TW202135831A - 含氟化合物、含氟化合物之製備方法及其抗癌醫藥用途 - Google Patents
含氟化合物、含氟化合物之製備方法及其抗癌醫藥用途 Download PDFInfo
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Abstract
本發明提供式II/III含氟化合物及抗癌醫藥用途。
Description
本發明涉及對專利申請PCT/US2016/021581,公開號WO2016145092A1,對應中國申請號2016800150788,公開號CN107530556A所公開的化合物的進一步研發,得到一系列AKR1C3酶活化的DNA烷化劑,屬於癌症治療化合物研發領域。
本申請引用申請人于2019年05月13日申請的中國發明專利申請CN201910392606.7,主題名稱含氟化合物及抗癌醫藥用途;以及申請人於2019年12月20日申請的中國發明專利申請CN201911324466.6,主題名稱含氟化合物及抗癌醫藥用途。
我公司開發的以過表達醛酮還原酶1C3(AKR1C3)為標靶的DNA烷化癌症治療藥物(DNA烷化劑,對應PCT申請號PCT/US2016/021581,公開號WO2016/145092,對應中國申請號2016800150788,公開號CN107530556A)中的化合物均為黃色油狀物。由於這些化合物不是固體,使得在後續的製劑研發上存在以下的困難:
(1) 離純化複雜,成本高。由於為油狀物,無法使用效率高/成本低的重結晶或是打漿純化(slurry),而只能使用柱層析方法進行純化,導致操作複雜,原料藥製備的成本高。
(2) 製劑不方便,穩定性差。由於為油狀物,在轉運/計量過程中都不便於操作,重要的是,對於油狀物無法或不方便進行製劑劑型的開發和多樣化選擇,一般只能開發為凍乾粉針或注射劑的方式進行給藥,給藥方式單一而且成本較高;另外凍乾粉針或注射劑的方式進行給藥對於某些患者而言,依從性不高。
為了解決上述技術問題,本發明基於專利申請PCT申請號PCT/US2016/021581,公開號WO2016/145092,對應中國申請號2016800150788,公開號CN107530556A,名稱為DNA烷化劑中公開的化合物進行了結構改造,並設計合成了一系列的含氟化合物。
為此,本發明將上述專利申請PCT申請號PCT/US2016/021581,公開號WO2016/145092,對應中國申請號2016800150788,公開號CN107530556A公開的內容引入本文。本文中對於定義概念有與上述申請不同或差別的,以本文為准;本文中出現的概念或是定義未有明確定義或是限制的,均遵照上述申請進行定義;其餘本文及上述申請未定義的以有機化學、藥物化學的教科書、手冊等為准。
已經證明,專利申請PCT/US2016/021581、PCT/US2016/025665和PCT/US2016/062114中公開的化合物3424作為國際首創的、高度腫瘤選擇性的小分子靶向治療藥物,在多種臨床前細胞和動物模型中已表現出非常出色的抗癌效果。這些化合物作為醛酮還原酶AKR1C3特異性底物,可僅在AKR1C3高表達的癌細胞內快速有效地還原,從而釋放細胞毒素導致高選擇性的癌細胞殺傷藥效。已經有文獻(文獻1:Richard B.Lock,Kathryn Evans,Raymond Yung,Tara Pritchard,Beverly A.Teicher,JianXin Duan,Yuelong Guo,Stephen W.Erickson,Malcolm A.Smith.The AKR1C3-Activated Prodrug OBI-3424 Exerts ProfoundIn Vivo
Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia(T-ALL);a Pediatric Preclinical Testing Consortiu LCM Study[abstract].In:Proceedings of the AACR-NCI-EORTC International Conference:Molecular Targetsand Cancer Therapeutics;2017 Oct 26-30;Philadelphia,PA.Philadelphia(PA):AACR;Mol Cancer Ther 2018;17(1Suppl):Abstractnr LB-B16;文獻2:Evans K,Duan J,Pritchard T,Jones CD,McDermottL,Gu Z,Toscan CE,El-ZeinN,MayohC,Erickson SW,Guo Y,Meng F,Jung D,Rathi KS,Roberts KG,Mullighan CG,Shia CS,Pearce T,Teicher BA,Smith MA,Lock RB.OBI-3424,a novel AKR1C3-activated prodrug,exhibits potent efficacy against preclinical models of T-ALL.Clin Cancer Res.2019 Apr 23.pii:clin canres.0551.2019.doi:10.1158/1078-0432.CCR-19-0551)等文獻證明AST-3424(OBI-3424)化合物(即2870號化合物的S構型異構體)在I期臨床中顯現出對白血病和肺癌等癌症具有較好的效果。
由於該系列化合物均為油狀物,存在種種不足:儲存、轉運或計量均不便於操作,為此需要開發出常溫下為固體的類似化合物。
研發團隊曾想到使用這樣的解決方法:通過成鹽的方法來將油狀物轉化為固體的鹽。但經過實驗發現,使用無機酸如硫酸/鹽酸等與含氮三元環進行成鹽反應,得不到預期的鹽:試驗證實,上述的CN107530556A公開化合物在酸性條件下,其中的含氮三元環會開環得到開環副產物。經過多次實驗嘗試表明以上的常規方法不可行。
發明團隊根據經驗和實驗結果,創造性地在上述化合物結構中的特別位置(比如硝基苯環和磷酸胺基團間)引入特別的三氟甲基、氟取代的芳基或雜芳基等含氟基團,經過此番改造後,發現所得的化合物均為固體(包括固體以及蠟狀物)。
而且進一步體外實驗證明,這些化合物具有較強的癌細胞體外增殖抑制活性,而且將化合物與AKR1C3抑制劑TH3021合用發現抑制活性減弱,由此證實特定位置引入特定含氟基團後,不僅能使得化合物為固體便於製劑、便於計量、便於儲存,而且依然能得到AKR1C3酶活化的DNA烷化劑。
其中,R1
是C6
-C10
芳基或Z取代的芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、7-15元的稠環或Z取代稠環;
R2
是氫、鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、1-6個碳原子的醚或Z取代的1-6個碳原子的烷氧基、-CONR6
R7
、-SO2
NR6
R7
、-SO2
R6
、-OCOO-R6
、-COOR6
、-NR6
COR7
、-OCOR6
、-NR6
SO2
R7
、-NR6
SO2
NR6
R7
或者R2
和與其所鍵結的R1
基團上的原子一起形成7-15元的稠環或Z取代稠環;
R3
是氫、鹵素、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1
-C6
烷氧基或Z取代的C1
-C6
烷氧基、-CONR6
R7
、-SO2
NR6
R7
、-SO2
R6
、-OCO-R6
、-OCOO-R6
、-COOR6
、-NR6
COR7
,-OCOR6
、-NR6
SO2
R7
;
R4
、R5
各自獨立地是氫、鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1
-C6
烷氧基或Z取代的C1
-C6
烷氧基、-CONR6
R7
、-SO2
NR6
R7
、-SO2
R6
、-OCOO-R6
、-COOR6 、
-NR6
COR6
、-OCOR6
、-NR6
SO2
R7
或者R4
、R5
和與其所鍵結的苯環上的原子一起形成7-15元的稠環或Z取代稠環;
R6
和R7
各自獨立地是氫、氰基或異氰基、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1
-C6
烷氧基或Z取代的C1
-C6
烷氧基,或者R6
、R7
基團與其所鍵結的原子一起形成5-7元雜環基或Z取代5-7元雜環基;
R8
、R10
各自獨立地為氫、氘、芳基或Z取代芳基、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基且必有一個為氫、氘;
R9
為至少具有一個氟原子或硝基取代的取代C6
-C10
芳基、至少具有一個氟原子或硝基取代的取代4-15元雜環、至少具有一個氟原子或硝基取代的取代5-15元雜芳基。
Z取代基為鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1
-C3
烷基或取代烷基、C1
-C3
烷氧基或取代烷氧基、C2
-C3
烯基或取代烯基、C2
-C3
炔基或取代炔基、C3
-C8
環烷基或取代環烷基、芳環、雜環、雜芳環和稠環或取代芳環、雜環、雜芳環和稠環,取代的方式為單取代或偕二取代;
R9
中的取代C6
-C10
芳基、取代4-15元雜環、取代5-15元雜芳基的取代基為鹵素原子、硝基、氰基或異氰基、羥基、胺基、C1
-C3
烷基或烷氧基、烯基、炔基、環烷基或苯環、取代苯環、C1
-C3
烷氧基或鹵原子取代烷氧基。
取代的含義是廣泛的,可以是單取代(在苯環等C原子上只能是一個H被取代),也可以是多取代:包括在某個C原子上取代多個即偕二取代、偕三取代(如偕二氟甲基、三氟甲基)或在一個環上的不同C原子上分別取代(如全氟苯)。
雜環、雜芳基包括三元環、四元環、五元環、六元環、七元環。以下舉例說明。
三元環:環氧乙烷、環氮乙烷、環硫乙烷;
四元環:吖丁啶、惡丁啶、噻丁啶、丁啶;
五元環:吡咯烷、吡咯啉、1-吡咯啉、3-吡咯啉、2-吡咯啉、吡咯、吡唑烷、2-吡唑啉、咪唑、吡唑、呋喃、四氫呋喃、二氫呋喃、四氫噻吩、噻吩、環丁碸、磷雜茂、惡唑、1,2,3-三唑、1,2,4-三唑、1,3,4-噻二唑;
六元環:呱啶、四氫吡喃、四氫噻喃、吡啶、吡喃、噻喃、二氫吡啶、嗎啉、呱嗪、噠嗪、吡嗪、1,3,5-三嗪、1,3,5-三噻烷;
七元環:吖庚烷(氮雜環庚烷)、惡庚烷、噻庚烷、氮雜䓬、氧雜䓬、硫雜䓬。
稠環定義為以上的雜環、雜芳基之間的駢合或者與環烷結構的駢合,駢合可以是通過單鍵的連結或者是共用一個、兩個甚至三個原子的形式(即螺環、稠環或橋環),以下給出一些常見的稠環結構:萘、喹啉、吲哚、異吲哚、異喹啉、噌啉、喹喔啉、聯苯、香豆素、芴、二苯哢喃、哢唑、蒽、氮蒽、噻吩嗪、金剛烷、薁、菲、蒽醌、黃酮、異黃酮。
顯然以上的化合物,其也包括同位素Z取代化合物,典型的Z取代方式為氫鹵素原子H被重氫原子氘D取代。
進一步的,上述提供的化合物:
R1
為苯基或Z取代苯基、六元含氮雜環或Z取代雜環、六元含氮雜芳基或Z取代雜芳基、9-14元的稠環或Z取代稠環;
R2
為氫、鹵素原子、氰基或異氰基、羥基、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元含氮雜環或Z取代含氮雜環、5-15元含氮雜芳基或取代含氮雜芳基、C1
-C6
烷氧基或氟取代的C1
-C6
烷氧基、-CONR6
R7
,-SO2
NR6
R7
、-SO2
R6
、-OCOO-R6
、-COOR6 、
-NR6
COR7
、-OCOR6
、-NR6
SO2
R7
、-NR6
SO2
NR6
R7
;
R6
和R7
各自獨立地是C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1
-C6
烷氧基或氟取代的C1
-C6
烷氧基,或者R6
和R7
基團與其所鍵結的氮原子一起形成5-7元雜環基或Z取代5-7元雜環基。
進一步的,上述提供的化合物:
R1
為苯基或Z取代苯基、六元含氮雜環或Z取代雜環、六元含氮雜芳基或Z取代雜芳基、9-14元的稠環或Z取代稠環;
R2
為氫、鹵素原子、氰基或異氰基、羥基、C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元含氮雜環或Z取代含氮雜環、5-15元含氮雜芳基或取代含氮雜芳基、C1
-C6
烷氧基或氟取代的C1
-C6
烷氧基、-CONR6
R7
、-SO2
R6
、-OCOO-R6
、-COOR6
、-NR6
COR6
、-OCOR6
、-NR6
SO2
R6
,-NR6
SO2
NR6
R7
;
R6
和R7
各自獨立地是C1
-C6
烷基或Z取代烷基、C2
-C6
烯基或Z取代烯基、C2
-C6
炔基或Z取代炔基、C3
-C8
環烷基或Z取代環烷基、C6
-C10
芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1
-C6
烷氧基或氟取代的C1
-C6
烷氧基,或者R6
和R7
基團與其所鍵結的氮原子一起形成5-7元雜環基或Z取代5-7元雜環基。
進一步的,上述提供的化合物:
其中,R1
為苯基、四氫吡喃、四氫噻喃、四氫呋喃、吡啶、呋喃、吡喃、噻喃、噻唑、二氫吡啶、嗎啉、呱嗪、噠嗪、吡嗪、1,3,5-三嗪、萘、奎琳、苯並噻唑、苯並噻喃、苯並呋喃、苯並咪唑、吲哚、咪唑吡啶或Z取代的苯基、呱啶、四氫吡喃、四氫噻喃、四氫呋喃、吡啶、呋喃、吡喃、噻喃、噻唑、二氫吡啶、嗎啉、呱嗪、噠嗪、吡嗪、1,3,5-三嗪、萘、奎琳、苯並噻唑、苯並噻喃、苯並呋喃、苯並咪唑、吲哚、咪唑吡啶;
R2
為-CON(CH3
)2
、-SO2
CH3
、-OCOO-CH3
、-COOCH3
、-NHCOCH3
、-NMeCOCH3
、-NHCOCF3
、-OCOCH3
、-NHSO2
CH3
、-NMeSO2
CH3
、-NHSO2
CF3
、-NMeSO2
CF3
、-CF3
、F、Cl、Me、苯、氟苯、氯苯、-OCF3
、吡啶基、氟代吡啶基、氯代吡啶基、呋喃基、噻喃、噻唑、-CONMePh、C5
-C6
的環烷基或F取代的C5
-C6
的環烷基、、、、、、、、、、、、、、、、。上述的波浪線表示化學鍵,其左邊連接另一個原子,且連接的位置可以是該被連接原子所在的環的任何一個原子。
進一步的,式I中R2
為H。
進一步的,R3
、R4
、R5
各自獨立地為H。
進一步的,R8
、R10
各自獨立地為H。
進一步的,R9
為單氟、一氟一氯、雙氟或四氟取代的苯基。
進一步的,上述提供的化合物,所述鹽為鹼式鹽或酸式鹽。
關於本文所述化合物,所述化合物還包括式II、III結構鹽的形式,即本發明提供所示化合物的藥學上可接受的鹽,所述鹽可以為鹼式鹽,包括所述化合物與無機鹼(例如鹼金屬氫氧化物、鹼土金屬氫氧化物等)或與有機鹼(例如單乙醇胺、二乙醇胺或三乙醇胺等)形成的鹽。或者,所述鹽可以為酸式鹽,包括所述化合物與無機酸(例如鹽酸、氫溴酸、氫碘酸、硝酸、高氯酸、硫酸或磷酸等)或與有機酸(例如甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、富馬酸、草酸、馬來酸、檸檬酸等)形成的鹽。選擇和製備化合物的可接受的鹽和溶劑化物等是本領域公知技術。
進一步的,上述提供的化合物,其中,所述溶劑合物為水合物或醇合物。
本文所述化合物還可以溶劑合物的形式使用,即本發明提供所示II、III化合物的藥學上可接受的溶劑合物,所述溶劑合物為水合物、醇合物等,醇合物包括乙醇合物。
進一步,本發明還提供上述的化合物II、III在製備治療腫瘤、癌症的藥品中的應用。
進一步,本發明還提供一種含有上述的化合物II、III的藥品或製劑,該藥品或製劑用於治療患者的腫瘤、癌症疾病。
其中腫瘤、癌症包括:
肺癌、非小細胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、結腸癌、卵巢癌、膀朧癌、子宮頸癌、黑色素瘤、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭狀癌、乳頭狀腺癌、囊性腺癌、囊性癌、髓狀癌、支氣管癌、骨細胞癌、上皮癌、膽管癌、絨毛膜癌、胚癌、精原細胞癌、維爾姆斯癌、膠質細胞癌、星形細胞瘤、成神經管細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、成血細胞瘤、聲帶神經瘤、腦膜瘤、成神經細胞瘤、成視神經細胞瘤、成視網膜細胞瘤、神經纖維瘤、纖維肉瘤、成纖維細胞瘤、纖維瘤、纖維腺瘤、纖維軟骨瘤、纖維囊瘤、纖維粘液瘤、纖維骨瘤、纖維粘液肉瘤、纖維乳頭狀瘤、粘液肉瘤、粘液囊瘤、粘液軟骨瘤、粘液軟骨肉瘤、粘液軟骨纖維肉瘤、粘液腺瘤、成粘液細胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂細胞瘤、脂肪軟骨瘤、脂肪纖維瘤、脂肪血管瘤、粘液脂瘤、軟骨肉瘤、軟骨瘤、軟骨肌瘤、脊索瘤、絨毛膜腺瘤、絨毛上皮瘤、成絨毛膜細胞瘤、骨肉瘤、成骨細胞瘤、骨軟骨纖維瘤、骨軟骨肉瘤、骨軟骨瘤、骨囊瘤、骨牙質瘤、骨纖維瘤、骨纖維肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管軟骨瘤、成血管細胞瘤、血管角質瘤、血管神經膠質瘤、血管內皮瘤、血管纖維瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神經瘤、血管粘液瘤、血管網狀內皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纖維瘤、淋巴細胞瘤、淋巴上皮瘤、成淋巴細胞瘤、內皮瘤、成內皮細胞瘤、滑膜瘤、滑膜肉瘤、間皮瘤、結締組織瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纖維瘤、橫紋肌瘤、橫紋肌肉瘤、橫紋肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病貧血、紅細胞增多症、淋巴瘤、子宮內膜癌、膠質瘤、結直腸癌、甲狀腺癌、尿路上皮癌或多發性骨髓瘤,優選為中樞神經系統的癌症或腫瘤。
經過實驗證實,本發明的部分化合物具有較好的細胞膜穿透性,可能能夠較好的穿過血腦屏障達到中樞神經系統,因而這類化合物能夠更容易對腦部顱腔內、中樞神經的脊髓部位的腫瘤、癌症發揮作用。
治療癌症或腫瘤的方法,其包含施加上述的藥品或製劑的步驟;以及使用AKR1C3抗體測定患者的癌細胞的AKR1C3還原酶含量或表達水準的步驟,如測得該AKR1C3還原酶含量或表達水準等於或大於預定值,則向該患者投與上述的藥品或製劑。
AKR1C3還原酶含量測定可以使用的方法包括ELISA法、ICH法。
可使用商業化的人醛酮還原酶1c3(AKR1C3)ELISA檢測試劑盒對血漿、血液等液體樣品進行直接檢測,其他樣本進行處理後進行檢測。
ICH法即免疫組織化學方法,適用於對實體腫瘤樣本進行檢測。
治療癌症或腫瘤的方法,其包含施加上述的藥品或製劑的步驟;以及AKR1C3還原酶含量調節步驟,當調節使得該AKR1C3還原酶含量等於或大於預定值,則向該患者投與上述的藥品或製劑。
有研究表明,放療後的頭頸癌患者的腫瘤組織的AKR1C3酶含量升高,因此通過放療輻射的放射線照射患者的腫瘤組織有可能提高AKR1C3酶的表達水準,放射線包括放射性同位素產生的α、β、γ射線和各類x射線治療機或加速器產生的x射線、電子線、質子束及其他粒子束等。
這種方法主要是針對患者的AKR1C3還原酶含量較低的情況,通過一定的調節治療/給藥過程,將該患者的AKR1C3還原酶含量水準調節到合適的水準。
本發明還提供以下化合物的製備方案:
進一步,上述的製備方法,其中:
Y為Cl、Br、I、-OTs、-ONO2
、-OLCMS、-OTf;
縮合反應使用有機胺作為縛酸劑,當然也可以使用無機鹼作為縛酸劑,無機鹼包括鹼金屬或鹼土金屬的親氧化物或碳酸鹽、碳酸氫鹽等。
進一步,上述的製備方法,其中,Y為Br,縮合反應使用N,N'-二異丙基乙胺DIPEA作為縛酸劑,並使用氧化銀Ag2
O作為催化劑。
本發明還提供以下製備方案:
製備上述的化合物的方法,其特徵在於使得:
VII與R2
R1
OH反應得到II,VIII與R2
R1
OH反應得到III,或者:
與YR1
R2
反應得到II、III,其中,Y是離去基(團),M是H或鹼金屬,其餘取代基同以上方案中所定義的相同。
進一步,上述的製備方法,其中,Y為F、Cl、Br、I、-OTs、-ONO2
、-OLCMS、-OTf,反應過程中加入鹼。
這裡的鹼可以為有機鹼(包括有機胺)或無機的鹼(MOH,M為鹼金屬或鹼土金屬):鹼金屬或鹼土金屬的碳酸鹽、碳酸氫鹽、亞硫酸鹽、亞硫酸氫鹽,鹼金屬或鹼土金屬的氫氧化物、氫化物,或者其他的拔氫試劑:鹼金屬烷基化物(RM,R為烷基,M為鹼金屬)、鹼金屬醇化物(MOR,R為烴基,M為鹼金屬)。
關於本文所述藥品或製劑,所制得的藥品包含特定劑量範圍的所示化合物或其鹽或溶劑合物,和/或所制得的藥物為特定劑型、特定給藥方式施用。
關於本文所述用途,所制得的藥品還可包含藥學上可接受的輔料或賦形劑。所述藥物可以為臨床施用的任何劑型,例如片劑、栓劑、分散片、腸溶片、咀嚼片、口崩片、膠囊、糖衣劑、顆粒劑、乾粉劑、口服溶液劑、注射用小針、注射用凍乾粉針或大輸液。根據具體劑型和施用方式,所述藥物中的藥學上可接受的輔料或賦形劑可以包括下述的一種或多種:稀釋劑、增溶劑、崩解劑、懸浮劑、潤滑劑、粘合劑、填充劑、矯味劑、甜味劑、抗氧化劑、表面活性劑、防腐劑、包裹劑、和色素等。
優選地,所述患者是哺乳動物,更優選是人。
以下參照具體的實施例來說明本發明。本領域技術人員能夠理解,這些實施例僅用於說明本發明,其不以任何方式限制本發明的範圍。
下述實施例中的實驗方法,如無特殊說明,均為常規方法。下述實施例中所用的藥材原料、試劑材料等,如無特殊說明,均為市售購買產品。
“患者”及“個體”可互換使用,是指需要癌症治療的哺乳動物。通常,患者是人類。通常,患者是診斷患有癌症的人類。在某些實施例中,“患者”或“個體”可指用於篩選、表徵及評估藥物及療法的非人類哺乳動物,例如非人類靈長類動物、狗、貓、兔、豬、小鼠或大鼠。
“前藥”是指投與或施用之後經新陳代謝或以其他方式轉化為關於至少一種性質的生物學活性或活性更高的化合物(或藥物)的化合物。相對於藥物,前藥以使其相對於藥物活性較低或無活性的方式化學修飾,但化學修飾使得在前藥投與之後通過代謝或其他生物過程產生相應藥物。前藥可相對於活性藥物具有改變的代謝穩定性或輸送特徵、較少副作用或較低毒性或經改良的風味(參見(例如)參考文獻Nogrady,1985,MedicinalChemistryABiochemicalApproach,0xfordUniversityPress,NewYork,第388頁至392頁,其以引用式併入本文中)。前藥可使用除相應藥物以外的反應物來合成。
“實體腫瘤”是指包括(但不限於)骨、腦、肝、肺、淋巴結、胰臟、前列腺、皮膚及軟組織(肉瘤)中的轉移腫瘤的實體腫瘤。
藥物的“治療有效量”是指當向患有癌症的患者投與或施用時,將具有預期的治療效應(例如患者中一或多種癌症的臨床表現的緩和、改善、緩解或消除)的藥物的量。治療效應不必通過投與或施用一個劑量而出現,且可僅在投與或施用一系列劑量後出現。因此,治療有效量可以一或多次來投與或施用。
病況或患者的“治療”是指採取步驟以獲得有益或期望結果(包括臨床結果)。出於本發明的目的,有益或期望臨床結果包括(但不限於)一或多種癌症症狀的緩和或改善;疾病程度的減弱;疾病進展的延遲或減緩;疾病狀態的改善、緩解或穩定;或其他有益結果。在一些情形下,癌症的治療可使得部分反應或穩定疾病。
“腫瘤細胞”是指任何適當物種(例如,哺乳動物,例如鼠類、犬、貓、馬或人類)的腫瘤細胞。
以上對本發明具體實施方式的描述並不限制本發明,本領域技術人員可以根據本發明作出各種改變或變形,只要不脫離本發明的精神,均應屬於本發明所附權利要求的範圍。
1、H460癌細胞抑制試驗資料
使用活體外人類腫瘤細胞系細胞毒性分析
H460非小細胞肺癌人類腫瘤細胞系的活體外增殖資料包告於下文化合物表中。
IC50
值是以納摩爾報告且自以下得到:將化合物以各濃度暴露達2小時,隨後洗滌步驟並添加新鮮培養基,然後生長及細胞存活率染色並與僅經培養基處理的對照比較。
特定而言,以4×103
個細胞/孔密度將指數生長的細胞接種於96孔板中且在37℃下在5%CO2
、95%空氣及100%相對濕度中培育24小時,然後添加測試化合物。將化合物以200倍的期望最終測試濃度溶解於100%DMSO中。在添加藥物時,使用完全培養基將化合物進一步稀釋至4倍的期望終濃度。將50μl特定濃度的化合物的等份試樣添加至已含有150μl培養基的微量孔中,得到所報告的最終藥物濃度。在藥物添加之後,將板在37℃、5%CO2
、95%空氣及100%相對濕度下再培育2小時,然後將藥物洗掉且添加新鮮培養基且將板在37℃、5%CO2
、95%空氣及100%相對濕度下再培育70小時。在此培育結束時,使用阿爾瑪藍試劑(AlamarBlue)分析來量化活細胞。使用電腦軟體計算導致50%生長抑制的藥物濃度(IC50
),且結果列示於下表中。
類似的,為了進一步驗證化合物為人AKR1C3(醛固酮類還原酶家族1成員C3)所活化,某些化合物對H460癌細胞增殖試驗是存在(3微摩爾濃度)特異性AKR1C3酶抑制劑的情況下進行。在進行化合物處理前2小時,將添加了抑制劑的化合物溶液添加至細胞培養物中。所用抑制劑為Flanagan等人,BioorganicandMedicinalChemistry(2014)第962-977頁中的化合物36即。
實驗事實證實,人類AKR1C3增進以上化合物的活化,同時該系列化合物具有抑制癌細胞增殖活性。
序號 | 化合物 | IC50 (nM) | 添加了AKR1C3抑制劑TH-3021時的IC50 (nM) |
1 | 1.97 | 460 | |
2 | 0.3518 | 大於1000 | |
3 | 0.4172 | 大於1000 | |
4 | 9.308 | 大於1000 | |
5 | 5.874 | 228.1 | |
6 | 1.268 | 813.1 | |
7 | 25.57 | 大於1000 | |
8 | 0.5265 | 大於1000 | |
9 | 18.45 | 大於1000 | |
10 | 未測試 | 未測試 | |
11 | 137.2 | 大於1000 | |
12 | 87.3 | 大於1000 | |
13 | 42.25 | 大於1000 | |
14 | 29.99 | 大於1000 | |
15 | 11.39 | 大於1000 | |
16 | 6.782 | 大於1000 | |
17 | 7.258 | 大於1000 | |
18 | 35.45 | 大於1000 | |
19 | 312.9 | 大於1000 | |
20 | 46.81 | 大於1000 | |
21 | 6.984 | 176.2 | |
22 | 1.374 | 139.2 | |
23 | 6.04 | 794.8 | |
24 | 4.325 | 大於1000 | |
25 | 1.859 | 179.1 | |
26 | 1.199 | 175.2 | |
27 | 9.316 | 大於1000 | |
28 | 2.364 | 649.2 | |
29 | 60.08 | 大於1000 | |
30 | 79.9 | 大於1000 | |
33 | 未檢測 | 未檢測 | |
34 | 38.54 | 大於1000 | |
35 | 未檢測 | 未檢測 | |
36 | <4.37 | 237.5 | |
37 | 12.34 | 136 | |
38 | 5.526 | 267.1 | |
39 | 7.794 | 137.3 | |
40 | 14.72 | 大於1000 | |
41 | 2.541 | 341.2 | |
42 | 29.3 | 大於1000 | |
43 | 30.42 | 102 | |
44 | 9.418 | 大於1000 | |
47 | 8.135 | 未檢測 | |
48 | 3.697 | 未檢測 | |
49 | 9.605 | 大於1000 |
2、化合物合成實施例
THF,四氫呋喃;DCM,二氯甲烷;EA或EtOAC,乙酸乙酯;TEA,三乙胺;HPLC,高效液相色譜儀;MTBE,甲基叔丁基醚;DMAP,4-二甲氨基吡啶;DBAD,偶氮二甲酸二叔丁酯;TFA,三氟乙酸;LCMS,液質聯用;EtOH,乙醇;t-BuOH,叔丁醇;DMF,二甲基甲醯胺;PE,石油醚,petroleum ether;eq,當量即摩爾比;TBAF,四丁基氟化銨;DIPEA,N,N-二異丙基乙胺;合成過程中未注明來源的化學試劑、藥品均為分析純或化學純,均從商業的試劑公司購買得到。其他出現的英文簡寫以有機化學領域中的解釋為準。
1-D(5g,38.4mmol)溶於TFA(40mL),加入烏洛托品(5.6g,38.4mmol,1eq,商業購買),回流過夜,反應完畢之後,降至室溫,濃縮掉溶劑,剩餘物溶於DCM(70mL)中,NaHCO3
溶液洗滌,然後用濃鹽酸調節pH=1,DCM萃取水相(50mLx2),合併有機相,Na2
SO4
乾燥,濃縮,得到1-E(2.5g,收率41.3%),為白色固體。1
H-NMR(300M,CDCl3
):δppm9.82(s,1H),7.49(d,J=6.6Hz,2H).LCMS:Calculated 158.1,found 157.0([M-H]-
)。
氮氣保護下,(1g,3.16mmol)和1-E(1g,6.32mmol)溶於超乾THF中(15mL),加入三苯基磷(1.66g,6.32mml,2eq),0℃,滴加入DBAD(1.46g,6.32mmol,2eq)的THF溶液(6mL),室溫反應,反應過夜,0℃滴加入8mL水,DCM萃取(20mL×3),乾燥濃縮,拌樣過柱(200-300目矽膠,石油醚:EA=3:1得產品),得到1-F(680mg,收率47%,含量80%),淡黃色固體。
氮氣保護下,1-F(510mg,1.11mmol)溶於THF(5mL),降溫0℃,分批加入硼氫化鈉(84mg,2.22mmol,2eq),保溫0℃。反應1h,完畢之後,滴加入飽和氯化銨水溶液(3mL),EA萃取(10mL×3),鹽水洗,乾燥濃縮,柱分離。(100-200目矽膠,DCM:甲醇=50:1得產品,得到1-B(300mg,收率=58.9%),為淡黃色固體。1
H-NMR(300M,CDCl3):δppm8.01(d,J=8.4Hz,1H),7.43(d,J=8.7Hz,2H),7.34-7.37(m,1H),6.86(d,J=8.4Hz,1H),5.14(s,2H),4.60(s,2H),3.09(brs,6H).LCMS:Calculated 458.4,found 459.0([M+H]+)。
氮氣保護下,1-B(300mg,0.65mmol)溶於THF中(5mL),加入三苯基磷(375mg,1.43mmol,2.2eq),Br-IPM(溴代異磷醯胺氮芥中間體,442mg,1.43mmol,2.2eq,商業購買),降溫0℃,滴加入DBAD(329mg,1.43mmol,2.2eq)的THF(3mL),常溫反應3h,滴加入3mL水,DCM萃取(10mL×3),乾燥濃縮,柱分離(200-300目矽膠,DCM:甲醇=30:1得產品(400mg,收率82%),為紅棕色固體。1
H-NMR(300M,CDCl3):δppm7.99(d,J=8.4Hz,1H),7.48-7.46(m,2H),7.33-7.31(m,1H),7.12(s,1H),7.00(d,J=8.1Hz,2H),6.93(d,J=8.4Hz,2H),5.16(s,2H),4.93(d,J=8.4Hz,2H),3.45-3.43(m,4H),3.37-3.32(m,4H),3.07(brs,6H).LCMS:Calculated 750.3,found 750.8([M+1]+)。
氮氣保護下,1-C(400mg,0.533mmol)溶於超乾THF(4mL),加入氧化銀(1.46g,6.29mmol,11.8eq),滴加入二異丙基乙胺(345mg,2.67mmol,5eq),升溫至回流,LCMS監測反應,2.5h反應完畢。矽藻土抽濾,THF多次洗滌,低溫濃縮,製備得到1號化合物(19mg,收率6.07%),為白色固體。1
H-NMR(400M,CDCl3):δppm7.99(d,J=7.2Hz,1H),7.45(d,J=7.8Hz,2H),7.32(d,J=8.4Hz,1H),7.16(d,J=1.6Hz,1H),7.04-7.06(m,2H),6.95(d,J=8.4Hz,2H),5.15(s,2H),5.05(d,J=8.0Hz,2H),3.11(s,3H),3.03(s,3H),2.23-2.13(m,8H).LCMS:Calculated 588.0,found 589.0([M+H]+)。
將2-A1(10.0g,50.99mmol),原甲酸三乙酯(9.8g,66.07mmol,1.32eq),12NHCl(0.15ml),加入至EtOH(30ml)中,回流過夜。反應完畢後,旋乾溶劑,即可得到2-A2(11.2g,粗品)。
將2-A2(11.2g,粗品,51.0mmol),KOH(2.3g,204.0mmol,4eq),在t-BuOH(150ml)中回流4h後反應完畢。降至室溫,加水(100ml),用EtOAc(100ml×3)萃取,水相用12N HCl調pH=3-4後攪拌過夜,再用EtOAc(100ml×3)萃取,Na2SO4乾燥,旋乾後用石油醚PE(20ml)打漿,可得2-A3(4.4g,收率為44.4%),為類白色固體。1
H-NMR(400M,CDCl3):δppm10.21(s,1H),6.46(s,1H).LCMS:Calculated 194.0,found 192.8([M-H]-)。
氮氣保護下,將2-B1(500mg,1.5mmol即),2-A3(1.45g,7.5mmol,5eq),DIEA(965mg,7.5mmol,5eq)加入至DMF(5ml)後升溫至50℃過夜,反應轉化至50%左右不再轉化。降至室溫後加入H2O(20ml),用EtOAc(20ml×3)萃取,有機相鹽水洗(15ml×3),水洗(15ml×5),有機相用Na2SO4乾燥,旋乾溶劑,200-300矽膠過柱(PE:EtOAc=3:1)可得2-A4(290mg,收率為33.9%),為淡黃色固體。1
H-NMR(400M,CDCl3):δppm10.15(s,1H),7.94(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,1H),7.04-6.99(m,3H),5.31(s,2H),3.06(s,3H),2.96(s,3H).LCMS:Calculated 492.1,found 493.1([M+H]+)。
氮氣保護,將2-A4(270mg,0.548mmol)溶於THF(3ml)後降溫至0℃,後將NaBH4
(42mg,1.1mmol,2eq)分批加入至體系,30min反應完畢。滴加H2
O(5ml),DCM萃取(10ml×3),有機相水洗(10ml×3),有機相用無水Na2SO4乾燥,旋乾過柱(PE:EtOAc=1:1)可得2-A5(95mg,收率為35.0%),為黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.01(d,J=8.4Hz,1H),7.45(d,J
=8.4Hz,2H),7.33-7.30(m,1H),7.00(d,J
=8.4Hz,2H),6.94(s,1H),5.20(s,2H),4.74(s,2H),3.10(s,3H),3.05(s,3H).LCMS:Calculated 495.1,found 495.1([M+H]+
)。
氮氣保護,將POCl3
(100mg,0.405mmol,2eq)溶於DCM(2ml)後降溫至-40℃,後將2-A5(100mg,0.202mmol,1eq)與TEA(51mg,0.506mmol,2.5eq)加入至體系,保溫-40℃6h後反應完畢,將2-溴乙胺氫溴酸鹽(338mg,1.618mmol,8eq)加入至體系後再將TEA(164mg,1.618mmol,8eq)滴加至體系,完畢後繼續保溫-40℃,30min後反應完畢。升至常溫後滴加NH4
Cl溶液(15ml),DCM萃取(10ml×3),有機相水洗(10ml×3),有機相用無水Na2SO4乾燥,旋乾後200-300矽膠過柱(EtOAc)可得AST-2-A6(50mg,含量約70%,收率為31.4%),為黃色固體。
氮氣保護,將2-A6(30mg,0.038mmol,1eq),Ag2
O(44mg,0.191mmol,5eq)與DIEA(26mg,0.191mmol,5eq)加入THF(1ml)中,升溫至65℃回流,2h後反應完畢。降至室溫後體系通過矽膠抽濾,THF洗滌,母液旋乾後中性製備液相分離,DCM萃取旋乾後凍乾,可得2號化合物(6mg,收率為25.2%),為棕色固體。1
H-NMR(400M,MeOD):δ
8.34(d,J
=8.4Hz,1H),7.50(d,J
=8.8Hz,2H),7.45-7.43(m,1H),7.30(s,1H),7.08(d,J
=8.8Hz,2H),5.38(s,2H),5.25(d,J
=7.6Hz,2H),3.10(s,3H),3.05(s,3H),2.20-2.15(m,8H).LCMS:Calculated 624.1,found 625.2([M+H]+
)。
氮氣保護,將3-B1(500mg,1.49mmol,),3-A0(1.45g,7.470mmol,5eq),DIEA(965mg,7.470mmol,5eq)加入至DMF(10ml)後升溫至50℃過夜,反應轉化至50%左右不再轉化。降溫後加入H2
O(20ml),用EtOAc(20ml×3)萃取,有機相用水洗(15ml×5),飽和鹽水洗(15ml×3),有機相乾燥旋乾,200-300矽膠過柱(PE:EtOAc=3:1)可得3-A1(295mg,收率為40.1%),為淡黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm10.22(s,1H),8.00(d,J=8.4Hz,1H),7.46-7.42(m,1H),7.30(d,J
=8.4Hz,1H),7.26-7.24(m,1H),7.10-7.08(m,3H),5.37(s,2H),3.11(s,3H),2.99(s,3H).LCMS:Calculated 492.1,found 493.1([M+H]+
)。
氮氣保護,將3-A1(290mg,0.589mmol)溶於THF(3ml)後降溫至0℃,後將NaBH4
(45mg,1.178mmol,2eq)分批加入至體系,30min反應完畢。滴加H2
O(5ml)至體系,DCM萃取(10ml×3),有機相水洗(10ml×3),有機相乾燥旋乾過柱(PE:EtOAc=1:1)可得3-A2(m=100mg,收率為35.0%)黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm7.99(d,J
=8.4Hz,1H),7.44(t,J=8.4Hz,1H),7.31(d,J=7.6Hz,1H),7.22(d,J=7.6Hz,1H),7.13(dd,d,J
=8.0,1.6Hz,1H),7.05(s,1H),6.91(s,1H),5.24(s,2H),4.73(s,2H),3.02(m,6H).LCMS:Calculated 494.1,found 495.1([M+H]+
)。
氮氣保護,將POCl3
(61mg,0.202mmol)溶於DCM(2ml)後降溫至-40℃後將3-A2(50mg,0.101mmol)與TEA(26mg,0.253mmol,2.5eq)加入至體系,保溫-40℃6h後反應完畢,將1-溴乙胺氫溴酸鹽(169mg,0.81mmol)加入至體系後再將TEA(82mg,0.809mmol,8eq)滴加至體系,完畢後繼續保溫-40℃30min後反應完畢。升至常溫後滴加NH4
Cl溶液(10ml),DCM萃取(8ml×3),有機相水洗(5ml×3),有機相乾燥旋乾200-300矽膠過柱(EtOAc)可得3-A3(62mg,80.0%,含量約70%投於下步),為黃色固體。
氮氣保護,將3-A3(60mg,0.08mmol,1eq),Ag2O(88mg,0.382mmol,商業購買)與DIEA(49mg,0.38mmol)加入THF(2ml)中,升溫至65℃回流,2h後反應完畢。降至室溫後體系通過矽膠抽濾,THF洗滌,母液旋乾後,製備,DCM萃取旋乾後凍乾,可得3號化合物(10mg,12%)為褐色固體。1
H-NMR(400M,MeOD):δ
8.03(d,J
=8.4Hz,1H),7.51(t,J
=8.0Hz,1H),7.43(d,J
=8.0Hz,1H),7.28-7.25(m,2H),7.13-7.10(m,2H),5.37(s,2H),5.25(d,J
=7.6Hz,2H),3.09(s,3H),3.00(s,3H),2.21-2.16(m,8H).LCMS:Calculated 624.1,found 625.1([M+H]+
)。
氮氣保護下,4-A1(3.7g,18.45mmol)、對三氟甲基苯酚(2g,12.3mmol,商業購買)溶於ACN(30mL)中,加入K2
CO3
(3.4g,24.6mmol),升溫80℃攪拌過夜。反應完畢後,矽藻土抽濾,濃縮,得粗品4-A2(5.6g,97.2%),為黃色固體,直接用於下一步。1
H-NMR(400M,CDCl3
):δ
ppm8.03-7.95(m,2H),7.76(d,J
=1.6Hz,1H),7.66(d,J
=8.8Hz,2H),7.11(d,J
=8.8Hz,2H),3.94(s,3H).LCMS:Calculated 341.1,found 342.1([M+H]+
)。
氮氣保護下,將4-A2(1.6g,4.7mmol)溶於THF(30mL),分批加入NaBH4
(1.4g,37.6mmol),升溫至60℃攪拌過夜。反應完畢後,降溫至5℃,滴加飽和NH4
Cl水溶液(15mL),DCM萃取(20mL),水洗(4×5mL),乾燥,濃縮,得4-A3粗品1.6g,為黃色油狀液體。直接用於下一步。1
H-NMR(400M,CDCl3
):δ
ppm8.02(d,J
=8.4Hz,1H),7.62(d,J
=8.8Hz,2H),7.31-7.28(m,1H),7.15(s,1H),7.08(d,J
=8.4Hz,2H),4.77(s,2H),1.86(s,1H).LCMS:Calculated 313.1,found 314.0342.1([M+H]+
)。
氮氣保護下,將上一步的粗品4-A3(600mg,1.92mmol),溶於超乾DCM(10mL),降溫至0℃緩慢滴加入SOCl2
(457mg,3.84mmol),1h後補加1eq的TEA(194mg,1.92mmol),30min反應完畢。降溫滴加飽和NaHCO3
溶液(10mL),DCM萃取(15mL×2),水洗(5mL×3),乾燥,濃縮得4-A4粗品(580mg,淡黃色液體),直接用於下一步。
氮氣保護下,4-A4(580mg,1.75mmol)及(692mg,4.375mmol)溶於DMF(10mL)中,後加入DIEA(1.4g,10.5mmol),40℃反應過夜。反應完畢後,EA萃取(15mL×2),水洗(5mL×6),乾燥,濃縮,柱分離(200~300目矽膠,正庚烷:EA=10:1~5:1得4-A5產品(300mg,55.0%),為黃色油狀液體。1
H-NMR(400M,CDCl3
):δ
ppm9.84-9.85(m,1H),8.04(d,J
=8.4Hz,1H),7.64(d,J
=8.8Hz,2H),7.46(d,J
=8.2Hz,2H),7.38(d,J
=8.4Hz,1H),7.21(s,1H),7.09(d,J
=8.4Hz,2H),5.32(s,2H)。
氮氣保護下,4-A5(300mg,0.66mmol)溶於THF(6mL)中,降溫0℃分批加入NaBH4
(50mg,1.32mmol,商業購買),30min反應完畢。0℃滴加NH4
Cl飽和溶液(5mL),DCM萃取(15mL×2),水洗(5mL×3),乾燥,濃縮,柱分離(200~300目矽膠,Heptane:EA=10︰1~5︰1得4-A6產品190mg,淡黃色固體,90.6%)。1
H-NMR(400M,CDCl3
):δ
ppm8.02(d,J
=8.4Hz,1H),7.63(d,J
=8.4Hz,2H),7.36-7.38(m,1H),7.23(s,1H),7.07(d,J
=8.4Hz,2H),6.90(d,J
=8.8Hz,2H),5.17(s,2H),4.63(s,2H).
氮氣保護下,POCl3
(130mg,0.84mmol,商業購買)滴入超乾DCM中(5mL),降溫至-30℃,滴加入4-A6(190mg,0.42mmol)的DCM(5mL)溶液,後滴入TEA(106mg,1.05mmol),保溫-30℃,6h後至原料完全消失。-30℃加入2-溴乙胺氫溴酸鹽(688mg,3.36mmol)後,再滴入TEA(340mg,3.36mmol),反應完畢後,降溫至0℃,加入NH4
Cl飽和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),乾燥,濃縮,柱分離(200~300目矽膠,Heptane:EA=1:2~EA出產品120mg,為黃色固體,收率為57.6%)。1
H-NMR(400M,CDCl3
):δ
ppm8.03(d,J
=8.4Hz,1H),7.64(d,J
=8.8Hz,2H),7.37(d,J
=8.0Hz,1H),7.24(s,1H),7.08(d,J
=8.4Hz,2H),6.95(d,J
=8.4Hz,2H),5.18(s,2H),4.94(d,J
=8.4Hz,2H),3.14-3.46(m,4H),3.33(m,4H),3.14(m,2H).LCMS:Calculated 747.0,found 748.0([M+H]+
)。
氮氣保護下,4-A7(120mg,0.16mmol)溶於THF(10mL)中,加入Ag2
O(222mg,0.96mmol,商業購買)及N,N-二異丙基乙胺(124mg,0.96mmol,商業購買),升溫至65℃反應。2h反應完畢後,矽藻土抽濾,DCM(20mL)洗滌固體,濃縮母液,高效液相製備得純品(14.3mg,28.4%),為黃色蠟狀固體。1
H-NMR(400M,CDCl3
):δ
ppm8.02(d,J
=8.4Hz,1H),7.64(d,J
=8.8Hz,2H),7.37(d,J
=8.4Hz,1H),7.24(s,1H),7.08(d,J
=8.8Hz,2H),6.96(d,J
=8.4Hz,2H),5.18(s,2H),5.06(d,J
=8.4Hz,2H),2.13-2.23(m,8H).LCMS:Calculated 585.1,found 586.1([M+H]+
)。
氮氣保護下,將5-A1(5.8g,28.9mmol)及2-氯-5羥基吡啶(2.5g,19.3mmol)溶於乙腈(50mL)中,加入碳酸鉀(5.3g,38.6mmol)後升溫至80℃攪拌過夜。反應完畢後,矽膠土抽濾,濃縮母液,正庚烷打漿,抽濾得5-A2純品(5.7g,95.7%),為淡黃色固體。1
H-NMR(400M,CDCl3):ppm8.20(s,1H),7.94-8.03(m,2H),7.69(s,1H),7.37(s,2H),3.93(s,3H).LCMS:Calculated 308.0,found 309.0([M+H]+
)。
氮氣保護下,將5-A2(2g,6.5mmol)溶於THF(30mL),後分批加入NaBH4
(1.97g,52mmol),升溫至60℃攪拌過夜。反應完畢後,降溫滴加飽和NH4
Cl水溶液(15mL),然後DCM萃取(20mL),水洗(4×5mL),乾燥,濃縮,柱分離(200-300目矽膠,正庚烷:EA=5:1到1:1得5-A3產品,m=800mg,收率=44.4%)為淡黃色固體。1
H-NMR(400M,CDCl3
):ppm8.16(s,1H),8.02(d,J
=8.4Hz,1H),7.34(s,2H),7.29(d,J
=8.4Hz,1H),7.12(s,1H),4.77(s,2H),1.84(s,1H).LCMS:Calculated 280.0,found 281.0([M+H]+
)。
氮氣保護下,5-A3(800mg,2.85mmol),溶於超乾DCM(10mL),降溫至0℃緩慢滴加入SOCl2
(1.19g,9.98mmol),4h反應完畢。降溫滴加飽和NaHCO3溶液(10mL),DCM萃取(15mL×3),NaHCO3溶液洗滌有機相(5mL×2),乾燥,濃縮得5-A4產品(440mg,淡黃色液體,51.6%),直接用於下一步。
氮氣保護下,5-A4(440mg,1.47mmol)及(581mg,3.675mmol)溶於DMF(10mL)中,後加入DIEA(1.14g,8.82mmol),反應過夜。反應完畢後,EA萃取(15mL×2),水洗(5mL×6),乾燥,濃縮,柱分離得到5-A5(200-300目矽膠,正庚烷:EA從10:1到5:1得5-A5產品,,m=340mg,收率=55.0%),為黃色油狀液體。1
H-NMR(400M,CDCl3
):
ppm9.85(t,J=1.6Hz,1H),8.16(d,J=1.2Hz,1H),8.03(d,J=8.4Hz,1H),7.46(d,J=8.0Hz,2H),7.34-7.38(m,3H),7.18(s,1H),5.32(s,2H).LCMS:Calculated 420.0,found 421.0([M+H]+
)。
氮氣保護下,5-A5(340mg,0.81mmol)溶於THF(6mL)中,降溫0℃分批加入硼氫化鈉(61mg,1.62mmol),30min反應完畢。0℃滴加入飽和NH4
Cl溶液(5mL),DCM萃取(10mL×2),水洗(5mL×3),乾燥,濃縮得5-A6產品310mg(淡黃色固體,90.6%),直接進行下一步。1
H-NMR(400M,DMSO-d6
):ppm8.03(d,J
=8.4Hz,1H),7.55(d,J
=2.8Hz,1H),7.46-7.34(m,2H),7.01(d,J
=1.2Hz,1H),6.90-6.87(m,2H),5.17(s,2H),4.61(d,J
=6.4Hz,2H).LCMS:Calculated 422.0,found 423.0([M+H]+
)。
氮氣保護下,三氯氧磷(224mg,1.46mmol)滴入超乾DCM中(5mL),降溫至-30℃,滴加入5-A6(310mg,0.73mmol)的DCM(5mL)溶液,後滴加入三乙胺(185mg,1.825mmol),保溫-30℃,5h後至原料完全消失。-30℃加入2-溴乙胺氫溴酸鹽(1.2g,5.84mmol),後再滴入三乙胺(591mg,5.84mmol),反應完畢後DCM萃取(15mL×2),水洗(5mL×4),乾燥,濃縮,柱分離(200-300目矽膠)得5-A4產品300mg,淡黃色油狀物,收率=57.6%。1
H-NMR(400M,CDCl3
):ppm8.10(s,1H),8.00(d,J=8.4Hz,1H),7.34-7.35(m,3H),7.18(s,1H),6.93(d,J=8.4Hz,2H),5.29(s,2H),5.17(s,2H),4.92(d,J=8.4Hz,2H),3.42-3.48(m,4H),3.29-3.36(m,4H),3.20-3.22(m,2H).LCMS:Calculated 713.9,found 714.9([M+H]+
)。
氮氣保護下,5-A7(300mg,0.42mmol)溶於THF(10mL)中,加入氧化銀(584mg,2.52mmol,商業購買)及N,N-二異丙基乙胺(326mg,2.52mmol),升溫至60℃反應。2.5小時反應完畢後,矽藻土抽濾,DCM(20mL)洗滌固體,濃縮母液,高效液相製備,製備得5號化合物純品(66mg,28.4%),為淡黃色固體。1
H-NMR(400M,CDCl3):ppm8.16(d,J=2.4Hz,1H),8.02(d,J=8.4Hz,1H),7.31-7.37(m,3H),7.20(s,1H),6.96(d,J=8.4Hz,2H),5.17(s,2H),5.06(d,J=8.0Hz,2H),2.24-2.14(m,8H)..LCMS:Calculated 552.1,found 553.1([M+H]+)。
氮氣保護下,將6-A1(1.5g,9.15mmol),商業購買)與(1g,6.10mmol)溶於乙腈中(20mL),升溫至80℃,5小時反應完畢。降至常溫,矽藻土抽濾,EA洗滌濾餅,濃縮母液,矽膠柱分離:200-300目矽膠,Heptane:EA=2:1-1:1得產品6-A2(1.2g,收率為63.2%),為淡黃色油狀液體。1
H-NMR(400M,CDCl3
):δ
ppm9.96(s,1H),8.04(d,J
=8.2Hz,1H),7.73(dd,J
=8.2,1.5Hz,1H),7.51(d,J
=1.4Hz,1H),7.49-7.43(m,1H),7.35-7.27(m,1H),7.14(dd,J
=7.9,1.3Hz,2H),3.09(s,3H),2.99(s,3H).LCMS:Calculated 314.1,found 315.1([M+H]+
)。
氮氣保護下,6-A2(550mg,1.75mmol)溶於THF中(10mL),加入(三氟甲基)-三甲基矽烷(373mg,2.62mmol),降溫至0℃,滴加入四丁基氟化銨(0.04mL,0.04mmol,1MinTHF),2小時後,滴加入3N的鹽酸(0.5mL),然後DCM萃取(10mL*2),NaHCO3
溶液洗滌(5mL*3),水洗,鹽水洗,乾燥濃縮,得6-A3粗品600mg,為淡黃色油狀液體,直接用於下一步。
氮氣保護下,三氯氧磷(376mg,2.45mmol)加入到超乾DCM中(15mL),降溫至-30℃,滴加入6-A3(470mg,1.22mmol,crude)的DCM溶液(5mL),然後滴加入三乙胺(312mg,3.03mmol),保溫-30℃4小時,原料轉化完畢。-30℃,加入2-溴乙胺氫溴酸鹽(2.0g,9.78mmol),然後滴加入三乙胺(940mg,9.78mmol),保溫-30℃,1小時後反應完畢。0℃,滴加入飽和氯化銨水溶液(8mL),二氯甲烷萃取(15mL*2),水洗乾燥濃縮,柱分離。(200-300目矽膠,PE:EA=1:2-EA得6-A4產品440mg,為黃色油狀液體,收率為53.4%)。1H-NMR: δ ppm 7.98 (d, J = 8.3 Hz, 1H), 7.49-7.46 (m, 1H), 7.29-7.21 (m, 4H), 7.07 (s, 1H), 5.71-5.67 (m, 1H), 3.46-3.12 (m, 10H), 3.07 (s, 3H), 2.99 (s, 3H). LCMS : Calculated 676.0, found:677.0 ([M+1]+
)。
氮氣保護下,6-A4(440mg,0.65mmol)溶於THF中(25mL),加入氧化銀(910mg,3.92mmol),然後加入DIEA(510mg,3.92mmol),升溫至65℃,2小時反應完畢。降至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,高效液相製備得6號化合物純品(90.0mg,27%),為白色固體。1
H-NMR(400M,CDCl3):δppm8.00(d,J=8.4Hz,1H),7.52-7.32(m,2H),7.26-7.23(m,2H),7.08-7.06(m,2H),5.72(dq,J=12.2,6.1Hz,1H),3.09(s,3H),2.97(s,3H),2.32-1.89(m,8H).LCMS:Calculated 514.1,found 515.1[(M+H)+
]。
氮氣保護下,將7-A1(1.5g,9.15mmol),商業購買)與對三氟甲基苯酚(990mg,6.10mmol)溶於乙腈中(20mL),加入碳酸鉀(1.7g,12.2mmol,商業購買)升溫至80℃,2.5小時反應完畢。降至常溫,矽藻土抽濾,EA洗滌濾餅,濃縮母液,柱分離(200-300目矽膠,Heptane:EA=5:1-1:1)得7-A2產品(1.1g收率為38.6%),為淡黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm10.01(s,1H),8.09(d,J
=8.2Hz,1H),7.79(dd,J
=8.2,1.6Hz,1H),7.68(d,J
=8.6Hz,2H),7.57(d,J
=1.5Hz,1H),7.15(d,J
=8.6Hz,2H)。
氮氣保護下,7-A2(400mg,1.29mmol)溶於THF中(10mL),加入(三氟甲基)-三甲基矽烷(274mg,1.93mmol),降溫至0℃,滴加入四丁基氟化銨(0.04mL,0.04mmol,1mol/L的THF溶液),2小時後,滴加入3N的鹽酸(0.5mL),然後DCM萃取(10mL×2),NaHCO3溶液洗滌(5mL×3),水洗,鹽水洗,乾燥濃縮,得7-A3粗品450mg,為淡黃色油狀液體,直接用於下一步。1
H-NMR(400M,CDCl3):δppm8.04(d,J=7.8Hz,1H),7.64(d,J=7.9Hz,2H),7.45(d,J=7.7Hz,1H),7.30(s,1H),7.09(d,J=8.0Hz,2H),5.09(s,1H),3.26(s,1H).LCMS:Calculated 381.2,found 382.0([M+1]+
)。
氮氣保護下,三氯氧磷(362mg,2.36mmol)加入到超乾DCM中(15mL),降溫至-30℃,滴加入7-A3(450mg,1.18mmol,粗品)的DCM溶液(5mL),然後滴加入三乙胺(300mg,2.95mmol),保溫-30℃4小時,原料轉化完畢。-30℃,加入2-溴乙胺氫溴酸鹽(1.9g,9.44mmol),然後滴加入三乙胺(960mg,9.44mmol),保溫-30℃,1小時後反應完畢。0℃,滴加入飽和氯化銨水溶液(6mL),DCM萃取(15mL×2),水洗乾燥濃縮,柱分離(200-300目矽膠,Heptane:EA=1:1-0:1)得7-A4產品(440mg,55.4%),為黃色油狀液體。1
H-NMR(400MHz,CDCl3):δ
ppm8.05(d,J=8.4Hz,1H),7.65(d,J=8.6Hz,2H),7.44(d,J=8.5Hz,1H),7.23(s,1H),7.10(d,J=8.5Hz,2H),5.72-5.64(m,1H),3.40-3.10(m,10H).LCMS:Calculated 672.9,found 673.9([M+1]+
)。
氮氣保護下,7-A4(400mg,0.59mmol)溶於THF中(25mL),加入氧化銀(826mg,3.57mmol),然後加入DIEA(461mg,3.57mmol),升溫至65℃,2小時反應完畢。降至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,高效液相製備得7號化合物純品(68mg,收率為22.5%),為白色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.05(d,J=8.5Hz,1H),7.65(d,J=8.6Hz,2H),7.45(d,J=8.5Hz,1H),7.27(s,1H),7.09(d,J=8.5Hz,2H),5.75(d,J=4.4Hz,1H),2.33-1.98(m,8H).LCMS:Calculated LCMS:511.1,found 512.0([M+H]+
)。
將8-A1(5.5g,27.6mmol)與對三氟甲基苯酚(3.0g,18.5mmol,商業購買)溶於乙腈(30mL)中,加入K2
CO3
(5.1g,37.0mmol,商業購買科技),升溫至80℃,攪拌過夜,反應完畢,自然冷卻至室溫,矽藻土抽濾,EA(10ml×3)洗滌濾餅,濃縮母液,甲基叔丁基醚結晶得到8-A2粗品(4.6g,72.9%),為黃色固體,直接投於下步反應。
將8-A2(2.5g,7.33mmol)溶於THF中,分批加入硼氫化鈉(2.2g,58.7mmol,商業購買),常溫攪拌30min,升溫至65℃,攪拌,檢測反應進程,2h反應完畢,將體系降溫至0℃,滴加入H2
O(20mL),攪拌20min,DCM萃取(50mL×3),水洗,無水Na2
SO4
乾燥,濃縮,得到8-A3粗品(1.5g,65.4%),為淡黃色固體。
氮氣保護下,將8-A3(1.5g,4.79mmol)溶於DCM(20mL)中,降溫至0℃,滴加入SOCl2
(1.1g,9.58mmol)和TEA(485mg,4.79mmol),攪拌,檢測反應進程,1h反應完畢。0℃時,滴入飽和NaHCO3
水溶液(5mL),DCM(20mL×3)萃取,NaHCO3
水溶液洗滌,無水Na2
SO4
乾燥,濃縮,得8-A5粗品(1.3g,81.8%),為紅褐色液體,直接用於下一步。
將8-A4(220mg,0.66mmol)和2,3,5,6-四氟-4-羥基苯甲醛(513mg,2.65mmol)溶於DMF(5mL)中,滴加入DIEA(430mg,3.32mmol),攪拌,升溫至45℃
,檢測反應進程,3h反應完畢,加H2
O(10mL),自然降至室溫,EA(8mL×3)萃取,無水Na2
SO4
乾燥,濃縮,得8-A5粗品70mg,為淡黃色液體,直接用於下一步。
將8-A5(70mg,0.14mmol)溶於THF(5mL)中,降溫至0℃,分批加入NaBH4
(11mg,0.37mmol),檢測反應進程,0.5h反應完畢。0℃下,滴加入H2
O(3mL),攪拌20min,DCM(10mL×3)萃取,水洗,無水Na2
SO4
乾燥,濃縮,得8-A6粗品50mg,為淡黃色液體,直接用於下一步。
將POCl3
(31mg,0.20mmol,商業購買)溶解於DCM(3mL)中,降溫至-30℃,滴加入8-A6(50mg,0.10mmol)的DCM溶液(1mL),然後滴加入三乙胺(26mg,0.26mmol)的DCM溶液(1mL),保溫-30℃反應,檢測反應進程,2h原料消失,降溫至-40℃,加入2-溴乙胺氫溴酸鹽(167mg,0.82mmol)和TEA(83mg,0.82mmol),-40℃保溫-40℃,30min反應完畢。升至5℃,加H2
O(5mL),DCM(5mL×3)萃取,水洗(3mL×2),無水Na2
SO4
乾燥,濃縮,柱色譜層析分離(200-300目矽膠,正庚烷:EA=1:1)得8-A7產品(50mg,62.7%),為淡黃色液體。
將8-A7(50mg,0.064mmol)溶解於THF(5mL)中,加入Ag2
O(74mg,0.32mmol,商業購買),DIEA(41mg,0.32mmol),升溫至65℃,檢測反應進程,1h反應完畢。降至室溫,矽藻土抽濾,THF(2ml×3)洗滌固體,濃縮母液,高效液相色譜法製備分離,得產品(2.2mg,5.5%),為白色蠟狀物。1
H-NMR(400M,CDCl3
)δ8.04(d,J
=8.4Hz,1H),7.65(d,J
=8.6Hz,2H),7.36(dd,J
=8.4,1.6Hz,1H),7.20(d,J
=1.5Hz,1H),7.09(d,J
=8.5Hz,2H),5.28(s,2H),5.23(d,J
=6.1Hz,2H),2.26-2.15(m,8H).LCMS:Calculated 621.1.,found 622.1([M+H]+
)。
氮氣保護下,將9-A1(500mg,2.97mmol)和4-氟-4'-羥基聯苯(723mg,3.84mmol,商業購買醫藥)溶於乙腈中(10mL),然後加入碳酸鉀(820mg,5.94mmol,商業購買),升溫至85℃,攪拌2小時,反應完畢。降至常溫,抽濾,濃縮母液,柱分離。(200-300目矽膠,正庚烷:EA=20:1得產品420mg,淡黃色固體,收率42.0%。)。1
H-NMR(400M,CDCl3
):δ
ppm9.98(s,1H),8.05(d,J
=8.0Hz,1H),7.70(dd,J1
=8.0Hz,J2
=1.6Hz,1H),7.56-7.60(m,2H),7.52-7.56(m,3H),7.12-7.17(m,4H)。
氮氣保護下,將9-A2(400mg,1.19mmol)溶於無水THF中(8mL),然後滴加入(三氟甲基)三甲基矽烷(254mg,1.79mmol),降溫至0℃,滴加入TBAF(0.03mL,1MinTHF),保溫0℃1.5小時,反應完畢。滴加入3N的鹽酸2mL,自然升至常溫,攪拌1小時。加入水5mL,DCM萃取(10m×3),水洗(5mL×3),乾燥濃縮,柱分離。(200-300目矽膠,正庚烷:EA=10:1得產品9-A3共380mg,淡黃色固體,收率78.4%。1
H-NMR(400M,CDCl3
):δ
ppm8.00(d,J
=8.4Hz,1H),7.51-7.57(m,4H),7.35(d,J
=8.4Hz),7.24(s,1H),7.10-7.16(m,4H),5.04-5.06(m,1H).LCMS:Calculated 407.0,found 430.0([M+Na]+
)。
氮氣保護下,將三氯氧磷(285mg,1.866mmol)滴加到無水DCM中(10mL),降溫至-40℃,滴加入9-A3(380mg,0.933mmol)的DCM溶液(4mL),然後滴加入三乙胺(236mg,2.333mmol),保溫-40℃-35℃兩小時,、LC-LCMS監測,9-A3消失,轉化為中間體。-40℃,加入2-溴乙胺氫溴酸鹽(1.53g,7.464mmol),然後滴加入三乙胺(755mg,7.464mmol)的DCM溶液(2ml),保溫-40℃一小時,中間體轉化完畢。自然升溫至0℃,滴加入飽和氯化銨水溶液(5mL),DCM萃取(10mL×3),純淨水洗(3mL×3),乾燥濃縮,柱分離。(200-300目矽膠,正庚烷:EA=1:1得產品,m=350mg,類白固體,收率=53.7%。)。1
H-NMR(400M,CDCl3
):δ
ppm8.01(d,J
=8.4Hz,1H),7.52-7.58(m,4H),7.34(d,J
=8.4Hz,1H),7.11-7.18(m,5H),5.61-5.68(m,1H),3.13-3.81(m,10H).LCMS Calculated:699.0,found 700.0([M+H]+
)。
氮氣保護下,將9-A4(350mg,0.5mmol)溶於THF中(10mL),然後加入氧化銀(700mg,3.0mmol),DIPEA(390mg,3.0mmol),升溫至65℃,攪拌3小時。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,製備色譜製備得純品(m=31.4mg,白色固體,
收率11.7%。)。1
H-NMR(400M,CD3
OD):δ
ppm8.08(d,J
=8.4Hz,1H),7.63-7.69(m,4H),7.50(d,J
=8.4Hz,1H),7.31(s,1H),7.16-7.20(m,4H),5.99-6.04(m,1H),2.03-2.24(m,8H).LCMS:Calculated 537.0,found 538.0([M+H]+
)。
氮氣保護下,將11-A1(500mg,2.97mmol)和對三氟甲氧基苯酚(684mg,3.84mmol,商業購買醫藥)溶於乙腈中(10mL),然後加入碳酸鉀(820mg,5.94mmol,商業購買),升溫至85℃,攪拌2小時,反應完畢。降至常溫,抽濾,濃縮母液,柱分離。(200-300目矽膠,正庚烷:EA=30:1得產品11-A2共520mg,淡黃色固體,收率53.5%。)。1
H-NMR(400M,CDCl3
):δ
ppm9.99(s,1H),8.06(d,J
=8.4Hz,1H),7.73(dd,J1
=8.4Hz,J2
=1.6Hz,1H),7.50(d,J2
=1.2Hz,1H),7.29(d,J
=8.4Hz,1H),7.10-7.14(m,2H)。
氮氣保護下,將11-A2(500mg,1.528mmol)溶於無水THF中(8mL),然後滴加入(三氟甲基)三甲基矽烷(370mg,2.598mmol),降溫至0℃,滴加入TBAF(0.03mL,1MinTHF),保溫0℃1.5小時,反應完畢。滴加入3N的鹽酸2mL,自然升至常溫,攪拌1小時。加入水5mL,DCM萃取(10mL×3),水洗(5mL×3),乾燥濃縮,柱分離。(200-300目矽膠,正庚烷:EA=20:1-10:1得產品(400mg,收率65.9%),為黃色油狀物。1
H-NMR(400M,CDCl3
):δ
ppm8.00(d,J
=8.4Hz,1H),7.38(d,J
=8.4Hz,1H),7.25(d,J
=8.8Hz,2H),7.21(s,1H),7.06(d,J
=8.8Hz,2H),5.04-5.09(m,1H),3.05(brs,1H)。
氮氣保護下,將三氯氧磷(310mg,2.014mmol)滴加到無水DCM中(10mL),降溫至-40℃,滴加入11-A3(400mg,1.007mmol)的DCM溶液(4mL),然後滴加入三乙胺(255mg,2.518mmol),保溫-40℃到-35℃範圍兩小時,LC-LCMS監測,11-A3消失,轉化為中間體。-40℃,加入2-溴乙胺氫溴酸鹽(1.65g,8.056mmol),然後滴加入三乙胺(815mg,8.056mmol)的DCM溶液(2ml),保溫-40℃一小時,中間體轉化完畢。自然升溫至0℃,滴加入飽和氯化銨水溶液(5mL),DCM萃取(10mL×3),純淨水洗(3mL×3),乾燥濃縮,柱分離。(200-300目矽膠,正庚烷:EA=1:1-100%EA得11-A4產品(m=160mg,收率為23.1%),為黃色油狀液體。1
H-NMR(400M,CDCl3
):δ
ppm8.02(d,J
=8.4Hz,1H),7.38(d,J
=8.4Hz,1H),7.27(d,J
=8.8Hz,2H),7.14(s,1H),7.08(d,J
=8.8Hz,2H),5.63-5.68(m,1H),3.46-3.49(m,2H),3.34-3.42(m,2H),3.26-3.32(m,2H),3.02-3.25(m,4H).LCMS:Calculated LCMS:688.9,found 689.8([M+H]+
)。
氮氣保護下,將11-A4(160mg,0.230mmol)溶於THF中(10mL),然後加入氧化銀(323mg,1.393mmol),DIPEA(180mg,1.393mmol),升溫至65℃,攪拌3小時。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,製備得11號化合物純品(m=26.3mg,收率21.7%),為黃色蠟狀物。1
H-NMR(400M,CDCl3
):δ
ppm8.01(d,J
=8.4Hz1H),7.39(d,J
=8.4Hz,1H),7.26(d,J
=8.8Hz,2H),7.18(s,1H),7.05-7.08(m,2H),5.60-5.74(m,1H),2.00-2.26(m,8H).LCMS:Calculated 527.1,found 528.0([M+H]+
)。
將12-A1(1.0g,5.9mmol)與4-氟-3(三氟甲基)苯酚(2.1g,11.8mmol,2eq,商業購買)溶於乙腈(20ml),氮氣下將K2
CO3
(1.6g,11.8mmol,2eq)加入至體系,升溫至80℃,監測1h後原料消失,反應完畢。後處理:降至室溫後矽藻土抽濾體系,DCM洗滌,母液旋乾後拌樣,300-400矽膠10倍flash過柱(正庚烷:EA=94%:6%)可得12-A2(1.15g,59.2%),為淡黃色油狀液體。1
H-NMR(400M,CDCl3
):δ
ppm10.00(s,1H),8.08(d,J
=8.0Hz,1H),7.76(dd,J1
=8.4Hz,J2
=1.6Hz,1H),7.46(d,J
=1.6Hz,1H),7.33-7.34(m,1H),7.27-7.28(m,1H),7.26-7.53(m,1H)。
氮氣保護,將12-A2(620mg,1.9mmol,)與TMSCF3
(539mg,3.8mmol,2eq)溶於THF(6mL)中,降溫至0℃,將TBAF(0.04ml,0.04mmol,1MinTHF,商業購買)滴加至體系,保溫0℃30min後12-A2全部消失,滴加3N HCl(3ml)至體系,體系變澄清,繼續0℃攪拌1h後全部成為產物。後處理:DCM萃取(5ml×3),有機相水洗(5ml×3),有機相乾燥旋乾拌樣,300-400矽膠7倍拌樣(正庚烷:EA=95:5)可得12-A3(600mg,79.1%),為淡黃色油狀物。1
H-NMR(400M,CDCl3
):δ
ppm8.02(d,J
=8.4Hz,1H),7.41(d,J
=8.4Hz,1H),7.29(dd,J1
=6.4Hz,J2
=2.8Hz,1H),7.24-7.18(m,3H),5.08(dd,J1
=12.4Hz,J2
=6.0Hz,1H)。
氮氣保護,將POCl3
(384mg,2.5mmol,2eq)溶於DCM(5ml)後降溫至-40℃,然後將12-A3(500mg,1.3mmol)溶於DCM(2ml)後與TEA(317mg,3.1mmol,2.5eq)滴加至體系,保溫-40℃2h後12-A3全部轉化為中間體,然後將2-溴乙胺溴酸鹽(2.1g,10.0mmol,8eq)與TEA(1.0g,10.0mmol)加入至體系,監測,30min後反應完畢。後處理:0℃加入飽和氯化銨水溶液(10ml),DCM萃取(20ml×3),有機相水洗鹽水洗,旋乾後200-300矽膠8倍,(正庚烷:EA=1:1)可得12-A4(350mg,39.0%),為淡黃色油狀物。1
H-NMR(400M,CDCl3
):δ
ppm8.06(d,J
=8.4Hz,1H),7.44(d,J
=8.4Hz,1H),7.33-7.35(m,1H),7.24-7.29(m,2),7.17(s,1H),5.70(dd,J=11.5,6.0Hz,1H),3.86-2.96(m,10H).LCMS:Calculated 690.9,found 691.8([M+1]+
)。
氮氣保護,將12-A4(350mg,0.5mmol)溶於THF(10ml)後將Ag2
O(587mg,2.5mmol)與DIEA(327mg,2.5mmol,5eq)加入至體系,升溫至回流,監測,2h後反應完畢。降至室溫,矽藻土抽濾,DCM洗滌,母液旋乾,中性製備。得12號化合物(74mg,26.4%),為淡黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.04(d,J
=8.4Hz,1H),7.43(dd,J
=8.4Hz,1H),7.28-7.26(m,1H),7.23-7.22(m,2H),7.18(s,1H),5.76-5.71(m,1H),2.27-2.02(m,8H).LCMS:Calculated 529.1,found 530.0([M+1]+
)。
氮氣保護下,13-A1(500mg,2.95mmol)、3-羥基喹啉(470mg,3.24mmol,商業購買)溶於乙腈ACN(5mL)中,加入碳酸鉀(830mg,6mmol),升溫80℃攪拌4小時。反應完畢後,矽藻土抽濾,濃縮,拌樣,柱層析分離(100-200目矽膠,正庚烷:EA=10:1),得產品(560mg,64.5%),為白色固體,直接用於下一步。1
H-NMR(300MHz,DMSO):δ
ppm10.02(s,1H),8.92(d,J
=2.6Hz,1H),8.34(d,J
=8.2Hz,1H),8.09(d,J
=8.6Hz,2H),7.94(t,J
=8.2Hz,2H),7.82(s,1H),7.76(t,J
=7.1Hz,1H),7.65(t,J
=7.2Hz,1H).LCMS:Calculated 294.0,found 295.0([M+H]+
)。
氮氣保護下,將13-A2(460mg,1.56mmol),三氟甲基三甲基矽烷(430mg,3mmol)溶於THF(5mL),零度滴加四丁基氟化銨的THF溶液(0.1mL,0.1mmol,1M),保溫6小時,加1N鹽酸(2mL)攪拌10分鐘。濃縮除掉THF,粗品加水(10mL)和DCM(20mL)萃取,有機相分離濃縮拌樣,粗品柱層析分離(100-200目矽膠,正庚烷:EA=10:1)得產品400mg,淡黃色固體。1
H-NMR(400MHz,DMSO):δ
ppm8.87(d,J
=2.8Hz,1H),8.23(d,J
=8.5Hz,1H),8.08(d,J
=8.4Hz,1H),8.00(d,J
=2.7Hz,1H),7.96(d,J
=7.4Hz,1H),7.76(ddd,J
=8.4,6.9,1.4Hz,1H),7.69-7.62(m,1H),7.58(d,J
=8.5Hz,1H),7.43(s,1H),7.19(d,J
=5.9Hz,1H),5.43-5.31(m,1H).LCMS:Calculated 364.0,found 365.0([M+H]+
)。
氮氣保護下,POCl3
(168mg,1.1mmol)滴入超乾DCM中(5mL),降溫至-30℃,滴加入13-A3(200mg,0.55mmol)的DCM(5mL)溶液,後滴入TEA(170mg,1.65mmol),保溫-30℃,6h後至原料完全消失。-30℃加入2-溴乙胺氫溴酸鹽(897mg,4.4mmol)後,再滴入TEA(440mg,4.4mmol),反應完畢後,降溫至0℃,加入NH4
Cl飽和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),乾燥,濃縮得粗品150mg,為黃色固體,直接用於下一步反應。
氮氣保護下,13-A4(150mg,0.23mmol)溶於THF(10mL)中,加入Ag2
O(170mg,1.38mmol)及N,N-二異丙基乙胺(163mg,1.38mmol),升溫至65℃反應。2h反應完畢後,矽藻土抽濾,DCM(20mL)洗滌固體,濃縮母液,高效液相製備得13號化合物純品(41mg,36%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm8.82(d,J=2.8Hz,1H),8.22(d,J=8.5Hz,1H),8.10(d,J=8.6Hz,1H),7.94-7.87(m,2H),7.77(ddd,J=8.4,6.9,1.4Hz,1H),7.69-7.62(m,2H),7.52(s,1H),6.13-6.02(m,1H),2.29-1.98(m,8H).LCMS:Calculated 494.1,found 495.0([M+H]+
)。
氮氣保護下將間溴苯酚(14-A0,1.5g,8.57mmol)與對氟苯硼酸(14-A1,1.0g,7.15mmol,商業購買)加入至二氧六環(30mL)與H2
O(5mL)的混合液中,抽充氮氣3次,將Pd(AcO)2
(80mg,0.36mmol),PPh3
(94mg,0.36mmol)與K2
CO3
(3.0g,21.44mmol)加入後再次抽充氮氣三次,升溫至100℃。監測1h,反應完畢。後處理:降至室溫,抽濾後EtOAc(50mL×3)萃取,有機相水洗鹽水洗,柱分離(200-300目矽膠,正庚烷:EA=12:1-9:1)得14-A2產品(1.1g,收率62.7%),為白色固體。1
H-NMR(300MHz,MeOD):δ
ppm7.59-7.54(m,2H),7.23-7.10(m,3H),7.04-6.99(m,2H),6.76(dd,J
=8.1,1.5Hz,1H).LCMS:Calculated 188.1,found 189.1([M+H]+
)。
將14-A2(580mg,3.08mmol)與3-氟-4硝基苯甲醛(434mg,2.57mmol,商業購買)溶於乙腈(10mL),氮氣下將K2
CO3
(887mg,6.42mmol)加入至體系,升溫至80℃,監測2h後,反應完畢。降至室溫後矽藻土抽濾,DCM洗滌,母液濃縮,柱分離(flash反相柱,乙腈:H2
0=50%:50%)得14-A3產品(320mg,33.7%),為黃色油狀物。1
H-NMR(400MHz,CDCl3
):δ
ppm9.98(s,1H),8.05(d,J
=8.4Hz,1H),7.71(d,J
=1.6Hz,1H),7.69-7.43(m,5H),7.28-7.27(m,1H),7.15-7.11(m,2H),7.08-7.05(m,1H)。
氮氣保護,將14-A3(350mg,1.04mmol,)與TMSCF3
(296mg,2.08mmol)溶於THF(4mL)中,降溫至0℃,將TBAF(0.01mL,0.01mmol,1M in THF)滴加至體系,保溫0℃30min後反應物14-A3全部消失,滴加3N HCl(2mL)至體系,體系變澄清,繼續0℃攪拌1h後全部成為產物。DCM萃取(5mL×3),有機相水洗(5mL×3),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=12:1-10:1)得產品(350mg,收率82.8%),為黃色固體。1
H-NMR(400MHz,CDCl3
):δ
ppm8.00(d,J
=8.4Hz,1H),7.53-7.34(m,5H),7.24-7.23(m,2H),7.15-7.11(m,2H),7.03-7.00(m,1H),5.03-5.02(m,1H).LCMS:Calculated 407.1,found 408.0([M+H]+
)。
氮氣保護,將POCl3
(188mg,1.23mmol)溶於DCM(5mL)後降溫至-40℃,然後將14-A4(250mg,0.61mmol)溶於DCM(2mL)後與TEA(155mg,1.53mmol)滴加至體系,保溫-40℃3h後15-A3全部轉化為中間體,然後將溴乙胺溴酸鹽(1.0g,4.91mmol)與TEA(497mg,4.91mmol)加入至體系,監測,30min後反應完畢。0℃加入飽和NH4
Cl(5mL),DCM萃取(20mL×3),有機相水洗鹽水洗,有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=2:1-1:1)得產品(200mg,46.6%),為黃色固體。1
H-NMR(400MHz,CDCl3
):δ
ppm8.01(d,J
=8.4Hz,1H),7.54-7.33(m,5H),7.25(d,J
=2.0Hz,1H),7.18(s,1H),7.15-7.10(m,2H),7.03(d,J
=1.2Hz,1H),5.70-5.60(m,1H),3.38-3.08(m,8H)。LCMS:Calculated 699.0,found 699.9([M+H]+
)。
氮氣保護下,將15-A5(150mg,0.22mmol)溶於THF中(15mL),然後加入氧化銀(497mg,2.1mmol),DIPEA(277mg,2.1mmol),升溫至65℃,攪拌1.5h。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,高效液相製備得純品(56mg,48.6%),為白色固體。1
H-NMR(400MHz,MeOD)δ8.08(d,J
=8.4Hz,1H),7.67-7.59(m,2H),7.56-7.46(m,3H),7.31(d,J
=2.2Hz,2H),7.22-7.13(m,2H),7.10-7.05(m,1H),6.05-5.95(m,1H),2.29-1.89(m,8H).LCMS:Calculated 537.1,found 538.1([M+H]+
)。
將15-A1(500mg,2.96mmol,商業購買)與15-A0(554mg,2.69mmol)溶於乙腈(10ml),氮氣下將K2
CO3
(743mg,5.38mmol)加入至體系,升溫至80℃,監測1.5h後,反應完畢。降至室溫後矽藻土抽濾,DCM洗滌,母液濃縮,柱分離(200-300目矽膠,正庚烷:EA=15:1-10:1)得產品(535mg,收率56.0%),為棕色油狀物。1
H-NMR(400MHz,CDCl3
):δ
ppm9.99(s,1H),8.05(d,J
=8.4Hz,1H),7.71(d,J
=8.4Hz,1H),7.56-7.55(m,3H),7.41(dd,J 1
=8.44.8Hz,1H),7.16(d,J
=8.4Hz,2H),7.00-6.91(m,2H)。
氮氣保護,將15-A2(400mg,1.13mmol,)與TMSCF3(320mg,2.25mmol)溶於THF(4mL)中,降溫至0℃,將TBAF(0.02ml,0.02mmol,1MinTHF)滴加至體系,保溫0℃30min後15-A2全部消失,滴加3NHCl(2ml)至體系,體系變澄清,繼續0℃攪拌1h後,DCM萃取(5ml×3),有機相水洗(5ml×3),有機相乾燥濃縮,得到粗品(405mg,收率56.4%),為黃色固體,直接投於下步反應。LCMS:Calculated 425.3,found 426.0([M+1]+
)。
氮氣保護,將POCl3
(209mg,1.36mmol,商業購買)溶於DCM(5ml)後降溫至-40℃,然後將15-A3(290mg,0.68mmol)溶於DCM(2ml)後與TEA(173mg,1.70mmol)滴加至體系,保溫-40℃2h後15-A3全部轉化為中間體,然後將溴乙胺溴酸鹽(1.1g,5.46mmol)與TEA(552mg,5.46mmol)加入至體系,監測,30min後反應完畢。0℃加入飽和NH4
Cl(5ml),DCM萃取(20ml×3),有機相水洗鹽水洗,有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=5:1-3:1)得到產品(250mg,收率51.1%),為黃色固體。1
H-NMR(400MHz,CDCl3
):δ
ppm8.00(d,J
=8.4Hz,1H),7.54(d,J
=7.6Hz,2H),7.44-7.38(m,1H),7.35(d,J
=8.4Hz,1H),7.21(s,1H),7.13(d,J
=8.8Hz,1H),7.00-6.95(m,2H),5.68-5.62(m,1H),3.42-3.11(m,8H).LCMS:Calculated 717.2,found 717.9([M+H]+
)。
氮氣保護下,將15-A4(230mg,0.32mmol)溶於THF中(15mL),然後加入氧化銀(372mg,1.60mmol),DIPEA(207mg,1.60mmol),升溫至65℃,攪拌1.5h。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,高效液相製備得純品(102mg,57.5%),為白色固體。1
H-NMR(400MHz,CDCl3
):δ
ppm8.01(d,J
=8.4Hz,1H),7.54(d,J
=1.6Hz,2H),7.51-7.36(m,2H),7.24(s,1H),7.12-7.11(m,2H),6.97-6.93(m,2H),5.72-5.69(m,1H),2.26-2.01(m,8H).LCMS:Calculated 555.1,found 556.1([M+H]+
)。
氮氣保護下,將3-氟-4-溴苯酚(5.0g,26.2mmol,商業購買,97%)與對氟苯硼酸(4.0g,28.8mmol,商業購買,97%)溶於二氧六環與水的混合溶劑中(100mL,二氧六環:水=9:1),然後加入碳酸鉀(10.8g,78.6mmol),抽充三次氣體,加入醋酸鈀(295mg,1.31mmol,商業購買,95%),三苯基磷(345mg,1.31mmol,商業購買,97%),再次抽充三次氣體,升溫至100℃,攪拌過夜。反應完畢之後,降至常溫,矽藻土抽濾,EA洗滌,濃縮母液,用1N的鹽酸調節至pH=3,EA萃取(50mL×3),水洗(10mL×3),鹽水洗,乾燥濃縮,柱分離(100-200目矽膠,正庚烷:EA=20:1)得產品16-A0(3.5g,64.8%),為白色固體。1
H-NMR(300M,DMSO-d6)
:δ
ppm10.02(s,1H),7.52-7.47(m,2H),7.34-7.23(m,3H),6.71-6.64(m,2H).LCMS:Calculated 206.1,found 204.8([M-H]-
)。
氮氣保護下,將16-A1(930mg,5.50mmol,商業購買,97%)和16-A0(1.36g,6.60mmol)溶於乙腈中(20mL),然後加入碳酸鉀(1.52g,11.0mmol,商業購買,99%),升溫至85℃,攪拌2小時,反應完畢。降至常溫,抽濾,濃縮母液,柱分離(200-300目矽膠,正庚烷:EA=15:1)得到16-A2(1.10g,56.4%),為淡黃色固體。1
H-NMR(400MHz,DMSO-d6
):δ
ppm10.05(s,1H),8.30(d,J
=8.3Hz,1H),7.92(dd,J
=8.3,1.5Hz,1H),7.78(d,J
=1.5Hz,1H),7.69-7.55(m,3H),7.36-7.28(m,2H),7.27-7.21(m,1H),7.09(dd,J
=8.5,2.3Hz,1H)。
氮氣保護下,將16-A2(700mg,1.970mmol)溶於無水THF中(10mL),然後滴加入(三氟甲基)三甲基矽烷(476mg,3.35mmol,商業購買,98%),降溫至0℃,滴加入TBAF(0.04mL,1MinTHF),保溫0℃1.5小時,反應完畢。滴加入3N的鹽酸2mL,自然升至常溫,攪拌1小時。加入水5mL,DCM萃取(10mL×3),水洗(5mL×3),乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=15:1-10:1得到產品(810mg,96.7%),為黃色油狀物16-A3。1
H-NMR(400MHz,DMSO-d6
):δ
ppm8.19(d,J
=8.5Hz,1H),7.63-7.52(m,4H),7.44(s,1H),7.32(t,J
=8.9Hz,2H),7.21(d,J
=5.8Hz,1H),7.14(dd,J
=11.7,2.4Hz,1H),6.97(dd,J
=8.5,2.1Hz,1H),5.44-5.37(m,1H)。
氮氣保護下,將三氯氧磷(580mg,3.76mmol,商業購買,97%)滴加到無水DCM中(10mL),降溫至-40℃,滴加入16-A3(800mg,1.88mmol)的DCM溶液(4mL),然後滴加入三乙胺(476mg,4.70mmol),保溫-40℃—-35℃兩小時,、LC-LCMS監測,16-A3消失,轉化為中間體。-40℃,加入2-溴乙胺氫溴酸鹽(3.08g,15.04mmol),然後滴加入三乙胺(1.52g,15.04mmol)的DCM溶液(2ml),保溫-40℃一小時,中間體轉化完畢。自然升溫至0℃,滴加入飽和氯化銨水溶液(5mL),DCM萃取(10mL*3),純淨水洗(3ml*3),乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-100)得產品16-A4共600mg,收率44.4%,為白色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.04(d,J
=8.4Hz,1H),7.55-7.47(m,2H),7.46-7.38(m,2H),7.27(s,1H),7.19-7.10(m,2H),6.95-6.83(m,2H),5.69(dd,J
=11.4,6.1Hz,1H),3.50-3.18(m,8H).LCMS:Calculated 716.9,found 717.8([M+H]+
)。
氮氣保護下,將16-A4(600mg,0.837mmol)溶於THF中(15mL),然後加入氧化銀(1.16mg,5.02mmol),DIPEA(649mg,5.02mmol),升溫至65℃,攪拌3小時。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,加入1.5mL無水乙醚結晶,抽濾得純品16號化合物(159mg,收率34.2%),為白色固體。1
H-NMR(400MHz,MeOD)δ
ppm8.12(t,J
=8.1Hz,1H),7.55(m,4H),7.45(s,1H),7.19(t,J
=8.8Hz,2H),6.98(dd,J
=7.8,5.3Hz,2H),6.15-5.98(m,1H),2.39-1.93(m,8H).LCMS:Calculated 555.1,found 556.1([M+H]+
)。
氮氣保護下,17-A1(1.7g,11mmol,商業購買)、17-A2(2g,10mmol)、乙酸鈀(21.5mg,0.1mmol)、三苯基膦(39mg,0.15mmol)和碳酸鉀(2.8,20mmol)溶於二氧六環(20mL)和水(2mL)中,升溫80℃攪拌過夜。反應完畢後,矽藻土抽濾,濃縮,拌樣,柱層析分離(100-200目矽膠,正庚烷:EA=5:1),得17-A3產品(900mg,40%),為白色固體)。1
H-NMR(300MHz,DMSO)δ10.17(s,1H),7.55-7.08(m,3H),6.79-6.50(m,3H).LCMS:Calculated 224.0,found 222.6[(M-H)-
]。
氮氣保護下,17-A3(500mg,2.2mmol)、3-氟-4-硝基苯甲醛(370mg,2.2mmol,商業購買)溶於ACN(5mL)中,加入碳酸鉀(830mg,6mmol),升溫80℃攪拌4小時。反應完畢後,矽藻土抽濾,濃縮,拌樣,柱層析分離(100-200目矽膠,正庚烷:EA=10:1),得17-A4粗品700mg(白色固體,80%純度),直接用於下一步。1
H-NMR(300MHz,DMSO)δ10.03(s,1H),8.31(d,J
=8.2Hz,1H),7.94(d,J
=8.4Hz,1H),7.83(s,1H),7.59-7.50(m,2H),7.40(t,J
=8.8Hz,1H),7.32-7.16(m,2H),7.10(d,J
=8.6Hz,1H)。
氮氣保護下,將17-A4(680mg,1.82mmol),三氟甲基三甲基矽烷(510mg,3.6mmol,商業購買)溶於THF(8mL),零度滴加四丁基氟化銨的THF溶液(0.1mL,0.1mmol,1M,商業購買),保溫6小時,加1N鹽酸(2mL)攪拌10分鐘。濃縮除掉THF,粗品加水(10mL)和DCM(20mL)萃取,有機相分離濃縮拌樣,粗品柱層析分離(100-200目矽膠,正庚烷:EA=10:1)得17-A5產品(400mg,收率為49.6%,純度90%),為淡黃色固體。1
H-NMR(300MHz,DMSO)δ8.19(d,J
=7.8Hz,1H),7.76(t,J
=8.5Hz,1H),7.57-7.51(m,2H),7.38(s,1H),7.28-7.19(m,3H),6.89(dd,J
=8.8,1.7Hz,1H),5.40-5.36(m,1H)。
氮氣保護下,POCl3
(168mg,1.1mmol,商業購買)滴入超乾DCM中(5mL),降溫至-30℃,滴加入17-A5(220mg,0.5mmol)的DCM(5mL)溶液,後滴入TEA(170mg,1.65mmol),保溫-30℃,6h後至原料完全消失。-30℃加入2-溴乙胺氫溴酸鹽(897mg,4.4mmol)後,再滴入TEA(440mg,4.4mmol),反應完畢後,降溫至0℃,加入NH4
Cl飽和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),乾燥,濃縮得17-A6粗品250mg,為黃色固體,直接用於下一步反應。LCMS:Calculated 732.9,found 733.9([M+H]+
)。
氮氣保護下,17-A6(250mg,0.34mmol)溶於THF(10mL)中,加入Ag2
O(210mg,1.7mmol,商業購買)及N,N-二異丙基乙胺(220mg,1.7mmol),升溫至65℃反應。2h反應完畢後,矽藻土抽濾,DCM(20mL)洗滌固體,濃縮母液,高效液相製備得17號化合物純品22mg(白色固體,11%)。1
H-NMR(400MHz,DMSO)δ8.26(d,J
=8.5Hz,1H),7.67(d,J
=8.5Hz,1H),7.59-7.48(m,3H),7.41(dt,J
=10.3,2.5Hz,1H),7.24-7.19(m,2H),7.03(dd,J
=8.5,2.3Hz,1H),6.36-6.32(m,1H),2.20-1.91(m,8H).LCMS:Calculated 573.1,found 574.1([M+H]+
)。
氮氣保護下,將2-溴-5-羥基吡啶(3.0g,17.2mmol,邢臺奧帆)與對氟苯硼酸(18-A0,2.7g,19.0mmol,商業購買)溶於二氧六環與水的混合溶劑中(60mL,二氧六環:水=9:1),然後加入碳酸鉀(4.7g,34.4mmol),抽充三次氣體,加入醋酸鈀(193mg,0.86mmol,商業購買),三苯基磷(225mg,0.86mmol,商業購買),再次抽充三次氣體,升溫至100℃,攪拌過夜。反應完畢之後,降至常溫,矽藻土抽濾,EA洗滌,濃縮母液,加入水15mL,EA萃取(50mL×3),水洗(10mL×3),鹽水洗,乾燥濃縮,柱分離。200-300目矽膠,正庚烷:EA=15:1得產品(1.2g,36.9%),為白色固體。1
H-NMR(400M,DMSO-d6)
:δ
ppm10.03(s,1H),8.20(d,J=2.7Hz,1H),8.00(dd,J=8.8,5.6Hz,2H),7.78(d,J=8.6Hz,1H),7.32-7.18(m,3H).LCMS:Calculated 189.1,found 190.2([M+H]+
)。
氮氣保護下,將18-A1(600mg,3.55mmol)和18-A0(806mg,4.26mmol)溶於乙腈中(15mL),然後加入碳酸鉀(980mg,7.1mmol,商業購買),升溫至85℃,攪拌2小時,反應完畢。降至常溫,抽濾,濃縮母液,柱分離(200-300目矽膠,正庚烷:EA=10:1)得到產品18-A2(760mg,63.3%),淡黃色固體。1
H-NMR(400MHz,DMSO-d6
):δ
ppm10.03(s,1H),8.59(d,J
=2.8Hz,1H),8.31(d,J
=8.3Hz,1H),8.19-8.11(m,2H),8.07(d,J
=8.7Hz,1H),7.90(dd,J
=8.3,1.6Hz,1H),7.78-7.70(m,2H),7.37-7.26(m,2H).LCMS:Calculated 338.1,found 339.0([M+H]+
)。
氮氣保護下,將18-A2(700mg,2.07mmol)溶於無水THF中(10mL),然後滴加入(三氟甲基)三甲基矽烷(500mg,3.52mmol),降溫至0℃,滴加入TBAF(0.03mL,1MinTHF),保溫0℃1.5小時,反應完畢。滴加入3N的鹽酸(2mL),自然升至常溫,攪拌1小時。加入水5mL,DCM萃取(10mL×3),水洗(5mL×3),乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=15:1-10:1)得產品(550mg,65.1%),為黃色油狀物。1
H-NMR(400MHz,DMSO-d6
):δ
ppm8.52(d,J
=2.9Hz,1H),8.19(d,J
=8.5Hz,1H),8.16-8.10(m,2H),8.06(d,J
=8.8Hz,1H),7.64(dd,J
=8.8,2.9Hz,1H),7.55(dd,J
=8.7,3.3Hz,1H),7.38(s,1H),7.36-7.28(m,2H),7.18(dd,J
=5.8,3.4Hz,1H),5.43-5.34(m,1H).LCMS:Calculated 408.1,found 409.2[M+H]+
)。
氮氣保護下,將三氯氧磷(414mg,2.70mmol,商業購買)滴加到無水DCM中(10mL),降溫至-40℃,滴加入18-A3(550mg,1.35mmol)的DCM溶液(4mL),然後滴加入三乙胺(342mg,3.36mmol),保溫-40℃至-35℃
兩小時,、LC-LCMS監測,18-A3消失,轉化為中間體。-40℃,加入2-溴乙胺氫溴酸鹽(2.2g,10.8mmol),然後滴加入三乙胺(1.1g,10.8mmol)的DCM溶液(2ml),保溫-40℃一小時,中間體轉化完畢。自然升溫至0℃,滴加入飽和氯化銨水溶液(5mL),DCM萃取(10mL×3),純淨水洗(3ml×3),乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-100%EA)得產品(520mg,55.0%),為白色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.49(d,J
=2.7Hz,1H),8.06(dd,J
=8.4,2.7Hz,1H),8.01-7.94(m,2H),7.77(d,J
=8.7Hz,1H),7.54-7.48(m,1H),7.43(d,J
=8.3Hz,1H),7.26-7.24(m,1H),7.18(t,J
=8.7Hz,2H),5.69(dq,J
=12.3,6.2Hz,1H),3.49-3.16(m,8H).LCMS:Calculated 700.0,found 700.9([M+H]+
)。
氮氣保護下,將18-A4(520mg,0.743mmol)溶於THF中(15mL),然後加入氧化銀(1.03g,4.46mmol,商業購買),DIPEA(580mg,4.46mmol),升溫至65℃,攪拌3小時。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,高效液相製備得18號化合物純品(106.7mg,26.7%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm8.43(d,J
=2.9Hz,1H),8.16(d,J
=8.5Hz,1H),8.07-7.97(m,2H),7.92(d,J
=8.8Hz,1H),7.65-7.54(m,2H),7.46(s1H),7.24-7.19(m,2H),6.13-6.03(m,1H),2.26-2.08(m,8H).LCMS:Calculated 538.1,found 539.1([M+H]+
)。
氮氣保護下,19-A1(500mg,2.65mmol,商業購買)、19-A2(460mg,2.65mmol,商業購買)、四三苯基膦鈀(373mg,0.3mmol)和氟化鉀(300mg,5.2mmol)溶於甲苯(10mL)和水(1mL)中,升溫80℃攪拌過夜。反應完畢後,矽藻土抽濾,濃縮,拌樣,柱層析分離(100-200目矽膠,正庚烷:EA=10:1),得19-A3產品(600mg,94.7%),為白色固體。1
H-NMR(300MHz,DMSO)δ10.24(s,1H),8.26(d,J
=2.4Hz,1H),8.19(d,J
=8.1Hz,2H),7.91(d,J
=8.7Hz,1H),7.78(d,J
=8.1Hz,2H),7.29(dd,J
=8.6,2.7Hz,1H).LCMS:Calculated 239.0,found 240.0([M+H]+
)。
氮氣保護下,19-A3(870mg,2.9mmol)、3-氟-4-硝基苯甲醛(490mg,2.9mmol,商業購買)溶於ACN(8mL)中,加入碳酸鉀(830mg,6mmol),升溫80℃攪拌4小時。反應完畢後,矽藻土抽濾,濃縮,拌樣,柱層析分離(100-200目矽膠,正庚烷:EA=10:1),得19-A4產品(640mg)為白色固體。1
H-NMR(300MHz,CDCl3
)δ10.03(s,1H),8.57(d,J
=2.7Hz,1H),8.15-8.12(m,3H),7.87-7.75(m,4H),7.60-7.51(m,2H).LCMS:Calculated 388.0,found 389.1([M+H]+
)。
氮氣保護下,將19-A4(640mg,1.64mmol),三氟甲基三甲基矽烷(430mg,3mmol,商業購買)溶於THF(5mL),0℃滴加四丁基氟化銨的THF溶液(0.1mL,0.1mmol,1M,商業購買),保溫6小時,加1N鹽酸(2mL)攪拌10分鐘。濃縮除掉THF,粗品加水(10mL)和DCM(20mL)萃取,有機相分離濃縮拌樣,粗品柱層析分離(100-200目矽膠,正庚烷:EA=10:1)得產品(640mg,85.2%),為淡黃色固體。1
H-NMR(300MHz,DMSO)δ8.59(d,J
=2.7Hz,1H),8.30(d,J
=7.5Hz,2H),8.19(t,J
=9.2Hz,2H),7.86(d,J
=8.5Hz,2H),7.72-7.65(m,1H),7.59-7.56(m,1H),7.43(s,1H),7.20(d,J
=5.8Hz,1H),5.39-5.37(m,1H).LCMS:Calculated 458.0,found 459.0([M+H]+
)。
氮氣保護下,POCl3
(200mg,1.3mmol)滴入超乾DCM中(5mL),降溫至-30℃,滴加入19-A5(300mg,0.65mmol)的DCM(5mL)溶液,後滴入TEA(270mg,2.6mmol),保溫-30℃,6h後至原料完全消失。-30℃加入2-溴乙胺氫溴酸鹽(1.1g,5.2mmol)後,再滴入TEA(530mg,5.2mmol),反應完畢後,降溫至0℃,加入NH4
Cl飽和溶液(10mL),DCM萃取(15mL×2),水洗(5mL×4),乾燥,濃縮得粗品200mg,為黃色固體,直接用於下一步反應。1
H-NMR(400MHz,CDCl3
)δ8.46(d,J
=2.6Hz,1H),8.07-7.99(m,3H),7.78-7.75(m,1H),7.68(d,J
=8.2Hz,2H),7.48-7.33(m,3H),5.65-5.61(m,1H),3.51-3.04(m,10H).LCMS:Calculated 747.9,found 748.9([M+H]+
)。
氮氣保護下,19-A6(150mg,0.23mmol)溶於THF(10mL)中,加入Ag2
O(170mg,1.38mmol,商業購買)及N,N-二異丙基乙胺(163mg,1.38mmol),升溫至65℃反應。2h反應完畢後,矽藻土抽濾,DCM(20mL)洗滌固體,濃縮母液,高效液相製備得純品(41mg,36%),為白色固體。1
H-NMR(400MHz,DMSO)δ8.61(d,J
=2.8Hz,1H),8.31(d,J
=8.2Hz,2H),8.27(d,J
=8.5Hz,1H),8.21(d,J
=8.8Hz,1H),7.87(d,J
=8.4Hz,2H),7.72(dd,J
=8.8,2.9Hz,1H),7.65(d,J
=8.5Hz,1H),7.56(s,1H),6.32-6.28(m,1H),2.17-1.90(m,8H).LCMS:Calculated 588.1,found 589.1([M+H]+
)。
氮氣保護下將2-溴-5-羥基吡啶(1.5g,8.52mmol,商業購買)與對羥基苯硼酸(1.4g,10.23mmol,商業購買)加入至DME(33mL)與H2
O(7mL)的混合液中,抽充氮氣3次,將Pd(PPh3
)4
(300mg,0.26mmol,商業購買)與Na2
CO3
(1.8g,17.05mmol)加入後再次抽充氮氣三次,升溫至80℃反應。監測2.5h,反應完畢。降至室溫,EtOAc(50mL×3)萃取,有機相水洗鹽水洗,柱分離(200-300目矽膠,正庚烷:EA=12:1-9:1)得產品(1.4g,收率86.8%),為白色固體。1
H-NMR(300MHz,MeOD):δ
ppm8.43(d,J
=2.7Hz,1H),7.81-7.77(m,3H),7.64-7.58(m,1H),6.87(d,J
=8.7Hz,2H).LCMS:Calculated 189.1,found 190.1([M+H]+
)。
氮氣保護下,將20-A3(即46號化合物,100mg,0.27mmol)溶於丙酮中(5mL),然後將20-A2(102mg,0.54mmol),Cs2
CO3
(309mg,0.95mmol),室溫攪拌2小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得20號化合物純品(17mg,11.7%),為棕褐色固體。1
H-NMR(400MHz,MeOD)δ8.52(d,J
=2.9Hz,1H),8.10(d,J
=8.5Hz,1H),8.06(d,J
=8.8Hz,2H),7.92(dd,J
=8.8,4.3Hz,1H),7.68(dt,J
=8.6,2.9Hz,1H),7.54(d,J
=8.6Hz,1H),7.37(s,1H),7.19(d,J
=8.8Hz,2H),6.06-5.99(m,1H),2.27-1.97(m,8H).LCMS:Calculated 538.1,found 539.1([M+H]+
)。
氮氣保護下將21-A1(2.0g,14.5mmol)與氯化亞碸(8ml)室溫攪拌1h,旋去氯化亞碸。加入THF10ml,體系降溫至0℃,加入呱啶(1.85g,21.8mmol)和TEA(2.2g,21.8mmol)的混合物。完畢後體系自然升溫至常溫。監測1h反應完畢。EtOAc(50mL)溶解,H2
O洗滌(30mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-0:1)得產品(720mg,收率24.3%),為白色固體。1
H-NMR(400MHz,DMSO-d6
):δ
ppm,9.64(s,1H)7.23(t,J
=8.0Hz,1H),6.79-6.82(m,1H),6.73(d,J
=7.6Hz,1H),6.70(d,J
=1.2Hz,1H)3.54(m,2H)3.26(m,2H),1.61-1.50(m,6H).LCMS:Calculated 205.1,found 206.2([M+H]+
)。
氮氣保護下,將21-A2(60mg,0.25mmol)溶於丙酮中(10mL),加入21-A3(即46號化合物,55.6mg,0.25mmol),Cs2
CO3
(245mg,0.75mmol),室溫攪拌2.5小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得21號化合物純品(25.0mg,16.9%),為類白色固體。1
H-NMR(400MHz,CD3
OD):δ
ppm,8.21(d,J
=8.0Hz,1H),7.60(d,J
=8.0Hz,1H),7.53(t,J
=8.0Hz,1H),7.41(s,1H),7.24(d,J
=8.0Hz,1H)7.20(dd,J
=8.0,2.4Hz,1H),7.05(s,1H),6.33-6.25(m,1H),3.55(m,2H),3.25(m,2H),2.15-1.93(m,8H),1.59-1.52(m,6H).LCMS:Calculated 554.2,found 555.2([M+H]+
)。
氮氣保護下將22-A1(0.2g,1.45mmol)與T3
P溶溶液(丙基磷酸酐偶聯試劑,CAS:68957-94-8,50%的EA溶液)與DCM5ml中,加入4,4-二氟呱啶(0.25g,1.6mmol)室溫攪拌。監測2h反應完畢。DCM(20mL)溶解,水洗(10mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1)得產品(190mg,收率54.4%),為白色固體。1
H-NMR(400MHz,CDCl3
):δ
ppm6.94-6.89(m,2H),6.87(d,J
=8.0Hz,1H),6.36(s,1H),3.87(m,2H),3.56(m,2H),2.04-1.97(m,4H).LCMS:Calculated 241.1,found 242.1([M+H]+
)。
氮氣保護下,將22-A2(60mg,0.25mmol)溶於丙酮中(10mL),然後將22-A3(即46號化合物,55.6mg,0.25mmol),Cs2
CO3
(245mg,0.75mmol),室溫攪拌2.5小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得22號化合物純品(25.0mg,16.9%),為淡黃色色固體。1
H-NMR(400MHz,MeOD):δ
ppm8.21(d,J
=8.4Hz,1H),7.60-7.54(m,2H),7.40(s,1H),7.33(d,J
=8.0Hz,1H),7.25-7.21(m,2H),6.33-6.26(m,1H),3.68(m,2H),3.40(m,2H)2.15-1.93(m,12H).LCMS:Calculated 590.1,found 591.1([M+H]+
)。
氮氣保護下將23-A1(2.0g,14.5mmol)與氯化亞碸(8ml)室溫攪拌1h,旋去氯化亞碸。加入THF10ml,體系降溫至0℃,加入四氫吡咯(1.5g,21.8mmol)和TEA(2.2g,21.8mmol)的混合物。完畢後體系自然升溫至常溫。監測1h反應完畢。EtOAc(40mL)溶解,H2
O洗滌(40mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1到EA)得粗品(850mg,30.7%,粗品含量為80%),為無色油狀物。
氮氣保護下,將23-A2(103mg,0.54mmol)溶於丙酮中(10mL),然後將23-A3(即46號化合物,120mg,0.54mmol),Cs2
CO3
(265mg,0.81mmol),室溫攪拌2.5小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得23號化合物純品(35.0mg,18.8%),為類白色固體。1
H-NMR(400MHz,MeOD):δ
ppm8.20(d,J
=8.0Hz,1H),7.59(d,J
=8.0Hz,1H)7.53(t,J
=8.0Hz,1H)7.39-7.38(m,2H),7.24-7.21(m,2H),6.32-6.25(m,1H).3.43(t,J
=6.8Hz,2H)3.36-3.34(m,2H)1.92-2.14(m,8H)1.84-1.77(m,4H).LCMS:Calculated 540.1,found 541.1([M+H]+
)。
氮氣保護下將24-A1(500mg,3.6mmol,商業購買)與T3
P(4.6g,14.4mmol,50%EA溶液)溶於DCM10ml中,加入4,4-二甲基呱啶鹽酸鹽(540mg,3.6mmol,上海安米克)室溫攪拌。監測2h反應完畢。DCM(20mL)溶解,H2
O洗滌(10mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-EA)得產品(600mg,收率71.4%),為淺黃色色固體。1
H-NMR(400MHz,MeOD):δ
ppm7.20(t,J
=8.0Hz,1H),6.82-6.81(m,1H),6.80-6.75(m,1H),6.73-6.72(m,1H),3.66(m,2H)3.34(s,2H),1.41(m,2H).1.30-1.29(m2H),0.97(s,6H).LCMS:Calculated 233.1,found 234.1([M+H]+
)。
氮氣保護下,將24-A2(103mg,0.54mmol)溶於丙酮中(10mL),然後將24-A3(即46號化合物,120mg,0.54mmol),Cs2
CO3
(265mg,0.81mmol),室溫攪拌2.5小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得24號化合物純品(35.0mg,18.8%)為類白色固體。1
H-NMR(400MHz,DMSO):δ
ppm8.21(d,J
=8.4Hz,1H),7.59(d,J
=8.4Hz,1H),7.53(t,J
=8.0Hz,1H),7.40(s,1H).7.24(d,J
=76Hz,1H)7.19(ddJ
=76,2.4Hz,1H),7.06-7.07(m,1H),6.32-6.27(m,1H),3.57(m,2H),3.26(m,2H)2.13-1.94(m,8H).1.23(m,2H)1.14(m,2H),0.94(s,6H).LCMS:Calculated 582.2,found 583.2([M+H]+
)。
氮氣保護下將25-A1(500mg,2.19mmol)與4-(三氟甲基)呱啶(1.0g,6.57mmol,商業購買)加入至DCM(10mL),後將T3
P(5.6g,8.77mmol,50%inEtOAc,商業購買)滴加入體系,然後將體系降溫至5℃,將DIEA(1.2g,8.77mmol,商業購買)滴加至體系,完畢後自然升至常溫。監測2h反應完畢。濃縮掉溶劑,EtOAc(20mL)溶解,H2
O洗滌(20mL×5),有機相乾燥濃縮得產品(790mg,收率98.9%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm7.42(d,J
=7.1Hz,2H),7.40-7.33(m,3H),7.32-7.26(m,1H),7.13-7.10(m,1H),6.98-6.95(m,2H),5.14(s,2H),4.70(m,1H),3.75-7.72(m,1H),3.08-3.08(m,1H),2.84(m,1H),2.54-2.46(m,1H),1.98(m,1H),1.81-1.76(m,1H),1.55-1.53(m,1H),1.44-1.35(m,1H).LCMS:Calculated 363.1,found 364.1([M+H]+
)。
氮氣保護下將25-A2(780mg,2.15mmol)與Pd(OH)2(90mg,商業購買)加入至EtOH(10mL),抽充氮氣三次,抽充氫氣三次後升溫至35℃過夜。次日監測反應完畢。矽藻土抽濾,用DCM洗滌,濃縮母液即可的得到25-A3(390mg,收率66.6%),為白色固體。1
H-NMR(400MHz,MeOD):δppm77.26(t,J=7.9Hz,1H),6.87(dd,J=8.1,2.3Hz,1H),6.83(d,J=7.5Hz,1H),6.80-6.76(m,1H),4.70(m,1H),3.84(m,1H),3.13(m,1H),2.85(m,1H),2.57-2.47(m,1H),2.06-1.79(m,2H),1.50-1.46(m,2H).LCMS:Calculated 273.1,found 274.2([M+H]+)。
氮氣保護下,將25-A4(即46號化合物,100mg,0.27mmol)溶於丙酮中(10mL),然後將25-A3(148mg,0.54mmol),Cs2
CO3
(309mg,0.95mmol,商業購買),室溫攪拌2小時反應完畢。後處理:矽藻土抽濾,丙酮洗滌,母液濃縮,高效液相製備得25號化合物純品(40.8mg,24.2%),為黃色固體。1
H-NMR(400MHz,DMSO)δ8.20(d,J
=8.5Hz,1H),7.59(d,J
=8.6Hz,1H),7.54(t,J
=7.9Hz,1H),7.39(s,1H),7.28(d,J
=7.6Hz,1H),7.22(dd,J
=8.2,2.0Hz,1H),7.13(s,1H),6.28(dq,J
=12.9,6.4Hz,1H),4.53(m,1H),3.60(m,1H),3.08(m,1H),2.78(m,1H),2.71-2.57(m,1H),2.13-1.92(m,8H),1.87-1.76(m,2H),1.39-1.37(m,2H).LCMS:Calculated 622.1,found 623.1([M+H]+
)。
氮氣保護下將26-A1(1.0g,4.38mmol)與對羥基呱啶(1.3g,13.12mmol)加入至DCM(20mL),後將T3
P(11.2g,8.77mmol,50%inEtOAc)滴加入體系,將體系降溫至5℃,再將DIEA(2.4g,17.54mmol,商業購買)滴加至體系,完畢後自然升常溫。監測5h反應完畢。後處理:濃縮體系,EtOAc(40mL)溶解,H2
O洗滌(40mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-0:1)得到26-A2(920mg,收率67.4%),為無色油狀物。1
H-NMR(400MHz,MeOD):δ
ppm7.43(d,J
=8.0Hz,2H),7.38(t,J
=7.6Hz,3H),7.32-7.28(m,1H),7.10(d,J
=8.4Hz,1H),6.98(m,1H),5.95(d,J
=8.0Hz,1H),5.13(s,2H),4.14(s,1H),3.89-3.85(m,1H),3.56(s,1H),3.17(s,1H),1.92(s,1H),1.74(s,1H),1.54(s,1H),1.40(s,1H),1.03(s,1H).LCMS:Calculated 311.2,found 312.2([M+H]+
)。
氮氣保護下將26-A2(900mg,2.89mmol)與PdOH催化劑(121mg)加入至EtOH(10mL)中,抽充氮氣三次,抽充氫氣三次後升溫至35℃過夜。次日監測反應完畢。後處理:氮氣保護下通過矽藻土抽濾,DCM洗滌,濃縮母液即可的得產品26-A3(460mg,收率71.9%),為無色油狀液體。1
H-NMR(400MHz,MeOD):δ
ppm7.26(d,J
=8.0Hz,1H),6.87(dd,J
=8.4,2.0Hz,1H),6.82(d,J
=7.2Hz,1H),6.79(d,J
=2.0Hz,1H),4.16(m,1H),3.91-3.85(m,1H),3.62(m,2H),3.31-3.22(s,1H),1.80-1.64(m,1H),1.54-1.45(m,2H).LCMS:Calculated 221.1,found 222.1([M+H]+
)。
氮氣保護下,將26-A4(即46號化合物,100mg,0.27mmol)與26-A3(120mg,0.54mmol)溶於丙酮中(10mL),然後將Cs2
CO3
(265mg,0.81mmol)加入,室溫攪拌2.5小時反應完畢。後處理:矽藻土抽濾,丙酮洗滌,濃縮母液,高效液相製備得26號化合物純品(29.0mg,18.8%),為類白色固體。1
H-NMR(400MHz,DMSO)δ8.20(d,J
=8.5Hz,1H),7.59(d,J
=8.5Hz,1H),7.53(t,J
=7.9Hz,1H),7.40(s,1H),7.25(d,J
=7.7Hz,1H),7.20(dd,J
=7.9,2.2Hz,1H),7.07(d,J
=1.4Hz,1H),6.29(dq,J
=13.0,6.4Hz,1H),4.77(d,J
=3.7Hz,1H),3.95(s,1H),3.72-3.71(m,1H),3.44(m,1H),3.20-3.11(m,2H),2.23-1.90(m,8H),1.76-1.66(m,2H),1.52-1.18(m,2H).LCMS:Calculated 570.1,found 571.2([M+H]+
)。
氮氣保護下,將27-A2(即46號化合物,100mg,0.27mmol)與27-A1(89mg,0.54mmol)溶於丙酮中(10mL),然後將Cs2
CO3
(265mg,0.81mmol)加入,室溫攪拌2小時反應完畢。後處理:矽藻土抽濾,丙酮洗滌,濃縮母液,高效液相製備得27號化合物純品(21.0mg,15.9%),為黃色蠟狀物。1
H-NMR(400MHz,DMSO)δ8.22(d,J
=8.5Hz,1H),7.61(d,J
=8.6Hz,1H),7.50(d,J
=8.6Hz,2H),7.42(s,1H),7.14(d,J
=8.6Hz,2H),6.31(dq,J
=13.0,6.4Hz,1H),2.97(s,3H),2.96(s,3
H),2.22-1.90(m,8H).LCMS:Calculated 514.1,found 515.1([M+H]+
)。
氮氣保護下將對羥基苯甲酸(28-A1,2.0g,14.48mmol,商業購買)加入至DCM(40mL),後將草醯氯(5.5g,43.44mmol)與DMF(53mg,0.72mmol)加入,室溫攪拌。監測2.5h後原料消失,濃縮除去草醯氯,再用DCM(50mL)溶解後,在氮氣保護下將呱啶(3.7g,43.44mmol)與TEA(5.9g,57.92mmol)滴加至體系,監測30min後反應完畢。後處理:濃縮反應混合物後,1N NaOH溶液(50mL)溶解後攪拌5min,DCM萃取(50mL×3),水相用6N HCl調至酸性後析出白色固體,抽濾烘乾後,得28-A2產品(2.0g,收率67.3%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm7.26(dd,d1
,J
=6.8,2.0Hz,2H),6.82(dd,J
=6.4,2.0Hz,2H),3.64-3.48(m,4H),1.72-1.60(m,6H).LCMS:Calculated 205.1,found 206.1([M+H]+
)。
氮氣保護下,將28-A3(即46號化合物,150mg,0.41mmol)與28-A2(167mg,0.81mmol)溶於丙酮中(10mL),然後將Cs2
CO3
(463mg,1.42mmol)加入至體系,室溫攪拌2小時反應完畢。後處理:通過矽藻土抽濾,丙酮洗滌,濃縮母液,高效液相製備得28號化合物純品(57mg,25.3%),為黃色固體。1
H-NMR(400MHz,DMSO)δ8.22(d,J
=8.5Hz,1H),7.61(d,J
=8.5Hz,1H),7.47-7.43(m,3H),7.13(t,J=5.6Hz,2H),6.30(dt,J=12.9,6.5Hz,1H),3.84-3.34(m,4H),2.25-1.86(m,8H),1.70-1.38(m,6H).LCMS:Calculated 554.2,found 555.1([M+H]+
)。
氮氣保護下將29-A1(500mg,2.19mmol)與4-(三氟甲基)呱啶(1.0g,6.57mmol,商業購買)加入至DCM(10mL),後將T3
P(5.6g,4.38mmol,50%inEtOAc,商業購買)滴加入體系,將體系降溫至5℃後將DIEA(1.2g,8.77mmol)滴加至體系,完畢後自然升至常溫。過夜後反應完畢。後處理:濃縮體系,EtOAc(20mL)溶解,H2
O洗滌(20mL×5),有機相乾燥濃縮,得到29-A2(790mg,收率98.9%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm7.44-7.31(m,7H),7.09-7.06(m,2H),5.14.(s,2H),4.66(m,1H),3.97(m,1H),3.04(m,2H),2.55-2.47(m,1H),1.92(m,2H),1.54-1.51(m,2H).LCMS:Calculated 363.1,found 364.2([M+H]+
)。
氮氣保護下將29-A2(790mg,2.20mmol)與PdOH(100mg)加入至EtOH(10mL),抽充氮氣三次,氫氣三次後升溫至35℃過夜。次日監測反應完畢。經過矽藻土抽濾,DCM洗滌,濃縮母液得到29-A3(450mg,收率75.2%),為白色固體。1
H-NMR(400MHz,MeOD):δ
ppm7.29(d,J
=8.4Hz,2H),6.84(d,J
=8.4Hz,2H),4.59(s,1H),4.06(s,1H),3.00(m,2H),2.55-2.47(m,1H),1.92(sm2H),1.54-1.50(m,2H).LCMS:Calculated 273.1,found 274.0([M+H]+
)。
氮氣保護下,將29-A4(即46號化合物,100mg,0.27mmol)與29-A3(118mg,0.54mmol)溶於丙酮中(10mL),然後將Cs2
CO3
(265mg,0.81mmol)加入,室溫攪拌3小時反應完畢。後處理:通過矽藻土抽濾,丙酮洗滌,濃縮母液,高效液相製備得29號化合物純品(55.0mg,32.6%),為淡黃色固體。1
H-NMR(400MHz,DMSO)δ8.22(d,J
=8.5Hz,1H),7.62(d,J
=8.5Hz,1H),7.51(d,J
=8.6Hz,2H),7.44(s,1H),7.14(d,J
=8.6Hz,2H),6.31(dq,J
=12.8,6.2Hz,1H),4.54(s,1H),3.71(s,1H),2.86(s,2H),2.67-2.63(m,1H),2.20-1.93(m,8H),1.84(m,2H),1.43(qd,J
=12.6,4.2Hz,2H).LCMS:Calculated 622.1,found 623.2([M+H]+
)。
氮氣保護下將30-A1(1.5g,4.95mmol,商業購買)與對氟碘苯(1.0g,4.50mmol,商業購買)加入至DMF(90mL),抽充氮氣3次後將1,1'-雙二苯基膦二茂鐵二氯化鈀即dppfPdCl2
(330mg,0.45mmol,商業購買)與K2
CO3
(1.9g,13.51mmol)加入至體系,完畢後再次抽充氮氣3次,將體系加熱至110℃過夜。次日監測反應完畢。降至室溫,倒入(100mL)水中,EtOAc萃取(100mL×3),有機相水洗鹽水洗,乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=15:1-10:1)得30-A2產品(920mg,收率73.6%),為淺綠色液體。1
H-NMR(400MHz,CDCl3
):δ
ppm7.34-7.31(m,2H),7.03-6.99(t,J
=8.8Hz,2H),5.97(m,1H),4.06(d,J
=2.4Hz,2H),3.64-3.61(m,2H),2.49(m,2H),1.49(s,9H).LCMS:Calculated 277.1,found 222.1([M-56+H]+
)。
將30-A2(800g,2.88mmol)溶於MTBE(甲基叔丁基醚,2mL),然後將鹽酸二氧六環溶液(4M,2mL,7.21mmol)滴加至體系,常溫過夜,次日監測反應完畢。抽濾,MTBE洗滌固體,得30-A3產品(460mg,74.70%),為類白色固體。1
H-NMR(400MHz,DMSO):δ
ppm9.18(s,2H),7.52(d,J=8.8,5.6Hz,2H),7.23-7.19(m,2H),6.16(s,1H),3.72(s,2H),3.29(m,2H),2.66(m,2H).LCMS:Calculated 213.1,found 178.1([M-HCl+H]+
)。
氮氣保護下將(350mg,1.53mmol)與30-A3(407mg,2.30mmol)加入至DCM(10mL),後將T3
P(3.90g,6.12mmol,50%inEtOAc)滴加入體系,將體系降溫至5℃再將DIEA(791mg,6.12mmol)滴加至體系,完畢後自然升至常溫,監測2h反應完畢,濃縮體系,EtOAc(10mL)溶解,H2
O洗滌(10mL×5),有機相乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=1:1-0:1)得30-A4產品(460mg,收率77.9%),為淺綠色油狀物。1
H-NMR(400MHz,MeOD):δ
ppm7.45-7.43(m,6H),7.39-7.36(m,2H),7.32(d,J
=7.2Hz,1H),7.10-7.03(m,4H),6.13-5.97(m,1H),5.15(s,2H),4.29-4.22(m,2H),3.93-3.69(m,2H),2.60(m,2H)。
氮氣保護下將30-A4(450mg,1.16mmol)與Pd(OH)2
(81mg,商業購買)加入至EtOH(10mL),抽充氮氣三次,抽充氫氣三次後升溫至35℃過夜。次日監測反應完畢。通過矽藻土抽濾,DCM洗滌,濃縮母液得到30-A5(310mg,收率89.2%),為無色油狀物。1
H-NMR(400MHz,MeOD):δ
ppm7.33-7.31(m,2H),7.29-7.25(m,2H),7.04-6.99(m,2H),6.87-6.84(m,2H),4.72(m,2H),4.00(m,1H),3.19-2.96(m,2H),1.86(m,2H),1.68-1.66(m,2H).LCMS
:Calculated 299.1,found 300.1([M+H]+
)。
氮氣保護下,將30-A6(即46號化合物,100mg,0.27mmol)溶於丙酮中(10mL),然後將30-A5(97mg,0.33mmol),Cs2
CO3
(265mg,0.81mmol),室溫攪拌3小時。反應完畢之後,矽藻土抽濾,丙酮洗滌固體,濃縮母液,高效液相製備得30號化合物純品(29.0mg,16.5%),為淡黃色固體。1
H-NMR(400MHz,DMSO-d6
):δppm8.22(d,J
=8.5Hz,1H),7.61(d,J
=8.5Hz,1H),7.53(d,J
=8.6Hz,2H),7.44(s,1H),7.34-7.31(m,2H),7.16-7.11(m,4H),6.38-6.26(m,1H),4.62(m,1H),3.72(m,1H),3.24-3.10(m,2H),2.83(m,1H),2.17-1.91(m,8H),1.86-1.59(m,4H).LCMS:Calculated 648.2,found 649.2([M+H]+
)。
氮氣保護下,(1g,3.16mmol)和33-A(886mg,6.33mmo,l.2eq,商業購買)溶於THF(15mL),加入三苯基磷(1.66g,6.33mmol,2eq,商業購買),降溫0℃,滴加入偶氮二甲酸二叔丁酯(1.46g,6.33mmol,2eq,商業購買)的THF溶液(8mL),室溫反應,4h反應完畢。加入10mL水,DCM萃取(25mL×3),乾燥濃縮,拌樣過柱(200-300目矽膠,EA:正庚烷=2:1)得到產品33-B(680mg,收率為49.3%),淡黃色固體。1
H-NMR(300M,CDCl3
):δ
ppm9.87(s,1H),8.04(d,J=7.8Hz,1H),7.63(d,J
=9.6Hz,2H),7.47(d,J
=8.1Hz,2H),7.34(d,J
=7.5Hz,1H),7.02-7.11(m,4H),5.19(s,2H),3.08(brs,6H).LCMS :
Calculated 438.4,found 439.0([M+H]+
)。
33-B(680mg,1.55mmol)溶於THF(10mL),降溫0℃,分批加入硼氫化鈉(117mg,3.10mmol,2eq),保溫0℃,1h反應完畢。滴加入飽和氯化銨水溶液(5mL),DCM萃取(10mL×3),乾燥濃縮,柱層析分離(100-200目矽膠,EA)得33-C產品(410mg,60.3%),為淡黃色固體。1
H-NMR(300M,CDCl3
):δ
ppm8.02(d,J
=8.1Hz,1H),7.43(d,J
=7.8Hz,2H),7.31(d,J
=6.0Hz,1H),7.12(d,J=12.3Hz,1H),6.99-7.03(m,4H),6.84(t,J
=8.4Hz,1H),5.16(s,2H),4.62(s,2H),3.08(brs,6H).LCMS:Calculated 440.4,found 441.0([M+H]+
).
氮氣保護下,33-C(400mg,0.91mmol)溶於THF(5mL),加入三苯基磷(480mg,1.82mmol),Br-IPM(564mg,1.82mmol,商業購買),降溫0℃,滴加入偶氮二甲酸二叔丁酯(420mg,1.82mmol)的THF溶液(5mL),室溫反應3小時,0℃,加入水(5mL),DCM萃取(10mL×3),乾燥濃縮,柱層析分離(200-300目矽膠,DCM:甲醇=50:1)得到33-D(300mg,收率45.0%),為淡黃色固體。1
H-NMR(400M,CDCl3
):δ
ppm8.01(d,J
=8.4Hz,1H),7.45(d,J
=8.8Hz,2H),7.32(d,J
=8.0Hz,1H),7.26(m,1H),7.16(dd,J
=11.5,1.6Hz,1H),7.10(s,1H),7.02(d,J
=8.4Hz,2H),6.89(t,J
=8.4Hz,1H),5.13(s,2H),4.95(d,J
=8.4Hz,2H),3.45-3.41(m,4H),3.34-3.30(m,4H),3.08(s,6H).LCMS :
Calculated 732.0,found 732.8([M+H]+
)。
氮氣保護下,33-D(200mg,0.27mmol)溶於THF(5mL),加入氧化銀(742mg,3.2mmol,11.8eq),滴加入二異丙基乙胺(176mg,1.365mmol,5eq),升溫至回流,反應2h,降至室溫,矽藻土抽濾,THF多次洗滌,低溫濃縮,製備,得到33號化合物(5mg,3.2%),為白色固體。1
H-NMR(400M,CDCl3
):δ
ppm7.99(d,J
=8.4Hz,1H),7.44(d,J
=8.8Hz,2H),7.31(d,J
=8.0Hz,1H),7.15(dd,J
=11.6,2.0Hz,1H),7.11(s,1H),7.03-7.07(m,3H),6.91(t,J
=8.4Hz,1H),5.09(s,2H),5.05(d,J
=8.0Hz,2H),3.09(s,3H),3.00(s,3H),2.18-2.08(m,8H).(retentiontime:7.359min).LCMS:Calculated 570.0,found 571.0([M+H]+
)。
將34-A(10.0g,71.4mmol,商業購買)加入到乙酸(30mL)中,然後加入磺醯氯(14.4g,107mmol,1.5eq),室溫反應17h,加入冰水300ml,用EA萃取(300mL×2),有機相用鹽水洗(20mL×2),無水Na2
SO4
乾燥,旋乾溶劑,得到粗品,甲基叔丁基醚打漿,抽濾得到34-B(3.0g,25%),為白色固體。1
H-NMR(400M,DMSO-d6
):δ
ppm9.98(s,1H),7.80(d,J
=4.4Hz,1H),6.89(d,J
=11.6Hz,1H).LCMS:Calculated 174.0,found 175.0([M+H]+
)。
氮氣保護下,34-B(375mg,2.15mmol,2eq)加入到THF(10mL)中,加入(340mg,1.08mmol),三苯基膦(563mg,2.15mmol,2eq,商業購買),0℃加入DBAD(494.5mg,2.15mmol,2eq,商業購買),室溫反應1h,加入DCM(50ml)稀釋,有機相用水洗(10ml×2),飽和食鹽水洗(10ml),乾燥旋乾,拌樣FLASH過柱(300-400目矽膠,EA和正庚烷,33%to100%),得到34-C(400mg,78.7%),為白色產物。1
H-NMR(400M,DMSO-d6
):δ
ppm10.04(s,1H),8.18(d,J
=8.4Hz,1H),7.87(d,J
=7.2Hz,1H),7.49(d,J
=8.4Hz,2H),7.44(d,J
=8.4Hz,1H),7.36(d,J
=8.4Hz,1H),7.31(s,1H),7.15(d,J
=8.4Hz,2H),5.44(s,2H),2.97(s,6H).LCMS:
Calculated 472.1,found 472.9([M+H]+
)。
氮氣保護下,34-C(200mg,0.42mmol)加入到THF(10mL)中,0℃加入硼氫化鈉(32mg,0.84mmol,2eq,商業購買),自然升溫反應0.5h,反應完畢,滴加飽和氯化銨水溶液(10mL),DCM萃取(20mL×3),依次用水洗(10mL),飽和食鹽水洗(10mL),乾燥旋乾,異丙醇打漿抽濾得到34-D
(100mg,50%),為白色固體。1
H-NMR(400M,DMSO-d6
):δ
ppm8.16(d,J
=8.4Hz,1H),7.49(d,J
=8.4Hz,2H),7.46(d,J
=8.0Hz,1H),7.43(d,J
=9.6Hz,1H),7.30(s,1H),7.15-7.12(m,3H),5.32(s,2H),5.27(t,J
=5.6Hz,1H),4.45(d,J
=5.6Hz,2H),2.97(s,6H).LCMS:
Calculated 474.1,found 475.0([M+H]+
)。
氮氣保護下,34-D(100mg,0.21mmol)加入到THF(10ml)中,加入三苯基膦(110mg,0.42mmol,2eq)Br-IPM(129mg,0.42mmol,2eq),0度加入偶氮二甲酸二叔丁基酯(97mg,0.42mmol,2eq),室溫反應4h,完畢後加入DCM(50ml),有機相用飽和食鹽水洗10ml,乾燥旋乾,flash過柱(300-400目矽膠,EA和正庚烷,0-100%,然後DCM:MeOH(20:1)得到34-E(70mg,43.7%),為黃色油狀物。1
H-NMR(400M,CDCl3
):δ
ppm7.96(d,J
=8.4Hz,1H),7.40-7.38(m,3H),7.25(d,J
=7.6Hz,1H),7.07(s,1H),6.99(d,J
=8.8Hz,2H),6.57(d,J
=10.8Hz,1H),5.04(s,2H),4.92(d,J
=8.0Hz,2H),3.36-3.39(m,4H),3.24-3.29(m,4H),3.01(s,6H).LCMS:
Calculated 766.0,found 766.8([M+H]+
)。
E(70mg,0.091mmol)加入到THF(5ml)中,加入氧化銀(250mg,1.08mmol,11.8eq),DIEA(55mg,0.428mmol,4.7eq),加熱至65℃,反應6h,反應完畢後,抽濾,THF洗濾餅(10mL×2),濾液用濾膜再次抽濾,濾液旋乾,得到粗品,製備HPLC得到34(5mg,9.1%),為白色固體。1
H-NMR(400M,CD3
OD):δ
ppm8.08(d,J
=8.4Hz,1H),7.54-7.47(m,4H),7.37(s,1H),7.12(d,J
=8.8Hz,2H),7.06(d,J
=11.2Hz,1H),5.29(s,2H),5.14(d,J
=8.0Hz,1H),3.13(s,3H),3.07(s,3H),2.15-2.14(m,8H).LCMS:
Calculated 604.0,found 605.0([M+H]+
)。
44/47-49號化合物的合成參見以上方法,以下提供性狀及核磁、質譜資料。
35號化合物
固體,1
H-NMR(400MHz,CDCl3)δ7.99(d,J=8.4Hz,1H),7.47(d,J=8.6Hz,2H),7.32(d,J=8.3Hz,1H),7.17(s,1H),7.05(d,J=8.6Hz,2H),6.95(t,J=6.9Hz,2H),5.54-5.48(m,1H),5.14(s,2H),3.11(s,3H),3.03(s,3H),2.21-2.00(m,8H),1.57(d,J=6.5Hz,3H).LCMS:Calculated 602.2,found 603.2([M+H]+
)。
36號化合物
固體,1
H-NMR(400MHz,CDCl3)δ8.01(d,J=8.4Hz,1H),7.71-7.62(m,2H),7.34(d,J=8.4Hz,1H),7.22(s,1H),7.04(d,J=8.8Hz,2H),6.95(d,J=8.5Hz,2H),5.47-5.28(m,1H),5.17(s,2H),5.06(d,J=8.1Hz,2H),4.62-4.48(m,2H),4.38(m,2H),2.32-2.04(m,8H).LCMS:Calculated 518.1,found 619.2([M+H]+
)。
37號化合物
蠟狀物,1
H-NMR(400MHz,CDCl3)δ8.05(d,J=8.4Hz,1H),7.71-7.63(m,2H),7.46-7.38(m,1H),7.31(s,1H),7.09-7.01(m,2H),6.97(d,J=8.6Hz,2H),5.20(s,2H),5.07(d,J=8.0Hz,2H),2.31-2.06(m,8H).LCMS:Calculated 542.1,found 543.1([M+H]+
)。
38號化合物
類白色固體,1
H-NMR(400MHz,CDCl3)δ8.02(d,J=8.4Hz,1H),7.68(d,J=8.7Hz,2H),7.36(d,J=8.5Hz,1H),7.24(s,1H),7.05(d,J=8.7Hz,2H),6.96(d,J=8.5Hz,2H),5.18(s,2H),5.06(d,J=8.1Hz,2H),4.59-4.53(m,4H),2.38-2.02(m,8H).LCMS:Calculated 536.1,found 637.1([M+H]+
)。
39號化合物
蠟狀物,1
H-NMR(400MHz,CDCl3)δ8.03(d,J=8.4Hz,1H),7.55-7.44(m,2H),7.37(d,J=8.4Hz,1H),7.30-7.26(m,1H),7.25-7.20(m,2H),7.02-6.90(m,2H),5.20(s,2H),5.06(d,J=8.0Hz,2H),2.28-2.10(m,8H).LCMS:Calculated 542.1,found 543.1([M+H]+
)。
40號化合物
類白色固體,1
H-NMR(400MHz,DMSO-d6):δppm8.90-8.89(s,1H),8.33(d,J=1.2Hz,1H),8.31(d,J=1.2Hz,1H),8.25(d,J=8.4Hz,1H),8.13(d,J=10.0Hz),7.63-7.55(m,4H),7.46(d,J=1.2Hz,1H),6.30-6.26(m,1H),2.11-1.92(m,8H).LCMS:Calculated 494.1,found 495.1([M+H]+
)。
41號化合物
類白色固體,1
H-NMR(400MHz,MeOD):δppm8.43(d,J=2.9Hz,1H),7.24-7.19(m,2H),6.13-6.03(m,1H),2.26-2.08(m,8H).LCMS:Calculated 576.1,found 577.2([M+H]+
)。
42號化合物
類白色固體,1
H-NMR(400MHz,DMSO-d6):δppm8.20(d,J=8.2Hz,1H),7.99-7.90(m,1H),7.89(s,1H)7.55(d,J=8.4Hz,1H),7.31-7.26(m,1H),6.28-6.24(m,1H),2.80(s,3H),2.10-1.91(m,8H).LCMS:Calculated 514.1,found 515.0([M+H]+
)。
43號化合物
類白色固體,1
H-NMR(400MHz,MeOD):δppm8.05(d,J=8.0Hz,1H),8.01(s,1H)7.68(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.43(d,J=8.0Hz,1H),7.27(dd,J=8.8,2.0Hz,1H),7.17(s,1H),5.99-5.94(m,1H),2.20-2.02(m,8H).LCMS:Calculated 497.1,found 498.1([M+H]+
)。
44號化合物
類白色固體,1
H-NMR(400MHz,MeOD)δ8.07(d,J=8.4Hz,1H),7.75-7.67(m,2H),7.65-7.59(m,2H),7.49(d,J=8.5Hz,1H),7.44(t,J=7.6Hz,2H),7.35(d,J=7.3Hz,1H),7.31(s,1H),7.20-7.14(m,2H),6.07-5.97(m,1H),2.26-2.03(m,8H).LCMS:Calculated 519.1,found 520.1([M+H]+
)。
47號化合物
類白色固體,1
H-NMR(400MHz,MeOD)δ8.03(d,J=8.4Hz,1H),7.43(d,J=8.4Hz,1H),7.34(d,J=8.5Hz,2H),7.19(s,1H),7.03(t,J=5.7Hz,2H),6.07-5.94(m,1H),3.09-2.99(m,1H),2.24-2.02(m,10H),1.87-1.83(m,2H),1.77-1.68(m,2H),1.65-1.56(m,2H).LCMS:Calculated 511.1,found 512.2([M+H]+
)。
48號化合物
類白色固體,1
H-NMR(400MHz,MeOD)δ8.03(d,J=8.4Hz,1H),7.43(d,J=8.6Hz,1H),7.31(d,J=8.5Hz,2H),7.19(s,1H),7.02(d,J=8.5Hz,2H),6.00-5.96(m,1H),2.56(m,1H),2.23-2.03(m,8H),1.87(m,4H),1.78-1.75(m,2H),1.49-1.43(m,5H).LCMS:Calculated 525.2,found 526.2([M+H]+
)。
49號化合物
黃色蠟狀物,1
H-NMR(400MHz,MeOD)δ8.04(d,J=8.4Hz,1H),7.45(d,J=8.2Hz,1H),7.35(d,J=8.6Hz,2H),7.21(s,1H),7.04(d,J=8.6Hz,2H),5.99(dd,J=9.9,6.2Hz,1H),2.74(t,J=12.5Hz,1H),2.23-2.04(m,10H),2.02-1.73(m,6H).LCMS:Calculated 561.1,found 562.2([M+H]+
)。
氮氣保護,將A2(2.0g,11.8mmol,商業購買)與TMSCF3(2.5g,17.7mmol,商業購買)溶於THF(20mL)中,降溫至0℃,將TBAF(2.6ml,0.26mmol,1mol/L的THF溶液,商業購買)滴加至體系,保溫0℃,30min後A2全部消失,滴加3N HCl(2ml)至體系,體系變澄清,繼續0℃攪拌1h後全部成為產物。DCM萃取(10ml×3),有機相水洗(10ml×3),乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=12:1-10:1)得產品A3(1.5g,收率53.2%),為黃色油狀物。1
H-NMR(400MHz,CDCl3
):δ
ppm8.13-8.09(m,1H),7.60(d,J
=11.6Hz,1H),7.43(d,J
=8.4Hz,1H),5.12-5.18(m,1H),3.06(d,J
=4.4Hz,1H)。
氮氣保護,將POCl3
(963mg,4.61mmol,商業購買)溶於DCM(10ml)後降溫至-40℃,然後將A3(1.5g,6.27mmol)溶於DCM(20ml)後與TEA(1.6g,15.70mmol)滴加至體系,保溫-40℃,2h後46-A3全部轉化為中間體,然後將溴乙胺溴酸鹽(11.99g,50.16mmol)與TEA(10.1g,0.1mol)加入至體系,監測,30min後反應完畢。0℃加入飽和NH4
Cl(20ml),DCM萃取(50ml×3),有機相水洗鹽水洗,乾燥濃縮,柱分離(200-300目矽膠,正庚烷:EA=5:1-1:1)得產品A4(1.6g,收率65.3%),為黃色油狀物。1
H-NMR(400MHz,CDCl3
):δ
ppm8.15-8.11(m,1H),7.47(d,J
=11.6Hz,1H),7.44(d,J
=8.8Hz,1H),5.78-5.30(m,1H),3.53-3.05(m,10H).LCMS:Calculated 529.9,found 531.9([M+H]+
)。
氮氣保護下,將A4(1.6g,3.0mmol)溶於THF中(20mL),然後加入氧化銀(4.2g,18.0mmol),DIPEA(2.3g,18.0mmol),升溫至65℃
,攪拌1.5h。反應完畢之後,冷卻至常溫,矽藻土抽濾,DCM洗滌固體,濃縮母液,柱分離(200-300目矽膠,正庚烷:EA=5:1-1:1)得粗品(520mg,收率為46.8%),高效液相製備即得46號化合物純品(30mg),為白色固體。 1
H-NMR(400MHz,MeOD):δ
ppm8.24-8.20(m,1H),7.70(d,J
=11.6Hz,1H),7.63(d,J
=8.8Hz,1H),6.14-6.10(m,1H),2.28-2.14(m,8H).LCMS:Calculated 369.1,found 370.1([M+H]+
)。
以上具體化合物實施例的實驗事實證實,本發明提供的化合物均為固體或蠟狀物(半固體),克服了先前的DNA烷化劑(PCT申請號PCT/US2016/021581,公開號WO2016/145092,對應中國申請號2016800150788,公開號CN107530556A)為油狀物的缺陷,更易於製劑操作。
無
無
Claims (21)
- 一種式II或III化合物或者其藥學上可接受的鹽或溶劑合物, 其中, R1 是C6 -C10 芳基或Z取代的芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、7-15元的稠環或Z取代稠環; R2 是氫、鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、1-6個碳原子的醚或Z取代的1-6個碳原子的烷氧基、-CONR6 R7 、-SO2 NR6 R7 、-SO2 R6 、-OCOO-R6 、-COOR6 、-NR6 COR7 、-OCOR6 、-NR6 SO2 R7 、-NR6 SO2 NR6 R7 或者R2 和與其所鍵結的R1 基團上的原子一起形成7-15元的稠環或Z取代稠環; R3 是氫、鹵素、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1 -C6 烷氧基或Z取代的C1 -C6 烷氧基、-CONR6 R7 、-SO2 NR6 R7 、-SO2 R6 、-OCO-R6 、-OCOO-R6 、-COOR6 、-NR6 COR7 ,-OCOR6 、-NR6 SO2 R7 ; R4 、R5 各自獨立地是氫、鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1 -C6 烷氧基或Z取代的C1 -C6 烷氧基、-CONR6 R7 、-SO2 NR6 R7 、-SO2 R6 、-OCOO-R6 、-COOR6 、 -NR6 COR6 、-OCOR6 、-NR6 SO2 R7 或者R4 、R5 和與其所鍵結的苯環上的原子一起形成7-15元的稠環或Z取代稠環; R6 和R7 各自獨立地是氫、氰基或異氰基、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1 -C6 烷氧基或Z取代的C1 -C6 烷氧基,或者R6 、R7 基團與其所鍵結的原子一起形成5-7元雜環基或Z取代5-7元雜環基; R8 、R10 各自獨立地為氫、氘、芳基或Z取代芳基、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基且必有一個為氫、氘; R9 為至少具有一個氟原子或硝基取代的取代C6 -C10 芳基、至少具有一個氟原子或硝基取代的取代4-15元雜環、至少具有一個氟原子或硝基取代的取代5-15元雜芳基, Z取代基為鹵素原子、氰基或異氰基、羥基、巰基、胺基、OTs、OLCMS、C1 -C3 烷基或取代烷基、C1 -C3 烷氧基或取代烷氧基、C2 -C3 烯基或取代烯基、C2 -C3 炔基或取代炔基、C3 -C8 環烷基或取代環烷基、芳環、雜環、雜芳環和稠環或取代芳環、雜環、雜芳環和稠環,取代的方式為單取代或偕二取代;以及 R9 中的取代C6 -C10 芳基、取代4-15元雜環、取代5-15元雜芳基的取代基為鹵素原子、硝基、氰基或異氰基、羥基、胺基、C1 -C3 烷基或烷氧基、烯基、炔基、環烷基或苯環、取代苯環、C1 -C3 烷氧基或鹵原子取代烷氧基。
- 如請求項1所述的化合物,其中, R1 為苯基或Z取代苯基、六元含氮雜環或Z取代雜環、六元含氮雜芳基或Z取代雜芳基、9-14元的稠環或Z取代稠環; R2 為氫、鹵素原子、氰基或異氰基、羥基、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元含氮雜環或Z取代含氮雜環、5-15元含氮雜芳基或取代含氮雜芳基、C1 -C6 烷氧基或氟取代的C1 -C6 烷氧基、-CONR6 R7 ,-SO2 NR6 R7 、-SO2 R6 、-OCOO-R6 、-COOR6 、 -NR6 COR7 、-OCOR6 、-NR6 SO2 R7 、-NR6 SO2 NR6 R7 ;以及 R6 和R7 各自獨立地是C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1 -C6 烷氧基或氟取代的C1 -C6 烷氧基,或者R6 和R7 基團與其所鍵結的氮原子一起形成5-7元雜環基或Z取代5-7元雜環基。
- 如請求項1所述的化合物,其中, R1 為苯基或Z取代苯基、六元含氮雜環或Z取代雜環、六元含氮雜芳基或Z取代雜芳基、9-14元的稠環或Z取代稠環; R2 為氫、鹵素原子、氰基或異氰基、羥基、C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元含氮雜環或Z取代含氮雜環、5-15元含氮雜芳基或取代含氮雜芳基、C1 -C6 烷氧基或氟取代的C1 -C6 烷氧基、-CONR6 R7 、-SO2 R6 、-OCOO-R6 、-COOR6 、-NR6 COR6 、-OCOR6 、-NR6 SO2 R6 ,-NR6 SO2 NR6 R7 ;以及 R6 和R7 各自獨立地是C1 -C6 烷基或Z取代烷基、C2 -C6 烯基或Z取代烯基、C2 -C6 炔基或Z取代炔基、C3 -C8 環烷基或Z取代環烷基、C6 -C10 芳基或Z取代芳基、4-15元雜環或Z取代雜環、5-15元雜芳基或Z取代雜芳基、C1 -C6 烷氧基或氟取代的C1 -C6 烷氧基,或者R6 和R7 基團與其所鍵結的氮原子一起形成5-7元雜環基或Z取代5-7元雜環基。
- 如請求項1所述的化合物,在式II、III中, R1 為苯基、四氫吡喃、四氫噻喃、四氫呋喃、吡啶、呋喃、吡喃、噻喃、噻唑、二氫吡啶、嗎啉、呱嗪、噠嗪、吡嗪、1,3,5-三嗪、萘、奎琳、苯並噻唑、苯並噻喃、苯並呋喃、苯並咪唑、吲哚、咪唑吡啶或Z取代的苯基、呱啶、四氫吡喃、四氫噻喃、四氫呋喃、吡啶、呋喃、吡喃、噻喃、噻唑、二氫吡啶、嗎啉、呱嗪、噠嗪、吡嗪、1,3,5-三嗪、萘、奎琳、苯並噻唑、苯並噻喃、苯並呋喃、苯並咪唑、吲哚、咪唑吡啶; R2 為-CON(CH3 )2 、-SO2 CH3 、-OCOO-CH3 、-COOCH3 、-NHCOCH3 、-NMeCOCH3 、-NHCOCF3 、-OCOCH3 、-NHSO2 CH3 、-NMeSO2 CH3 、-NHSO2 CF3 、-NMeSO2 CF3 、-CF3 、F、Cl、CN、Me、苯、氟苯、氯苯、-OCF3 、C5 -C6 的環烷基或F取代的C5 -C6 的環烷基、吡啶基、氟代吡啶基、氯代吡啶基、呋喃基、噻喃、噻唑、-CONMePh、、、、、、、、、、、、、、、、,或。
- 如請求項1所述的化合物,其中,R3 、R4 、R5 各自獨立地為H。
- 如請求項1所述的化合物,其中,R8 、R10 各自獨立地為H。
- 如請求項1所述的化合物,其中,R9 為單氟、一氟一氯、雙氟或四氟取代的苯基。
- 如請求項1至10中任一項所述的化合物,其中,所述的鹽為鹼式鹽或酸式鹽,所述的溶劑合物為水合物或醇合物。
- 如請求項1至11中任一項所述的化合物在製備治療腫瘤、癌症的藥品中的應用。
- 一種含有如請求項1至11中任一項所述的化合物的藥品或製劑。
- 如請求項13所述的藥品或製劑,該藥品或製劑用於治療患者的腫瘤、癌症疾病,其中該腫瘤、該癌症包括: 肺癌、非小細胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、結腸癌、卵巢癌、膀朧癌、子宮頸癌、黑色素瘤、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭狀癌、乳頭狀腺癌、囊性腺癌、囊性癌、髓狀癌、支氣管癌、骨細胞癌、上皮癌、膽管癌、絨毛膜癌、胚癌、精原細胞癌、維爾姆斯癌、膠質細胞癌、星形細胞瘤、成神經管細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、成血細胞瘤、聲帶神經瘤、腦膜瘤、成神經細胞瘤、成視神經細胞瘤、成視網膜細胞瘤、神經纖維瘤、纖維肉瘤、成纖維細胞瘤、纖維瘤、纖維腺瘤、纖維軟骨瘤、纖維囊瘤、纖維粘液瘤、纖維骨瘤、纖維粘液肉瘤、纖維乳頭狀瘤、粘液肉瘤、粘液囊瘤、粘液軟骨瘤、粘液軟骨肉瘤、粘液軟骨纖維肉瘤、粘液腺瘤、成粘液細胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂細胞瘤、脂肪軟骨瘤、脂肪纖維瘤、脂肪血管瘤、粘液脂瘤、軟骨肉瘤、軟骨瘤、軟骨肌瘤、脊索瘤、絨毛膜腺瘤、絨毛上皮瘤、成絨毛膜細胞瘤、骨肉瘤、成骨細胞瘤、骨軟骨纖維瘤、骨軟骨肉瘤、骨軟骨瘤、骨囊瘤、骨牙質瘤、骨纖維瘤、骨纖維肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管軟骨瘤、成血管細胞瘤、血管角質瘤、血管神經膠質瘤、血管內皮瘤、血管纖維瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神經瘤、血管粘液瘤、血管網狀內皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纖維瘤、淋巴細胞瘤、淋巴上皮瘤、成淋巴細胞瘤、內皮瘤、成內皮細胞瘤、滑膜瘤、滑膜肉瘤、間皮瘤、結締組織瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纖維瘤、橫紋肌瘤、橫紋肌肉瘤、橫紋肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病貧血、紅細胞增多症、淋巴瘤、子宮內膜癌、膠質瘤、結直腸癌、甲狀腺癌、尿路上皮癌或多發性骨髓瘤。
- 一種治療癌症或腫瘤的方法,其包含: 施加如請求項13所述的藥品或製劑的步驟;以及 使用AKR1C3抗體測定患者的癌細胞或組織的AKR1C3還原酶含量或表達水準的步驟, 其中,如測得該AKR1C3還原酶含量或表達水準等於或大於預定值,則向該患者投與如請求項13所述的藥品或製劑。
- 一種治療癌症或腫瘤的方法,其包含: 施加如請求項13所述的藥品或製劑的步驟;以及 AKR1C3還原酶含量或表達水準調節步驟, 其中,當調節使得該AKR1C3還原酶含量或表達水準等於或大於預定值,則向該患者投與權利要求13所述的藥品或製劑。
- 如請求項17所述的製備方法,其中, Y為Cl、Br、I、-OTs、-ONO2 、-OLCMS,或-OTf,以及 縮合反應使用有機胺作為縛酸劑。
- 如請求項18所述的製備方法,其中, Y為Br,縮合反應使用N,N'-二異丙基乙胺DIPEA作為縛酸劑,並使用氧化銀Ag2 O作為催化劑。
- 如請求項20所述的製備方法,其中,Y為F、Cl、Br、I、-OTs、-ONO2、-OLCMS,或-OTf。
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