JP3548133B2 - Method for producing piperidylidene derivative having biological activity - Google Patents
Method for producing piperidylidene derivative having biological activity Download PDFInfo
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- JP3548133B2 JP3548133B2 JP2001149896A JP2001149896A JP3548133B2 JP 3548133 B2 JP3548133 B2 JP 3548133B2 JP 2001149896 A JP2001149896 A JP 2001149896A JP 2001149896 A JP2001149896 A JP 2001149896A JP 3548133 B2 JP3548133 B2 JP 3548133B2
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- 0 *CN(CC1)CCC1=O Chemical compound *CN(CC1)CCC1=O 0.000 description 3
- AQPPNIXZXSLFPM-UHFFFAOYSA-N O=C1c2ncccc2COc2c1ccc(F)c2 Chemical compound O=C1c2ncccc2COc2c1ccc(F)c2 AQPPNIXZXSLFPM-UHFFFAOYSA-N 0.000 description 1
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Description
【0001】
【発明の属する技術分野】
この発明は、抗アレルギー剤として有用なベンゾオキセピノ−11−ピぺリジリデン化合物又はその中間体の製造方法に関する。
【0002】
【従来の技術】
本発明が目的とする化合物の1つは、Journal of Medicinal Chemistry Vol.38 No.3 p496〜507及び特開平06−192263に記載された3−[4−(8−フルオロ5,11−ジヒドロ[1]ベンゾオキセピノ[4,3−b]ピリジン−11−イリデン)ピペリジノ]プロピオン酸であり、この化合物は両性基型の抗アレルギー剤であって、選択的ヒスタミンH1受容体拮抗作用を示す。当該化合物は、前記公開公報においては、2−シアノ−3−メチルピリジンを出発物質として2−シアノ−3−ブロモメチルピリジン、2−シアノ−3−(3−フルオロフェノキシメチル)ピリジンを経て8−フルオロ−5,11−ジヒドロベンズ〔b〕オキセピノ〔4,3−b〕ピリジン−11−オンを製造した後、11位のケトン基にGrignard反応、次いで脱水して1−メチルピペリジリデンを生成し、さらに1−エトキシカルボニルピペリジリデンを経由してピペリジリデンを遊離し、アクリル酸エステルによってプロピオン酸エステル体として、更に苛性ソーダ又は酸でエステル基を外して製造されている。
【0003】
【発明が解決しようとする課題】
前記化合物は優れた薬効を示すと共に、良好な安定性を保持しており薬剤として好ましい性質を有しているが、ベンゾオキセピノ化合物から最終目的物までの工程数が多く、収率も問題となる個所があり、医薬品とする際の大きな障害となっていた。
【0004】
【課題を解決するための手段】
本発明者等は、公知である従来の製造方法は工程数が多く、収率も問題となることから、まず前記ベンゾオキセピノ化合物である三環化合物以降の工程について鋭意検討を重ねた結果、前記三環化合物から直接、プロピオン酸エステル体及び遊離のプロピオン酸体を高収率で得る製造方法の開発に成功し、本発明を完成させた。
【0005】
即ち、本発明は、亜鉛又は亜鉛−銅合金に四塩化チタン又は三塩化チタンを加え、加熱還流した沸騰混合物に、一般式(1):
【0006】
【化4】
【0007】
(式中XはCH又はN;X'は O;X''は反応に関与しない基を示す)で表されるベンゾオキセピノ化合物と、一般式(2):
【0008】
【化5】
【0009】
(式中、R'はエステル化若しくはアミド化されているカルボキシルで置換されたアルキル基、非置換のアルキル基、又はエステル化若しくはアミド化されているカルボキシル基を示す)で表されるピペリジン−4−オン化合物とを添加して反応させ、所望によりエステル結合又はアミド結合を分解することを特徴とする、一般式(1):
【0010】
【化6】
【0011】
(式中、Rはエステル化若しくはアミド化されているカルボキシルで置換されたアルキル基、カルボキシアルキル基、非置換のアルキル基、エステル化若しくはアミド化されているカルボキシル基、又はカルボキシル基を示し;X、X’及びX’’は前記の通りである)
で表されるベンゾオキセピノ−11−ピぺリジリデン化合物、その塩又はそれらの水和物の製造方法である。
【0012】
【発明の実施の形態】
式(1)および式(3)の化合物において、X’’で示される反応に関与しない基としては、水素原子、ハロゲン原子、アルキル基等が挙げられる。ここで、アルキル基としては、通常炭素数1〜5のアルキル基が挙げられる。また、式(1)および式(3)の化合物において、Xは好ましくは窒素であり;X’は好ましくは酸素であり、そしてX’’は好ましくはハロゲン原子である。ここでハロゲン原子としては、フッ素原子、塩素原子、臭素原子が挙げられるが、フッ素原子が特に好ましい。
式(2)の化合物において、R’は、好ましくはエステル化されたカルボキシル基で置換された若しくは非置換の、炭素数1〜5、特に炭素数1〜2のアルキル基、又はエステル化されたカルボキシル基である。該エステルとしては、メチル、エチル、t−ブチル等のアルキル基、メトキシメチル、メトキシエトキシメチル等のアルコキシアルキルのエステル等、酸又はアルカリ条件下で加水分解される基が好適である。
式(3)の化合物において、Rは好ましくはエステル化されたカルボキシル基で置換された若しくは非置換の、炭素数1〜5、特に炭素数1〜2のアルキル基、エステル化されたカルボキシル基、又はカルボキシル基である。ここで該エステルとしては、R’について記載したエステルが好ましい。
式(3)のベンゾオキセピノ−11−ピぺリジリデン化合物の塩としては、塩酸塩、臭素酸塩等のハロゲン酸塩;酒石酸塩、メタンスルホン酸塩、クエン酸塩等の有機酸塩等が例示され、好ましくはハロゲン酸塩、特に塩酸塩又は臭素酸塩である。またそれらの水和物(即ち、上記ピぺリジリデン化合物の水和物、および該ピぺリジリデン化合物の塩の水和物、特に該化合物の塩の水和物)としては、一ないし二水和物が代表的に例示される。
【0013】
式(1)のベンゾオキセピノ化合物と式(2)のピペリジン−4−オン化合物との配合モル比は、通常2:1〜1:2、好ましくは約1:1である。
【0014】
低原子価チタンとは、原子価が3価未満のチタンを云い、塩化チタン、臭化チタン等の通常市販されている3価又は4価のハロゲン化チタンの1種又は2種以上に還元剤を使用して反応系中で発生させることができる。前記ハロゲン化チタンとして具体的には四塩化チタンおよび三塩化チタンが代表的である。
還元剤としては、亜鉛、亜鉛・銅合金、マグネシウム、リチウム、水素化リチウムアルミニウム、カリウムグラファイト等が挙げられる。好ましい還元剤は亜鉛、又は亜鉛・銅合金である。
低原子価チタンの使用量は、式(1)の化合物に対して通常2〜4倍モル、好ましくは約2倍モルである。従って、ハロゲン化チタンの配合量は、低原子価チタンの使用量とほぼ同モル量又はそれ以上である。還元剤の配合量は、使用したハロゲン化チタンの原子価によって変わり、ハロゲン化チタンの配合量とほぼ等モル量又はそれ以上が好ましい。
この反応系にトリメチルシリルクロリドを存在させると、ハロゲン化チタンの節約ともなり、生成物の回収及び溶媒等の処理にも有効である。
【0015】
本発明における反応時間は数分から数10分である。反応温度は室温から120℃、望ましくは使用する溶媒の沸点付近で実施するのが好ましい。
【0016】
反応に使用できる溶媒はエーテル系の溶媒が好ましく、例えばテトラヒドロフラン、ジオキサン、ジメトキシエタン、ジイソプロピルエーテル等が使用可能である。好ましい溶媒はテトラヒドロフラン及び1,4−ジオキサンである。
【0017】
式(1)のベンゾオキセピノ化合物と式(2)のピペリジン−4−オン化合物との反応終了後、所望によりエステル結合又はアミド結合を常法により分解すれば、式(3)においてRがカルボキシアルキル基又はカルボキシル基である化合物が得られる。
エステル分解反応には酸又はアルカリが用いられ、酸、例えば塩酸、硫酸、臭素酸等の鉱酸、又はそれ等の酸の有機酸溶液若しくはアルコール溶液を用いて行うのが好ましい。また、アルカリとしては苛性ソーダ、KOH、K2CO3、LiOH等のアルカリを用いて、加水分解してもよい。
また、式(3)の化合物を塩の形態で単離するには、例えば反応終了後、式(3)の化合物の有機溶媒溶液に塩酸、臭素酸等の酸を添加すればよい。
反応混合物から目的物を単離するには、常法、例えばろ過、洗浄、抽出、再結晶、各種クロマトグラフィー等によればよい。
【0018】
【実施例】
以下に本発明を実施例により具体的に説明するが、本発明はこれらに限定されるものではない。
実施例1
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 t−ブチル エステル (3)の製造
【0019】
【化7】
【0020】
アルゴン気流下、無水テトラヒドロフラン 5.6mL に亜鉛 443.7mg (90%) を加え、次いで、氷浴下、四塩化チタン 0.22mLを滴下し、30分間加熱還流した。この沸騰混合物に8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−オン (1) 228.7mg と3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸t−ブチル エステル (2) 226.7mg の無水テトラヒドロフラン4.0mL 溶液を素早く滴下し、20分間加熱還流した。放冷後、10%炭酸カリウム水溶液 15mL と酢酸エチル15mL を加え、室温で20分間撹拌し、不溶物をセライトろ過した。ろ液に水20mLを加えて分液し、有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣の黄色油状物をNHシリカゲルカラムクロマトグラフィー (クロロホルム:n−ヘキサン=2:1) に付し、淡黄色油状物として標題化合物 (3) 269.2mgを得た。また、この反応液中に化合物(3)のt−Buエステル基が分解した遊離体がHPLCで確認された。
1H−NMR (270MHz, CDCl3) ; δ(ppm)8.55 (1H, dd, J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.5, 1.5 Hz), 7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.05 (1H, dd, J = 8.7, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.9, 2.6 Hz), 6.50 (1H, dd,J = 10.3, 2.5 Hz), 5.64 (1H, d, J = 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.83−2.17 (11H, m), 2.06 (1H, ddd, J = 10.4, 10.3, 3.3 Hz), 1.44 (9H, s).
【0021】
実施例2
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 エチル エステル (5) の製造
【0022】
【化8】
【0023】
3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸 t−ブチル エステルの替わりに3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸 エチル エステル (4) 199.6mg を用いて実施例1と同様に反応を行い、淡黄色油状物として標題化合物 (5) 286.3mgを得た。
1H−NMR (270MHz, CDCl3) ; δ(ppm)8.55 (1H, dd, J = 5.1, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1.6 Hz), 7.22 (1H, dd, J = 7.6, 5.1 Hz), 7.06 (1H, dd, J = 8.6, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.9, 2.6 Hz), 6.50 (1H, dd,J = 10.4, 2.6 Hz), 5.64 (1H, d, J = 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 4.14 (2H, dd, J = 14.2, 7.1 Hz), 2.85−2.47 (9H, m), 2.37−2.23 (2H, m),2.09 (1H, ddd, J = 10.4, 9.9, 3.3 Hz), 1.25 (3H, t, J = 7.1 Hz).
【0024】
実施例 3
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 エチルエステル (5) の製造
亜鉛の替わりに亜鉛−銅合金714.4mgを用いて実施例2と同様に反応を行い、標題の化合物 (5)271.5mg を得た。
【0025】
実施例 4
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 エチルエステル (5) の製造
反応溶媒としてテトロヒドロフランの替わりに1,4−ジオキサン5.6mLを用いて実施例2と同様に反応を行い、目的の標題化合物 (5)120.0mg を得た。
【0026】
実施例 5
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 エチルエステル (5) の製造
四塩化チタンの替わりに三塩化チタン309.0mgを用いて実施例 2と同様に反応させて、目的の標題化合物 (5) 218.0mgを得た。
【0027】
実施例 6
8−フルオロ−5−(1−メチル−ピペリジン−4−イリデン)−5,11−ジヒドロ−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン(7)の製造
【0028】
【化9】
【0029】
3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸t−ブチル エステルの替わりに1−メチル−ピペリジン−4−オン(6)109.7mg を用いて実施例 1と同様に反応を行い、淡黄色油状物として標題化合物 (7) 182.2mg を得た。
1H−NMR (270MHz, CDCl3) ;δ(ppm) 8.56 (1H, dd, J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1.7 Hz), 7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.07 (1H, dd, J = 8.6, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.8, 2.6 Hz), 6.51 (1H, dd,J = 10.4, 2.6 Hz), 5.65 (1H, d, J = 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.81−2.51 (4H, m), 2.39−2.16 (3H, m), 2.28 (3H, s), 2.01 (1H, ddd, J =
10.4, 10.3, 3.3 Hz).
【0030】
実施例 7
4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロエプテン−5−イリデン)−ピペリジン−1−カルボン酸 エチル エステル(9)の製造
【0031】
【化10】
【0032】
3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸t−ブチル エステルの替わりに4−オキソ−ピペリジン−1−カルボン酸エチル エステル(8)184.7mg を用いて実施例1と同様に反応を行い、淡黄色油状物として標題化合物(9)270.8mg を得た。
1H−NMR (270MHz, CDCl3) ; δ(ppm)8.56 (1H, dd, J = 4.9, 1.7 Hz), 7.69 (1H, dd, J = 7.6, 1.7 Hz), 7.25 (1H, dd, J = 7.7, 5.1 Hz), 7.04 (1H, dd, J = 8.6, 6.4 Hz), 6.60 (1H, ddd, J = 8.2, 7.8, 2.6 Hz), 6.52 (1H, dd,J = 10.3, 2.6 Hz), 5.61 (1H, d, J = 12.4 Hz), 4.84 (1H, d, J = 12.4 Hz), 4.15 (2H, dd, J = 14.2, 7.1 Hz), 3.83 (2H, m), 3.26 (1H, ddd, J = 13.1, 9.0, 4.3 Hz), 3.10 (1H, ddd, J = 13.0, 9.3, 4.0 Hz), 2.67−2.44 (3H, m), 2.29 (1H, m), 1.26 (3H, t, J = 7.1 Hz).
【0033】
実施例 8
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸(10)塩酸塩の製造
【0034】
【化11】
【0035】
3−[4−(8−フルオロ−11H−10−オキサ−4−アザ−ジベンゾ[a,d]シクロヘプテン−5−イリデン)−ピペリジン−1−イル]−プロピオン酸 エチル エステル (5) 2.9gに2規定の苛性ソーダ 6.4mLを加えて常法によりエステル分解反応を行い、そして塩酸を滴下して、淡黄色結晶 として標題化合物(10)塩酸塩 2.7g を得た。
1H−NMR (270MHz, DMSO−d6) ; δ(ppm)8.55 (1H, d, J = 4.8 Hz), 7.97 (1H, d, J = 7.6 Hz), 7.40 (1H, dd, J = 7.3, 5.3 Hz), 7.14 (1H, t, J = 8.1 Hz), 6.77 (1H, t, J = 8.2 Hz), 6.67 (1H, dd, J = 10.6, 2.3 Hz), 5.67 (1H, d, J = 12.4 Hz), 5.03 (1H, d, J = 12.5 Hz), 3.50−3.15 (8H, m), 2.90−2.65 (3H, m), 2.51−2.40 (1H, m).
【0036】
参考例1
3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸 エチル エステル(4)の製造
【0037】
【化12】
【0038】
4−ピペリドン塩酸塩1水和物(12) 25.3g とアクリル酸エチル21.4mLのイソプロパノール溶液 60mL に、室温撹拌下20%K2CO3 60mLを加え、6.5時間加熱還流した。冷却後、溶媒と過剰のアクリル酸エチルを減圧下留去し、残渣を酢酸エチル (150mL×2) で抽出した。抽出液を飽和食塩水 で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去して黄色油状物として標題化合物 (4)30.8gを得た。
1H−NMR (270MHz, CDCl3) ; δ (ppm) 4.17 (2H, dd, J = 14.2, 7.1 Hz), 2.83 (2H, t, J = 7.3 Hz), 2.78 (4H, t, J = 5.9 Hz), 2.53 (2H, t, J = 7.1 Hz),2.44 (4H, t, J = 6.1 Hz), 1.27 (3H, t, J = 7.1 Hz).
【0039】
参考例2
3−(4−オキソ−ピペリジン−1−イル)−プロピオン酸 t−ブチル エステル(2)の製造
4−ピペリドン塩酸塩1水和物 2.13g とアクリル酸 t−ブチル1.78gとを用いて、参考例1と同様にして、標題化合物(2)2.94gを得た。
1H−NMR (270MHz, CDCl3) ; δ (ppm) 2.82〜2.72 (6H, m), 2.50〜2.40 (6H, m), 1.46 (9H, s).
【0040】
【発明の効果】
本発明の製造方法によると、ベンゾオキセピノ化合物から、少ない工程数で且つ高収率でベンゾオキセピノ−11−ピぺリジリデン化合物を製造することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a benzooxepino-11-piperidylidene compound or an intermediate thereof useful as an antiallergic agent.
[0002]
[Prior art]
One of the compounds aimed at by the present invention is described in Journal of Medicinal Chemistry Vol. 38 No. 3-p-496-507 and 3- [4- (8-fluoro5,11-dihydro [1] benzoxepino [4,3-b] pyridine-11-ylidene) piperidino] propionic acid described in JP-A-06-192263. Yes, this compound is an amphoteric antiallergic agent and exhibits selective histamine H1 receptor antagonism. According to the publication, 8-cyano-3-methylpyridine and 2-cyano-3- (3-fluorophenoxymethyl) pyridine are used as starting materials in the above-mentioned publication. After producing fluoro-5,11-dihydrobenz [b] oxepino [4,3-b] pyridin-11-one, a 11-ketone group is subjected to a Grignard reaction and then dehydrated to form 1-methylpiperidylidene. Further, piperidylidene is liberated via 1-ethoxycarbonylpiperidylidene, produced as a propionate by an acrylate ester, and further removed from the ester group with caustic soda or an acid.
[0003]
[Problems to be solved by the invention]
The compound exhibits excellent medicinal properties, retains good stability, and has favorable properties as a drug, but it has many steps from the benzoxepino compound to the final target, and the yield is also a problem. This has been a major obstacle to making it a pharmaceutical product.
[0004]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on the steps subsequent to the tricyclic compound which is the benzoxepino compound since the known conventional production method has many steps and the yield is also a problem. The present inventors have succeeded in developing a production method for directly obtaining a propionate and a free propionate in high yield from a ring compound, and completed the present invention.
[0005]
That is, the present invention relates to a boiling mixture obtained by adding titanium tetrachloride or titanium trichloride to zinc or a zinc-copper alloy, and heating and refluxing the mixture to obtain the general formula (1):
[0006]
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[0007]
(Wherein X is CH or N; X 'is O; X''is a group which does not participate in the reaction) and expressed in behenate Nzookisepino compounds, one general formula (2):
[0008]
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[0009]
Wherein R ′ represents an esterified or amidated carboxyl-substituted alkyl group, an unsubstituted alkyl group, or an esterified or amidated carboxyl group. - by adding with one compounds are reacted, characterized by decomposing the desired ester bond or an amide bond, general formula (1):
[0010]
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[0011]
Wherein R represents an esterified or amidated carboxyl-substituted alkyl group, a carboxyalkyl group, an unsubstituted alkyl group, an esterified or amidated carboxyl group, or a carboxyl group; , X ′ and X ″ are as defined above)
And a method for producing a benzoxepino-11-piperidylidene compound, a salt thereof, or a hydrate thereof.
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
In the compounds of the formulas (1) and (3), the group not participating in the reaction represented by X ″ includes a hydrogen atom, a halogen atom, an alkyl group and the like. Here, the alkyl group usually includes an alkyl group having 1 to 5 carbon atoms. Also, in the compounds of formulas (1) and (3), X is preferably nitrogen; X 'is preferably oxygen, and X "is preferably a halogen atom. Here, examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom, and a fluorine atom is particularly preferred.
In the compounds of the formula (2), R ′ is preferably an alkylated group, preferably substituted or unsubstituted with an esterified carboxyl group, having 1 to 5 carbon atoms, especially 1 to 2 carbon atoms, or esterified. It is a carboxyl group. As the ester, a group hydrolyzed under acid or alkaline conditions, such as an alkyl group such as methyl, ethyl and t-butyl, and an alkoxyalkyl ester such as methoxymethyl and methoxyethoxymethyl are preferable.
In the compound of formula (3), R is preferably an alkylated group substituted or unsubstituted with an esterified carboxyl group, having 1 to 5 carbon atoms, especially 1 to 2 carbon atoms, an esterified carboxyl group, Or a carboxyl group. Here, the ester is preferably the ester described for R ′.
Examples of the salt of the benzoxepino-11-piperidylidene compound of the formula (3) include halogenates such as hydrochloride and bromate; and organic acid salts such as tartrate, methanesulfonate and citrate. , Preferably halogenates, especially hydrochlorides or bromates. The hydrates thereof (that is, the hydrates of the above-mentioned pyridylidene compounds and the hydrates of the salts of the above-mentioned pyridylidene compounds, especially the hydrates of the salts of the above-mentioned compounds) include mono- and di-hydrates. Things are typically illustrated.
[0013]
The molar ratio of the benzoxepino compound of the formula (1) to the piperidin-4-one compound of the formula (2) is usually 2: 1 to 1: 2, preferably about 1: 1.
[0014]
Low-valent titanium refers to titanium having a valence of less than trivalent, and one or two or more of commercially available trivalent or tetravalent titanium halides such as titanium chloride and titanium bromide are reduced to a reducing agent. Can be generated in the reaction system. Specific examples of the titanium halide include titanium tetrachloride and titanium trichloride.
Examples of the reducing agent include zinc, zinc-copper alloy, magnesium, lithium, lithium aluminum hydride, potassium graphite and the like. Preferred reducing agents are zinc or zinc-copper alloys.
The amount of the low-valent titanium to be used is generally 2 to 4 moles, preferably about 2 moles, per mole of the compound of the formula (1). Therefore, the blending amount of the titanium halide is substantially the same as or higher than the amount of the low-valent titanium used. The amount of the reducing agent varies depending on the valence of the titanium halide used, and is preferably approximately equimolar or more than the amount of the titanium halide.
The presence of trimethylsilyl chloride in this reaction system saves titanium halide, and is also effective in recovering products and treating solvents and the like.
[0015]
The reaction time in the present invention is several minutes to several tens of minutes. The reaction temperature is preferably from room temperature to 120 ° C., preferably around the boiling point of the solvent used.
[0016]
As a solvent that can be used for the reaction, an ether-based solvent is preferable, and for example, tetrahydrofuran, dioxane, dimethoxyethane, diisopropyl ether, and the like can be used. Preferred solvents are tetrahydrofuran and 1,4-dioxane.
[0017]
After completion of the reaction between the benzoxepino compound of the formula (1) and the piperidin-4-one compound of the formula (2), if necessary, an ester bond or an amide bond is decomposed by a conventional method, and in the formula (3), R is a carboxyalkyl group. Alternatively, a compound that is a carboxyl group is obtained.
An acid or alkali is used for the ester decomposition reaction, and it is preferable to use an acid, for example, a mineral acid such as hydrochloric acid, sulfuric acid, or bromic acid, or an organic acid solution or an alcohol solution of such acid. The alkali may be hydrolyzed using an alkali such as caustic soda, KOH, K 2 CO 3 , and LiOH.
In order to isolate the compound of the formula (3) in the form of a salt, for example, an acid such as hydrochloric acid or bromic acid may be added to a solution of the compound of the formula (3) in an organic solvent after completion of the reaction.
The target compound can be isolated from the reaction mixture by a conventional method, for example, filtration, washing, extraction, recrystallization, various types of chromatography and the like.
[0018]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
Example 1
3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid t-butyl ester (3) Manufacturing [0019]
Embedded image
[0020]
In an argon stream, 443.7 mg (90%) of zinc was added to 5.6 mL of anhydrous tetrahydrofuran, and then 0.22 mL of titanium tetrachloride was added dropwise in an ice bath, and the mixture was heated under reflux for 30 minutes. To this boiling mixture was added 8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cyclohepten-5-one (1) (228.7 mg) and 3- (4-oxo-piperidin-1-yl)-. A solution of t-butyl propionate (2) (226.7 mg) in anhydrous tetrahydrofuran (4.0 mL) was quickly added dropwise, and the mixture was heated under reflux for 20 minutes. After cooling, 15 mL of a 10% aqueous potassium carbonate solution and 15 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 20 minutes, and the insolubles were filtered through celite. 20 mL of water was added to the filtrate, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual yellow oil was subjected to NH silica gel column chromatography (chloroform: n-hexane = 2: 1) to obtain 269.2 mg of the title compound (3) as a pale yellow oil. In this reaction solution, a free form in which the t-Bu ester group of compound (3) was decomposed was confirmed by HPLC.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 8.55 (1H, dd, J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.5, 1) 5.5 Hz), 7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.05 (1H, dd, J = 8.7, 6.8 Hz), 6.59 (1H) , Ddd, J = 8.2, 7.9, 2.6 Hz), 6.50 (1H, dd, J = 10.3, 2.5 Hz), 5.64 (1H, d, J = 12) .4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.83-2.17 (11H, m), 2.06 (1H, ddd, J = 10.4, 10. 3, 3.3 Hz), 1.44 (9H, s).
[0021]
Example 2
Preparation of 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) [ [0022]
Embedded image
[0023]
Using 199.6 mg of 3- (4-oxo-piperidin-1-yl) -propionic acid ethyl ester (4) instead of 3- (4-oxo-piperidin-1-yl) -propionic acid t-butyl ester The reaction was carried out in the same manner as in Example 1 to obtain 286.3 mg of the title compound (5) as a pale yellow oil.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 8.55 (1H, dd, J = 5.1, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1) 6.6 Hz), 7.22 (1H, dd, J = 7.6, 5.1 Hz), 7.06 (1H, dd, J = 8.6, 6.8 Hz), 6.59 (1H) , Ddd, J = 8.2, 7.9, 2.6 Hz), 6.50 (1H, dd, J = 10.4, 2.6 Hz), 5.64 (1H, d, J = 12) .4 Hz), 4.83 (1H, d, J = 12.4 Hz), 4.14 (2H, dd, J = 14.2, 7.1 Hz), 2.85-2.47 (9H) , M), 2.37-2.23 (2H, m), 2.09 (1H, ddd, J = 10.4, 9.9, 3.3 Hz). 1.25 (3H, t, J = 7.1 Hz).
[0024]
Example 3
Preparation of 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) The reaction was carried out in the same manner as in Example 2 except that 714.4 mg of a zinc-copper alloy was used instead, to obtain 271.5 mg of the title compound (5).
[0025]
Example 4
Production reaction of 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) The reaction was carried out in the same manner as in Example 2 using 5.6 mL of 1,4-dioxane instead of tetrahydrofuran as a solvent, to obtain 120.0 mg of the title compound (5).
[0026]
Example 5
Production of ethyl 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid (5) The reaction was carried out in the same manner as in Example 2 except that 309.0 mg of titanium trichloride was used instead of titanium chloride, to obtain 218.0 mg of the desired title compound (5).
[0027]
Example 6
Preparation of 8-fluoro-5- (1-methyl-piperidine-4-ylidene) -5,11-dihydro-10-oxa-4-aza-dibenzo [a, d] cycloheptene (7)
Embedded image
[0029]
The reaction was carried out in the same manner as in Example 1 using 109.7 mg of 1-methyl-piperidin-4-one (6) instead of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate. Thus, 182.2 mg of the title compound (7) was obtained as a pale yellow oil.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 8.56 (1H, dd, J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1) 0.7 Hz), 7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.07 (1H, dd, J = 8.6, 6.8 Hz), 6.59 (1H) , Ddd, J = 8.2, 7.8, 2.6 Hz), 6.51 (1H, dd, J = 10.4, 2.6 Hz), 5.65 (1H, d, J = 12) .4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.81-2.51 (4H, m), 2.39-2.16 (3H, m), 2.28 (3H, s), 2.01 (1H, ddd, J =
10.4, 10.3, 3.3 Hz).
[0030]
Example 7
Preparation of ethyl 4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloepten-5-ylidene) -piperidine-1-carboxylate (9)
Embedded image
[0032]
As in Example 1 using 184.7 mg of 4-oxo-piperidine-1-carboxylic acid ethyl ester (8) instead of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate The reaction was carried out to obtain 270.8 mg of the title compound (9) as a pale yellow oil.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 8.56 (1H, dd, J = 4.9, 1.7 Hz), 7.69 (1H, dd, J = 7.6, 1) 0.7 Hz), 7.25 (1H, dd, J = 7.7, 5.1 Hz), 7.04 (1H, dd, J = 8.6, 6.4 Hz), 6.60 (1H) , Ddd, J = 8.2, 7.8, 2.6 Hz), 6.52 (1H, dd, J = 10.3, 2.6 Hz), 5.61 (1H, d, J = 12) .4 Hz), 4.84 (1H, d, J = 12.4 Hz), 4.15 (2H, dd, J = 14.2, 7.1 Hz), 3.83 (2H, m), 3.26 (1H, ddd, J = 13.1, 9.0, 4.3 Hz), 3.10 (1H, ddd, J = 13.0, 9.3, 4.0 Hz), 2.67-2.44 (3H, m), 2.29 (1H, m), 1.26 (3H, t, J = 7.1 Hz).
[0033]
Example 8
Production of 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid (10) hydrochloride [ [0034]
Embedded image
[0035]
3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) 2.9 g Then, 6.4 mL of 2N caustic soda was added to the mixture, and an ester decomposition reaction was carried out by a conventional method, and hydrochloric acid was added dropwise to obtain 2.7 g of the title compound (10) hydrochloride as pale yellow crystals.
1 H-NMR (270 MHz, DMSO-d 6 ); δ (ppm) 8.55 (1 H, d, J = 4.8 Hz), 7.97 (1H, d, J = 7.6 Hz), 7 .40 (1H, dd, J = 7.3, 5.3 Hz), 7.14 (1H, t, J = 8.1 Hz), 6.77 (1H, t, J = 8.2 Hz) , 6.67 (1H, dd, J = 10.6, 2.3 Hz), 5.67 (1H, d, J = 12.4 Hz), 5.03 (1H, d, J = 12.5) Hz), 3.50-3.15 (8H, m), 2.90-2.65 (3H, m), 2.51-2.40 (1H, m).
[0036]
Reference Example 1
Preparation of ethyl 3- (4-oxo-piperidin-1-yl) -propionate (4)
Embedded image
[0038]
Isopropanol solution 60mL of 4-piperidone hydrochloride monohydrate (12) 25.3 g of ethyl acrylate 21.4 mL, was added under stirring at room temperature 20% K 2 CO 3 60mL, was heated under reflux for 6.5 hours. After cooling, the solvent and excess ethyl acrylate were distilled off under reduced pressure, and the residue was extracted with ethyl acetate (150 mL × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30.8 g of the title compound (4) as a yellow oil.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 4.17 (2H, dd, J = 14.2, 7.1 Hz), 2.83 (2H, t, J = 7.3 Hz) , 2.78 (4H, t, J = 5.9 Hz), 2.53 (2H, t, J = 7.1 Hz), 2.44 (4H, t, J = 6.1 Hz), 1 .27 (3H, t, J = 7.1 Hz).
[0039]
Reference Example 2
Preparation of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate (2) Using 2.13 g of 4-piperidone hydrochloride monohydrate and 1.78 g of t-butyl acrylate. In the same manner as in Reference Example 1, 2.94 g of the title compound (2) was obtained.
1 H-NMR (270 MHz, CDCl 3 ); δ (ppm) 2.82 to 2.72 (6H, m), 2.50 to 2.40 (6H, m), 1.46 (9H, s).
[0040]
【The invention's effect】
According to the production method of the present invention, a benzooxepino-11-pyridylidene compound can be produced from a benzoxepino compound in a small number of steps and in a high yield.
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