TWI398428B - 製備阿戈美拉汀（ａｇｏｍｅｌａｔｉｎｅ）之新穎方法 - Google Patents

製備阿戈美拉汀（ａｇｏｍｅｌａｔｉｎｅ）之新穎方法 Download PDF

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TWI398428B
TWI398428B TW098126191A TW98126191A TWI398428B TW I398428 B TWI398428 B TW I398428B TW 098126191 A TW098126191 A TW 098126191A TW 98126191 A TW98126191 A TW 98126191A TW I398428 B TWI398428 B TW I398428B
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synthesis
agomelatine
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Christophe Hardouin
Jean-Pierre Lecouve
Nicolas Bragnier
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Description

製備阿戈美拉汀(AGOMELATINE)之新穎方法
本發明係關於一種工業合成式(I)之阿戈美拉汀(或N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺)之新穎方法。
阿戈美拉汀(或N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺)具有有價值的藥理學性質。
實際上，其具有一方面為褪黑素能系統受體的激動劑且另一方面為5-HT2C 受體的拮抗劑之雙重特徵。此等性質使其於中樞神經系統中具有活性，且尤其用於治療重度抑鬱症、季節性情緒失調、睡眠障礙、心血管病症、消化系統病症、因時差引起的失眠與疲勞、食慾失調與肥胖。
阿戈美拉汀、其製備與其在治療中之用途已在歐洲專利說明書EP 0 447 285與EP 1 564 202中闡述。
鑒於該化合物的醫藥價值，重要的在於可利用有效的工業合成方法進行製造，該合成方法可輕易轉換為工業規模且以良好產率提供具有極佳純度的阿戈美拉汀。
專利說明書EP 0 447 285闡述自7-甲氧基-1-四氫萘酮開始以八個步驟製得阿戈美拉汀，平均產率小於30%。
在專利說明書EP 1 564 202中，申請者發展一種僅四步的自7-甲氧基-1-四氫萘酮開始之更有效且可工業化之新穎合成途徑，其可以高度再現的方式獲得明確晶形的阿戈美拉汀。
但是，新穎合成途徑的研究目前仍具有重要性，尤其係以較7-甲氧基-1-四氫萘酮廉價的初始物質開始。
申請者繼續其研究且發展出一種自7-甲氧基-1-萘酚開始合成阿戈美拉汀之新穎方法：該新穎初始物質具有簡單、可以較低成本輕易大量取得的益處。且，7-甲氧基-1-萘酚亦具有在其結構中具有萘環系統，其可避免在合成時包含芳構化反應的益處，該步驟一直以來就工業角度而言係為疑難。
且，此新穎方法可以可再現的方式獲得阿戈美拉汀且無需費力的純化，其純度適宜作為醫藥活性成分。
更明確而言，本發明係關於一種用於工業合成式(I)化合物之方法：
該方法特徵在於使式(II)之7-甲氧基-1-萘酚起反應：
在將羥基官能團轉化為離去基團(例如鹵素、甲苯磺酸酯或三氟甲磺酸酯基團)後，在鈀存在下，使式(III):CH2 =CH-R(III)之化合物與其縮合，其中R表示，其中R'與R"可相同或不同，各表示直鏈或支鏈(C1 -C6 )烷基或R'與R"一起形成(C2 -C3 )伸烷基鏈且形成的環可與苯基稠合，以得到式(IV)化合物：
其中R係如前定義，其經催化氫化反應得到式(V)化合物：
其中R係如前定義，其經鹼或酸水解或經二元還原劑/酸系統得到式(VI)化合物或其鹽酸鹽：
其陸續與乙酸鈉與隨後的乙酸酐反應得到式(I)化合物，將其以固體形式分離。
根據本發明方法，式(III)化合物較佳為酞醯亞胺化合物，更佳為N-乙烯基酞醯亞胺。式(III)化合物最有利亦為丙烯醯胺。
根據本發明，得到式(IV)化合物之式(III)化合物的縮合反應最好係利用四(三苯基膦)鈀進行；該反應較佳係在甲苯回流下進行。
式(IV)化合物至式(V)化合物之氫化反應較佳係利用碳載鈀進行，更佳為具有5%最低鈀含量的碳載鈀。
以有利方式，式(V)化合物之水解反應較佳係利用二元還原劑/酸系統，例如NaBH4 及隨後的乙酸進行，或當R表示基團C(O)NH2 時，式(V)化合物至式(VI)化合物之轉化較佳係利用鹼，例如NaOBr或NaOCl進行。
此方法之特殊價值在於以下緣由：
-　可在工業規模上，由簡單、低廉的初始物質開始以極佳產率獲得式(I)化合物；
-　在與式(III)化合物偶合期間，根據本發明選擇的操作條件可完全控制區域選擇性；
-　因萘環系統存在於初始物質中，故可避免芳構化反應；
-　最終，獲得的式(I)化合物以可再現的方式具有專利說明書EP 1564202中所述的晶形特徵。
根據本發明方法獲得的式(IV)化合物係新穎的且適用作為合成阿戈美拉汀的中間體，其中其經還原反應，然後經水解反應及隨後與乙酸酐發生偶合反應。
以下實例闡述本發明，但不以任何方式作限制。
實例1：N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺
步驟A：三氟甲磺酸7-甲氧基-1-萘酯
將2.7g 7-甲氧基-1-萘酚、1.1當量三氟甲磺酸酐與1.1當量2,6-二-第三丁基-4-甲基-吡啶引入反應器中的二氯甲烷(45ml)中。在回流下加熱該混合物12小時然後過濾，溶液先以1N HCl溶液及隨後以飽和NaCl溶液洗滌。蒸發有機相且於矽膠上藉由層析法純化所得殘餘物(溶離液：CH2 Cl2 /甲基-環己烷1/9)，而以91%產率得到油形式的標題產物且化學純度大於99%。
步驟B：2-[2-(7-甲氧基-1-萘基)乙烯基]-1H-異吲哚-1,3(2H)-二酮
將2g步驟A中所得的化合物、2當量N-乙烯基酞醯亞胺、1.25當量二異丙基乙胺與0.05當量四(三苯基膦)鈀引入反應器中的甲苯中且在回流下加熱。該反應在回流下持續12小時且隨後使該反應混合物冷卻至室溫。添加乙酸乙酯，然後用水與1N HCl溶液進行洗滌。蒸發溶劑後，於矽膠上藉由層析法純化所得殘餘物(溶離液：二氯甲烷/庚烷1/1，及隨後的二氯甲烷)，而以80%產率得到標題產物且化學純度大於95%。
熔點：146℃
步驟C：2-[2-(7-甲氧基-1-萘基)乙基]-1H-異吲哚-1,3(2H)-二酮
在氫氣壓與室溫下，將2g步驟B中所得的化合物與1g 5%碳載鈀引入反應器中的甲醇/THF 1/2混合物中。反應8小時後，過濾該反應混合物。蒸發溶劑後，定量獲得具有95%化學純度的標題產物。
熔點： 154℃
步驟D：2-(7-甲氧基-1-萘基)乙胺
將1g步驟C中獲得的化合物與5當量NaBH4 引入在反應器中的2-丙醇/水6/1混合物中，且在室溫下攪拌該混合物。然後添加乙酸(0.2當量)且在80℃下加熱該反應混合物8小時。蒸發溶劑及共蒸發水與甲苯後，所得的粗殘餘物直接用於乙醯化反應而未經進一步純化。
步驟E：N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺
將5g步驟D中所得的化合物與2g醋酸鈉引入在反應器中的乙醇中。攪拌該混合物，然後添加2.3g乙酸酐，加熱該反應混合物至回流並添加20ml水。使該反應混合物回至室溫且濾出所得沉澱物並用乙醇/水35/65混合物洗滌，而以對於D與E兩步驟而言80%的產率得到標題產物，化學純度大於99%。
熔點： 108℃
實例2：N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺
步驟A：3-(7-甲氧基-1-萘基)-2-丙烯醯胺
在20℃下，藉由將實例1的步驟A中所得化合物(12.1g)之80mL DMF溶液於氮氣中冒泡10分鐘而使之脫氣。連續將三乙胺(6.6mL)、丙烯醯胺(5.6g)、新亞銅(neocuproine)水合物(454mg)與Pd(OAc)2 (445mg)加入所得溶液中。
使該混合物在100℃下受熱1小時及隨後冷卻至20℃。由AcOEt(100mL)稀釋及隨後添加飽和NH4 Cl溶液後，相分離。在減壓下濃縮有機相且殘留物於AcOEt(50mL)中稀釋。過濾沉澱物以得到粉末形式的標題產物。
步驟B：3-(7-甲氧基-1-萘基)丙醯胺
將0.12g 5% Pd/C(50%濕度)加入步驟A中所得化合物(0.5g)之MeOH(6.5mL)/THF(6.5mL)混合物溶液中。該混合物由氮氣及隨後由氫氣淨化後，在大氣壓下，於50℃受熱1小時。然後在矽藻土上過濾該懸浮液且以MeOH(5mL)/THF(5mL)之混合物洗滌該過濾器。在減壓下濃縮該溶液得到固體形式的標題產物，其直接用於以下步驟而未經進一步純化。
步驟C：2-(7-甲氧基-1-萘基)乙胺鹽酸鹽
將二乙酸氧碘苯(0.88g)加至水(3mL)/乙腈(3mL)之溶液中。在20℃下攪拌10分鐘後，逐份添加步驟B中所得的化合物(500mg)，然後使該混合物在20℃下保持2小時。初始物質耗盡後，在減壓下餾除乙腈。用H2 O(10mL)溶解殘餘物，然後用濃HCl溶液(0.4mL)處理。過濾後，所得沉澱物用乙酸乙酯洗滌且隨後在烘箱中乾燥而得到標題產物。
熔點 ：243℃
步驟D：N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺
將5g步驟C中獲得的化合物與2g乙酸鈉加入在反應器中的乙醇中。攪拌該混合物，然後添加2.3g乙酸酐，加熱該反應混合物至回流並添加20ml水。使該反應混合物回至室溫且濾出所得沉澱物，用乙醇/水35/65混合物洗滌得到標題產物。
熔點： 108℃
實例3：測定實例1與2中獲得的化合物N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺之晶形
利用具有如下參數之來自Bruker AXS的D8高解析度繞射儀記錄數據：3°-90°之2θ角度範圍，每步0.01°且每步30s。將實例1與2所得的N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺粉末沉積於透射裝置托盤上。X-射缐源為銅管(λCuKα1 =1.54056)。該裝置包含一前單色儀(Ge(111)晶體)與一能量解析固態偵測器(MXP-D1,Moxtec-SEPH)。
該化合物結晶良好：就2θ而言，半高缐寬約為0.07°。
因此測得以下參數：
-　單位晶胞之晶體結構：單斜晶
-　單位晶胞參數：a=20.0903，b=9.3194，c=15.4796，β=108.667°
-　空間群：P21 /n
-　單位晶胞内之分子數：8
-　單位晶胞之體積：V單位晶胞 =2746.742
-　密度：d=1.13g/cm3 。
實例4：藉由X-射缐粉末繞射圖測定實例1與2獲得的N-[2-(7-甲氧基-1-萘基)乙基]乙醯胺化合物晶形
實例1與2中所獲得的化合物晶形特徵在於以下的X-射缐粉末繞射圖，其係利用Siemens D5005繞射儀(銅對陰極)測量且以晶面間距d、布拉格(Bragg)角2θ、與相對強度(表示為相對於最強缐的百分比)表示：

Claims (12)

  1. 一種工業合成式(I)化合物之方法 該方法特徵在於使式(II)之7-甲氧基-1-萘酚起反應： 在將羥基官能團轉化為離去基團後，在鈀存在下，使式(III)：CH2 =CH-R(III)之化合物與其縮合，得到式(IV)化合物：其中R表示基團或，其中R'與R"可相同或不同，各表示直鏈或支鏈(C1 -C6 )烷基或R'與R"一起形成(C2 -C3 )伸烷基鏈且形成的環可與苯基稠合， 其中R係如前定義，其經催化氫化反應得到式(V)化合物： 其中R係如前定義，其經鹼或酸水解或經二元還原劑/酸系統得到式(VI)化合物或其鹽酸鹽： 使其陸續與乙酸鈉與隨後的乙酸酐反應得到式(I)化合物，將其以固體形式分離。
  2. 如請求項1之合成式(I)化合物之方法，其中，該離去基團選自鹵素、甲苯磺酸酯或三氟甲磺酸酯基團。
  3. 如請求項1之合成式(I)化合物之方法，其特徵在於該式(III)化合物為N-乙烯基酞醯亞胺。
  4. 如請求項1之合成式(I)化合物之方法，其特徵在於該式(III)化合物為丙烯醯胺。
  5. 如請求項1之合成式(I)化合物之方法，其特徵在於得到式(IV)化合物之式(III)化合物的縮合反應係利用四(三苯基膦)鈀進行。
  6. 一種如請求項1之式(IV)化合物，其係在阿戈美拉汀之合成中使用作為中間體。
  7. 一種如請求項6之式(IV)化合物用於合成阿戈美拉汀之用 途。
  8. 一種如請求項1之式(II)化合物用於合成阿戈美拉汀之用途。
  9. 一種如請求項1之式(V)化合物用於合成阿戈美拉汀之用途。
  10. 一種自式(IV)化合物開始合成如請求項1之式(I)化合物之方法，其特徵在於該式(IV)化合物係藉由如請求項1至5中任一項之合成方法獲得。
  11. 一種自式(V)化合物開始合成如請求項1之式(I)化合物之方法，其特徵在於該式(V)化合物係藉由如請求項1至5中任一項之合成方法獲得。
  12. 一種自式(VI)化合物開始合成如請求項1之式(I)化合物之方法，其特徵在於該式(VI)化合物係藉由如請求項1至5中任一項之合成方法獲得。
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