JP2009091290A - Method of producing dibenzoxepin compound - Google Patents
Method of producing dibenzoxepin compound Download PDFInfo
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- JP2009091290A JP2009091290A JP2007262591A JP2007262591A JP2009091290A JP 2009091290 A JP2009091290 A JP 2009091290A JP 2007262591 A JP2007262591 A JP 2007262591A JP 2007262591 A JP2007262591 A JP 2007262591A JP 2009091290 A JP2009091290 A JP 2009091290A
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- 0 *CCC=C1c2cc(C*(*)*)ccc2OCc2ccccc12 Chemical compound *CCC=C1c2cc(C*(*)*)ccc2OCc2ccccc12 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N CN(C)CC/C=C1\c2cc(CC(O)=O)ccc2OCc2ccccc12 Chemical compound CN(C)CC/C=C1\c2cc(CC(O)=O)ccc2OCc2ccccc12 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
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- 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
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Abstract
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製造方法に関し、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−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸の製造方法に関する。 The present invention relates to a method for producing a dibenzooxepin compound useful as a pharmaceutical, and more specifically, (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin. The present invention relates to a method for producing -2-acetic acid.
（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸（一般名：オロパタジン）は、式［ＩＶ］：
で示される化合物である。この化合物また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（特許文献１）。
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (generic name: olopatadine) has the formula [IV]:
It is a compound shown by these. This compound or its acid addition salt is a pharmaceutical compound useful as an antiallergic agent applied to allergic rhinitis, urticaria, etc. (Patent Document 1).
（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸を化学合成法で製造する場合、異性体であるＥ体と同時に生成するため、目的物であるＺ体を効率よく取得するには、異性化が必要である。 When (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid is produced by a chemical synthesis method, simultaneously with the isomer E, Therefore, isomerization is necessary to efficiently obtain the target Z form.
特許文献１および２には、目的物がシス−トランスの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、所望によりシス型（Ｚ体）を、酢酸還流中、パラトルエンスルホン酸などの適当な酸触媒の存在下、１〜２４時間処理することによりトランス型（Ｅ体）に異性化できることが記載されている。しかしながら、この文献には、Ｅ体からＺ体への異性化については記載されていない。
また、非特許文献１には、１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸メチルエステルをケン化して対応するカルボン酸をＥ体：Ｚ体＝１：２の混合物として取得し、該混合物からＥ体をカラムで単離し、次いでＥ体の酢酸溶液をパラトルエンスルホン酸の存在下、１００℃で２１時間加熱すると異性化が起こり、Ｅ体：Ｚ体＝６５：３５の混合物が得られることが記載されている。
In Patent Documents 1 and 2, when the target product is obtained in a cis-trans mixture, the separation can be performed by column chromatography, recrystallization, and the like. It is described that it can be isomerized to a trans form (E form) by treating for 1 to 24 hours in the presence of a suitable acid catalyst such as paratoluenesulfonic acid during reflux of acetic acid. However, this document does not describe isomerization from E form to Z form.
Non-Patent Document 1 discloses that saponification of 11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid methyl ester and the corresponding carboxylic acid as E Is obtained as a mixture of isomer: Z isomer = 1: 2, and isomer E is isolated from the mixture by column, and then an acetic acid solution of isomer E is heated at 100 ° C. for 21 hours in the presence of paratoluenesulfonic acid, whereby isomerization It occurs that a mixture of E-form: Z-form = 65: 35 is obtained.
しかしながら、上記異性化の方法は、効率的にＺ体の目的物を取得するには難点があった。
本発明は、医薬品として有用なオロパタジン、すなわち（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸を効率的にかつ工業的有利に製造する方法を提供することを目的とする。 The present invention efficiently and industrially uses olopatadine useful as a pharmaceutical product, that is, (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid. It is an object of the present invention to provide a method for producing the product advantageously.
本発明者らは、上記課題を解決する為に研究を推し進めたところ、下記式［Ｉ］で示されるエステル化合物を、脱水剤で処理して、下記式［ＩＩ］で示される化合物と下記式［ＩＩＩ］で示される化合物の混合物に誘導した後、該混合物を酸で処理することで下記式［ＩＶ］で示されるＺ体が効率よく生成することを見出し、本発明を完成するに至った。 The inventors of the present invention proceeded with research to solve the above-mentioned problems. As a result, the ester compound represented by the following formula [I] was treated with a dehydrating agent, and the compound represented by the following formula [II] and the following formula After derivatizing into a mixture of compounds represented by [III], it was found that the Z-form represented by the following formula [IV] was efficiently produced by treating the mixture with an acid, thereby completing the present invention. .
すなわち、本発明は、
［１］ 式［Ｉ］：
で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルを、脱水剤で処理することを特徴とする式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルおよび式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物の製造方法、
［２］ 脱水剤が、酸無水物または塩素化合物である前記［１］に記載の製造方法、
［３］ 脱水剤が、無水酢酸、無水プロピオン酸、無水酪酸、無水トリフルオロ酢酸および無水トリクロロ酢酸からなる群から選択される１種以上の酸無水物である前記［１］に記載の製造方法、
［４］ 脱水剤が、塩化チオニル、オキシ塩化リン、五塩化リン、三塩化リンおよび塩化水素からなる群から選択される１種以上の塩素化合物である前記［１］に記載の製造方法、
［５］ 脱水剤が、無水トリフルオロ酢酸または無水酢酸である前記［１］に記載の製造方法、
［６］ 式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルと式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物を、酸で処理することを特徴とする式［ＩＶ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸またはその酸付加塩の製造方法、
［７］ 式［Ｉ］：
で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルを脱水剤で処理して式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルおよび式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物を得、次いでこの混合物を酸で処理することを特徴とする式［ＩＶ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸またはその酸付加塩の製造方法、
［８］ 式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルまたはその酸付加塩、および
［９］ 式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルまたはその酸付加塩、
に関する。
That is, the present invention
[1] Formula [I]:
11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula is treated with a dehydrating agent. Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
A process for producing a mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula:
[2] The production method according to [1], wherein the dehydrating agent is an acid anhydride or a chlorine compound.
[3] The production method according to [1], wherein the dehydrating agent is one or more acid anhydrides selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, trifluoroacetic anhydride, and trichloroacetic anhydride. ,
[4] The production method according to [1], wherein the dehydrating agent is at least one chlorine compound selected from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and hydrogen chloride.
[5] The production method according to [1], wherein the dehydrating agent is trifluoroacetic anhydride or acetic anhydride,
[6] Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
Treating a mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by Formula [IV] characterized by:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid or an acid addition salt thereof represented by
[7] Formula [I]:
11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [II] ]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
A mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula Formula [IV], characterized by treatment with an acid:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid or an acid addition salt thereof represented by
[8] Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester or an acid addition salt thereof represented by: Formula [III]:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester or an acid addition salt thereof represented by:
About.
本発明の方法によれば、医薬品として有用な（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸を効率的かつ工業的有利に製造することができる。 According to the method of the present invention, (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid useful as a pharmaceutical is efficiently and industrially produced. Can be produced in a particularly advantageous manner.
以下、本発明を説明する。
本発明では、式［Ｉ］：
で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステル（以下、化合物［Ｉ］ともいう。）を脱水剤で処理することにより、式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステル（以下、化合物［ＩＩ］ともいう。）および式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステル（以下、化合物［ＩＩＩ］ともいう。）の混合物を製造することができる。
The present invention will be described below.
In the present invention, the formula [I]:
11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester (hereinafter also referred to as compound [I]). ) With a dehydrating agent to give a compound of formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester (hereinafter also referred to as compound [II]) And formula [III]:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester (hereinafter also referred to as compound [III]) .)) Can be produced.
Ｒ１、Ｒ２およびＲ３が示すアルキル基の具体例としては、メチル基、エチル基が挙げられる。 Specific examples of the alkyl group represented by R 1 , R 2 and R 3 include a methyl group and an ethyl group.
本発明において、上記式［Ｉ］で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルとしては、下記式［Ｖ］：
で示される１１−ヒドロキシ（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］−ジベンゾオキセピン−２−酢酸ｔ−ブチルエステルが好ましい。
In the present invention, 11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the above formula [I] is used. Is the following formula [V]:
11-hydroxy (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] -dibenzooxepin-2-acetic acid t-butyl ester represented by
脱水剤としては、無水酢酸、無水プロピオン酸、無水酪酸、無水トリフルオロ酢酸、無水トリクロロ酢酸などの酸無水物および塩化チオニル、オキシ塩化リン、五塩化リン、三塩化リンおよび塩化水素などの塩素化合物などが挙げられ、無水トリフルオロ酢酸が好ましい。これらの脱水剤は１種単独で使用してもよく、また２種以上を混合して使用してもよい。脱水剤の使用量としては、化合物［Ｉ］１モルに対し、通常約１モル〜１０モル、好ましくは約１モル〜２モルである。 Dehydrating agents include acetic anhydride, propionic anhydride, butyric anhydride, trifluoroacetic anhydride, trichloroacetic anhydride and other acid anhydrides, and chlorine compounds such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and hydrogen chloride. Trifluoroacetic anhydride is preferred. These dehydrating agents may be used alone or in combination of two or more. The amount of the dehydrating agent to be used is generally about 1 mol to 10 mol, preferably about 1 mol to 2 mol, per 1 mol of compound [I].
脱水の反応温度は、通常約２０℃〜７０℃、好ましくは約４０℃〜６０℃で行う。脱水反応時間は、反応温度、原材料の使用量などにもよるが、通常、約１時間〜８時間、好ましくは、約２時間〜４時間である。この反応は、攪拌下に実施するのが好ましい。 The reaction temperature of dehydration is usually about 20 ° C to 70 ° C, preferably about 40 ° C to 60 ° C. The dehydration reaction time is usually about 1 to 8 hours, preferably about 2 to 4 hours, although it depends on the reaction temperature and the amount of raw materials used. This reaction is preferably carried out with stirring.
また、本発明では、上記化合物［Ｉ］を脱水剤で処理することにより得られた上記化合物［ＩＩ］および化合物［ＩＩＩ］の混合物を酸で処理することにより、式［ＩＶ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸またはその酸付加塩を製造することができる。
In the present invention, the mixture of the above compound [II] and the compound [III] obtained by treating the above compound [I] with a dehydrating agent is treated with an acid to give a compound of the formula [IV]:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid or an acid addition salt thereof can be produced.
酸としては、塩酸、硫酸、塩化水素が挙げられるが、とりわけ塩化水素が好ましい。また、酸の使用量は化合物［ＩＩ］および化合物［ＩＩＩ］の混合物１モルに対して、約１モル〜５モルが好ましい。 Examples of the acid include hydrochloric acid, sulfuric acid, and hydrogen chloride, and hydrogen chloride is particularly preferable. The amount of acid used is preferably about 1 mol to 5 mol with respect to 1 mol of the mixture of compound [II] and compound [III].
仕込み方として、溶媒に溶かした化合物［ＩＩ］および化合物［ＩＩＩ］の混合物を加熱溶媒中に滴下して仕込むことが望ましい。滴下時間は、溶媒量にもよるが、通常約３０分〜１０時間、好ましくは約１時間〜５時間である。酸として塩化水素を用いる場合は、塩化水素をバブリングしながら滴下することが好ましい。 As a charging method, it is desirable to drop a mixture of compound [II] and compound [III] dissolved in a solvent into a heated solvent. The dropping time is usually about 30 minutes to 10 hours, preferably about 1 hour to 5 hours, depending on the amount of solvent. When hydrogen chloride is used as the acid, it is preferable to add hydrogen chloride dropwise while bubbling.
反応温度は、通常約５０℃〜１５０℃、好ましくは約８０℃〜１１０℃である。反応時間は、反応温度、原材料の使用量などにもよるが、通常約３時間〜２０時間、好ましくは約５時間〜１０時間である。この反応は、攪拌下に実施するのが好ましい。 The reaction temperature is generally about 50 ° C to 150 ° C, preferably about 80 ° C to 110 ° C. The reaction time is usually about 3 hours to 20 hours, preferably about 5 hours to 10 hours, although it depends on the reaction temperature and the amount of raw materials used. This reaction is preferably carried out with stirring.
溶媒としては有機溶媒が好ましい。ここで有機溶媒としては例えば、ケトン溶媒（例えば、メチルエチルケトン、メチルイソブチルケトン、シクロヘキサノン、シクロペンタノンなど）、芳香族溶媒（例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼンなど）が挙げられるが、好ましくはクロロベンゼンである。溶媒の使用量は、化合物［Ｉ］が完全に溶解する量であれば、特に制限されないが、通常、化合物［Ｉ］１ｋｇに対し、約５Ｌ〜４０Ｌ、好ましくは約１０Ｌ〜２０Ｌである。 As the solvent, an organic solvent is preferable. Here, examples of the organic solvent include ketone solvents (eg, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, etc.) and aromatic solvents (eg, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, etc.). Is preferably chlorobenzene. The amount of the solvent to be used is not particularly limited as long as compound [I] is completely dissolved, but is usually about 5 L to 40 L, preferably about 10 L to 20 L with respect to 1 kg of compound [I].
かくして化合物［ＩＩ］および［ＩＩＩ］の脱エステル化反応と共に、生成した化合物のＥ体からＺ体への異性化が進行する。異性化がほぼ完全に進行した反応溶液を冷却、濾過し、析出した結晶を濾別した後、適当な溶媒（例えばアセトンなど）で洗浄することにより、用いた酸に対応する酸付加塩として化合物［ＩＶ］を取得することができる。
なお、本発明において、例えば１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルは、（１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−イル）酢酸ｔ−ブチルエステルとも命名できる。
Thus, along with the deesterification reaction of the compounds [II] and [III], the isomerization of the resulting compound from E form to Z form proceeds. The reaction solution in which isomerization has proceeded almost completely is cooled, filtered, and the precipitated crystals are separated by filtration and washed with an appropriate solvent (for example, acetone) to give a compound as an acid addition salt corresponding to the acid used. [IV] can be acquired.
In the present invention, for example, 11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester is represented by (11-hydroxy- 11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-yl) acetic acid t-butyl ester can also be named.
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。なお、実施例においてＥ体、Ｚ体の純度測定は下記条件のＨＰＬＣで行った。
（ＨＰＬＣ条件）
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−２ ５μｍ（４．６ｍｍＩＤ×１５ｃｍ）
移動相：Ａ＝５ｍｍｏｌ Sodium Dodecylsulfate水溶液（ｐＨ＝３．０ Ｈ３ＰＯ４）
Ｂ＝アセトニトリル
Ａ／Ｂ＝５／５→３／７（２０分）
流速：１．０ｍｌ／分
カラム温度．：３０℃
検出波長：ＵＶ２５４ｎｍ
The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In Examples, the purity of E-form and Z-form was measured by HPLC under the following conditions.
(HPLC conditions)
Column: Inertsil ODS-2 5 μm (4.6 mm ID × 15 cm)
Mobile phase: A = 5 mmol Sodium Dodecylsulfate aqueous solution (pH = 3.0 H 3 PO 4 )
B = acetonitrile A / B = 5/5 → 3/7 (20 minutes)
Flow rate: 1.0 ml / min column temperature. : 30 ° C
Detection wavelength: UV254nm
［実施例１］
（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルおよび（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルの製造
フラスコに、１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステル２０．０ｇ（０．０４８６モル）とトルエン６０ｍｌを仕込み、攪拌しながら室温でトリフルオロ酢酸無水物（＝無水トリフルオロ酢酸）１１．２ｇ（０．０５３５モル）を滴下した。滴下後、５０℃の温浴につけて２時間攪拌した後、２５℃に冷却した。この反応溶液に水９０ｍｌを加え分液した。更に水６０ｍｌを加え分液した後、炭酸カリウム７．３４ｇ（０．０５３モル）と水６０ｍｌの溶液を加え洗浄、分液した後、硫酸マグネシウム１０ｇを添加して脱水し、濾過した。この溶液を濃縮して（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルおよび（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルの混合物１８．９４ｇ（０．０４８１モル）を得た。見かけ収率は９９％で、ＨＰＬＣで測定した純度は、Ｚ体は１９．９％、Ｅ体が７７．４％であった。
[Example 1]
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester and (Z) -11- (3′-dimethylamino) Preparation of propylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester Into a flask was added 11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydro 10. 20.0 g (0.0486 mol) of dibenz [b, e] oxepin-2-acetic acid t-butyl ester and 60 ml of toluene are charged, and trifluoroacetic anhydride (= trifluoroacetic anhydride) is added at room temperature while stirring. 2 g (0.0535 mol) was added dropwise. After dropping, the mixture was placed in a 50 ° C. warm bath and stirred for 2 hours, and then cooled to 25 ° C. To this reaction solution, 90 ml of water was added for liquid separation. Further, 60 ml of water was added for liquid separation, then a solution of 7.34 g (0.053 mol) of potassium carbonate and 60 ml of water was added for washing and liquid separation, and 10 g of magnesium sulfate was added for dehydration and filtration. The solution was concentrated to (E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester and (Z) -11- 18.94 g (0.0481 mol) of a mixture of (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester was obtained. The apparent yield was 99%, and the purity measured by HPLC was 19.9% for Z form and 77.4% for E form.
（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステル
１Ｈ ＮＭＲ（ＭＨｚ、ＣＤＣｌ３）δ １．４４（ｓ，９Ｈ）， ２．１６（ｓ，６Ｈ）， ２．３４（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ）， ２．３６（ｄｔ，Ｊ＝７．６，７．６Ｈｚ，２Ｈ）， ３．４２（ｓ，２Ｈ）， ４．７５（ｂｒｓ，１Ｈ）， ５．５６（ｂｒｓ，１Ｈ）， ６．０３（ｔ，Ｊ＝７．６Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８．４，１Ｈ），７．０２（ｄｄ，Ｊ＝８．８，１．６Ｈｚ，１Ｈ），７．１７−７．３５（ｍ，５Ｈ）
（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステル
１Ｈ ＮＭＲ（ＭＨｚ、ＣＤＣｌ３）δ １．４２（ｓ，９Ｈ）， ２．２２（ｓ，６Ｈ）， ２．４４（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ）， ２．６０（ｄｔ，Ｊ＝７．２，７．２Ｈｚ，２Ｈ）， ３．４２（ｓ，２Ｈ）， ５．１９（ｂｒｓ，２Ｈ）， ５．７０（ｔ，Ｊ＝７．２Ｈｚ，１Ｈ）， ６．８０（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ）， ７．０５（ｄｄ，Ｊ＝８．８，２．０Ｈｚ，１Ｈ）， ７．０６（ｓ，１Ｈ）， ７．２２−７．３２（ｍ，４Ｈ）
融点 ６８．８℃。
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester
1 H NMR (MHz, CDCl 3 ) δ 1.44 (s, 9H), 2.16 (s, 6H), 2.34 (t, J = 7.6 Hz, 2H), 2.36 (dt, J = 7.6, 7.6 Hz, 2H), 3.42 (s, 2H), 4.75 (brs, 1H), 5.56 (brs, 1H), 6.03 (t, J = 7.6 Hz) , 1H), 6.70 (d, J = 8.4, 1H), 7.02 (dd, J = 8.8, 1.6 Hz, 1H), 7.17-7.35 (m, 5H)
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester
1 H NMR (MHz, CDCl 3 ) δ 1.42 (s, 9H), 2.22 (s, 6H), 2.44 (t, J = 7.2 Hz, 2H), 2.60 (dt, J = 7.2, 7.2 Hz, 2H), 3.42 (s, 2H), 5.19 (brs, 2H), 5.70 (t, J = 7.2 Hz, 1H), 6.80 (d) , J = 8.0 Hz, 1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 7.06 (s, 1H), 7.22-7.32 (m, 4H)
Melting point 68.8 ° C.
［実施例２］
（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸・塩酸塩の製造
[Example 2]
Production of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid / hydrochloride
フラスコに、モノクロロベンゼン１９０ｍｌを仕込み、浴温を１００〜１０５℃で撹拌した（内温は９６℃まで上昇）。この溶液に、実施例１で得た（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルおよび（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸ｔ−ブチルエステルの混合物１９ｇ（０．０４８モル）をモノクロロベンゼン７６ｍｌに溶かした溶液を３０分かけて滴下し、滴下中、塩化水素５．４ｇ（０．１４８モル）をバブリングし、１２時間攪拌した。この時点でのＥ体：Ｚ体＝２．５：９７．５であった。反応液を室温まで冷却し、結晶を濾過した。結晶をトルエン３０ｍｌずつ２回洗浄した後、アセトン５０ｍｌずつ２回洗浄した。５０℃、７ｈＰａで減圧乾燥し、（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸・塩酸塩１７．８１ｇを得た。見かけ収率は９８．０％で、ＨＰＬＣで測定した純度は、Ｚ体は９３．９％、Ｅ体が２．５％であった。 The flask was charged with 190 ml of monochlorobenzene and stirred at a bath temperature of 100 to 105 ° C. (internal temperature increased to 96 ° C.). To this solution, (E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester obtained in Example 1 and (Z ) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid t-butyl ester 19 g (0.048 mol) was dissolved in monochlorobenzene 76 ml. The solution was added dropwise over 30 minutes, and 5.4 g (0.148 mol) of hydrogen chloride was bubbled during the addition and stirred for 12 hours. At this time, E-form: Z-form = 2.5: 97.5. The reaction was cooled to room temperature and the crystals were filtered. The crystals were washed twice with 30 ml of toluene and then twice with 50 ml of acetone. This was dried under reduced pressure at 50 ° C. and 7 hPa to obtain 17.81 g of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid / hydrochloride. It was. The apparent yield was 98.0%, and the purity measured by HPLC was 93.9% for Z form and 2.5% for E form.
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−ジヒドロベンズ［ｂ，ｅ］オキセピン−２−酢酸およびその酸付加塩を効率的にかつ工業的有利に製造でき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-dihydrobenz [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 that can be produced industrially and advantageously.
Claims (9)
で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルを、脱水剤で処理することを特徴とする式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルおよび式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物の製造方法。 Formula [I]:
11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula is treated with a dehydrating agent. Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
A method for producing a mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula:
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルと式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物を、酸で処理することを特徴とする式［ＩＶ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸またはその酸付加塩の製造方法。 Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
Treating a mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by Formula [IV] characterized by:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid or an acid addition salt thereof represented by the formula:
で示される１１−ヒドロキシ−１１−（３’−ジメチルアミノプロピル）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルを、脱水剤で処理して式［ＩＩ］：
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルおよび式［ＩＩＩ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルの混合物を得、次いでこの混合物を酸で処理することを特徴とする式［ＩＶ］：
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸またはその酸付加塩の製造方法。 Formula [I]:
11-hydroxy-11- (3′-dimethylaminopropyl) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula [III]:
A mixture of (Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the formula Formula [IV], characterized by treatment with an acid:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid or an acid addition salt thereof represented by the formula:
で示される（Ｅ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルまたはその酸付加塩。 Formula [II]:
(E) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester or an acid addition salt thereof represented by:
で示される（Ｚ）−１１−（３’−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸第３級アルキルエステルまたはその酸付加塩。 Formula [III]:
(Z) -11- (3′-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid tertiary alkyl ester represented by the above or an acid addition salt thereof.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007262591A JP5248078B2 (en) | 2007-10-05 | 2007-10-05 | Method for producing dibenzooxepin compound |
| CH00490/10A CH700067B8 (en) | 2007-10-05 | 2008-09-26 | Tertiary alkyl esters of (E, Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid and process for their preparation. |
| CN200880109972.7A CN101815709B (en) | 2007-10-05 | 2008-09-26 | The manufacture method of dibenzo oxa-* compound |
| CH17642011A CH703810B8 (en) | 2007-10-05 | 2008-09-26 | Process for the preparation of a dibenzoxepin compound. |
| PCT/JP2008/067982 WO2009044838A1 (en) | 2007-10-05 | 2008-09-26 | Method for producing dibenzoxepin compound |
| ES201090015A ES2344291B1 (en) | 2007-10-05 | 2008-09-26 | METHOD TO PRODUCE A COMPOUND OF DIBENZOXEPINE. |
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| JP2007262591A JP5248078B2 (en) | 2007-10-05 | 2007-10-05 | Method for producing dibenzooxepin compound |
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| JP2009091290A true JP2009091290A (en) | 2009-04-30 |
| JP5248078B2 JP5248078B2 (en) | 2013-07-31 |
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| JP (1) | JP5248078B2 (en) |
| CN (1) | CN101815709B (en) |
| CH (2) | CH703810B8 (en) |
| ES (1) | ES2344291B1 (en) |
| WO (1) | WO2009044838A1 (en) |
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| WO2011033532A1 (en) | 2009-09-17 | 2011-03-24 | Indoco Remedies Limited | Process for preparation of olopatadine hydrochloride |
| CN107488161A (en) * | 2016-06-13 | 2017-12-19 | 江苏吉贝尔药业股份有限公司 | A kind of light method for transformation of olopatadine N-butyl isomers |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6310784A (en) * | 1986-03-03 | 1988-01-18 | Kyowa Hakko Kogyo Co Ltd | Dibenz(b,e)oxepin derivative, antiallergic agent and anti-inflammatory agent |
| JPH11279158A (en) * | 1998-02-09 | 1999-10-12 | Pfizer Prod Inc | Production of quinazoline-4-one derivative |
| WO2006010459A1 (en) * | 2004-07-28 | 2006-02-02 | Urquima S.A. | Process for the preparation of 11-[(z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl]-acetic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105234A2 (en) * | 2006-03-14 | 2007-09-20 | Usv Limited | A PROCESS FOR THE PREPARATION OF ISOMERS OF 11-[3-(DIMETHYLAMINO)PROPYLIDENE]-6, 11-DIHYDRODIBENZ [b, e] OXEPIN-2-ACETIC ACID HYDROCHLORIDE AND POLYMORPHS THEREOF |
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2007
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2008
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6310784A (en) * | 1986-03-03 | 1988-01-18 | Kyowa Hakko Kogyo Co Ltd | Dibenz(b,e)oxepin derivative, antiallergic agent and anti-inflammatory agent |
| JPH11279158A (en) * | 1998-02-09 | 1999-10-12 | Pfizer Prod Inc | Production of quinazoline-4-one derivative |
| WO2006010459A1 (en) * | 2004-07-28 | 2006-02-02 | Urquima S.A. | Process for the preparation of 11-[(z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl]-acetic acid |
Non-Patent Citations (1)
| Title |
|---|
| JPN6008057846; Ｔｈｅｏｄｏｒａ Ｗ． ＧＲＥＥＮＥ ａｎｄ Ｐｅｔｅｒ Ｇ． Ｍ． ＷＵＴＳ: ＰＲＯＴＥＣＴＩＶＥ ＧＲＯＵＰＳ ＩＮ ＯＲＧＡＮＩＣ ＳＹＮＴＨＥＳＩＳ ２ｎｄ Ｅｄｉｔｉｏｎ, 19981002, 第２４５頁, ＪＯＨＮ ＷＩＬＥＹ ＆ ＳＯＮＳ， ＩＮＣ． * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101815709B (en) | 2015-09-02 |
| CH703810B8 (en) | 2012-06-15 |
| ES2344291A1 (en) | 2010-08-23 |
| CH700067B1 (en) | 2012-03-15 |
| CH700067B8 (en) | 2012-04-30 |
| CN101815709A (en) | 2010-08-25 |
| ES2344291B1 (en) | 2011-05-13 |
| CH703810B1 (en) | 2012-03-30 |
| JP5248078B2 (en) | 2013-07-31 |
| WO2009044838A1 (en) | 2009-04-09 |
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