JP2007031363A - Method for producing dibenz[b,e]oxepin derivative and intermediate thereof - Google Patents

Method for producing dibenz[b,e]oxepin derivative and intermediate thereof Download PDF

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JP2007031363A
JP2007031363A JP2005218011A JP2005218011A JP2007031363A JP 2007031363 A JP2007031363 A JP 2007031363A JP 2005218011 A JP2005218011 A JP 2005218011A JP 2005218011 A JP2005218011 A JP 2005218011A JP 2007031363 A JP2007031363 A JP 2007031363A
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Shigeki Takaoka
茂樹 高岡
Koji Kagara
耕二 加々良
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Ohara Pharmaceutical Co Ltd
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for profitably producing a dibenz[b,e]oxepin derivative useful as an anti-allergic agent from commercially available compounds used as starting raw materials, and to provide a new intermediate for producing the compound. <P>SOLUTION: The compound (I) is subjected to four process reactions to obtain the dibenz[b,e]oxepin derivative (VII), as shown in the figure. Therein, X and Y are each a halogen, and R is a lower alkyl. The compound (III) obtained in the first process is a new intermediate. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、抗アレルギー剤として有用な下記のジベンズ［ｂ，ｅ］オキセピン誘導体［化合物（VII）（一般名：オロパタジン）］の製造方法と、その新規中間体（III）に関する。

Figure 2007031363
（式中、Ｒは低級アルキル基を示す。） The present invention relates to a method for producing the following dibenz [b, e] oxepin derivative [compound (VII) (generic name: olopatadine)] useful as an antiallergic agent, and a novel intermediate (III) thereof.
Figure 2007031363
 (In the formula, R represents a lower alkyl group.)

化合物（VII）の製造方法は多数開示されているが、化合物（III）を合成中間体として使用する方法は知られていない。 Many methods for producing compound (VII) have been disclosed, but no method using compound (III) as a synthetic intermediate is known.

ジャーナル オブ メディシナル ケミストリー（J.Med.Chem.）１９（７），９４１（１９７６）Journal of Medicinal Chemistry (J. Med. Chem.) 19 (7), 941 (1976) ジャーナル オブ メディシナル ケミストリー（J.Med.Chem.）２０（１１），１４９９（１９７７）Journal of Medicinal Chemistry (J. Med. Chem.) 20 (11), 1499 (1977) 特公昭５１−９５０８５号公報Japanese Patent Publication No.51-95085 特公昭６０−９５１０号公報Japanese Patent Publication No. 60-9510 特公平５−８６９２５号公報Japanese Patent Publication No. 5-86925

前記の化合物（VII）を従来の方法により製造する場合、途中の工程に危険を伴う酸化反応が必要であったり、精製困難な類縁化合物を副生するなどの理由により、精製工程が増え、収率が低下するなどの問題があった。
したがって本発明の課題は、市販の化合物を出発原料として使用し、高純度の化合物（VII）を工業的有利に製造する方法を提供するとともに、その製造の新規中間体を提供することにある。 When the above compound (VII) is produced by a conventional method, the number of purification steps increases due to the fact that a dangerous oxidation process is necessary in the middle of the process or a related compound that is difficult to purify is produced as a by-product. There was a problem such as a decrease in rate.
Accordingly, an object of the present invention is to provide a method for producing a highly pure compound (VII) in an industrially advantageous manner using a commercially available compound as a starting material, and to provide a novel intermediate for its production.

本発明者らは、市販の２−ブロモメチルベンゾニトリルを出発原料として使用することにより、所期の目的を達成することができることを見出し、さらに検討を加え本発明を完成することができた。   The present inventors have found that the intended purpose can be achieved by using commercially available 2-bromomethylbenzonitrile as a starting material, and have further studied and completed the present invention.

すなわち本発明によれば、
［１］式（Ｉ）

Figure 2007031363
（式中、Ｘは脱離基を示す。）で表される化合物と、式（II）
Figure 2007031363
 （式中、Ｒは低級アルキル基を示す。）で表される化合物とを反応させて式（III）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物とし、これを加水分解して式（IV）
Figure 2007031363
 で表される化合物を得、これを溶媒に溶解し、酸無水物と強酸性物質を加え、反応させて式（Ｖ）
Figure 2007031363
 で表される化合物とし、これに式（VI）
Figure 2007031363
 （式中、Ｙはハロゲン原子を示す。）で表される化合物を反応させて式（VII）
Figure 2007031363
 で表される化合物又はその薬理上許容される塩を製造する方法、 That is, according to the present invention,
[1] Formula (I)
Figure 2007031363
 (Wherein X represents a leaving group), a compound represented by formula (II)
Figure 2007031363
 (Wherein R represents a lower alkyl group) is reacted with a compound represented by the formula (III)
Figure 2007031363
 (Wherein R is the same as defined above), which is hydrolyzed to give a compound of formula (IV)
Figure 2007031363
 A compound represented by the formula (V) is obtained, dissolved in a solvent, an acid anhydride and a strongly acidic substance are added, and the reaction is carried out.
Figure 2007031363
 A compound represented by formula (VI)
Figure 2007031363
 (Wherein Y represents a halogen atom) is reacted with a compound represented by the formula (VII)
Figure 2007031363
 Or a method for producing a pharmacologically acceptable salt thereof,

［２］式（III)

Figure 2007031363
（式中、Ｒは低級アルキル基を示す。）で表される化合物、 [2] Formula (III)
Figure 2007031363
 (Wherein R represents a lower alkyl group),

［３］式（Ｉ）

Figure 2007031363
（式中、Ｘは脱離基を示す。）で表される化合物と、式（II）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物とを反応させて式（III）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物を製造する方法を提供することができる。 [3] Formula (I)
Figure 2007031363
 (Wherein X represents a leaving group), a compound represented by formula (II)
Figure 2007031363
 (Wherein, R is the same as defined above) is reacted with a compound represented by the formula (III)
Figure 2007031363
 (Wherein, R is as defined above) can be provided.

前記［１］の発明によれば、抗アレルギー剤として有用なジベンズ［ｂ，ｅ］オキセピン誘導体（VII）（一般名：オロパタジン）を高純度かつ高収率で製造することができる。また、前記［２］の発明によれば、そのジベンズ［ｂ，ｅ］オキセピン誘導体（VII）の中間体（III）を提供することができ、さらに前記［３］の発明によれば、中間体（III）の工業的に有利な製造方法を提供することができる。   According to the invention of [1], the dibenz [b, e] oxepin derivative (VII) (generic name: olopatadine) useful as an antiallergic agent can be produced with high purity and high yield. In addition, according to the invention [2], an intermediate (III) of the dibenz [b, e] oxepin derivative (VII) can be provided. Further, according to the invention [3], the intermediate An industrially advantageous production method (III) can be provided.

本発明において、化合物（Ｉ）のＸとしては、例えば塩素原子、臭素原子、沃素原子、メシル基、トシル基等を挙げることができ、好ましくは臭素原子である。化合物（Ｉ）と化合物（II）との反応は、化合物（Ｉ）に対し化合物（II）を通常１倍〜１．５倍モル使用し、溶媒中、塩基の存在下で行われる。その溶媒としては、トルエン、アセトニトリル、テトラヒドロフラン、ジオキサン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、メタノール、エタノール、２−プロパノール、ｔ−ブタノール、酢酸エチル、アセトン、塩化メチレン等を挙げることができ、好ましくはトルエン、Ｎ，Ｎ−ジメチルホルムアミドである。ここで用いる塩基としては、有機塩基、無機塩基ともに使用でき、トリエチルアミン、ピリジン、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム等が好ましく、中でも炭酸カリウムが好ましい。この反応は前記溶媒中で塩基の存在下０℃〜１２０℃で行うことができ、好ましくは８０℃〜９０℃で１時間〜３時間行うとよい。
前記反応で得られた化合物（III）は、溶媒を留去した状態で特に精製することなく次の反応に使用することができる。 In the present invention, examples of X of the compound (I) include a chlorine atom, a bromine atom, an iodine atom, a mesyl group, and a tosyl group, and a bromine atom is preferable. The reaction between the compound (I) and the compound (II) is carried out in the presence of a base in a solvent by using the compound (II) in an amount of usually 1 to 1.5 times the amount of the compound (I). Examples of the solvent include toluene, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, 2-propanol, t-butanol, ethyl acetate, acetone, methylene chloride, and the like. Is toluene, N, N-dimethylformamide. As the base used here, both organic bases and inorganic bases can be used, and triethylamine, pyridine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like are preferable, and potassium carbonate is particularly preferable. . This reaction can be performed in the solvent in the presence of a base at 0 ° C. to 120 ° C., preferably 80 ° C. to 90 ° C. for 1 hour to 3 hours.
The compound (III) obtained by the above reaction can be used in the next reaction without purification in the state where the solvent is distilled off.

化合物（III）の加水分解は、特に困難はなく、常法により化合物（IV）を高収率で得ることができる。 Hydrolysis of compound (III) is not particularly difficult, and compound (IV) can be obtained in a high yield by a conventional method.

次に、化合物（IV）を溶媒中、酸無水物及び強酸性物質の存在下で反応させることにより、化合物（Ｖ）を得る。ここで用いる溶媒としては、トルエン、アセトニトリル、テトラヒドロフラン、ジオキサン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトン等を挙げることができ、好ましくはトルエンである。酸無水物は、化合物（IV）に対して通常１倍〜３倍モル使用し、例えば無水酢酸、無水桂皮酸、無水マレイン酸、無水フタル酸等が好適に使用できる。強酸性物質としては、トリフルオロメタンスルホン酸、パラトルエンスルホン酸等の有機酸、ナフィオン等の強酸性樹脂、ポリリン酸、硫酸等の鉱酸を挙げることができ、好ましくはトリフルオロメタンスルホン酸やナフィオンである。その使用量は、例えばナフィオンの場合、化合物（IV）に対し重量比で０．１倍〜０．５倍、好ましくは０．２５倍〜０．３倍であり、トリフルオロメタンスルホン酸の場合、触媒量程度でよい。反応温度は、０℃〜１５０℃が好ましく、より好ましくは１００℃〜１１０℃である。反応は通常０．５時間〜３時間で終了する。 Next, compound (V) is obtained by reacting compound (IV) in a solvent in the presence of an acid anhydride and a strong acid substance. Examples of the solvent used here include toluene, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone and the like, preferably toluene. The acid anhydride is usually used in an amount of 1 to 3 moles relative to the compound (IV), and for example, acetic anhydride, cinnamic acid anhydride, maleic acid anhydride, phthalic acid anhydride and the like can be preferably used. Examples of strongly acidic substances include organic acids such as trifluoromethanesulfonic acid and p-toluenesulfonic acid, strongly acidic resins such as Nafion, and mineral acids such as polyphosphoric acid and sulfuric acid, preferably trifluoromethanesulfonic acid and Nafion. is there. The amount used is, for example, 0.1 to 0.5 times, preferably 0.25 to 0.3 times by weight with respect to compound (IV) in the case of Nafion, and in the case of trifluoromethanesulfonic acid, A catalytic amount may be sufficient. The reaction temperature is preferably 0 ° C to 150 ° C, more preferably 100 ° C to 110 ° C. The reaction is usually completed in 0.5 to 3 hours.

化合物（Ｖ）と化合物（VI）の反応は、化合物（Ｖ）に対し化合物（VI）を１倍〜３倍モル使用し、テトラヒドロフラン、ジオキサン、ヘキサン、塩化メチレン等の溶媒中で行ない、−２０℃〜２０℃、好ましくは−１０℃〜１０℃で１時間〜５時間程度行えばよい。 The reaction of the compound (V) and the compound (VI) is carried out in a solvent such as tetrahydrofuran, dioxane, hexane, methylene chloride, etc., using the compound (VI) 1 to 3 times the mole of the compound (V), and −20 It may be carried out at a temperature of -20 ° C, preferably -10 ° C to 10 ° C for about 1 to 5 hours.

（１）２−（４−カルボキシメチルフェノキシ）メチル安息香酸
アセトニトリル５０ｍｌに２−ブロモメチルベンゾニトリル１０ｇ（０．０５１モル）、ｐ−ヒドロキシフェニル酢酸メチル８．０ｇ（０．０４８モル）および
炭酸カリウム８．６ｇ（０．０６２モル）を加えて混合し、８０〜９０℃で２時間撹拌した。この反応混合物に４０％水酸化ナトリウム水溶液６０ｍｌを加え、溶媒の約半分を減圧留去し、１００℃前後で２時間撹拌した後、氷水と濃塩酸を加えてｐＨ１とした。析出した結晶を濾取し２−（４−カルボキシメチルフェノキシ）メチル安息香酸の白色結晶１３．５ｇ（収率９３％）を得た。 (1) 2- (4-Carboxymethylphenoxy) methylbenzoic acid 10 g (0.051 mol) of 2-bromomethylbenzonitrile, 8.0 g (0.048 mol) of methyl p-hydroxyphenylacetate and potassium carbonate in 50 ml of acetonitrile 8.6 g (0.062 mol) was added and mixed, and the mixture was stirred at 80 to 90 ° C. for 2 hours. To this reaction mixture, 60 ml of 40% aqueous sodium hydroxide solution was added, and about half of the solvent was distilled off under reduced pressure. After stirring at around 100 ° C. for 2 hours, ice water and concentrated hydrochloric acid were added to adjust the pH to 1. The precipitated crystals were collected by filtration to obtain 13.5 g (yield 93%) of 2- (4-carboxymethylphenoxy) methylbenzoic acid white crystals.

（２）６，１１−ジヒドロ−１１−オキソジベンズ［ｂ，ｅ］オキセピン−２−酢酸
２−（４−カルボキシメチルフェノキシ）メチル安息香酸５ｇ（１７．５ミリモル）及び無水酢酸３．４６ｍｌをトルエン２５ｍｌに溶解し、この溶液を１００〜１１０℃に保って１時間撹拌後、放冷しナフィオン樹脂１．２５ｇを加え、反応溶液を再び１００〜１１０℃に保って９時間撹拌した。室温まで放冷後、ナフィオン樹脂を濾去して溶媒を減圧留去した。残渣をトルエンとヘプタンの混合液から再結晶して６，１１−ジヒドロ−１１−オキソジベンズ［ｂ，ｅ］オキセピン−２−酢酸の結晶４．２ｇ（収率８９％）を得た。 (2) 6,11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid 5 g (17.5 mmol) of 2- (4-carboxymethylphenoxy) methylbenzoic acid and 3.46 ml of acetic anhydride were added to 25 ml of toluene. The resulting solution was kept at 100 to 110 ° C. and stirred for 1 hour, allowed to cool, 1.25 g of Nafion resin was added, and the reaction solution was kept again at 100 to 110 ° C. and stirred for 9 hours. After cooling to room temperature, the Nafion resin was removed by filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solution of toluene and heptane to obtain 4.2 g (yield 89%) of 6,11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid crystals.

（３）（１１Ｚ）−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
（３−ジメチルアミノプロピル）トリフェニルホスホニウムブロミド臭化水素酸塩１９．２ｇ（０．０３７７モル）をテトラヒドロフラン２５ｍｌに懸濁し、氷水浴にて冷却、撹拌下、１．６規定のｎ−ブチルリチウムヘキサン溶液３６ｍｌを加えた。この混合液を、テトラヒドロフラン２５ｍｌに６，１１−ジヒドロ−１１−オキソジベンズ［ｂ，ｅ］オキセピン−２−酢酸５ｇ（０．０１８７モル）を溶かした溶液に滴下し、室温にて２時間撹拌した。次いで溶媒を減圧留去し、残渣に水２５ｍｌを加え、ジイソプロピルエーテルで洗浄後、水層に塩酸を加えてｐＨを１〜２とし、減圧濃縮した。得られた残渣に２−プロパノールを加え、かき混ぜることにより析出した白色結晶を濾取し、（１１Ｚ）−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−酢酸の塩酸塩４．２ｇ（ＨＰＬＣ純度：９９％、換算収率６５．８％）を得た。
融点：２５０℃（分解）
元素分析：理論値（％）：Ｃ ６７．４６ Ｈ ６．４７ Ｎ ３．７５
実測値（％）：Ｃ ６７．３６ Ｈ ６．４２ Ｎ ３．７７
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ（ｐｐｍ）：７．３８−７．２８（４Ｈ，ｍ），７．１０−７．０７（２Ｈ，ｍ），６．７８（１Ｈ，ｄ），５．６４（１Ｈ，ｔ），
３．５６（２Ｈ，ｓ），３．２５（２Ｈ，ｔ），２．８０（２Ｈ，ｍ），２．７１（１Ｈ，ｔ） (3) (11Z) -11- [3- (Dimethylamino) propylidene] -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (3-Dimethylaminopropyl) triphenylphosphonium bromide hydrogen bromide 19.2 g (0.0377 mol) of the acid salt was suspended in 25 ml of tetrahydrofuran, cooled in an ice-water bath, and 36 ml of 1.6 N n-butyllithium hexane solution was added with stirring. This mixed solution was added dropwise to a solution in which 5 g (0.0187 mol) of 6,11-dihydro-11-oxodibenz [b, e] oxepin-2-acetic acid was dissolved in 25 ml of tetrahydrofuran and stirred at room temperature for 2 hours. Next, the solvent was distilled off under reduced pressure, 25 ml of water was added to the residue, washed with diisopropyl ether, hydrochloric acid was added to the aqueous layer to adjust the pH to 1-2, and the mixture was concentrated under reduced pressure. 2-Propanol is added to the resulting residue and the white crystals precipitated by stirring are collected by filtration, and (11Z) -11- [3- (dimethylamino) propylidene] -6,11-dihydrodibenz [b, e There was obtained 4.2 g of oxepin-2-acetic acid hydrochloride (HPLC purity: 99%, conversion yield: 65.8%).
Melting point: 250 ° C (decomposition)
Elemental analysis: Theoretical value (%): C 67.46 H 6.47 N 3.75
Found (%): C 67.36 H 6.42 N 3.77
1H-NMR (DMSO-d 6 ) δ (ppm): 7.38-7.28 (4H, m), 7.10-7.07 (2H, m), 6.78 (1H, d), 5 .64 (1H, t),
3.56 (2H, s), 3.25 (2H, t), 2.80 (2H, m), 2.71 (1H, t)

本発明により、抗アレルギーとして有用なジベンズ［ｂ，ｅ］オキセピン誘導体
（一般名：オロパタジン）を工業的に有利に製造することができる。 According to the present invention, a dibenz [b, e] oxepin derivative (generic name: olopatadine) useful as an antiallergy can be advantageously produced industrially.

Claims (3)

式（Ｉ）
Figure 2007031363
 （式中、Ｘは脱離基を示す。）で表される化合物と、式（II）
Figure 2007031363
 （式中、Ｒは低級アルキル基を示す。）で表される化合物とを反応させて式（III）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物とし、これを加水分解して式（IV）
Figure 2007031363
 で表される化合物を得、これを溶媒に溶解し、酸無水物と強酸性物質を加え、反応させて式（Ｖ）
Figure 2007031363
 で表される化合物とし、これに式（VI）
Figure 2007031363
 （式中、Ｙはハロゲン原子を示す。）で表される化合物を反応させて式（VII）
Figure 2007031363
 で表される化合物又はその薬理上許容される塩を製造する方法。 Formula (I)
Figure 2007031363
 (Wherein X represents a leaving group), a compound represented by formula (II)
Figure 2007031363
 (Wherein R represents a lower alkyl group) is reacted with a compound represented by the formula (III)
Figure 2007031363
 (Wherein R is the same as defined above), which is hydrolyzed to give a compound of formula (IV)
Figure 2007031363
 A compound represented by the formula (V) is obtained, dissolved in a solvent, an acid anhydride and a strongly acidic substance are added, and the reaction is carried out.
Figure 2007031363
 A compound represented by formula (VI)
Figure 2007031363
 (Wherein Y represents a halogen atom) is reacted with a compound represented by the formula (VII)
Figure 2007031363
 Or a pharmacologically acceptable salt thereof. 式（III)
Figure 2007031363
 （式中、Ｒは低級アルキル基を示す。）で表される化合物。 Formula (III)
Figure 2007031363
 (Wherein R represents a lower alkyl group). 式（Ｉ）
Figure 2007031363
 （式中、Ｘは脱離基を示す。）で表される化合物と、式（II）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物とを反応させて式（III）
Figure 2007031363
 （式中、Ｒは前記と同じ。）で表される化合物を製造する方法。 Formula (I)
Figure 2007031363
 (Wherein X represents a leaving group), a compound represented by formula (II)
Figure 2007031363
 (Wherein, R is the same as defined above) is reacted with a compound represented by the formula (III)
Figure 2007031363
 (Wherein, R is the same as defined above).
JP2005218011A 2005-07-27 2005-07-27 Method for producing dibenz[b,e]oxepin derivative and intermediate thereof Pending JP2007031363A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099900A1 (en) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Process for production of dibenzoxepin compound
JP2009114166A (en) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd Method for producing dibenzoxepin compound
WO2011033532A1 (en) 2009-09-17 2011-03-24 Indoco Remedies Limited Process for preparation of olopatadine hydrochloride
CN102757339A (en) * 2012-08-01 2012-10-31 北京联本医药化学技术有限公司 Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid
CN105693685A (en) * 2016-02-01 2016-06-22 山东罗欣药业集团股份有限公司 Preparation technique of olopatadine hydrochloride

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099900A1 (en) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Process for production of dibenzoxepin compound
JP2009114166A (en) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd Method for producing dibenzoxepin compound
WO2011033532A1 (en) 2009-09-17 2011-03-24 Indoco Remedies Limited Process for preparation of olopatadine hydrochloride
CN102757339A (en) * 2012-08-01 2012-10-31 北京联本医药化学技术有限公司 Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid
CN105693685A (en) * 2016-02-01 2016-06-22 山东罗欣药业集团股份有限公司 Preparation technique of olopatadine hydrochloride
CN105693685B (en) * 2016-02-01 2018-05-22 山东罗欣药业集团股份有限公司 The preparation process of Olopatadine hydrochloride

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