenzoxepin compound useful as a pharmaceutical, and more particularly, (Z) — 1 1- (3-dimethylaminopropylidene) 1, 6, 1 1-dihydrodibenzo. [b, e] Oxepin 1-2-Acetic acid and its acid addition salt. Background art
  • This compound or its acid addition salt is a pharmaceutical compound that is useful as an antiallergic agent applied to allergic rhinitis, urticaria, etc.
  • Japanese Patent Publication No. 5-86925 and Japanese Patent Publication No. 7-1 1 6 1 It is known in publication No. 74.
  • the present invention provides (Z) — 1 1- (3-dimethylaminopropylidene) 1,6,1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or an acid addition salt thereof efficiently. And it aims at providing the method of refine
  • dibenzoxepin acetic acid represented by the following formula [I] or an acid addition salt thereof is dissolved in a mixed solvent of water and a ketone solvent, and then recrystallized from the mixed solvent. High purity crystals are obtained.
  • (Z) — 1 1— (3-Dimethylaminopropylidene) -1,6 1 1-dihydrodibenzo [b, e] oxepin-2-acetic acid (olopatadine) or its acid addition salt is a solvent After adding, it can be dissolved by heating.
  • acid addition salts of lobatadine include hydrochloride and sulfate, with hydrochloride being preferred.
  • a mixed solvent of water and a ketone solvent is used.
  • the ketone solvent include methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone, cyclopentanone, and a mixture thereof, and methyl ethyl ketone is preferable.
  • the amount of the solvent used is not particularly limited, but if it is too much, the yield will decrease, and if it is too small, the crystals will not dissolve or the purity will be lowered.
  • the ratio is usually about 10 to 20 L of methyl ethyl ketone, about 1 to 2 water, preferably about 12 to 17 L of methyl ethyl ketone and about 1.2 to 1 L of water.
  • the temperature at which olopatadine is dissolved in a mixed solvent of water and a can solvent is usually about 40 to 90 ° C, preferably about 50 to 70 ° C.
  • an adsorbent for example, alumina, activated carbon, etc.
  • the amount of the adsorbent is about 10 to 70 g, preferably about 20 to 50 g, per 1 kg of olopatadine. After adding the adsorbent, remove the adsorbent by filtration.
  • Azeotropic distillation can be performed using a known distillation method.
  • the amount of distillation is about 3 to 15 and preferably about 5 to 1 0. Since the amount of the solvent is insufficient after the distillation, it is preferable to add a ketone solvent.
  • the additional amount is about 3 to 15 L, preferably about 5 to 1 OL.
  • the solution can be isolated by cooling to about 0-30 ° C, preferably about 5-20 ° C, and filtering the precipitated crystals.
  • the cooling rate is usually about 5 to 20 ° C. per hour, preferably about 5 to 15 ° C. per hour.
  • the solution may be stirred.
  • the stirring time is not particularly limited, and is, for example, 1 to 100 hours.
  • An acid can be added when the crystals are precipitated.
  • the acid include hydrochloric acid and sulfuric acid, and hydrochloric acid is preferred. These acids may be used alone or in combination of two or more.
  • the acid may be added before or after cooling, but preferably before cooling.
  • the amount of the acid added is generally about 0.5 to 1.5 equivalents of proton equivalent to olopatadine. For example, when 350/0 hydrochloric acid is used, it is usually about 100 to 400 g, preferably about "! 50 to 300 g, per 1 kg of olopatadine.
  • the filtrate was heated to 75 ° C. to perform azeotropic dehydration, and 560 g was distilled off.
  • the filtrate was cooled to 30 ° C at a rate of 15 ° C per hour, subjected to azeotropic dehydration at a temperature of 30 to 35 ° C under reduced pressure, and 57.9 kg was distilled off. Then, 72.0 L of methyl ethyl ketone was added at about 35 ° C. over 3 hours. After stirring at about 35 ° C for 30 minutes, the mixture was cooled to 10 ° C at a rate of 10 ° C per hour and stirred at the same temperature for 3 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed is a method for purifying (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz- [b,e]oxepin-2-acetic acid represented by the formula [I] or an acid addition salt thereof, which comprises dissolving (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz- [b,e]oxepin-2-acetic acid or the acid addition salt thereof in a mixed solvent of water and a ketone solvent and causing a crystal to be precipitated from the solution. The method can purify (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrobenz[b,e]- oxepin-2-acetic acid, which is useful as a medicinal substance, or an acid addition salt thereof efficiently in an industrially advantageous manner.

Description

明 細 書 ジベンゾォキセピン化合物の精製方法 技術分野  Description Method for purifying dibenzoxepin compounds Technical Field
本発明は、医薬品として有用なジベンゾォキセピン化合物の精製方法に関し、 さ らに詳しくは （Z) — 1 1— (3—ジメチルァミノプロピリデン） 一 6， 1 1—ジ ヒドロジべンゾ [b, e] ォキセピン一 2—酢酸及びその酸付加塩の精製方法に関 する。 背景技術  The present invention relates to a method for purifying a dibenzoxepin compound useful as a pharmaceutical, and more particularly, (Z) — 1 1- (3-dimethylaminopropylidene) 1, 6, 1 1-dihydrodibenzo. [b, e] Oxepin 1-2-Acetic acid and its acid addition salt. Background art
(Z) - 1 1 - (3—ジメチルァミノプロピリデン） 一6, 1 1—ジヒドロジべ ンゾ [b， e] ォキセピン一 2—酢酸（一般名：ォロパタジン） は、下記式 [ I ] ：
Figure imgf000002_0001
(Z)-1 1-(3-Dimethylaminopropylidene) 1,6 1 1-dihydrodibenzo [b, e] oxepin 1 2-acetic acid (generic name: olopatadine) is represented by the following formula [I]:
Figure imgf000002_0001
で示される化合物である。 この化合物又はその酸付加塩が、 アレルギー性鼻炎、蓴 麻疹などに適用される抗アレルギー薬として有用な医薬化合物であることは、特公 平 5— 86925号公報及び特公平 7— 1 1 6 1 74号公報において知られてい る。 It is a compound shown by these. This compound or its acid addition salt is a pharmaceutical compound that is useful as an antiallergic agent applied to allergic rhinitis, urticaria, etc. Japanese Patent Publication No. 5-86925 and Japanese Patent Publication No. 7-1 1 6 1 It is known in publication No. 74.
ジベンゾォキセピン化合物を化学合成する場合、他の異性体 （E体） をはじめと する不純物が含まれているので、 純度を高める為には精製が必要である。  When chemically synthesizing dibenzoxepin compounds, impurities such as other isomers (E) are included, so purification is necessary to increase the purity.
特公平 5— 86925号公報及び特公平 7— 1 1 6 1 74号公報には、目的物が シス一トランスの混合物 （EZ混合物） で得られた場合、 それらの分離はカラムク ロマトグラフィー、再結晶などにより分離することができると記載されている。 し かしな力《ら、 これらの文献には（Z) — 1 1 - (3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒドロべンゾ [b, e] ォキセピン一 2—酢酸そのものの精製につ いては具体的な記載はない。 発明の開示 In Japanese Examined Patent Publication Nos. 5-86925 and 7- 1 1 6 1 74, when the target substance was obtained as a cis-trans mixture (EZ mixture), the separation of them was performed by column chromatography, recrystallization. It is described that it can be separated by, for example. However, these references include (Z) — 1 1-(3-Dimethylaminopropylidene) 1, 6, 1 1-dihydrobenzo [b, e] oxepin 1 2-acetic acid itself. There is no specific description of the purification of the product. Disclosure of the invention
本発明は、 （Z) — 1 1— (3—ジメチルァミノプロピリデン） 一6， 1 1ージ ヒドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を効率的にかつ 工業的有利に精製する方法を提供することを目的とする。  The present invention provides (Z) — 1 1- (3-dimethylaminopropylidene) 1,6,1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or an acid addition salt thereof efficiently. And it aims at providing the method of refine | purifying industrially advantageous.
本発明によれば、下記式 [ I ] で示されるジベンゾォキセピン酢酸又はその酸付 加塩を水とケトン溶媒の混合溶媒に溶解させた後、該混合溶媒よリ結晶を析出させ ることで、 純度の高い結晶が得られる。  According to the present invention, dibenzoxepin acetic acid represented by the following formula [I] or an acid addition salt thereof is dissolved in a mixed solvent of water and a ketone solvent, and then recrystallized from the mixed solvent. High purity crystals are obtained.
即ち、 本発明は、  That is, the present invention
[1 ] 式 [ I ] ：
Figure imgf000003_0001
[1] Formula [I]:
Figure imgf000003_0001
で示される （Z) - 1 1 - (3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒ ドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、 得られた溶液から結晶を析出させる （Z) — 1 1一 （3— ジメチルァミノプロピリデン） 一6， 1 1ージヒドロジべンゾ [b, e] ォキセピ ン一 2—酢酸又はその酸付加塩の精製方法、 (Z)-1 1-(3-Dimethylaminopropylidene) 1, 6, 1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt with water and ketone solvent (Z) — 1 1 1 (3-dimethylaminopropylidene) 1,6 1-dihydrodibenzo [b, e] oxepine 1 2 -Purification method of acetic acid or acid addition salt thereof,
[2] 式 [ I ] :
Figure imgf000003_0002
[2] Formula [I] :
Figure imgf000003_0002
で示される （Z) — 1 1 — （3—ジメチルァミノプロピリデン） 一6, 1 1—ジヒ ドロジべンゾ [b， e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、得られた溶液を共沸留去により濃縮し、次いで濃縮液から 結晶を析出させる [1 ] に記載の精製方法、 (Z) — 1 1 — (3-Dimethylaminopropylidene) 1,6 1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt in water and ketone solvent The purification method according to [1], wherein the resultant solution is dissolved by azeotropic distillation, and then crystals are precipitated from the concentrate.
[3] 式 [ I ] :
Figure imgf000004_0001
[3] Formula [I] :
Figure imgf000004_0001
で示される （Z) — 1 1— (3—ジメチルァミノプロピリデン） 一 6, 1 1ージヒ ドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、得られた溶液を共沸留去により濃縮し、次いで濃縮液に酸 を加えた後、 結晶を析出させる [1 ] に記載の精製方法、 (Z) — 1 1— (3-Dimethylaminopropylidene) 1,6,1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt of water and ketone solvent The purification method according to [1], wherein the resulting solution is dissolved in a mixed solvent, concentrated by azeotropic distillation, and then acid is added to the concentrated solution, followed by precipitation of crystals.
[4] 式 [ I ] :
Figure imgf000004_0002
[4] Formula [I] :
Figure imgf000004_0002
で示される （Z) — 1 1 — (3—ジメチルァミノプロピリデン） 一6， 1 1ージヒ ドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、 得られた溶液に酸を加えた後、 結晶を析出させる [1 ] に 記載の精製方法、 (Z) — 1 1 — (3-Dimethylaminopropylidene) 1,6 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt of water and ketone solvent The method of purification according to [1], wherein the crystal is precipitated after dissolving in a mixed solvent and adding an acid to the resulting solution.
[5] 酸が、 塩化水素である前記 [3] 又は [4] に記載の精製方法、 及び  [5] The purification method according to the above [3] or [4], wherein the acid is hydrogen chloride, and
[6] ケトン溶媒がメチルェチルケトンである前記 [1 ]〜 [4] のいずれかに 記載の精製方法、  [6] The purification method according to any one of [1] to [4], wherein the ketone solvent is methyl ethyl ketone.
に関する。 以下、 本発明を説明する。 なお、 ％は特に指定しない限り、 重量％を意味する。 下記式 [ I ] ：
Figure imgf000004_0003
About. The present invention will be described below. % Means% by weight unless otherwise specified. The following formula [I]:
Figure imgf000004_0003
で示される （Z) — 1 1— （3—ジメチルァミノプロピリデン）一6, 1 1—ジヒ ドロジべンゾ [b， e] ォキセピン一 2—酢酸 （ォロパタジン） 又はその酸付加塩 は溶媒に添加した後、加熱することで溶解させることができる。本発明に用いるォ ロパタジンの酸付加塩としては、塩酸塩、硫酸塩などが挙げられ、塩酸塩が好まし い。 (Z) — 1 1— (3-Dimethylaminopropylidene) -1,6 1 1-dihydrodibenzo [b, e] oxepin-2-acetic acid (olopatadine) or its acid addition salt is a solvent After adding, it can be dissolved by heating. Used in the present invention Examples of acid addition salts of lobatadine include hydrochloride and sulfate, with hydrochloride being preferred.
本発明に用いる溶媒としては、水とケトン溶媒の混合溶媒が用いられる。水とケ トン溶媒との混合割合は、 通常、 容量割合で、 水：ケトン溶媒 = 1 ： 5〜 1 : 20 の範囲内である。 ケトン溶媒としては、 例えば、 メチルイソプチルケトン、 メチル ェチルケトン、 シクロへキサノン、 シクロペンタノン、 これらの混合物などが挙げ られ、好ましくはメチルェチルケトンである。溶媒の使用量は特に制限されないが、 多すぎると収率が下がり、少なすぎると結晶が溶けないか純度が落ちるため、ォロ バタジン 1 k gに対し、例えばメチルェチルケトンと水の混合溶媒を使用する場合、 通常メチルェチルケトン約 1 0〜20 L、水約 1〜2し、好ましくはメチルェチル ケトン約 1 2〜 1 7 L、 水約 1. 2~ 1. フ Lの割合である。  As the solvent used in the present invention, a mixed solvent of water and a ketone solvent is used. The mixing ratio of water and keton solvent is usually in a volume ratio of water: ketone solvent = 1: 5 to 1:20. Examples of the ketone solvent include methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone, cyclopentanone, and a mixture thereof, and methyl ethyl ketone is preferable. The amount of the solvent used is not particularly limited, but if it is too much, the yield will decrease, and if it is too small, the crystals will not dissolve or the purity will be lowered. When used, the ratio is usually about 10 to 20 L of methyl ethyl ketone, about 1 to 2 water, preferably about 12 to 17 L of methyl ethyl ketone and about 1.2 to 1 L of water.
ォロパタジンを水とケ卜ン溶媒の混合溶媒に溶解させる際の温度は、通常約 40 〜 90°C、好ましくは約 50〜 70°Cである。溶解後、吸着剤（例えば、アルミナ、 活性炭など） を添加し、脱色や不純物の吸着を行っても良い。 吸着剤の量はォロパ タジン 1 k gに対し約 1 0〜 70 g、好ましくは約 20〜 50 gである。吸着剤を 添加した後、 濾過により吸着剤を取り除く。  The temperature at which olopatadine is dissolved in a mixed solvent of water and a can solvent is usually about 40 to 90 ° C, preferably about 50 to 70 ° C. After dissolution, an adsorbent (for example, alumina, activated carbon, etc.) may be added to decolorize or adsorb impurities. The amount of the adsorbent is about 10 to 70 g, preferably about 20 to 50 g, per 1 kg of olopatadine. After adding the adsorbent, remove the adsorbent by filtration.
ォロパタジンを上記溶媒に溶解させた後、得られた溶液を共沸留去により濃縮す るのが好ましい。共沸留去は、 公知の蒸留方法を用いて行うことができる。ォロパ タジン又はその酸付加塩 1 k gに対し、ケトン溶媒約 1 0〜20 L、水約 1〜2 L を使用した場合、 留去量は、 約 3〜 1 5し、 好ましくは約 5〜 1 0しである。 留去 後、溶媒量が不足する為、 ケトン溶媒を追加することが好ましい。 その追加量は約 3〜 1 5 L、好ましくは約 5〜 1 O Lである。濃縮操作を行った場合、結晶の析出 は、 例えば、 約 50〜90°C、 通常、 約 60〜80°Cで始まるが、 結晶の熟成のた めに攪拌し続けるのがよい。  It is preferable to dissolve olopatadine in the above solvent and then concentrate the resulting solution by azeotropic distillation. Azeotropic distillation can be performed using a known distillation method. When about 10 to 20 L of ketone solvent and about 1 to 2 L of water are used per 1 kg of olopatadine or its acid addition salt, the amount of distillation is about 3 to 15 and preferably about 5 to 1 0. Since the amount of the solvent is insufficient after the distillation, it is preferable to add a ketone solvent. The additional amount is about 3 to 15 L, preferably about 5 to 1 OL. When the concentration operation is carried out, the precipitation of crystals starts, for example, at about 50 to 90 ° C., usually about 60 to 80 ° C., but stirring should be continued for the ripening of the crystals.
溶液を約 0〜30°C、好ましくは約 5〜20°Cに冷却し、析出した結晶を濾過す ることによリ単離することができる。その際、冷却速度は通常 1時間当たり約 5〜 20°C、 好ましくは 1時間当たり約 5〜 1 5°Cである。 上記冷却時又は冷却後に、 溶液を撹拌してもよい。冷却後に溶液を撹桦する場合には、撹拌時間は特に制限さ れず、 例えば、 1〜 1 00時間である。 The solution can be isolated by cooling to about 0-30 ° C, preferably about 5-20 ° C, and filtering the precipitated crystals. In this case, the cooling rate is usually about 5 to 20 ° C. per hour, preferably about 5 to 15 ° C. per hour. During or after cooling, The solution may be stirred. When stirring the solution after cooling, the stirring time is not particularly limited, and is, for example, 1 to 100 hours.
結晶を析出させる際に酸を加えることができる。酸としては、塩酸、硫酸などが 挙げられ、 好ましくは塩酸である。 これらの酸は、 単独で用いても良いし、 2種以 上を組み合わせても良い。酸を加える時期は、冷却前でも冷却中でもよいが、好ま しくは冷却前である。酸の添加量は、ォロパタジンに対して、 プロトン当量で通常 約 0.5〜1.5当量である。 例えば 350/0塩酸を使用する場合、 ォロパタジン 1 k g に対し、 通常約 1 00〜400 g、 好ましくは約"！ 50〜300 gである。  An acid can be added when the crystals are precipitated. Examples of the acid include hydrochloric acid and sulfuric acid, and hydrochloric acid is preferred. These acids may be used alone or in combination of two or more. The acid may be added before or after cooling, but preferably before cooling. The amount of the acid added is generally about 0.5 to 1.5 equivalents of proton equivalent to olopatadine. For example, when 350/0 hydrochloric acid is used, it is usually about 100 to 400 g, preferably about "! 50 to 300 g, per 1 kg of olopatadine.
結晶を単離する際には、 濾過、 洗浄、 乾燥などの公知の方法を利用できる。 なお、 本発明において、 1 1 — (3—ジメチルァミノプロピリデン） 一6， 1 1 ージヒドロべンゾ [b, e] ォキセピン一 2—酢酸は、 （1 1一 （3—ジメチルァ ミノプロピリデン）一6, 1 1—ジヒドロべンゾ [b, e]ォキセピンー2—ィル） 酢酸とも命名される。 実施例  In isolating the crystals, known methods such as filtration, washing and drying can be used. In the present invention, 1 1-(3-dimethylaminopropylidene) 1,6 1 1-dihydrobenz [b, e] oxepin 1 2-acetic acid is (1 1 1 (3-dimethylaminopropylidene) 1 6, 1 1-Dihydrobenzo [b, e] oxepin-2-yl) Also named acetic acid. Example
以下に実施例を用いて本発明を説明するが、本発明はこれらに限定されるもので はない。  The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
実施例 1 Example 1
(2) — 1 1 - (3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒドロべンゾ [b, e] ォキセピン一 2—酢酸■塩酸塩の精製  (2) — 1 1-(3-Dimethylaminopropylidene) 1, 6, 1 1-Dihydrobenzo [b, e] oxepin 1 2-acetic acid ■ Purification of hydrochloride
純度 96. 9%、 E： Z = 0. 7 : 99. 3の粗製 （ Z) — 1 1 - ( 3—ジメチ ルァミノプロピリデン） 一6, 1 1—ジヒドロべンゾ [b, e] ォキセピン一 2— 酢酸'塩酸塩 80. 0 g (0. 2 1モル） にメチルェチルケトン 1 1 2 Om Lを加 え、攪拌しながら 70°Cに加熱した。 この溶液に水を 1 1 2mL滴下し、 20分攪 拌して結晶を溶解させた。 活性炭 2. 4 gを加え、 70°Cで 1時間半攪拌した後、 濾過して、 活性炭を取り除いた。 濾液を 75°Cまで加熱し、 共沸脱水を行い、 56 0 gを留去した。 70°Cでメチルェチルケトン 67 OmLを加え、攪拌しながら 3 5%塩酸 1 6 gを滴下した。 70°Cで 30分間熟成した後、 1時間当たり 1 0°Cの 割合で冷却し、 1 0°Cで 1 6時間攪抻した。 Purity 96.9%, E: Crude (Z) — 1 1-(3 -dimethylaminopropylidene) with Z = 0.7: 99.3 1 6, 1 1-dihydrobenzo [b, e] Methyl ethyl ketone 1 1 2 OmL was added to 80.0 g (0.2 1 mol) of oxepin-2-acetic acid hydrochloride and heated to 70 ° C. with stirring. To this solution, 1 1 2 mL of water was dropped and stirred for 20 minutes to dissolve the crystals. 2.4 g of activated carbon was added, and the mixture was stirred at 70 ° C for 1 hour and a half, and then filtered to remove the activated carbon. The filtrate was heated to 75 ° C. to perform azeotropic dehydration, and 560 g was distilled off. Add 70 mL of methyl ethyl ketone at 70 ° C and mix with stirring. 16 g of 5% hydrochloric acid was added dropwise. After aging at 70 ° C for 30 minutes, the mixture was cooled at a rate of 10 ° C per hour and stirred at 10 ° C for 16 hours.
結晶を濾別し、 1 0°Cに冷却したァセトン 32 Omしで結晶を洗浄した。得られ た結晶を減圧乾燥し、 （Z) - 1 1 - (3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒドロべンゾ [b， e]ォキセピン一 2—酢酸'塩酸塩を 70. 5 g得た。 純度は 99. 92 %、 E： Z = 0. 01 : 99. 99であった。見かけ収率は 88 % であった。 平均粒子径は 1 7. 6 imであった。  The crystals were filtered off and washed with Aceton 32 Om cooled to 10 ° C. The obtained crystals were dried under reduced pressure, and (Z)-1 1-(3-dimethylaminopropylidene) 1,6,1 1-dihydrobenzo [b, e] oxepin mono 2-acetic acid 'hydrochloride was added. Obtained 5 g. The purity was 99.92%, E: Z = 0.01: 99.99. The apparent yield was 88%. The average particle size was 17.6 im.
実施例 2 Example 2
(Z) - 1 1 - (3—ジメチルァミノプロピリデン）一 6， 1 1ージヒドロべンゾ [b, e] ォキセピン一 2—酢酸の精製  Purification of (Z)-1 1-(3-Dimethylaminopropylidene) -1,6,1-dihydrobenzo [b, e] oxepin-2-acetic acid
純度 96. 2%、 E ： Z = 0. 8 : 99. 2の粗製 （Z) - 1 1一 （3—ジメチ ルァミノプロピリデン） 一6， 1 1ージヒドロべンゾ [b， e] ォキセピン一 2— 酢酸 7. 5 k g (20. 1モル） にメチルェチルケトン 1 05 L、 水 1 0. 5 L及 び活性炭 0. 2 k gを加え、攪拌しながら約 70°Cに加熱した。 同温度で 30分間 攪拌した後、 活性炭を濾過し、 水 0. 75 Lとメチルェチルケトン 7. 5 Lを混合 し 70°Cに温度調整したもので活性炭を洗浄した。濾液を 1時間当たり 1 5°Cの割 合で 30°Cまで冷却し、減圧下に 30〜 35 °Cの温度で共沸脱水を行い、 57. 9 k gを留去した。次いで、約 35 °Cでメチルェチルケトン 72. 0 Lを 3時間かけ て加えた。 30分間約 35°Cで攪抻した後、 1時間当たり 1 0°Cの割合で 1 0°Cま で冷却し、 同温度で 3時間攪拌した。  Purity 96. 2%, E: Crude (Z)-1 1 1 (3-dimethylaminopropylidene) 1, 6, 1 1-dihydrobenzo [b, e] oxepin with Z = 0.8: 99.2 2-To 7.5 kg (20.1 mol) of acetic acid, 105 L of methylethylketone, 10.5 L of water and 0.2 kg of activated carbon were added and heated to about 70 ° C. with stirring. After stirring for 30 minutes at the same temperature, the activated carbon was filtered, and the activated carbon was washed with a mixture of 0.75 L of water and 7.5 L of methyl ethyl ketone and adjusted to a temperature of 70 ° C. The filtrate was cooled to 30 ° C at a rate of 15 ° C per hour, subjected to azeotropic dehydration at a temperature of 30 to 35 ° C under reduced pressure, and 57.9 kg was distilled off. Then, 72.0 L of methyl ethyl ketone was added at about 35 ° C. over 3 hours. After stirring at about 35 ° C for 30 minutes, the mixture was cooled to 10 ° C at a rate of 10 ° C per hour and stirred at the same temperature for 3 hours.
析出した結晶を濾別し、 1 0°Cに温度調整したアセトン 37. 5 Lで洗浄した。 得られた結晶を減圧乾燥し、 （Z) — 1 1一 （3—ジメチルァミノプロピリデン） 一 6， 1 1—ジヒドロべンゾ [b, e] ォキセピン一 2—酢酸 （純度 1 00%) を 6. 0 k g得た。 見かけ収率は 80%であった。結晶の平均粒子径は 1 7. 5〃m であった。 産業上の利用可能性 本発明によれば、 医薬として有用な （Z) — 1 1— (3—ジメチルァミノプロピ リデン） 一6, 1 1—ジヒドロべンゾ [b, e] ォキセピン一 2—酢酸及びその酸 付加塩を効率的にかつ工業的有利に精製する方法を提供することができる。 The precipitated crystals were separated by filtration and washed with 37.5 L of acetone adjusted to a temperature of 10 ° C. The obtained crystals were dried under reduced pressure. (Z) — 1 1 1 (3-Dimethylaminopropylidene) 1 6, 1 1-Dihydrobenzo [b, e] oxepin 1 2-acetic acid (purity 100% ) 6.0 kg. The apparent yield was 80%. The average particle size of the crystals was 17.5〃m. Industrial applicability According to the present invention, (Z) — 1 1- (3-dimethylaminopropylidene) 1,6 1 1-dihydrobenzo [b, e] oxepin 1 2-acetic acid and its acid addition are useful as pharmaceuticals. A method for efficiently and industrially purifying the salt can be provided.

Claims

1. 式 [ I ]
Figure imgf000009_0001
1. Formula [I]
Figure imgf000009_0001
青  Blue
で示される （Ζ) — 1 1一 （3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒ ドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、 得られた溶液から結晶を析出させる （Z) -1 1一 （3— ョー. (Ζ) — 1 1 1 (3-dimethylaminopropylidene) 1 6, 1 1-dihydrodibenzo [b, e] oxepin 1 2-acetic acid or its acid addition salt in water and ketone solvent (Z) -1 1 ichi (3-—.
ジメチルァミノプロピリデン） 一 6， 1 1ージヒドロジべンゾ [b， e] ォキセピ 囲 Dimethylaminopropylidene) 1,1,1-dihydrodibenzo [b, e] oxepi
ンー 2—酢酸又はその酸付加塩の精製方法。 N-2-Purification method of acetic acid or its acid addition salt.
2. 式 [ I ] ： 2. Formula [I]:
Figure imgf000009_0002
で示される （Z) - 1一 （3—ジメチルァミノプロピリデン） 一 6, 1 1—ジヒ ドロジべンゾ [b, e] 才キセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、得られた溶液を共沸留去により濃縮し、次いで濃縮液から 結晶を析出させる請求項 1に記載の精製方法。
Figure imgf000009_0002
(Z)-1 1 (3-dimethylaminopropylidene) 1 6, 1 1-dihydrodibenzo [b, e] 1-year-old xepin 1-acetic acid or its acid addition salt in water and ketone solvent 2. The purification method according to claim 1, wherein the resultant solution is dissolved in a mixed solvent, and the resulting solution is concentrated by azeotropic distillation, and then crystals are precipitated from the concentrated solution.
3. 式 [ I ] ： 3. Formula [I]:
Figure imgf000009_0003
で示される （Z) - 1 1 - (3—ジメチルァミノプロピリデン） 一 6， 1 1—ジヒ ドロジべンゾ [b， e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、得られた溶液を共沸留去によリ濃縮し、次いで濃縮液に酸 を加えた後、 結晶を析出させる請求項 1に記載の精製方法。
Figure imgf000009_0003
(Z)-1 1-(3-Dimethylaminopropylidene) 1, 6, 1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt with water and ketone solvent The purification method according to claim 1, wherein the resultant solution is dissolved in a mixed solvent of (2), concentrated by azeotropic distillation, acid is added to the concentrated solution, and crystals are precipitated.
4. 式 [ I ] ：
Figure imgf000010_0001
4. Formula [I]:
Figure imgf000010_0001
で示される （Z) - 1 1 - (3—ジメチルァミノプロピリデン） 一6, 1 1—ジヒ ドロジべンゾ [b, e] ォキセピン一 2—酢酸又はその酸付加塩を水とケトン溶媒 の混合溶媒に溶解させ、得られた溶液に酸を加えた後、結晶を析出させる請求項 1 に記載の精製方法。 (Z)-1 1-(3-Dimethylaminopropylidene) 1,6 1 1-dihydrodibenzo [b, e] oxepin mono 2-acetic acid or its acid addition salt in water and ketone solvent The purification method according to claim 1, wherein the crystal is precipitated after being dissolved in the mixed solvent and adding an acid to the obtained solution.
5. 酸が、 塩化水素である請求項 3又は 4に記載の精製方法。  5. The purification method according to claim 3 or 4, wherein the acid is hydrogen chloride.
6.ケトン溶媒がメチルェチルケトンである請求項 1〜 4のいずれかに記載の精製 方法。  6. The purification method according to any one of claims 1 to 4, wherein the ketone solvent is methyl ethyl ketone.
PCT/JP2008/068325 2007-10-12 2008-10-02 Method for purification of dibenzoxepin compound WO2009048086A1 (en)

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