TWI540121B - 曲前列環素二乙醇胺之合成方法及新穎中間體 - Google Patents
曲前列環素二乙醇胺之合成方法及新穎中間體 Download PDFInfo
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Description
本發明係關於一種曲前列環素二乙醇胺之合成方法,亦有關一種可供製備曲前列環素二乙醇胺之一種新穎中間體。
曲前列環素(Treprostinil)或其衍生物有助於促進血管舒張、抑制血小板聚集及血栓形成、刺激血栓溶解、抑制細胞增殖、提供細胞保護作用、預防動脈粥樣硬化形成及誘導血管生成等作用,因此,曲前列環素可應用於治療多種疾病的藥物。然而,目前曲前列環素之合成方法通常繁複且耗時,且需考量所製備之曲前列環素之光學純度。
因此,目前亟需一種新穎的曲前列環素二乙醇胺之合成方法,以減少合成步驟,並提高所獲得之曲前列
環素二乙醇胺之光學純度。
本發明之一目的係在提供一種可供製備曲前列環素二乙醇胺新穎中間體,該中間體係如下式(II)所示:
其中,R1及R2係各自獨立為C1-6烷基。
於本發明之一實施態樣中,於上述之式(II)所示之化合物中,R1可為甲基。
於本發明之一實施態樣中,於上述之式(II)所示之化合物中,R2可為甲基。
根據本發明之一實施態樣,上述式(II)所示之化合物之合成方法可包括以下步驟:(i)提供一如下所示之5-烷氧基-2-四氫萘酮(5-alkoxy-2-tetralone):(5-alkoxy-2-tetralone);其中,R2可為C1-6烷基,並使得該5-烷氧基-2-四氫萘酮經烷氧羰基反應生成如以下式(I)所示之化合物:
;以及(ii)將式(I)所示之化合物行烷基化反應,以生成如式(II)所示之化合物。
本發明所揭露如式(II)所示之該新穎中間體主要係於製備式(IV)所示之化合物合成步驟中,所產生之中間體。
因此,本發明之另一目的係在於提供如式(IV)所示之化合物之合成方法:
該方法包括以下步驟:
(1)將式(II)所示之化合物轉化生成式(IV)所示之化合物。
其中,R1及R2係各自獨立為C1-6烷基。
於本發明之一較佳實施態樣中,上述之步驟(1)可包括:
(1-1)將式(II)所示之化合物進行去甲氧羰基反應,以生成式(III)所示之化合物;以及
(1-2)將式(III)所示之化合物進行內酯化反應以生成式(IV)所示之化合物;其中,R2係C1-6烷基,較佳為甲基。
藉由上述所提供之新穎中間體,以及藉由該新穎中間體所製備之式(IV)所示之化合物,可進一步用於下文所述之製備曲前列環素之合成方法中。
本發明之又一目的係在於提供一種曲前列環素二乙醇胺之合成方法,該曲前列環素二乙醇胺係如式(XII)所示,其合成方法包括以下(A)至(J)步驟:
該合成方法可包括以下步驟:
步驟(A):將式(IV)所示之化合物:
與進行合環反應,以生成式(V)所示之化合物:
其中,R2係C1-6烷基,R3係一保護羥基之保護基;
步驟(B):將式(V)所示之化合物進行氫化反應,以生成式(VI)所示之化合物:
步驟(C):將式(VI)所示之化合物進行還原反應,以生成式(VII)所示之化合物:
步驟(D):將式(VII)所示之化合物進行去保護反應,以生成式(VIII)所示之化合物:
步驟(E):於脂肪酶的存在下,將式(VIII)所示之化合物進行立體選擇性乙醯化反應,以獲得式(VIII-1)所示之化合物:
步驟(F):將式(VIII-1)所示之化合物進行去乙醯化反應,以生成式(VIII’)所示之化合物:
步驟(G):將式(VIII’)所示之化合物進行去烷基反應,以生成式(IX)所示之化合物:
步驟(H):利用將式(IX)所示之化合物進行烷基化反應,以生成式(X)所示之化合物:
其中,R4係C1-5之烷基;
步驟(I):將式(X)所示之化合物進行水解反應,以生成式(XI)所示之曲前列環素;
以及,步驟(J):將乙二醇胺與式(XI)所示之化合物行鹽化反應,以生成如式(XII)所示之曲前列環素二乙醇胺。
於本發明之一較佳實施態樣中,R2及R4係分別為甲基。
另外,於本發明之一實施態樣中,步驟(A)中,保護羥基之保護基團(R3)可為本發明領域中習知之羥基保護基,並無特別的限制,然而較佳可為選自由甲基、乙基、第三丁基、乙醯基、特戊醯基(Piv)、苯甲基(Bn)、對甲氧基苯甲基(PMB)、9-茀基甲基(Fm)、二苯基甲基(DPM)、三
甲基矽烷基(TMS)、叔丁基二甲基矽基(TBDMS)、三異丙基矽基(TIPS)、2-甲氧基乙基甲基醚(MEM)、甲硫甲基醚(MTM)、甲氧甲基醚(MOM)、及四氫吡喃(THP)所組成之群組。此外,根據步驟(A)中所使用之羥基保護基團之種類,於步驟(D)之去保護反應需搭配不同種類之保護基團而進行。舉例而言,當使用四氫吡喃(THP)作為羥基之保護基團時,其去保護反應可利用溶於甲醇中之對甲苯磺酸(p-Toluenesulfonic acid)以進行反應,使得保護基團脫去。
再者,步驟(E)係於脂肪酶(lipase)的存在下,將式(VIII)所示之化合物進行立體選擇性乙醯化反應後,經分離以及去保護後收集式(VIII’)所示之化合物後,可進一步地利用再結晶的方法提高該中間體之純度。再結晶所使用之溶劑係本領域之習知常識,可由本領域之技術人員而選擇使用,並無特別的限制。舉例而言,在此所使用之再結晶溶劑可為含氯溶劑,如二氯甲烷、三氯甲烷、或四氯化碳等;醇類,如甲醇、乙醇、異丙醇、或正丙醇等;酮類,如丙酮、丁酮、甲基異丁基酮、或苯乙酮等;酯類,如乙酸乙酯、乙酸甲酯、乙酸異丙酯、或乙酸叔丁酯;醚類,如四氫呋喃、乙醚、或甲基第三丁基醚;或者可為乙腈、C5-8烷烴等。
另外,於本發明之一實施態樣中,於步驟(H)中之R4係甲基。
本發明之又一目的係在於提供另一種可供製備曲前列環素二乙醇胺新穎中間體,該中間體係由式(VIII-1)所示:
其中,R2係C1-6烷基。且於本發明之一較佳實施態樣中,R2較佳為甲基。
於本發明中所揭露之每一反應步驟中,所使用之反應試劑、反應條件、以及反應參數等皆可為本領域之技術人員,依習知技術而得知。而以下實施例係本發明一實施態樣之具體描述,然不受限於此,可為本發明之技術人員改良及變更。
本發明所提供之曲前列環素二乙醇胺之合成方法,可有效改善目前習知製程冗長的步驟,且於製程中,藉由立體選擇性乙醯化反應,提高該中間體之純度,進而提供具有高光學純度之曲前列環素二乙醇胺。
圖1係實施例11所製備之化合物9之X-射線繞射分析之圖譜。
以下實施例1-4係製備式(IV)所示之化合物之詳細方法,該方法如流程圖1所示。且於本實施例中,R2為甲基。
然而,以下之流程圖1所示之反應流程僅為本發明之實施態樣之一,其每一反應步驟所使用之反應參數以及試劑皆可為本領域之技術人員替換及改良,只要可達成相同的反應結果即可。
[實施例1]-化合物1之製備-甲氧羰基反應(i)
將500克之5-甲氧基-2-四氫萘酮(5-methoxy-2-tetralone)溶於3.75公升之碳酸二甲酯(dimethyl
carbonate),於15℃下加入633毫升之30%甲醇鈉(CH3ONa)甲醇溶液,接著加熱至70℃反應1小時,待反應冷卻至室溫後,加入1.2公升3N之鹽酸水溶液終止反應,分離有機層,水層用1公升之乙酸乙酯(ethyl acetate)萃取,合併的有機層係經減壓濃縮。得到的粗產物利用3.29公升之正己烷萃取並過濾、濃縮乾燥得531克之黃色固體化合物1。
[實施例2]-化合物2之製備-烷基化反應(ii)
將143毫升的二異丙胺(diisopropylamine)溶於1公升的四氫呋喃(THF)中,於-60℃下滴加入272毫升1.6M的正丁基鋰(n-butyl lithium)正己烷溶液,且於-60℃反應15分鐘,然後再滴加入92克的化合物1溶於600毫升四氫呋喃(THF)的溶液中,於-60℃下反應1小時。接著,於5℃下加入68克之溴乙酸鋰(lithium bromoacetate)以及29克之四丁基碘化銨(tetrabutylammonium iodide,TBAI),並於室溫下反應22小時。接著,於5℃下加入1.5公升2N之鹽酸水溶液終止反應,有機層分離後,利用1.5公升2N之鹽酸水溶液洗滌有機層兩次,減壓濃縮後得到110克之灰白色固體化合物2。其中,該化合物2係本發明所揭示之
新穎中間體之一較佳實施態樣。1H NMR(CDCl3,400MHz)δ 7.33-7.31(d,J=8.0Hz,1H),7.18-7.14(t,J=8.0Hz,1H),6.73-6.71(d,J=8.0Hz,1H),3.91(s,3H),3.82(s,3H),3.10-3.07(m,2H),2.79-2.75(m,1H),2.75-2.70(m,1H),2.47-2.41(m,1H);13C NMR(CDCl3,100MHz)δ 178.9,176.7,173.3,156.8,132.7,127.5,120.4,119.4,108.7,100.5,56.3,52.6,36.0,34.5,25.8.
[實施例3]-化合物3之製備-去甲氧羰基反應(1-1)
將340克之化合物2及54克之氯化鋰(lithium chloride,LiCl)溶解於二甲基乙醯胺(DMAc)/水中(1.7公升/68毫升),加熱至100℃反應2小時後回到室溫。加入1.5公升之飽和食鹽水、以及1公升之乙酸乙酯進行分層(partition),使用4.5公升之飽和食鹽水洗滌有機層後,減壓濃縮得到225克之橘黃色固體化合物3。
[實施例4]-化合物4之製備-內酯化反應(1-2)
將225克之化合物3溶解於2.25公升之二氯甲烷(DCM),於5℃下加入335毫升之三乙胺(triethylamine,TEA)與90毫升之乙酸酐(acetic anhydride,Ac2O),並於室溫下反應1小時。加入2公升之飽和食鹽水(brine)進行分層(partition),有機層用1公升之鹽酸水溶液洗滌後減壓濃縮得到殘餘物,利用矽膠管柱純化與二氯甲烷和正己烷(1:1)作為沖提液,快速沖提將溶劑移除後得到的固體,利用乙酸乙酯與正己烷(1公升/2公升)再結晶得到173克白色固體化合物4。1H NMR(CDCl3,400MHz)δ 7.19~7.15(m,1H),6.76-6.73(m,2H),6.10(d,J=5.6Hz,1H),3.84(s,3H),3.61(dd,J=7.2Hz,5.6Hz,1H),3.23-3.11(m,1H),2.95(dd,J=17.6Hz,9.6Hz,1H),2.49(dd,J=17.6Hz,10.4Hz,1H),2.36(t,J=15.6Hz,1H),1.58(s,2H);13C NMR(CDCl3,100MHz)δ□174.1,156.2,154.8,134.9,127.7,119.5,119.4,109.0,101.1,55.4,34.7,33.1,27.2.
以下實施例5-14係製備化合物12(式(XII)所示之化合物)所示之化合物之詳細方法,該方法如流程圖2所示。
然而,以下之流程圖2所示之反應流程僅為本發明之實施態樣之一,其每一反應步驟所使用之反應參數以及試劑皆可為本領域之技術人員替換及改良,只要可達成相同的反應結果即可。
[實施例5]-化合物Mix-5之製備-合環反應(a)
將99克的膦酸酯(dimethyl-(4S)-4-(tetrahydro-2H-pyran-2-yloxy)nonylphosphon
ate)溶於1.92公升的四氫呋喃(THF)中,於-60℃下滴加入367毫升溶於正己烷中之1.6M的正丁基鋰(BuLi)溶液,並於-60℃反應1小時,然後再滴加入溶於640毫升四氫呋喃(THF)的64克之化合物4溶液,於-60℃反應1小時。接著升溫至-40℃,反應1小時後加入22毫升冰醋酸(AcOH)反應30分鐘,反應加熱至55℃反應2.5小時。反應降溫至5℃,加入2公升之飽和食鹽水與7毫升12N鹽酸水溶液稀釋,再加入2公升之乙酸乙酯萃取。利用2公升飽和食鹽水洗滌有機層後減壓濃縮抽乾。殘餘物利用矽膠管柱純化以乙酸乙酯和正己烷(1:9)為沖提液,純化後將溶劑移除得到45克之淡黃色液體化合物Mix-5。
[實施例6]-化合物Mix-6之製備-氫化反應(b)
將45克之化合物Mix-5、1.0克之碳酸鉀(potassium carbonate)和5.6克之10%鈀碳催化劑(10% palladium on carbon,Pd/C)溶於360毫升乙醇(EtOH),氫氣下加壓至50psi,並於室溫下反應7小時。接著,利用矽藻土(Celite)過濾,濾液濃縮抽乾利用矽膠管柱純化,以乙酸乙酯和正己烷(1:19)為沖提液,純化後將溶劑移除得到40克無色液體化合物Mix-6。
[實施例7]-化合物Mix-7之製備-還原反應(c)
將30克之化合物Mix-6溶於600毫升之乙醇中,於-10℃下滴加氫氧化鈉(NaOH)水溶液(28g氫氧化鈉溶於140毫升水),反應攪拌30分鐘。接著,於-10℃下加入2.7克硼氫化鈉(NaBH4)攪拌1小時,再加入2.7克之硼氫化鈉(NaBH4)攪拌2小時。之後加入冰醋酸終止反應,減壓濃縮除去溶劑,殘留物溶於52毫升之乙酸乙酯利用碳酸氫鈉水溶液與飽和食鹽水洗滌有機層,減壓濃縮後得到31克之無色液體之化合物Mix-7。
[實施例8]-化合物Mix-8之製備-去保護反應(d)
將64克之化合物Mix-7、以及1.3克之對甲苯磺酸(p-Toluenesulfonic acid,PTSA)溶於640毫升甲醇,於室溫下反應2小時。反應液濃縮後利用矽膠管柱純化,以乙酸乙酯和正己烷(3:7)為沖提液,純化後將溶劑移除得到40克無色液體化合物Mix-8。
[實施例9]-化合物8 OAc之製備-乙醯化反應(e)
將38克之化合物Mix-8、以及17克之脂解脢(Lipase AK“AMANO”)溶於750毫升正己烷與146毫升醋酸乙烯酯(vinyl acetate)中,於室溫下反應22小時。反應液過濾,減壓濃縮後利用矽膠管柱純化,以乙酸乙酯和正己烷(1:7)為沖提液,純化後將溶劑移除得到19克之無色液體化合物8 OAc。1H NMR(CDCl3,400MHz)δ 7.11(t,J=7.8Hz,1H),6.77(d,J=7.3Hz,1H),6.75(d,J=8.1Hz,1H),4.78-4.72(m,1H),3.81(s,3H),3.62-3.54(m,1H),2.81(dd,J=15.0,5.7Hz,1H),2.78(dd,J=15.4,6.3Hz,1H),2.50(dd,J=12.0,6.3Hz,1H),2.47(dd,J=12.7,6.1Hz,1H),2.35-2.25(m,2H),1.98(s,3H),1.98-1.89(m,1H),1.63-1.52(m,3H),1.52-1.25(m,10H),1.23-1.12(m,1H),0.89(t,J=6.9Hz,3H);13C NMR(CDCl3,100MHz)δ 171.2,156.7,140.2,126.4,120.7,126.8,108.5,79.1,72.3,55.7,49.2,40.7,37.9,37.6,33.7,35.1,33.6,32.1,28.5,25.8,25.5,22.8,21.5,14.3.
此反應係進行一立體選擇性之乙醯化反應,利用Lipase將Mix-8中特定位向的羥基(OH)進行選擇性保護(OAc),再藉由矽膠管柱純化,以得到高光學純度之中間體化合物8。
[實施例10]-化合物8之製備-去乙醯化反應(f)
將15克之化合物8OAc和4.4克之氫氧化鉀(KOH)溶於225毫升之甲醇與75毫升之水(MeOH/H2O)中,加熱至迴流反應5小時。減壓濃縮移除甲醇,並使用乙酸乙酯萃取水層,減壓濃縮該有機層以得到10克無色液體化合物8。
[實施例11]-化合物9之製備-去甲基化反應(g)
將37克的二苯基磷(diphenylphosphine)溶於245毫升的四氫呋喃(THF),於5℃下滴加入150毫升1.6M的正丁基鋰正己烷溶液攪拌1小時。於5℃將上述3/7之二苯基磷化鋰溶液加入含有11克化合物8的49毫升四氫呋喃的溶液中,加熱迴流2小時。反應液降溫至室溫後,將剩餘的4/7二苯基磷化鋰溶液加入,並加熱迴流17小時。待反應液降溫至5℃時,加入鹽酸水溶液終止反應,分離有機層後,水層用二氯甲烷萃取,合併的有機層減壓濃縮,利
用矽膠管柱純化,以甲醇和二氯甲烷(1:19)為沖提液,純化後將溶劑移除所得的產物,再利用乙酸乙酯與二氯甲烷進行再結晶得到8.3克白色固體化合物9。本實施例所製備之化合物9具有一晶型結構,其X-射線繞射分析之圖譜係如圖1所示。
[實施例12]-化合物10之製備-烷基化反應(h)
將1.0克之化合物9、0.58克之溴乙酸甲酯(methyl bromoacetate)、0.83克之碳酸鉀(potassium carbonate,K2CO3)溶解於15毫升之丙酮(Acetone)中,加熱迴流8小時。待反應降至室溫,反應液過濾移除碳酸鉀。濾液濃縮真空乾燥後得到1.4公克化合物10。
[實施例13]-化合物11(曲前列環素)之製備-水解反應(i)
將1.4克之化合物10、0.34克之氫氧化鉀(KOH)溶解於10毫升之甲醇與10毫升之水中,加熱迴流2小時,結束後回到室溫。加入5.5毫升之2N鹽酸水溶液攪拌2小
時,過濾後利用甲醇與水(5毫升/10毫升)洗滌固體。將固體真空乾燥後得到1.2公克之化合物11(曲前列環素)。。1H NMR(MeOD,400MHz)δ 7.04(t,J=7.9Hz,1H),6.79(d,J=7.3Hz,1H),6.70(d,J=8.2Hz,1H),4.62(s,2H),3.66-3.58(m,1H),3.56-3.49(m,1H),2.77(dd,J=14.7,6.2Hz,1H),2.73(dd,J=14.2,6.2Hz,1H),2.64(dd,J=14.7,6.0Hz,1H),2.50(dd,J=14.3,6.0Hz,1H),2.33-2.21(m,1H),2.12-2.04(m,1H),1.96-1.87(m,1H),1.76-1.66(m,1H),1.66-1.53(m,2H),1.53-1.26(m,9H),1.25-1.16(m,1H),1.15-1.06(m,1H),0.92(t,J=6.8Hz,3H);13C NMR(MeOD,100MHz)δ□173.1,156.7,142.3,128.9,127.3,122.6,111.0,77.8,73.1,66.7,52.6,42.5,42.2,38.4,36.2,34.7,34.2,33.3,29.8,26.8,26.6,23.9,14.6.
[實施例14]-化合物12(曲前列環素二乙醇胺)之製備-成鹽反應(j)
將1.1克的化合物11(曲前列環素)、0.35克的二乙醇胺(diethanolamine)溶解於4毫升的乙醇及28毫升的乙酸乙酯(EtOH/EA)加熱至70℃攪拌0.5h。降溫至55℃,加入0.01克的晶型B的曲前列環素二乙醇胺作為晶種攪拌1小時。再降溫至室溫攪拌16小時。過濾之後利用20毫升之乙酸乙酯洗滌固體。將固體真空乾燥後得到1.3公克的化合
物12(曲前列環素二乙醇胺)。1H NMR(MeOD,400MHz)δ 7.01(t,J=7.8Hz,1H),6.74(d,J=7.4Hz,1H),6.70(d,J=8.2Hz,1H),4.34(s,2H),3.78(t,J=5.3Hz,4H),3.66-3.58(m,1H),3.56-3.49(m,1H),3.11(t,J=5.2Hz,4H),2.83(dd,J=14.7,6.1Hz,1H),2.73(dd,J=14.2,6.1Hz,1H),2.62(dd,J=14.7,6.1Hz,1H),2.48(dd,J=14.1,6.1Hz,1H),2.31-2.22(m,1H),2.14-2.05(m,1H),1.94-1.84(m,1H),1.77-1.67(m,1H),1.67-1.52(m,2H),1.52-1.39(m,4H),1.39-1.26(m,5H),1.26-1.18(m,1H),1.18-1.07(m,1H),0.92(t,J=6.8Hz,3H);13C NMR(MeOD,100MHz)δ 177.2,157.2,141.9,128.6,127.0,121.7,111.1,77.7,72.9,69.3,57.9,52.8,50.4,42.4,42.1,38.3,36.1,34.8,34.2,33.1,29.7,26.8,26.4,23.7,14.4.
上述實施例僅係為了方便說明而舉例而已,本發明所主張之權利範圍自應以申請專利範圍所述為準,而非僅限於上述實施例。
Claims (12)
- 一種如下式(II)所示之化合物:
- 如申請專利範圍第1項所述之化合物,其中,R1係甲基。
- 如申請專利範圍第1項所述之化合物,其中,R2係甲基。
- 一種如下式(IV)所示之化合物之合成方法:
- 如申請專利範圍第4項所述之合成方法,其中,步驟(3)包括:將式(III)所示之化合物進行內酯化反應以生成式(IV)所示之化合物。
- 如申請專利範圍第5項所述之合成方法,其中,R2係甲基。
- 一種曲前列環素二乙醇胺之合成方法,該曲前列環素二乙醇胺係如式(XII)所示:
- 如申請專利範圍第7項所述之合成方法,其中,R2係甲基。
- 如申請專利範圍第7項所述之合成方法,於步驟(A)中,該羥基保護基係選自由甲基、乙基、第三丁基、乙醯基、特戊醯基(Piv)、苯甲基(Bn)、對甲氧基苯甲基(PMB)、9-茀基甲基(Fm)、二苯基甲基(DPM)、三甲基矽烷基(TMS)、叔丁基二甲基矽基(TBDMS)、三異丙基矽基(TIPS)、2-甲氧基乙基甲基醚(MEM)、甲硫甲基醚(MTM)、甲氧甲基醚(MOM)、及四氫吡喃(THP)所組成之群組。
- 如申請專利範圍第7項所述之合成方法,於步驟(H)中,R4係甲基。
- 一種如式(VIII-1)所示之化合物:
- 如申請專利範圍第11項所述之化合物,其中,R2係甲基。
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CN103880801B (zh) | 2012-12-20 | 2017-11-03 | 江苏盛迪医药有限公司 | 一种制备曲前列尼尔的中间体、其制备方法以及通过其制备曲前列尼尔的方法 |
JP6542128B2 (ja) * | 2013-01-11 | 2019-07-10 | コルセア ファーマ インコーポレイテッド | トレプロスチニルのプロドラッグ |
CN103709194B (zh) | 2014-01-06 | 2016-06-08 | 苏州鹏旭医药科技有限公司 | 光学活性的羟基保护的脂肪族磷酸酯的制备方法 |
CN104086374B (zh) | 2014-06-12 | 2016-01-20 | 天泽恩源(天津)制药有限公司 | 一种曲前列尼尔(Treprostinil)中间体的合成方法 |
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US20160152548A1 (en) | 2016-06-02 |
CN105801419A (zh) | 2016-07-27 |
TW201620864A (zh) | 2016-06-16 |
CN105801419B (zh) | 2018-03-20 |
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