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TWI376365B - New process for the synthesis of agomelatine - Google Patents

New process for the synthesis of agomelatine Download PDF

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TWI376365B
TWI376365B TW098125264A TW98125264A TWI376365B TW I376365 B TWI376365 B TW I376365B TW 098125264 A TW098125264 A TW 098125264A TW 98125264 A TW98125264 A TW 98125264A TW I376365 B TWI376365 B TW I376365B
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compound
formula
agomelatine
synthesis
synthesizing
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TW201018658A (en
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Christophe Hardouin
Jean-Pierre Lecouve
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Servier Lab
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Description

1376365 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種工業合成式（I)之阿戈美拉汀 (AGOMELATINE)或N-[2-(7-曱氧基-1-萘基）乙基]乙醯胺之 新穎方法：
MeO
NHCOMe 0)·
【先前技術】 阿戈美拉汀（AGOMELATINE)或N-[2-(7-甲氧基-1-萘基） 乙基]乙醯胺具有重要的藥理學性質。 事實上，其雙重特性一方面為褪黑素能系統之受體拮抗 劑及另一方面為5-HT2C受體的拮抗劑。此等性質使其在中 樞神經系統中提供活性及更特定言之用於治療嚴重抑鬱 症、季節性情感障礙、睡眠障礙、心血管病、消化系統 病、由時差引起之失眠及疲勞、食慾紊亂及肥胖。 阿戈美拉汀（AGOMELATINE)、其製備及其治療應用在 在歐洲專利說明書EP 0 1 564 202中已有敍 述。 鑒於該化合物之醫藥價值，重要的是其能藉由一種有效 的工業合成方法製備，該方法可容易轉換成工業規模及供 應優良產率及具有傑出純度的阿戈美拉汀 (AGOMELATINE)。 專利說明書EP 0 447 285敍述以7-曱氧基-1-四氫萘酮起 141692.doc 1376365 始之八個步驟來本產阿戈美拉汀（AGOMELATINE)，其平 均產率低於30%。 在專利說明書EP 1 564 202中，申請人發展出一種以7-甲氧基-1-四氫萘酮起始之僅有四個步驟的新穎、更有效且 可工業化之合成途徑，使得以高度可再現方式獲得明確結 晶形狀的阿戈美拉汀（AGOMELATINE)成為可能。 然而，當前仍在尋求相關之新穎合成途徑，尤其始於成 本低於7-曱氧基-1-四氫萘酮質z。 .、 本發明者已持續其研究，並已發展出一種從3」甲氧基^ 醌開始合成阿戈美拉汀（AGOMELATINE)之新穎方法：該新 穎起始物質的優點在於以較低成本即可簡單且容易大量獲 得。此外，3-曱氧基苊醌之優點亦在於其結構中具有萘環 系，可避免在合成中包括從工業觀點看總是存在問題的芳 構化步驟。 而且，此等新穎方法可能以可再現方式及不需費力純化 即可獲得阿戈美拉汀（AGOMELATINE)，其具有與用作醫 藥活性成分相容之純度。 【發明内容】 更特定言之，本發明係關於一種工業合成式（I)之化合物 的方法：
NHCOMe
MeO
(I)， 其中該方法之特徵在於由式（II)之3-曱氧基苊醌： 141692.doc 1376365
——^ MeO
(Π) 在強鹼存在下反應，產生式（ΠΙ)之化合物
(III)， 其進行胺化作用，產生式（IV)之化合物：
MeO h2n
(IV)， 其受到還原系統之作用，產生式（V)之化合物：
MeO
(V)， 其依序受到乙酸鈉及乙酸酐之連續作用，產生式（I)之化合 物，該化合物係以固體形式分離。 擅長此項技藝者可藉由常規化學反應及/或在文獻中敍 述之化學反應獲得式（II)之化合物。 有利地，利用 NaNH2 、（（CH3)3-Si)2NLi(LiHMDS)或 ((CH3)3-Si)2NNa(NaHMDS)，將式（II)之化合物轉化成根據 本發明之式（III)之化合物。 本胺化反應較佳係利用NH4C1及丙基膦酸酐進行。 用在式（IV)之化合物轉化成根據本發明之式（V)之化合物 141692.doc 1376365 的反應中之還原系統以LiAlH4或成對之BH3.THF/A1C13較 佳。 #於以下原因，該方法尤其有價值： -其可忐從簡單、低成本的起始物質開始，依工業規模獲 得極佳產率之式（I)之化合物； -因為本起始受質中含有萘環系，因此可避免芳構化反 應； -最後’所得之式（I)之化合物可依可再現之方式具有如專 利說明書EP1564202中敍述之結晶型的特徵。 根據本發明方法獲得之式（IV)之化合物為新穎化合物， 且適用為阿戈美拉汀（AGOMELATINE)合成法之中間物， 其中經過還原反應後，與乙酸酐進行偶聯反應。 【實施方式】 下文實例將說明本發明，而不以任何方式加以限制。 實例1 : N-[2-(7-甲氧基-1-萘基）乙基】乙醢胺 步驟A: (7-甲氧基-1-萘基）(側氧基）乙酸 在反應器中’將4毫克18 -冠-6謎以及230毫克NaNH〗依次 加至100毫克3-曱氧基苊醌於1毫升DMSO之懸浮液中。混 合物在周溫下攪拌30分鐘。然後添加水（2毫升），繼之添加 2N HC1溶液（3毫升）。在用乙酸乙酯萃取二次後，溶劑經 NajO4乾燥，然後蒸發排除，產生產率88%之黃色固體形 式及化學純度大於94%之標題產物。
熔點：99°G 步称B : 2-(7-甲氧基-1-萘基）-2-側氧基乙醢胺 141692.doc 1376365 在反應裔令，在周溫下，將i克步驟A所得化合物加至3〇 毫升乙腈中，然後添加4_39克丙基膦酸酐及438毫克 NH4C1，最後添加3.8毫升二異丙胺。溶液在氮氣下授拌4 小時，然後瘵發排除溶劑，殘餘物溶於飽和水NaCl水溶液 中，及用乙酸乙酯萃取。然後將溶劑經]^&28〇4乾燥，進而 蒸發排除，產生產率80%之橙色固體形式及化學純廋90〇/〇 之標題產物。 熔點：112°c 步驟C : 2-(7-甲氧基-i_萘基）乙胺 將480毫克步驟B所得化合物溶於THF (2〇毫升）後，加至 反應器中，繼之添加2 eq. A1C13及最後緩慢添加6 eq. BH3·THF>谷液，及授拌該反應混合物達2 5小時。然後添加 水（12毫升），繼之一同添加25毫升in氫氧化鈉溶液舆8〇〇 毫克氫氧化鈉固體，使用甲基第三丁基醚（2〇毫升）萃取三 次。然後將溶劑經NajO4乾燥，進而蒸發排除，產生產率 80%之黃色油狀物及化學純度95%之標題產物。 步驟D : N-[2-(7-甲氧基-1-萘基）乙基]己醮胺 在反應器中’將5克步驟C所得化合物及2克乙酸納加至 乙醇中。攪拌該混合物，然後添加2.3克乙酸gf，加熱該 反應混合物達回流’並添加20毫升水。允許該反應混合物 回至周溫，濾出所得之沉澱物，用乙醇/水3 5/65混合物洗 蘇’產生化學純度99%及產率80%之標題產物。
炼點：108°C 實例2 :實例1中獲得之化合物N-【2-(7·甲氧基萘基 141692.doc 1376365 基]乙酿胺的結晶形狀測定 利用自Bruker AXS之D8高解析度衍射儀，依據以下參數 記錄數據：以2Θ表示之角度範圍3。_9〇。，每步進〇.〇1。及3〇 s。將實例1中獲得之N-[2-(7-甲氧基·ι_萘基）乙基]乙醯胺 粉末沉積在透射架台上。χ射線源是銅管（λ(：υΚαΐ = 1.54056 Α)。該架台包括前面一部單色器（Ge(ul)晶體）及 一個能量解析固態檢測器（MXP-D1，Moxtec-SEPH)。 該化合物完全結晶：在一半高度下以2Θ表示之行距為 0.07° 〇 因此測定以下參數·· -晶胞之晶體結構：單斜晶 "晶胞參數：a=20.0903 A、b=9.3 194 A、c=15.4796 A、 β=108.667° -晶空間群：P2,/!! -晶胞中之分子數：8 -晶胞體積：Va胞=2746.742 A3 -密度：d=l. 13 g/cm3。 實例3 :藉由X射線粉末衍射圈測定實例i中獲得tN_[2 (7·甲氧基-1-萘基）乙基】乙醢胺化合物的結晶形狀 由以下X射線粉末衍射圖判別實例1中獲得之化合物的結 晶形狀特性，其係由Simens D5005衍射儀（鋼-對陰極）測 定’以晶面間距d ' Bragg角度2Θ及相對強度表示（以相對 於最大強度線之百分比表示]: 141692.doc 1376365
*«»« 9.26 9.544 23 10.50 8.419 13 15.34 5.771 24 17.15 5.165 100 141692.doc

Claims (1)

1376365
1. 一種工業合成式（I)之化合物的方法 第098125264號專利申請案 中文中靖鲁利範圍替換本(1 gi 丨公告本 'NHCOMe MeO' (I), 其特徵在於：由式（Π)之；3-甲一氧基苊醍 〇、 y〇 MeO (Π) 在強鹼存在下反應，產生式（III)之化合物 MeO ⑽， 其經過胺化作用，產生式（IV)之化合物 .0 ,0 Η,Ν- MeO (IV), 其受到還原系統作用，產生式（V)之化合物 NH, MeO (V), 其受到乙酸鈉及隨後乙酸酐之連續作用，產生式（I)之化 141692-1010507.doc 1376365 合物，該化合物係呈固體形式分離》 2. 如請求項1之合成式（I)之化合物的方法，其特徵在於： 式（II)之化合物轉化成式（III)之化合物之反應係使用 NaNH2進行。 3. 如請求項1之合成式（I)之化合物的方法，其特徵在於： 式（IV)之化合物轉化成式（V)之化合物之反應係使用成對 之 BH3.THF/A1C13 進行。 4. 一種式（IV)之化合物： 〇
其係用為阿戈美拉汀（AGOMELATINE)合成法之中間物。 5. —種以如請求項4之式（IV)之化合物於阿戈美拉汀 (AGOMELATINE)之合成法上之用途。 6. 一種以如請求項1之式（II)之化合物於阿戈美拉汀 (AGOMELATINE)之合成法上之用途。 7. 一種以如請求項1之式（III)之化合物於阿戈美拉汀 (AGOMELATINE)之合成法上之用途。 8. 如請求項1之合成阿戈美拉汀（AGOMELATINE)的方法’ 其起始於式（III)之化合物，特徵在於：根據請求項1或2 中任一項之合成法獲得式（III)之化合物。 9. 如請求項1之合成阿戈美拉汀（AGOMELATINE)的方法， 其起始於式（IV)之化合物，特徵在於：根據請求項1或2 中任一項之合成法獲得式（IV)之化合物。 141692-1010507.doc 1376365 10.如請求項1之合成阿戈美拉汀（AGOMELATINE)的方法， 其起始於式（V)之化合物，特徵在於：根據請求項1至3中 任一項之合成法獲得式（V)之化合物。
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