TW201900616A - 經取代之n-芳基乙基-2-胺基喹啉-4-甲醯胺及其用途 - Google Patents
經取代之n-芳基乙基-2-胺基喹啉-4-甲醯胺及其用途 Download PDFInfo
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- TW201900616A TW201900616A TW107111781A TW107111781A TW201900616A TW 201900616 A TW201900616 A TW 201900616A TW 107111781 A TW107111781 A TW 107111781A TW 107111781 A TW107111781 A TW 107111781A TW 201900616 A TW201900616 A TW 201900616A
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Abstract
本案係關於新穎之經取代之N-芳基乙基-2-胺基喹啉-4-甲醯胺衍生物、其製法、其單獨或組合用於治療/及預防疾病之用途,及其製造用於治療/及預防疾病,特別是用於治療及/或預防纖維變性與發炎性疾病之藥物的用途
Description
本申請案係有關一種新穎之經取代之N-芳基乙基-2-胺基喹啉-4-甲醯胺衍生物、其製備方法、其於單獨或組合用於治療及/或預防疾病上之用途、及其於製造供治療及/或預防疾病,尤指供治療及/或預防纖維化與發炎病變之醫藥上之用途。
前列腺素F2 α(PGF2α)為生物活性前列腺素家族之一部份,其等係花生四烯酸之衍生物。從膜磷脂受到A2磷脂酶作用而釋出花生四烯酸後,即被環氧合酶氧化成前列腺素H2(PGH2),其再被PGF合成酶轉化成PGF2 α。PGF2 α亦可由酵素方式形成,但比例比其他前腺素(如:PGE2或PGD2)少得多[Watanabe等人,J.Biol.Chem. 1985,260,7035-7041]。PGF2 α不會儲存,而是在合成後立即釋出,因此僅展現局部效力。PGF2 α為一種不穩定分子(t1/2<1分鐘),會在肺、肝與腎臟中透過酵素方式快速重組,形成無活性代謝物:15-酮基二氫-PGF2 α[Basu等人,Acta Chem.Scand. 1992,46,108-110]。在生理與病理生理條件下均可以在血漿中及後來的尿液中檢測到相當多量之15-酮基二氫-PGF2 α。
PGF2 α之生物效應係透過膜上之受體,PGF2 α受體或稱為FP受體之結合與活化。FP受體為其中一種G蛋白質-偶合受體,特徵在於七個跨膜功能域。如同人類FP受體,其亦可能選殖出小鼠與大鼠之FP受體[Abramovitz等人,J.Biol.Chem. 1994,269,2632-2636;Sugimoto等人,J.Biol.Chem. 1994,269,1356-1360;Kitanaka等人,Prostaglandins 1994,48,31-41]。人體中有兩種FP 受體之同型:FPA與FPB。FP受體為選擇性最低之前列腺素類受體,因為不僅PGF2 α,而且PGD2與PGE2均以奈莫耳濃度之親和力與其結合[Woodward等人,Pharmacol.Rev. 2011,63,471-538]。刺激FP受體主要造成磷脂酶C之依賴Gq之活作用,造成鈣釋出及蛋白質激酶C(PKC)依賴二醯基甘油之活化作用。細胞內鈣濃度升高造成肌球蛋白輕鏈激酶(MLCK)受調鈣素介導之刺激作用。如同與G蛋白質Gq之偶合,FP受體經由G12/G13亦會刺激Rho/Rho激酶訊號轉導級聯,並經由Gi偶合,亦會刺激Raf/MEK/MAP訊號轉導途徑[Woodward等人,Pharmacol.Rev. 2011,63,471-538]。
PGF2 α涉及調節許多種生理功能,例如:卵巢功能、胚胎發育、子宮內膜的變化、子宮收縮與黃體退化、及誘發收縮與分娩。PGF2 α亦在子宮內膜中之上皮細胞中合成,在其中刺激細胞增生[Woodward等人,Pharmacol.Rev. 2011,63,471-538]。此外,PGF2 α為平滑肌收縮、血管收縮、與支氣管收縮的強力刺激劑,並涉及急性與慢性發炎過程[Basu,Mol.Cells 2010,30,383-391]。因此已顯示可在罹患類風濕關節炎、乾癬性關節炎與骨關節炎之患者全身檢測到PGF2 α之穩定代謝物:15-酮基-二氫-PGF2 α。在腎臟中,PGF2 α涉及水吸收、尿鈉排泄及利尿。在眼睛中,PGF2 α調節眼內壓。PGF2 α亦在骨代謝作用中扮演重要角色:前列腺素刺激無機磷酸鹽依賴鈉轉運至成骨細胞中,促進成骨細胞釋出間白素-6與血管內皮生長因子(VEGF);此外,PGF2 α為成骨細胞之強力促細胞分裂劑與存活因子[Agas等人,J.Cell Physiol. 2013,228,25-29]。
PGF2 α/FP受體活性提高時,亦造成上調腫瘤生成性與血管生成性基因,如:COX-2[Sales等人,2007,Endocrinology 148:3635-44]、FGF-2與VEGF[Sales等人,2010 Am J Pathol 176:431],此表示FP受體藉由調節血管功能來刺激子宮內膜腫瘤生長。此外,FP受體涉及調節子宮內膜上皮細胞增生,並會影響其與細胞外基質之附著性及運動性。此等發現顯示PGF2 α/FP受體在子宮內膜腺癌瘤中扮演多功能角色[Yang等人,2013 J Recept Signal Transduct,33(1):14-27]。
寡突膠細胞之前體細胞(OPC)中FP受體之表現升高可能為寡突膠細胞與活性髓磷脂損傷之標記[Soldan等人,Neurology 2015,84]。罹患多發性硬化(MS)之 患者在驗屍之後,在組織中觀察到FP受體表現在MS斑周圍附近的OPC上。白腦質之對照檢體中則未發現FP受體表現。此表示FP受體在多發性硬化之病因學中扮演某種角色[Carlson等人,2015,Mult.Sclerosis.23(11)467-468]。腦傷害會造成前列腺素(特定言之促炎性PGF2 α)上調,並過度活化FP受體。例如:FP受體-缺陷小鼠中,經過FP拮抗劑AL-8810處理時,在腦動脈閉鎖後顯示顯著之神經保護效應[Kim等人,2012,Neurobiol Disease 48,58-65]。此外,其顯示PGF2 α-FP受體活化作用涉及各種不同心血功能障礙,如:心肌纖維化、心肌梗塞與高血壓[Zhang等人,Frontiers in Pharmacol. 2010,1,1-7;Ding等人,Int.J.Biochem.Cell.Biol., 2012,44,1031-1039;Ding等人,J.Mol.Med. ,2014, 6 ,629-640]。
因此,處於心血管高風險生活條件下的人體中,PGF2 α之主要代謝物:15-酮基-二氫-PGF2 α會升高[Helmersson-Karlquist等人,Eur Heart J 2015,36,238-243],例如:亦出現在吸菸者[Helmersson等人,2005 Atherosclerosis 181,201-207]、肥胖[Sinaiko等人,2005 Circulation 111,1985-1991]、第I型糖尿病[Basu等人,2005,28,1371-1375]與第II型糖尿病[Helmersson等人,2004,Circulation 109,1729-1734]。[Zhang等人,Frontiers in Pharmacol 2010,1:1-7]。亦顯示中國人亞群中之基因多形性造成FP基因之轉錄升高及血管收縮性升高[Xiao等人,2015,Arterioscler Thromb Vasc Biol.35:1687-1695]。
此外,PGF2 α受體(FP)涉及關節病變,調節骨塑型蛋白質(BMP)之訊號級聯並促進軟骨細胞分化[Kim等人,Biochim.Biophys.Acta, 2015,1853,500-512]。較安定之PGF2 α之類似物已發展用於發情期同步化並用於影響人類生殖功能,亦用於降低眼內壓,供治療青光眼[Basu,Mol.Cells 2010,30,383-391]。在後來的應用中,使用化學上更安定的PGF2 α類似物(例如:拉坦前列素(latanoprost))觀察到的副作用為刺激毛髮(例如:眼睫毛)生長。[Johnston等人,Am J Ophthalmol 1997,124-544-547]。FP受體之基因亦表現在人類頭皮毛囊中[Khidhir等人,J Invest Dermatol, 2009,Abstr 607]。此等發現表示FP受體涉及調節毛髮生長,可能亦涉及例如,如:多毛症之疾病。
FP受體在內臟疼痛(痛經)之病因學之訊號級聯中的角色亦已有良好說明。因此,痛經式疼痛與月經期間之PGF釋出率有最佳相關性(參見Powell等人, Prostaglandins 1985,29,273-290;Dawood與Khan-Dawood,Am.J.Obstet.Gynecol. 2007,196,35.e1-35.e5;Hsia等人,Endocrinology 2011,152,2090-2099)。迄今仍未曾說明FP受體訊號途徑與周邊介導之發炎疼痛之相關性。本文所提交之數據首次顯示此驚人的相關性。
在罹患特發性肺纖維化(IPF)之患者中,已顯示血漿中安定的PGF2 α代謝物15-酮基二氫-PGF2 α顯著提高,且15-酮基二氫-PGF2 α之含量與功能性參數(例如:用力肺活量(FVC)、肺中一氧化碳擴散距離(DLCO)與6-分鐘步行試驗)呈相關性。此外,已檢測血漿中升高的15-酮基二氫-PGF2 α與患者死亡率的關係[Aihara等人,PLoS One 2013,8,1-6]。依據此關係亦已顯示,受到天然矽石塵粉刺激的人類肺纖維母細胞導致人體因慢性吸入所發生矽肺病中,造成顯著上調PGF2 α合成[O'Reilly等人,Am.J.Physiol.Lung Cell.Mol.Physiol. 2005,288,L1010-L1016]。在博來黴素(bleomycin)誘發小鼠肺纖維化中,藉由擊弱而消除FP受體(FP -/-),造成肺纖維化比野生型小鼠顯著降低[Oga等人,Nat.Med. 2009,15,1426-1430]。在FP -/-小鼠中,投與博來黴素後,觀察到羥基脯胺酸含量顯著降低,及減少誘發肺組織中之促纖維化基因。此外,FP -/-小鼠之肺功能比野生型小鼠顯著改善。在人類肺纖維母細胞中,PGF2 α經由FP受體刺激增生及產生膠原蛋白。由於此過程與促纖維化介導因子TGFβ分別獨立,因此PGF2 α/FP受體訊號級聯在引發肺纖維化時構成獨立的途徑[Oga等人,Nat.Med. 2009,15,1426-1430]。此等發現顯示FP受體為用於治療IPF之醫療性目標蛋白質[Olman,Nat.Med. 2009,15,1360-1361]。涉及誘發纖維化損傷之PGF2 α亦已出現在小鼠心臟纖維母細胞[Ding等人,Int.J.Biochem.& Cell Biol. 2012 ,44,1031-1039]、硬皮病之動物模式[Kanno等人,Arthritis Rheum. 2013,65,492-502]及膝關節病患者之滑膜细胞[Bastiaansen等人,Arthritis Rheum. 2013,65,2070-2080]。
因此推斷FP受體在其病因及/或演進與發炎過程及/或增生及纖維增生組織及血管重塑有關之許多種疾病、傷害、及病理損傷中扮演重要角色。此等尤其指對肺、心血管系統或腎臟之病變及/或傷害,或該病變可能為血液病變、新生瘤疾病或另一種發炎病變。
本文應述及的肺發炎與纖維化病變及肺部傷害係特別指特發性肺纖維化、與 類風濕關節炎有關之間質性肺病變、肺高血壓、閉塞性細支氣管炎症候群(BOS)、慢性阻塞性肺疾病(COPD)、氣喘與囊性纖維化。其中涉及FP受體之心血管系統之病變與傷害為例如:心肌梗塞後及與心臟衰退有關之組織損傷。腎病變為例如:腎功能不全與腎衰竭。血液病變之實例之一為鎌狀細胞型貧血症。在新生瘤過程中之組織降解與重塑之實例為癌細胞入侵健康組織(形成轉移)及形成新血管(新血管生成)。其中FP受體扮演某種角色的其他發炎疾病為例如:關節病與多發性硬化。
肺部特發性纖維化或特發性肺纖維化(IPF)為一種漸進式肺病,若未治療,平均在確診後2.5至3.5年死亡。確診時的患者通常約60歲以上,男性頻率略高於女性。IPF之發病不知不覺,其特徵在於呼吸逐漸縮短及發癢乾咳。IPF為特發性間質性肺炎(IIP)群組中之一種,係一種不同性質群組之肺部病變,其特徵在於不同嚴重程度之纖維化與發炎,可採用臨床、顯影及精密組織標準來區分。在此群組中,特發性肺纖維化基於其頻率與高度的惡化而特別重要[Ley等人,Am.J.Respir.Crit.Care Med. 2011,183,431-440]。IPF可能偶然發生或遺傳發生。迄今仍未知其原因。然而,近年來已經有許多慢性傷害肺泡上皮細胞的疾病造成促纖維化細胞素/介導因子釋出,繼而提高纖維母細胞增生及增加形成膠原蛋白纖維,造成肺部塊狀纖維化及典型蜂巢結構[Strieter等人,Chest 2009,136,1364-1370]。纖維化的臨床後果為肺部組織彈性下降、降低肺瀰散量及發展出嚴重缺氧。在肺功能方面,相應地會觀察到用力肺活量(FVC)與肺瀰散量(DLCO)惡化。IPF之必然與預後的重要共病症為急性惡化及肺高血壓[von der Beck等人,Der Pneumologe 2013,10(2),105-111]。間質性肺病變之肺高血壓普及率為10-40%[Lettieri等人,Chest 2006,129,746-752;Behr等人,Eur.Respir.J. 2008,31,1357-1367]。目前除了肺部移殖外,仍無法治癒IPF。
類風濕關節炎(RA)為一種漸進式全身自體免疫病變,其特徵在於慢性侵蝕性滑液膜發炎。間質性肺病變(ILD)為RA最常見之一種關節外病徵[Wells等人,Nat Rev Rheumatol 2014,10,728-739]。約10%RA患者已在臨床上證實患有間質性肺病變(RA-ILD);另有三分之一在胸部CT掃瞄時出現無症狀性ILD。RA-ILD患者之死亡率比無ILD之RA患者高三倍,確診ILD後之平均預期 壽命僅2.6年[Olson等人,Am J Respir Crit Care Med 2011 183,372-378;Doyle等人,Chest 2014,145(3),454-463]。
肺部之發炎與自體免疫病變連同各種不同環境誘發因子(例如:吸菸、細粉塵、化學刺激物)及遺傳特性在RA-ILD之發展與演進中扮演重要角色[Catrina等人,Nat Rev Rheumatol 2014,10(11),645-653]。
肺高血壓(PH)為一種漸進式肺病,若未治療,平均在確診後2.8年內死亡。以慢性肺高血壓為例,其定義為平均肺動脈壓(mPAP)為靜止時>25mmHg或運動時>30mmHg(正常值<20mmHg)。肺高血壓之病理生理學特徵在於血管收縮及肺部血管重塑。慢性PH中,在主要非肌化肺血管上現新肌化,血管之脈管肌肉周圍已經增加肌化。此點導致肺循環閉塞,造成右邊心臟逐漸加壓,繼而減少右邊心臟輸出,最後造成右心衰竭[M.Humbert等人,J.Am.Coll.Cardiol. 2004,43,13S-24S]。特發性(或原發性)肺動脈高血壓(IPAH)為一種極罕見病變,而繼發性肺高血壓(非-PAH PH,NPAHPH)則極常見,認為後者係繼冠狀動脈心臟病與全身性高血壓之後第三類常見之心血管病變[Naeije:A.J.Peacock等人(編輯),Pulmonary Circulation.Diseases and their treatment,第3版,Hodder Arnold Publ.,2011,3]。自從2008年,肺高血壓即依據達納角分類標準(Dana Point classification),根據各病因分成各種不同亞群[D.Montana與G.Simonneau:A.J.Peacock等人(編輯),Pulmonary Circulation.Diseases and their treatment,第3版,Hodder Arnold Publ.,2011,197-206]。
儘管PH之醫療法已有進步,但這種嚴重病變仍然無法治癒。市面上可以取得的標準療法(例如:前列腺素類似物、內皮肽受體拮抗劑、磷酸二酯酶抑制劑)可以改善生活品質、運動耐性及患者的預後。此等為全身投藥的醫療原則,主要藉由調節血管張力產生血液動力學作用。此等醫藥的應用受到其副作用(其中有些為嚴重副作用)與/或複雜投藥型式的限制。可藉由特定單方療法改善或穩定患者臨床狀態的時間期受到限制(f例如:因為發展出耐受性)。最後,該療法要升級,而採用組合療法,其中必需同時投與許多醫藥。目前,此等標準療法僅核准用於治療肺動脈高血壓(PAH)。在續發型PH(如:PH-COPD)中,此等醫療原則(例如:昔多芬(sildenafil)、波生坦(bosentan))均因其無選擇性之血管舒張作用而在臨床試驗中失敗,造成患者動脈氧含量下降(不飽和)。 其中可能的原因為全身性投與無選擇性血管舒張劑時,在不同性質之肺病變中對肺部的換氣-血液灌流調適有不利的效應[I.Blanco等人,Am.J.Respir.Crit.Care Med. 2010,181,270-278;D.Stolz等人,Eur.Respir.J. 2008,32,619-628]。新穎之組合療法為治療肺高血壓之其中一種最可靠的療法選項。基於此關係,尋求治療PH的新藥理機轉則特別值得注意[Ghofrani等人,Herz 2005,30,296-302;E.B.Rosenzweig,Expert Opin.Emerging Drugs 2006,11,609-619;T.Ito等人,Curr.Med.Chem. 2007,14,719-733]。特定言之,此等可以組合市面上已有的醫療概念的新穎醫療法可能形成更有效治療法的基礎,因此更有利於患者。
本發明內容中,術語「肺高血壓」包括原發性與繼發性亞型(NPAHPH),其係依據達納角分類標準,分別根據其病因定義[D.Montana與G.Simonneau:A.J.Peacock等人(編輯),Pulmonary Circulation.Diseasesand their treatment,第3版,Hodder Arnold Publ.,2011,197-206;Hoeper等人,J.Am.Coll.Cardiol.,2009,54(1),Suppl.S,S85-S96]。特定言之,第1類包括肺動脈高血壓(PAH),其中特別包括特發型與家族型(分別為IPAH與FPAH)。此外,PAH亦包括新生兒的持續性肺高血壓及相關型肺動脈高血壓(APAH),其係與膠原變性、先天性全身性肺分流損傷、門脈高血壓、HIV感染、服用某些藥物與醫藥(例如:壓制食慾劑)有關,與具有顯著靜脈/毛細血管組份之病變有關(如:肺靜脈閉鎖病變與肺毛細血管瘤)、或與其他病變有關,如:甲狀腺病變、肝醣儲積疾病、高雪氏症(Gaucher disease)、遺傳性血管擴張症、血紅素病變、骨髓增生性病變與脾切除。達納角分類標準的第二類包括患有肇因性左邊心臟病變(如:心室、動脈或瓣膜病變)之PH患者。第3類包括與肺病變相關之肺高血壓型式,例如:與慢性阻塞性肺病(COPD)、間質性肺病(ILD)、肺纖維化(IPF)、及/或血氧不足(例如:睡眠呼吸中止症候群、肺泡通氣不足、慢性高山症、遺傳性畸形)有關。第4類包括罹患慢性血栓與/或栓塞病變之PH患者,例如:肺動脈近端與遠端血栓栓塞(CTEPH)或非血栓性栓塞(例如:因腫瘤病變、寄生蟲、外來物體所致)。較不常見的肺高血壓型式,如:罹患類肉瘤、組織球增生症X或淋巴管瘤病之患者則歸於第5類。
閉塞性細支氣管炎症候群(BOS)為一種在肺部移植後的慢性排斥反應。在肺 部移植後的頭5年內,受影響的患者佔所有患者約50-60%,且在頭9年影響超過90%患者[Estenne等人,Am.J.Respir.Crit.Care Med. 2003,166,440-444]。該疾病的原因尚未明瞭。儘管在治療移植患者上已有許多改進,但仍有許多BOS病例在最近幾年幾乎沒有變化。BOS為肺部移植之最重要長期併發症,被視為存活率仍顯著低於其他器官移植患者的主要原因。BOS為發炎事件,係與主要影響小呼吸道的肺部組織變化有關。較小呼吸道之上皮細胞與上皮下結構之傷害與發炎變化會因為上皮之無效再生及異常組織修復而造成過度纖維增生。支氣管有結疤及最後被破壞,亦在較小呼吸道與濾泡中有顆粒組織之凝塊,有時候亦涉及血管。其係依據肺部功能診斷。BOS中,相較於在手術後測定的兩個最佳數值平均值,FEV1有惡化。目前,無法治癒BOS。有些患者在強化免疫抑制作用下出現改善;沒有出現任何反應的患者則經歷持續惡化,將進行再度移植。
慢性阻塞性肺病(COPD)為一種緩慢演進的肺病,其特徵在於由肺氣腫與/或慢性支氣管炎引起的呼吸道阻塞。該疾病之第一個症狀通常在生命的第40年或第50年期間出現。以後幾年生命呼吸短促會經常惡化,有時候會咳嗽及膿痰,呼吸短促甚至氣短(呼吸困難)。COPD主要為吸菸者的疾病:在所有COPD病例中,吸菸肇因佔90%及在所有與COPD相關之死亡病例中佔80-90%。COPD為嚴重的醫學問題,為全世界第六大死因。45歲以上的人中,影響約4-6%。雖然呼吸道阻塞可能僅為部份且暫時,但COPD無法治癒。因此,治療目標在於改善生活品質、減輕症狀、防止急性惡化、及減緩肺功能逐漸損傷。目前的醫藥療法在過去二十或三十年來幾乎沒有改變,仍採用支氣管擴張劑來打開受阻的呼吸道,有時候使用皮質類固醇來控制肺部發炎[P.J.Barnes,N.Engl.J.Med. 2000,343,269-280]。由香菸或其他刺激物引起的慢性發炎即為驅使該疾病發展的原因。其基本機轉包括免疫細胞在肺部發炎反應期間釋出蛋白酶與各種不同細胞素,造成肺氣腫與支氣管重塑。
本發明之目的在於判別及提供新穎之物質,其係FP受體之強效且在化學與代謝上安定之非前列腺素類拮抗劑,因此特別適合治療與/或預防纖維化與發炎病變。
WO 95/32948-A1、WO 96/02509-A1、WO 97/19926-A1與WO 2000/031038-A1特別揭示2-芳基喹啉-4-甲醯胺為NK3或雙重NK2/NK3拮抗劑,適合治療肺與中樞神經系統的病變。WO 2016/004035揭示2-芳基喹啉-4-甲醯胺為TSH受體促效劑,可用於治療功能性病變與惡性甲狀腺損傷。WO 2000/064877主張喹啉-4-甲醯胺衍生物,其可用為NK3拮抗劑,供治療各種不同病變,特別指肺與中樞神經系統的病變。WO 2004/045614-A1特別說明喹啉甲醯胺為葡激酶配體,供治療糖尿病。WO 2006/094237-A2揭示喹啉衍生物作為長壽基因(sirtuin)調控劑,可用於治療各種不同病變。WO 2011/153553-A2主張各種不同雙環狀雜芳基化合物作為激酶抑制劑,特別治療新生瘤病變。EP 2 415 755-A1特別說明喹啉衍生物,適合治療與血纖維蛋白溶酶原活化劑抑制劑1(PAI-1)之活性有關之病變。WO 2013/074059-A2詳述各種不同喹啉-4-甲醯胺衍生物,其可作為胞嘧啶脫胺酶之抑制劑,加強細胞之DNA轉染。WO 2013/164326-A1揭示N,3-二苯基萘-1-甲醯胺作為EP2前列腺素受體之促效劑,供治療呼吸道病變。WO 2014/117090-A1說明各種不同2-芳基喹啉衍生物,作為金屬酶之抑制劑。WO 2012/122370-A2揭示喹啉-4-甲醯胺衍生物,其可用於治療自體免疫與新生瘤病變。WO 2015/094912-A1特別揭示經取代之N,2-二苯基喹啉-4-甲醯胺衍生物,其適用為前列腺素EP4受體之拮抗劑,供治療關節炎及相關之疼痛病狀。WO 2016/061280揭示具有4-胺基-2-芳基喹啉基本結構之蛋白質酪胺酸磷酸酶調控劑,其可特別用於治療代謝病變、糖尿病與心血管病變。
本發明係有關一種通式(I)化合物
其中Ar 為苯基或為吡啶基,其中苯基可經至多四取代,及吡啶基可經至多二取代,其分別經下列相同或相異基團取代:氟、氯、經氟至多三取代之(C1-C4)-烷基、經氟至多四取代之(C3-C4)-環烷基、經氟至多三取代之(C1-C2)-烷氧基、或經氟至多三取代之(C1-C2)-烷基硫基,或其中苯基或吡啶基中兩個取代基若鍵結在相鄰環原子上時,可視需要彼此鍵結而共同形成亞甲基二氧或伸乙基二氧基團,或其中苯基可經氟至多五取代,Y 為一個鍵結或下式基團#1-X-(CR10AR10B)k-#2
其中#1 為碳原子之附接位點,#2 為羧基之附接位點,X 為一個鍵結、-CH2-、-O-、-S(=O)m-或-N(R11)-,其中m 為0、1或2,及R11 為氫或甲基,R10A與R10B 分別獨立為氫、氟或甲基,或R10A與R10B與其等所鍵結之碳原子共同形成環丙基,k 為1、2、3或4,R1 為鹵素、經氟至多五取代之(C1-C4)-烷基、經氟至多三取代之甲氧基、(三氟甲基)硫基、五氟硫基、三甲基矽烷基、乙炔基、環丙基或環丁基,其中環丙基與環丁基可經氟至多四取代,R2、R3與R4 分別獨立為氫、鹵素或經氟至多三取代之甲基,R5 為鹵素、經氟至多五取代之(C1-C4)-烷基、經氟至多三取代之甲氧基、羥基、甲基硫基、(三氟甲基)硫基、氰基、乙烯基、環丙基或環丁基,其中環丙基與環丁基可經氟至多四取代, R6 為-NR12R13
其中R12 為氫或(C1-C3)-烷基,及R13 為(C1-C4)-烷基或(C3-C7)-環烷基,其中(C3-C7)-環烷基可經氟至多四取代,及(C1-C4)-烷基可經氟至多五取代,或經(C3-C6)-環烷基、甲氧基、三氟甲氧基或苯基單取代,其中苯基可經氟至多三取代,或為飽和或部份不飽和之4-至8-員單環狀或6-至10-員雙環狀雜環,其利用氮原子附接,而且可能再包含一個選自N、O、S、SO與SO2之相同或相異雜原子作為環組員,其中該4-至8-員單環狀與6-至10-員雙環狀雜環分別可經1至3個獨立選自下列群中之取代基取代:(C1-C4)-烷基、羥基、側氧基、(C1-C3)-烷氧基、二氟甲氧基、三氟甲氧基、氰基、胺基、單甲基胺基、二甲基胺基、胺基羰基、單甲基胺基羰基、二甲基胺基羰基,並可再經氟至多四取代,其中(C1-C4)-烷基可經氟至多五取代,或經羥基或甲氧基單取代,R7A與R7B 分別獨立為氫或甲基,或R7A與R7B與其等所鍵結之碳原子共同形成環丙基,R8 為氫、氟、甲基、三氟甲基、乙基或羥基,R9 為氫或甲基,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、及N-氧化物與鹽類之溶劑合物。
本發明化合物為式(I)化合物及其鹽類、溶劑合物、與鹽類之溶劑合物,若包括在式(I)且在下文中述及之化合物尚未呈其鹽類、溶劑合物、及鹽類之溶劑合物時,仍為包括在式(I)且係如下文所述及化學式之化合物與其鹽類、溶劑合物、及鹽類之溶劑合物,及包括在式(I)及如下文操作實施例所述及之化合物與其鹽類、溶劑合物、及鹽類之溶劑合物。
本發明化合物同樣為式(I)化合物與其鹽類、溶劑合物、及鹽類之溶劑合物之 N-氧化物。
本發明內容中,較佳鹽類為本發明化合物之生理上可接受之鹽類。亦包括本身不適合醫藥用途,但可用於例如:單離、純化或儲存之本發明化合物之鹽類。
本發明化合物之生理上可接受之鹽類特別包括衍生自習知鹼類之鹽類,例如:較佳為鹼金屬鹽類(例如:鈉與鉀鹽類)、鹼土金屬鹽類(例如:鈣與鎂鹽類)、鋅鹽、及衍生自氨或具有1至16個碳原子之有機胺類之銨鹽類,例如:較佳為乙基胺、二乙基胺、三乙基胺、DIPEA、單乙醇胺、二乙醇胺、三乙醇胺、二甲基胺基乙醇、二乙基胺基乙醇、參(羥基甲基)胺基甲烷、膽鹼(2-羥基-N,N,N-三甲基乙銨)、普魯卡因、二環己基胺、二苯甲基胺、N-甲基嗎啉、N-甲基哌啶、精胺酸、離胺酸、與1,2-伸乙基二胺。
此外,本發明化合物之生理上可接受之鹽類包括礦物酸、羧酸與磺酸之酸加成鹽類,例如:鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘二磺酸、甲酸、乙酸、三氟乙酸、丙酸、琥珀酸、富馬酸、馬來酸、乳酸、酒石酸、蘋果酸、檸檬酸、葡糖酸、苯甲酸、與雙羥萘酸(embonic acid)之鹽類。
本發明內容中,溶劑合物係指彼等由本發明化合物與溶劑分子配位形成之固態或液態複合物型式。水合物為與水配位之特定溶劑合物型式。本發明內容中之較佳溶劑合物為水合物。
本發明化合物依據其結構可能出現不同立體異構物型式,亦即呈組態異構物,或若適當時,可呈構形異構物(對映異構物與/或非對映異構物,包括彼等阻轉異構物)。本發明因此包括對映異構物與非對映異構物、及其各混合物。可依已知方式,從此等對映異構物與/或非對映異構物之混合物中單離出立體異構性上均一之組成份。為了此目的較佳係採用層析法,尤指於非對掌相或對掌相上進行之HPLC層析法。若以羧酸作為中間物或終產物時,亦可使用對掌性胺鹼,經由非對映異構性鹽分離。
本發明內容中,咸了解術語「純對映異構性」係指該相關化合物依據其對掌中心之絕對組態之含量係對映異構性超量超過95%,較佳係超過98%。此時, 對映異構性超量「ee」係於HPLC分析層析法中,於對掌相上,採用下列公式計算:
若本發明化合物出現互變異構型時,則本發明包括所有互變異構型。
本發明亦包括根據本發明化合物之所有合適同位素變體。咸了解,根據本發明化合物之同位素變體係指根據本發明化合物其中至少一個原子被具有與天然界中常見或主要出現的原子具有相同原子數但不同原子質量的另一個原子置換的化合物。可納入根據本發明化合物中之同位素實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴、與碘之同位素,如:2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I與131I。根據本發明化合物之特定同位素變異體,如,尤指彼等其中已納入一個或多個放射性同位素者可能比較有利於例如:用於探討作用機轉或體內之活性成份分佈;基於相當容易之製法及可檢測度,尤以標記3H或14C同位素之化合物適合本目的。
此外,納入例如:氘之同位素可能得到提高化合物代謝安定性之特別醫療效益,例如:延長其在體內之半衰期或降低所需活性成份之劑量;因此根據本發明化合物之此等修飾法有時候亦可能構成本發明之較佳具體實施例。根據本發明化合物之同位素變異體可依熟悉此相關技藝之人士習知之方法製備,例如:下文說明之方法及操作實施例中說明之方法,在其中採用經過相應同位素修飾之特定試劑及/或起始化合物製備。
本發明另亦包括根據本發明化合物之前藥。「前藥」一詞係指其本身可能具有生物活性或沒有生物活性,但可於體內停留期間反應(例如:經過代謝或水解途徑)轉化成本發明化合物之化合物。
本發明包括之前藥特定言之為本發明式(I)羧酸之可水解之酯衍生物。咸了解,其等係指可於生理介質中,於下文說明之生物試驗條件下,特定言之於活體內,經過酵素或化學途徑水解成游離羧酸(係主要生物活性化合物)之酯類。這種較佳酯類為式(IV)之(C1-C4)-烷基,其中烷基可為直鏈或分支鏈。特別佳為甲酯、乙酯或第三丁酯。
本發明內容中,除非另有其他說明,否則取代基之定義如下:表述法「鹵素」或「鹵原子」係指例如:氟、氯、溴或碘原子。
表述法「C1-C4-烷基」係指具有1、2、3或4個碳原子之直鏈或分支之單不飽和單價烴基,例如:甲基、乙基、丙基、異丙基、丁基、第二丁基、異丁基或第三丁基或其異構物。
表述法「C3-C7-環烷基」係有關一種具有3、4、5、6或7個碳原子之飽和單價單環或雙環狀烴環(「C3-C7-環烷基」)。C3-C7-環烷基為例如:單環狀烴環,例如:環丙基、環丁基、環戊基、環己基或環庚基。
表述法「C1-C3-烷氧基」係指如式(C1-C3-烷基)-O-之直鏈或分支之飽和單價基團,其中表述法「C1-C3-烷基」係如上述定義,例如:甲氧基、乙氧基、正丙氧基、或異丙氧基、或其異構物。
表述法「4-至8-員單環狀雜環」在本發明內容中代表共具有4至8個環原子且可能再包含一個選自N、O、S、SO與SO2之另一個環雜原子且可利用環氮原子鍵結之單環狀飽和或部份不飽和雜環。較佳係具有一個環氮原子且可視需要再包含一個選自N、O、與S之另一個環雜原子之5-至7-員雜環烷基。特別佳係具有一個環氮原子之5-、6-、或7-員雜環烷基。例如:可述及下列:氮雜環丁烷基、氧雜環丁烷基、硫雜環丁烷基、吡咯啶基、吡唑啶基、咪唑啶基、四氫呋喃基、硫雜環戊烷基、1,1-二氧離子基硫雜環戊烷基、1,2-唑啶基、1,3-唑啶基、1,3-噻唑啶基、哌啶基、哌基、四氫哌喃基、四氫硫哌喃基、1,3-二氧雜環己烷基、1,4-二氧雜環己烷基、1,2-氧氮雜環己烷基、嗎啉基、硫嗎啉基、1,1-二氧離子基硫嗎啉基、氮雜環庚烷基、1,4-二氮雜環庚烷基、1,4-氧氮雜環庚烷基、2,5-二氫-1H-吡咯-1-基、3,6-二氫吡啶-1(2H)-基與3,6-二氫-2H-1,2--2-基。較佳係氮雜環丁烷基、吡咯啶基、咪唑啶基、1,2-唑啶基、哌啶基、哌基、1,2-氧氮雜環己烷基、嗎啉基、硫嗎啉基、2,5-二氫-1H-吡咯-1-基、3,6-二氫吡啶-1(2H)-基與3,6-二氫-2H-1,2--2-基。特別佳為吡咯啶基、哌啶基與氮雜環庚烷基。
表述法「6-至10-員雙環狀雜環」在本發明內容中代表雙環狀飽和或部份不飽和雜環,其共具有6至10個環原子,且可能再包含另一個選自N、O、S、SO與SO2群中之環雜原子,且可利用環氮原子鍵結。較佳為具有一個環氮原 子且可視需要再包含另一個選自N、O與S群中之環雜原子之7-至10-員雜環烷基。雙環狀螺環雜環基在本發明內容中應包括在「雙環狀雜環」之定義內。較佳實例包括下列:氮雜雙環[3.1.1]庚-3-基、3-氮雜雙環[3.2.1]辛-3-基、3,4-二氫異喹啉-2(1H)-基、八氫-2H-異吲哚-2-基與5-氮雜螺[2.5]辛-5-基。
表述法「C1-C2-烷基硫基」係指如式(C1-C2-烷基)-S-之直鏈或分支之飽和單價基團,其中表述法「C1-C2-烷基」係如上述定義,例如:甲基硫基或乙基硫基。側氧基在本發明內容中係指利用雙鍵與碳原子鍵結之氧原子。
在本發明內容中,所有出現一次以上之基團之定義均分別獨立。當本發明化合物中之基團經取代時,該等基團可經單取代或多取代,除非另有明確說明。較佳係經一個取代基或經兩個相同或相異取代基取代。特別佳為經一個取代基取代。
在本發明內容中,較佳為式(I)化合物,其中Ar 為苯基,其中苯基可經氟至多四取代,或經以下相同或相異基團至多三取代:氟、氯、甲基、三氟甲基、二氟甲基、甲氧基、二氟甲氧基或三氟甲氧基,Y 為一個鍵結或下式基團#1-(CH2)n-#2
其中#1 為碳原子之附接位點,#2 為羧基之附接位點,n 為1、2或3,R1 為溴或乙炔基,R2、R3與R4 分別為氫,R5 為氯或甲基,及R6 為-NR12R13
其中R12 為氫或甲基,及R13 為(C1-C4)-烷基, 其中(C1-C4)-烷基可經氟至多三取代,或可經苯基單取代,或為飽和或部份不飽和之5-至7-員單環狀或7-至10-員雙環狀雜環,其係利用氮原子附接,且可能再包含另一個選自N、O與S之群中之相同或相異雜原子作為環組員。
其中5-至7-員單環狀與7-至10-員雙環狀雜環可分別經1或2個分別獨立選自下列之群中之取代基取代:甲基、二氟甲基、三氟甲基、乙基、2,2,2-三氟乙基、2,2-二氟乙基、異丙基,並可再經氟至多四取代,R7A、R7B、R8與R9 分別為氫,及其鹽類、溶劑合物與鹽類之溶劑合物。
在本發明內容中,特別佳為式(I)化合物,其中Ar 為苯基,其中苯基可經以下相同或相異基團至多三取代:氟、氯、甲基、三氟甲基、二氟甲氧基或三氟甲氧基,Y 為下式基團#1-CH2CH2-#2
其中#1 為碳原子之附接位點,#2 為羧基之附接位點,R1 為溴,R2、R3、R4 分別為氫,R5 為甲基,R6 為下式基團
其中 #3 為與其餘分子之附接位點,R14 為氟或甲基,R15 為氟、甲基或乙基,R7A、R7B、R8與R9 分別為氫,及其鹽類、溶劑合物與鹽類之溶劑合物。
本發明之特定具體實施例包括式(I)化合物,其中R1 為溴,及R2、R3與R4 分別為氫,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中R5 為甲基,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中R6 為下式基團
其中#3 為與其餘分子之附接位點,R14 為氟或甲基,R15 為氟、甲基或乙基,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中R6 為吡咯啶, 及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中Y 為下式基團#1-CH2-#2
其中#1 為碳原子之附接位點,#2 為羧基之附接位點,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中Y 為下式基團#1-CH2CH2-#2
其中#1 為碳原子之附接位點,#2 為羧基之附接位點,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中Ar 為苯基,其中苯基可經以下相同或相異基團至多三取代:氟、氯、甲基、三氟甲基、二氟甲氧基或三氟甲氧基,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中R1 為溴,R2、R3、R4 分別為氫,R5 為甲基,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之 溶劑合物。
本發明之另一項特定具體實施例包括式(I)化合物,其中R7A、R7B、R8與R9 分別為氫,及其N-氧化物、鹽類、溶劑合物、N-氧化物之鹽類、與N-氧化物或鹽類之溶劑合物。
基團之各組合或較佳組合中指明之個別基團定義係與各指明基團之各組合分別獨立,亦可依需要以其他組合之基團定義置換。
極特別佳為兩個或更多個上述較佳範圍之組合。
較佳、特別佳、與極特別佳指明之基團均適用於式(I)化合物及其對應之所有中間物。
本發明進一步提供一種製備本發明式(I)化合物之方法,其特徵在於由式(II)化合物
其中R1、R2、R3、R4、R5、R7A、R7B、R8、R9與Ar均如上述定義,及T 為酯保護基,尤指(C1-C4)-烷基,於第一步驟中
[A]與式(III)胺化合物反應R6-H (III)
其中R6具有如上述定義,及於第二步驟中
[B]由步驟[A]所得式(IV)化合物之酯基T在與胺化合物(III)反應後脫除
其中R1、R2、R3、R4、R5、R6、R7A、R7B、R8、R9與Ar均如上述定義,及T 為酯保護基,尤指(C1-C4)-烷基,及由所得式(I)化合物
其中R1、R2、R3、R4、R5、R6、R7A、R7B、R8、R9與Ar均如上述定義,可視需要分離成其對映異構物與/或非對映異構物與/或使用適當之(i)溶劑與/或(ii)鹼或酸類,轉化成其溶劑合物、鹽類與/或鹽類之溶劑合物。
步驟[A]:(II)+(III)→(IV)中之反應可經由親核性取代反應進行。
該親核性取代反應較佳係使用超量胺化合物,可視需要於鹼之存在下進行。合適鹼為常用之無機或有機鹼類。此等較佳包括鹼金屬氫氧化物,例如:氫氧化鋰、氫氧化鈉或氫氧化鉀,鹼金屬或鹼土金屬碳酸鹽如:碳酸鋰、碳酸鈉、碳酸鉀或碳酸銫,鹼金屬醇鹽如:第三丁醇鋰、第三丁醇鈉或第三丁醇鉀,鹼金屬氫化物如:氫化鈉或氫化鉀,或有機胺類如:N,N-二異丙基乙基胺(DIPEA)、1,5-重氮雙環[4.3.0]壬-5-烯(DBN)與1,8-重氮雙環[5.4.0]十一碳-7-烯(DBU)。較佳為使用N,N-二異丙基乙基胺(DIPEA)。該反應通常在30℃至+130℃,較佳在+90℃至+110℃之溫度範圍內進行。
製法步驟[A]之惰性溶劑為例如:醚類,如:乙醚、二烷、四氫呋喃、乙二醇二甲基醚或二乙二醇二甲基醚,醇類如:甲醇、乙醇、丙醇、丁醇、異丙醇、與第三丁醇,烴類如:苯、甲苯、二甲苯、己烷,環己烷或礦物油餾份,鹵烴類如:二氯甲烷、三氯甲烷、四氯甲烷、1,2-二氯乙烷、三氯乙烯或氯苯,或其他溶劑如:丙酮、乙酸乙酯、乙腈、吡啶、二甲亞碸、N,N-二甲基甲醯胺(DMF)、N,N'-二甲基伸丙基脲(DMPU)或N-甲基吡咯啶酮(NMP)。同樣可能使用上述溶劑之混合物。較佳為使用丁醇或N-甲基吡咯啶酮(NMP)。
製法步驟[B]:(IV)→(I)中之酯保護基T之脫除法係採用習知方法進行,其係於惰性溶劑中,使用酸或鹼處理該酯,先形成羧酸鹽後,接著使用酸處理,轉化成游離羧酸。以第三丁基酯為例,較佳係使用酸裂解酯。甲酯與乙酯較佳係使用鹼裂解。苯甲基酯亦可於合適觸媒(例如:活性碳載鈀)之存在下藉由氫化作用(氫解)裂解。矽烷基酯可利用酸或氟化物(例如:四丁基銨化氟)處理而裂解。
適合此等反應之惰性溶劑為水及常用於裂解酯之有機溶劑。其等特別包括醇類,如:甲醇、乙醇、正丙醇、異丙醇、正丁醇、或第三丁醇,酯類,如:乙醚、四氫呋喃、1,4-二烷或1,2-二甲氧基乙烷,或其他溶劑,如:二氯甲烷、乙腈、N,N-二甲基甲醯胺或二甲亞碸。同樣可以使用此等溶劑之混合物。以鹼性酯水解作用為例,較佳係使用水與四氫呋喃、1,4-二烷、甲醇與/或乙醇之混合物。若與三氟乙酸反應時,較佳係使用二氯甲烷,及若與鹽酸反應時,較佳係使用1,4-二烷,其分別在無水條件下進行。
適合水解反應之鹼類為常用之無機鹼類。此等特別包括鹼金屬或鹼土金屬氫氧化物,例如:氫氧化鋰、氫氧化鈉、氫氧化鉀或氫氧化鋇,或鹼金屬或鹼土金屬碳酸鹽,如:碳酸鈉、碳酸鉀或碳酸鈣。較佳為使用氫氧化鋰水溶液或氫氧化鈉水溶液。
適合酯水解之酸類通常為硫酸、氯化氫/鹽酸、溴化氫/氫溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲烷磺酸、或其混合物,可視需要添加水。較佳為使用鹽酸或三氟乙酸。
酯之裂解通常在-20℃至+100℃,較佳在0℃至+80℃之溫度範圍內進行。
式(I)化合物可採用習知之方法,由鹼或酸衍生,轉化成其相應鹽類。酸性鹽 類(酸加成鹽)可轉化成相應之酸加成鹽類,例如:藉由添加強酸(如:鹽酸或硫酸等礦物酸)至式(I)化合物中。較佳酸性鹽類為鹽酸之鹽類。較佳係使用含鹽酸之二烷溶液。該酸性鹽之製法亦可由強酸(如:鹽酸或硫酸等礦物酸)加至式(IV)之酯化合物中,先脫除酯基T,於原位(亦即未單離游離羧酸)直接形成所需之鹽。適合使用酸脫除之酯基T為第三丁基。
自習知鹼類衍生式(I)化合物之鹽類之製法可例如:添加鹼(如:鹼金屬與鹼土金屬氫氧化物溶液)至式(I)化合物中。較佳為使用氫氧化物水溶液(例如:氫氧化鈉溶液)。氫氧化物水溶液(例如:氫氧化鉀溶液)亦可由有機金屬化合物溶於有機溶劑(例如:第三丁醇鉀之THF溶液)中,與水或水溶液反應,於原位產生。該衍生自鹼之鹽類之製法亦可添加鹼(如:鹼金屬與鹼土金屬氫氧化物溶液)至式(IV)酯化合物中,先脫除酯基T,於原位(亦即未單離游離羧酸)直接形成所需之鹽。適合使用鹼脫除之酯基T為甲基與乙基。
式(II)化合物之製法可由式(V)羰基氯
其中R1、R2、R3、R4與R5均如上述定義,與式(VI)胺化合物反應
其中R7A、R7B、R8、R9與Ar均如上述定義,及T 為酯保護基,尤指(C1-C4)-烷基,且可視需要使用輔助鹼,產生本發明式(II)化合物
其中R1、R2、R3、R4、R5、R7A、R7B、R8、R9與Ar均如上述定義,及T 為酯保護基,尤指(C1-C4)-烷基。
反應(V)+(VI)→(II)較佳係在習知鹼之存在下進行,例如:碳酸鈉或碳酸鉀、碳酸氫鈉或碳酸氫鉀、三乙基胺、DIPEA、N-甲基嗎啉(NMM)、N-甲基哌啶(NMP)、吡啶、2,6-二甲基吡啶、4-N,N-二甲基胺基吡啶(DMAP)、1,8-重氮雙環[5.4.0]十一碳-7-烯(DBU)、1,5-重氮雙環[4.3.0]壬-5-烯(DBN)、甲醇鈉或甲醇鉀、乙醇鈉或乙醇鉀、第三丁醇鈉或第三丁醇鉀、氫化鈉或氫化鉀或碳酸氫鈉或碳酸氫鉀。較佳為使用DIPEA作為鹼。
根據所使用之方法,上述偶合反應之惰性溶劑為例如:醚類,如:乙醚、二異丙基醚、甲基第三丁基醚、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷或雙(2-甲氧基乙基)醚,烴類如:苯、甲苯、二甲苯、戊烷、己烷或環己烷,鹵化烴類,如:二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、三氯乙烯或氯苯,極性非質子性溶劑,如:丙酮、甲基乙基酮、乙酸乙酯、乙腈、丁腈、吡啶、二甲亞碸(DMSO)、N,N-二甲基甲醯胺(DMF)、N,N'-二甲基伸丙基脲(DMPU)或N-甲基吡咯啶酮(NMP),或醇類,如:甲醇、乙醇與異丙醇。亦可能使用此等溶劑之混合物。較佳為使用二氯甲烷。該偶合反應通常在0℃至+130℃,較佳在+20℃至+80℃之溫度範圍下進行。
合適之酯保護基T通常為習此相關技藝已知之所有保護基,例如:經適當取取代之甲基(如:甲基硫甲基(MTM)、四氫哌喃基(THP)、2-(三甲基矽烷基)乙氧甲基(SEM)、苯甲基氧甲基(BOM)、苯甲醯基與N-酞醯亞胺基甲基)、經適當2-取代之乙基(如:4-甲基苯基磺醯基乙基(TSE)、2,2,2-三氯乙基、2-(三甲 基矽烷基)乙基與2-(2′-吡啶基)乙基(PET))、烯丙基、苯甲基、經適當取代之苯甲基(如:二苯基甲基(DPM)、雙(鄰-硝基苯基)甲基、9-蒽基甲基、2,4,6-三甲基苯甲基、4-溴苯甲基、4-甲氧基苯甲基(PMB))、胡椒基、與經適當取代之矽烷基(如:三乙基矽烷基(TES)、第三丁基二甲基矽烷基(TBDMS)與二-第三丁基甲基矽烷基(DTBMS));根據本發明使用之酯保護基T特別指較佳之(C1-C4)-烷基。
式(V)化合物依據其各取代型態,可採用類似文獻中已知之方法製備(J.Med.Chem.2005,48(10),3564-3575),其係由式(VII)靛紅衍生物與酸酐(VIII)於醯化反應中反應,產生式(IX)化合物,後者再於重排反應中與氫氧化鈉溶液反應,產生式(X)羧酸。或者,式(VII)靛紅衍生物亦可與酸酐(VIII)直接反應,不需單離中間物(IX),直接轉化成式(X)羧酸。式(XI)醯基氯亦可由式(X)羧酸採用習此相關技藝者已知之方法製得,例如:與磷醯氯或亞硫醯氯反應(反應圖1)。
[R1、R2、R3、R4與R5係如上述說明;a)△T,例如:一夜;b)△T,例如:1-3h;c)NaOH,△T;d)POCl3或SOCl2,△T]。
式(VI)化合物依隨其各個取代型態,可例如:採用下列反應圖2至8及各實施例之實驗中說明之合成途徑,及類似文獻中已知合成途徑來製備:
[烷基=甲基、乙基;Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;n=0、1、2、3;a):當n=0:二碳酸二-第三丁基酯、LDA、-78℃;當n=1:溴乙酸第三丁基酯、LDA或LiHMDS、-78℃;當n=2:3-溴丙酸第三丁基酯、LDA或LiHMDS、-78℃;或丙烯酸第三丁基酯、碳酸鉀或氫化鈉;當n=3:4-溴丁酸第三丁基酯、LDA、-78℃;b):H2、阮來鎳(Raney nickel)或PtO2。LDA=二異丙基胺化鋰;LiHMDS=雙(三甲基矽烷基)胺化鋰]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;n=0、1、2、3;a):例如:KCN或TMSCN;b)DAST;c):H2、觸媒,例如:阮來鎳或PtO2。DAST=二乙基胺基硫三氟化物]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;a):硝基乙烷,鹼,例如:2-第三丁基-1,1,3,3-四甲基胍;b)鋅粉,鹽酸]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;a):LDA,-78℃;b)鋅;c)H2,阮來鎳;d)H2,PtO2.LDA=二異丙基胺化鋰]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;a):TMS-CN;b)H2,阮來鎳]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;a)例如:於DCM中;b)SnCl2;c)保護胺基官能基,例如:呈NH-Boc:二碳酸二-第三丁基酯,三乙基胺;d)mCPBA;e)脫除胺基官能基之保護,例如:HCl/二烷。Boc=第三丁基氧羰基;DCM=二氯甲烷]。
[Ar=經取代之苯基、經取代之吡啶基;T=酯保護基,例如:甲基、乙基、第三丁基;PG=保護基,例如:Boc;a)Rh2(OAc)4;b)脫除胺基官能基之保護,例如:HCl/二烷。Boc=第三丁基氧羰基]。
若適當時,根據本發明化合物亦可在早期中間物(II)、(IV)或(VIII)階段分離成相應之對映異構物與/或非對映異構物,然後再呈分離型式,依上述反應順序進一步反應。可能在此等分離法之前針對中間物(III-A)與(III-B)之胺官能基適當提供保護基,例如:Boc,然後在分離後再脫除保護基。分離中間物之立體異構物時,同樣較佳係採用非對掌性或對掌性分離相之層析法進行。
式(VII)、(VIII)、(XII)、(XIV)、(XVI)、(XVIII)、(XIX)、(XXI)、(XXIII)、(XXIV)、(XXVI)、(XVII)與(XXVIII)化合物同樣可自商品取得或如文獻中之說明,或其等可由其他自商品取得之化合物類似文獻中說明之方法,依簡單方式製備。詳細製程與進一步參考文獻可參見實驗章節、起始化合物與中間物製法章節中。
其他本發明式(I)化合物若適當時,亦可由來自其他式(I)化合物或依上述製程所得到其前體之各基團或取代基之官能基(尤指彼等如R1與R5所列者)經過轉形製得。此等轉形法係採用習此相關技藝者習知之方法進行,包括例如,如:親核性或親電子性取代反應、過渡金屬介導偶合反應、金屬有機物(例如:格林納化合物(Grignard compound)或鋰有機物(lithium organyl))之製備與加成反應、氧化與還原反應、氫化、鹵化(例如:氟化、溴化)、脫除鹵化、胺化、烷基化、與醯化、形成羧酸酯、甲醯胺與磺醯胺、酯之裂解與水解、及引進與脫除臨時保護基等反應。
本發明化合物具有有價值的醫藥性質,可用於治療及/或預防人類與動物之病變。
本發明化合物為FP受體之強效且在化學與代謝上安定之拮抗劑(「FP拮抗 劑」),因此適合治療與/或預防病變與病理過程,尤指彼等其中FP受體涉及發炎事件與/或組織或血管再造之過程。
在本發明內容中,此等尤其包括以下病變,如:間質性特發性肺炎族群,包括:特發性肺纖維化(IPF)、急性間質性肺炎、非特異性間質性肺炎、淋巴性間質性肺炎、呼吸性細支氣管炎間質性肺病、隱源性器質化肺炎、脫屑性間質性肺炎與未分類之特發性間質性肺炎、及肉芽腫間質性肺病、出現間質性肺病之類風濕關節炎、已知原因之間質性肺病與其他未知原因之間質性肺病、肺動脈高血壓(PAH)與其他型式之肺高血壓(PH)、閉塞性細支氣管炎症候群(BOS)、慢性阻塞性肺疾病(COPD)、肺類肉瘤、急性呼吸困難症候群(ARDS)、急性肺傷害(ALI)、α-1-抗胰蛋白酶缺陷(AATD)、肺氣腫(例如:因吸菸引起之肺氣腫)、囊性纖維化(CF)、腎臟發炎與纖維化病變、慢性間質性發炎(IBD,克隆氏症(Crohn's disease)、潰瘍性結腸炎)、腹膜炎、腹膜纖維化、類風濕病變、多發性硬化、發炎與纖維化皮膚病變、鎌狀細胞型貧血症、及發炎與纖維化眼睛病變。
本發明化合物亦可用於治療及/或預防具有間歇性或持續性特徵之不同嚴重性之氣喘性病變(頑抗型氣喘、支氣管性氣喘、過敏性氣喘、內因性氣喘、外因性氣喘、醫藥-或粉塵誘發之氣喘)、各種不同型式之支氣管炎(慢性支氣管炎、感染性支氣管炎、嗜酸粒細胞性支氣管炎)、支氣管擴張症、肺炎、農夫肺與相關疾病、咳嗽與著涼(慢性發炎咳嗽、醫原性咳嗽)、鼻黏膜發炎(包括藥物相關性鼻炎、血管運動性鼻炎與季節性過敏性鼻炎,例如:花粉熱)、及息肉。
本發明化合物亦可用於治療及/或預防心血管病變,例如:高血壓、心臟衰竭、冠狀動脈心臟病、穩定性與不穩定性心絞痛、腎臟高血壓、周邊與心血管病變、心律不整、心房與心室心律不整、及傳導障礙(例如:房室傳導第I-III級阻滯)、上心室心搏過速、心房顫動、心房撲動、心室顫動、心室撲動、心室心搏過速、尖端扭轉性室性心搏過速、心房與心室期前收縮、AV-交界區期前收縮、病竇症候群、昏厥、AV結折返性心動過速、沃爾夫-巴金森-懷特氏症候群(Wolff-Parkinson-White syndrome)、急性冠狀動脈症候(ACS)、自體免疫性心臟病(心包炎、心內膜炎、心瓣膜炎、大動脈炎、心 肌症)、拳擊手心肌病、動脈瘤、休克(如:心源性休克、敗血性休克與過敏性休克);亦供治療及/或預防血栓性栓塞病變與絕血,如:心肌絕血、心肌梗塞、中風、心臟肥大、短暫性與絕血發作、子癇前症、發炎性心血管病變、冠狀動脈與周邊動脈痙攣、水腫形成(如,例如:肺水腫、腦水腫、腎水腫或因心臟衰竭造成之水腫)、周邊循環紊亂、再灌流傷害、動脈與靜脈血栓形成、微量白蛋白尿、心肌功能不全、內皮功能障礙、微血管與大血管傷害(脈管炎);亦供預防術後再狹窄(例如:經過溶栓術療法、經皮血管腔內血管成形術(PTA)、經皮血管腔內冠狀動脈血管成形術(PTCA)、心臟移植與繞道手術後)。
本發明內容中,「心臟衰竭」一詞包括心臟衰竭之急性型與慢性型,及更專一性或相關之疾病型態,如:急性失代償性心臟衰竭、右心臟衰竭、左心臟衰竭、全部心臟衰竭、絕血性心肌病變、擴張型心肌病變、肥大型心肌病變、特發性心肌病變、糖尿病性心肌病變、先天性心臟缺陷、心臟瓣膜缺陷、與心臟瓣膜缺陷相關之心臟衰竭、二尖瓣狹窄、二尖瓣閉鎖不全、主動脈瓣狹窄、主動脈瓣閉鎖不全、三尖瓣狹窄、三尖瓣閉鎖不全、肺動脈瓣狹窄、肺動脈瓣閉鎖不全、綜合心臟瓣膜缺陷、心肌發炎(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心臟衰竭、酒精性心肌病變、心臟儲積病變、及舒張性心臟衰竭與收縮性心臟衰竭。
本發明化合物亦適合治療及/或預防腎病變,特定言之腎功能不全與腎衰竭。本發明內容中,術語「腎功能不全」與「腎衰竭」一詞包括其急性與慢性癥兆二者,及本身或相關腎疾病,如:腎灌流不足、透析中低血壓、阻塞性尿路疾病、腎絲球病變、腎絲球腎炎、急性腎絲球腎炎、腎絲球硬化症、腎小管間質腎炎疾病、腎病變疾病(如:原發性與先天性腎臟疾病)、腎炎、免疫性腎臟疾病(如:腎臟移植排斥與免疫複合症誘發之腎臟疾病)、由毒性物質誘發之腎病變、由顯影劑誘發之腎病變、糖尿病性與非糖尿病性腎病變、腎盂腎炎、腎囊腫、腎硬化、高血壓性腎硬化,及可採用診斷法判別特徵之腎病症候群,例如:異常降低之肌酸酐與/或水排泄、血中異常升高之尿素、氮、鉀與/或肌酸酐濃度、腎酵素(例如:麩胺醯基合成酶)活性改變、尿液滲透壓或尿液體積改變、微量白蛋白尿增加、巨量白蛋白尿、腎 絲球與小動脈損傷、細管擴張、高磷酸血症與/或需要洗腎。本發明亦涵括一種以本發明化合物於治療及/或預防腎功能不全後遺症上之用途,例如:高血壓、肺水腫、心臟衰竭、尿毒症、貧血、電解質異常(例如:高血鈣症、低血鈉症)及骨骼與碳水化合物代謝障礙。
此外,本發明化合物適合治療及/或預防泌尿系統病變,例如:良性攝護腺症候群(BPS)、良性攝護腺增生(BPH)、良性攝護腺肥大(BPE)、膀胱出口阻塞(BOO)、下泌尿道症候群(LUTS)、神經性膀胱過動症(OAB)、失禁(例如:混合型尿失禁、急迫性尿失禁、應力性尿失禁或溢流型尿失禁(MUI、UUI、SUI、OUI))、骨盆腔疼痛、及勃起功能障礙與女性性功能障礙。
本發明化合物亦可用於治療女性生殖系統病變,如:子宮肌瘤、子宮內膜異位症、經痛與提早收縮,及周邊介導之發炎疼痛(例如:症狀性子宮內膜異位)。此外,其等適合預防或治療多毛症或毛髮增多症。
此外,本發明化合物具有抗發炎作用,因此可用為消炎劑,供治療及/或預防敗血病(SIRS)、多發性器官衰竭(MODS、MOF)、腎臟發炎性病變、慢性腸部發炎(IBD、克隆氏症(Crohn's disease)、潰瘍性結腸炎)、胰臟炎、腹膜炎、膀胱炎、尿道炎、攝護腺炎、附睾炎、卵巢炎、輸卵管炎、外陰陰道炎、類風濕病變、骨關節炎、中樞神經系統的發炎性病變、多發性硬化、發炎性皮膚病變與發炎性眼睛病變。
根據本發明化合物亦適合治療及/或預防內部器官之纖維化病變,例如:肺、心臟、腎臟、骨髓及特定言之肝臟,及皮膚纖維化與眼睛之纖維化病變。本發明內容中,「纖維化病變」術語特定言之包括下列病變,如:肝纖維化、肝硬化、肺纖維化、心肌內膜纖維化、腎病變、腎絲球腎炎、腎間質性纖維化、因糖尿病造成之纖維化傷害、骨髓纖維化、腹膜纖維化與類似纖維化病變、硬皮症、硬斑病、蟹足腫、肥厚疤、痣、糖尿病性視網膜病變、增生性玻璃體視網膜病變、及結締組織病變(例如:類肉瘤病)。本發明化合物同樣亦適合促進傷口癒合,控制手術後結疤,例如:青光眼手術後,及用在老化及角質化皮膚之美容。
本發明化合物亦可用於治療及/或預防貧血,如:溶血性貧血,特定言之血紅素病變,如:鐮刀狀細胞貧血與地中海貧血、巨胚紅血球貧血、缺鐵性 貧血、因急性失血造成之貧血、骨髓浸潤性貧血與再生不良性貧血。
此外,本發明化合物適合治療癌症,例如:皮膚癌、腦腫瘤、乳癌、骨髓腫瘤、白血病、脂肪肉瘤、胃腸道、肝、胰、肺、腎、輸尿管、攝護腺與生殖道之癌瘤,及淋巴增生系統之惡性腫瘤,例如:霍奇金氏(Hodgkin’s)與非霍奇金氏淋巴瘤。
此外,本發明化合物可用於治療及/或預防動脈硬化、脂質代謝失常與血脂異常(低脂蛋白血症、高三酸甘油酯血症、高脂血症、混合型高脂血症、高膽固醇血症、無β脂蛋白血症、豆固醇血症)、黃瘤症、丹吉爾症(Tangier disease)、脂肪過多症、肥胖症、代謝病變(代謝症候群、高血糖症、胰島素-依賴性糖尿病、非胰島素-依賴性糖尿病、妊娠糖尿病、高胰島素血症、胰島素抗性、葡萄糖失耐症、與糖尿病後遺症,如:視網膜病變、腎病變與神經病變)、胃腸道與腹部病變(舌炎、牙齦炎、牙周病、食道炎、嗜伊紅性胃腸炎、肥大細胞增生症、克隆氏症(Crohn’s disease)、大腸炎、直腸炎、肛門瘙癢症、下痢、乳糜瀉、肝炎、肝纖維化、肝硬化、胰炎與膽囊炎)、中樞神經系統病變、與神經退化性病變(中風、阿茲海默症、帕金森氏症、失智、癲癇、抑鬱、多發性硬化)、免疫病變、甲狀腺病變(甲狀腺機能亢進)、皮膚病變(乾癬、痤瘡、濕疹、神經性皮膚炎、各種型式之皮膚炎,例如:皮膚炎(dermatitis abacribus)、光化性皮膚炎、過敏性皮膚炎、氨皮膚炎、人為性皮膚炎、自發性皮膚炎、異位性皮膚炎、熱激性皮膚炎、灼傷性皮膚炎、凍傷性皮膚炎、化妝品性皮膚炎、焦痂性皮膚炎、剝脫性皮膚炎、壞疽性皮膚炎、血鬱滯性皮膚炎、皰疹樣皮膚炎、地衣樣皮膚炎、線狀皮膚炎、惡性皮膚炎、藥物疹皮膚炎、乾性掌蹠皮膚炎、寄生蟲性皮膚炎、光敏性接觸皮膚炎、光毒性皮膚炎、膿皰性皮膚炎、脂溢性皮膚炎、日曬性皮膚炎、中毒性皮膚炎、梅勒尼氏潰瘍(Meleney's ulcer)、接觸性皮膚炎、感染性皮膚炎、膿性皮膚炎與酒渣鼻樣皮膚炎、以及角膜炎、大皰生成、脈管炎、蜂窩性組織炎、脂膜炎、紅斑性狼瘡、紅斑、淋巴瘤、皮膚癌、斯威特症候群(Sweet syndrome)、韋-克症候群(Weber-Christian syndrome)、瘢痕形成、疣形成、凍瘡)、炎性眼疾(類肉瘤病、瞼炎、結膜炎、虹膜炎、眼色素層炎、脈絡膜炎、眼炎)、病毒疾病(由流行性感冒病毒、腺病毒和冠 狀病毒引起、例如HPV、HCMV、HIV、SARS)、骨骼骨和骨關節及骨骼肌之病變(各種形式關節炎,例如:黑尿症性關節炎、強直性關節炎、痢疾性關節炎(arthritis dysenterica)、滲出性關節炎、黴菌性關節炎、淋菌性關節炎、殘毀性關節炎(arthritis mutilans)、乾癬性關節炎、化膿性關節炎、風濕性關節炎、漿液性關節炎、梅毒性關節炎、結核性關節炎、痛風性關節炎、色素性絨毛結節性關節炎、非典型關節炎、血友病性關節炎、幼年慢性關節炎、類風濕性關節炎和轉移性關節炎、及斯蒂爾症候群(Still syndrome)、費爾蒂症候群(Felty)症候群、修葛蘭症候群(Sjörgen syndrome)、克拉頓症候群(Clutton syndrome)、彭塞症候群(Poncet syndrome)、波特症候群(Pott syndrome)與賴特症候群(Reiter syndrome),各種形式關節病,例如:變形性關節病、神經病性關節病、絕經期關節病、乾癬性關節病、與癆性關節病、全身性硬化、多種形式的炎性肌病,例如:流行性肌病、纖維性肌病、肌紅蛋白尿肌病、骨化性肌病、骨化性神經機能肌病、多發性進行性骨化性肌病(myopathie ossificans progressiva multiplex)、化膿性肌病、風濕性肌病、旋毛蟲病肌病、熱帶肌病與傷寒肌病、及京特症候群(Günther syndrome)和明希邁爾症候群(Münchmeyer syndrome))、動脈的炎性變化(各種形式的動脈炎,例如:動脈內膜炎、動脈中層炎、動脈周炎、全身動脈炎、風濕性動脈炎、變形性動脈炎、顳動脈炎、頭側動脈炎、巨細胞性動脈炎(arteritis gigantocellularis)與肉芽腫性動脈炎(arteritis granulomatosa)、及霍頓症候群(Horton syndrome)、丘-斯症候群(Churg-Strauss syndrome)和高安動脈炎(Takayasu arteritis))、及穆-韋症候群(Muckle-Well syndrome)、菊池症(Kikuchi disease)、多軟骨炎、硬皮病及其他具有炎性或者免疫成分的病變,例如白內障、惡病質、骨質疏鬆症、痛風、失禁、麻風、凱撒里症候群(Sezary syndrome)、及腫瘤相關症候群、器官移植後的排斥反應事件、及傷口癒合與血管新生,特別是在慢性傷口情況下。
本發明化合物基於其生化及藥理性質型態,特別適合治療及/或預防間質性肺病,尤指特發性肺纖維化(IPF),及肺高血壓(PH)、閉塞性細支氣管炎症候群(BOS)、發炎與纖維化皮膚與眼睛病變、及內部器官之纖維化病變。
上述詳細說明特徵之人類疾病亦可能依類似病原學發生在其他哺乳動物, 且同樣可採用本發明化合物治療。
本發明內容中,術語「治療」或「處理」包括抑制、延遲、檢查、減輕、減弱、限制、降低、壓制、驅除或治癒疾病、病症、病變、損傷或健康問題、或此等狀態與/或此等狀態之症狀之發展、過程或演進。咸了解,術語「醫療」係術語「治療」之同義字。
在本發明內容中,術語「預防」、「防止」或「排除」係以同義字使用,並意指避免或降低感染、經歷、罹患或患有疾病、病症、病變、損傷或健康問題、或此等狀態與/或此等狀態之症狀之發展、過程或演進之風險。
可能部份或完全治療或預防疾病、病症、病變、損傷或健康問題。
本發明因此進一步提供以本發明化合物於治療及/或預防病變,尤指上述病變上之用途。
本發明進一步提供以本發明化合物於製造供治療及/或預防病變,尤指上述病變之醫藥上之用途。
本發明進一步提供一種包含至少一種本發明化合物之醫藥,供治療及/或預防病變,尤指上述病變。
本發明進一步提供以本發明化合物於治療及/或預防病變,尤指上述病變之方法上之用途。
本發明進一步提供治療及/或預防病變,尤指上述病變之方法,其係使用有效量之至少一種本發明化合物。
本發明化合物可以單獨使用,或若需要時,可與一種或多種其他醫藥活性物質組合使用,只要此組合不會產生不期望且不可接受之副作用即可。本發明因此進一步提供一種醫藥,其包含至少一種本發明化合物與一或多種其他藥物,尤指供治療及/或預防上述病變之藥物。適合此目的之較佳組合活性成份實例包括:●有機硝酸鹽與NO供體,例如:硝普鈉(sodium nitroprusside)、硝酸甘油(nitroglycerin)、單硝酸異山梨醇(isosorbide mononitrate)、二硝酸異山梨醇(isosorbide dinitrate)、嗎多明(molsidomine)或SIN-1,與吸入性NO;●抑制環狀鳥苷單磷酸(cGMP)及/或環狀腺苷單磷酸(cAMP)降解之化合物,例如:磷酸二酯酶(PDE)之抑制劑1、2、3、4與/或5,尤指PDE 5抑制 劑,如:昔多芬(sildenafil)、伐地那非(vardenafil)、他達拉非(tadalafil)、烏地那非(udenafil)、達生他非(dasantafil)、阿伐那菲(avanafil)、米羅那非(mirodenafil)或羅地那非(lodenafil);●不依賴NO與血色素之可溶性鳥苷酸環化酶(sGC)活化劑,如,特定言之WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462與WO02/070510中說明之化合物;●不依賴NO,但依賴血色素之可溶性鳥苷酸環化酶(sGC)刺激劑,如,特定言之利奥西呱(riociguat)及WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647與WO 2012/059549中說明之化合物;●前列環素類似物與IP受體促效劑,其較佳實例係伊洛前列素(iloprost)、貝前列素(beraprost)、曲前列素(treprostinil)、依前列醇(epoprostenol)或希樂普(selexipag);●內皮肽受體拮抗劑,其較佳實例係:波生坦(bosentan)、達盧生坦(darusentan)、安倍生坦(ambrisentan)或希塔生坦(sitaxsentan);●抑制人類嗜中性球彈性蛋白酶(HNE)之化合物,其較佳實例係:西維來斯他(sivelestat)或DX-890(利他(reltran));●可抑制訊號轉導級聯之化合物,其較佳實例係選自激酶抑制劑之群中,特定言之選自酪胺酸激酶與/或絲胺酸/蘇胺酸激酶抑制劑之群中,其較佳實例係:尼達尼布(nintedanib)、達沙替尼(dasatinib)、尼祿替尼(nilotinib)、波舒替尼(bosutinib)、瑞格拉非尼(regorafenib)、蕾莎瓦(sorafenib)、紓癌特(sunitinib)、西地尼布(cediranib)、阿西替尼(axitinib)、替拉替尼(telatinib)、伊馬替尼(imatinib)、布立尼布(brivanib)、帕唑帕尼(pazopanib)、瓦他拉尼(vatalanib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)、卡紐替尼(canertinib)、來他替尼(lestaurtinib)、培利替尼(pelitinib)、舒馬賽尼(semaxanib)或坦度替尼(tandutinib);●抑制細胞外基質降解與變化之化合物,其較佳實例係:基質金屬蛋白酶(MMP)抑制劑,尤指基質裂解素(stromelysin)、膠原酶、明膠酶與蛋白聚醣酶(其中特別指MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11 與MMP-13)與金屬彈性蛋白酶(MMP-12)之抑制劑;●阻斷血清素與其受體結合之化合物,其較佳實例係:5-HT2B受體之拮抗劑,如:PRX-08066;●生長因子、細胞素與化學激素之拮抗劑,其較佳實例係:TGF-β、CTGF、IL-1、IL-4、IL-5、IL-6、IL-8、IL-13與整合素之拮抗劑;●ρ-激酶抑制性化合物,其較佳實例係:法舒地爾(fasudil)、Y-27632、SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;●抑制可溶性環氧化物水解酶(sEH)之化合物,例如:N,N'-二環己基脲、12-(3-金剛烷-1-基-脲基)十二烷酸或1-金剛烷-1-基-3-{5-[2-(2-乙氧基乙氧基)乙氧基]戊基}脲;●影響心臟能量代謝之化合物,其較佳實例係乙莫克舍(etomoxir)、二氯乙酸鹽(dichloracetate)、雷諾嗪(ranolazine)或曲美他嗪(trimetazidine);●抗阻塞劑,用於例如:治療慢性阻塞性肺病(COPD)或支氣管性氣喘,其較佳實例係選自下列之群中:吸入性或全身性投與β-腎上腺素激導性受體促效劑(β-擬似物)及吸入性投與抗毒蕈鹼激導性物質;●抗發炎、免疫調節性、免疫抑制性及/或細胞毒性劑,其較佳實例係選自下列之群中:全身性或吸入性投與之皮質類固醇,以及乙醯基半胱胺酸、蒙鲁司特(montelukast)、硫唑嘌呤(azathioprine)、環磷醯胺、羥基脲(hydroxycarbamide)、阿奇黴素(azithromycin)、吡非尼酮(pirfenidone)或恩博(etanercept);●抗纖維化劑,其較佳實例係:多激酶抑制劑尼達尼布(nintedanib)、腺苷A2b受體拮抗劑、神經鞘胺醇-1-磷酸受體3(S1P3)拮抗劑、自分泌運動因子(autotaxin)抑制劑、溶血磷脂酸受體1(LPA-1)與溶血磷脂酸受體2(LPA-2)拮抗劑、離胺醯基氧化酶(LOX)抑制劑、離胺醯基氧化酶樣2抑制劑、CTGF抑制劑、IL-4拮抗劑、IL-13拮抗劑、αvβ6-整合素拮抗劑、TGF-β拮抗劑、Wnt訊號轉導途徑之抑制劑或CCR2拮抗劑;●抗血栓劑,其較佳實例係選自下列之群中:血小板凝集抑制劑、抗凝血劑與促纖維蛋白分解物質;●降血壓活性成份,其較佳實例係選自下列之群中:鈣拮抗劑、血管收縮 素AII拮抗劑、ACE抑制劑、血管活性肽酶抑制劑、內皮肽拮抗劑、腎素抑制劑、α-受體阻斷劑、β-受體阻斷劑、礦物皮質酮受體拮抗劑、及利尿劑;●脂質代謝修飾劑,其較佳實例係選自:甲狀腺受體促效劑、膽固醇合成抑制劑之群中,其較佳實例係:HMG-CoA還原酶抑制劑或鯊烯合成抑制劑、ACAT抑制劑、CETP抑制劑、MTP抑制劑、PPAR-α、PPAR-γ,及/或PPAR-δ促效劑、膽固醇吸收抑制劑、脂酶抑制劑、聚合性膽酸吸附劑、膽酸再吸收抑制劑與脂蛋白(a)拮抗劑;及/或●化療劑,如彼等用於例如:治療肺或其他器官之新生贅瘤。
本發明較佳具體實施例中,本發明化合物係與β-腎上腺素激導性受體促效劑組合投藥,其較佳實例係:沙丁胺醇(albuterol)、異丙腎上腺素(isoproterenol)、異丙喘寧(metaproterenol)、特布他林(terbutalin)、菲諾特洛(fenoterol)、福莫特羅(formoterol)、瑞普特羅(reproterol)、沙布坦(salbutamol)或沙美特羅(salmeterol)。
本發明較佳具體實施例中,本發明化合物係與抗膽鹼激導性物質組合投藥,其較佳實例係:異丙托溴銨(ipratropium bromide)、噻托溴銨(tiotropium bromide)或氧托溴銨(oxitropium bromide)。
本發明較佳具體實施例中,本發明化合物係與皮質類固醇組合投藥,其較佳實例係:潑尼松(prednisone)、潑尼松龍(prednisolone)、甲基潑尼松龍、氟羥潑尼松龍(triamcinolone)、地塞米松(dexamethasone)、倍氯米松(beclomethasone)、倍他美松(betamethasone)、氟尼縮松(flunisolide)、布地縮松(budesonide)或氟地縮松(fluticasone)。
咸了解,抗血栓劑較佳係選自血小板凝集抑制劑、抗凝血劑與促纖維蛋白分解物質之群中。
本發明較佳具體實施例中,本發明化合物係與血小板凝集抑制劑組合投藥,其較佳實例係:阿斯匹靈(aspirin)、氯吡格雷(clopidogrel)、噻氯匹定(ticlopidin)或雙嘧達莫(dipyridamol)。
本發明較佳具體實施例中,本發明化合物係與凝血酶抑制劑組合投藥,其較佳實例係:希美加群(ximelagatran)、美拉加群(melagatran)、達比加群 (dabigatran)、比伐盧定(bivalirudin)或克立生(clexane)。
本發明較佳具體實施例中,本發明化合物係與GPIIb/IIIa拮抗劑組合投藥,其較佳實例係:替羅非班(tirofiban)或阿昔單抗(abciximab)。
本發明較佳具體實施例中,本發明化合物係與Xa因子抑制劑組合投藥,其較佳實例係:利伐沙班(rivaroxaban)、阿哌沙班(apixaban)、菲得沙班(fidexaban)、雷扎沙班(razaxaban)、磺達肝素(fondaparinux)、抑達肝素(idraparinux)、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV 803、SSR-126512或SSR-128428。
本發明較佳具體實施例中,本發明化合物係與肝素或低分子量(LMW)肝素衍生物組合投藥。
本發明較佳具體實施例中,本發明化合物係與維生素K拮抗劑組合投藥,其較佳實例為:香豆素。
咸了解,降血壓劑較佳係指選自鈣拮抗劑、血管收縮素AII拮抗劑、ACE抑制劑、內皮肽拮抗劑、腎素抑制劑、α-受體阻斷劑、β-受體阻斷劑、礦物皮質酮受體拮抗劑、與利尿劑之群中之化合物。
本發明較佳具體實施例中,本發明化合物係與鈣拮抗劑組合投藥,其較佳實例係:硝苯地平(nifedipine)、氨氯地平(amlodipine)、維拉帕米(verapamil)或地爾硫卓(diltiazem)。
本發明較佳具體實施例中,本發明化合物係與α1-受體阻斷劑組合投藥,其較佳實例係:哌唑嗪(prazosin)。
本發明較佳具體實施例中,本發明化合物係與β-受體阻斷劑組合投藥,其較佳實例係:普萘洛爾(propranolol)、阿替洛爾(atenolol)、汀洛爾(timolol)、本得洛爾(pindolol)、阿普洛爾(alprenolol)、歐普洛爾(oxprenolol)、本布洛爾(penbutolol)、布普洛爾(bupranolol)、美替洛爾(metipranolol)、納多洛爾(nadolol)、甲吲洛爾(mepindolol)、咔唑洛爾(carazalol)、索他洛爾(sota1ol)、美托洛爾(metoprolol)、貝他洛爾(betaxolol)、塞利洛爾(celiprolol)、匹梭洛爾(bisoprolol)、卡替洛爾(carteolol)、艾司洛爾(esmolol)、拉貝洛爾(labetalol)、卡維地洛(carvedilol)、阿達洛爾(adaprolol)、蘭地洛爾(landiolol)、奈必洛爾 (nebivolol)、依泮洛爾(epanolol)或布新洛爾(bucindolol)。
本發明較佳具體實施例中,本發明化合物係與血管收縮素AII拮抗劑組合投藥,其較佳實例係:氯沙坦(losartan)、坎地沙坦(candesartan)、維沙坦(valsartan)、特米沙坦(telmisartan)或恩布沙坦(embusartan)。
本發明較佳具體實施例中,本發明化合物係與ACE抑制劑組合投藥,其較佳實例係:依那普利(enalapril)、卡特普利(captopril)、利希普利(lisinopril)、阮米普利(ramipril)、得拉普利(delapril)、弗辛普利(fosinopril)、奎諾普利(quinopril)、普靈普利(perindopril)或散得普利(trandopril)。
本發明較佳具體實施例中,本發明化合物係與內皮肽拮抗劑組合投藥,其較佳實例係:波生坦(bosentan)、達盧生坦(darusentan)、安倍生坦(ambrisentan)或希塔生坦(sitaxsentan)。
本發明較佳具體實施例中,本發明化合物係與腎素抑制劑組合投藥,其較佳實例係:阿利克倫(aliskiren)、SPP-600或SPP-800。
本發明較佳具體實施例中,本發明化合物係與礦物皮質酮受體拮抗劑組合投藥,其較佳實例係:螺旋內酯固醇(spironolactone)、依普利酮(eplerenon)或吩瑞酮(finerenone)。
本發明較佳具體實施例中,本發明化合物係與利尿劑組合投藥,其較佳實例係:服樂泄麥(furosemide)、布美他尼(bumetanide)、托拉塞米(torsemide)、芐氟噻嗪(bendroflumethiazide)、氯噻嗪(chlorthiazide)、氫氯噻嗪(hydrochlorothiazide)、氫氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methyclothiazide)、泊利噻嗪(polythiazide)、三氯噻嗪(trichlormethiazide)、氯噻酮(chlorthalidone)、吲達帕胺(indapamide)、甲苯喹唑酮(metolazone)、喹噻酮(quinethazone)、乙醯唑胺(acetazolamide)、二氯磺胺(dichlorphenamide)、甲醋唑胺(methazolamide)、甘油、異山梨醇酯(isosorbide)、甘露糖醇、阿米洛利(amiloride)或三胺蝶呤(triamterene)。
咸了解,脂質代謝修飾劑較佳係指選自CETP抑制劑、甲狀腺受體促效劑、膽固醇合成抑制劑(如:HMG-CoA還原酶抑制劑或鯊烯合成抑制劑)、ACAT抑制劑、MTP抑制劑、PPAR-α、PPAR-γ,及/或PPAR-δ促效劑、膽固醇吸收抑制劑、聚合性膽酸吸附劑、膽酸再吸收抑制劑、脂酶抑制劑與脂蛋白(a) 拮抗劑之群中。
本發明較佳具體實施例中,本發明化合物係與CETP抑制劑組合投藥,其較佳實例係:托徹普(torcetrapib)(CP-529 414)、JJT-705或CETP疫苗(Avant)。
本發明較佳具體實施例中,本發明化合物係與甲狀腺受體促效劑組合投藥,其較佳實例係:D-甲狀腺素、3,5,3'-三碘甲狀腺原胺酸(T3)、CGS 23425或阿昔替羅(axitirome)(CGS 26214)。
本發明較佳具體實施例中,本發明化合物係與史達汀抑制素類(statins)之HMG-CoA還原酶抑制劑組合投藥,其較佳實例係:羅瓦斯達汀(lovastatin)、辛伐達汀(simvastatin)、普伐達汀(pravastatin)、弗瓦達汀(fluvastatin)、阿伐達汀(atorvastatin)、樂瓦達汀(rosuvastatin)或皮瓦達汀(pitavastatin)。
本發明較佳具體實施例中,本發明化合物係與鯊烯合成抑制劑組合投藥,其較佳實例係:BMS-188494或TAK-475。
本發明較佳具體實施例中,本發明化合物係與ACAT抑制劑組合投藥,其較佳實例係:阿伐麥布(avasimibe)、亞油甲苄胺(melinamide)、帕替麥布(pactimibe)、依鲁麥布(eflucimibe)或SMP-797。
本發明較佳具體實施例中,本發明化合物係與MTP抑制劑組合投藥,其較佳實例係:英普他派(implitapide)、BMS-201038、R-103757或JTT-130。
本發明較佳具體實施例中,本發明化合物係與PPAR-γ促效劑組合投藥,其較佳實例係:皮利酮(pioglitazone)或羅格列酮(rosiglitazone)。
本發明較佳具體實施例中,本發明化合物係與PPAR-δ促效劑組合投藥,其較佳實例係:GW 501516或BAY 68-5042。
本發明較佳具體實施例中,本發明化合物係與膽固醇吸收抑制劑組合投藥,其較佳實例係:依澤替米貝(ezetimibe)、替奎安(tiqueside)或帕馬苷(pamaqueside)。
本發明較佳具體實施例中,本發明化合物係與脂酶抑制劑組合投藥,其較佳實例係:羅氏鮮(orlistat)。
本發明較佳具體實施例中,本發明化合物係與聚合性膽酸吸附劑組合投藥,其較佳實例係:消胆胺(cholestyramine)、降胆寧(colestipol)、克利凡 (colesolvam)、考來膠(CholestaGel)或克利美(colestimide)。
本發明較佳具體實施例中,本發明化合物係與膽酸再吸收抑制劑組合投藥,其較佳實例係:ASBT(=IBAT)抑制劑,例如:AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
本發明較佳具體實施例中,本發明化合物係與脂蛋白質(a)拮抗劑組合投藥,其較佳實例係:真卡本鈣(gemcabene calcium)(CI-1027)或菸鹼酸。
特別佳係本發明化合物與選自下列所組成群中之一或多種其他活性成份之組合:PDE5抑制劑、sGC活化劑、sGC刺激劑、前列環素類似物、IP受體促效劑、內皮肽拮抗劑、抑制訊號轉導級聯之化合物與吡非尼酮(pirfenidone)。
本發明進一步提供一種醫藥,其包含至少一種本發明化合物,通常共同使用一種或多種惰性無毒之醫藥上合適之賦形劑,且其係供上述目的之用途。
本發明化合物可產生全身作用及/或局部作用。基於此目的,其可依合適方式投藥,例如:經口、非經腸式、經肺、鼻、舌下、舌部、頰內、直腸、陰道、皮膚、穿皮式、經結膜或經耳朵途徑,或呈植入物或人工支架投藥。本發明化合物可針對此等投藥途徑,呈合適之投藥劑型投藥。
適合經口投藥之劑型為可依據先前技藝操作且可快速釋放及/或依修飾方式釋放本發明化合物之劑型,其包含呈結晶及/或非晶型及/或溶解型之本發明化合物,例如:錠劑(無包衣或有包衣錠劑,例如:包覆腸溶性包衣或可延緩溶解或不溶解以控制本發明化合物釋放之包衣)、可於口腔中迅速崩解之錠劑、或膜衣錠/嚼錠、膜衣錠/冷凍乾燥物、膠囊(例如:硬式或軟式明膠囊)、糖衣錠、粒劑、丸劑、粉劑、乳液、懸浮液、氣霧劑或溶液。
非經腸式投藥法可繞過吸收步驟進行(例如:經靜脈內、經動脈內、經心臟內、經脊柱內或經腰椎內投藥),或包括吸收作用進行(例如:經肌內、皮下、皮內、經皮膚、經玻璃體內、或經腹膜內途徑)。適合非經腸式投藥之投藥劑型特別包括呈溶液、懸浮液、乳液、冷凍乾燥物或無菌粉末之注射或輸液製劑。
其他投藥途徑之合適投藥劑型為例如:吸入性醫藥型(包括粉劑吸入器、噴 霧劑)、鼻用滴劑、溶液或噴液;經舌部、舌下或頰內投藥之錠劑、膜衣錠/嚼錠或膠囊、栓劑、滴眼劑、眼藥膏、洗眼液、眼植入劑、耳滴劑、噴液、粉劑、洗液或棉條、陰道用膠囊、水性懸浮液(洗劑、搖溶混合物)、親脂性懸浮液、乳液、微乳液、油膏、乳霜、穿皮式醫療系統(例如:貼布)、乳劑、糊劑、泡沫劑、灑粉、植入物或人工支架。
以口服及非經腸式投藥法較佳,尤指口服、經靜脈內與經肺內(吸入性)投藥較佳。
根據本發明化合物可轉化成上述投藥劑型。其可依本身已知方式,與醫藥上合適之賦形劑混合來達成。此等賦形劑包括:●填料與載劑(例如:纖維素、微晶纖維素(例如:Avicel®)、乳糖、甘露糖醇、澱粉、磷酸鈣(例如:Di-Cafos®)),●油膏基質(例如:凡士林、石蠟、三酸甘油酯、蠟類、羊毛蠟、羊毛蠟醇、羊毛脂、親水性油膏、聚乙二醇),●栓劑基質(例如:聚乙二醇、可可脂、硬脂),●溶劑(例如:水、乙醇、異丙醇、甘油、丙二醇、中鏈三酸甘油酯、脂肪油、液態聚乙二醇、石蠟),●界面活性劑、乳化劑、勻散劑或濕化劑(例如:十二烷基硫酸鈉、卵磷脂、磷脂類、脂肪醇(例如:Lanette®)、山梨糖醇酐脂肪酸酯類(例如:Span®)、聚氧乙烯山梨糖醇酐脂肪酸酯類(例如:Tween®)、聚氧乙烯脂肪酸甘油酯類(例如:Cremophor®)、聚氧乙烯脂肪酸酯類、聚氧乙烯脂肪醇醚類、甘油脂肪酸酯類、泊洛沙姆(poloxamer)(例如:Pluronic®)),●緩衝物質,及酸類與鹼類(例如:磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉、碳酸銨、三羥基胺基甲烷、三乙醇胺),●等滲劑(例如:葡萄糖、氯化鈉),●吸附劑(例如:細粒矽石),●提高黏度劑、凝膠形成劑、增稠劑或結合劑(例如:聚乙烯吡咯烷酮、甲基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、羧甲基纖維 素鈉、澱粉、卡波姆(carbomer)、聚丙烯酸(例如:Carbopol®)、藻酸鹽、明膠),●崩解劑(例如:改質澱粉、羧甲基纖維素鈉、澱粉乙醇酸鈉(例如:Explotab®)、交聯聚乙烯吡咯烷酮、交聯羧甲纖維素鈉(例如:AcDiSol®)),●流動調節劑、潤滑劑、助滑劑與釋模劑(例如:硬脂酸鎂、硬脂酸、滑石、細粒矽石(例如:Aerosil®)),●包衣劑(例如:糖、蟲膠)及可以快速或修飾溶解之膜片或擴散膜之膜形成劑(例如:聚乙烯吡咯烷酮(例如:Kollidon®)、聚乙烯醇、羥基丙基甲基纖維素、羥基丙基纖維素、乙基纖維素、羥基丙基甲基纖維素酞酸酯、纖維素乙酸酯、纖維素乙酸酯酞酸酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如:Eudragit®)),●膠囊材料(例如:明膠、羥基丙基甲基纖維素),●合成性聚合物(例如:聚丙交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如:Eudragit®),聚乙烯吡咯烷酮(例如:Kollidon®)、聚乙烯醇、聚乙酸乙烯酯、聚環氧乙烷、聚乙二醇與其共聚物與嵌段共聚物),●增塑劑(例如:聚乙二醇、丙二醇、甘油、三乙酸甘油酯、三乙醯基檸檬酸酯、酞酸二丁酯),●滲透加強劑,●安定劑(例如:抗氧化劑,例如:抗壞血酸、棕櫚酸抗壞血基酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙基酯),●防腐劑(例如:對羥基苯甲酸酯、山梨酸、硫柳汞、氯化烷基二甲基苄基銨、醋酸氯己定(chlorhexidine acetate)、苯甲酸鈉),●染劑(例如:無機色素,例如:氧化鐵、二氧化鈦),●風味劑、甜味劑、調味劑與/或矯味劑。
通常,若非經腸式投藥時,已發現有利之投藥量為約0.001至1mg/kg體重,較佳為約0.01至0.5mg/kg體重,以得到有效結果。若經口投藥時,其劑量為約0.01至100mg/kg,較佳為約0.01至20mg/kg,最佳為0.1至10mg/kg 體重。若經肺內投藥時,其劑量通常為每次吸入約0.1至50mg。
儘管如此,有時候可能必需偏離上述劑量,明確言之,依體重、投藥途徑、個人對活性成份之反應、製劑性質、及投藥時間或間隔而定。因此,有些病例可能低於上述最低劑量已足夠,但其他病例可能需超過上述劑量上限才足夠。若投與較大量時,建議在一天內分成許多小劑量投藥。
本發明進一步提供一種醫藥組成物,其包含至少一種根據本發明化合物,通常共同使用一種或多種醫藥上合適之賦形劑,且其係供上述目的之用途。
下列操作實施例說明本發明。本發明並未受到此等實施例限制。
[α]D 20 比旋光度(偏光儀)
atm 大氣壓;壓力單位
br. 寬峰(NMR)
c 濃度
ca. 約
d 雙峰(NMR)
DAD 二極排列檢測器(HPLC)
DBU 1,8-重氮雙環[5.4.0]十一碳-7-烯
dd 雙重雙峰(NMR)
DIPEA N,N-二異丙基乙胺
DMF N,N-二甲基甲醯胺
DMSO 二甲亞碸
△T 加熱,升溫(反應圖中)
ee 對映異構性超量
EI 電子撞擊電離化(MS)
eq. 當量
ESI 電噴灑電離化(MS)
Et 乙基
wt% 重量百分比
h 小時
HPLC 高壓高效液相層析法
IPr 異丙基
LC 液相層析法
LC-MS 液相層析法-偶聯質譜儀
LDA 二異丙基胺化鋰
m 多峰(NMR)
M 莫耳濃度
Me 甲基
min 分鐘
MS 質譜儀
MWD 多重波長檢測器(HPLC,UV檢測器)
NMP N-甲基-2-吡咯啶酮
NMR 核磁共振光譜儀
MTB醚 第三丁基甲基醚
MTP 多重滴定盤
q 肆裂峰(NMR)
qd 四重雙裂峰(NMR)
RP 逆相(HPLC)
RT 室溫
Rt 滯留時間(HPLC,LC/MS)
s 單峰(NMR)
SFC 超臨界流體層析法
t 參裂峰(NMR)
td 三重雙裂峰(NMR)
TFA 三氟乙酸
tert 第三-
THF 四氫呋喃
ULC 超液相層析法
UPLC 超效液相層析法
UV 紫外線光譜儀
%by vol. 體積百分比
其他縮寫具有習此相關技藝者習知之定義。
MS儀器機型Thermo Scientific FT-MS;UHPLC+儀器機型Thermo Scientific UltiMate 3000;管柱Waters,HSST3,2.1 x 75mm,C18 1.8μm;溶析液A 1升水+0.01%甲酸;溶析液B 1升乙腈+0.01%甲酸;梯度0.0min 10%B→2.5min 95%B→3.5min 95%B;爐溫50℃;流速0.90ml/min;UV檢測210nm/最 佳積分路徑210-300nm。
儀器:Waters ACQUITY SQD UPLC System;管柱:Waters Acquity UPLC HSS T3 1.8μm 50 x 1mm;溶析液A:1升水+0.25ml 99%甲酸,溶析液B:1升乙腈+0.25ml 99%甲酸;梯度:0.0min 90%A→1.2min 5%A→2.0min 5%A;爐溫:50℃;流速:0.40ml/min;UV檢測:208-400nm。
儀器:Waters Single Quad MS System;儀器:Waters UPLC Acquity;管柱:Waters BEH C18 1.7μm 50 x 2.1mm;溶析液A:1升水+1.0ml(25%氨)/l,溶析液B:1升乙腈;梯度:0.0min 92%A→0.1min 92%A→1.8min 5%A→3.5min 5%A;爐溫:50℃;流速:0.45ml/min;UV檢測:210nm(208-400nm)。
儀器:Agilent MS Quad 6150;HPLC:Agilent 1290;管柱:Waters Acquity UPLC HSS T3 1.8μm 50 x 2.1mm;溶析液A:1升水+0.25ml 99%甲酸,溶析液B:1升乙腈+0.25ml 99%甲酸;梯度:0.0min 90%A→0.3min 90%A→1.7min 5%A→3.0min 5%A;爐溫:50℃;流速:1.20ml/min;UV檢測:205-305nm。
儀器:Thermo Scientific DSQII,Thermo Scientific Trace GC Ultra;管柱:Restek RTX-35MS,15m x 200μm x 0.33μm;恆定氦流速:1.20ml/min;爐溫:60℃;入口:220℃;梯度:60℃,30℃/min→300℃(保持3.33min)。
管柱:Chromatorex C18,10μm,250 x 40mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 30%B→6.0min 30%B→27min 95%B→38min 95%B→39min 30%B→40.2min 30%B;流速:50ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,125 x 30mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 30%B→5.5min30%B→17.65min 95%B →19.48min 95%B→19.66min 30%B→20.51min 30%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,250 x 40mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→6.0min 10%B→27min 95%B→38min 95%B→39min 10%B→40.2min 10%B;流速:50ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,250 x 40mm;溶析液A:水+0.1%TFA,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→6.0min 10%B→27min 95%B→38min 95%B→39min 10%B→40.2min 10%B;流速:50ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,125 x 30mm;溶析液A:水+0.1%TFA,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→5.5min 10%B→17.65min 95%B→19.48min 95%B→19.66min 10%B→20.51min 10%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,125 x 30mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→5.5min 10%B→17.65min 95%B→19.48min 95%B→19.66min 10%B→20.51min 10%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,250 x 40mm;溶析液A:水+0.1%TFA,溶析液B:乙腈;在3min時注射;梯度:0.0min 30%B→6.0min 30%B→27min 95%B→38min 95%B→39min 30%B→40.2min 30%B;流速:50ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,125mm x 30mm;溶析液A:水+0.1%甲酸, 溶析液B:乙腈+0.1%甲酸;在3min時注射;梯度:0.0min 10%B→6.0min 10%B→27min 95%B→38min 95%B→39min 10%B→40min 10%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,250mm x 40mm;溶析液A:水+0.1%甲酸,溶析液B:乙腈+0.1%甲酸;梯度:0.0min 10%B→6.0min 10%B→27min 95%B→38min 95%B→39min 10%B→40min 10%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C18,10μm,250mm x 40mm;溶析液A:水+0.1%甲酸,溶析液B:甲醇+甲酸;梯度:0.0min 20%B→6.2min 20%B→6.5min 40%B→15.5min 60%B→16min 100%B→23min 100%B→23.6min 20%B→25.8min 20%B;流速:75ml/min,UV檢測:210nm。
儀器MS:Waters SQD;儀器HPLC:Waters UPLC;管柱:Zorbax SB-Aq(Agilent),50mm x 2.1mm,1.8μm;溶析液A:水+0.025%甲酸,溶析液B:乙腈(ULC)+0.025%甲酸;梯度:0.0min 98%A→0.9min 25%A→1.0min 5%A→1.4min 5%A→1.41min 98%A→1.5min 98%A;爐溫:40℃;流速:0.600ml/min;UV檢測:DAD;210nm。
MS儀器:Waters;HPLC儀器:Waters(管柱:Phenomenex,Luna,5μm,C18(2)100Å,AXIA Tech.50 x 21.2mm),溶析液A:水+0.0375%甲酸,溶析液B:乙腈(ULC)+0.0375%甲酸,梯度;流速:40ml/min;UV檢測:DAD;210-400nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 20%B→2min 20%B→7min 92%B→9min 92%B→20%B;UV檢測:210nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 30%B→2min 30%B→2.2min 50%B→7min 90%B→7.5min 92%B→9min 92%B→30%B;UV檢測:200-400nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 10%B→2min 10%B→2.2min 30%B→7min 70%B→7.5min 92%B→9min 92%B→10%B;UV檢測:200-400nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 10%B→2min 10%B→2.2min 20%B→7min 60%B→7.5min 92%B→9min 92%B→10%B;UV檢測:200-400nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 7.5%B→2min 7.5%B→7min 35%B→7.5min 92%B→9min 92%B→10%B;UV檢測:200-400nm。
儀器:Waters Prep LC/MS系統,管柱:Phenomenex Kinetex,C18,5μm,100 x 30mm;管柱注射(完全注射);溶析液A:水,溶析液B:乙腈,溶析液C:2%甲酸水溶液;溶析液(A+B)之流速:65ml/min溶析液C之流速:恆定5ml/min;梯度(A/B):0.0min 50%B→2min 50%B→2.2min 70%B→7min 92%B→9min 92%B→10%B;UV檢測:200-400nm。
管柱:Chromatorex C18,10μm,125mm x 30mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→6min 10%B→27min 95%B→38min 95%B→39min 10%B→40min 10%B;流速:75ml/min,UV檢測:210nm。
儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7μm 50 x 2.1mm;溶析液A:水+0.1%by vol.of甲酸(99%),溶析液B:乙腈;梯度:0-1.6min 1-99%B,1.6-2.0min 99%B;流速:0.8ml/min;溫度:60℃;DAD掃瞄:210-400nm。
儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7μm 50 x 2.1mm;溶析液A:水+0.2%體積比之氨水(32%),溶析液B:乙腈;梯度:0-1.6min 1-99%B,1.6-2.0min 99%B;流速:0.8ml/min;溫度:60℃;DAD掃瞄:210-400nm。
儀器:Waters Autopurification MS SingleQuad;管柱:Waters XBrigde C18 5μm 100 x 30mm;溶析液A:水+0.2%體積比之氨水(32%),溶析液B:乙腈;梯度:0-5.5min 5-100%B;流速70ml/min;溫度:25℃;DAD掃瞄:210-400nm。
Waters XBridge C18 5μm 100 x 30mm;溶析液A:水+0.1%甲酸,溶析液B:乙腈;梯度:0min 5%B→5.5min 100%B;流速70ml/min;DAD檢測:210-400nm。
管柱:Reprosil C18 10μm;250mm x 40mm,流速:75ml/min,在210nm下檢測;溶析液A:水,溶析液B:乙腈;0-6min 10%B;6-27min:梯度至95%B;27-38min 95%B;38-39min梯度至10%B;39-40min 10%B。
管柱:Reprosil C18 10μm,250mm x 40mm;溶析液A:水+0.1%甲酸,溶析液B:乙腈+0.1%甲酸;0-6min 10%B;6-27min:梯度至95%B;27-38min 95%B;38-39min梯度至10%B;39-40min 10%B;流速:75ml/min,UV檢測:210nm。
管柱:Chromatorex C1810μm;125mm x 30mm,流速:75ml/min,在210nm下檢測;溶析液A:水+0.1%甲酸,溶析液B:甲醇+甲酸;0-7.2min 5%B;7.2-7.45min:梯度至20%B;7.45-14.5min梯度至40%B;14.5-15min梯度至100%B;15-24.3min 100%B;24.2-24.5min梯度至5%B;24.5-27.3min 5%B。
Reprosil C18,10μm,205 x 50mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 30%B→5.5min 30%B→17.65min 95%B→20.79min 95%B→20.97min 30%B→22.65min 30%B;流速:150ml/min,UV檢測:210nm。
Reprosil C18,10μm,205 x 50mm;溶析液A:水,溶析液B:乙腈;在3min時注射;梯度:0.0min 10%B→5.5min 10%B→17.65min 95%B→20.79min 95%B→20.97min 10%B→22.65min 10%B;流速:150ml/min,UV檢測:210nm。
採用外標準物測定離子;儀器:Thermo Scientific ICS 5000+;毛細管IC管柱:IonPac AS11-HC與IonPac CS16;溶析液:溶析液梯度[H]+[OH]-;檢測器:導電性檢測
以下實施例及隨後之試驗說明中之百分比係重量百分比,除非另有說明;份數係重量份數。液體/液體溶液之溶劑比例、稀釋比例與濃度係分別以體積為基準計。
當利用上述方法,採用製備型HPLC純化本發明化合物時,若本發明化合物含有足夠鹼性或酸性官能基時,當溶析液包含添加物,例如:三氟乙酸、甲酸或氨時,則可得到呈例如:三氟乙酸鹽、甲酸鹽或銨鹽等鹽型式之本 發明化合物。此等鹽型可採用熟悉此相關技術者已知之各種不同方法轉化成相應游離鹼或酸。
純度數值通常依據LC/MS圖譜中相應波峰之積分值,但其可能另外藉助於1H-NMR光譜測定。化合物可能仍含有殘留溶劑,通常不納入純度報告中。若沒有出示純度,則依據其在LC/MS圖譜中之自動波峰積分值之純度通常為100%或未明確測定其純度。
若純度<100%時,以%理論值表示之產率通常已經過純度校正。若含有溶劑或雜質時,正式產率可能「>100%」;此等例子中之產率則未經過溶劑或純度校正。
1H NMR訊號之後之偶合型態說明有時候直接來自ACD SpecManager之建議(ACD/Labs Release 12.00,12.5版產品)或ACD/Spectrus Processor 2014(File Version S20S41,Build 72444,21 Aug 2014)或ACD/Spektrus Processor 2015 Pack 2(File Version S40S41,Build 79720,30 Jul 2015),且不一定經過嚴格詳審。有時候,手動調整SpecManager之建議。手動調整或指定說明通常係依據該相關訊號之光學表現,不一定對應於嚴格之物理性校正解讀。通常,所述之化學位移係指該相關訊號之中心。若為寬的多裂峰則出示間隔範圍。被溶劑或水遮蔽或部份遮蔽的訊號係暫時指定或不列出。由例如:分子部份基團快速旋轉或因質子交換所致顯著變寬的訊號,同樣係暫時指定(經常稱為寬多裂峰或寬單峰)或不列出。
所選定實施例之1H NMR數據係以1H NMR波峰列表型式出示。每個訊號峰先出示以ppm表示之δ數值,接著為列於圓括號中之訊號強度。所列出不同訊號峰之每對δ數值/訊號強度數字之間以分號作為分隔。因此某一實施例之波峰列表型式為下列型式:δ1(強度1),δ2(強度2),...,δi(強度i),...,δn(強度n)。
陡峰訊號強度係與印出之NMR光譜實施例中訊號高度(以cm計)呈相關性,且顯示訊號強度與其他訊號比較之真實比例。在寬峰訊號中,則可出示複數個峰或中間訊號及其相較於光譜中最高強度訊號之相對強度。1H NMR波峰列表類似印出之典型1H NMR圖,因此通常包含列於典型NMR解讀中之所有波峰。此外,可如同印出之典型1H NMR圖,其等亦顯示溶劑訊號、目標 化合物之立體異構物(其同樣由本發明提供)訊號、及/或雜質之波峰。目標化合物之立體異構物波峰與/或雜質波峰之平均強度通常低於目標化合物(例如:純度>90%)之波峰強度。此等立體異構物與/或雜質係典型出現在特定製法中。因此其波峰有助於藉由「副產物指印」辨識吾等製法之再現性。採用已知方法(MestreC,ACD-模擬法,或採用實驗性分析之預期數值)計算目標化合物波峰之專家若需要時,可以視需要另外選用其他強度濾波器,單離出目標化合物之波峰。此單離法即類似典型1H NMR解讀中相關波峰挑選法。
有關以波峰列表型式呈現NMR之進一步詳細內容可參見公開文獻:「Citation of NMR Peaklist Data within Patent Applications」(參見Research Disclosure Database Number 605005,2014,1 August 2014或http://www.researchdisclosure.com/searching-disclosure)。在Research Disclosure Database Number 605005中例行說明之波峰挑選法中,「最小高度」參數可設在1%至4%之間。依所分析化合物之化學結構型態及/或化合物濃度而定,建議將「最小高度」參數設定在<1%之數值。
若出示熔點與熔點範圍時,其係未經過校正。
下文中未明確說明其製法之所有反應物或試劑係購自一般市售商品來源。同樣未在下文中明確說明其製法且無法自商品取得或無法從一般來源取得之所有其他反應物或試劑,則可參考已說明其製法之公開文獻。
取含5-溴-1H-吲哚-2,3-二酮(35.0g,155mmol)與丙酸酐(150ml,1.2mol)之混合物攪拌加熱至回流3h。冷卻至室溫後,濾出所出現之固體,使用第三丁基甲基醚洗滌,及減壓乾燥。在產物混合物中得到16.20g(由1H NMR測得60%純度,22%理論值)標題化合物。依據產物混合物之1H NMR,有些標題化合物 已重排產生6-溴-2-羥基-3-甲基喹啉-4-羧酸轉化產物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.23(d,1H),8.03-7.86(m,2H),3.01(q,2H),1.14(t,3H).
於RT下,在含5-溴-1-丙醯基-1H-吲哚-2,3-二酮(16.2g,57.4mmol,未校正純度,實施例1A)之水(100ml)混合物中添加氫氧化鈉(13.8g,345mmol),混合物於回流下攪拌2h。冷卻至室溫後,混合物使用3M鹽酸酸化,濾出所形成之固體。固體溶於1M氫氧化鈉溶液(400ml),使用乙酸乙酯洗滌溶液5次(每次200ml)。隨後,使用濃鹽酸酸化該水溶液,濾出所形成固體,使用水洗滌,及減壓乾燥。得到8.30g(95%純度,49%理論值)標題化合物。
LC-MS(方法1):Rt=0.65min;MS(ESIpos):m/z=282/284[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:14.28(br.s,1H),12.13(br.s,1H),7.85-7.07(m,3H),2.09(br.s,3H).
從依類似方式進行之預備實驗中,利用製備型HPLC純化,得到下列產物:取粗產物(4.4g,由LC-S測得9%純度)於加熱下溶於50ml含甲醇、DMSO與THF之混合物中,利用製備型HPLC純化[管柱:Chromatorex Spring管柱,C18,10μm,290mm x 100mm;流速:250ml/min;檢測:210nm;溫度:22℃;注射:30ml;乙腈/水梯度0:100→9:1;運行時間41min]。得到248mg(100%純度)標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:14.26(br.s,1H),12.13(s,1H),7.67(dd,1H),7.50(d,1H),7.30(d,1H),2.09(s,3H).
取含5-溴-1-丙醯基-1H-吲哚-2,3-二酮(99.3g,352mmol,實施例1A)、水(615ml) 與氫氧化鈉(84.5g,2.11mol)之混合物於100℃下攪拌2h。冷卻至室溫後,混合物與水(1400ml)混合,及使用乙酸乙酯(1400ml)洗滌。水相使用濃鹽酸固化,抽吸濾出所形成之固體,及減壓乾燥。得到74.4g(由LC-MS測得100%純度,75%理論值)標題化合物。
LC-MS(方法1):Rt=0.65min;MS(ESIpos):m/z=282/284[M+H]+.
取含5-溴-1H-吲哚-2,3-二酮(58.8g,260.2mmol)與丙酸酐(250ml,1.95mol)之混合物於氬氣下攪拌加熱至回流(內溫:160℃)一夜。隨後,混合物冷卻至0℃,添加MTB醚(500ml),混合物於0℃下乾燥1h。濾出所出現之固體,使用MTB醚洗滌,及風乾。得到43.0g(100%純度,59%理論值)標題化合物。
LC-MS(方法1):Rt=0.69min;MS(ESIpos):m/z=282/284[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:14.26(br.s,1H),12.13(s,1H),7.67(dd,1H),7.50(d,1H),7.30(d,1H),2.09(s,3H).
取含6-溴-2-羥基-3-甲基喹啉-4-羧酸(8.30g,29.4mmol,實施例2A)與磷醯氯(60ml,641mmol)之混合物於氬氣下回流加熱3h。冷卻至室溫後,混合物逐漸倒至冰-水(600ml)上。所得溶液使用二氯甲烷萃取3次(每次300ml)。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(320g矽膠,先使用環己烷,然後環己烷/乙酸乙酯98:2,然後環己烷/乙酸乙酯96:4,Isolera)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到3.74g(83%純度,33%理論值)第一批標題化合物與1.90g(88%純度,18%理論值,參見分析法)第二批標題化合物。
LC-MS(方法2):Rt=1.35min;MS(ESIpos):m/z=320[M+H]+
於氬氣及RT下,在含6-溴-2-羥基-3-甲基喹啉-4-羧酸(20.0g,70.9mmol)之乙腈(400ml)混合物中添加亞硫醯氯(52ml,710mmol)與DMF(11ml,140mmol)。混合物於減壓下逐漸加熱至回流,此過程中觀察到有氣體釋出。於回流下攪拌約1小時後,讓混合物冷卻至RT,於旋轉蒸發器上排除揮發性組成份。所得殘質利用快速管柱層析法純化(200g矽膠,二氯甲烷)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到16.4g(97%純度,70%理論值)標題化合物。
LC-MS(方法4):Rt=1.66min;MS(ESIpos):m/z=320[M+H]+
在含6-氯-2,3-二氟苯甲醛(5.00g,28.3mmol)之THF(20ml)溶液中,於RT下分批添加硼氫化鈉(1.39g,36.8mmol)(有氣體釋出)。隨後,再添加20ml THF,混合物於室溫下攪拌45min。然後添加二氯甲烷(100ml)、水(100ml)與飽和氯化銨水溶液(50ml)至混合物中,攪拌。在其間使用濃乙酸酸化水相。分相後,取有機相使用飽和氯化鈉水溶液洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質於減壓下短暫乾燥。得到5.35g(100%純度,「>106%理論值」,未完全乾燥)標題化合物。
GC-MS(方法5):Rt=3.23min,MS(EIpos):m/z=178[M]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.45(dd,1H),7.36(ddd,1H),5.36(t,1H),4.59(dd,3H).
於-15℃下,在含(6-氯-2,3-二氟苯基)甲醇(5.34g,29.9mmol,實施例4A)之二 氯甲烷(30ml)溶液中攪拌滴加三溴化磷(1.6ml,16mmol)。隨後,離開冷卻槽,混合物於室溫下再攪拌2h。然後慢慢添加飽和碳酸氫鈉水溶液、水與二氯甲烷(各50ml)至混合物中,攪拌。分相後,取有機相使用飽和氯化鈉水溶液(100ml)洗滌,經硫酸鈉脫水,過濾及濃縮,殘質於減壓下短暫乾燥。得到3.88g(由GC-MS測得94%純度,51%理論值)標題化合物。
GC-MS(方法5):Rt=3.57min,MS(EIpos):m/z=240[M]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.55(dd,1H),7.45(ddd,1H),4.71(d,3H).
於-15℃下,在含[2-(二氟甲氧基)-6-氟苯基]甲醇(9.90g,51.5mmol,可以依據WO 2016/168633 A1,p.71製備)之二氯甲烷(60ml)溶液中攪拌滴加三溴化磷(1.6ml,16mmol)之二氯甲烷(20ml)溶液。隨後,離開冷卻槽,混合物於室溫下再攪拌2h。然後慢慢添加飽和碳酸氫鈉水溶液、水與二氯甲烷(各100ml)至混合物中,攪拌。分相後,取有機相使用飽和氯化鈉水溶液(200ml)洗滌,經硫酸鈉脫水,過濾及濃縮,殘質於減壓下短暫乾燥。得到9.60g(95%純度,69%理論值)標題化合物。
GC-MS(方法5):Rt=3.38min,MS(EIpos):m/z=254/256[M]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.238(0.57),1.255(1.12),1.273(0.58),4.610(15.58),4.614(16.00),7.105(3.32),7.126(3.80),7.161(2.02),7.184(8.39),7.205(2.57),7.366(8.46),7.470(2.03),7.487(2.27),7.491(3.74),7.508(3.68),7.512(2.00),7.529(1.66),7.549(4.14).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.60-7.03(m,4H),4.61(d,2H).
於攪拌下,在含1-(溴甲基)-2-氯-3-氟苯(6.96g,31.1mmol)之二氯甲烷(60ml)溶液中添加水(60ml)與四丁基溴化銨(1.00g,3.11mmol)。隨後,添加氰化鉀(6.08g,93.4mmol)之水(60ml)溶液,混合物於室溫下攪拌2.5h。隨後,分相,有機相使用飽和碳酸氫鈉水溶液洗滌三次,經硫酸鈉脫水,過濾及濃縮,殘質簡短地減壓乾燥。得到4.98g(100%純度,94%理論值)標題化合物。
GC-MS(方法5):Rt=4.03min,MS(EIpos):m/z=169[M]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:4.175(16.00),7.400(0.90),7.408(1.10),7.414(1.15),7.417(1.13),7.424(2.60),7.440(2.84),7.443(2.99),7.459(5.37),7.468(1.52),7.474(1.39).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.50-7.37(m,3H),4.18(s,2H).
在含2-(溴甲基)-1-氯-3,4-二氟苯(3.87g,16.0mmol,實施例5A)之乙腈(48ml)溶液中攪拌添加三甲基矽烷基氰化物(2.5ml,18mmol)與1M四丁基銨化氟之THF溶液(19ml,19mmol),混合物於80℃下攪拌30min。冷卻至室溫後,於旋轉蒸發器上排除溶劑。殘質溶於乙酸乙酯(80ml),溶液使用水與飽和氯化鈉水溶液洗滌(每次80ml),經硫酸鈉脫水,過濾與濃縮。殘質溶於二氯甲烷,採用快速層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.24g(由GC-MS測得71%純度,96%理論值)標題化合物。
GC-MS(方法5):Rt=3.92min,MS(EIpos):m/z=187[M]+
LC-MS(方法1):Rt=1.57min;MS(ESIneg):m/z=186[M-H]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.58(dd,1H),7.49(ddd,1H),4.16(d,2H).
在含2-(溴甲基)-3-氯-1,4-二氟苯(4.80g,19.9mmol,CAS-RN 90292-67-4,可自商品取得)之二氯甲烷(40ml)溶液中攪拌添加水(40ml)與四丁基溴化銨(641mg,1.99mmol)。隨後,添加含氰化鉀(3.88g,59.6mmol)之水(40ml)溶液,混合物於室溫下攪拌2.5h。隨後,分相,與取有機相使用飽和碳酸氫鈉水溶液洗滌三次,經硫酸鈉脫水,過濾及濃縮,殘質於減壓下短暫乾燥。得到3.80g(94%純度,96%理論值)標題化合物。
LC-MS(方法1):Rt=1.59min;MS(ESIneg):m/z=186[M-H]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.57(td,1H),7.44(td,1H),4.15(d,2H).
在攪拌下,在含2-(溴甲基)-1-(二氟甲氧基)-3-氟苯(9.60g,37.6mmol,實施例6A)之二氯甲烷(60ml)溶液中添加水(60ml)與四丁基溴化銨(1.21g,3.76mmol)。隨後,添加含氰化鉀(7.35g,113mmol)之水(120ml)溶液,混合物於室溫下攪拌2.5h。隨後,分相,取有機相使用飽和碳酸氫鈉水溶液洗滌2次(每次100ml),經硫酸鈉脫水,過濾及濃縮,殘質於減壓下短暫乾燥。得到7.26g(98%純度,94%理論值)標題化合物。
GC-MS(方法5):Rt=3.70min,MS(EIpos):m/z=201[M]+
LC-MS(方法1):Rt=1.56min
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.937(0.68),3.164(0.78),3.177(0.77),3.952(16.00),7.152(3.20),7.171(6.16),7.215(2.00),7.237(3.89),7.259(2.35),7.353(6.55),7.489(1.60),7.509(2.98),7.526(3.04),7.531(1.93),7.535(3.48),7.547(1.32).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.58-7.43(m,1H),7.39-7.05(m,3H),3.95(s,2H).
於氬氣下,在含(2-氯-5-氟苯基)乙腈(25.0g,147mmol)之THF(200ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(110ml,220mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加溴乙酸第三丁基酯(33ml,220mmol)。讓混合物在3h內回到RT後,添加水(100ml),混合物於室溫下攪拌10min。再度加水(200ml)後,添加乙酸乙酯(200ml),及分相。水相使用乙酸乙酯(200ml)萃取。合併之有機相使用飽和氯化鈉水溶液洗滌一次(300ml),經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(1kg矽膠,環己烷/乙酸乙酯9:1)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到15.2g(64%純度,23%理論值)第一批標題化合物與28.6g(87%純度,59%理論值,參見分析法)第二批標題化合物。
LC-MS(方法2):Rt=1.09min;MS(ESIpos):m/z=284[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:0.934(1.18),0.947(1.27),1.343(16.00),1.392(1.87),1.401(1.18),2.976(0.49),2.991(0.48),3.081(0.60),3.316(0.94),4.854(0.42),7.452(0.69),7.500(0.48),7.512(0.47).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.55-7.47(m,1H),7.47-7.42(m,1H), 7.40-7.33(m,1H),4.85(td,1H),3.10(dd,1H),2.97(dd,1H),1.34(s,9H).
於氬氣下,在含(2-氯-5-氟苯基)乙腈(10.0g,59.0mmol)之THF(75ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(44ml,88mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於78℃及攪拌下慢慢滴加3-溴丙酸第三丁基酯(11ml,71mmol)。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,慢慢加水至混合物中,使用乙酸乙酯萃取2次。合併之有機相使用飽和氯化鈉水溶液洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(340g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→3:7,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到14.8g(93%純度,78%理論值)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=298[M+H]+
於氬氣下,在含(2-氯苯基)乙腈(5.00g,33.0mmol)之THF(46ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(25ml,49mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加3-溴丙酸第三丁基酯(8.28g,39.6mmol)。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,慢慢加水至混合物中,使用乙酸乙酯萃取2次。合併之有機相使用飽和氯化鈉水溶液洗滌一次,經硫酸鈉脫水,過濾 及濃縮,殘質經製備型HPLC純化(方法8)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到5.20g(75%純度,42%理論值)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=280[M+H]+
於氬氣下,在含[2-(三氟甲基)苯基]乙腈(14.8g,79.8mmol,CAS-RN 3038-47-9,可自商品取得)之THF(100ml)溶液中,在攪拌下慢慢添加2M LDA之THF溶液(48ml,96mmol),此過程之內溫保持在-70℃與-60℃之間。讓混合物回到0℃,15min後,再度冷卻至-70℃。隨後,於-70℃及攪拌下慢慢滴加含3-溴丙酸第三丁基酯(15ml,96mmol)之THF(70ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水(200ml)與乙酸乙酯(250ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(150ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(250ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(400g矽膠,環己烷/乙酸乙酯9:1)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到18.7g(100%純度,75%理論值)標題化合物。
LC-MS(方法1):Rt=2.26min;MS(ESIpos):m/z=314[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.91-7.75(m,3H),7.62(t,1H),4.35(dd,1H),2.44-2.33(m,2H),2.31-2.19(m,1H),2.18-2.06(m,1H),1.39(s,9H).
於氬氣下,在含[2-(三氟甲氧基)苯基]乙腈(5.00g,24.9mmol)之THF(65ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(15ml,30mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加含3-溴丙酸第三丁基酯(4.7ml,30mmol)之THF(45ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到3.13g(80%純度,31%理論值)標題化合物。
LC-MS(方法1):Rt=2.27min;MS(ESIpos):m/z=330[M+H]+
於氬氣下,在含(2-氯-3-氟苯基)乙腈(4.00g,23.6mmol,實施例7A)之THF(30ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(14ml,28mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加含3-溴丙酸第三丁基酯(4.5ml,28mmol)之THF(20ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到4.36g(95%純度,59%理論值)標題化合物。
LC-MS(方法1):Rt=2.24min;MS(ESIpos):m/z=298[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.14),1.174(0.02),1.222(0.06),1.342(0.84),1.346(0.35),1.382(16.00),1.429(0.05),1.539(0.06),1.987(0.03),2.071(0.04),2.090(0.09),2.106(0.20),2.125(0.45),2.142(0.53),2.162(0.44),2.182(0.23),2.196(0.08),2.217(0.06),2.252(0.02),2.302(0.07),2.317(0.08),2.343(0.38),2.358(0.60),2.362(0.45),2.376(0.75),2.395(0.29),2.417(0.12),2.436(0.04),2.669(0.03),2.709(0.02),3.730(0.02),4.174(0.10),4.566(0.34),4.586(0.43),4.603(0.33),7.426(0.24),7.431(0.29),7.444(0.48),7.449(0.60),7.460(0.54),7.466(0.30),7.476(0.47),7.482(0.52),7.491(0.55),7.508(0.28),7.529(0.09).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.55-7.40(m,3H),4.59(dd,1H),2.45-2.29(m,2H),2.23-2.06(m,2H),1.38(s,9H).
在氬氣下,在含(6-氯-2,3-二氟苯基)乙腈(2.23g,11.9mmol,未校正純度,實施例8A)之THF(15ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(7.1ml,14mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加含3-溴丙酸第三丁基酯(4.5ml,28mmol)之THF(10ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水(50ml)與乙酸乙酯(100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(50ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(80ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.29g(83%純度,51%理論值)標題化合物。
LC-MS(方法1):Rt=2.17min;MS(ESIpos):m/z=316[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.73-7.53(m,1H),7.52-7.41(m,1H),4.68(t,1H),2.43-2.32(m,2H),2.32-2.18(m,1H),2.18-2.04(m,1H),1.37(s,9H).
在氬氣下,在含(5-氟-2-甲基苯基)乙腈(4.00g,26.8mmol)之THF(30ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(16ml,32mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加3-溴丙酸第三丁基酯(5.1ml,32mmol)之THF(20ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到4.94g(100%純度,66%理論值)標題化合物。
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=278[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.29(dd,1H),7.23(dd,1H),7.11(td,1H),4.34(dd,1H),2.42-2.34(m,2H),2.30(s,3H),2.17-1.96(m,2H),1.40(s,9H).
於氬氣下,在含(2-氯-3,6-二氟苯基)乙腈(3.84g,20.5mmol,實施例9A)之THF(15ml)溶液中,於-78℃及攪拌下,慢慢添加2M LDA之THF溶液(12ml,25mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下,慢慢滴加含3-溴丙酸第三丁基酯(2.6ml,16mmol)之THF(10ml)溶液。繼續攪拌混合物一夜,此過程中,讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(150mml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到4.14g(95%純度,61%理論值)標題化合物。
LC-MS(方法1):Rt=2.17min;MS(ESIpos):m/z=338[M+Na]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.58(td,1H),7.45(td,1H),4.68(t,1H),2.39-2.32(m,2H),2.29-2.17(m,1H),2.17-2.05(m,1H),1.37(s,9H).
該反應係在氬氣下進行。製備LDA溶液時,於15℃下慢慢添加丁基鋰(1.6M己烷溶液,27ml,43mmol)至含二異丙基胺(6.2ml,44mmol)之THF(27ml)溶液中,混合物再於0℃下攪拌10min。慢慢滴加此溶液至已冷卻至-78℃之含[2-氟-6-(三氟甲基)苯基]乙腈(8.01g,98%純度,38.7mmol,CAS-RN 179946-34-0,可自商品取得)之74ml THF溶液中。一旦添加完畢即離開冷卻槽,讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,慢慢滴加含3-溴丙酸第三丁基酯(8.0ml,97%純度,46mmol)之27ml THF溶液,混合物再於-78℃下攪拌1h。離開冷卻槽,繼續於RT下攪拌反應混合物一夜。操作時,添加氯化銨溶液(10%水溶液,300ml),激烈攪拌混合物5min後,使用乙酸乙酯萃取2次。合併之 有機相依序使用1M鹽酸、飽和碳酸氫鈉水溶液與飽和氯化鈉水溶液洗滌,每次重覆2次,然後經硫酸鈉脫水,及減壓濃縮。殘質溶於環己烷、少量乙酸乙酯與二氯甲烷之混合物中,採用快速層析法,於矽膠上純化(環己烷/乙酸乙酯梯度100:0至70:30)。取合併之目標溶出份濃縮,殘質減壓乾燥後,再利用製備型HPLC純化(方法24)。取含產物溶出份濃縮,殘質減壓乾燥。得到4.52g(100%純度,35%理論值)標題化合物。
LC-MS(方法1):Rt=2.23min;MS(ESIpos):m/z=332[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.219(0.06),1.379(16.00),1.536(0.07),2.073(0.16),2.091(0.22),2.107(0.28),2.125(0.26),2.144(0.10),2.213(0.07),2.231(0.19),2.250(0.22),2.267(0.18),2.285(0.13),2.302(0.08),2.327(0.07),2.365(0.07),2.384(0.36),2.393(0.38),2.402(0.59),2.410(0.56),2.420(0.29),2.428(0.27),2.452(0.06),2.669(0.06),4.373(0.20),4.390(0.39),4.407(0.19),7.698(0.31),7.711(1.11),7.722(0.54),7.748(0.35),7.766(0.11).
該反應係在氬氣下進行。製備LDA溶液時,於-15℃下慢慢添加丁基鋰(1.6M己烷溶液,30ml,48mmol)至含二異丙基胺(7.1ml,51mmol)之THF(30ml)溶液中,混合物再於0℃下攪拌10min。慢慢滴加此溶液至已冷卻至-78℃之含(2,3,6-三氯苯基)乙腈(10.0g,97%純度,44.0mmol,CAS-RN 3215-65-4,可自商品取得)之THF(84ml)溶液中。一旦添加完畢即離開冷卻槽,讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,慢慢滴加含3-溴丙酸第三丁基酯(9.1ml,97%純度,53mmol)之THF(30ml)溶液,混合物再於-78℃下攪拌1h。離開冷卻槽,繼續於RT下攪拌反應混合物一夜。操作時,添加氯化銨溶液(10%含於300ml水中),激烈攪拌混合物5min後,使用乙酸乙酯萃取2次。合併之有機相依序使用1M鹽酸、飽和碳酸氫鈉水溶液與飽和氯化鈉水溶液洗滌,每 次重覆2次,然後經硫酸鈉脫水,及減壓濃縮。殘質經製備型HPLC純化(方法24)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到10.2g(95%純度,63%理論值)標題化合物。
LC-MS(方法1):Rt=2.41min;MS(ESIpos):m/z=348[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.382(16.00),1.997(0.45),2.316(0.42),2.367(0.45),2.381(0.71),2.403(0.63),3.322(0.80),5.002(0.48),7.620(0.69),7.637(0.90),7.746(0.92),7.763(0.70).
在氬氣下,在含[2-(二氟甲氧基)-6-氟苯基]乙腈(7.24g,36.0mmol,實施例10A)之THF(30ml)溶液中,於約-70至-60℃及攪拌下逐漸添加2M LDA之THF溶液(22ml,43mmol)。讓混合物回到0℃,15min後,再度冷卻至-70℃。隨後,在約-70至-60℃下,在攪拌下慢慢滴加3-溴丙酸第三丁基酯(6.8ml,43mmol)之THF(15ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/異丙醇)逐漸回到RT。隨後,於約0℃下,慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(400g矽膠,環己烷/乙酸乙酯梯度10:1)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到7.11g(74%純度,45%理論值)標題化合物。
LC-MS(方法2):Rt=1.10min;MS(ESIpos):m/z=330[M+H]+
在含(+/-)-3-(2-氯-6-氟苯基)-3-氰基丙酸第三丁基酯(43.9g,79%純度,122mmol,實施例11A)之第三丁醇(500ml)溶液中添加阮來鎳(7.15g,122mmol),於標準壓力(1atm)下氫化四天。隨後,再次添加阮來鎳(7.15g,122mmol)至混合物中,再次於標準壓力(1atm)下氫化24h。然後通過矽藻土濾除觸媒,使用第三丁醇(每次15ml)徹底洗滌2次。取濾液濃縮,殘質溶於乙酸乙酯(300ml),及使用1M鹽酸(每次250ml)萃取2次。隨後,水相使用飽和碳酸氫鈉水溶液調至pH 8-9,使用乙酸乙酯(每次200ml)萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到20.11g(99%純度,57%理論值)標題化合物。
LC-MS(方法2):Rt=0.55min;MS(ESIpos):m/z=288[M+H]+
在含(+/-)-4-(2-氯-5-氟苯基)-4-氰基丁酸第三丁基酯(14.0g,93%純度,43.7mmol,實施例12A)之第三丁醇(260ml)溶液中添加阮來鎳(2.57g,43.7mmol),於標準壓力(1atm)下氫化一夜。隨後,再次添加阮來鎳(2.57g,43.7mmol)至混合物中,再次於標準壓力(1atm)下氫化24h。隨後,再次添加阮來鎳(2.57g,43.7mmol)至混合物中,再次於標準壓力(1atm)下氫化24h。然後通過矽藻土濾除觸媒,取母液濃縮。得到14.4g(60%純度,65%理論值)標題化合物。
LC-MS(方法1):Rt=1.14min;MS(ESIpos):m/z=302[M+H]+
在含(+/-)-4-(2-氯苯基)-4-氰基丁酸第三丁基酯(4.50g,16.1mmol,實施例13A)之第三丁醇(90ml)溶液中添加阮來鎳(944mg,16.1mmol),於標準壓力(1atm)下氫化一夜。隨後,再次添加阮來鎳(944mg,16.1mmol)至混合物中,再次於標準壓力(1atm)下氫化24h。然後通過矽藻土濾除觸媒,取母液濃縮。殘質溶於二氯甲烷,採用快速層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到1.62g(91%純度,32%理論值)標題化合物。
LC-MS(方法3):Rt=1.70min;MS(ESIpos):m/z=284[M+H]+
在含(+/-)-4-氰基-4-[2-(三氟甲基)苯基]丁酸第三丁基酯(18.6g,59.5mmol,實施例14A)之第三丁醇(200ml)溶液中添加阮來鎳(3.49g,59.5mmol),於標準壓力(1atm)下氫化24h。然後通過矽藻土濾除觸媒,使用第三丁醇(每次50ml)徹底洗滌2次。取濾液濃縮,殘質減壓乾燥。得到17.8g(82%純度,77%理論值)標題化合物。
LC-MS(方法1):Rt=1.23min;MS(ESIpos):m/z=318[M+H]+
在含(+/-)-4-氰基-4-[2-(三氟甲氧基)苯基]丁酸第三丁基酯(3.13g,80%純度,7.59mmol,實施例15A)之第三丁醇(45ml)溶液中添加阮來鎳(446mg,7.59mmol),於標準壓力(1atm)下氫化一夜。隨後,再次添加阮來鎳(446mg,7.59mmol),混合物再次於標準壓力(1atm)下氫化24h。然後,通過矽藻土濾除觸媒,取濾液濃縮,及減壓乾燥。得到3.00g(83%純度,98%理論值)標題化合物。
LC-MS(方法1):Rt=1.29min;MS(ESIpos):m/z=334[M+H]+
在含(+/-)-4-(2-氯-3-氟苯基)-4-氰基丁酸第三丁基酯(4.32g,14.5mmol,實施例16A)之第三丁醇(85ml)溶液中添加阮來鎳(852mg,14.5mmol),於標準壓力(1atm)下氫化一夜。隨後,通過矽藻土濾除觸媒,使用第三丁醇(15ml)徹底洗滌2次,取母液濃縮。殘質溶於乙酸乙酯(80ml),依序使用1M鹽酸與水(每次80ml)萃取。合併之水相使用飽和碳酸氫鈉水溶液調至pH 8-9,使用乙酸乙酯(80ml)萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到2.43g(85%純度,47%理論值)標題化合物。
LC-MS(方法1):Rt=1.28min;MS(ESIpos):m/z=302[M+H]+
在含(+/-)-4-(6-氯-2,3-二氟苯基)-4-氰基丁酸第三丁基酯(2.26g,83%純度,5.95mmol,實施例17A)之第三丁醇(35ml)溶液中添加阮來鎳(349mg,5.95mmol),於標準壓力(1atm)下氫化一夜。隨後,通過矽藻土濾除觸媒,使用第三丁醇(10ml)徹底洗滌2次,取濾液濃縮。殘質溶於乙酸乙酯(50ml),依序使用1M鹽酸與水(每次50ml)萃取。合併之水相使用飽和碳酸氫鈉水溶液調至pH 8-9,使用乙酸乙酯(50ml)萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到1.05g(97%純度,53%理論值)標題化合物。
LC-MS(方法4):Rt=1.82min;MS(ESIpos):m/z=320[M+H]+
在含(+/-)-4-氰基-4-(5-氟-2-甲基苯基)丁酸第三丁基酯(4.92g,17.7mmol,實施例18A)之第三丁醇(100ml)溶液中添加阮來鎳(1.04g,17.7mmol),於標準壓力(1atm)下氫化24h。隨後,通過矽藻土濾除觸媒,使用第三丁醇(15ml)徹底洗滌2次,取濾液濃縮。殘質溶於乙酸乙酯(80ml),依序使用1M鹽酸與水(每次80ml)萃取。合併之水相使用飽和碳酸氫鈉水溶液調至pH 8-9,使用乙酸乙酯(80ml)萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到2.04g(92%純度,38%理論值)標題化合物。
LC-MS(方法4):Rt=1.94min;MS(ESIpos):m/z=282[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.109(0.34),1.197(0.07),1.293(0.03),1.357(16.00),1.394(0.15),1.513(0.24),1.609(0.11),1.621(0.11),1.638(0.25),1.648(0.17),1.663(0.22),1.681(0.14),1.709(0.06),1.927(0.05),1.943(0.10),1.950 (0.13),1.964(0.28),1.986(1.50),1.995(1.06),2.011(0.26),2.018(0.20),2.072(0.03),2.232(3.57),2.303(0.20),2.366(0.03),2.641(0.07),2.659(0.11),2.672(0.57),2.681(0.59),2.690(0.75),2.696(0.71),2.711(0.09),2.728(0.08),2.851(0.21),2.863(0.20),3.172(0.05),3.312(0.65),6.866(0.17),6.873(0.21),6.887(0.37),6.894(0.43),6.909(0.20),6.916(0.23),6.968(0.43),6.974(0.37),6.994(0.42),7.001(0.36),7.105(0.03),7.150(0.35),7.166(0.40),7.187(0.30).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:7.17(dd,1H),6.99(dd,1H),6.89(td,1H),2.93-2.80(m,1H),2.74-2.62(m,2H),2.23(s,3H),2.06-1.87(m,3H),1.74-1.60(m,1H),1.50(br.s,2H),1.36(s,9H).
在含(+/-)-4-(2-氯-3,6-二氟苯基)-4-氰基丁酸第三丁基酯(4.10g,13.0mmol,實施例19A)之第三丁醇(75ml)溶液中添加阮來鎳(762mg,13.0mmol),於標準壓力(1atm)下氫化24h。隨後,通過矽藻土濾除觸媒,使用第三丁醇(15ml)徹底洗滌2次,取母液濃縮。殘質溶於乙酸乙酯(80ml),該溶液依序使用1M鹽酸與水(每次80ml)萃取。合併之水相使用飽和碳酸氫鈉水溶液調至pH 8-9,使用乙酸乙酯(每次100ml)萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到1.76g(100%純度,42%理論值)標題化合物。
LC-MS(方法1):Rt=1.21min;MS(ESIpos):m/z=320[M+H]+
在含(+/-)-4-氰基-4-[2-氟-6-(三氟甲基)苯基]丁酸第三丁基酯(4.52g,13.6mmol,實施例20A)之第三丁醇(100ml)與甲醇(15ml)溶液中添加阮來鎳(801mg,13.6mmol),混合物於標準壓力(1atm)下氫化一夜。再次添加阮來鎳(2g,34.0mmol)至反應混合物中,在標準壓力(1atm)氫氣下激烈攪拌40h。隨後,通過矽藻土濾除觸媒,使用甲醇(每次30ml)徹底洗滌三次,取濾液減壓濃縮。殘質溶於200ml乙酸乙酯。此有機相使用200ml 1M鹽酸萃取2次。合併之水相藉由逐漸添加碳酸氫鈉而調至pH 8-9後,每次使用200ml乙酸乙酯萃取2次。合併之有機相經硫酸鈉脫水,及於旋轉蒸發器上濃縮。殘質減壓乾燥。得到3.32g(92%純度,67%理論值)標題化合物。
LC-MS(方法1):Rt=1.21min;MS(ESIpos):m/z=336[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.109(0.25),1.156(0.06),1.167(0.07),1.174(0.12),1.191(0.06),1.327(16.00),1.390(0.40),1.484(0.07),1.882(0.09),1.905(0.14),1.930(0.25),1.946(0.23),1.965(0.29),1.979(0.15),1.987(0.45),2.006(0.19),2.034(0.10),2.055(0.30),2.074(0.35),2.093(0.31),2.118(0.16),2.129(0.11),2.150(0.04),2.310(0.07),2.365(0.02),2.669(0.02),2.782(0.10),2.799(0.17),2.812(0.24),2.828(0.25),2.872(0.18),2.876(0.18),2.890(0.29),2.895(0.30),2.920(0.37),3.494(0.02),3.522(0.03),4.019(0.05),4.037(0.05),7.476(0.66),7.485(0.49),7.489(0.49),7.501(0.31),7.509(0.87),7.521(0.09),7.550(0.51),7.557(0.32),7.564(0.37),7.573(0.26),7.614(0.04),7.637(0.04).
在含(+/-)-4-氰基-4-(2,3,6-三氯苯基)丁酸第三丁基酯(10.2g,95%純度,27.9mmol,實施例21A)之第三丁醇(210ml)與甲醇(9.1ml)溶液中添加阮來鎳(1.64g,27.9mmol),混合物於攪拌下,在標準壓力(1atm)下氫化一夜。再添加阮來鎳(2.0g,34.0mmol),於攪拌下,在標準壓力(1atm)下再氫化三天。隨後,通過矽 藻土濾除觸媒,使用甲醇(每次30ml)徹底洗滌3次,取濾液濃縮。殘質溶於乙酸乙酯(400ml)。有機相使用1M鹽酸(300ml)萃取2次。合併之水相藉由逐漸添加碳氫鈉調至pH 8-9後,使用乙酸乙酯(每次300ml)萃取2次。合併之有機相經硫酸鈉脫水,及於旋轉蒸發器上濃縮。經減壓乾燥,產生2.54g(89%純度,23%理論值)標題化合物。
LC-MS(方法1):Rt=1.30min;MS(ESIpos):m/z=352[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.336(16.00),1.352(1.85),1.492(0.42),2.013(0.65),2.022(0.61),2.030(0.63),2.042(0.89),2.055(0.81),2.070(0.42),2.082(0.42),2.097(0.43),3.049(0.54),3.069(0.57),7.426(0.52),7.506(0.64),7.532(0.56),7.544(0.61),7.553(0.41).
在含(+/-)-4-氰基-4-[2-(二氟甲氧基)-6-氟苯基]丁酸第三丁基酯(7.07g,74%純度,16.0mmol,實施例22A)之第三丁醇(97ml)溶液中添加阮來鎳(937mg,16.0mmol),於標準壓力(1atm)下氫化三天。隨後,通過矽藻土濾除觸媒,使用第三丁醇(每次30ml)徹底洗滌2次。取濾液濃縮,殘質減壓乾燥。得到6.21g(65%純度,76%理論值)標題化合物。
LC-MS(方法1):Rt=1.16min;MS(ESIpos):m/z=334[M+H]+
於RT下,在含(+/-)-4-胺基-3-(2-氯-6-氟苯基)丁酸第三丁基酯(541mg,1.88mmol,實施例23A)之二氯甲烷(10ml)懸浮液中添加DIPEA(820μl,4.7mmol)。隨後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(500mg,1.57mmol,實施例3A)之二氯甲烷(5ml)懸浮液,混合物於室溫下攪拌16h。隨後,添加二氯甲烷與水(各30ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(30ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到804mg(96%純度,86%理論值)標題化合物。
LC-MS(方法2):Rt=1.30min;MS(ESIpos):m/z=569/571[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.241(16.00),1.397(0.24),2.250(0.33),2.755(0.40),2.770(0.37),3.730(0.13),4.051(0.16),7.206(0.19),7.219(0.23),7.246(0.21),7.340(0.65),7.882(0.19),7.905(1.60),7.934(0.13),8.968(0.22),8.983(0.44),8.998(0.22).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.98(t,1H),7.97-7.86(m,2H),7.86-7.43(br.,1H),7.38-7.31(m,2H),7.26-7.17(m,1H),4.16-3.92(m,1H),3.91-3.55(m,2H),2.85-2.62(m,2H),2.25(br.s,3H),1.24(s,9H).
於RT下,在含(+/-)-5-胺基-4-(2-氯-5-氟苯基)戊酸第三丁基酯(2.73g,9.03mmol,實施例24A)之二氯甲烷(50ml)懸浮液中添加DIPEA(3.9ml,23mmol)。隨後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(2.45g,98%純度,7.53mmol,實施例3A)之二氯甲烷(35ml)懸浮液,混合物於室溫下攪拌一夜。隨後,混合物再於50℃下攪拌20h。冷卻至室溫後,添加二氯甲烷與水(各50ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。 取合併之目標溶出份濃縮,殘質減壓乾燥。得到1.49g(98%純度,33%理論值)標題化合物。
LC-MS(方法1):Rt=2.58min;MS(ESIpos):m/z=583/585[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.87(t,1H),7.93-7.86(m,2H),7.65(br.m,1H,部份遮蔽),7.51(dd,1H),7.43(dd,1H),7.19-7.11(m,1H),3.73(br.s,2H),3.58(br.s,1H),2.23(br.s,3H),2.14-2.07(m,2H),2.06-1.96(m,1H),1.88-1.73(m,1H),1.37(s,9H).
於RT下,在含(+/-)-5-胺基-4-(2-氯苯基)戊酸第三丁基酯(800g,80%純度,22.6mmol,實施例25A)之二氯甲烷(200ml)懸浮液中添加DIPEA(9.8ml,56mmol)。隨後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(5.99g,18.8mmol,實施例3A)之二氯甲烷(30ml)懸浮液,混合物於室溫下攪拌一夜。隨後,添加二氯甲烷與水(各50ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(340g矽膠Biotage Snap-Cartridge,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,得到兩份產物溶出份,取殘質減壓乾燥。得到2.52g(92%純度,22%理論值,參見分析法)第一批標題化合物。來自層析法之第二份產物溶出份再度溶於二氯甲烷,再利用快速層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。得到1.35g(88%純度,11%理論值)第二批標題化合物。
LC-MS(方法1):Rt=2.54min;MS(ESIpos):m/z=565/567[M+H]+
於RT下,在含(+/-)-5-胺基-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(12.0g,82%純度,30.9mmol,實施例26A)之二氯甲烷(250ml)懸浮液中添加DIPEA(13ml,77mmol)。隨後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(8.22g,25.8mmol,實施例3A)之二氯甲烷(50ml)懸浮液,混合物於室溫下攪拌18h。隨後,添加水(400ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(200ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液洗滌,經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→75:25,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到11.7g(100%純度,76%理論值)標題化合物。
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=599/601[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.188(0.07),1.318(0.14),1.349(16.00),1.398(0.94),1.505(0.07),1.871(0.13),1.894(0.17),1.909(0.20),2.004(0.25),2.024(0.50),2.039(0.49),2.058(0.33),2.087(0.27),2.240(0.18),2.366(0.11),2.670(0.06),3.670(0.14),3.752(0.17),5.754(0.11),7.487(0.36),7.505(0.24),7.692(0.19),7.712(0.44),7.728(0.81),7.747(0.98),7.765(0.28),7.904(2.33),7.930(0.08),8.907(0.34).
取標題化合物(7.0g)溶於異丙醇(140ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例39A與40A)[管柱:Daicel Chiralcel OD-H,5μm,250mm x 50mm;流速:175ml/min;注射:1.2ml;溶析液:17%異丙醇/83%二氧化 碳;運行時間15min,等濃度,UV檢測210nm,溫度38℃]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例38A說明之對映異構物之分離法中,得到3.37g(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-19.3°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=599/601[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.17),0.007(0.15),1.029(2.07),1.044(2.09),1.187(0.07),1.310(0.10),1.317(0.13),1.348(16.00),1.503(0.06),1.871(0.11),1.894(0.15),1.908(0.18),1.918(0.15),1.941(0.10),1.963(0.05),1.984(0.07),2.003(0.23),2.023(0.46),2.038(0.45),2.057(0.31),2.080(0.22),2.087(0.25),2.100(0.18),2.117(0.18),2.130(0.14),2.151(0.11),2.239(0.15),2.365(0.07),2.669(0.04),3.669(0.12),3.751(0.22),3.762(0.20),3.766(0.22),3.777(0.19),3.782(0.16),3.792(0.14),4.323(0.26),4.334(0.26),7.467(0.17),7.485(0.32),7.503(0.21),7.691(0.18),7.710(0.40),7.727(0.74),7.745(0.90),7.764(0.24),7.881(0.08),7.902(2.20),7.929(0.06),8.907(0.31).
在實施例38A說明之對映異構物之分離法中,得到3.32g(100%純度,ee 99%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+18.0°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=599/601[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.029(2.26),1.044(2.27),1.187(0.07),1.317(0.13),1.347(16.00),1.503(0.06),1.870(0.12),1.894(0.16),1.908(0.19),1.941(0.10),2.003(0.24),2.023(0.48),2.038(0.47),2.057(0.32),2.086(0.26),2.117(0.18),2.222(0.16),2.365(0.08),2.669(0.05),3.669(0.13),3.751(0.24),3.762 (0.22),3.766(0.24),3.777(0.21),3.792(0.15),4.323(0.32),4.333(0.31),7.466(0.17),7.484(0.34),7.503(0.23),7.691(0.18),7.710(0.42),7.727(0.77),7.745(0.94),7.764(0.25),7.881(0.08),7.902(2.28),7.929(0.07),8.906(0.32).
於RT下,在含(+/-)-5-胺基-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(10.0g,78%純度,23.4mmol,實施例27A)之二氯甲烷(250ml)懸浮液中添加DIPEA(10ml,58mmol)。隨後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(6.21g,19.5mmol,實施例3A)之二氯甲烷(50ml)懸浮液,混合物於室溫下攪拌18h。隨後,添加水(400ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(200ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液洗滌,經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→75:25,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到9.91g(92%純度,76%理論值)標題化合物。
LC-MS(方法1):Rt=2.63min;MS(ESIpos):m/z=615/617[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.202(0.07),1.300(0.34),1.361(16.00),1.787(0.09),1.807(0.20),1.830(0.19),2.038(0.28),2.062(0.92),2.069(1.14),2.096(0.23),2.219(0.18),2.308(0.23),2.365(0.08),3.385(0.19),3.632(0.13),3.650(0.24),3.665(0.31),3.683(0.28),3.702(0.29),3.720(0.24),7.370(0.40),7.405(0.64),7.428(0.48),7.554(0.40),7.567(0.37),7.578(0.29),7.879(0.11),7.901(1.98),8.882(0.34).
取標題化合物(5.26g)溶於異丙醇(120ml)。隨後過濾,濾出之殘質使用12ml異丙醇洗滌,溶液利用製備性SFC,於對掌相上分離成對映異構物(參見實施例42A與43A)[管柱:Daicel Chiralcel OD-H,5μm,250mm x 50mm;流速:175ml/min;注射:0.8ml;溶析液:15%異丙醇/85%二氧化碳;運行時間14.5min,等濃度,UV檢測210nm,溫度40℃]。取合併之目標溶出份濃縮,取各殘質冷凍乾燥。
在實施例41A說明之對映異構物之分離法中,得到2.37g(100%純度,ee 100%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=+16.3°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法1):Rt=2.64min;MS(ESIpos):m/z=615/617[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.029(0.18),1.044(0.18),1.201(0.07),1.300(0.06),1.317(0.07),1.325(0.09),1.361(16.00),1.517(0.07),1.788(0.10),1.807(0.21),1.830(0.21),1.877(0.06),2.038(0.31),2.063(1.04),2.069(1.28),2.096(0.25),2.223(0.20),2.365(0.06),2.669(0.05),3.384(0.22),3.617(0.08),3.632(0.14),3.650(0.27),3.665(0.35),3.683(0.32),3.702(0.31),3.720(0.26),3.735(0.13),3.754(0.08),7.370(0.43),7.405(0.68),7.422(0.54),7.428(0.52),7.554(0.44),7.567(0.41),7.577(0.32),7.879(0.11),7.901(2.03),7.928(0.08),8.882(0.39).
在實施例41A說明之對映異構物之分離法,得到2.40g(100%純度,ee 99%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=-15.9°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.63min;MS(ESIpos):m/z=615/617[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.029(0.50),1.044(0.50),1.201(0.07),1.316(0.07),1.325(0.09),1.361(16.00),1.517(0.06),1.788(0.09),1.807(0.20),1.830(0.20),2.038(0.28),2.063(0.96),2.069(1.20),2.096(0.22),2.222(0.17),2.308(0.19),2.365(0.06),2.669(0.05),3.384(0.20),3.617(0.08),3.632(0.13),3.650(0.25),3.666(0.32),3.683(0.29),3.702(0.29),3.720(0.24),3.736(0.12),3.754(0.08),4.323(0.07),4.333(0.07),7.369(0.40),7.405(0.64),7.421(0.50),7.428(0.50),7.554(0.40),7.567(0.37),7.577(0.31),7.879(0.11),7.901(1.97),8.882(0.36).
於RT下,在含(+/-)-5-胺基-4-(2-氯-3-氟苯基)戊酸第三丁基酯(1.40g,85%純度,3.94mmol,實施例28A)之二氯甲烷(45ml)溶液中添加DIPEA(1.7ml,9.9mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.07g,98%純度,3.29mmol,實施例3A),混合物於室溫下攪拌20h。隨後,添加水與二氯甲烷(各150ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(150ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到206mg(100%純度,11%理論值)標題化合物。
LC-MS(方法2):Rt=1.32min;MS(ESIpos):m/z=583/585[M-H]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.210(0.08),1.370(16.00),1.397(2.57),1.828(0.24),2.035(0.25),2.052(0.26),2.071(0.32),2.090(1.00),2.106(1.01),2.126 (0.40),2.218(0.37),3.603(0.25),3.733(0.32),7.313(0.33),7.335(0.25),7.355(0.33),7.374(0.52),7.419(0.29),7.896(2.22),7.923(0.14),8.855(0.29),8.870(0.52).
於RT下,在含(+/-)-5-胺基-4-(6-氯-2,3-二氟苯基)戊酸第三丁基酯(400mg,96%純度,1.20mmol,實施例29A)之二氯甲烷(12ml)溶液中添加DIPEA(520μl,3.0mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(326mg,98%純度,1.00mmol,實施例3A),混合物於室溫下攪拌20h。隨後,添加水與二氯甲烷(各10ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(100ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(25g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到156mg(87%純度,23%理論值)標題化合物。
LC-MS(方法2):Rt=1.34min;MS(ESIpos):m/z=601/603[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.31),1.203(0.08),1.260(0.09),1.309(0.11),1.363(16.00),1.397(2.44),1.970(0.12),2.056(0.23),2.075(0.22),2.159(0.48),2.176(0.70),2.242(1.02),2.351(0.88),2.365(0.11),2.669(0.08),2.709(0.08),3.097(0.10),3.702(0.26),3.804(0.30),7.402(0.45),7.737(0.19),7.878(0.19),7.901(1.91),7.908(1.10),7.929(0.48),8.965(0.37).
於RT下,在含(+/-)-5-胺基-4-(5-氟-2-甲基苯基)戊酸第三丁基酯(1.40g,92%純度,4.58mmol,實施例30A)之二氯甲烷(45ml)溶液中添加DIPEA(2.0ml,11mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.25g,97%純度,3.81mmol,實施例3A),混合物於室溫下攪拌20h。隨後,添加水與二氯甲烷(各150ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(100ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到538mg(100%純度,25%理論值)標題化合物。
LC-MS(方法2):Rt=1.34min;MS(ESIpos):m/z=563/565[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.21),1.211(0.07),1.300(0.11),1.332(0.11),1.372(16.00),1.397(2.79),1.755(0.12),1.789(0.19),1.812(0.17),1.969(0.16),1.982(0.20),1.999(0.20),2.019(0.15),2.032(0.13),2.067(0.69),2.084(0.98),2.103(0.46),2.283(1.44),3.504(0.12),3.517(0.18),3.537(0.20),3.551(0.24),3.565(0.15),3.706(0.13),3.724(0.19),3.744(0.16),3.758(0.14),6.957(0.24),7.156(0.31),7.162(0.31),7.183(0.32),7.206(0.36),7.221(0.40),7.242(0.31),7.876(0.11),7.898(2.22),7.925(0.09),8.851(0.31).
於RT下,在含(+/-)-5-胺基-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(9.53g,81%純度,24.0mmol,實施例31A)之二氯甲烷(200ml)溶液中添加DIPEA(10ml,60mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(6.38g,20.0mmol,實施例3A),混合物於室溫下攪拌20h。隨後,添加水與二氯甲烷(各150ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(150ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到8.40g(90%純度,63%理論值)標題化合物。
LC-MS(方法1):Rt=2.54min;MS(ESIpos):m/z=601/603[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.157(0.23),1.175(0.45),1.193(0.24),1.202(0.08),1.268(0.07),1.311(0.35),1.321(0.40),1.363(16.00),1.380(0.76),1.407(0.25),1.519(0.07),1.989(0.95),2.046(0.21),2.060(0.26),2.077(0.24),2.097(0.18),2.143(0.58),2.161(0.76),2.237(0.60),2.351(0.07),2.366(0.05),2.670(0.04),2.711(0.03),3.697(0.24),3.800(0.28),4.003(0.08),4.021(0.21),4.039(0.21),4.057(0.08),7.312(0.25),7.327(0.19),7.417(0.21),7.750(0.05),7.882(0.18),7.905(2.10),7.934(0.14),8.950(0.24),8.964(0.43).
取標題化合物(4.8g)溶於乙腈,利用製備型HPLC於對掌相上分離成對映異構物(參見實施例48A與49A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:20ml/min;檢測:220nm;溫度:30℃;注射:30ml;溶析液:20%異丙醇/80%庚烷;運行時間18min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。
在實施例47A說明之對映異構物之分離法中,得到1.52g(81%純度,ee 100%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=+31.9°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=2.56min;MS(ESIpos):m/z=601/603[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.151(0.03),1.009(0.23),1.029(3.00),1.044(3.00),1.105(0.49),1.108(0.83),1.120(0.35),1.139(0.06),1.201(0.08),1.267(0.07),1.309(0.32),1.362(16.00),1.406(0.23),1.518(0.07),1.595(0.04),1.681(0.12),1.979(0.14),2.045(0.23),2.059(0.28),2.075(0.27),2.096(0.21),2.142(0.65),2.160(0.82),2.236(0.67),2.350(0.12),2.417(0.04),2.669(0.04),3.533(0.53),3.696(0.29),3.741(0.21),3.756(0.35),3.772(0.47),3.787(0.49),3.802(0.40),7.311(0.29),7.326(0.21),7.417(0.25),7.748(0.07),7.881(0.20),7.904(2.30),7.928(0.16),8.963(0.48).
在實施例47A說明之對映異構物之分離法中,得到1.46g(82%純度,ee 97%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=-32.3°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.56min;MS(ESIpos):m/z=601/603[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.850(0.05),1.009(0.34),1.029(2.07),1.044(2.03),1.104(0.77),1.108(1.13),1.120(0.64),1.139(0.11),1.155(0.06),1.201(0.08),1.267(0.10),1.309(0.37),1.320(0.47),1.362(16.00),1.378(0.57),1.406(0.24),1.518(0.07),1.681(0.09),1.974(0.16),2.044(0.25),2.061(0.32),2.075(0.30),2.095(0.24),2.142(0.72),2.159(0.86),2.236(0.75),2.669(0.05),3.533(0.56),3.567(0.54),3.697(0.34),3.756(0.32),3.771(0.43),3.787(0.47),3.802 (0.41),4.270(0.05),7.311(0.32),7.326(0.22),7.417(0.28),7.763(0.07),7.881(0.28),7.904(2.52),7.932(0.15),8.963(0.51).
於RT下,在含(+/-)-5-胺基-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(2.15g,92%純度,5.91mmol,實施例32A)與DIPEA(2.6ml,15mmol)之二氯甲烷(57ml)溶液中添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.57g,4.92mmol,實施例3A)之少量二氯甲烷之溶液。混合物於室溫下攪拌一夜。操作時,添加水與二氯甲烷(各200ml),分相。水相使用二氯甲烷(200ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(200ml)洗滌,經硫酸鈉脫水,過濾,及減壓濃縮。殘質溶於少量環己烷與乙酸乙酯,利用管柱層析法純化(Biotage,100g矽膠,Snap-Cartridge Ultra,溶析液:環己烷/乙酸乙酯8:2)。取所得產物溶出份減壓濃縮,殘質減壓乾燥。得到2.20g(97%純度,70%理論值)標題化合物。
LC-MS(方法1):Rt=2.57min;MS(ESIpos):m/z=617[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.96(t,1H),7.94-7.86(m,2H)7.87-7.25(m,4H),3.93(br.s,1H),3.73(br.s,1H),3.34-3.24(1H,隱蔽),2.45-1.99(m,7H),1.34(s,9H).
於RT下,在含(+/-)-5-胺基-4-(2,3,6-三氯苯基)戊酸第三丁基酯(1.84g,89%純度,4.64mmol,實施例33A)與DIPEA(2.0ml,12mmol)之二氯甲烷(45ml)溶液中添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.23g,3.87mmol,實施例3A)之少量二氯甲烷之溶液。混合物於室溫下攪拌2h。操作時,添加水與二氯甲烷(各200ml)。分相,水相使用二氯甲烷(200ml)萃取一次。合併之有機相使用飽和氯化鈉水溶液(200ml)洗滌,經硫酸鈉脫水,過濾,及減壓濃縮。殘質溶於少量DMSO,利用製備型HPLC純化(方法13)。取所得產物溶出份減壓濃縮,殘質減壓乾燥。得到2.03g(93%純度,77%理論值)標題化合物。
LC-MS(方法4):Rt=1.75min;未檢測目標質量即進行電離化
1H-NMR(500MHz,DMSO-d 6):δ[ppm]=8.98-8.88(m,1H),7.97-7.34(m,5H),4.22-3.95(m,2H),3.95-3.79(m,1H),2.35-1.99(m,7H),1.37-1.34(m,9H).
於RT下,在含(+/-)-5-胺基-4-[2-(二氟甲氧基)-6-氟苯基]戊酸第三丁基酯(5.51g,65%純度,10.7mmol,實施例34A)之二氯甲烷(100ml)溶液中添加DIPEA(4.7ml,27mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(2.85g,8.94mmol,實施 例3A),混合物於室溫下攪拌20h。隨後,添加水與二氯甲烷(各150ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(150ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到4.78g(91%純度,79%理論值)標題化合物。
LC-MS(方法1):Rt=2.49min;MS(ESIpos):m/z=615/617[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.158(0.05),1.175(0.11),1.199(0.07),1.292(0.08),1.308(0.28),1.320(0.37),1.337(1.76),1.360(16.00),1.372(0.72),1.394(0.28),1.516(0.07),1.957(0.22),1.989(0.32),1.998(0.30),2.011(0.25),2.031(0.28),2.047(0.23),2.067(0.18),2.086(0.80),2.103(0.80),2.120(0.32),2.224(0.28),2.343(0.12),2.635(0.07),2.672(0.09),2.848(0.04),3.522(0.22),3.741(0.20),3.797(0.16),4.021(0.05),4.039(0.05),6.965(0.07),6.985(0.12),7.028(0.46),7.048(0.53),7.069(0.41),7.097(0.32),7.120(0.46),7.144(0.34),7.161(0.08),7.179(0.10),7.253(0.70),7.288(0.09),7.305(0.11),7.323(0.07),7.364(0.17),7.385(0.25),7.402(0.24),7.436(0.37),7.751(0.07),7.878(0.17),7.901(1.98),7.930(0.15),8.918(0.25),8.933(0.50),8.948(0.26).
在含(+/-)-4-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-3-(2-氯-6-氟苯基)丁酸第三丁基酯(300mg,526μmol,實施例35A)之1-丁醇(3.8ml)懸浮液中添加哌啶 (160μl,1.6mmol),混合物於100℃下攪拌16h。冷卻至室溫後,添加水與乙酸乙酯(各50ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,利用快速管柱層析法純化(25g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。隨後再利用製備型HPLC純化(方法9)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到184mg(98%純度,55%理論值)標題化合物。
LC-MS(方法1):Rt=2.74min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.236(16.00),1.613(0.55),1.678(1.07),2.169(1.96),2.758(0.44),2.772(0.40),3.161(1.37),3.704(0.19),4.052(0.23),7.213(0.31),7.239(0.27),7.326(1.03),7.333(0.91),7.354(0.27),7.647(0.36),7.669(1.51),7.678(0.99),7.683(0.88),7.705(0.21),8.825(0.26),8.840(0.53),8.855(0.26).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.84(t,1H),7.72-7.63(m,2H),7.50(br.s,1H),7.39-7.30(m,2H),7.25-7.17(m,1H),4.13-3.96(m,1H),3.87-3.57(m,2H),3.16(br.s,4H),2.86-2.60(m,2H),2.17(s,3H),1.79-1.55(m,6H),1.24(s,9H).
在含(+/-)-4-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-3-(2-氯-6-氟苯基)丁酸第三丁基酯(300mg,526μmol,實施例35A)之1-丁醇(3.8ml)懸浮液中添加2- 苯基乙胺(200μl,1.6mmol),混合物於100℃下攪拌一夜。隨後,混合物於130℃下再攪拌24h。冷卻至室溫後,添加水與乙酸乙酯(各50ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(25g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。然後再利用製備型HPLC純化(方法9)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到162mg(98%純度,46%理論值)標題化合物。
LC-MS(方法1):Rt=2.41min;MS(ESIpos):m/z=654/656[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.88(br.s,1H),7.68(br.s,1H),7.41-7.15(m,11H),4.04(br.s,1H),3.90-3.62(m,4H),2.97(br.t,2H),2.82-2.66(m,2H),2.10-1.88(m,3H),1.24(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(1.10g,1.88mmol,實施例36A)之1-丁醇(14ml)懸浮液中添加哌啶(560μl,5.6mmol),混合物於100℃下攪拌三天。冷卻至室溫後,添加水與乙酸乙酯(各50ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到676mg(98%純度,56%理論值)標題化合物。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.47(br.s,1H,部份遮蔽),7.41(dd,1H),7.14(td,1H),3.74-3.64(m,2H),3.63-3.53(m,1H),3.17-3.10(m,4H),2.17-1.94(m,6H),1.86-1.74(m,1H),1.72-1.55(m,6H),1.37(s,9H).
取標題化合物(675mg)溶於乙醇(7ml),利用製備型HPLC於對掌相上分離成對映異構物(參見實施例56A與57A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:40ml/min;注射:0.1ml;溶析液:20%乙醇/80%庚烷;運行時間10min,等濃度]。取合併之目標溶出份濃縮,殘質冷凍乾燥。
在實施例55A說明之對映異構物之分離法中,得到237mg(98%純度,ee 99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-12.8°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.47(br.s,1H,部份遮蔽),7.41(dd,1H),7.14(td,1H),3.74-3.64(m,2H),3.63-3.53(m,1H),3.17-3.09(m,4H),2.16-1.97(m,6H),1.87-1.74(m,1H),1.72-1.55(m,6H),1.37(s,9H).
在實施例55A說明之對映異構物之分離法中,得到207mg(98%純度,ee 99%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+13.1°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.70-7.60(m,2H),7.50(dd, 1H),7.47(br.s,1H,部份遮蔽),7.41(dd,1H),7.14(td,1H),3.74-3.64(m,2H),3.63-3.53(m,1H),3.17-3.10(m,4H),2.16-1.96(m,6H),1.87-1.74(m,1H),1.73-1.54(m,6H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(135mg,231μmol,實施例36A)之1-丁醇(1.7ml)懸浮液中添加4,4-二氟哌啶(84mg,693μmol),混合物於100℃下攪拌四天。冷卻至室溫後,添加水與乙酸乙酯(各20ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(20ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(25g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→5:5,Isolera One)。然後再利用製備型HPLC純化(方法9)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到19mg(72%純度,9%理論值)標題化合物。
LC-MS(方法1):Rt=2.72min;MS(ESIpos):m/z=668/670[M+H]+
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(135mg,231μmol,實施例36A)之1-丁醇(1.7ml)懸浮液中添加嗎啉(60μl,690μmol),混合物於100℃下攪拌四天。冷卻至室溫後,添加水與乙酸乙酯(各20ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(20ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(25g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。然後再利用製備型HPLC純化(方法9)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到61mg(98%純度,41%理論值)標題化合物。
LC-MS(方法1):Rt=2.55min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.21),0.007(0.19),1.211(0.06),1.296(0.07),1.328(0.09),1.371(16.00),1.527(0.06),1.773(0.12),1.790(0.14),1.808(0.16),1.829(0.13),1.999(0.14),2.011(0.18),2.029(0.18),2.050(0.15),2.063(0.12),2.085(0.65),2.102(0.88),2.122(0.35),2.147(1.79),2.327(0.04),2.365(0.04),2.669(0.04),2.709(0.04),3.172(1.20),3.177(1.21),3.185(0.93),3.587(0.21),3.692(0.46),3.753(1.33),3.764(1.83),3.775(1.35),3.838(0.55),7.115(0.13),7.123(0.15),7.137(0.24),7.143(0.26),7.157(0.15),7.165(0.15),7.395(0.34),7.402(0.35),7.420(0.36),7.428(0.34),7.483(0.48),7.496(0.50),7.505(0.47),7.518(0.43),7.661(0.18),7.683(1.46),7.691(0.90),7.708(0.11),7.713(0.13),8.731(0.20),8.746(0.40),8.760(0.19).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.75(t,1H),7.73-7.65(m,2H),7.50(dd,1H),7.46(br.s,1H,隱蔽),7.41(dd,1H),7.14(td,1H),3.80-3.65(m,6H,部份遮 蔽),3.59(br.s,1H),3.25-3.12(m,4H),2.20-1.95(m,6H),1.87-1.73(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加1,2,3,6-四氫吡啶(43mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到50mg(98%純度,45%理論值)標題化合物。
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.07),-0.009(0.56),0.007(0.62),0.146(0.07),1.213(0.06),1.297(0.06),1.331(0.09),1.373(16.00),1.529(0.07),1.780(0.12),1.814(0.18),1.836(0.14),2.007(0.15),2.019(0.18),2.037(0.18),2.057(0.17),2.070(0.16),2.086(0.71),2.103(0.93),2.124(0.46),2.140(2.18),2.302(0.44),2.365(0.07),2.669(0.07),2.709(0.06),3.274(0.31),3.587(0.19),3.689(0.35),3.795(0.79),5.817(0.15),5.843(0.49),5.863(0.45),5.888(0.14),7.123(0.16),7.144(0.28),7.158(0.16),7.165(0.16),7.397(0.35),7.404(0.37),7.422(0.38),7.429(0.37),7.482(0.48),7.496(0.48),7.504(0.45),7.517(0.41),7.619(0.38),7.641(1.32),7.654(0.81),7.659(0.75),7.677(0.22),7.682(0.24),8.720(0.21),8.734(0.41),8.748(0.20).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.73(t,1H),7.69-7.61(m,2H),7.50(dd, 1H),7.47(br.s,1H),7.41(dd,1H),7.14(td,1H),5.91-5.79(m,2H),3.80(br.s,2H),3.69(br.s,2H),3.59(br.s,1H),3.27(br.s,2H,部份遮蔽),2.30(br.s,2H),2.18-1.97(m,6H),1.88-1.74(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加硫嗎啉(53mg,513μmol),混合物於100℃下攪拌18h。隨後,再次添加硫嗎啉(53mg,513μmol),混合物於100℃下再攪拌四天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到55mg(98%純度,48%理論值)標題化合物。
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.07),-0.009(0.65),0.007(0.57),0.145(0.08),1.212(0.06),1.298(0.07),1.329(0.09),1.372(16.00),1.528(0.07),1.775(0.12),1.809(0.18),1.830(0.15),2.000(0.15),2.013(0.19),2.030(0.19),2.051(0.16),2.064(0.14),2.084(0.71),2.101(0.99),2.128(2.24),2.327(0.06),2.365(0.05),2.669(0.07),2.709(0.06),2.785(1.20),2.797(1.13),3.424(1.18),3.583(0.20),3.687(0.35),7.124(0.16),7.144(0.28),7.165(0.17),7.395(0.35),7.402(0.36),7.420(0.37),7.427(0.36),7.482(0.49),7.495(0.51),7.504(0.48),7.517(0.44),7.656(0.22),7.678(1.47),7.683(1.07),7.688(0.88),7.706(0.15),7.710 (0.17),8.714(0.22),8.728(0.43),8.742(0.21).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.73(t,1H),7.72-7.65(m,2H),7.50(dd,1H),7.46(br.s,1H,部份遮蔽),7.41(dd,1H),7.14(td,1H),3.69(br.s,2H),3.58(br.s,1H),3.46-3.39(m,4H),2.82-2.75(m,4H),2.17-1.97(m,6H),1.88-1.74(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加順-2,6-二甲基嗎啉(59mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到70mg(98%純度,60%理論值)標題化合物。
LC-MS(方法1):Rt=2.71min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.06),0.007(0.42),0.146(0.06),1.133(3.52),1.148(3.54),1.212(0.07),1.299(0.08),1.330(0.09),1.372(16.00),1.528(0.07),1.813(0.18),2.017(0.18),2.035(0.17),2.055(0.15),2.067(0.15),2.085(0.69),2.101(0.90),2.121(0.34),2.156(2.32),2.327(0.08),2.366(0.07),2.669(0.09),2.709(0.08),3.431(0.58),3.461(0.54),3.581(0.19),3.685(0.31),3.777(0.41),7.124(0.16),7.145(0.28),7.159(0.16),7.393(0.35),7.400(0.35),7.418(0.36),7.425(0.35),7.483(0.49),7.496(0.50),7.505(0.46),7.518(0.42),7.655 (0.08),7.676(2.30),8.707(0.22),8.721(0.42).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.71-7.64(m,2H),7.50(dd,1H),7.46(br.s,1H,部份遮蔽),7.41(dd,1H),7.14(td,1H),3.84-3.73(m,2H),3.69(br.s,2H),3.58(br.s,1H),3.45(br.d,2H),2.54-2.48(隱蔽,2H),2.16(s,3H),2.13-1.96(m,3H),1.87-1.75(m,1H),1.37(s,9H),1.15(s,3H),1.13(s,3H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加吡咯啶(43μl,510μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法20)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到63mg(98%純度,58%理論值)標題化合物。
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.06),-0.008(0.54),0.007(0.50),0.146(0.06),1.211(0.06),1.299(0.08),1.332(0.11),1.343(0.12),1.371(16.00),1.527(0.07),1.775(0.13),1.791(0.16),1.809(0.20),1.831(0.21),1.870(1.32),1.999(0.16),2.012(0.20),2.030(0.20),2.050(0.18),2.083(0.71),2.100(0.91),2.120(0.36),2.155(1.44),2.327(0.05),2.366(0.05),2.669(0.06),2.709(0.06),3.567(1.08),3.670(0.36),7.118(0.15),7.138(0.27),7.152(0.16),7.385(0.41),7.392(0.43),7.410(0.41),7.418(0.40),7.466(0.74),7.474(0.45),7.488(1.61),7.496(0.45),7.510(0.39),7.544(0.66),7.549(0.62),7.566(0.39),7.572(0.38),8.674 (0.39).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.67(t,1H),7.56(dd,1H),7.52-7.46(m,2H),7.40(dd,1H),7.37(br.s,1H,隱蔽),7.14(td,1H),3.67(br.s,2H),3.57(br.s,5H),2.20-1.96(m,6H),1.91-1.74(m,5H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加1,2-唑啶(37.5mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法23)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到35mg(98%純度,32%理論值)標題化合物。
LC-MS(方法1):Rt=2.57min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.04),-0.009(0.31),0.145(0.04),1.212(0.06),1.288(0.06),1.324(0.09),1.373(16.00),1.529(0.07),1.757(0.05),1.775(0.13),1.792(0.16),1.810(0.19),1.831(0.15),2.000(0.16),2.013(0.20),2.031(0.20),2.051(0.18),2.062(0.13),2.087(0.71),2.104(0.92),2.122(0.32),2.210(1.47),2.239(0.64),2.257(0.85),2.275(0.62),2.293(0.19),2.331(0.05),2.365(0.04),2.669(0.04),2.709(0.04),3.590(0.20),3.686(0.39),3.700(0.53),3.773(0.37),3.819(0.64),3.837(1.08),3.856(0.58),7.124(0.15),7.145(0.27),7.159(0.16),7.394(0.36),7.401(0.36),7.419(0.36),7.426(0.35),7.486(0.43),7.499(0.46),7.508(0.45),7.521(0.43),7.709(0.11),7.731(2.33),7.757(0.09),8.772 (0.22),8.787(0.42),8.800(0.21).
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.79(t,1H),7.77-7.69(m,2H),7.53(br.s,1H,隱蔽),7.50(dd,1H),7.41(dd,1H),7.14(td,1H),3.84(t,2H),3.77(br.s,2H),3.74-3.65(m,2H),3.65-3.54(m,1H),2.31-2.17(m,5H),2.15-2.07(m,2H),2.07-1.97(m,1H),1.88-1.73(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加2,5-二氫-1H-吡咯(36mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法23)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到32mg(81%純度,25%理論值)標題化合物。
LC-MS(方法1):Rt=2.55min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.69(t,1H),7.57(dd,1H),7.52-7.46(m,2H),7.40(dd,1H),7.36(寬,隱蔽,1H),7.17-7.10(m,1H),5.96(s,2H),4.53(br.s,4H),3.77-3.52(m,3H),2.25(br.s,3H),2.14-1.95(m,3H),1.87-1.74(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加(+/-)-吡咯啶-3-醇(45mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法20)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到60mg(98%純度,54%理論值)標題化合物。
LC-MS(方法1):Rt=2.02min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.82),0.008(0.78),1.371(16.00),1.832(0.42),2.084(0.90),2.101(1.17),2.122(0.54),2.146(1.73),3.669(0.41),4.331(0.42),4.897(0.43),4.905(0.74),4.912(0.46),7.390(0.51),7.416(0.50),7.466(0.85),7.478(0.44),7.488(1.75),7.497(0.43),7.500(0.41),7.545(0.70),7.548(0.65),7.567(0.41),8.696(0.44).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.70(br.t,1H),7.59-7.53(m,1H),7.52-7.46(m,2H),7.43-7.38(m,1H),7.36(br.s,部分隱蔽,1H),7.18-7.09(m,1H),4.90(t,1H),4.33(br.s,1H),3.90-3.46(m,7H),2.19-1.72(m,9H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加(+/-)-3-甲基哌啶(51mg,513μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到78mg(98%純度,69%理論值)標題化合物。
LC-MS(方法1):Rt=2.89min;MS(ESIpos):m/z=646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(0.63),0.919(1.45),0.936(1.34),1.373(16.00),1.794(0.50),2.084(0.80),2.101(1.03),2.132(2.37),3.459(0.49),3.678(0.42),7.483(0.57),7.496(0.55),7.505(0.51),7.518(0.42),7.648(1.52),7.656(0.95),8.717(0.41).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.68-7.62(m,2H),7.50(dd,1H),7.46(br.s,部分隱蔽,1H),7.41(dd,1H),7.19-7.10(m,1H),3.78-3.39(m,5H),2.69(br.d,1H),2.45-2.41(隱蔽,1H),2.18-1.94(m,6H),1.86-1.58(m,5H),1.37(s,9H),1.17-1.01(m,1H),0.93(d,3H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加4-甲基哌啶(51mg,513μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到72mg(98%純度,64%理論值)標題化合物。
LC-MS(方法1):Rt=2.88min;MS(ESIpos):m/z=646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.32),0.007(0.30),0.865(0.06),0.964(1.71),0.980(1.80),1.212(0.06),1.285(0.31),1.314(0.35),1.372(16.00),1.562(0.16),1.717(0.43),1.747(0.39),1.774(0.14),1.809(0.17),1.829(0.14),2.001(0.14),2.014(0.18),2.031(0.18),2.051(0.17),2.065(0.15),2.084(0.69),2.100(0.98),2.119(2.48),2.327(0.06),2.365(0.07),2.669(0.07),2.709(0.10),2.756(0.29),2.777(0.32),2.805(0.16),3.508(0.47),3.540(0.46),3.580(0.20),3.683(0.41),7.123(0.16),7.144(0.28),7.157(0.17),7.165(0.17),7.391(0.36),7.398(0.37),7.416(0.38),7.424(0.36),7.481(0.49),7.495(0.48),7.503(0.44),7.517(0.40),7.618(0.33),7.640(1.38),7.650(0.88),7.655(0.78),7.673(0.19),7.678(0.21),8.704(0.21),8.719(0.42),8.733(0.21).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.47(br.s,部份遮蔽,1H),7.41(dd,1H),7.14(td,1H),3.74-3.64(m,2H), 3.63-3.56(m,1H),3.52(br.d,2H),2.83-2.70(m,2H),2.15-1.97(m,6H),1.86-1.76(m,1H),1.73(br.d,2H),1.62-1.50(m,1H),1.37(s,9H),1.36-1.22(m,2H),0.97(d,3H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加(+/-)-3-甲氧基哌啶(59.1mg,513μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到68mg(98%純度,58%理論值)標題化合物。
LC-MS(方法1):Rt=2.66min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.53),1.233(0.14),1.373(16.00),1.573(0.15),1.794(0.35),2.035(0.36),2.085(0.75),2.102(0.96),2.133(2.46),2.731(0.18),2.840(0.18),3.301(6.14),3.425(0.25),3.585(0.45),3.614(0.33),3.687(0.47),7.122(0.18),7.143(0.30),7.156(0.18),7.395(0.37),7.402(0.37),7.420(0.38),7.428(0.36),7.479(0.54),7.493(0.55),7.502(0.49),7.515(0.43),7.635(0.30),7.657(1.46),7.664(1.01),7.669(0.84),7.691(0.18),8.721(0.43).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.70-7.62(m,2H),7.50(dd,1H),7.46(br.s,部份遮蔽,1H),7.41(dd,1H),7.14(td,1H),3.76-3.64(m,2H),3.64-3.54(m,2H),3.47-3.38(m,1H),3.30(s,部份遮蔽,3H),2.92-2.79(m,1H), 2.78-2.67(m,1H),2.18-1.95(m,7H),1.87-1.74(m,2H),1.65-1.52(m,1H),1.46-1.32(m,部份遮蔽,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加(+/-)-嗎啉-2-基甲醇(60mg,513μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法23)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到35mg(98%純度,30%理論值)標題化合物。
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.40),0.007(0.40),1.213(0.06),1.329(0.08),1.372(16.00),1.529(0.06),1.776(0.12),1.810(0.17),1.832(0.14),2.000(0.14),2.013(0.18),2.031(0.17),2.051(0.15),2.086(0.66),2.103(0.89),2.123(0.35),2.153(1.90),2.327(0.08),2.366(0.07),2.669(0.23),2.692(0.17),2.710(0.12),2.898(0.16),3.380(0.32),3.417(0.42),3.481(0.21),3.494(0.42),3.508(0.51),3.522(0.45),3.535(0.25),3.549(0.29),3.618(0.29),3.680(0.41),3.708(0.52),3.737(0.22),3.908(0.32),3.935(0.26),4.748(0.34),4.762(0.68),4.776(0.32),7.123(0.15),7.144(0.27),7.158(0.15),7.396(0.30),7.403(0.31),7.421(0.32),7.428(0.30),7.482(0.48),7.496(0.50),7.504(0.47),7.517(0.43),7.661(0.14),7.683(1.97),7.689(0.99),7.711(0.12),8.749(0.37).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.75(t,1H),7.72-7.65(m,2H),7.50(dd,1H),7.47(br s,1H),7.41(dd,1H),7.14(td,1H),4.76(t,1H),3.92(br d,1H),3.77-3.47(m,7H),3.46-3.35(m,2H),2.96-2.82(m,1H),2.74-2.60(m,1H),2.15(s,3H),2.13-2.07(m,2H),2.07-1.96(m,1H),1.88-1.73(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-5-氟苯基)戊酸第三丁基酯(100mg,171μmol,實施例36A)之1-丁醇(1.2ml)懸浮液中添加(+/-)-哌啶-3-基甲醇(59mg,513μmol),混合物於100℃下攪拌三天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法23)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到63mg(98%純度,54%理論值)標題化合物。
LC-MS(方法1):Rt=2.43min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.154(0.04),0.142(0.04),1.118(0.19),1.141(0.21),1.209(0.07),1.295(0.07),1.326(0.10),1.369(16.00),1.525(0.07),1.640(0.17),1.747(0.56),1.773(0.71),1.807(0.34),1.999(0.16),2.011(0.20),2.029(0.20),2.049(0.18),2.062(0.16),2.081(0.76),2.098(1.02),2.128(2.35),2.323(0.05),2.362(0.04),2.665(0.06),2.721(0.17),2.741(0.19),3.356(0.20),3.368(0.37),3.381(0.33),3.394(0.23),3.407(0.13),3.438(0.24),3.468(0.21),3.585(0.48),3.613(0.36),3.680(0.34),4.505(0.34),4.517(0.69),4.530(0.33),7.118(0.17),7.139(0.31),7.153(0.18),7.160(0.18),7.388(0.36),7.395(0.37),7.413 (0.38),7.421(0.37),7.477(0.50),7.490(0.50),7.499(0.45),7.513(0.41),7.623(0.21),7.645(1.52),7.654(0.92),7.676(0.15),8.728(0.41).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.73(t,1H),7.69-7.62(m,2H),7.50(dd,1H),7.47(br.s,部份遮蔽,1H),7.41(dd,1H),7.14(td,1H),4.52(t,1H),3.75-3.53(m,4H),3.46(br.d,1H),3.42-3.35(m,1H),3.33-3.26(m,隱蔽,2H),2.81-2.64(m,1H),2.18-1.96(m,6H),1.87-1.71(m,4H),1.69-1.57(m,1H),1.37(s,9H),1.21-1.05(m,1H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(1.10g,1.94mmol,實施例37A)之1-丁醇(14ml)懸浮液中添加哌啶(580μl,5.8mmol),混合物於100℃下攪拌三天。冷卻至室溫後,添加水與乙酸乙酯(各50ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(50ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到557mg(84%純度,39%理論值)標題化合物。
LC-MS(方法1):Rt=2.82min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.69-7.61(m,2H),7.51-7.43(m,2H),7.49(br.,1H),7.40-7.34(m,1H),7.30-7.24(m,1H),3.73-3.53(m,3H),3.13(br s,4H),2.17-2.00(m,6H),1.87-1.75(m,1H),1.71-1.55(m,6H),1.37(s,9H).
取標題化合物(550mg)溶於甲醇(20ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例73A與74A)[管柱:Daicel Chiralpak OX-H,5μm,250mm x 20mm;流速:80ml/min;檢測:210nm;溫度:40℃;注射:0.3ml;溶析液:15%異丙醇/85%庚烷;運行時間16min,等濃度]。取合併之目標溶出份濃縮,殘質減壓乾燥。
在實施例72A說明之對映異構物之分離法中,得到預純化之標題化合物,為先溶離出之對映異構物(ee 99%)。然後再利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到150mg(95%純度)再純化之標題化合物。
[α]D 20=-8.4°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法2):Rt=1.51min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.208(0.07),1.312(0.09),1.333(0.12),1.368(16.00),1.525(0.08),1.604(0.60),1.668(1.18),1.814(0.26),2.045(0.27),2.074(1.54),2.085(0.84),2.108(0.38),2.131(1.97),3.132(1.52),3.584(0.27),3.671(0.49),7.251(0.23),7.270(0.53),7.289(0.37),7.351(0.32),7.370(0.57),7.388(0.30),7.438(0.79),7.458(0.67),7.479(0.73),7.497(0.64),7.623(0.30),7.645(1.58),7.652(1.07),7.675(0.20),8.705(0.28),8.720(0.54),8.733(0.26).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.69-7.61(m,2H),7.47(dd,2H),7.49(br.,隱蔽,1H),7.37(t,1H),7.27(t,1H),3.74-3.50(m,3H),3.13(br.s,4H),2.17-1.98(m,6H),1.89-1.74(m,1H),1.72-1.55(m,6H),1.37(s,9H).
在實施例72A說明之對映異構物之分離法中,得到預純化之標題化合物,為後溶離岀之對映異構物(ee 98%)。然後再利用製備型HPLC純化(方法6)。取 合併之目標溶出份濃縮,殘質減壓乾燥。得到141mg(98%純度)再純化之標題化合物。
[α]D 20=+8.0°,589nm,c=0.26g/100ml,甲醇
LC-MS(方法2):Rt=1.51min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.368(16.00),1.604(0.61),1.669(1.21),1.814(0.27),2.073(1.61),2.085(0.85),2.107(0.39),2.131(2.06),3.132(1.57),3.584(0.28),3.672(0.51),7.251(0.24),7.270(0.55),7.289(0.39),7.351(0.33),7.370(0.60),7.388(0.31),7.438(0.83),7.458(0.71),7.479(0.78),7.498(0.66),7.622(0.31),7.645(1.57),7.653(1.05),7.675(0.20),8.720(0.56).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.70-7.61(m,2H),7.47(dd,2H),7.49(br.,1H),7.37(t,1H),7.27(t,1H),3.74-3.52(m,3H),3.13(br.s,4H),2.18-1.99(m,6H),1.88-1.74(m,1H),1.72-1.54(m,6H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(250mg,91%純度,402μmol,實施例37A)之1-丁醇(2.9ml)懸浮液中添加硫嗎啉(124mg,1.21mmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到77mg(98%純度,30%理論值)標題化合物。
LC-MS(方法2):Rt=1.42min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.51),0.008(0.46),1.369(16.00), 2.073(1.08),2.086(0.66),2.132(1.34),2.774(0.88),2.786(1.01),2.798(0.95),3.413(0.94),3.419(0.94),3.426(0.99),3.437(0.86),7.372(0.41),7.438(0.61),7.441(0.57),7.458(0.51),7.461(0.48),7.479(0.49),7.482(0.49),7.499(0.41),7.678(1.34),7.684(0.99),7.688(0.81).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.74-7.62(m,2H),7.60-7.42(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.67(br.s,2H),3.62-3.53(m,1H),3.46-3.38(m,4H),2.83-2.74(m,4H),2.19-1.97(m,6H),1.88-1.73(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(100mg,88%純度,155μmol,實施例37A)之1-丁醇(1.1ml)懸浮液中添加4,4-二氟哌啶(94mg,777μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到28mg(98%純度,27%理論值)標題化合物。
LC-MS(方法1):Rt=2.71min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.67),1.369(16.00),2.075(1.36),2.088(0.85),2.111(0.57),2.167(1.98),2.523(0.67),7.272(0.44),7.373(0.48),7.439(0.66),7.459(0.57),7.486(0.59),7.503(0.48),7.682(1.32),7.691(0.87),7.695(0.76),8.738(0.45).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.74(t,1H),7.74-7.64(m,2H),7.59-7.42(m,3H),7.37(t,1H),7.30-7.23(m,1H),3.68(br.s,2H),3.62-3.53(m,1H),2.23-1.94(m,11H),1.89-1.70(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(250mg,91%純度,402μmol,實施例37A)之1-丁醇(2.9ml)懸浮液中添加1,2,3,6-四氫吡啶(100mg,1.21mmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到158mg(98%純度,63%理論值)標題化合物。
LC-MS(方法1):Rt=2.75min;MS(ESIpos):m/z=612/614[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.370(16.00),2.077(1.26),2.089(0.70),2.144(1.50),2.303(0.46),3.797(0.80),5.844(0.51),5.864(0.46),7.273(0.41),7.374(0.45),7.439(0.61),7.441(0.64),7.458(0.53),7.461(0.54),7.485(0.60),7.502(0.47),7.642(1.32),7.655(0.81),7.660(0.74),8.732(0.44).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.73(t,1H),7.70-7.60(m,2H),7.58-7.41(m,3H),7.37(t,1H),7.31-7.23(m,1H),5.95-5.77(m,2H),3.80(br.s,2H),3.68(br.s,2H),3.63-3.53(m,1H),3.28(br.s,2H),2.30(br.s,2H),2.18-1.98(m,6H),1.87-1.74(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(100mg,88%純度,155μmol,實施例37A)之1-丁醇(1.1ml)懸浮液中添加1,2-烷(67.7mg,777μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到24mg(98%純度,25%理論值)標題化合物。
LC-MS(方法1):Rt=2.75min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.369(16.00),1.697(0.63),1.870(0.56),1.884(0.67),1.898(0.45),2.075(1.56),2.086(0.82),2.145(1.44),3.573(0.69),3.680(0.54),4.041(0.59),4.053(0.94),4.065(0.59),7.274(0.52),7.371(0.56),7.444(0.75),7.464(0.65),7.479(0.65),7.498(0.50),7.731(2.67),8.805(0.54).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.81(t,1H),7.73(s,2H),7.55(br.s,1H),7.47(dd,2H),7.37(t,1H),7.31-7.24(m,1H),4.05(t,2H),3.77-3.48(m,5H),2.20-1.98(m,6H),1.93-1.75(m,3H),1.74-1.64(m,2H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(500mg,91%純度,803μmol,實施例37A)之1-丁醇(5.8ml)懸浮液中添加吡咯啶(200μl,2.4mmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到450mg(96%純度,89%理論值)標題化合物。
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=600/602[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.67(t,1H),7.56(dd,1H),7.52-7.40(m,4H),7.37(t,1H),7.30-7.23(m,1H),3.76-3.47(m,7H),2.23-1.98(m,6H),1.92-1.73(m,5H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(100mg,88%純度,155μmol,實施例37A)之1-丁醇(1.1ml)懸浮液中添加(+/-)-3-甲基吡咯啶鹽酸鹽(95mg,777μmol)與DIPEA(140μl,780μmol),混合物於 100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法19)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到27mg(由LC-MS測得98%純度,28%理論值)標題化合物,係與相應正丁酯之混合物。
LC-MS(方法1):Rt=2.41min;MS(ESIpos):m/z=614/616[M+H]+
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(100mg,88%純度,155μmol,實施例37A)之1-丁醇(1.1ml)懸浮液中添加二氟吡咯啶鹽酸鹽(112mg,777μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法18)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到32mg(由LC-MS測得98%純度,32%理論值)標題化合物,係與相應正丁酯之混合物。
LC-MS(方法1):Rt=2.66min;MS(ESIpos):m/z=636/638[M+H]+
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(250mg,91%純度,402μmol,實施例37A)之1-丁醇(2.9ml)懸浮液中添加1,2-唑啶(88mg,1.21mmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到137mg(98%純度,55%理論值)標題化合物。
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.326(0.11),1.345(0.22),1.368(16.00),1.812(0.20),2.051(0.20),2.073(1.19),2.085(0.63),2.102(0.25),2.212(0.90),2.239(0.67),2.257(0.83),2.275(0.61),2.293(0.19),3.594(0.21),3.681(0.40),3.773(0.40),3.819(0.60),3.838(1.03),3.856(0.56),7.253(0.18),7.272(0.41),7.291(0.29),7.352(0.24),7.371(0.44),7.390(0.23),7.443(0.65),7.461(0.53),7.483(0.54),7.501(0.42),7.708(0.11),7.730(2.34),8.783(0.42),8.797(0.22).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.78(t,1H),7.79-7.69(m,2H),7.55(br.s,1H),7.51-7.43(m,2H),7.37(t,1H),7.31-7.23(m,1H),3.84(t,2H),3.80-3.52(m,5H),2.31-2.15(m,5H),2.12-1.98(m,3H),1.89-1.74(m,1H),1.37(s,9H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(100mg,88%純度,155μmol,實施例37A)之1-丁醇(1.1ml)懸浮液中添加(+/-)-3-甲氧基吡咯啶鹽酸鹽(107mg,777μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物經製備型HPLC純化(方法19)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到36mg(98%純度,36%理論值)標題化合物。
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.841(6.92),0.859(16.00),0.878(8.20),1.242(0.62),1.260(2.27),1.279(3.99),1.297(4.01),1.316(2.45),1.335(0.68),1.472(1.34),1.488(3.43),1.508(4.15),1.525(3.19),1.542(0.92),1.836(0.66),1.849(0.86),1.870(1.04),1.884(0.78),1.904(0.42),2.050(0.40),2.070(1.08),2.082(1.26),2.101(1.32),2.123(1.34),2.132(1.26),2.170(7.46),2.190(4.09),2.209(1.68),2.229(0.50),2.327(0.46),2.422(0.74),2.440(1.52),2.458(2.17),2.476(3.21),2.669(0.40),3.585(1.18),3.675(1.62),3.783(2.51),3.910(0.72),3.926(1.48),3.937(3.09),3.944(3.49),3.953(5.65),3.961(5.89),3.970(3.85),3.978(3.23),3.988(1.62),4.004(1.04),7.252(0.96),7.271(2.27),7.289(1.70),7.351(1.40),7.369(2.51),7.388(1.38),7.436(4.09),7.455(3.47),7.480(3.31),7.500(2.49),7.570(3.37),7.592(6.68),7.630(3.79),7.636(3.45),7.653(1.86),7.658(1.76),8.693(1.22),8.706(2.39),8.720(1.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(500mg,883μmol,實施例37A)之1-丁醇(6.4ml)懸浮液中添加3,3-二甲基哌啶(370μl,2.6mmol),混合物於100℃下攪拌2天。隨後,再次添加3,3-二甲基哌啶(370μl,2.6mmol),混合物於100℃下再攪拌三天。冷卻至室溫後,混合物濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到420mg(94%純度,69%理論值)標題化合物。
LC-MS(方法2):Rt=1.58min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.70-7.61(m,2H),7.59-7.42(m,3H),7.37(t,1H),7.30-7.24(m,1H),3.75-3.62(m,2H),3.62-3.53(m,1H),3.05(br.s,2H),2.86(s,2H),2.17(s,3H),2.13-1.99(m,3H),1.92-1.75(m,1H),1.75-1.65(m,2H),1.44-1.35(m,2H,部份遮蔽),1,37(s,9H),1.00(s,6H).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(1.10g,1.94mmol,實施例37A)之1-丁醇(14ml)懸浮液中添加(+/-)-3-甲基哌啶(680μl,5.8mmol),混合物於100℃下攪拌2天。冷卻至室溫後,混合物濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到982mg(96%純度,77%理論值)標題化合物。
LC-MS(方法2):Rt=1.54min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.72(t,1H),7.71-7.60(m,2H),7.59-7.41(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.67(br.s,2H),3.62-3.54(m,1H),3.46(br.t,2H),2.78-2.64(m,1H),2.48-2.39(m,1H),2.19-2.00(m,6H),1.89-1.57(m,5H),1.37(s,9H),1.15-1.02(m,1H),0.93(d,3H).
取標題化合物(850mg)溶於異丙醇(5ml)與庚烷(6ml)之混合物中,先利用製備型HPLC於對掌相上預先分離[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:15ml/min;注射:0.13ml;溶析液:20%異丙醇/80%庚烷;運行時間16min,等濃度]。得到一份夠乾淨之溶出份(波峰1,參見實施例86A)與兩份混合溶出份。取第一份混合溶出份(波峰2與波峰3),利用製備型HPLC於對掌相上純化[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:15ml/min;溶析液:15%異丙醇/85%庚烷](參見實施例87A與88A)。第二份混合之溶出份(主要波峰4)同樣利用製備型HPLC於對掌相上純化[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:15ml/min;溶析液:10%異丙 醇/90%庚烷](參見實施例89A)。取合併之目標溶出份分別濃縮,取各殘質冷凍乾燥。
在實施例85A說明之非對映異構物之分離法中,得到194mg(96%純度,ee 99%)標題化合物,為第一個溶離出之非對映異構物(波峰1)。
[α]D 20=-16.2°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.945(1.66),0.961(1.68),1.103(0.18),1.131(0.20),1.159(0.16),1.177(0.21),1.195(0.10),1.235(0.07),1.340(0.34),1.359(0.12),1.395(16.00),1.420(0.31),1.551(0.07),1.645(0.16),1.676(0.19),1.755(0.33),1.790(0.37),1.817(0.52),1.846(0.44),2.056(0.20),2.073(0.25),2.082(0.22),2.100(1.31),2.111(0.75),2.127(0.30),2.134(0.28),2.162(1.64),2.353(0.03),2.392(0.03),2.443(0.15),2.472(0.24),2.711(0.14),2.737(0.26),2.768(0.14),2.928(0.08),2.947(0.08),3.463(0.27),3.486(0.45),3.514(0.24),3.610(0.23),3.698(0.40),7.280(0.20),7.296(0.45),7.314(0.35),7.351(0.07),7.379(0.28),7.397(0.47),7.415(0.24),7.464(0.64),7.466(0.61),7.483(0.54),7.507(0.60),7.523(0.51),7.652(0.18),7.674(1.58),7.682(0.94),7.699(0.12),7.704(0.14),8.727(0.22),8.741(0.43),8.755(0.20).
在實施例85A說明之非對映異構物之分離法中,得到157mg(100%純度,ee 99%)標題化合物,為第二個溶離出之非對映異構物(波峰2)。
[α]D 20=+15.5°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.919(1.60),0.935(1.63),1.077(0.18),1.101(0.19),1.139(0.11),1.157(0.10),1.176(0.05),1.208(0.07),1.311(0.08),1.333 (0.11),1.368(16.00),1.525(0.07),1.619(0.15),1.649(0.18),1.729(0.31),1.764(0.36),1.791(0.51),1.820(0.43),2.046(0.24),2.056(0.21),2.074(1.34),2.085(0.75),2.101(0.29),2.107(0.27),2.136(1.68),2.327(0.04),2.365(0.04),2.417(0.15),2.446(0.24),2.475(0.18),2.685(0.14),2.710(0.26),2.741(0.13),3.437(0.27),3.461(0.45),3.488(0.24),3.584(0.23),3.672(0.40),7.253(0.19),7.271(0.44),7.288(0.31),7.353(0.27),7.371(0.48),7.389(0.25),7.440(0.63),7.457(0.54),7.480(0.62),7.497(0.52),7.625(0.20),7.648(1.58),7.655(0.94),7.673(0.12),7.678(0.14),8.701(0.23),8.715(0.44),8.729(0.21).
在實施例85A說明之非對映異構物之分離法中,得到169mg(100%純度,ee 99%)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
[α]D 20=+9.6°,436nm,c=0.42g/100ml,甲醇
LC-MS(方法1):Rt=2.91min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.920(1.65),0.936(1.68),1.078(0.18),1.101(0.19),1.139(0.15),1.157(0.18),1.176(0.09),1.208(0.07),1.314(0.08),1.331(0.10),1.369(16.00),1.525(0.07),1.626(0.16),1.656(0.19),1.728(0.33),1.760(0.36),1.794(0.49),1.820(0.43),2.047(0.23),2.056(0.21),2.074(1.37),2.085(0.79),2.102(0.29),2.137(1.81),2.327(0.04),2.365(0.04),2.431(0.17),2.459(0.27),2.669(0.16),2.699(0.24),2.728(0.13),2.923(0.03),3.434(0.28),3.462(0.49),3.492(0.23),3.583(0.23),3.668(0.37),7.253(0.19),7.272(0.44),7.292(0.31),7.353(0.27),7.372(0.49),7.390(0.26),7.440(0.66),7.460(0.56),7.481(0.65),7.498(0.52),7.626(0.18),7.649(1.66),7.655(0.96),7.677(0.14),8.702(0.25),8.716(0.49),8.730(0.24).
在實施例85A說明之非對映異構物之分離法中,得到158mg(96%純度,ee 99%)標題化合物,為最後溶離出之非對映異構物(波峰4)。
[α]D 20=-10.4°,436nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.920(1.61),0.936(1.63),1.077(0.17),1.100(0.18),1.139(0.09),1.157(0.06),1.208(0.06),1.314(0.10),1.331(0.09),1.369(16.00),1.525(0.06),1.626(0.15),1.657(0.18),1.728(0.32),1.761(0.34),1.794(0.46),1.820(0.40),2.047(0.22),2.056(0.20),2.074(1.27),2.086(0.74),2.102(0.28),2.137(1.67),2.327(0.04),2.365(0.04),2.431(0.16),2.460(0.25),2.669(0.16),2.699(0.22),2.728(0.12),3.433(0.26),3.462(0.46),3.493(0.21),3.583(0.21),3.667(0.34),7.254(0.18),7.272(0.43),7.288(0.33),7.325(0.05),7.353(0.26),7.372(0.46),7.390(0.24),7.437(0.63),7.440(0.64),7.457(0.54),7.460(0.54),7.481(0.60),7.498(0.48),7.626(0.18),7.649(1.60),7.655(0.94),7.678(0.14),8.702(0.23),8.716(0.45),8.730(0.22).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(1.50g,98%純度,2.60mmol,實施例37A)之NMP(24ml)懸浮液中添加3,3-二氟哌啶鹽酸鹽(3.27g,20.8mmol)與DIPEA(5.42ml,31.15mmol),混合物於120℃下攪拌18h。冷卻至室溫後,添加水(200ml)與乙酸乙酯(100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯重覆萃取(每次100ml)。合併之有機 相經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→9:1,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到933mg(96%純度,53%理論值)標題化合物。
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.04),0.146(0.04),1.210(0.08),1.234(0.04),1.311(0.07),1.333(0.09),1.370(16.00),1.398(3.71),1.526(0.08),1.764(0.07),1.797(0.17),1.817(0.23),1.880(0.52),2.046(0.34),2.056(0.38),2.076(1.68),2.088(1.06),2.110(0.55),2.152(1.68),2.327(0.05),2.366(0.05),2.670(0.04),2.710(0.04),3.167(0.60),3.447(0.40),3.476(0.76),3.505(0.38),3.587(0.24),3.683(0.40),7.254(0.20),7.273(0.48),7.291(0.35),7.355(0.28),7.374(0.51),7.392(0.26),7.441(0.69),7.461(0.57),7.485(0.60),7.504(0.47),7.674(0.26),7.696(1.50),7.703(0.97),7.707(0.83),7.729(0.17),8.718(0.24),8.732(0.49),8.746(0.24).
取標題化合物(1.51g)溶於甲醇(40ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例91A與92A)[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 30mm;流速:114ml/min;注射:0.40ml;溶析液:22%甲醇/78%二氧化碳;運行時間9min,等濃度]。取合併之目標溶出份濃縮,取各殘質減壓乾燥。
在實施例90A說明之對映異構物之分離法中,得到672mg(97%純度,ee 98%)標題化合物,為先溶離出之對映異構物。
Rt=2.35min(對掌性分析性SFC;Agilent苯基纖維素-2管柱,3μm,50mm x 4.6mm,溶析液:二氧化碳/甲醇95:5→4:6;流速3ml/min;溫度40℃;檢測220nm)
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.28),0.007(0.29),1.038(0.05), 1.055(0.10),1.073(0.05),1.209(0.06),1.310(0.07),1.332(0.10),1.369(16.00),1.525(0.06),1.795(0.14),1.816(0.18),1.879(0.44),2.045(0.28),2.075(1.41),2.087(0.90),2.109(0.46),2.151(1.41),2.327(0.05),2.669(0.06),2.709(0.04),3.162(0.52),3.446(0.34),3.475(0.65),3.504(0.32),3.586(0.20),3.681(0.34),7.255(0.17),7.273(0.40),7.290(0.30),7.355(0.24),7.373(0.43),7.391(0.22),7.439(0.60),7.442(0.58),7.459(0.50),7.462(0.48),7.486(0.50),7.502(0.40),7.674(0.24),7.696(1.37),7.702(0.97),7.707(0.83),7.724(0.15),7.729(0.17),8.716(0.21),8.731(0.43),8.745(0.21).
在實施例90A說明之對映異構物之分離法中,得到634mg(98%純度,ee 98%)標題化合物,為後溶離岀之對映異構物。
Rt=2.67min(對掌性分析性SFC;Agilent苯基纖維素-2管柱,3μm,50mm x 4.6mm,溶析液:二氧化碳/甲醇95:5→4:6;流速3ml/min;溫度40℃;檢測220nm)
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.038(0.09),1.055(0.18),1.073(0.09),1.208(0.06),1.310(0.06),1.332(0.09),1.369(16.00),1.525(0.07),1.796(0.15),1.816(0.20),1.878(0.45),2.045(0.28),2.075(1.47),2.087(0.94),2.110(0.47),2.151(1.50),2.327(0.05),2.669(0.06),3.162(0.54),3.446(0.36),3.475(0.67),3.504(0.33),3.587(0.21),3.681(0.36),4.335(0.06),7.254(0.17),7.273(0.41),7.290(0.29),7.355(0.24),7.373(0.45),7.391(0.23),7.439(0.64),7.459(0.53),7.483(0.52),7.502(0.42),7.674(0.24),7.696(1.40),7.702(0.97),7.707(0.82),7.724(0.15),7.729(0.17),8.717(0.22),8.731(0.45),8.745(0.22).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(250mg,98%純度,433μmol,實施例37A)之NMP(4ml)懸浮液中添加(+/-)-3-(三氟甲基)哌啶(530mg,3.46mmol)與DIPEA(602μl,3.46mmol),混合物於120℃下攪拌2天。冷卻至室溫後,混合物濃縮,殘質溶於乙腈,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到156mg(98%純度,52%理論值)標題化合物。
LC-MS(方法1):Rt=2.85min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.153(3.05),1.181(2.46),1.268(0.43),1.284(0.44),1.308(0.41),1.370(16.00),1.504(0.40),1.521(0.50),2.076(1.13),2.089(0.66),2.144(1.11),7.271(0.44),7.373(0.43),7.436(0.60),7.456(0.49),7.484(0.58),7.488(0.55),7.503(0.47),7.689(2.18).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,98%純度,346μmol,實施例37A)之NMP(4ml)懸浮液中添加1-甲基哌(277mg,2.77mmol)與DIPEA(482μl,2.77mmol),混合物於120℃下攪拌2天。冷卻至室溫後,混合物濃縮,殘質溶於乙腈,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到135mg(98%純度,61%理論值)標題化合物。
LC-MS(方法1):Rt=1.72min;MS(ESIpos):m/z=629/631[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.023(0.08),-0.008(0.22),0.008(0.24),1.027(0.04),1.208(0.06),1.234(0.21),1.312(0.07),1.333(0.09),1.368(16.00),1.525(0.06),1.793(0.13),1.813(0.17),2.052(0.17),2.073(1.11),2.085(0.60),2.102(0.29),2.108(0.28),2.132(1.31),2.242(3.22),2.327(0.06),2.366(0.06),2.670(0.06),2.710(0.06),3.178(1.02),3.584(0.19),3.672(0.32),7.253(0.17),7.272(0.37),7.289(0.27),7.353(0.23),7.371(0.42),7.388(0.21),7.438(0.59),7.441(0.57),7.458(0.50),7.461(0.48),7.481(0.52),7.497(0.44),7.640(0.20),7.662(1.35),7.666(1.05),7.671(0.81),7.688(0.12),7.693(0.14),8.712(0.20),8.727(0.40),8.741(0.19).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,98%純度,346μmol,實施例37A)之NMP(3ml)懸浮液中添加(+/-)-哌啶-3-醇(280mg,2.77mmol)與DIPEA(482μl,2.77mmol),混合物於120℃下攪 拌2天。冷卻至室溫後,混合物濃縮,殘質溶於乙腈,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到154mg(98%純度,69%理論值)標題化合物。
LC-MS(方法1):Rt=2.39min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.24),0.008(0.23),1.209(0.06),1.313(0.17),1.369(16.00),1.526(0.07),1.603(0.13),1.783(0.25),1.813(0.28),1.922(0.18),1.943(0.17),2.052(0.18),2.074(1.10),2.087(0.64),2.110(0.30),2.132(1.38),2.327(0.05),2.366(0.06),2.635(0.16),2.665(0.13),2.710(0.07),2.778(0.17),3.356(0.21),3.387(0.19),3.512(0.22),3.543(0.22),3.589(0.19),3.677(0.47),4.852(0.66),4.864(0.65),7.254(0.16),7.272(0.37),7.291(0.27),7.353(0.22),7.372(0.41),7.391(0.21),7.439(0.62),7.442(0.63),7.458(0.53),7.462(0.52),7.482(0.55),7.501(0.44),7.621(0.36),7.643(1.27),7.656(0.83),7.661(0.76),7.678(0.23),7.684(0.24),8.713(0.19),8.727(0.39),8.741(0.19).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,98%純度,346μmol,實施例37A)之NMP(3ml)懸浮液中添加(+/-)-哌啶-3-基胺甲酸第三丁基酯(555mg,2.77mmol)與DIPEA(482μl,2.77mmol),混合物於120℃下攪拌2天。冷卻至室溫後,混合物濃縮,殘質溶於乙腈,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到162mg(98%純度,63%理論值)標題化合物。
LC-MS(方法1):Rt=2.78min;MS(ESIpos):m/z=729/731[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.209(0.07),1.235(0.09),1.369(16.00),1.395(10.53),1.525(0.08),1.551(0.07),1.643(0.13),1.797(0.32),1.831(0.36),2.073(1.14),2.086(0.69),2.103(0.26),2.155(0.93),2.328(0.06),2.615(0.10),2.670(0.10),2.752(0.19),3.369(0.20),3.401(0.18),3.473(0.18),3.501(0.18),3.581(0.33),3.679(0.35),6.961(0.19),7.251(0.16),7.269(0.39),7.289(0.27),7.352(0.22),7.371(0.41),7.389(0.22),7.436(0.57),7.455(0.49),7.482(0.55),7.499(0.46),7.631(0.31),7.653(1.19),7.665(0.76),7.670(0.69),7.687(0.20),7.692(0.21),8.730(0.34).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(2.50g,98%純度,4.33mmol,實施例37A)之NMP(37ml)懸浮液中添加(+/-)-3-乙基哌啶(3.92g,34.6tmmol)與DIPEA(6.0ml,34.6mmol),混合物於120℃下攪拌4h。冷卻至室溫後,混合物濃縮,殘質溶於二氯甲烷,使用水與飽和氯化鈉水溶液洗滌。隨後,合併之水相使用二氯甲烷萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質減壓乾燥。得到2.40g(98%純度,85%理論值)標題化合物。
LC-MS(方法1):Rt=3.04min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.078(0.08),0.218(0.08),0.962(0.85),0.980(2.01),0.999(1.05),1.135(0.19),1.158(0.20),1.187(0.09),1.228(0.15),1.246 (0.30),1.264(0.15),1.281(0.08),1.329(0.39),1.347(0.51),1.364(0.36),1.403(0.11),1.440(16.00),1.636(0.22),1.817(0.28),1.849(0.27),1.889(0.24),1.917(0.27),1.948(0.22),2.059(0.56),2.118(0.24),2.146(1.40),2.157(0.81),2.201(1.34),2.816(0.18),3.566(0.40),3.591(0.36),3.658(0.24),3.744(0.46),4.092(0.14),4.110(0.13),5.825(0.10),7.322(0.20),7.341(0.49),7.359(0.36),7.423(0.27),7.442(0.51),7.460(0.26),7.506(0.65),7.526(0.55),7.554(0.67),7.571(0.54),7.697(0.19),7.720(1.78),7.749(0.15),8.772(0.24),8.787(0.50),8.801(0.24).
取標題化合物(2.4g)溶於甲醇(60ml),利用製備性SFC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel OX-H,5μm,250mm x 30mm;流速:80ml/min;檢測:210nm;溫度:40℃,注射:0.40ml;溶析液:22%甲醇/78%二氧化碳,等濃度]。得到一份混合之溶出份(波峰1與波峰2)與兩份分別夠純之溶出份(波峰3,參見實施例100A;與波峰4,參見實施例101A)。混合之溶出份再度利用製備性SFC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:80ml/min;檢測:210nm;溫度:40℃,注射:2.20ml;溶析液:15%異丙醇/85%二氧化碳,等濃度]。得到兩份分別夠純之溶出份(波峰1,參見實施例98A;與波峰2,參見實施例99A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例97A說明之非對映異構物之分離法中,得到200mg(100%純度,ee >99%)標題化合物,為第一個溶離出之非對映異構物(波峰1)。
[α]D 20=+7.7°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法1):Rt=3.03min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.976(0.88),0.995(2.21),1.014(1.10),1.121(0.06),1.149(0.17),1.179(0.17),1.200(0.08),1.294(0.07),1.325(0.13),1.342(0.35),1.360(0.47),1.377(0.32),1.397(0.17),1.415(0.11),1.454(16.00),1.611 (0.12),1.649(0.22),1.682(0.20),1.713(0.17),1.831(0.24),1.872(0.23),1.902(0.21),1.930(0.23),1.961(0.19),2.131(0.24),2.140(0.20),2.158(1.28),2.169(0.75),2.203(1.17),2.413(0.04),2.755(0.04),2.804(0.13),2.832(0.23),2.861(0.13),3.584(0.38),3.607(0.28),3.671(0.21),3.757(0.39),7.336(0.18),7.354(0.42),7.371(0.30),7.436(0.25),7.455(0.46),7.473(0.23),7.519(0.57),7.537(0.47),7.568(0.57),7.584(0.48),7.711(0.19),7.733(1.47),7.741(0.89),7.759(0.12),7.764(0.14),8.786(0.21),8.801(0.43),8.815(0.21).
在實施例97A說明之非對映異構物之分離法中,得到219mg(100%純度,ee 95%)標題化合物,為第二個溶離出之非對映異構物(波峰2)。
[α]D 20=-23.1°,589nm,c=0.42g/100ml,甲醇
LC-MS(方法1):Rt=3.02min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.961(0.87),0.979(2.07),0.998(1.02),1.107(0.07),1.135(0.17),1.157(0.17),1.187(0.08),1.280(0.08),1.311(0.15),1.329(0.34),1.346(0.45),1.364(0.31),1.385(0.18),1.440(16.00),1.597(0.15),1.629(0.19),1.675(0.18),1.706(0.16),1.816(0.25),1.849(0.24),1.888(0.21),1.917(0.23),1.948(0.19),2.118(0.22),2.128(0.23),2.147(1.23),2.158(0.74),2.180(0.37),2.201(1.75),2.239(0.09),2.399(0.04),2.473(0.12),2.776(0.11),2.803(0.20),2.831(0.11),3.559(0.38),3.588(0.35),3.658(0.21),3.744(0.41),3.791(0.10),3.896(0.07),4.109(0.04),7.324(0.19),7.342(0.41),7.362(0.30),7.425(0.25),7.443(0.44),7.461(0.23),7.507(0.62),7.509(0.57),7.526(0.53),7.529(0.49),7.554(0.60),7.570(0.47),7.697(0.19),7.720(1.51),7.727(0.87),7.744(0.12),7.749(0.14),7.960(0.11),8.773(0.23),8.787(0.45),8.801(0.21).
在實施例97A說明之非對映異構物之分離法中,得到462mg(100%純度,ee >99%)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
[α]D 20=-6.9°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=3.03min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.077(0.11),0.093(0.12),0.976(0.84),0.995(2.12),1.014(1.04),1.121(0.06),1.150(0.16),1.179(0.16),1.201(0.08),1.294(0.07),1.325(0.13),1.342(0.33),1.359(0.45),1.377(0.31),1.397(0.16),1.416(0.11),1.454(16.00),1.611(0.12),1.649(0.20),1.682(0.19),1.713(0.15),1.831(0.23),1.863(0.22),1.901(0.20),1.930(0.22),1.961(0.18),2.131(0.22),2.140(0.19),2.158(1.19),2.169(0.70),2.203(1.05),2.413(0.04),2.755(0.04),2.805(0.12),2.832(0.21),2.861(0.11),3.584(0.35),3.605(0.26),3.671(0.19),3.757(0.36),7.336(0.17),7.354(0.39),7.371(0.29),7.437(0.24),7.455(0.43),7.474(0.22),7.517(0.53),7.520(0.55),7.537(0.44),7.539(0.45),7.565(0.52),7.568(0.53),7.584(0.45),7.711(0.18),7.734(1.41),7.736(1.18),7.741(0.85),7.759(0.12),7.764(0.14),8.786(0.20),8.801(0.40),8.815(0.20).
在實施例97A說明之非對映異構物之分離法中,得到483mg(100%純度,ee 93%)標題化合物,為最後溶離出之非對映異構物(波峰4)。
[α]D 20=+23.3°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法1):Rt=3.02min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.931(0.89),0.950(2.16),0.968(1.10),1.077(0.07),1.106(0.18),1.136(0.19),1.156(0.08),1.251(0.08),1.282(0.15),1.299(0.35),1.317(0.48),1.334(0.34),1.356(0.18),1.374(0.13),1.411(16.00),1.599(0.20),1.646(0.19),1.677(0.19),1.787(0.27),1.819(0.26),1.858(0.23),1.886(0.26),1.919(0.21),2.089(0.21),2.099(0.21),2.117(1.38),2.129(0.83),2.151(0.35),2.172(2.06),2.370(0.04),2.445(0.13),2.472(0.21),2.746(0.12),2.775(0.23),2.804(0.13),3.530(0.42),3.559(0.40),3.628(0.24),3.715(0.46),7.294(0.20),7.312(0.47),7.330(0.33),7.395(0.28),7.414(0.51),7.432(0.27),7.478 (0.68),7.498(0.58),7.524(0.68),7.541(0.54),7.668(0.17),7.691(1.78),7.697(0.99),7.719(0.14),8.743(0.25),8.758(0.50),8.772(0.24).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,98%純度,346μmol,實施例37A)之NMP(3.0ml)懸浮液中添加(+/-)-3-甲基哌啶-3-醇鹽酸鹽(420mg,2.77mmol)與DIPEA(482μl,2.77mmol),混合物於120℃下攪拌2天。冷卻至室溫後,混合物濃縮,殘質利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到148mg(98%純度,65%理論值)標題化合物。
LC-MS(方法1):Rt=2.52min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.024(0.28),1.190(2.69),1.333(0.13),1.356(0.61),1.370(16.00),1.558(0.67),1.571(0.73),1.612(0.18),1.819(0.32),2.047(0.21),2.075(1.34),2.087(0.74),2.103(0.26),2.167(1.65),2.327(0.05),2.393(0.05),2.411(0.05),3.022(1.29),3.076(0.57),3.587(0.22),3.672(0.40),4.100(0.08),4.603(0.40),4.617(0.43),7.254(0.20),7.273(0.46),7.290(0.32),7.354(0.28),7.372(0.50),7.391(0.26),7.439(0.70),7.459(0.60),7.483(0.66),7.500(0.53),7.616(0.38),7.638(1.32),7.651(0.85),7.656(0.75),7.674(0.23),7.678(0.23),8.709(0.24),8.723(0.48),8.737(0.23).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(+/-)-(順-反)-3,5-二甲基哌啶(80mg,706μmol,非對映異構物混合物,CAS-RN35794-11-7)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(+/-)-(順-反)-3,5-二甲基哌啶(40mg,353μmol,非對映異構物混合物,CAS-RN 35794-11-7)與DIPEA(76μl,425μmol),混合物繼續於100℃下攪拌。共經過42h後,混合物冷卻至RT,及過濾。濾液利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到91mg(100%純度,40%理論值)標題化合物。
LC-MS(方法2):Rt=1.59min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(0.63),0.719(0.19),0.749(0.22),0.897(2.28),0.913(2.32),1.007(0.49),1.020(0.49),1.234(0.32),1.369(16.00),1.438(0.18),1.807(0.53),1.988(0.18),2.074(1.32),2.085(0.78),2.137(1.33),2.170(0.39),2.327(0.25),3.490(0.35),3.518(0.33),3.583(0.21),3.669(0.33),5.754(1.78),7.255(0.17),7.272(0.41),7.290(0.29),7.354(0.24),7.373(0.45),7.391(0.25),7.440(0.61),7.458(0.53),7.481(0.59),7.498(0.47),7.649(2.04),8.708(0.37).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(+/-)-3-(二氟甲基)哌啶鹽酸鹽(121mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(+/-)-3-(二氟甲基)哌啶鹽酸鹽(60mg,353μmol)與DIPEA(70μl,390μmol),混合物於100℃下再攪拌24h。然後,混合物於微波裝置(Biotage)之密封玻璃瓶中,於100℃攪拌15min。冷卻至室溫後,混合物與飽和碳酸氫鈉水溶液混合,及使用二氯甲烷重覆萃取。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度95:5→20:80,Isolera One)。取兩份合併之目標溶出份濃縮,各殘質減壓乾燥。得到98mg(41%純度,17%理論值)第一批標題化合物與18g(54%純度,4%理論值,參見分析法)第二批標題化合物,隨後合併。
LC-MS(方法1):Rt=2.75min;MS(ESIpos):m/z=664/666[M+H]+
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(3S)-3-氟吡咯啶鹽酸鹽(89mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(3S)-3-氟吡咯啶鹽酸鹽(45mg,353μmol)與DIPEA(76μl,425μmol),混合物於100℃下再攪拌24h。冷卻至室溫後,混合物過濾。濾液利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到141mg(89%純度,57%理論值)標題化合物。
LC-MS(方法2):Rt=1.26min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.32),-0.008(3.09),0.007(3.00),0.146(0.31),1.156(0.38),1.175(0.78),1.192(0.41),1.366(15.46),1.370(16.00),1.818(0.30),1.988(1.44),2.074(1.85),2.175(1.40),2.327(0.23),2.366(0.27),2.523(0.66),2.669(0.21),2.709(0.24),3.598(0.58),3.867(0.24),4.020(0.45),4.038(0.40),5.330(0.35),5.464(0.34),7.260(0.44),7.277(0.49),7.362(0.56),7.380(0.52),7.435(0.94),7.454(0.79),7.476(0.57),7.504(0.83),7.526(1.00),7.531(1.04),7.575(0.54),7.581(0.97),7.587(0.53),7.603(0.55),7.895(0.27),8.688(0.52).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.6ml)混合物中添加(3R)-3-氟吡咯啶鹽酸鹽(89mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(3R)-3-氟吡咯啶鹽酸鹽(45mg,353μmol)與DIPEA(76μl,425μmol),混合物於100℃下再攪拌24h。冷卻至室溫後,混合物與飽和碳酸氫鈉水溶液混合,及使用二氯甲烷重覆萃取。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→4:6,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到98mg(41%純度,17%理論值)標題化合物。
LC-MS(方法1):Rt=2.50min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.50),0.008(0.91),1.157(0.46),1.175(0.91),1.192(0.46),1.366(16.00),1.370(14.31),1.817(0.28),1.988(1.65),2.074(1.82),2.085(1.02),2.174(1.43),2.327(0.20),2.366(0.24),2.669(0.21),2.709(0.24),3.595(0.63),3.867(0.27),4.020(0.51),4.038(0.47),5.330(0.36),5.465(0.36),7.261(0.44),7.278(0.48),7.344(0.31),7.363(0.56),7.379(0.49),7.435(0.95),7.455(0.80),7.476(0.59),7.504(0.86),7.508(0.77),7.526(1.06),7.530(1.06),7.575(0.58),7.581(1.00),7.587(0.55),7.598(0.33),7.603(0.57),7.609(0.32),8.689(0.55).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(+/-)-反-3,4-二氟吡咯啶鹽酸鹽(101mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(+/-)-反-3,4-二氟吡咯啶鹽酸鹽(50mg,353μmol)與DIPEA(70μl,390μmol),混合物於100℃下再攪拌24h。然後,混合物於微波裝置(Biotage)中,於密封玻璃容器中,於100℃下攪拌15min。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到169mg(77%純度,58%理論值)標題化合物。
LC-MS(方法2):Rt=1.33min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(0.49),1.157(2.03),1.175(4.09),1.193(2.07),1.333(0.19),1.367(13.18),1.371(16.00),1.820(0.30),1.988(7.63),2.076(1.81),2.089(1.06),2.106(0.39),2.192(1.13),2.327(0.11),2.366(0.09),3.596(0.32),3.714(0.37),4.003(0.63),4.021(1.85),4.039(1.84),4.056(0.69),4.185(0.19),5.360(0.41),5.494(0.41),7.261(0.39),7.280(0.47),7.345(0.22),7.364(0.49),7.382(0.47),7.437(0.79),7.457(0.66),7.480(0.48),7.490(0.55),7.508(0.39),7.549(0.48),7.568(0.84),7.571(0.84),7.617(0.73),7.639(0.40),7.895(0.86),8.696(0.43),8.859(0.16).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加順-3,4-二氟吡咯啶鹽酸鹽(101mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加順-3,4-二氟吡咯啶鹽酸鹽(50mg,353μmol)與DIPEA(70μl,390μmol),混合物於100℃下再攪拌24h。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。得到60mg(97%純度,26%理論值)第一批標題化合物與100mg(88%純度,39%理論值)第二批標題化合物,其等合併用於下一個反應。
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.157(1.14),1.175(2.31),1.192(1.17),1.308(0.09),1.335(0.15),1.368(16.00),1.818(0.20),1.988(4.34),2.074(1.23),2.086(0.67),2.103(0.28),2.159(0.85),3.581(0.22),3.670(0.24),3.782(0.23),4.002(0.52),4.020(1.17),4.038(1.12),4.056(0.38),5.298(0.23),5.426(0.20),5.435(0.20),5.461(0.22),7.251(0.17),7.269(0.39),7.289(0.28),7.353(0.25),7.371(0.44),7.389(0.25),7.435(0.70),7.455(0.58),7.481(0.56),7.498(0.41),7.542 (0.67),7.564(1.21),7.610(0.68),7.616(0.62),7.633(0.36),7.638(0.35),8.690(0.40).
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.47),0.007(0.35),1.156(1.58),1.174(3.21),1.192(1.61),1.208(0.07),1.308(0.10),1.335(0.15),1.368(16.00),1.524(0.06),1.817(0.19),1.988(5.93),2.046(0.19),2.074(1.20),2.086(0.64),2.103(0.26),2.158(0.75),2.327(0.06),2.365(0.06),3.582(0.21),3.670(0.22),3.779(0.20),4.002(0.61),4.020(1.51),4.038(1.48),4.056(0.49),5.298(0.20),5.324(0.16),5.426(0.17),5.435(0.18),5.460(0.20),7.251(0.15),7.269(0.34),7.288(0.25),7.353(0.22),7.371(0.40),7.390(0.23),7.434(0.64),7.437(0.62),7.454(0.55),7.481(0.51),7.497(0.39),7.542(0.63),7.564(1.13),7.610(0.63),7.616(0.57),7.632(0.34),7.638(0.33),7.894(0.26),8.690(0.36).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(+/-)-3-氟-3-甲基吡咯啶鹽酸鹽(99mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(+/-)-3-氟-3-甲基吡咯啶鹽酸鹽(50mg,353μmol)與DIPEA(76μl,425μmol),混合物於100℃下再攪拌24h。冷卻至室溫後,混合物與飽和碳酸氫鈉水溶液混合,及使用二氯甲烷重覆萃取。合併之有機相 經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→4:6,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到98mg(41%純度,17%理論值)標題化合物。
LC-MS(方法1):Rt=2.58min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.89),0.007(0.80),1.366(11.66),1.370(10.65),1.398(16.00),1.539(2.15),1.591(2.13),1.815(0.21),2.073(1.38),2.084(0.84),2.100(0.38),2.169(1.12),2.327(0.17),2.365(0.21),2.669(0.18),2.709(0.21),3.608(0.44),3.798(0.16),3.920(0.28),7.259(0.33),7.278(0.37),7.343(0.23),7.362(0.42),7.378(0.36),7.434(0.71),7.454(0.59),7.473(0.40),7.494(0.66),7.499(0.63),7.517(0.80),7.521(0.79),7.567(0.41),7.573(0.72),7.579(0.39),7.595(0.43),8.688(0.37).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加(+/-)-3,3,4,4-四氟吡咯啶鹽酸鹽(127mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加(+/-)-3,3,4,4-四氟吡咯啶鹽酸鹽(64mg,353μmol)與DIPEA(76μl,425μmol),混合物於100℃下再攪拌24h。然後,混合物於微波裝置(Biotage)中,於密封玻璃容器中,於100℃下攪拌15min。隨後,混合 物於微波裝置(Biotage)中,於密封玻璃容器中,於120℃下攪拌1h。冷卻至室溫後,混合物與飽和碳酸氫鈉水溶液混合,及使用二氯甲烷重覆萃取。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到71mg(9%純度,3%理論值)標題化合物。
LC-MS(方法2):Rt=1.43min;MS(ESIpos):m/z=672/674[M+H]+
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(1.9ml)混合物中添加3-氮雜雙環[3.1.1]庚烷鹽酸鹽(92mg,689μmol)與DIPEA(150μl,860μmol),混合物於100℃下攪拌四天。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法8)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到66mg(100%純度,31%理論值)標題化合物。
LC-MS(方法1):Rt=2.81min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.16),1.330(0.12),1.367(16.00),1.438(0.73),1.444(0.67),1.454(0.69),1.460(0.77),1.816(0.21),2.045(0.25),2.074(1.55),2.086(1.09),2.102(0.76),2.192(1.21),3.584(0.24),3.663(0.33),3.868(0.34),7.249(0.19),7.269(0.44),7.287(0.32),7.351(0.28),7.370(0.51),7.388(0.29),7.436(0.77),7.456(0.61),7.480(0.59),7.497(0.43),7.524(0.63),7.546 (1.26),7.583(0.68),7.588(0.63),7.605(0.33),7.610(0.32),8.713(0.45).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(108mg,98%純度,185μmol,實施例37A)之NMP(1.0ml)混合物中添加3-氮雜雙環[3.2.1]辛烷鹽酸鹽(219mg,1.48mmol)與DIPEA(390μl,2.2mmol),混合物於100℃下攪拌48h。冷卻至室溫後,添加水與乙酸乙酯(各50ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯萃取2次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質經製備型HPLC純化(方法8)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到80mg(100%純度,67%理論值)標題化合物。
LC-MS(方法1):Rt=3.01min;MS(ESIpos):m/z=640/642[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.028(0.90),-0.013(0.70),0.848(0.17),1.229(2.08),1.254(0.24),1.364(16.00),1.547(0.92),1.659(0.41),1.742(0.48),1.761(0.50),1.810(0.21),2.040(0.21),2.068(1.18),2.079(0.59),2.095(0.22),2.178(1.29),2.292(0.63),2.361(0.15),2.664(0.12),2.705(0.16),2.906(0.35),2.932(0.29),3.577(0.20),3.662(0.35),7.251(0.17),7.270(0.38),7.286(0.28),7.349(0.24),7.368(0.43),7.386(0.22),7.440(0.60),7.460(0.54),7.475(0.59),7.491(0.44),7.602(0.41),7.624(1.25),7.642(0.77),7.647(0.69),7.664(0.25),7.669(0.25),8.728(0.42).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(200mg,353μmol,實施例37A)之NMP(2.5ml)混合物中添加3,3-二氟氮雜環丁烷鹽酸鹽(92mg,706μmol)與DIPEA(140μl,780μmol),混合物於100℃下攪拌18h。隨後,再次添加3,3-二氟氮雜環丁烷鹽酸鹽(46mg,353μmol)與DIPEA(76μl,425μmol),混合物於100℃下再攪拌24h。然後混合物於微波裝置(Biotage)中,於密封玻璃容器中,於100℃下攪拌15min。冷卻至室溫後,混合物與飽和碳酸氫鈉水溶液混合,及使用二氯甲烷重覆萃取。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度95:5→5:5,Isolera One)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到32mg(96%純度,14%理論值)標題化合物。
LC-MS(方法2):Rt=1.35min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.48),-0.008(4.16),0.008(4.20),0.146(0.48),1.367(16.00),1.398(1.97),2.070(1.48),2.084(0.81),2.327(0.52),2.366(0.69),2.523(1.89),2.670(0.58),2.710(0.67),4.581(0.48),4.613(0.89),4.645(0.44),7.435(0.60),7.455(0.50),7.475(0.50),7.492(0.40),7.589(0.60),7.611(1.20),7.648(0.64),7.654(0.60).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(250mg,441μmol,實施例37A)之NMP(2.0ml)混合物中添加(+/-)-哌啶-3-甲腈(389mg,3.53mmol)與DIPEA(620μl,3.5mmol),混合物於110℃下攪拌42h。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法8)。取合併之目標溶出份濃縮,殘質冷凍乾燥。得到197mg(91%純度,63%理論值)標題化合物。
LC-MS(方法1):Rt=2.58min;MS(ESIpos):m/z=639/641[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.209(0.07),1.309(0.05),1.333(0.10),1.369(16.00),1.526(0.08),1.714(0.17),1.819(0.35),1.876(0.37),1.889(0.55),1.902(0.46),2.046(0.19),2.075(1.26),2.088(0.72),2.104(0.25),2.183(1.43),2.327(0.05),2.365(0.05),2.669(0.05),2.709(0.05),3.020(0.16),3.268(0.30),3.293(0.34),3.444(0.22),3.458(0.22),3.475(0.18),3.490(0.14),3.588(0.21),3.683(0.36),7.254(0.18),7.272(0.41),7.292(0.29),7.354(0.25),7.373(0.45),7.391(0.23),7.441(0.59),7.461(0.49),7.486(0.54),7.505(0.42),7.671(0.21),7.693(1.42),7.697(1.08),7.702(0.83),7.724(0.14),7.894(0.21),8.723(0.21),8.737(0.42),8.751(0.20).
在(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(300mg,530μmol,實施例37A)之NMP(3.0ml)混合物中添加3,6-二氫-2H-1,2-鹽酸鹽(515mg,4.24mmol)與DIPEA(920μl,5.3mmol),混合物於120℃下攪拌44h。冷卻至室溫後,混合物過濾,取濾液濃縮。殘質溶於DMSO,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到70mg(100%純度,21%理論值)標題化合物。
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.08),-0.023(0.15),0.007(0.69),0.146(0.08),1.233(0.28),1.312(0.08),1.330(0.11),1.370(16.00),1.826(0.20),2.051(0.24),2.079(1.25),2.090(0.67),2.106(0.25),2.188(0.96),2.327(0.08),2.669(0.08),3.596(0.21),3.691(0.36),4.069(0.88),4.503(0.49),5.991(0.19),6.017(0.46),6.050(0.40),6.075(0.17),7.259(0.21),7.275(0.39),7.294(0.27),7.356(0.23),7.375(0.42),7.393(0.22),7.445(0.61),7.465(0.51),7.486(0.48),7.502(0.37),7.749(2.16),7.752(2.17),8.830(0.21),8.844(0.42).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(3.00g,98%純度,5.19mmol,實施例37A)之NMP(48ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(3.99g,28.6mmol)與DIPEA(5.0ml,29mmol),混合物於120℃下攪拌2天。冷卻至室溫後,添加水(200ml)與乙酸乙酯(100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯重覆萃取(每次100ml)。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度95:5→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.61g(98%純度,78%理論值)標題化合物。
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.209(0.07),1.333(0.09),1.369(16.00),1.398(5.31),1.526(0.07),1.644(0.17),1.813(0.31),1.898(0.28),2.054(0.19),2.074(1.20),2.087(0.67),2.103(0.27),2.144(1.42),2.327(0.06),2.670(0.06),3.093(0.19),3.160(0.20),3.376(0.18),3.406(0.10),3.433(0.17),3.466(0.11),3.586(0.20),3.677(0.36),4.815(0.13),4.938(0.13),7.254(0.17),7.272(0.41),7.290(0.30),7.354(0.24),7.373(0.45),7.391(0.23),7.439(0.61),7.458(0.52),7.484(0.54),7.500(0.45),7.647(0.26),7.669(1.41),7.676(0.96),7.681(0.83),7.699(0.17),7.704(0.18),8.712(0.21),8.726(0.43),8.740(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(450mg,795μmol,實施例37A)之NMP(4.0ml)混合物中添加(2S)-2-甲基吡咯啶(650μl,6.4mmol)與DIPEA(1.4ml,7.9mmol),混合物於100℃下攪拌3h。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到391mg(100%純度,80%理論值)標題化合物。
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.42),0.008(0.37),1.142(2.75),1.157(2.75),1.208(0.09),1.234(0.15),1.301(0.11),1.330(0.16),1.366(16.00),1.369(14.87),1.541(0.23),1.557(0.27),1.579(0.27),1.607(0.18),1.687(0.22),1.812(0.28),1.897(0.31),2.045(0.38),2.072(1.98),2.084(1.41),2.103(1.71),2.327(0.10),2.366(0.10),2.669(0.09),2.710(0.09),3.610(0.34),3.694(0.29),3.716(0.45),3.736(0.45),4.361(0.23),4.376(0.38),4.398(0.35),4.414(0.21),7.241(0.17),7.259(0.47),7.278(0.52),7.296(0.22),7.341(0.28),7.360(0.62),7.379(0.55),7.398(0.22),7.434(0.98),7.454(0.83),7.474(0.62),7.499(0.87),7.503(0.82),7.521(1.03),7.526(1.04),7.569(0.53),7.575(0.94),7.580(0.52),7.591(0.30),7.597(0.51),7.603(0.30),8.698(0.57).
取標題化合物(376mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物/差向異構物(參見實施例118A與119A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:1.0ml;溶析液:17%乙醇/83%二氧化碳;運行時間11min,等濃度,UV檢測210nm,溫度40℃]。取合併之目標溶出份濃縮,取各殘質冷凍乾燥。
在實施例117A說明之差向異構物之分離法中,得到150mg(100%純度,ee >99%)標題化合物,為先溶離岀之差向異構物/對映異構物。
[α]D 20=-29.3°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.67min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.140(1.67),1.155(1.68),1.205(0.07),1.300(0.10),1.333(0.09),1.365(16.00),1.540(0.14),1.556(0.16),1.562(0.16),1.578(0.16),1.606(0.10),1.662(0.14),1.688(0.14),1.708(0.09),1.794(0.13),1.812(0.18),1.895(0.18),2.050(0.22),2.072(1.24),2.085(1.14),2.124(0.28),2.327(0.03),2.669(0.03),3.285(0.15),3.580(0.24),3.625(0.16),3.691(0.14),3.715(0.33),3.732(0.36),3.755(0.21),4.360(0.14),4.375(0.23),4.390(0.19),4.397(0.22),4.413(0.14),7.259(0.15),7.277(0.35),7.295(0.25),7.360(0.26),7.379(0.43),7.397(0.25),7.434(0.62),7.436(0.60),7.454(0.50),7.456(0.48),7.481(0.42),7.499(0.90),7.521(1.12),7.568(0.59),7.573(0.55),7.590(0.32),7.596(0.32),8.683(0.19),8.697(0.32).
在實施例117A說明之差向異構物之分離法中,得到147mg(100%純度,ee 97%)標題化合物,為後溶離岀之差向異構物/對映異構物。
[α]D 20=-10.3°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法1):Rt=2.64min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.142(2.01),1.157(2.03),1.209(0.07),1.318(0.08),1.329(0.15),1.369(16.00),1.512(0.06),1.527(0.12),1.540(0.15), 1.556(0.18),1.563(0.17),1.579(0.17),1.591(0.13),1.607(0.12),1.659(0.14),1.684(0.14),1.793(0.15),1.813(0.19),1.896(0.20),1.910(0.19),2.045(0.28),2.073(1.27),2.105(1.49),2.156(0.20),2.202(0.04),2.327(0.03),2.669(0.03),3.605(0.29),3.695(0.27),3.712(0.27),3.720(0.35),3.736(0.31),3.744(0.19),3.760(0.13),4.362(0.15),4.377(0.24),4.392(0.20),4.399(0.23),4.414(0.14),7.240(0.20),7.259(0.44),7.275(0.32),7.278(0.32),7.340(0.29),7.359(0.53),7.376(0.28),7.432(0.65),7.435(0.65),7.452(0.59),7.470(0.64),7.474(0.65),7.490(0.49),7.504(0.76),7.526(1.26),7.575(0.72),7.580(0.63),7.597(0.39),7.602(0.36),8.685(0.22),8.699(0.41).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(450mg,795μmol,實施例37A)之NMP(4.0ml)混合物中添加(2R)-2-甲基吡咯啶(650μl,6.4mmol)與DIPEA(1.4ml,7.9mmol),混合物於100℃下攪拌3h。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到391mg(100%純度,80%理論值)標題化合物。
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.141(2.84),1.156(2.86),1.207(0.09),1.234(0.15),1.300(0.09),1.329(0.14),1.365(16.00),1.369(15.64),1.540(0.25),1.557(0.29),1.579(0.29),1.607(0.20),1.662(0.25),1.812(0.31),1.896(0.33),2.044(0.39),2.072(2.12),2.084(1.52),2.103(1.85),2.327(0.07),2.365(0.06),2.669 (0.08),2.709(0.06),3.610(0.37),3.694(0.31),3.718(0.49),3.735(0.50),4.361(0.23),4.376(0.39),4.398(0.37),4.413(0.23),7.240(0.18),7.259(0.50),7.278(0.56),7.295(0.24),7.340(0.30),7.359(0.66),7.378(0.59),7.397(0.23),7.434(1.03),7.454(0.88),7.474(0.66),7.499(0.93),7.503(0.87),7.521(1.07),7.525(1.10),7.568(0.54),7.574(0.96),7.580(0.54),7.591(0.31),7.596(0.54),7.602(0.31),8.698(0.61).
取標題化合物(376mg)溶於甲醇與乙腈(5ml)之混合物中,利用製備性SFC,於對掌相上分離成對映異構物/差向異構物(參見實施例121A與122A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:0.3ml;溶析液:17%異丙醇/83%二氧化碳;運行時間15min,等濃度,UV檢測210nm,溫度40℃]。取合併之目標溶出份濃縮,取各殘質冷凍乾燥。
在實施例120A說明之差向異構物之分離法中,得到144mg(95%純度,ee >99%)標題化合物,為先溶離岀之差向異構物/對映異構物。
[α]D 20=+7.9°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法2):Rt=1.37min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.142(2.00),1.157(2.00),1.209(0.08),1.231(0.05),1.317(0.09),1.329(0.16),1.369(16.00),1.511(0.06),1.526(0.13),1.540(0.16),1.556(0.19),1.562(0.19),1.578(0.18),1.606(0.12),1.658(0.15),1.684(0.16),1.702(0.10),1.794(0.17),1.812(0.21),1.895(0.22),1.909(0.21),2.033(0.19),2.045(0.32),2.073(1.39),2.105(1.59),2.156(0.22),2.202(0.04),2.327(0.03),2.365(0.03),2.669(0.02),2.709(0.02),3.605(0.32),3.694(0.29),3.711(0.29),3.719(0.36),3.735(0.32),3.760(0.13),4.361(0.15),4.377(0.25),4.392(0.21),4.399(0.24),4.414(0.14),7.240(0.21),7.258(0.47),7.275(0.35),7.340(0.31),7.357(0.55),7.376(0.30),7.432(0.68),7.452(0.62),7.470(0.69),7.490 (0.53),7.504(0.73),7.526(1.19),7.575(0.69),7.580(0.61),7.597(0.38),7.602(0.35),7.845(0.02),8.685(0.23),8.699(0.42).
在實施例120A說明之差向異構物之分離法中,得到142mg(100%純度,ee 96%)標題化合物,為後溶離岀之差向異構物/對映異構物。
[α]D 20=+25.9°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法2):Rt=1.36min;MS(ESIpos):m/z=614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.141(1.99),1.155(1.99),1.205(0.10),1.232(0.06),1.301(0.11),1.334(0.13),1.365(16.00),1.540(0.17),1.556(0.22),1.579(0.21),1.606(0.13),1.663(0.20),1.687(0.20),1.794(0.20),1.812(0.27),1.896(0.26),2.072(1.75),2.085(1.56),2.327(0.04),3.285(0.22),3.581(0.34),3.625(0.25),3.690(0.20),3.715(0.43),3.732(0.47),3.755(0.28),4.360(0.18),4.376(0.31),4.397(0.29),4.413(0.17),7.258(0.24),7.277(0.49),7.295(0.35),7.360(0.39),7.378(0.60),7.397(0.35),7.435(0.82),7.454(0.66),7.481(0.59),7.499(1.04),7.521(1.19),7.569(0.66),7.591(0.36),8.697(0.45).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(1.50g,2.65mmol,實施例37A)之NMP(15ml)混合物中添加氮雜環庚烷 (2.4ml,21mmol)與DIPEA(4.6ml,26mmol),混合物於100℃下攪拌3h。冷卻至室溫後,混合物濃縮,殘質溶於DMSO,利用製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到1.40g(97%純度,84%理論值)標題化合物。
LC-MS(方法1):Rt=2.89min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.16),1.368(16.00),1.602(1.61),1.779(1.14),2.046(0.30),2.073(1.46),2.085(0.83),2.126(1.55),2.731(2.95),2.890(3.44),3.489(1.34),3.503(1.82),3.518(1.20),3.582(0.26),3.662(0.35),7.251(0.21),7.270(0.46),7.289(0.33),7.352(0.30),7.371(0.51),7.389(0.29),7.436(0.80),7.456(0.65),7.479(0.61),7.498(0.44),7.526(0.69),7.548(1.23),7.593(0.70),7.598(0.62),7.615(0.37),7.621(0.34),7.952(0.45),8.696(0.47).
取標題化合物(1.4g)溶於甲醇/乙腈混合物(70ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例124A與125A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:1.50ml;UV檢測:210nm,溫度:40℃;溶析液:17%乙醇/83%二氧化碳;運行時間14min,等濃度]。取合併之目標溶出份濃縮,殘質冷凍乾燥。
在實施例123A說明之對映異構物之分離法中,得到496mg(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-7.2°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.208(0.07),1.309(0.09),1.330(0.12),1.368(16.00),1.524(0.07),1.602(1.44),1.779(0.99),1.838(0.14),2.046(0.23),2.055(0.20),2.074(1.33),2.085(0.74),2.107(0.35),2.127(1.42),3.489(1.18),3.503(1.67),3.517(1.15),3.583(0.22),3.661(0.30),7.252(0.18),7.270(0.42),7.288(0.31),7.352(0.26),7.371(0.47),7.389(0.26),7.437(0.73),7.455(0.58),7.480 (0.56),7.497(0.40),7.526(0.66),7.548(1.22),7.592(0.66),7.598(0.62),7.615(0.35),7.620(0.34),8.682(0.22),8.696(0.43),8.710(0.21).
在實施例123A說明之對映異構物之分離法中,得到490mg(100%純度,ee 97%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+8.6°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.208(0.07),1.309(0.09),1.331(0.14),1.368(16.00),1.524(0.08),1.601(1.71),1.779(1.22),1.838(0.16),2.046(0.29),2.074(1.56),2.085(0.86),2.108(0.48),2.127(1.68),2.327(0.03),2.669(0.03),3.488(1.38),3.503(1.93),3.517(1.26),3.584(0.28),3.661(0.37),7.251(0.22),7.270(0.48),7.288(0.33),7.351(0.31),7.370(0.54),7.388(0.30),7.436(0.82),7.456(0.67),7.479(0.65),7.498(0.47),7.526(0.69),7.548(1.24),7.593(0.69),7.597(0.62),7.615(0.36),7.620(0.34),8.682(0.28),8.696(0.50),8.710(0.25).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(1.00g,1.67mmol,實施例38A)之NMP(6ml)混合物中添加哌啶(1.3ml,13mmol)與DIPEA(2.3ml,13mmol),混合物於110℃下攪拌2天。冷卻至室溫後, 混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到648mg(100%純度,60%理論值)標題化合物。
LC-MS(方法1):Rt=2.84min;MS(ESIpos):m/z=648/650[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.31),0.008(0.32),0.924(0.26),0.939(1.95),0.955(1.87),1.186(0.07),1.346(16.00),1.398(0.63),1.503(0.09),1.613(0.43),1.679(0.81),1.919(0.14),1.949(0.10),1.971(0.09),1.989(0.24),2.012(0.34),2.024(0.27),2.033(0.32),2.054(0.25),2.074(0.09),2.094(0.21),2.166(1.19),2.328(0.07),2.366(0.07),2.417(0.11),2.435(0.11),2.670(0.07),2.968(0.10),3.151(1.04),3.225(0.08),3.680(0.18),7.462(0.25),7.481(0.41),7.500(0.24),7.636(0.22),7.658(1.37),7.663(1.06),7.668(0.86),7.685(0.27),7.706(0.42),7.722(0.85),7.733(0.64),8.761(0.20),8.776(0.41),8.791(0.19).
取標題化合物(560mg)溶於異丙醇與庚烷(各4ml)之混合物中,利用製備型HPLC於對掌相上分離成對映異構物(參見實施例127A與128A)[管柱:Daicel Chiralpak IA,5μm,250mm x 20mm;流速:15ml/min;注射:0.14ml;UV檢測:220nm,溫度:40℃;溶析液:15%異丙醇/85%庚烷;運行時間11min,等濃度]。取合併之目標溶出份分別濃縮,各殘質自乙腈/水中冷凍乾燥。
在實施例126A說明之對映異構物之分離法中,得到241mg(100%純度,ee 99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-14.5°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.50min;MS(ESIpos):m/z=648/650[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.187(0.07),1.243(0.06),1.258(0.07),1.273(0.05),1.312(0.11),1.324(0.17),1.347(16.00),1.503(0.08),1.613(0.49),1.679(0.96),1.888(0.16),1.897(0.16),1.909(0.16),1.920(0.16),1.949(0.12),1.972(0.10),1.990(0.27),2.003(0.20),2.013(0.39),2.025(0.32),2.034(0.36),2.056 (0.28),2.075(0.11),2.096(0.24),2.110(0.18),2.128(0.24),2.167(1.40),2.328(0.03),2.671(0.02),3.151(1.24),3.640(0.20),3.662(0.18),3.680(0.22),3.696(0.17),7.462(0.30),7.481(0.47),7.499(0.29),7.636(0.21),7.658(1.49),7.663(1.15),7.668(0.90),7.686(0.29),7.706(0.48),7.721(0.97),7.734(0.78),7.751(0.24),8.763(0.23),8.778(0.46),8.792(0.22).
在實施例126A說明之對映異構物之分離法中,得到249mg(100%純度,ee 99%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+14.3°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.50min;MS(ESIpos):m/z=648/650[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.187(0.07),1.243(0.08),1.258(0.09),1.273(0.06),1.312(0.09),1.324(0.16),1.347(16.00),1.503(0.08),1.612(0.48),1.679(0.94),1.897(0.15),1.908(0.16),1.920(0.16),1.949(0.12),1.971(0.09),1.990(0.26),2.012(0.38),2.025(0.31),2.034(0.36),2.055(0.28),2.074(0.10),2.095(0.24),2.109(0.17),2.128(0.23),2.167(1.39),2.328(0.04),2.670(0.03),3.151(1.22),3.639(0.20),3.662(0.18),3.680(0.21),3.696(0.17),7.462(0.30),7.481(0.47),7.499(0.29),7.636(0.21),7.658(1.47),7.663(1.14),7.667(0.91),7.685(0.29),7.706(0.48),7.721(0.97),7.734(0.76),7.750(0.24),8.762(0.23),8.777(0.46),8.792(0.22).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4ml)混合物中添加吡咯啶(670μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到551mg(100%純度,87%理論值)標題化合物。
LC-MS(方法1):Rt=2.27min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.58),0.008(0.56),0.923(0.30),0.938(2.40),0.955(2.28),1.344(16.00),1.398(1.68),1.879(1.44),1.942(0.15),1.965(0.11),1.983(0.24),2.006(0.30),2.018(0.37),2.034(0.32),2.056(0.27),2.074(0.12),2.093(0.27),2.182(0.53),2.327(0.08),2.416(0.14),2.434(0.14),2.967(0.12),3.584(1.09),3.689(0.17),7.457(0.19),7.478(0.97),7.501(1.24),7.553(0.65),7.558(0.60),7.575(0.36),7.580(0.35),7.684(0.16),7.703(0.47),7.713(0.66),7.731(1.08),7.747(0.20),8.719(0.37).
取標題化合物(463mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例130A與131A)[管柱:Daicel Chiralcel OD-H,5μm,250mm x 20mm;流速:80ml/min;注射:1.0ml;UV檢測:210nm,溫度:40℃;溶析液:15%乙醇/85%二氧化碳;運行時間10min,等濃度]。取合併之目標溶出份分別濃縮,各殘質自乙腈/水中冷凍乾燥。
在實施例129A說明之對映異構物之分離法中,得到177mg(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=+13.9°,589nm,c=0.43g/100ml,甲醇
LC-MS(方法1):Rt=2.26min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.184(0.07),1.312(0.12),1.323(0.19),1.344(16.00),1.501(0.07),1.880(1.62),1.944(0.17),1.967(0.12),1.985(0.28),1.998(0.19),2.007(0.35),2.019(0.42),2.035(0.37),2.057(0.31),2.076(0.14),2.094(0.31),2.122(0.25),2.138(0.26),2.183(0.61),2.281(0.04),2.327(0.04),2.670(0.03),3.585(1.24),3.689(0.20),7.344(0.07),7.457(0.21),7.480(0.76),7.503(0.95),7.554(0.56),7.559(0.55),7.577(0.32),7.582(0.32),7.684(0.18),7.704(0.52),7.714(0.75),7.731(1.21),7.748(0.24),8.707(0.21),8.721(0.41),8.736(0.21).
在實施例129A說明之對映異構物之分離法中,得到183mg(100%純度,ee 96%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=-11.9°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=2.27min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.183(0.07),1.311(0.28),1.343(16.00),1.499(0.07),1.878(1.68),1.942(0.18),1.966(0.13),1.984(0.29),2.006(0.37),2.018(0.44),2.034(0.38),2.056(0.32),2.075(0.15),2.093(0.32),2.121(0.27),2.137(0.30),2.180(0.64),2.279(0.05),2.327(0.04),2.669(0.03),3.583(1.31),3.688(0.21),7.347(0.07),7.456(0.24),7.479(0.86),7.502(1.07),7.553(0.64),7.558(0.57),7.575(0.36),7.580(0.33),7.683(0.21),7.703(0.58),7.712(0.81),7.730(1.20),7.746(0.24),8.705(0.24),8.720(0.43),8.734(0.21).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4ml)混合物中添加3,3-二氟哌啶鹽酸鹽(1.26g,8.00mmol)與DIPEA(1.7ml,10mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到415mg(98%純度,59%理論值)標題化合物。
LC-MS(方法1):Rt=2.72min;MS(ESIpos):m/z=684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.79),0.919(0.53),0.934(4.45),0.950(4.42),1.345(16.00),1.397(0.88),1.889(0.53),1.992(0.25),2.014(0.44),2.033(0.37),2.054(0.35),2.093(0.42),2.187(1.12),2.327(0.16),2.391(0.18),2.408(0.52),2.426(0.52),2.444(0.19),2.944(0.28),2.960(0.37),2.976(0.28),3.183(0.51),3.462(0.31),3.491(0.60),3.519(0.29),3.689(0.17),5.753(1.38),7.483(0.46),7.502(0.29),7.686(0.32),7.708(1.77),7.716(1.09),7.738(1.04),8.785(0.41).
取標題化合物(327mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例133A與134A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 30mm;流速:100ml/min;注射:3.0ml;UV檢測:210nm,溫度: 40℃;溶析液:15%甲醇/85%二氧化碳;運行時間15min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例132A說明之對映異構物之分離法中,得到104mg(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-12.1°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法1):Rt=2.71min;MS(ESIpos):m/z=684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.185(0.06),1.305(0.17),1.311(0.11),1.322(0.16),1.345(16.00),1.502(0.06),1.889(0.64),1.946(0.12),1.974(0.09),1.993(0.27),2.016(0.49),2.034(0.42),2.055(0.40),2.095(0.51),2.119(0.41),2.141(0.36),2.188(1.32),2.327(0.03),2.669(0.03),3.183(0.62),3.463(0.37),3.492(0.71),3.520(0.36),3.648(0.19),3.689(0.20),7.463(0.27),7.482(0.52),7.500(0.33),7.686(0.34),7.708(2.09),7.715(1.26),7.721(0.97),7.738(1.17),7.755(0.24),8.772(0.24),8.787(0.48),8.801(0.23).
在實施例132A說明之對映異構物之分離法中,得到75mg(100%純度,ee 97%) 標題化合物,為後溶離岀之對映異構物。
[α]D 20=+13.5°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.18),1.185(0.06),1.311(0.08),1.322(0.14),1.345(16.00),1.502(0.06),1.889(0.54),1.945(0.10),1.974(0.08),1.993(0.24),2.016(0.43),2.034(0.37),2.055(0.35),2.095(0.44),2.119(0.35),2.188(1.15),2.327(0.04),3.184(0.52),3.463(0.33),3.492(0.63),3.520(0.31),3.648(0.16),3.689(0.17),7.463(0.24),7.482(0.47),7.501(0.30),7.686(0.32),7.708 (1.90),7.715(1.12),7.721(0.84),7.738(1.08),7.755(0.22),8.772(0.21),8.787(0.43),8.802(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4ml)混合物中添加氮雜環庚烷(900μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到303mg(100%純度,46%理論值)標題化合物。
LC-MS(方法1):Rt=2.91min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.09),-0.009(0.77),0.007(0.77),0.146(0.09),0.926(0.28),0.941(2.02),0.957(1.89),1.184(0.07),1.345(16.00),1.501(0.07),1.609(1.32),1.789(0.86),1.905(0.16),1.946(0.13),1.987(0.25),2.009(0.38),2.029(0.34),2.051(0.26),2.070(0.10),2.092(0.19),2.153(0.93),2.327(0.10),2.366(0.11),2.440(0.12),2.669(0.08),2.709(0.10),2.973(0.08),3.505(1.11),3.519(1.48),3.534(1.07),3.623(0.14),3.680(0.16),7.389(0.08),7.461(0.19),7.479(0.39),7.498(0.24),7.538(0.60),7.560(1.16),7.601(0.65),7.607(0.60),7.624(0.33),7.629(0.33),7.686(0.16),7.705(0.45),7.717(0.69),7.735(1.02),7.751(0.20),8.734(0.20),8.749(0.41),8.764(0.19).
取標題化合物(215mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例136A與137A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:1.0ml;UV檢測:210nm,溫度:40℃;溶析液:17%甲醇/83%二氧化碳;運行時間9min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例135A說明之對映異構物之分離法中,得到86mg(99%純度,ee >9p%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-12.1°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法2):Rt=1.53min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.185(0.07),1.311(0.12),1.346(16.00),1.502(0.08),1.610(1.59),1.790(1.05),1.908(0.19),1.947(0.16),1.970(0.11),1.988(0.30),2.011(0.46),2.023(0.36),2.031(0.42),2.052(0.32),2.072(0.13),2.094(0.24),2.109(0.24),2.154(1.14),2.327(0.05),2.670(0.05),3.505(1.26),3.520(1.78),3.534(1.23),3.625(0.18),3.682(0.20),7.393(0.10),7.461(0.23),7.480(0.47),7.498(0.30),7.539(0.64),7.561(1.22),7.602(0.67),7.607(0.62),7.625(0.34),7.630(0.33),7.686(0.19),7.706(0.54),7.718(0.85),7.736(1.20),7.751(0.26),8.735(0.24),8.751(0.48),8.765(0.24).
在實施例135A說明之對映異構物之分離法中,得到83mg(100%純度,ee 97%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+12.6°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法2):Rt=1.53min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.185(0.06),1.310(0.09),1.322(0.15), 1.344(16.00),1.501(0.07),1.609(1.35),1.789(0.88),1.907(0.16),1.946(0.14),1.969(0.09),1.987(0.26),2.010(0.38),2.023(0.30),2.030(0.36),2.052(0.28),2.071(0.11),2.094(0.20),2.154(0.96),3.504(1.11),3.519(1.52),3.533(1.10),3.623(0.15),3.681(0.17),7.390(0.09),7.460(0.20),7.479(0.41),7.497(0.26),7.538(0.62),7.560(1.18),7.601(0.65),7.606(0.63),7.623(0.33),7.629(0.33),7.686(0.17),7.705(0.47),7.717(0.73),7.734(1.07),7.751(0.22),8.735(0.20),8.750(0.41),8.765(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4.0ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(1.12g,8.00mmol)與DIPEA(1.7ml,10mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物過濾,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到452mg(100%純度,68%理論值)標題化合物。
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=666/668[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.52),0.923(0.29),0.939(2.28),0.955(2.16),1.345(16.00),1.397(1.13),1.652(0.17),1.906(0.40),1.990(0.32),2.013(0.41),2.033(0.34),2.054(0.26),2.093(0.24),2.178(1.15),2.435(0.12),2.669(0.12),3.115(0.19),3.173(0.19),3.393(0.19),3.451(0.17),3.684(0.18),4.823 (0.14),4.942(0.14),7.463(0.27),7.482(0.45),7.500(0.27),7.659(0.19),7.681(1.39),7.685(1.19),7.690(0.93),7.707(0.53),7.721(0.80),7.738(0.86),8.780(0.39).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4.0ml)混合物中添加(+/-)-3-乙基哌啶(906mg,8.00mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物過濾,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到546mg(100%純度,81%理論值)標題化合物。
LC-MS(方法1):Rt=3.04min;MS(ESIpos):m/z=676/678[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(0.88),0.913(2.18),0.934(3.62),0.950(2.84),1.072(0.17),1.102(0.18),1.185(0.09),1.263(0.33),1.281(0.44),1.346(16.00),1.397(2.53),1.569(0.21),1.641(0.17),1.753(0.24),1.884(0.32),1.990(0.26),2.012(0.49),2.027(0.45),2.051(0.24),2.140(0.56),2.166(0.81),2.327(0.08),2.390(0.14),2.408(0.42),2.426(0.43),2.443(0.27),2.669(0.08),2.727(0.13),2.755(0.23),2.784(0.13),2.927(0.08),2.943(0.19),2.960(0.24),2.976(0.18),2.993(0.07),3.514(0.34),3.536(0.31),3.635(0.20),3.696(0.21),5.753(0.93),7.461(0.28),7.479(0.46),7.497(0.27),7.637(0.13),7.659(1.99),7.686 (0.26),7.706(0.49),7.720(0.60),7.735(1.01),7.753(0.22),8.753(0.22),8.768(0.44),8.782(0.21).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(600mg,1.00mmol,實施例38A)之NMP(4.0ml)混合物中添加(+/-)-3-甲基哌啶(940μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到543mg(100%純度,82%理論值)標題化合物。
LC-MS(方法1):Rt=2.93min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.26),0.927(1.58),0.936(2.24),0.942(1.80),0.953(1.81),1.086(0.16),1.109(0.17),1.186(0.07),1.305(0.09),1.322(0.14),1.346(16.00),1.397(0.61),1.502(0.07),1.633(0.14),1.662(0.17),1.737(0.28),1.797(0.34),1.828(0.22),1.908(0.15),1.948(0.11),1.970(0.08),1.989(0.25),2.011(0.46),2.029(0.38),2.051(0.26),2.070(0.09),2.096(0.14),2.110(0.17),2.169(1.03),2.327(0.06),2.365(0.05),2.413(0.12),2.431(0.18),2.466(0.24),2.694(0.12),2.722(0.23),2.750(0.12),2.948(0.07),2.964(0.08),2.980(0.06),3.453(0.24),3.480(0.44),3.510(0.21),3.679(0.18),7.461(0.26),7.481(0.42),7.500(0.25),7.638(0.13),7.660(2.06),7.665(1.00),7.687(0.26),7.706 (0.45),7.721(0.82),7.737(0.80),7.751(0.21),8.757(0.21),8.771(0.42),8.786(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(1.00g,1.62mmol,實施例41A)之NMP(6ml)混合物中添加哌啶(1.3ml,13mmol)與DIPEA(2.3ml,13mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到351mg(92%純度,30%理論值)標題化合物。
LC-MS(方法1):Rt=2.86min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.40),0.007(0.37),0.922(0.14),0.937(1.10),0.953(1.05),1.200(0.07),1.301(0.27),1.325(0.11),1.360(16.00),1.373(0.47),1.381(0.28),1.397(0.20),1.516(0.08),1.610(0.44),1.674(0.84),1.805(0.19),1.829(0.19),1.855(0.11),2.033(0.24),2.066(1.13),2.088(0.27),2.142(0.91),2.208(0.15),2.327(0.08),2.366(0.07),2.430(0.08),2.669(0.08),2.709(0.07),2.965(0.07),3.143(1.07),3.386(0.18),3.612(0.21),3.628(0.40),3.643(0.37),3.661(0.20),7.362(0.35),7.386(0.19),7.398(0.69),7.403(0.52),7.410(0.51),7.416(0.48),7.422(0.61),7.472(0.12),7.544(0.44),7.557(0.35),7.568(0.30),7.631(0.24),7.653(1.28),7.661(0.88),7.665(0.76),7.683(0.18),7.688(0.17),8.729(0.19),8.744(0.39),8.758(0.19).
取標題化合物(262mg)溶於乙醇(3ml)與乙腈(2ml)混合物中,利用製備型HPLC,於對掌相上分離成對映異構物(參見實施例142A與143A)[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:20ml/min;注射:0.04ml;UV檢測:220nm,溫度:40℃;溶析液:20%乙醇/80%庚烷;運行時間7min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例141A說明之對映異構物之分離法中,得到104mg(89%純度,ee 100%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-11.9°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.86min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.03),0.857(0.03),1.038(0.14),1.055(0.28),1.073(0.15),1.199(0.09),1.210(0.06),1.242(0.24),1.257(0.25),1.272(0.18),1.301(0.54),1.316(0.11),1.325(0.13),1.360(16.00),1.381(0.51),1.516(0.09),1.609(0.55),1.673(1.07),1.787(0.10),1.805(0.23),1.830(0.22),1.855(0.13),2.015(0.07),2.034(0.27),2.045(0.33),2.066(1.36),2.089(0.32),2.142(1.11),2.208(0.29),2.327(0.04),2.669(0.04),2.974(0.07),3.143(1.36),3.369(0.25),3.386(0.24),3.431(0.10),3.449(0.09),3.466(0.04),3.612(0.26),3.628(0.49),3.644(0.46),3.661(0.25),7.362(0.41),7.378(0.22),7.385(0.25),7.398(0.84),7.410(0.60),7.416(0.56),7.421(0.67),7.434(0.15),7.474(0.15),7.544(0.52),7.557(0.40),7.568(0.33),7.631(0.26),7.653(1.42),7.661(0.97),7.665(0.83),7.683(0.20),7.687(0.17),8.730(0.23),8.744(0.46),8.758(0.23).
在實施例141A說明之對映異構物之分離法中,得到95mg(97%純度,ee 97%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+13.8°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.86min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.857(0.06),1.101(0.05),1.119(0.05),1.199(0.08),1.242(0.43),1.257(0.43),1.272(0.28),1.325(0.11),1.359(16.00),1.373(0.55),1.516(0.08),1.609(0.49),1.673(0.95),1.805(0.22),1.830(0.22),1.856(0.12),2.034(0.28),2.066(1.32),2.089(0.30),2.143(1.07),3.144(1.24),3.369(0.27),3.613(0.26),3.628(0.48),3.644(0.43),3.662(0.21),7.362(0.40),7.385(0.18),7.398(0.76),7.410(0.57),7.416(0.55),7.421(0.67),7.474(0.16),7.544(0.45),7.557(0.38),7.568(0.32),7.631(0.26),7.653(1.39),7.660(0.96),7.665(0.82),7.683(0.16),7.687(0.17),8.730(0.22),8.744(0.44),8.759(0.21).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(4ml)混合物中添加吡咯啶(650μl,7.8mmol)與DIPEA(1.4ml,7.8mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到564mg(95%純度,85%理論值)標題化合物。
LC-MS(方法1):Rt=2.41min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.920(0.21),0.935(1.75),0.951(1.69), 1.198(0.08),1.301(0.37),1.314(0.09),1.326(0.12),1.358(16.00),1.380(0.40),1.397(0.73),1.514(0.07),1.805(0.23),1.827(0.26),1.875(1.57),2.033(0.27),2.043(0.32),2.064(1.48),2.085(0.30),2.160(0.54),2.239(0.17),2.327(0.06),2.365(0.05),2.391(0.06),2.409(0.17),2.427(0.17),2.444(0.07),2.669(0.05),2.944(0.10),2.961(0.13),2.977(0.10),3.367(0.22),3.384(0.23),3.575(1.25),3.627(0.32),3.645(0.31),3.663(0.24),7.355(0.49),7.379(0.30),7.394(0.81),7.405(0.62),7.417(0.64),7.475(0.67),7.497(1.15),7.541(0.49),7.552(0.93),7.557(0.88),7.564(0.41),7.574(0.40),7.579(0.37),8.679(0.21),8.693(0.40),8.707(0.21).
取標題化合物(475mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例145A與146A)[管柱:Daicel Chiralcel OH-X,5μm,250mm x 30mm;流速:100ml/min;注射:1.00ml;UV檢測:210nm,溫度:40℃;溶析液:20%甲醇/80%二氧化碳;運行時間9min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例144A說明之對映異構物之分離法中,得到159mg(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-13.2°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.145(0.03),1.198(0.07),1.301(0.28),1.314(0.08),1.327(0.12),1.358(16.00),1.380(0.29),1.514(0.07),1.786(0.10),1.805(0.22),1.828(0.25),1.875(1.49),2.034(0.25),2.043(0.31),2.065(1.44),2.085(0.29),2.161(0.52),2.240(0.07),2.327(0.04),2.669(0.03),3.311(6.84),3.367(0.22),3.384(0.23),3.627(0.31),3.646(0.28),3.663(0.22),7.355(0.47),7.379(0.27),7.394(0.78),7.405(0.61),7.417(0.63),7.429(0.15),7.475(0.66),7.497 (1.12),7.541(0.48),7.552(0.91),7.557(0.87),7.564(0.39),7.574(0.38),7.579(0.36),8.680(0.20),8.694(0.39),8.708(0.20).
在實施例144A說明之對映異構物之分離法中,得到146mg(100%純度,ee 98%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+14.4°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.33min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.198(0.07),1.315(0.08),1.327(0.12),1.358(16.00),1.515(0.07),1.806(0.24),1.828(0.28),1.876(1.60),2.034(0.28),2.044(0.34),2.065(1.61),2.086(0.32),2.161(0.57),2.327(0.04),3.311(7.94),3.367(0.24),3.385(0.25),3.628(0.33),3.646(0.31),3.663(0.23),7.356(0.52),7.380(0.27),7.394(0.84),7.405(0.66),7.417(0.71),7.430(0.17),7.475(0.70),7.498(1.19),7.541(0.51),7.553(1.00),7.557(0.92),7.564(0.44),7.574(0.41),7.579(0.38),8.680(0.23),8.694(0.43),8.708(0.23).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(4ml)混合物中添加3,3-二氟哌啶鹽酸鹽(1.23g,7.79mmol)與DIPEA(1.4ml,7.8mmol),混合物於110℃ 下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到493mg(92%純度,66%理論值)標題化合物。
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=700/702[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.937(0.80),0.953(0.74),1.301(0.37),1.360(16.00),1.398(0.44),1.808(0.24),1.831(0.25),1.884(0.57),2.067(1.68),2.098(0.61),2.161(1.10),2.227(0.16),2.327(0.12),2.366(0.11),3.176(0.67),3.370(0.24),3.455(0.39),3.484(0.73),3.512(0.38),3.638(0.46),3.654(0.43),7.363(0.43),7.401(0.82),7.413(0.62),7.424(0.67),7.549(0.49),7.561(0.43),7.572(0.35),7.683(0.24),7.704(1.40),7.710(1.04),7.732(0.18),8.755(0.46).
取標題化合物(405mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例148A與149A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 30mm;流速:100ml/min;注射:0.7ml;UV檢測:210nm,溫度:40℃;溶析液:12%甲醇/88%二氧化碳;運行時間11min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例147A說明之對映異構物之分離法中,得到134mg(98%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-12.4°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=700/702[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.199(0.07),1.269(0.03),1.301(0.37),1.314(0.07),1.325(0.09),1.360(16.00),1.380(0.42),1.516(0.07),1.789(0.09),1.808(0.23),1.832(0.24),1.885(0.53),2.017(0.08),2.036(0.30),2.067(1.63),2.098(0.58),2.162(1.09),2.327(0.04),2.669(0.03),3.177(0.64),3.371(0.23),3.388(0.23),3.455(0.39),3.484(0.74),3.513(0.37),3.623(0.25),3.639(0.46),3.654 (0.42),3.673(0.21),7.363(0.41),7.387(0.19),7.400(0.78),7.412(0.60),7.418(0.56),7.424(0.67),7.436(0.13),7.511(0.14),7.549(0.50),7.561(0.43),7.572(0.36),7.682(0.23),7.704(1.46),7.709(1.06),7.714(0.88),7.732(0.14),7.736(0.16),8.740(0.24),8.755(0.48),8.769(0.24).
在實施例147A說明之對映異構物之分離法中,得到122mg(100%純度,ee 98%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+13.3°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=700/702[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.200(0.07),1.315(0.08),1.325(0.11),1.360(16.00),1.516(0.07),1.790(0.09),1.809(0.23),1.833(0.24),1.885(0.51),2.018(0.08),2.037(0.30),2.068(1.61),2.099(0.56),2.162(1.07),2.326(0.04),3.177(0.62),3.371(0.22),3.388(0.22),3.456(0.38),3.485(0.72),3.513(0.36),3.624(0.24),3.639(0.45),3.655(0.41),3.673(0.20),7.363(0.42),7.387(0.18),7.400(0.78),7.412(0.59),7.418(0.56),7.424(0.67),7.436(0.13),7.509(0.14),7.549(0.49),7.561(0.42),7.572(0.35),7.682(0.24),7.704(1.48),7.709(1.07),7.714(0.88),7.736(0.16),8.741(0.24),8.755(0.48),8.770(0.24).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(4ml)混合物中添加氮雜環庚烷(880μl,7.8mmol)與DIPEA(1.4ml,7.8mmol),混合物於110℃下攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(120ml)洗滌一次,及使用含1M鹽酸(20ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到557mg(100%純度,84%理論值)標題化合物。
LC-MS(方法1):Rt=2.94min;MS(ESIpos):m/z=678/680[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.15),0.007(0.15),1.199(0.06),1.234(0.05),1.301(0.35),1.313(0.08),1.324(0.10),1.359(16.00),1.373(0.45),1.382(0.35),1.397(1.92),1.515(0.07),1.606(1.33),1.786(0.91),1.829(0.22),1.856(0.12),2.014(0.06),2.033(0.25),2.044(0.27),2.065(1.16),2.089(0.32),2.097(0.28),2.128(0.68),2.201(0.10),2.327(0.04),2.669(0.03),3.369(0.18),3.387(0.19),3.496(1.06),3.511(1.44),3.525(1.04),3.602(0.18),3.618(0.24),3.631(0.24),3.646(0.24),3.663(0.18),7.358(0.37),7.362(0.34),7.384(0.23),7.397(0.75),7.401(0.60),7.408(0.60),7.414(0.57),7.420(0.68),7.432(0.18),7.534(0.65),7.545(0.46),7.557(1.42),7.569(0.32),7.600(0.64),7.606(0.60),7.623(0.34),7.628(0.33),8.704(0.19),8.718(0.37),8.733(0.19).
取標題化合物(450mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例151A與152A)[管柱:Daicel Chiralcel OH-X,5μm,250mm x 20mm;流速:80ml/min;注射:0.40ml;UV檢測:210nm,溫度:40℃;溶析液:20%甲醇/80%二氧化碳;運行時間5min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例150A說明之對映異構物之分離法中,得到154mg(100%純度,ee >99%)標題化合物,為先溶離岀之對映異構物。
[α]D 20=-12.0°,589nm,c=0.47g/100ml,甲醇
LC-MS(方法1):Rt=2.95min;MS(ESIpos):m/z=678/680[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.200(0.08),1.301(0.35),1.313(0.09),1.324(0.11),1.359(16.00),1.381(0.38),1.515(0.08),1.606(1.70),1.786(1.21),1.856(0.15),2.033(0.31),2.066(1.56),2.089(0.40),2.129(0.92),2.201(0.09),3.369(0.24),3.387(0.25),3.496(1.27),3.511(1.87),3.525(1.28),3.602(0.24),3.618(0.33),3.631(0.32),3.646(0.31),3.663(0.23),7.358(0.47),7.397(0.94),7.408(0.75),7.420(0.83),7.534(0.71),7.546(0.53),7.557(1.60),7.569(0.39),7.601(0.64),7.605(0.67),7.623(0.35),7.627(0.36),8.704(0.25),8.718(0.49),8.733(0.25).
在實施例150A說明之對映異構物之分離法中,得到149mg(100%純度,ee 97%)標題化合物,為後溶離岀之對映異構物。
[α]D 20=+13.3°,589nm,c=0.40g/100ml,甲醇
LC-MS(方法1):Rt=2.95min;MS(ESIpos):m/z=678/680[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.03),0.145(0.03),1.199(0.06),1.313(0.08),1.324(0.10),1.359(16.00),1.515(0.07),1.606(1.36),1.786(0.95),1.829(0.23),1.856(0.12),2.014(0.07),2.033(0.27),2.044(0.29),2.065(1.27),2.089(0.32),2.096(0.28),2.128(0.72),2.327(0.04),2.669(0.04),3.369(0.20),3.386(0.20),3.496(1.10),3.511(1.53),3.525(1.08),3.602(0.20),3.618(0.27),3.630(0.26),3.645(0.24),3.663(0.18),7.358(0.39),7.384(0.20),7.397(0.78),7.408(0.64),7.414(0.61),7.420(0.72),7.432(0.19),7.534(0.65),7.546(0.46),7.556(1.45),7.569(0.34),7.600(0.62),7.606(0.59),7.623(0.33),7.628(0.32),8.703(0.21),8.718(0.40),8.732(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(3.9ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(1.09g,7.79mmol)與DIPEA(1.7ml,9.7mmol),混合物於110℃下攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(120ml)洗滌一次,及使用含1M鹽酸(25ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到463mg(92%純度,64%理論值)標題化合物。
LC-MS(方法1):Rt=2.74min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.199(0.07),1.233(0.05),1.301(0.32),1.314(0.07),1.325(0.09),1.360(16.00),1.381(0.37),1.397(3.74),1.516(0.07),1.646(0.18),1.807(0.33),1.831(0.31),1.855(0.18),1.902(0.27),1.952(0.17),2.036(0.24),2.067(1.20),2.089(0.27),2.156(0.93),2.222(0.14),2.327(0.04),3.104(0.18),3.181(0.18),3.333(0.26),3.353(0.21),3.387(0.36),3.412(0.15),3.444(0.16),3.472(0.10),3.618(0.21),3.634(0.38),3.650(0.35),4.818(0.14),4.938(0.14),7.362(0.37),7.386(0.19),7.399(0.69),7.410(0.52),7.417(0.49),7.422(0.59),7.434(0.12),7.491(0.13),7.546(0.43),7.559(0.38),7.570(0.30),7.656 (0.23),7.677(1.30),7.683(0.96),7.688(0.80),7.706(0.17),7.711(0.16),7.901(0.04),8.735(0.20),8.750(0.39),8.765(0.19).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(4.0ml)混合物中添加(+/-)-3-乙基哌啶(882mg,7.79mmol)與DIPEA(1.4ml,7.8mmol),混合物於110℃下攪拌2天。冷卻至室溫後,混合物利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→8:2,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到501mg(98%純度,73%理論值)標題化合物。
LC-MS(方法1):Rt=3.07min;MS(ESIpos):m/z=692/694[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.964(0.91),0.983(2.24),1.002(1.37),1.023(0.48),1.141(0.18),1.170(0.19),1.271(0.09),1.333(0.37),1.350(0.49),1.372(0.61),1.432(16.00),1.452(0.35),1.469(0.15),1.636(0.22),1.822(0.26),1.855(0.25),1.873(0.25),1.898(0.22),1.924(0.31),1.952(0.22),2.103(0.27),2.137(1.26),2.188(0.46),2.215(0.65),2.272(0.11),2.398(0.08),2.437(0.09),2.741(0.08),2.823(0.23),2.852(0.13),3.458(0.21),3.569(0.37),3.598(0.35),3.701(0.31),3.716(0.34),3.733(0.27),3.750(0.17),7.430(0.34),7.468(0.71),7.480(0.54),7.492(0.61),7.549(0.12),7.620(0.40),7.632(0.34),7.643(0.28),7.705(0.17),7.727(1.51),7.757(0.11),8.795(0.22),8.810(0.42),8.825(0.21).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(600mg,974μmol,實施例41A)之NMP(3.9ml)混合物中添加(+/-)-3-甲基哌啶(910μl,7.8mmol)與DIPEA(1.4ml,7.8mmol),混合物於110℃下攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(120ml)洗滌一次,及使用含1M鹽酸(20ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到646mg(100%純度,98%理論值)標題化合物。
LC-MS(方法1):Rt=2.97min;MS(ESIpos):m/z=678/680[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.833(0.04),0.849(0.05),0.922(1.43),0.938(1.46),1.082(0.16),1.111(0.18),1.200(0.08),1.233(0.08),1.301(0.35),1.324(0.10),1.360(16.00),1.381(0.36),1.397(3.29),1.516(0.07),1.628(0.15),1.657(0.17),1.733(0.30),1.765(0.31),1.804(0.43),1.830(0.37),2.014(0.07),2.033(0.25),2.066(1.17),2.092(0.29),2.146(0.69),2.210(0.14),2.327(0.03),2.435(0.12),2.461(0.19),2.687(0.12),2.717(0.21),2.747(0.12),3.369(0.19),3.386(0.20),3.442(0.24),3.471(0.44),3.502(0.21),3.611(0.21),3.629(0.35),3.647(0.31),3.666(0.20),7.361(0.38),7.378(0.15),7.385(0.20),7.398(0.74),7.403(0.56),7.410(0.55),7.416(0.51),7.421(0.63),7.434(0.15),7.472(0.14),7.546 (0.43),7.558(0.35),7.570(0.29),7.634(0.17),7.657(1.59),7.663(0.95),7.681(0.13),7.685(0.12),8.725(0.20),8.739(0.40),8.754(0.20).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3-氟苯基)戊酸第三丁基酯(204mg,349μmol,實施例44A)之NMP(3.4ml)混合物中添加哌啶(280μl,2.8mmol)與DIPEA(490μl,2.8mmol),混合物於100℃下攪拌一夜。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到175mg(100%純度,79%理論值)標題化合物。
LC-MS(方法1):Rt=2.81min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.06),-0.023(0.27),0.007(0.41),0.145(0.05),1.208(0.07),1.233(0.57),1.303(0.08),1.327(0.10),1.368(16.00),1.525(0.07),1.606(0.45),1.670(0.88),1.808(0.14),1.826(0.19),2.048(0.17),2.061(0.18),2.086(1.12),2.100(0.81),2.130(1.45),2.327(0.06),2.365(0.06),2.669(0.06),2.709(0.06),3.134(1.16),3.604(0.21),3.692(0.32),7.286(0.18),7.306(0.40),7.329(0.27),7.345(0.30),7.363(0.54),7.394(0.26),7.413(0.35),7.427(0.36),7.447(0.19),7.624(0.26),7.646(1.35),7.653(0.89),7.658(0.80),7.675(0.17),7.680(0.19),8.716(0.21),8.730(0.45),8.744(0.22).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(6-氯-2,3-二氟苯基)戊酸第三丁基酯(154mg,87%純度,222μmol,實施例45A)之NMP(2ml)混合物中添加哌啶(180μl,1.8mmol)與DIPEA(310μl,1.8mmol),混合物於100℃下攪拌一夜。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到126mg(100%純度,87%理論值)標題化合物。
LC-MS(方法1):Rt=2.82min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.07),-0.023(0.47),1.202(0.10),1.233(0.72),1.362(16.00),1.518(0.09),1.606(0.59),1.670(1.09),1.981(0.14),2.064(0.26),2.143(3.28),2.169(0.73),2.327(0.09),2.365(0.09),2.670(0.08),2.709(0.07),3.134(1.42),3.689(0.24),3.766(0.34),7.377(0.42),7.389(0.49),7.412(0.33),7.433(0.29),7.627(0.40),7.649(1.50),7.659(0.92),7.664(0.81),7.681(0.21),7.686(0.21),8.811(0.45).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(5-氟-2-甲基苯基)戊酸第三丁基酯(200mg,355μmol,實施例46A)之NMP(2ml)混合物中添加哌啶(280μl,2.8mmol)與DIPEA(620μl,3.5mmol),混合物於100℃下攪拌一夜。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到190mg(100%純度,87%理論值)標題化合物。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=612/614[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.023(0.35),0.852(0.06),1.211(0.08),1.233(0.83),1.317(0.07),1.337(0.10),1.371(16.00),1.528(0.08),1.606(0.47),1.669(0.92),1.754(0.13),1.787(0.20),1.811(0.16),2.000(0.19),2.016(0.18),2.036(0.20),2.061(0.78),2.077(0.97),2.099(1.51),2.291(2.74),2.365(0.06),2.669(0.07),2.709(0.06),3.135(1.22),3.478(0.17),3.497(0.20),3.512(0.23),3.635(0.15),3.653(0.23),3.671(0.21),3.686(0.17),3.706(0.10),6.928(0.17),6.943(0.33),6.949(0.37),6.971(0.20),7.136(0.36),7.142(0.37),7.163(0.37),7.169(0.36),7.198(0.35),7.213(0.40),7.234(0.31),7.455(0.20),7.628(0.26),7.650(1.44),7.657(0.95),7.662(0.83),7.679(0.16),7.684(0.18),8.702(0.23),8.717(0.39),8.730(0.23).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(5-氟-2-甲基苯基)戊酸第三丁基酯(336mg,596μmol,實施例46A)之NMP(4.0ml)混合物中添加3,3-二氟哌啶鹽酸鹽(751mg,4.77mmol)與DIPEA(1.0ml,6.0mmol),混合物於100℃下攪拌44h。隨後,提高溫度至120℃,混合物再攪拌24h。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到265mg(100%純度,69%理論值)標題化合物。
LC-MS(方法1):Rt=2.70min;MS(ESIpos):m/z=648/650[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.212(0.07),1.316(0.06),1.337(0.10),1.372(16.00),1.528(0.07),1.757(0.13),1.790(0.21),1.814(0.18),1.829(0.12),1.878(0.50),1.988(0.16),2.002(0.21),2.018(0.21),2.064(0.98),2.080(1.25),2.099(0.84),2.119(1.49),2.291(2.79),3.166(0.61),3.449(0.39),3.478(0.84),3.507(0.56),3.523(0.27),3.646(0.16),3.664(0.25),3.681(0.22),3.698(0.18),3.717(0.10),6.930(0.19),6.945(0.35),6.951(0.38),6.972(0.20),7.142(0.38),7.148(0.38),7.169(0.39),7.175(0.37),7.199(0.37),7.215(0.43),7.236(0.33),7.492(0.19),7.679(0.24),7.701(1.55),7.706(1.07),7.711(0.88),7.734(0.16),8.716(0.25),8.730(0.42),8.744(0.25).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(314mg,521μmol,實施例47A)之NMP(3.1ml)混合物中添加哌啶(410μl,4.2mmol)與DIPEA(730μl,4.2mmol),混合物於100℃下攪拌一夜。冷卻至室溫後,混合物過濾,及經製備型HPLC純化(方法6)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到272mg(100%純度,80%理論值)標題化合物。
LC-MS(方法1):Rt=2.80min;MS(ESIpos):m/z=650/652[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.022(0.18),-0.008(0.77),0.008(0.66),1.234(0.33),1.361(16.00),1.608(0.43),1.673(0.83),2.142(2.24),2.366(0.22),2.710(0.22),3.138(1.09),3.759(0.22),7.303(0.24),7.317(0.19),7.421(0.24),7.630(0.32),7.652(1.33),7.662(0.94),7.667(0.81),7.684(0.21),7.690(0.22),8.814(0.34).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(600mg,996μmol,實施例47A)之NMP(4.0ml)混合物中添加吡咯啶(670μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌5h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,依序使用水與1M鹽酸(各100ml)洗滌。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到90mg(100%純度,14%理論值)標題化合物。
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.21),1.211(0.07),1.300(0.11),1.332(0.11),1.372(16.00),1.397(2.79),1.755(0.12),1.789(0.19),1.812(0.17),1.969(0.16),1.982(0.20),1.999(0.20),2.019(0.15),2.032(0.13),2.067(0.69),2.084(0.98),2.103(0.46),2.283(1.44),3.504(0.12),3.517(0.18),3.537(0.20),3.551(0.24),3.565(0.15),3.706(0.13),3.724(0.19),3.744(0.16),3.758(0.14),6.957(0.24),7.156(0.31),7.162(0.31),7.183(0.32),7.206(0.36),7.221(0.40),7.242(0.31),7.876(0.11),7.898(2.22),7.925(0.09),8.851(0.31).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(536mg,890μmol,實施例47A)之NMP(3.6ml)混合物中添加3,3-二氟哌啶鹽酸鹽(1.12g,7.12mmol)與DIPEA(1.6ml,8.9mmol),混合物於110℃ 下攪拌三天。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(120ml)洗滌一次,及使用含1M鹽酸(25ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到204mg(100%純度,33%理論值)標題化合物。
LC-MS(方法1):Rt=2.67min;MS(ESIpos):m/z=686/688[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.156(0.07),1.174(0.12),1.200(0.08),1.233(0.12),1.269(0.09),1.315(0.44),1.360(16.00),1.377(0.68),1.406(0.22),1.517(0.07),1.883(0.55),1.987(0.32),2.082(0.53),2.097(0.54),2.136(0.81),2.163(2.62),2.327(0.07),2.669(0.05),3.171(0.66),3.450(0.40),3.479(0.77),3.508(0.39),3.696(0.24),3.771(0.26),4.020(0.06),4.038(0.05),7.270(0.14),7.281(0.16),7.294(0.28),7.305(0.29),7.319(0.22),7.330(0.20),7.410(0.28),7.421(0.27),7.681(0.32),7.703(1.51),7.711(1.02),7.716(0.87),7.734(0.20),7.738(0.21),8.828(0.41).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(600mg,996μmol,實施例47A)之NMP(4.0ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(1.11g,7.97mmol)與DIPEA(1.7ml,10mmol),混合物於110℃下攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用 水(120ml)洗滌一次,及使用含1M鹽酸(25ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到463mg(100%純度,69%理論值)標題化合物。
LC-MS(方法1):Rt=2.68min;MS(ESIpos):m/z=668/670[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.17),1.157(0.10),1.175(0.20),1.193(0.11),1.201(0.08),1.235(0.07),1.268(0.07),1.316(0.43),1.361(16.00),1.378(0.68),1.398(2.22),1.518(0.07),1.646(0.20),1.808(0.18),1.901(0.32),1.920(0.30),1.952(0.27),1.989(0.53),2.067(0.21),2.084(0.21),2.103(0.18),2.137(0.65),2.157(2.66),2.260(0.06),2.670(0.04),3.099(0.21),3.168(0.22),3.349(0.16),3.380(0.21),3.410(0.11),3.437(0.19),3.468(0.12),3.698(0.22),3.767(0.25),4.003(0.04),4.021(0.09),4.039(0.09),4.057(0.04),4.820(0.15),4.940(0.15),7.269(0.13),7.280(0.15),7.293(0.26),7.304(0.28),7.318(0.21),7.329(0.19),7.410(0.26),7.421(0.26),7.499(0.08),7.655(0.32),7.677(1.46),7.686(0.97),7.691(0.89),7.709(0.21),7.713(0.23),7.906(0.04),8.823(0.37).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(600mg,996μmol,實施例47A)之NMP(4.0ml)混合物中添加(+/-)-3-甲基哌啶(940μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下 攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(120ml)洗滌一次,及使用含1M鹽酸(20ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到550mg(100%純度,83%理論值)標題化合物。
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.867(0.06),0.884(0.06),0.954(1.62),0.970(1.65),1.114(0.19),1.142(0.20),1.165(0.08),1.235(0.08),1.267(0.11),1.303(0.07),1.348(0.51),1.395(16.00),1.411(0.72),1.431(5.54),1.551(0.07),1.663(0.17),1.686(0.19),1.765(0.35),1.796(0.33),1.826(0.41),1.857(0.26),2.017(0.12),2.102(0.22),2.118(0.22),2.138(0.22),2.181(2.31),2.280(0.06),2.361(0.04),2.478(0.17),2.752(0.17),3.470(0.28),3.498(0.51),3.528(0.24),3.730(0.23),3.795(0.26),7.301(0.14),7.312(0.16),7.325(0.27),7.336(0.28),7.351(0.22),7.362(0.20),7.421(0.18),7.432(0.21),7.443(0.28),7.454(0.28),7.465(0.18),7.476(0.15),7.667(0.24),7.689(1.52),7.694(1.18),7.698(0.95),7.716(0.16),7.721(0.18),8.828(0.22),8.842(0.38),11.235(0.02).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(600mg,996μmol,實施例47A)之NMP(4.0ml)混合物中添加 (+/-)-3-乙基哌啶(1.1ml,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌30h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(150ml)洗滌一次,及使用含1M鹽酸(20ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到558mg(100%純度,83%理論值)標題化合物。
LC-MS(方法1):Rt=3.00min;MS(ESIpos):m/z=678/680[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.890(0.96),0.909(2.20),0.927(1.16),1.065(0.24),1.095(0.25),1.200(0.09),1.259(0.54),1.276(0.70),1.294(0.48),1.313(0.75),1.360(16.00),1.377(0.79),1.396(1.93),1.566(0.29),1.747(0.34),1.779(0.23),1.847(0.29),1.877(0.29),1.973(0.15),2.066(0.28),2.082(0.29),2.139(2.33),2.241(0.08),2.424(0.20),2.695(0.12),2.752(0.22),3.490(0.54),3.519(0.51),3.694(0.28),3.763(0.32),7.276(0.19),7.290(0.33),7.300(0.34),7.314(0.25),7.325(0.22),7.404(0.35),7.415(0.35),7.632(0.27),7.654(1.72),7.686(0.19),8.809(0.48).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(600mg,996μmol,實施例47A)之NMP(4.0ml)混合物中添加氮雜環庚烷(900μl,8.0mmol)與DIPEA(1.4ml,8.0mmol),混合物於110℃下攪拌5h。 冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用含1M鹽酸(20ml)之水(100ml)混合物洗滌一次,及使用水(150ml)洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到599mg(100%純度,90%理論值)標題化合物。
LC-MS(方法1):Rt=2.85min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.851(0.05),1.200(0.08),1.234(0.20),1.267(0.10),1.312(0.62),1.360(16.00),1.377(0.75),1.397(4.30),1.517(0.09),1.602(1.91),1.780(1.21),1.882(0.08),1.901(0.11),1.920(0.13),1.972(0.15),2.065(0.25),2.082(0.27),2.133(2.63),2.150(1.06),2.195(0.12),2.236(0.07),2.328(0.05),2.670(0.04),2.695(0.40),3.285(0.13),3.492(1.43),3.506(2.16),3.520(1.38),3.708(0.30),7.266(0.15),7.277(0.18),7.290(0.31),7.301(0.33),7.315(0.24),7.326(0.22),7.407(0.35),7.418(0.34),7.532(0.71),7.554(1.27),7.602(0.76),7.607(0.67),7.624(0.42),7.629(0.39),8.789(0.43).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(300mg,97%純度,471μmol,實施例50A)之NMP(4.0ml)混合物中添加哌啶(230μl,2.4mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,及利用加熱攪拌器於100℃下攪拌一 夜。接著再於130℃下攪拌24h。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到258mg(100%純度,82%理論值)標題化合物。
LC-MS(方法4):Rt=1.80min;未檢測目標質量即進行電離化
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.10),-0.008(0.85),0.008(0.95),0.146(0.10),1.307(0.15),1.340(16.00),1.613(0.43),1.678(0.85),2.042(0.25),2.073(0.48),2.093(0.35),2.114(0.48),2.141(0.39),2.168(1.23),2.328(0.11),2.670(0.11),3.151(1.11),3.700(0.12),3.849(0.11),5.754(0.33),7.561(0.48),7.571(0.44),7.594(0.69),7.622(0.44),7.634(0.51),7.656(1.32),7.661(0.97),7.666(0.84),7.688(0.17),8.803(0.21),8.818(0.42),8.833(0.21).
取標題化合物(188mg),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例168A與169A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;流速:60ml/min;UV檢測:260nm,溫度:25℃;溶析液:10%甲醇/90%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。
在實施例167A說明之對映異構物之分離法中,得到85mg(100%純度,ee 99%)標題化合物,為先溶離出之對映異構物。
Rt=11.5min(對掌性分析性HPLC;管柱:Chiralpak IE,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺80:20:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.48min;MS(ESIpos):m/z=666/668[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.348(16.00),1.621(0.41),1.687(0.81),2.080(0.44),2.122(0.46),2.177(1.18),3.158(1.06),7.569(0.47),7.579(0.44),7.603 (0.69),7.631(0.44),7.642(0.51),7.664(1.33),7.669(1.00),7.674(0.86),8.826(0.40).
在實施例167A說明之對映異構物之分離法中,得到93mg(100%純度,ee 97%)標題化合物,為後溶離出之對映異構物。
Rt=10.3min(對掌性分析性HPLC;管柱:Chiralpak IE,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺80:20:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.48min;MS(ESIpos):m/z=666/668[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.46),0.007(0.43),1.029(0.54),1.044(0.55),1.235(0.26),1.307(0.15),1.340(16.00),1.613(0.42),1.678(0.83),2.041(0.24),2.072(0.47),2.092(0.34),2.114(0.47),2.140(0.39),2.167(1.21),2.327(0.11),2.669(0.11),3.154(1.12),3.714(0.12),3.847(0.11),7.561(0.47),7.570(0.43),7.594(0.69),7.622(0.44),7.633(0.49),7.655(1.31),7.661(0.93),7.666(0.80),7.688(0.16),8.802(0.20),8.817(0.41),8.832(0.20).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(300mg,97%純度,471μmol, 實施例50A)之NMP(4.0ml)混合物中添加吡咯啶(200μl,2.4mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,及利用加熱攪拌器於100℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到239mg(100%純度,78%理論值)標題化合物。
LC-MS(方法4):Rt=1.46min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.10),-0.008(0.85),0.008(0.95),0.146(0.10),1.290(0.07),1.308(0.14),1.337(16.00),1.879(1.23),2.038(0.27),2.067(0.53),2.093(0.41),2.115(0.61),2.144(0.39),2.178(0.48),2.328(0.11),2.669(0.10),3.581(0.86),3.867(0.11),5.754(0.65),7.476(0.63),7.499(1.10),7.552(0.74),7.557(0.95),7.574(0.65),7.580(0.59),7.590(0.62),7.613(0.41),8.745(0.19),8.760(0.38),8.775(0.20).
取標題化合物(163mg),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例171A與172A)[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:60ml/min;UV檢測:230nm,溫度:25℃;溶析液:20%(甲醇+1%二乙基胺)/80%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。
在實施例170A說明之對映異構物之分離法中,得到75mg(98%純度,ee 98%)標題化合物,為先溶離出之對映異構物。
Rt=10.8min(對掌性分析性HPLC;管柱:Chiralpak IC,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測260nm)
LC-MS(方法2):Rt=1.11min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.029(0.47),1.045(0.47),1.337(16.00),1.879(1.24),2.038(0.29),2.067(0.55),2.092(0.43),2.115(0.62),2.144(0.40),2.179 (0.49),2.327(0.16),2.669(0.15),3.581(0.87),7.476(0.64),7.498(1.12),7.552(0.76),7.557(0.98),7.574(0.67),7.580(0.60),7.590(0.64),7.613(0.42),8.760(0.38).
在實施例170A說明之對映異構物之分離法中,得到79mg(97%純度,ee 98%)標題化合物,為後溶離出之對映異構物。
Rt=13.4min(對掌性分析性HPLC;管柱:Chiralpak IC,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測260nm)
LC-MS(方法2):Rt=1.11min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.030(1.27),1.045(1.26),1.235(0.11),1.308(0.16),1.337(16.00),1.879(1.30),1.960(0.11),2.037(0.29),2.067(0.56),2.093(0.44),2.115(0.64),2.144(0.41),2.178(0.52),2.327(0.12),3.580(0.92),3.864(0.12),7.476(0.67),7.498(1.16),7.552(0.83),7.557(1.01),7.574(0.69),7.580(0.63),7.589(0.66),7.613(0.43),8.760(0.40).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(300mg,98%純度,476μmol,實 施例50A)之NMP(4.0ml)混合物中添加3,3-二氟哌啶鹽酸鹽(387mg,97%純度,2.38mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,及利用加熱攪拌器於100℃下攪拌一夜。接著再於130℃下攪拌24h。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到248mg(100%純度,74%理論值)標題化合物。
LC-MS(方法1):Rt=2.72min;MS(ESIpos):m/z=702/704[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.05),-0.008(0.42),0.008(0.38),0.146(0.05),1.180(0.06),1.290(0.07),1.307(0.14),1.340(16.00),1.497(0.06),1.889(0.41),2.049(0.30),2.078(0.59),2.100(0.65),2.117(0.70),2.141(0.44),2.189(1.10),2.328(0.07),2.670(0.07),3.181(0.46),3.462(0.32),3.491(0.63),3.520(0.31),3.717(0.11),3.864(0.10),5.754(0.18),7.565(0.44),7.574(0.43),7.598(0.65),7.625(0.43),7.634(0.28),7.648(0.20),7.684(0.20),7.706(1.32),7.710(1.02),7.715(0.83),7.733(0.12),7.737(0.15),8.815(0.20),8.831(0.42),8.846(0.20).
取標題化合物(179mg),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例174A與175A)[管柱:Daicel Chiralpak AD-H,5μm,250mm x 30mm;流速:120ml/min;UV檢測:260nm,溫度:25℃;溶析液:10%異丙醇/90%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。
在實施例173A說明之對映異構物之分離法中,得到91mg(100%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
Rt=18.1min(對掌性分析性HPLC;管柱:Chiralpak IC,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺90:10:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.43min;MS(ESIpos):m/z=702/704[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.91),0.008(0.87),1.030(1.67),1.045(1.69),1.237(0.39),1.340(16.00),1.888(0.40),2.100(0.64),2.117(0.68),2.141(0.43),2.189(1.08),2.328(0.16),2.670(0.17),3.187(0.45),3.462(0.32),3.491(0.62),3.520(0.31),4.323(0.21),4.334(0.21),7.565(0.44),7.575(0.42),7.598(0.64),7.625(0.42),7.684(0.20),7.706(1.29),7.710(1.00),7.715(0.82),7.737(0.15),8.830(0.40).
在實施例173A說明之對映異構物之分離法中,得到93mg(100%純度,ee>99%)標題化合物,為後溶離出之對映異構物。
Rt=21.4min(對掌性分析性HPLC;管柱:Chiralpak IC,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺90:10:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.43min;MS(ESIpos):m/z=702/704[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.007(0.93),1.029(1.51),1.044(1.53),1.236(0.47),1.340(16.00),1.889(0.45),2.100(0.71),2.115(0.76),2.140(0.47),2.188(1.18),2.327(0.16),2.669(0.17),3.183(0.50),3.462(0.34),3.490(0.67),3.519(0.33),4.322(0.21),4.333(0.20),7.564(0.46),7.574(0.46),7.597(0.67),7.624(0.45),7.683(0.20),7.705(1.37),7.709(1.07),7.714(0.86),7.737(0.15),8.830(0.43).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(400mg,98%純度,634μmol,實施例50A)之NMP(4.0ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(457mg,97%純度,3.17mmol)與DIPEA(550μl,3.2mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到351mg(100%純度,81%理論值)標題化合物。
LC-MS(方法1):Rt=2.71min;MS(ESIpos):m/z=684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.42),0.008(0.45),1.307(0.13),1.340(16.00),1.654(0.14),1.813(0.14),1.906(0.24),2.075(0.45),2.097(0.36),2.116(0.48),2.142(0.31),2.181(1.06),2.328(0.11),2.670(0.12),3.113(0.17),3.179(0.17),3.391(0.18),3.449(0.16),3.482(0.10),3.705(0.11),3.861(0.11),4.825(0.12),4.945(0.12),5.754(0.82),7.562(0.45),7.573(0.42),7.595(0.65),7.623(0.43),7.636(0.28),7.657(0.21),7.679(1.15),7.712(0.12),8.824(0.35).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-氟-6-(三氟甲基)苯基]戊酸第三丁基酯(400mg,98%純度,634μmol,實施例50A)之NMP(4.0ml)混合物中添加(+/-)-3-乙基哌啶(378mg,95%純度,3.17mmol)與DIPEA(550μl,3.2mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到383mg(100%純度,87%理論值)標題化合物。
LC-MS(方法1):Rt=3.01min;MS(ESIpos):m/z=684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.009(0.42),0.007(0.45),1.306(0.13),1.339(16.00),1.653(0.14),1.812(0.14),1.905(0.24),2.075(0.45),2.096(0.36),2.116(0.48),2.141(0.31),2.180(1.06),2.327(0.11),2.669(0.12),3.112(0.17),3.178(0.17),3.390(0.18),3.448(0.16),3.482(0.10),3.704(0.11),3.860(0.11),4.825(0.12),4.944(0.12),5.753(0.82),7.562(0.45),7.572(0.42),7.595(0.65),7.622(0.43),7.635(0.28),7.656(0.21),7.679(1.15),7.711(0.12),8.823(0.35).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,3,6-三氯苯基)戊酸第三丁基酯(300mg,475μmol,實施例51A)之NMP(4.0ml)混合物中添加哌啶(230μl,2.4mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到242mg(100%純度,75%理論值)標題化合物。
LC-MS(方法4):Rt=1.87min;未檢測目標質量即進行電離化
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.20),0.008(1.31),1.351(14.79),1.355(16.00),1.610(0.78),1.674(1.51),2.073(3.11),2.138(2.16),2.156(0.92),2.169(3.50),2.327(0.31),2.670(0.18),3.141(1.94),3.819(0.29),4.033(0.51),7.473(0.58),7.495(0.81),7.532(0.71),7.554(1.23),7.593(0.84),7.614(0.57),7.631(0.37),7.637(0.35),7.653(1.38),7.659(1.35),7.669(1.22),7.674(0.69),7.691(0.30),8.806(0.51).
取標題化合物(194mg),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例179A與180A)[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:60ml/min;UV檢測:260nm,溫度:25℃;溶析液:35%(異丙醇+1%二乙基胺)/65%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。得到波峰2,再利用對掌性HPLC分離[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:20ml/min;UV檢測:260nm,溫度:25℃;溶析液:20%乙酸乙酯/80%庚烷,等濃度]
在實施例178A說明之對映異構物之分離法中,得到92mg(100%純度,ee 98%)標題化合物,為先溶離出之對映異構物。
Rt=8.3min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.58min;MS(ESIpos):m/z=682/684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.84),0.008(0.66),1.029(4.38),1.045(4.40),1.236(0.62),1.351(15.34),1.355(16.00),1.609(0.80),1.673(1.53),2.083(0.46),2.098(0.48),2.112(0.60),2.137(2.18),2.156(0.97),2.169(3.55),2.523(0.44),3.141(1.98),4.032(0.52),4.323(0.54),4.334(0.53),7.473(0.56),7.495(0.78),7.532(0.67),7.554(1.18),7.593(0.80),7.599(0.70),7.615(0.56),7.653(1.35),7.659(1.31),7.662(1.07),7.669(1.19),7.674(0.67),8.792(0.44),8.806(0.51).
在實施例178A說明之對映異構物之分離法中,得到96mg(100%純度,ee>99%)標題化合物,為後溶離出之對映異構物。
Rt=11.0min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1:流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.58min;MS(ESIpos):m/z=682/684/686[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.62),0.008(0.63),0.854(0.49),0.858(0.46),1.237(2.83),1.249(1.11),1.258(0.60),1.336(0.75),1.351(15.06),1.355(16.00),1.610(0.78),1.673(1.51),2.083(0.45),2.098(0.47),2.111(0.58),2.137(2.17),2.156(0.95),2.169(3.50),3.141(1.96),4.032(0.52),7.473(0.54),7.495 (0.77),7.532(0.67),7.554(1.15),7.593(0.79),7.599(0.69),7.615(0.55),7.653(1.32),7.658(1.27),7.662(1.06),7.668(1.15),7.674(0.65),8.791(0.43),8.806(0.50).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,3,6-三氯苯基)戊酸第三丁基酯(300mg,472μmol,實施例51A)之NMP(4.0ml)混合物中添加吡咯啶(200μl,2.4mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到261mg(100%純度,82%理論值)標題化合物。
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=668/670/672[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.69),-0.008(5.80),0.008(5.56),0.146(0.67),1.349(16.00),1.353(15.98),1.875(2.13),2.073(0.92),2.095(0.52),2.121(0.82),2.134(1.09),2.158(1.22),2.174(0.95),2.193(2.16),2.327(0.75),2.669(0.62),3.575(1.49),4.035(0.47),7.473(1.07),7.480(0.77),7.495(1.59),7.502(1.19),7.522(0.70),7.544(1.21),7.553(0.77),7.560(0.99),7.566(0.60),7.576(0.52),7.587(0.94),7.608(0.50),8.754(0.54).
取標題化合物(199mg),利用製備性SFC,於對掌相上分離成對映異構物(參 見實施例182A與183A)[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:60ml/min;UV檢測:230nm,溫度:25℃;溶析液:40%(異丙醇+1%二乙基胺)/60%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。
在實施例181A說明之對映異構物之分離法中,得到92mg(100%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
Rt=12.0min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.21min;MS(ESIpos):m/z=668/670/672[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.88),0.008(0.72),1.030(1.55),1.045(1.56),1.236(1.18),1.349(15.95),1.353(16.00),1.875(2.18),2.080(0.50),2.095(0.55),2.108(0.59),2.121(0.86),2.135(1.11),2.158(1.23),2.174(0.99),2.193(2.17),2.327(0.41),3.574(1.54),4.037(0.49),7.473(1.01),7.480(0.76),7.495(1.53),7.502(1.18),7.522(0.66),7.544(1.14),7.554(0.74),7.560(0.96),7.566(0.59),7.576(0.51),7.588(0.95),7.609(0.51),8.755(0.50).
在實施例181A說明之對映異構物之分離法中,得到98mg(100%純度,ee 99%)標題化合物,為後溶離出之對映異構物。
Rt=16.7min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.21min;MS(ESIpos):m/z=668/670/672[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.95),0.008(0.59),0.854(0.51), 1.030(1.60),1.045(1.59),1.092(0.52),1.236(2.83),1.259(0.57),1.331(0.85),1.349(16.00),1.353(15.73),1.875(2.07),1.961(0.65),2.081(0.48),2.095(0.54),2.108(0.58),2.120(0.84),2.134(1.06),2.158(1.19),2.174(0.97),2.193(2.12),2.327(0.40),3.574(1.44),4.037(0.47),7.473(1.00),7.480(0.76),7.495(1.52),7.502(1.18),7.522(0.67),7.544(1.15),7.554(0.74),7.560(0.97),7.567(0.59),7.576(0.49),7.588(0.93),7.609(0.51),8.756(0.50).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,3,6-三氯苯基)戊酸第三丁基酯(300mg,472μmol,實施例51A)之NMP(4.0ml)混合物中添加3,3-二氟哌啶鹽酸鹽(372mg,2.36mmol)與DIPEA(410μl,2.4mmol)。使用氬氣吹掃容器,密封,及利用加熱攪拌器,於130℃下攪拌一夜。然後於140℃下攪拌24h。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到241mg(100%純度,71%理論值)標題化合物。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=718/720/722[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.55),0.008(2.50),1.331(0.53),1.351(14.99),1.355(16.00),1.883(0.79),2.100(0.98),2.115(0.97),2.128(1.23),2.159(1.91),2.189(3.51),2.328(0.53),3.177(0.91),3.453(0.61),3.483(1.16),3.511(0.61),4.035(0.51),7.476(0.52),7.498(0.75),7.534(0.65),7.556(1.20),7.595 (0.89),7.617(0.61),7.704(1.44),7.711(1.65),7.718(1.30),7.724(0.76),8.819(0.53).
取標題化合物(172mg),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例185A與186A)[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:60ml/min;UV檢測:260nm,溫度:25℃;溶析液:25%異丙醇/75%二氧化碳;出口壓力150bar,等濃度]。取合併之目標溶出份分別濃縮,取各殘質減壓乾燥。得到波峰2,再利用對掌性HPLC分離[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;流速:20ml/min;UV檢測:260nm,溫度:25℃;溶析液:20%乙酸乙酯/80%庚烷,等濃度]
在實施例184A說明之對映異構物之分離法中,得到79mg(100%純度,ee 97%)標題化合物,為先溶離出之對映異構物。
Rt=7.9min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.49min;MS(ESIpos):m/z=718/720/722[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.18),0.008(1.05),1.029(2.87),1.045(2.90),1.236(1.65),1.330(0.53),1.351(15.41),1.355(16.00),1.884(0.77),2.085(0.83),2.100(0.95),2.115(0.96),2.128(1.21),2.159(1.89),2.173(0.76),2.189(3.45),3.176(0.89),3.453(0.59),3.482(1.14),3.511(0.60),4.036(0.49),7.476(0.50),7.498(0.72),7.534(0.62),7.556(1.17),7.595(0.80),7.617(0.56),7.704(1.34),7.711(1.51),7.718(1.22),7.724(0.71),8.805(0.43),8.819(0.52).
在實施例184A說明之對映異構物之分離法中,得到100mg(100%純度,ee >99%)標題化合物,為後溶離出之對映異構物。
Rt=10.1min(對掌性分析性HPLC;管柱:Chiralpak IG,5μm,250mm x 4.6mm,溶析液:庚烷/異丙醇/二乙基胺70:30:0.1;流速1ml/min;溫度25℃;檢測225nm)
LC-MS(方法2):Rt=1.49min;MS(ESIpos):m/z=718/720/722[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.56),0.008(1.36),0.836(0.55),0.854(1.20),0.858(0.83),0.870(0.53),1.237(6.54),1.249(2.69),1.259(1.82),1.298(1.07),1.335(1.81),1.351(15.42),1.355(16.00),1.883(0.75),2.085(0.81),2.100(0.95),2.115(0.92),2.128(1.16),2.159(1.85),2.189(3.47),2.322(0.42),2.327(0.45),3.176(0.87),3.453(0.60),3.482(1.12),3.511(0.57),4.036(0.49),7.476(0.51),7.498(0.72),7.534(0.62),7.556(1.16),7.595(0.80),7.617(0.57),7.704(1.36),7.711(1.52),7.718(1.22),7.724(0.72),8.806(0.41),8.819(0.51).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,3,6-三氯苯基)戊酸第三丁基酯(400mg,630μmol,實施例51A)之NMP(4.0ml)混合物中添加(+/-)-3-氟哌啶鹽酸鹽(440mg,3.15mmol)與DIPEA(550μl,3.1mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到355mg(100%純度,80%理論值)標題化合物。
LC-MS(方法4):Rt=1.80min;未檢測目標質量即進行電離化
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.330(0.83),1.351(14.93),1.354(16.00),1.899(0.53),2.085(0.47),2.099(0.52),2.126(0.99),2.139(1.04),2.155(2.15),2.182(3.06),2.327(0.43),4.036(0.55),5.754(0.98),7.475(0.50),7.496(0.70),7.533(0.63),7.554(1.12),7.593(0.76),7.615(0.53),7.677(1.36),7.683(1.42),7.692(1.25),8.800(0.49),8.814(0.55).
在厚壁玻璃瓶(微波瓶)中,在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,3,6-三氯苯基)戊酸第三丁基酯(400mg,630μmol,實施例51A)之NMP(4.0ml)混合物中添加(+/-)-3-乙基哌啶(356mg,3.15mmol)與DIPEA(550μl,3.1mmol)。使用氬氣吹掃容器,密封,利用加熱攪拌器於130℃下攪拌一夜。冷卻至室溫後,混合物直接(未進一步操作)經過製備型HPLC純化(方法14)。取合併之目標溶出份濃縮,殘質溶於二氯甲烷,再濃縮一次,及減壓乾燥。得到383mg(100%純度,85%理論值)標題化合物。
LC-MS(方法4):Rt=1.80min;未檢測目標質量即進行電離化
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.66),0.008(1.50),0.893(1.23),0.912(2.91),0.930(1.51),1.263(0.60),1.281(0.76),1.303(0.62),1.352(15.56),1.356(16.00),2.086(0.46),2.099(0.52),2.133(1.62),2.158(2.77),2.163(1.99),3.494(0.64),3.525(0.59),4.025(0.41),4.037(0.41),5.754(1.33),7.473(0.59),7.495 (0.85),7.527(0.71),7.549(1.21),7.588(0.74),7.596(0.78),7.610(0.51),7.617(0.44),7.656(1.49),7.660(2.02),7.665(1.35),8.790(0.44).
在含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(二氟甲氧基)-6-氟苯基]戊酸第三丁基酯(1.00g,1.62mmol,實施例52A)之NMP(5.8ml)混合物中添加哌啶(1.3ml,13mmol)與DIPEA(2.3ml,13mmol),混合物於110℃下攪拌5h。冷卻至室溫後,添加二氯甲烷(150ml)至混合物中,使用水(150ml)洗滌一次,及使用1M鹽酸(40ml)之水(100ml)混合物洗滌一次。取有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到933mg(96%純度,83%理論值)標題化合物。
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.833(0.05),0.850(0.06),1.196(0.08),1.234(0.17),1.289(0.08),1.307(0.33),1.311(0.43),1.356(16.00),1.369(0.64),1.397(5.74),1.512(0.08),1.607(0.50),1.672(0.95),1.881(0.06),1.901(0.09),1.920(0.12),1.937(0.14),1.954(0.18),2.027(0.16),2.042(0.21),2.056(0.20),2.079(1.01),2.093(0.71),2.114(0.39),2.133(1.36),2.175(0.13),2.195(0.07),2.240(0.10),2.294(0.03),2.327(0.03),2.669(0.03),2.694(0.32),3.137(1.23),3.284(0.10),3.516(0.18),3.661(0.08),3.676(0.13),3.693(0.24),3.709(0.30),3.727 (0.24),3.746(0.21),3.765(0.17),3.799(0.06),7.019(0.42),7.039(0.45),7.060(0.33),7.089(0.29),7.111(0.42),7.135(0.31),7.244(0.63),7.357(0.17),7.378(0.33),7.395(0.31),7.415(0.15),7.428(0.34),7.485(0.11),7.627(0.32),7.650(1.43),7.659(0.90),7.664(0.80),7.682(0.20),7.686(0.21),8.772(0.23),8.787(0.45),8.801(0.22).
取標題化合物(810mg)溶於甲醇(30ml),利用製備性SFC,於對掌相上分離成對映異構物(參見實施例190A與191A)[管柱:Daicel Chiralcel OX-H,5μm,250mm x 30mm;流速:90ml/min;注射:0.3ml;UV檢測:210nm,溫度:40℃;溶析液:15%甲醇/85%二氧化碳;運行時間6min,等濃度]。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例189A說明之對映異構物之分離法中,得到810mg(96%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
[α]D 20=-23.0°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法2):Rt=1.47min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.889(5.96),0.908(13.53),0.926(6.80),1.034(0.52),1.062(1.29),1.085(1.31),1.114(0.57),1.240(1.11),1.256(2.40),1.274(3.14),1.283(2.64),1.291(2.25),1.301(1.76),1.558(1.43),1.604(1.33),1.635(1.24),1.665(0.54),1.745(1.84),1.779(1.51),1.813(1.49),1.835(2.39),1.854(2.18),1.877(1.62),2.033(1.16),2.048(3.43),2.077(3.31),2.085(3.74),2.093(4.43),2.124(16.00),2.138(2.92),2.162(0.92),2.402(0.93),2.429(1.47),2.701(0.89),2.730(1.56),2.757(0.85),3.484(2.87),3.515(2.61),3.596(1.53),3.661(1.81),3.675(2.56),7.254(1.40),7.271(3.10),7.289(2.16),7.355(1.92),7.374(3.34),7.392(1.74),7.438(4.62),7.458(4.18),7.481(4.49),7.500(3.11),7.624(1.31),7.647(11.41),7.671(0.73),7.675(0.82),8.697(1.73),8.712(3.17),8.726(1.55),12.043(3.31).
在實施例189A說明之對映異構物之分離法中,得到159mg(100%純度,ee 94%)標題化合物,為後溶離出之對映異構物。
[α]D 20=+24.9°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.47min;MS(ESIneg):m/z=664/666[M+H]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.197(0.07),1.290(0.06),1.311(0.12),1.356(16.00),1.513(0.08),1.608(0.51),1.672(0.99),1.955(0.20),2.043(0.23),2.056(0.21),2.079(1.09),2.093(0.76),2.134(1.45),3.138(1.29),3.518(0.20),3.676(0.14),3.694(0.25),3.709(0.31),3.727(0.26),3.747(0.24),3.765(0.19),7.019(0.44),7.040(0.49),7.061(0.33),7.089(0.29),7.112(0.45),7.136(0.33),7.245(0.65),7.358(0.17),7.378(0.34),7.395(0.32),7.416(0.16),7.429(0.36),7.489(0.12),7.628(0.33),7.650(1.42),7.659(0.88),7.664(0.86),7.682(0.19),7.686(0.22),8.772(0.24),8.787(0.47),8.802(0.24).
取5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸第三丁基酯(非對映異構物混合物,2.53g,實施例116A)溶於乙醇(60ml),過濾,先利用製備性SFC,於對掌相上進行初次分離[管柱:Daicel Chiralpak OX-H,5μm,250mm x 30mm;流速:125ml/min;注射:0.6ml;溫度38℃,UV檢測210nm,溶析液:80%二氧化碳/20%乙醇;運行時間19min,等濃度]。得到一份混合溶出份(波峰1)與兩份夠乾淨之溶出份(波峰2與波峰3,參見實施例194A與195A)。取混合溶出份(波峰1),利用製備性SFC純化[管柱:Daicel Chiralpak IC,5μm,250mm x 20mm;流速:80ml/min;注射:0.35ml;溫度40℃,UV檢測210nm,溶析液:76%二氧化碳/24%乙醇;運行時間10.5min, 等濃度](參見實施例192A與193A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在所說明之混合溶出份之非對映異構物之分離法(波峰1,參見上文)中,得到485mg(100%純度,ee>99%)標題化合物,為第一個溶離出之非對映異構物(波峰1-1)。
[α]D 20=-6.3°,589nm,c=0.40g/100ml,甲醇
LC-MS(方法1):Rt=2.66min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.370(16.00),1.639(0.22),1.795(0.34),1.815(0.41),1.837(0.27),1.898(0.35),1.917(0.31),1.948(0.22),2.027(0.17),2.047(0.24),2.055(0.24),2.075(1.54),2.087(0.82),2.104(0.33),2.110(0.30),2.145(1.93),3.092(0.24),3.160(0.26),3.177(0.25),3.292(0.20),3.341(0.17),3.380(0.23),3.437(0.22),3.589(0.26),3.678(0.51),4.817(0.18),4.937(0.18),7.252(0.21),7.271(0.50),7.289(0.36),7.352(0.30),7.371(0.55),7.389(0.29),7.439(0.71),7.459(0.59),7.482(0.67),7.501(0.56),7.648(0.27),7.670(1.50),7.677(1.05),7.681(0.86),7.699(0.17),7.704(0.18),8.712(0.27),8.727(0.54),8.741(0.26).
在實施例192A說明之混合溶出份之非對映異構物之分離法中(波峰1,參見上文),得到437mg(100%純度,ee>99%)標題化合物,為第二個溶離出之非對映異構物(波峰1-2)。
[α]D 20=-11.5°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.66min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.369(16.00),1.644(0.19),1.802(0.30),1.814(0.35),1.837(0.23),1.900(0.32),1.921(0.26),1.947(0.16),2.046(0.20),2.055(0.21),2.075(1.37),2.087(0.76),2.104(0.30),2.110(0.28),2.144(1.53),3.102 (0.22),3.148(0.23),3.164(0.22),3.295(0.18),3.324(0.30),3.377(0.21),3.434(0.19),3.586(0.23),3.676(0.39),7.254(0.19),7.273(0.44),7.292(0.31),7.354(0.27),7.373(0.49),7.391(0.25),7.439(0.64),7.441(0.64),7.459(0.54),7.484(0.60),7.503(0.51),7.648(0.25),7.670(1.41),7.676(0.97),7.681(0.83),7.703(0.17),8.712(0.24),8.726(0.46),8.740(0.23).
在實施例192A說明之非對映異構物之分離法中,得到593mg(100%純度)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
[α]D 20=+7.2°,436nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.40),0.008(0.38),1.369(16.00),1.640(0.16),1.795(0.24),1.813(0.29),1.836(0.19),1.897(0.25),1.918(0.22),2.047(0.17),2.053(0.17),2.074(1.13),2.086(0.61),2.103(0.24),2.109(0.23),2.144(1.45),2.523(0.16),3.092(0.17),3.161(0.19),3.178(0.18),3.380(0.18),3.438(0.16),3.589(0.19),3.677(0.36),7.254(0.17),7.272(0.38),7.289(0.27),7.292(0.27),7.354(0.24),7.372(0.43),7.391(0.22),7.439(0.59),7.441(0.58),7.458(0.50),7.462(0.48),7.480(0.51),7.484(0.52),7.500(0.43),7.503(0.42),7.648(0.26),7.670(1.32),7.677(0.92),7.682(0.81),7.704(0.18),8.712(0.21),8.726(0.42),8.741(0.20).
在實施例192A說明之非對映異構物之分離法中,得到621mg(100%純度)標題化合物,為第四個溶離出之非對映異構物(波峰4)。
[α]D 20=+20.8°,589nm,c=0.49g/100ml,DMSO
LC-MS(方法1):Rt=2.69min;MS(ESIpos):m/z=632/634[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.038(0.20),1.056(0.41),1.073(0.21), 1.369(16.00),1.644(0.19),1.795(0.28),1.814(0.34),1.837(0.22),1.900(0.32),1.921(0.26),1.948(0.16),2.045(0.19),2.054(0.21),2.075(1.31),2.087(0.75),2.103(0.29),2.109(0.28),2.143(1.52),3.101(0.22),3.147(0.23),3.162(0.33),3.175(0.25),3.376(0.21),3.426(0.26),3.438(0.22),3.456(0.17),3.585(0.22),3.675(0.39),7.255(0.19),7.273(0.43),7.291(0.30),7.354(0.26),7.373(0.48),7.392(0.25),7.441(0.63),7.459(0.52),7.484(0.59),7.501(0.50),7.648(0.26),7.670(1.41),7.676(0.95),7.681(0.82),7.699(0.16),7.703(0.17),8.711(0.24),8.726(0.47),8.740(0.23).
取5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(非對映異構物混合物,364mg,實施例138A)溶於甲醇與乙腈之混合物(5ml)中,利用製備性SFC,於對掌相上純化[管柱:Daicel Chiralpak OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:0.35ml;溫度40℃,UV檢測210nm,溶析液:86%二氧化碳/14%乙醇;運行時間15min,等濃度]。得到一份混合溶出份(波峰1)與兩份夠乾淨之溶出份(波峰2與波峰3,參見實施例196A與197A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。混合溶出份(波峰1)直接用於實施例191說明之反應中。
在所說明之非對映異構物之分離法中,得到72mg(100%純度,ee>99%)標題化合物,為波峰2。
[α]D 20=+10.9°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法2):Rt=1.45min;MS(ESIpos):m/z=666/668[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.323(0.17),1.347(16.00),1.650(0.21),1.813(0.20),1.875(0.22),1.907(0.50),1.921(0.44),1.953(0.29),1.973(0.18),1.992 (0.39),2.005(0.26),2.015(0.49),2.027(0.37),2.035(0.42),2.057(0.32),2.095(0.29),2.108(0.18),2.126(0.24),2.143(0.25),2.180(1.55),3.114(0.24),3.174(0.25),3.190(0.24),3.340(0.48),3.359(0.23),3.395(0.23),3.452(0.21),3.631(0.18),3.646(0.22),3.667(0.23),3.684(0.25),3.700(0.19),4.824(0.17),4.943(0.17),7.462(0.34),7.481(0.58),7.500(0.35),7.661(0.24),7.683(1.73),7.707(0.62),7.722(1.07),7.738(0.99),7.753(0.27),8.768(0.26),8.783(0.53),8.797(0.25).
在實施例196A說明之非對映異構物之分離法中,得到72mg(100%純度,ee>99%)標題化合物,為波峰3。
[α]D 20=+16.2°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法2):Rt=1.45min;MS(ESIpos):m/z=666/668[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.324(0.18),1.347(16.00),1.652(0.22),1.812(0.20),1.830(0.18),1.907(0.53),1.920(0.46),1.944(0.28),1.953(0.30),1.974(0.19),1.992(0.41),2.016(0.56),2.027(0.39),2.034(0.45),2.056(0.33),2.095(0.29),2.108(0.20),2.126(0.25),2.143(0.27),2.179(1.49),3.117(0.25),3.172(0.25),3.187(0.24),3.341(0.50),3.359(0.23),3.394(0.24),3.452(0.22),3.628(0.19),3.644(0.23),3.671(0.18),3.688(0.24),3.704(0.20),4.823(0.18),4.942(0.18),7.463(0.34),7.482(0.56),7.500(0.35),7.660(0.21),7.682(1.69),7.708(0.67),7.722(0.98),7.738(1.19),7.754(0.28),8.766(0.26),8.780(0.52),8.795(0.26).
取5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基) 苯基]戊酸第三丁基酯(非對映異構物混合物,548mg,677μmol,實施例139A)溶於甲醇(20ml)與乙腈(20ml)之混合物中,並利用製備性SFC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 30mm;流速:100ml/min;注射:0.3ml;溫度40℃,UV檢測210nm,溶析液:80%二氧化碳/20%甲醇;運行時間9.8min,等濃度]。得到四份溶出份(波峰1至波峰4,參見實施例198A與201A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在所說明之非對映異構物之分離法中,得到63mg(100%純度)標題化合物,為第一個溶離出之非對映異構物(波峰1)。
[α]D 20=+19.1°,436nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=3.02min;MS(ESIpos):m/z=676/678[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(0.93),0.914(2.23),0.932(1.13),1.070(0.18),1.101(0.20),1.264(0.37),1.281(0.50),1.299(0.36),1.321(0.27),1.347(16.00),1.570(0.23),1.608(0.22),1.639(0.18),1.754(0.27),1.786(0.18),1.884(0.36),1.991(0.29),2.014(0.51),2.031(0.44),2.053(0.32),2.094(0.28),2.140(1.02),2.431(0.21),2.758(0.27),3.514(0.39),3.536(0.35),3.619(0.19),3.637(0.21),3.680(0.17),3.697(0.29),3.713(0.24),7.461(0.35),7.480(0.56),7.498(0.33),7.661(2.27),7.687(0.30),7.706(0.58),7.714(0.73),7.724(0.54),7.735(1.21),7.755(0.27),8.755(0.24),8.770(0.47),8.785(0.24).
在實施例198A說明之非對映異構物之分離法中,得到57mg(100%純度)標題化合物,為第二個溶離出之非對映異構物(波峰2)。
[α]D 20=-25.0°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=3.03min;MS(ESIpos):m/z=676/678[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(0.88),0.914(2.18),0.932(1.09), 1.073(0.17),1.102(0.18),1.263(0.32),1.281(0.45),1.293(0.39),1.310(0.31),1.346(16.00),1.570(0.20),1.612(0.19),1.643(0.17),1.753(0.24),1.786(0.16),1.853(0.24),1.886(0.33),1.917(0.16),1.993(0.27),2.014(0.51),2.029(0.56),2.050(0.27),2.113(0.18),2.133(0.26),2.168(1.42),2.444(0.23),2.473(0.16),2.753(0.22),3.508(0.36),3.540(0.33),3.621(0.18),3.637(0.21),3.684(0.21),3.699(0.18),7.461(0.27),7.480(0.46),7.499(0.28),7.660(2.23),7.687(0.27),7.707(0.49),7.720(0.80),7.737(1.06),7.754(0.23),8.754(0.23),8.769(0.47),8.784(0.22).
在實施例198A說明之非對映異構物之分離法中,得到72mg(100%純度)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
LC-MS(方法1):Rt=3.02min;MS(ESIpos):m/z=676/678[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(0.90),0.913(2.13),0.932(1.03),1.071(0.16),1.093(0.17),1.246(0.17),1.263(0.36),1.281(0.46),1.287(0.39),1.298(0.36),1.306(0.38),1.312(0.35),1.322(0.43),1.347(16.00),1.570(0.21),1.596(0.19),1.606(0.19),1.753(0.23),1.850(0.24),1.884(0.32),1.991(0.27),2.014(0.46),2.032(0.37),2.053(0.27),2.094(0.27),2.139(0.86),2.432(0.18),2.755(0.23),3.505(0.34),3.515(0.35),3.535(0.30),3.619(0.18),3.636(0.19),3.697(0.25),3.713(0.21),7.461(0.32),7.479(0.48),7.497(0.28),7.639(0.19),7.661(2.09),7.666(1.01),7.688(0.28),7.706(0.54),7.714(0.66),7.724(0.49),7.735(1.00),7.755(0.22),8.755(0.22),8.770(0.40),8.785(0.19).
在實施例198A說明之非對映異構物之分離法中,得到62mg(100%純度)標題化合物,為第四個溶離出之非對映異構物(波峰4)
[α]D 20=+27.0°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法2):Rt=1.63min;MS(ESIpos):m/z=676/678[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(0.96),0.914(2.24),0.932(1.16),1.072(0.21),1.101(0.22),1.246(0.17),1.263(0.37),1.280(0.53),1.292(0.48),1.310(0.38),1.346(16.00),1.569(0.24),1.612(0.23),1.643(0.21),1.753(0.29),1.784(0.20),1.862(0.29),1.884(0.41),1.992(0.32),2.013(0.61),2.028(0.66),2.049(0.32),2.098(0.17),2.112(0.22),2.132(0.29),2.167(1.77),2.415(0.18),2.443(0.29),2.501(6.18),2.754(0.27),3.508(0.44),3.538(0.40),3.619(0.22),3.637(0.25),3.652(0.17),3.666(0.18),3.682(0.27),3.699(0.21),7.461(0.32),7.480(0.54),7.499(0.33),7.659(2.38),7.686(0.30),7.706(0.57),7.720(0.97),7.736(1.22),7.753(0.27),8.754(0.27),8.768(0.55),8.783(0.27).
取5-[({6-溴-3-甲基-2-[5-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(非對映異構物混合物,455mg,實施例140A)溶於甲醇與乙腈之混合物(6ml),並利用製備性SFC,於對掌相上純化[管柱:Daicel Chiralpak OX-H,5μm,250mm x 20mm;流速:80ml/min;注射:0.25ml;溫度40℃,UV檢測210nm,溶析液:89%二氧化碳/11%乙醇;運行時間19min,等濃度]。得到一份混合溶出份(波峰1)與兩份夠乾淨的溶出份(波峰2與波峰3,參見實施例202A與203A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。混合之溶出份(波峰1)直接用於實施例199中說明之反應。
在所說明之非對映異構物之分離法中,得到80mg(100%純度)標題化合物,為波峰2。
[α]D 20=+17.0°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法2):Rt=1.59min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.927(1.56),0.943(1.58),1.085(0.17),1.116(0.17),1.324(0.18),1.347(16.00),1.662(0.17),1.737(0.30),1.772(0.30),1.798(0.37),1.828(0.23),1.908(0.16),1.990(0.27),2.013(0.47),2.031(0.39),2.052(0.28),2.097(0.16),2.111(0.18),2.130(0.24),2.166(1.28),2.465(0.25),2.723(0.25),3.454(0.25),3.480(0.47),3.510(0.23),3.640(0.19),3.659(0.21),3.677(0.22),3.694(0.17),7.462(0.29),7.481(0.47),7.500(0.29),7.661(2.16),7.688(0.27),7.707(0.48),7.721(0.89),7.737(0.91),7.752(0.24),8.757(0.21),8.772(0.44),8.787(0.21).
在實施例202A說明之非對映異構物之分離法中,得到82mg(100%純度)標題化合物,為波峰3。
[α]D 20=+7.3°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法2):Rt=1.59min;MS(ESIpos):m/z=662/664[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.928(1.80),0.944(1.86),1.087(0.22),1.115(0.23),1.324(0.21),1.347(16.00),1.635(0.20),1.665(0.23),1.738(0.39),1.771(0.38),1.798(0.48),1.829(0.30),1.889(0.20),1.898(0.20),1.909(0.22),1.920(0.21),1.990(0.33),2.013(0.63),2.030(0.55),2.052(0.35),2.099(0.18),2.114(0.23),2.133(0.28),2.174(1.76),2.440(0.22),2.469(0.35),2.694(0.17),2.722(0.30),2.751(0.16),3.455(0.35),3.482(0.62),3.513(0.29),3.619(0.21),3.634(0.24),3.683(0.26),3.698(0.21),7.463(0.34),7.482(0.56),7.501(0.34),7.661(2.34),7.688(0.31),7.707(0.59),7.722(1.10),7.737(1.07),7.752(0.29),8.759(0.29),8.774(0.57),8.788(0.28).
取5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(非對映異構物混合物,359mg,486μmol,實施例153A),利用製備型HPLC[方法1:管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:20ml/min;溫度25℃,溶析液:90%庚烷/10%乙醇;UV檢測255nm,等濃度;方法2:管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:20ml/min;溫度25℃,溶析液:90%庚烷/10%異丙醇,UV檢測255nm,等濃度]分離成非對映異構物。得到四個溶出份(波峰1至波峰4,參見實施例204A與207A)。取合併之目標溶出份分別濃縮(條件:25℃,40mbar)。
在所說明之非對映異構物之分離法中,得到85mg(90%純度,ee>98%)標題化合物,為首先溶離出之非對映異構物(波峰1)。
[α]D 20=-9.4°,436nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.43min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.80),1.258(0.70),1.301(0.94),1.336(0.21),1.360(16.00),1.381(0.64),1.646(0.25),1.808(0.42),1.831(0.39),1.855(0.23),1.903(0.37),1.922(0.32),1.954(0.23),2.036(0.29),2.068(1.52),2.089(0.32),2.156(1.22),2.222(0.27),3.106(0.24),3.168(0.25),3.186(0.25),3.333(0.33),3.352(0.27),3.388(0.45),3.413(0.20),3.445(0.21),3.619(0.28),3.634(0.50),3.650(0.49),3.666(0.27),4.820(0.18),4.940(0.19),7.363(0.48),7.379(0.23),7.386(0.26),7.399(0.90),7.411(0.64),7.417(0.60),7.422(0.70),7.495(0.17),7.547(0.52),7.559(0.48),7.570(0.36),7.656(0.27),7.678(1.54),7.685(1.05),7.689(0.93),7.707(0.21),8.736(0.25),8.751(0.50),8.765(0.25).
在實施例204A說明之非對映異構物之分離法中,得到85mg(100%純度,ee 97%)標題化合物,為非對映異構物(波峰2)。
[α]D 20=-14.3°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法2):Rt=1.42min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.853(0.18),1.234(1.31),1.249(0.44),1.259(1.44),1.299(1.16),1.326(0.17),1.336(0.40),1.360(16.00),1.381(0.22),1.646(0.21),1.808(0.39),1.831(0.36),1.856(0.20),1.903(0.32),1.924(0.27),1.951(0.18),2.036(0.27),2.067(1.41),2.090(0.29),2.156(1.05),3.109(0.21),3.164(0.22),3.179(0.21),3.337(0.29),3.356(0.26),3.387(0.42),3.412(0.16),3.444(0.19),3.618(0.24),3.635(0.44),3.651(0.38),3.671(0.21),4.938(0.16),7.363(0.45),7.388(0.19),7.400(0.79),7.412(0.61),7.418(0.58),7.424(0.68),7.548(0.45),7.560(0.40),7.571(0.33),7.656(0.24),7.678(1.42),7.684(1.00),7.689(0.87),7.707(0.18),7.711(0.19),8.736(0.22),8.751(0.44),8.765(0.23).
在實施例204A說明之非對映異構物之分離法中,得到79mg(98%純度,ee>98%)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
[α]D 20=+14.1°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法2):Rt=1.43min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.360(16.00),1.644(0.23),1.808(0.45),1.830(0.42),1.854(0.24),1.901(0.38),1.922(0.32),1.953(0.23),2.036(0.38),2.067(1.64),2.089(0.34),2.156(1.32),3.100(0.25),3.168(0.28),3.185(0.26),3.332(0.40),3.353(0.30),3.388(0.49),3.413(0.21),3.445(0.23),3.620(0.33),3.634(0.56),3.649(0.52),3.666(0.26),4.820(0.18),4.939(0.19),7.363(0.47),7.386(0.25),7.399(0.89),7.410(0.66),7.417(0.62),7.422(0.72),7.495(0.17),7.547(0.53),7.559(0.45),7.570(0.37),7.656(0.31),7.678(1.54),7.684(0.98),7.688(0.86),7.711(0.16),8.737(0.29),8.751(0.53),8.765(0.25).
在實施例204A說明之非對映異構物之分離法中,得到79mg(100%純度,ee> 99%)標題化合物,為第四個溶離出之非對映異構物(波峰4)。
[α]D 20=+55.1°,436nm,c=0,081g/100ml,甲醇
LC-MS(方法2):Rt=1.42min;MS(ESIpos):m/z=682/684[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.20),1.258(0.18),1.360(16.00),1.646(0.22),1.789(0.23),1.808(0.43),1.831(0.41),1.855(0.23),1.903(0.36),1.923(0.30),1.953(0.20),2.036(0.30),2.068(1.63),2.090(0.33),2.156(1.21),3.110(0.24),3.169(0.27),3.335(0.42),3.356(0.32),3.387(0.49),3.412(0.20),3.443(0.22),3.618(0.28),3.635(0.50),3.652(0.43),3.670(0.24),4.819(0.17),4.938(0.17),7.363(0.46),7.388(0.20),7.400(0.86),7.412(0.65),7.418(0.63),7.423(0.73),7.435(0.16),7.486(0.17),7.548(0.49),7.560(0.44),7.571(0.36),7.656(0.26),7.678(1.51),7.684(1.05),7.688(0.92),7.711(0.17),8.737(0.26),8.752(0.50),8.766(0.25).
取5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(非對映異構物混合物,458mg,648μmol,實施例154A)溶於甲醇(12ml)與乙腈(5ml)之混合物,並利用製備性SFC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel OZ-H,5μm,250mm x 20mm;流速:80ml/min;注射:0.3ml;溫度40℃,UV檢測210nm,溶析液:88%二氧化碳/12%甲醇;運行時間9.5min,等濃度]。得到四個溶出份(波峰1至波峰4,參見實施例208A與211A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在所說明之非對映異構物之分離法中,得到64mg(99%純度,ee>95%)標題化合物,為第一個溶離出之非對映異構物(波峰1)。
[α]D 20=+17.0°,436nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=3.05min;MS(ESIpos):m/z=692/694[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(0.87),0.912(2.16),0.930(1.06),1.069(0.16),1.098(0.17),1.260(0.35),1.278(0.46),1.301(0.60),1.315(0.18),1.360(16.00),1.382(0.29),1.565(0.20),1.600(0.18),1.751(0.23),1.784(0.23),1.802(0.23),1.827(0.20),1.854(0.28),1.881(0.19),2.033(0.24),2.065(1.20),2.089(0.38),2.118(0.69),2.422(0.17),2.755(0.23),3.370(0.19),3.388(0.19),3.497(0.33),3.525(0.32),3.609(0.23),3.625(0.27),3.644(0.26),3.661(0.28),3.679(0.23),7.356(0.37),7.383(0.18),7.396(0.70),7.408(0.57),7.414(0.51),7.420(0.62),7.549(0.44),7.555(0.28),7.562(0.37),7.573(0.32),7.635(0.19),7.657(1.45),7.664(0.92),8.725(0.20),8.740(0.38),8.754(0.20).
在實施例208A說明之非對映異構物之分離法中,得到48mg(100%純度,ee>95%)標題化合物,為第二個溶離出之非對映異構物(波峰2)。
[α]D 20=-25.7°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=3.05min;MS(ESIpos):m/z=692/694[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(0.84),0.912(2.08),0.930(1.04),1.070(0.16),1.101(0.17),1.261(0.31),1.270(0.28),1.279(0.42),1.287(0.37),1.297(0.32),1.325(0.18),1.361(16.00),1.564(0.19),1.607(0.18),1.640(0.17),1.749(0.23),1.784(0.22),1.803(0.23),1.828(0.21),1.854(0.28),1.883(0.20),2.033(0.26),2.047(0.31),2.067(1.23),2.092(0.29),2.144(1.08),2.437(0.20),2.749(0.20),3.370(0.20),3.388(0.20),3.499(0.35),3.530(0.33),3.617(0.27),3.632(0.46),3.647(0.43),3.663(0.22),7.359(0.37),7.385(0.17),7.398(0.72),7.410(0.57),7.416(0.53),7.421(0.65),7.547(0.42),7.560(0.36),7.571(0.30),7.634(0.16),7.657(1.61),7.663(0.91),8.725(0.22),8.739(0.44),8.754(0.22).
在實施例208A說明之非對映異構物之分離法中,得到59mg(98%純度,ee>93%)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
[α]D 20=-17.5°,436nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=3.05min;MS(ESIpos):m/z=692/694[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(0.89),0.912(2.18),0.930(1.08),1.069(0.17),1.091(0.17),1.261(0.36),1.278(0.48),1.296(0.34),1.315(0.18),1.361(16.00),1.565(0.21),1.601(0.20),1.633(0.16),1.750(0.23),1.784(0.23),1.802(0.24),1.828(0.22),1.853(0.30),1.880(0.20),2.033(0.26),2.065(1.28),2.090(0.38),2.119(0.72),2.422(0.18),2.754(0.24),3.371(0.20),3.388(0.20),3.495(0.35),3.526(0.33),3.610(0.24),3.625(0.29),3.643(0.28),3.662(0.28),3.679(0.24),7.356(0.38),7.396(0.72),7.408(0.57),7.414(0.52),7.420(0.65),7.550(0.45),7.555(0.29),7.562(0.38),7.573(0.33),7.635(0.19),7.657(1.52),7.665(0.91),8.726(0.20),8.740(0.41),8.754(0.20).
在實施例208A說明之非對映異構物之分離法中,得到65mg(100%純度,ee>95%)標題化合物,為第四個溶離出之非對映異構物(波峰4)。
[α]D 20=+26.9°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=3.05min;MS(ESIpos):m/z=692/694[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(0.99),0.912(2.18),0.930(1.09),1.071(0.20),1.092(0.21),1.261(0.41),1.269(0.39),1.279(0.52),1.287(0.46),1.297(0.39),1.305(0.36),1.325(0.40),1.361(16.00),1.565(0.24),1.607(0.22),1.639(0.20),1.749(0.29),1.784(0.27),1.803(0.29),1.828(0.28),1.854(0.36),1.884(0.23),2.033(0.35),2.048(0.45),2.066(1.46),2.092(0.36),2.144(1.32),2.408(0.17),2.436(0.27),2.747(0.25),3.369(0.25),3.387(0.25),3.498(0.46),3.529 (0.40),3.618(0.36),3.632(0.57),3.648(0.52),3.663(0.26),7.359(0.46),7.385(0.25),7.398(0.86),7.410(0.67),7.416(0.62),7.421(0.72),7.434(0.20),7.466(0.19),7.547(0.50),7.560(0.42),7.571(0.34),7.633(0.22),7.656(1.87),8.725(0.29),8.740(0.51),8.754(0.24).
取5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(非對映異構物混合物,539mg,781μmol,實施例155A),利用製備型HPLC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel AD-H,5μm,250mm x 20mm;流速:7ml/min;溫度25℃,UV檢測240nm,溶析液:95%庚烷/5%異丙醇;等濃度]。得到四份溶出份(波峰1至波峰4,參見實施例212A與215A)。取合併之目標溶出份分別濃縮,並分別採用相同方法再純化一至三次,然後濃縮(40℃之旋轉蒸發器),及減壓乾燥。
在所說明之非對映異構物之分離法中,得到55mg(100%純度)標題化合物,為第一個溶離出之非對映異構物(波峰1)。
LC-MS(方法1):Rt=2.99min;MS(ESIpos):m/z=678/680[M+H]+
在實施例212A說明之非對映異構物之分離法中,得到54mg(100%純度)標題化合物,為第二個溶離出之非對映異構物(波峰2)。
LC-MS(方法1):Rt=2.99min;MS(ESIpos):m/z=678/680[M+H]+
在實施例212A說明之非對映異構物之分離法中,得到43mg(100%純度)標題化合物,為第三個溶離出之非對映異構物(波峰3)。
LC-MS(方法1):Rt=2.99min;MS(ESIpos):m/z=678/680[M+H]+
在實施例212A說明之非對映異構物之分離法中,得到53mg(100%純度)標題化合物,為第四個溶離出之非對映異構物(波峰4)。
LC-MS(方法1):Rt=2.99min;MS(ESIpos):m/z=678/680[M+H]+
取(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(消旋物,185mg,269μmol,實施例162A),利用製備性SFC,於對掌相上分離成對映異構物[管柱:Daicel Chiralpak AD-H,5μm,250mm x 30mm;流速:120ml/min;溫度25℃,UV檢測230nm,溶析液:85%庚烷/15%異丙醇;等濃度]。取合併之目標溶出份分別於30℃/30mbar下濃縮。
在所說明之對映異構物之分離法中,得到85mg(98%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
[α]D 20=+32.2°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法2):Rt=1.40min;MS(ESIpos):m/z=686/688[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(0.22),1.311(0.16),1.362(16.00),1.884(0.53),2.066(0.38),2.083(0.51),2.099(0.52),2.115(0.43),2.137(0.79),2.165(2.62),3.172(0.64),3.451(0.40),3.480(0.76),3.509(0.38),3.699(0.23),3.774(0.26),7.295(0.27),7.306(0.28),7.321(0.21),7.332(0.19),7.390(0.16),7.402(0.20),7.412(0.27),7.423(0.26),7.682(0.31),7.704(1.50),7.712(0.98),7.717(0.88),7.735(0.19),7.739(0.20),8.815(0.22),8.830(0.41),8.844(0.21).
在實施例216A說明之對映異構物之分離法中,得到85mg(100%純度,ee>98%)標題化合物,為後溶離出之對映異構物。
[α]D 20=-28.0°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.40min;MS(ESIpos):m/z=686/688[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(0.31),1.361(16.00),1.884(0.70),1.975(0.18),2.082(0.68),2.098(0.69),2.115(0.58),2.137(1.03),2.164(3.20),3.172(0.85),3.451(0.49),3.480(0.92),3.508(0.47),3.699(0.31),3.773(0.36),7.271(0.16),7.282(0.19),7.295(0.34),7.305(0.35),7.320(0.26),7.331(0.23),7.391(0.21),7.412(0.34),7.422(0.33),7.444(0.17),7.681(0.34),7.704(1.55),7.712(1.11),7.716(0.97),7.735(0.21),7.739(0.22),8.829(0.52).
取(+/-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(消旋物,489mg,735μmol,實施例166A),利用製備性SFC,於對掌相上分離成對映異構物[管柱:Daicel Chiralpak AD-H,5μm,250mm x 20mm;流速:80ml/min;注射:0.3ml;溫度40℃,UV檢測210nm,溶析液:85%庚烷/15%異丙醇;運行時間13min,等濃度]。取合併之目標溶 出份分別濃縮,各殘質分別從乙腈/水中冷凍乾燥。
在所說明之對映異構物之分離法中,得到39mg(93%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
LC-MS(方法2):Rt=1.50min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.360(16.00),1.371(1.06),1.603(1.40),1.780(0.84),2.080(0.23),2.133(1.95),2.150(0.79),3.492(1.08),3.506(1.58),3.521(1.04),3.706(0.25),7.278(0.16),7.290(0.27),7.302(0.27),7.316(0.21),7.327(0.19),7.408(0.31),7.420(0.29),7.532(0.64),7.554(1.12),7.602(0.66),7.607(0.60),7.624(0.35),7.629(0.34),8.788(0.31).
在實施例218A說明之對映異構物之分離法中,得到32mg(93%純度,ee 89%)標題化合物,為後溶離出之對映異構物。
LC-MS(方法2):Rt=1.50min;MS(ESIpos):m/z=664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.309(0.17),1.361(16.00),1.603(1.35),1.780(0.81),2.066(0.24),2.082(0.22),2.103(0.22),2.134(1.94),2.151(0.80),3.492(1.06),3.507(1.53),3.521(1.01),3.711(0.25),7.278(0.16),7.290(0.27),7.301(0.27),7.316(0.22),7.327(0.19),7.386(0.20),7.398(0.24),7.408(0.31),7.419(0.29),7.532(0.60),7.555(1.06),7.602(0.61),7.607(0.55),7.624(0.34),7.630(0.32),8.775(0.18),8.789(0.32)。
取5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基) 戊酸第三丁基酯(非對映異構物混合物,294mg,419μmol,實施例187A),利用製備型HPLC,採用三種不同分離法,於對掌相上分離成非對映異構物[方法1:管柱:Daicel Chiralpak AD-H,5μm,250mm x 20mm;流速:14ml/min;溫度25℃,UV檢測240nm,溶析液:90%庚烷/10%異丙醇;等濃度;方法2:管柱:Daicel Chiralpak AD-H,5μm,250mm x 20mm;流速:9ml/min;溫度25℃,UV檢測240nm,溶析液:100%乙醇;方法3:管柱:Daicel Chiralcel OD-H,5μm,250mm x 20mm;流速:9ml/min;溫度25℃,UV檢測240nm,溶析液:90%庚烷/10%異丙醇;等濃度]。得到四份溶出份(參見實施例219A與222A),有些例子中波峰之順序依所採用之製備性分離法而定。實施例219A-222A之順序係與下列分析性HPLC法中波峰1-4之溶離序相關:管柱:Daicel Chiralpak OD-H,5μm,250mm x 4.6mm;流速:0.3ml/min;溫度25℃,UV檢測240nm,溶析液:90%庚烷/10%異丙醇;等濃度。取合併之目標溶出份分別濃縮(40℃之旋轉蒸發器),然後減壓乾燥。
在所說明之非對映異構物之分離法中,得到14mg(100%純度)標題化合物(分析性HPLC之波峰1,參見上文)。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=700/702/704[M+H]+
在實施例220A說明之非對映異構物之分離法中,得到17mg(100%純度)標題化合物(分析性HPLC中之波峰2,參見實施例220A)。
LC-MS(方法1):Rt=2.84min;MS(ESIpos):m/z=700/702/704[M+H]+
在實施例220A說明之非對映異構物之分離法中,得到32mg(100%純度)標題化合物(分析性HPLC中之波峰3,參見實施例220A)。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=700/702/704[M+H]+
在實施例220A說明之非對映異構物之分離法中,得到27mg(94%純度)標題化合物(分析性HPLC中之波峰4,參見實施例220A)。
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=700/702/704[M+H]+
於氬氣下製備LDA溶液,其係於-78℃下慢慢添加正丁基鋰(1.6M己烷溶液,44ml,70mmol)至先加入之含二異丙基胺(10ml,74mmol)之THF(44ml)中。添加完畢後,溶液再於0℃下攪拌10min。,慢慢滴加此LDA溶液至冷卻至-78℃之含(2,5-二氟苯基)乙腈(8.1ml,98%純度,64mmol)之THF(120ml)溶液中。添加完畢時,離開冷卻槽,讓反應混合物回到0℃,15min後,再次冷卻至-78℃。然後滴加含3-溴丙酸第三丁基酯(13ml,97%純度,77mmol)之44ml THF溶液,混合物再於-78℃下攪拌1h後,回升至RT,於RT下攪拌一夜。操作時,添加氯化銨溶液(300ml,10%水溶液)。混合物激烈攪拌5分鐘後,使用乙酸乙酯萃取2次。合併之有機相依序使用1M鹽酸、飽和碳酸氫鈉溶液、與飽和氯化鈉溶液各洗滌2次。然後取有機相經硫酸鈉脫水,及於旋轉蒸發器上濃縮。殘質溶於少量DMSO,分成四份利用製備型HPLC純化(方法29)。合併含產物溶出份,及於旋轉蒸發器上濃縮。得到8.05g(100%純度,45%理論值)標題化合物。
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=282[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.381(16.00),2.313(0.86),2.332(1.28),2.350(0.44),4.414(0.63),7.353(0.40),7.366(0.62),7.374(0.51),7.377(0.49).
在先加入之含(+/-)-4-氰基-4-(2,5-二氟苯基)丁酸第三丁基酯(消旋物,8.05g,100%純度,28.6mmol)(得自實施例224A)之第三丁醇(210ml,2.2mol)與甲醇(9.3ml)中添加阮來鎳(1.68g,28.6mmol)。反應混合物於標準氫氣壓下攪拌9天。儘管未完全轉化,仍中止反應。通過矽藻土濾除觸媒,使用甲醇洗滌3次(每次30ml)。濾液經旋轉蒸發法濃縮。殘質溶於乙酸乙酯(200ml)。取有機相使用1M鹽酸萃取2次(每次200ml)。在合併之水相中慢慢添加碳酸氫鈉調至pH 8後,使用二氯甲烷萃取2次(每次200ml)。合併之有機相經硫酸鈉脫水,過濾與濃縮。得到3.84g(100%純度,47%理論值)標題化合物。
LC-MS(方法1):Rt=1.12min;MS(ESIpos):m/z=286[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=7.29-7.04(m,3H),2.92-2.84(m,1H),2.79-2.67(m,2H),2.05-1.91(m,3H),1.74-1.61(m,1H),1.35(s,9H).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.111(0.42),1.354(16.00),2.012(1.26),2.025(0.85),2.728(0.47),2.736(0.51),2.747(0.69),2.751(0.69).
於RT下,在先加入之含(+/-)-5-胺基-4-(2,5-二氟苯基)戊酸第三丁基酯(消旋物,3.00g,10.5mmol)(得自實施例225A)之二氯甲烷(80ml)中添加DIPEA(4.6ml,26mmol)後,添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(2.79g,8.76mmol,實施例3A)之二氯甲烷(20ml)溶液。反應混合物攪拌2小時後,使用二氯甲烷(100ml)稀釋,使用1M鹽酸洗滌2次後,使用飽和碳酸氫鈉溶液洗滌2次。取有機相經硫酸鈉脫水,過濾與濃縮。殘質減壓乾燥。得到4.92g(99%純度,98%理論值)標題化合物。
LC-MS(方法1):Rt=2.48min;MS(ESIneg):m/z=565/567[M-H]-
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.89(t,1H),7.94-7.86(m,2H),7.82-7.40(br.m,1H),7.34-7.29(m,1H),7.24(td,1H),7.19-7.07(m,1H),3.81-3.62(m,2H),3.41-3.34(m,1H),2.30-2.15(m,3H),2.14-2.06(m,2H),2.05-1.98(m,1H),1.88-1.73(m,1H),1.37(s,9H).
在厚壁微波容器中,在先加入之含5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,5-二氟苯基)戊酸第三丁基酯(400mg,704μmol,實施例226A)之NMP(4.5ml)中依序添加3-乙基哌啶(399mg,3.52mmol)與DIPEA(610μl,3.5mmol)。容器密封,及於130℃下攪拌一夜。讓反應溶液冷卻至RT,直接(未進一步操作)利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。所得殘質溶於少量二氯甲烷,及在減壓下起泡。得到375mg(100%純度,83%理論值)標題化合物。
LC-MS(方法1):Rt=2.90min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.73(br t,1H),7.70-7.60(m,2H),7.44(br s,1H),7.33-7.27(m,1H),7.26-7.19(m,1H),7.16-7.09(m,1H),3.74-3.59(m,2H),3.55-3.42(m,2H),3.40-3.34(m,1H),2.80-2.69(m,1H),2.48-2.37(m,1H),2.16-1.98(m,6H),1.91-1.72(m,3H),1.68-1.51(m,2H),1.37(s,9H),1.34-1.21(m,2H),1.13-1.02(m,1H),0.91(t,3H).
取標題化合物(316mg,490μmol)溶於甲醇(12ml),試圖利用製備性SFC,於對掌相上分離成非對映異構物[管柱:Daicel Chiralcel OX-H,5μm,250mm x 20mm;注射:0.30ml;溶析液:82%二氧化碳/18%甲醇;流速:80ml/min;溫度40℃,UV檢測210nm,運行時間6.1min,等濃度]。得到3份溶出份(波峰1-3),其中得到之波峰1為兩種非對映異構物/對映異構物之混合物(參見實施例228A),及分別得到波峰2與波峰3,為分離之非對映異構物(參見實施例229A與230A)。取合併之目標溶出份分別濃縮,取各殘質分別冷凍乾燥。
在實施例227A說明之非對映異構物之分離法中,得到125mg(100%純度)標題化合物,為溶出份1(兩種非對映異構物之混合物)。
LC-MS(方法1):Rt=2.92min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:0.893(0.86),0.908(1.93),0.923(0.96),1.084(0.16),1.090(0.16),1.244(0.19),1.258(0.30),1.272(0.40),1.281(0.30),1.286(0.31),1.294(0.24),1.372(16.00),1.560(0.17),1.748(0.23),1.754(0.20),1.774(0.26),1.799(0.17),1.848(0.19),1.873(0.18),2.010(0.19),2.025(0.20),2.085(0.63),2.099(1.07),2.104(0.83),2.113(1.02),2.741(0.18),3.340(1.17),3.358(0.24),3.360(0.22),3.494(0.35),3.512(0.29),3.642(0.21),3.651(0.22),7.122(0.24),7.203(0.20),7.212(0.21),7.222(0.33),7.231(0.32),7.240(0.17),7.289(0.20),7.296(0.27),7.304(0.20),7.632(0.23),7.649(1.27),7.655(0.79),7.658(0.68),8.725(0.21),8.736(0.36),8.747(0.20).
在實施例227A說明之非對映異構物之分離法中,得到43mg(100%純度)標題化合物,為波峰2。
LC-MS(方法1):Rt=2.92min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:0.894(0.95),0.909(2.24),0.924(1.09),1.084(0.16),1.090(0.16),1.244(0.20),1.258(0.30),1.272(0.42),1.286(0.35),1.294(0.23),1.372(16.00),1.560(0.18),1.567(0.16),1.748(0.23),1.754(0.20),1.773(0.27),1.786(0.20),1.792(0.16),1.800(0.18),1.806(0.16),1.849(0.19),1.873(0.18),2.010(0.20),2.024(0.21),2.051(0.17),2.085(0.68),2.098(1.17),2.111(0.81),2.743(0.21),3.494(0.35),3.511(0.26),3.631(0.20),3.642(0.27),3.689(0.16),7.122(0.23),7.203(0.19),7.212(0.21),7.221(0.32),7.231(0.31),7.240(0.16),7.277(0.17),7.283(0.21),7.288(0.21),7.295(0.29),7.302(0.21),7.306(0.20),7.313(0.16),7.632(0.26),7.650(1.35),7.655(0.95),7.659(0.81),7.673(0.16),7.677(0.17),8.723(0.23),8.734(0.39),8.746(0.22).
在實施例227A說明之非對映異構物之分離法中,得到48mg(100%純度)標題化合物,為波峰3。
LC-MS(方法1):Rt=2.92min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:0.892(1.06),0.907(2.36),0.922(1.19),1.066(0.21),1.084(0.22),1.245(0.24),1.260(0.41),1.274(0.54),1.287(0.40),1.372(16.00),1.558(0.23),1.580(0.20),1.606(0.21),1.631(0.22),1.748(0.31),1.773(0.34),1.783(0.30),1.797(0.25),1.804(0.22),1.817(0.20),1.848(0.26),1.872(0.25),1.999(0.20),2.010(0.25),2.024(0.25),2.041(0.18),2.050(0.19),2.085(0.75),2.099(1.24),2.114(1.70),2.421(0.19),2.737(0.25),3.490(0.48),3.512(0.43),3.624(0.19),3.639(0.29),3.651(0.40),3.662(0.30),3.682(0.23),7.105 (0.16),7.122(0.32),7.138(0.21),7.203(0.24),7.213(0.27),7.222(0.40),7.231(0.39),7.241(0.20),7.250(0.18),7.279(0.22),7.285(0.27),7.290(0.28),7.297(0.37),7.304(0.28),7.315(0.20),7.631(0.27),7.649(1.49),7.653(1.13),7.657(0.93),7.671(0.18),7.675(0.18),8.725(0.30),8.737(0.53),8.748(0.28).
取(2-甲基苯基)乙腈(7.08g,54.0mmol)溶於DMF,慢慢添加氫化鈉,混合物於室溫下再攪拌10min,隨後,慢慢滴加3-溴丙酸第三丁基酯(9.0ml,54mmol),此過程中溫和起泡並發熱至約35℃。添加期間,反應容器於水浴中冷卻。然後離開水浴,繼續於RT下攪拌2.5h。反應混合物加至水中,使用二氯甲烷萃取,脫水(硫酸鈉)及於旋轉蒸發器上濃縮。粗產物利用快速管柱層析法純化(Isolera,KP-Sil,溶析液:己烷/乙酸乙酯,梯度:1-30%)。得到8.32g(74%純度,44%理論值)標題化合物。
LC-MS(方法25):Rt=1.39min;MS(ESIpos):m/z=260[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.494(16.00),2.146(0.44),2.148(0.40),2.382(0.77),2.411(3.67),2.491(0.43),2.522(0.58),3.702(0.51),7.241(0.45),7.279(0.68),7.288(0.62).
在先加入之含(+/-)-4-氰基-4-(2-甲基苯基)丁酸第三丁基酯(消旋物,8.32g,74%純度,23.8mmol,實施例231A)之第三丁醇(200ml)中添加阮來鎳(1.88g, 32.1mmol)。使用氫氣,於標準壓力下氫化6h。隨後,再次添加阮來鎳(1.88g,32.1mmol),再氫化8h。然後再次添加同量觸媒,再氫化5h。反應混合物通過矽藻土過濾,濾液於旋轉蒸發器上濃縮。殘質利用管柱層析法純化(Isolera,RP18,溶析液:水+0.1%體積比之甲酸/乙腈,梯度:5-95%乙腈)。得到5.74g(98%純度,90%理論值)標題化合物。
LC-MS(方法25):Rt=0.71min;MS(ESIpos):m/z=264[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.517(16.00),2.171(1.18),2.178(0.59),2.432(3.54),3.574(2.02),7.250(0.67),7.254(0.75),7.256(0.51),7.400(1.05),8.286(0.70).
取(+/-)-5-胺基-4-(2-甲基苯基)戊酸第三丁基酯(5.74g,98%純度,21.4mmol,實施例232A)與6-溴-2-氯-3-甲基喹啉-4-羰基氯(6.32g,19.8mmol,實施例3A)溶於二氯甲烷,添加碳酸氫鈉水溶液(240ml,1.0M,240mmol),反應混合物於RT下激烈攪拌1.5h。添加反應混合物至水中,使用二氯甲烷萃取,取有機相使用1M鹽酸與飽和氯化鈉水溶液洗滌,經硫酸鈉脫水,過濾及於旋轉蒸發器上濃縮。粗產物利用管柱層析法純化(Isolera,KP-Sil,溶析液:己烷/乙酸乙酯,梯度:0-100%)。得到7.72g(84%純度,61%理論值)標題化合物。
LC-MS(方法26):Rt=1.59min;MS(ESIpos):m/z=545/547[M+H]+
取(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲基苯基)戊酸第三丁基酯(消旋物,7.72g,84%純度,11.9mmol,實施例233A)溶於二氯甲烷(25ml)。隨後,添加TFA(22ml,280mmol),混合物於室溫下攪拌一夜。反應混合物濃縮,殘質利用管柱層析法純化(Isolera,LiChroprep RP-18(40-63μm),溶析液:水+0.1%體積比之氨/乙腈,梯度:10-90%乙腈)。得到6.71g(86%純度,99%理論值)標題化合物。
LC-MS(方法26):Rt=0.76min;MS(ESIneg):m/z=487/489[M-H]-
於氬氣下,於-78℃及攪拌下,在含(2-甲氧基苯基)乙腈(2.00g,13.6mmol)之THF(17ml)溶液中慢慢添加2M LDA之THF溶液(10ml,20mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加3-溴丙酸第三丁基酯(2.6ml,16mmol)。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,慢慢加水至混合物中,使用乙酸乙酯萃取2次。合併之有機相使用飽和氯化鈉溶液洗滌一次,經硫酸鈉脫水,過濾及濃縮, 殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge KP-Sil,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。然後再利用製備型HPLC純化(方法12)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到495mg(98%純度,13%理論值)標題化合物。
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=276[M+H]+
取(2-甲氧基苯基)乙腈(7.98g,54.2mmol)溶於DMF(200ml),慢慢添加氫化鈉,混合物於室溫下攪拌10min。隨後,在冷卻下(水浴),慢慢滴加3-溴丙酸第三丁基酯(11.3g,54.2mmol),此過程中,反應溶液發熱至約35℃。於RT下攪拌3h後,添加反應混合物至水中,使用二氯甲烷萃取。取有機相經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(矽膠,梯度:1-30%乙酸乙酯之己烷溶液)。得到9.79g(62%純度,40%理論值)標題化合物。
LC-MS(方法25):Rt=1.32-1.35min;MS(ESIpos):m/z=276[M+H]+
在含(+/-)-4-氰基-4-(2-甲氧基苯基)丁酸第三丁基酯(495mg,1.80mmol,實施例235A,方法A)之第三丁醇(11ml)溶液中添加阮來鎳(106mg,1.80mmol),於標準壓力下氫化一夜。隨後,通過矽藻土濾除觸媒,取母液濃縮。得到269mg(85%純度,46%理論值)標題化合物。
LC-MS(方法2):Rt=0.68min;MS(ESIpos):m/z=280[M+H]+
在含(+/-)-4-氰基-4-(2-甲氧基苯基)丁酸第三丁基酯(9.79g,62%純度,22.4mmol,實施例235A,方法B)之第三丁醇(350ml)溶液中添加阮來鎳(2.09g,35.6mmol),於標準壓力下氫化6h。隨後,再次添加阮來鎳(2.09g,35.6mmol)至混合物中, 再氫化8h。再次添加阮來鎳(2.09g,35.6mmol)後,再次氫化5h。通過矽藻土濾出固體,使用乙酸乙酯洗滌,取濾液濃縮。粗產物利用快速層析法純化(LiChroprep RP-18 40-63μm;梯度:5-95%乙腈含於0.1%甲酸水溶液)。得到2.69g(99%純度,42%理論值)標題化合物。
LC-MS(方法25):Rt=0.74min;MS(ESIpos):m/z=280[M+H]+
取標題化合物(2.69g,99%純度,來自方法B)利用製備型HPLC,於對掌相上分離成對映異構物[管柱:Cellulose SC 10μ 250 x 50mm;流速:120ml/min;溶析液:20%異丙醇/(80%己烷+0.1%二乙基胺),等濃度]。取合併之目標溶出份分別濃縮,殘質減壓乾燥。
在實施例236A說明之對映異構物之分離法中,得到1.16g(45%純度,ee 99%)標題化合物,為先溶離出之對映異構物(於分離法中得到雜質)。
LC-MS(方法25):Rt=0.74min;MS(ESIpos):m/z=280[M+H]+
在實施例236A說明之對映異構物之分離法中,得到1.19g(33%純度,ee 99%)標題化合物,為後溶離出之對映異構物(於分離法中得到雜質)。
LC-MS(方法25):Rt=0.75min;MS(ESIpos):m/z=280[M+H]+
在含6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.21g,3.78mmol,實施例3A)與5-胺基-4-(2-甲氧基苯基)戊酸第三丁基酯(1.16g,45%純度,1.87mmol,對映異構物1,實施例237A)之二氯甲烷(25ml)混合物中添加1M碳酸氫鈉水溶液(25ml),反應混合物於RT下激烈攪拌2h。排出有機相,經硫酸鈉脫水,過濾與濃縮。殘質利用快速管柱層析法純化(LiChroprep RP-18 40-63μm;梯度:50-100%乙腈之水溶液)。得到1.27g(73%純度,88%理論值)標題化合物。
LC-MS(方法25):Rt=1.54min;MS(ESIpos):m/z=561/563[M+H]+
在含6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.24g,3.90mmol,實施例3A)與5-胺基-4-(2-甲氧基苯基)戊酸第三丁基酯(1.19g,33%純度,1.41mmol,對映異構物2,實施例238A)之二氯甲烷(25ml)混合物中添加1M碳酸氫鈉水溶液(25ml),反應混合物於RT下激烈攪拌2h。排出有機相,經硫酸鈉脫水,過濾及濃縮,殘質利用快速管柱層析法純化(LiChroprep RP-18 40-63μm;梯度:50-100%乙腈之溶液)。得到693mg(97%純度,85%理論值)標題化合物。
LC-MS(方法25):Rt=1.54min;MS(ESIpos):m/z=561/563[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.390(0.43),1.428(16.00),2.160(0.41),2.190(0.50),2.280(1.48),3.751(5.16),6.858(0.50),6.878(0.54),6.994(0.51),7.218(0.55),7.237(0.47),7.243(0.46),7.720(0.49),7.725(0.70),7.761(1.42),7.783(0.51).
在含5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸第三丁基酯(1.27g,73%純度,1.65mmol,對映異構物1,實施例239A)之二氯甲烷(15ml)溶液中添加TFA(3.5ml),混合物於室溫下攪拌一夜。隨後,反應混合物濃縮,殘質利用快速管柱層析法純化(LiChroprep RP-18 40-63μm;梯度:20-90%乙腈之溶液)。得到800mg(85%純度,81%理論值)標題化合物。
LC-MS(方法25):Rt=1.19min;MS(ESIpos):m/z=505/507[M+H]+
在含5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸第三丁基酯(690mg,97%純度,1.19mmol,對映異構物2,實施例240A)之二氯甲烷(7ml)溶液中添加TFA(1.9ml),混合物於室溫下攪拌一夜。隨後,反應混合物濃縮,殘質利用快速管柱層析法純化(LiChroprep RP-18 40-63μm;梯度:20-80%乙腈之溶液)。得到482mg(87%純度,70%理論值)標題化合物。
LC-MS(方法25):Rt=1.19min;MS(ESIpos):m/z=505/507[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.262(0.78),2.044(0.43),2.049(0.43),2.132(0.59),2.144(0.71),2.152(0.41),2.165(0.59),2.279(4.28),2.291(1.50),2.301(1.46),2.306(1.22),2.311(1.15),2.320(1.60),2.340(0.70),2.472(0.42),3.480(0.50),3.492(0.62),3.504(0.52),3.713(0.42),3.760(16.00),3.861(0.44),3.875(0.40),3.943(0.42),3.957(0.72),3.972(0.45),3.991(0.41),5.945(0.48),5.959(0.94),5.972(0.47),6.867(1.49),6.887(1.60),6.977(0.69),6.980(0.68),6.996(1.56),6.998(1.55),7.015(0.94),7.017(0.87),7.218(1.09),7.221(1.57),7.233 (1.33),7.237(1.62),7.240(1.40),7.254(1.31),7.693(0.80),7.698(0.88),7.715(1.75),7.720(2.24),7.750(3.37),7.761(1.28),7.772(1.63).
取(2,6-二氯苯基)乙腈(10.0g,54.0mmol)溶於DMF(200ml,2.6mol),慢慢添加NaH(2.59g,60%純度,64.8mmol),混合物於室溫下再攪拌10min。隨後,慢慢滴加3-溴丙酸第三丁基酯(9.0ml,54mmol),此過程中溫和起泡,並觀察到發熱至約35℃。在此再添加期間,反應容器於水浴中冷卻,然後離開水浴,混合物於室溫下攪拌2.5h。添加反應混合物至水中,使用二氯甲烷萃取。取有機相脫水,及於旋轉蒸發器上濃縮。粗產物利用管柱層析法純化(Isolera,KP-Sil,溶析液:己烷/乙酸乙酯,梯度:1-30%)。得到13.2g(75%純度,59%理論值)標題化合物。
LC-MS(方法25):Rt=1.43min;MS(ESIpos):m/z=314[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.170(0.43),1.369(16.00),1.957(0.77),2.323(0.44),2.343(0.91),2.354(0.40),4.770(0.57),7.128(0.41),7.147(0.55),7.150(0.58),7.169(0.69).
在先加入之含(+/-)-4-氰基-4-(2,6-二氯苯基)丁酸第三丁基酯(消旋物,2.00g,75%純度,4.78mmol,實施例243A)之第三丁醇(3.9ml,67mmol)中添加阮來鎳。反應混合物於標準壓力下,使用氫氣氫化6h。隨後,再次添加觸媒,再氫 化8h。通過矽藻土濾除觸媒,取濾液於旋轉蒸發器上濃縮。殘質利用管柱層析法純化(Isolera,LiChroprep RP-18,溶析液:水+0.1%體積比之甲酸/乙腈,梯度:5-95%乙腈)。得到660mg(99%純度,44%理論值)標題化合物。
LC-MS(方法25):Rt=0.76min;MS(ESIpos):m/z=318[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.403(16.00),7.115(0.42),7.135(1.08),7.155(0.65),7.287(0.47),7.290(0.46),7.321(0.70),7.324(0.62),7.341(0.67),7.344(0.61).
取6-溴-2-氯-3-甲基喹啉-4-羰基氯(4.31g,13.5mmol,實施例3A)與(+/-)-5-胺基-4-(2,6-二氯苯基)戊酸第三丁基酯(消旋物,4.74g,14.9mmol,實施例244A)溶於二氯甲烷(25ml,390mmol),添加碳酸氫鈉水溶液(25ml,1.0M,25mmol)至該溶液中。反應混合物於RT下激烈攪拌1.5h。隨後,添加反應混合物至水中,使用二氯甲烷萃取,取有機相使用1M鹽酸與飽和氯化鈉水溶液洗滌,經硫酸鈉脫水,及於旋轉蒸發器上濃縮。粗產物利用管柱層析法純化(Isolera,LiChroprep RP-18,溶析液:水/乙腈,梯度:40-100%乙腈)。得到2.33g標題化合物(含雜質),未進一步純化即用於下一個步驟。
LC-MS(方法25):Rt=1.60min;MS(ESIneg):m/z=597/599[M-H]-
取(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氯苯基)戊酸第三丁基酯(消旋物,2.33g,實施例245A)溶於二氯甲烷(29ml,460mmol)。於RT下,添加TFA(6.0ml,77mmol),混合物於室溫下攪拌16h。隨後,反應混合物於旋轉蒸發器上濃縮,再次重覆溶於二氯甲烷,再次濃縮。粗產物利用管柱層析法純化(Isolera,LiChroprep RP-18,溶析液:水+0.1%體積比之氨/乙腈,梯度:5-40%乙腈,然後使用甲醇沖洗,以使產物被完全沖洗至底部)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到950mg(72%純度,兩個步驟達26%理論值)標題化合物。
LC-MS(方法26):Rt=0.74min;MS(ESIpos):m/z=543/545[M+H]+
於氬氣下,在含(2,6-二氟苯基)乙腈(5.00g,32.7mmol)之THF(30ml)溶液中,於-78℃及攪拌下慢慢添加2M LDA之THF溶液(20ml,39mmol)。讓混合物回到0℃,15min後,再度冷卻至-78℃。隨後,於-78℃及攪拌下慢慢滴加含3-溴丙酸第三丁基酯(6.2ml,39mmol)之THF(10ml)溶液。繼續攪拌混合物一夜,此過程中讓冷卻槽(乾冰/丙酮)逐漸回到RT。隨後,於約0℃下慢慢添加水與乙酸乙酯(各100ml)至混合物中,攪拌。分相後,水相使用乙酸乙酯(100 ml)萃取一次。合併之有機相使用飽和氯化鈉溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到4.87g(76%純度,40%理論值)標題化合物。
LC-MS(方法1):Rt=2.06min;MS(ESIpos):m/z=282[M+H]+
於氬氣下製備LDA溶液,其係於-15℃下慢慢添加正丁基鋰溶液(1.6M己烷溶液,43ml,68mmol)至先加入之含二異丙基胺(10ml,71mmol)之THF(43ml)中。添加完畢後,溶液於0℃下再攪拌10min。慢慢滴加此LDA溶液至已冷卻至-78℃之含(2,6-二氟苯基)乙腈(9.90g,96%純度,62.1mmol)之THF(119ml)溶液中。添加完畢時,讓反應混合物回到0℃,15min後,再次冷卻至-78℃。然後慢慢滴加含3-溴丙酸第三丁基酯(13ml,97%純度,74mmol)之45ml THF溶液。混合物於-78℃下攪拌1h後,於RT下攪拌一夜。操作時,添加氯化銨溶液(400ml,10%水溶液)。激烈攪拌混合物5分鐘後,使用乙酸乙酯萃取2次。合併之有機相依序使用1M鹽酸、飽和碳酸氫鈉溶液、與飽和氯化鈉溶液分別洗滌2次。然後取有機相經硫酸鈉脫水,及於旋轉蒸發器上濃縮。取油狀殘質溶於二氯甲烷,添加矽藻土,混合物於旋轉蒸發器上濃縮。吸附之殘質多次通過快速管柱層析法純化(矽膠,Isolera,100g Ultra Snap卡管;梯度:環己烷/乙酸乙酯100:0至70:30)。取含產物溶出份一起濃縮。得到12.9g(100%純度,74%理論值)標題化合物。
LC-MS(方法1):Rt=2.08min;MS(ESIpos):m/z=282[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.374(16.00),2.313(0.89),2.331(1.31),2.349(0.45),4.499(0.52),7.197(0.60),7.219(1.24),7.240(0.68),7.519(0.45).
在含(+/-)-4-氰基-4-(2,6-二氟苯基)丁酸第三丁基酯(4.80g,17.1mmol,實施例247A,方法A)之第三丁醇(100ml)溶液中添加阮來鎳(1.00g,17.1mmol),於標準壓力下氫化一夜。隨後,通過矽藻土濾除觸媒,取母液濃縮。得到4.06g(81%純度,67%理論值)標題化合物。
LC-MS(方法2):Rt=0.64min;MS(ESIpos):m/z=286[M+H]+
在先加入之含(+/-)-4-氰基-4-(2,6-二氟苯基)丁酸第三丁基酯(12.9g,100%純度,46.0mmol,實施例247A,方法B)之第三丁醇(340ml)與甲醇(15ml)混合物中添加阮來鎳(2.00g,34.1mmol)。反應混合物於標準氫氣壓下攪拌一夜。然後再添加2g阮來鎳至反應混合物中,反應再於標準氫氣壓下攪拌兩夜。通過矽藻土濾除觸媒,使用甲醇洗滌三次(每次50ml)。濾液濃縮,殘質溶於400ml乙酸乙酯。該溶液使用1M鹽酸萃取兩次(每次400ml)。合併之水相分裝在三個錐型燒瓶中。三份中之一份使用碳酸氫鈉(粉末)調至pH 8-9,使用200ml乙酸乙酯萃取兩次。由於需要大量碳酸氫鈉,因此隨後兩份係使用氫氧化鋰調至pH 8-10,分別使用200ml乙酸乙酯萃取兩次。合併之有機相經硫酸鈉脫水,過濾與濃縮。殘質使用乙酸乙酯與水處理。分相後,水相使用乙酸乙酯萃取兩次。合併之有機相濃縮,殘質減壓乾燥。得到7.76g(76%純度,45%理論值)標題化合物。
LC-MS(方法1):Rt=1.05min;MS(ESIpos):m/z=286[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=7.35-7.24(m,1H),7.08-6.98(m,2H),3.10-2.95(m,1H),2.91-2.73(m,2H),2.09-1.99(m,3H),1.85-1.70(m,1H),1.60-1.40(m,2H),1.34(s,9H).
取(+/-)-5-胺基-4-(2,6-二氟苯基)戊酸第三丁基酯(消旋物,3.12g,76%純度,8.31mmol,實施例248A,方法B)先加至RT下之二氯甲烷(65ml)中。添加DIPEA(3.6ml,21mmol),然後添加含6-溴-2-氯-3-甲基喹啉-4-羰基氯(2.21g,6.93mmol,實施例3A)之二氯甲烷(15ml)溶液。反應混合物攪拌一夜後,添加水與二氯甲烷(各200ml)。分相,使用二氯甲烷(200ml)萃取水相。合併之有機相使用飽和氯化鈉溶液(200ml)洗滌,經硫酸鈉脫水,過濾與濃縮。殘質溶於少量DMSO,分成兩份利用製備型HPLC純化(方法30)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到3.77g(98%純度,94%理論值)標題化合物。
LC-MS(方法2):Rt=1.30min;MS(ESIneg):m/z=565/567[M-H]-
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.97(t,1H),7.94-7.86(m,2H),7.84-7.46(極寬m,1H),7.43-7.29(m,1H),7.09(t,2H),3.83-3.68(m,2H),3.57-3.41(m,1H),2.35-1.99(m,6H),1.96-1.83(m,1H),1.37(s,9H).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氟苯基)戊酸第三丁基酯(300mg,98%純度,518μmol,實施例249A)之NMP(4.4ml)中依序添加哌啶(260μl,2.6mmol)與DIPEA(450μl,2.6mmol)。容器密封,經由導管填充氬氣。反應溶液於100℃下攪拌一夜後,再於130℃下20h。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物之溶出份濃縮,及減壓乾燥。殘質溶於二氯甲烷,於減壓下起泡。得到252mg(100%純度,79%理論值)標題化合物。
LC-MS(方法1):Rt=2.76min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.81(t,1H),7.71-7.61(m,2H),7.57-7.42(m,1H),7.42-7.30(m,1H),7.08(t,2H),3.83-3.63(m,2H),3.56-3.42(m,1H),3.13(br.d,4H),2.22-2.00(m,6H),1.97-1.84(m,1H),1.73-1.54(m,6H),1.36(s,9H)
取標題化合物(169mg)利用製備型HPLC,於對掌相上分離成對映異構物(參見實施例251A與252A)[管柱:Daicel Chiralpak IG,5μm,250mm x 20mm;溶析液:正庚烷/異丙醇90:10;流速:25ml/min;UV檢測:225nm,溫度:25℃]。取合併之目標溶出份分別濃縮(22℃,40mbar)。
在實施例250A說明之對映異構物之分離法中,得到88mg(99%純度,ee>95%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IG,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇90:10;流速:1ml/min;UV檢測:225nm,溫度:25℃]:Rt=28.9min。
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.236(0.76),1.259(0.48),1.364(16.00),1.607(0.49),1.671(0.94),2.096(0.45),2.113(0.86),2.135(1.82),3.134(1.22),3.707(0.42),7.057(0.50),7.079(0.89),7.102(0.58),7.647(1.36),7.658(0.88),7.663(0.81),8.811(0.46).
在實施例250A說明之對映異構物之分離法中,得到66mg(95%純度,ee 98%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IG,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇90:10;流速:1ml/min;UV檢測:225nm,溫度:25℃]:Rt=34.9min。
LC-MS(方法1):Rt=2.73min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.236(0.63),1.259(0.47),1.364(16.00),1.606(0.44),1.670(0.85),2.095(0.41),2.112(0.81),2.135(1.69),3.133(1.12),7.057(0.47),7.079(0.84),7.101(0.55),7.647(1.32),7.658(0.86),7.663(0.75),8.811(0.44).
在微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氟苯基)戊酸第三丁基酯(300mg,98%純度,518μmol,實施例249A)之NMP(4.4ml)中依序添加吡咯啶(220μl,2.6mmol)與DIPEA(450μl,2.6mmol)。容器密封,經由導管填充氬氣。反應溶液於100℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物之溶出份濃縮,及減壓乾燥。殘質溶於少量二氯甲烷,於減壓下起泡。得到193mg(100%純度,62%理論值)標題化合物。
LC-MS(方法4):Rt=1.37min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.76(t,1H),7.56(dd,1H),7.48(d,1H),7.42-7.27(m,2H),7.07(t,2H),3.73-3.66(m,2H),3.57(br s,4H),3.52-3.40(m,1H),2.22-2.01(m,6H),1.95-1.82(m,5H),1.36(s,9H).
取119mg標題化合物,利用製備型HPLC於對掌相上分離成對映異構物(參見實施例254A與255A)[管柱:Daicel Chiralpak IC,5μm,250mm x 30mm;溶析液:正庚烷/異丙醇80:20;流速:42.5ml/min;UV檢測:225nm,溫度:25℃]。取合併之目標溶出份分別濃縮(22℃,40mbar)。
在實施例253A說明之對映異構物之分離法中,得到57mg(95%純度,ee 96%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IC,5μm,250mm x 4.6mm;溶 析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:260nm,溫度:25℃]:Rt=23.1min。
LC-MS(方法1):Rt=2.14min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(0.87),1.258(0.56),1.298(0.40),1.362(16.00),1.871(1.37),2.095(0.48),2.111(0.81),2.129(0.63),2.160(0.80),3.566(0.86),7.050(0.50),7.072(0.90),7.094(0.57),7.467(0.69),7.489(1.13),7.549(0.60),7.554(0.55),8.763(0.47).
在實施例253A說明之對映異構物之分離法中,得到50mg(95%純度,ee 99%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IC,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:260nm,溫度:25℃]:Rt=28.2min。
LC-MS(方法1):Rt=2.14min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.15),0.008(0.74),0.859(0.62),1.245(0.48),1.362(16.00),1.872(1.21),2.096(0.42),2.111(0.72),2.129(0.57),2.160(0.70),2.523(0.69),3.566(0.77),7.050(0.45),7.072(0.79),7.095(0.51),7.468(0.69),7.490(1.11),7.549(0.62),7.555(0.57),8.763(0.41).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氟苯基)戊酸第三丁基酯(消旋物,300mg,98%純度,518μmol,實施例249A)之NMP(4.4ml)中依序添加3,3-二氟哌啶鹽酸鹽(421mg,97%純度,2.59mmol)與DIPEA(450μl,2.6mmol)。容器密封,及經由導管填充氬氣。反應溶液於100℃下攪拌一夜後,再於130℃下20h。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。殘質溶於二氯甲烷,及在減壓下起泡。得到234mg(100%純度,69%理論值)標題化合物。
LC-MS(方法1):Rt=2.64min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.83(t,1H),7.76-7.65(m,2H),7.61-7.43(m,1H),7.42-7.30(m,1H),7.08(t,2H),3.83-3.64(m,2H),3.53-3.42(m,3H),3.22-3.11(m,2H),2.22-1.99(m,8H),1.97-1.82(m,3H),1.36(s,9H).
取170mg標題化合物,利用製備型HPLC於對掌相上分離成對映異構物(參見實施例257A與258A)[管柱:Daicel Chiralpak OX-H,5μm,250mm x 20mm;溶析液:正庚烷/異丙醇82:18;流速:30ml/min;UV檢測:220nm,溫度:RT]。取合併之目標溶出份分別於旋轉蒸發器上濃縮。
在實施例256A說明之對映異構物之分離法中,得到82mg(98%純度,ee 98%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-H,5μm,250mm x 4.6mm; 溶析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:30℃]:Rt=2.13min。
LC-MS(方法1):Rt=2.65min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.49),0.008(0.47),1.105(0.66),1.120(0.67),1.364(16.00),1.887(0.54),2.071(0.51),2.097(0.69),2.114(0.87),2.135(0.66),2.154(1.54),3.166(0.53),3.448(0.62),3.478(1.91),7.059(0.45),7.081(0.83),7.104(0.53),7.698(1.28),7.707(0.88),7.712(0.77),8.825(0.44).
在實施例256A說明之對映異構物之分離法中,得到73mg(98%純度,ee 95%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-H,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:30℃]:Rt=3.23min。
LC-MS(方法1):Rt=2.65min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.50),0.008(0.51),1.105(0.61),1.120(0.60),1.364(16.00),1.888(0.54),2.072(0.50),2.097(0.68),2.114(0.86),2.136(0.64),2.154(1.50),3.166(0.52),3.475(1.28),3.504(0.56),7.059(0.46),7.081(0.80),7.104(0.52),7.698(1.25),7.707(0.84),7.712(0.75),8.825(0.43).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氟苯基)戊酸第三丁基酯(消旋物,400mg,98%純度,690μmol,實施例249A)之NMP(4.0ml)中依序添加3-氟哌啶鹽酸鹽(497mg,97%純度,3.45mmol)與DIPEA(600μl,3.5mmol)。容器密封,及於130℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。殘質溶於少量二氯甲烷,及在減壓下起泡。得到343mg(100%純度,78%理論值)標題化合物。
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.82(t,1H),7.72-7.64(m,2H),7.61-7.43(m,1H),7.41-7.30(m,1H),7.08(d,2H),4.98-4.76(m,1H),3.82-3.63(m,2H),3.56-3.30(m,3H),3.24-3.02(m,2H),2.23-1.72(m,10H),1.70-1.57(m,1H),1.36(s,9H).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氟苯基)戊酸第三丁基酯(消旋物,400mg,98%純度,690μmol,實施例249A)之NMP(4.0ml)中依序添加3-乙基哌啶(411mg,95%純度,3.45mmol)與DIPEA(600μl,3.5mmol)。容器密封,及於130℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。殘質溶於少量二氯甲烷,及在減壓下起泡。得到365mg(100%純度,82%理論值)標題化合物。
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.81(t,1H),7.71-7.59(m,2H),7.56-7.42(m,1H),7.42-7.29(m,1H),7.08(t,2H),3.80-3.64(m,2H),3.57-3.42(m,3H),2.83-2.69(m,1H),2.48-2.36(m,1H),2.24-1.99(m,6H),1.98-1.81(m,2H),1.81-1.70(m,1H),1.68-1.48(m,2H),1.36(s,9H),1.32-1.20(m,2H),1.16-1.00(m,1H),0.97-0.83(m,3H).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,5-二氟苯基)戊酸第三丁基酯(消旋物,300mg,528μmol,實施例226A)之NMP(4.0ml)中依序添加哌啶(260μl,2.6mmol)與DIPEA(460ml,2.6mmol)。容器密封,及於130℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC分離(方法14)。取含產物溶出份濃縮,及減壓乾燥。殘質溶於少量二氯甲烷,及在減壓下起泡。得到265mg(100%純度,81%理論值)標題化合物。
LC-MS(方法1):Rt=2.72min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.81-8.67(m,1H),7.73-7.58(m,2H),7.55-7.36(m,1H),7.33-7.27(m,1H),7.27-7.19(m,1H),7.18-7.06(m,1H),3.76-3.56(m,2H),3.40-3.33(m,1H),3.19-3.07(m,4H),2.16-2.07(m,5H),2.06-1.96(m,1H),1.86-1.73(m,1H),1.73-1.55(m,6H),1.37(s,9H).
取標題化合物(268mg)利用製備型HPLC,於對掌相上分離成對映異構物(參見中間物262與263)[管柱:Daicel Chiralpak OX-H,5μm,250mm x 20mm;溶析液:正庚烷/乙醇80:20;流速:20ml/min;UV檢測:210nm,溫度:23℃]。取合併之目標溶出份分別於旋轉蒸發器上濃縮。各殘質與2ml乙腈及15ml水混合及冷凍乾燥。
在實施例261A說明之對映異構物之分離法中,得到82mg(99%純度,ee 100%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-3,3μm,50mm x 4.6mm;溶析液:異己烷/乙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:25℃]:Rt=2.24min。
LC-MS(方法1):Rt=2.74min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.46),0.008(0.40),1.371(16.00),1.607(0.40),1.670(0.79),2.079(0.65),2.096(0.94),2.115(1.18),3.132(1.05),7.646(1.28),7.655(0.84),7.660(0.76).
在實施例261A說明之對映異構物之分離法中,得到90mg(98%純度,ee 97%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-3,3μm,50mm x 4.6mm;溶析液:異己烷/乙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:25℃]: Rt=2.60min。
LC-MS(方法1):Rt=2.74min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.44),1.372(16.00),1.605(0.43),1.670(0.83),2.080(0.67),2.096(0.97),2.115(1.24),3.133(1.10),7.646(1.31),7.655(0.88),7.660(0.81),8.740(0.40).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,5-二氟苯基)戊酸第三丁基酯(消旋物,300mg,528μmol,實施例226A)之NMP(4.0ml)中依序添加吡咯啶(220μl,2.6mmol)與DIPEA(460μl,2.6mmol)。容器密封,及於130℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。得到245mg(100%純度,77%理論值)標題化合物。
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.69(t,1H),7.56(dd,1H),7.48(d,1H),7.44-7.18(m,3H),7.17-7.08(m,1H),3.73-3.50(m,6H),3.39-3.33(m,1H),2.20-1.97(m,6H),1.91-1.84(m,4H),1.85-1.73(m,1H),1.37(s,9H).
取標題化合物(173mg)利用製備型HPLC,於對掌相上分離成對映異構物(參見實施例265A與266A)[管柱:Daicel Chiralpak IC,5μm,250mm x 30mm;溶析液:正庚烷/異丙醇80:20;流速:42.5ml/min;UV檢測:260nm,溫度: 25℃]。取合併之目標溶出份分別濃縮(25℃,40mbar)。
在實施例264A說明之對映異構物之分離法中,得到83mg(90%純度,含溶劑,ee 96%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IC,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:260nm,溫度:25℃]:Rt=19.2min。
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.81),0.008(0.79),1.236(0.96),1.259(0.72),1.298(0.54),1.370(16.00),1.871(1.18),2.078(0.65),2.095(0.85),2.115(0.44),2.142(0.50),2.523(0.56),3.565(0.80),7.466(0.63),7.488(1.07),7.545(0.55),7.551(0.50).
在實施例264A說明之對映異構物之分離法中,得到86mg(90%純度,含溶劑,ee 96%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak IC,5μm,250mm x 4.6mm;溶析液:正庚烷/異丙醇80:20;流速:1ml/min;UV檢測:260nm,溫度:25℃]:Rt=23.1min。
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.66),0.008(0.62),0.839(0.47),1.235(1.44),1.259(1.15),1.298(0.84),1.352(0.50),1.370(16.00),1.871(1.21),2.078(0.67),2.095(0.87),2.115(0.46),2.141(0.51),2.523(0.47),3.567(0.83),7.466(0.64),7.488(1.07),7.545(0.55),7.551(0.51).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,5-二氟苯基)戊酸第三丁基酯(消旋物,300mg,528μmol,實施例226A)之NMP(4.0ml)中依序添加3,3-二氟哌啶鹽酸鹽(416mg,2.64mmol)與DIPEA(460μl,2.6mmol)。容器密封,於130℃下攪拌一夜及再於140℃ 20h。冷卻至室溫後,反應溶液利用製備型HPLC分離(方法14)。取含產物溶出份濃縮,及減壓乾燥。殘質溶於少量二氯甲烷,及在減壓下起泡。得到253mg(100%純度,73%理論值)標題化合物。
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.75(t,1H),7.74-7.67(m,2H),7.48(br s,1H),7.39-7.20(m,2H),7.17-7.09(m,1H),3.78-3.56(m,2H),3.48(t,2H),3.40-3.29(m,1H),3.17(br s,2H),2.20-1.97(m,8H),1.92-1.75(m,3H),1.39-1.29(m,9H).
取標題化合物(202mg)利用製備型HPLC,於對掌相上分離成對映異構物(參見中間物268A與269A)[管柱:Daicel Chiralpak OX-H,5μm,250mm x 30mm;溶析液:正庚烷/乙醇85:15;流速:42.5ml/min;UV檢測:220nm,溫度:20℃]。合併之目標化合物分別濃縮,取各殘質減壓乾燥。
在實施例267A說明之對映異構物之分離法中,得到71mg(99%純度,ee 99%)標題化合物,為先溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-3,3μm,50mm x 4.6mm;溶析液:異己烷/乙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:25℃]:Rt=1.10min。
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.84),0.008(0.94),1.358(0.70),1.371(16.00),1.880(0.44),2.081(0.90),2.098(1.18),2.120(0.74),2.134(1.11),3.164(0.56),3.475(0.68),7.697(1.31),7.704(0.89),7.709(0.81),8.752(0.43).
在實施例267A說明之對映異構物之分離法中,得到71mg(95%純度,ee 93%)標題化合物,為後溶離出之對映異構物。
對掌性分析性HPLC[管柱:Daicel Chiralpak OX-3,3μm,50mm x 4.6mm;溶析液:異己烷/乙醇80:20;流速:1ml/min;UV檢測:220nm,溫度:25℃]:Rt=1.10min。
LC-MS(方法1):Rt=2.60min;MS(ESIpos):m/z=652/654[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.68),0.008(1.48),1.372(16.00),1.879(0.41),2.081(0.84),2.098(1.10),2.119(0.69),2.134(1.02),3.165(0.52),3.475(0.62),7.697(1.27),7.704(0.89),7.709(0.79),8.752(0.41).
在厚壁微波容器中,在先加入之含(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,5-二氟苯基)戊酸第三丁基酯(消旋物,400mg,704μmol,實施例226A)之NMP(4.5ml)中依序添加3-氟哌啶鹽酸鹽(492mg,3.52mmol)與DIPEA(610μl,3.5mmol)。容器密封,及於130℃下攪拌一夜。冷卻至室溫後,反應溶液利用製備型HPLC純化(方法14)。取含產物溶出份濃縮,及減壓乾燥。得到293mg(100%純度,66%理論值)標題化合物。
LC-MS(方法1):Rt=2.59min;MS(ESIpos):m/z=634/636[M+H]+
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=8.75(t,1H),7.71-7.64(m,2H),7.60-7.36(m,1H),7.33-7.20(m,2H),7.17-7.08(m,1H),4.98-4.76(m,1H),3.77-3.57(m,2H),3.50-3.35(m,2H),3.23-3.14(m,1H),3.13-3.03(m,1H),2.16-1.87(m,8H),1.86-1.73(m,2H),1.71-1.57(m,1H),1.37(s,9H),1H隱蔽.
於RT下,在含(+/-)-5-胺基-4-(2-氯苯基)戊酸第三丁基酯(6.57g,83%純度,19.2mmol,實施例25A)之二氯甲烷(40ml)混合物中添加三乙基胺(3.0ml,21.5mmol)與二碳酸二-第三丁基酯(4.70g,21.5mmol)(有氣體釋出),混合物先於RT下攪拌,然後靜置5天。隨後,混合物與二氯甲烷(60ml)混合,使用碳酸氫鈉溶液洗滌一次,及使用飽和氯化鈉溶液洗滌一次。取有機相經硫酸鈉脫水,過濾與濃縮。殘質利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份於旋轉蒸發器上,於20℃下濃縮,殘質減壓乾燥。得到兩份純度稍微不同之標題化合物溶出份:溶出份1:4.33g(100%純度,59%理論值,參見分析法)與溶出份2:1.66g(94%純度,21%理論值)。
LC-MS(方法2):Rt=1.26min;MS(ESIpos):m/z=384[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.333(9.46),1.353(16.00),1.398(0.17),1.692(0.21),1.708(0.24),1.716(0.21),1.731(0.18),1.933(0.16),1.947(0.27),1.957(0.23),1.976(0.92),1.999(0.31),2.012(0.23),3.038(0.18),3.055(0.25),3.072(0.28),3.087(0.19),3.183(0.25),3.200(0.23),3.335(0.25),3.352(0.23),3.363(0.16),6.843(0.18),6.857(0.33),6.871(0.17),7.220(0.26),7.227(0.32),7.238(0.32),7.248(0.27),7.311(0.94),7.320(1.08),7.395(0.60),7.415(0.50).
取兩份合併之標題化合物溶出份(5.9g)溶於乙醇(100ml),過濾,利用製備性SFC,於對掌相上分離成對映異構物(參見實施例272A與273A)[管柱:Daicel Chiralcel OX,20μm,380mm x 50mm;流速:300ml/min;注射:1.2ml;UV檢測:210nm,溫度:40℃;溶析液:90%二氧化碳/10%乙醇;運行時間10min,等濃度]。取合併之目標溶出份分別濃縮,及減壓乾燥。
在實施例271A說明之對映異構物之分離法中,得到2.59g(99%純度,ee>99%)標題化合物,為先溶離出之對映異構物。
[α]D 20=+8.5°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=2.42min;MS(ESIpos):m/z=384[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.332(9.45),1.352(16.00),1.691(0.22),1.706(0.24),1.715(0.21),1.730(0.18),1.946(0.27),1.955(0.24),1.975(0.91),2.011(0.23),3.037(0.17),3.054(0.24),3.071(0.28),3.086(0.19),3.182(0.25),3.198(0.23),3.334(0.28),3.351(0.24),6.843(0.19),6.857(0.33),6.871(0.18),7.219(0.26),7.227(0.33),7.238(0.32),7.247(0.27),7.311(0.98),7.320(1.08),7.395(0.60),7.415(0.51).
在實施例271A說明之對映異構物之分離法中,得到2.47g(100%純度,ee>99%)標題化合物,為後溶離出之對映異構物。
[α]D 20=-8.2°,589nm,c=0.65g/100ml,甲醇
LC-MS(方法1):Rt=2.42min;MS(ESIpos):m/z=384[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.33),0.008(0.34),1.332(8.75),1.352(16.00),1.691(0.19),1.706(0.22),1.715(0.19),1.730(0.16),1.946(0.22),1.955(0.20),1.975(0.81),2.012(0.21),3.053(0.22),3.071(0.25),3.086(0.17),3.162(0.18),3.175(0.18),3.181(0.23),3.198(0.20),3.333(0.28),3.351(0.22),6.858(0.30),7.219(0.23),7.227(0.30),7.238(0.30),7.248(0.25),7.311(0.89),7.320(0.99),7.396(0.57),7.415(0.48).
於RT下,在含(+)-5-[(第三丁氧基羰基)胺基]-4-(2-氯苯基)戊酸第三丁基酯(2.55g,6.64mmol,實施例272A)之二烷(13ml)混合物中慢慢滴加4M鹽酸之二烷溶液(3.3ml,13.28mmol),混合物於室溫下攪拌22h。隨後,再次滴加4M鹽酸之二烷溶液(830μl,3.32mmol),混合物於室溫下再攪拌1小時。隨後,再次滴加4M鹽酸之二烷溶液(830μl,3.32mmol),混合物於室溫下再攪拌2小時。 然後濃縮混合物,重覆添加二氯甲烷後再濃縮一次。殘質減壓乾燥。得到2.29g(67%純度,72%理論值)標題化合物。
[α]D 20=-4.4°,589nm,c=0.72g/100ml,甲醇
LC-MS(方法1):Rt=1.14min;MS(ESIpos):m/z=284[M+H]+
於RT下,在含(-)-5-[(第三丁氧基羰基)胺基]-4-(2-氯苯基)戊酸第三丁基酯(2.42g,6.30mmol,實施例273A)之二烷(12ml)混合物中慢慢滴加4M鹽酸之二烷溶液(3.2ml,12.61mmol),混合物於室溫下攪拌22h。隨後,再次滴加4M鹽酸之二烷溶液(790μl,3.16mmol),混合物於室溫下再攪拌1小時。隨後,再次滴加4M鹽酸之二烷溶液(790μl,3.16mmol),混合物於室溫下再攪拌2小時。然後濃縮混合物,重覆添加二氯甲烷後再濃縮一次。殘質減壓乾燥。得到2.15g(68%純度,73%理論值)標題化合物。
[α]D 20=+5.9°,589nm,c=0.66g/100ml,甲醇
LC-MS(方法1):Rt=1.12min;MS(ESIpos):m/z=284[M+H]+
於RT下,在含(-)-5-胺基-4-(2-氯苯基)戊酸第三丁基酯鹽酸鹽(2.25g,67%純度,5.29mmol,實施例274A)之二氯甲烷(50ml)懸浮液中添加DIPEA(2.3ml,13.22mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.41g,4.41mmol,實施例3A),混合物於室溫下攪拌16h。隨後,添加水(100ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(100ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.26g(100%純度,91%理論值)標題化合物。
[α]D 20=+12.8°,589nm,c=0.59g/100ml,甲醇
LC-MS(方法2):Rt=1.33min;MS(ESIpos):m/z=565/567/569[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.157(0.24),1.175(0.47),1.193(0.24),1.371(16.00),1.816(0.18),1.820(0.18),1.989(0.88),2.028(0.18),2.033(0.17),2.045(0.19),2.051(0.17),2.065(0.28),2.077(0.96),2.093(0.81),2.110(0.29),2.114(0.28),2.213(0.28),3.569(0.16),3.589(0.19),3.713(0.29),4.021(0.20),4.039(0.20),7.279(0.27),7.297(0.20),7.360(0.17),7.378(0.29),7.396(0.16),7.448(0.58),7.451(0.58),7.468(0.48),7.471(0.48),7.491(0.44),7.509(0.33),7.894(2.14),7.899(1.08),8.847(0.21),8.861(0.40),8.874(0.20).
於RT下,在含(+)-5-胺基-4-(2-氯苯基)戊酸第三丁基酯鹽酸鹽(2.12g,68%純度,5.08mmol,實施例275A)之二氯甲烷(50ml)懸浮液中添加DIPEA(2.2ml,12.70mmol)。隨後,添加6-溴-2-氯-3-甲基喹啉-4-羰基氯(1.35g,4.23mmol,實施例3A),混合物於室溫下攪拌16h。隨後,添加水(100ml)至混合物中,攪拌。分相後,水相使用二氯甲烷(100ml)萃取一次。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(100g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度97:3→7:3,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.21g(99%純度,91%理論值)標題化合物。
[α]D 20=-12.2°,589nm,c=0.43g/100ml,甲醇
LC-MS(方法2):Rt=1.33min;MS(ESIpos):m/z=565/567/569[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.24),0.008(0.21),1.157(0.30),1.175(0.59),1.193(0.30),1.371(16.00),1.815(0.17),1.989(1.13),2.027(0.17),2.045(0.18),2.050(0.16),2.064(0.27),2.076(0.96),2.092(0.80),2.109(0.28),2.210(0.28),3.588(0.19),3.712(0.28),4.021(0.26),4.039(0.26),7.279(0.27),7.298(0.19),7.359(0.17),7.377(0.29),7.396(0.16),7.448(0.59),7.451(0.63),7.468(0.50),7.470(0.52),7.491(0.44),7.509(0.33),7.894(2.22),8.846(0.20),8.860(0.39),8.874(0.20).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(283mg,0.5mmol,實施例276A)之NMP(2ml)溶液中添加哌啶-D11(148μl,1.50mmol),混合物於110℃下攪拌2h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生284mg(92%純度,83%理論值)標題化合物。
[α]D 20=+9.2°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法1):Rt=2.79min;MS(ESIpos):m/z=624/626[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.087(1.47),1.369(16.00),1.814(0.16),2.055(0.21),2.075(1.01),2.085(0.55),2.099(0.27),2.104(0.27),2.129(1.02),2.695(0.24),3.585(0.18),3.671(0.28),7.255(0.18),7.271(0.36),7.285(0.23),7.356(0.22),7.371(0.39),7.385(0.20),7.440(0.61),7.442(0.58),7.456(0.53),7.458(0.48),7.479(0.49),7.482(0.50),7.495(0.41),7.624(0.34),7.641(1.25),7.651(0.85),7.655(0.79),7.669(0.21),7.673(0.23),8.709(0.23),8.720(0.41),8.732(0.19).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基 酯(283mg,0.5mmol,實施例277A)之NMP(2ml)溶液中添加哌啶-D11(148μl,1.50mmol),混合物於110℃下攪拌4h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生276mg(100%純度,88%理論值)標題化合物。
[α]D 20=-9.3°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.78min;MS(ESIpos):m/z=624/626[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.087(0.22),1.369(16.00),1.807(0.17),2.041(0.18),2.045(0.16),2.053(0.21),2.056(0.23),2.073(1.08),2.083(0.72),2.095(0.33),2.098(0.34),2.126(0.65),2.695(0.20),3.585(0.20),3.670(0.22),7.262(0.16),7.274(0.33),7.286(0.21),7.361(0.21),7.373(0.37),7.385(0.20),7.444(0.62),7.446(0.64),7.458(0.55),7.459(0.55),7.487(0.49),7.499(0.40),7.628(0.47),7.643(1.32),7.656(0.76),7.660(0.72),7.671(0.26),7.674(0.27),8.734(0.24),8.744(0.45),8.753(0.23).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(234mg,391μmol,實施例39A)之NMP(1.6ml)溶液中添加哌啶-D11(116μl,1.17mmol),混合物於110℃下攪拌4h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生228mg(86%純度,97%理論值)標題化合物。
[α]D 20=-14.0°,589nm,c=0.48g/100ml,甲醇
LC-MS(方法1):Rt=2.80min;MS(ESIpos):m/z=658/660[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.346(16.00),1.889(0.17),1.903(0.18),1.913(0.17),1.991(0.23),2.001(0.18),2.006(0.26),2.015(0.21),2.022(0.23),2.034(0.30),2.049(0.29),2.116(0.17),2.128(0.26),2.140(0.30),2.163(0.54),2.696(0.21),3.303(0.21),3.315(0.26),7.470(0.21),7.483(0.41),7.495(0.24),7.640(0.39),7.655(1.29),7.665(0.77),7.669(0.70),7.680(0.22),7.684(0.24),7.697(0.18),7.709(0.43),7.726(0.60),7.739(0.99),7.752(0.27),8.790(0.23),8.800(0.46),8.809(0.23).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(234mg,391μmol,實施例40A)之NMP(1.6ml)溶液中添加哌啶-D11(116μl,1.17mmol),混合物於110℃下攪拌4h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生221mg(100%純度,86%理論值)標題化合物。
[α]D 20=+13.9°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法1):Rt=2.80min;MS(ESIpos):m/z=658/660[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.346(16.00),1.890(0.18),1.898(0.18),1.905(0.19),1.913(0.18),1.991(0.24),2.001(0.19),2.006(0.28),2.016(0.22),2.023(0.25),2.034(0.32),2.049(0.31),2.116(0.19),2.129(0.28),2.140(0.33),2.163(0.58),3.303(0.19),3.314(0.26),3.322(0.25),7.470(0.23),7.482(0.45),7.495(0.27),7.641(0.40),7.655(1.33),7.665(0.80),7.669(0.72),7.680(0.23),7.683(0.24),7.696(0.20),7.709(0.47),7.726(0.64),7.739(1.05),7.752(0.29),8.790(0.25),8.800(0.49),8.810(0.24).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(241mg,391μmol,實施例42A)之NMP(1.6ml)溶液中添加哌啶-D11(116μl,1.17mmol),混合物於110℃下攪拌4h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生211mg(100%純度,80%理論值)標題化合物。
[α]D 20=+12.4°,589nm,c=0.45g/100ml,DMSO
LC-MS(方法1):Rt=2.82min;MS(ESIpos):m/z=674/676[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.360(16.00),1.374(0.22),1.809(0.20),1.824(0.21),2.038(0.29),2.052(0.31),2.055(0.30),2.065(1.21),2.085(0.35),2.089(0.32),2.097(0.18),2.138(0.38),3.383(0.27),3.615(0.18),3.626(0.22),3.636(0.22),3.648(0.20),3.659(0.16),7.352(0.25),7.364(0.40),7.394(0.18),7.407(0.67),7.413(0.58),7.419(0.65),7.554(0.41),7.564(0.31),7.569(0.31),7.637(0.43),7.652(1.21),7.665(0.69),7.668(0.64),7.679(0.23),7.683(0.23),8.758(0.21),8.767(0.40),8.777(0.21).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(241mg,391μmol,實施例43A)之NMP(1.6ml)溶液中添加哌啶-D11(116μl,1.17mmol),混合物於110℃下攪拌4h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓 乾燥,產生196mg(94%純度,69%理論值)標題化合物。
[α]D 20=-11.9°,589nm,c=0.49g/100ml,DMSO
LC-MS(方法1):Rt=2.83min;MS(ESIpos):m/z=674/676[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.360(16.00),1.817(1.14),2.064(3.81),2.137(2.64),2.694(0.27),3.635(1.64),7.362(1.83),7.410(3.01),7.562(1.69),7.657(2.27),8.767(1.34).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(283mg,0.5mmol,實施例276A)之NMP(2ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(150μl,1.50mmol),混合物於110℃下攪拌2h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生254mg(93%純度,77%理論值)標題化合物。
[α]D 20=+9.0°,589nm,c=0.47g/100ml,甲醇
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.085(1.40),1.334(0.21),1.367(16.00),1.798(0.21),1.815(0.28),2.028(0.20),2.038(0.23),2.044(0.23),2.052(0.34),2.073(1.32),2.083(0.78),2.097(0.37),2.103(0.32),2.156(0.92),2.694(0.20),3.578(0.30),3.655(0.31),7.250(0.26),7.266(0.49),7.281(0.32),7.352(0.34),7.367(0.56),7.381(0.34),7.434(0.82),7.449(0.69),7.468(0.97),7.474(0.78),7.486 (1.43),7.545(0.71),7.549(0.68),7.562(0.47),7.567(0.44),8.658(0.31),8.669(0.50),8.680(0.26).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(283mg,0.5mmol,實例277A)之NMP(2ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(150μl,1.50mmol),混合物於110℃下攪拌2h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生274mg(100%純度,90%理論值)標題化合物。
[α]D 20=-9.2°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.085(0.23),1.367(16.00),1.809(0.17),2.039(0.17),2.051(0.20),2.055(0.24),2.072(0.92),2.081(0.59),2.093(0.27),2.098(0.25),2.152(0.30),2.162(0.29),2.175(0.22),2.694(0.25),3.580(0.19),7.268(0.25),7.280(0.18),7.357(0.18),7.369(0.29),7.381(0.17),7.437(0.60),7.439(0.60),7.451(0.53),7.452(0.51),7.471(0.89),7.482(0.51),7.486(1.32),7.493(0.39),7.550(0.57),7.553(0.53),7.564(0.40),7.568(0.38),8.686(0.18),8.695(0.32),8.703(0.18).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(234mg,391μmol,實施例39A)之NMP(1.6ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(98μl,1.17mmol),混合物於110℃下攪拌3h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生218mg(100%純度,87%理論值)標題化合物。
[α]D 20=-13.1°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.324(0.18),1.345(16.00),1.890(0.20),1.898(0.21),1.904(0.21),1.913(0.21),1.987(0.25),1.997(0.20),2.002(0.28),2.012(0.21),2.027(0.24),2.038(0.33),2.053(0.33),2.065(0.17),2.103(0.18),2.113(0.24),2.125(0.32),2.136(0.33),2.148(0.28),2.163(0.25),2.177(0.27),2.190(0.23),2.696(0.25),3.302(0.24),3.313(0.29),7.465(0.22),7.478(0.42),7.484(0.92),7.499(1.13),7.559(0.59),7.562(0.58),7.574(0.41),7.577(0.41),7.694(0.20),7.706(0.48),7.719(0.84),7.736(0.81),7.750(0.34),8.746(0.35).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲基)苯基]戊酸第三丁基酯(234mg,391μmol,實施例40A)之NMP(1.6ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(98μl,1.17mmol),混合物於110℃下攪拌3h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。 經減壓乾燥,產生239mg(100%純度,95%理論值)標題化合物。
[α]D 20=+14.1°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=642/644[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.345(16.00),1.890(0.16),1.897(0.17),1.904(0.17),1.913(0.17),1.987(0.22),1.997(0.17),2.002(0.24),2.012(0.18),2.027(0.21),2.038(0.30),2.053(0.30),2.112(0.19),2.125(0.27),2.136(0.27),2.144(0.22),2.148(0.22),2.159(0.20),2.176(0.21),2.186(0.18),2.696(0.17),3.302(0.19),3.313(0.23),7.465(0.18),7.477(0.35),7.484(0.89),7.499(1.12),7.559(0.56),7.562(0.52),7.573(0.39),7.577(0.37),7.694(0.17),7.706(0.41),7.719(0.73),7.736(0.68),7.750(0.28),8.736(0.17),8.745(0.30).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(241mg,391μmol,實施例42A)之NMP(1.6ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(98μl,1.17mmol),混合物於110℃下攪拌2h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生241mg(98%純度,91%理論值)標題化合物。
[α]D 20=+13.9°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=658/660[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.358(16.00),1.372(0.17),1.806(0.22), 1.823(0.20),2.039(0.27),2.049(0.34),2.062(1.24),2.080(0.32),2.084(0.26),2.16(0.14),3.369(0.20),3.381(0.20),3.61(0.14),3.65(0.15),7.345(0.26),7.357(0.41),7.402(0.47),7.407(0.47),7.414(0.50),7.478(0.71),7.493(0.98),7.550(0.42),7.557(0.64),7.561(0.73),7.565(0.37),7.572(0.36),7.575(0.33),8.715(0.25).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-[2-(三氟甲氧基)苯基]戊酸第三丁基酯(241mg,391μmol,實例43A)之NMP(1.6ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(98μl,1.17mmol),混合物於110℃下攪拌3h。冷卻至室溫後,添加水(75ml)至混合物中,濾出所出現之固體,使用水洗滌2次(每次4ml)。經減壓乾燥,產生225mg(100%純度,88%理論值)標題化合物。
[α]D 20=-13.7°,589nm,c=0.43g/100ml,甲醇
LC-MS(方法1):Rt=2.24min;MS(ESIpos):m/z=658/660[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.359(16.00),1.807(0.21),1.824(0.20),2.040(0.26),2.050(0.33),2.064(1.21),2.081(0.31),2.086(0.25),2.16(0.14),3.383(0.24),3.61(0.13),3.65(0.13),7.345(0.25),7.355(0.33),7.358(0.41),7.402(0.47),7.408(0.47),7.414(0.49),7.480(0.71),7.495(0.99),7.550(0.40),7.553(0.33),7.558(0.60),7.562(0.71),7.565(0.38),7.573(0.35),7.576(0.33),8.718(0.24).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(241mg,400μmol,實施例48A)之NMP(1.6ml)中溶液添加吡咯啶-2,2,3,3,4,4,5,5-D8(100μl,1.20mmol),混合物於110℃下攪拌20h。冷卻至室溫後,添加水(100ml)至混合物中,使用乙酸乙酯萃取2次(每次80ml)。合併之有機相經硫酸鈉脫水,過濾及濃縮,殘質經製備型HPLC純化(方法32)。取合併之目標溶出份濃縮,殘質從乙腈/水中冷凍乾燥。得到兩份溶出份:得到溶出份1為34mg(100%純度)(+)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸(參見實施例281,方法B)。得到溶出份2為42mg(93%純度,15%理論值,參見分析法)標題化合物。
LC-MS(方法1):Rt=2.14min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.231(0.25),1.359(16.00),2.053(0.22),2.061(0.26),2.074(0.26),2.084(0.19),2.139(0.80),2.151(1.21),2.162(0.89),3.689(0.28),7.302(0.28),7.413(0.24),7.475(1.03),7.490(1.40),7.558(0.72),7.562(0.66),7.573(0.51),7.576(0.48),8.786(0.36).
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸第三丁基酯(241mg,400μmol,實施例49A)之NMP(1.6ml)溶液中添加吡咯啶-2,2,3,3,4,4,5,5-D8(100μl,1.20mmol),混合物於110℃下攪拌20h。冷卻至室溫後,添加水(100ml)至混合物中,使用乙酸乙酯萃取2次(每次80ml)。合併 之有機相經硫酸鈉脫水,過濾及濃縮,殘質經製備型HPLC純化(方法32)。取合併之目標溶出份濃縮,殘質從乙腈/水中冷凍乾燥。得到兩份溶出份:得到溶出份1為55mg(100%純度)說明於實施例282之(-)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸。得到溶出份2為24mg(100%純度,9%理論值,參見分析法)標題化合物。
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.231(0.36),1.359(16.00),1.962(0.21),2.054(0.30),2.063(0.36),2.075(0.36),2.086(0.28),2.097(0.23),2.141(1.07),2.152(1.57),3.692(0.39),3.751(0.22),7.301(0.37),7.412(0.33),7.476(0.97),7.491(1.32),7.558(0.76),7.573(0.56),8.786(0.47).
在含(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(2.30g,4.06mmol,實施例276A)之NMP(34ml)溶液中添加吡咯啶(1.0ml,12.18mmol),混合物於100℃下攪拌17h。冷卻至室溫後,混合物濃縮,添加水(100ml)與乙酸乙酯(100ml)至殘質中,攪拌。分相後,水相使用乙酸乙酯(75ml)萃取一次。合併之有機相使用飽和氯化鈉溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.19g(100%純度,90%理論值)標題化合物。
[α]D 20=+6.3°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=600/602[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.175(0.27),1.367(16.00),1.794(0.16),1.814(0.23),1.870(1.42),1.988(0.49),2.034(0.17),2.044(0.23),2.051(0.21),2.072(1.29),2.083(0.65),2.100(0.28),2.107(0.25),2.158(0.97),3.567(1.19),3.657(0.32),7.248(0.18),7.266(0.42),7.285(0.31),7.349(0.28),7.368(0.50),7.386 (0.30),7.432(0.66),7.434(0.67),7.452(0.54),7.454(0.54),7.467(0.78),7.473(0.61),7.490(1.36),7.544(0.64),7.550(0.60),7.567(0.38),7.572(0.37),8.657(0.22),8.671(0.42),8.685(0.22).
化合物之絕對組態係利用VCD光譜儀測定(參見Kuppens等人,"Determination of absolute configuration via vibrational circular dichroism",Drug Discovery Today:Technologies 2004,1,269-275(2004);Stephens,P.J.,"Vibrational circular dichroism spectroscopy:A new tool for the stereochemical characterization of chiral molecules",Computational Medicinal Chemistry for Drug Discovery 2004,699-725)。
因此標題化合物具有R組態。
在含(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸第三丁基酯(2.25g,3.97mmol,實施例277A)之NMP(34ml)溶液中添加吡咯啶(1.0ml,11.92mmol),混合物於100℃下攪拌17h。冷卻至室溫後,混合物濃縮,添加水(100ml)與乙酸乙酯(100ml)至殘質中,攪拌。分相後,水相使用乙酸乙酯(75ml)萃取一次。合併之有機相使用飽和氯化鈉溶液(150ml)洗滌一次,經硫酸鈉脫水,過濾及濃縮,殘質溶於二氯甲烷,及利用快速管柱層析法純化(50g矽膠Biotage Snap-Cartridge Ultra,環己烷/乙酸乙酯梯度93:7→6:4,Isolera One)。取合併之目標溶出份濃縮,殘質減壓乾燥。得到2.14g(98%純度,88%理論值)標題化合物。
[α]D 20=-10.4°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=600/602[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.157(0.18),1.175(0.36),1.192(0.18),1.367(16.00),1.814(0.20),1.870(1.24),1.988(0.67),2.044(0.20),2.051(0.18),2.072(1.15),2.083(0.57),2.100(0.24),2.108(0.22),2.158(0.85),3.311(8.02),3.657(0.27),7.248(0.16),7.266(0.37),7.286(0.27),7.349(0.25),7.368(0.45),7.386(0.27),7.432(0.64),7.434(0.64),7.451(0.53),7.454(0.52),7.467(0.78),7.473 (0.55),7.476(0.54),7.490(1.36),7.544(0.64),7.550(0.59),7.567(0.37),7.572(0.36),8.657(0.20),8.671(0.38),8.686(0.19).
(+/-)-4-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-3-(2-氯-6-氟苯基)丁酸三級丁酯(150mg,242μmol,外消旋物,實施例53A)於二氯甲烷(2.3ml)之溶液中加入TFA(370μl,4.8mmol)並在室溫(RT)下攪拌混合物16小時。再將混合物濃縮及重複加入二氯甲烷及再次濃縮混合物。將殘餘物溶於乙腈中及藉由製備型HPLC(方法11)純化。將合併之目標餾分濃縮及將殘餘物冷凍乾燥。取得125mg(98%純度,90%之理論值)標的化合物。
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.57),0.008(2.96),0.146(0.41),1.611(4.57),1.676(8.94),2.072(0.69),2.150(16.00),2.327(0.68),2.366(0.48),2.670(0.79),2.709(0.98),2.774(1.22),2.796(3.04),2.812(3.09),2.835(1.38),2.851(1.09),3.153(11.54),3.711(1.62),3.816(1.22),4.070(2.46),4.089(3.00),4.106(2.39),7.176(1.51),7.186(1.95),7.200(2.59),7.208(2.12),7.227(2.29),7.303(2.07),7.315(8.43),7.323(9.04),7.341(2.19),7.362(0.73),7.481(0.59),7.637(3.03),7.659(13.06),7.669(8.47),7.673(7.54),7.691(1.75),7.695(1.86),8.799(2.25),8.815(4.44),8.829(2.18).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.21(s,1H),8.81(t,1H),7.68(dd,1H),7.66(d,1H),7.48(br.s,1H),7.37-7.29(m,2H),7.24-7.16(m,1H),4.14-4.06(m,1H),3.82(br.s,1H),3.71(br.s,1H),3.19-3.12(m,4H),2.89-2.62(m,2H),2.15(s,3H),1.74-1.52(m,6H).
將標題化合物(100mg)溶於異丙醇(2.5ml)中及藉由製備型HPLC在手性相(參見實施例2及3)[管柱:Daicel Chiralpak ID,5μm,250mm x 20mm;流速:20ml/min;注入:0.06ml;溶析液:30%異丙醇/70%庚烷;操作時間15min,等度]上分離為對映異構物。將合併之目標級分濃縮及將殘餘物冷凍乾燥。接著藉由製備型HPLC在非手性相(乙腈/水梯度)上再純化。將殘餘物再次冷凍乾燥。
在實施例1中所述的對映異構體分離中,獲得29mg(ee 99%)預純化的標題化合物作為較早洗脫的對映異構體。隨後通過製備型HPLC(方法9)進行再純化。將合併的目標級分濃縮並將殘餘物溶於二氯甲烷中並用飽和碳酸氫鈉水溶液洗滌。有機相用硫酸鈉乾燥,過濾並濃縮,殘餘物冷凍乾燥。得到13mg(98%純度,理論值的13%)的再純化標題化合物。
[α]D 20=-16.9°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.61),-0.008(16.00),0.008(13.21),0.146(1.69),0.959(0.44),1.040(0.73),1.235(2.64),1.374(0.95),1.607(3.23),1.673(6.17),2.150(9.39),2.327(2.50),2.366(2.57),2.518(10.06),2.523(8.00),2.670(3.23),2.674(2.50),2.710(3.38),2.777(1.25),3.140(7.93),3.510(1.54),3.689(1.03),3.819(0.81),4.076(1.39),7.193(1.47),7.216(1.17),7.317(5.06),7.624(1.91),7.646(8.22),7.657(5.28),7.661(4.70),7.684(1.25),8.900(0.73).
在實施例1中描述的對映異構體分離中,獲得26mg(ee 96%)預純化標題化合物作為稍後洗脫的對映異構體。隨後通過製備型HPLC(方法9)進行再純化。將合併的目標級分濃縮並將殘餘物溶於二氯甲烷中並用飽和碳酸氫鈉水溶液洗滌。有機相用硫酸鈉乾燥,過濾並濃縮,殘餘物冷凍乾燥。獲得12mg(純度98%,理論值的12%)的再純化標題化合物。
[α]D 20=+15.6°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法1):Rt=2.13min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(1.51),-0.008(16.00),0.008(12.20),0.146(1.58),1.234(2.73),1.372(1.87),1.610(1.72),1.669(3.23),2.149(5.60),2.327(3.01),2.366(2.65),2.523(10.48),2.669(3.23),2.709(3.30),2.799(1.00),3.139(4.23),3.509(0.93),3.707(0.86),4.084(0.86),7.198(1.08),7.321(3.01),7.625(1.22),7.647(4.74),7.658(3.09),7.663(2.58),7.680(1.00),8.842(0.57).
(+/-)-4-[({6-溴-3-甲基-2-[(2-苯乙基)胺基]喹啉-4-基}羰基)胺基]-3-(2-氯-6-氟苯基)丁酸三級丁酯(150mg,229μmol,外消旋物,實施例54A)在二氯甲烷(2.2ml)的溶液中加入TFA(350μl,4.6mmol),並將混合物 在室溫下攪拌16小時。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈中並通過製備型HPLC(方法9)純化。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到55mg(98%純度,理論值的39%)標題化合物。
LC-MS(方法2):Rt=0.92min;MS(ESIpos):m/z=598/600[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.23(br.s,1H),8.88(br.s,1H),8.02-7.06(m,11H),4.07(br.s,部分隱藏,1H),3.93-3.63(m,部分隱蔽,4H),3.04-2.90(m,2H),2.88-2.68(m,2H),2.11-1.83(m,3H).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(90mg,98%純度,139μmol,外消旋物,實施例55A)在二氯甲烷(990μl)的溶液中加入TFA(210μl,2.8mmol),並將混合物在室溫下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物通過製備型HPLC(方法9)純化。濃縮合併的目標級分,將殘餘物與乙酸乙酯和飽和碳酸氫鈉水溶液(各20ml)混合及攪拌。相分離後,水相用乙酸乙酯萃取兩次(每次20ml)。合併的有機相用硫酸鈉乾燥,過濾並濃縮,殘餘物在減壓下乾燥。得到45mg(98%純度,理論值的55%)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(2.02),1.605(3.36),1.670(6.76), 1.768(0.41),1.782(0.67),1.804(1.37),1.824(1.54),1.835(1.07),1.865(0.45),1.899(0.47),2.020(1.25),2.041(2.87),2.068(2.26),2.080(2.13),2.090(2.63),2.101(1.69),2.128(16.00),2.160(1.18),2.176(0.61),2.689(0.94),2.731(0.90),2.890(1.03),3.132(8.80),3.585(1.45),3.689(3.38),7.124(1.14),7.144(2.04),7.159(1.20),7.165(1.14),7.385(2.26),7.392(2.36),7.410(2.44),7.417(2.40),7.484(2.83),7.497(2.85),7.506(2.61),7.519(2.32),7.622(1.58),7.644(8.32),7.651(5.86),7.655(5.07),7.674(1.01),7.678(1.08),8.719(1.55),8.734(2.96),8.747(1.48).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.73(t,1H),7.70-7.60(m,2H),7.50(dd,1H),7.46(br.s,1H,部分隱蔽),7.40(dd,1H),7.14(td,1H),3.78-3.51(m,3H),3.13(br.s,4H),2.20-1.96(m,6H),1.91-1.75(m,1H),1.72-1.52(m,6H).
(-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(230mg,純度98%,356μmol,對映異構物1,實施例56A)的二氯甲烷(2.5ml)溶液中加入TFA(550μl,7.1mmol),並將混合物在RT下攪拌過夜。隨後,再次加入TFA(270μl,3.6mmol),並將混合物在室溫下再攪拌過夜。隨後濃縮混合物,重複加入二氯甲烷,然後再濃縮。殘餘物通過製備型HPLC(方法8)純化。將合併的目標級分濃縮並將殘餘物在減壓下乾燥。得到165mg(理論值98%,理論值99%,理論值的79%)標題化合物。
[α]D 20=-18.7°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.97),0.008(1.54),1.604(2.79),1.670(5.48),1.786(0.53),1.808(1.09),1.829(1.31),1.850(0.77),2.012(0.76),2.023(1.05),2.041(1.18),2.055(2.69),2.082(2.31),2.095(2.27),2.102(2.81),2.128(16.00),2.149(2.04),2.172(0.75),3.132(7.19),3.590(1.09),3.692(2.69),7.119(0.93),7.126(1.05),7.140(1.72),7.147(1.83),7.160(1.06),7.168 (1.05),7.390(2.22),7.397(2.22),7.415(2.32),7.422(2.27),7.457(0.69),7.485(3.00),7.499(2.98),7.508(2.75),7.521(2.53),7.622(1.66),7.644(8.81),7.652(5.93),7.657(5.03),7.674(1.03),7.679(1.13),8.711(1.34),8.726(2.72),8.740(1.29),12.066(0.66).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.07(br.s,1H),8.73(t,1H),7.70-7.60(m,2H),7.50(dd,1H),7.46(br.s,1H,部分隱蔽),7.41(dd,1H),7.14(td,1H),3.74-3.64(m,2H),3.63-3.54(m,1H),3.17-3.09(m,4H),2.20-1.98(m,6H),1.89-1.76(m,1H),1.72-1.55(m,6H).
(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(200mg,98%純度,310μmol,對映異構物2,實施例57A)在二氯甲烷(2.2ml)的溶液中加入TFA(480μl,6.2mmol),並將混合物在RT下攪拌過夜。隨後,再次加入TFA(240μl,3.1mmol),並將混合物在室溫下再攪拌過夜。隨後濃縮混合物,重複加入二氯甲烷,再次濃縮。殘餘物通過製備型HPLC(方法8)純化。將合併的目標級分濃縮並將殘餘物在減壓下乾燥。得到150mg(98%純度,ee 99%,理論值的82%)標題化合物。
[α]D 20=+17.4°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.88),0.008(1.49),1.605(2.71),1.670(5.29),1.786(0.50),1.809(1.07),1.830(1.30),1.850(0.76),2.011(0.75),2.024(0.98),2.042(1.13),2.056(2.63),2.083(2.20),2.097(2.19),2.103(2.78),2.128(16.00),2.150(2.00),2.173(0.74),3.134(6.98),3.591(1.11),3.692(2.69),7.119(0.86),7.127(1.00),7.141(1.66),7.147(1.80),7.161(1.03),7.168(1.04),7.390(2.13),7.398(2.20),7.416(2.28),7.423(2.26),7.486(2.99),7.499(2.96),7.508(2.77),7.521(2.58),7.624(1.61),7.646(8.66),7.654(5.91),7.658(5.11),7.676(1.01),7.681(1.11),8.712(1.32),8.727(2.75),8.741(1.30).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(br.s,1H),8.73(t,1H),7.70-7.61(m,2H),7.50(dd,1H),7.46(br.s,1H,部分隱蔽),7.41(dd,1H),7.14(td,1H),3.75-3.64(m,2H),3.63-3.53(m,1H),3.19-3.08(m,4H),2.21-1.98(m,6H),1.88-1.75(m,1H),1.72-1.52(m,6H).
(+/-)-5-({[6-溴-2-(4,4-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(19mg,72%純度,20.4μmol,外消旋物,實施例58A)在二氯甲烷(140μl)的溶液中加入TFA(32μl,410μmol),並將混合物在RT下攪拌過夜。隨後,再次加入TFA(32μl,410μmol),並將混合物在RT下再攪拌過夜。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC(方法10)純化。將合併的目標級分濃縮並將殘餘物在減壓下乾燥。得到8mg(98%純度,理論值的61%)標題化合物。
LC-MS(方法2):Rt=1.14min;MS(ESIpos):m/z=612/614[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.242(0.50),1.789(0.50),1.811(1.11),1.832(1.34),1.854(0.80),2.012(0.86),2.025(1.09),2.044(1.23),2.058(2.67),2.085(2.29),2.105(3.75),2.119(3.73),2.134(4.47),2.167(16.00),3.302(5.23),3.315(7.55),3.598(1.20),3.702(2.68),4.410(1.45),6.962(0.45),7.090(0.51),7.121(0.84),7.128(0.99),7.148(1.77),7.163(1.04),7.169(1.00),7.218(0.48), 7.398(2.06),7.405(2.18),7.423(2.18),7.430(2.11),7.486(2.77),7.499(2.87),7.508(2.68),7.521(2.39),7.661(1.50),7.684(7.74),7.691(5.10),7.696(4.49),7.714(0.99),7.718(1.05),8.736(1.40),8.750(2.79),8.764(1.38).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.75(t,1H),7.73-7.63(m,2H),7.50(dd,1H),7.46(br.s,1H,隱蔽),7.41(dd,1H),7.15(td,1H),3.70(br.s,2H),3.60(br.s,1H),3.38-3.24(m,4H),2.24-1.97(m,10H),1.89-1.74(m,1H).
(+/-)-5-({[6-溴-3-甲基-2-(嗎啉-4-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(55mg,98%純度,84.9μmol,外消旋物,實施例59A)在二氯甲烷(600μl)的溶液中加入TFA(130μl,1.7mmol)並將混合物在室溫下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。通過製備型HPLC(方法9)純化殘餘物。濃縮合併的目標級分,將殘餘物與乙酸乙酯和飽和碳酸氫鈉水溶液(各20ml)混合併攪拌。相分離後,水相用乙酸乙酯萃取兩次(每次20ml)。合併的有機相用硫酸鈉乾燥,過濾並濃縮,殘餘物在減壓下乾燥。得到37mg(98%純度,理論值的74%)的標題化合物。
LC-MS(方法1):Rt=1.89min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.061(0.65),0.854(0.64),1.175(0.42),1.235(4.42),1.769(0.44),1.783(0.75),1.805(1.56),1.826(1.77),1.837(1.11),1.847(0.98),1.866(0.49),1.988(0.93),2.005(1.13),2.019(1.47),2.045 (3.35),2.072(2.85),2.084(2.55),2.093(3.17),2.105(1.88),2.123(3.22),2.151(16.00),2.690(0.60),2.890(0.46),3.175(11.00),3.184(8.56),3.510(0.50),3.586(1.72),3.696(3.93),3.755(9.55),3.766(12.93),3.777(8.58),7.119(1.16),7.125(1.35),7.140(2.19),7.146(2.28),7.160(1.31),7.167(1.25),7.390(2.73),7.397(2.79),7.415(2.82),7.423(2.73),7.485(3.89),7.499(3.92),7.507(3.56),7.521(3.08),7.659(1.54),7.682(12.34),7.688(7.12),7.706(0.79),7.711(0.94),8.743(1.86),8.757(3.48),8.771(1.67).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.03(br.s,1H),8.76(t,1H),7.73-7.63(m,2H),7.50(dd,1H),7.46(br.s,1H,隱蔽),7.41(dd,1H),7.14(td,1H),3.82-3.64(m,6H),3.59(br.s,1H),3.20-3.12(m,4H),2.21-1.95(m,6H),1.88-1.75(m,1H).
(+/-)-5-({[6-溴-2-(3,6-二氫吡啶-1(2H)-基)-3-甲基喹啉-4-基]羰基胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(50mg,79.2μmol,外消旋物,實施例60A)在二氯甲烷(580μl)的溶液中加入TFA(61μl,790μmol),並將該混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮並將殘餘物冷凍乾燥。得到25mg(98%純度,理論值的53%)標題化合物。
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=574/576[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.369(0.42),1.787(0.60),1.809(1.26),1.829(1.41),1.841(0.94),1.870(0.43),1.989(0.41),2.010(0.86),2.027(1.19),2.046(2.98),2.073(2.55),2.085(2.25),2.093(2.89),2.106(1.49),2.124(2.93),2.141(16.00),2.163(1.30),2.180(0.59),2.304(2.87),3.275(3.32),3.309(3.34),3.590(1.31),3.795(5.16),5.817(0.94),5.843(3.17),5.863(2.80),5.889(0.85),7.117(0.97),7.124(1.11),7.139(1.80),7.145(1.90),7.159(1.09),7.166(1.06),7.390(2.34),7.398(2.37),7.416(2.44),7.423(2.38),7.484(3.06),7.497(3.07),7.506(2.86),7.519(2.63),7.617(2.21),7.639(8.00),7.653(5.10),7.658(4.43),7.675(1.38),7.680(1.36),8.731(1.43),8.745(2.71),8.759(1.30).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.15(br.s,1H),8.75(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.46(br.s,1H,部分隱蔽),7.41(dd,1H),7.14(td,1H),5.92-5.79(m,2H),3.80(br.s,2H),3.75-3.65(m,2H),3.59(br.s,1H),3.35-3.22(隱蔽,2H),2.30(br.s,2H),2.22-1.96(m,6H),1.90-1.73(m,1H).
(+/-)-5-({[6-溴-3-甲基-2-(硫代嗎啉-4-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(55mg,84.5μmol,外消旋物,實施例61A)在二氯甲烷(620μl)之溶液中加入TFA(65μl,840μmol),並將混合物在 RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮並將殘餘物冷凍乾燥。得到41mg(98%純度,理論值的80%)標題化合物。
LC-MS(方法2):Rt=1.10min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.05),0.008(0.98),1.788(0.49),1.810(1.08),1.820(0.71),1.831(1.32),1.852(0.79),2.011(0.78),2.024(1.04),2.042(1.18),2.056(2.70),2.074(0.77),2.083(2.28),2.097(2.36),2.103(2.82),2.131(16.00),2.149(2.40),2.172(0.86),2.189(0.44),2.523(0.52),2.775(6.19),2.787(7.27),2.798(6.78),3.413(6.57),3.419(6.69),3.426(7.12),3.436(6.16),3.590(1.20),3.695(2.52),7.120(0.86),7.127(1.01),7.141(1.67),7.147(1.76),7.161(1.04),7.169(1.00),7.393(2.19),7.401(2.24),7.418(2.29),7.426(2.20),7.485(3.17),7.499(3.20),7.507(2.93),7.521(2.65),7.656(1.27),7.678(9.12),7.683(6.85),7.687(5.30),7.705(0.85),7.709(0.91),8.720(1.43),8.734(2.85),8.748(1.36),12.055(0.73).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(br.s,1H),8.73(t,1H),7.73-7.63(m,2H),7.50(dd,1H),7.46(br.s,1H,部分隱蔽),7.41(dd,1H),7.14(td,1H),3.69(br.s,2H),3.59(br.s,1H),3.46-3.39(m,4H),2.83-2.75(m,4H),2.21-1.97(m,6H),1.89-1.75(m,1H).
(+/-)-5-[({6-溴-2-[順式-2,6-二甲基嗎啉-4-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(70mg,106μmol,外消旋物,實施例62A)在二氯甲烷之眾溶液中加入TFA(81μl,1.1mmol),並將混合物在RT攪拌2天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮並將殘餘物冷凍乾燥。得到47mg(98%純度,理論值的71%)標題化合物。
LC-MS(方法2):Rt=1.10min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.134(16.00),1.149(15.70),1.793(0.43),1.814(0.86),1.835(1.00),1.856(0.57),2.013(0.68),2.026(0.87),2.045(1.01),2.057(2.01),2.084(1.82),2.098(1.82),2.104(2.14),2.119(1.55),2.132(2.14),2.157(11.42),2.190(0.41),2.469(1.68),3.431(2.87),3.462(2.59),3.589(0.93),3.693(1.77),3.756(1.66),3.776(2.04),7.120(0.71),7.127(0.80),7.142(1.27),7.148(1.30),7.162(0.75),7.169(0.70),7.391(1.65),7.398(1.65),7.416(1.69),7.423(1.58),7.486(2.10),7.499(2.07),7.508(1.83),7.521(1.63),7.655(0.55),7.676(9.58),8.710(1.15),8.725(2.08),8.739(0.98),12.063(4.18).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(s,1H),8.72(t,1H),7.72-7.63(m,2H),7.50(dd,1H),7.47(br.s,1H,部分隱蔽),7.41(dd,1H),7.14(td,1H),3.84-3.53(m,5H),3.45(br.d,2H),2.53-2.45(隱蔽,2H),2.21-1.97(m,6H),1.91-1.75(m,1H),1.15(s,3H),1.13(s,3H).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2氯-5-氟苯基)戊酸三級丁酯(63mg,102μmol,外消旋物,實施例63A)在二氯甲烷(750μl)的溶液中加入TFA(78μl,1.0mmol)並將混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到36mg(98%純度,理論值的62%)標題化合物。
LC-MS(方法2):Rt=0.77min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(br.s,1H),8.68(t,1H),7.59-7.53(m,1H),7.50(dd,2H),7.40(dd,1H),7.35(br.s,部分隱蔽),7.14(td,1H),3.68(br.s,2H),3.57(br.s,5H),2.26-1.97(m,6H),1.94-1.74(m,5H).
(+/-)-5-({[6-溴-3-甲基-2-(1,2-唑基-2-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(35mg,56.4μmol,外消旋物,實施例64A)在二氯甲烷(410μl)的溶液中加入TFA(43μl,560μmol),並將混合物在RT攪拌兩天。然後濃縮混合物並重複加入二氯甲烷,並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到24mg(95%純度,理論值的72%)標題化合物。
LC-MS(方法2):Rt=0.96min;MS(ESIpos):m/z=564/566[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.04),0.008(0.83),1.134(1.33),1.150(1.34),1.788(0.58),1.810(1.36),1.820(0.87),1.831(1.64),1.853(1.06),1.873(0.44),1.989(0.45),2.010(0.97),2.023(1.32),2.041(1.43),2.057(3.36),2.073(2.58),2.085(2.55),2.098(2.36),2.106(2.63),2.120(1.78),2.134(2.29),2.138(2.23),2.156(2.79),2.179(1.33),2.209(10.75),2.242(4.23),2.260(5.79),2.278(4.24),2.296(1.31),2.523(0.63),3.432(0.53),3.463(0.64),3.658(0.84),3.693(2.87),3.706(3.75),3.777(2.81),3.825(4.26),3.844(7.14),3.862(3.86),7.121(0.95),7.128(1.11),7.142(1.89),7.149(1.96),7.163(1.16),7.170(1.12),7.394(2.57),7.401(2.60),7.419(2.65),7.426(2.51),7.489(3.30),7.502(3.52),7.511(3.35),7.525(3.11),7.677(0.86),7.712(0.64),7.733(16.00),7.759(0.50),8.775(1.61),8.790(3.19),8.804(1.53).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.79(t,1H),7.78-7.70(m,2H),7.51(dd,1H),7.46(br.s,1H,隱蔽),7.41(dd,1H),7.15(td,1H),3.84(t,2H),3.78(br.s,2H),3.74-3.67(m,2H),3.65-3.55(m,1H),2.32-1.95(m,8H),1.90-1.74(m,1H).
(+/-)-5-({[6-溴-2-(2,5-二氫-1H-吡咯-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)戊酸三級丁酯(32mg,51.9μmol,外消旋物,實施例65A)在二氯甲烷(380μl)中的溶液中加入TFA(40μl,520μmol),並將混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到20mg(90%純度,理論值的61%)標題化合物。
LC-MS(方法2):Rt=0.87min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.773(0.50),1.787(0.88),1.808(1.83),1.819(1.42),1.829(2.14),1.840(1.55),1.851(1.30),1.870(0.65),2.026(1.76),2.048(4.09),2.075(3.34),2.087(3.15),2.097(3.64),2.108(2.21),2.128(2.86),2.145(2.35),2.169(1.45),2.188(2.40),2.247(7.74),2.324(0.57),3.586(1.76),3.677(2.88),4.527(3.34),5.964(16.00),6.305(1.64),6.311(2.40),6.316(1.56),7.141(2.44),7.256(1.95),7.262(2.79),7.267(1.88),7.384(3.11),7.391(3.20),7.409(3.34),7.416(3.32),7.439(0.90),7.446(0.82),7.474(5.90),7.479(3.94),7.496(10.52),7.501(4.70),7.515(3.18),7.525(0.90),7.553(4.95),7.558(4.50),7.575(2.94),7.580(2.80),7.880(3.13),8.688(1.91),8.702(3.51),8.716(1.74),8.886(0.68).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.09(br.s,1H),8.70(t,1H),7.56(dd,1H),7.53-7.46(m,2H),7.46(寬,隱蔽,1H),7.40(dd,1H),7.18-7.10(m,1H),5.96(s,2H),4.53(br.s,4H),3.78-3.53(m,3H),2.29-1.97(m,6H),1.88-1.72(m,1H).
5-[({6-溴-2-[3-羥基吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(60mg,94.5μmol,非對映異構物混合物,實施例66A)在二氯甲烷(690μl)的溶液中加入TFA(73μl,940μmol),並將混合物在RT攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到50mg(98%純度,理論值的90%)標題化合物。
LC-MS(方法2):Rt=0.69min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.27),0.008(1.10),1.772(0.54),1.786(0.97),1.808(2.80),1.830(3.88),1.850(3.12),1.920(1.78),1.938(1.54),1.988(0.75),2.023(1.72),2.040(1.99),2.053(4.47),2.081(3.66),2.094(3.39),2.102(4.12),2.115(3.02),2.147(16.00),2.171(1.97),2.189(1.08),2.327(0.57),2.523(1.83),2.669(0.59),2.710(0.40),3.356(2.29),3.569(2.21),3.667(3.45),3.678(3.50),3.782(2.75),4.331(3.12),4.898(3.56),4.905(5.60),4.912(3.39),7.130(2.10),7.138(2.24),7.149(2.13),7.262(0.51),7.381(2.88),7.388(3.99),7.406(2.94),7.414(3.80),7.466(5.93),7.480(3.91),7.488(11.07),7.500(3.34),7.514(3.02),7.544(5.14),7.566(2.99),8.699(3.26),12.057(4.53).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(br.s,1H),8.70(br.t,1H),7.58-7.53(m,1H),7.52-7.45(m,2H),7.40(br.dt,1H),7.34(br.s,部分隱蔽, 1H),7.19-7.09(m,1H),4.91(t,1H),4.33(br.s,1H),3.88-3.47(m,7H),2.19-1.78(m,9H).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(75mg,116μmol,非對映異構物混合物,實施例67A)在二氯甲烷(850μl)的溶液中加入TFA(89μl,1.2mmol),並將混合物在RT攪拌兩天。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法12)純化。將合併的目標級分濃縮並將殘餘物與乙酸乙酯和飽和碳酸氫鈉水溶液(各10ml)混合並攪拌。相分離後,將水相用乙酸乙酯萃取兩次(每次10ml)。將合併的有機相用硫酸鈉乾燥、過濾並濃縮,並將殘餘物冷凍乾燥。得到57mg(98%純度,理論值的82%)標題化合物。
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=590/592[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.022(0.66),-0.008(1.50),0.008(1.14),0.920(8.53),0.936(8.61),0.963(0.41),1.077(0.96),1.099(1.00),1.127(0.40),1.233(1.61),1.627(0.77),1.650(0.89),1.729(1.77),1.767(1.86),1.783(2.28),1.791(2.42),1.801(2.33),1.823(2.39),2.001(0.74),2.015(1.13),2.034(2.73),2.048(0.97),2.060(2.13),2.072(1.97),2.083(2.19),2.093(1.23),2.115(2.53),2.131(16.00),2.153(1.13),2.169(0.45),2.417(0.53),2.458(0.99),2.523(0.79),2.670(0.67),2.696(0.88),2.710(1.15),3.432(1.94),3.459(2.87),3.487 (1.47),3.579(1.20),3.686(2.45),7.116(0.84),7.123(0.97),7.137(1.62),7.144(1.72),7.158(0.99),7.165(0.98),7.381(2.07),7.389(2.10),7.407(2.19),7.414(2.11),7.456(0.62),7.482(2.69),7.495(2.67),7.504(2.47),7.517(2.35),7.624(0.93),7.647(9.27),7.654(5.14),7.672(0.63),7.676(0.73),8.719(1.20),8.733(2.27),8.746(1.13).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.26(br.s,1H),8.73(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.46(br.s,部分隱蔽,1H),7.40(dd,1H),7.14(td,1H),3.76-3.40(m,5H),2.80-2.61(m,1H),2.48-2.34(m,1H),2.20-1.95(m,6H),1.88-1.55(m,5H),1.17-1.01(m,1H),0.93(d,3H).
(+/-)-5-({[6-溴-3-甲基-2-(4-甲基哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-5-氟苯基)羧酸三級丁酯(70mg,108μmol,外消旋物,實施例68A)在二氯甲烷(790μl)中的溶液中加入TFA(83μl,1.1μmol),並將混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法12)純化。濃縮合併的目標級分,將殘餘物與乙酸乙酯和飽和碳酸氫鈉水溶液(各10ml)混合並攪拌。相分離後,將水相用乙酸乙酯萃取兩次(每次10ml)。將合併的有機相用硫酸鈉乾燥、過濾並濃縮,並將殘餘物冷凍乾燥。得到35mg(98%純度,理論值的53%)標題化合物。
LC-MS(方法1):Rt=2.33min;MS(ESIpos):m/z=590/592[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.964(10.37),0.980(10.93),1.233(0.56),1.256(0.68),1.286(1.96),1.315(2.22),1.345(0.95),1.552(0.89),1.562(1.05),1.578(0.95),1.588(0.80),1.718(2.85),1.746(2.59),1.780(0.68),1.802(1.29),1.821(1.41),1.833(0.90),1.844(0.79),1.863(0.41),2.001(0.79),2.017(1.16),2.036(3.01),2.063(2.22),2.075(2.05),2.086(2.34),2.097(1.62),2.119(16.00),2.156(0.97),2.173(0.46),2.730(1.03),2.759(2.00),2.774(2.10),2.802(1.10),3.302(2.59),3.314(2.67),3.508(3.25),3.540(3.16),3.580(1.37),3.688(2.97),7.116(0.92),7.123(1.05),7.137(1.77),7.144(1.90),7.157(1.08),7.165(1.08),7.383(2.21),7.390(2.26),7.408(2.34),7.415(2.30),7.457(0.72),7.482(2.87),7.495(2.84),7.504(2.61),7.517(2.39),7.617(1.88),7.639(8.36),7.648(5.27),7.653(4.59),7.671(1.10),7.676(1.17),8.719(1.41),8.734(2.79),8.748(1.35).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.16(br.s,1H),8.73(t,1H),7.69-7.61(m,2H),7.50(dd,1H),7.46(br.s,部分隱蔽,1H),7.40(dd,1H),7.14(td,1H),3.74-3.48(m,5H),2.82-2.69(m,2H),2.19-1.96(m,6H),1.88-1.67(m,3H),1.63-1.50(m,1H),1.38-1.19(m,2H),0.97(d,3H).
5-[({6-溴-2-[3-甲氧基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(65mg,98.0μmol,非對映異構物混合物,實 施例69A)在二氯甲烷(720μl)的溶液中加入TFA(76μl,980μmol),將混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再濃縮。將殘餘物溶於乙腈中並通過製備型HPLC(方法12)純化。濃縮合併的目標級分,並將沉澱物與乙酸乙酯和飽和碳酸氫鈉水溶液(各10ml)混合並攪拌。相分離後,將水相用乙酸乙酯萃取兩次(每次10ml)。將合併的有機相用硫酸鈉乾燥、過濾並濃縮,並將殘餘物冷凍乾燥。得到35mg(98%純度,理論值的57%)標題化合物。
LC-MS(方法1):Rt=2.04min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.400(0.45),1.806(0.89),1.817(0.65),1.828(0.90),2.020(0.80),2.048(1.24),2.076(0.89),2.089(0.77),2.097(1.04),2.131(6.49),2.732(0.44),2.845(0.41),2.861(0.42),3.301(16.00),3.313(7.33),3.425(0.66),3.434(0.65),3.588(1.07),3.616(0.82),3.694(1.18),7.123(0.42),7.138(0.70),7.144(0.75),7.158(0.43),7.165(0.42),7.390(0.84),7.398(0.87),7.416(0.89),7.423(0.87),7.481(1.16),7.495(1.15),7.503(1.03),7.517(0.93),7.633(0.58),7.656(3.28),7.662(2.19),7.667(1.89),8.714(0.52),8.727(1.00),8.741(0.50).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.09(br.s,1H),8.73(t,1H),7.70-7.62(m,2H),7.50(dd,1H),7.46(br.s,部分隱蔽,1H),7.41(dd,1H),7.14(td,1H),3.75-3.66(m,2H),3.65-3.54(m,2H),3.47-3.39(m,1H),3.30(s,部分隱蔽,3H),2.93-2.80(m,1H),2.78-2.65(m,1H),2.18-1.96(m,7H),1.89-1.75(m,2H),1.66-1.51(m,1H),1.46-1.32(m,1H).
5-[({6-溴-2-[2-(羥基甲基)嗎福啉-4-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(35mg,52.6μmol,非對映異構物混合物,實施例70A)在二氯甲烷(390μl)的溶液中加入TFA(41μl,530μmol),並將混合物在室溫下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再濃縮。將殘餘物溶於乙腈中並通過製備型HPLC(方法12)純化。濃縮合併的目標級分,並將沉澱物與乙酸乙酯和飽和碳酸氫鈉水溶液(各10ml)混合並攪拌。相分離後,將水相用乙酸乙酯萃取兩次(每次10ml)。將合併的有機相用硫酸鈉乾燥,過濾並濃縮,並將殘餘物冷凍乾燥。得到26mg(98%純度,理論值的78%)標題化合物。
LC-MS(方法1):Rt=1.67min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.788(0.65),1.810(1.36),1.831(1.64),1.852(0.96),1.871(0.44),1.991(0.46),2.011(0.97),2.024(1.28),2.042(1.48),2.055(3.21),2.082(2.67),2.095(2.49),2.102(3.16),2.116(1.97),2.131(3.02),2.157(16.00),2.189(0.75),2.643(0.63),2.670(1.36),2.691(1.24),2.710(0.74),2.717(0.78),2.891(1.17),2.921(0.67),3.385(3.18),3.415(3.71),3.428(2.50),3.490(2.32),3.502(3.16),3.517(3.57),3.529(2.32),3.551(2.26),3.605(2.21),3.619(2.39),3.644(1.89),3.659(1.32),3.688(3.34),3.710(4.45),3.739(1.84),3.909(2.58),3.936(2.02),4.762(0.56),7.120(1.03),7.126(1.19),7.141(2.03),7.147(2.14),7.161(1.24),7.168(1.20),7.394(2.43),7.401(2.44),7.419(2.54),7.426(2.41),7.486(3.59),7.499(3.61),7.508(3.33),7.521(2.98),7.661(0.94),7.683(14.87),7.706(0.58),7.710(0.70),8.743(1.59),8.756(2.91),8.770(1.45).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.07(br.s,1H),8.76(t,1H), 7.72-7.64(m,2H),7.50(dd,1H),7.47(br.s,部分隱蔽,1H),7.41(dd,1H),7.14(td,1H),4.76(br.s,1H),3.92(br.d,1H),3.78-3.36(m,9H),2.97-2.80(m,1H),2.77-2.60(m,1H),2.21-1.95(m,6H),1.90-1.71(m,1H).
5-[({6-溴-2-[3-(羥基甲基)哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-5-氟苯基)戊酸三級丁酯(63mg,95.0μmol,非對映異構物混合物,實施例71A)在二氯甲烷(700μl)的溶液中加入TFA(73μl,950μmol),並將混合物在RT下攪拌兩天。然後濃縮混合物並重複加入二氯甲烷並將混合物再濃縮。將殘餘物溶於乙腈中並通過製備型HPLC(方法12)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到20mg(98%純度,理論值的34%)標題化合物。
LC-MS(方法1):Rt=1.80min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.089(0.50),1.117(1.29),1.140(1.38),1.622(1.10),1.648(1.20),1.676(0.84),1.746(5.89),1.773(5.29),1.812(1.66),1.833(1.70),1.857(2.04),1.871(1.27),1.885(1.70),1.904(1.40),1.917(1.31),1.924(1.32),1.959(0.47),2.151(16.00),2.566(0.62),2.723(1.19),2.747(1.22),2.776(0.57),3.336(11.62),3.450(2.50),3.481(3.01),7.083(1.12),7.090(1.27),7.105(2.10),7.111(2.23),7.125(1.26),7.132(1.23),7.298(2.44),7.305(2.40),7.323(2.44),7.330(2.25),7.458(3.55),7.471(3.44),7.479(3.00),7.493(2.57),7.621(1.06),7.643(11.76),7.672(0.74),8.997(1.74).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:9.00(br.s,1H),7.69-7.60(m,1H),7.48(dd,1H),7.43(br.s,部分隱蔽,1H),7.31(dd,1H),7.11(td,1H),4.63(br.s,1H),3.74-3.18(m,部分隱蔽,8H),2.82-2.62(m,1H),2.15(s,3H),1.99-1.55(m,8H),1.21-1.04(m,1H).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(100mg,163μmol,外消旋物,實施例72A)在二氯甲烷(2.9ml)的溶液中加入TFA(130μl,1.6mmol),在RT下攪拌混合物66小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮。將殘餘物重複加入二氯甲烷處理並再次濃縮,然後減壓乾燥。得到62mg(100%純度,理論值的68%)標題化合物。
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.58),-0.008(7.08),0.008(4.63),0.146(0.60),1.235(0.47),1.370(2.53),1.605(4.27),1.670(8.18),1.793(0.89),1.811(1.74),1.834(2.19),1.857(1.16),2.045(4.22),2.081(5.18),2.089(5.36),2.103(3.13),2.130(16.00),2.159(1.61),2.327(0.92),2.366(0.92),2.518(4.78),2.523(4.22),2.669(1.05),2.710(0.87),3.119(8.34),3.132(10.53),3.591(1.94),3.674(3.53),5.754(4.60),7.257(1.83),7.275(3.80),7.291(2.79),7.295(2.66),7.356(2.55),7.373(4.60),7.391(2.66),7.441(6.50),7.444(6.06),7.461 (5.90),7.464(5.52),7.479(5.92),7.482(5.83),7.498(4.36),7.622(2.73),7.643(12.72),7.651(9.12),7.656(7.69),7.673(1.72),7.678(1.77),8.707(2.17),8.722(4.09),8.736(1.92),12.039(6.06).
(-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(70mg,114μmol,對映異構物1,實施例73A)在二氯甲烷(2.0ml)溶液中加入TFA(88μl,1.1mmol),並將混合物在室溫下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到48mg(98%純度,ee 99%,理論值的73%)標題化合物。
[α]D 20=-17.0°,589nm,c=0.27g/100ml,甲醇
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.060(0.99),-0.008(2.24),0.008(1.64),0.084(0.74),1.607(4.12),1.672(7.98),1.782(0.53),1.793(0.79),1.812(1.62),1.835(2.14),1.858(1.17),2.014(0.51),2.035(1.18),2.046(4.07),2.073(4.15),2.082(4.75),2.089(5.01),2.103(2.60),2.132(16.00),2.159(1.48),2.327(0.44),2.366(0.43),2.523(1.22),2.670(0.41),3.143(10,38),3.595(3.12),3.620(2.84),3.676(7.44),3.690(7.13),7.257(1.62),7.275(3.74),7.292(2.72),7.295(2.61),7.356(2.25),7.374(4.12),7.392(2.14),7.441(5.77),7.444(5.50),7.461(5.08),7.464(4.86),7.480(5.49),7.482(5.54),7.499(4.21),7.630(2.09),7.652(11.83),7.658(8.30),7.663(7.08),7.680(1.37),7.685(1.52),8.712(2.04),8.726(4.16),8.740(2.01).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.02(br.s,1H),8.73(t,1H),7.71-7.62(m,2H),7.54-7.42(m,3H),7.37(t,1H),7.31-7.24(m,1H),3.95-3.45(m,3H,部分隱蔽),3.19-3.08(m,4H),2.20-2.01(m,6H),1.95-1.73(m,1H),1.72-1.49(m,6H).
(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(70mg,114μmol,對映異構物2,實施例74A)在二氯甲烷(2.0ml)之溶液中加入TFA(88μl,1.1mmol),並將混合物在RT攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到43mg(98%純度,理論值96%,理論值的66%)標題化合物。
[α]D 20=+8.1°,589nm,c=0.26g/100ml,甲醇
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.47),-0.008(3.94),0.008(4.07),0.146(0.50),1.606(3.77),1.671(7.49),1.793(0.66),1.810(1.47),1.834(2.05),1.857(1.10),2.024(0.78),2.044(3.30),2.077(4.23),2.086(4.55),2.094(2.58),2.131(16.00),2.155(1.53),2.327(0.52),2.366(0.40),2.523(1.73),2.670(0.61),2.710(0.46),3.133(9.79),3.591(1.72),3.674(3.17),3.687(2.47),7.256(1.53),7.274(3.55),7.291(2.47),7.294(2.51),7.355(2.17),7.374(3.95),7.392(2.04),7.441(5.56),7.444(5.59),7.461(4.94),7.464(4.94),7.481(5.29),7.497(3.95),7.622(2.32),7.644(12.05),7.651(8.27),7.656(7.28),7.673(1.50),7.678(1.62),8.712(1.84),8.726(3.79),8.740(1.84).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.73(t,1H),7.69-7.61(m,2H),7.53-7.42(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.76-3.62(m,2H),3.62-3.53(m,1H),3.20-3.06(m,4H),2.20-1.98(m,6H),1.90-1.75(m,1H),1.72-1.50(m,6H).
(+)-5-({[6-溴-3-甲基-2-(硫代嗎福啉-4-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(70mg,111μmol,外消旋物,實施例75A)在二氯甲烷(810μl)的溶液中加入TFA(85μl,1.1mmol),並將混合物在RT過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到58mg(98%純度,理論值的89%)標題化合物。
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.022(0.68),1.004(2.17),1.234(1.54),1.394(0.86),1.809(1.65),1.831(2.44),1.854(1.44),2.037(3.90),2.064(5.65),2.072(5.19),2.085(3.39),2.095(2.40),2.134(16.00),2.196(0.47),2.327(0.57),2.670(0.65),2.710(0.50),2.787(11.08),2.798(10.38),2.864(0.71),3.045(0.42),3.414(11.05),3.425(11.71),3.584(2.28),3.676(3.53),7.255(1.81),7.273(4.16),7.293(2.93),7.353(2.45),7.372(4.50),7.391(2.36),7.442(6.27),7.462(5.42),7.478(5.58),7.495(4.58),7.655(2.31),7.677(13.29),7.681(10.73),7.686(8.04),7.704(1.13),7.708(1.41),8.732(2.04),8.745(3.71),8.759(1.92).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.01(br.s,1H),8.75(t,1H),7.73-7.64(m,2H),7.58-7.42(m,3H),7.37(t,1H),7.28(t,1H),3.78-3.63(m, 2H),3.62-3.53(m,1H),3.46-3.39(m,4H),2.85-2.74(m,4H),2.22-1.98(m,6H),1.92-1.74(m,1H).
將標題化合物(50mg)溶於甲醇(50ml)中,並通過製備型SFC在手性相上分離成對映異構物(參見實施例26和27)[管柱:Daicel Chiralpak ID,5μm,250mm x 20毫米;流速:70毫升/分鐘;注入:0.40毫升;溶析液:30%甲醇/70%二氧化碳;操作時間7分鐘,等度]。將合併的目標級分濃縮並將殘餘物冷凍乾燥。
在實施例25中所述的對映異構物分離中,獲得8mg(98%純度,ee99%)標題化合物,為先前洗脫的對映異構物。
[α]D 20=+8.9°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=2.08min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.02),0.068(1.62),0.146(1.00),0.940(0.50),0.955(0.52),1.139(0.50),1.157(0.52),1.811(1.54),1.835(2.04),1.857(1.14),2.042(3.63),2.076(4.73),2.083(5.00),2.133(16.00),2.327(1.22),2.366(1.12),2.402(0.95),2.669(1.42),2.710(1.29),2.788(10.55),3.425(10.48),3.587(1.94),3.677(3.31),7.256(1.72),7.275(3.73),7.294(2.66),7.355(2.26),7.374(4.08),7.391(2.24),7.443(5.60),7.463(4.80),7.481(5.08),7.499(4.23),7.655(1.74),7.677(11.84),7.686(7.42),7.709(1.39),8.720(1.84),8.735(3.66),8.749(1.97),12.054(0.80).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.74(t,1H),7.74-7.62(m,2H),7.58-7.42(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.76-3.63(m,2H),3.62-3.54(m,1H),3.47-3.38(m,4H),2.83-2.74(m,4H),2.19-1.99(m,6H),1.89-1.76(m,1H).
在實施例25中所述的對映異構物分離中,獲得8mg(98%純度,ee 93%)標題化合物,作為稍後洗脫的對映異構物。
[α]D 20=-6.4°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法1):Rt=2.08min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.15),0.008(8.73),0.069(2.56),0.146(1.10),1.812(1.58),1.834(2.06),1.859(1.15),2.043(3.66),2.083(5.02),2.133(16.00),2.328(1.39),2.366(0.98),2.523(6.60),2.670(1.39),2.709(1.15),2.786(10.64),3.425(10.43),3.588(2.08),3.677(3.35),7.256(1.77),7.274(3.85),7.292(2.63),7.354(2.37),7.374(4.14),7.391(2.20),7.441(6.07),7.461(5.33),7.481(5.14),7.498(4.21),7.655(2.20),7.677(13.30),7.686(7.49),7.709(1.43),8.734(3.56),12.050(0.84).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.73(t,1H),7.73-7.63(m,2H),7.59-7.41(m,3H),7.37(t,1H),7.31-7.22(m,1H),3.76-3.63(m,2H),3.62-3.53(m,1H),3.47-3.38(m,4H),2.83-2.73(m,4H),2.18-1.98(m,6H),1.89-1.74(m,1H).
(+/-)-5-({[6-溴-2-(4,4-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(28mg,43.0μmol,外消旋物,實施例76A)在二氯甲烷(320μl)的溶液中加入TFA(33μl,430μmol),在室溫攪拌混合物過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到6mg(98%純度,理論值的23%)標題化合物。
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.57),-0.008(8.43),0.008(4.79),0.146(0.52),1.234(0.75),1.810(1.45),1.831(1.86),1.854(1.14),2.034(3.35),2.062(5.16),2.093(2.83),2.118(5.33),2.170(16.00),2.327(1.03),2.366(0.89),2.523(6.12),2.669(0.98),2.710(0.58),3.586(1.93),3.681(3.12),7.255(1.54),7.272(3.22),7.290(2.24),7.355(2.13),7.373(3.61),7.391(1.95),7.440(5.04),7.459(4.37),7.481(4.37),7.499(3.62),7.658(2.37),7.680(10.19),7.688(6.97),7.693(5.96),7.710(1.28),7.715(1.33),8.771(2.79).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.14(br.s,1H),8.77(t,1H),7.74-7.62(m,2H),7.59-7.41(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.76-3.62(m,2H),3.62-3.53(m,1H),2.24-1.97(m,11H),1.89-1.75(m,1H).
(+/-)-5-({[6-溴-2-(3,6-二氫吡啶-1(2H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(80mg,131μmol,外消旋物,實施例77A)在二氯甲烷(960μl)之溶液中加入TFA(100μl,1.3mmol),並將混合物在RT下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到65mg(98%純度,理論值的88%)標題化合物。
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=556/558[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.195(1.62),1.211(1.64),1.233(0.51),1.242(0.74),1.257(0.81),1.272(0.44),1.800(0.79),1.819(1.67),1.842(2.17),1.865(1.23),2.052(3.96),2.086(5.33),2.093(5.55),2.143(16.00),2.303(4.60),3.271(3.84),3.596(2.12),3.680(3.38),3.796(7.68),5.818(1.47),5.844(4.74),5.863(4.13),5.889(1.26),7.256(1.75),7.274(3.79),7.293(2.71),7.357(2.33),7.376(4.04),7.394(2.21),7.442(5.66),7.462(5.13),7.484(5.68),7.502(4.18),7.618(2.71),7.640(9.36),7.653(6.42),7.657(5.51),7.675(1.77),7.680(1.64),8.721(2.17),8.735(3.91),8.748(1.96),12.047(4.68).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(s,1H),8.73(t,1H),7.70-7.60(m,2H),7.57-7.41(m,3H),7.37(t,1H),7.28(t,1H),5.93-5.79(m,2H),3.80(br.s,2H),3.73-3.63(m,2H),3.63-3.54(m,1H),3.27(br.s,2H,部分隱蔽),2.30(br.s,2H),2.19-1.99(m,6H),1.91-1.72(m,1H).
在超音波浴中將標題化合物(60mg)溶於異丙醇(3ml)、庚烷(2ml)和乙 腈(1ml)的混合物中,過濾並通過製備型HPLC在手性相上(見實施例30和31)分離為對映異構物[管柱:Daicel Chiralcel OX-H,5μm,250mm×20mm;流速:15毫升/分鐘;檢測:220nm;溫度:35℃;注入:0.40毫升;溶析液:80%庚烷/20%異丙醇;操作時間16分鐘,等度]。將合併的目標級分濃縮,並將各別的殘餘物在乙腈/水中冷凍乾燥。
在實施例29中描述的對映異構物分離中,預純化的標題化合物作為較早洗脫的對映異構物獲得(ee 99%)。隨後通過製備型HPLC(方法7)進行再純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到22mg(98%純度,理論值的37%)的再純化的標題化合物。
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=556/558[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(1.15),0.145(1.01),1.234(0.91),1.836(2.69),1.859(1.58),2.044(4.28),2.072(6.37),2.143(16.00),2.302(4.72),2.366(1.79),2.669(1.95),2.709(1.62),3.589(2.46),3.677(3.54),3.796(7.65),5.844(4.82),5.863(4.28),7.253(2.12),7.273(4.35),7.291(3.03),7.356(2.86),7.374(4.65),7.392(2.49),7.441(6.91),7.461(6.23),7.481(6.16),7.498(4.58),7.617(3.40),7.639(11.59),7.652(7.07),7.657(6.27),7.674(2.19),8.750(3.57).
在實施例29中描述的對映異構物分離中,預純化的標題化合物作為稍後洗脫的對映異構物(ee 99%)獲得。隨後通過製備HPLC(方法7)進行再純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到11mg(98%純度,理論值的18%)的再純化的標題化合物。
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=556/558[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(2.35),0.146(2.13),0.936(2.03),0.952(2.03),1.234(6.29),1.795(2.13),1.996(4.48),2.154(16.00),2.327(8.96),2.366(4.59),2.670(6.72),2.709(5.01),3.545(3.09),3.661(4.16),3.801(10.77),5.844(6.61),7.260(4.05),7.362(4.27),7.429(6.08),7.450(6.93),7.615(3.84),7.637(14.83),7.650(10.03),8.925(1.71).
(+)-5-({[6-溴-3-甲基-2-(1,2-四氫-2-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(24mg,38.9μmol,外消旋物,實施例78A)在二氯甲烷(1.0ml)之溶液中加入TFA(30μl,390μmol),在室溫攪拌混合物過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到12mg(純度98%,理論值的56%)標題化合物。
LC-MS(方法2):Rt=1.11min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(1.62),1.172(0.42),1.189(0.42),1.696(3.60),1.708(2.94),1.784(0.42),1.795(0.61),1.813(1.31),1.836(1.81),1.868(3.31),1.883(3.96),1.897(2.58),2.046(3.08),2.081(3.58),2.089(3.69),2.141(10.12),3.575(3.73),3.647(0.92),3.667(1.81),3.681(2.72),3.695(1.97),3.723(1.12),4.041(3.52),4.054(5.58),4.066(3.45),7.255(1.27),7.274(2.96),7.293(2.11),7.354(1.73),7.373(3.18),7.391(1.68),7.445(4.44),7.465(3.92),7.478(3.64),7.497(2.80),7.533(0.87),7.727(16.00),8.789(1.61),8.804(3.12),8.818(1.54),12.028(0.59).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.03(br.s,1H),8.80(t,1H),7.73(s,2H),7.53(br.s,1H),7.47(dd,2H),7.37(t,1H),7.31-7.24(m,1H),4.05(t,2H),3.80-3.47(m,5H),2.21-1.98(m,6H),1.94-1.77(m,3H),1.75-1.64(m,2H).
(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(380mg,632μmol,外消旋物,實施例79A)在二氯甲烷(4.6ml)中的溶液中加入TFA(490μl,6.3mmol),並將混合物在室溫下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到256mg(98%純度,理論值的73%)標題化合物。
LC-MS(方法1):Rt=1.43min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.19),0.008(1.14),1.241(0.73),1.256(0.78),1.271(0.46),1.785(0.59),1.796(0.85),1.814(1.80),1.838(3.17),1.871(12.01),2.026(1.00),2.047(3.97),2.080(4.63),2.090(4.73),2.111(1.81),2.119(1.82),2.138(3.86),2.161(9.89),3.322(16.00),3.659(2.60),7.251(1.67),7.268(3.84),7.286(2.77),7.352(2.63),7.370(4.65),7.389(2.83),7.435(6.55),7.437(6.28),7.455(5.45),7.457(5.19),7.474(6.87),7.494(8.62),7.547(4.32),7.551(4.10),7.569(2.55),7.573(2.43),8.662(1.99),8.677(3.85),8.690(1.92),12.041(3.75).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.68(t,1H),7.56(dd,1H),7.52-7.40(m,4H),7.37(t,1H),7.31-7.23(m,1H),3.78-3.48(m,7H),2.22-1.98(m,6H),1.93-1.75(m,5H).
將標題化合物(220mg)溶在甲醇(15ml)中,過濾並通過製備型SFC在手性相上(參見實施例34和35)[管柱:Daicel Chiralcel OX-H,5μm,250mm×20mm;流速:80ml/min;檢測:210nm;溫度:40℃;注入:0.15 毫升;溶析液:35%甲醇/65%二氧化碳;操作時間5分鐘,等度]分離成對映異構物。將合併的目標級分濃縮並將殘餘物冷凍乾燥。
在實施例33中描述的對映異構物分離中,預純化的標題化合物以較早洗脫的對映異構物(ee99%)獲得。隨後通過製備型HPLC(方法6)進行再純化。將合併的目標級分濃縮,並將殘餘物減壓乾燥。獲得35mg(98%純度)的再純化的標題化合物。
[α]D 20=-11.4°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.49min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.811(2.39),1.835(4.10),1.871(16.00),2.043(5.13),2.076(6.19),2.086(6.23),2.134(4.98),2.158(13.15),2.286(0.46),2.328(1.03),2.366(0.61),2.670(1.10),2.710(0.68),3.567(13.61),3.656(3.65),7.251(2.39),7.268(5.05),7.287(3.69),7.352(3.53),7.370(6.08),7.388(3.80),7.435(8.06),7.455(6.95),7.466(9.27),7.474(6.88),7.488(14.78),7.543(7.22),7.548(6.31),7.565(4.14),7.570(3.76),8.661(2.89),8.676(5.21),8.690(2.58),12.038(0.57).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.04(br.s,1H),8.68(t,1H),7.55(dd,1H),7.52-7.40(m,4H),7.37(t,1H),7.31-7.23(m,1H),3.77-3.48(m,7H),2.24-1.97(m,6H),1.95-1.75(m,5H).
(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(2.11g,3.51mmol,對映異構物2,實施例293A)在二氯甲烷(27ml)的溶液中加入TFA(6.0ml,77.24mmol),並將混合物在RT放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法6)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得1.44g(100%純度,理論值的75%)標題化合物。
[α]D 20=-13.1°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=1.44min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.795(0.23),1.814(0.53),1.837(0.93),1.871(3.68),2.026(0.28),2.046(1.18),2.079(1.39),2.089(1.41),2.110(0.55),2.118(0.54),2.137(1.15),2.160(3.09),3.316(16.00),3.658(0.81),7.251(0.50),7.269(1.13),7.289(0.82),7.352(0.77),7.371(1.38),7.389(0.85),7.437(1.84),7.457(1.53),7.469(1.47),7.477(1.68),7.491(2.55),7.545(1.30),7.549(1.32),7.567(0.78),7.571(0.80),8.661(0.60),8.675(1.17),8.689(0.60),12.039(1.84).
在實施例33中描述的對映異構物分離中,預純化的標題化合物作為稍後洗脫的對映異構物(ee93%)獲得。隨後通過製備型HPLC(方法6)進行再純化。將合併的目標級分濃縮,並將殘餘物減壓乾燥。獲得37mg(98%純度)的再純化的標題化合物。
[α]D 20=+11.4°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=1.49min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.794(1.17),1.811(2.44),1.836(4.11),1.872(16.00),2.045(5.39),2.078(6.39),2.088(6.44),2.117(2.50),2.136(5.11),2.159(13.11),2.241(0.50),2.288(0.50),2.327(0.83),2.366(0.67),2.670(0.83),2.710(0.67),3.570(13.00),3.656(3.56),7.251(2.33),7.269(5.06),7.287(3.61),7.352(3.56),7.371(6.17),7.389(3.78),7.435(8.33),7.437(8.00),7.455(6.94),7.457(6.67),7.473(8.39),7.493(11.33),7.546(5.61),7.551(5.22),7.568(3.33),7.573(3.17),8.661(2.72),8.676(5.11),8.689(2.56),12.040(3.78).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.04(br.s,1H),8.68(t,1H),7.59-7.53(m,1H),7.53-7.40(m,4H),7.37(t,1H),7.30-7.23(m,1H),3.79-3.48(m,7H),2.21-2.00(m,6H),1.92-1.77(m,5H).
(4R)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(2.16g,3.59mmol,對映異構物1,實施例292A)在二氯甲烷(28ml)之溶液中加入TFA(6.1ml,79.07mmol),並將混合物在RT放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法6)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到1.37g(100%純度,理論值的70%)標題化合物。對於起始化合物,通過VCD光譜學確定為R構型(參見實施例292A),並且因此該標題化合物同樣具有R構型。
[α]D 20=+11.3°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.44min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.784(0.16),1.795(0.23),1.813(0.53),1.837(0.95),1.870(3.74),2.026(0.28),2.046(1.18),2.079(1.40),2.089(1.42),2.110(0.56),2.118(0.55),2.137(1.18),2.159(3.13),3.315(16.00),3.658(0.81),7.249(0.49),7.268(1.13),7.287(0.82),7.352(0.77),7.370(1.38),7.388(0.85),7.435(1.80),7.455(1.49),7.467(1.84),7.475(1.60),7.489(3.11),7.543(1.54),7.548(1.45),7.565(0.91),7.570(0.88),8.660(0.62),8.674(1.23),8.688(0.62),12.038(2.54).
5-[({6-溴-3-甲基-2-[3-甲基吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(25mg,40.6μmol,非對映異構物混合物,實施例80A)在二氯甲烷(1.0ml)中的溶液中加入TFA(31μl,410μmol),並將混合物在RT過夜。隨後,再次加入TFA(31μl,410μmol),並將混合物在室溫再攪拌24小時。隨後,再次加入TFA(31μl,410μmol),並將混合物在60℃再攪拌6小時。隨後再次加入TFA(31μl,410μmol),並將混合物在60℃再攪拌8小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到7mg(98%純度,理論值的31%)標題化合物。
LC-MS(方法1):Rt=1.59min;MS(ESIpos):m/z=560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.99),-0.008(14.17),0.008(8.09),0.062(1.26),0.146(1.04),1.059(16.00),1.075(15.93),1.235(1.80),1.367(2.66),1.472(1.69),1.494(2.37),1.522(1.83),1.806(2.03),1.827(2.59),1.851(1.76),2.029(6.85),2.057(7.53),2.114(3.25),2.159(12.03),2.237(2.23),2.327(1.40),2.366(0.95),2.670(1.78),2.689(10.39),2.709(1.31),2.731(5.54),2.890(6.63),3.209(2.70),3.230(4.30),3.592(4.55),3.653(6.72),7.264(3.47),7.283(2.64),7.363(4.26),7.372(3.74),7.433(8.11),7.460(8.29),7.482(12.53),7.539(6.04),7.561(3.58),7.951(0.86),8.699(3.61).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.74-8.65(m,1H),7.59-7.51(m,1H),7.51-7.40(m,4H),7.40-7.33(m,1H),7.31-7.22(m,1H),3.76-3.52(m,6H),3.28-3.17(m,1H,部分隱蔽),2.29-1.97(m,8H),1.90-1.76(m,1H),1.58-1.42(m,1H),1.07(d,3H).
(+/-)-5-({[6-溴-2-(3,3-二氟吡咯啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(30mg,47.1μmol,外消旋物,實施例81A)在二氯甲烷(1.0ml)之溶液中加入TFA(36μl,470μmol),混合物在室溫攪拌過夜。隨後,再次加入TFA(31μl,410μmol),並將混合物在室溫再攪拌24小時。隨後,再次加入TFA(31μl,410μmol),並將混合物在60℃再攪拌6小時。隨後再次加入TFA(31μl,410μmol),並將混合物在60℃再攪拌8小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得12mg(98%純度,理論值的44%)標題化合物。
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.00),-0.008(8.49),0.008(8.89),0.049(0.70),0.063(1.25),0.146(1.05),0.943(1.12),0.960(1.05),1.235(0.75),1.813(2.12),1.836(3.07),1.860(1.72),2.041(5.02),2.071(6.34),2.082(6.27),2.104(2.65),2.130(4.19),2.165(12.61),2.327(1.40),2.366(0.92),2.421(1.70),2.440(3.49),2.457(4.82),2.475(7.21),2.523(5.14),2.669(1.50),2.689(10.68),2.709(1.05),2.731(5.17),2.890(6.34),3.584(2.77),3.671(3.42),3.781(5.62),3.965(3.17),7.253(2.12),7.271(4.89),7.290(3.59),7.354(3.10),7.372(5.57),7.391(3.17),7.437(8.89),7.440(8.96),7.457(7.54),7.460(7.51),7.480(6.99),7.497(5.12),7.568(8.01),7.590(16.00),7.628(8.79),7.633(8.11),7.650(4.27),7.655(4.19),7.952(0.85),8.699(2.67),8.712(5.19),8.726(2.70).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.04(br.s,1H),8.71(t,1H),7.64(dd,1H),7.58(d,1H),7.52-7.42(m,3H),7.37(t,1H),7.31-7.23(m,1H),4.11-3.87 (m,2H),3.85-3.50(m,5H),2.51-2.40(m,2H,隱蔽),2.23-1.96(m,6H),1.90-1.74(m,1H).
(+)-5-({[6-溴-3-甲基-2-(1,2-唑啶-2-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(110mg,182μmol,外消旋物,實施例82A)在二氯甲烷(1.3ml)的溶液中加入TFA(140μl,1.8mmol),在室溫攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到80mg(純度98%,理論值的79%)標題化合物。
LC-MS(方法1):Rt=1.83min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.94),0.008(1.90),1.782(0.41),1.793(0.66),1.814(1.34),1.835(1.71),1.858(0.99),2.033(0.92),2.045(3.57),2.073(2.81),2.081(3.16),2.093(3.30),2.121(1.33),2.129(1.23),2.141(2.11),2.164(1.10),2.210(7.16),2.240(4.55),2.257(5.85),2.276(4.31),2.294(1.35),3.604(1.49),3.651(0.90),3.670(1.66),3.684(2.28),3.698(2.02),3.714(1.56),3.771(3.06),3.822(4.25),3.840(7.28),3.859(3.97),7.257(1.29),7.275(2.94),7.293(2.07),7.356(1.72),7.375(3.14),7.393(1.64),7.445(4.53),7.447(4.50),7.465(3.83),7.467(3.73),7.486(3.85),7.502(3.01),7.707(0.71),7.729(16.00),7.756(0.60),8.767(1.66),8.782(3.27),8.796(1.64),12.043(3.12).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.04(s,1H),8.78(t,1H),7.78-7.69 (m,2H),7.53(br.s,1H),7.51-7.43(m,2H),7.37(t,1H),7.31-7.24(m,1H),3.84(t,2H),3.81-3.52(m,5H),2.31-1.99(m,8H),1.90-1.74(m,1H).
將標題化合物(70mg)溶於異丙醇(2ml)和庚烷(2ml)的混合物中,用製備型HPLC在手性相上分離成對映異構物(參見實施例39和40)[管柱:Daicel Chiralpak ID,5μm,250mm×20mm;流速:15毫升/分鐘;注入:0.4毫升;溶解液:50%異丙醇/50%(庚烷+0.2%TFA);操作時間13分鐘,等度]。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。
在實施例38中描述的對映異構物分離中,預純化的標題化合物以較早洗脫的對映異構物(ee99%)獲得。隨後通過製備型HPLC(方法7)進行再純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到39mg(98%純度)的再純化的標題化合物。
[α]D 20=-8.0°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法2):Rt=0.94min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.87),-0.008(7.75),0.008(6.54),0.146(0.84),1.809(1.24),1.832(1.61),1.856(0.90),2.039(2.88),2.073(3.07),2.084(2.79),2.133(1.83),2.209(6.54),2.240(4.16),2.257(5.49),2.276(4.09),2.294(1.27),2.327(1.27),2.366(1.27),2.523(3.57),2.669(1.36),2.710(1.27),3.600(1.43),3.667(1.55),3.682(2.14),3.697(1.86),3.771(2.82),3.822(4.09),3.840(6.98),3.859(3.88),7.256(1.27),7.274(2.79),7.292(1.98),7.355(1.58),7.374(2.95),7.392(1.55),7.444(4.43),7.464(3.78),7.484(3.53),7.501(2.79),7.707(0.68),7.729(16.00),8.777(1.33),8.791(2.73),8.805(1.43).
在實施例38中描述的對映異構物分離中,預純化的標題化合物作為稍後洗 脫的對映異構物(ee 97%)獲得。隨後通過製備HPLC(方法7)進行再純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到30mg(98%純度)的再純化的標題化合物。
[α]D 20=+14.0°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法2):Rt=0.94min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.52),0.146(0.52),1.790(0.55),1.808(1.29),1.831(1.85),1.854(0.98),2.014(0.69),2.036(2.96),2.067(3.48),2.078(3.21),2.088(2.20),2.102(1.35),2.128(2.06),2.152(0.94),2.211(7.24),2.240(4.66),2.258(6.01),2.276(4.41),2.294(1.36),2.327(0.74),2.366(0.66),2.670(0.77),2.710(0.69),3.595(1.54),3.648(0.94),3.667(1.68),3.681(2.27),3.695(2.04),3.712(1.60),3.732(1.47),3.772(3.13),3.822(4.34),3.841(7.47),3.859(4.08),7.256(1.29),7.274(2.92),7.294(2.04),7.355(1.74),7.373(3.20),7.392(1.67),7.446(4.48),7.466(3.78),7.483(3.92),7.502(3.00),7.707(0.67),7.729(16.00),7.756(0.66),8.784(1.45),8.799(2.85),8.812(1.52).
5-({[6-溴-2-(3-甲氧基吡咯啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸丁酯(30mg,47.5μmol,非對映異構物混合物,實施例83A)在二氯甲烷(1.0ml)之溶液中加入TFA(37μl,480μmol),並將混合物在RT過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並 通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到10mg(98%純度,理論值的37%)標題化合物。
LC-MS(方法2):Rt=0.80min;MS(ESIpos):m/z=574/576[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.41),0.008(1.36),1.812(0.64),1.834(0.89),1.858(0.55),1.954(0.60),2.018(1.00),2.040(1.85),2.068(2.03),2.079(1.86),2.103(0.85),2.129(1.23),2.158(3.82),2.523(0.81),3.199(0.60),3.245(16.00),3.417(0.42),3.511(1.14),3.551(0.87),3.572(0.89),3.591(0.88),3.659(0.88),3.714(0.98),3.778(0.79),3.807(0.63),4.017(1.34),7.245(0.44),7.263(0.96),7.275(0.93),7.293(0.63),7.346(0.69),7.364(1.23),7.378(1.10),7.395(0.66),7.435(2.45),7.437(2.36),7.455(2.05),7.457(1.93),7.478(2.83),7.500(3.63),7.556(1.97),7.561(1.29),7.579(1.19),8.694(1.08).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.69(br.s,1H),7.62-7.53(m,1H),7.53-7.41(m,4H),7.40-7.33(m,1H),7.31-7.22(m,1H),4.02(br.s,1H),3.84-3.46(m,7H),3.24(s,3H),2.22-1.77(m,9H).
(+/-)-5-({[6-溴-2-(3,3-二甲基哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(80mg,124μmol,外消旋物,實施例84A)在二氯甲烷(910μl)的溶液中加入TFA(96μl,1.2mmol),將混合物在室溫下攪拌過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈 並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到65mg(98%純度,理論值的87%)標題化合物。
LC-MS(方法1):Rt=2.43min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.007(16.00),1.377(1.50),1.386(2.45),1.392(2.05),1.723(2.48),1.731(2.30),1.740(1.95),1.753(1.20),1.762(0.78),1.818(0.64),1.829(0.83),1.839(0.50),1.919(0.68),1.929(0.67),2.182(3.52),2.386(0.52),2.614(0.58),2.868(3.61),3.043(1.14),3.476(0.92),3.635(0.64),7.232(0.61),7.244(1.47),7.256(1.05),7.339(0.71),7.351(1.38),7.364(0.79),7.420(2.16),7.433(2.83),7.442(1.31),7.632(0.62),7.646(4.36),7.668(0.51),9.138(0.94).
1H-NMR(600MHz,DMSO-d6)δ[ppm]:9.14(br.s,1H),7.69-7.60(m,2H),7.48(br.s,1H),7.45-7.40(m,2H),7.35(t,1H),7.27-7.21(m,1H),3.64(br.s,2H),3.52-3.44(m,1H),3.04(br.s,2H),2.87(s,2H),2.18(br.s,3H),1.98-1.88(m,1H),1.87-1.78(m,1H),1.78-1.68(m,4H),1.41-1.34(m,2H),1.01(s,6H).
將標題化合物(50mg)溶於甲醇(25ml)中,通過製備型SFC在手性相分離為對映異構物(參見實施例43和44)[管柱:Daicel Chiralpak AD,5μm,250mm x 20毫米;流速:80ml/min;注入:3毫升;溶析液:25%異丙醇/75%二氧化碳;操作時間9分鐘,等度]。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。
在實施例42中所述的對映異構物分離中,獲得10mg(98%純度,ee 99%)標題化合物,作為較早洗脫的對映異構物。
[α]D 20=-12.0°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.83),0.008(3.24),1.004(16.00),1.373(1.13),1.387(1.81),1.402(1.39),1.721(1.36),1.805(0.50),1.827 (0.66),1.850(0.42),2.024(1.09),2.054(1.93),2.070(1.15),2.106(0.65),2.165(5.23),2.710(0.41),2.864(4.18),3.044(1.53),3.576(0.67),3.669(0.97),7.253(0.55),7.272(1.28),7.289(0.91),7.353(0.75),7.371(1.38),7.389(0.74),7.438(1.91),7.440(1.92),7.458(1.75),7.461(1.78),7.475(1.85),7.491(1.37),7.628(0.41),7.650(5.99),7.655(2.96),8.762(0.98).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.15(br.s,1H),8.76(t,1H),7.70-7.61(m,2H),7.58-7.41(m,3H),7.37(t,1H),7.30-7.24(m,1H),3.75-3.62(m,2H),3.61-3.54(m,1H),3.04(br.s,2H),2.86(s,2H),2.17(s,3H),2.13-1.97(m,3H),1.90-1.77(m,1H),1.76-1.65(m,2H),1.45-1.32(m,2H),1.00(s,6H).
在實施例42中所述的對映異構物分離中,獲得10mg(98%純度,ee 99%)標題化合物,其為稍後洗脫的對映異構物。
[α]D 20=+9.3°,589nm,c=0.25g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.58),0.008(3.59),0.146(0.41),1.004(16.00),1.372(1.15),1.386(1.87),1.401(1.40),1.720(1.37),1.810(0.50),1.833(0.71),1.857(0.42),2.039(1.14),2.067(1.73),2.122(0.84),2.163(5.31),2.327(0.42),2.669(0.46),2.863(4.18),3.044(1.59),3.583(0.66),3.673(1.01),7.256(0.55),7.274(1.29),7.291(0.94),7.355(0.79),7.373(1.42),7.393(0.73),7.440(2.01),7.442(2.03),7.460(1.83),7.478(1.90),7.495(1.41),7.628(0.41),7.650(6.13),7.655(3.12),7.678(0.41),8.737(1.17).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.1(br.s,1H),8.74(t,1H),7.71-7.59(m,2H),7.58-7.41(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.76-3.62(m,2H),3.62-3.53(m,1H),3.04(br.s,2H),2.86(s,2H),2.16(s,3H),2.14-2.00(m,3H),1.90-1.76(m,1H),1.76-1.67(m,2H),1.43-1.34(m,2H),1.00(s,6H).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(100mg,159μmol,非對映異構物混合物,實施例85A)在二氯甲烷(1.2ml)的溶液中加入TFA(120μl,1.6mmol),並將混合物在RT過夜。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈並通過製備型HPLC(方法6)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到82mg(98%純度,理論值的88%)標題化合物。
LC-MS(方法1):Rt=2.33min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.921(4.93),0.936(4.95),1.077(0.56),1.107(0.57),1.625(0.46),1.654(0.54),1.730(1.03),1.761(1.00),1.793(1.35),1.821(1.21),1.837(1.07),1.860(0.44),2.049(1.51),2.083(1.79),2.091(1.94),2.135(6.39),2.160(0.58),2.431(0.42),2.501(16.00),2.675(0.41),2.709(0.64),3.489(3.11),3.574(1.10),3.591(1.05),3.677(1.20),7.255(0.62),7.274(1.47),7.292(1.12),7.355(0.86),7.374(1.53),7.392(0.80),7.441(2.18),7.461(1.95),7.480(2.10),7.499(1.51),7.626(0.50),7.648(5.52),8.704(0.73),8.719(1.40),8.732(0.68).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.72(t,1H),7.70-7.61(m,2H),7.58-7.41(m,3H),7.37(t,1H),7.32-7.23(m,1H),3.82-3.26(m,5H,部分隱蔽),2.78-2.62(m,1H),2.48-2.38(m,1H,部分隱蔽),2.20-1.98(m,6H),1.90-1.54(m,5H),1.17-1.01(m,1H),0.93(d,3H).
(-)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(185mg,294μmol,非對映異構物1,實施例86A)在二氯甲烷(2.2ml)之溶液中加入TFA(230μl,2.9mmol),混合物靜置在RT下24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到117mg(98%純度,ee>99%,理論值的68%)標題化合物。
[α]D 20=-20.6°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法2):Rt=1.20min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.52),0.920(13.64),0.936(13.90),1.048(0.47),1.077(1.44),1.106(1.50),1.128(0.61),1.234(0.50),1.589(0.44),1.621(1.24),1.651(1.47),1.679(0.69),1.729(2.53),1.765(2.53),1.791(3.56),1.821(3.15),1.837(2.76),1.861(1.16),2.016(0.54),2.029(0.87),2.049(3.74),2.082(4.70),2.090(5.03),2.134(16.00),2.160(1.56),2.186(0.52),2.419(1.30),2.447(2.04),2.476(1.42),2.523(0.75),2.682(1.18),2.710(2.27),2.738(1.14),3.439(2.24),3.460(3.55),3.486(1.99),3.577(1.53),3.593(1.74),3.680(3.29),7.256(1.62),7.274(3.82),7.291(2.89),7.355(2.22),7.374(4.05),7.392(2.09),7.441(5.61),7.443(5.48),7.461(4.98),7.463(4.84),7.482(5.43),7.498(4.02),7.624(1.48),7.647(14.26),7.654(7.96),7.672(0.97),7.676(1.18),8.700(1.90),8.715(3.84),8.729(1.85),12.043(2.06).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.04(br.s,1H),8.71(t,1H),7.70-7.60(m,2H),7.53-7.42(m,3H),7.37(t,1H),7.31-7.23(m,1H),3.78-3.63(m,2H),3.63-3.52(m,1H),3.51-3.38(m,2H),2.71(t,1H),2.45(t,1H),2.21-1.98(m,6H),1.91-1.55(m,5H),1.17-1.02(m,1H),0.93(d,3H).
(+)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(185mg,294μmol,非對映異構物2,實施例87A)在二氯甲烷(1.6ml)之溶液中加入TFA(170μl,2.2mmol),並將混合物靜置於RT 24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到117mg(98%純度,ee>99%,理論值的68%)標題化合物。
[α]D 20=+24.9°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法2):Rt=1.20min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.59),0.008(2.07),0.921(13.42),0.937(13.48),1.055(0.46),1.081(1.40),1.105(1.43),1.134(0.56),1.623(1.22),1.653(1.43),1.682(0.67),1.732(2.48),1.766(2.50),1.793(3.54),1.814(2.99),1.823(3.07),1.837(2.80),1.861(1.12),2.048(3.60),2.083(4.54),2.091(4.85),2.136(16.00),2.160(1.50),2.432(1.28),2.461(2.09),2.524(0.99),2.670(0.41),2.695(1.08),2.724(1.92),2.752(1.03),3.448(2.22),3.471(3.55),3.497(1.95),3.577(1.64),3.593(1.85),3.681(3.38),3.973(1.31),7.257(1.61),7.275(3.65),7.292(2.61),7.295(2.61),7.357(2.19),7.375(4.01),7.394(2.04),7.441(5.78),7.444(5.83),7.461(5.09),7.464(5.09),7.483(5.41),7.499(3.99),7.634(1.40),7.657(14.87),7.663(8.60),7.680(0.93),7.685(1.10),8.706(1.85),8.720(3.73),8.734(1.82).
(+)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(150mg,238μmol,非對映異構物3,實施例88A)在二氯甲烷(1.8ml)溶液中加入TFA(180μl,2.4mmol),並將混合物靜置於RT 24小 時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到102mg(100%純度,ee>99%,理論值的74%)標題化合物。
[α]D 20=+7.5°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.20min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.921(11.56),0.937(11.71),1.050(0.44),1.077(1.30),1.106(1.33),1.128(0.54),1.234(0.56),1.626(1.13),1.657(1.35),1.686(0.66),1.729(2.37),1.760(2.30),1.794(2.97),1.821(2.75),1.836(2.48),1.860(1.04),2.048(3.26),2.083(4.03),2.090(4.31),2.104(2.16),2.135(16.00),2.159(1.29),2.429(1.25),2.458(1.97),2.669(1.11),2.697(1.76),2.726(0.96),3.434(2.04),3.461(3.58),3.492(1.67),3.592(1.60),3.670(2.24),7.256(1.35),7.274(3.19),7.292(2.26),7.356(1.92),7.374(3.51),7.392(1.85),7.441(4.84),7.461(4.35),7.480(4.74),7.499(3.41),7.625(1.11),7.648(12.30),7.654(6.45),7.672(0.76),7.676(0.88),8.703(1.72),8.717(3.36),8.731(1.65),12.052(0.67).
(-)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(140mg,223μmol,非對映異構物4,實施例89A)在二氯甲烷(1.6ml)的溶液中加入TFA(170μl,2.2mmol),混合物靜置在RT下30小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物在乙腈/水中冷凍乾燥。得到78mg(97%純度,ee>99%,理論值的59%)標題化合物。
[α]D 20=-17.3°,436nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.20min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.921(6.01),0.936(6.18),1.077(0.69), 1.106(0.70),1.626(0.59),1.657(0.70),1.729(1.24),1.760(1.21),1.792(1.61),1.812(1.34),1.820(1.42),1.834(1.41),1.858(0.57),2.045(1.68),2.078(2.14),2.086(2.32),2.134(8.43),2.155(0.82),2.429(0.64),2.500(16.00),2.669(0.63),2.698(0.92),2.726(0.50),3.433(1.14),3.461(1.93),3.491(0.91),3.574(0.74),3.590(0.85),3.669(1.16),7.255(0.73),7.273(1.75),7.292(1.28),7.355(1.03),7.374(1.87),7.392(0.98),7.441(2.63),7.461(2.35),7.480(2.52),7.498(1.77),7.624(0.61),7.647(6.71),7.675(0.51),8.705(0.85),8.719(1.68),8.733(0.85).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(100mg,154μmol,外消旋物,實施例90A)在二氯甲烷(1.1ml)的溶液中加入TFA(120μl,1.5mmol),將混合物在室溫放置16小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。將殘餘物溶於乙腈中並通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到70mg(98%純度,理論值的75%)標題化合物。
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.73),0.008(2.65),1.795(0.82),1.814(1.76),1.838(2.35),1.881(4.53),2.047(5.28),2.082(7.13),2.091(7.78),2.150(16.00),2.225(0.40),2.327(0.75),2.366(0.66),2.670(0.74),2.709(0.63),3.164(5.24),3.447(3.36),3.476(6.42),3.505(3.20),3.593(1.89),3.686 (3.35),7.256(1.75),7.275(4.05),7.293(2.86),7.358(2.48),7.375(4.44),7.394(2.29),7.443(6.36),7.462(5.35),7.486(5.22),7.502(4.30),7.673(2.44),7.695(13.97),7.700(9.61),7.705(8.12),7.723(1.34),7.728(1.56),8.720(2.31),8.734(4.37),8.748(2.09),12.047(1.44).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.05(br.s,1H),8.73(t,1H),7.76-7.64(m,2H),7.59-7.42(m,3H),7.38(t,1H),7.32-7.22(m,1H),3.80-3.64(m,2H),3.63-3.54(m,1H),3.48(t,2H),3.23-3.07(m,2H),2.20-2.00(m,8H),1.94-1.74(m,3H).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(660mg,1.01mmol,對映異構物1,實施例91A)在二氯甲烷(8.0ml)之溶液中加入TFA(1.6ml,20mmol),將混合物放置在RT下18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法6)純化殘餘物。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到479mg(100%純度,ee>99%,理論值的79%)標題化合物。
[α]D 20=-17.6°,589nm,c=0.39g/100ml,DMSO
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.52),-0.008(6.12),0.008(4.60),0.146(0.48),1.797(0.95),1.815(1.92),1.838(2.60),1.881(4.78),2.048(5.58),2.083(7.57),2.092(8.27),2.150(16.00),2.327(0.76),2.366(0.59),2.669(0.62),2.710(0.52),3.162(5.51),3.447(3.52),3.476(6.45),3.504(3.21),3.596(2.04),3.686(3.52),7.258(1.92),7.276(4.03),7.296(2.81),7.358(2.54),7.377(4.41),7.395(2.25),7.442(6.36),7.445(6.48),7.462(5.42),7.465(5.37),7.486(5.36),7.503(4.30),7.673(2.60),7.695(13.64),7.700(10.23),7.705(8.55),7.723(1.42),7.728(1.67),8.719(2.31),8.734(4.43),8.748(2.10),12.048(3.00).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(620mg,952μmol,對映異構物2,實施例92A)在二氯甲烷(8.0ml)之溶液中加入TFA(1.5ml,19mmol),並將混合物在RT持續18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法6)純化殘餘物。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到397mg(100%純度,理論值98%,理論值的70%)標題化合物。
[α]D 20=+12.1°,589nm,c=0.37g/100ml,DMSO
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.83),0.008(3.53),0.146(0.41),1.784(0.53),1.795(0.82),1.814(1.73),1.837(2.38),1.881(4.61),2.013(0.53),2.047(5.23),2.082(7.24),2.090(7.79),2.110(4.09),2.150(16.00),2.327(0.51),2.366(0.50),2.670(0.53),2.709(0.51),3.163(5.34),3.447(3.40),3.476(6.48),3.504(3.25),3.594(1.94),3.685(3.39),7.258(1.69),7.275(3.92),7.293(2.77),7.358(2.34),7.376(4.30),7.393(2.26),7.442(6.13),7.445(5.76),7.462(5.14),7.465(4.75),7.486(5.18),7.503(4.26),7.673(2.10),7.695(13.05),7.700(9.57),7.705(8.01),7.723(1.37),7.728(1.62),8.720(2.18),8.734(4.42),8.748(2.14),12.051(1.27).
5-[({6-溴-3-甲基-2-[3-(三氟甲基)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(156mg,228μmol,非對映異構物混合物,實施例93A)在二氯甲烷(1.7ml)之溶液中加入TFA(180μl,2.3mmol),在RT下攪拌混合物16小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到89mg(98%純度,理論值的61%)標題化合物。
LC-MS(方法1):Rt=2.33min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.367(0.99),1.466(0.45),1.487(1.20),1.496(1.31),1.517(1.47),1.525(1.47),1.547(0.69),1.555(0.65),1.656(1.14),1.680(1.14),1.815(3.30),1.838(2.92),2.004(1.84),2.034(2.50),2.048(3.94),2.083(3.91),2.092(4.19),2.140(13.11),2.753(1.91),2.871(1.12),2.900(1.56),2.926(0.80),3.482(1.80),3.513(1.67),3.599(1.70),3.686(2.90),3.713(3.39),3.742(2.39),7.255(1.45),7.274(3.31),7.292(2.33),7.356(2.00),7.375(3.62),7.393(1.90),7.440(4.78),7.459(4.01),7.487(4.49),7.506(3.81),7.668(0.50),7.689(16.00),8.714(1.66),8.727(3.04),8.741(1.61),12.057(0.83).
(+/-)-5-({[6-溴-3-甲基-2-(4-甲基哌-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(135mg,214μmol,外消旋物,實施例94A)在二氯甲烷(1.6ml)的溶液中加入TFA(170μl,2.1mmol),在室溫下攪拌混合物16小時。然後濃縮混合物並加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到115mg(98%純度,理論值的92%)標題化合物。
LC-MS(方法1):Rt=1.23min;MS(ESIpos):m/z=573/575[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.30),0.008(2.32),1.784(0.56),1.795(0.95),1.815(1.86),1.837(2.38),1.861(1.34),2.034(1.33),2.046(5.04),2.082(4.92),2.092(5.43),2.104(2.68),2.143(16.00),2.236(0.40),2.328(0.48),2.366(0.50),2.524(3.16),2.670(0.68),2.710(0.66),2.923(3.22),3.599(2.22),3.650(1.13),3.670(2.61),3.684(4.10),3.699(3.14),7.254(1.94),7.274(4.49),7.293(3.29),7.356(2.73),7.374(4.99),7.392(2.56),7.441(7.40),7.444(6.82),7.461(6.18),7.464(5.59),7.484(5.88),7.487(5.82),7.503(4.97),7.664(2.93),7.686(13.99),7.694(9.19),7.699(7.80),7.717(1.75),7.721(1.89),8.719(2.52),8.734(5.03),8.748(2.36).
5-[({6-溴-2-[3-羥基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(154mg,244μmol,非對映異構物混合物,實施例95A)在二氯甲烷(1.8ml)的溶液中加入TFA(190μl,2.4mmol),在室溫放置混合物16小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到55mg(98%純度,理論值的38%)標題化合物。
LC-MS(方法1):Rt=1.71min;MS(ESIpos):m/z=574/576[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.27),0.008(3.32),0.146(0.42),1.284(0.43),1.295(0.55),1.315(1.31),1.347(1.48),1.368(0.70),1.378(0.62),1.576(1.16),1.604(1.23),1.775(1.85),1.783(1.97),1.795(1.76),1.810(2.61),1.835(2.19),1.857(1.20),1.882(0.40),1.913(1.55),1.922(1.62),1.944(1.55),2.044(3.61),2.078(4.46),2.086(4.74),2.133(16.00),2.156(1.71),2.327(0.48),2.366(0.49),2.523(1.40),2.631(1.40),2.664(1.04),2.710(0.51),2.745(0.93),2.775(1.64),2.804(0.95),3.357(2.61),3.388(1.92),3.512(2.02),3.543(1.94),3.593(1.70),3.682(4.41),4.864(1.31),7.256(1.56),7.274(3.58),7.294(2.49),7.355(2.13),7.374(3.85),7.393(2.01),7.441(5.79),7.444(5.77),7.461(5.11),7.464(5.07),7.481(5.24),7.501(3.83),7.619(3.18),7.642(11.39),7.654(7.20),7.659(6.40),7.676(1.90),7.682(1.95),8.721(1.91),8.735(3.83),8.749(1.84).
5-{[(6-溴-2-{3-[(三級丁氧基羰基)胺基]哌啶-1-基}-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(162mg,222μmol,非對映異構物混合物,實施例96A)在二氯甲烷之溶液(1.6ml)中加入TFA(170μl,2.2mmol),並將混合物在室溫放置16小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到38mg(98%純度,理論值的29%)標題化合物。
LC-MS(方法1):Rt=1.27min;MS(ESIpos):m/z=573/575[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.47),-0.008(4.19),0.008(4.66),0.146(0.47),1.442(1.31),1.469(1.48),1.676(1.39),1.836(4.04),1.859(2.54),1.961(1.72),1.985(1.67),2.043(3.81),2.074(5.01),2.081(5.07),2.129(2.81),2.164(16.00),2.327(0.88),2.366(0.73),2.670(0.84),2.710(0.82),2.875(1.93),3.228(2.34),3.303(2.21),3.578(3.96),3.671(3.59),3.685(3.79),7.257(1.85),7.276(4.22),7.295(2.95),7.356(2.51),7.375(4.55),7.393(2.37),7.444(6.60),7.463(5.53),7.484(5.50),7.504(4.53),7.647(4.15),7.669(12.29),7.686(7.15),7.691(6.32),7.709(2.23),7.713(2.15),8.751(1.26),8.765(2.72),8.782(2.10).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(157mg,244μmol,非對映異構物混合物,實施例97A)在二氯甲烷(1.8ml)的溶液中加入TFA(190μl,2.4mmol),並將混合物放置在室溫放置16小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到93mg(98%純度,理論值的64%)標題化合物。
LC-MS(方法1):Rt=2.43min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.890(7.22),0.909(15.43),0.927(7.98),1.033(0.70),1.062(1.77),1.085(1.79),1.114(0.79),1.239(1.58),1.256(3.34),1.274(4.29),1.291(3.01),1.563(2.10),1.598(1.87),1.631(1.58),1.745(2.50),1.780(2.02),1.814(2.13),1.837(3.69),1.876(2.18),2.049(4.75),2.080(5.39),2.093(6.18),2.124(14.79),2.163(1.56),2.367(0.47),2.426(1.73),2.710(1.27),2.738(1.77),3.493(3.77),3.516(3.09),3.596(2.29),3.678(3.79),7.252(1.99),7.271(4.31),7.290(2.97),7.354(2.63),7.373(4.57),7.392(2.44),7.437(6.02),7.457(5.32),7.483(6.32),7.502(4.67),7.624(1.86),7.647(16.00),7.676(1.20),8.699(2.34),8.713(4.23),8.727(2.09).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:11.86(br.s,1H),8.71(t,1H),7.71-7.59(m,2H),7.56-7.42(m,3H),7.37(t,1H),7.27(t,1H),3.78-3.43(m,5H),2.82-2.61(m,1H),2.48-2.34(m,1H),2.21-1.97(m,6H),1.94-1.69(m,3H),1.68-1.46(m,2H),1.37-1.18(m,2H),1.16-0.98(m,1H),0.91(t,3H).
(+)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(180mg,280μmol,非對映異構物1,實施例98A)在二氯甲烷(2.4ml)之溶液中加入TFA(470μl,6.2mmol),將混合物靜置在RT下18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到139mg(100%純度,理論值的85%)標題化合物。
[α]D 20=+4.8°,589nm,c=0.42g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.892(6.73),0.910(16.00),0.929(8.30),1.034(0.54),1.064(1.47),1.093(1.52),1.115(0.67),1.240(1.18),1.257(2.88),1.275(3.82),1.292(2.63),1.563(1.82),1.598(1.77),1.629(1.43),1.658(0.62),1.746(2.07),1.780(1.69),1.812(1.62),1.837(2.98),1.855(2.28),1.876(1.78),2.025(0.94),2.046(3.88),2.080(4.53),2.091(5.07),2.114(11.74),2.138(3.29),2.162(1.21),2.390(0.94),2.418(1.59),2.445(0.97),2.713(1.14),2.742(2.05),2.772(1.11),3.475(2.07),3.498(3.51),3.520(2.33),3.596(1.74),3.678(3.39),3.693(2.66),7.252(1.52),7.271(3.65),7.289(2.67),7.353(2.16),7.372(3.99),7.390(2.07),7.436(5.20),7.456(4.37),7.484(5.31),7.502(4.33),7.624(1.33),7.647(13.21),7.676(1.03),8.697(1.87),8.711(3.78),8.725(1.91),12.043(4.25).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(200mg,311μmol,非對映異構物2,實施例99A)在二氯甲烷(2.6ml)之溶液中加入TFA(530μl,6.8mmol),並將混合物靜置於RT 18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過 製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到143mg(100%純度,理論值的78%)標題化合物。
[α]D 20=-26.0°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.889(5.96),0.908(13.53),0.926(6.80),1.034(0.52),1.062(1.29),1.085(1.31),1.114(0.57),1.240(1.11),1.256(2.40),1.274(3.14),1.283(2.64),1.291(2.25),1.301(1.76),1.558(1.43),1.604(1.33),1.635(1.24),1.665(0.54),1.745(1.84),1.779(1.51),1.813(1.49),1.835(2.39),1.854(2.18),1.877(1.62),2.033(1.16),2.048(3.43),2.077(3.31),2.085(3.74),2.093(4.43),2.124(16.00),2.138(2.92),2.162(0.92),2.402(0.93),2.429(1.47),2.701(0.89),2.730(1.56),2.757(0.85),3.484(2.87),3.515(2.61),3.596(1.53),3.661(1.81),3.675(2.56),7.254(1.40),7.271(3.10),7.289(2.16),7.355(1.92),7.374(3.34),7.392(1.74),7.438(4.62),7.458(4.18),7.481(4.49),7.500(3.11),7.624(1.31),7.647(11.41),7.671(0.73),7.675(0.82),8.697(1.73),8.712(3.17),8.726(1.55),12.043(3.31).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(420mg,650μmol,非對映異構物3,實施例100A)在二氯甲烷(5.5ml)之溶液中加入TFA(1.1ml,14mmol),並將混合物靜置於RT 18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到348mg(100%純度,理論值的91%)標題化合物。
[α]D 20=-5.1°,589nm,c=0.48g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.891(6.76),0.910(16.00),0.928(8.20),1.034(0.55),1.063(1.49),1.085(1.52),1.093(1.51),1.114(0.67),1.239(1.17),1.257(2.87),1.274(3.81),1.292(2.60),1.563(1.83),1.597(1.73),1.629 (1.44),1.660(0.62),1.745(2.09),1.779(1.67),1.812(1.63),1.836(3.03),1.853(2.24),1.876(1.77),2.013(0.54),2.025(0.97),2.046(3.88),2.080(4.59),2.090(5.07),2.114(11.27),2.138(3.27),2.162(1.16),2.390(0.94),2.418(1.57),2.713(1.09),2.742(1.95),2.771(1.06),3.474(2.09),3.498(3.43),3.520(2.33),3.596(1.71),3.678(3.31),3.693(2.57),7.252(1.56),7.271(3.74),7.289(2.72),7.353(2.19),7.372(4.02),7.390(2.08),7.436(5.26),7.456(4.43),7.484(5.27),7.502(4.30),7.624(1.39),7.647(13.75),7.676(1.02),8.697(1.88),8.712(3.76),8.726(1.87),12.047(1.45).
(+)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(463mg,720μmol,非對映異構物4,實施例101A)在二氯甲烷(6.1ml)之溶液中加入TFA(1.2ml,16mmol),並將混合物靜置於RT 18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到360mg(100%純度,理論值的85%)標題化合物。
[α]D 20=+27.7°,589nm,c=0.48g/100ml,甲醇
LC-MS(方法1):Rt=2.45min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.888(5.59),0.907(13.71),0.925(6.95),1.033(0.43),1.062(1.18),1.084(1.19),1.092(1.20),1.113(0.54),1.123(0.48),1.238(0.87),1.256(2.08),1.265(1.91),1.273(2.87),1.282(2.43),1.290(2.12),1.300(1.70),1.317(0.67),1.557(1.25),1.565(1.23),1.573(1.20),1.603(1.20),1.635(1.16),1.665(0.50),1.744(1.64),1.778(1.28),1.793(0.94),1.814(1.27),1.836(2.25),1.854(1.87),1.876(1.47),2.033(0.90),2.049(3.07),2.078(2.80),2.085(3.19),2.094(3.73),2.125(16.00),2.139(2.89),2.163(0.88),2.402(0.81),2.430(1.33),2.458(0.81),2.701(0.82),2.731(1.48),2.759(0.82),3.485(2.59),3.515(2.44),3.599(1.42),3.624(0.88),3.642(0.73),3.662(1.56),3.676(2.32),7.253(1.31),7.272(3.02),7.292(2.12),7.355(1.80),7.374(3.28),7.392 (1.70),7.440(4.50),7.460(3.99),7.483(4.32),7.501(2.96),7.624(1.00),7.647(12.31),7.652(6.71),7.670(0.66),7.675(0.81),8.699(1.53),8.713(3.02),8.727(1.49),12.053(0.70).
5-[({6-溴-2-[3-羥基-3-甲基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(148mg,229μmol,非對映異構物混合物,實施例102A)在二氯甲烷(1.7ml)的溶液中加入TFA(180μl,2.3mmol),將混合物放置在RT下16小時。然後濃縮混合物並重複加入二氯甲烷並將混合物再濃縮。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到106mg(98%純度,理論值的77%)標題化合物。
LC-MS(方法1):Rt=1.83min;MS(ESIpos):m/z=588/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.69),1.190(16.00),1.557(3.93),1.570(4.21),1.613(1.10),1.627(1.00),1.796(0.66),1.814(1.72),1.836(2.49),1.859(1.71),2.045(2.66),2.061(1.71),2.079(3.37),2.086(4.47),2.134(2.03),2.165(10.97),2.855(0.60),3.021(7.70),3.075(3.50),3.592(1.35),3.676(2.23),4.614(1.55),7.254(1.18),7.274(2.80),7.292(1.97),7.356(1.67),7.374(3.07),7.392(1.61),7.441(4.38),7.461(3.98),7.481(4.14),7.499(2.92),7.614(2.20),7.636(7.81),7.649(5.05),7.654(4.49),7.671(1.34),7.676(1.37),8.712(1.50),8.727(2.91),8.741(1.39).
5-[({6-溴-2-[3,5-二甲基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(91mg,142μmol,非對映異構物混合物,實施例103A)在二氯甲烷(4.8ml)的溶液中加入TFA(110μl,1.4mmol),在RT下攪拌混合物42小時。隨後,再次加入TFA(105μl,0.7mmol),並將混合物在室溫再攪拌66小時。隨後濃縮混合物,並重複加入二氯甲烷,隨後再濃縮。首先通過製備型HPLC(方法6)將殘餘物預純化,然後通過製備型HPLC(方法7)再純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得47mg(100%純度,理論值的57%)標題化合物。
LC-MS(方法1):Rt=2.42 & 2.44min;MS(ESIpos):m/z=586/586[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.718(1.40),0.748(1.54),0.778(0.50),0.898(15.75),0.913(16.00),1.005(3.11),1.021(3.17),1.234(0.86),1.424(0.56),1.437(1.00),1.451(0.61),1.808(3.64),1.839(3.30),1.861(1.10),2.049(3.42),2.083(3.96),2.090(4.17),2.134(11.83),2.164(3.04),2.266(1.30),2.294(2.05),2.323(1.27),2.848(0.48),3.116(0.65),3.146(0.56),3.488(2.66),3.517(2.54),3.592(1.54),3.674(2.27),7.256(1.27),7.274(2.92),7.292(2.07),7.356(1.74),7.375(3.20),7.393(1.71),7.440(4.43),7.460(4.05),7.480(4.37),7.499(3.07),7.625(0.76),7.647(13.38),7.673(0.59),8.692(1.42),8.705(2.74),12.049(1.42).
5-[({6-溴-2-[3-(二氟甲基)哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(116mg,48%純度,83.0μmol,非對映異構物混合物,實施例104A)在二氯甲烷(2.9ml)的溶液中加入TFA(64μl,830μmol),將混合物在室溫下攪拌18小時。隨後,再次加入TFA(64μl,830μmol),並將混合物在室溫再攪拌24小時。隨後,再次加入TFA(64μl,830μmol),並將混合物再次在室溫下再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到34mg(93%純度,理論值的63%)標題化合物。
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.13),-0.008(16.00),0.008(9.90),0.146(1.18),1.235(0.65),1.397(0.96),1.427(1.09),1.664(0.92),1.812(2.31),1.853(2.49),2.044(2.96),2.088(3.57),2.139(9.68),2.327(1.57),2.366(1.57),2.523(9.59),2.669(1.96),2.710(2.40),2.838(1.48),3.413(1.57),3.553(2.18),3.581(2.75),3.681(2.44),5.754(0.70),5.941(0.70),6.083(1.40),6.096(1.31),6.237(0.74),7.257(1.26),7.274(2.57),7.293(1.87),7.356(1.61),7.375(2.92),7.392(1.66),7.439(4.40),7.459(3.75),7.485(3.79),7.502(3.10),7.677(13.34),8.734(2.31),12.043(1.13).
5-[({6-溴-2-[(3S)-3-氟吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(141mg,89%純度,203μmol,表異構物混合物,實施例105A)在二氯甲烷(2.2ml)之溶液中加入TFA(160μl,2.0mmol),將混合物在RT下攪拌42小時。隨後,再次加入TFA(80μl,1.0mmol),並將混合物在室溫再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC(方法7)純化。將合併的目標級分濃縮,冷凍乾燥殘留物。得到44mg(94%純度,理論值的36%)標題化合物。
LC-MS(方法1):Rt=1.75min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.50),-0.008(4.85),0.008(4.45),0.146(0.45),1.235(0.77),1.797(1.23),1.818(2.56),1.838(3.44),1.862(1.98),1.988(0.79),2.047(7.30),2.076(7.77),2.088(7.95),2.138(4.97),2.176(16.00),2.327(0.92),2.366(0.79),2.669(0.79),2.709(0.74),3.600(6.02),3.866(2.36),3.884(2.32),3.911(2.23),3.944(1.37),4.013(1.48),4.046(1.24),5.330(3.51),5.464(3.44),5.754(5.44),7.245(1.57),7.261(4.38),7.280(5.05),7.297(2.40),7.346(2.58),7.364(5.51),7.382(5.14),7.401(2.31),7.437(10.14),7.440(9.69),7.457(8.61),7.459(8.00),7.473(5.24),7.476(5.21),7.491(5.14),7.504(8.41),7.508(7.91),7.526(10.05),7.530(9.68),7.574(5.17),7.579(8.88),7.585(4.72),7.596(2.97),7.602(5.05),7.607(2.72),7.893(1.57),8.694(4.86),12.050(1.46).
5-[({6-溴-2-[(3R)-3-氟吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(120mg,96%純度,187μmol,表異構物混合物,實施例106A)在二氯甲烷(2.4ml)中的溶液中加入TFA(140μl,1.9mmol),將混合物在RT下攪拌42小時。隨後,再次加入TFA(80μl,1.0mmol),並將混合物在室溫再攪拌24小時。隨後,再次加入TFA(80μl,1.0mmol),並將混合物在室溫再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到86mg(97%純度,理論值的79%)標題化合物。
LC-MS(方法1):Rt=1.76min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.49),0.146(0.51),1.798(1.12),1.817(2.38),1.839(3.22),1.862(1.84),2.049(7.23),2.078(7.50),2.089(7.59),2.121(3.46),2.139(4.86),2.176(16.00),2.327(0.85),2.366(0.67),2.670(0.79),2.710(0.70),3.600(5.99),3.626(4.79),3.657(4.00),3.867(2.42),3.883(2.41),3.912(2.32),3.945(1.44),4.012(1.54),4.046(1.33),5.331(3.59),5.465(3.56),5.754(6.66),7.245(1.53),7.263(4.27),7.280(4.74),7.297(2.23),7.326(0.79),7.346(2.69),7.364(5.42),7.383(4.83),7.400(2.08),7.437(9.28),7.440(9.14),7.457(7.78),7.477(5.10),7.492(4.88),7.504(7.74),7.508(7.57),7.526(9.34),7.530(9.61),7.574(4.77),7.580(8.37),7.585(4.71),7.596(2.81),7.602(4.80),7.607(2.77),8.693(4.97),12.045(3.38).
將標題化合物(72mg)溶於甲醇(12ml)中,並通過製備型SFC在手性相上分離為對映異構物/表異構物(參見實施例67和68)[管柱:Daicel Chiralcel OX-H,5μm,250mm×30mm;流速:100毫升/分鐘;注入:1.0毫升;溶析液:20%甲醇/80%二氧化碳;操作時間21分鐘,等度,UV檢測210nm,溫度40℃]。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。
在實施例66中所述的對映異構物分離中,獲得16mg(100%純度,ee>99%)標題化合物作為較早洗脫出的表異構物/對映異構物。
[α]D 20=+22.1°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=1.79min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.64),-0.008(5.27),0.008(5.32),0.070(0.55),0.146(0.62),1.236(0.44),1.359(1.61),1.754(0.54),1.819(2.40),1.840(3.08),1.865(1.93),2.025(2.41),2.051(6.86),2.078(7.50),2.092(6.21),2.100(4.56),2.115(3.52),2.141(5.17),2.177(16.00),2.295(0.60),2.327(0.93),2.670(0.75),2.994(0.93),3.207(0.79),3.601(5.46),3.672(4.92),3.840(1.34),3.867(2.43),3.884(2.44),3.913(2.25),3.946(1.30),4.023(1.47),4.047(1.26),5.331(3.06),5.466(3.06),6.311(0.64),7.246(2.55),7.264(5.98),7.283(4.16),7.347(3.88),7.366(6.57),7.384(3.70),7.437(8.61),7.440(9.05),7.457(7.58),7.460(7.75),7.477(7.69),7.493(5.77),7.496(5.99),7.508(8.92),7.530(14.54),7.580(8.24),7.585(7.42),7.602(4.52),7.608(4.33),7.879(0.83),8.680(2.80),8.695(5.16),8.708(2.51),12.041(3.60).
在實施例66中所述的對映異構物分離中,獲得14mg(100%純度,ee>82%)標題化合物作為較晚洗脫出的表異構物/對映異構物。
[α]D 20=+40.7°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.79min;MS(ESIpos):m/z=562/564[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.09),-0.008(9.27),0.008(8.56),0.069(2.49),0.146(1.09),1.235(0.52),1.359(1.59),1.754(0.45),1.798(1.61),1.819(2.89),1.839(3.82),1.861(2.49),2.048(7.89),2.089(9.53),2.136(6.02),2.174(14.55),2.327(1.47),2.366(0.43),2.670(1.33),2.994(0.52),3.207(1.14),3.462(0.47),3.578(4.81),3.602(6.35),3.627(5.43),3.640(5.24),3.703(2.56),3.857(2.49),3.876(2.44),3.903(2.23),3.944(1.37),4.011(1.49),4.044(1.23),5.330(3.56),5.464(3.51),6.305(0.71),6.310(1.02),6.316(0.69),7.260(4.27),7.280(5.78),7.298(3.93),7.365(4.76),7.383(6.42),7.400(3.96),7.421(1.75),7.437(10.38),7.440(10.05),7.457(8.53),7.460(8.18),7.486(6.83),7.504(13.27),7.525(16.00),7.574(8.23),7.579(8.63),7.596(4.62),7.601(5.03),7.879(1.37),8.675(3.25),8.689(5.67),8.703(3.18),9.688(0.50),12.040(7.44).
5-[({6-溴-2-[反式-3,4-二氟吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(169mg,77%純度,204μmol,非對映異構物混合物,實施例107A)在二氯甲烷(2.3ml)之溶液中加入TFA(160μl,2.0mmol),並將混合物在RT下攪拌42小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備HPLC純化(方法6)。將合併的目標級分各自濃 縮,並將各殘留物冷凍乾燥。得到8mg(100%純度,理論值的7%)第一批標題化合物和57mg(98%純度,理論值的47%)第二批標題化合物。
LC-MS(方法1):Rt=1.96min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.235(1.28),1.258(0.52),1.372(6.58),1.822(1.87),1.836(3.94),1.851(4.34),1.866(2.51),1.986(0.72),2.065(8.57),2.083(9.10),2.108(4.07),2.130(4.83),2.141(4.69),2.162(3.43),2.198(16.00),2.308(0.51),3.613(3.36),3.645(3.02),3.758(4.47),4.101(3.01),4.175(3.15),5.378(6.46),5.468(6.57),5.743(0.97),7.252(2.23),7.264(4.72),7.278(4.83),7.352(2.93),7.365(5.53),7.377(4.90),7.441(9.98),7.454(9.21),7.477(6.06),7.490(8.21),7.501(4.48),7.555(5.84),7.570(8.53),7.616(6.75),7.630(4.65),7.888(1.25),8.680(7.05),12.012(1.02).
LC-MS(方法1):Rt=1.96min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.66),-0.008(6.04),0.008(5.65),0.146(0.64),1.157(0.68),1.175(1.34),1.192(0.75),1.234(0.57),1.367(1.36),1.801(1.23),1.819(2.68),1.842(3.65),1.865(2.07),1.988(2.50),2.049(6.83),2.077(7.97),2.089(8.19),2.114(3.09),2.139(3.90),2.192(16.00),2.304(0.43),2.327(1.16),2.366(0.91),2.523(3.13),2.670(1.02),2.710(1.00),3.600(3.25),3.647(2.77),3.741(3.54),4.020(0.79),4.038(0.93),4.074(2.36),4.100(2.22),4.183(2.45),5.354(5.11),5.360(5.45),5.494(5.49),5.500(5.36),5.754(2.75),7.246(1.66),7.264(4.63),7.282(5.06),7.301(2.25),7.348(2.63),7.366(5.81),7.385(5.15),7.403(2.16),7.439(10.44),7.458(8.76),7.476(5.56),7.479(5.83),7.494(6.33),7.509(3.43),7.544(5.83),7.548(6.45),7.566(10.80),7.571(11.57),7.609(5.56),7.615(9.74),7.621(5.65),7.631(3.13),7.637(5.38),7.643(3.27),7.893(0.68),8.688(3.29),8.702(6.42),8.716(3.43),12.035(0.98).
(+/-)-5-[({6-溴-2-[順式-3,4-二氟吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(160mg,93%純度,233μmol,外消旋物,實施例108A)在二氯甲烷(2.3ml)中的溶液中加入TFA(180μl,2.3mmol),並將該混合物在RT下攪拌66小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到68mg(理論值的93%純度,理論值的47%)標題化合物的標題化合物。
LC-MS(方法1):Rt=1.93min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.26),-0.008(12.03),0.008(11.85),0.146(1.32),1.157(0.60),1.174(1.32),1.192(0.60),1.236(0.54),1.368(0.42),1.797(1.08),1.816(2.41),1.839(3.25),1.862(1.80),1.988(2.47),2.046(5.95),2.080(7.04),2.090(7.22),2.137(6.02),2.160(14.20),2.297(0.42),2.327(1.80),2.366(1.86),2.523(6.44),2.669(2.11),2.710(2.05),3.586(2.89),3.671(3.55),3.782(3.19),3.994(2.53),4.021(2.47),5.298(3.07),5.311(2.29),5.324(2.41),5.333(2.47),5.426(2.65),5.435(2.77),5.448(2.41),5.460(3.07),5.754(7.10),7.254(2.35),7.271(5.17),7.290(3.73),7.356(3.25),7.374(5.95),7.392(3.43),7.438(9.32),7.440(9.44),7.458(7.70),7.460(7.58),7.482(7.46),7.499 (5.53),7.541(8.78),7.563(16.00),7.609(8.54),7.614(8.18),7.631(4.63),7.636(4.69),8.678(3.13),8.693(6.38),8.707(3.13),12.043(7.52).
5-[({6-溴-2-[3-氟-3-甲基吡咯啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(120mg,96%純度,181μmol,非對映異構物混合物,實施例109A)在二氯甲烷(2.4ml)的溶液中加入TFA(140μl,1.8mmol),並將混合物在RT下攪拌42小時。隨後,再次加入TFA(70μl,0.9mmol),並將混合物在室溫再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到83mg(100%純度,理論值的79%)標題化合物。
LC-MS(方法1):Rt=1.89min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(2.03),1.157(4.22),1.175(8.34),1.192(4.18),1.541(8.21),1.593(8.22),1.817(0.84),1.839(1.06),1.862(0.58),1.988(16.00),2.018(0.92),2.048(2.34),2.078(2.77),2.088(2.72),2.114(1.68),2.134(2.41),2.170(5.51),2.327(0.45),2.523(1.92),2.670(0.43),3.616(1.97),3.798(0.72),3.829(0.51),3.890(0.85),3.921(1.25),3.947(0.84),4.003(1.38),4.021(3.82),4.038(3.71),4.056(1.22),7.246(0.61),7.262(1.49),7.281(1.62),7.298(0.74),7.346(1.01),7.365(1.86),7.382(1.59),7.401(0.70),7.437(3.28),7.457(2.76),7.474(1.73),7.494(3.00),7.499(2.45),7.516(3.28),7.521(3.10), 7.566(1.68),7.572(2.81),7.578(1.55),7.589(0.99),7.594(1.61),7.600(0.88),8.692(1.46),12.038(3.86).
(+/-)-5-({[6-溴-3-甲基-2-(3,3,4,4-四氟吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(69mg,9%純度,9.49μmol,外消旋物,實施例110A)在二氯甲烷(910μl)的溶液中加入TFA(7.3μl,95μmol),並將混合物在室溫下攪拌18小時。隨後再次加入TFA(7.3μl,95μmol),並將混合物在室溫再攪拌48小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到4mg(100%純度,理論值的68%)標題化合物。
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=616/618[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.052(0.83),0.854(0.54),0.901(1.54),0.911(1.52),1.236(2.63),1.262(1.41),1.300(0.66),1.338(0.74),1.369(1.41),1.820(1.99),1.834(4.21),1.848(4.54),1.864(2.58),2.047(3.16),2.060(9.95),2.078(9.12),2.083(7.22),2.092(4.10),2.099(3.52),2.107(3.71),2.125(4.63),2.132(5.17),2.139(6.68),2.156(4.33),2.184(16.00),2.256(0.78),2.313(0.61),2.383(0.51),2.611(0.63),3.512(0.66),3.589(4.04),3.689(4.56),4.258(10.47),7.261(3.41),7.274(6.97),7.286(4.66),7.360(4.30),7.373(7.46),7.385(4.17),7.443(11.50),7.457(10.28),7.482(9.64),7.495(8.17),7.648(9.39), 7.662(15.42),7.697(9.84),7.712(5.70),7.888(0.93),8.680(4.82),8.689(8.49),8.698(4.46),12.010(4.14).
(+/-)-5-[({2-[3-氮雜雙環[3.1.1]庚-3-基]-6-溴-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(63mg,100μmol,外消旋物,實施例111A)在二氯甲烷(2.5ml)之溶液中加入TFA(120μl,1.5mmol),並將該混合物在RT下攪拌24小時。隨後再次加入TFA(7.3μl,95μmol),並將混合物在室溫再攪拌48小時。隨後濃縮混合物,並重複加入二氯甲烷,隨後再濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到38mg(100%純度,理論值的66%)標題化合物。
LC-MS(方法1):Rt=2.07min;MS(ESIpos):m/z=570/572[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.04),-0.008(9.81),0.008(9.81),0.146(1.07),1.235(0.70),1.369(1.83),1.426(1.48),1.439(9.09),1.445(8.32),1.455(8.53),1.461(9.55),1.474(1.76),1.796(1.00),1.814(2.18),1.838(3.04),1.861(1.76),1.885(0.56),2.046(5.15),2.076(9.00),2.087(12.29),2.102(8.74),2.108(8.81),2.124(4.50),2.134(4.24),2.158(2.02),2.195(16.00),2.274(0.46),2.300(0.56),2.327(0.86),2.366(0.93),2.670(0.83),2.710(0.93),3.591(2.83),3.666(3.99),3.867(3.83),7.253(2.32),7.272(5.24),7.291(3.69),7.354(3.39),7.373(6.14),7.391(3.73),7.438(8.74),7.441(8.70),7.458(7.05),7.461(6.91),7.480(6.61),7.498(4.78),7.524(7.63),7.546(15.61),7.581(8.77),7.587 (8.16),7.603(4.20),7.609(4.20),8.705(2.81),8.720(5.43),8.734(2.81),11.983(0.42).
(+/-)-5-[({2-[3氮雜雙環[3.2.1]辛-3-基]-6-溴-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(77mg,120μmol,外消旋物,實施例112A)在二氯甲烷(2.0ml)之溶液中加入TFA(140μl,1.8mmol),並將該混合物在室溫下攪拌48小時。隨後,再次加入TFA(140μl,1.8mmol),並將混合物在室溫再攪拌18小時。隨後濃縮混合物,並重複加入二氯甲烷,隨後再濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到38mg(100%純度,理論值的54%)標題化合物。
LC-MS(方法1):Rt=2.40min;MS(ESIpos):m/z=584/586[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.42),-0.008(3.49),0.008(3.22),0.147(0.42),1.236(0.97),1.325(1.08),1.349(4.20),1.552(10.36),1.652(4.29),1.664(4.68),1.702(1.24),1.749(5.47),1.768(5.29),1.808(2.02),1.830(2.75),1.853(1.69),2.039(4.17),2.067(6.22),2.074(5.47),2.088(3.49),2.097(2.29),2.123(3.05),2.146(1.53),2.182(16.00),2.226(0.73),2.299(7.19),2.366(0.81),2.670(0.80),2.710(0.78),2.890(2.64),2.907(3.61),2.934(3.27),3.133(0.41),3.583(2.22),3.668(3.76),7.256(2.02),7.274(4.53),7.292(3.24),7.354(2.83),7.373(5.00),7.391(2.71),7.443(7.29),7.445(7.37),7.466(7.25),7.475(6.63),7.494(4.54),7.605(4.66),7.627(14.17),7.643(8.36),7.648(7.56),7.666 (2.56),7.671(2.59),8.734(2.17),8.748(4.20),8.762(2.05).
(+/-)-5-({[6-溴-2-(3,3-二氟吖呾-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(30mg,96%純度,46.2μmol,外消旋物,實施例113A)在二氯甲烷(1.9ml)中的溶液中加入TFA(36μl,460μmol),並將該混合物在RT下攪拌18小時。隨後,再次加入TFA(36μl,460μmol),並將混合物在室溫再攪拌24小時。隨後,再次加入TFA(18μl,230μmol),並將混合物在室溫再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到18mg(100%純度,理論值的69%)標題化合物。
LC-MS(方法1):Rt=2.00min;MS(ESIpos):m/z=566/568[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.80),0.008(14.73),0.146(1.67),1.236(1.47),1.367(1.27),1.793(1.20),1.813(2.47),1.835(3.20),1.858(1.80),2.041(9.47),2.066(14.00),2.085(9.27),2.113(3.20),2.133(3.93),2.156(1.80),2.327(2.40),2.366(2.07),2.523(8.00),2.669(2.73),2.710(2.13),3.585(2.80),3.673(3.73),4.581(6.73),4.613(12.67),4.644(6.60),5.754(9.53),7.254(2.20),7.271(5.00),7.290(3.53),7.352(3.00),7.371(5.47),7.389(3.00),7.438(9.33),7.458(8.07),7.476(7.53),7.493(5.67),7.588(7.87),7.610(16.00),7.647(8.87),7.652(7.80),7.669(4.27),7.674(4.07),8.693(3.07),8.707(5.87),8.722(2.93),12.045(3.13).
5-[({6-溴-2-[3-氰基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(197mg,308μmol,非對映異構物混合物,實施例114A)在二氯甲烷(4.0ml)的溶液中加入TFA(360μl,4.6mmol),並將混合物在RT攪拌過夜。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。首先通過製備型HPLC(方法8)將殘餘物預純化,然後通過相同的方法再純化兩次。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到55mg(95%純度,理論值的29%)標題化合物。
LC-MS(方法1):Rt=1.97min;MS(ESIpos):m/z=583/585[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.11),0.008(3.20),0.938(0.76),0.955(0.75),1.488(9.73),1.656(0.56),1.667(0.80),1.719(1.80),1.802(2.69),1.825(3.97),1.846(2.65),1.876(4.02),1.888(5.87),1.901(4.88),2.003(1.54),2.015(3.69),2.041(6.06),2.063(3.89),2.073(3.24),2.100(2.40),2.122(1.26),2.181(16.00),2.239(0.56),2.327(0.59),2.366(0.58),2.523(1.43),2.665(0.46),2.670(0.55),2.710(0.66),2.756(4.54),3.020(2.08),3.212(2.91),3.268(4.82),3.276(4.72),3.295(4.84),3.328(5.24),3.441(3.75),3.456(3.51),3.473(2.89),3.487(2.47),3.580(2.53),3.681(3.48),7.252(1.84),7.270(4.21),7.287(2.95),7.352(2.53),7.371(4.60),7.389(2.37),7.436(6.16),7.440(5.96),7.456(5.23),7.459(4.98),7.478(5.40),7.495(4.41),7.669(1.98),7.691(14.43),7.694 (12.09),7.699(8.72),7.717(1.14),7.721(1.37),7.891(0.91),8.753(2.20),8.767(4.21),8.781(2.02).
(+/-)-5-({[6-溴-2-(3,6-二氫-2H-1,2--2-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(65mg,106μmol,外消旋物,實施例115A)在二氯甲烷(2.0ml)之溶液中加入TFA(160μl,2.1mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到51mg(97%純度,理論值的83%)標題化合物。
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.935(1.33),0.952(1.27),1.066(1.35),1.082(1.38),1.531(8.69),1.809(1.67),1.830(1.32),1.945(1.75),1.972(2.68),1.992(3.01),2.006(3.92),2.033(2.92),2.187(8.46),2.327(0.72),2.365(0.70),2.669(0.84),2.730(4.10),3.334(2.23),3.556(1.91),3.673(2.35),4.069(6.50),4.505(4.29),5.990(1.44),6.015(3.42),6.049(2.99),6.074(1.24),7.246(1.38),7.264(3.21),7.282(2.18),7.346(1.76),7.365(3.36),7.384(1.70),7.436(4.65),7.459(5.68),7.481(2.65),7.548(0.84),7.743(15.75),7.745(16.00),8.955(2.23).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(75mg,118μmol,非對映異構物混合物,實施例116A)在二氯甲烷(870μl)的溶液中加入TFA(91μl,1.2mmol),並將混合物放置在室溫16小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到56mg(98%純度,理論值的80%)標題化合物。
LC-MS(方法2):Rt=1.09min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.24),0.008(2.48),1.642(1.63),1.765(0.52),1.793(1.91),1.810(3.01),1.819(2.66),1.834(3.26),1.858(1.97),1.900(2.78),1.920(2.26),1.950(1.57),1.982(0.97),2.011(0.73),2.034(1.27),2.045(4.21),2.079(5.00),2.088(5.22),2.143(16.00),2.217(0.40),2.327(0.45),2.366(0.51),2.523(1.47),2.669(0.48),2.710(0.56),3.094(1.88),3.159(2.00),3.377(2.00),3.410(1.07),3.434(1.75),3.465(1.09),3.593(1.93),3.679(3.48),4.816(1.35),4.936(1.31),7.256(1.72),7.274(4.01),7.294(2.80),7.356(2.44),7.374(4.45),7.393(2.29),7.441(6.25),7.444(6.25),7.461(5.34),7.464(5.25),7.484(5.69),7.500(4.68),7.647(2.48),7.669(13.43),7.675(9.66),7.680(8.33),7.697(1.60),7.702(1.84),8.715(2.20),8.730(4.40),8.744(2.14),12.062(0.87).
首先將(+/-)-2-甲基吡咯啶(9mg,100μmol)加入到96孔MTP的孔中,並將(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)在NMP(800μl)之溶液,然後加入DIPEA(50μl,287μmol)。將MTP用黏著膜密封並在120℃攪拌過夜。隨後,在離心乾燥器中除去溶劑,並將TFA(800μl,10.4mmol)加入殘餘物中。用黏著膜再次密封MTP並在室溫攪拌過夜。隨後,在離心乾燥器中除去TFA,並將殘餘物溶於DMF(600μl)中。藉助濾板過濾溶液,濾液藉由製備型HPLC-MS純化(方法17)。除去溶劑並減壓乾燥,得到6mg(100%純度,理論值的11%)標題化合物。
LC-MS(方法16):Rt=0.95min;MS(ESIpos):m/z=558/560[M+H]+
(-)-5-[({6-溴-3-甲基-2-[(2S)-2-甲基吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(135mg,220μmol,表異構物1,實施例118A)在二氯甲烷(1.7ml)的溶液中加入TFA(370μl,4.8mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到56mg(100%純度,理論值的46%)標題化合物。
[α]D 20=-33.3°,589nm,c=0.40g/100ml,甲醇
LC-MS(方法1):Rt=1.88min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.141(15.77),1.156(16.00),1.370(0.82),1.512(0.44),1.539(1.29),1.557(1.57),1.579(1.54),1.606(0.94),1.663(1.38),1.689(1.45),1.709(0.94),1.792(0.79),1.810(1.53),1.832(1.99),1.854(1.21),1.896(1.94),2.041(4.08),2.097(10.55),2.127(4.78),2.327(0.46),2.669(0.44),3.587(2.86),3.610(1.84),3.623(2.08),3.691(1.33),3.716(2.88),3.732(3.30),3.756(2.27),4.360(1.38),4.375(2.28),4.397(2.15),4.413(1.32),7.260(1.69),7.278(3.73),7.297(2.73),7.362(2.89),7.381(4.34),7.398(2.39),7.436(6.24),7.455(5.02),7.481(4.21),7.498(8.03),7.520(9.92),7.566(5.37),7.571(4.99),7.588(2.85),7.594(2.78),8.688(2.06),8.702(3.28).
(-)-5-[({6-溴-3-甲基-2-[(2S)-2-甲基吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(130mg,211μmol,表異構物2,實施例119A)在二氯甲 烷(1.6ml)的溶液中加入TFA(360μl,4.7mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到71mg(100%純度,理論值的60%)標題化合物。
[α]D 20=-9.2°,589nm,c=0.47g/100ml,甲醇
LC-MS(方法1):Rt=1.87min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.142(15.85),1.157(16.00),1.346(0.61),1.511(0.44),1.540(1.31),1.556(1.56),1.563(1.55),1.579(1.52),1.607(0.99),1.660(1.32),1.684(1.35),1.705(0.86),1.793(0.68),1.813(1.62),1.835(2.04),1.859(1.20),1.897(1.92),1.912(1.82),2.021(0.92),2.047(4.11),2.075(5.50),2.104(14.49),2.142(4.74),2.164(2.34),2.201(0.49),3.611(2.35),3.661(2.85),3.678(2.70),3.695(2.70),3.712(2.42),3.720(2.96),3.737(2.63),3.761(1.12),4.362(1.27),4.377(2.15),4.392(1.83),4.399(2.04),4.414(1.23),7.242(1.76),7.260(4.06),7.279(2.87),7.343(2.51),7.362(4.68),7.380(2.49),7.438(6.32),7.458(5.90),7.472(5.71),7.491(4.08),7.503(5.93),7.525(9.65),7.573(5.51),7.579(5.04),7.596(2.97),7.601(2.83),8.689(2.01),8.703(3.73),11.998(0.66).
(+)-5-[({6-溴-3-甲基-2-[(2R)-2-甲基吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(135mg,220μmol,表異構物1,實施例121A)在二 氯甲烷(1.6ml)之溶液中加入TFA(360μl,4.7mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到66mg(100%純度,理論值的56%)標題化合物。
[α]D 20=+10.3°,589nm,c=0.27g/100ml,甲醇
LC-MS(方法1):Rt=1.83min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.99),0.008(1.83),0.069(0.74),1.142(15.94),1.157(16.00),1.512(0.42),1.540(1.20),1.556(1.41),1.563(1.38),1.579(1.40),1.591(1.01),1.607(0.94),1.659(1.18),1.684(1.19),1.703(0.76),1.813(1.41),1.832(1.75),1.857(1.04),1.897(1.67),1.911(1.60),2.014(0.79),2.041(3.65),2.068(4.96),2.103(12.77),2.135(4.21),2.158(2.42),2.200(0.41),2.327(0.42),2.669(0.40),3.616(1.97),3.661(2.55),3.676(2.39),3.695(2.33),3.712(2.11),3.720(2.73),3.736(2.47),3.745(1.54),3.761(1.03),4.361(1.20),4.377(2.01),4.392(1.64),4.399(1.83),4.414(1.14),7.242(1.70),7.260(3.70),7.277(2.72),7.280(2.68),7.342(2.47),7.361(4.37),7.377(2.29),7.435(5.99),7.438(5.94),7.455(5.61),7.458(5.42),7.469(5.23),7.473(5.18),7.489(3.79),7.502(6.11),7.524(10.25),7.573(6.05),7.578(5.39),7.595(3.25),7.601(3.05),8.693(1.77),8.708(3.30).
(+)-5-[({6-溴-3-甲基-2-[(2R)-2-甲基吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(130mg,211μmol,表異構物2,實施例122A)在二氯甲烷(1.6ml)的溶液中加入TFA(360μl,4.7mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到67mg(100%純度,理論值的57%)標題化合物。
[α]D 20=+32.3°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=1.82min;MS(ESIpos):m/z=558/560[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.45),0.008(1.37),0.070(1.15),1.141(15.90),1.156(16.00),1.234(0.48),1.511(0.49),1.540(1.33),1.556(1.56),1.563(1.54),1.578(1.53),1.591(1.12),1.607(1.00),1.618(0.48),1.646(0.89),1.663(1.38),1.688(1.40),1.708(0.86),1.792(0.76),1.810(1.48),1.832(1.92),1.854(1.17),1.879(1.22),1.895(1.83),1.910(1.71),1.924(1.44),2.040(3.92),2.082(7.77),2.097(9.79),2.127(4.49),2.149(2.42),3.551(1.52),3.586(2.61),3.609(1.77),3.623(1.97),3.636(1.06),3.691(1.34),3.708(1.88),3.715(2.78),3.732(3.09),3.740(2.44),3.756(2.09),4.360(1.33),4.375(2.20),4.382(1.74),4.391(1.81),4.397(2.08),4.413(1.27),7.260(1.62),7.278(3.41),7.297(2.41),7.362(2.67),7.381(3.92),7.399(2.14),7.435(5.68),7.438(5.69),7.455(4.64),7.458(4.55),7.481(3.87),7.498(7.60),7.520(9.64),7.566(5.08),7.572(4.98),7.588(2.76),7.594(2.84),8.688(1.91),8.703(3.11),8.715(1.87).
首先將1,2,3,4-四氫異喹啉(13mg,100μmol)加入到96孔MTP的孔中,並將(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)在NMP(800μl)之溶液加入,然後加入DIPEA(50μl,287μmol)。將MTP用黏著膜密封並在120℃攪拌過夜。隨後,在離心乾燥器中除去溶劑,並將TFA(800μl,10.4mmol)加入殘餘物中。用黏著膜再次密封MTP並在室溫攪拌過夜。隨後,在離心乾燥器中除去 TFA,並將殘餘物溶於DMF(600μl)中。藉助濾板過濾溶液,濾液通過製備型HPLC-MS純化(方法17)。除去溶劑並減壓乾燥,得到12mg(96%純度,理論值的19%)標題化合物。
LC-MS(方法16):Rt=1.26min;MS(ESIpos):m/z=606/608[M+H]+
從(+/-)-哌啶-3-甲醯胺(13mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得11mg(95%純度,理論值的18%)標題化合物。
LC-MS(方法16):Rt=1.00min;MS(ESIpos):m/z=601/603[M+H]+
從八氫-1H-異吲哚鹽酸鹽(13mg,100μmol,以游離胺為基準之莫耳量,立體化學未知)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到8mg(100%純度,理論值的13%)標題化合物。
LC-MS(方法16):Rt=0.95min;MS(ESIpos):m/z=598/600[M+H]+
從硫代嗎福1,1-二氧化物(14mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基 喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到1mg(100%純度,理論值的2%)標題化合物。
LC-MS(方法16):Rt=1.08min;MS(ESIpos):m/z=608/610[M+H]+
從咪唑啶-4-酮鹽酸鹽(9mg,100μmol,以游離胺為基準之莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A),類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得1.7mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=1.00min;MS(ESIpos):m/z=559/561[M+H]+
從(+/-)-2-甲基嗎福啉(10mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得1.7mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=1.14min;MS(ESIpos):m/z=574/576[M+H]+
從1,4-氧雜氮雜環庚烷鹽酸鹽(10mg,100μmol,以游離胺為基準之莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得3.4mg(100%純度,理論值的6%)標題化合物。
LC-MS(方法16):Rt=1.10min;MS(ESIpos):m/z=574/576[M+H]+
從(+/-)-3-異丙基哌啶(13mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到10mg(99%純度,理論值的16%)標題化合物。
LC-MS(方法16):Rt=1.28min;MS(ESIpos):m/z=600/602[M+H]+
從3-甲氧基吖呾鹽酸鹽(9mg,100μmol,以游離胺為基準之莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A),類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-yl)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到3.2mg(100%純度,理論值的7%)標題化合物。
LC-MS(方法16):Rt=0.88min;MS(ESIpos):m/z=560/562[M+H]+
從(+/-)-3-(甲氧基甲基)哌啶(13mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-yl)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得10mg(100%純度,理論值的16%)標題化合物。
LC-MS(方法16):Rt=1.18min;MS(ESIpos):m/z=602/604[M+H]+
從2-苯基乙胺(12mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得8.5mg(純度97%,理論值的14%)的標題化合物。
LC-MS(方法16):Rt=0.97min;MS(ESIpos):m/z=594/596[M+H]+
從N-甲基-2-苯基乙胺(14mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得8mg(98% 純度,理論值的12%)標題化合物。
LC-MS(方法16):Rt=1.23min;MS(ESIpos):m/z=608/610[M+H]+
從1-苯基甲胺(11mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得4mg(純度94%,理論值的6%)的標題化合物。
LC-MS(方法16):Rt=1.04min;MS(ESIpos):m/z=580/582[M+H]+
從環丁胺鹽酸鹽(7mg,100μmol,以游離胺為基準的莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得2mg(100%純度,理論值的4%)標題化合物。
LC-MS(方法16):Rt=0.87min;MS(ESIpos):m/z=544/546[M+H]+
從3,3,3-三氟丙-1-胺(11mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到1.5mg(98%純度,理論值的2%)標題化合物。
LC-MS(方法16):Rt=1.09min;MS(ESIpos):m/z=586/588[M+H]+
從1-環己基甲胺(11mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得5mg(純度98%,理論值的9%)的標題化合物。
LC-MS(方法16):Rt=0.96min;MS(ESIpos):m/z=586/588[M+H]+
從1-環丙基甲胺鹽酸鹽(7mg,100μmol,以游離胺為基準的莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得1.7mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=0.86min;MS(ESIpos):m/z=544/546[M+H]+
從丁-1-胺(7.31mg,100μmol)和(+/-)-1.7-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得1.7mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=0.88min;MS(ESIpos):m/z=546/548[M+H]+
從2-甲基丙-1-胺(7mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,獲得1.6mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=0.88min;MS(ESIpos):m/z=546/548[M+H]+
從環戊胺(8.5mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得6mg(98%純度%,理論值的10%)的標題化合物。
LC-MS(方法16):Rt=0.89min;MS(ESIpos):m/z=558/560[M+H]+
從2-甲氧基乙胺(7.5mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得5mg(純度100%,理論值的10%)的標題化合物。
LC-MS(方法16):Rt=0.83min;MS(ESIpos):m/z=548/550[M+H]+
從氮雜環庚烷(10mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,得到9mg(100%純度,理論值的15%)標題化合物。
LC-MS(方法16):Rt=1.14min;MS(ESIpos):m/z=572/574[M+H]+
(-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(460mg,731μmol,對映異構物1,實施例124A)在二氯甲烷(5.6ml)的溶液中加入TFA(1.2ml,16mmol),並將混合物在RT下放置22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。取得353mg(100%純度,理論值的84%)標題化合物。
[α]D 20=-11.0°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法1):Rt=2.24min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.92),1.602(13.71),1.781(9.13),1.838(2.48),1.861(1.35),1.885(0.41),2.015(0.52),2.027(0.93),2.047(3.94),2.080(5.20),2.088(5.61),2.097(3.42),2.126(16.00),2.158(1.47),2.188(0.52),3.488(10.68),3.503(15.64),3.517(10.53),3.575(1.79),3.591(2.07),3.666(2.69),7.254(1.70),7.273(4.00),7.292(2.84),7.355(2.46),7.374(4.52),7.392(2.65),7.440(6.52),7.460(5.09),7.481(5.13),7.500(3.64),7.525(5.49),7.547(10.22),7.591(5.50),7.596(5.36),7.613(2.93),7.618(2.95),8.684(2.11),8.698(4.20),8.712(2.10),12.061(0.74).
(+)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(460mg,731μmol,對映異構物2,實施例125A)在二氯甲烷(5.6ml)之溶液中加入TFA(1.2ml,16mmol),並將混合物在RT下放置22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。取得312mg(100%純度,理論值的74%)標題化合物。
[α]D 20=+12.5°,589nm,c=0.50g/100ml,甲醇
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=572/574[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.602(13.76),1.780(9.07),1.839(2.47),1.861(1.35),1.884(0.43),2.048(3.93),2.082(5.18),2.089(5.61),2.126(16.00),2.159(1.44),2.188(0.56),3.488(10.85),3.503(15.65),3.517(10.64),3.592(2.07),3.666(2.71),7.255(1.73),7.273(4.04),7.293(2.84),7.355(2.51),7.374(4.61),7.392(2.69),7.438(6.62),7.441(6.85),7.458(5.22),7.461(5.35),7.482(5.16),7.499(3.67),7.525(5.79),7.547(10.73),7.591(5.94),7.596(5.65),7.613(3.13),7.618(3.13),8.684(2.16),8.698(4.31),8.712(2.14),12.058(0.92).
從(+/-)-2-甲基哌啶(10mg,100μmol)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得2mg標題化合物(純度94%,理論值的3%)。
LC-MS(方法16):Rt=1.13min;MS(ESIpos):m/z=572/574[M+H]+
從乙胺鹽酸鹽(5mg,100μmol,以游離胺為基準的莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似於(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得1.8mg(100%純度,理論值的3%)標題化合物。
LC-MS(方法16):Rt=0.8min;MS(ESIpos):m/z=518/520[M+H]+
從5-氮雜螺[2.5]辛烷鹽酸鹽(11mg,100μmol,以游離胺為基準的莫耳量)和(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯苯基)戊酸三級丁酯(57mg,100μmol,外消旋物,實施例37A)開始,類似(+/-)-5-({[6-溴-2-(3,4-二氫異喹啉-2(1H)-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(實施例84)之製備,取得2.6mg(100%純度,理論值的4%)標題化合物。
LC-MS(方法16):Rt=1.23min;MS(ESIpos):m/z=584/586[M+H]+
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,131μmol,外消旋物,實施例126A)於二氯甲烷(1.5ml)之溶液中加入TFA(200μl,2.6mmol),在RT下攪拌混合物18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到52mg(100%純度,理論值的67%)標題化合物。
LC-MS(方法1):Rt=2.23min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.611(5.32),1.679(10.54),1.897(1.82),1.907(1.73),1.928(2.08),1.942(1.97),1.962(1.64),1.979(2.69),1.992(1.70),2.003(3.05),2.023(0.92),2.040(1.68),2.055(3.02),2.078(3.08),2.096(1.81),2.114(3.33),2.165(16.00),3.150(13.69),3.606(1.32),3.623(2.06),3.639(2.27),3.684(1.45),3.700(2.32),3.716(1.96),3.733(1.31),7.435(1.23),7.463(2.79),7.482(4.90),7.501(3.01),7.634(2.00),7.656(15.77),7.664(9.55),7.687(3.06),7.707(5.08),7.724(11.45),7.733(8.28),7.742(6.88),8.767(2.49),8.782(4.97),8.796(2.45),12.044(0.78).
(-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(225mg,347μmol,對映異構物1,實施例127A)在二氯甲烷(2.6ml)之溶液中加入TFA(590μl,7.6mmol),並將混合物放置在室溫放置24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到142mg(100%純度,理論值的69%)標題化合物。
[α]D 20=-20.5°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.163(1.22),1.181(2.62),1.199(1.29),1.614(4.47),1.681(8.91),1.897(1.55),1.907(1.43),1.928(1.72),1.942(1.72),1.964(1.35),1.981(2.37),1.993(1.47),2.005(2.77),2.024(0.81),2.041(1.51),2.055(2.72),2.078(2.75),2.096(1.57),2.114(2.87),2.166(13.61),2.328(0.45),3.077(0.70),3.089(0.80),3.095(0.79),3.107(0.82),3.160(11.47),3.324(2.20),3.345(2.07),3.589(2.39),3.605(2.50),3.622(2.85),3.638(2.83),3.685(1.74),3.700(2.38),3.716(2.02),3.733(1.42),7.432(0.97),7.464(2.39),7.483(4.25),7.501(2.59),7.643(1.56),7.665(16.00),7.672(8.78),7.689(2.46),7.708(4.46),7.724(9.86),7.734(6.97),7.742(5.94),8.769(2.26),8.784(4.59),8.799(2.17).
(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(230mg,355μmol,對映異構物2,實施例128A)於二氯甲烷(2.7ml)之溶液中加入TFA(600μl,7.8mmol),並將混合物在室溫下留置24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)純化。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到158mg(100%純度,理論值的75%)標題化合物。
[α]D 20=+22.7°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.614(4.61),1.681(9.03),1.896(1.62), 1.907(1.52),1.928(1.80),1.942(1.79),1.963(1.45),1.980(2.43),1.993(1.57),2.004(2.84),2.025(0.92),2.040(1.60),2.055(2.81),2.078(2.82),2.096(1.75),2.113(3.02),2.165(13.52),2.328(0.42),3.160(11.56),3.324(2.39),3.492(2.62),3.589(1.71),3.606(1.97),3.622(2.44),3.639(2.48),3.684(1.64),3.699(2.30),3.716(1.91),3.732(1.31),7.463(2.54),7.483(4.26),7.501(2.53),7.643(1.92),7.666(16.00),7.672(8.62),7.689(2.69),7.694(2.06),7.708(4.85),7.724(10.06),7.734(7.01),7.742(5.89),8.769(2.40),8.784(4.53),8.799(2.10).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,134μmol,外消旋物,實施例129A)在二氯甲烷(1.5ml)的溶液中加入TFA(210μl,2.7mmol),並將該混合物在RT下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到40mg(100%純度,理論值的52%)標題化合物。
LC-MS(方法1):Rt=1.54min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.879(16.00),1.924(3.02),1.951(2.34),1.968(2.79),1.980(1.68),1.992(2.98),2.011(1.08),2.037(1.55),2.053(3.01),2.076(3.20),2.093(2.11),2.113(3.51),2.181(6.81),2.281(0.57),2.327(0.41),3.318(6.26),3.709(2.16),3.725(1.96),3.741(1.48),7.341(0.65),7.434(0.44),7.457(2.26),7.477(11.20),7.500(13.68),7.550(6.77),7.555(6.41), 7.572(3.79),7.578(3.74),7.685(1.86),7.705(5.30),7.716(8.48),7.733(10.38),7.747(2.43),8.715(2.47),8.729(4.76),8.744(2.37).
(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(160mg,252μmol,對映異構物1,實施例130A)在二氯甲烷(1.9ml)之溶液中加入TFA(430μl,5.5mmol),將混合物留置在室溫下22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到73mg(100%純度,理論值的50%)標題化合物。
[α]D 20=+18.9°,589nm,c=0.47g/100ml,甲醇
LC-MS(方法1):Rt=1.52min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.879(16.00),1.925(2.74),1.954(2.21),1.971(2.77),1.984(1.69),1.996(3.01),2.014(1.13),2.041(1.58),2.055(3.04),2.079(3.17),2.096(2.13),2.115(3.52),2.138(2.71),2.181(6.83),2.281(0.59),2.328(0.43),3.583(12.90),3.693(1.38),3.709(2.16),3.725(1.92),3.742(1.48),7.335(0.61),7.459(2.16),7.477(10.75),7.500(13.45),7.551(6.29),7.556(6.19),7.573(3.60),7.578(3.64),7.686(1.82),7.706(5.20),7.717(8.11),7.734(10.70),7.749(2.41),8.711(2.44),8.726(4.79),8.741(2.38),12.044(0.69).
(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(170mg,268μmol,對映異構物2,實施例131A)在二氯甲烷(2.1ml)的溶液中加入TFA(450μl,5.9mmol),將混合物留置在室溫下22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。濃縮合併的目標級分,並將殘餘物冷 凍乾燥。得到81mg(100%純度,理論值的52%)標題化合物。
[α]D 20=-17.5°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=1.52min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.236(0.42),1.885(16.00),1.935(2.55),1.957(2.22),1.974(2.98),1.986(1.84),1.998(3.37),2.016(1.29),2.041(1.73),2.056(3.35),2.080(3.42),2.097(2.31),2.115(3.73),2.137(2.74),2.186(6.71),2.328(0.54),2.670(0.46),3.597(11.63),3.711(2.35),3.727(2.10),3.744(1.60),7.246(0.44),7.334(0.66),7.459(2.46),7.478(5.04),7.497(4.57),7.519(2.99),7.567(3.96),7.588(2.35),7.687(1.96),7.706(5.62),7.717(8.55),7.734(12.13),7.750(2.51),8.719(2.21),8.734(4.05),8.748(2.14),12.028(1.34).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,124μmol,外消旋物,實施例132A)在二氯甲烷(1.5ml)之溶液中加入TFA(190μl,2.5mmol),並將該混合物在室溫下攪拌18小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到46mg(100%純度,理論值的59%)標題化合物。
LC-MS(方法1):Rt=2.17min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.896(6.19),1.980(2.25),2.004(2.45),2.055(3.73),2.078(4.51),2.114(5.44),2.136(4.06),2.185(12.02),2.670(0.22), 3.180(6.09),3.463(3.22),3.492(5.91),3.520(3.16),3.648(1.96),3.710(1.91),7.465(2.61),7.483(4.20),7.501(2.79),7.707(16.00),7.725(9.34),7.738(8.33),8.793(3.72),12.049(0.53).
(-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,124μmol,對映異構物1,實施例133A)在二氯甲烷(960μl)之溶液中加入TFA(210μl,2.7mmol),並將混合物在室溫留置22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得65mg(100%純度,理論值的83%)標題化合物。
[α]D 20=-18.2°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.899(4.56),1.946(1.50),1.953(1.22),1.967(1.16),1.984(1.98),1.997(1.22),2.008(2.30),2.028(0.88),2.043(1.59),2.057(3.11),2.065(2.55),2.081(3.82),2.099(3.51),2.118(4.18),2.137(2.87),2.152(2.34),2.186(10.54),2.227(0.62),3.182(4.64),3.464(2.89),3.493(5.52),3.522(2.77),3.617(0.87),3.634(1.31),3.649(1.45),3.712(1.41),3.727(1.22),7.467(2.12),7.486(3.75),7.504(2.35),7.685(1.58),7.692(1.59),7.708(16.00),7.713(10.69),7.727(7.64),7.743(7.02),7.758(1.87),8.777(1.83),8.792(3.78),8.807(1.84),12.035(1.20).
(+)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(60mg,87.6μmol,對映異構物2,實施例134A)在二氯甲烷(670μl)之溶液中加入TFA(150μl,1.9mmol),並將混合物在室溫放置22小時。然後濃縮混合物並重複加入二氯甲烷並再次濃縮混合物。 殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到38mg(100%純度,理論值的69%)標題化合物。
[α]D 20=+18.9°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.898(4.75),1.944(1.51),1.965(1.18),1.982(1.96),1.995(1.22),2.006(2.25),2.026(0.88),2.041(1.53),2.055(3.13),2.063(2.55),2.079(3.69),2.097(3.46),2.116(4.22),2.136(2.97),2.150(2.39),2.185(10.76),2.225(0.69),3.180(4.82),3.463(2.94),3.492(5.61),3.520(2.84),3.632(1.38),3.648(1.51),3.710(1.47),3.726(1.28),7.466(2.20),7.485(3.79),7.503(2.39),7.684(1.67),7.691(1.73),7.707(16.00),7.726(7.79),7.742(6.86),7.757(1.83),8.777(1.83),8.791(3.69),8.806(1.78),12.037(0.82).
(+/-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,128μmol,外消旋物,實施例135A)在二氯甲烷(1.5ml)之溶液中加入TFA(200μl,2.6mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到60mg(100%純度,理論值的77%)標題化合物。
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.610(14.32),1.791(9.69),1.899 (1.71),1.908(1.60),1.930(2.04),1.945(1.85),1.961(1.78),1.978(2.56),1.990(1.59),2.002(2.80),2.011(1.67),2.041(1.48),2.056(2.80),2.079(3.00),2.097(1.87),2.116(3.51),2.152(11.34),3.505(10.82),3.519(16.00),3.533(10.80),3.609(1.63),3.624(1.73),3.705(1.75),3.720(1.56),7.371(0.83),7.463(2.07),7.482(4.24),7.501(2.63),7.537(5.32),7.559(10.25),7.599(5.62),7.604(5.69),7.622(2.80),7.626(2.98),7.689(1.75),7.709(4.73),7.722(8.25),7.739(9.99),7.754(2.31),8.739(2.25),8.754(4.52),8.769(2.24),12.037(1.01).
(-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(70mg,106μmol,對映異構物1,實施例136A)在二氯甲烷(810μl)的溶液中加入TFA(180μl,2.3mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到44mg(100%純度,理論值的69%)標題化合物。
[α]D 20=-17.2°,589nm,c=0.43g/100ml,甲醇
LC-MS(方法1):Rt=2.30min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.609(14.30),1.790(9.46),1.896(1.66),1.905(1.58),1.927(2.05),1.942(1.89),1.957(1.86),1.973(2.51),1.986(1.54),1.997(2.79),2.007(1.65),2.037(1.43),2.052(2.75),2.075(2.90),2.093(1.79),2.112(3.33),2.150(11.02),2.328(0.44),2.670(0.42),3.504(11.33),3.518(16.00),3.533(11.13),3.607(1.63),3.621(1.70),3.704(1.72),7.369(0.84),7.462(2.12),7.481(4.20),7.500(2.62),7.536(5.72),7.558(10.90),7.599(6.17),7.604(5.82),7.621(3.10),7.626(3.06),7.688(1.73),7.707(4.75),7.721(8.19),7.737(9.36),7.752(2.20),8.740(2.23),8.755(4.40),8.770(2.18),12.042(0.47).
(+)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲基)苯基]戊酸三級丁酯(65mg,98.1μmol,對映異構物2,實施例137A)在二氯甲烷(750μl)的溶液中加入TFA(170μl,2.2mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到44mg(100%純度,理論值的74%)標題化合物。
[α]D 20=+16.9°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.30min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.46),1.341(0.42),1.353(0.63),1.371(2.44),1.609(14.42),1.790(9.61),1.896(1.69),1.906(1.59),1.927(2.08),1.942(1.89),1.957(1.81),1.974(2.47),1.987(1.58),1.998(2.65),2.038(1.46),2.053(2.67),2.076(2.81),2.094(1.80),2.114(3.37),2.151(11.17),3.504(11.21),3.518(16.00),3.533(11.08),3.608(1.66),3.622(1.72),3.704(1.75),3.720(1.56),7.367(0.82),7.462(2.06),7.481(4.17),7.499(2.61),7.536(5.40),7.558(10.42),7.599(5.89),7.604(5.66),7.621(2.99),7.626(2.99),7.688(1.66),7.707(4.67),7.721(8.20),7.737(9.48),7.752(2.35),8.740(2.22),8.755(4.42),8.770(2.21).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,128μmol,非對映異構物混合物,實施例138A)在二氯甲烷(1.5ml)的溶液中加入TFA(200μl,2.6mmol),並將該混合物在 室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到55mg(100%純度,理論值的71%)標題化合物。
LC-MS(方法1):Rt=2.12min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.652(1.93),1.773(0.54),1.812(1.78),1.829(1.51),1.908(4.68),1.928(4.50),1.943(3.34),1.952(3.13),1.982(3.45),1.994(2.44),2.006(3.39),2.041(1.73),2.057(2.96),2.080(3.00),2.097(1.82),2.116(3.20),2.140(2.39),2.178(14.18),3.084(1.27),3.114(2.24),3.170(2.37),3.186(2.31),3.214(1.29),3.317(12.17),3.395(2.33),3.428(1.26),3.452(2.01),3.480(1.30),3.613(1.25),3.628(1.89),3.644(2.09),3.707(1.99),4.824(1.57),4.945(1.58),7.465(2.95),7.484(4.87),7.502(3.00),7.658(2.05),7.681(16.00),7.688(10.91),7.710(6.16),7.725(10.19),7.741(8.20),7.755(2.49),8.772(2.36),8.787(4.50),8.801(2.20),12.043(0.89).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,126μmol,非對映異構物混合物,實施例139A)在二氯甲烷(1.5ml)的溶液中加入TFA(190μl,2.5mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到45mg(100%純度,理論值的58%)標題化合物。
LC-MS(方法1):Rt=2.48min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(6.54),0.913(16.00),0.932(8.08),1.042(0.48),1.070(1.30),1.092(1.32),1.099(1.35),1.121(0.59),1.131(0.54),1.245(1.03),1.262(2.36),1.279(3.38),1.296(2.77),1.310(1.63),1.570(1.54),1.578(1.49),1.596(1.25),1.611(1.37),1.642(1.23),1.752(1.86),1.785(1.25),1.853(1.69),1.892(2.33),1.926(1.42),1.939(1.34),1.948(1.17),1.961(1.05),1.978(1.80),1.991(1.10),2.002(2.03),2.019(0.80),2.041(1.16),2.056(2.01),2.079(2.14),2.097(1.54),2.115(3.36),2.133(4.50),2.159(7.40),2.417(0.90),2.443(1.33),2.474(0.85),2.721(1.01),2.749(1.83),2.778(1.01),3.513(2.86),3.534(2.38),3.614(1.11),3.628(1.30),3.701(0.98),3.717(1.62),3.734(1.43),3.751(0.99),3.767(0.53),7.462(1.95),7.481(3.47),7.499(2.ll),7.635(0.82),7.657(15.46),7.686(1.56),7.707(3.81),7.723(5.27),7.738(7.56),7.756(1.73),8.753(1.67),8.768(3.28),8.782(1.65),12.055(0.48).
5-[({6-溴-3-methyl-2-[3-methyl哌啶-1-yl]喹啉-4-yl}羰基)-amino]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(85mg,128μmol,非對映異構物混合物,實施例140A)在二氯甲烷(1.5ml)的溶液中加入TFA(200μl,2.6mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分 濃縮,並將殘餘物冷凍乾燥。得到66mg(100%純度,理論值的85%)標題化合物。
LC-MS(方法1):Rt=2.36min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.961(11.43),0.977(11.69),1.119(1.33),1.142(1.37),1.170(0.55),1.668(1.15),1.698(1.36),1.772(2.38),1.805(2.36),1.831(3.01),1.861(1.82),1.931(1.31),1.942(1.22),1.963(1.52),1.977(1.40),1.995(1.27),2.012(1.97),2.025(1.20),2.036(2.22),2.045(1.32),2.073(1.16),2.088(2.19),2.112(2.28),2.129(1.30),2.148(2.41),2.202(9.83),2.362(0.23),2.401(0.17),2.472(1.26),2.724(1.08),2.753(1.97),2.781(1.07),3.488(2.15),3.514(3.81),3.543(1.91),3.647(1.13),3.663(1.43),3.678(1.25),3.745(1.32),7.468(0.77),7.498(1.91),7.517(3.49),7.535(2.12),7.670(0.83),7.692(16.00),7.721(1.57),7.742(3.68),7.758(7.71),7.770(5.90),8.795(1.69),8.809(3.31),8.824(1.65),12.057(0.39).
(+/-)-5-({[6-溴-3-methyl-2-(哌啶-1-yl)喹啉-4-yl]羰基}amino)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,128μmol,外消旋物,實施例141A)在二氯甲烷(1.5ml)的溶液中加入TFA(200μl,2.6mmol),將混合物在RT下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。濃縮合併的目標級分,並將殘餘物冷凍乾燥。得到58mg(100%純度,理論值的75%)標題化合物。
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.609(5.45),1.674(10.79),1.802(1.40),1.816(1.97),1.826(1.94),1.836(2.70),1.860(2.03),1.888(0.49),2.034(0.85),2.048(3.13),2.062(3.86),2.074(15.09),2.105(2.80),2.141(13.35),2.223(0.46),3.142(14.21),3.358(1.72),3.378(2.31),3.389(2.71),3.405(2.55),3.585(0.80),3.600(1.32),3.618(2.89),3.634(3.97),3.644(3.21),3.659(3.20),3.677(2.34),3.693(1.16),3.711(0.65),7.362(4.71),7.366(4.18),7.380(1.52),7.386(2.11),7.401(8.29),7.411(6.88),7.418(6.54),7.423(7.52),7.436(2.09),7.462(1.58),7.548(5.03),7.554(3.43),7.561(4.22),7.572(3.66),7.630(2.79),7.652(16.00),7.658(11.38),7.663(9.59),7.680(1.69),7.685(1.88),8.732(2.66),8.746(5.24),8.761(2.61),12.069(0.60).
(-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(90mg,135μmol,對映異構物1,實施例142A)在二氯甲烷(1.0ml)的溶液中加入TFA(230μl,3.0mmol),將混合物放置在室溫下22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到50mg(100%純度,理論值的61%)標題化合物。
[α]D 20=-18.0°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法1):Rt=2.29min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.609(5.83),1.674(11.45),1.803(1.47),1.817(2.13),1.826(2.21),1.837(2.80),1.861(2.09),1.888(0.51),2.051(3.70),2.077(16.00),2.107(3.39),2.140(13.75),2.222(0.47),3.142(14.84),3.390(2.52),3.405(2.42),3.585(0.89),3.600(1.48),3.618(3.15),3.634(4.30),3.648(3.40),3.659(3.41),3.677(2.42),3.693(1.19),3.711(0.64),7.358(3.80),7.362(4.85),7.366(4.34),7.381(1.93),7.387(2.65),7.401(8.69),7.412(7.29),7.418(6.79),7.424(7.60),7.436(2.21),7.443(1.73),7.458(1.58),7.549(5.35), 7.554(3.69),7.561(4.42),7.572(3.74),7.630(3.18),7.651(15.85),7.658(11.08),7.663(9.30),7.680(1.75),7.685(1.89),8.729(2.97),8.744(5.43),8.758(2.65),12.048(9.94).
(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(80mg,120μmol,對映異構物2,實施例143A)在二氯甲烷(930μl)的溶液中加入TFA(200μl,2.6mmol),將混合物放置在室溫下22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。濃縮合併的目標級分,並將殘餘物冷凍乾燥。得到45mg(100%純度,理論值的62%)標題化合物。
[α]D 20=+18.6°,589nm,c=0.42g/100ml,甲醇
LC-MS(方法1):Rt=2.29min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.609(5.47),1.674(10.78),1.802(1.28),1.815(1.94),1.825(1.99),1.836(2.69),1.860(2.04),1.887(0.50),2.049(3.08),2.075(15.31),2.105(2.79),2.140(13.35),2.222(0.46),2.327(0.57),2.670(0.58),3.142(14.18),3.390(2.48),3.403(2.39),3.585(0.80),3.599(1.32),3.617(2.90),3.633(3.99),3.659(3.26),3.676(2.36),3.693(1.16),3.709(0.65),7.362(4.65),7.380(1.46),7.387(2.06),7.401(8.36),7.412(6.83),7.418(6.44),7.424(7.64),7.436(2.15),7.460(1.59),7.548(5.00),7.561(4.22),7.572(3.68),7.629(2.93),7.651(16.00),7.658(10.68),7.662(9.54),7.680(1.74),7.685(1.95),8.729(2.66),8.744(5.30),8.758(2.62),12.050(3.04).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,131μmol,外消旋物,實施例144A)在二氯甲烷(1.5ml)中的溶液中加入TFA(200μl,2.6mmol),並將該混合物在RT下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。濃縮合併的目標級分,並將殘餘物冷凍乾燥。得到53mg(100%純度,理論值的68%)標題化合物。
LC-MS(方法1):Rt=1.60min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.22),0.008(1.27),1.803(0.93),1.816(1.30),1.825(1.46),1.837(2.26),1.875(10.81),2.032(0.74),2.046(2.32),2.056(1.86),2.073(10.27),2.081(6.67),2.103(1.93),2.115(1.46),2.125(1.55),2.161(4.17),3.315(16.00),3.356(0.63),3.386(1.60),3.401(1.57),3.613(2.82),3.628(1.60),3.643(1.41),3.660(1.95),3.677(1.62),3.694(0.98),3.712(0.55),7.337(1.93),7.341(2.10),7.346(2.33),7.351(2.89),7.356(3.69),7.360(3.24),7.375(1.47),7.381(1.74),7.398(5.84),7.407(4.63),7.415(4.68),7.432(1.15),7.473(5.13),7.495(8.79),7.549(6.82),7.555(6.12),7.571(4.26),7.577(2.97),8.680(1.74),8.695(3.33),8.709(1.70),12.049(1.68).
(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(140mg,215μmol,對映異構物1,實施例145A)在二氯 甲烷(1.7ml)的溶液中加入TFA(360μl,4.7mmol),將混合物放置在室溫下22小時。然後濃縮混合物並再次加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到97mg(100%純度,理論值的76%)標題化合物。
[α]D 20=-16.7°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=1.58min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.825(0.44),1.836(0.68),1.875(3.31),2.046(0.70),2.074(2.84),2.103(0.59),2.116(0.44),2.125(0.47),2.162(1.28),3.313(16.00),3.386(0.48),3.401(0.47),3.612(0.87),3.628(0.48),3.643(0.43),3.660(0.59),3.677(0.50),7.346(0.74),7.355(1.15),7.359(1.03),7.375(0.46),7.381(0.54),7.398(1.81),7.407(1.42),7.415(1.45),7.473(1.56),7.495(2.67),7.549(2.09),7.555(1.90),7.571(1.31),7.577(0.92),8.679(0.54),8.694(1.03),8.709(0.52),12.043(2.77).
(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(130mg,200μmol,對映異構物2,實施例146A)在二氯甲烷(1.5ml)的溶液中加入TFA(340μl,4.4mmol),將混合物放置在室溫下22小時。然後濃縮混合物並再次加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到94mg(100%純度,理論值的79%)標題化合物。
[α]D 20=+48.5°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法1):Rt=1.58min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.65),1.815(2.03),1.825(2.29),1.836(3.45),1.879(16.00),2.007(0.46),2.032(1.10),2.046(3.63),2.055(2.83),2.074(14.77),2.102(2.92),2.124(2.33),2.163(6.20),2.327(0.57),2.669(0.50),3.385(2.83),3.401(2.67),3.581(11.94),3.612(5.50),3.628(2.90),3.644(2.39),3.661(3.14),3.678(2.59),3.694(1.61),3.712(0.91),7.346(3.62),7.356 (5.66),7.375(2.23),7.381(2.65),7.398(9.07),7.407(7.10),7.416(7.30),7.433(1.86),7.482(2.36),7.504(3.73),7.546(6.03),7.559(7.96),7.569(5.48),7.578(3.09),8.685(2.29),8.699(4.21),8.713(2.32),12.044(3.05).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,121μmol,外消旋物,實施例147A)在二氯甲烷(1.5ml)的溶液中加入TFA(190μl,2.4mmol),並將混合物在室溫下攪拌18小時。然後濃縮混合物並重複加入二氯甲烷並再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到56mg(100%純度,理論值的72%)標題化合物。
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.805(1.11),1.818(1.77),1.828(1.91),1.839(2.54),1.887(5.28),2.050(4.05),2.077(16.00),2.115(4.22),2.159(11.45),2.245(0.46),3.174(6.42),3.360(1.50),3.391(2.46),3.406(2.34),3.456(3.91),3.485(7.30),3.513(3.66),3.595(0.77),3.610(1.24),3.628(2.53),3.644(3.42),3.657(3.10),3.672(2.69),3.689(1.99),3.705(1.05),3.722(0.56),7.363(4.21),7.382(1.32),7.388(1.84),7.403(7.29),7.414(6.03),7.421(5.78),7.425(6.39),7.438(1.46),7.495(1.18),7.553(4.60),7.566(3.87),7.576(3.35),7.680(2.13),7.702(14.18),7.707(10.77),7.712(8.50),7.729(1.33),7.734(1.48),8.743(2.48),8.758(4.81),8.772(2.40),12.069(0.56).
(-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(115mg,164μmol,對映異構物1,實施例148A)在二氯甲烷(1.3ml)之溶液中加入TFA(280μl,3.6mmol),並將混合物在室溫放置22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到92mg標題化合物(100%純度,理論值的86%)。
[α]D 20=-15.9°,589nm,c=0.39g/100ml,甲醇
LC-MS(方法2):Rt=1.17min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.806(0.97),1.818(1.67),1.829(1.78),1.840(2.38),1.887(4.81),2.054(3.60),2.080(16.00),2.093(6.95),2.115(3.93),2.159(10.72),2.245(0.45),3.174(5.85),3.362(0.96),3.392(2.07),3.407(2.04),3.456(3.60),3.485(6.81),3.513(3.40),3.595(0.68),3.611(1.12),3.628(2.37),3.644(3.21),3.658(2.83),3.671(2.52),3.689(1.85),3.704(0.96),3.722(0.52),7.364(4.04),7.368(3.55),7.383(1.21),7.389(1.74),7.404(6.92),7.414(5.86),7.421(5.49),7.426(6.17),7.439(1.40),7.494(1.13),7.554(4.44),7.559(3.07),7.566(3.66),7.577(3.23),7.680(2.15),7.702(14.00),7.707(10.50),7.712(8.41),7.730(1.33),7.734(1.49),8.741(2.35),8.755(4.60),8.770(2.27),12.052(2.47).
(+)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(105mg,150μmol,對映異構物2,實施例149A)在二氯甲烷(1.2ml)的溶液中加入TFA(250μl,3.3mmol),並將該混合物在室溫放置22小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到81mg(99%純度,理論值的83%)標題化合物。
[α]D 20=+17.2°,589nm,c=0.42g/100ml,甲醇
LC-MS(方法2):Rt=1.17min;MS(ESIpos):m/z=644/646[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.53),0.008(1.48),1.806(1.02),1.819(1.71),1.829(1.81),1.840(2.41),1.887(4.81),2.053(3.70),2.079(16.00),2.093(6.81),2.116(3.90),2.159(10.73),2.245(0.44),3.174(5.91),3.392(2.02),3.406(1.98),3.456(3.65),3.485(6.90),3.513(3.41),3.595(0.67),3.610(1.11),3.628(2.38),3.644(3.22),3.658(2.82),3.672(2.49),3.689(1.85),3.704(0.95),3.722(0.52),7.354(2.52),7.359(3.13),7.364(4.16),7.368(3.61),7.382(1.24),7.389(1.78),7.404(7.08),7.414(6.10),7.421(5.65),7.426(6.34),7.439(1.47),7.496(1.14),7.554(4.57),7.559(3.07),7.566(3.74),7.577(3.32),7.680(2.29),7.702(14.75),7.707(10.95),7.712(8.88),7.729(1.44),7.734(1.59),8.741(2.36),8.756(4.69),8.770(2.33),12.055(2.70).
(+/-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,125μmol,外消旋物,實施例150A)在二氯甲烷(1.1ml)之溶液中加入TFA(210μl,2.8mmol),並將該混合物在室溫放置18小時。然後濃縮混合物並再次加入二氯甲烷,再次濃縮混合物。通過製備型HPLC純化殘餘物(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到52mg(100%純度,理論值的67%)標題化合物。
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.234(0.73),1.605(14.46),1.784(9.83),1.835(2.54),1.859(1.84),1.886(0.52),2.032(0.83),2.046(2.81),2.073(13.10),2.124(8.68),2.215(0.46),2.327(0.46),2.669(0.49),3.357(1.19),3.387(2.23),3.402(2.13),3.494(11.26),3.509(16.00),3.523(10.92),3.571(0.90),3.586(1.30),3.604(2.18),3.618(2.63),3.635(1.81),3.662(2.15),3.679(1.80),7.358(4.37),7.385(2.48),7.399(7.73),7.410(6.56),7.417(6.14),7.421(6.49),7.434(1.57),7.531(6.00),7.553(13.64),7.562(4.00),7.573(3.14),7.597(6.11),7.602(5.59),7.619(3.18),7.625(3.00),8.702(2.26),8.717(4.27),8.731(2.14),12.058(0.97).
(-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(145mg,214μmol,對映異構物1,實施例151A)在二氯甲烷(1.6ml)的溶液中加入TFA(360μl,4.7mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到75mg(100%純度,理論值的56%)標題化合物。
[α]D 20=-16.5°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.64),0.008(2.00),1.371(0.52),1.605(14.32),1.613(12.24),1.784(9.58),1.824(2.16),1.836(2.49),1.860(1.82),1.887(0.48),2.032(0.82),2.046(2.82),2.061(3.46),2.073(12.90),2.079(9.89),2.124(8.41),2.215(0.43),3.388(2.27),3.404(2.15),3.495(11.59),3.509(16.00),3.524(11.30),3.571(0.87),3.586(1.27),3.604(2.17),3.619(2.60),3.635(1.74),3.645(1.58),3.663(2.15),3.679(1.76),3.694(1.07),3.714(0.57),7.353(3.36),7.358(4.32),7.362(3.85),7.378(1.75),7.385(2.43),7.399(7.64),7.410(6.64),7.417(6.07),7.421(6.62),7.435(1.61),7.532(6.31),7.554(14.24), 7.562(4.07),7.573(3.33),7.597(6.38),7.603(5.95),7.620(3.35),7.625(3.23),8.704(2.31),8.718(4.42),8.732(2.22),12.060(0.53).
(+)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(140mg,206μmol,對映異構物2,實施例152A)在二氯甲烷(1.6ml)的溶液中加入TFA(350μl,4.5mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到88mg(100%純度,理論值的68%)標題化合物。
[α]D 20=+16.9°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.606(14.31),1.784(9.86),1.837(2.55),1.861(1.79),1.888(0.53),2.049(2.72),2.076(13.15),2.125(8.84),2.215(0.47),2.328(0.42),2.670(0.44),3.390(2.07),3.403(2.07),3.495(10.87),3.510(16.00),3.524(10.86),3.572(0.92),3.587(1.31),3.605(2.21),3.620(2.66),3.637(1.81),3.664(2.19),3.680(1.85),7.359(4.31),7.385(2.45),7.400(7.84),7.410(6.35),7.422(6.61),7.435(1.62),7.532(5.57),7.554(13.16),7.563(3.91),7.574(3.13),7.598(5.67),7.603(5.52),7.620(2.99),7.625(3.00),8.701(2.25),8.716(4.35),8.730(2.19),12.046(2.47).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,125μmol,非對映異構物混合物,實施例153A)在二氯甲烷(1.1ml)的溶液中加入TFA(210μl,2.7mmol),並將混合物放置在室溫下18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到55mg(100%純度,理論值的71%)標題化合物。
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.06),0.008(2.52),1.236(0.83),1.646(1.98),1.768(0.68),1.815(3.36),1.826(3.43),1.837(3.81),1.861(2.67),1.902(3.30),1.922(2.78),1.953(1.96),1.987(1.15),2.010(0.72),2.050(2.99),2.077(14.97),2.104(2.52),2.153(12.67),2.328(0.48),2.670(0.45),3.074(1.28),3.104(2.25),3.163(2.42),3.176(2.36),3.208(1.25),3.350(2.24),3.387(4.28),3.411(3.01),3.438(2.24),3.472(1.37),3.590(0.69),3.605(1.17),3.622(2.52),3.639(3.61),3.652(3.10),3.680(1.90),4.820(1.66),4.939(1.69),7.362(4.58),7.366(4.02),7.381(1.37),7.387(1.93),7.402(7.98),7.412(6.54),7.419(6.20),7.424(7.11),7.437(1.74),7.474(1.39),7.551(4.96),7.563(4.09),7.574(3.61),7.654(2.68),7.675(16.00),7.681(11.09),7.686(9.41),7.704(1.75),7.708(1.85),8.736(2.62),8.750(5.19),8.765(2.57),12.057(1.66).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,123μmol,非對映異構物混合物,實施例154A)在二氯甲烷(1.5ml)的溶液中加入TFA(190μl,2.5mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到60mg(100%純度,理論值的77%)標題化合物。
LC-MS(方法1):Rt=2.52min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.892(6.52),0.911(16.00),0.930(8.01),1.039(0.62),1.059(1.34),1.067(1.35),1.090(1.31),1.097(1.32),1.119(0.60),1.128(0.53),1.242(1.02),1.260(2.47),1.277(3.35),1.295(2.40),1.564(1.51),1.573(1.45),1.590(1.24),1.601(1.32),1.635(1.16),1.749(1.81),1.782(1.45),1.801(0.96),1.814(1.34),1.825(1.40),1.837(2.34),1.858(2.39),1.884(1.66),2.051(2.07),2.078(10.33),2.109(4.06),2.135(5.81),2.409(0.86),2.435(1.21),2.464(0.70),2.715(0.95),2.745(1.75),2.775(0.94),3.363(0.67),3.393(1.53),3.406(1.51),3.495(2.71),3.525(2.53),3.585(0.64),3.600(1.01),3.618(1.79),3.633(2.24),3.649(1.67),3.660(1.23),3.677(1.52),3.695(1.19),7.357(2.77),7.385(1.24),7.400(5.23),7.410(4.34),7.421(4.73),7.435(1.32),7.456(0.83),7.554(2.88),7.566(2.50),7.576(2.07),7.631(1.14),7.654(12.66),7.682(0.77),8.718(1.71),8.733(3.25),8.747(1.66),12.046(0.84).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(85mg,125μmol,非對映異構物混合物,實施例155A)在二氯甲烷(1.1ml)的溶液中加入TFA(210μl,2.8mmol),並將該混合物在室溫放置18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到56mg(100%純度,理論值的71%)標題化合物。
LC-MS(方法1):Rt=2.42min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.923(14.04),0.939(14.42),1.054(0.58),1.080(1.68),1.109(1.75),1.132(0.71),1.235(0.89),1.628(1.42),1.658(1.67),1.685(0.79),1.733(3.00),1.766(3.19),1.800(3.96),1.816(3.37),1.825(3.80),1.835(3.76),1.860(1.79),1.888(0.45),2.050(2.61),2.076(13.15),2.106(2.82),2.140(8.43),2.433(1.30),2.458(2.15),2.684(1.32),2.713(2.46),2.742(1.32),3.358(0.97),3.389(2.11),3.404(2.09),3.440(2.69),3.469(4.76),3.500(2.26),3.598(1.01),3.617(1.92),3.631(2.43),3.647(2.54),3.665(2.40),3.682(1.87),3.698(1.04),3.716(0.56),7.361(3.79),7.387(1.64),7.400(6.96),7.412(5.56),7.423(6.36),7.436(1.82),7.550(4.02),7.563(3.50),7.573(2.95),7.631(1.47),7.654(16.00),7.682(1.06),8.720(2.23),8.735(4.29),8.749(2.17),12.048(3.54).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-3-氟苯基)戊酸三級丁酯(172mg,272μmol,外消旋物,實施例156A)在二氯甲烷(4.0ml)的溶液中加入TFA(310μl,4.1mmol),並將混合物在室溫下攪拌18小時。隨後,再次加入TFA(155μl,2.05mmol),並將混合物在室溫下攪拌26小時。隨後濃縮混合物,並重複添加二氯甲烷,然後再濃縮。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到143mg(100%純度,理論值的91%)標題化合物。
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.606(4.25),1.672(8.45),1.790(0.50),1.806(0.96),1.824(1.50),1.845(1.97),1.867(1.12),1.883(0.52),2.020(0.49),2.039(1.16),2.063(3.60),2.075(1.70),2.090(4.80),2.100(8.16),2.130(16.00),2.165(1.21),2.328(0.48),2.366(0.44),2.669(0.52),2.709(0.44),3.135(11.08),3.616(1.87),3.697(3.00),7.288(1.68),7.309(3.78),7.331(2.61),7.344(2.90),7.363(4.95),7.396(2.49),7.411(2.98),7.416(3.42),7.430(3.39),7.450(1.62),7.624(2.09),7.646(11.69),7.653(7.79),7.658(6.74),7.675(1.30),7.680(1.47),8.718(2.07),8.732(4.17),8.746(2.03),12.059(0.63).
將標題化合物(125mg)溶於甲醇(20ml)中,藉由製備型SFC在手性相上分離成對映異構物(參見實施例142和143)[管柱:Daicel Chiralcel OX-H, 5μm,250毫米×20毫米;流速:80ml/min;檢測:210nm;溫度:40℃;注入:1.0毫升;溶析液:17%乙醇/83%二氧化碳;操作時間13分鐘,等度]。將合併的目標級分各自濃縮,並將各殘餘物冷凍乾燥。
在實施例141中所述的對映異構物分離中,獲得43mg(100%純度,ee>99%)標題化合物,作為較早洗脫的對映異構物。
[α]D 20=-13.8°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.03),0.008(2.00),1.596(3.88),1.605(4.29),1.671(8.19),1.792(0.54),1.807(1.05),1.826(1.62),1.833(1.58),1.846(2.10),1.868(1.23),1.884(0.62),2.021(0.60),2.040(1.29),2.064(3.77),2.077(1.88),2.091(4.95),2.101(8.41),2.131(16.00),2.166(1.27),2.182(0.56),3.121(7.95),3.134(10.68),3.617(1.89),3.644(1.14),3.699(2.96),7.289(1.83),7.309(3.92),7.332(2.80),7.346(2.97),7.364(5.02),7.397(2.62),7.411(3.07),7.416(3.55),7.430(3.51),7.450(1.68),7.624(2.18),7.645(11.92),7.652(7.95),7.657(7.09),7.674(1.32),7.679(1.53),8.719(2.03),8.733(4.07),8.747(2.01),12.066(5.30).
在實施例141中所述的對映異構物分離中,獲得37mg(100%純度,ee 95%)標題化合物,其為稍後洗脫的對映異構物。
[α]D 20=+13.4°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.605(4.31),1.671(8.37),1.793(0.53),1.808(1.01),1.827(1.61),1.834(1.61),1.847(2.06),1.869(1.22),1.885(0.62),2.023(0.56),2.041(1.26),2.065(3.63),2.077(1.87),2.092(4.86),2.102(8.13), 2.131(16.00),2.167(1.31),2.183(0.60),3.134(10.81),3.618(1.95),3.644(1.18),3.699(3.03),7.288(1.74),7.309(3.75),7.331(2.65),7.346(2.89),7.364(4.84),7.397(2.46),7.411(3.00),7.416(3.41),7.430(3.37),7.450(1.67),7.624(1.92),7.646(10.90),7.652(7.58),7.657(6.58),7.675(1.19),7.679(1.36),8.719(1.99),8.734(3.94),8.748(1.97),12.068(3.84).
(+/-)-5-({[6-溴-3-methyl-2-(哌啶-1-yl)喹啉-4-yl]羰基}amino)-4-(6-chloro-2,3-di氟苯基)戊酸三級丁酯(123mg,189μmol,外消旋物,實施例157A)在二氯甲烷(3ml)的溶液中加入TFA(220μl,2.8mmol),並將該混合物在室溫下攪拌18小時。隨後,再次加入TFA(110μl,1.4mmol),並將混合物在室溫下攪拌26小時。隨後濃縮混合物,並重複添加二氯甲烷,然後再濃縮。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到124mg(94%純度,理論值的103%)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.023(0.44),-0.008(2.46),0.008(2.14),1.234(0.89),1.367(4.68),1.606(2.38),1.656(4.36),1.671(4.64),1.979(0.61),2.073(2.70),2.101(1.76),2.128(2.50),2.144(16.00),2.187(0.81),2.327(0.46),2.332(0.40),2.347(0.61),2.366(0.85),2.670(0.52),2.710(0.85),3.135(6.17),3.734(0.97),3.770(1.43),7.376(1.80),7.389(2.16),7.412(1.47),7.433 (1.39),7.456(0.69),7.626(1.67),7.648(6.98),7.658(4.62),7.663(4.00),7.680(1.01),7.685(1.05),8.807(1.03),8.822(2.00),8.835(0.99).
將標題化合物(110mg)溶於甲醇(15ml)中,並藉由製備型SFC在手性相上分離為對映異構物(參見實施例145和146)[管柱:Daicel Chiralpak AD,5μm,250mm x 20mm;流速:80ml/min;檢測:210nm;溫度:40℃;注入:2.0毫升;溶析液:30%異丙醇/70%二氧化碳;操作時間7分鐘,等度]。將合併的目標級分各自濃縮,並將各殘留物冷凍乾燥。
在實施例144中所述的對映異構物分離中,獲得43mg(100%純度,ee>99%)標題化合物作為較早洗脫的對映異構物。
[α]D 20=-31.8°,589nm,c=0.41g/100ml,甲醇
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.069(0.50),1.367(3.93),1.606(2.74),1.671(5.29),1.983(0.77),2.065(1.26),2.076(1.30),2.095(1.33),2.110(1.94),2.144(16.00),2.172(2.18),2.195(0.93),2.434(0.58),3.135(6.96),3.738(1.19),3.771(1.70),7.377(2.00),7.389(2.43),7.412(1.72),7.434(1.70),7.456(1.02),7.486(0.51),7.626(1.66),7.648(6.84),7.658(4.26),7.663(4.01),7.681(0.93),7.685(1.02),8.803(1.17),8.817(2.27),8.831(1.13).
在實施例144中所述的對映異構物分離中,獲得31mg(98%純度,ee>99%)標題化合物作為稍後洗脫的對映異構物。
[α]D 20=+34.1°,589nm,c=0.40g/100ml,甲醇
LC-MS(方法2):Rt=1.14min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.37),0.008(0.74),1.368 (0.77),1.596(2.49),1.606(2.69),1.671(5.00),1.982(0.72),2.067(1.07),2.079(1.22),2.097(1.31),2.116(2.21),2.145(16.00),2.178(2.09),2.200(0.82),3.122(5.17),3.135(6.49),3.739(1.21),3.771(1.63),7.355(0.86),7.378(2.03),7.390(2.38),7.413(1.64),7.435(1.43),7.457(0.74),7.627(1.88),7.649(7.16),7.659(4.59),7.664(4.01),7.681(1.00),7.686(1.02),8.802(1.22),8.816(2.19),8.830(1.05).
(+/-)-5-({[6-溴-3-methyl-2-(哌啶-1-yl)喹啉-4-yl]羰基}amino)-4-(5-氟-2-methyl苯基)戊酸三級丁酯(185mg,302μmol,外消旋物,實施例158A)在二氯甲烷(4毫升)的溶液中加入TFA(350μl,4.5mmol),並將混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到149mg(100%純度,理論值的89%)標題化合物。
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=556/558[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.37),0.008(2.26),1.606(3.10),1.670(6.11),1.739(0.41),1.756(0.83),1.772(0.96),1.797(1.23),1.828(0.55),1.993(0.96),2.006(1.24),2.023(1.21),2.043(1.30),2.063(4.89),2.079(5.98),2.100(10.78),2.293(16.00),2.327(0.60),2.669(0.46),3.135(8.13),3.460(1.02),3.473(1.34),3.493(1.53),3.507(1.68),3.521(1.03),3.653(1.00),3.672(1.51),3.690(1.34),3.705(1.15),3.725(0.70),6.921(1.05),6.928(1.22), 6.942(2.27),6.949(2.54),6.963(1.30),6.970(1.35),7.132(2.32),7.139(2.36),7.159(2.39),7.166(2.29),7.197(2.30),7.213(2.66),7.218(2.51),7.234(2.07),7.439(1.06),7.626(1.65),7.648(9.38),7.654(6.97),7.659(5.99),7.676(1.07),7.681(1.21),8.711(1.47),8.726(2.38),8.740(1.48).
將標題化合物(135mg)溶於甲醇(20ml)中,藉由製備型SFC在手性相上分離成對映異構物(見實施例148和149)[管柱:Daicel Chiralcel OX-H,5μm,250mm×20mm;流速:80ml/min;檢測:210nm;溫度:40℃;注入:2.0毫升;溶析液:30%乙醇/70%二氧化碳;操作時間8分鐘,等度]。將合併的目標級分各自濃縮,並將各殘餘物冷凍乾燥。
在實施例147中所述的對映異構物分離中,獲得57mg(100%純度,ee>99%)標題化合物,作為較早洗脫的對映異構物。
[α]D 20=-13.8°,589nm,c=0.49g/100ml,甲醇
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=556/558[M-H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.609(3.14),1.673(6.11),1.746(0.41),1.764(0.84),1.780(1.02),1.788(1.06),1.798(1.19),1.803(1.18),1.818(1.00),1.836(0.56),1.980(0.44),1.999(1.06),2.012(1.31),2.030(1.30),2.049(1.40),2.062(1.59),2.075(5.10),2.091(7.94),2.103(10.32),2.294(16.00),3.147(7.87),3.320(1.45),3.432(0.41),3.450(0.52),3.463(1.20),3.476(1.60),3.496(1.88),3.510(2.09),3.524(1.47),3.656(1.37),3.674(1.84),3.693(1.62),3.708(1.41),3.727(0.90),6.924(1.07),6.930(1.25),6.945(2.28),6.951(2.50),6.966(1.28),6.972(1.33),7.137(2.34),7.144(2.41),7.164(2.39),7.171(2.32),7.200(2.34),7.215(2.65),7.220(2.47),7.236(2.02),7.444(1.01),7.638(1.21),7.660(9.17),7.664(7.93),7.669(5.88),7.686(0.75),7.691(0.88),8.714(1.52),8.729(2.41),8.743(1.46).
在實施例147所述的對映異構物分離中,得到51mg(100%純度,ee 96%)標題化合物作為稍後洗脫的對映異構物。
[α]D 20=+13.4°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=556/558[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.34),0.008(1.21),1.030(0.40),1.046(0.41),1.609(3.05),1.673(5.95),1.745(0.41),1.763(0.85),1.779(1.01),1.787(1.04),1.797(1.17),1.803(1.15),1.820(1.02),1.835(0.58),1.979(0.43),1.999(1.03),2.012(1.29),2.030(1.29),2.049(1.38),2.062(1.54),2.075(5.05),2.091(7.75),2.103(10.14),2.294(16.00),3.149(7.64),3.319(1.39),3.450(0.41),3.463(1.08),3.476(1.46),3.496(1.72),3.510(1.90),3.524(1.28),3.656(1.43),3.674(1.91),3.693(1.69),3.708(1.48),3.727(0.98),6.923(1.08),6.930(1.25),6.944(2.29),6.951(2.50),6.965(1.28),6.972(1.31),7.137(2.34),7.143(2.38),7.164(2.38),7.170(2.30),7.199(2.38),7.215(2.66),7.220(2.45),7.236(2.05),7.443(0.99),7.640(1.11),7.662(9.23),7.669(5.86),7.687(0.70),7.692(0.82),8.715(1.52),8.730(2.36),8.744(1.44).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(5-氟-2-甲基苯基)戊酸三級丁酯(263mg,406μmol,外消旋物,實施例159A)在二氯甲烷(4ml)的溶液中加入TFA(620μl,8.1mmol),並將該混合物在室溫下攪拌18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到211mg(100%純度,理論值的88%)標題化合物。
LC-MS(方法1):Rt=2.17min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.15),0.008(1.52),1.763(0.87),1.779(1.10),1.787(1.11),1.796(1.27),1.802(1.23),1.820(1.00),1.835(0.72),1.880(3.31),1.976(0.53),1.996(1.11),2.009(1.35),2.027(1.46),2.046(2.40),2.071(6.38),2.087(8.11),2.117(10.60),2.292(16.00),2.322(0.52),2.327(0.56),2.524(1.64),3.164(4.06),3.449(2.71),3.479(5.41),3.505(3.74),3.518(2.18),3.533(1.13),3.665(1.08),3.683(1.64),3.702(1.40),3.716(1.20),3.736(0.71),6.924(1.18),6.931(1.33),6.945(2.41),6.952(2.57),6.966(1.34),6.973(1.35),7.141(2.55),7.147(2.54),7.167(2.57),7.174(2.42),7.200(2.58),7.215(2.84),7.221(2.58),7.237(2.16),7.476(0.90),7.678(1.75),7.699(10.07),7.704(7.52),7.709(6.08),7.727(0.97),7.731(1.10),8.722(1.71),8.736(2.53),8.751(1.53).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(269mg,413μmol,外消旋物,實施例160A)在二氯甲烷(5ml)的溶液中加入TFA(480μl,6.2mmol),並將該混合物在室溫下攪拌18小時。隨後,再次加入TFA(240μl,3.lmmol),並將混合物在室溫再攪拌24小時。隨後濃縮混合物,並重複加入二氯甲烷,然後再次濃縮。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到221mg(100%純度,理論值的90%)標題化合物。
LC-MS(方法1):Rt=2.19min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.84),0.008(2.84),1.606(3.28),1.673(6.38),1.980(0.76),2.073(2.12),2.095(2.56),2.122(4.17),2.143(16.00),2.172(1.53),2.194(0.58),2.327(0.55),2.366(0.54),2.669(0.59),2.710(0.57),3.137(8.46),3.722(1.94),7.267(0.88),7.278(1.02),7.290(1.81),7.301(1.87),7.316(1.43),7.327(1.33),7.389(1.13),7.400(1.34),7.410(1.91),7.421(1.92),7.433(1.20),7.444(1.12),7.629(2.29),7.650(9.72),7.660(6.52),7.665(5.84),7.683(1.37),7.687(1.47),8.821(2.50).
將標題化合物(200mg)溶於甲醇(20ml)中,並藉由製備型SFC在手性相上分離為對映異構物(參見實施例152和153)[管柱:Daicel Chiralcel OJ-H,5μm,250毫米×20毫米;流速:80ml/min;檢測:210nm;溫度:40℃;注入:0.5毫升;溶解液:17%甲醇/83%二氧化碳;操作時間5分鐘,等度]。將合併的目標級分各自濃縮,並將各殘餘物冷凍乾燥。
在實施例151中所述的對映異構物分離中,獲得70mg(99%純度,ee>99%)標題化合物,作為較早洗脫的對映異構物。
[α]D 20=-35.9°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.78),0.008(0.73),1.597 (2.64),1.607(2.93),1.673(5.58),1.980(0.71),2.073(1.02),2.082(1.14),2.089(1.23),2.103(2.10),2.144(16.00),2.161(3.72),2.179(1.26),2.201(0.46),3.125(5.49),3.137(7.35),3.726(1.72),7.268(0.79),7.279(0.89),7.291(1.58),7.302(1.63),7.317(1.24),7.328(1.14),7.390(1.02),7.401(1.20),7.411(1.67),7.422(1.65),7.433(1.05),7.445(0.95),7.629(1.92),7.651(8.28),7.661(5.32),7.665(4.77),7.683(1.12),7.688(1.20),8.804(1.22),8.819(2.19),12.101(1.08).
在實施例151中所述的對映異構物分離中,得到67mg(98%純度,ee99%)標題化合物,其為稍後洗脫的對映異構物。
[α]D 20=+36.3°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法2):Rt=1.13min;MS(ESIpos):m/z=594/596[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.16),0.008(1.02),1.607(2.99),1.673(5.69),1.980(0.73),2.102(2.13),2.144(16.00),2.159(3.78),2.178(1.27),2.201(0.47),3.125(5.63),3.137(7.50),3.725(1.78),7.268(0.83),7.279(0.95),7.291(1.66),7.302(1.69),7.317(1.28),7.328(1.17),7.390(1.09),7.401(1.28),7.411(1.75),7.422(1.72),7.433(1.10),7.445(0.99),7.629(2.00),7.651(8.50),7.661(5.45),7.666(4.83),7.683(1.13),7.688(1.20),8.804(1.26),8.818(2.23),12.101(0.71).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(84mg,131μmol,外消旋物,實施例161A)在二氯甲烷(1.1ml)的溶液中加入TFA(220μl,2.9mmol),並將混合物在室溫放置24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到24mg(100%純度,理論值的32%)標題化合物。
LC-MS(方法1):Rt=1.46min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.854(0.47),1.236(2.28),1.271(0.43),1.873(16.00),1.969(1.55),2.091(4.87),2.118(6.28),2.131(8.95),2.169(15.24),2.327(0.58),2.342(0.50),2.670(0.47),3.317(4.55),3.713(4.24),7.261(1.77),7.273(2.08),7.285(3.43),7.296(3.55),7.311(2.67),7.322(2.43),7.382(2.28),7.392(2.69),7.403(3.45),7.413(3.29),7.436(1.69),7.471(8.63),7.493(14.06),7.551(7.71),7.556(7.15),7.573(4.50),7.579(4.32),8.756(2.66),8.770(4.44).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(68mg,83%純度,82.2μmol,外消旋物,實施例162A)在二氯甲烷(690μl)之溶液中加入TFA(140μl,1.8mmol),並將混合物在室溫放置18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到35mg(100%純度,理論值的67%)標題化合物。
LC-MS(方法1):Rt=2.14min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.30),0.008(1.39),1.236(0.67),1.885(2.91),1.980(0.64),2.082(2.77),2.100(3.27),2.106(3.21),2.134(4.76),2.147(4.55),2.165(16.00),3.170(3.69),3.451(2.24),3.480(4.31),3.509(2.17),3.736(1.60),7.271(0.76),7.282(0.86),7.295(1.56),7.305(1.62),7.320(1.22),7.331(1.11),7.392(0.94),7.403(1.13),7.414(1.56),7.425(1.52),7.436(0.92),7.447(0.78),7.680(1.80),7.702(8.65),7.710(5.87),7.715(5.09),7.733(1.08),7.738(1.16),8.818(1.29),8.833(2.32),12.100(1.60).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(85mg,127μmol,非對映異構物混合物,實施例163A)在二氯甲烷(1.1ml)的溶液中加入TFA(220μl,2.8mmol),並將混合物放置在室溫下18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到51mg(100%純度,理論值的65%)標題化合物。
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=612/614[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.33),1.235(0.52),1.647(1.14),1.808(1.08),1.901(1.96),1.921(1.82),1.953(1.67),1.984(1.23),2.099(2.21),2.127(3.58),2.139(4.40),2.157(16.00),2.198(0.59),3.100(1.31),3.166(1.35),3.174(1.35),3.381(1.62),3.413(0.83),3.438(1.26),3.467(0.80),3.728(1.77),4.820(0.94),4.938(0.95),7.268(0.78),7.279(0.90),7.292(1.63),7.303(1.69),7.318(1.28),7.329(1.18),7.390(0.96),7.411(1.63),7.422(1.63),7.445(0.87),7.653(1.94),7.676(8.85),7.684(5.74),7.689(5.25),7.706(1.15),7.711(1.24),8.814(1.27),8.828(2.28).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(85mg,28μmol,非對映異構物混合物,實施例164A)在二氯甲烷(1.1ml)的溶液中加入TFA(220μl,2.8mmol),並將混合物放置在室溫下18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到53mg(100%純度,理論值的69%)標題化合物。
LC-MS(方法1):Rt=2.33min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.922(10.55),0.938(10.81),1.051(0.41),1.080(1.22),1.108(1.27),1.131(0.52),1.235(0.49),1.630(0.96),1.657(1.13),1.732(2.16),1.765(2.08),1.793(2.57),1.824(1.63),1.983(0.80),2.104(2.45),2.145(16.00),2.161(4.62),2.179(1.52),2.203(0.55),2.461(1.21),2.679(0.77),2.711(1.36),2.741(0.72),3.436(1.83),3.464(3.30),3.493(1.55),3.725(1.98),7.268(0.89),7.279(1.01),7.292(1.83),7.303(1.89),7.317(1.40),7.329(1.28),7.390(1.15),7.401(1.39),7.412(1.93),7.423(1.91),7.433(1.23),7.445(1.09),7.632(1.57),7.654(9.91),7.658(7.43),7.663(5.90),7.681(0.88),7.685(1.00),8.796(1.39),8.811(2.45),12.100(2.08).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(85mg,125μmol,非對映異構物混合物,實施例165A)在二氯甲烷(1.1ml)的溶液中加入TFA(210μl,2.8mmol),並將混合物放置在室溫下18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到59mg(100%純度,理論值的76%)標題化合物。
LC-MS(方法1):Rt=2.44min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(2.12),0.891(5.97),0.910(13.55),0.928(7.25),1.038(0.57),1.066(1.50),1.088(1.54),1.096(1.54),1.117(0.72),1.241(1.46),1.259(3.18),1.277(4.17),1.294(2.81),1.566(1.70),1.600(1.55),1.633(1.32),1.748(2.11),1.781(1.43),1.847(1.75),1.878(1.71),1.972(0.97),2.067(1.41),2.104(3.81),2.136(16.00),2.162(4.53),2.181(1.63),2.203(0.64),2.327(0.43),2.423(1.35),2.670(0.43),2.745(1.52),3.488(3.26),3.518(3.03),3.725(2.52),7.266(1.04),7.277(1.19),7.290(2.16),7.300(2.21),7.315(1.62),7.326(1.46),7.386(1.42),7.397(1.68),7.408(2.33),7.419(2.32),7.429(1.44),7.441(1.30),7.631(1.77),7.653(11.15),7.684(1.03),8.794(1.74),8.809(3.01),12.096(8.21).
(+/-)-5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(85mg,128μmol,外消旋物,實施例166A)在二氯甲烷(1.1ml)的溶液中加入TFA(210μl,2.8mmol),並將混合物在室溫放置3.5小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC純化Resi-due(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到54mg(100%純度,理論值的69%)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.603(11.39),1.781(7.18),1.972(0.89),2.104(2.93),2.134(16.00),2.161(4.26),2.179(1.62),2.202(0.64),3.492(8.81),3.506(13.30),3.521(8.69),3.722(2.42),7.267(1.00),7.278(1.15),7.291(2.00),7.301(2.10),7.316(1.57),7.327(1.47),7.388(1.42),7.400(1.68),7.410(2.19),7.421(2.12),7.444(1.08),7.531(4.68),7.553(8.36),7.600(4.67),7.606(4.40),7.622(2.52),7.628(2.47),8.792(2.66),12.101(1.23).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(55mg,82.5μmol,外消旋物,實施例167A)在二氯甲烷(1.1ml)的溶液中加入TFA(610μl,8.3mmol),並將該混合物在室溫下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到45mg(100%純度,理論值的89%)標題化合物。
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.21),-0.008(15.78),0.008(11.37),0.146(1.24),1.234(1.30),1.340(0.44),1.611(5.24),1.677(10.32),2.017(1.79),2.030(3.50),2.060(4.14),2.092(2.65),2.121(5.79),2.136(5.10),2.167(15.23),2.268(0.63),2.327(1.41),2.366(0.44),2.670(1.41),3.148(13.24),3.703(1.54),3.873(1.46),7.383(0.58),7.562(5.88),7.571(5.05),7.577(4.94),7.587(4.08),7.595(8.17),7.626(5.79),7.652(16.00),7.658(11.67),7.663(9.57),7.680(1.57),7.685(1.77),8.808(2.37),8.824(4.50),8.839(2.21),12.075(1.49).1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.08(br.s,1H),8.82(t,1H),7.74-7.51(m,5H),7.38(br.s,1H),3.87(br.s,1H),3.70(br.s,1H),3.33-3.27(1H,隱蔽,tentative),3.20-3.10(m,4H),2.25-1.95(m,7H),1.70-1.55(m,6H).
5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(85mg,128μmol,對映異構物1,實施例168A)在二氯甲 烷(1.7ml)之溶液中加入TFA(950μl,13mmol),在RT下攪拌混合物1小時。隨後,濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法20)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將凍乾物溶於甲醇中並合併,並將混合物在環境條件下留置乾燥。隨後在減壓下乾燥殘餘物後,獲得63mg(理論值98%,理論值的79%)標題化合物。
[α]D 20=-40.1°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.24min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.84),0.146(0.81),1.612(5.48),1.678(10.55),2.019(1.74),2.031(3.64),2.062(4.46),2.084(2.72),2.122(6.02),2.137(5.09),2.167(16.00),2.268(0.57),2.327(1.29),2.366(0.72),2.670(1.38),2.710(0.81),3.149(13.62),3.162(14.23),3.174(7.58),3.511(0.50),3.694(1.67),3.877(1.54),4.076(1.83),4.089(1.77),7.370(0.63),7.563(5.36),7.577(5.14),7.595(7.85),7.627(5.54),7.652(14.78),7.684(1.70),8.806(2.22),8.821(4.53),8.836(2.38),12.061(1.47).
5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(93mg,140μmol,對映異構物2,實施例169A)在二氯甲烷(1.9ml)之溶液中加入TFA(1.0ml,14mmol),在RT下攪拌混合物1小時。隨後,濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法20)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,得到68mg(理論值98%,理論值的78%)標題化合物。
[α]D 20=+45.9°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.70),-0.008(5.63),0.008(5.76),0.146(0.70),1.613(4.93),1.679(9.47),2.019(1.64),2.032(3.34),2.062(4.01),2.093(2.39),2.122(5.44),2.137(4.54),2.167(14.53),2.268(0.52),2.327 (1.02),2.366(0.57),2.670(1.02),2.710(0.56),3.149(12.27),3.162(10.30),3.174(4.19),3.707(1.42),3.876(1.33),4.075(0.66),4.089(0.66),7.370(0.56),7.563(5.67),7.572(4.77),7.578(4.68),7.587(3.90),7.596(8.06),7.626(5.40),7.653(16.00),7.658(11.01),7.663(9.24),7.681(1.51),7.685(1.70),8.807(2.26),8.822(4.55),8.837(2.29),12.062(1.62).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(55mg,84.3μmol,外消旋物,實施例170A)在二氯甲烷(1.1ml)的溶液中加入TFA(630μl,8.4mmol),並將該混合物在室溫下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到41mg(100%純度,理論值的82%)標題化合物。
LC-MS(方法1):Rt=1.51min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.17),-0.008(10.78),0.008(13.42),0.146(1.33),1.879(16.00),2.012(2.39),2.026(3.42),2.056(4.94),2.085(2.81),2.118(5.81),2.125(5.56),2.154(6.67),2.171(6.97),2.328(2.11),2.366(0.53),2.669(1.75),3.581(11.19),3.895(1.53),7.474(8.50),7.496(14.53),7.549(8.83),7.555(10.11),7.571(10.28),7.577(8.56),7.592(8.33),7.617(5.47),7.629(3.89),7.640(2.44),8.139(1.83),8.748(2.86),8.763(5.56),8.778(2.81),12.088(1.00).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.09(br.s,1H),8.76(t,1H),7.72-7.52(m,4H),7.51-7.39(m,1H),7.28(br.s,1H),3.90(br.s,1H),3.73-3.49(m,5H),3.33-2.26(1H,隱蔽,tentative),2.27-1.95(m,7H),1.82-1.83(m,4H).
5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(75mg,115μmol,對映異構物1,實施例171A)在二氯甲烷(1.5ml)之溶液中加入TFA(850μl,11mmol),在RT下攪拌混合物1小時。隨後濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法22)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,獲得55mg(99%純度,理論值的79%)標題化合物。
[α]D 20=+38.1°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=1.54min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.69),-0.008(13.12),0.146(1.65),1.880(16.00),2.012(2.46),2.027(3.61),2.056(5.18),2.089(2.95),2.118(5.99),2.125(5.83),2.154(6.79),2.176(6.98),2.328(2.53),2.366(1.42),2.670(2.30),2.710(1.50),2.998(0.42),3.071(2.07),3.169(2.76),3.581(11.20),3.926(2.19),4.072(0.42),4.154(3.65),7.431(0.58),7.474(7.60),7.497(13.47),7.549(8.02),7.555(9.63),7.571(10.24),7.577(8.75),7.592(8.71),7.617(5.83),7.629(4.34),7.676(1.96),8.136(1.23),8.748(2.95),8.763(5.76),8.779(2.88),12.062(1.73).
5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(79mg,121μmol,對映異構物2,實施例172A)在二氯甲烷(1.6ml)之溶液中加入TFA(900μl,12mmol),在RT下攪拌混合物1 小時。隨後,濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法21)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,獲得49mg(97%純度,理論值的66%)標題化合物。
[α]D 20=-41.4°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=1.53min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(1.29),-0.008(10.93),0.008(10.93),0.146(1.33),1.879(16.00),2.012(2.80),2.026(3.87),2.056(5.56),2.092(3.20),2.118(6.40),2.124(6.22),2.153(6.98),2.171(7.07),2.293(0.58),2.327(2.18),2.366(0.98),2.669(2.22),2.709(1.29),3.162(0.62),3.174(0.71),3.210(0.58),3.472(0.93),3.580(11.02),3.897(1.87),7.393(0.58),7.409(0.62),7.432(0.89),7.474(6.98),7.496(12.49),7.549(7.78),7.555(9.56),7.571(10.22),7.592(8.93),7.617(5.91),7.628(4.44),7.640(2.89),8.748(3.11),8.763(5.69),8.778(2.89),9.693(0.44),12.054(6.53).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(55mg,78.3μmol,外消旋物,實施例173A)在二氯甲烷(1.0ml)之溶液中加入TFA(580μl,7.8mmol),並在室溫下攪拌混合物1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。 得到50mg(100%純度,理論值的99%)標題化合物。
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.66),-0.008(8.90),0.008(6.39),0.146(0.64),1.890(5.53),2.037(4.19),2.067(7.01),2.087(6.21),2.099(6.24),2.122(8.03),2.137(6.44),2.155(5.81),2.188(14.73),2.293(0.54),2.327(0.78),2.670(0.80),3.175(6.37),3.186(5.71),3.462(4.30),3.491(7.92),3.520(3.94),3.699(1.55),3.891(1.37),7.420(0.55),7.566(5.81),7.575(5.24),7.581(5.08),7.591(4.30),7.599(7.83),7.628(5.37),7.638(3.85),7.652(2.57),7.681(2.59),7.704(16.00),7.707(13.15),7.712(9.58),7.730(1.41),7.734(1.57),8.820(2.64),8.835(4.85),8.850(2.43),12.072(2.23).
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=12.07(br.s,1H),8.84(t,1H),7.77-7.52(m,5H),7.52-7.17(m,1H),4.01-3.81(m,1H),3.81-3.61(m,1H),3.49(t,2H),3.25-3.10(m,2H),2.30-1.99(m,10H),1.89(br.s,2H).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(91mg,130μmol,對映異構物1,實施例174A)在二氯甲烷(1.7ml)之溶液中加入TFA(960μl,13mmol),並在室溫下攪拌該混合物1小時。隨後濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法19)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,獲得61mg(97%純度,理論值的71%)標題化合物。
[α]D 20=-40.8°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.45),0.146(0.47),1.891(5.64),2.038(4.28),2.068(7.20),2.088(6.27),2.099(6.42),2.123(8.16),2.137(6.54),2.155(5.94),2.189(15.09),2.293(0.57),2.328(0.70),2.366(0.41),2.670 (0.67),2.710(0.41),3.163(11.92),3.175(14.69),3.462(4.32),3.491(8.03),3.520(4.01),3.703(1.56),3.895(1.38),4.063(1.08),4.076(2.53),4.089(2.43),4.102(0.90),7.422(0.55),7.566(5.90),7.575(5.37),7.581(5.29),7.591(4.40),7.599(7.94),7.628(5.40),7.638(3.92),7.651(2.59),7.681(2.56),7.703(16.00),7.712(9.63),7.730(1.32),7.734(1.55),8.819(2.73),8.834(5.02),8.849(2.47),12.066(3.48).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(93mg,132μmol,對映異構物2,實施例175A)在二氯甲烷(1.8ml)的溶液中加入TFA(980μl,13mmol),並將該混合物在室溫下攪拌1小時。隨後濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法19)。將合併的目標級分濃縮,並將各殘留物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,獲得61mg(理論值98%,理論值的70%)標題化合物。
[α]D 20=-40.8°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.31),0.146(1.38),1.890(5.50),2.034(3.86),2.067(6.68),2.086(6.14),2.097(5.80),2.121(8.32),2.136(6.41),2.153(5.43),2.188(15.23),2.292(0.50),2.327(1.78),2.366(1.11),2.670(2.05),2.710(1.21),3.162(12.11),3.175(15.19),3.462(4.33),3.491(8.18),3.519(4.13),3.708(1.54),3.894(1.44),4.063(0.97),4.074(2.62),4.088(2.65),4.100(1.01),7.424(0.57),7.566(5.47),7.575(5.03),7.599(8.02),7.628(5.27),7.638(3.89),7.651(2.58),7.680(2.11),7.703(16.00),7.734(1.61),8.821(2.28),8.837(4.46),8.851(2.38),12.068(1.31).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(55mg,80.3μmol,非對映異構物混合物,實施例176A)在二氯甲烷(1.1ml)之溶液中加入TFA(600μl,8.0mmol),並將該混合物在室溫下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到43mg(100%純度,理論值的85%)標題化合物。
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.05),-0.008(8.09),0.008(9.08),0.146(1.02),1.654(2.10),1.811(1.98),1.907(3.49),1.927(3.06),1.957(2.29),2.002(1.61),2.021(2.10),2.035(4.08),2.065(5.07),2.087(3.12),2.123(6.15),2.137(4.76),2.156(5.44),2.181(16.00),2.286(0.59),2.328(1.33),2.670(1.36),3.118(2.38),3.178(2.53),3.356(2.47),3.392(2.47),3.424(1.42),3.449(2.29),3.482(1.45),3.705(1.67),3.888(1.51),4.827(1.70),4.939(1.76),7.417(0.65),7.565(6.15),7.573(5.50),7.589(4.36),7.597(8.93),7.627(5.93),7.636(4.26),7.652(3.37),7.677(15.14),7.708(1.64),8.815(2.44),8.829(4.76),8.844(2.44),12.073(2.35).
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=12.07(br.s,1H),8.83(t,1H),7.73-7.54(m,5H),7.52-7.26(m,1H),4.88(br.d,1H),4.00-3.80(m,1H), 3.77-3.60(m,1H),3.52-3.33(m,3H,部分隱藏,tentative),3.25-3.03(m,2H),2.26-1.72(m,10H),1.70-1.57(m,1H).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-氟-6-(三氟甲基)苯基]戊酸三級丁酯(57mg,82μmol,非對映異構物混合物,實施例177A)在二氯甲烷(1.1ml)之溶液中加入TFA(610μl,8.2mmol),並將該混合物在室溫下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到51mg(100%純度,理論值的97%)標題化合物。
LC-MS(方法1):Rt=2.46min;MS(ESIpos):m/z=638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.26),-0.008(16.00),0.008(10.04),0.146(1.32),0.896(5.78),0.914(13.57),0.933(6.59),1.071(1.05),1.092(1.14),1.263(2.01),1.280(2.73),1.290(2.22),1.308(1.53),1.574(1.32),1.640(1.02),1.753(1.53),1.853(1.32),1.882(1.20),2.031(1.92),2.062(2.58),2.086(1.74),2.122(3.69),2.137(4.58),2.162(6.14),2.327(1.44),2.669(1.38),2.710(0.81),2.739(1.05),3.512(2.52),3.688(0.84),3.900(0.84),7.563(3.09),7.573(2.85),7.595(4.28),7.626(2.67),7.654(9.32),7.657(9.41),7.680(0.60),8.813(2.10),12.069(1.14).
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=12.07(br.s,1H),8.81(t,1H),7.70-7.52(m,5H),7.51-7.19(br.m,1H),3.99-3.82(m,1H),3.76-3.62(m,1H), 3.58-3.45(m,2H),2.84-2.69(m,1H),2.50-2.37(m,1H,部分隱藏),2.24-1.99(m,8H),1.93-1.82(m,1H),1.82-1.71(m,1H),1.70-1.49(m,2H),1.38-1.20(m,2H),1.08(br.q,1H),0.91(t,3H).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(55mg,80.4μmol,外消旋物,實施例178A)在二氯甲烷(1.1ml)的溶液中加入TFA(600μl,8.0mmol),並將該混合物在RT下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到49mg(100%純度,理論值的97%)標題化合物。
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=626/628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.91),-0.008(16.00),0.008(14.22),0.146(1.95),1.234(0.51),1.610(3.52),1.675(6.66),2.071(1.40),2.085(1.95),2.099(2.63),2.120(3.18),2.136(7.09),2.155(3.52),2.169(14.39),2.180(3.35),2.203(1.49),2.282(1.40),2.327(2.55),2.366(0.42),2.670(2.04),2.710(0.55),3.140(8.79),3.807(1.23),4.065(1.99),7.476(2.50),7.498(3.56),7.533(3.18),7.555(5.43),7.596(3.78),7.617(2.59),7.630(1.74),7.635(1.61),7.652(6.24),7.657(5.90),7.661(4.63),7.667(5.94),7.672(3.01),7.689(1.57),8.813(2.25),12.108(1.10).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.10(br.s,1H),8.92-8.69(m,1H), 7.77-7.39(m,5H),4.20-3.92(m,2H),3.90-3.75(m,1H),3.14(br.s,4H),2.32-2.22(m,1H),2.21-2.01(m,6H),1.67(br.s,4H),1.65-1.55(m,2H).
5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(92mg,95%純度,128μmol,對映異構物1,實施例179A)在二氯甲烷(1.1ml)之溶液中加入TFA(960μl,13mmol),將混合物在室溫下攪拌2小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到68mg(100%純度,理論值的85%)標題化合物。
[α]D 20=+31.4°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.36min;MS(ESIpos):m/z=626/628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.92),-0.008(15.84),0.146(1.96),1.609(3.95),1.676(7.70),2.075(1.68),2.101(3.23),2.122(4.27),2.136(8.34),2.169(16.00),2.183(3.27),2.206(1.56),2.230(0.76),2.282(1.56),2.327(2.91),2.366(1.52),2.669(2.31),2.710(1.52),3.143(10.13),3.808(1.44),4.057(2.19),7.477(2.67),7.498(3.91),7.533(3.47),7.555(5.79),7.597(4.27),7.618(2.99),7.631(1.76),7.654(6.46),7.658(6.34),7.668(6.30),7.691(1.52),8.808(2.79),12.101(0.48).
5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(96mg,95%純度,133μmol,對映異構物2,實施例180A)在二氯甲烷(1.1ml)之溶液中加入TFA(1.0ml,13mmol),將混合物在室溫下攪拌2小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到62mg(100%純度,理論值的74%)標題化合物。
[α]D 20=-28.8°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.36min;MS(ESIpos):m/z=626/628/630[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.14),0.147(1.14),1.607(4.08),1.675(8.11),2.072(1.61),2.086(2.39),2.099(3.19),2.120(4.11),2.136(8.64),2.156(4.33),2.169(16.00),2.181(3.50),2.203(1.67),2.282(1.64),2.327(2.25),2.367(1.03),2.669(1.69),2.710(1.14),3.141(10.56),3.807(1.42),4.054(2.42),7.476(2.58),7.497(3.81),7.533(3.39),7.555(5.50),7.598(4.42),7.618(3.11),7.629(2.06),7.651(6.64),7.656(6.81),7.666(6.50),7.688(1.56),8.810(2.67),12.111(1.14).
(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(55mg,82.1μmol,外/消旋物,實施例181A)在二氯甲烷(1.1ml)的溶液中加入TFA(610μl,8.2mmol),並將該混合物在RT下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到41mg(100%純度,理論值的81%)標題化合物。
LC-MS(方法1):Rt=1.66min;MS(ESIpos):m/z=612/614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(1.74),-0.008(16.00),0.146(1.82),1.875(15.55),2.070(2.64),2.097(4.97),2.118(5.12),2.158(8.72),2.194(15.11),2.277(2.23),2.327(2.78),2.669(2.04),3.573(11.14),3.784(2.12), 4.068(3.34),7.472(8.09),7.494(13.07),7.499(8.76),7.522(4.64),7.544(8.24),7.552(5.31),7.558(7.39),7.580(5.16),7.590(5.79),7.611(3.56),8.146(2.26),8.757(4.08).
1H-NMR(400MHz,DMSO-d6)δ[ppm]:12.06(br.s,1H),8.76(br.s,1H),7.73-7.15(m,5H),4.23-3.92(m,2H),3.92-3.69(m,1H),3.57(br.s,4H),2.39-2.02(m,7H),1.88(br.s,4H).
5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(92mg,97%純度,133μmol,對映異構物1,實施例182A)在二氯甲烷(1.1ml)之溶液中加入TFA(990μl,13mmol),將混合物在室溫下攪拌2小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到48mg(100%純度,理論值的59%)標題化合物。
[α]D 20=+31.4°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=1.63min;MS(ESIpos):m/z=612/614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.80),-0.008(15.65),0.008(16.00),0.147(1.97),1.875(15.71),2.067(2.90),2.096(4.93),2.108(5.22),2.157(8.64),2.194(15.19),2.276(2.38),2.327(4.81),2.366(1.62),2.669(3.59),2.710(1.39),3.576(11.13),3.785(2.09),4.057(3.36),7.472(9.10),7.494(14.03),7.500(8.93),7.523(5.28),7.544(9.28),7.552(5.74),7.558(7.71),7.580(5.22),7.590(5.97),7.611(3.59),8.206(1.74),8.759(4.00),12.141(0.93).
5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(98mg,94%純度,138μmol,對映異構物2,實施例183A)在二氯甲烷(1.2ml)之溶液中加入TFA(1.0ml,14mmol),將混合物在室溫下攪拌2小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到51mg(100%純度,理論值的56%)標題化合物。
[α]D 20=-29.4°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=1.65min;MS(ESIpos):m/z=612/614/616[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.68),-0.008(6.08),0.008(5.30),0.146(0.67),1.876(7.64),2.070(1.42),2.085(1.86),2.097(2.48),2.110(2.55),2.118(2.55),2.131(2.05),2.159(4.35),2.194(7.61),2.231(0.86),2.281(1.11),2.305(1.13),2.327(1.39),2.366(0.65),2.670(0.99),2.674(0.75),2.710(0.62),3.143(0.56),3.574(5.49),3.769(0.86),3.785(1.00),3.800(1.07),4.034(1.42),4.069(1.66),4.085(0.92),4.102(0.67),7.472(4.33),7.477(2.93),7.495(7.02),7.500(4.41),7.523(2.67),7.544(4.63),7.552(2.80),7.558(3.90),7.564(1.99),7.574(1.77),7.580(2.63),7.590(2.85),7.612(1.83),8.145(16.00),8.757(2.02).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(56mg,77.8μmol,外消旋物,實施例184A)在二氯甲烷(1.0ml)的溶液中加入TFA μl,7.8mmol),並將該混合物在室溫下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到48mg(100%純度,理論值的93%)標題化合物。
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=662/664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.885(3.71),2.103(4.93),2.116(5.04),2.135(3.96),2.159(9.28),2.188(16.00),2.307(1.63),2.328(1.61),2.670(1.01),3.174(4.63),3.453(2.74),3.483(5.27),3.511(2.65),3.819(1.27),4.071(2.16),7.479(2.26),7.501(3.20),7.535(3.02),7.556(5.36),7.599(4.05),7.620(2.74),7.681(1.38),7.703(6.38),7.709(6.79),7.716(6.35),7.739(1.34),8.822(2.49),12.109(1.24).
1H-NMR(400MHz,DMSO-d 6):δ[ppm]=12.10(br.s,1H),8.95-8.67(m,1H),7.78-7.66(m,2H),7.65-7.47(m,3H),4.17-3.96(m,2H),3.92-3.76(m,1H),3.48(br.t,2H),3.17(br.s,2H),2.19(s,9H),1.94-1.82(m,2H).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(79mg,95%純度,104μmol,對映異構物1,實施例185A)在二氯甲烷(890μl)中的溶液中加入TFA(780μl,10μmol),並將 該混合物在室溫下攪拌1小時。隨後濃縮混合物並將殘餘物吸收在DMSO中並通過製備型HPLC純化(方法19)。將合併的目標級分濃縮,並將各殘餘物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥。隨後在減壓下乾燥殘餘物後,獲得49mg(98%純度,理論值的69%)標題化合物。
[α]D 20=+30.4°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=662/664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.91),0.146(0.82),1.886(3.76),2.102(4.96),2.117(5.16),2.136(4.03),2.158(9.41),2.188(16.00),2.229(0.82),2.307(1.69),2.328(1.71),2.366(0.74),2.669(1.07),2.710(0.60),3.162(13.82),3.175(14.53),3.453(2.72),3.483(5.34),3.512(2.63),3.819(1.31),3.833(1.23),4.062(2.91),4.076(4.18),4.088(3.40),7.479(2.31),7.500(3.29),7.534(2.87),7.556(5.16),7.598(4.34),7.620(2.89),7.685(1.49),7.703(6.67),7.709(7.06),7.716(6.21),7.738(1.33),8.822(2.47),12.100(1.47).
5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,3,6-三氯苯基)戊酸三級丁酯(100mg,97%純度,134μmol,對映異構物2,實施例186A)在二氯甲烷(1.2ml)的溶液中加入TFA,13mmol),並將該混合物在室溫下攪拌1小時。隨後濃縮混合物並將殘餘物溶在DMSO中並通過製備型HPLC純化(方法19)。將合併的目標級分濃縮,並將各殘餘物冷凍乾燥。隨後,將冷凍乾燥物溶在甲醇中並合併,並將混合物在環境條件下放置乾燥隨後在減壓下乾燥殘餘物後,獲得49mg(98%純度,理論值的69%)標題化合物。
[α]D 20=-26.7°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.25min;MS(ESIpos):m/z=662/664/666[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.65),-0.008(5.21),0.008(3.92),0.146(0.56),1.884(3.63),2.065(2.12),2.078(3.31),2.103(4.75),2.117 (4.92),2.136(3.88),2.158(9.19),2.188(16.00),2.206(1.67),2.229(0.81),2.279(1.29),2.307(1.58),2.327(1.60),2.366(0.65),2.670(1.04),2.710(0.56),3.162(6.10),3.175(6.79),3.453(2.73),3.482(5.23),3.511(2.58),3.802(0.90),3.817(1.25),3.833(1.21),4.048(1.81),4.074(2.58),4.106(0.85),7.479(2.23),7.500(3.19),7.535(2.83),7.556(5.19),7.598(4.19),7.620(2.79),7.680(1.40),7.685(1.35),7.703(6.46),7.709(6.79),7.716(6.08),7.738(1.33),8.821(2.46),12.100(2.10).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(55mg,78.4μmol,非對映異構物混合物,實施例187A)在二氯甲烷(1.0毫升)的溶液中加入TFA(580微升,7.8毫摩爾),並將該混合物在RT下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到46mg(100%純度,理論值的91%)標題化合物。
LC-MS(方法1):Rt=2.22min;MS(ESIpos):m/z=644/646/648[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.84),-0.008(16.00),0.008(15.66),0.146(1.80),1.234(0.68),1.641(1.24),1.811(1.24),1.903(1.88),2.072(1.33),2.100(2.40),2.112(2.70),2.153(7.06),2.182(12.62),2.306(1.37),2.327(2.52),2.366(0.81),2.669(1.84),2.709(0.64),3.105(1.33),3.171(1.45),3.385(1.37),3.441(1.16),3.472(0.68),3.832(0.98),4.060(1.71),4.819(0.98),4.940 (0.94),7.477(2.05),7.499(2.82),7.533(2.87),7.555(4.96),7.597(3.17),7.617(2.10),7.654(1.33),7.676(5.48),7.680(5.18),7.690(5.39),7.712(1.28),8.819(1.97),12.102(0.98).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(55mg,77.3μmol,非對映異構物混合物,實施例188A)在二氯甲烷(1.0ml)之溶液中加入TFA(570μl,7.7mmol),並將該混合物在RT下攪拌1.5小時。隨後濃縮混合物並將殘餘物溶於DMSO中並通過製備型HPLC純化(方法15)。將合併的目標級分濃縮,並將殘餘物減壓乾燥。得到45mg(100%純度,理論值的89%)標題化合物。
LC-MS(方法1):Rt=2.58min;MS(ESIpos):m/z=654/656/658[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.89),-0.008(16.00),0.008(15.48),0.146(1.85),0.893(5.12),0.912(12.22),0.930(6.41),1.068(1.29),1.092(1.25),1.261(2.41),1.279(3.14),1.571(1.42),1.640(1.20),1.751(1.76),1.850(1.42),1.880(1.46),2.073(1.46),2.127(5.85),2.154(11.44),2.159(9.81),2.184(2.37),2.206(1.29),2.230(0.82),2.276(1.38),2.327(2.37),2.366(0.77),2.426(1.25),2.669(2.11),2.710(1.12),2.754(1.16),3.493(2.80),3.523(2.62),3.819(1.08),4.047(1.76),4.080(1.76),7.475(2.58),7.497(3.74),7.527(3.35),7.549(5.59),7.590(3.44),7.596(3.61),7.612(2.37),7.632(1.25),7.658(8.82),7.663(6.24),7.684(1.03),8.802(2.06),12.107(1.38).
(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(二氟甲氧基)-6-氟苯基]戊酸三級丁酯(85mg,128μmol,外消旋物,實施例189A)在二氯甲烷(1.1ml)之溶液中加入TFA(220μl,2.8mmol),並將該混合物在室溫放置3.5小時。然後濃縮混合物並重複加入二氯甲烷及再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到52mg(100%純度,理論值的67%)標題化合物。
LC-MS(方法1):Rt=2.16min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.21),1.608(4.52),1.673(8.82),1.908(0.41),1.924(0.72),1.941(1.34),1.963(1.75),1.986(1.24),2.004(0.65),2.036(1.55),2.055(3.62),2.093(8.19),2.134(16.00),3.139(11.63),3.534(1.87),3.665(0.84),3.680(1.39),3.697(2.25),3.713(2.67),3.728(1.44),3.745(1.52),3.762(2.00),3.781(1.70),3.794(1.07),3.815(0.62),7.020(4.00),7.041(4.62),7.050(3.53),7.091(2.63),7.114(4.09),7.138(2.96),7.234(5.54),7.359(1.55),7.380(3.08),7.397(3.02),7.418(4.11),7.478(0.95),7.628(2.91),7.650(13.17),7.659(8.54),7.664(7.65),7.681(1.71),7.686(1.86),8.775(2.20),8.790(4.37),8.805(2.16),12.045(0.54).
(-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(二氟甲氧基)-6-氟苯基]戊酸三級丁酯(180mg,271μmol,對映異構物1,實施例190A)在二氯甲烷(2.1ml)之溶液中加入TFA(460μl,6.0mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到121mg(100%純度,理論值的73%)標題化合物。
[α]D 20=-30.4°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.66),1.608(4.73),1.673(9.37),1.921(0.69),1.939(1.41),1.959(1.86),1.984(1.30),2.003(0.64),2.034(1.58),2.050(3.83),2.087(8.86),2.133(16.00),2.327(0.43),2.670(0.46),3.137(12.32),3.532(1.88),3.663(0.85),3.678(1.42),3.696(2.33),3.711(2.76),3.726(1.49),3.744(1.58),3.761(2.09),3.780(1.82),3.793(1.14),3.814(0.67),7.020(4.17),7.040(4.81),7.049(3.58),7.091(2.74),7.113(4.27),7.138(3.06),7.233(5.70),7.359(1.62),7.379(3.26),7.396(3.13),7.417(4.27),7.474(1.00),7.626(3.16),7.648(13.68),7.658(8.84),7.662(8.24),7.680(1.79),7.685(2.02),8.776(2.26),8.791(4.44),8.805(2.18),12.067(0.62).
(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-[2-(二氟甲氧基)-6-氟苯基]戊酸三級丁酯(145mg,218μmol,對映異構物2,實施例191A)在二氯甲烷(1.7ml)的溶液中加入TFA(370μl,4.8mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到95mg(100%純度,理論值的72%)標題化合物。
[α]D 20=+29.9°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.070(0.53),1.608(4.56),1.673(9.01), 1.921(0.70),1.939(1.37),1.959(1.76),1.984(1.24),2.000(0.64),2.034(1.52),2.052(3.62),2.090(8.27),2.133(16.00),2.669(0.44),3.137(11.85),3.532(1.81),3.664(0.80),3.678(1.36),3.696(2.21),3.712(2.64),3.727(1.46),3.744(1.54),3.763(2.00),3.781(1.73),3.815(0.63),7.020(4.01),7.041(4.64),7.049(3.41),7.091(2.61),7.114(4.15),7.138(2.97),7.234(5.33),7.359(1.49),7.380(3.11),7.397(2.99),7.417(4.01),7.474(0.98),7.626(2.92),7.648(12.70),7.658(7.83),7.662(7.47),7.680(1.63),7.684(1.80),8.775(2.16),8.789(4.27),8.804(2.14),12.053(1.06).
(-)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(470mg,742μmol,非對映異構物1,實施例192A)在二氯甲烷(13ml)之溶液中加入TFA(1.3ml,16mmol),將混合物放置在室溫16小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法32)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到372mg(100%純度,理論值的68%)標題化合物。
[α]D 20=-9.3°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.06min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.49),0.006(1.24),1.640(2.13),1.775(0.87),1.793(2.38),1.801(2.71),1.818(3.92),1.835(3.85),1.853(2.01),1.906(3.85),1.916(2.80),1.923(3.08),1.944(1.86),1.966(1.19),1.973(1.24),1.990(0.72),2.022(0.95),2.032(1.71),2.049(6.03),2.070(5.11),2.077(5.53),2.094(4.64),2.117(3.43),2.134(7.30),2.146(15.75),3.067(1.67),3.087(2.43),3.161(2.60),3.175(2.56),3.196(1.61),3.281(1.64),3.295(2.57),3.307(3.21),3.320(3.36),3.335(2.14),3.389(2.50),3.410(1.66),3.415(1.66),3.436(2.25),3.457(1.57),3.595(2.39),4.829(1.80),4.919(1.56),4.925(1.81),4.931(1.50),7.259(2.37),7.273(4.84),7.287(3.20),7.289(3.16),7.358(3.08),7.373 (5.30),7.387(2.77),7.443(8.03),7.445(8.07),7.459(6.96),7.461(6.79),7.482(6.24),7.485(6.43),7.498(5.40),7.500(5.27),7.651(4.10),7.669(16.00),7.676(11.40),7.680(9.95),7.694(2.38),7.698(2.47),8.720(3.02),8.731(5.62),8.743(2.74).
(-)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(420mg,664μmol,非對映異構物2,實施例193A)在二氯甲烷(12ml)之溶液中加入TFA(1.1ml,15mmol),將混合物放置在室溫16小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法32)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到331mg(100%純度,理論值的86%)標題化合物。
[α]D 20=-16.5°,589nm,c=0.43g/100ml,甲醇
LC-MS(方法1):Rt=2.06min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.47),0.007(1.09),1.644(1.88),1.650(1.80),1.772(0.62),1.791(2.00),1.799(2.22),1.815(3.30),1.833(3.44),1.851(1.68),1.905(3.34),1.922(2.59),1.943(1.35),1.949(1.32),1.967(1.01),1.975(1.02),1.983(0.67),1.991(0.54),2.019(0.68),2.029(1.29),2.038(1.58),2.046(5.27),2.066(4.31),2.073(4.72),2.090(4.20),2.113(2.61),2.130(5.56),2.144(12.88),2.518(0.57),2.522(0.43),3.073(1.31),3.094(2.18),3.108(1.92),3.150(2.24),3.163(2.22),3.185(1.32),3.282(1.40),3.297(2.20),3.309(2.83),3.322(3.01),3.337(1.88),3.385(2.32),3.406(1.51),3.411(1.50),3.427(2.03),3.432(2.11),3.453(1.48),3.592(2.08),3.651(1.20),3.665(2.13),3.676(2.72),3.686(2.31),4.820(1.33),4.826(1.57),4.915(1.34),4.921(1.57),4.927(1.30),7.257(1.94),7.260(2.01),7.273(4.31),7.288(2.95),7.290(2.80),7.359(2.64),7.374(4.73),7.388(2.45),7.442(8.34),7.445(7.88),7.458(7.21),7.461(6.59),7.482(5.70),7.484(5.71),7.497(4.85),7.651(3.74),7.668(16.00),7.675 (11.47),7.679(9.85),7.693(2.33),7.697(2.46),8.720(2.73),8.732(5.23),8.743(2.55).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(580mg,916μmol,非對映異構物3,實施例194A)在二氯甲烷(8ml)之溶液中加入TFA(1.4ml,18mmol),將混合物放置在室溫18小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。濃縮合併的目標組分,並將殘餘物從乙腈/水中冷凍乾燥。得到470mg(100%純度,ee>99%,理論值的89%)標題化合物。
[α]D 20=+10.0°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.12),0.008(2.34),1.641(1.61),1.793(1.81),1.811(2.86),1.835(3.14),1.858(1.83),1.898(2.57),1.917(2.18),1.948(1.57),1.982(0.97),2.012(0.69),2.045(4.00),2.079(4.65),2.088(4.76),2.143(16.00),2.327(0.60),2.366(0.43),2.670(0.60),3.060(1.10),3.093(1.78),3.158(1.92),3.175(1.84),3.202(1.07),3.380(1.98),3.406(1.07),3.438(1.66),3.464(1.06),3.594(1.82),3.680(3.53),4.817(1.32),4.937(1.32),7.256(1.68),7.274(3.88),7.291(2.78),7.356(2.33),7.374(4.34),7.392(2.23),7.441(6.24),7.444(5.85),7.461(5.31),7.464(4.93),7.484(5.31),7.500(4.60),7.647(2.38),7.668(13.37),7.675(9.32),7.680(8.01),7.698(1.56),7.702(1.76),8.716(2.06),8.730(4.24),8.745(2.04),12.062(0.71).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(609mg,962μmol,非對映異構物4,實施例195A)在二氯甲烷(8ml)之溶液中加入TFA(1.5ml,19mmol),將混合物放置在室溫18小時。 然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。濃縮合併的目標組分,並將殘餘物從乙腈/水中冷凍乾燥。得到485mg(100%純度,ee>95%,理論值的87%)標題化合物。
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=576/578[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.646(1.83),1.765(0.56),1.792(1.99),1.811(3.13),1.819(2.79),1.834(3.36),1.858(2.09),1.901(2.96),1.921(2.38),1.948(1.57),1.983(1.04),2.011(0.79),2.045(4.41),2.080(5.20),2.088(5.48),2.101(2.64),2.142(16.00),2.218(0.42),2.327(0.45),2.366(0.42),2.670(0.47),2.710(0.44),3.068(1.11),3.100(2.08),3.147(2.16),3.162(2.10),3.190(1.11),3.376(2.35),3.409(1.20),3.433(1.91),3.461(1.20),3.593(2.05),3.645(1.01),3.664(2.25),3.678(3.47),4.814(1.44),4.934(1.43),7.257(1.79),7.275(4.15),7.293(2.91),7.357(2.52),7.375(4.58),7.394(2.42),7.441(6.19),7.444(6.08),7.461(5.32),7.464(5.20),7.484(5.92),7.501(4.82),7.646(2.35),7.668(13.36),7.675(9.12),7.679(7.80),7.697(1.46),7.702(1.63),8.716(2.26),8.730(4.52),8.744(2.19),12.050(0.58).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(60mg,90μmol,非對映異構物1,實施例196A)在二氯甲烷(690μl)之溶液中加入TFA(150μl,2.0mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到43mg(100%純度,理論值的77%)標題化合物。
[α]D 20=+15.8°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(2.36),0.069(0.58),1.652(1.85),1.773(0.52),1.812(1.73),1.905(4.46),1.925(4.44),1.935(3.90),1.957(3.44),1.974(3.09),1.987(2.33),1.998(3.21),2.036(1.48),2.051(2.71),2.074(2.78),2.092(1.69),2.110(2.91),2.135(2.12),2.177(14.09),2.328(0.51),2.670(0.49),3.113(2.20),3.169(2.39),3.187(2.31),3.213(1.42),3.320(11.51),3.394(2.51),3.420(1.33),3.452(2.05),3.479(1.32),3.627(1.84),3.643(2.09),3.702(2.12),3.718(1.77),3.733(1.19),4.824(1.57),4.944(1.56),7.463(2.86),7.482(4.75),7.500(2.94),7.658(1.91),7.680(16.00),7.687(11.53),7.706(5.71),7.724(10.67),7.733(7.57),7.741(6.70),8.778(2.25),8.793(4.51),8.808(2.24).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(60mg,90μmol,非對映異構物2,實施例197A)在二氯甲烷(690μl)之溶液中加入TFA(150μl,2.0mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。濃縮合併的目標級分,並將殘餘物從乙腈/水中冷凍乾燥。得到38mg(100%純度,理論值的70%)標題化合物。
[α]D 20=+21.1°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.069(0.92),1.651(1.87),1.771(0.52),1.811(1.72),1.903(4.20),1.923(4.35),1.952(3.26),1.968(3.32),1.981(2.34),1.992(3.53),2.030(1.48),2.046(2.71),2.069(2.78),2.086(1.60),2.105(2.86),2.131(2.09),2.177(13.12),2.327(0.52),2.670(0.49),3.083(1.26),3.114(2.23),3.169(2.41),3.184(2.37),3.212(1.51),3.309(7.64),3.322(8.73),3.338(7.32),3.395(2.74),3.420(1.48),3.452(2.14),3.479(1.38),3.605(1.26),3.622(1.90),3.639(2.06),3.708(2.01),3.724(1.76),3.741(1.22),4.824(1.52),4.944(1.52),7.463(2.71),7.482(4.63),7.500(2.86),7.657(1.95),7.679(16.00),7.686(11.33), 7.708(5.90),7.723(10.09),7.734(7.42),7.739(7.24),8.784(2.18),8.799(4.37),8.813(2.19).
將實施例196A中描述的混合級分(峰1)溶於二氯甲烷(1.5ml)中,加入TFA(340μl,4.4mmol),並將混合物放置在室溫24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。收集含有產物的級分(在此出現物質損失),合併並濃縮,並將殘餘物從乙腈/水中冷凍乾燥。取得45mg(100%純度)5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸(非對映異構物混合物)。
將14mg這種非對映異構物混合物溶於乙腈和甲醇的混合物(8ml)中,並藉由製備型SFC在手性相上純化(參見實施例191和192)[管柱:Daicel Chiralcel OD-H,5μm,250mm×20mm;流速:80ml/min;注入:2.0毫升;溫度40℃,UV檢測210nm,溶析液:80%二氧化碳/20%乙醇;操作時間6.5分鐘,等度]。將合併的目標級分各自濃縮,並將每個殘餘物冷凍乾燥。
在所述非對映異構物分離中,獲得3mg(100%純度)標題化合物,作為首先洗脫的非對映異構物。
LC-MS(方法1):Rt=2.12min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(0.29),0.006(0.25),0.069(0.38),0.843(0.31),1.033(0.89),1.045(0.90),1.236(0.47),1.296(0.21),1.483(0.16),1.498(0.17),1.652(1.74),1.813(1.61),1.829(1.36),1.907(4.05),1.914(4.49),1.924(3.83),1.947(2.99),1.965(2.07),1.979(3.03),1.989(2.09),1.998(2.78),2.007(1.91),2.045(1.72),2.057(2.46),2.076(2.68),2.090(1.44),2.107(2.78),2.118(1.61),2.133(2.08),2.177(10.18),2.215(0.82),2.359(0.30),2.363 (0.36),2.432(1.68),2.637(0.45),2.640(0.34),3.087(1.24),3.106(1.94),3.173(2.21),3.188(2.24),3.208(1.55),3.229(3.57),3.396(3.72),3.422(2.39),3.448(2.66),3.469(1.89),3.604(1.48),3.614(1.57),3.629(1.80),3.642(1.90),3.705(1.90),3.717(1.73),3.922(0.24),3.933(0.24),3.962(0.30),3.985(0.27),4.836(1.52),4.923(1.82),4.931(1.65),4.938(1.32),7.467(2.66),7.483(4.72),7.497(2.92),7.662(3.02),7.679(16.00),7.685(12.54),7.689(11.15),7.703(3.21),7.707(6.31),7.724(9.33),7.735(6.85),7.740(6.75),7.749(2.78),7.826(0.92),8.777(2.43),8.789(4.78),8.801(2.35).
在實施例191中所述的非對映異構物分離中,獲得3mg(100%純度)標題化合物,作為第二洗脫的非對映異構物。
LC-MS方法1):Rt=2.12min;MS(ESIpos):m/z=610/612[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.03),0.145(0.03),1.199(0.06),1.313(0.08),1.324(0.10),1.359(16.00),1.515(0.07),1.606(1.36),1.786(0.95),1.829(0.23),1.856(0.12),2.014(0.07),2.033(0.27),2.044(0.29),2.065(1.27),2.089(0.32),2.096(0.28),2.128(0.72),2.327(0.04),2.669(0.04),3.369(0.20),3.386(0.20),3.496(1.10),3.511(1.53),3.525(1.08),3.602(0.20),3.618(0.27),3.630(0.26),3.645(0.24),3.663(0.18),7.358(0.39),7.384(0.20),7.397(0.78),7.408(0.64),7.414(0.61),7.420(0.72),7.432(0.19),7.534(0.65),7.546(0.46),7.556(1.45),7.569(0.34),7.600(0.62),7.606(0.59),7.623(0.33),7.628(0.32),8.703(0.21),8.718(0.40),8.732(0.20).
(+)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(45mg,67μmol,非對映異構物1,實施例198A)在 二氯甲烷(510μl)的溶液中加入TFA(110μl,1.5mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到33mg(100%純度,理論值的81%)標題化合物。
[α]D 20=+11.5°,436nm,c=0.44g/100ml,甲醇
LC-MS(方法2):Rt=1.28min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(1.56),0.913(3.64),0.932(1.85),1.263(0.63),1.281(0.82),1.298(0.59),1.571(0.42),1.753(0.48),1.887(0.65),1.921(0.41),1.965(0.46),1.989(0.49),2.049(0.52),2.072(0.57),2.089(0.48),2.130(1.77),2.434(0.42),2.501(16.00),2.749(0.48),3.511(0.75),3.532(0.62),3.716(0.46),3.732(0.40),7.459(0.53),7.479(0.88),7.497(0.53),7.657(3.86),7.685(0.50),7.706(0.96),7.715(1.30),7.735(2.15),7.754(0.48),8.778(0.74).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(40mg,59μmol,非對映異構物2,實施例199A)在二氯甲烷(450μl)之溶液中加入TFA(100μl,1.3mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到33mg(100%純度,理論值的81%)標題化合物。
[α]D 20=-42.9°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法2):Rt=1.28min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.146(0.17),0.896(6.44),0.915(16.00),0.934(7.90),1.060(0.48),1.087(1.16),1.113(1.24),1.139(0.55),1.234(0.82),1.247(1.07),1.264(2.26),1.281(3.55),1.299(3.26),1.315(1.91),1.333(0.76),1.578(1.42),1.618(1.33),1.651(1.17),1.763(1.74),1.797(1.17),1.858 (1.58),1.895(2.34),1.927(1.27),1.945(1.22),1.967(0.98),1.985(1.74),1.997(1.06),2.008(2.11),2.025(0.80),2.041(1.12),2.057(2.00),2.080(2.04),2.097(1.20),2.110(2.27),2.165(10.84),2.328(0.56),2.367(0.30),2.671(0.47),2.711(0.25),2.779(0.72),2.809(1.32),3.326(1.42),3.546(2.56),3.577(2.59),3.618(1.37),3.634(1.42),3.724(1.28),4.333(0.69),7.415(0.63),7.465(1.66),7.484(3.16),7.502(2.03),7.706(10.33),7.724(6.22),7.741(8.10),7.758(1.71),8.778(1.46),8.792(2.81),8.807(1.49).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(55mg,81μmol,非對映異構物3,實施例200A)在二氯甲烷(625μl)之溶液中加入TFA(138μl,1.78mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到33mg(100%純度,理論值的81%)標題化合物。
LC-MS(方法2):Rt=1.28min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.896(6.71),0.915(16.00),0.933(7.95),1.060(0.50),1.089(1.32),1.118(1.37),1.140(0.62),1.233(0.74),1.248(1.12),1.265(2.52),1.275(2.32),1.283(3.35),1.292(2.79),1.301(2.42),1.310(1.90),1.344(0.28),1.580(1.69),1.606(1.47),1.616(1.53),1.648(1.30),1.678(0.58),1.763(1.92),1.796(1.31),1.856(1.82),1.895(2.61),1.920(1.46),1.927(1.46),1.943(1.42),1.965(1.14),1.982(1.98),1.995(1.20),2.006(2.34),2.023(1.04),2.044(1.28),2.059(2.27),2.082(2.50),2.137(6.50),2.328(0.40),2.367(0.31),2.671(0.37),2.711(0.24),2.784(0.87),2.812(1.60),2.840(0.89),3.324(1.56),3.545(2.89),3.576(2.80),3.609(1.15),3.626(1.48),3.643(1.56),3.708(1.13),3.725(1.89),3.742(1.68),3.759(1.21),3.775(0.66),4.374(0.60),7.465 (2.03),7.483(3.62),7.502(2.29),7.690(1.98),7.710(13.25),7.728(4.42),7.739(8.10),7.761(2.15),8.780(1.62),8.795(3.23),8.809(1.68).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(45mg,67μmol,非對映異構物4,實施例201A)在二氯甲烷(512μl)之溶液中加入TFA(113μl,1.46mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到22mg(100%純度,理論值的54%)標題化合物。
[α]D 20=+36.5°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法2):Rt=1.28min;MS(ESIpos):m/z=620/622[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.895(6.49),0.914(16.00),0.933(7.87),1.045(0.48),1.074(1.22),1.097(1.27),1.126(0.56),1.245(1.11),1.262(2.28),1.279(3.44),1.296(3.11),1.312(1.94),1.330(0.77),1.572(1.42),1.615(1.37),1.644(1.20),1.755(1.80),1.788(1.19),1.853(1.63),1.894(2.29),1.926(1.31),1.942(1.33),1.965(1.02),1.982(1.75),1.994(1.19),2.006(2.13),2.024(0.84),2.041(1.16),2.056(2.06),2.079(2.04),2.097(1.29),2.110(2.32),2.159(11.74),2.328(0.58),2.367(0.41),2.429(1.18),2.458(1.97),2.670(0.49),2.710(0.42),2.733(0.86),2.759(1.56),2.790(0.85),3.325(1.61),3.522(5.03),3.543(4.60),3.595(2.21),3.614(2.34),3.631(2.17),3.716(1.56),7.414(0.69),7.464(1.69),7.483(3.14),7.501(1.93),7.643(0.61),7.665(14.63),7.690(1.70),7.709(3.46),7.723(6.19),7.740(7.10),7.756(1.65),8.756(1.60),8.770(3.12),8.785(1.58).
(+)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(70mg,106μmol,非對映異構物1,實施例202A)在二氯甲烷(810μl)的溶液中加入TFA(180μl,2.32mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到45mg(100%純度,理論值的70%)標題化合物。
[α]D 20=+22.2°,589nm,c=0.27g/100ml,甲醇
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.18),-0.008(1.58),0.008(1.81),0.069(0.44),0.146(0.19),0.927(10.77),0.943(10.98),0.984(0.16),1.056(0.36),1.084(1.12),1.114(1.17),1.135(0.48),1.235(0.33),1.633(0.97),1.663(1.14),1.691(0.56),1.737(2.00),1.771(1.99),1.797(2.53),1.827(1.55),1.893(1.08),1.902(1.01),1.924(1.40),1.938(1.28),1.952(1.21),1.968(1.64),1.981(0.97),1.992(1.83),2.001(1.10),2.032(0.90),2.047(1.77),2.071(1.84),2.088(1.01),2.108(1.88),2.162(8.48),2.328(0.30),2.367(0.19),2.436(1.04),2.465(1.69),2.670(0.37),2.691(0.96),2.718(1.71),2.747(0.94),3.452(1.85),3.479(3.26),3.508(1.63),3.608(0.78),3.625(1.19),3.641(1.32),3.696(1.34),3.712(1.15),3.729(0.76),7.435(0.73),7.462(1.67),7.481(2.99),7.499(1.81),7.636(0.90),7.657(16.00),7.661(8.05),7.684(1.57),7.707(3.18),7.722(6.86),7.732(4.91),7.739(4.39),8.766(1.46),8.781(2.92),8.795(1.44),12.101(0.17).
(+)-5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(70mg,106μmol,非對映異構物2,實施例203A)在二氯甲烷(810μl)的溶液中加入TFA(180μl,2.3mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。 殘餘物通過製備HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到47mg(100%純度,理論值的73%)標題化合物。
[α]D 20=+11.7°,589nm,c=0.29g/100ml,甲醇
LC-MS(方法1):Rt=2.34min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.27),0.008(1.49),0.069(0.30),0.146(0.17),0.928(11.12),0.944(11.35),1.059(0.37),1.085(1.15),1.115(1.18),1.136(0.47),1.235(0.19),1.635(0.98),1.665(1.19),1.695(0.56),1.737(2.01),1.771(1.99),1.797(2.48),1.828(1.54),1.897(1.09),1.907(1.03),1.927(1.25),1.942(1.18),1.961(1.04),1.978(1.67),1.990(1.02),2.002(1.92),2.011(1.17),2.039(1.00),2.053(1.87),2.076(1.89),2.094(1.09),2.113(1.91),2.168(10.24),2.328(0.43),2.366(0.20),2.438(1.20),2.468(1.84),2.670(0.48),2.689(0.90),2.718(1.63),2.746(0.89),3.452(1.81),3.480(3.20),3.508(1.54),3.612(1.12),3.629(1.22),3.707(1.17),3.723(1.04),7.424(0.65),7.465(1.63),7.483(2.97),7.501(1.79),7.636(0.89),7.658(16.00),7.662(7.92),7.685(1.30),7.709(3.20),7.724(6.78),7.735(4.84),7.741(4.46),8.760(1.53),8.775(3.04),8.789(1.47),12.012(0.45).
將實施例202A中描述的混合級分(峰1)溶解於二氯甲烷(1.8ml)中,加入TFA(390μl,5.05mmol),並將混合物在室溫放置24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。取得106mg(100%純度)5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸(非對映異構物混合物)。
將78mg這種非對映異構物混合物溶於乙腈和甲醇的混合物(8ml)中,並藉由製備型SFC在手性相上純化(參見實施例199和200)[管柱:Daicel Chiralcel OD-H,5μm,250mm×20mm;流速:80ml/min;注入:2.0毫升;溫度40℃,UV檢測210nm,溶解液:80%二氧化碳/20%乙醇;操作時間6.5分鐘,等度]。合併的目標級分各自濃縮,並將每個殘餘物冷凍乾燥。
在所述的非對映異構物分離中,獲得24mg(100%純度,ee>99%)標題化合物,作為首先洗脫的非對映異構物。
LC-MS(方法2):Rt=1.22min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.79),0.008(0.76),0.069(0.28),0.927(10.81),0.943(10.94),1.056(0.42),1.084(1.13),1.108(1.18),1.136(0.48),1.237(0.16),1.633(1.00),1.663(1.16),1.737(2.02),1.744(1.93),1.772(2.02),1.797(2.51),1.828(1.59),1.898(1.22),1.909(1.22),1.929(1.37),1.942(1.31),1.963(1.20),1.979(1.84),1.992(1.24),2.004(2.13),2.012(1.20),2.040(1.15),2.055(2.08),2.079(2.19),2.096(1.33),2.114(2.35),2.162(8.78),2.328(0.42),2.366(0.31),2.436(1.08),2.466(1.74),2.670(0.48),2.691(0.94),2.718(1.67),2.747(0.93),3.452(1.70),3.479(3.15),3.509(1.53),3.628(1.16),3.644(1.35),3.697(1.39),3.713(1.17),7.432(0.80),7.464(1.77),7.483(3.21),7.502(1.99),7.636(0.94),7.658(16.00),7.662(7.86),7.685(1.53),7.709(3.51),7.724(6.91),7.740(5.40),7.754(1.76),8.756(1.54),8.770(3.12),8.785(1.54),12.030(2.34).
在實施例199中所述的非對映異構物分離中,獲得23mg(100%純度,ee>99%)標題化合物,作為第二洗脫出的非對映異構物。
LC-MS(方法2):Rt=1.22min;MS(ESIpos):m/z=606/608[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.008(0.84),0.069(0.29),0.928(11.23),0.944(11.35),1.085(1.20),1.115(1.22),1.136(0.52),1.634(1.04),1.665(1.28),1.692(0.64),1.737(2.13),1.771(2.10),1.797(2.59),1.828(1.65), 1.897(1.30),1.909(1.29),1.929(1.44),1.943(1.42),1.963(1.22),1.980(1.93),1.993(1.27),2.004(2.23),2.014(1.33),2.040(1.25),2.055(2.17),2.078(2.26),2.096(1.43),2.114(2.23),2.168(10.68),2.255(0.24),2.328(0.50),2.367(0.27),2.438(1.21),2.469(1.90),2.670(0.59),2.690(0.94),2.718(1.67),2.746(0.93),3.453(1.89),3.480(3.27),3.509(1.63),3.613(1.27),3.630(1.33),3.708(1.29),3.724(1.16),7.425(0.71),7.465(1.79),7.484(3.29),7.502(2.08),7.636(0.78),7.658(16.00),7.662(8.26),7.690(1.53),7.709(3.65),7.725(7.44),7.735(5.58),7.742(5.23),8.758(1.60),8.773(3.25),8.788(1.62),12.029(2.27).
(-)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(70mg,101μmol,非對映異構物1,實施例204A)在二氯甲烷(1.8ml)的溶液中加入TFA(172μl,2.23mmol),並將混合物放置在室溫下16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到40mg(100%純度,理論值的62%)標題化合物。
[α]D 20=-20.0°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.74),0.006(1.29),0.117(0.17),1.234(0.48),1.358(0.18),1.647(2.01),1.777(0.83),1.794(1.85),1.807(3.28),1.815(3.49),1.825(3.10),1.833(3.74),1.851(2.21),1.910(3.53),1.926(2.82),1.948(1.55),1.970(1.09),1.978(1.12),1.995(0.62),2.010(0.51),2.031(1.08),2.042(2.73),2.068(9.82),2.072(8.73),2.093(2.44),2.106(1.59),2.153(8.47),2.242(0.33),2.358(0.31),2.362(0.41),2.519(0.94),2.523(0.70),2.632(0.31),2.636(0.41),2.639(0.31),3.079(1.46),3.100(2.29),3.163(2.39),3.177(2.41),3.198(1.53),3.292(1.73),3.305(2.59),3.318(3.24),3.331(3.42),3.345 (2.27),3.390(4.35),3.395(4.39),3.415(2.52),3.441(2.30),3.463(1.61),3.594(1.07),3.605(1.65),3.620(2.70),3.632(3.18),3.645(1.99),3.656(1.71),3.670(2.44),3.684(2.05),3.696(1.26),3.711(0.70),4.831(1.64),4.920(1.40),4.926(1.64),4.932(1.37),7.343(2.70),7.347(2.74),7.351(2.93),7.355(3.78),7.359(4.72),7.362(3.77),7.384(1.38),7.389(2.08),7.399(6.05),7.403(8.73),7.410(7.42),7.417(7.35),7.431(1.78),7.468(0.96),7.550(4.55),7.554(3.30),7.562(3.39),7.569(3.42),7.657(3.58),7.674(16.00),7.681(10.84),7.685(9.37),7.699(2.17),7.703(2.30),8.746(2.70),8.757(4.94),8.769(2.51).
(-)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(70mg,103μmol,非對映異構物2,實施例205A)在二氯甲烷(1.8ml)中的溶液中加入TFA(174μl,2.26mmol),並將混合物放置在室溫下16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到37mg(100%純度,理論值的58%)標題化合物。
[α]D 20=-14.2°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.120(0.23),-0.007(2.56),0.006(1.91),0.070(0.24),0.117(0.21),1.234(0.27),1.249(0.18),1.365(0.16),1.646(1.97),1.779(0.86),1.795(1.89),1.809(3.39),1.818(3.31),1.827(3.12),1.835(3.65),1.854(2.25),1.910(3.52),1.920(2.49),1.927(2.86),1.949(1.66),1.970(1.11),1.978(1.13),2.017(0.45),2.048(2.62),2.070(10.21),2.096(2.46),2.154(9.21),2.240(0.34),2.362(0.39),2.519(0.85),2.523(0.58),2.636(0.37),3.078(1.46),3.098(2.24),3.167(2.44),3.181(2.44),3.202(1.56),3.290(1.92),3.304(2.85),3.316(3.52),3.329(3.62),3.343(2.38),3.395(4.37),3.416(2.57),3.442(2.19),3.464(1.51),3.599(0.89),3.611(1.41),3.625(2.70),3.638(3.40),3.650 (3.29),3.664(2.72),3.678(2.12),3.690(1.14),3.705(0.62),4.826(1.45),4.832(1.71),4.921(1.45),4.927(1.72),4.933(1.42),7.345(2.69),7.348(2.70),7.352(2.89),7.356(3.79),7.360(4.70),7.363(3.78),7.384(1.46),7.389(2.13),7.399(6.05),7.403(8.97),7.410(7.38),7.417(7.59),7.431(1.73),7.480(0.99),7.551(4.79),7.555(3.42),7.563(3.46),7.570(3.57),7.658(3.77),7.675(16.00),7.682(10.74),7.686(9.28),7.700(2.17),7.704(2.26),8.743(2.56),8.755(4.81),8.766(2.44),12.171(0.19).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(64mg,92μmol,非對映異構物3,實施例206A)在二氯甲烷(1.62ml)之溶液中加入TFA(156μl,2.02mmol),並將混合物放置在室溫下16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到38mg(100%純度,理論值的65%)標題化合物。
[α]D 20=+14.9°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.72),0.006(1.14),0.070(0.25),1.233(0.53),1.333(0.22),1.353(0.39),1.371(0.25),1.646(2.02),1.779(0.85),1.795(1.93),1.809(3.59),1.819(3.45),1.827(3.18),1.835(3.82),1.854(2.40),1.911(3.61),1.920(2.55),1.927(2.93),1.949(1.71),1.971(1.13),1.978(1.15),2.015(0.49),2.036(1.12),2.047(2.88),2.069(10.49),2.096(2.64),2.111(1.57),2.154(9.53),2.241(0.34),2.362(0.36),2.519(0.74),2.522(0.54),2.636(0.34),3.078(1.52),3.099(2.33),3.167(2.56),3.181(2.58),3.202(1.69),3.289(1.77),3.303(2.69),3.316(3.34),3.329(3.53),3.343(2.33),3.395(4.62),3.416(2.75),3.442(2.37),3.464(1.65),3.599(0.94),3.611(1.50),3.625(2.85),3.638(3.63),3.650(3.47),3.664(2.87),3.678(2.24),3.690(1.23),3.705(0.71),4.832(1.74),4.921(1.49),4.927(1.76),4.933(1.46),7.345(2.68),7.348(2.69),7.352 (2.86),7.357(3.85),7.360(4.78),7.384(1.37),7.389(2.04),7.399(6.17),7.403(9.14),7.410(7.53),7.417(7.95),7.431(1.82),7.481(1.02),7.551(5.06),7.555(3.52),7.563(3.66),7.570(3.84),7.658(3.63),7.675(16.00),7.683(10.62),7.686(9.13),7.700(2.21),7.704(2.30),8.744(2.82),8.756(5.44),8.767(2.75).
(+)-5-[({6-溴-2-[3-氟哌啶-1-基]-3-methyl喹啉-4-yl}羰基)amino]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(64mg,94μmol,diastereomer 4,實施例207A)在二氯甲烷(1.66ml)的溶液中加入TFA(159μl,2.06mmol),並將混合物放置在室溫下16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到31mg(100%純度,理論值的53%)標題化合物。
[α]D 20=+20.0°,589nm,c=0.35g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=626/628[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.120(0.20),-0.007(2.68),0.006(1.93),0.117(0.20),1.131(3.23),1.235(0.50),1.353(0.28),1.386(0.19),1.646(2.21),1.778(0.95),1.795(2.07),1.807(3.59),1.816(3.73),1.825(3.47),1.833(4.07),1.852(2.39),1.910(3.89),1.926(3.11),1.947(1.73),1.971(1.24),1.978(1.26),2.047(2.74),2.068(11.03),2.093(2.58),2.153(9.32),2.242(0.35),2.362(0.50),2.636(0.46),3.080(1.61),3.099(2.52),3.163(2.63),3.176(2.67),3.198(1.69),3.291(2.30),3.305(3.33),3.318(4.05),3.331(4.17),3.345(2.80),3.390(4.88),3.415(2.76),3.441(2.48),3.462(1.70),3.594(1.14),3.605(1.76),3.620(2.90),3.632(3.47),3.645(2.18),3.656(1.95),3.670(2.71),3.683(2.24),3.696(1.38),3.711(0.77),4.254(0.23),4.265(0.19),4.831(1.80),4.926(1.80),7.213(0.24),7.286(0.23),7.302(0.26),7.344(2.98),7.347(3.03),7.351(3.22),7.355(4.05),7.359(4.92),7.389(2.26),7.400(6.52),7.403(9.12),7.411(7.68),7.418(7.84),7.432(1.90),7.473(1.07),7.551(4.79),7.562(3.74),7.569(3.59),7.657 (3.65),7.674(16.00),7.681(10.76),7.685(9.35),7.699(2.19),7.703(2.29),8.745(2.59),8.756(4.66),8.768(2.45),12.196(0.18).
(+)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(45mg,65μmol,非對映異構物1,實施例208A)在二氯甲烷(0.5ml)的溶液中加入TFA(110μl,1.43mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到38mg(100%純度,理論值的92%)標題化合物。
[α]D 20=+12.7°,436nm,c=0.30g/100ml,甲醇
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(6.77),0.911(16.00),0.930(8.24),1.045(0.61),1.067(1.37),1.102(1.47),1.140(0.77),1.242(1.36),1.260(2.97),1.278(3.89),1.296(2.68),1.567(1.79),1.603(1.66),1.636(1.39),1.753(2.05),1.785(1.75),1.812(1.58),1.836(2.59),1.857(2.73),1.882(1.90),1.909(1.96),2.051(2.59),2.077(12.08),2.111(7.17),2.229(0.46),2.246(0.53),2.327(0.72),2.675(0.63),2.739(1.08),2.769(1.95),2.799(1.06),3.390(1.88),3.510(3.52),3.540(3.41),3.567(1.51),3.584(1.48),3.599(1.93),3.617(2.79),3.633(3.32),3.648(2.34),3.661(2.48),3.678(3.22),3.696(2.83),3.711(2.05),3.731(1.49),7.355(3.26),7.385(1.48),7.397(5.85),7.409(4.92),7.420(5.18),7.476(1.21),7.555(3.56),7.567(3.02),7.578(2.59),7.674(15.79),8.734(1.88),8.749(3.42),8.763(1.76).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(30mg,43μmol,非對映異構物2,實施例209A)在二氯甲烷(330μl)的溶液中加入TFA(73μl,950μmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到14mg(100%純度,理論值的50%)標題化合物。
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.069(0.21),0.894(6.49),0.913(16.00),0.931(8.01),1.086(1.30),1.114(1.33),1.138(0.60),1.245(1.15),1.262(2.51),1.280(3.24),1.291(2.89),1.298(2.89),1.309(1.93),1.574(1.48),1.614(1.40),1.645(1.26),1.760(1.81),1.792(1.65),1.815(1.52),1.838(1.92),1.858(2.48),1.885(1.73),1.909(0.69),2.054(2.32),2.079(10.90),2.141(9.25),2.328(0.48),2.367(0.29),2.671(0.47),2.710(0.27),2.803(1.31),3.406(1.46),3.536(2.86),3.566(2.69),3.603(1.12),3.621(1.93),3.637(2.39),3.653(1.91),3.675(1.73),3.691(1.41),4.286(0.64),7.358(2.99),7.387(1.36),7.401(5.34),7.412(4.79),7.419(4.47),7.424(5.17),7.437(1.59),7.554(3.13),7.566(2.68),7.577(2.30),7.702(8.48),8.747(1.57),8.762(2.93).
(-)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(45mg,65μmol,非對映異構物3,實施例210A)在二氯甲烷(0.5ml)的溶液中加入TFA(110μl,1.43mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到22mg(100%純度,理論值的53%)標題化合物。
[α]D 20=-10.6°,436nm,c=0.35g/100ml,甲醇
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(6.49),0.912(16.00),0.930(7.83),1.069(1.16),1.098(1.20),1.121(0.54),1.243(1.11),1.260(2.52),1.278(3.35),1.296(2.24),1.564(1.46),1.602(1.36),1.634(1.14),1.751(1.72),1.784(1.42),1.814(1.24),1.825(1.32),1.836(2.15),1.857(2.26),1.883(1.55),2.050(2.20),2.077(10.21),2.109(5.78),2.328(0.41),2.367(0.34),2.404(0.80),2.430(1.31),2.458(0.96),2.670(0.35),2.723(0.91),2.755(1.66),2.783(0.94),3.409(2.32),3.498(3.72),3.528(3.05),3.584(0.97),3.599(1.25),3.617(1.88),3.633(2.25),3.648(1.36),3.660(1.49),3.677(1.98),3.696(1.66),3.712(0.97),3.730(0.63),7.355(2.78),7.384(1.19),7.399(4.88),7.410(4.38),7.417(3.92),7.421(4.57),7.434(1.17),7.472(0.98),7.555(3.27),7.560(2.08),7.567(2.60),7.578(2.44),7.637(1.08),7.660(13.23),7.665(7.07),7.683(0.77),7.688(0.90),8.722(1.55),8.736(2.95),8.750(1.56),12.021(0.18).
(+)-5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(50mg,72μmol,非對映異構物4,實施例211A)在二氯甲烷(550μl)的溶液中加入TFA(122μl,1.60mmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到29mg(100%純度,理論值的64%)標題化合物。
[α]D 20=+33.2°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法2):Rt=1.31min;MS(ESIpos):m/z=636/638[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.893(2.80),0.911(6.69),0.930(3.44),1.040(0.22),1.068(0.60),1.098(0.62),1.120(0.28),1.242(0.50),1.260(1.07),1.277(1.46),1.288(1.30),1.306(0.89),1.323(0.36),1.565(0.68),1.608(0.66),1.638(0.61),1.669(0.27),1.749(0.86),1.783(0.69),1.813(0.64),1.825(0.64),1.837(1.03),1.857(1.17),1.883(0.79),2.052(0.97),2.078(4.80),2.104(0.89), 2.134(4.71),2.408(0.49),2.436(0.80),2.501(16.00),2.711(0.49),2.743(0.82),2.772(0.45),3.391(0.71),3.405(0.71),3.495(1.33),3.525(1.23),3.585(0.29),3.600(0.45),3.618(0.88),3.633(1.10),3.650(1.01),3.668(0.85),3.686(0.68),3.702(0.37),3.721(0.20),7.357(1.35),7.385(0.60),7.400(2.46),7.410(2.05),7.422(2.29),7.435(0.73),7.551(1.40),7.564(1.20),7.574(1.03),7.630(0.49),7.653(5.71),7.681(0.35),8.718(0.80),8.733(1.55),8.747(0.78),12.050(0.93).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(55mg,81μmol,非對映異構物1,實施例212A)在二氯甲烷(620μl)的溶液中加入TFA(140μl,1.78mmol),將混合物放置在RT下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到31mg(100%純度,理論值的62%)標題化合物。
[α]D 20=-10.3°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.926(16.00),0.936(15.61),1.064(0.58),1.078(1.42),1.084(1.41),1.097(1.41),1.102(1.47),1.117(0.60),1.123(0.56),1.231(0.22),1.613(0.50),1.634(1.34),1.654(1.48),1.675(0.64),1.735(2.32),1.740(2.10),1.757(2.38),1.782(1.39),1.798(2.50),1.805(2.60),1.814(2.76),1.821(2.68),1.828(2.74),1.844(1.25),1.863(0.27),2.010(0.25),2.020(0.39),2.037(0.85),2.046(2.13),2.064(6.16),2.069(7.11),2.090(2.07),2.101(1.52),2.140(3.50),2.223(0.26),2.388(0.21),2.438(1.09),2.457(1.74),2.476(1.11),2.616(0.17),2.685(0.84),2.703(1.42),2.722(0.81),3.446(3.21),3.470(3.69),3.495(2.02),3.599(1.21),3.611(1.68),3.621(1.82),3.671(1.25),7.349(2.25),7.362(3.62),7.394(1.37),7.407(4.92),7.413(4.94),7.419(5.18),7.432 (1.39),7.556(3.06),7.567(2.56),7.572(2.44),7.641(2.35),7.655(10.60),7.661(6.80),7.665(6.00),7.676(1.43),7.679(1.49),8.756(2.07),8.765(3.88),8.775(2.04).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(54mg,80μmol,非對映異構物2,實施例213A)在二氯甲烷(612μl)的溶液中加入TFA(135μl,1.75mmol),將混合物放置在RT下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中凍乾。得到32mg(100%純度,理論值的65%)標題化合物。
[α]D 20=-21.8°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.924(16.00),0.935(15.74),1.056(0.52),1.063(0.63),1.076(1.57),1.082(1.58),1.096(1.60),1.100(1.67),1.115(0.68),1.121(0.63),1.231(0.24),1.630(1.33),1.650(1.46),1.736(2.56),1.741(2.31),1.758(2.71),1.777(1.77),1.783(1.70),1.803(3.04),1.812(3.22),1.820(3.18),1.827(3.32),1.843(1.39),1.861(0.33),1.912(0.18),2.015(0.47),2.033(1.03),2.042(2.40),2.060(6.59),2.068(7.94),2.088(2.88),2.098(2.41),2.128(2.87),2.183(1.04),2.203(0.44),2.388(0.27),2.448(1.37),2.616(0.22),2.689(1.13),2.707(2.01),2.727(1.10),3.444(3.52),3.470(3.91),3.494(2.73),3.596(0.97),3.606(1.40),3.617(1.98),3.627(2.24),3.637(1.42),3.668(1.72),3.679(1.54),7.349(2.52),7.361(4.01),7.393(1.55),7.406(5.60),7.412(5.50),7.418(5.79),7.431(1.52),7.482(0.41),7.539(0.39),7.557(3.59),7.568(2.93),7.572(2.82),7.640(3.18),7.655(13.58),7.661(7.95),7.665(7.00),7.676(1.83),7.679(1.86),7.691(0.24),7.694(0.24),8.756(1.89),8.765(3.35),8.774(1.84).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(43mg,63μmol,非對映異構物3,實施例214A)在二氯甲烷(490μl)的溶液中加入TFA(107μl,1.39mmol),將混合物放置在RT下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中凍乾。得到32mg(100%純度,理論值的65%)標題化合物。
[α]D 20=+28.2°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.926(16.00),0.937(15.62),1.073(0.62),1.087(1.54),1.092(1.54),1.111(1.60),1.126(0.64),1.132(0.60),1.232(0.37),1.635(1.27),1.654(1.37),1.742(2.59),1.747(2.38),1.753(1.94),1.764(2.85),1.770(2.57),1.782(1.70),1.788(1.71),1.802(2.90),1.810(2.73),1.825(3.13),1.832(3.13),1.848(1.67),1.866(0.40),2.030(0.47),2.048(1.13),2.057(2.98),2.075(10.52),2.082(8.56),2.096(3.00),2.104(2.18),2.110(2.35),2.128(2.72),2.216(0.36),2.389(0.23),2.478(1.40),2.617(0.18),2.720(1.08),2.739(1.95),2.759(1.06),3.394(1.70),3.466(1.91),3.496(2.75),3.518(2.09),3.611(1.33),3.623(1.95),3.633(2.23),3.643(1.46),3.673(1.78),3.684(1.62),4.021(3.98),7.351(2.40),7.361(3.19),7.364(4.04),7.396(1.42),7.405(3.71),7.410(5.53),7.415(5.55),7.422(5.89),7.434(1.58),7.562(3.71),7.573(3.06),7.577(3.13),7.662(2.25),7.677(12.80),7.681(8.38),7.684(7.38),7.696(1.44),7.699(1.60),8.763(1.83),8.773(3.46),8.783(1.97).
5-[({6-溴-3-甲基-2-[3-甲基哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(53mg,78μmol,非對映異構物4,實施例215A)在二氯 甲烷(600μl)的溶液中加入TFA(132μl,1.72mmol),並將混合物放置在RT下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到26mg(100%純度,理論值的53%)標題化合物。
[α]D 20=+11.8°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=622/624[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.925(16.00),0.936(15.89),1.064(0.59),1.078(1.47),1.083(1.49),1.097(1.49),1.102(1.57),1.116(0.65),1.123(0.61),1.230(0.21),1.613(0.51),1.634(1.38),1.655(1.54),1.675(0.66),1.735(2.39),1.740(2.19),1.757(2.49),1.781(1.46),1.798(2.63),1.804(2.79),1.813(2.92),1.821(2.88),1.828(2.98),1.843(1.28),1.862(0.30),2.018(0.36),2.035(0.83),2.044(2.11),2.063(6.09),2.068(7.27),2.086(2.04),2.089(2.21),2.099(1.65),2.140(3.69),2.222(0.30),2.388(0.20),2.438(1.12),2.457(1.81),2.476(1.13),2.616(0.20),2.684(0.89),2.704(1.50),2.722(0.88),3.447(3.51),3.470(3.99),3.495(2.22),3.599(1.31),3.610(1.79),3.620(1.95),3.670(1.33),7.349(2.41),7.361(3.73),7.393(1.49),7.407(5.12),7.412(5.06),7.419(5.28),7.431(1.38),7.556(3.17),7.567(2.64),7.571(2.47),7.640(2.43),7.655(10.78),7.661(6.89),7.664(6.03),7.676(1.37),7.679(1.44),8.756(2.16),8.766(3.93),8.776(2.02).
(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-yl)-3-methyl喹啉-4-yl]羰基}amino)-4-(5-氟-2-methyl苯基)戊酸(外消旋物,183mg,309μmol,實施例150)透過製備型SFC在手性相上分離為對映異構物(參見實施例213和214)[管柱:Daicel Chiralcel OX-H,5μm,250mm×20mm;流速:60毫升/分鐘;UV檢測:230nm, 溫度:25℃;溶析液:80%二氧化碳/20%乙醇;等度]。合併的目標級分各自在30℃/30毫巴下濃縮。
在所描述的對映異構物分離中,獲得90mg(>99%純度,ee>97%)標題化合物作為先洗脫的對映異構物。
[α]D 20=-10.8°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.17),0.069(0.30),0.146(0.19),1.235(0.96),1.745(0.36),1.763(0.84),1.779(1.06),1.797(1.31),1.819(1.05),1.835(0.71),1.880(3.50),1.976(0.55),1.997(1.12),2.009(1.39),2.028(1.49),2.046(2.35),2.072(5.97),2.088(7.64),2.117(11.26),2.293(16.00),2.366(0.29),2.670(0.41),2.710(0.21),3.165(4.29),3.450(2.65),3.479(5.58),3.506(3.83),3.533(1.13),3.665(1.00),3.683(1.61),3.702(1.43),3.717(1.21),3.736(0.69),6.930(1.26),6.945(2.35),6.951(2.51),6.966(1.32),6.972(1.35),7.141(2.38),7.147(2.44),7.168(2.44),7.174(2.35),7.200(2.42),7.216(2.84),7.237(2.08),7.479(1.02),7.677(1.46),7.699(9.77),7.708(5.87),7.731(0.97),8.722(1.64),8.736(2.62),8.749(1.57),12.074(0.51).
在實施例213中描述的對映異構物分離中,獲得91mg(>99%純度,ee>95%)標題化合物作為稍後洗脫的對映異構物。
[α]D 20=+15.6°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=592/594[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.22),0.069(0.40),0.146(0.25),0.854(0.28),1.236(1.91),1.743(0.33),1.761(0.79),1.776(1.03),1.795(1.26),1.817(1.00),1.833(0.64),1.880(3.52),1.974(0.55),1.995(1.09),2.008(1.35),2.025(1.40),2.044(2.36),2.067(5.71),2.083(7.36),2.117(11.16),2.292 (16.00),2.327(0.76),2.366(0.39),2.669(0.53),2.710(0.36),3.164(4.38),3.449(2.80),3.479(5.80),3.506(3.89),3.532(1.17),3.665(1.03),3.683(1.64),3.701(1.45),3.717(1.24),3.736(0.71),6.924(1.15),6.930(1.27),6.945(2.41),6.951(2.58),6.966(1.37),6.972(1.37),7.140(2.43),7.146(2.46),7.167(2.48),7.173(2.37),7.199(2.53),7.215(2.93),7.220(2.73),7.236(2.18),7.477(1.00),7.677(1.54),7.699(10.24),7.704(7.44),7.708(5.90),7.727(0.92),7.731(1.00),8.724(1.65),8.737(2.63),8.752(1.58),12.098(0.31).
(+/-)-5-{[(6-溴-2-碌-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(301mg,500μmol,實施例48A)在NMP(2.0ml)之溶液中加入吡咯啶(125μl,1.50mmol),混合物在110℃攪拌2小時。冷卻至RT後,將混合物與乙酸乙酯(100ml)混合並用水(100ml)洗滌一次。水相用乙酸乙酯(100ml)萃取一次。將合併的有機相用飽和氯化鈉溶液洗滌一次,用硫酸鈉乾燥,過濾並濃縮,並將殘餘物通過製備型HPLC純化(方法33)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。直接獲得標題化合物(不進行三級丁酯之分離和隨後的水解步驟),因為所使用的反應物顯然已經以部分水解的形式存在。得到27mg(100%純度,理論值的9%)標題化合物。
[α]D 20=+25.1°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=1.45min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.81),1.020(0.81),1.029(0.43),1.036(0.81),1.245(0.78),1.261(0.79),1.277(0.42),1.402(0.68),1.838(0.86),1.898(16.00),1.938(2.12),2.066(2.00),2.077(2.29),2.102(4.07),2.129(6.46),2.142(7.04),2.159(7.73),2.178(7.47),2.196(11.68),2.328(0.69),2.367(0.78),2.667(0.96),2.686(1.84),2.695(8.17),2.710(0.72),3.285(2.20),3.303(3.04),3.321(2.14),3.718(7.64),3.816(7.02),7.266(1.61),7.277(1.87),7.290 (3.14),7.301(3.22),7.315(2.42),7.326(2.20),7.386(2.00),7.407(3.05),7.418(2.99),7.566(1.86),7.588(3.77),7.615(5.18),7.635(2.29),8.817(3.70).
(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(301mg,500μmol,實施例49A)在NMP(2.0ml)的溶液中加入吡咯啶(125μl,1.50mmol),並將混合物在110℃攪拌2小時。冷卻至RT後,將混合物與乙酸乙酯(100ml)混合並用水(100ml)洗滌一次。水相用乙酸乙酯(100ml)萃取一次。將合併的有機相用飽和氯化鈉溶液洗滌一次,用硫酸鈉乾燥,過濾並濃縮,並將殘餘物通過製備型HPLC純化(方法33)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。直接獲得標題化合物(不進行三級丁酯之分離和隨後的水解步驟),因為所使用的反應物顯然已經以部分水解的形式存在。得到15mg(100%純度,理論值的5%)標題化合物。
[α]D 20=-26.9°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=1.45min;MS(ESIpos):m/z=580/582[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.024(3.21),0.853(0.68),1.120(0.42),1.135(0.88),1.150(0.46),1.234(8.39),1.606(0.89),1.667(1.32),1.689(2.77),1.713(2.12),1.872(16.00),1.919(2.19),1.938(1.34),1.987(2.25),2.174(10.50),2.227(1.01),2.248(0.88),2.328(0.52),2.346(0.56),2.366(0.42),2.670(0.49),2.694(6.62),2.710(0.54),3.285(4.71),3.303(8.01),3.526(6.69),3.571(9.55),3.653(3.61),3.822(1.24),7.226(1.39),7.236(1.65),7.249(2.96),7.258(3.79),7.274(2.59),7.279(2.66),7.285(2.57),7.336(2.05),7.348(2.38),7.358(3.09),7.369(2.96),7.391(1.71),7.466(7.59),7.488(12.49),7.544(6.80),7.549(6.31),7.566(3.94),7.571(3.80),7.589(0.63),7.615(0.53),8.526(0.60),8.859(0.49),8.938(3.00).
(+)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(70mg,99μmol,對映異構物1,實施例216A)在二氯甲烷(1.8ml)的溶液中加入TFA(169μl,2.19mmol),並將混合物在室溫放置16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到18mg(100%純度,理論值的28%)標題化合物。
[α]D 20=+33.1°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.41),0.006(1.38),0.071(0.81),1.235(0.63),1.353(0.24),1.361(0.68),1.885(4.28),1.969(0.95),2.070(2.84),2.097(5.30),2.111(4.98),2.122(5.25),2.165(16.00),2.292(0.18),2.304(0.18),2.362(0.41),2.523(0.97),2.636(0.39),3.170(5.56),3.317(1.07),3.457(3.41),3.480(6.14),3.503(3.20),3.727(2.01),7.274(1.01),7.283(1.19),7.293(2.09),7.302(2.18),7.313(1.54),7.322(1.36),7.411(2.06),7.419(2.03),7.683(3.35),7.701(12.28),7.711(8.00),7.715(7.27),7.728(2.00),7.732(2.13),8.838(2.94).
(-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(70mg,102μmol,對映異構物2,實施例217A)在二氯甲烷(1.8ml)的溶液中加入TFA(173μl,2.24mmol),並將該混合物在室溫放置16小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法7)。將合併的目標級分濃縮,並將 殘餘物從乙腈/水中冷凍乾燥。得到27mg(100%純度,理論值的42%)標題化合物。
[α]D 20=-33.8°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=630/632[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.120(0.21),-0.007(2.56),0.006(1.56),0.069(0.21),0.117(0.20),1.234(0.54),1.353(0.21),1.361(0.19),1.370(0.20),1.885(4.23),1.967(0.93),2.069(2.85),2.084(4.22),2.094(5.84),2.114(4.95),2.127(5.76),2.164(16.00),2.304(0.18),2.358(0.39),2.362(0.50),2.519(1.30),2.522(0.91),2.635(0.48),3.169(5.45),3.314(1.22),3.457(3.35),3.480(6.01),3.503(3.07),3.730(1.95),7.274(1.09),7.283(1.25),7.293(2.14),7.302(2.17),7.313(1.56),7.322(1.38),7.411(2.05),7.419(1.97),7.683(3.38),7.701(12.40),7.710(8.28),7.715(7.26),7.728(2.01),7.732(2.08),8.826(1.80),8.837(3.09).
5-({[2-(氮雜環庚烷-1-基)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(35mg,49μmol,對映異構物1,實施例218A)在二氯甲烷(378μl)的溶液中加入TFA(83μl,1.08mmol),並將混合物放置在室溫下4天。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到15mg(100%純度,理論值的51%)標題化合物。
[α]D 20=+31.4°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.18),1.234(0.71),1.259(0.35),1.298(0.28),1.360(1.00),1.602(13.68),1.781(8.50),1.891(0.92),1.965(1.10),2.071(3.58),2.107(7.74),2.133(15.66),2.272(0.34),2.327(0.34),2.366(0.31),2.669(0.32),2.710(0.31),3.318(2.40),3.491(10.92),3.505(16.00), 3.520(10.56),3.711(2.90),7.262(1.06),7.273(1.27),7.285(2.29),7.296(2.42),7.311(1.84),7.322(1.74),7.384(1.63),7.395(1.94),7.405(2.60),7.416(2.58),7.438(1.37),7.529(5.55),7.551(10.09),7.599(5.55),7.604(5.36),7.621(3.13),7.626(3.13),8.804(3.10).
5-({[2-(氮雜環庚烷-1-yl)-6-溴-3-甲基喹啉-4-基]羰基}胺基)-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(28mg,39μmol,對映異構物2,實施例219A)在二氯甲烷(300μl)的溶液中加入TFA(66μl,858μmol),並將混合物放置在室溫下4天。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法6)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到9mg(100%純度,理論值的39%)標題化合物。
LC-MS(方法1):Rt=2.21min;MS(ESIpos):m/z=608/610[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(0.90),1.259(0.51),1.298(0.35),1.360(0.94),1.602(13.49),1.781(8.38),1.880(2.79),1.946(1.09),2.055(3.52),2.085(6.46),2.132(15.36),2.274(0.37),2.326(0.42),2.366(0.38),2.669(0.41),2.710(0.34),3.320(1.46),3.490(10.99),3.505(16.00),3.519(10.58),3.703(2.91),7.259(1.22),7.270(1.40),7.282(2.43),7.293(2.56),7.308(1.90),7.319(1.76),7.401(2.69),7.412(2.69),7.528(6.05),7.551(10.65),7.598(5.94),7.603(5.52),7.620(3.18),7.625(3.14),8.810(3.11).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(14mg,20μmol,非對映異構物1,實施例220A)在二氯甲烷(153μl)的溶液中加入TFA(34μl,439μmol),並將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物 通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到7mg(100%純度,理論值的51%)標題化合物。
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=644/646/648[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.024(0.18),0.852(0.29),0.923(0.20),1.232(1.22),1.369(0.28),1.648(2.02),1.723(1.34),1.809(1.91),1.910(3.93),1.924(3.45),2.040(1.60),2.154(4.33),2.183(8.36),2.299(0.27),2.388(0.31),2.618(0.25),2.695(0.22),3.097(2.45),3.164(2.36),3.330(5.54),3.413(16.00),3.765(1.57),4.002(1.26),4.100(1.07),4.839(1.36),4.919(1.34),7.459(1.70),7.473(1.94),7.519(2.29),7.533(3.23),7.573(2.41),7.658(2.35),7.673(5.57),7.689(4.72),7.704(1.81),8.972(1.67).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(17mg,24μmol,非對映異構物2,實施例220A)在二氯甲烷(186μl)的溶液中加入TFA(41μl,533μmol),將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到7mg(100%純度,理論值的51%)標題化合物。
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=644/646/648[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.854(0.19),1.233(0.77),1.645(1.59),1.817(1.51),1.912(2.83),1.925(2.37),1.945(1.40),1.968(0.93),2.060(0.51),2.073(1.19),2.083(1.71),2.097(3.37),2.108(3.12),2.114(3.29),2.128(2.50),2.151(3.80),2.160(4.09),2.184(16.00),2.197(2.28),2.214(0.72),2.290(1.68),2.301(1.57),2.389(0.24),2.617(0.24),3.086(1.75),3.180(1.65),3.192(1.74),3.326(1.77),3.336(1.90),3.395(1.70),3.415(1.17),3.434(1.69),3.453(1.22),3.805(3.40),3.816(3.99),3.826(4.27),3.835(4.43),3.912(6.65),4.040(3.28),4.055(3.16),4.064(3.35),4.073(3.57),4.079(3.71),4.088(2.70),4.098(2.22),4.113(1.56),4.846(1.43),4.925(1.41),7.486(1.89),7.501(2.34),7.543(2.74), 7.558(4.14),7.605(2.65),7.619(2.28),7.666(2.31),7.671(2.15),7.680(6.02),7.686(5.41),7.694(3.96),7.697(4.31),7.703(3.05),7.709(1.79),7.712(1.82),7.718(1.29),8.838(2.29),8.848(2.59).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(32mg,46μmol,非對映異構物3,實施例220A)在二氯甲烷(351μl)的溶液中加入TFA(77μl,1.0mmol),將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到15mg(100%純度,理論值的52%)標題化合物。
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=644/646/648[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.232(0.37),1.244(0.46),1.255(0.44),1.259(0.38),1.270(0.31),1.646(1.40),1.817(1.34),1.912(2.53),1.926(2.11),1.944(1.31),1.968(0.82),2.009(0.20),2.060(0.58),2.074(1.12),2.083(1.63),2.097(3.20),2.109(2.88),2.114(3.11),2.129(2.31),2.151(3.35),2.160(3.84),2.184(16.00),2.197(2.11),2.214(0.68),2.289(1.54),2.301(1.44),2.306(1.31),2.389(0.24),2.617(0.21),3.074(1.12),3.089(1.58),3.185(1.49),3.197(1.59),3.214(1.04),3.320(1.20),3.330(1.56),3.340(1.66),3.351(0.95),3.398(1.52),3.420(1.00),3.437(1.49),3.456(1.05),3.806(1.52),3.817(1.72),3.827(1.71),3.834(1.57),4.040(4.13),4.049(4.31),4.056(4.60),4.064(5.06),4.071(5.46),4.079(5.82),4.088(5.09),4.099(4.83),4.113(4.27),4.847(1.34),4.926(1.33),7.028(0.27),7.113(0.32),7.198(0.28),7.486(1.95),7.501(2.41),7.543(3.07),7.558(4.54),7.605(2.56),7.619(2.13),7.668(2.51),7.674(2.27),7.683(6.65),7.689(5.63),7.696(4.24),7.700(4.26),7.702(3.33),7.706(2.72),7.711(1.61),7.715(1.64),7.717(1.20),7.721(1.08),8.835(2.19),8.846(2.41),9.683(0.16).
5-[({6-溴-2-[3-氟哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,3,6-三氯苯基)戊酸三級丁酯(27mg,38μmol,非對映異構物4,實施例220A在二氯甲烷(296μl)中的溶液中加入TFA(65μl,846μmol),將混合物放置在室溫下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物從乙腈/水中冷凍乾燥。得到9mg(100%純度,理論值的36%)標題化合物。
LC-MS(方法1):Rt=2.20min;MS(ESIpos):m/z=644/646/648[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.841(0.19),0.853(0.24),0.913(0.21),1.231(0.86),1.552(0.61),1.648(2.28),1.674(0.65),1.812(2.09),1.825(1.79),1.910(4.02),1.924(2.87),1.947(1.51),1.970(1.30),2.061(1.95),2.076(2.56),2.083(3.02),2.096(3.15),2.109(2.63),2.121(2.60),2.145(5.67),2.166(4.32),2.180(16.00),2.278(1.99),2.389(0.46),2.616(0.26),3.077(1.94),3.093(2.84),3.174(2.89),3.427(5.68),3.449(3.64),3.783(0.87),3.791(1.60),3.802(1.66),3.812(1.93),3.822(1.47),4.054(1.96),4.062(1.76),4.070(1.68),4.077(1.98),4.088(1.51),4.099(1.29),4.109(1.07),4.124(0.59),4.839(1.68),4.919(1.66),7.484(2.30),7.498(2.76),7.539(4.21),7.554(6.01),7.603(3.12),7.617(2.69),7.662(3.82),7.667(2.96),7.677(9.70),7.682(7.07),7.690(6.12),7.694(6.22),7.700(3.79),7.705(2.38),7.709(2.46),7.715(1.52),8.837(2.65),8.846(3.25).
將5-[({6-溴-2-(3-乙基哌啶-1-基)-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸三級丁酯(非對映異構物混合物,56mg,86.9μmol,實施例227A)溶於二氯甲烷(1.2ml)中。在室溫下,加入TFA(650μl,8.7mmol)並將混合物在室溫下攪拌90分鐘。在旋轉蒸發器上除去揮發性組分。將殘餘物溶於少量DMSO中並通過製備型HPLC純化(方法15)。目標級分一起通過旋轉蒸發濃縮,殘餘物在減壓下乾燥。得到48mg(100%純度,理論值的94%)標題化合物。
LC-MS(方法1):Rt=2.37min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(3.01),0.890(6.60),0.908(16.00),0.927(8.11),1.035(0.56),1.064(1.36),1.093(1.40),1.116(0.62),1.238(1.14),1.256(2.65),1.275(3.54),1.292(2.47),1.560(1.54),1.602(1.47),1.632(1.31),1.747(1.98),1.786(1.98),1.809(1.45),1.842(1.85),1.877(1.52),2.002(1.18),2.015(1.54),2.034(1.67),2.054(1.89),2.063(1.63),2.108(12.92),2.119(6.84),2.139(2.27),2.160(0.71),2.327(0.67),2.422(1.36),2.670(0.80),2.709(1.23),2.737(1.87),2.766(1.05),3.481(2.87),3.513(2.74),3.616(1.09),3.634(1.63),3.649(2.32),3.662(1.38),3.677(1.11),3.696(1.45),7.122(2.01),7.143(1.43),7.198(1.72),7.209(1.78),7.221(2.79),7.232(2.72),7.244(1.31),7.256(1.20),7.291(1.65),7.300(2.36),7.315(1.65),7.426(0.71),7.624(1.40),7.647(11.57),7.654(6.46),7.677(1.03),8.729(2.85),12.061(5.15).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸三級丁酯(118mg,183μmol,二非對映異構物之混合物,實施例228A)在二氯甲烷(1.4ml)的溶液中加入TFA(310μl,4.03mmol)及將混合物放置在RT下24小時。然後將混合物濃縮並反復加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物凍乾。得到88mg(100%純度,理論值的81%)標題化合物。
[α]D 20=-32.2°,589nm,c=0.46g/100ml,甲醇
LC-MS(方法1):Rt=2.35min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.021(1.21),0.839(0.16),0.851(0.32),0.862(0.18),0.895(7.27),0.907(16.00),0.919(8.17),1.036(0.49),1.042(0.58),1.057(1.40),1.062(1.43),1.076(1.48),1.081(1.49),1.096(0.64),1.103(0.57),1.227(2.36),1.245(1.25),1.257(2.57),1.269(3.67),1.280(3.10),1.292(1.60),1.551(1.33),1.556(1.48),1.574(0.99),1.585(0.77),1.606(1.26),1.627(1.34),1.647(0.55),1.748(2.00),1.769(1.82),1.775(1.61),1.791(1.33),1.805(1.44),1.814(1.08),1.829(0.61),1.853(1.68),1.870(1.64),1.997(0.58),2.010(1.28),2.018(1.73),2.032(1.83),2.041(1.27),2.053(1.10),2.064(1.27),2.073(1.48),2.078(1.64),2.091(4.12),2.104(7.92),2.116(7.21),2.130(3.21),2.144(1.34),2.157(0.68),2.414(0.84),2.714(0.86),2.733(1.45),2.752(0.82),3.494(3.60),3.510(2.68),3.627(1.33),3.637(1.69),3.640(1.59),3.649(2.00),3.709(1.15),7.127(1.84),7.140(1.20),7.211(1.72),7.219(1.85),7.226(2.96),7.234(2.92),7.242(1.44),7.250(1.30),7.301(1.79),7.309(2.30),7.317(1.78),7.448(0.24),7.635(2.37),7.649(9.88),7.657(5.87),7.672(1.32),8.744(1.47),8.754(2.67).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸三級丁酯(37mg,57μmol,非對映異構物1,實施例229A)的二氯甲烷(442μl)溶液中加入TFA(97μl,1.26mmol),並將混合物留置在室溫24 小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到20mg(100%純度,理論值的60%)標題化合物。
[α]D 20=+17.1°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.021(1.57),0.839(0.20),0.851(0.40),0.862(0.20),0.895(6.95),0.908(16.00),0.920(7.91),1.036(0.39),1.042(0.45),1.057(1.08),1.062(1.11),1.076(1.14),1.081(1.15),1.096(0.50),1.103(0.45),1.228(3.22),1.245(1.13),1.256(2.13),1.268(3.04),1.280(2.59),1.292(1.39),1.539(0.79),1.545(0.94),1.550(1.07),1.557(1.21),1.562(1.04),1.574(0.82),1.605(0.92),1.626(0.99),1.646(0.43),1.747(1.60),1.752(1.34),1.764(1.31),1.769(1.42),1.774(1.36),1.787(1.08),1.796(1.06),1.802(1.15),1.811(0.88),1.817(0.65),1.826(0.52),1.854(1.30),1.862(0.90),1.870(1.27),1.993(0.47),2.006(1.01),2.014(1.35),2.027(1.49),2.036(0.99),2.041(1.03),2.053(1.23),2.062(1.16),2.079(2.91),2.094(4.55),2.108(4.56),2.121(2.74),2.135(1.28),2.148(0.71),2.417(0.69),2.695(0.28),2.713(0.72),2.733(1.24),2.752(0.70),3.478(2.03),3.495(3.09),3.511(2.04),3.612(0.89),3.621(1.38),3.634(1.50),3.643(1.98),3.652(1.12),3.709(1.00),7.125(1.33),7.209(1.28),7.217(1.39),7.225(2.20),7.232(2.18),7.240(1.10),7.247(0.98),7.290(1.07),7.295(1.34),7.299(1.42),7.305(1.91),7.310(1.40),7.314(1.34),7.320(1.05),7.499(0.20),7.634(2.33),7.649(9.46),7.656(5.17),7.659(4.64),7.671(1.16),7.674(1.22),8.745(1.67),8.755(2.75),8.764(1.62).
5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸三級丁酯(43mg,67μmol,非對映異構物2,實施例230A)在二氯甲烷(513μl)的溶液中加入TFA(113μl,1.47mmol),並將混合物留置在室溫 24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。殘餘物通過製備型HPLC純化(方法11)。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。得到25mg(100%純度,理論值的63%)標題化合物。
[α]D 20=+47.3°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.38min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.022(1.15),0.852(0.27),0.895(6.90),0.907(16.00),0.919(7.82),1.037(0.38),1.043(0.44),1.058(1.06),1.063(1.08),1.077(1.11),1.083(1.12),1.097(0.50),1.104(0.44),1.230(2.23),1.247(0.91),1.258(1.89),1.270(2.65),1.281(2.16),1.290(1.20),1.557(1.06),1.586(0.60),1.606(1.01),1.628(1.08),1.648(0.45),1.750(1.53),1.755(1.31),1.760(1.16),1.771(1.65),1.783(1.27),1.791(1.07),1.799(1.12),1.807(0.84),1.813(0.64),1.822(0.50),1.855(1.27),1.871(1.24),1.990(0.41),2.003(0.94),2.012(1.23),2.025(1.35),2.034(0.86),2.038(0.86),2.046(0.75),2.055(0.78),2.064(0.82),2.082(2.33),2.095(4.70),2.108(7.35),2.121(2.98),2.135(1.06),2.148(0.51),2.412(0.62),2.730(0.98),3.491(2.76),3.509(2.34),3.614(0.80),3.623(1.33),3.636(1.50),3.645(2.05),3.654(1.10),3.701(0.84),7.126(1.43),7.140(0.93),7.210(1.32),7.217(1.42),7.225(2.26),7.233(2.23),7.240(1.11),7.248(1.00),7.292(1.09),7.297(1.34),7.301(1.40),7.307(1.90),7.313(1.37),7.317(1.32),7.322(1.04),7.632(1.89),7.647(7.35),7.654(4.76),7.658(4.23),7.669(1.08),7.672(1.12),8.748(1.37),8.757(2.29),8.767(1.29).
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲基苯基)戊酸(外消旋物,500mg,86%純度,0.88mmol,實施例234A)與3,3-二氟哌啶鹽酸鹽(804mg,5.10mmol)在NMP(2.6ml)中加入DIPEA(2.1ml,12mmol),並將該混合物在120℃下攪拌4天。隨後,將混合物冷卻至RT,並將反應混合物加入到1M鹽酸中。混合物用二氯甲烷萃取,有機相用硫酸鈉乾燥並在旋轉蒸發器上濃縮。通過管柱層析術(Isolera,KP-Sil,溶析液:二氯甲烷/甲醇,梯度:0-40%甲醇)預純化殘餘物,然後通過製備型HPLC再純化(方法27)。得到212mg(99%純度,理論值的42%)標題化合物。
LC-MS(方法26):Rt=0.80min;MS(ESIpos):m/z=574/576[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.262(1.33),1.935(1.64),1.950(1.86),1.957(1.72),1.967(1.54),1.974(1.08),1.985(0.60),1.991(0.70),2.009(0.48),2.022(0.57),2.039(0.67),2.055(1.10),2.071(1.05),2.087(0.88),2.106(0.65),2.121(0.52),2.142(0.63),2.155(0.73),2.173(0.67),2.190(0.41),2.208(0.49),2.212(0.57),2.244(16.00),2.277(2.20),2.295(3.73),2.315(1.53),2.366(15.79),2.389(2.69),2.628(2.33),3.127(1.35),3.138(1.70),3.389(0.46),3.396(0.53),3.402(0.53),3.410(0.81),3.433(1.79),3.447(0.50),3.461(2.58),3.489(1.35),3.677(0.49),3.690(0.54),3.699(0.48),3.711(1.03),3.725(0.66),3.732(0.61),3.746(0.54),3.933(0.69),3.949(1.16),3.965(0.97),3.982(0.92),3.998(0.46),5.949(0.59),5.963(1.00),5.977(0.56),7.114(0.46),7.122(0.56),7.127(0.44),7.133(1.21),7.142(1.42),7.154(1.65),7.167(2.44),7.185(0.96),7.193(0.71),7.199(0.74),7.204(0.97),7.208(0.67),7.219(2.04),7.223(3.71),7.231(3.85), 7.234(3.60),7.602(1.21),7.607(1.30),7.624(2.59),7.629(2.96),7.659(4.47),7.682(2.17),7.692(3.39),7.697(2.97).
將標題化合物(197mg)溶於二氯甲烷/甲醇(1:1,3.3ml)中,並通過製備型HPLC在手性相上分離成對映異構物(見實施例230和231)[管柱:Daicel Chiralpak LA,5μm,250mm x 30mm;流速:50毫升/分鐘;檢測:UV 254nm;注入:0.3毫升;溶析液:己烷+0.1%(體積)TFA(80%)/異丙醇(20%),等度]。將合併的目標級分各自濃縮,並將各個殘餘物冷凍乾燥。
在實施例229中描述的對映異構物分離中,得到71mg(98%純度,ee>99%)標題化合物,為先前洗脫的對映異構物。
[α]D 20=-5.0°,589nm,c=0.34g/100ml,甲醇
在實施例229中描述的對映異構物分離中,得到85mg(88%純度,ee87%)標題化合物,作為稍後洗脫的對映異構物。
[α]D 20=+7.8°,589nm,c=0.28g/100ml,甲醇
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲基苯基)戊酸(外消旋物,500mg,86%純度,0.88mmol,實施例234A)在吡咯啶(3.0ml,2.2mmol)中於100℃攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中,用二氯甲烷萃取混合物。將有機相用硫酸鈉乾燥並在旋轉蒸發器上濃縮。通過管柱色譜法(Isolera,KP-Sil,溶液液:二氯甲烷/甲醇,梯度:0-40%甲醇)對殘餘物進行預純化,並通過製備型HPLC(方法27)再純化。獲得375mg(99%純度,理論值的80%)標題化合物。
LC-MS(方法26):Rt=0.77min;MS(ESIpos):m/z=524/526[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:0.084(0.46),0.087(0.42),0.838(0.57),0.850(0.55),0.871(0.52),0.888(0.83),1.184(0.44),1.217(0.82),1.262(7.00),1.391(0.53),1.918(2.72),1.927(3.16),1.935(8.00),1.942(3.26),1.951(3.35),1.968(1.08),1.977(0.98),1.987(0.95),1.993(0.93),2.012(0.96),2.028(0.87),2.037(0.70),2.049(0.87),2.054(0.66),2.063(0.63),2.075(0.71),2.090(0.74),2.102(0.46),2.108(0.41),2.118(0.55),2.123(0.58),2.147(0.43),2.166(0.78),2.179(0.93),2.186(0.64),2.199(0.90),2.224(15.03),2.282(0.60),2.301(2.74),2.320(3.62),2.339(1.34),2.368(16.00),2.385(1.42),2.392(11.83),2.518(0.66),2.535(0.58),2.545(0.67),2.560(1.05),2.567(0.84),2.574(0.82),2.582(0.76),2.629(3.84),3.246(0.40),3.258(0.54),3.266(0.45),3.273(0.42),3.284(0.50),3.292(0.49),3.297(0.85),3.325(1.15),3.352(0.62),3.401(0.45),3.410(0.84),3.421(1.22),3.431(0.88),3.436(0.94),3.448(0.68),3.459(0.48),3.586(2.41),3.602(6.38),3.618(2.37),3.671(0.54),3.684(0.58),3.693(0.54),3.705(0.95),3.718(0.69),3.727(0.59),3.741(0.56),3.933(0.55),3.949(0.98),3.966(0.89), 3.983(0.81),3.999(0.42),5.785(0.65),7.006(0.54),7.114(0.46),7.121(0.50),7.128(0.52),7.133(1.29),7.141(1.26),7.146(1.19),7.154(1.89),7.166(2.94),7.181(1.44),7.193(2.67),7.198(2.32),7.207(4.20),7.221(2.42),7.229(3.00),7.235(4.04),7.238(3.76),7.249(0.51),7.507(5.43),7.528(0.70),7.576(2.43),7.579(3.98).
將標題化合物(360mg)溶於DMSO/二氯甲烷/甲醇(1:1:1,6ml)中,並通過製備型SFC在手性相上分離成對映異構物(參見實施例233和234)。[管柱:Chiralpak IG,5μm,250mm x 30mm;流速:100毫升/分鐘;檢測:MWD 220nm;注入:1.0毫升;溶析液:28%甲醇/72%二氧化碳,等度]。將合併的目標級分各自濃縮,並將各個殘餘物冷凍乾燥。
在實施例232中描述的對映異構異構物分離中,獲得190mg(98%純度,ee 98%)標題化合物,作為先洗脫的對映異構物。
[α]D 20=+12.7°,589nm,c=0.27g/100ml,甲醇
在實施例232中描述的對映異構物分離中,得到135mg(%%純度,ee 96%)標題化合物,作為稍後洗脫的對映異構物。
[α]D 20=-4.43°,589nm,c=0.35g/100ml,甲醇
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物1,200mg,85%純度,336μmol,實施例241A)和哌啶(5.0ml)之混合物在100℃下攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得160mg(99%純度,理論值的85%)標題化合物。
[α]D 20=+4.73°,589nm,c=0.36g/100ml,氯仿
LC-MS(方法25):Rt=1.29min;MS(ESIpos):m/z=554/556[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.643(1.02),1.653(1.13),1.711(2.01),1.721(2.28),2.018(0.40),2.031(0.46),2.039(0.46),2.054(0.43),2.131(0.52),2.144(0.65),2.151(0.45),2.165(0.67),2.189(8.51),2.279(0.84),2.293(1.56),2.299(0.99),2.313(1.58),2.323(0.57),2.334(0.69),3.173(2.55),3.447(0.48),3.460(0.61),3.472(0.51),3.551(0.42),3.709(0.51),3.740(16.00),3.815(0.58),3.828(0.51),3.838(0.46),3.852(0.42),3.931(0.47),3.946(0.87),3.960(0.54),3.979(0.58),5.824(0.55),6.845(1.50),6.865(1.54),6.958(0.68),6.960(0.70),6.979(1.59),6.995(0.95),6.998(0.90),7.210(1.95),7.212(1.90),7.230(2.18),7.251(0.81),7.255(0.63),7.561(0.88),7.566(1.02),7.583(1.45),7.589(1.81),7.630(2.05),7.635(1.95),7.664(0.46).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物2,200mg,87%純度,344umol,實施例242A)和哌啶(5.0ml)之混合 物在100℃下攪拌1.5小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得166mg(99%純度,理論值的86%)標題化合物。
[α]D 20=-2.58°,589nm,c=0.8g/100ml,氯仿.
LC-MS(方法25):Rt=1.35min;MS(ESIpos):m/z=554/556[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.036(0.66),1.194(0.73),1.261(0.62),1.276(16.00),1.282(1.00),1.295(0.60),1.610(0.44),1.623(0.62),1.638(0.83),1.650(0.82),1.707(1.46),1.717(1.68),1.745(0.88),1.760(0.72),2.179(6.04),2.225(0.48),2.238(0.80),2.258(0.82),2.299(0.42),2.995(0.57),3.009(0.76),3.023(0.54),3.148(1.64),3.162(2.07),3.173(1.50),3.439(0.43),3.729(11.07),3.791(0.41),3.924(0.61),3.957(0.41),5.978(0.72),6.832(0.97),6.853(1.08),6.942(0.51),6.945(0.50),6.962(1.06),6.963(1.09),6.980(0.68),6.982(0.65),7.199(2.09),7.218(2.39),7.235(0.57),7.552(0.71),7.557(0.73),7.574(1.23),7.579(1.51),7.625(2.89),7.628(1.65),7.634(1.32),7.646(1.30).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物1,200mg,85%純度,336μmol,實施例241A)和吡咯啶(1.5ml)之混合物在100℃下攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得65mg(99%純度,理論值的35%)標題化合物。
[α]D 20=+5.19°,589nm,c=0.24g/100ml,氯仿
LC-MS(方法25):Rt=0.85min;MS(ESIpos):m/z=540/542[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.914(1.96),1.923(2.41),1.930(5.41),1.937(2.38),1.946(2.04),1.962(0.41),1.973(0.52),1.993(0.40),2.007(0.47),2.015(0.41),2.019(0.50),2.028(0.51),2.032(0.50),2.043(0.45),2.126(0.75),2.150(4.86),2.172(0.56),2.179(0.40),2.239(0.55),2.272(0.92),2.285(1.36),2.292(1.07),2.304(1.54),2.324(0.67),2.374(0.50),2.635(2.71),3.462(0.51),3.475(0.63),3.487(0.53),3.566(1.94),3.577(2.68),3.583(4.90),3.599(1.79),3.717(0.65),3.741(16.00),3.753(0.68),3.828(0.47),3.841(0.44),3.896(0.41),3.911(0.69),3.926(0.48),6.082(0.69),6.847(1.55),6.867(1.61),6.954(0.76),6.956(0.75),6.974(1.66),6.991(1.01),6.993(0.94),7.211(3.38),7.230(3.74),7.249(0.85),7.253(0.61),7.408(0.72),7.430(1.91),7.450(1.96),7.456(2.06),7.473(0.66),7.478(0.82),7.528(1.65).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物2,127mg,87%純度,218μmol,實施例242A)與吡咯啶(1.0ml)之混合物在100℃下攪拌1.5小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得24mg(99%純度,理論值的20%)標題化合物。為了確定旋光度,將標題化合物樣品溶解在二氯甲烷中並用水洗滌。濃縮有機相,乾燥殘餘物並溶於氯仿中,測量旋光度。
[α]D 20=-2.0°,589nm,c=0.33g/100ml,氯仿
LC-MS(方法25):Rt=0.85min;MS(ESIpos):m/z=540/542[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.260(1.06),1.649(2.69),1.790(1.96),1.911(2.71),1.928(7.02),1.944(3.21),1.978(0.87),1.998(0.87),2.016(0.86),2.035(0.46),2.085(0.76),2.099(0.91),2.118(0.91),2.139(0.64),2.171(6.76),2.220(1.98),2.238(1.97),2.257(0.91),3.028(2.58),3.042(3.03),3.056(2.57), 3.423(0.94),3.435(1.21),3.448(1.02),3.568(3.20),3.584(7.25),3.665(0.70),3.727(16.00),3.767(0.91),3.786(1.16),3.799(1.04),3.822(0.82),3.884(0.81),3.899(1.23),3.913(0.97),3.931(0.85),6.149(1.09),6.827(1.86),6.848(2.18),6.935(1.01),6.953(2.11),6.971(1.26),7.192(1.35),7.206(3.26),7.225(2.36),7.452(0.52),7.476(4.64),7.504(0.56),7.551(2.52).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物1,200mg,85%純度,336μmol,實施例241A)和氮雜環庚烷(1.5ml)之混合物在100℃下攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得65mg(99%純度,理論值的34%)標題化合物。
為了確定旋光度,將標題化合物樣品溶解在二氯甲烷中並用水洗滌。濃縮有機相,乾燥殘餘物並溶於甲醇中以測量旋光度。
[α]D 20=+11.0°,589nm,c=0.47g/100ml,甲醇.
LC-MS(方法25):Rt=1.26min;MS(ESIpos):m/z=568/570[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.261(0.55),1.654(1.36),1.660(2.71),1.669(3.59),1.677(3.06),1.684(2.08),1.815(2.31),2.019(0.45),2.032(0.49),2.041(0.52),2.055(0.47),2.066(0.43),2.130(0.58),2.144(0.76),2.151(0.58), 2.171(7.20),2.278(0.94),2.292(1.65),2.299(1.06),2.313(1.86),2.332(0.76),2.632(0.59),3.446(0.53),3.459(0.68),3.471(0.60),3.495(2.65),3.509(3.27),3.524(2.42),3.563(0.58),3.715(0.51),3.739(16.00),3.808(0.60),3.821(0.53),3.831(0.48),3.845(0.45),3.922(0.49),3.936(0.88),3.951(0.55),3.969(0.59),5.825(0.48),6.843(1.57),6.863(1.56),6.956(0.77),6.958(0.74),6.977(1.60),6.993(1.04),7.210(2.73),7.229(3.12),7.249(0.85),7.253(0.63),7.523(0.48),7.528(0.63),7.545(1.76),7.549(1.96),7.561(0.89),7.590(1.96).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲氧基苯基)戊酸(對映異構物2,70mg,87%純度,120μmol,實施例242A)和氮雜環庚烷(0.5ml)之混合物在100℃下攪拌1.5小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法28)純化粗產物。獲得58mg(99%純度,理論值的84%)標題化合物。
為了確定旋光度,將標題化合物樣品溶解在二氯甲烷中並用水洗滌。濃縮有[α]D 20=-8.8°,589nm,c=0.40g/100ml,甲醇.
LC-MS(方法25):Rt=1.38min;MS(ESIpos):m/z=568/570[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.287(0.66),1.430(0.60),1.435(0.60),1.440(0.59),1.447(0.68),1.451(0.68),1.459(0.66),1.464(0.82),1.475(0.64),1.480(0.66),1.487(0.79),1.589(0.72),1.620(0.90),1.671(2.26),1.676(2.27),1.681(2.15),1.688(2.69),1.692(2.40),1.700(2.08),1.706(2.52),1.710(2.46),1.715(1.42),1.722(1.23),1.728(1.45),1.739(0.58),1.746(0.66),2.074(9.60),2.080(9.89),2.088(10.03),2.225(8.25),2.392(1.01),2.413(1.28),2.427(1.51),2.449(1.17),2.463(0.78),2.508(1.34),2.523(1.47),2.542(1.59),2.562(3.91),2.583(5.23),2.597(6.79),2.607(4.51),2.618(6.43),2.636(2.19),2.653(2.10),2.673(1.04),3.403(1.36),3.408(1.53),3.413(1.92),3.427(2.90),3.432(3.63),3.437(4.40),3.442(4.50),3.448(3.86),3.453(4.66),3.460(4.20),3.467(3.15), 3.476(2.60),3.481(1.25),3.488(1.49),3.852(1.68),3.879(2.23),3.885(2.31),3.915(6.23),3.930(6.53),3.944(4.69),3.966(2.11),4.116(4.77),4.120(4.83),4.126(4.65),4.133(5.54),4.136(5.90),4.139(5.58),4.144(5.35),4.150(8.43),4.154(7.75),4.160(4.77),4.166(5.01),4.173(7.65),4.188(0.85),4.202(1.00),4.223(0.87),4.324(0.95),4.338(1.27),4.358(1.14),4.372(0.79),6.547(1.48),7.235(1.36),7.251(1.79),7.292(1.11),7.347(1.00),7.364(1.59),7.382(2.13),7.400(1.78),7.420(0.70),7.580(0.44),7.585(0.42),7.599(1.69),7.604(1.77),7.609(1.76),7.620(2.87),7.628(2.62),7.635(3.96),7.660(12.32),7.664(11.67),7.670(10.66),7.677(12.09),7.680(12.39),7.683(11.15),7.688(11.09),7.694(15.57),7.699(14.56),7.702(2.63),7.704(10.36),7.710(10.63),7.715(12.08),7.717(16.00),7.931(0.88),7.936(1.58),7.942(1.97),7.948(2.49),7.954(2.68),7.960(2.75),7.965(3.65),7.970(3.52),7.981(3.59),7.988(3.08),7.995(3.43),8.001(3.64),8.015(1.81),8.031(2.10),8.049(1.69).
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氯苯基)戊酸(外消旋物,45.0mg,72%純度,59.5μmol,實施例246A)與哌啶(1.0ml,180μmol)在100℃下攪拌1.5小時。
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氯苯基)戊酸(外消旋物,123mg,72%純度,163μmol,實施例246A)和哌啶(50μl,500μmol)在1-丁醇(6ml)中在100℃下攪拌8小時。
將來自方法A和方法B的組合反應混合物加入到1M氯代乙酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並在旋轉蒸發器上濃縮。通過製備型HPLC(Chromatorex C-18,10μm,125mm×30mm,溶析液A:水+0.1%甲酸,溶液液B:乙腈;梯度:50-)純化粗產物。95%B)。獲得69mg(97%純度,理論值的50%)標題化合物。
LC-MS(方法25):Rt=1.39min;MS(ESIpos):m/z=592/594/596[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:0.959(0.56),1.185(1.50),1.200(2.54),1.205(0.61),1.219(0.63),1.370(12.44),1.561(0.53),1.604(1.80),1.614(1.57),1.650(3.36),1.659(3.52),2.069(0.76),2.079(0.72),2.085(0.73),2.088(0.75),2.102(1.06),2.113(0.71),2.121(0.58),2.133(1.46),2.158(16.00),2.172(1.46),2.187(1.38),2.205(1.47),2.223(1.78),2.242(1.01),2.264(0.61),2.283(0.41),2.287(0.43),2.307(0.42),2.313(0.79),2.317(0.72),2.336(0.48),2.353(0.58),2.366(0.61),2.378(0.60),2.390(0.61),2.534(1.04),2.931(0.65),3.214(4.22),3.783(3.91),3.991(0.77),4.006(0.82),4.019(1.17),4.033(1.38),4.045(0.93),4.059(0.85),4.072(0.85),4.083(0.65),4.090(0.95),4.107(0.60),4.118(0.79),4.133(0.70),6.816(0.42),6.836(0.47),7.049(1.92),7.070(4.35),7.089(2.79),7.219(2.59),7.222(3.11),7.239(2.35),7.242(2.40),7.261(0.43),7.273(2.98),7.277(2.73),7.294(2.59),7.297(2.53),7.317(0.41),7.527(1.62),7.532(1.85),7.549(2.11),7.554(2.61),7.587(2.49),7.636(3.49),7.658(2.29).
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲基苯基)戊酸(外消旋物,500mg,86%純度,0.88mmol,實施例234A)和哌啶(3.0ml,2.2mmol)在100℃下攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過管柱色譜法(Isolera,KP-Sil,溶析液:二氯甲烷/甲醇,梯度:0-40%甲醇)預純化粗產物,並通過製備型HPLC(方法27)再純化。獲得330mg(99%純度,理論值的69%)標題化合物。
LC-MS(方法26):Rt=0.82min;MS(ESIpos):m/z=538/540[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.565(0.89),1.577(0.89),1.660(2.48),1.672(2.38),1.689(2.28),1.704(2.76),1.716(2.87),1.885(0.46),1.907(0.57),1.913(0.68),1.920(0.65),1.942(0.49),2.079(0.56),2.092(0.70),2.111(0.70),2.130(0.42),2.180(2.18),2.198(3.83),2.207(16.00),2.218(1.80),2.262(0.53),2.356(14.53),2.391(4.38),2.874(2.02),2.888(2.61),2.902(1.88),3.145(2.77),3.159(3.54),3.169(2.59),3.316(0.45),3.343(0.53),3.352(0.51),3.369(0.68),3.382(0.54),3.652(0.46),3.665(0.52),3.673(0.45),3.685(1.01),3.698(0.61),3.706(0.58),3.720(0.52),3.913(0.55),3.929(1.06),3.945(0.91),3.962(0.86),3.979(0.43),6.165(0.58),6.179(1.00),6.193(0.56),7.087(0.47),7.091(0.49),7.107(1.30),7.111(1.31),7.122(1.34),7.126(1.68),7.141(2.27),7.155(0.79),7.178(0.74),7.183(0.61),7.190(1.05),7.197(1.99),7.202(1.60),7.205(1.91),7.217(3.58),7.221(2.59),7.237(0.66),7.554(1.42),7.559(1.49),7.577(2.49),7.582(2.70),7.628(4.42),7.650(2.37),7.664(3.39),7.669(3.15).
(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-甲基苯基)戊酸(外消旋物,500mg,86%純度,0.88mmol,實施例234A)和氮雜環庚烷(3.0ml,2.2mmol)在100℃下攪拌2小時。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過製備型HPLC(方法27)純化粗產物。獲得315mg(99%純度,理論值的64%)標題化合物。
LC-MS(方法26):Rt=0.87min;MS(ESIpos):m/z=552/554[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.262(0.44),1.622(0.65),1.629(1.23),1.637(1.69),1.652(2.55),1.657(3.68),1.665(4.74),1.674(4.04),1.680(2.70),1.812(3.00),1.898(0.58),1.908(0.52),1.924(0.51),1.931(0.58),1.942(0.65),1.965(0.57),2.111(0.66),2.125(0.74),2.144(0.71),2.160(0.48),2.177(0.48),2.194(16.00),2.207(0.84),2.230(2.25),2.248(3.63),2.266(1.71),2.357(15.85),2.390(2.68),2.626(1.58),3.005(1.99),3.020(1.81),3.034(1.87),3.369(0.52),3.385(0.72),3.398(0.58),3.406(0.49),3.486(4.69),3.501(5.26),3.515(4.60),3.551(0.41),3.648(0.50),3.661(0.57),3.670(0.49),3.682(1.07),3.696(0.67),3.704(0.61),3.717(0.56),3.907(0.61),3.923(1.16),3.940(1.00),3.957(0.93),3.973(0.47),5.949(0.63),5.963(1.10),5.977(0.62),7.096(0.45),7.102(0.49),7.116(1.30),7.122(1.17),7.129(1.28),7.136(1.72),7.148(2.58),7.165(0.88), 7.185(0.51),7.192(0.68),7.197(0.67),7.205(2.43),7.208(2.22),7.215(2.91),7.219(3.74),7.222(3.61),7.234(0.49),7.519(0.65),7.523(0.61),7.541(3.29),7.546(3.86),7.553(5.15),7.574(0.96),7.608(0.42),7.616(3.08),7.620(2.89).
從(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(外消旋物,55mg,89.2μmol,實施例250A)開始,與TFA反應和如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)進行產物的純化。獲得44mg(100%純度,理論值的88%)標題化合物。
LC-MS(方法1):Rt=2.10min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.65),-0.008(5.92),0.008(5.82),0.146(0.65),1.607(3.47),1.671(6.81),1.873(0.73),1.888(0.94),1.905(1.25),2.051(1.10),2.065(1.33),2.082(1.41),2.101(1.80),2.116(7.07),2.135(16.00),2.327(0.73),2.669(0.89),3.133(9.00),3.489(1.25),3.677(0.84),3.695(1.88),3.710(3.03),3.724(2.17),7.057(3.63),7.079(6.66),7.102(4.28),7.322(0.57),7.340(1.41),7.359(2.04),7.378(1.31),7.396(0.55),7.468(0.63),7.623(2.35),7.645(9.74),7.656(6.19),7.661(5.74),7.678(1.46),7.683(1.59),8.798(1.62),8.813(3.26),8.827(1.67),12.078(4.36).
將5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物1,85mg,138μmol,實施例251A)溶於二氯甲烷(1.8ml)中。在室溫下,加入TFA(1.0ml,14mmol),將混合物在室溫下攪拌1小時。在旋轉蒸發器上除去揮發性組分。將殘餘物溶於少量DMSO中,並通過製備型HPLC純化(方法31)。濃縮合併的目標級分,並將殘餘物在減壓下乾燥。獲得64mg(99%純度,理論值的82%)標題化合物。
[α]D 20=+40.8°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.63),0.008(3.76),0.146(0.46),0.839(0.69),1.234(0.67),1.607(3.61),1.671(6.99),1.903(1.28),2.051(1.15),2.064(1.45),2.081(1.45),2.116(7.35),2.135(16.00),2.327(1.49),2.366(0.97),2.670(1.49),2.710(0.92),3.133(9.28),3.162(1.97),3.175(1.74),3.496(1.22),3.677(0.82),3.695(1.89),3.710(3.13),3.725(2.14),7.057(3.84),7.079(7.06),7.102(4.58),7.341(1.47),7.359(2.10),7.378(1.36),7.477(0.67),7.623(2.54),7.645(10.62),7.656(6.64),7.661(6.07),7.678(1.72),7.683(1.72),8.798(1.66),8.813(3.38),8.827(1.76),12.080(2.94).
從5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物2,63mg,102μmol,實施例252A)開始,產物的反應和純化如5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物1,實施例245)所述進行。獲得48mg(100%純度,理論值的84%)標題化合物。
[α]D 20=-46.7°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.52),-0.008(3.81),0.008(3.85),0.146(0.46),1.606(3.56),1.671(7.01),1.902(1.29),2.050(1.14),2.063(1.35),2.081(1.41),2.115(7.45),2.135(16.00),2.327(1.39),2.366(0.73),2.669(1.60),2.710(0.92),3.133(9.32),3.493(1.29),3.676(0.87),3.694(1.89),3.710(3.14),3.724(2.23),7.057(3.85),7.079(7.03),7.101(4.51),7.340(1.48),7.359(2.10),7.379(1.37),7.396(0.60),7.470(0.67),7.623(2.50),7.645(10.42),7.656(6.45),7.661(6.01),7.678(1.50),7.683(1.64),8.798(1.69),8.813(3.39),8.828(1.75),12.083(2.29).
從(+/-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(外消旋物,56mg,92.9μmol,實施例253A)開始,產物的反應和純化如5-[({6-溴-2-[3-ethyl哌啶-1-yl]-3-methyl喹啉-4-yl}羰基)amino]-4-(2,5-di氟苯基)戊酸(實施例225)所述進行。獲得20mg(100%純度,理論值的36%)標題化合物(存在之甲酸源自HPLC方法)。
LC-MS(方法1):Rt=1.39min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.79),0.008(16.00),0.146(1.79),1.872(13.83),2.061(1.98),2.079(2.02),2.114(8.78),2.129(7.73),2.163(9.28),2.328(2.17),2.670(2.10),3.566(8.93),3.680(2.52),3.695(3.53),3.709(2.80),7.050(5.01),7.072(9.09),7.095(5.79),7.354(2.87),7.372(2.14),7.466 (7.03),7.488(11.61),7.547(6.21),7.553(5.86),7.570(3.77),7.575(3.61),8.137(14.49),8.750(2.29),8.765(4.50),8.779(2.29),12.103(0.50).
從5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物1,54mg,89.6μmol,實施例254A)開始,與TFA的反應和產物的純化如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。獲得20mg(純度96%,理論值的39%)標題化合物。
LC-MS(方法1):Rt=1.39min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.41),0.146(1.22),1.141(5.31),1.235(3.97),1.356(1.09),1.872(13.06),2.086(16.00),2.115(9.79),2.130(8.19),2.165(8.58),2.328(3.90),2.366(2.69),2.669(4.54),2.710(3.14),3.564(8.13),3.694(3.65),4.538(0.83),7.051(4.99),7.073(8.96),7.095(5.44),7.354(3.14),7.466(6.53),7.489(10.50),7.548(5.63),7.553(5.31),7.570(3.39),7.575(3.14),7.838(0.96),8.133(5.63),8.750(2.43),8.765(4.10),12.071(1.73).
從5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊 酸三級丁酯(對映異構物2,47mg,78.0μmol,實施例255A)開始,與TFA的反應和產物的純化如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。獲得33mg(純度96%,理論值的74%)標題化合物。
[α]D 20=-41.1°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.39min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.73),0.146(1.64),1.147(0.95),1.872(16.00),2.114(10.29),2.129(9.25),2.162(10.64),2.327(5.88),2.366(2.34),2.669(5.71),2.710(2.51),3.565(9.95),3.693(3.98),7.050(5.79),7.072(10.81),7.095(6.40),7.351(3.11),7.466(8.13),7.488(13.15),7.547(6.83),7.553(6.66),7.575(4.15),8.134(10.90),8.763(4.84),12.069(1.38).
從(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(外消旋物,55mg,84.3μmol,實施例256A)開始,與TFA的反應和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。獲得48mg(100%純度,理論值的95%)標題化合物。
LC-MS(方法1):Rt=2.07min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.57),-0.008(4.89),0.146(0.61),1.234(0.46),1.890(4.70),2.064(2.82),2.082(3.71),2.101(3.95),2.118 (8.92),2.134(9.20),2.155(16.00),2.327(0.69),2.670(0.74),3.165(5.06),3.448(3.31),3.477(6.93),3.505(4.20),3.686(0.95),3.704(2.05),3.719(3.23),3.733(2.39),7.059(4.20),7.081(7.65),7.104(4.95),7.324(0.61),7.343(1.58),7.361(2.22),7.379(1.43),7.398(0.58),7.511(0.64),7.674(2.48),7.696(11.37),7.705(7.37),7.710(6.84),7.728(1.50),7.732(1.69),8.814(1.90),8.828(3.82),8.842(1.95),12.091(1.33).
從5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物1,82mg,126μmol,實施例257A)開始,與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。通過製備型HPLC純化產物(方法19)。獲得48mg(98%純度,理論值的63%)標題化合物。
[α]D 20=+44.1°,589nm,c=0.48g/100ml,甲醇
LC-MS(方法1):Rt=2.09min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.59),0.146(0.64),1.889(4.78),2.081(3.71),2.100(3.95),2.118(8.73),2.133(9.08),2.154(16.00),2.365(0.46),2.709(0.55),3.162(10.75),3.174(9.58),3.446(3.22),3.476(6.83),3.504(4.20),3.703(2.08),3.719(3.25),4.063(0.59),4.075(1.40),4.087(1.37),7.058(3.98),7.080(7.57),7.103(4.68),7.342(1.63),7.360(2.24),7.377(1.44),7.501(0.70),7.673(2.24),7.695(10.13),7.705(6.46),7.731(1.48),8.812(1.86),8.827(3.59),8.841(1.87),12.083(1.83).
從5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸三級丁酯(對映異構物2,73mg,112μmol,實施例258A)開始,與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯 基)戊酸(實施例245)所述進行。通過製備型HPLC純化產物(方法19)。獲得40mg(98%純度,理論值的59%)標題化合物。
[α]D 20=-38.2°,589nm,c=0.37g/100ml,甲醇
LC-MS(方法1):Rt=2.06min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.890(4.67),2.065(2.78),2.082(3.62),2.101(3.76),2.119(8.55),2.135(9.19),2.155(16.00),2.327(0.66),2.670(0.70),2.710(0.43),3.162(9.09),3.175(8.05),3.447(3.23),3.476(6.83),3.504(4.13),3.687(0.97),3.703(2.09),3.719(3.30),3.734(2.38),4.062(0.43),4.075(1.22),4.088(1.19),4.102(0.40),7.059(4.21),7.081(7.74),7.104(4.91),7.323(0.64),7.342(1.64),7.361(2.27),7.378(1.46),7.398(0.56),7.511(0.67),7.674(2.44),7.696(11.21),7.705(6.99),7.710(6.16),7.728(1.40),7.732(1.46),8.812(1.93),8.827(3.80),8.841(1.89),12.081(4.01).
從5-[({6-溴-2-(3-氟哌啶-1-基)-3-甲基喹啉-4-基}羰基)胺基]-4-(2,6-二氟苯基)戊酸三級丁酯(56mg,88μmol,實施例259A)開始,與TFA的反應和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。獲得44mg(100%純度,理論值的88%)標題化合物。
LC-MS(方法1):Rt=2.01min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.03),-0.008(8.38),0.008 (8.14),0.146(0.93),1.644(1.51),1.806(1.39),1.902(3.86),2.051(1.37),2.064(1.63),2.082(1.68),2.116(7.76),2.132(8.29),2.150(16.00),2.328(1.27),2.670(1.27),3.094(1.82),3.169(1.75),3.379(1.96),3.405(1.08),3.437(1.77),3.470(1.84),3.714(2.97),4.817(1.29),4.937(1.20),7.057(4.38),7.080(7.98),7.102(5.17),7.341(1.68),7.359(2.32),7.377(1.49),7.491(0.77),7.648(2.80),7.670(11.98),7.680(7.57),7.684(7.16),7.702(1.77),7.707(1.80),8.807(1.82),8.822(3.74),8.836(1.96),12.087(1.51).
從5-[({6-溴-2-(3-乙基哌啶-1-基)-3-甲基喹啉-4-基}羰基)胺基]-4-(2,6-二氟苯基)戊酸三級丁酯(非對映異構構物混合物,55mg,85.3μmol,實施例260A)開始,與TFA的反應和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。得到48mg(100%純度,理論值的96%)標題化合物。
LC-MS(方法1):Rt=2.37min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.62),-0.008(5.31),0.008(4.88),0.146(0.62),0.892(5.28),0.909(12.18),0.911(12.13),0.928(6.42),1.035(0.46),1.065(1.21),1.086(1.24),1.116(0.56),1.240(1.12),1.257(2.48),1.275(3.28),1.293(2.31),1.398(0.50),1.563(1.35),1.603(1.26),1.632(1.09),1.747(1.69),1.780(1.17),1.854(1.61),1.887(2.01),2.030(0.44),2.049(1.06),2.063(1.30),2.081(1.38),2.100(1.76),2.118(8.16),2.132(16.00),2.150(2.62), 2.327(0.62),2.396(0.74),2.423(1.15),2.451(0.74),2.670(0.71),2.710(0.96),2.738(1.43),2.768(0.80),3.493(3.67),3.515(2.99),3.679(0.74),3.696(1.61),3.712(2.60),3.726(1.88),7.053(3.55),7.075(6.48),7.097(4.26),7.319(0.53),7.338(1.33),7.357(1.92),7.376(1.26),7.394(0.56),7.473(0.53),7.625(1.61),7.647(9.98),7.654(6.34),7.658(5.28),7.676(0.99),7.680(1.02),8.790(1.48),8.805(2.94),8.819(1.52),12.082(1.72).
從(+/-)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(外消旋物,56mg,90.8μmol,實施例261A)開始,與TFA的反應(反應時間:45分鐘)和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。得到49mg(100%純度,理論值的%%)標題化合物。
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.150(0.88),0.146(0.88),1.371(0.59),1.605(4.49),1.670(8.78),1.805(1.66),2.003(1.56),2.015(2.05),2.035(1.95),2.054(2.24),2.090(5.07),2.117(16.00),2.327(1.76),2.366(0.54),2.669(1.95),3.132(11.56),3.612(1.46),3.631(2.10),3.645(3.02),3.695(1.76),7.127(2.54),7.204(2.05),7.215(2.24),7.227(3.32),7.239(3.32),7.250(1.61),7.262(1.46),7.300(3.12),7.436(1.02),7.622(2.54),7.644(12.63),7.653(8.44),7.658(7.66),7.680(1.76),8.723(2.15),8.738(3.90),8.752(2.10),12.064(1.46).
從5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物1,81mg,131μmol,實施例262A)開始,與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。通過製備型HPLC(方法20)製備產物。獲得40mg(98%純度,理論值的59%)標題化合物。
[α]D 20=-28.8°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=2.10min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.04),0.146(0.87),1.606(4.57),1.670(8.65),1.807(1.78),2.003(1.72),2.016(2.23),2.035(2.23),2.055(2.53),2.063(2.20),2.090(5.31),2.117(16.00),2.137(3.69),2.327(1.78),2.366(1.04),2.669(1.65),2.710(0.81),3.132(11.40),3.162(5.70),3.175(5.54),3.612(1.49),3.631(2.07),3.646(2.98),3.659(1.68),3.694(1.65),4.062(0.52),4.075(1.49),4.088(1.43),4.100(0.49),7.127(2.49),7.147(1.68),7.204(2.23),7.216(2.36),7.227(3.47),7.239(3.43),7.250(1.65),7.262(1.59),7.278(1.78),7.287(2.11),7.293(2.17),7.301(3.01),7.316(2.11),7.324(1.68),7.422(0.94),7.622(2.66),7.644(12.70),7.653(7.90),7.658(7.13),7.675(1.46),7.680(1.68),8.724(2.17),8.739(3.92),8.753(2.14),12.061(2.36).
從5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物2,90mg,146μmol,實施例263A)開始,與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。通過製備型HPLC(方法20)製備產物。獲得69mg(97%純度,理論值的82%)標題化合物。
[α]D 20=+34.2°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.11min;MS(ESIpos):m/z=560/562[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.51),-0.008(4.19),0.008(4.29),0.146(0.51),1.605(4.49),1.670(8.69),1.750(0.60),1.773(1.12),1.785(1.50),1.808(1.80),1.984(0.65),2.003(1.58),2.016(2.12),2.035(2.10),2.055(2.37),2.063(2.03),2.091(5.24),2.117(16.00),2.137(3.73),2.157(1.03),2.327(0.70),2.366(0.41),2.670(0.81),2.710(0.49),3.132(11.49),3.162(9.35),3.175(9.18),3.195(0.52),3.599(0.84),3.612(1.50),3.632(2.10),3.645(3.04),3.659(1.77),3.675(1.35),3.694(1.74),3.712(1.47),4.062(0.93),4.075(2.52),4.088(2.42),4.101(0.85),7.105(1.19),7.127(2.47),7.136(2.01),7.147(1.69),7.204(2.06),7.215(2.25),7.227(3.34),7.239(3.26),7.250(1.60),7.262(1.46),7.278(1.77),7.286(2.06),7.292(2.15),7.301(3.04),7.310(2.10),7.316(2.07),7.324(1.68),7.422(0.90),7.622(2.45),7.644(12.19),7.653(7.77),7.657(6.84),7.675(1.47),7.680(1.60),8.724(2.17),8.739(3.97),8.753(2.14),12.060(2.50).
從(+/-)-5-({[6-溴-3-methyl-2-(吡咯啶-1-yl)喹啉-4-yl]羰基}amino)-4-(2,5-di氟苯基)戊酸三級丁酯(外消旋物,55mg,91.3μmol,實施例264A)開始,與TFA的反應和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。獲得29mg(100%純度,理論值的58%)標題化合物。
LC-MS(方法1):Rt=1.41min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.78),-0.008(5.94),0.008(6.57),0.146(0.78),1.235(0.57),1.750(0.63),1.773(1.30),1.786(1.77),1.806(2.19),1.830(1.93),1.871(16.00),1.981(0.83),2.001(1.98),2.013(2.61),2.033(2.81),2.052(3.07),2.060(2.66),2.088(5.37),2.102(7.09),2.118(8.44),2.138(9.07),2.323(0.99),2.327(1.25),2.332(0.94),2.665(0.99),2.670(1.30),2.674(1.04),2.710(0.42),3.566(11.15),3.597(3.80),3.617(3.28),3.631(4.12),3.644(2.35),3.688(2.08),7.099(1.41),7.120(2.87),7.140(2.03),7.196(2.92),7.208(3.07),7.219(4.53),7.231(4.59),7.242(2.40),7.254(2.24),7.271(2.55),7.279(2.92),7.285(3.13),7.294(4.22),7.303(3.02),7.309(3.02),7.317(2.61),7.465(8.55),7.488(14.59),7.544(7.35),7.549(6.98),7.566(4.33),7.571(4.27),8.133(1.98),8.678(2.76),8.693(4.95),8.707(2.76),12.057(2.24).
從5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物1,80mg,133μmol,實施例265A)開始,與TFA的反應和產物的純化如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。獲得59mg(100%純度,理論值的81%)標題化合物。
[α]D 20=+30.2°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.42min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.42),-0.008(10.42),0.008(9.95),0.146(1.26),1.148(0.74),1.806(2.42),1.871(16.00),2.001(2.11),2.013(2.68),2.033(2.95),2.052(3.21),2.060(2.74),2.088(5.53),2.101(7.47),2.118(8.79),2.137(9.00),2.327(3.63),2.332(2.74),2.366(1.95),2.669(4.11),2.710(2.11),3.169(0.74),3.566(10.89),3.617(3.47),3.631(4.32),3.645(2.58),3.685(2.26),7.119(2.95),7.196(2.95),7.207(3.16),7.219(4.68),7.231(4.74),7.242(2.58),7.254(2.37),7.271(2.63),7.285(3.16),7.294(4.32),7.303(3.21),7.317(2.74),7.466(5.63),7.488(9.68),7.544(5.95),7.550(5.58),7.567(3.53),7.572 (3.58),7.834(0.42),8.133(2.00),8.679(2.74),8.693(4.84),8.707(2.74),12.057(2.84),12.732(0.58).
從5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物2,83mg,138μmol,實施例266A)開始,與TFA的反應和產物的純化如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。獲得56mg(100%純度,理論值的74%)標題化合物。
[α]D 20=-28.6°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.42min;MS(ESIpos):m/z=546/548[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.11),-0.008(8.91),0.008(10.55),0.146(1.15),1.147(0.53),1.806(2.44),1.871(16.00),2.001(1.99),2.013(2.61),2.033(2.75),2.052(3.10),2.088(5.50),2.102(7.31),2.118(8.60),2.138(9.00),2.327(2.75),2.366(1.60),2.669(3.01),2.710(1.68),3.207(0.58),3.565(11.21),3.617(3.28),3.631(4.08),3.644(2.30),3.686(2.13),7.120(3.01),7.196(2.75),7.208(3.06),7.219(4.43),7.231(4.43),7.242(2.26),7.254(2.26),7.271(2.57),7.285(3.19),7.294(4.21),7.303(3.06),7.317(2.48),7.465(7.40),7.487(12.59),7.544(6.47),7.549(6.12),7.566(3.81),7.571(3.77),8.132(0.49),8.678(2.84),8.693(4.92),8.707(2.57),12.055(6.43).
從(+/-)-5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(外消旋物,55mg,84.3μmol,實施例267A)開始,與TFA反應(反應時間:40分鐘)並純化產物如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。獲得47mg(100%純度,理論值的93%)標題化合物。
LC-MS(方法1):Rt=2.07min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.53),-0.008(4.53),0.008(4.37),0.146(0.53),1.372(1.58),1.788(1.68),1.811(1.95),1.881(5.11),2.004(1.84),2.017(2.37),2.037(2.95),2.056(4.21),2.063(3.89),2.092(8.63),2.106(8.47),2.119(10.53),2.136(15.47),2.327(1.53),2.366(0.42),2.670(1.63),2.710(0.53),3.163(6.42),3.446(4.05),3.475(7.63),3.504(3.84),3.622(1.68),3.641(2.42),3.655(3.42),3.670(2.00),3.701(1.79),7.107(1.21),7.128(2.79),7.138(2.26),7.149(1.95),7.206(2.53),7.217(2.74),7.229(4.11),7.241(4.16),7.252(2.00),7.264(1.84),7.285(2.05),7.292(2.42),7.298(2.58),7.307(3.58),7.316(2.42),7.322(2.47),7.330(2.16),7.469(0.89),7.673(2.89),7.695(16.00),7.702(10.95),7.707(9.63),7.724(1.95),7.729(2.11),8.739(2.53),8.754(4.79),8.768(2.58),12.069(1.58).
從5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物1,55mg,84.3μmol,實施例268A)開始, 與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。通過製備型HPLC(方法20)純化產物。獲得23mg(98%純度,理論值的35%)標題化合物。
[α]D 20=-30.7°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.07min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.99),-0.008(12.44),0.146(0.96),1.812(2.13),1.882(5.42),2.005(2.03),2.017(2.55),2.037(3.26),2.057(4.72),2.093(9.47),2.109(9.62),2.119(11.50),2.136(16.00),2.327(1.24),2.366(0.72),2.669(1.46),2.710(0.82),3.162(13.03),3.175(11.43),3.446(4.30),3.475(7.79),3.504(3.88),3.540(0.67),3.622(1.83),3.641(2.65),3.656(3.59),3.669(2.28),3.702(2.08),4.075(1.63),4.088(1.58),7.128(2.97),7.149(2.05),7.206(2.52),7.217(2.72),7.229(4.06),7.241(4.03),7.252(2.05),7.264(1.85),7.285(2.23),7.298(2.74),7.307(3.66),7.316(2.60),7.322(2.57),7.330(2.08),7.474(1.04),7.673(2.99),7.695(15.06),7.702(10.51),7.707(9.15),7.725(1.76),7.729(1.98),8.739(2.72),8.753(4.77),8.768(2.62),12.065(1.78).
從5-({[6-溴-2-(3,3-二氟哌啶-1-基)-3-甲基喹啉-4-基]羰基}胺基)-4-(2,5-二氟苯基)戊酸三級丁酯(對映異構物2,71mg,95%純度,103μmol,實施例269A)開始,與TFA的反應如(+)-5-({[6-溴-3-甲基-2-(哌啶-1-基)喹啉-4-基]羰基}胺基)-4-(2,6-二氟苯基)戊酸(實施例245)所述進行。通過製備型HPLC(方法20)純化產物。獲得28mg(99%純度,理論值的45%)標題化合物。
[α]D 20=+34.0°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.06min;MS(ESIpos):m/z=596/598[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.62),0.146(0.69),1.371(0.58),1.754(0.65),1.790(1.79),1.810(2.06),1.881(5.45),2.004(1.92),2.017(2.47),2.038(3.17),2.056(4.63),2.092(9.35),2.108(9.58),2.119(11.35),2.136(16.00),2.327(0.91),2.366(0.44),2.669(1.00),2.709(0.49),3.163(7.70),3.447 (4.16),3.475(7.62),3.504(3.78),3.622(1.83),3.642(2.58),3.655(3.47),3.669(2.14),3.703(1.99),7.128(2.87),7.148(1.86),7.206(2.42),7.217(2.60),7.229(3.79),7.240(3.68),7.252(1.83),7.263(1.66),7.285(2.14),7.298(2.63),7.307(3.52),7.316(2.47),7.329(1.86),7.467(0.96),7.673(2.87),7.695(14.19),7.702(9.23),7.706(8.04),7.729(1.64),8.739(2.76),8.753(4.69),8.767(2.46),12.063(1.15).
從5-[({6-溴-2-(3-氟哌啶-1-基)-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸三級丁酯(非對映異構物混合物,55mg,86.7μmol,實施例270A)開始,與TFA的反應和產物的純化如5-[({6-溴-2-[3-乙基哌啶-1-基]-3-甲基喹啉-4-基}羰基)胺基]-4-(2,5-二氟苯基)戊酸(實施例225)所述進行。獲得43mg(100%純度,理論值的86%)標題化合物。
LC-MS(方法1):Rt=2.02min;MS(ESIpos):m/z=578/580[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.90),-0.008(10.95),0.008(6.96),0.017(0.58),0.146(0.90),1.643(2.02),1.806(3.83),1.899(3.35),1.948(2.02),1.983(1.70),2.003(2.29),2.016(2.55),2.035(2.60),2.055(2.82),2.063(2.39),2.091(6.01),2.105(7.44),2.128(14.41),2.327(1.54),2.523(3.88),2.665(1.38),2.670(1.70),2.711(0.43),3.094(2.29),3.153(2.39),3.170(2.34),3.369(3.99),3.401(1.75),3.434(2.29),3.460(1.54),3.540(0.64),3.618(1.59),3.636(2.34),3.650(3.08),3.700(1.97),4.817(1.70),4.935(1.70),7.127(2.92),7.147 (1.97),7.204(2.76),7.216(2.92),7.227(4.36),7.239(4.25),7.251(2.07),7.262(1.91),7.281(2.23),7.289(2.60),7.295(2.71),7.304(3.72),7.313(2.66),7.319(2.50),7.327(2.13),7.450(1.06),7.647(3.40),7.669(16.00),7.676(10.95),7.681(9.51),7.699(1.97),7.704(2.13),8.732(2.71),8.747(4.73),8.761(2.50),12.068(2.29).
將(+/-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2,6-二氯苯基)戊酸(外消旋物,401mg,72%純度,5μmol,實施例246A)、3,3-二氟哌啶鹽酸鹽(580mg,3.68mmol)和DIPEA(1.5ml,8.8mmol)在NMP(1.9ml)的混合物在120℃下攪拌4天。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過管柱色譜法(Isolera,LiChroprep RP-18,溶析液:水/乙腈,梯度:20-100%乙腈)純化粗產物。將產物級分(238mg)溶於二氯甲烷/甲醇(1:1,5ml)中,並通過製備型HPLC在手性相上分離成對映異構物[管柱:Daicel Chiralpak IA,5μm,250mm x 30毫米;流速:50毫升/分鐘;檢測:UV 254nm;注入:1.0毫升;溶析液:70%己烷+0.1%(體積)三氟乙酸/30%異丙醇,等度]。將合併的目標級分各自濃縮,並將各個殘餘物冷凍乾燥。
得到標題化合物(52mg,98%純度,ee>99%),為較早洗脫的對映異構物。
[α]D 20=-10.2°,589nm,c=0.50g/100ml,氯仿
LC-MS(方法25):Rt=1.37min;MS(ESIpos):m/z=628/630/632[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:0.888(0.45),0.894(0.47),1.215(0.47),1.226(1.52),1.241(1.34),1.263(2.42),1.286(1.77),1.304(0.89),1.379(4.12),1.395(4.07),1.999(2.53),2.115(1.08),2.152(2.73),2.163(3.07),2.180(2.45),2.244(0.69),2.310(16.00),2.331(2.78),2.436(0.45),2.451(0.79),2.476(0.98),2.485(0.84),2.493(0.84),2.503(1.20),3.048(0.51),3.538(2.47),3.709(1.54),3.737(2.47),3.761(1.32),3.848(0.43),4.055(0.46),4.071(0.96),4.086(1.16),4.101(1.99),4.112(1.96),4.231(0.65),4.247(0.86),4.260(1.13),4.273(0.87),6.758(1.37),7.152(2.35),7.172(5.73),7.192(3.52),7.225(0.51),7.242(0.74),7.302(0.56),7.321(3.36),7.324(3.85),7.341(3.30),7.344(3.50),7.352(0.95),7.364(4.49),7.367(3.81),7.385(3.43),7.388(2.99),7.761(2.77),7.768(3.04),7.790(2.66),7.859(2.44),7.881(1.58),8.350(0.78).
在實施例265中描述的對映異構物分離中,獲得50mg(95%純度,ee 98%)標題化合物,作為稍後洗脫的對映異構物。
[α]D 20=+14.8°,589nm,c=0.50g/100ml,氯仿.
1H-NMR(400MHz,氯仿-d)δ[ppm]:0.861(0.55),0.876(0.59),0.888(0.89),0.894(0.86),0.901(0.64),0.913(0.48),1.199(0.55),1.215(0.70),1.227(1.84),1.242(1.70),1.263(4.61),1.379(3.69),1.395(3.79),2.005(2.59),2.164(2.71),2.179(2.35),2.315(16.00),2.342(2.09),2.478(1.02),2.507(1.24),3.540(2.34),3.736(2.05),4.079(1.03),4.115(2.36),4.228(0.74),4.242(0.88),4.256(1.23),4.268(0.91),6.702(1.37),7.154(2.59),7.174(6.12),7.194(3.69),7.322(3.68),7.326(4.24),7.343(3.18),7.345(3.19),7.367(4.49),7.370(3.96),7.386(3.70),7.390(3.25),7.529(0.51),7.767(3.80),7.791(3.05),7.863(2.27),7.884(1.87),7.947(0.79).
(+)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(262mg,419μmol,對映異構物1,實施例278A)在二氯甲烷(3.2ml)之溶液中加入TFA(711μl,9.23mmol),並將混合物留至在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得187mg(100%純度,理論值的79%)標題化合物。
[α]D 20=+13.3°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=2.15min;MS(ESIpos):m/z=568/570[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.021(0.35),1.232(0.75),1.540(0.53),1.613(0.41),1.792(0.63),1.800(0.99),1.818(2.03),1.835(2.41),1.853(1.25),1.873(0.28),2.024(0.57),2.036(1.20),2.041(1.40),2.052(5.86),2.074(4.33),2.081(4.40),2.097(4.07),2.127(15.83),2.154(2.03),2.196(0.35),2.363(0.20),2.636(0.22),3.078(0.18),3.086(0.20),3.593(2.03),3.674(3.19),7.258(1.99),7.261(2.01),7.274(4.38),7.288(3.00),7.291(2.84),7.359(2.69),7.374(4.82),7.388(2.54),7.443(8.16),7.446(7.64),7.459(7.24),7.462(6.59),7.480(6.24),7.482(6.15),7.496(4.97),7.623(4.16),7.640(16.00),7.650(10.72),7.654(9.32),7.667(2.58),7.671(2.69),8.710(2.72),8.721(5.30),8.733(2.56),12.042(0.39).
(-)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(244mg,391μmol,對映異構物2,實施例279A)在二氯甲烷(3.0ml)之溶液中加入TFA(662μl,8.59mmol),並將混合物留至在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得180mg(100%純度,理論值的81%)標題化合物。
[α]D 20=-11.1°,589nm,c=0.40g/100ml,甲醇
LC-MS(方法1):Rt=2.17min;MS(ESIpos):m/z=568/570[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.538(0.58),1.611(0.46),1.799(1.21),1.814(2.79),1.828(3.08),1.843(1.64),2.028(0.83),2.043(1.96),2.053(7.45),2.071(6.42),2.076(5.14),2.087(2.91),2.092(2.98),2.099(3.62),2.125(13.11),2.131(11.82),2.148(3.42),2.195(0.42),2.386(0.17),2.613(0.16),3.074(0.19),3.081(0.19),3.592(2.59),3.673(3.20),7.263(2.39),7.276(5.09),7.288(3.29),7.363(3.08),7.376(5.48),7.388(2.98),7.448(9.82),7.461(8.60),7.488(6.94),7.500(5.71),7.626(5.57),7.641(16.00),7.654(9.27),7.656(8.85),7.668(3.13),7.671(3.26),8.734(3.59),8.744(7.01),8.753(3.50),12.078(1.77).
(-)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)amino]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(231mg,352μmol,對映異構物1,實施例280A) 於二氯甲烷(2.7ml)之溶液中加入TFA(596μl,7.74mmol),及使混合物在RT下靜置24小時。再將混合物濃縮及重複加入二氯甲烷,再次濃縮混合物。殘留物藉由製備型HPLC(方法11)純化。濃縮合病之目標級分,及將殘留物冷凍乾燥。取得166mg(100%純度,理論值之79%)標題化合物。
[α]D 20=-19.1°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=2.18min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.005(0.22),1.229(0.23),1.546(0.54),1.620(0.59),1.876(0.59),1.885(0.81),1.892(1.34),1.900(1.97),1.907(1.66),1.915(1.99),1.923(1.82),1.939(1.08),1.953(1.49),1.962(1.01),1.969(1.61),1.980(2.72),1.989(1.82),1.996(2.72),2.005(2.10),2.047(2.24),2.058(3.02),2.063(2.06),2.074(3.61),2.078(1.32),2.085(1.93),2.101(1.97),2.116(1.74),2.125(2.27),2.139(3.57),2.162(6.96),2.191(1.27),2.388(0.17),2.616(0.17),3.096(0.32),3.633(1.56),3.707(1.54),7.471(2.48),7.484(4.85),7.497(2.90),7.639(4.67),7.654(16.00),7.662(9.66),7.666(8.77),7.677(2.62),7.680(2.72),7.698(2.13),7.711(5.07),7.724(4.34),7.729(7.06),7.741(10.81),7.753(3.07),8.793(3.05),8.803(6.14),8.813(3.01),12.085(0.33).
(+)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(204mg,310μmol,對映異構物2,實施例281A)在二氯甲烷(2.4ml)的溶液中加入TFA(525μl,6.82mmol),將混合物在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得157mg(100%純度,理論值的84%)標題化合物。
[α]D 20=+19.1°,589nm,c=0.45g/100ml,甲醇
LC-MS(方法1):Rt=2.23min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.546(0.56),1.620(0.64),1.877(0.74),1.892(1.70),1.900(2.53),1.907(2.16),1.915(2.60),1.923(2.32),1.939(1.35), 1.954(1.73),1.963(1.23),1.970(1.91),1.981(3.42),1.990(2.23),1.997(3.23),2.006(2.55),2.048(2.67),2.059(3.62),2.074(4.25),2.086(2.28),2.101(2.44),2.117(2.22),2.126(3.06),2.162(9.18),2.387(0.23),2.614(0.20),3.096(0.31),3.632(2.08),3.705(2.06),7.472(3.23),7.484(6.23),7.497(3.72),7.638(4.69),7.653(16.00),7.663(10.11),7.679(2.87),7.698(2.74),7.711(6.46),7.729(8.95),7.742(13.87),7.753(3.91),8.792(3.69),8.802(7.25),8.812(3.62),12.063(7.55).
(+)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(181mg,268μmol,對映異構物1,實施例282A)在二氯甲烷(2.1ml)的溶液中加入TFA(460μl,5.90mmol),將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得140mg(100%純度,理論值的84%)標題化合物。
[α]D 20=+19.7°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.28min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.231(0.17),1.543(0.59),1.615(0.66),1.788(0.36),1.799(0.68),1.812(2.24),1.819(2.71),1.826(2.26),1.834(3.75),1.849(2.42),1.867(0.57),2.031(0.65),2.048(1.50),2.057(4.09),2.077(16.00), 2.098(4.42),2.105(3.31),2.111(3.54),2.135(6.56),2.219(0.49),2.388(0.21),2.616(0.21),3.089(0.29),3.393(2.89),3.403(2.82),3.599(1.13),3.609(1.93),3.620(3.25),3.631(3.89),3.641(2.48),3.664(2.81),3.674(2.40),7.282(0.18),7.352(4.12),7.364(6.45),7.394(2.55),7.408(8.73),7.414(8.57),7.421(8.95),7.433(2.43),7.559(5.83),7.569(4.84),7.573(4.73),7.634(5.43),7.649(15.94),7.661(9.19),7.664(9.30),7.679(3.24),8.756(3.78),8.765(7.15),8.775(3.68),12.083(13.49).
(-)-5-[({6-溴-3-甲基-2-[(2 H 10)哌啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(215mg,320μmol,對映異構物2,實施例283A)在二氯甲烷(2.5ml)的溶液中加入TFA(540μl,7.03mmol),將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得166mg(100%純度,理論值的84%)標題化合物。
[α]D 20=-17.5°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=2.23min;MS(ESIpos):m/z=618/620[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.005(0.31),1.230(0.24),1.543(0.56),1.615(0.58),1.786(0.29),1.799(0.52),1.811(1.78),1.819(2.11),1.826(1.75),1.833(2.88),1.849(2.02),1.866(0.46),2.030(0.51),2.035(0.44),2.047(1.22),2.056(3.38),2.075(11.92),2.078(11.58),2.082(10.29),2.097(3.39),2.105(2.47),2.110(2.68),2.135(4.84),2.219(0.43),2.387(0.17),2.615(0.17),3.089(0.30),3.392(2.55),3.402(2.34),3.598(0.88),3.608(1.48),3.620(2.50),3.630(2.95),3.641(1.87),3.652(1.45),3.663(2.07),3.674(1.76),7.351(3.20),7.361(4.27),7.364(5.30),7.394(2.04),7.403(5.07),7.408(6.93),7.414(7.35),7.420(7.47),7.423(5.23),7.433(1.99),7.558(4.77),7.569(3.85),7.573(3.74),7.634(5.48),7.649(16.00),7.661(8.72),7.664(8.01),7.676(2.81),7.679(2.85),8.756(3.09),8.765(5.88),8.775(3.00),12.090(0.88).
(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(241mg,400μmol,對映異構物1,實施例48A)在NMP(1.6ml)的溶液中加入哌啶-D11(120μl,1.20mmol),並在110℃下攪拌混合物20小時。冷卻至室溫後,將水(100ml)加入混合物中,用乙酸乙酯(每次80ml)萃取兩次。將合併的有機相用硫酸鈉乾燥,過濾並濃縮,並通過製備型HPLC(方法32)純化殘餘物。濃縮合併的目標餾分,將殘餘物從乙腈/水中冷凍乾燥。直接得到標題化合物(不分離相應的三級丁酯)。獲得32mg(100%純度,理論值的13%)標題化合物。
[α]D 20=+37.3°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=2.12min;MS(ESIpos):m/z=604/606[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.022(0.32),0.070(0.18),1.095(0.19),1.106(0.18),1.228(1.01),1.312(0.88),1.343(0.85),1.353(0.90),1.377(0.85),1.402(0.51),1.539(0.67),1.612(0.55),1.950(1.96),2.069(4.94),2.084(5.40),2.135(16.00),2.388(0.38),2.616(0.42),2.694(0.48),3.084(0.84),3.394(4.23),3.714(4.00),7.293(3.51),7.299(3.54),7.309(2.55),7.413(3.39),7.632(6.05),7.646(14.75),7.661(9.57),7.665(8.43),7.676(3.85),7.679(3.58),8.842(4.13).
(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(241mg,400μmol,對映異構物2,實施例49A)在NMP(1.6ml)的溶液中加入哌啶-D11(120μl,1.20mmol),並在110℃下攪拌混合物20小時。冷卻至室溫後,將水(100ml)加入混合物中,用乙酸乙酯(每次80ml)萃取兩次。將合併的有機相用硫酸鈉乾燥,過濾並濃縮,並通過製備型HPLC(方法32)純化殘餘物。濃縮合併的目標餾分,將殘餘物從乙腈/水中冷凍乾燥。直接得到標題化合物(不分離相應的三級丁酯)。獲得42mg(100%純度,理論值的17%)標題化合物。
[α]D 20=-29.2°,589nm,c=0.33g/100ml,甲醇
LC-MS(方法1):Rt=2.12min;MS(ESIpos):m/z=604/606[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.022(0.18),0.072(0.21),1.228(1.00),1.343(0.66),1.354(0.71),1.361(0.75),1.402(0.20),1.540(0.68),1.613(0.55),1.954(1.87),2.071(4.75),2.088(5.11),2.135(16.00),2.388(0.30),2.616(0.35),2.695(0.50),3.085(0.78),3.394(3.81),7.294(3.41),7.300(3.44),7.310(2.45),7.413(3.29),7.632(6.00),7.647(14.77),7.662(9.74),7.665(8.27),7.677(3.79),7.680(3.41),8.842(4.09).
(+)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(232mg,380μmol,對映異構物1,實施例284A)在二氯甲烷(2.9ml)的溶液中加入TFA(645μl,8.37mmol),將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得170mg(100%純度,理論值的81%)標題化合物。
[α]D 20=+12.8°,589nm,c=0.38g/100ml,甲醇
LC-MS(方法1):Rt=1.42min;MS(ESIpos):m/z=552/554[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:1.232(0.37),1.792(0.70),1.800(1.02),1.818(2.38),1.835(2.71),1.853(1.37),2.022(0.70),2.032(1.39),2.041(1.72),2.049(5.62),2.070(4.67),2.072(4.71),2.076(5.09),2.093(4.12),2.117(2.81),2.134(4.96),2.155(9.05),2.237(0.36),2.284(0.43),2.362(0.18),2.636(0.18),3.587(2.38),3.654(2.45),7.254(2.02),7.269(4.23),7.283(2.85),7.355(2.96),7.370(5.05),7.384(2.96),7.436(8.59),7.439(8.21),7.452(7.33),7.455(6.80),7.468(10.62),7.475(6.17),7.477(6.21),7.486(16.00),7.490(5.16),7.543(7.85),7.548(7.12),7.561(4.96),7.566(4.68),8.663(2.87),8.674(5.45),8.686(2.67).
(-)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯苯基)戊酸三級丁酯(236mg,388μmol,對映異構物2,實施例285A)在二氯甲烷 (3.0ml)的溶液中加入TFA(657μl,8.53mmol),並將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得177mg(100%純度,理論值的83%)標題化合物。
[α]D 20=-11.5°,589nm,c=0.48g/100ml,甲醇
LC-MS(方法1):Rt=1.43min;MS(ESIpos):m/z=552/554[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.800(1.03),1.815(2.52),1.829(2.74),1.845(1.38),2.027(0.69),2.035(1.39),2.051(6.12),2.069(5.24),2.088(2.40),2.099(2.00),2.117(3.32),2.132(5.50),2.148(5.66),2.238(0.37),2.283(0.33),3.585(2.21),3.651(2.02),7.258(1.88),7.270(3.56),7.282(2.45),7.360(2.37),7.372(3.84),7.384(2.29),7.441(8.20),7.455(7.11),7.469(8.21),7.484(16.00),7.495(4.67),7.548(5.71),7.551(5.48),7.562(4.01),7.565(3.91),8.686(3.02),8.695(5.74),8.704(2.88),12.077(1.33).
(-)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(200mg,311μmol,對映異構物1,實施例286A)在二氯甲烷(2.4ml)的溶液中加入TFA(528μl,6.85mmol),將混合物在室溫下靜置24小時。然後濃縮混合物並重新加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘 物冷凍乾燥。獲得151mg(100%純度,理論值的83%)標題化合物。
[α]D 20=-18.0°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.51min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.829(0.40),1.874(0.82),1.883(1.18),1.890(1.90),1.898(2.80),1.905(2.37),1.913(2.80),1.920(2.63),1.937(1.64),1.946(2.11),1.955(1.34),1.962(2.15),1.972(3.71),1.981(2.35),1.989(3.43),1.997(2.66),2.049(2.83),2.059(3.89),2.075(4.72),2.086(2.77),2.102(3.03),2.113(2.77),2.121(3.45),2.135(4.67),2.145(4.69),2.159(4.40),2.169(3.85),2.178(3.42),2.278(0.75),2.387(0.30),2.615(0.24),3.598(2.01),3.722(2.08),7.247(0.41),7.394(0.44),7.467(3.00),7.480(14.90),7.495(16.00),7.555(7.51),7.558(7.44),7.570(5.29),7.573(5.31),7.696(2.72),7.709(6.63),7.722(12.22),7.736(13.62),7.751(4.23),8.737(3.79),8.746(7.33),8.756(3.77),12.063(3.78).
(+)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲基)苯基]戊酸三級丁酯(184mg,287μmol,對映異構物2,實施例287A)在二氯甲烷(2.2ml)的溶液中加入TFA(486μl,6.32mmol),將混合物在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得139mg(100%純度,理論值的82%)標題化合物。
[α]D 20=+19.2°,589nm,c=0.30g/100ml,甲醇
LC-MS(方法1):Rt=1.47min;MS(ESIpos):m/z=586/588[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.005(0.36),1.232(0.17),1.830(0.45),1.876(0.97),1.884(1.37),1.891(2.25),1.899(3.28),1.907(2.78),1.914(3.26),1.922(3.14),1.938(1.95),1.948(2.59),1.957(1.61),1.964(2.69),1.975(4.42),1.983(2.89),1.991(4.33),1.999(3.30),2.050(3.56),2.061(4.90),2.066(3.43),2.077(6.09),2.088(3.47),2.104(3.78),2.114(3.37),2.122(4.01),2.136(5.33), 2.147(5.35),2.152(5.03),2.161(5.04),2.170(4.40),2.180(3.85),2.281(0.77),2.387(0.31),2.616(0.25),3.325(4.10),3.601(2.25),3.724(2.31),7.118(0.19),7.247(0.51),7.396(0.52),7.467(3.62),7.483(11.19),7.498(11.31),7.557(7.64),7.561(7.43),7.572(5.45),7.575(5.28),7.696(3.26),7.709(7.80),7.722(14.33),7.737(16.00),7.751(4.94),8.739(4.26),8.748(8.09),8.758(4.19),12.062(8.04).
(+)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(221mg,335μmol,對映異構物1,實施例288A)在二氯甲烷(2.6ml)的溶液中加入TFA(569μl,7.38mmol),將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得173mg(100%純度,理論值的86%)標題化合物。
[α]D 20=+17.6°,589nm,c=0.44g/100ml,甲醇
LC-MS(方法1):Rt=1.52min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.005(0.45),1.232(0.18),1.371(0.16),1.785(0.41),1.797(0.70),1.809(2.46),1.817(2.57),1.824(2.21),1.832(4.22),1.847(2.31),1.863(0.70),2.025(0.79),2.043(1.94),2.052(4.74),2.057(2.57),2.062(4.02),2.070(16.00),2.077(11.82),2.080(12.48),2.095(4.14),2.099 (3.35),2.110(3.35),2.128(2.33),2.154(2.44),2.299(0.39),2.387(0.29),2.521(0.34),2.615(0.27),3.388(2.82),3.539(0.29),3.576(1.26),3.586(1.99),3.597(2.89),3.608(3.17),3.618(1.85),3.665(2.28),3.675(2.12),7.279(0.39),7.342(3.44),7.345(4.50),7.355(5.69),7.357(7.09),7.360(5.29),7.389(2.33),7.404(6.74),7.409(7.73),7.417(7.25),7.429(2.39),7.478(5.56),7.492(7.70),7.555(10.48),7.566(6.58),7.570(8.36),8.707(3.14),8.716(5.60),8.726(3.03),12.080(6.24).
(-)-5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-[2-(三氟甲氧基)苯基]戊酸三級丁酯(188mg,286μmol,對映異構物2,實施例289A)在二氯甲烷(2.2ml)的溶液中加入TFA(484μl,6.28mmol),將混合物在室溫下放置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。濃縮合併的目標級分,並將殘餘物冷凍乾燥。獲得140mg(100%純度,理論值的81%)標題化合物。
[α]D 20=-14.4°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=1.57min;MS(ESIpos):m/z=602/604[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.786(0.41),1.799(0.79),1.811(2.56),1.819(2.97),1.833(4.47),1.848(2.43),1.865(0.72),2.026(0.76),2.044(1.92),2.053(4.55),2.071(16.00),2.081(13.66),2.096(4.73),2.111(3.63),2.130(2.70),2.156(2.87),2.298(0.47),2.386(0.22),2.614(0.20),3.391(3.10),3.539(0.31),3.577(1.37),3.587(2.26),3.598(3.23),3.609(3.59),3.619(2.09),3.666(2.65),3.676(2.45),7.278(0.44),7.345(4.72),7.357(7.31),7.389(2.62),7.405(7.34),7.409(8.25),7.417(7.84),7.429(2.59),7.477(8.39),7.492(11.72),7.556(12.90),7.570(9.71),8.707(3.63),8.717(6.58),8.726(3.55),12.080(13.05).
5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(38mg,59μmol,對映異構物1,實施例290A)在二氯甲烷(1.0ml)的溶液中加入TFA(100μl,1.30mmol),將混合物在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得9mg(100%純度,理論值的25%)標題化合物。
LC-MS(方法1):Rt=1.43min;MS(ESIpos):m/z=588/560[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.022(0.55),1.232(1.37),1.825(0.38),1.966(2.96),2.072(4.00),2.079(4.99),2.092(5.37),2.105(8.11),2.128(11.23),2.139(14.79),2.151(15.29),2.160(16.00),2.171(11.89),2.341(0.60),2.387(0.49),2.616(0.55),3.440(0.93),3.536(0.44),3.708(6.36),7.301(5.26),7.415(4.77),7.478(9.92),7.493(13.42),7.560(10.14),7.562(9.70),7.574(7.34),7.577(7.07),7.649(0.55),8.792(7.56),12.132(4.16).
如實施例290A中所述,從(+)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(241mg,400μmol,實施例48A)開始,直接獲得標題化合物(不分離相應的三級丁基酯)作為級分1(34mg,100%純度,理論值的14%)。
[α]D 20=+41.9°,589nm,c=0.32g/100ml,甲醇
LC-MS(方法1):Rt=1.43min;MS(ESIpos):m/z=588/560[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.071(0.24),1.085(0.75),1.232(0.38),1.357(0.72),1.368(0.31),1.825(0.35),1.956(1.60),2.081(4.26),2.098(4.30),2.157(7.33),2.338(0.36),2.387(0.36),2.615(0.42),3.703(3.89),7.297(3.26),7.410(2.92),7.473(11.97),7.488(16.00),7.555(7.89),7.559(7.36),7.570(5.57),7.573(5.29),8.792(4.04).
5-[({6-溴-3-甲基-2-[(2 H 8)吡咯啶-1-基]喹啉-4-基}羰基)胺基]-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(20mg,31μmol,對映異構物2,實施例291A)在二氯甲烷(1.0ml)的溶液中加入TFA(52μl,682μmol),將混合物在室溫下靜置24小時。然後濃縮混合物並重複加入二氯甲烷,再次濃縮混合物。通過製備型HPLC(方法11)純化殘餘物。將合併的目標級分濃縮,並將殘餘物冷凍乾燥。獲得7mg(100%純度,理論值的40%)標題化合物。
LC-MS(方法1):Rt=1.43min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.023(0.78),0.841(0.28),0.853(0.58),0.864(0.25),1.232(2.98),1.824(0.24),1.965(1.80),2.078(2.77),2.090(3.00),2.104(4.61),2.126(5.66),2.136(7.73),2.149(8.42),2.158(9.21),2.338(0.40),2.387(0.34),2.426(0.43),2.478(0.57),2.615(0.40),2.655(0.45),3.507(0.69),3.709(3.84),6.739(0.25),7.302(3.16),7.410(2.83),7.474(11.76),7.489(16.00),7.556(7.66),7.560(7.21),7.571(5.50),7.575(5.26),8.791(4.57),12.136(0.40).
如實施例291A中所述,從(-)-5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-(2-氯-3,6-二氟苯基)戊酸三級丁酯(241mg,400μmol,實施例49A)開始,直接獲得標題化合物(不分離相應的三級丁酯)作為級分1(55mg,100%純度,理論值的23%)。
[α]D 20=-35.2°,589nm,c=0.34g/100ml,甲醇
LC-MS(方法1):Rt=1.40min;MS(ESIpos):m/z=588/590[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.071(0.17),1.231(0.19),1.357(0.26),1.825(0.27),1.964(1.63),2.076(2.62),2.099(4.96),2.118(4.75),2.130(5.92),2.153(8.09),2.339(0.43),2.387(0.35),2.615(0.33),3.708(3.65),7.300(3.01),7.414(2.67),7.474(11.71),7.489(16.00),7.556(7.50),7.560(7.17),7.571(5.41),7.574(5.25),8.790(4.30).
為了準備實驗,三批不同的(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(對映異構物1,總量1.386g,2.54mmol,實施例34)各自溶解在幾毫升甲醇中,將溶液合併,並且在大多數甲醇在旋轉蒸發器上再次除去。隨後,將殘餘物溶於二烷(14ml)中,並在室溫下滴加4M氯化氫的二烷溶液(3.2ml,12.72mmol)。將混合物在室溫下靜置1小時。此後,濾出形成的固體並在減壓下乾燥。因為根據LC-MS,由於用於實驗製備的甲醇,也形成了對應於標題化合物的甲酯,首先通過製備型HPLC(方法32)純化殘餘物。將合併的目標級分濃縮,並將殘餘物在減壓下乾燥。隨後將殘餘物(960mg)溶於二噁烷(10ml)中,在室溫下,逐漸加入4M氯化氫的二噁烷溶液(3.2ml,12.72mmol),並將混合物靜置於室溫2小時。隨後,濾出形成的固體,並將殘餘物從乙腈/水中冷凍乾燥。獲得603mg(100%純度,理論值的41%)標題化合物。
[α]D 20=-17.0°,589nm,c=0.42g/100ml,甲醇
LC-MS(方法1):Rt=1.42min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:0.006(0.51),1.699(0.22),1.797(0.88),1.808(1.38),1.825(2.64),1.842(2.97),1.859(1.76),1.875(0.81),1.971(16.00),2.016(1.20),2.054(6.83),2.075(5.25),2.084(4.69),2.092(3.14),2.099(3.96),2.123(3.41),2.136(3.36),2.155(1.81),2.167(1.04),2.258(3.04),2.457(0.43),2.637(0.27),3.391(1.40),3.567(9.59),3.589(5.02),3.883(6.69),7.192(0.27),7.278(3.55),7.293(2.99),7.374(3.48),7.429(0.87),7.443(9.54),7.445(8.90),7.459(7.85),7.462(7.11),7.492(5.89),7.507(4.80),7.804(2.56),7.821(2.63),8.192(0.78),8.921(3.10).
氬氣及室溫下緩慢滴加4M氯化氫的二烷溶液(460μl,1.89mmol)至(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(200mg,367μmol,對映異構物2,實施例35)在二烷(2ml)的溶液中。將混合物在室溫下攪拌16小時。隨後,濾出形成的固體並在減壓下乾燥。獲得195mg(100%純度,理論值的89%)標題化合物。
離子色譜法(方法34):氯化物質量比例:9.9重量%(1.7當量)。
LC-MS(方法1):Rt=1.49min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.061(0.36),-0.007(1.38),0.007(0.75),1.085(0.25),1.368(1.02),1.799(0.66),1.809(1.07),1.827(2.10),1.843(2.36),1.861(1.33),1.877(0.54),1.911(0.37),1.989(13.81),2.055(5.55),2.076(4.32),2.085(3.94),2.093(2.67),2.099(2.82),2.123(2.59),2.136(2.33),2.155(1.09),2.167(0.49),2.256(2.66),2.347(2.35),2.479(0.87),2.639(0.16),3.567(16.00),3.586(1.74),3.950(5.56),5.329(0.39),7.281(2.32),7.373(2.16),7.444(8.14),7.447(7.62),7.460(6.83),7.463(6.17),7.495(3.99),7.510(3.54),7.850 (3.33),7.868(3.51),8.371(2.22),8.387(2.08),8.972(2.46),8.984(4.49),8.995(2.33).
然後將一部分標題化合物從乙腈/水中冷凍乾燥並再次分析:離子色譜法(方法34):氯化物質量比例:4.6重量%(0.8當量)。
LC-MS(方法1):Rt=1.47min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.061(0.46),-0.007(0.68),0.007(0.49),1.086(0.47),1.143(0.19),1.368(1.75),1.795(0.91),1.806(1.50),1.824(2.91),1.840(3.33),1.858(1.93),1.874(0.82),1.962(16.00),2.015(1.18),2.053(7.92),2.074(5.96),2.082(5.25),2.091(3.40),2.098(4.54),2.118(3.35),2.123(3.80),2.135(3.95),2.153(2.00),2.165(1.04),2.248(3.53),2.363(0.78),2.637(0.43),3.679(5.00),3.839(5.70),7.277(4.13),7.292(3.05),7.361(2.86),7.375(4.27),7.389(2.53),7.442(11.82),7.445(10.93),7.458(9.93),7.461(8.79),7.491(6.84),7.506(5.46),7.786(2.10),8.063(0.54),8.875(2.69).
在室溫下將4%氯化氫的二烷溶液(7.6ml,30.37mmol)緩慢滴加至(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(3.31g,6.08mmol,對映異構物2,實施例35)在二烷(33ml)的溶液中,將混合物在室溫下靜置4小時。隨後,濾出形成的固體,溶於水/乙腈中並冷凍乾燥,得到第一種凍乾物。將濾液在室溫下放置過夜,濾出形成過夜的沉澱物。將得到的沉澱物與上述凍乾物合併,將混合物溶於水/乙腈中並冷凍乾燥,得到第二種凍乾物。獲得3.21g(100%純度,理論值的91%,ee 99%)標題化合物。
離子色譜法(方法34):氯化物質量比例:4.8%(重量)(0.9當量)。
LC-MS(方法1):Rt=1.47min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.005(0.73),1.799(0.90),1.808(1.47),1.823(3.13),1.837(3.31),1.851(1.89),1.865(0.77),1.974(16.00),2.021(1.18),2.045(3.16),2.056(7.95),2.074(5.59),2.081(4.92),2.088(2.71),2.097(3.16),2.119(3.61),2.133(3.29),2.148(1.72),2.159(0.86),2.235(3.75),2.335(3.01),3.389(0.71),3.567(3.96),3.589(3.99),3.897(5.37),7.286(3.18),7.376(2.64), 7.448(10.89),7.449(10.57),7.461(9.38),7.463(8.90),7.500(5.06),7.512(4.82),7.824(2.61),7.834(2.66),8.266(0.69),8.970(3.38).
在室溫下將4%氯化氫的二烷溶液(100ml,400mmol)緩慢滴加至(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸三級丁酯(6.50g,10.82mmol,對映異構物1,實施例292A)在二烷(70ml)的溶液中,將混合物在室溫下攪拌6小時。逐滴加入另外的4M氯化氫的二噁烷溶液(40ml,40mmol),並將混合物在室溫下再攪拌16小時。因為根據HPLC,仍然存在1-2%的反應物,故用超音波處理混合物1小時。隨後,將二異丙基醚(300ml)逐漸加入混合物中,濾出存在的固體,依次用三份二異丙醚(每次50ml)洗滌,然後在60℃下減壓乾燥。獲得6.18g(100%純度,理論值的89%)標題化合物。
LC-MS(方法1):Rt=1.42min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]:-0.007(1.43),0.007(0.81),1.030(1.11),1.042(1.11),1.086(0.20),1.368(1.75),1.595(0.60),1.797(0.87),1.808(1.42),1.825(2.76),1.842(3.11),1.859(1.78),1.877(0.74),1.971(16.00),2.016(1.24),2.047(3.15),2.055(7.39),2.076(5.65),2.084(5.03),2.093(3.33),2.099(4.13),2.120(3.19),2.124(3.52),2.136(3.47),2.155(1.73),2.167(0.87),2.251(3.11),2.457(0.39),2.637(0.21),3.567(3.96),3.589(2.60),3.682(3.45),7.278(3.61),7.291(2.86),7.375(3.60),7.443(10.86),7.446(9.79),7.459(9.09),7.462(7.90),7.493(6.15),7.508(5.00),7.821(2.31),8.219(0.58),8.924(2.84).
在室溫下(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(125mg,229mol,對映異構物1,實施例34)在水(10ml)的懸浮液中加入1M氫氧化鈉水溶液(229μl,229μmol)。用超音波處理混合物並與THF(2ml)混合,隨後形成溶液。在室溫下攪拌1小時後,濃縮混合物,並將殘餘物從乙腈/水中冷凍乾燥。獲得110mg(98%純度,理論值的83%)標題化合物。
離子色譜法(方法34):鈉的質量比例:3.5重量%(0.9當量)
[α]D 20=-10.6°,589nm,c=0.36g/100ml,甲醇
LC-MS(方法1):Rt=1.45min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.355(2.06),1.695(1.15),1.707(2.06),1.729(4.57),1.738(3.79),1.753(5.65),1.768(3.60),1.782(2.15),1.807(3.30),1.833(4.04),1.872(16.00),1.916(2.99),1.933(3.03),2.178(13.86),2.256(0.54),2.267(0.63),2.710(0.42),3.465(2.14),3.480(3.21),3.497(2.73),3.514(1.48),3.572(12.27),3.618(3.97),7.215(2.22),7.233(5.04),7.251(3.56),7.325(2.98),7.343(5.56),7.361(3.60),7.407(8.57),7.426(8.75),7.438(4.80),7.462(6.70),7.484(11.36),7.536(6.50),7.541(5.90),7.558(3.81),7.564(3.51),9.051(2.89).
在室溫下(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(125mg,229μmol,對映異構物2,實施例35)在水(10ml)的懸浮 液中加入1M氫氧化鈉水溶液(229μl,229μmol)。用超音波處理混合物並與THF(2ml)混合,隨後形成溶液。在室溫下攪拌1小時後,濃縮混合物,並將殘餘物從乙腈/水中冷凍乾燥。獲得129mg(100%純度,99%理論值,ee>99%)標題化合物。
離子色譜法(方法34):鈉的質量比例:4.7重量%(1.2當量)
[α]D 20=+11.4°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=1.41min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.354(3.55),1.366(1.65),1.701(1.24),1.710(2.34),1.731(5.80),1.743(5.24),1.748(5.40),1.758(4.03),1.770(2.04),1.823(4.25),1.832(3.64),1.841(6.72),1.867(15.69),1.907(3.02),1.925(3.71),1.940(2.01),2.163(6.98),2.245(0.69),2.268(0.64),3.489(4.06),3.567(10.12),3.600(5.64),3.611(4.58),7.223(2.64),7.236(5.49),7.248(3.68),7.332(3.31),7.345(5.80),7.357(3.71),7.413(10.88),7.426(16.00),7.439(6.16),7.466(11.09),7.481(15.50),7.542(7.81),7.545(7.58),7.556(5.65),7.560(5.53),8.942(3.81),8.952(7.12),8.961(3.87).
在室溫下(-)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(125mg,229μmol,對映異構物1,實施例34)在水(10ml)的懸浮液中加入1M的叔丁醇鉀溶液(229μl,229μmol)。用超音波處理混合物並與THF(2ml)混合,隨後形成溶液。在室溫下攪拌1小時後,濃縮混合物, 並將殘餘物從乙腈/水中冷凍乾燥。獲得110mg(98%純度,理論值的81%)標題化合物。
離子色譜法(方法34):鈉的質量比例:6.9重量%(1.0當量)
[α]D 20=-11.1°,589nm,c=0.50g/100ml,甲醇
LC-MS(方法1):Rt=1.45min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.299(0.67),1.612(0.45),1.694(2.98),1.717(3.05),1.730(2.65),1.758(2.16),1.782(2.10),1.794(1.32),1.863(12.88),1.947(0.70),2.184(16.00),2.227(1.36),2.237(1.34),2.709(0.40),3.552(11.72),3.597(2.67),3.617(2.06),3.650(0.84),7.054(0.49),7.137(0.50),7.181(2.23),7.200(1.66),7.223(0.61),7.289(1.71),7.307(3.07),7.325(1.86),7.361(2.90),7.381(2.64),7.403(4.69),7.420(5.12),7.442(3.90),7.482(2.93),7.503(2.19).
在室溫下(+)-5-({[6-溴-3-甲基-2-(吡咯啶-1-基)喹啉-4-基]羰基}胺基)-4-(2-氯苯基)戊酸(125mg,229μmol,對映異構物2,實施例35)在水(10ml)的懸浮液中加入1M的叔丁醇鉀溶液(229μl,229μmol)。用超音波處理混合物並與THF(2ml)混合,隨後形成溶液。在室溫下攪拌1小時後,濃縮混合物,並將殘餘物從乙腈/水中冷凍乾燥。得到137mg(100%純度,理論值“102%”,ee>99%)標題化合物。
離子色譜法(方法34):鉀的質量比例:5.8重量%(0.9當量)
[α]D 20=+11.3°,589nm,c=0.31g/100ml,甲醇
LC-MS(方法1):Rt=1.41min;MS(ESIpos):m/z=544/546[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.109(1.62),1.354(3.30),1.366(1.60),1.683(1.38),1.692(2.50),1.707(5.61),1.712(5.58),1.724(5.74),1.733(3.59),1.748(1.84),1.758(1.21),1.764(1.24),1.781(4.21),1.790(2.78),1.798(5.09),1.808(3.45),1.825(2.13),1.870(13.58),1.916(2.38),2.182(8.32),2.263(0.72),3.438(2.92),3.450(4.06),3.461(4.99),3.472(4.00),3.574(10.43),7.221(2.77), 7.233(5.99),7.246(3.94),7.330(3.46),7.342(6.22),7.354(3.92),7.410(12.30),7.417(8.36),7.423(11.97),7.469(11.20),7.483(16.00),7.543(7.97),7.546(7.69),7.557(5.73),7.561(5.54),9.146(3.89),9.155(7.29),9.164(3.93).
5-{[(6-溴-2-氯-3-甲基喹啉-4-基)羰基]胺基}-4-2-甲氧基苯基)戊酸(對映異構物1,200mg,85%純度,將336μmol,實施例241A)、3,3-二氟哌啶鹽酸鹽(312mg,1.98mmol)和DIPEA(830μl,4.7mmol)在NMP(1.0ml)的溶液在120℃下攪拌4天。冷卻至室溫後,將反應混合物加入1M鹽酸中並用二氯甲烷萃取。將有機相用硫酸鈉乾燥並濃縮。通過管柱色譜法(Isolera,KP-Sil,溶液液:二氯甲烷/甲醇,梯度:0-40%甲醇)對粗產物進行預純化,並通過製備型HPLC(方法27)再純化。獲得54mg(99%純度,理論值的27%)。
[α]D 20=+6.7°,589nm,c=0.50g/100ml,氯仿.
LC-MS(方法26):Rt=0.80min;MS(ESIpos):m/z=590/592[M+H]+
1H-NMR(400MHz,氯仿-d)δ[ppm]:1.262(0.43),1.953(1.11),1.965(0.97),1.981(0.52),2.025(0.71),2.038(0.82),2.057(1.02),2.072(1.08),2.087(0.84),2.108(0.48),2.116(0.44),2.136(0.57),2.149(0.66),2.170(0.63),2.191(1.16),2.213(7.96),2.287(0.88),2.301(1.65),2.307(1.08),2.321(1.76),2.340(0.84),2.348(0.58),3.147(1.27),3.432(1.19),3.445(0.50),3.459(2.36),3.488(1.21), 3.582(0.42),3.715(0.43),3.744(16.00),3.827(0.57),3.840(0.51),3.850(0.47),3.864(0.42),3.942(0.56),3.957(0.88),3.971(0.57),3.989(0.59),5.786(0.50),5.800(1.00),5.814(0.52),6.853(1.55),6.873(1.58),6.965(0.71),6.967(0.71),6.983(1.56),6.985(1.54),7.001(0.96),7.216(1.85),7.220(1.39),7.224(0.68),7.235(1.67),7.238(1.56),7.259(0.89),7.263(0.94),7.602(0.82),7.607(0.89),7.624(1.77),7.630(2.19),7.649(0.42),7.659(3.62),7.671(2.06),7.676(1.81),7.680(1.92).
本發明化合物的藥理活性可以通過本領域技術人員已知的體外和體內研究來證明。下面的應用實施例描述了本發明化合物的生物作用,而不是將本發明限制於這些實施例。
CRTH2 在T輔助細胞2型細胞上表現之化學引誘物受體-同源分子
DMEM Dulbecco修改之Eagle培養基
DMSO 二甲亞碸
DP PGD2受體
EC50 半-最大有效濃度
em. 放射
EP PGE2受體
ex. 激發
來自 公司(來源)
FCS 胎牛血清
FP PGF2α受體
HEPES 2-[4-(2-羥乙基)哌-1-基]乙烷磺酸
IC50 半-最大抑制濃度
IP PGI2受體
lit. 文獻(參考資料)
MES 2-(N-嗎福啉)乙烷磺酸
Pen/Strep 青黴素/鏈黴素
PGD2 前列腺素D2
PGE2 前列腺素E2
PGF2α 前列腺素F2α
PGI2 前列腺素I2
TC 組織培養
TP 凝血脂素A2受體
Tris 三(羥基甲基)胺基甲烷
v/v 體積與體積比(溶液)
w/w 重量與重量比(溶液)
為了表徵關於FP拮抗作用的測試物質,使用表現FP的CHEM1細胞(Millipore,HTS093C)中PGF2α誘導的鈣通量。
30μl全培養基中的3000個細胞[DMEM F12,10%FCS,1.35mM丙酮酸鈉,20mM HEPES,4mM GlutaMAXTM,2%碳酸氫鈉,1%青黴素/鏈黴素,1%100x非必需胺基酸]於384多滴定盤(來自Greiner,TC板,黑色,帶有透明底部)每孔播種,並在33℃,5%CO2下培育24小時。在測量之前,將培養基替換為30μl Fluo-8 AM裝載緩衝液[無鈣Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4),2mM CaCl2,6.3mM丙磺舒,5μMFluo-8AM,0.0112%Pluronic®],並在37℃,5%CO2下培育30分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋倍數3.16),並使用無鈣Tyrode,2mM CaCl2,0.002%SmartBlock(來自CANDOR Bioscience GmbH)預先稀釋1:50。將10μl預稀釋的物質溶液加入到富含Fluo-8的細胞中,並在37℃,5%CO2下培育10分鐘。通過加入40μl在無鈣Tyrode、2mM CaCl2、0.002%SmartBlock中之2nM(終濃度)PGF2α激活FP受體,並通過在螢光測量儀器(FLIPR Tetra,Molecular Devices)中測量ex.470nm/em.525nm,持續120秒的螢光來測定鈣通量。
下表1列出了本發明個別實施例之此測定的IC50值(一些作為來自多個獨立個別測定的平均值):
對於FP受體結合試驗,使用在改良MES緩衝液(pH6.0)中於HEK293細胞中表現的的人重組前列腺素類FP受體。該測試在商業上進行(在Eurofins Panlabs,目錄號268510)。將80μg膜與1nM[3H]-PGF2α在25℃培育60分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在1μM氯前列醇存在下測定非特異性結合。將膜過濾,洗滌然後分析以確定[3H]-PGF2α的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Abramovitz et al.,J.Biol.Chem.1994,269(4):2632]。
對於此試驗,使用改良Tris-HCl緩衝液(pH7.4)中在CHO-K1細胞中表現的的人重組前列腺素類CRTH2受體。此測試在商業上進行(在Eurofins Panlabs,目錄號268030)。將4μg膜與1nM[3H]-PGD2在25℃下培育120分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在1μM PPD2存在下測定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-PGD2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Sugimoto et al.,J.Pharmacol.Exp.Ther.2003,305(1):347]。
於此測試,使用在HEPES緩衝液(pH7.4)中的Chem-1細胞中表現的修飾的人重組前列腺素類DP受體。此測試在商業上進行(在Eurofins Panlabs,目錄# 268060)。將10μg膜與2nM[3H]-PGD2在25℃培育120分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在1μM PPD2存在下確定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-PGD2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Wright et al.,Br.J.Pharmacol.1998,123(7):1317;Sharif et al.,Br.J.Pharmacol.2000,131(6):1025]。
對於該測試,使用在MES緩衝液(pH6.0)中的HEK293細胞中表現的改良人重組前列腺素EP1受體。該測試在商業上進行(在Eurofins Panlabs,目錄號268110)。將14μg膜與1nM[3H]-PGE2在25℃下培育60分鐘。膜蛋白的 量可以隨批次而變化,並且如果需要可以調整。在10μM PGE2存在下測定非特異性結合。將膜過濾,洗滌,然後分析,以確定[3H]-PGE2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Abramovitz et al.,Biochim.Biophys.Acta 2000,1483(2):285;Funk et al.,J.Biol.Chem.1993,268(35):26767]。
對於此測試,使用在改良MES/KOH緩衝液(pH6.0)中的HEK293細胞中表現的人重組前列腺素EP2受體。此測試是在商業上進行的(在Eurofins Panlabs,目錄# 268200)。將25mg/ml的膜與4nM[3H]-PGE2在25℃下培育120分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在10μM PGE2存在下測定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-PGE2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Bastien et al.,J.Biol.Chem.1994,269(16):11873;Boie et al.,Eur.J.Pharmacol.1997,340(2-3):227]。
對於此測試,使用在改良MES緩衝液(pH 6.0)中之HEK293細胞中表現的人重組前列腺素EP3受體。此測試在商業上進行(在Eurofins Panlabs,目錄號268310)。將3μg膜與0.5nM[3H]-PGE2在25℃培育120分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在10μM PGE2存在下測定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-PGE2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Schmidt et al.,Eur.J.Biochem.1995,228(1):23]。
對於此測試,使用在改良MES緩衝液(pH 6.0)中Chem-1細胞中表現的人重組前列腺素EP4受體。此測試在商業上進行(在Eurofins Panlabs,目錄號268420)。將3μg膜與1nM[3H]-PGE2在25℃培育120分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在10μM PGE2存在下測定非特異性結合。將膜過濾,洗滌,然後分析,以確定[3H]-PGE2的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit。: Davis等,Br。J.Pharmacol。2000,130(8):1919]。
對於此測試,使用在改良HEPES緩衝液(pH6.0)中於HEK293細胞中表現的人重組前列腺素類IP受體。此測試在商業上進行(在Eurofins Panlabs,目錄# 268600)。將15μg膜與5nM[3H]-伊洛前列素在25℃下培育60分鐘。膜蛋白的量可以隨批次而變化,並且如果需要可以調整。在10μM伊洛前列素存在下確定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-伊洛前列素的特異性結合。測試物質在10μM濃度下的抑制活性或以劑量-反應曲線的形式測試[lit.:Armstrong et al.,Br.J.Pharmacol.1989,97(3):657;Boie et al.,J.Biol.Chem.1994,269(16):12173]。
對於此測試,使用改良Tris/HCl緩衝液(pH7.4)中在HEK-293 EBNA細胞中表現的人重組前列腺素類TP受體。此測試在商業上進行(在Eurofins Panlabs,目錄號285510)。將18.4μg膜與5nM[3H]-SQ-29 548在25℃下固定30分鐘。膜片蛋白質的量可以因批次而異,並且如果需要可以調整。在1μM SQ-29 548存在下測定非特異性結合。將膜過濾,洗滌,然後分析以確定[3H]-SQ-29 548的特異性結合。物質的抑制活性以濃度為10μM或以劑量-反應曲線的形式測試[lit.:Saussy Jr.et al.,J.Biol.Chem.1986,261:3025;Hedberg et al.,J.Pharmacol.Exp.Ther.1988,245:786]。
為了表徵關於DP激動和拮抗作用的測試物質,使用表現DP的CHEM1細胞(Millipore,HTS091C)中經PGD2誘導的鈣通量:在384多滴定盤(來自Greiner,TC板,黑色,底色清澈)的每個孔中播種25μl全培養基[DMEM,4.5g/1葡萄糖,10%熱滅活FCS,1%100x非必需胺基酸,10mM HEPES,0.25mg/ml遺傳黴素(G418),100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR Calcium Assay,Molecular Devices),並在37℃/5%CO2下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如,使用 無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。對於DP激動作用的測量,在螢光測量儀器(FLIPR Tetra,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,並通過測量ex.470nm/em.525nm持續120秒的螢光來測定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量DP拮抗作用,通過加入例如無鈣Tyrode/2mM CaCl2中20μl×76nM(2×EC50,終濃度)PGD2,在DPIPRTetra®中激活DP受體,以及,和通過測量ex.470nm/em.525nm持續120秒的螢光來確定鈣通量。[lit.:T.Matsuoka et al.(2000)Science 287:2013-2017;S.Narumiya and G.A.Fitzgerald(2001)J.Clin.Invest.108:25-30]。
為了表徵關於EP1激動和拮抗作用的測試物質,使用PGE2誘導的表現EP1的CHEM1細胞(Millipore,HTS099C)中的鈣通量:在384多滴定盤(來自Greiner,TC板,黑色,底色清澈)的每個孔中播種25μl全培養基[DMEM,4.5g/1葡萄糖,10%熱滅活FCS,1%100x非必需胺基酸,10mM HEPES,0.25mg/ml遺傳黴素(G418),100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如,使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。為了測量EP1激動作用,在螢光測量儀器(FLIPRTetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,並通過測量ex.470nm/em.525nm持續120秒的螢光來測定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量EP1拮抗作用,通過加入,例如20μl無鈣的Tyrode/2mM CaCl2中的~2nM(2×EC50,終濃度)PGE2,使EP1受體在FLIPRTetra®中活化,和通過測量ex.470nm/em.525nm處持續120秒的螢光來確定鈣通量。[lit.:Y.Matsuoka et al.(2005)Proc.Natl.Acad.Sci.USA 102:16066-16071;S.Narumiya and G.A.Fitzgerald(2001)J.Clin. Invest.108:25-30;K.Watanabe et al.(1999)Cancer Res.59:5093-5096]。
為了表徵EP2激動和拮抗作用的測試物質,使用表現EP2的CHEM9細胞(Millipore,HTS185C)中經PGE2誘導的鈣通量:在384多滴定盤(來自Greiner,TC盤,黑色,透明底部)的每個孔中播種在25μl培養基[DMEM,4.5g/1葡萄糖,4mM谷胺醯胺,10%熱滅活FCS,1%100x非必需胺基酸,10mM HEPES,100U/ml青黴素和鏈黴素]中的3000個細胞,在37℃/5%CO2培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如,使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。為了測量EP2激動作用,在螢光測量儀器(FLIPRTetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,通過測量ex.470nm/em.525nm持續120秒的螢光來測定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量EP2拮抗作用,通過加入在例如無鈣的Tyrode/2mM CaCl2中之20μl的~22nM(2×EC50,終濃度)PGE2,使EP2受體在FLIPRTetra®中活化,和通過測量ex.470nm/em.525nm處持續120秒的螢光來確定鈣通量。[lit.:C.R.Kennedy et al.(1999)Nat.Med.5:217-220;S.Narumiya and G.A.Fitzgerald(2001)J.Clin.Invest.108:25-30;N.Yang et al.(2003)J.Clin.Invest.111:727-735].
為了表徵EP3激動劑和拮抗劑的測試物質,使用EP3(剪接變體6)-表現CHEM1細胞(Millipore,HTS092C)中經PGE2誘導的鈣通量:在384多滴定盤(來自Greiner,TC板,黑色,底部清澈)的每個孔中播種在25μl培養基[DMEM,4.5g/1葡萄糖,4mM谷胺醯胺,10%熱滅活FCS,1%100x非必需胺基酸,10mM HEPES,100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2 下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如,使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。為了測量EP3激動作用,在螢光測量儀器(FLIPRTetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,並通過測量ex 470nm/em 525nm持續120秒的螢光來確定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量EP3拮抗作用,通過加入例如無鈣的Tyrode/2mM CaCl2中20μl的~2nM(2×EC50,終濃度)PGE2,使EP3受體在FLIPRTetra®中活化,和通過測量ex 470nm/em 525nm持續120秒的螢光來確定鈣通量。[lit.:M.Kotani et al.(1995)Mol.Pharmacol.48:869-879;M.Kotani et al.(1997)Genomics 40:425-434;T.Kunikata et al.(2005)Nat.Immunol.6:524-531;S.Narumiya and G.A.Fitzgerald(2001)J.Clin.Imvest.108:25-30;F.Ushikubi et al.(1998)Nature 395:281-284].
為了表徵EP4激動和拮抗作用的測試物質,使用了表現EP4的CHEM1細胞(Millipore,HTS142C)中的PGE2誘導的鈣通量:在384多滴定盤(來自Greiner,TC盤,黑色,底部清澈)的每個孔中播種在25μl培養基[DMEM,4.5g/1]葡萄糖,4mM谷胺醯胺,10%熱滅活的FCS,1%100x非必需胺基酸,10mM HEPES,100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。為了測量EP4激動作用,在螢光測量儀器(FLIPRTetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,通過測量ex 470nm/em 525nm持續120秒的螢光來測定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量EP4拮抗作用,在實施例中加入20μl 例如無鈣Tyrode/2mM CaCl2中~26nM(2×EC50,終濃度)PGE2,在FLIPRTetra®中激活EP4受體,以及通過測量ex 470nm/em 525nm處持續120秒的螢光來確定鈣通量。[lit.:S.Narumiya and G.A.Fitzgerald(2001)J.Clin.Invest.108:25-30;M.Nguyen et al.(1997)Nature 390:78-81;K.Yoshida et al.(2002)Proc.Natl.Acad.Sci.USA 99:4580-4585]。
為了表徵關於IP激動和拮抗作用的測試物質,使用表現IP的CHEM1細胞(Millipore,HTS131C)中經伊洛前列素(iloprost)誘導的的鈣通量:在384多滴定盤(來自Greiner,TC盤,黑色,底部清澈)的每個孔中播種在25μl培養基[DMEM,4.5g/1葡萄糖,4mM谷胺醯胺,10%熱滅活FCS,1%100x非必需胺基酸,10mM HEPES,100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2下培育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl 2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。對於IP激動作用的測量,在螢光測量儀器(FLIPR Tetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,並通過測量ex 470nm/em 525nm持續120秒的螢光來確定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量IP拮抗作用,通過加入20μl例如無鈣Tyrode/2mM CaCl2中~106nM(2×EC50,終濃度)伊洛前列素,在IPIP拮抗劑中激活IP受體,以及通過測量ex 470nm/em 525nm持續120秒的螢光來確定鈣通量。[lit.:S.Narumiya et al.(1999)Physiol.Rev.79:1193-1226;T.Murata et al.(1997)Nature 388:678-682;Y.Cheng et al.(2002)Science 296:539-541;C.H.Xiao et al.(2001)Circulation 104:2210-2215;G.A.Fitzgerald(2004)N.Engl.J.Med.351:1709-1711]。
為了表徵TP激動和拮抗作用的測試物質,使用U46619誘導的TP表達CHEM1細胞(Millipore,HTS081C)中的鈣通量:在384多滴定盤板(來自 Greiner,TC盤,黑色,底部清澈)的每個孔中播種在25μl平板接種(plating)培養基[DMEM,10%熱滅活FCS 1%100x非必需胺基酸,10mM HEPES,0.25mg/ml遺傳黴素(G418),100U/ml青黴素和鏈黴素]中的3000個細胞並在37℃/5%CO2下培育24小時。在測量之前,將培養基替換為30μl鈣染料裝載緩衝液(FLIPR鈣試驗,Molecular Devices),並在37℃/5%CO2下培孵育60分鐘。測試物質在DMSO中以各種濃度製備,供劑量-反應曲線使用(起始濃度10mM,稀釋因子3.16)並預先稀釋1:50,例如使用無鈣的Tyrode(130mM NaCl,5mM KCl,20mM HEPES,1mM MgCl2,4.8mM NaHCO3,pH 7.4)/2mM CaCl2。對於TP激動作用的測量,在螢光測量儀器(FLIPR Tetra®,Molecular Devices)中,將10μl預稀釋的物質溶液加入到含鈣染料的細胞中,並通過測量ex 470nm/em 525nm持續120秒的螢光來測定鈣通量。此後,將細胞在37℃/5%CO2下培育10分鐘。為了測量TP拮抗作用,通過加入20μl例如無鈣Tyrode/2mM CaCl2中~88nM(2×EC50,終濃度)U46619,在TPIPRTetra®中激活TP受體,以及通過測量ex 470nm/em 525nm持續120秒的螢光來確定鈣通量。[lit.:S.Ali et al.(1993)J.Biol.Chem.268:17397-17403;K.Hanasaki et al.(1989)Biochem.Pharmacol.38:2967-2976;M.Hirata et al.(1991)Nature 349:617-620]。
博萊黴素誘導的小鼠或大鼠肺纖維化是廣泛使用的肺纖維化動物模型。博來黴素是一種糖肽類抗生素,用於腫瘤學治療睾丸腫瘤和霍奇金淋巴瘤和非霍奇金淋巴瘤。它被腎臟消除,具有約3小時的半衰期,並且作為細胞增殖抑制劑,影響分裂週期的各個階段[Lazo等,Cancer Chemother.Biol.Response Modif.15,44-50(1994)]。它的抗腫瘤作用是基於對DNA的氧化損傷作用[Hay等人,Arch.Toxicol.65,81-94(1991)]。當暴露於博來黴素時,肺組織處於特別的風險,因為它僅含有少量的半胱胺酸水解酶,在其他組織中,這導致博來黴素的失活化。給予博來黴素後,動物患有急性呼吸窘迫綜合徵(ARDS),隨後發展為肺纖維化。
博來黴素的給藥可以通過單次或重複氣管內、吸入、靜脈內或腹膜內給藥。用測試物質(藉由管飼法、藉由添加到飼料或飲用水中、使用滲透性微型泵、 藉由皮下或腹膜內注射或藉由吸入)治療動物在第一次給予博來黴素的當天或治療3-14天後開始並持續2-6週。在研究結束時,進行支氣管-肺泡灌洗以確定細胞含量和促炎和促纖維化標記以及肺功能的測量和肺纖維化的組織學評估。
DQ12石英誘導的小鼠或大鼠肺纖維化是一種廣泛使用的肺纖維化動物模型[Shimbori等人,Exp.Lung Res.36,292-301(2010)]。DQ12石英是由於破碎或研磨而具有高活性之石英。在小鼠和大鼠中,氣管內或吸入給予DQ12石英導致肺泡蛋白沉積症,然後是間質性肺纖維化。動物接受單次或重複氣管內或吸入滴注DQ12石英。用測試物質(藉由管飼法、藉由添加到飼料或飲用水中、使用滲透性微型泵、藉由皮下或腹膜內注射或藉由吸入)治療動物係在第一次矽酸鹽滴注當天或治療3-14天之後開始,延續3-12週。在研究結束時,進行支氣管-肺泡灌洗以確定細胞含量和促炎和促纖維化標記以及肺功能的測量和肺纖維化的組織學評估。
在小鼠和大鼠中,氣管內給予DQ12石英導致肺部炎症[Shimbori等,Exp.Lung Res.36,292-301(2010)]。在滴注DQ12石英的那天或一天后,用測試物質處理動物24小時至7天(通過管飼、通過添加到飼料或飲用水中、使用滲透微型泵、通過皮下或腹膜內注射或吸入)。在實驗結束時,進行支氣管肺泡灌洗以確定細胞含量以及促炎和促纖維化標記。
將60隻C57BL/6J小鼠(Charles River,雄性,8週齡)隨機分組並分成4組(每組15隻小鼠)。第1組用作未治療的健康對照組,而第2-4組用作患有肝纖維化的小鼠。在整個研究期間,通過腹膜內註射50μlCCl4/橄欖油懸浮液(CCl4+橄欖油,1+9v/v)每週三次(週一,週三和周五)誘導肝纖維化。CCl4是用於觸發毒性誘導的肝纖維化的最古老和最廣泛使用的物質(Starkel和Leclercq,Best Pract.Res.Clin.Gastroenterol. 2011,25,319-333)。第2組的CCl4處理的小鼠用作疾病對照組並且沒有接受任何進一步的治療,而第3組的CCl4處理的小鼠最初用載劑處理,因此用作載劑對照組。第4組的CCl4 處理的小鼠用作式(I)化合物處理組。第3組用載劑溶液和第4組用式(I)化合物口服治療在第1天開始,並在兩週的完整研究期間每天(早晨和晚上)繼續兩次。在研究結束時,在麻醉下處死所有動物,並在4%緩衝甲醛溶液中固定取出肝臟用於隨後的組織學處理和分析。為此目的,將所有動物的肝臟樣品包埋在石蠟中,並產生3μm厚的石蠟切片。此後,將所有切片脫石蠟並用Picro-Sirius Red(Waldeck,Germany)染色以確定肝纖維化。Picro-Sirius Red染色是用於組織中膠原蛋白染色和纖維化染色的組織學技術。使用連接到計算機的Carl Zeiss顯微鏡(Axio Observer)掃描Picro-Sirius Red染色的肝臟切片以產生相應的圖像。將這些切片以20倍放大和4.8V的光強度掃描。然後將由此產生的圖像轉換成JPG格式,並通過ImageJ軟件(National Institute of Health,USA)定量紅色染色區域。結果以每單位面積的天狼星(Sirius)紅色報告。
在2週的肝纖維化小鼠研究中,用來自實施例284的化合物治療導致纖維化進展顯著減少(p<0.01;使用Dunnett事後檢驗的雙向ANOVA統計分析,平均值±SD)(見表2)。
小鼠和大鼠中的單側輸尿管阻塞是間質性腎纖維化的廣泛使用的動物模型 (Chevalier等,Kidney Int. 2009,75,1145-1152)。由於尿液的持續積聚,輸尿管的永久性閉塞導致增加的炎性細胞浸潤到間質中,導致腎小管細胞死亡和腎實質的不可逆損失。5至7天后,由於細胞外基質蛋白的沉積增加,出現間質纖維化。將重量為20-22g的成年雄性C57Bl6J小鼠(Charles River Laboratories,Sulzfeld,Germany)用異氟烷麻醉,然後在打開腹腔後結紮輸尿管並在結紮線下切斷。在假手術對照小鼠(SHAM)中,僅打開腹腔,但輸尿管未結紮。在操作後開始用實施例284的化合物(10和30mg/kg口服(po)每天兩次(bid))處理物質組中的動物,並繼續進行另外10天。在UUO後10天,將動物麻醉並通過放血處死。此後,取出腎臟並基於促炎和促纖維化標記的表現以及腎組織的組織學評估來評估腎纖維化。結果顯示在表3和4中。
UUO導致阻塞腎臟中促炎和促纖維化基因(例如:αSMA,膠原蛋白,TGF-β,KC,MCP-1)的基因表現升高。用該物質治療導致SMA、Col1α1、Col4α1、TGF-β和KC之表現呈劑量依賴性降低。Col3α1、CTGF、MCP-1、IL-6和IL1-β的基因表現不受治療的影響。
與SHAM手術的小鼠相比,組織學染色顯示UUO腎中αSMA和膠原(SR/FG)含量升高。用60[mg/kg]物質治療導致αSMA陽性區域顯著減少。阻塞腎臟的膠原蛋白含量不受治療的影響。
將重量為18-20g的成年雌性C57Bl6J小鼠(Charles River Laboratories, Sulzfeld,Germany)在具有異氟烷(3%v/v)的室中麻醉,並用溶解在70μL中的2.5mg結晶DQ12二氧化矽氣管內處理。無菌磷酸鹽緩衝鹽水。未處理的對照組小鼠接受相同體積的磷酸鹽緩衝鹽水。在二氧化矽處理後第10天,用實施例35的化合物(10和30mg/kg口服(po)每天兩次(bid))處理物質組中的動物20天。在吸入二氧化矽後30天,通過腹膜內注射氯胺酮/美托咪定(50mg/kg和0.33mg/kg)並皮下注射Temgesic(0.06mg/kg)麻醉動物並通過放血處死。此後,將氣管插管,並用0.5ml冰冷的磷酸鹽緩衝鹽水將動物的肺灌洗三次。此後,取出肺,稱重並在乾冰中震盪冷凍。在肺組織均質化後,通過HPLC測定羥脯胺酸[Paroni等,Clin.Chem. 1992,38,407-411;管柱:Phenomenex Synergi Hydro RP 4μm 80A,75×4.6mm;梯度:溶析液A:水(6毫升/升三乙胺,3毫升/升乙酸)pH 4.3;溶劑B:乙腈;流速:1.3毫升/分鐘)。數據是每組8-12隻動物的平均值±SEM。使用未配對的Student's t檢驗進行統計分析。P值<0.05被認為是顯著的。結果如表5所示。
與未處理的對照組相比,二氧化矽處理導致羥脯胺酸顯著增加,羥脯胺酸是二氧化矽處理的動物的肺中膠原蛋白積聚和纖維化的標記。用實施例35(10 和30mg/kg口服,一天二次)的化合物治療。與二氧化矽處理的對照組相比,導致處理組中羥脯胺酸形成和纖維化的顯著降低。
在注射後使用von Frey試驗在注射和未注射後爪上以檢查機械性異常性疼痛數次。
機械異常性疼痛用8 Semmes-Weinstein細絲(Stölting©;Wood Dale,IL,USA)通過上下方法測量,具有不同的剛度(0.04;0.07;0.16;0.4;1,0.4,0和8.0g)(Chaplan等,J.Neurosci.Meth.1994,53,56-63)。將完整的雄性ND4小鼠(~30g,每組10隻動物)置於金屬網格表面上的各個丙烯酸室中,並在測試前使其適應其環境至少15分鐘。每根細絲以足夠的力與爪子的下側成直角地按壓,以便引起對爪子的輕微彎曲,並保持約6秒或直到記錄到正響應(爪子快速撤回)。用0.4克長絲開始測試。如果爪子沒有撤回,則使用下一個最強刺激。在爪子撤回的情況下,使用下一個最弱的刺激。重複該過程,直到在回應的初始變化之後獲得多達4個回應(在正面回應之後沒有回應或沒有回應之後的正面回應)。如果在達到最強的細絲後動物沒有反應或者在達到最弱的細絲後動物發生反應,則在該時間點停止測試。使用以下公式計算50%爪子回應閾值:
Xf=使用的最後一個von Frey細絲的值(以對數單位表示)
k=正面/負面回應模式的表列數值(參見Chaplan等,J.Neurosci.Meth. 1994,53,56-63,Annex 1,page 62)
δ=刺激之間的平均差異(以對數單位表示)
對於每個時間點的每個治療組,確定每個爪的測量值(SEM)的平均值和標準偏差。
IPL:intraplantary;PO:口服
為了評估FP拮抗劑對氟前列醇誘導的機械敏感性的鎮痛作用,在注射氟前列醇前2小時和8小時和22小時給予試驗物質。在施用氟前列醇之前和施用後0.5、2,6和24小時檢查同側和對側50%爪反應閾值。
本發明化合物可以如下轉化為藥物製劑:
100mg本發明化合物、50mg乳糖(單水合物)、50mg玉米澱粉(天然)、10mg聚乙烯吡咯烷酮(PVP25)(BASF,Ludwigshafen,Germany)和2mg硬脂酸鎂。
錠劑重量212毫克。直徑8毫米,曲率半徑12毫米。
將本發明化合物、乳糖和澱粉的混合物用5%PVP水溶液(w/w)製粒。將顆粒乾燥,然後與硬脂酸鎂混合5分鐘。使用常規製錠機壓製該混合物(參見上面的錠劑形式)。用於壓製的引導值是15kN的壓力。
1000mg本發明化合物、1000mg乙醇(96%)、400mg Rhodigel(來自FMC,賓夕法尼亞州,美國的黃原膠)和99g水。
10ml口服懸浮劑對應於單劑量的100mg本發明化合物。
Rhodigel懸浮在乙醇中;將本發明化合物加入懸浮液中。在攪拌下加入水。
將混合物攪拌約6小時,直至Rhodigel完全溶脹。
500mg本發明化合物、2.5g聚山梨醇酯和97g聚乙二醇400.20g口服溶液對應於單劑量的100mg本發明化合物。
在攪拌下將本發明化合物懸浮在聚乙二醇和聚山梨醇酯的混合物中。繼續攪拌操作直至本發明化合物的溶解完成。
將本發明化合物以低於飽和溶解度的濃度溶解在生理學上可接受的溶劑(例如等滲鹽水溶液,5%葡萄糖溶液和/或30%PEG 400溶液)中。將溶液進行無菌過濾並分配到無菌和無熱原的注射容器中。
Claims (11)
- 一種通式(I)化合物,
- 如請求項1之式(I)化合物,其中Ar 為苯基,其中苯基可經氟至多四取代,或經以下相同或相異基團至多三取代:氟、氯、甲基、三氟甲基、二氟甲基、甲氧基、二氟甲氧基或三氟甲氧基,Y 為一個鍵結或下式基團# 1-(CH 2) n-# 2其中# 1 為碳原子之附接位點,# 2 為羧基之附接位點,n 為1、2或3,R 1 為溴或乙炔基,R 2、R 3與R 4 分別為氫,R 5 為氯或甲基,及R 6 為-NR 12R 13其中R 12 為氫或甲基,及R 13 為(C 1-C 4)-烷基,其中(C 1-C 4)-烷基可經氟至多三取代,或可經苯基單取代,或為飽和或部份不飽和之5-至7-員單環狀或7-至10-員雙環狀雜環,其係利用氮原子附接,且可能再包含另一個選自N、O與S之群中之相同或相異雜原子作為環組員。其中5-至7-員單環狀與7-至10-員雙環狀雜環可分別經1或2個分別獨立選自下列之群中之取代基取代:甲基、二氟甲基、三氟甲基、乙基、2,2,2-三氟乙基、2,2-二氟乙基、異丙基,並可再經氟至多四取代, R 7A、R 7B、R 8與R 9 分別為氫,及其鹽類、溶劑合物與鹽類之溶劑合物。
- 如請求項1或2之式(I)化合物,其中Ar 為苯基,其中苯基可經以下相同或相異基團至多三取代:氟、氯、甲基、三氟甲基、二氟甲氧基或三氟甲氧基,Y 為下式基團# 1-CH 2CH 2-# 2其中# 1 為碳原子之附接位點,# 2 為羧基之附接位點,R 1 為溴,R 2、R 3、R 4 分別為氫,R 5 為甲基,R 6 為下式基團
- 一種製備如請求項1至3中式(I)化合物之方法,其特徵在於式(II)化合物
- 如請求項1至3中任一項之化合物,用於治療及/或預防疾病。
- 如請求項1至3中任一項之化合物,用於治療和/或預防特發性肺纖維化,肺性高血壓,閉塞性細支氣管炎綜合徵狀,炎性和纖維化皮膚和眼睛疾病以及內臟器官纖維化疾病的方法。
- 一種如請求項1至3中任一項之化合物,其用於製造治療和/或預防特發性肺纖維化,肺性高血壓,閉塞性細支氣管炎綜合徵狀,炎性和纖維化皮膚和眼病以及內臟器官纖維化病症的藥物。
- 一種藥物,其包含如請求項1至3中任一項之化合物與一或多種惰性、無毒之醫藥上適當賦形劑組合。
- 一種藥物,其包含如請求項1至3中任一項之化合物與一或多種選自下列組成之群組的另一活性成分組合:PDE5抑制劑,sGC激活劑,sGC刺激劑,前列環素類似物,IP受體激動劑,內皮素拮抗劑,抑制信號轉導級聯的化合物和吡非尼酮(pirfenidone)。
- 如請求項8或9之藥物,用於治療和/或預防特發性肺纖維化,肺性高血壓,閉塞性細支氣管炎綜合徵狀,炎性和纖維化皮膚和眼睛疾病以及內臟器官的纖維化疾病。
- 一種治療和/或預防人類與動物特發性肺纖維化、肺性高血壓、閉塞性細支氣管炎綜合徵狀、炎性和纖維化皮膚和眼睛疾病以及內臟器官的纖維化疾 病之方法,其藉由投予有效量之至少一種如請求項1至3中任一項之化合物,或如請求項8至10中任一項之藥物實現。
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BR112019021130A2 (pt) | 2020-09-01 |
CA3059954A1 (en) | 2018-10-18 |
EP3609870A1 (de) | 2020-02-19 |
PH12019502315A1 (en) | 2020-07-06 |
CN110709384A (zh) | 2020-01-17 |
EA201992389A1 (ru) | 2020-04-03 |
AU2018251087B2 (en) | 2021-11-18 |
JP7125420B2 (ja) | 2022-08-24 |
US20200157073A1 (en) | 2020-05-21 |
JP2020513026A (ja) | 2020-04-30 |
CO2019011227A2 (es) | 2019-10-21 |
AR111367A1 (es) | 2019-07-03 |
KR20190138825A (ko) | 2019-12-16 |
WO2018189012A1 (de) | 2018-10-18 |
IL269836B (en) | 2022-04-01 |
UY37671A (es) | 2018-11-30 |
PE20191738A1 (es) | 2019-12-12 |
TWI770157B (zh) | 2022-07-11 |
UA125660C2 (uk) | 2022-05-11 |
AU2018251087A1 (en) | 2019-10-31 |
US11149018B2 (en) | 2021-10-19 |
MX2019012152A (es) | 2019-11-21 |
IL269836A (en) | 2019-11-28 |
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