JP5325517B2 - Method for purifying dibenzooxepin compounds - Google Patents

Method for purifying dibenzooxepin compounds Download PDF

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JP5325517B2
JP5325517B2 JP2008256257A JP2008256257A JP5325517B2 JP 5325517 B2 JP5325517 B2 JP 5325517B2 JP 2008256257 A JP2008256257 A JP 2008256257A JP 2008256257 A JP2008256257 A JP 2008256257A JP 5325517 B2 JP5325517 B2 JP 5325517B2
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dimethylaminopropylidene
oxepin
acetic acid
addition salt
water
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JP2009108039A (en
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正 桂
健人 林
慶 小松
正英 田中
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Sumitomo Chemical Co Ltd
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    • 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
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Description

本発明は、医薬品として有用なジベンゾオキセピン化合物の精製方法に関し、さらに詳しくは（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸及びその酸付加塩の精製方法に関する。   The present invention relates to a method for purifying a dibenzooxepin compound useful as a pharmaceutical, and more specifically, (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin- The present invention relates to a method for purifying 2-acetic acid and acid addition salts thereof.

（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸（一般名：オロパタジン）は、下記式［Ｉ］：

Figure 0005325517
で示される化合物である。この化合物又はその酸付加塩は、アレルギー性鼻炎、蕁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が知られている（特許文献１、２）。 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid (generic name: olopatadine) is represented by the following formula [I]:
Figure 0005325517
 It is a compound shown by these. This compound or its acid addition salt is known to be a pharmaceutical compound useful as an antiallergic agent applied to allergic rhinitis, urticaria, etc. (Patent Documents 1 and 2).

ジベンゾオ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最終的な精製が必要である。
特許文献１及び２には、目的物がシス−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。しかしながら、これらの文献には（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸そのものの精製については具体的な記載はない。
特公平５−８６９２５号公報 特公平７−１１６１７４号公報 When a dibenzooxepin compound is chemically synthesized, impurities such as other isomers (E isomers) are contained. Therefore, final purification is necessary to increase the purity.
Patent Documents 1 and 2 describe that when the target product is obtained as a cis-trans mixture (EZ mixture), the separation can be performed by column chromatography, recrystallization, or the like. However, these references do not specifically describe the purification of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid itself. .
Japanese Patent Publication No. 5-86925 Japanese Patent Publication No.7-116174

本発明は、化学合成された（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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 efficiently and chemically adds (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or an acid addition salt thereof. 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オ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、該混合溶媒より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, the dibenzooxepin acetic acid or its acid addition salt represented by the following formula [I] is dissolved in a mixed solvent of water and a ketone solvent, and then crystals are precipitated from the mixed solvent. High crystals are obtained.

即ち、本発明は、
［１］ 式［Ｉ］：

Figure 0005325517
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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ことを特徴とする（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸又はその酸付加塩の精製方法、
［２］ 式［Ｉ］：
Figure 0005325517
 で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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、ついで濃縮液から結晶を析出させることを特徴とする前記［１］に記載の精製方法、
［３］ 式［Ｉ］：
Figure 0005325517
 で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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、ついで濃縮液に酸を加えた後、結晶を析出させることを特徴とする前記［１］に記載の精製方法、
［４］ 式［Ｉ］：
Figure 0005325517
 で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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、結晶を析出させることを特徴とする前記［１］に記載の精製方法、
［５］ 酸が、ＨＣｌである前記［３］又は［４］に記載の精製方法、及び
［６］ ケトン溶媒が、メチルエチルケトンである前記［１］〜［５］のいずれかに記載の精製方法、
に関する。 That is, the present invention
[1] Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or its acid addition salt represented by the formula (1) is dissolved in a mixed solvent of water and a ketone solvent. And (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or its crystal, wherein crystals are precipitated from the resulting solution. Purification method of acid addition salt,
[2] Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or its acid addition salt represented by the formula (1) is dissolved in a mixed solvent of water and a ketone solvent. And concentrating the resulting solution by azeotropic distillation, and then precipitating crystals from the concentrated solution,
[3] Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or its acid addition salt represented by the formula (1) is dissolved in a mixed solvent of water and a ketone solvent. And concentrating the resulting solution by azeotropic distillation, and then adding an acid to the concentrated solution, and then precipitating crystals, [1],
[4] Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or its acid addition salt represented by the formula (1) is dissolved in a mixed solvent of water and a ketone solvent. And adding the acid to the resulting solution, and then precipitating crystals, the purification method according to the above [1],
[5] The purification method according to [3] or [4], wherein the acid is HCl, and [6] the purification method according to any one of [1] to [5], wherein the ketone solvent is methyl ethyl ketone. ,
About.

本発明の方法によれば、化学合成された（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−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ことができる。   According to the method of the present invention, chemically synthesized (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or an acid addition salt thereof is obtained. It can be purified efficiently and industrially advantageously.

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 0005325517
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸（オロパタジン）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。本発明に用いるオ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。 The present invention will be described below. Unless otherwise specified, “%” means “% by weight”.
The following formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid (olopatadine) or an acid addition salt thereof represented by It can be dissolved by heating. Examples of the acid addition salt of olopatadine used in the present invention include hydrochloride and sulfate, and hydrochloride is 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、メチルイソブチルケトン、メチルエチルケトン、シクロヘキサノン、シクロペンタノン、これらの混合物などが挙げられ、好ましくはメチルエチルケトンである。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、オロパタジンまたはその酸付加塩１ｋｇに対し、例えばメチルエチルケトンと水の混合溶媒を使用する場合、通常メチルエチルケトン約１０〜２０Ｌ、水約１〜２Ｌ、好ましくはメチルエチルケトン約１２〜１７Ｌ、水約１．２〜１．７Ｌ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 the ketone solvent is usually a volume ratio and is in the range 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 little, the crystals will not dissolve or the purity will be lowered. In this case, the ratio is usually about 10 to 20 L of methyl ethyl ketone and about 1 to 2 L of water, preferably about 12 to 17 L of methyl ethyl ketone and about 1.2 to 1.7 L of water.

オロパタジンを水とケトン溶媒の混合溶媒に溶解させる際の温度は、通常約４０〜９０℃、好ましくは約５０〜７０℃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。吸着剤の量はオロパタジンまたはその酸付加塩１ｋｇに対し約１０〜７０ｇ、好ましくは約２０〜５０ｇ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 ketone 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 or an acid addition salt thereof. After adding the adsorbent, the adsorbent is removed by filtration.

オ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。オロパタジンまたはその酸付加塩１ｋｇに対し、ケトン溶媒約１０〜２０Ｌ、水約１〜２Ｌを使用した場合、留去量は、約３〜１５Ｌ、好ましくは約５〜１０Ｌ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３〜１５Ｌ、好ましくは約５〜１０Ｌ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℃、通常、約６０〜８０℃で始まるが、結晶の熟成のために攪拌し続けるのがよい。   After dissolving olopatadine in the above solvent, the resulting solution is preferably concentrated 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 for 1 kg of olopatadine or an acid addition salt thereof, the amount of distillation is about 3 to 15 L, preferably about 5 to 10 L. Since the amount of solvent is insufficient after the distillation, it is preferable to add a ketone solvent. The additional amount is about 3-15 L, preferably about 5-10 L. When the concentration operation is performed, the precipitation of crystals begins at, for example, about 50 to 90 ° C., usually about 60 to 80 ° C., but it is preferable to continue stirring for the ripening of the crystals.

溶液を約０〜３０℃、好ましくは約５〜２０℃に冷却し、析出した結晶を濾過することにより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℃、好ましくは１時間当たり約５〜１５℃である。上記冷却時又は冷却後に、溶液を撹拌してもよい。冷却後に溶液を撹拌する場合には、撹拌時間は特に制限されず、例えば、１〜１００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. The solution may be stirred at the time of cooling or after cooling. 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、溶液に酸を加えることができる。酸としては、ＨＣｌ、塩酸、硫酸などが挙げられる。酸としてはＨＣｌが好ましい。ＨＣｌとしては、塩化水素ガス、塩酸が挙げられる。これらは、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、オ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３５％塩酸を使用する場合、その添加量は、オロパタジンまたはその酸付加塩１ｋｇに対し、通常約１００〜４００ｇ、好ましくは約１５０〜３００ｇである。   An acid can be added to the solution when the crystals are precipitated. Examples of the acid include HCl, hydrochloric acid, sulfuric acid and the like. HCl is preferred as the acid. Examples of HCl include hydrogen chloride gas and hydrochloric acid. These may be used alone or in combination of two or more. The acid may be added before cooling or during cooling, but is preferably before cooling. The amount of acid added is usually about 0.5 to 1.5 equivalents in terms of proton equivalent to olopatadine. For example, when 35% hydrochloric acid is used, the amount added is usually about 100 to 400 g, preferably about 150 to 300 g, per 1 kg of olopatadine or an acid addition salt thereof.

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、１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸は、（１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−イル）酢酸とも命名できる。 In isolating the crystals, known methods such as filtration, washing and drying can be used.
In the present invention, 11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid is represented by (11- (3′-dimethylaminopropylidene) -6. , 11-dihydrobenzo [b, e] oxepin-2-yl) acetic acid.

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］
（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸・塩酸塩の精製
純度９６．９％、Ｅ：Ｚ＝０．７：９９．３の粗製（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸塩酸塩８０．０ｇ（０．２１モル）にメチルエチルケトン１１２０ｍＬを加え、攪拌しながら７０℃に加熱した。この溶液に水を１１２ｍＬ滴下し、２０分攪拌して結晶を溶解させた。活性炭２．４ｇを加え、７０℃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℃まで加熱し、共沸脱水を行い、５６０ｇを留去した。７０℃でメチルエチルケトン６７０ｍＬを加え、攪拌しながら３５％塩酸１６ｇを滴下した。７０℃で３０分間熟成した後、１時間当たり１０℃の割合で冷却し、１０℃で１６時間攪拌した。
結晶を濾別し、１０℃に冷却したアセトン３２０ｍＬで結晶を洗浄した。得られた結晶を減圧乾燥し、（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸塩酸塩を７０．５ｇ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１７．５９５μｍであった。 [Example 1]
Purification of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid hydrochloride hydrochloride purity 96.9%, E: Z = 0.7 99.3 of crude (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid hydrochloride to 80.0 g (0.21 mol) 1120 mL of methyl ethyl ketone was added and heated to 70 ° C. with stirring. 112 mL of water was dropped into this solution and stirred for 20 minutes to dissolve the crystals. After adding 2.4 g of activated carbon and stirring at 70 ° C. for 1 hour and a half, filtration was performed to remove the activated carbon. The filtrate was heated to 75 ° C. to perform azeotropic dehydration, and 560 g was distilled off. At 70 ° C., 670 mL of methyl ethyl ketone was added, and 16 g of 35% hydrochloric acid was added dropwise with stirring. 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.
The crystals were separated by filtration and washed with 320 mL of acetone cooled to 10 ° C. The obtained crystals were dried under reduced pressure to obtain 70.5 g of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid hydrochloride. The purity was 99.92% and E: Z = 0.01: 99.99. The apparent yield was 88%. The average particle size was 17.595 μm.

［実施例２］
（Ｚ）−１１−（３−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸の精製
純度９６．２％、Ｅ：Ｚ＝０．８：９９．２の粗製（Ｚ）−１１−（３−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸７．５ｋｇ（２０．１モル）にメチルエチルケトン１０５Ｌ、水１０．５Ｌ及び活性炭０．２ｋｇを加え、攪拌しながら約７０℃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０．７５Ｌとメチルエチルケトン７．５Ｌを混合し７０℃に温度調整した溶液で活性炭を洗浄した。濾液を１時間当たり１５℃の割合で３０℃まで冷却し、減圧下に３０〜３５℃の温度で共沸脱水を行い、５７．９ｋｇを留去した。次いで、約３５℃でメチルエチルケトン７２．０Ｌを３時間かけて加えた。３０分間約３５℃で攪拌した後、１時間当たり１０℃の割合で１０℃まで冷却し、同温度で３時間攪拌した。
析出した結晶を濾別し、１０℃に温度調整したアセトン３７．５Ｌで洗浄した。得られた結晶を減圧乾燥し、（Ｚ）−１１−（３−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−２−酢酸（純度１００％）を６．０ｋｇ得た。見かけ収率は８０％であった。結晶の平均粒子径は１７．６μｍであった。 [Example 2]
Purification of (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid, purity 96.2%, E: Z = 0.8: 99.2 Crude (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid 7.5 kg (20.1 mol), methyl ethyl ketone 105 L, water 10.5 L And 0.2 kg of activated carbon was 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 solution prepared by mixing 0.75 L of water and 7.5 L of methyl ethyl ketone and adjusting the temperature to 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. Next, 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.
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 to obtain 6.0 kg of (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid (purity 100%). It was. The apparent yield was 80%. The average particle size of the crystals was 17.6 μm.

本発明によれば、医薬として有用な（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロベンゾ［ｂ，ｅ］オキセピン−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。   According to the present invention, (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrobenzo [b, e] oxepin-2-acetic acid and its acid addition salt, which are useful as pharmaceuticals, are efficiently produced. In addition, it is possible to provide a method for purification in an industrially advantageous manner.

Claims (5)

式［Ｉ］：
Figure 0005325517
 で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸又はその酸付加塩を、水とメチルエチルケトンの混合溶媒に溶解させ、得られた溶液に活性炭を添加した後、濾過により活性炭を取り除き、得られた溶液を共沸留去により濃縮し、ついで濃縮液から結晶を析出させることを特徴とする（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸又はその酸付加塩の精製方法。 Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or an acid addition salt thereof represented by the following formula is dissolved in a mixed solvent of water and methyl ethyl ketone: After adding activated carbon to the obtained solution, the activated carbon is removed by filtration, the obtained solution is concentrated by azeotropic distillation, and then crystals are precipitated from the concentrated solution (Z) -11. -(3'-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or an acid addition salt thereof. 前記酸付加塩が塩酸塩であることを特徴とする請求項１に記載の精製方法。   The purification method according to claim 1, wherein the acid addition salt is hydrochloride. 水とメチルエチルケトンとの混合割合が、水：メチルエチルケトン＝１：５〜１：２０であることを特徴とする請求項１又は２に記載の精製方法。   3. The purification method according to claim 1, wherein the mixing ratio of water and methyl ethyl ketone is water: methyl ethyl ketone = 1: 5 to 1:20. 式［Ｉ］：
Figure 0005325517
 で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンゾ［ｂ，ｅ］オキセピン−２−酢酸又はその酸付加塩１ｋｇに対し、混合溶媒のメチルエチルケトンが１０〜２０Ｌであり、水が１〜２Ｌであり、共沸留去の留去量が３〜１５Ｌであることを特徴とする請求項１〜３のいずれかに記載の精製方法。 Formula [I]:
Figure 0005325517
 (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid or 1 kg of its acid addition salt represented by The purification method according to any one of claims 1 to 3, wherein the amount is -20 L, water is 1-2 L, and the amount of azeotropic distillation is 3-15 L. さらに、共沸留去した後に、メチルエチルケトンを追加することを特徴とする請求項１〜４のいずれかに記載の精製方法。   Furthermore, methyl ethyl ketone is added after azeotropic distillation, The purification method in any one of Claims 1-4 characterized by the above-mentioned.
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