TW201623324A - 具有hiv成熟抑制活性之三萜化合物 - Google Patents
具有hiv成熟抑制活性之三萜化合物 Download PDFInfo
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- TW201623324A TW201623324A TW104111466A TW104111466A TW201623324A TW 201623324 A TW201623324 A TW 201623324A TW 104111466 A TW104111466 A TW 104111466A TW 104111466 A TW104111466 A TW 104111466A TW 201623324 A TW201623324 A TW 201623324A
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- Prior art keywords
- alkyl
- group
- substituted
- coor
- mmol
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- 230000035800 maturation Effects 0.000 title abstract description 13
- 150000003648 triterpenes Chemical class 0.000 title abstract description 5
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- 208000030507 AIDS Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 6
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 198
- 125000000217 alkyl group Chemical group 0.000 claims description 123
- -1 substituted Chemical class 0.000 claims description 99
- 125000001072 heteroaryl group Chemical group 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 48
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 9
- 208000031886 HIV Infections Diseases 0.000 claims description 8
- 208000037357 HIV infectious disease Diseases 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 7
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 7
- 230000000670 limiting effect Effects 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004599 antimicrobial Substances 0.000 claims description 4
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- 230000002519 immonomodulatory effect Effects 0.000 claims description 3
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- 238000006467 substitution reaction Methods 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 abstract description 10
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- 239000000203 mixture Substances 0.000 description 292
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- 238000005481 NMR spectroscopy Methods 0.000 description 218
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 154
- 239000000243 solution Substances 0.000 description 153
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- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 131
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- 238000006243 chemical reaction Methods 0.000 description 39
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- MJEQUKHBEDFOSW-UHFFFAOYSA-N benzyl cyclohex-3-ene-1-carboxylate Chemical compound C1CC=CCC1C(=O)OCC1=CC=CC=C1 MJEQUKHBEDFOSW-UHFFFAOYSA-N 0.000 description 38
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 38
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
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- CMUTXJXHVDKYAN-UHFFFAOYSA-L tetrabutylazanium difluoride Chemical compound [F-].[F-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC CMUTXJXHVDKYAN-UHFFFAOYSA-L 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本發明係關於具有藥物及生物影響特性之化合物、其醫藥組合物及使用方法。詳言之,本發明提供如式I化合物所表示的具獨特抗病毒活性之三萜化合物作為HIV成熟抑制劑:
□其中X選自C4-8環烷基、C4-8環烯基、C4-9螺環烷基、C4-9螺環烯基、C4-8氧雜環烷基、C4-8二氧雜環烷基、C6-8氧雜環烯基、C6-8二氧雜環烯基、C6環二烯基、C6氧雜環二烯基、C6-9氧雜螺環烷基及C6-9氧雜螺環烯基環,使得X經A取代,其中A為-C1-6烷基-鹵基。此等化合物適用於治療HIV及AIDS。
Description
本申請案主張2014年4月11日提交之美國臨時申請案第61/978,306號之權益,其以全文引用的方式併入本文中。
本發明係關於適用於針對HIV之新穎化合物,且更特定言之係關於適用作HIV成熟抑制劑的衍生自樺木酸之化合物及其他結構上相關化合物,且係關於含有其之醫藥組合物,以及其製備方法。
HIV-1(人類免疫缺陷病毒-1)感染仍為主要醫學問題,據估算2010年末全世界有45,000,000-50,000,000人感染。HIV及AIDS(後天免疫缺乏症候群)之病例數快速上升。在2005年,報導約5,000,000例新感染,且3,100,000人死於AIDS。當前可用於治療HIV之藥物包括核苷逆轉錄酶(RT)抑制劑或經批准之單一藥九組合:齊多夫定(zidovudine)(或AZT或RETROVIR®)、地達諾新(didanosine)(或VIDEX®)、司他夫定(stavudine)(或ZERIT®)、拉米夫定(lamivudine)(或3TC或EPIVIR®)、紮西他濱(zalcitabine)(或DDC或HIVID®)、丁二酸阿巴卡韋(abacavir succinate)(或ZIAGEN®)、泰諾福韋酯反丁烯二酸鹽(Tenofovir disoproxil fumarate salt)(或VIREAD®)、恩曲他濱(emtricitabine)(或FTC-EMTRIVA®)、COMBIVIR®(含有3TC加AZT)、
TRIZIVIR®(含有阿巴卡韋、拉米夫定及齊多夫定)、EPZICOM®(含有阿巴卡韋及拉米夫定)、TRUVADA®(含有VIREAD®及EMTRIVA®);非核苷逆轉錄酶抑制劑:奈韋拉平(nevirapine)(或VIRAMUNE®)、地拉韋啶(delavirdine)(或RESCRIPTOR®)及依法韋侖(efavirenz)(或SUSTIVA®)、ATRIPLA®(TRUVADA®+SUSTIVA®)及依曲韋林(etravirine);及肽模擬蛋白酶抑制劑或經批准之調配物:沙奎那韋(saquinavir)、茚地那韋(indinavir)、利托那韋(ritonavir)、奈非那韋(nelfinavir)、安普那韋(amprenavir)、洛匹那韋(lopinavir)、KALETRA®(洛匹那韋及利托那韋)、地瑞那韋(darunavir)、阿紮那韋(atazanavir)(REYATAZ®)及替拉那韋(tipranavir)(APTIVUS®)及考比西他(cobicistat);及整合酶抑制劑,諸如雷特格韋(raltegravir)(ISENTRESS®);及進入抑制劑,諸如恩夫韋地(enfuvirtide)(T-20)(FUZEON®)及馬拉維若(maraviroc)(SELZENTRY®)。
此等藥物中之每一者在單獨使用時僅能夠短暫地限制病毒複製。然而,當組合使用時,此等藥物對病毒敗血症及疾病進展具有深遠影響。實際上,最近已記錄AIDS患者之死亡率由於廣泛應用組合療法而顯著降低。然而,儘管此等結果令人印象深刻,但組合藥物療法最終可能對30%至50%患者無效。某些細胞類型內之藥物效能不足、不順應、組織滲透受限制及藥物特異性限制(例如大部分核苷類似物在靜止細胞中不能磷酸化)可說明敏感病毒未被完全抑制。此外,當存在次最佳藥物濃度時,HIV-1的高複製速率及快速轉換與頻繁併入之突變組合導致出現耐藥性變異體及治療失敗。因此,需要展現特殊抗性模式及有利藥物動力學以及安全概況的新穎抗HIV劑以提供更多治療選擇。改良型HIV融合抑制劑及HIV進入輔助受體拮抗劑為許多研究人員正在進一步研究之新類別抗HIV劑的兩個實例。
HIV吸附抑制劑為結合於HIV表面醣蛋白gp120且干擾表面蛋白gp120與宿主細胞受體CD4之相互作用的另一子類抗病毒化合物。因而,其在HIV生命週期之初期防止HIV吸附於人類CD4 T細胞且阻斷HIV複製。已改良HIV吸附抑制劑之特性以努力獲得具有最大效用及效力的化合物作為抗病毒劑。詳言之,US 7,354,924及US 7,745,625說明HIV連接抑制劑。
另一類用於治療HIV之新興化合物稱為HIV成熟抑制劑。成熟是HIV複製或HIV生命週期中多達10個或10個以上步驟的最後一個,在該步驟中HIV因最終導致衣殼(CA)蛋白釋放之gag蛋白中之由若干HIV蛋白酶介導之裂解事件而變得具有傳染性。成熟抑制劑防止HIV衣殼適當組裝及成熟、防止形成保護性外被或防止出現於人類細胞中。相反,產生無傳染性病毒,從而防止隨後之HIV感染週期。
現已顯示樺木酸之某些衍生物展現作為HIV成熟抑制劑之有效抗HIV活性。舉例而言,US 7,365,221揭示單醯化樺木醇及二氫樺木醇衍生物及其作為抗HIV劑之用途。如'221參考文獻中所論述,用某些經取代之醯基(諸如3',3'-二甲基戊二醯基及3',3'-二甲基丁二醯基)使樺木酸(1)發生酯化可產生具有增強活性之衍生物(Kashiwada,Y.等人,J.Med.Chem.39:1016-1017(1996))。醯基化樺木酸及二氫樺木酸衍生物為有效抗HIV劑,其亦描述於美國專利第5,679,828號中。樺木醇之3碳中的羥基與丁二酸酯化亦產生能夠抑制HIV-1活性之化合物(Pokrovskii,A.G.等人,“Synthesis of derivatives of plant triterpenes and study of their antiviral and immunostimulating activity,”Khimiya y Interesakh Ustoichivogo Razvitiya,第9卷,第3號,第485頁-第491頁(2001)(英文摘要)。
使用衍生自樺木酸之化合物治療HIV感染之用途的其他參考文獻包括US 2005/0239748及US 2008/0207573,以及WO2006/053255、
WO2009/100532及WO2011/007230。
已在研發中之一種HIV成熟化合物已鑑別為貝韋立馬(Bevirimat)或PA-457,其化學式為C36H56O6且IUPAC名為3β-(3-羧基-3-甲基-丁醯氧基)羽扇-20(29)-烯-28-酸。
本文亦參考Bristol-Myers Squibb題為「MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS」USSN 13/151,706,2011年6月2日申請(現在US 8,754,068)及「C-28 AMIDES OF MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS」USSN 13/151,722,2011年6月2日申請(現在US 8,802,661)之申請案。亦參考題為「C-28 AMINES OF C-3 MODIFIED BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS」USSN 13/359,680,2012年1月27日申請(現在US 8,748,415)之申請案。此外,參考題為「C-17 AND C-3 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY」USSN 13/359,727,2012年1月27日申請(現在US 8,846,647)之申請案。另外亦參考申請案「C-3 CYCLOALKENYL TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY」,2013年2月6日申請之USSN 13/760,726(現在US 8,906,889)。
此項技術中目前需要適用作HIV成熟抑制劑之新穎化合物以及含有此等化合物之新穎醫藥組合物。
本發明提供以下式I化合物,包括其醫藥學上可接受之鹽、其醫藥調配物及其於罹患諸如HIV之病毒或對該病毒敏感之患者。式I化合物為有效抗病毒劑,尤其HIV之抑制劑。其適用於治療HIV及AIDS。
本發明之一個實施例係針對式I化合物,包括其醫藥學上可接受
之鹽:
其中R1為異丙烯基或異丙基;X係選自以下之群:C4-8環烷基、C4-8環烯基、C4-9螺環烷基、C4-9螺環烯基、C4-8氧雜環烷基、C4-8二氧雜環烷基、C6-8氧雜環烯基、C6-8二氧雜環烯基、C6環二烯基、C6氧雜環二烯基、C6-9氧雜螺環烷基及C6-9氧雜螺環烯基環,其中X經A取代,且其中A為-C1-6烷基-鹵基;Y係選自以下之群:-COOR2、-C(O)NR2SO2R3、-C(O)NHSO2NR2R2、-NR2SO2R2、-SO2NR2R2、-C3-6環烷基-COOR2、-C2-6烯基-COOR2、-C2-6炔基-COOR2、-C1-6烷基-COOR2、-烷基取代之C1-6烷基、-CF2-COOR2、-NHC(O)(CH2)n-COOR2、-SO2NR2C(O)R2、-四唑及-CONHOH,其中n=1-6;R2為-H、-C1-6烷基、-烷基取代之C1-6烷基或-芳基取代之C1-6烷基;W不存在或為-CH2或-CO;R3為-H、-C1-6烷基或-烷基取代之C1-6烷基;R4係選自以下之群:-H、-C1-6烷基、-C1-6烷基-C3-6環烷基、-C1-6取代之-C1-6烷基、-C1-6烷基-Q1、-C1-6烷基-C3-6環烷基-Q1、芳基、雜芳基、經取代之雜芳基、-COR6、-SO2R7、-SO2NR2R2,及
其中G係選自以下之群:-O-、-SO2-及-NR12;
其中Q1係選自以下之群:-C1-6烷基、-C1-6氟烷基、雜芳基、經取代之雜芳基、鹵素、-CF3、-OR2、-COOR2、-NR8R9、-CONR8R9及-SO2R7;R5係選自以下之群:-H、-C1-6烷基、-C3-6環烷基、-C1-6烷基取代之烷基、-C1-6烷基-NR8R9、-COR3、-SO2R7及-SO2NR2R2;其限制條件為當W為-CO時,R4或R5不可為-COR6;另外限制條件為R4或R5中僅一者可選自以下之群:--COR6、-COCOR6、-SO2R7及-SO2NR2R2;或當W不存在或為-CH2時,則R4及R5可與相鄰N一起形成
R6係選自以下之群:-H、-C1-6烷基、-C1-6烷基-取代之烷基、-C3-6環烷基、-C3-6取代之環烷基-Q2、-C1-6烷基-Q2、-C1-6烷基-取代之烷基-Q2、-C3-6環烷基-Q2、芳基-Q2、-NR13R14及-OR15;其中Q2係選自以下之群:芳基、雜芳基、經取代之雜芳基、-OR2、-COOR2、-NR8R9、SO2R7、-CONHSO2R3及-CONHSO2NR2R2;R7係選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基、-C3-6環烷基、-CF3、芳基及雜芳基;R8及R9獨立地選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基、芳基、雜芳基、經取代之芳基、經取代之雜芳基、-C1-6烷基-Q2及-COOR3,或R8及R9與相鄰N一起形成選自以下之群的環:
M係選自以下之群:-R15、-SO2R2、-SO2NR2R2、-OH及-NR2R12;V係選自以下之群:-CR10R11-、-SO2-、-O-及-NR12-;其限制條件為R8或R9中僅一者可為-COOR3;R10及R11獨立地選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基及-C3-6環烷基;R12係選自以下之群:-H、-C1-6烷基、-烷基經取代之C1-6烷基、-CONR2R2、-SO2R3、-SO2NR2R2;R13及R14獨立地選自以下之群:-H、-C1-6烷基、-C3-6環烷基、-C1-6取代之烷基、-C1-6烷基-Q3、-C1-6烷基-C3-6環烷基-Q3、C1-6取代之烷基-Q3及
Q3係選自以下之群:雜芳基、經取代之雜芳基、-NR2R12、-CONR2R2、-COOR2、-OR2及-SO2R3;R15係選自以下之群:-C1-6烷基、-C3-6環烷基、-C1-6取代之烷
基、-C1-6烷基-Q3、-C1-6烷基-C3-6環烷基-Q3及-C1-6經取代之烷基-Q3;R16係選自以下之群:-H、-C1-6烷基、-NR2R2及-COOR2;其限制條件為當V為-NR12-時;R16不可為-NR2R2;及R17係選自以下之群:-H、-C1-6烷基、-COOR3及芳基。
在另一實施例中,提供一種用於治療感染病毒之哺乳動物之方法,尤其其中該病毒為HIV,其包含向該哺乳動物投與抗病毒有效量的選自式I化合物之群的化合物及一或多種醫藥學上可接受之載劑、賦形劑或稀釋劑。視情況地,式I化合物可與抗病毒有效量的選自由以下組成之群的另一AIDS治療劑組合投與:(a)AIDS抗病毒劑;(b)抗感染劑、(c)免疫調節劑;以及(d)其他HIV進入抑制劑。
本發明之另一實施例為一種醫藥組合物,其包含一或多種式I化合物及一或多種醫藥學上可接受之載劑、賦形劑及/或稀釋劑;且視情況與選自由組成之群的另一AIDS治療劑組合:(a)AIDS抗病毒劑;(b)抗感染劑;(c)免疫調節劑;以及(d)其他HIV進入抑制劑。
在本發明之另一實施例中,提供一或多種用於製備本文的式I化合物之方法。
本文亦提供適用於製備本文之式I化合物的中間化合物。
本發明係針對此等以及下文所述的其他重要目的。
除非上下文另外明確規定,否則如本文所用之單數形式「一(a)」、「一(an)」及「該」包括複數個參考物。
因為本發明化合物可具有不對稱中心,且因此以非對映異構體之混合物形式存在,所以本發明除式I化合物之混合物外,還包括式I化合物之個別非對映異構形式。
除非在本申請案之別處另外特定闡述,否則一或多個以下術語可用於本文中且應具有以下含義:「H」係指氫,包括其同位素,諸如氘。
如本文及申請專利範圍中所使用之術語「C1-6烷基」(除非另外規定)意謂直鏈或分支鏈烷基,諸如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基、己基及其類似基團。
「C1-C4氟烷基」係指經F取代之C1-C4烷基,其中至少一個H原子被F原子取代,且各H原子可獨立地經F原子取代;「鹵素」或「鹵基」係指氯、溴、碘或氟。
「芳基」或「Ar」基團係指具有完全共軛之π電子系統的全碳單環或稠環多環(亦即共用一對相鄰碳原子的環)基團。芳基之實例(非限制性)為苯基、萘基及蒽基。芳基可經取代或未經取代。取代時,取代基較佳為選自以下中之一或多者:烷基、環烷基、芳基、雜芳基、雜脂環基、羥基、烷氧基、芳氧基、雜芳氧基、雜脂環基氧基、硫羥基、硫代芳氧基、硫代雜芳氧基、硫代雜脂環基氧基、氰基、鹵素、硝基、羰基、O-胺甲醯基、N-胺甲醯基、C-醯胺基、N-醯胺基、C-羧基、O-羧基、亞磺醯基、磺醯基、磺醯胺基、三鹵基甲基、脲基、胺基及-NRxRy(其中Rx及Ry係獨立地選自由以下組成之群:氫、烷基、環烷基、芳基、羰基、C-羧基、磺醯基、三鹵基甲基),及組合之5或6員雜脂環。
如本文所使用,「雜芳基」係指環中具有一或多個選自由氮、氧及硫組成之群的原子且另外具有完全共軛之π電子系統的單環或稠環(亦即共用一對相鄰原子的環)基團。除非另外指示,否則雜芳基可於雜芳基內之碳或氮原子處連接。應注意,術語雜芳基意欲涵蓋親本雜芳基之N-氧化物,只要此類N-氧化物如此項技術中已知化學上可行。
雜芳基之實例(非限制性)為呋喃基、噻吩基、苯并噻吩基、噻唑基、咪唑基、噁唑基、噁二唑基、噻二唑基、苯并噻唑基、三唑基、四唑基、異噁唑基、異噻唑基、吡咯基、哌喃基、四氫哌喃基、吡唑基、吡啶基、嘧啶基、喹啉基、異喹啉基、嘌呤基、咔唑基、苯并噁唑基、苯并咪唑基、吲哚基、異吲哚基、吡嗪基、二嗪基、吡嗪、三嗪基、四嗪基及四唑基。取代時,取代基較佳為選自以下中之一或多者:烷基、環烷基、芳基、雜芳基、雜脂環基、羥基、烷氧基、芳氧基、雜芳氧基、雜脂環基氧基、硫代烷氧基、硫羥基、硫代芳氧基、硫代雜芳氧基、硫代雜脂環基氧基、氰基、鹵素、硝基、羰基、O-胺甲醯基、N-胺甲醯基、C-醯胺基、N-醯胺基、C-羧基、O-羧基、亞磺醯基、磺醯基、磺醯胺基、三鹵基甲基、脲基、胺基及-NRxRy,其中Rx及Ry如上文所定義。
如本文所使用,「雜脂環」基係指環中具有一或多個選自由氮、氧及硫組成之群的原子的單環或稠環基團。各環係選自提供穩定鍵排列之環且不意欲涵蓋不存在之系統。該等環亦可具有一或多個雙鍵。然而,該等環不具有完全共軛之π電子系統。雜脂環基之實例(非限制性)為氮雜環丁烷基、哌啶基、哌嗪基、咪唑啉基、噻唑啶基、3-吡咯啶-1-基、嗎啉基、硫代嗎啉基及其S氧化物及四氫哌喃基。取代時,取代基較佳為選自以下中之一或多者:烷基、環烷基、芳基、雜芳基、雜脂環基、羥基、烷氧基、芳氧基、雜芳氧基、雜脂環基氧基、硫羥基、硫代烷氧基、硫代芳氧基、硫代雜芳氧基、硫代雜脂環基氧基、氰基、鹵素、硝基、羰基、硫代羰基、O-胺甲醯基、N-胺甲醯基、O-硫代胺甲醯基、N-硫代胺甲醯基、C-醯胺基、C-硫代醯胺基、N-醯胺基、C-羧基、O-羧基、亞磺醯基、磺醯基、磺醯胺基、三鹵基甲磺醯胺基、三鹵基甲磺醯基、矽烷基、甲脒基、胍基、脲基、膦醯基、胺基及-NRxRy,其中Rx及Ry如上文所定義。
「烷基」係指飽和脂族烴,包括直鏈及分支鏈基團。烷基較佳具有1至20個碳原子(每當本文陳述數值範圍(例如「1至20」)時,其意謂該基團(在此情況下為烷基)可含有1個碳原子、2個碳原子、3個碳原子等,至多且包括20個碳原子)。更佳地,其為具有1至10個碳原子之中等尺寸烷基。最佳地,其為具有1至4個碳原子的低碳烷基。烷基可經取代或未經取代。取代時,取代基較佳為個別選自以下之一或多者:三鹵基烷基、環烷基、芳基、雜芳基、雜脂環基、羥基、烷氧基、芳氧基、雜芳氧基、雜脂環基氧基、硫羥基、硫代烷氧基、硫代芳氧基、硫代雜芳氧基、硫代雜脂環基氧基、氰基、鹵基、硝基、羰基、硫羰基、O-胺甲醯基、N-胺甲醯基、O-硫代胺甲醯基、N-硫代胺甲醯基、C-醯胺基、C-硫代醯胺基、N-醯胺基、C-羧基、O-羧基、亞磺醯基、磺醯基、磺醯胺基、三鹵基甲磺醯胺基、三鹵基甲磺醯基,及組合之5或6員雜脂環。
「環烷基」係指一或多個環不具有完全共軛之π電子系統的全碳單環或稠環(亦即共用一對相鄰碳原子的環)基團。環烷基之實例(非限制性)為環丙烷、環丁烷、環戊烷、環戊烯、環己烷、環己烯、環庚烷、環庚烯及金剛烷。環烷基可經取代或未經取代。取代時,取代基較佳為個別選自以下之一或多者:烷基、芳基、雜芳基、雜脂環基、羥基、烷氧基、芳氧基、雜芳氧基、雜脂環基氧基、硫羥基、硫代烷氧基、硫代芳氧基、硫代雜芳氧基、硫代雜脂環基氧基、氰基、鹵基、硝基、羰基、硫羰基、O-胺甲醯基、N-胺甲醯基、O-硫代胺甲醯基、N-硫代胺甲醯基、C-醯胺基、C-硫代醯胺基、N-醯胺基、C-羧基、O-羧基、亞磺醯基、磺醯基、磺醯胺基、三鹵基甲磺醯胺基、三鹵基甲磺醯基、矽烷基、甲脒基、胍基、脲基、膦醯基、胺基及-NRxRy,其中Rx及Ry如上文所定義。
如本文所定義,「烯基」係指具有至少兩個碳原子及至少一個碳-
碳雙鍵之烷基。
如本文所定義,「炔基」係指具有至少兩個碳原子及至少一個碳-碳參鍵之烷基。
「羥基」係指-OH基團。
如本文所定義,「烷氧基」係指-O-烷基及-O-環烷基。
如本文所定義,「芳氧基」係指-O-芳基及-O-雜芳基。
「雜芳氧基」係指雜芳基-O-基團,其中雜芳基如本文所定義。
「雜脂環基氧基」係指雜脂環-O-基團,其中雜脂環如本文所定義。
「硫羥基」係指-SH基團。
如本文所定義,「硫代烷氧基」係指-S-烷基及-S-環烷基。
如本文所定義,「硫代芳氧基」係指-S-芳基及-S-雜芳基。
「硫代雜芳氧基」係指雜芳基-S-基團,其中雜芳基如本文所定義。
「硫代雜脂環基氧基」係指雜脂環-S-基團,其中雜脂環如本文所定義。
「羰基」係指-C(=O)-R"基團,其中R"係選自由氫、烷基、烯基、炔基、環烷基、芳基、雜芳基(經環碳鍵結)及雜脂環基(經環碳鍵結)組成之群,各自如本文所定義。
「醛」基係指R"為氫的羰基。
「硫代羰基」係指-C(=S)-R"基團,其中R"如本文所定義。
「酮基」係指-CC(=O)C-基團,其中處於C=O任一側或兩側之碳可為烷基、環烷基、芳基或者雜芳基或雜脂環基之碳。
「三鹵基甲烷羰基」係指Z3CC(=O)-基團,其中該Z為鹵素。
「C-羧基」係指-C(=O)O-R"基團,其中R"如本文所定義。
「O-羧基」係指R"C(-O)O-基團,其中R"如本文所定義。
「羧酸」基係指C-羧基,其中R"為氫。
「三鹵基甲基」係指-CZ3基團,其中Z為如本文所定義之鹵素基團。
「三鹵基甲磺醯基」係指Z3CS(=O)2-基團,其中Z如上文所定義。
「三鹵基甲磺醯胺基」係指Z3CS(=O)2NRx-基團,其中Z如上文所定義,且Rx為H或(C1-6)烷基。
「亞磺醯基」係指-S(=O)-R"基團,其中R"為(C1-6)烷基。
「磺醯基」係指-S(=O)2R"基團,其中R"為(C1-6)烷基。
「S-磺醯胺基」係指-S(=O)2NRXRY,其中RX及RY獨立地為H或(C1-6)烷基。
「N-磺醯胺基」係指R"S(=O)2NRX-基團,其中RX為H或(C1-6)烷基。
「O-胺甲醯基」係指-OC(=O)NRxRy基團,其中RX及RY獨立地為H或(C1-6)烷基。
「N-胺甲醯基」係指RxOC(=O)NRy基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「O-硫代胺甲醯基」係指-OC(=S)NRxRy基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「N-硫代胺甲醯基」係指RxOC(=S)NRy-基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「胺基」係指-NH2基團。
「C-醯胺基」係指-C(=O)NRxRy基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「C-硫代醯胺基」係指-C(=S)NRxRy基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「N-醯胺基」係指RxC(=O)NRy-基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「脲基」係指-NRxC(=O)NRyRy2基團,其中Rx、Ry及Ry2獨立地為H或(C1-6)烷基。
「胍基」係指-RxNC(=N)NRyRy2基團,其中Rx、Ry及Ry2獨立地為H或(C1-6)烷基。
「甲脒基」係指RxRyNC(=N)-基團,其中Rx及Ry獨立地為H或(C1-6)烷基。
「氰基」係指-CN基團。
「矽烷基」係指-Si(R")3,其中R"為(C1-6)烷基或苯基。
「膦醯基」係指P(=O)(ORx)2,其中Rx為(C1-6)烷基。
「肼基」係指-NRxNRyRy2基團,其中Rx、Ry及Ry2獨立地為H或(C1-6)烷基。
「4、5或6員環環狀N-內醯胺」基團係指、或
「螺」基團為各環僅經一個原子連接之雙環有機基團。各環的性質可不同或相同。連接原子亦稱為螺原子,最通常四級碳(「螺碳」)。
「側氧基螺」或「氧雜螺」基團為雙環環結構內含有氧的螺基團。「二側氧基螺」或「二氧雜螺」基團在雙環環結構內具有兩個氧。
任何兩個相鄰R基團可組合形成稠合至最初帶有該等R基團之環的另一芳基、環烷基、雜芳基或雜環。
此項技術中已知雜芳基系統中之氮原子可「參與雜芳基環雙
鍵」,且此係指包含5員環雜芳基之兩個互變異構結構中之雙鍵形式。此指示氮是否可如此項技術的化學家所理解經取代。本發明之揭示內容及申請專利範圍是基於化學鍵結的已知通用原理。應理解,申請專利範圍不涵蓋基於文獻已知不穩定或不能存在的結構。
本文所揭示之化合物的醫藥學上可接受之鹽及前藥在本發明之範疇內。如本文及申請專利範圍中所用之術語「醫藥學上可接受之鹽」意欲包括無毒鹼加成鹽。適合鹽包括衍生自有機酸及無機酸之鹽,諸如(但不限於)鹽酸、氫溴酸、磷酸、硫酸、甲磺酸、乙酸、酒石酸、乳酸、亞磺酸、檸檬酸、順丁烯二酸、反丁烯二酸、山梨酸、烏頭酸、水楊酸、鄰苯二甲酸及其類似物。如本文所使用之術語「醫藥學上可接受之鹽」亦意欲包括酸性基團(諸如羧酸根)與相對離子形成之鹽,諸如銨鹽、鹼金屬鹽(尤其鈉或鉀)、鹼土金屬鹽(尤其鈣或鎂);及與諸如低碳烷基胺(甲胺、乙胺、環己胺及其類似物)之適合有機鹼形成之鹽;或與經取代之低碳烷基胺(例如經羥基取代之烷基胺,諸如二乙醇胺、三乙醇胺或參(羥甲基)胺基甲烷)形成之鹽;或與諸如哌啶或嗎啉之鹼形成之鹽。
如上所述,本發明化合物亦包括「前藥」。如本文所使用之術語「前藥」涵蓋術語「前藥酯」及術語「前藥醚」。
如上文所述,本發明係針對式I化合物,包括其醫藥學上可接受之鹽:
其中R1為異丙烯基或異丙基;X係選自以下之群:C4-8環烷基、C4-8環烯基、C4-9螺環烷基、C4-9
螺環烯基、C4-8氧雜環烷基、C4-8二氧雜環烷基、C6-8氧雜環烯基、C6-8二氧雜環烯基、C6環二烯基、C6氧雜環二烯基、C6-9氧雜螺環烷基及C6-9氧雜螺環烯基環,其中X經A取代,且其中A為-C1-6烷基-鹵基;Y係選自以下之群:-COOR2、-C(O)NR2SO2R3、-C(O)NHSO2NR2R2、-NR2SO2R2、-SO2NR2R2、-C3-6環烷基-COOR2、-C2-6烯基-COOR2、-C2-6炔基-COOR2、-C1-6烷基-COOR2、-烷基經取代之C1-6烷基、-CF2-COOR2、-NHC(O)(CH2)n-COOR2、-SO2NR2C(O)R2、-四唑及-CONHOH,其中n=1-6;R2為-H、-C1-6烷基、-烷基取代之C1-6烷基或-芳基取代之C1-6烷基;W不存在或為-CH2或-CO;R3為-H、-C1-6烷基或-烷基取代之C1-6烷基;R4係選自以下之群:-H、-C1-6烷基、-C1-6烷基-C3-6環烷基、-C1-6取代之-C1-6烷基、-C1-6烷基-Q1、-C1-6烷基-C3-6環烷基-Q1、芳基、雜芳基、經取代之雜芳基、-COR6、-SO2R7、-SO2NR2R2,及
其中G係選自以下之群:-O-、-SO2-及-NR12;其中Q1係選自以下之群:-C1-6烷基、-C1-6氟烷基、雜芳基、經取代之雜芳基、鹵素、-CF3、-OR2、-COOR2、-NR8R9、-CONR8R9及-SO2R7;R5係選自以下之群:-H、-C1-6烷基、-C3-6環烷基、-C1-6烷基取代之烷基、-C1-6烷基-NR8R9、-COR3、-SO2R7及-SO2NR2R2;其限制條件為當W為-CO時,R4或R5不可為-COR6;
另外限制條件為R4或R5中僅一者可選自以下之群:--COR6、-COCOR6、-SO2R7及-SO2NR2R2;或當W不存在或為-CH2時,則R4及R5可與相鄰N一起形成
R6係選自以下之群:-H、-C1-6烷基、-C1-6烷基-取代之烷基、-C3-6環烷基、-C3-6取代之環烷基-Q2、-C1-6烷基-Q2、-C1-6烷基-取代之烷基-Q2、-C3-6環烷基-Q2、芳基-Q2、-NR13R14及-OR15;其中Q2係選自以下之群:芳基、雜芳基、經取代之雜芳基、-OR2、-COOR2、-NR8R9、SO2R7、-CONHSO2R3及-CONHSO2NR2R2;R7係選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基、-C3-6環烷基、-CF3、芳基及雜芳基;R8及R9獨立地選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基、芳基、雜芳基、經取代之芳基、經取代之雜芳基、-C1-6烷基-Q2及-COOR3,或R8及R9與相鄰N一起形成選自以下之群的環:
M係選自以下之群:-R16、-SO2R2、-SO2NR2R2、-OH及-NR2R12;V係選自以下之群:-CR10R11-、-SO2-、-O-及-NR12-;其限制條件為R8或R9中僅一者可為-COOR3;R10及R11獨立地選自以下之群:-H、-C1-6烷基、-C1-6取代之烷基及-C3-6環烷基;R12係選自以下之群:-H、-C1-6烷基、-烷基取代之C1-6烷基、-CONR2R2、-SO2R3、-SO2NR2R2;R13及R14獨立地選自以下之群:-H、-C1-6烷基、-C3-6環烷基、-C1-6取代之烷基、-C1-6烷基-Q3、-C1-6烷基-C3-6環烷基-Q3、C1-6取代之烷基-Q3及
Q3係選自以下之群:雜芳基、經取代之雜芳基、-NR2R12、-CONR2R2、-COOR2、-OR2及-SO2R3;R15係選自以下之群:-C1-6烷基、-C3-6環烷基、-C1-6取代之烷基、-C1-6烷基-Q3、-C1-6烷基-C3-6環烷基-Q3及-C1-6取代之烷基-Q3;R16係選自以下之群:-H、-C1-6烷基、-NR2R2及-COOR2;其限制條件為當V為-NR12-時;R16不可為-NR2R2;及R17係選自以下之群:-H、-C1-6烷基、-COOR3及芳基。
更佳化合物包括R1為異丙烯基之化合物。
亦較佳為W不存在的化合物。
其他較佳化合物包括X為C4-8環烯基,且更佳C6環烯基之化合物。
此外,式I化合物較佳為其中A為C1-C3烷基-鹵基,且更佳甲基-鹵基,且更佳甲基-氟。
亦較佳為A在取代基X上經對位取代之化合物。
亦較佳為Y為-COOR2,且更佳-COOH之式I化合物。在某些實施例中,亦較佳為Y為-COOH且A為甲基-氟。
亦較佳為Y在對位中之式I化合物。
更佳為取代基A及取代基Y共用取代基X上,更佳取代基X的對位上之相同連接點的式I化合物。
在許多實施例中,亦較佳R4為C1-6烷基-Q1,其中Q1為-NR8R9。
在一些實施例中,較佳R4為-C1-6烷基-C3-6環烷基。
在某些實施例中,亦較佳R5為C1-6烷基-NR8R9。
許多時候,亦較佳-NR8R9形成如上文所述之環結構。
作為本發明部分之較佳化合物,包括其醫藥學上可接受之鹽,包括以下:
作為本發明之部分的較佳化合物,包括其醫藥學上可接受之鹽,包括以下:
上文之化合物表示非對映異構體之混合物及兩種個別非對映異構體。在某些實施例中,特定非對映異構體中之一者可尤其較佳。
根據所有上文所述之多種實施例,本發明化合物可以含有熟習此項技術者可利用之醫藥學上可接受之無毒載劑、賦形劑及稀釋劑之劑量單位調配物的形式經口、非經腸(包括皮下注射、靜脈內、肌肉內、胸骨內注射或輸注技術)、藉由吸入噴霧或經直腸及其他方式投與。亦可包括一或多種佐劑。
因此,根據本發明,另外提供一種用於治療病毒感染(諸如HIV感染及AIDS)之治療方法及醫藥組合物。治療涉及向需要此類治療之患者投與醫藥組合物,其含有抗病毒有效量之一或多種式I化合物以及一或多種醫藥學上可接受之載劑、賦形劑或稀釋劑。如本文所使用之術語「抗病毒有效量」意謂組合物及方法之各活性組分之總量足以顯示有意義之患者益處,亦即以抑制HIV感染為特徵之抑制、改善或治癒急性病狀。當應用於單獨投與之個別活性成份時,該術語係指單獨彼成份。當應用於組合時,該術語係指無論連續或同時以組合方式投與,產生治療作用之活性成份之組合量。如本文及申請專利範圍中所使用之術語「治療(treat、treating、treatment)」意謂預防、抑制、改善及/或治癒與HIV感染有關之疾病及病狀。
本發明之醫藥組合物可呈可經口投與之懸浮液或錠劑形式;以及經鼻噴霧、無菌可注射製劑,例如呈無菌可注射水溶液或油質懸浮液或栓劑形式。醫藥學上可接受之載劑、賦形劑或稀釋劑可用於醫藥組合物中,且其為醫藥製備技術中可利用者。
當以懸浮液形式經口投與時,此等組合物根據醫藥調配技術中通常已知之技術製備,且可含有用於賦予塊狀的微晶纖維素、作為懸浮劑的海藻酸或海藻酸鈉、作為黏度增強劑之甲基纖維素及此項技術中已知的甜味劑/調味劑。作為立即釋放錠劑,此等組合物可含有微晶纖維素、磷酸二鈣、澱粉、硬脂酸鎂及乳糖及/或此項技術中已知的其他賦形劑、黏合劑、增量劑、崩解劑、稀釋劑及潤滑劑。
可使用適合無毒、非經腸可接受之稀釋劑或溶劑,諸如甘露糖醇、1,3-丁二醇、水、林格氏溶液(Ringer's solution)或等張氯化鈉溶液或適合分散劑或濕潤劑及懸浮劑,諸如無菌無刺激性不揮發性油,包括合成單酸甘油酯或二酸甘油酯,及脂肪酸,包括油酸,根據已知技術來調配可注射溶液或懸浮液。
本文所述之化合物可以每公斤體重約1至100mg之劑量範圍以分次給藥形式向人類經口投與,通常經較長時段,諸如數天、數週、數月或甚至數年。一個較佳劑量範圍為每公斤體重約1至10mg,經口分次給藥。另一較佳劑量範圍為每公斤體重約1至20mg,分次給藥。然而,應理解,用於任何特定患者之特定劑量及給藥頻率均可改變,且將視各種因素而定,包括所用特定化合物之活性、該化合物之代謝穩定性及作用時長、年齡、體重、一般健康情況、性別、飲食、投與模式及時間、排泄速率、藥物組合、特定病狀之嚴重程度及經受治療之主體。
本文亦涵蓋本文所述之式I化合物與一或多種適用於治療AIDS的其他試劑的組合。舉例而言,不論是在暴露前及/或暴露後之時段,本發明化合物可與有效量之諸如以下非限制性表格中之AIDS抗病毒劑、免疫調節劑、抗感染劑或疫苗組合而有效地投與:
此外,本文所述的本發明之化合物可與HIV進入抑制劑組合使用。此類HIV進入抑制劑之實例論述於DRUGS OF THE FUTURE 1999,24(12),第1355頁-第1362頁;CELL,第9卷,第243頁-第246頁,1999年10月29日;及DRUG DISCOVERY TODAY,第5卷,第5期,2000年5月,第183頁-第194頁以及Inhibitors of the entry of HIV into host cells中。同時,Nicholas A.;Kadow,John F.,Current Opinion in Drug Discovery & Development(2003),6(4),451-461。特定言之,化合物可與連接抑制劑、融合抑制劑及針對CCR5或CXCR4共同受體之趨化因子受體拮抗劑組合使用。HIV連接抑制劑亦闡述於US 7,354,924及US 7,745,625中。
應理解本申請案之化合物與AIDS抗病毒劑、免疫調節劑、抗傳染劑、HIV進入抑制劑或疫苗的組合的範圍不限於上文表格之清單
中,而是大體上包括與適用於治療AIDS之任何醫藥組合物的任何組合。
較佳組合為本發明化合物及HIV蛋白酶抑制劑及/或HIV逆轉錄酶之非核苷抑制劑的同時或交替處理。組合中的視情況存在之第四組分為HIV逆轉錄酶之核苷抑制劑,諸如AZT、3TC、ddC或ddI。HIV蛋白酶之較佳抑制劑為REYATAZ®(活性成分阿紮那韋)。通常每天投與一次300至600mg劑量。此可與低劑量之利托那韋(50至500mg)共同投與。HIV蛋白酶之另一較佳抑制劑為KALETRA®。HIV蛋白酶之另一適用抑制劑為茚地那韋,其為N-(2(R)-羥基-1-(S)-茚滿基)-2(R)-苯基甲基-4-(S)-羥基-5-(1-(4-(3-吡啶基-甲基))-2(S)-N'-(第三丁基羧醯胺基)-哌嗪基))-戊醯胺乙醇化物之硫酸鹽,且根據U.S.5,413,999合成。茚地那韋一般以800mg之劑量每天三次投與。其他較佳蛋白酶抑制劑為奈非那韋及利托那韋。HIV蛋白酶之另一較佳抑制劑為沙奎那韋,其以600或1200mg之劑量每天三次投與。HIV逆轉錄酶之較佳非核苷抑制劑包括依法韋侖。此等組合可具有出人意料的限制HIV感染之擴散及程度的作用。較佳組合包括具有以下者:(1)茚地那韋與依法韋侖,及視情況存在之AZT及/或3TC及/或ddI及/或ddC;(2)茚地那韋,及AZT及/或ddI及/或ddC及/或3TC中之任一者,詳言之,茚地那韋及AZT及3TC;(3)司他夫定及3TC及/或齊多夫定;(4)泰諾福韋酯反丁烯二酸鹽及恩曲他濱。
在此類組合中,本發明之化合物及其他活性劑可分別或組合投與。另外,投與一個要素可在投與其他藥劑之前、同時或之後進行。
本發明包含式I化合物、其醫藥調配物及其於患有HIV感染或對HIV感染敏感之患者中的用途。式I化合物亦包括其醫藥學上可接受之鹽。以下流程中描述建構式I化合物之通用程序及適用於其合成的中
間物(在縮寫之後)。
本發明之描述及實例全文中可使用以下縮寫中之一或多者,其中大多數為熟習此項技術者熟知的習知縮寫。
RT=室溫
BHT=2,6-二-第三丁基-4-羥基甲苯
CSA=樟腦磺酸
LDA=二異丙基胺基鋰
KHMDS=雙(三甲基矽烷基)胺基鋰
SFC=超臨界流體層析法
Quant=定量
TBDMS=第三丁基二甲基矽烷
PTFE=聚四氟乙烯
NMO=4-甲氧基嗎啉-N-氧化物
THF=四氫呋喃
TLC=薄層層析法
DCM=二氯甲烷
DCE=二氯乙烷
TFA=三氟乙酸
LCMS=液相層析質譜
Prep=製備型
HPLC=高效液相層析法
DAST=(二乙基胺基)三氟化硫
TEA=三乙胺
DIPEA=N,N-二異丙基乙胺
HATU=[六氟磷酸O-(7-氮雜苯丙三唑-1-基)-1,1,3,3-四甲基]
DCC=N,N'-二環己基碳化二亞胺
DMAP=二甲基胺基吡啶
TMS=三甲基矽烷基
NMR=核磁共振
DPPA=疊氮磷酸二苯酯
AIBN=偶氮二異丁腈
TBAF=氟化四丁基銨
DMF=二甲基甲醯胺
TBTU=四氟硼酸O-(苯丙三唑-1-基)-N,N,N',N'-四甲基
Min(s)=分鐘
h=小時
sat.=飽和
TEA=三乙胺
EtOAc=乙酸乙酯
TFA=三氟乙酸
PCC=氯鉻酸吡錠
TLC=薄層層析法
Tf2NPh=(三氟甲基磺醯基)甲磺醯胺
二噁烷=1,4-二噁烷
PG=保護基
atm=大氣壓
mol=莫耳
mmol=毫莫耳
mg=毫克
μg=微克
μl=微升
μm=微克
mm=毫米
術語「C-3」及「C-28」係指根據IUPAC法則編號的三萜核心的特定位置(下文關於說明性三萜:樺木醇描繪位置):
當在流程及方法之通用描述中提及化合物系列時,保留相同編號。
式I化合物可藉由以下流程中所述之化學方法自市售(Aldrich,其他)樺木酸製備。
下文闡述整體反應流程:
式I化合物可如流程1中所述自樺木酸製備。可不對C-3羥基進行保護以使C-17異氰酸酯在酸水解時產生C-17胺來實現樺木酸的柯蒂斯重排(Curtis rearrangement)。C-17胺接著用胺保護基(亦即F-moc、Boc)選擇性保護,接著在標準條件((亦即PCC、戴斯-馬丁試劑等)下將C-3羥基氧化成酮。可藉由熟習此項技術者已知之方法實現酮轉化成其三氟甲磺酸酯。接著除去胺基中之保護基產生C-17未經取代之胺。如上文所述經三氟甲磺酸酯與相應酸的鈴木偶合(Suzuki
coupling)實現C-3部分之安裝。或者,可在對C-17胺進行脫除保護基之前使三氟甲磺酸酯與相應酸偶合。脫除保護基後,C-17胺基可接著藉由熟習此項技術者已知之方法(諸如烷基化、還原胺化、醯化等)另外衍生。以下流程(流程2-7)中描述了若干此等方法。在一些情況下,需要額外步驟來揭發可用保護基官能化之任何官能基(亦即當Y為COOH時,在此最後步驟之前一直遮蔽為相應酯COOR)。
C-17一級胺可使用熟習此項技術者已知的標準方法進一步改質。以下流程中顯示了一些實例。
C-17醯胺可藉由使羧酸與C-17一級胺在足夠偶合試劑(諸如HATU、DCC及熟習此項技術者已知的其他偶合試劑)存在下,在鹼(諸如惠寧鹼(Hunig'sbase)、TEA等)存在下,在適當溶劑(DCM、THF、DMF等)中反應來製備。羧酸酯水解獲得苯甲酸。或者,一些醯胺可藉由用相應羧酸氯化物試劑代替酸來處理C-17一級胺來製備。類似地,可藉由使用磺醯基氯化物作為磺醯化試劑自C-17一級胺製備磺醯胺。
C-17脲可藉由使相應胺甲醯基氯或異氰酸酯在鹼(諸如惠寧鹼、TEA等)存在下,在適當溶劑(DCM、THF、DMF等)中反應來製備。C-
17胺基甲酸酯可以類似方式使用氯甲酸酯代替胺甲醯基氯來製備。
可用醛在還原胺化條件(例如NaBH(OAc)3,在AcOH/NaOAc或Ti(OPr)4存在下,在諸如THF、1,4-二噁烷、DCE或DCM之溶劑中)處理C-17一級胺獲得C-17二級胺。
可藉由用烷基化劑(R-LG),其中LG為離去基,諸如(但不限於)Br、Cl、I、甲磺酸酯基、甲苯磺酸酯基或三氟甲磺酸酯基,在鹼存在下,使C-17一級胺烷基化,製備一些C-17胺。在一些情況下可能需要加熱。羧酸酯水解獲得苯甲酸產物。
在一些情況下,藉由延長反應時間及加熱反應混合物,亦可形成二烷基化產物。
流程7
或者,一些C-17胺可藉由1,4-加成至邁克爾受體(Michael acceptor)來製備。
取代基R、R'及R"可含有官能團(亦即COOH、COOR、OH、NHR),其可藉由熟習此項技術者已知的方法進一步改質。可在羧酸的最終脫除保護基之前或之後進行改質,視官能基性質而進行。
或者,C-17二級胺可使用上文所述之一些方法或熟習此項技術者已知之其他標準方法進一步改質(亦即烷基化、醯基化、磺化劑等)。
以下實例說明如上文一般描述的式I化合物之典型合成。此等實例僅為說明性的且不欲以任何方式限制本發明。試劑及起始材料為一般技術者容易獲得的。
除非另外規定,否則溶劑及試劑以獲自商業來源時原樣使用,且反應在氮氣氛圍下進行。在矽膠60(0.040-0.063粒徑;EM Science供應)上進行急驟層析法。在Bruker DRX-500f上於500MHz下(或Bruker AV 400MHz、Bruker DPX-300B或Varian Gemini 300,300MHz,如所述)記錄1H NMR光譜。在δ量表上以ppm為單位相對於δ TMS=0報導化學位移。以下溶劑中之殘餘質子使用以下內部參考:CDCl3(δH 7.26)、CD3OD(δH 3.30)、乙酸-d4(乙酸d 4 )(δH 11.6,2.07),DMSO混合物或DMSO-D6-CDCl3(δH 2.50及8.25)(比率75%:25%),及DMSO-D6(δH 2.50)。採用標準首字母縮寫詞來描述多重性模式:s
(單峰),br.s(單寬峰),d(二重峰),t(三重峰),q(四重峰),m(多重峰),b(寬峰),app(表觀)。偶合常數(J)以赫茲為單位。所有液相層析(LC)資料均在使用SPD-10AV UV-Vis偵測器的Shimadzu LC-10AS液相層析儀上記錄,質譜(MS)資料係使用用於LC之Micromass Platform以電噴霧模式測定。
部分1
LC/MS方法
方法1
起始B%=0,經2分鐘梯度最終B%=100,保持為100% B
流動速率=1mL/min
長度=220nm
溶劑A=90%水、10%甲醇、0.1% TFA
溶劑B=10%水、90%甲醇、0.1% TFA
管柱=Phenomenex Luna C18,3μm,2.0×30mm
方法2
起始B%=0,經4分鐘梯度最終B%=100,保持為100% B
流動速率=0.8mL/min
長度=220nm
溶劑A=90%水、10%甲醇、0.1% TFA
溶劑B=10%水、90%甲醇、0.1% TFA
管柱=Phenomenex Luna C18,3μm,2.0×50mm
方法3
起始B%=0,經2分鐘梯度最終B%=100,保持為100% B
流動速率=1mL/min
長度=220nm
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Phenomenex Luna C18,3μm,2.0×30mm
方法4
起始B%=20,經2分鐘梯度最終B%=100,保持為100% B
流動速率=0.8mL/min
長度=220nm
溶劑A=90%水、10%甲醇、0.1% TFA
溶劑B=10%水、90%甲醇、0.1% TFA
管柱=Waters Xbridge Phenyl,2.5μm,2.1×50mm
方法5
起始B%=20,最終B%=100,梯度時間=1.5min
流動速率=0.8mL/min
長度=220
溶劑A=10% MeOH-90%水-0.1% TFA
溶劑B=90% MeOH-10%水-0.1% TFA
管柱=Waters Xbridge Phenyl 2.1×50mm 2.5μm
方法6
起始B%=2,經1.5分鐘梯度最終B%=98,保持為98% B
流動速率=0.8mL/min
長度=220nm
溶劑A=100%水、0.05%TFA
溶劑B=100%乙腈、0.05% TFA
管柱=Waters Aquity UPLC BEH C18,2.1×50mm,1.7μm
方法7
起始B%=20,最終B%=100,梯度時間=3min
流動速率=0.6mL/min
長度=220
溶劑A=10% MeOH-90%水-0.1% TFA
溶劑B=90% MeOH-10%水-0.1% TFA
管柱=Waters Xbridge Phenyl 2.1×50mm 2.5μm
方法8
起始B%=20,最終B%=100,梯度時間=2min
流動速率=0.6mL/min
長度=220
溶劑A=10% MeOH-90%水-0.1% TFA
溶劑B=90% MeOH-10%水-0.1% TFA
管柱=Waters Xbridge Phenyl 2.1×50mm 2.5μm
方法9
起始B%=0,經2分鐘梯度最終B%=100,保持為100% B
流動速率=0.6mL/min
長度=220nm
溶劑A=90%水、10%甲醇、0.1% TFA
溶劑B=10%水、90%甲醇、0.1% TFA
管柱=Xbridge Phenyl,2.5μm,2.1×50mm
方法10
起始B%=30,經4分鐘梯度最終B%=100,保持為100% B
流動速率=.8mL/min
長度=220
溶劑對=水-甲醇-0.1% TFA
溶劑A=90%水-10%甲醇-0.1% TFA
溶劑B=10%水-90%甲醇-0.1% TFA
管柱2=(2)PHENOMENEX-LUNA 2.0×50mm 3μm
方法11
起始B%=40,經4分鐘梯度最終B%=100,保持為100% B
流動速率=.8mL/min
長度=220
溶劑對=乙腈:水:10mM乙酸銨
溶劑A=5%乙腈:95%水:10mM乙酸銨
溶劑B=95%乙腈:5%水:10mM乙酸銨
管柱2=2.)PHENOMENEX-LUNA 2.0×50mm 3μm
方法12
起始B%=20,經4分鐘梯度最終B%=100,保持為100% B
流動速率=.8mL/min
長度=220
溶劑對=乙腈:水:10mM乙酸銨
溶劑A=5%乙腈:95%水:10mM乙酸銨
溶劑B=95%乙腈:5%水:10mM乙酸銨
管柱2=2.)PHENOMENEX-LUNA 2.0×50mm 3μm
SFC方法:
方法1
儀器=SFC Thar 350/A5
流動速率=220mL/min
長度=220nm
移動相=CO2/[庚烷/IPA=4:1(v:v)]=80/20等度
管柱=Whelko(rr)50×5cm,10μm
注射體積=1.0mL[溶質濃度=100mg/mL庚烷/IPA 4:1(v:v)]
注射程式:堆疊注射(每2分鐘1.0mL)
製備型HPLC方法:
製備型HPLC方法1
起始B%=30,經16分鐘梯度最終B%=67,變為100%B持續10分鐘
流動速率=100mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,50×250mm
製備型HPLC方法2
起始B%=0,經20分鐘梯度最終B%=100,保持為100%B持續4分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters XBridge Phenyl,5μm,30×100mm
製備型HPLC方法3
起始B%=15,經20分鐘梯度最終B%=100,保持100%B持續4分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters XBridge Phenyl,5μm,30×100mm
製備型HPLC方法4
起始B%=20,經20分鐘梯度最終B%=100,保持100%B持續5分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法5
起始B%=30,經15分鐘梯度最終B%=100,保持100%B持續5分鐘
流動速率=20mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Xbridge Phenyl,5μm,19×250mm
製備型HPLC方法6
起始B%=20,經20分鐘梯度最終B%=65,變為100%B持續5分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法7
起始B%=20,經30分鐘梯度最終B%=100,保持100%B持續4分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法8
起始B%=30,經18分鐘梯度最終B%=100,保持100%B持續2分鐘
流動速率=25mL/min
藉由ELSD收集
溶劑A=95%水、5%乙腈、10mM乙酸銨
溶劑B=5%水、95%乙腈、10mM乙酸銨
管柱=XBridge OBD Prep Shield RP18 19×100mm 5μm
製備型HPLC方法9
起始B%=10,經10分鐘梯度最終B%=100,保持100%B持續5分鐘
流動速率=50mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,30×100mm
製備型HPLC方法10
起始B%=10,經10分鐘梯度最終B%=100,保持100%B持續5分鐘
流動速率=50mL/min
溶劑A=95%水、5%乙腈、10mM乙酸銨
溶劑B=5%水、95%乙腈、10mM乙酸銨
管柱=Xbridge OBD Prep Shield RP,5μm,19×100mm
製備型HPLC方法11
起始B%=25,經15分鐘梯度最終B%=100,保持100% B
流動速率=40mL/min
溶劑A=90%水、10%乙腈、0.1% TFA
溶劑B=10%水、90%乙腈、0.1% TFA
管柱=Waters Sunfire C18,5μm,30×100mm
製備型HPLC方法12
起始B%=20,經15分鐘梯度最終B%=100,保持為100% B持續4分鐘
流動速率=50mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法13
起始B%=30,經15分鐘梯度最終B%=100,保持為100% B持續15分鐘
流動速率=50mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法14
起始B%=30,經20分鐘梯度最終B%=100,保持為100% B持續6分鐘
流動速率=50mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法15
起始B%=30,經15分鐘梯度最終B%=100,保持為100% B持續5分鐘
流動速率=50mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法16
起始B%=20,經10分鐘梯度最終B%=100,保持為100% B持續4分鐘
流動速率=50mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=Waters Sunfire C18,5μm,30×150mm
製備型HPLC方法17
起始B%=30,經30分鐘梯度最終B%=50,保持為50% B持續5分鐘
流動速率=25mL/min
長度=220
溶劑對=水-乙腈-TFA
溶劑A=90%水-10%乙腈-0.1% TFA
溶劑B=10%水-90%乙腈-0.1% TFA
管柱=YMC-OBD 20×100mm S5
步驟1. 製備1-(羥基甲基)-4-((三甲基矽烷基)氧基)環己-3-烯甲酸乙酯
用氮氣吹掃2-(羥基甲基)丙烯酸乙酯(5.21g,40mmol)及(丁-1,3-二烯-2-基氧基)三甲基矽烷(8.54g,60.0mmol)於甲苯(100mL)中之溶液,密封且在壓力燒瓶中在150℃下加熱48小時。所得淡黃色反應混合物冷卻至室溫且真空濃縮獲得呈油狀之粗產物,其未經純化即用於下一步驟。MS:m/e 201.05(M+H-矽烷基)+,0.839min(方法4)。
步驟2. 製備1-(羥基甲基)-4-側氧基環己烷甲酸乙酯
向1-(羥基甲基)-4-((三甲基矽烷基)氧基)環己-3-烯甲酸乙酯(10.9
g,40.0mmol)於THF(5mL)中之溶液中添加HCl(0.005N)(1mL,5.00μmol)。在室溫下攪拌所得溶液18小時。反應混合物用EtOAc(2×10mL)萃取,用NaHCO3飽和水溶液(5mL)隨後鹽水(10mL)洗滌。有機萃取物經Na2SO4乾燥,過濾且減壓濃縮。藉由矽膠層析法使用乙酸乙酯/己烷純化粗產物獲得呈無色油狀之標題化合物(3g,37.4%)。MS:m/e 200.95(M+H)+,0.853min(方法4)。1H NMR(400MHz,氯仿-d)δ 4.28(q,J=7.3Hz,2H),3.75(s,2H),2.57-2.45(m,2H),2.45-2.33(m,4H),1.86-1.71(m,2H),1.39-1.30(m,3H)。
步驟3. 製備4-側氧基-1-((((三氟甲基)磺醯基)氧基)甲基)環己烷甲酸乙酯
在-10℃下,向1-(羥基甲基)-4-側氧基環己烷甲酸乙酯(1,170mg,5.84mmol)及吡啶(0.614mL,7.60mmol)於DCM(10mL)中之經攪拌混合物中逐滴添加三氟甲磺酸酐(7.60mL,7.60mmol)。在-10℃下攪拌所得混合物30分鐘,且用冰冷之1N HCl溶液及鹽水洗滌。將經分離之有機層經硫酸鈉乾燥。移除溶劑且殘餘物未經純化即使用。MS:m/e 333.05(M+H)+,1.969min(方法4)。
步驟4. 製備1-(氟甲基)-4-側氧基環己烷甲酸乙酯
在25℃下,向4-側氧基-1-((((三氟甲基)磺醯基)氧基)甲基)環己烷甲酸乙酯(1.941g,5.84mmol)於DCM(10mL)中之經攪拌混合物中逐滴添加二氟化四丁基銨(3.63mL,7.01mmol)。在25℃下攪拌所得混合物18小時。真空濃縮反應混合物。在50mL己烷中攪拌所獲得之殘餘物形成兩個層。將頂層傾析至燒瓶中且真空乾燥獲得無色油狀物。
藉由急驟層析法使用12g矽膠管柱及0-35%含EtOAc之己烷梯度純化此殘餘物獲得呈無色油狀之標題化合物(0.20g,9.0%)。MS:m/e 203.15(M+H)+,1.470min(方法4)。1H NMR(400MHz,氯仿-d)δ 4.49-4.30(m,2H),4.25-4.11(m,2H),2.50-2.35(m,4H),2.33-2.20(m,2H),1.80-1.64(m,2H),1.30-1.20(m,3H)。19F NMR(376MHz,氯仿-d)δ -223.02 - -225.00(m,1F)。
步驟5. 製備1-(氟甲基)-4-(((三氟甲基)磺醯基)氧基)環己-3-烯甲酸乙酯
在-78℃下,向1-(氟甲基)-4-側氧基環己烷甲酸乙酯(0.20g,0.98mmol)及1,1,1-三氟-N-苯基-N-((三氟甲基)磺醯基)甲磺醯胺(0.38g,1.07mmol)於THF(20mL)中之淺黃色溶液中添加KHMDS(1.27mL,1.27mmol)。在-78℃下攪拌所得黃色溶液2小時。反應混合物用氯化銨飽和水溶液淬滅且用10mL EtOAc萃取一次。有機層用鹽水(10mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。藉由急驟層析法使用12g矽膠管柱及0-10%含EtOAc之己烷梯度純化粗產物獲得呈無色油狀之標題化合物(179mg,54.7%)。1H NMR(400MHz,氯仿-d)δ 5.84-5.69(m,1H),4.60-4.37(m,2H),4.30-4.15(m,2H),2.89-2.70(m,1H),2.56-2.33(m,2H),2.32-2.14(m,2H),2.07-1.81(m,1H),1.34-1.22(m,3H)。19F NMR(376MHz,氯仿-d)δ -225.18 - -225.70(m,1F)。
步驟6. 向含有1-(氟甲基)-4-(((三氟甲基)磺醯基)氧基)環己-3-烯甲酸乙酯(0.179g,0.53mmol)之燒瓶中添加雙(頻哪醇根基)二硼(0.143g,0.56mmol)、乙酸鉀(0.156g,1.59mmol)及二氯化1,1'-雙(二苯膦基)二茂鐵(II)(0.013g,0.016mmol)。混合物用二噁烷(8mL)
稀釋,用氮氣吹掃,且加熱至70℃持續5小時。冷卻至室溫後,混合物用水(25mL)稀釋且用乙酸乙酯(2×20mL)萃取。將經合併之有機層用鹽水洗滌且經硫酸鎂乾燥。藉由過濾移除乾燥劑且減壓濃縮濾液。藉由急驟層析法使用12g Isco矽膠管柱及0-10%含EtOAc之己烷梯度純化殘餘物。合併含有預期產物之溶離份且減壓濃縮獲得呈澄清無色油狀之標題化合物(91mg,54%)。MS:m/e 313.20(M+H)+,2.299min(方法4)。1H NMR(400MHz,氯仿-d)δ 6.50(td,J=3.9,2.0Hz,1H),4.59-4.32(m,2H),4.23-4.13(m,2H),2.74-2.52(m,1H),2.30-2.08(m,3H),1.98-1.69(m,2H),1.32-1.20(m,15H)。19F NMR(376MHz,氯仿-d)δ -225.59 - -226.36(m,1F)。
步驟1. 製備2-(氟甲基)丙烯酸乙酯
在-78℃下,向2-(羥基甲基)丙烯酸乙酯(5g,38.4mmol)於DCM(50mL)中之溶液中添加DAST(6.60mL,49.9mmol)。在-78℃下攪拌反應混合物1小時。將混合物升溫至25℃且再持續攪拌3小時。藉由添加CH2Cl2(20mL)及NaHCO3飽和水溶液(20mL)淬滅反應混合物。分離有機層,且用CH2Cl2(20mL)萃取水層兩次。經合併之有機萃取物經硫酸鈉乾燥且蒸發獲得殘餘油狀物,其未經純化即用於下一步驟
中。1H NMR(500MHz,氯仿-d)δ 6.49-6.33(m,1H),6.03-5.87(m,1H),6.45-5.84(m,2H),4.27(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H)。19F NMR(470MHz,氯仿-d)δ -220.33 - -221.86(m,1F)。
步驟2. 製備1-(氟甲基)-4-((三甲基矽烷基)氧基)環己-3-烯甲酸乙酯
2-(氟甲基)丙烯酸乙酯(4.7g,35.6mmol)及(丁-1,3-二烯-2-基氧基)三甲基矽烷(10.12g,71.1mmol)於甲苯(100mL)中之溶液用氮氣吹掃,密封且在150℃下在壓力容器中加熱48小時。所得淺黃色溶液冷卻至室溫且減壓濃縮獲得呈油狀之標題化合物,其未經進一步純化即用於下一步驟。1H NMR(400MHz,氯仿-d)δ 4.83(t,J=3.3Hz,1H),4.64-4.38(m,2H),4.25-4.12(m,2H),2.62-2.48(m,1H),2.19-1.99(m,4H),1.93-1.78(m,1H),1.34-1.22(m,3H),0.24-0.15(m,9H)。19F NMR(470MHz,氯仿-d)δ -224.80 - -225.37(m,1F)。
步驟3. 製備1-(氟甲基)-4-側氧基環己烷甲酸乙酯
向1-(氟甲基)-4-((三甲基矽烷基)氧基)環己-3-烯甲酸乙酯(9.76g,35.6mmol)於THF(5mL)中之溶液中添加HCL(0.005N)(1mL,5.00μmol)。在室溫下攪拌所得溶液隔夜。反應混合物用EtOAc(2×10mL)萃取,用NaHCO3飽和水溶液(5mL)隨後鹽水(10mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。粗產物藉由急驟層析法使用80g矽膠管柱及0-25%含EtOAc之己烷梯度純化。收集含有預期產物之部分且減壓濃縮獲得呈無色油狀之標題化合物(6.5g,90.2%)。1H NMR
(400MHz,氯仿-d)δ 4.59-4.42(m,2H),4.30(q,J=7.0Hz,2H),2.58-2.34(m,6H),1.88-1.73(m,2H),1.33(t,J=7.2Hz,3H)。19F NMR(376MHz,氯仿-d)δ -223.54 - -223.99(m,1F)。
步驟1. 製備1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯.
向3L 3頸圓底燒瓶中置入4-側氧基環己烷甲酸乙酯(100g,570mmol)、乙-1,2-二醇(0.159l,2849mmol)、((1S,4R)-7,7-二甲基-2-側氧基雙環[2.2.1]庚-1-基)甲磺酸(1.324g,5.70mmol)及無水甲苯(1.2L)。安裝迪恩-斯塔克分水器及冷凝器且在攪拌下加熱混合物至回流。將不可混溶的餾出物收集於迪安-斯塔克分水器中且定期移除。28小時總回流時間後,總計從迪安-斯塔克分水器移除了82mL不可混
溶的餾出物。混合物冷卻至約40℃之後,在快速攪拌下向反應混合物中添加飽和NaHCO3(400mL)。將混合物轉移至分液漏斗中,振盪及分離各相。有機層用水(4×500mL),接著用5% NaHCO3(200mL),接著用鹽水(100mL)洗滌。有機材料經無水MgSO4乾燥,過濾且減壓濃縮獲得微黃色黏稠油狀物(118.50g,97%產率)。1H NMR(400MHz,氯仿-d)δ 4.15(q,J=7.3Hz,2H),3.96(s,4H),2.41-2.27(m,1H),1.96(dt,J=8.7,4.3Hz,2H),1.89-1.74(m,4H),1.68-1.49(m,2H),1.27(t,J=7.1Hz,3H)。13C NMR(101MHz,氯仿-d)δ 175.2,108.1,64.3,60.3,41.6,33.8,26.3,14.3。
步驟2:製備基8-甲醯基-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯.
經套管經5分鐘向1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯(32.31g,151mmol)於THF(250mL)中之-78℃溶液中添加2M二異丙基胺基鋰(98mL,196mmol)於THF中之溶液。在-78℃下攪拌所得褐色溶液。1小時後,用冷浴槽替換冰浴且在0℃下攪拌反應混合物1小時。反應混合物再冷淬至-78℃且用經45分鐘逐滴添加之甲酸乙酯(18.65mL,226mmol)於THF(40mL)中之溶液處理。在-78℃下攪拌所得淡棕色反應混合物1小時。移除冷浴槽且向混合物中逐滴添加NH4Cl飽和水溶液(250mL)且在環境溫度下攪拌混合物30分鐘。用EtOAc(3×300mL)萃取所得黃色混合物。合併之有機相用0.5N HCl(300mL),接著用鹽水洗滌,經MgSO4乾燥,過濾且濃縮成褐色黏稠油狀物。藉由急驟管柱層析法經矽膠(750g二氧化矽,逐步溶離9:1己烷/EtOAc及5:1己烷/EtOAc)純化粗物質獲得回收之起始物質1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯(8.6g,40.1mmol,26.6%產率)及所要產物8-甲醯基-1,4-二氧
雜螺[4.5]癸烷-8-甲酸乙酯(20.1g,83mmol,55.0%產率),其皆為黏稠黃色油狀物。1H NMR(400MHz,氯仿-d)δ 9.50(s,1H),4.17(q,J=7.2Hz,2H),3.94-3.86(m,4H),2.24-2.09(m,2H),2.01(ddd,J=13.5,8.3,5.1Hz,2H),1.75-1.48(m,4H),1.23(t,J=7.2Hz,3H)。
步驟3:製備8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯.
向8-甲醯基-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯(28.9g,119mmol)於乙醇(300mL)中之0℃溶液中添加硼氫化鈉(5.30g,137mmol)且所得混合物在0℃下攪拌。3小時後,反應混合物用經滴液漏斗逐滴添加之NH4Cl飽和水溶液(200mL)淬滅。移除冰浴且用H2O(150mL)緩慢處理所得漿液。過濾所得混合物移除少量白色固體。濃縮液體濾液以移除大部分有機溶劑,且剩餘部分用EtOAc(4×250mL)萃取。經合併之有機相用鹽水洗滌,經MgSO4乾燥,過濾,濃縮且減壓乾燥獲得呈澄清黏稠油狀之8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯(27.7g,113mmol,95%產率)。來自此實驗之材料未經進一步純化即直接用於下一步驟中。在各別實驗中,藉由急驟管柱層析法(SiO2,溶離3:1己烷:EtOAc)純化粗物質獲得8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯,91%產率。1H NMR(400MHz,氯仿-d)δ 4.18(q,J=7.1Hz,2H),3.98-3.87(m,4H),3.61(d,J=6.1Hz,2H),2.23(br.s.,1H),2.17-2.07(m,2H),1.72-1.51(m,6H),1.32-1.20(m,3H)。
步驟4. 製備8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯.
向8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸乙酯(27.6g,113mmol)於THF(150mL)及MeOH(50mL)中之溶液中添加3N氫氧化鋰水溶液(45.2mL,136mmol)且在攪拌下將混合物加熱至60℃持續17小時。接著添加額外3N氫氧化鋰水溶液(30.1mL,90mmol)且將混合物加熱至60℃再持續14小時。濃縮反應混合物且減壓乾燥獲得含有相應羧酸酯之殘餘物(24.5g,107mmol),其未經進一步純化即可使用。
向含此殘餘物之DMF(200mL)中添加苯甲基溴(12.98mL,107mmol)且在室溫下攪拌所得混合物17小時。將反應混合物濃縮至初始體積之約一半,用EtOAc(250mL)稀釋且用1N HCl(200mL)洗滌。用3×250mL EtOAc萃取水相。經合併之有機相用H2O(100mL)、鹽水洗滌,經MgSO4乾燥,過濾且濃縮成淡黃色黏稠油狀物。藉由急驟管柱層析法(SiO2,溶離步驟梯度70:30己烷:EtOAc,接著1:1己烷:EtOAc)純化粗物質且減壓乾燥獲得8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯(23.1g,71.6mmol,3個步驟63%產率)。1H NMR(400MHz,氯仿-d)δ 7.40-7.28(m,5H),5.16(s,2H),3.91(s,4H),3.64(s,2H),2.34(br.s.,1H),2.22-2.12(m,2H),1.70-1.63(m,4H),1.62-1.54(m,2H)。13C NMR(101MHz,氯仿-d)δ 175.3,135.8,128.5(s,2C),128.1,127.8,108.3,68.5,66.4,64.2,64.1,48.1,31.3,27.9。
步驟5. 製備8-((((三氟甲基)磺醯基)氧基)甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯.
在500mL圓底燒瓶中組合8-(羥基甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯(14.9g,48.6mmol)與無水DCM(250mL)。溶液在冰/丙酮浴中冷淬至約-10℃,且向其中添加吡啶(5.31mL,65.7mmol),隨後經30分鐘逐滴添加Tf2O(11.09mL,65.7mmol)。在0℃(冰水浴)下攪拌微黃色懸浮液1.5小時。所得具有大量懸浮固體之深橙色混合物減壓濃縮留下殘餘物,將其置於真空下移除過量三氟甲磺酸酐,接著將殘餘物再溶解於DCM(150mL)中。過濾混合物以移除大量白色固體,將其用DCM沖洗。濃縮深淡紅/橙色濾液且藉由急驟矽膠管柱層析法(330g二氧化矽,溶離100% DCM)純化。合併產物溶離份且濃縮成濃稠橙色油狀物,其在攪拌下置於高度真空下隔夜。顏色變為藍色/綠色。因此獲得呈藍色/綠色黏稠油狀之所要產物(20.94g,98%產率)。1H NMR(400MHz,氯仿-d)δ 7.48-7.30(m,5H),5.21(s,2H),4.53(s,2H),4.04-3.87(m,4H),2.30-2.14(m,2H),1.76-1.56(m,6H)。19F NMR(376MHz,氯仿-d)δ -74.39(s,1F)。
步驟6. 製備8-(氟甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯.
在氮氣氛圍下,在500mL圓底燒瓶中組合8-((((三氟甲基)磺醯基)氧基)甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯(20.76g,47.4mmol)與經套管引入之無水THF(150mL)。經加料漏斗經15分鐘向藍色溶液中逐滴添加TBAF,THF中1.0M(71.0mL,71.0mmol)。當添加TBAF時混合物立即變為淡黃色。在室溫下攪拌混合物1小時。濃縮粗混合物留下濃稠油狀物,其用乙酸乙酯(700mL)稀釋且用水(2×250mL)及鹽水(100mL)洗滌。有機相經MgSO4乾燥,過濾且濃縮成濃稠黃色殘餘物。藉由急驟矽膠管柱層析法(330g二氧化矽,溶離梯度
100%己烷至2:1己烷:EtOAc)純化獲得呈黃色油狀之所要產物(13.73g,94%產率)。LCMS:m/e 309.2(M+H)+,1.27min(方法6)。1H NMR(400MHz,氯仿-d)δ 7.44-7.31(m,5H),5.21(s,2H),4.45(d,J=47.2Hz,2H),4.01-3.89(m,4H),2.28-2.16(m,2H),1.75-1.55(m,6H)。19F NMR(376MHz,氯仿-d)δ -223.25(t,J=46.8Hz,1F)。
步驟7. 在冰浴中冷卻之2L圓底燒瓶中組合8-(氟甲基)-1,4-二氧雜螺[4.5]癸烷-8-甲酸苯甲酯(13.72g,44.5mmol)與THF(500mL),接著經2分鐘緩慢添加鹽酸,1.5M水溶液(534mL,801mmol)。移除冰浴且在室溫下攪拌混合物1.5小時。減壓濃縮混合物以移除有機物,且用乙酸乙酯(300mL)萃取殘餘物。乙酸乙酯相用水(2×200mL)及鹽水(50mL)洗滌。減壓濃縮獲得呈黃色油狀之所要產物(12.13g,定量)。LCMS:m/e 265.3(M+H)+,1.19min(方法6)。1H NMR(400MHz,氯仿-d)δ 7.47-7.32(m,5H),5.27(s,2H),4.52(d,J=47.2Hz,2H),2.57-2.42(m,4H),2.42-2.31(m,2H),1.87-1.76(m,2H)。19F NMR(376MHz,氯仿-d)δ -223.41(t,J=46.8Hz,1F)。
步驟1. 製備2-(羥基甲基)丙烯酸苯甲酯
向1-L燒瓶中置入丙烯酸苯甲酯(44.6mL,292mmol)、二噁烷(290mL)、1,4-二氮雜雙環[2.2.2]辛烷(32.7g,292mmol)及水(270mL)。在室溫下劇烈攪拌混合物形成乳液。向攪拌混合物中添加甲醛水溶液(37%,23.9mL,321mmol)且在室溫下繼續攪拌14小時。粗反應混合物用二氯甲烷(3×150mL)萃取。分離有機層,合併且用氯化
銨飽和水溶液與HCl之50:50混合物(0.2N)洗滌。蒸發且在45℃下減壓(2cm Hg)濃縮獲得49.1g自由流動糊漿。在矽膠管柱上用EtOAc/己烷之梯度混合物溶離純化粗產物獲得呈澄清無色糊漿狀之標題化合物(27g,141mmol,48%)。LCMS:m/e 193.05(M+H)+,1.78min(方法1)。1H NMR(500MHz,氯仿-d)δ 7.50-7.30(m,5H),6.34(s,1H),5.89(s,1H),5.25(s,2H),4.38(d,J=6.4Hz,2H),2.20(t,J=6.6Hz,1H);13C NMR(126MHz,氯仿-d)δ 166.1,139.3,135.7,128.7,128.4,128.2,126.2,66.6,62.7。
步驟2. 製備2-(氟甲基)丙烯酸苯甲酯
在氮氣下將2-(羥基甲基)丙烯酸苯甲酯(13.7g,71.3mmol)溶解於無水二氯甲烷(100mL)中且在-78℃下冷卻混合物。使用聚乙烯移液管經5分鐘之時段向此攪拌溶液中分4份添加三氟化二乙基胺基硫(DAST,13.0mL,98mmol)。形成淺橙色溶液。添加完成後,移除乾冰浴且使反應溫度升至室溫。在室溫下繼續總計4小時。將反應混合物逐滴轉移到碳酸氫鈉飽和水溶液與水的50:50冷淬混合物(約4℃)中。轉移全部粗反應混合物之後,將其用BHT穩定之乙醚(3×150mL)萃取。合併有機層,且用水(50mL)洗滌一次。在次環境溫度(約15℃)下自有機相減壓移除溶劑直至恆重(14.2g,定量)。將粗物質直接用於下一步驟。1H NMR(500MHz,氯仿-d)δ 7.44-7.34(m,5H),6.49-6.43(m,1H),5.99(dt,J=2.8,1.5Hz,1H),5.26(s,2H),5.13(d,J=46.5Hz,2H);19F NMR(470MHz,氯仿-d)δ -220.91(t,J=46.2Hz)。
步驟3-製備1-(氟甲基)-4-((三甲基矽烷基)氧基)環己-3-烯甲酸苯甲酯
向500mL可重新密封之壓力容器中添加粗起始物質含2-(氟甲基)丙烯酸苯甲酯(14.2g,73.1mmol)及(丁-1,3-二烯-2-基氧基)三甲基矽烷(以供應時之狀態使用之Sigma Aldrich材料,18.73g,132mmol)之甲苯(200mL)。在-78℃下將容器抽真空至80微米Hg,隨後用氮氣吹洗。該方法重複兩次。密封燒瓶,且升溫至室溫,隨後在125℃下將其浸沒至油浴中22小時。使混合物冷卻至室溫。自粗反應物移除小等分試樣(25μL),在室溫下真空乾燥用於1H及19F的NMR分析。NMR結果與形成標題化合物及少量相應狄爾斯-阿德區位異構體(Diels-Alder regioisomer)相符。1H NMR(400MHz,氯仿-d)δ 7.43-7.29(m,5H),5.18(s,2H),4.80(d,J=3.0Hz,1H),4.52(dq,J=46.9,8.4Hz,2H),2.65-2.49(m,1H),2.21-2.00(m,4H),1.92-1.78(m,1H),0.24-0.12(m,9H);19F NMR(376MHz,氯仿-d)δ -224.76(t,J=47.7Hz,1F)及少量19F NMR(376MHz,氯仿-d)δ -225.20(t,J=46.8Hz,0.06F)。蒸發粗物質且在約35℃下真空乾燥(20微米Hg)直至恆重(24.6g,定量)。此粗物質未經進一步純化即原樣用於下一步驟中。
步驟4. 在室溫下將來自前述步驟之粗物質(24.6gm,73mmol)溶解於THF(200mL)中形成澄清溶液。添加1N HCl水溶液(2mL,2mmol)及4mL水。在室溫下攪拌澄清溶液總計16小時。粗反應混合物用碳酸氫銨鈉與水的150mL 50:50混合物淬滅。用EtOAc(3×75mL)萃取有機層。合併有機層,且蒸發至乾燥獲得18.8g濃稠糊漿。使用330g矽膠管柱用含0至25體積%乙酸乙酯之己烷的梯度混合物以約25管柱體積溶離純化粗殘餘物獲得標題化合物(15.6g,81.0%)。LCMS:m/e 265.15(M+H)+,1.60min(方法3)。1H NMR(400MHz,氯仿-d)δ 7.50-7.30(m,5H),5.26(s,2H),4.43(d,J=46.9Hz,2H),2.54-2.29(m,6H),
1.90-1.71(m,2H);19F NMR(376MHz,氯仿-d)δ -223.47(t,J=46.8Hz,1F)。
步驟1. 製備1-(氟甲基)-4-(((三氟甲基)磺醯基)氧基)環己-3-烯甲酸苯甲酯.
在500mL圓底燒瓶中在無水四氫呋喃(250mL)中組合1-(氟甲基)-4-側氧基環己烷甲酸苯甲酯(12.65g,47.9mmol)及N,N-雙(三氟甲基磺醯基)苯胺(18.81g,52.7mmol)。溶液在乾冰/丙酮浴中冷卻至-78℃。經30分鐘向冷溶液中逐滴添加六甲基二矽烷胺基鉀,甲苯中0.5M(105mL,52.7mmol)。在-78℃下攪拌混合物總計2.5小時且接著從冷浴槽中提出來且在室溫下再攪拌20分鐘。將混合物放置回-78℃浴槽中且在攪拌下向其中添加125mL氯化銨飽和水溶液。自冷浴
槽移除所得懸浮液且在攪拌下使其達到室溫。減壓濃縮混合物以移除有機溶劑,接著向混合物中添加乙酸乙酯(600mL)及水(300mL),且振盪混合物及分離各相。有機層用水(2×200mL)及鹽水(50mL)洗滌。有機層經MgSO4乾燥,過濾且減壓濃縮留下黃色/橙色油狀物。藉由急驟矽膠管柱層析法(800g二氧化矽,3:2己烷:DCM等度溶離)純化粗殘餘物。合併產物溶離份且減壓濃縮獲得呈極微黃色油狀之所要產物(17.43g,92%產率)。1H NMR(400MHz,氯仿-d)δ 7.43-7.31(m,5H),5.78(br.s.,1H),5.26-5.15(m,2H),4.52(dm,J=46.7Hz,2H),2.78(d,J=16.9Hz,1H),2.52-2.33(m,2H),2.33-2.17(m,2H),1.94(dt,J=13.8,6.9Hz,1H)。19F NMR(376MHz,氯仿-d)δ -73.88(s,1F),-225.02(t,J=46.8Hz,1F)。
步驟2. 製備1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯.
在500mL圓底燒瓶中組合1-(氟甲基)-4-(((三氟甲基)磺醯基)氧基)環己-3-烯甲酸苯甲酯(17.42g,44.0mmol)、乙酸鉀(0.030g,0.307mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧雜硼戊環)(11.72g,46.1mmol)、二氯化1,1'-雙(二苯膦基)二茂鐵把(II)(3.03mg,3.69μmol)及無水二噁烷(200mL)。將燒瓶置於氮氣氛圍下且加熱至70℃。5小時後,使混合物冷卻至室溫且靜置隔夜。減壓濃縮反應混合物且粗深紅色殘餘物用乙酸乙酯(600mL)及水(300mL)稀釋。振盪混合物且分離各相。有機物用水(250mL),接著鹽水(100mL)洗滌。有機相經無水MgSO4乾燥,過濾且減壓濃縮獲得深紅色黏稠油狀
物。藉由急驟矽膠管柱層析法(800g二氧化矽;逐步溶離1:3己烷:DCM,4L,接著100% DCM,5L,來自第一純化之混合溶離份之2g材料經80g矽膠用100%己烷至100% DC梯度溶離再純化)純化粗混合物,獲得呈無色濃稠油狀之所要產物(13.06g,79.4%產率)。LCMS:m/e 375.3(M+H)+,1.52min(方法6)。1H NMR(400MHz,氯仿-d)δ 7.44-7.30(m,5H),6.54(br.s.,1H),5.25-5.11(m,2H),4.51(dm,J=47.4Hz,2H),2.67(d,J=19.3Hz,1H),2.29-2.10(m,3H),2.02-1.89(m,1H),1.86-1.74(m,1H),1.28(s,12H)。19F NMR(376MHz,氯仿-d)δ -225.62(t,J=45.1Hz,1F)。
步驟3. 藉由超臨界流體層析法(SFC方法1)純化外消旋1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(11.15g,0.0298mmol)獲得經分離之單異構體標題化合物:
(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯. 此為自SFC對掌性分離溶離的第一異構體。分離呈黃色油狀之產物(5.45g,98%SFC回收,99.2%對掌性純度)。1H NMR(400MHz,氯仿-d)δ 7.42-7.30(m,5H),6.54(br.s.,1H),5.24-5.12(m,2H),4.51(dm,J=47.2Hz,2H),2.67(d,J=19.3Hz,1H),2.27-2.10(m,3H),2.00-1.90(m,1H),1.85-1.75(m,1H),1.28(s,12H)。19F NMR(376MHz,氯仿-d)δ -225.62(t,J=46.8Hz,1F)。
(S)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯. 此為自SFC對掌性分離溶離的第二異構體。分離呈黃色油狀之產物(4.94g,89%SFC回收,99.3%對掌性純度)。1H NMR(400MHz,氯仿-d)δ 7.43-7.31(m,5H),6.54(br.s.,1H),5.24-5.13(m,2H),4.52(dm,J=47.2Hz,2H),2.68(d,J=19.3Hz,1H),2.27-2.10(m,3H),2.01-1.90(m,1H),1.85-1.75(m,1H),1.28(s,12H)。19F NMR(376MHz,氯仿-d)δ -225.61(t,J=48.6Hz,1F)。
步驟1 製備2-(二氫-2H-亞硫代哌喃-4(3H)-基)乙酸乙酯
根據Lammek,Derdowska及Rekowski在Polish Journal of Chemistry 64,351(1990)中所報導製備標題中間物。
步驟2:製備2-(四氫-2H-硫代哌喃-4-基)乙酸乙酯
根據PCT WO 00/44713公開製備標題中間物,兩個步驟(1及2)64%產率。
步驟3:製備2-(四氫-2H-硫代哌喃-4-基)乙醇
向500mL燒瓶中的2-(四氫-2H-硫代哌喃-4-基)乙酸乙酯(6.4g,34.0mmol)於乙醚(100mL)中之經冷卻(冰浴,0℃)溶液中逐滴添加氫化鋰銨(34.0mL,34.0mmol)於THF中之1M儲備溶液。初始形成渾濁
懸浮液且觀測到逸出氫氣。當添加約2/3 LiAlH4試劑時,反應混合物變得澄清。移除冰浴且使反應混合物升溫至環境溫度(約19-21℃)持續4小時。反應物用含半飽和NH4Cl溶液之0.5N HCl逐滴淬滅直至形成可自由攪拌的白色懸浮液。藉由過濾移除固體且用額外溶劑洗滌。合併濾液及洗滌液且真空濃縮獲得標題中間物(4.9gm,99%)。1H NMR(400MHz,氯仿-d)δ 3.71(t,J=6.4Hz,2H),2.78-2.53(m,4H),2.03(d,J=13.3Hz,2H),1.52(dd,J=6.8,3.3Hz,3H),1.46-1.33(m,2H)。
步驟4:製備4-(2-羥基乙基)四氫-2H-硫代哌喃1,1-二氧化物
在室溫下,向2-(四氫-2H-硫代哌喃-4-基)乙醇(182mg,1.244mmol)於丙酮(3mL)中之溶液中添加Oxone®(1.53gm,2.5mmol)於水(7mL)中之懸浮液。偵測到輕度放熱且在室溫下繼續攪拌2小時。粗反應懸浮液用乙酸乙酯(3×20mL)萃取。合併有機層且真空濃縮獲得含有標題化合物之濃稠糊漿(66mg,29.8%)。1H NMR(400MHz,氯仿-d)δ 3.74(t,J=6.3Hz,2H),3.12-2.92(m,4H),2.15(dd,J=13.8,2.5Hz,2H),1.96-1.84(m,2H),1.84-1.73(m,1H),1.61(q,J=6.4Hz,2H)
步驟5:製備甲磺酸2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙酯
在氮氣下,在冰浴中冷卻4-(2-羥基乙基)四氫-2H-硫代哌喃1,1-二氧化物(30mg,0.168mmol)於DCM(1mL)中之溶液。添加DIPEA
(0.088mL,0.505mmol),隨後甲磺醯氯(0.020mL,0.252mmol)。在0℃下攪拌反應混合物30分鐘。反應混合物用水(2mL)稀釋且用DCM(3×5mL)萃取。經合併之有機層用鹽水(5mL)洗滌,經Na2SO4乾燥且減壓濃縮。藉由使用ELS偵測器的矽膠管柱上之急驟層析法用50-100% EtOAc/己烷溶離純化粗產物獲得呈油狀之所要化合物(37mg,86%)。LCMS m/e 257.10(M+H)+,1.086min(方法3)。1H NMR(400MHz,氯仿-d)δ 4.29(t,J=5.9Hz,2H),3.03(s,3H),3.11-2.94(m,4H),2.14(dt,J=14.2,1.2Hz,2H),1.98-1.73(m,5H)。
步驟6:製備4-(2-溴乙基)四氫-2H-硫代哌喃1,1-二氧化物
向甲磺酸2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙酯(37mg,0.144mmol)於THF(2mL)中之溶液中添加溴化鋰(37.6mg,0.433mmol)。在室溫下攪拌混合物18小時。移除溶劑且將殘餘物溶解於DCM(20mL)中且用鹽水(20mL)洗滌。用DCM(2×20mL)萃取水層。經Na2SO4乾燥經合併之DCM層,且減壓濃縮。藉由使用ELS偵測器的矽膠管柱上之急驟層析法用40-75% EtOAc/己烷溶離純化粗產物獲得呈固體狀之所要產物(30mg,86%)。LCMS m/e 241.05(M+H)+,1.5分鐘(方法3)。1H NMR(400MHz,氯仿-d)δ 3.46(t,J=6.4Hz,2H),3.12-2.94(m,4H),2.17-2.07(m,2H),1.96-1.80(m,5H)。
步驟1:製備N-(2-胺基-2-甲基丙基)乙醯胺
根據US專利:4906661中公開之程序製備標題中間物,82%。1H NMR(500MHz,氯仿-d)δ 6.01(br.s.,1H),3.15(d,J=5.8Hz,2H),2.04(s,3H),1.14(s,6H)。
步驟2:製備N-(2-(1,1-二氧離子基N-硫代嗎啉基)-2-甲基丙基)乙醯胺
在可重新密封壓力容器中,向N-(2-胺基-2-甲基丙基)乙醯胺(2.3g,17.67mmol)於2-丙醇(28mL)中之溶液中添加(乙烯基磺醯基)乙烷(2.3g,19.47mmol)。將其用氮氣吹掃且在100℃下加熱4小時。冷卻至室溫後,固體開始分離。過濾固體,用異丙醇洗滌且乾燥獲得所要產物(2.7gm,61.5%)。1H NMR(500MHz,氯仿-d)d 5.73(br.s.,1H),3.28(d,J=5.2Hz,2H),3.12-3.00(m,8H),2.04(s,3H),1.15-1.10(m,6H)。
步驟3:製備4-(1-胺基-2-甲基丙-2-基)硫代嗎啉1,1-二氧化物
向N-(2-(1,1-二氧離子基N-硫代嗎啉基)-2-甲基丙基)乙醯胺(100mg,0.403mmol)於MeOH(2mL)中之溶液中添加1N NaOH(2.013mL,2.013mmol)且混合物在70℃下攪拌18小時。添加額外NaOH(2.013mL,2.013mmol)且在90℃下攪拌溶液24小時。減壓濃縮反應混合物以移除MeOH,且用EtOAc(2×20mL)萃取殘餘物。經合併之有機層經Na2SO4乾燥,過濾且減壓濃縮。藉由使用ELS偵測器的矽膠管柱上之急驟層析法用5-10% MeOH/CH2Cl2溶離純化粗產物獲得呈油狀之所要產物,定量產量。LCMS m/e 207.20(M+H)+,0.268分鐘(方法3)。1H NMR(400MHz,氯仿-d)δ 3.07(s,8H),2.71(s,2H),1.11(s,6H)。
步驟1. 製備1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-
1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸乙酯
在氮氣下,將(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(240mg,0.321mmol)(如WO2013123019中所述製備)、外消旋1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸乙酯(91mg,0.291mmol)、碳酸鈉水合物(108mg,0.874mmol)與肆鈀(20.21mg,0.017mmol)之混合物溶解於二噁烷(4mL)中。形成橙色溶液,其添加水(1mL)時變為極淺黃色懸浮液。混合物冷淬至-78℃且進行抽真空/吹洗循環3次。燒瓶浸沒在85℃下加熱的油浴中總計兩小時。所得黑色懸浮液用乙酸乙酯(20mL)稀釋且用水(30mL)洗滌。收集有機相且經硫酸鈉乾燥,過濾且減壓濃縮。藉由急驟層析純化粗產物獲得白色固體(180mg,79%)。MS:m/e 783.47(M+H)+,2.36min(方法1)1H NMR(400MHz,氯仿-d)δ 5.32(d,J=3.5Hz,1H),5.18(d,J=5.5Hz,1H),4.75(d,J=1.5Hz,1H),4.62(s,1H),458-4.37(m,2H),4.25-4.15(m,2H),3.24-2.41(m,14H),2.27-1.76(m,20H),1.70(s,3H),1.64-1.31(m,13H),1.10-1.04(m,5H),1.00-0.88(m,8H),0.85(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.42(s,1F)。
步驟2. 向1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸乙酯(180mg,0.230mmol)於1,4-二噁烷(4mL)及MeOH(2mL)中之溶液中添加NaOH(1N,2mL,2.0mmol)。在66℃下攪拌混合物2小時,形成澄清溶液。藉由製備型
HPLC(Xbridge OBD製備型屏蔽RP C18 19×100mm)(MeCN/H2O/AcONH4)純化粗反應混合物獲得呈白色固體狀之1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(29mg,16.7%)。MS:m/e 755.50(M+H)+,2.548min(方法4)1H NMR(400MHz,氯仿-d)δ 5.34(br.s.,1H),5.19(br.s.,1H),4.74(br.s.,1H),4.61-4.49(m,3H),3.18(d,J=10.5Hz,2H),2.97-2.40(m,12H),2.35-1.78(m,14H),1.73-1.60(m,6H),1.58-1.17(m,11H),1.13(br.s.,3H),1.08(m,4H),1.01-0.90(m,8H),0.86(br.s.,3H)。19F NMR(376MHz,氯仿-d)δ -217.84 - -231.26(m,1F)。
將實例1 HPLC分離成(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(實例1a)及(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(實例1b)
使用製備型HPLC(方法17)分離兩種非對映異構體。溶離之第一產物識別為(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(實例1a)(白色固體,18mg,29.6%)。MS:m/e 755.55(M+H)+,2.620min(方法4)。1H NMR(400MHz,甲醇-d4)δ 5.35(br.s.,1H),5.21(d,J=4.8Hz,1H),4.85(s,1H),4.74(s,1H),4.63-4.39(m,2H),3.51-3.43(m,1H),3.41-3.37(m,3H),3.28(d,J=4.0Hz,1H),3.20(d,J=10.0Hz,1H),3.10(br.s.,1H),3.02-2.96(m,3H),2.85-2.68(m,2H),2.63-2.51(m,2H),2.35-1.78(m,16H),1.77(s,3H),1.74-1.28(m,15H),1.21(s,3H),1.11(s,3H),0.99(s,3H),0.97(s,3H),0.93(s,3H)。19F NMR(376MHz,甲醇-d4)δ -227.00(s,1F)。
分離之第一產物識別為:(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸,(實例1b),(白色固體,20mg,32.8%)MS:m/e 755.55(M+H)+,2.626min(方法4)1H NMR(400MHz,甲醇-d4)δ 5.35(br.s.,1H),5.21(d,J=4.5Hz,1H),4.85(br.s.,1H),4.75(s,
1H),4.61-4.36(m,2H),3.38-3.19(m,6H),3.05(m,1H),2.98(s,3H),2.89(d,J=7.8Hz,1H),2.82-2.70(m,1H),2.67-2.50(m,2H),2.45-1.97(m,14H),1.92-1.80(m,3H),1.78(s,3H),1.73-1.28(m,14H),1.21(br.s.,3H),1.14-1.08(m,3H),1.01-0.99(m,3H),0.97-0.94(m,3H),0.93(s,3H)。19F NMR(376MHz,甲醇-d4)δ -227.04(s,1F)。
實例1a之替代製備方法:(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸雙鹽酸鹽
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯.
在具有螺紋塞之350mL玻璃壓力容器中組合(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(9.00g,12.05mmol)、(S)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(4.96g,13.25mmol)及氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(H)(氯化X-Phos胺基聯苯基鈀預催化劑,XPhos-Pd-G2,0.569g,0.723mmol)。容器用氮氣吹洗,且向反應燒瓶中添加無水THF(180mL)。新鮮製備之0.5M K3PO4水溶液用氮氣吹洗且添加至容器中(60.2mL,30.1mmol)。密封容器且在80℃下攪拌所得黃色溶液。混合物之顏色經30分鐘變暗成極深綠色。加熱混合物18小時。橄欖綠色反應混合物用EtOAc(700mL)稀釋且用5%碳酸氫鈉水溶液(250mL×2),接著鹽水(100mL)洗滌。水相用2×100mL氯仿萃取且合併有機相,經MgSO4乾燥,過濾且濃縮成黃色發泡體狀固體。藉由急驟管柱層析法(800g二氧化矽,逐步溶離3:1己烷:丙酮,8L,接著1:1己烷:丙酮,4L)純化粗物質。來自第一層析法之混合溶離份(1.0g材料)藉由急驟二氧化矽層析法(80g二氧化矽,溶離梯度經8管柱體積100%己烷至3:1己烷:丙酮,保持3:1己烷:丙酮持續10管柱體積)再純化。因此獲得呈黃色發泡體狀固體之所要材料(7.18g,70.5%產率)。LCMS:m/e 845.6(M+H)+,1.57min(方法6)。1H NMR(400MHz,氯仿-d)δ
7.41-7.31(m,5H),5.32(s,2H),5.23-5.15(m,2H),5.13(dd,J=6.0,1.6Hz,1H),4.73(d,J=2.2Hz,1H),4.64-4.44(m,3H),3.13(dd,J=15.4,13.0Hz,2H),2.89-2.78(m,4H),2.68-2.53(m,4H),2.52-2.41(m,2H),2.21-1.16(m,31H),1.13-0.99(m,7H),0.97(s,3H),0.91(s,3H),0.90(s,3H),0.85(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.07(t,J=46.8Hz,1F)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.
在500mL圓底燒瓶中組合(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(7.17g,8.48mmol)與氫氧化鋰,1.0M水溶液(42.4mL,42.4mmol)及四氫呋喃(50mL)及MeOH(50mL)。將混合物加熱至75℃持續2.5小時。減壓濃縮幾乎黑色混合物留下固體殘餘物。將殘餘物再溶解於乙腈(50mL)與氯仿(50mL)之混合物中,且黑色溶液用三氟乙酸(6.54mL,85mmol)逐滴處理。混合物接著減壓濃縮留下兩相混合物(黑色油狀物,上面浮著澄清液體)。此混合物用乙腈:氯仿(150mL)稀釋且再減壓濃縮。此溶解/再濃縮再重複一次獲得黑色油狀物,將其置於高度真空下隔夜。黑色油狀物固化隔
夜成發泡體。粗黑色固體溶解於氯仿(20mL)與丙酮(5mL)之混合物中且裝載至由頂部有矽藻土(約25g)之二氧化矽(約60g)構成的短管柱上。用1:1丙酮:氯仿(500mL)隨後3:1丙酮:氯仿(1000mL)溶離移除黑色,且產物溶離為黃色條帶。合併產物溶離份且減壓濃縮留下吸濕黃色發泡體狀固體(16g)。一部分此固體(約1.4g)容易地溶解於5mL 80:20乙腈:水中且裝載至130g Isco Redisep Rf Gold C18濾芯上。溶劑A=90%水,10%乙腈,0.1% TFA。溶劑B=10%水,90%乙腈,0.1% TFA。溶離梯度經8管柱體積30-100% B,接著保持100% B持續8管柱體積。減壓濃縮含產物之溶離份獲得乾淨白色粉末。此純材料留為批料1。剩餘粗物質(約14.5g)容易地溶解於20mL 80:20乙腈:水混合物中。藉由逆相製備型HPLC以9次注射使用製備型HPLC方法1純化此粗物質。以此方式獲得之純材料與先前獲得之批料1純材料合併獲得6.32g乾淨白色粉末(批料2)以及來自混合溶離份的略微不純之材料(1.40g)。混合溶離份材料(1.40g)在最少80:20乙腈:水中裝載至130g Isco Redisep Rf Gold C18濾芯上。溶劑A=90%水,10%乙腈,0.1% TFA。溶劑B=10%水,90%乙腈,0.1% TFA。溶離梯度經10管柱體積30-100% B,接著保持100% B持續4管柱體積。減壓濃縮含產物之溶離份獲得乾淨白色發泡體(1.17g)。此材料與乾淨批料2材料合併獲得TFA鹽形式的標題化合物(7.41g,89%產率,白色泡沫)。LCMS:m/e 755.6(M+H)+,1.29min(方法6)。1H NMR(400MHz,乙酸)δ 5.39(br.s.,1H),5.24(d,J=4.6Hz,1H),4.85(s,1H),4.74(s,1H),4.56(dm,J=47.2Hz,2H),3.93-3.65(m,6H),3.43(tt,J=11.3,3.9Hz,1H),3.26(t,J=12.3Hz,2H),3.02(s,3H),2.86-2.73(m,1H),2.61(d,J=16.6Hz,1H),2.43(d,J=13.0Hz,2H),2.35-2.13(m,7H),2.13-2.09(m,1H),2.01-1.78(m,4H),1.78-1.70(m,4H),1.69-1.45(m,9H),1.45-1.27(m,3H),1.24-1.12(m,5H),1.10(s,3H),1.01(s,3H),0.99(s,3H),
0.95(s,3H)。19F NMR(376MHz,乙酸)δ -76.46(s,1F),-225.82(t,J=46.8Hz,1F)。
步驟3. 在具有磁性攪拌棒之500mL圓底燒瓶中組合乙腈(150mL)與鹽酸,6.0M水溶液(37.1mL,223mmol)。經滴液漏斗向經快速攪拌之混合物中添加(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸,TFA鹽(7.30g,7.42mmol)溶解於乙腈(60mL)中之溶液。幾乎立即形成白色沈澱物且隨著添加進行變得較重。添加總共經20分鐘完成。在室溫下攪拌乳白色懸浮液1.25小時。懸浮液在冰浴中冷淬且因此產生之極細白色固體藉由過濾分離,用冰冷之乙腈沖洗,使其風乾,接著在室溫下在高度真空下乾燥。因此分離出呈白色粉末狀之所要產物(5.857g,95%產率)。LCMS:m/e 755.5(M+H)+,1.27min(方法6)。1H NMR(400MHz,乙酸)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.89(s,1H),4.75(s,1H),4.55(dm,J=47.2Hz,2H),4.13-3.87(m,4H),3.82(br.s.,2H),3.55-3.42(m,2H),3.39(br.s.,1H),3.03(s,3H),3.01-2.90(m,1H),2.62(d,J=17.9Hz,1H),2.55-2.43(m,2H),2.43-2.14(m,8H),1.95-1.79(m,3H),1.79-1.71(m,4H),1.69-1.47(m,9H),1.47-1.28(m,4H),1.22(s,3H),1.19-1.12(m,2H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.96(s,3H)。19F NMR(376MHz,乙酸)δ -225.81(t,J=45.1Hz,1F)。
製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八
氫-1H-環戊并[a]-9-基)環己-3-烯甲酸
步驟1. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
向含有(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并
[a]-9-基酯(3.0g,5.38mmol)、(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(2.013g,5.38mmol)(如WO2013169578中所述製備)及磷酸三鉀(3.43g,16.14mmol)之燒瓶中添加第二代Buchwald X-Phos預催化劑(0.042g,0.134mmol)。混合物用THF(20mL)及水(4mL)稀釋,用氮氣吹掃且加熱至50℃。加熱混合物15.5小時後,將其冷卻至室溫且部分減壓濃縮。混合物用水(75mL)稀釋且用乙酸乙酯(3×75mL)萃取。有機層經硫酸鎂乾燥,過濾且減壓濃縮。藉由急驟層析法使用0-10%甲醇/二氯甲烷梯度及220g矽膠管柱純化殘餘物獲得呈灰白色發泡體狀之標題產物(3.34g,95%產率)。LCMS:m/e:656.6(M+H)+,2.30min(方法1)。1H NMR(500MHz,氯仿-d)δ=7.39-7.30(m,5H),5.32(br.s.,1H),5.21-5.15(m,2H),5.11(dd,J=6.1,1.9Hz,1H),4.73(d,J=2.0Hz,1H),4.61(dd,J=2.1,1.3Hz,1H),4.53(dm,J=47.3Hz,2H),2.64-2.51(m,2H),2.23-1.93(m,7H),1.70(s,3H),1.07(s,3H),0.96(s,3H),0.93(s,3H),0.87(s,3H),0.85(s,3H),1.85-0.83(m,22H)。
步驟2. 製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向含有4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-
五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(3.34g,5.09mmol)的可重新密封之燒瓶中添加磷酸,鉀鹽(5.40g,25.5mmol)、碘化鉀(0.930g,5.60mmol)及1-(2-氯乙基)-4-(甲基磺醯基)哌啶.HCl(4.01g,15.28mmol)。混合物用乙腈(50mL)稀釋,用氮氣吹掃,接著密封燒瓶且加熱至100℃。加熱4小時後,混合物冷卻至室溫且在室溫下攪拌隔夜。混合物用50mL乙腈稀釋且添加額外1g 1-(2-氯乙基)-4-(甲基磺醯基)哌啶.HCl。密封燒瓶且將混合物加熱至100℃ 2小時。混合物冷卻至室溫且減壓濃縮。殘餘物用水(75mL)稀釋且用二氯甲烷(3×75mL)萃取。經合併之有機層經硫酸鈉乾燥,過濾且減壓濃縮。藉由急驟層析法使用含0-8% MeOH之二氯甲烷梯度及220g矽膠管柱純化殘餘物。合併含有產物之溶離份且減壓濃縮。藉由逆相層析法(150g C18管柱,含30-90%乙腈之水梯度,添加有0.1% TFA)再純化殘餘物獲得呈白色發泡體狀之標題產物之TFA鹽(3.17g,3.30mmol,64.9%產率)。LCMS:m/e:845.6(M+H)+,2.10min(方法1)。1H NMR(500MHz,氯仿-d)δ=7.39-7.30(m,5H),5.32(br.s.,1H),5.21-5.15(m,2H),5.11(dd,J=6.1,1.7Hz,1H),4.78(s,1H),4.70(s,1H),4.53(dm,J=47.1Hz,2H),3.44-3.21(m,6H),3.17-3.08(m,1H),3.05-2.97(m,1H),2.90(s,3H),2.79-2.57(m,4H),1.69(s,3H),1.12(s,3H),1.02(s,3H),0.92(s,3H),0.87(s,3H),0.86(s,3H),2.37-0.83(m,31H)。
步驟3. 向(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(3.17g,3.75mmol)於1,4-二噁烷(30mL)及甲醇(10mL)中之溶液中添加NaOH(3N)(7.50mL,
22.50mmol),且將混合物加熱至80℃持續17小時。使混合物冷卻至室溫,且部分減壓濃縮。藉由添加1N HCl使混合物呈酸性,且藉由過濾收集所形成之固體。向所收集之固體材料中添加20mL水及1N NaOH溶液(9.38mL,9.38mmol)。攪拌混合物10分鐘,接著減壓濃縮。殘餘物用水(20mL)及乙腈(30mL)稀釋且用TFA(1.445mL,18.75mmol)處理。混合物接著減壓濃縮且吸附至矽膠上,且使用含20-30%氯仿之丙酮梯度及220g矽膠管柱純化。合併含有預期產物之溶離份且減壓濃縮獲得TFA鹽形式之產物。為了轉化成HCl鹽,殘餘物用200mL乙腈稀釋且添加6N HCl溶液(6.66mL,40.0mmol)。形成之固體及混合物用20mL氯仿稀釋。固體不溶解,因此減壓濃縮混合物。殘餘物用乙腈及氯仿再次稀釋且添加6N HCl(6.66mL,40.0mmol)。減壓濃縮混合物且所述程序重複第三次。固體接著用乙腈稀釋且加熱至回流,接著冷卻至室溫且藉由過濾收集獲得預期產物之HCl鹽。因為仍存在約1.5%之雜質,所以藉由添加20mL水及1N NaOH(8.26mL,8.26mmol),攪拌若干分鐘,接著減壓濃縮將混合物再轉化成TFA鹽來純化。殘餘物接著用水(20mL)及乙腈(30mL)稀釋且用TFA(1.273mL,16.52mmol)處理。混合物減壓濃縮且吸附至矽膠上,且使用含20-30%氯仿之丙酮梯度及220g矽膠管柱純化。合併含有標題化合物之溶離份且減壓濃縮獲得TFA鹽形式之產物。殘餘物之HPLC仍顯示存在少量雜質。使用150g C18管柱及添加0.1% TFA的含30-90%乙腈之水梯度再純化混合物。合併含有預期產物之溶離份且減壓濃縮獲得呈白色固體狀之產物,標題產物之TFA鹽。為了轉化成HCl鹽,將殘餘物溶解於乙腈中且用6N HCl溶液(6.66mL,40.0mmol)處理,接著減壓濃縮。此方法再重複兩次,接著固體用乙腈稀釋,加熱至回流,冷卻且藉由過濾收集獲得呈白色固體狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五
甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸,雙HCl鹽(1.6g,1.859mmol,49.6%產率)。LCMS:m/e:755.5(M+H)+,1.69min(方法1)。1H NMR(400MHz,乙酸-d4)δ=5.37(br.s.,1H),5.22(d,J=4.8Hz,1H),4.86(s,1H),4.72(s,1H),4.53(dm,J=47.0Hz,2H),4.09-3.72(m,6H),3.51-3.27(m,3H),3.01(s,3H),2.98-2.88(m,1H),2.59(d,J=17.6Hz,1H),2.52-2.40(m,2H),1.74(s,3H),1.19(s,3H),1.08(s,3H),2.39-1.04(m,29H),1.00(s,3H),0.95(s,3H),0.93(s,3H)。C45H71FN2O4S˙2.0HCl˙1.530 H2O。
步驟1. 製備4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-
1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸乙酯
遵照上文針對1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸乙酯所述之程序,使用(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(如WO2013123019中所述製備)代替(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-三氟甲磺酸五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯作為反應物製得標題化合物,82%產率。MS:m/e 755.55(M+H)+,2.706min(方法4)。1H NMR(400MHz,氯仿-d)δ 5.32(d,J=3.5Hz,1H),5.18(d,J=5.8Hz,1H),4.73(d,J=1.8Hz,1H),4.66-4.58(m,1H),4.56-4.39(m,2H),4.26-4.15(m,2H),3.17-2.92(m,8H),2.83-2.45(m,6H),2.22-2.05(m,3H),2.03-1.72(m,5H),1.69(s,3H),1.65-1.26(m,16H),1.23(br.s.,3H),1.18-1.02(m,7H),1.01-0.89(m,8H),0.86(s,3H),19F NMR(376MHz,氯仿-d)δ -225.41(s,1F)。
步驟2. 遵照上文步驟2中針對製備1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸乙酯所述之程序,使用4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-
硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸乙酯代替1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸乙酯作為反應物製得標題化合物,11.5%產率。MS:m/e 727.55(M+H)+,2.527min(方法4)。1H NMR(400MHz,氯仿-d)δ 5.34(br.s.,1H),5.18(br.s.,1H),4.76(br.s.,1H),4.64-4.56(m,2H),4.48(br.s.,1H),3.26-2.94(m,8H),2.90-2.38(m,6H),2.32-1.77(m,10H),1.70(m,6H),1.61-1.17(m,12H),1.15-1.03(m,6H),1.01-0.91(m,8H),0.87(br.s.,3H),19F NMR(470MHz,氯仿-d)δ -225.02(br.s.,1F)。
將實例2 HPLC分離成(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(實例2a)及(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(實例2b)
使用製備型HPLC(方法17)分離兩種非對映異構體。溶離之第一產物識別為(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(實例2a)(白色固體,7mg,33%)。MS:m/e 727.55(M+H)+,2.650min(方法4)。1H NMR(400MHz,甲醇-d4)δ 5.35(br.s.,1H),5.27-5.15(m,1H),4.87-4.80(m,1H),4.73(br.s.,1H),4.62-4.37(m,2H),3.29-3.17(m,8H),3.16-3.05(m,3H),3.02-2.86(m,1H),2.80(td,J=11.0,5.5Hz,1H),2.63-2.46(m,1H),2.36-1.80(m,12H),1.76(br.s.,3H),1.75-1.29(m,15H),1.20(s,3H),1.13(s,3H),1.00(s,3H),0.98(s,3H),0.95(s,3H).19F NMR(376MHz,甲醇-d4)δ -227.04(s,1F)。
分離之第二溶離化合物識別為(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,(實例2b)(白色固體,7mg,33%)。MS:m/e 727.55(M+H)+,2.644min(方法4)。1H NMR(400MHz,甲醇-d4)δ 5.36(br.s.,1H),5.22(d,J=4.5Hz,1H),4.88-4.81(m,1H),4.78-4.68(m,1H),4.64-4.36(m,2H),3.30-3.15(m,
8H),3.17-3.03(m,3H),2.99-2.88(m,1H),2.86-2.72(m,1H),2.63-2.50(m,1H),2.37-1.97(m,8H),1.92-1.80(m,4H),1.78(s,3H),1.74-1.28(m,15H),1.22-1.19(m,3H),1.15-1.11(m,3H),0.99(br.s.,3H),0.97(s,3H),0.95-0.92(m,3H)。19F NMR(376MHz,甲醇-d4)δ -227.05(br.s.,1F)。
方法A:(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,經對掌性(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯
步驟1:製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在N2下,將(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺
酸3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(1.75g,2.434mmol)、(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(1.00g,2.68mmol)、Na2CO3.H2O(0.91g,7.30mmol)及Pd(Ph3P)4(0.17g,0.15mmol)於二噁烷(40mL)及水(10.00mL)中之混合物冷卻至-78℃。溶液變成固體。進行抽真空/用N2吹洗循環三次。在70℃下攪拌混合物1小時。顏色變為微暗褐色。減壓濃縮反應混合物。殘餘物用H2O(100mL)稀釋且用EtOAc(3×100mL)萃取。經合併之有機層用鹽水(50mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。在矽膠管柱上用0-35% EtOAc/己烷溶離純化粗產物獲得呈固體狀之標題化合物(1.12g,56%)。1H NMR(500MHz,氯仿-d)δ 7.39-7.30(m,5H),5.32(s,1H),5.22-5.14(m,2H),5.11(d,J=5.0Hz,1H),4.71(s,1H),4.60(s,1H),4.60-4.45(m,2H),3.13-2.98(m,8H),2.72-2.54(m,5H),2.51-2.43(m,1H),2.23-1.00(m,27H),1.69(s,3H),1.06(s,3H),0.96(s,3H),0.93(s,3H),0.87(s,3H),0.85(s,3H)。13C NMR(126MHz,氯仿-d)δ 174.30,150.72,147.90,139.10,135.94,128.52,128.13,127.97,121.41,121.30,109.41,87.60,86.21,66.62,62.72,57.21,52.91,51.29,51.00,49.71,49.39,47.38,45.84,45.70,41.98,41.64,40.64,38.71,37.46,36.80,36.09,34.14,33.61,30.05,29.74,29.18,29.14,29.06,28.66,26.79,26.43,26.39,25.24,21.52,21.36,19.66,19.56,16.30,16.04,14.34。19F NMR(470MHz,氯仿-d)δ -225.09(t,J=47.3Hz,1F)。MS m/e 817.50(M+H)+,2.32min(方法5)。
步驟2:在冰浴中冷卻(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十
八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(2.3g,2.81mmol)於1,4-二噁烷(60mL)及H2O(30mL)中之溶液,且添加1N NaOH(28mL,28mmol)。所得混濁混合物升溫至室溫,接著在70℃下攪拌2小時。反應混合物冷卻至室溫,接著置於冰浴中,隨後用0.5N HCl中和。攪拌混合物隔夜。藉由過濾收集沈澱之固體,用MeOH-H2O洗滌且真空乾燥。將固體溶解於MeCN(80mL)及二噁烷(20mL)中,且逐滴添加6N HCl(50mL)。攪拌混合物1小時。藉由過濾收集沈澱之固體,用MeCN洗滌且真空乾燥獲得雙HCl鹽形式之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(1.95g,90%)。1H NMR(400MHz,甲醇-d4)δ 5.34(s,1H),5.20(dd,J=6.1,1.6Hz,1H),4.87(s,1H),4.74(s,1H),4.58-4.39(m,2H),3.45-3.11(m,12H),2.87(td,J=11.0,5.5Hz,1H),2.55(d,J=16.6Hz,1H),2.34-1.08(m,27H),1.77(s,3H),1.19(s,3H),1.11(s,3H),0.99(s,3H),0.95(s,3H),0.93(s,3H)。13C NMR(126MHz,甲醇-d4)δ 178.20,149.71,149.37,140.47,123.31,122.51,112.28,89.36,87.98,73.56,54.52,51.90,50.64,50.43,49.82,47.03,46.91,46.76,43.44,42.95,42.13,40.78,38.87,38.77,37.41,34.96,33.19,30.55,30.46,30.42,30.38,29.37,27.91,27.72,27.67,27.54,26.53,22.26,20.82,19.41,17.33,17.09,14.85。19F NMR(470MHz,甲醇-d4)δ -227.03(s,1F)。MS m/e 727.45(M+H)+,2.55min(方法4)。
方法B:
步驟1. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
向含有(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(8.9g,15.96mmol)、(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(6.57g,17.55mmol)及磷酸三鉀(10.16g,47.9mmol)之燒瓶中添加Buchwald第2代Xphos預催化劑(0.313g,0.399mmol)。混合物用THF(50mL)及水(10mL)稀釋,用氮氣吹掃,接著加熱至50℃持續22小時。混合物冷卻至室溫,部分濃縮且用水(150mL)稀釋,用乙酸乙酯(3×150mL)萃取(第一次提取時注意到各層之間有一些固體,因此添加過量乙酸乙酯以確保產物溶解),經硫酸鎂乾燥,過濾且減壓濃縮。藉由急驟層析法使用含0-10%甲醇之二氯甲烷梯度及220g矽膠管柱純化殘餘物。合併含有產物之溶離份且減壓濃縮獲得呈黃色固體狀之存在少量雜質之產物,
其將帶入下一步驟。
步驟2. 向含有(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(10.5g,16.0mmol)之可重新密封之燒瓶中添加磷酸三鉀(13.59g,64.0mmol)、碘化鉀(3.99g,24.01mmol)及4-(2-氯乙基)硫代嗎啉1,1-二氧化物,HCl(9.37g,40.0mmol)。混合物用乙腈(200mL)稀釋,用氮氣吹掃,密封且加熱至100℃。加熱混合物16小時後,將其冷卻至室溫,使用二氯甲烷轉移至rb燒瓶,接著減壓濃縮。殘餘物用水(200mL)稀釋且用乙酸乙酯(200mL,接著2×150mL)萃取。有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且減壓濃縮。藉由急驟層析法使用含0-6%甲醇之二氯甲烷梯度及330g矽膠管柱純化殘餘物。合併含有預期產物之溶離份且減壓濃縮獲得呈濃稠紅色油狀的連同其他雜質之產物。將殘餘物溶解於乙腈中且分成三份溶離份且使用25-100%A至B梯度(A=添加有0.1% TFA之9:1水:乙腈,B=添加有0.1% TFA之1:9水:乙腈)及275g C18管柱再純化。合併含有產物之溶離份且減壓濃縮獲得產物之TFA鹽。合併及濃縮較少純溶離份,接著使用與上文相同之逆相方法再純化。產物之TFA鹽用NaHCO3飽和水溶液(150mL)稀釋且用二氯甲烷(150mL,接著3×75mL)萃取。經合併之有機層經硫酸鈉乾燥,過濾且減壓濃縮獲得呈白色固體狀之產物(7.52g,9.2mmol,經兩步驟57.5%產率)。
步驟3. 向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.6g,
0.734mmol)於1,4-二噁烷(10mL)及甲醇(2mL)中之溶液中添加NaOH(1N)(2.94mL,2.94mmol)。將混合物加熱至60℃持續2.5小時,接著冷卻至室溫。
步驟4. 向混合物中添加1N HCl溶液(5mL,5.00mmol)且將其部分減壓濃縮直至開始形成固體,接著將混合物置於冰箱中隔夜。
藉由過濾收集所形成之固體且用水洗滌獲得呈白色固體狀之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯的HCl鹽(0.55g,0.706mmol,96%產率)。標題化合物之新分析資料與針對使用不同方法製備的相同化合物事先獲得之資料相匹配。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
在75mL玻璃壓力容器中組合(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(0.850g,1.524mmol)、(S)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(0.599g,1.600mmol)及XPhos-Pd-G2(0.036g,0.046mmol)。容器用橡膠隔膜密封。向隔膜中插入針且將容器反覆抽真空,接著在室溫下在真空烘箱中經10分鐘時段用氮氣吹掃四次。向氮氣吹掃之反應容器中添加無水THF(20mL)及新鮮製備的0.5M K3PO4的氮氣噴射水溶液(7.62mL,3.81mmol)。用PTFE塞子密封容器且在80℃下攪拌所得黃色溶液。顏色經30分鐘變暗成極深綠色。加熱混合物20小時。反應混合物用EtOAc(70mL)稀釋且用5%碳酸氫鈉水溶液(25mL×2),接著鹽水(10mL)洗滌。水層用2×10mL氯仿萃取且合併有機相,經MgSO4乾燥,過濾且濃縮成黃色發泡體狀固體。粗黃色材料藉由急驟管柱層析法(40g二氧化矽,溶離梯度100% DCM至20:1 DCM:MeOH)純化。合併產物溶離份且濃縮成黃色濃稠油狀物,其在高度真空下放置時變成泡
沫。微黃色泡沫的總回收率=0.493g(49%產率)。LCMS:m/e 656.5(M+H)+,1.59min(方法6)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物CD3OD鎖定)δ 7.38-7.26(m,5H),5.31(br.s.,1H),5.21-5.12(m,2H),5.12-5.06(m,1H),4.77-4.71(m,1H),4.63(s,1H),4.57(dm,J=47.4Hz,2H),2.59(d,J=17.6Hz,1H),2.50(td,J=10.6,5.3Hz,1H),2.16-1.93(m,6H),1.78-1.65(m,7H),1.60(dd,J=12.0,9.0Hz,5H),1.55-1.39(m,8H),1.38-1.22(m,4H),1.11-1.03(m,4H),1.03-0.93(m,4H),0.89(s,3H),0.88(s,3H),0.86(s,3H)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-N-嗎啉基乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯.
在15mL玻璃壓力容器中在無水乙腈(5mL)中組合(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.091g,0.139mmol)與4-(2-氯乙基)嗎啉鹽酸鹽(0.077g,0.416mmol)、磷酸三鉀(0.147g,0.694mmol)及碘化鉀(0.046g,0.277mmol)。密封容器且在油浴中在攪拌下加熱至120℃持續19小時。粗混合物在氮氣流下濃縮,溶解於EtOAc(30mL)中且用水(3×10mL)及鹽水(5mL)洗滌。經
合併之水相用氯仿(10mL)萃取且合併有機相且減壓濃縮。因此獲得之粗殘餘物直接用於下一步驟中。LCMS:m/e 769.6(M+H)+,2.47min(方法1)。
步驟3. 在具有PTFE螺帽之1打蘭小瓶中組合來自步驟2的含有(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-N-嗎啉基乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯之粗混合物與氫氧化鋰,1.0M水溶液(0.973mL,0.973mmol)、MeOH(1mL)及四氫呋喃(1mL)。將小瓶加蓋且加熱至75℃持續45分鐘。藉由逆相製備型HPLC(製備型HPLC方法2)純化粗混合物。因此獲得之材料接著藉由逆相製備型HPLC(製備型HPLC方法3)再純化獲得呈白色固體TFA鹽之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.0191g,2步驟17.3%產率)。LCMS:m/e 679.5(M+H)+,4.26min(方法2)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.23-5.15(m,1H),4.80(s,1H),4.72(s,1H),4.49dm,J=47.4Hz,2H),3.84-3.68(m,4H),3.18-3.09(m,2H),2.98-2.85(m,1H),2.82-2.76(m,1H),2.71(dd,J=13.7,3.4Hz,3H),2.63-2.50(m,3H),2.30-2.11(m,2H),2.11-1.91(m,7H),1.83-1.75(m,3H),1.73(s,4H),1.67-1.30(m,12H),1.19(s,3H),1.17-1.09(m,2H),1.07(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H)。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-二氧離子基-2-硫雜-5-氮雜雙環[2.2.1]庚-5-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
在15mL玻璃壓力容器中,在無水乙腈(5mL)中組合(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.091g,0.139mmol)與(1S,4S)-5-(2-氯乙基)-2-硫雜-5-氮雜雙環[2.2.1]庚烷2,2-二氧
化物(0.075g,0.358mmol)(如WO2013169578中所述製備)、磷酸三鉀(0.147g,0.694mmol)及碘化鉀(0.046g,0.277mmol)。密封容器且在油浴中在攪拌下加熱至120℃持續19小時。在粗混合物氮氣流下濃縮,溶解於EtOAc(30mL)中且用水(3×10mL),接著鹽水(5mL)洗滌。經合併之水相用氯仿(10mL)萃取且合併有機相且減壓濃縮。因此獲得之粗殘餘物直接用於下一步驟中。LCMS:m/e 829.6(M+H)+,2.44min(方法1)。
步驟2. 在具有PTFE螺帽之1打蘭小瓶中組合來自步驟1的含有(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-二氧離子基-2-硫雜-5-氮雜雙環[2.2.1]heptan-5-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.115g,0.139mmol)之粗混合物與氫氧化鋰,1.0M水溶液(0.695mL,0.695mmol)、MeOH(0.7mL)及四氫呋喃(0.7mL)。將小瓶加蓋且加熱至75℃持續45分鐘。粗混合物藉由逆相製備型HPLC(製備型HPLC方法4)純化且因此獲得之黃色固體接著藉由逆相製備型HPLC(製備型HPLC方法5),隨後第三及最終逆相製備型HPLC純化(製備型HPLC方法6)再純化獲得呈白色粉末TFA鹽之47.4mg(經2步驟39.2%產率)(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-二氧離子基-2-硫雜-5-氮雜雙環[2.2.1]庚-5-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲苯甲酯。LCMS:m/e 739.5(M+H)+,4.22min(方法2)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.6Hz,1H),4.79(s,1H),4.71(s,1H),4.48(dm,J=47.2Hz,2H),4.00(br.s.,1H),3.69-3.63(m,1H),3.23-3.13(m,2H),3.13-2.95(m,4H),2.79
(td,J=11.1,5.0Hz,1H),2.63-2.55(m,1H),2.53(br.s.,1H),2.42(d,J=12.5Hz,1H),2.28-2.06(m,4H),2.06-1.91(m,6H),1.86-1.74(m,3H),1.73(s,4H),1.69-1.55(m,4H),1.54-1.38(m,7H),1.38-1.23(m,3H),1.20-1.14(m,1H),1.13-1.08(m,4H),1.07(s,3H),0.96(s,3H),0.93(s,3H),0.89(s,3H)。
步驟1. 製備4-(2-氯乙基)-1,4-噻氮呯1,1-二氧化物.
向1,4-噻氮呯1,1-二氧化物(200mg,1.340mmol)及2-氯乙醛,水中之50重量%溶液(0.234mL,1.877mmol)於甲醇(5mL)及乙酸(1mL)
中之混合物中添加2-甲吡啶硼烷複合物(158mg,1.474mmol)。所得混合物在室溫下攪拌隔夜。減壓濃縮反應混合物獲得殘餘物,將其用飽和Na2CO3(10mL)洗滌且用乙酸乙酯(3×10mL)萃取。水相用氯仿(10mL)萃取。經合併之有機相經無水MgSO4乾燥,過濾且減壓濃縮獲得334mg(定量)呈粗淡紅色-褐色油狀之所要產物,其靜置時部分固化。此粗物質直接原樣用於下一步驟。LCMS:m/e 212.0(M+H)+,0.18min(方法1)。
步驟2. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基-1,4-噻氮呯-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
在15mL玻璃壓力容器中,在無水乙腈(5mL)中組合來自步驟1的含有4-(2-氯乙基)-1,4-噻氮呯1,1-二氧化物(0.065g,0.305mmol)與(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯之粗物質(0.100g,0.152mmol)、磷酸三鉀(0.162g,0.762mmol)及碘化鉀(0.051g,0.305mmol)。密封容器且在油浴中在攪拌下加熱至120℃持續17小時。反應混合物減壓濃縮,溶解於EtOAc(30mL)中且用水(3×10mL)及鹽水(5mL)洗滌。經合併之水相用氯仿(10mL)萃取且合併有機相
且減壓濃縮。因此獲得之粗殘餘物未經進一步純化即原樣用於皂化步驟中。LCMS:m/e 831.6(M+H)+,2.39min(方法1)。
步驟3. 在具有PTFE螺帽之1打蘭小瓶中組合來自步驟2的含有(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基-1,4-噻氮呯-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯之粗混合物(0.126g,0.152mmol)與氫氧化鋰,1.0M水溶液(1.064mL,1.064mmol)、MeOH(1mL)及四氫呋喃(1mL)。將小瓶加蓋且將混合物加熱至75℃持續45分鐘。過濾混合物且藉由逆相製備型HPLC(製備型HPLC方法7)純化獲得呈白色固體TFA鹽的(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基-1,4-噻氮呯-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(36.7mg,2步驟28.2%產率)。LCMS:m/e 741.5(M+H)+,2.26min(方法1)。1H NMR(400MHz,CDCl3與CD3OD的1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.6Hz,1H),4.80(s,1H),4.71(s,1H),4.49(dm,J=47.4Hz,1H),3.47-3.37(m,1H),3.35(br.s.,1H),3.28-3.17(m,2H),3.15-3.02(m,5H),3.02-2.93(m,1H),2.79(td,J=11.0,4.6Hz,1H),2.55(d,J=17.1Hz,1H),2.29-2.14(m,2H),2.13-1.91(m,9H),1.86-1.74(m,3H),1.73(s,4H),1.68-1.55(m,4H),1.55-1.42(m,6H),1.41-1.24(m,3H),1.19-1.09(m,5H),1.07(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H).
步驟1. 製備1-(2-氯乙基)-4-(甲基磺醯基)哌嗪.
向1-(甲基磺醯基)哌嗪(0.200g,1.218mmol)及2-氯乙醛,50重量%水溶液(0.212mL,1.705mmol)於甲醇(5mL)及乙酸(1mL)中的混合物中添加2-甲吡啶-硼烷-複合物(0.143g,1.340mmol)。所得混合物在室溫下攪拌隔夜。減壓濃縮反應混合物留下殘餘物,將其用飽和Na2CO3(10mL)洗滌且用乙酸乙酯(3×10mL)萃取。水相用氯仿(10mL)萃取。經合併之有機相經無水MgSO4乾燥,過濾且減壓濃縮獲得394mg(>100%產率)呈無色油狀之所要產物,其靜置時固化成蠟質微黃色固體。此粗物質直接原樣用於下一步驟。LCMS:m/e 227.0(M+H)+,0.19min(方法1)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌嗪-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯.
在15mL玻璃壓力容器中,在無水乙腈(5mL)中組合來自步驟1的含有1-(2-氯乙基)-4-(甲基磺醯基)哌嗪(0.069g,0.305mmol)的粗物質與(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.100g,0.152mmol)、磷酸三鉀(0.162g,0.762mmol)及碘化鉀(0.051g,0.305mmol)。密封容器且在油浴中在攪拌下加熱至120℃持續15小時。減壓濃縮反應混合物,將殘餘物溶解於EtOAc(30mL)中且用水(3×10mL)及鹽水(5mL)洗滌。經合併之水相用氯仿(10mL)萃取且合併有機相且減壓濃縮。因此獲得之粗殘餘物未經進一步純化即原樣用於皂化步驟中。LCMS:m/e 846.7(M+H)+,2.43min(方法1)。
步驟3. 在具有PTFE螺帽之1打蘭小瓶中組合來自步驟2的含有(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌嗪-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯之粗混合物(0.129g,0.152mmol)與
1.0M氫氧化鋰水溶液(1.064mL,1.064mmol)、MeOH(1mL)及四氫呋喃(1mL)。將小瓶加蓋且將混合物加熱至75℃持續45分鐘。過濾混合物且藉由逆相製備型HPLC(製備型HPLC方法7)純化獲得呈白色固體TFA鹽之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(4-(甲基磺醯基)哌嗪-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(47.4mg,2步驟35.8%產率)。LCMS:m/e 756.5(M+H)+,4.21min(方法2)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.6Hz,1H),4.79(s,1H),4.71(s,1H),4.48(dm,J=47.2Hz,1H),3.30-3.22(m,2H),3.19-3.09(m,2H),3.00-2.90(m,1H),2.87(s,3H),2.84-2.64(m,6H),2.55(d,J=17.6Hz,1H),2.29-2.14(m,2H),2.14-1.91(m,7H),1.86-1.75(m,3H),1.73(s,4H),1.65-1.47(m,7H),1.45-1.34(m,4H),1.29(dd,J=17.7,5.0Hz,1H),1.17(s,3H),1.16-1.08(m,2H),1.07(s,3H),0.96(s,3H),0.93(s,3H),0.89(s,3H)。
步驟1:製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(45mg,0.069mmol)、4-(2-溴乙基)四氫-2H-硫代哌喃1,1-二氧化物(17mg,0.069mmol)、K3PO4(44mg,0.206mmol)及NaI(17mg,0.103mmol)於MeCN(1mL)中之懸浮液用氮氣吹洗,密封且在100℃下攪拌18小時。過濾反應混合物且減壓濃縮濾液。藉由使用ELS偵測器之矽膠管柱急驟層析法(0-40% EtOAc/己烷)純化粗產物獲得呈固體狀之標題產物(28mg,50%)。LCMS m/e 816.45(M+H)+,3.864min(方法7)。1H NMR(400MHz,氯仿-d)δ 7.40-7.28(m,5H),5.32(s.,1H),5.17(d,J=1.3Hz,2H),5.15-5.09(m,1H),4.70(d,J=1.8Hz,1H),4.63-4.55(m,2H),4.50-4.43(m,1H),3.13-2.90(m,4H),2.64-2.41(m,4H),2.21-0.80(m,34H),1.69(s,3H),1.03(s,3H),0.95(s,3H),0.90(s,3H),0.89(s,3H),0.85(s,3H)。
步驟2. 向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(28mg,0.034mmol)於1,4-二噁烷(2mL)及MeOH(1mL)中之溶液中添加1N NaOH(1mL,1.0mmol)。在60℃下攪拌混合物3小時。藉由製備型HPLC(方法8)純化反應混合物獲得呈固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(16mg,64%)。LCMS m/e 726.50(M+H)+,3.528min(方法7)。1H NMR(400MHz,氯仿-d)δ 5.34(s,1H),5.18(d,J=4.5Hz,1H),4.71(s,1H),4.60(s,2H),4.48(s,1H),3.10-2.89(m,4H),2.66-2.48(m,4H),2.27-0.91(m,34H),1.68(s,3H),1.06(s,3H),0.96(s,3H),0.95(s,3H),0.93(s,3H),0.86(s,3H)。19F NMR(376MHz,氯仿-d)δ -224.87(s,1F)。
步驟1:製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(2-(四氫-2H-哌喃-4-基)乙醯胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及2-(四氫-2H-哌喃-4-基)乙酸(13mg,0.091mmol)於CH2Cl2(1mL)中之混合物中添加DIPEA(0.05mL,0.305mmol),隨後HATU(44mg,0.114mmol)。在室溫下攪拌溶液1小時。減壓濃縮反應混合物。藉由使用ELS偵測器之矽膠管柱急驟層析法(20-45% EtOAc/己烷)純化粗產物獲得呈固體狀之所要產物(定量產量)。LCMS m/e 782.55(M+H)+,4.346min(方法8)。1H NMR(400MHz,氯仿-d)δ 7.39-7.29(m,5H),5.32(s,1H),5.21-5.14(m,2H),5.12(d,J=4.5Hz,1H),5.10(s,1H),4.73(d,J=1.3Hz,1H),4.63(s,1H),4.61-4.56(m,1H),4.50-4.44(m,1H),3.96(dd,J=11.3,3.5Hz,2H),3.47-3.38(m,2H),2.73-2.65(m,1H),2.60(d,J=17.3Hz,1H),2.51(dd,J=12.4,8.2Hz,1H),2.42(td,J=10.5,5.3Hz,1H),2.19-0.92(m,32H),1.70(s,
3H),1.01(s,3H),0.97(s,3H),0.90(s,3H),0.88(s,3H),0.85(s,3H)。
步驟2. 向(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(2-(四氫-2H-哌喃-4-基)乙醯胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(60mg,0.077mmol)於1,4-二噁烷(3mL)及MeOH(1.5mL)中之溶液中添加1N NaOH(1.5mL,1.5mmol)。在60℃下攪拌混合物3小時。藉由製備型HPLC(方法8)純化反應混合物獲得呈固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-(2-(四氫-2H-哌喃-4-基)乙醯胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(45mg,85%)。LCMS m/e 692.55(M+H)+,3.141min(方法8)。1H NMR(400MHz,氯仿-d)δ 5.33(s,1H),5.18(d,J=4.5Hz,1H),5.13(s,1H),4.73(s,1H),4.63(s,1H),4.59(s,1H),4.48(s,1H),3.97(d,J=8.5Hz,2H),3.43(t,J=11.8Hz,2H),2.70(d,J=12.8Hz,1H),2.63-2.36(m,3H),2.28-0.95(m,32H),1.70(s,3H),1.02(s,3H),0.97(s,3H),0.94(s,3H),0.92(s,3H),0.86(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.31(s,1F)。
步驟1:製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(四氫-2H-哌喃-4-基)乙基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)、4-(2-溴乙基)四氫-2H-哌喃(15mg,0.076mmol)、K3PO4(49mg,0.229mmol)及NaI(19mg,0.114mmol)於MeCN(1mL)中之懸浮液用氮氣吹洗,密封且在90℃下攪拌18小時。過濾反應混合物且減壓濃縮濾液。藉由使用ELS偵測器之矽膠管柱急驟層析法(0-40% EtOAc/己烷)純化粗產物獲得呈固體狀之所要產物(30mg,51%)。LCMS m/e 768.55(M+H)+,3.033min(方法8)。1H NMR(400MHz,氯仿-d)δ 7.39-7.29(m,5H),5.32(s,1H),5.22-5.14(m,2H),5.14-5.10(m,1H),4.71(d,J=2.0Hz,1H),4.62-4.55(m,1H),4.58(s,1H),4.51-4.43(m,1H),4.01-3.93(m,4H),2.65-2.52(m,2H),2.50-2.36(m,2H),2.18-0.87(m,34H),1.69(s,3H),1.05(s,3H),0.95(s,3H),0.90(s,3H),0.89(s,3H),0.85(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.06(s,1F)。
步驟2. 向(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(四氫-2H-哌喃-4-基)乙基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(30mg,0.039mmol)於1,4-二噁烷(2mL)及MeOH(1mL)中之溶液中添加1N NaOH(1mL,1.0mmol)。在60℃下攪拌混合物2小時。藉由製備型HPLC(方法8)純化反應混合物獲得呈固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((2-(四氫-2H-哌喃-4-基)乙基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(12mg,45%)。LCMS m/e 678.50(M+H)+,2.968min(方法8)。1H NMR(400MHz,氯仿-d)δ 5.34(s,1H),5.18(d,J=4.5Hz,1H),4.72(d,J=2.0Hz,1H),4.60(s,2H),4.48(s,1H),3.97(d,J=11.3Hz,2H),3.39(tdd,J=11.8,4.5,2.1Hz,2H),2.67-2.48(m,4H),2.19-0.89(m,34H),1.69(s,3H),1.07(s,3H),0.96(s,3H),0.95(s,3H),0.93(s,3H),0.86(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.04(s,1F)。
步驟1:製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(2.0g,3.50mmol)、(S)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(1.44g,3.85mmol)、Na2CO3 H2O(1.3g,10.5mmol)及Pd(Ph3P)4(0.24g,0.21mmol)於二噁烷(40mL)中之混合物用氮氣吹洗,密封及在70℃下攪拌1小時。使混合物冷卻至室溫且減壓濃縮。殘餘物用H2O(100mL)稀釋且用EtOAc(3×100mL)萃取。經合併之有機層用鹽水(50mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。藉由使用ELS偵測器之矽膠管柱急驟層析法(0-15% EtOAc/己烷溶離)純化粗產物獲得呈固體狀之所要產物
(1.85g,79%)。1H NMR(400MHz,氯仿-d)δ 9.69(d,J=1.5Hz,1H),7.39-7.31(m,5H),5.31(br.s.,1H),5.21-5.14(m,2H),5.12(dd,J=6.3,1.8Hz,1H),4.77(d,J=2.0Hz,1H),4.65-4.62(m,1H),4.62-4.55(m,1H),4.50-4.44(m,1H),2.89(td,J=11.1,5.9Hz,1H),2.60(d,J=16.3Hz,1H),2.17-1.72(m,11H),1.71(s,3H),1.53-1.19(m,14H),1.11-1.01(m,2H),0.98(s,3H),0.94(s,3H),0.90(s,3H),0.88(s,3H),0.84(s,3H)。19F NMR(376MHz,氯仿-d)δ -225.07(s,1F)
步驟2:製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧離子基N-硫代嗎啉基)-2-甲基丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(70mg,0.105mmol)及4-(1-胺基-2-甲基丙-2-基)硫代嗎啉1,1-二氧化物(32mg,0.157mmol)於DCE(1mL)中之懸浮液1小時。向所得溶液中添加氰基硼氫化鈉(20mg,0.314mmol)及AcOH(0.012mL,0.209mmol)。在室溫下攪拌混合物18小時。混合物用飽和NaHCO3(5mL)稀釋且用CH2Cl2(3×10mL)萃取。經合併之有機層經Na2SO4乾燥,過濾且減壓濃縮。藉由使用ELS偵測器之矽膠管柱急驟層析法(20-80% EtOAc/己烷)純化粗產物獲得呈固體狀之所要產物(18mg,20%)。LCMS m/e 859.55(M+H)+,3.113min(方法8)。1H NMR(400MHz,氯仿-d)δ 7.40-7.29(m,5H),5.32(s,1H),5.21-5.14(m,2H),5.12(d,J=4.5Hz,1H),4.69(d,J=1.5Hz,1H),4.63-4.55(m,1H),4.59(s,1H),4.51-4.44(m,1H),3.07(m,8H),2.73-2.55(m,3H),2.42(td,J=11.0,5.6Hz,1H),2.18-0.92(m,
29H),1.69(s,3H),1.16(s,3H),1.15(s,3H),1.04(s,3H),0.98(s,3H),0.90(s,3H),0.89(s,3H),0.84(S,3H)。19F NMR(376MHz,氯仿-d)δ -225.06(s,1F)。
步驟3:向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧離子基N-硫代嗎啉基)-2-甲基丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(18mg,0.021mmol)於1,4-二噁烷(1mL)及MeOH(0.5mL)中之溶液中添加1N NaOH(0.5mL,0.5mmol)。在60℃下攪拌混合物2小時。藉由製備型HPLC(方法8)純化反應混合物獲得呈固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((2-(1,1-二氧離子基N-硫代嗎啉基)-2-甲基丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(6mg,37%)。LCMS m/e 769.55(M+H)+,2.816min(方法8)。1H NMR(400MHz,氯仿-d)δ 5.33(s,1H),5.17(d,J=4.3Hz,1H),4.69(s,1H),4.60(s,1H),4.56(s,1H),4.44(s,1H),3.13-3.01(m,8H),3.01-0.89(m,33H),1.68(s,3H),1.15(s,6H),1.03(s,3H),0.97(s,3H),0.96(s,3H),0.92(s,3H),0.85(s,3H)。19F NMR(376MHz,氯仿-d)δ -224.76(s,1F)。
步驟1. 製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在25mL壓力容器中,在N2下將(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(164mg,0.287mmol)、(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(118mg,0.316mmol)、Na2CO3.H2O(107mg,0.862mmol)及Pd(Ph3P)4(19.92mg,0.017mmol)於二噁烷(2mL)及水(0.500mL)中之混合物冷卻至-78℃。混合物固化且抽真空/用N2吹掃循環進行三次。在70℃下攪拌混合物1小時,且顏色變為微暗褐色。反應混合物用H2O(100mL)稀釋且用
EtOAc(3×100mL)萃取。經合併之有機層用鹽水(50mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。純化(24g矽膠管柱;0-25%,25% EtOAc/己烷;ELS偵測器)粗產物獲得呈白色固體狀之標題化合物(122mg,63.5%)。LCMS:m/e 691.45(M+Na)+,4.428min(方法9)。1H NMR(400MHz,氯仿-d)δ 9.73(d,J=1.5Hz,1H),7.47-7.25(m,5H),5.35(br.s.,1H),5.20(d,J=1.8Hz,2H),5.16-5.09(m,1H),4.79(d,J=1.8Hz,1H),4.71-4.64(m,1H),4.61-4.53(m,1H),4.51-4.41(m,1H),2.89(td,J=11.1,5.9Hz,1H),2.63(d,J=18.3Hz,1H),2.31-1.85(m,8H),1.85-1.76(m,3H),1.73(s,3H),1.61-1.20(m,14H),1.15-1.05(m,2H),1.04-1.00(m,3H),0.99(br.s.,3H),0.96(s,3H),0.90(s,3H),0.87(s,3H)。
步驟2. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧離子基N-硫代嗎啉基)丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
向(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-甲醯基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(122mg,0.182mmol)於DCE(2mL)中之溶液中添加乙酸(0.021mL,0.365mmol)及4-(3-胺基丙基)硫代嗎啉1,1-二氧化物(70.1mg,0.365mmol)。溶液首先變得渾濁,且10分鐘後變澄清。在室溫下攪拌混合物2小時。添加三乙醯氧基硼氫化鈉(193mg,0.912mmol)且攪拌所得混合物18小時。添加酸性酸(0.2mL)及三乙醯氧基硼氫化鈉(193mg,0.912mmol)且攪拌混合物18小時。混合物接著用飽和NaHCO3(7mL)稀釋且用二氯甲烷(3×7mL)萃取。經Na2SO4乾燥經合併之有機層。藉由過濾移除乾燥劑且濃縮濾
液。純化(矽膠)粗產物。收集含有預期產物之溶離份且減壓濃縮獲得呈白色固體狀之標題化合物(130mg,84%)。LCMS:m/e 845.60(M+H)+,3.116min(方法9)。1H NMR(400MHz,氯仿-d)δ 7.41-7.29(m,5H),5.34-5.29(m,1H),5.18(d,J=2.3Hz,2H),5.11(s,1H),4.70(s,1H),4.63-4.53(m,2H),4.47(d,J=4.5Hz,1H),3.14-2.97(m,12H),2.95-2.82(m,3H),2.68-2.51(m,4H),2.48-2.33(m,2H),2.24-2.07(m,3H),2.03-1.91(m,4H),1.91-1.73(m,6H),1.71(br.s.,3H),1.63-1.30(m,11H),1.08(br.s.,3H),0.98(s,3H),0.92(s,3H),0.87(s,3H),0.84(s,3H)。
步驟3. 向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧離子基N-硫代嗎啉基)丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(130mg,0.154mmol)於1,4-二噁烷(6mL)及MeOH(3mL)中之溶液中添加1N NaOH(3mL,3.00mmol)。在66℃下攪拌混合物2小時,且獲得澄清溶液。藉由製備型HPLC(方法9)純化反應混合物獲得呈白色固體裝之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧離子基N-硫代嗎啉基)丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(55mg,45%)。LCMS:m/e 755.50(M+H)+,2.837min(方法9)。1H NMR(400MHz,氯仿-d)δ 5.29(br.s.,1H),5.15(d,J=4.5Hz,1H),4.71(s,1H),4.60(s,1H),4.50(q,J=8.8Hz,1H),4.39(q,J=8.6Hz,1H),3.36(d,J=6.0Hz,4H),3.33-3.28(m,4H),3.23-3.10(m,3H),2.95(t,J=7.2Hz,2H),2.82(d,J=13.1Hz,1H),2.56-2.40(m,2H),2.31-2.17(m,1H),2.14-1.89(m,7H),1.85-1.61(m,10H),1.60-1.13(m,13H),1.12-1.04(m,4H),
1.01(s,3H),0.94(s,3H),0.90(s,3H),0.87(s,3H)。19F NMR(376MHz,氯仿-d)δ -222.66 - -223.63(m,1F)。
向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-二氧離子基N-硫代嗎啉基)丙基)胺基)甲基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(20mg,0.026mmol)於CH2Cl2(1mL)中之溶液中添加乙酸酐(0.012mL,0.132mmol)及DMAP(0.324mg,2.65μmol)。在50℃下加熱所得混合物24小時。減壓濃縮反應混合物。殘餘物再溶解於MeOH(4mL)中且藉由製備型HPLC(方法10)純化獲得呈白色固體狀之標題化合物(3mg,13.5%)。LCMS:m/e 797.55(M+H)+,3.103min(方法9)。1H NMR(400MHz,甲醇-d4)δ 5.35(br.s.,1H),5.21(d,J=4.8Hz,1H),4.76(d,J=2.0Hz,1H),4.82-4.72(m,1H),4.62(s,1H),4.60-4.52(m,1H),4.50-4.36(m,1H),3.64(d,J=13.8Hz,1H),3.49(t,J=7.4Hz,2H),3.27(m,1H),3.18-3.08(m,4H),3.03(d,J=5.5Hz,4H),2.68-2.47(m,4H),2.27(d,J=6.0Hz,1H),2.22-1.93(m,9H),1.89-1.23(m,21H),1.17(s,3H),1.16-1.07(m,3H),1.05(s,3H),1.00(s,3H),0.96(s,3H),0.92
(s,3H)。19F NMR(376MHz,甲醇-d4)δ -226.56 - -227.82(m,1F)。
步驟1. 製備((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
將(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(669mg,1.788mmol)、(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(950mg,1.703mmol)、碳酸鈉水合物(634mg,5.11mmol)與肆鈀(118mg,0.102mmol)之混合物置於氮氣氛圍
下。添加二噁烷(16mL)且形成橙色溶液。添加水(4mL)且形成極淺黃色懸浮液。全部混合物冷淬至-78℃且進行抽真空/吹掃循環三次且最終進行氮氣吹掃。燒瓶浸沒至65℃-85℃的油浴中。混合物之顏色經10分鐘時段從淺黃色懸浮液變成深褐色。在85℃進行加熱總計5小時。反應混合物用H2O(100mL)稀釋且用EtOAc(3×100mL)萃取。經合併之有機層用鹽水(50mL)洗滌,經Na2SO4乾燥,過濾且減壓濃縮。藉由矽膠層析法純化粗物質獲得呈白色固體狀之標題化合物(0.78g,69.8%)。LCMS:m/e 656.50(M+H)+,3.003min(方法9)。1H NMR(400MHz,氯仿-d)δ 7.46-7.29(m,5H),5.43-5.28(m,1H),5.24-5.16(m,2H),5.13(dd,J=6.1,2.0Hz,1H),4.75(d,J=2.0Hz,1H),4.62(s,1H),4.61-4.56(m,1H),4.52-4.44(m,1H),2.68-2.51(m,2H),2.26-1.94(m,6H),1.84-1.72(m,4H),1.72(s,3H),1.65-1.28(m,12H),1.27(s,3H),1.14(d,J=13.9Hz,2H),1.09(s,3H),1.06(m,2H),0.98(s,3H),0.95(s,3H),0.89(s,3H),0.87(s,3H)。
步驟2. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮丙啶-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在直火烘乾之75mL厚壁可重複密封之容器中置入(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.78g,1.189mmol)及直火烘乾之磷酸鉀(1.262g,5.95mmol),隨後1,2-二氯乙烷(20mL)及乙腈(10mL)。反應混合物用氮氣吹洗,密封且升溫至130℃持續36小時。粗反應混合物經矽膠短墊過濾且用乙酸乙酯洗滌獲得極淺橙色溶液。減壓濃縮溶液獲得呈灰白色固體狀之標題化合物。化
合物未經進一步純化即原樣使用。LCMS:m/e 682.50(M+H)+,700.55(M+H2O)+,714.55(M+MeOH)+,3.053min(方法9)。
步驟3. 製備1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯
將(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮丙啶-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.147mmol)置於15mL密封試管中。添加CH3CN(2mL),隨後哌啶-4,4-二甲酸二乙酯(67.2mg,0.293mmol)。向此懸浮液中添加碘化鈉(24.18mg,0.161mmol)及磷酸鉀(93mg,0.440mmol)。在125℃下加熱所得混合物15小時。反應混合物用乙酸乙酯(50mL)稀釋且藉由碳酸氫鈉及鹽水洗滌。收集有機層,經硫酸鈉乾燥且減壓濃縮。在矽膠(0-25%乙酸乙酯/己烷)上純化粗物質獲得呈白色固體狀之標題化合物(60mg,48%)。LCMS:m/e 911.65(M+H)+,3.213min(方法9)。1H NMR(400MHz,氯仿-d)δ 7.41-7.31(m,5H),5.31(br.s.,1H),5.22-5.14(m,2H),5.10(d,J=4.5Hz,1H),4.71(d,J=2.5Hz,1H),4.63-4.53(m,2H),4.50-4.41(m,1H),4.28-4.20(m,4H),3.01-2.79(m,2H),2.69-2.55(m,2H),2.54-2.29(m,2H),2.20-2.10(m,6H),2.00-1.73(m,15H),1.70-1.67(s,3H),1.67-1.49(m,10H),1.26(t,J=7.2Hz,11H),1.07(s,3H),0.97-0.93(m,3H),0.92(s,3H),0.86(s,3H),0.84(s,3H)。
步驟4. 製備1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-(((第三丁基二甲基矽烷基)氧基)羰基)-4-(氟甲基)環己-1-烯-
1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯
向1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯(60mg,0.066mmol)於DCE(3mL)中之溶液中添加TEA(0.015mL,0.105mmol)、第三丁基二甲基矽烷(0.022mL,0.132mmol)及乙酸鈀(II)(3.70mg,0.016mmol)。混合物用N2吹洗且加熱至60℃。加熱3小時後,混合物冷卻至室溫且經矽藻土墊及矽膠(用含50% EtOAc之己烷,接著二氯甲烷洗滌)過濾。減壓濃縮濾液獲得呈固體狀之標題化合物(61mg,100%)。粗產物未經額外純化即用於下一步驟中。LCMS:m/e 935.70(M+H)+,3.247min(方法9)。
步驟5. 向1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-(((第三丁基二甲基矽烷基)氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯(15mg,0.016mmol)於THF(4mL)中之溶液中添加TBAF(THF中1M)(0.024mL,0.024mmol)。在室溫下攪拌混合物30分鐘。藉由製備型HPLC(方法9)純化混合物獲得呈白色固體狀之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4,4-雙(乙氧羰基)哌啶-1-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(7mg,53.2%)。LCMS:m/e
821.60(M+H)+,2.901min(方法9)。1H NMR(400MHz,氯仿-d)δ 5.38-5.32(m,1H),5.17(d,J=4.8Hz,1H),4.79(s,1H),4.72-4.40(m,3H),4.32-4.21(m,4H),3.54-3.24(m,4H),3.10(br.s.,3H),2.90-2.60(m,2H),2.36(br.s.,4H),2.28-1.73(m,12H),1.69(s,3H),1.66-1.50(m,6H),1.44(br.s.,3H),1.38-1.33(m,3H),1.32-1.24(m,9H),1.12(s,3H),1.08(d,J=8.3Hz,2H),1.02(s,3H),0.97(s,3H),0.92(s,3H),0.87(s,3H)。
步驟1. 製備4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉基-3-甲酸乙酯
遵照上文針對製備1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯所述的程序,使用硫代嗎啉-3-甲酸乙酯鹽酸鹽代替哌啶-4,4-二甲酸二乙酯作為起始物質,製得標題化合物,26.3%產率。MS:m/e 857.65.(M+H)+,3.876min(方法9)。1H NMR(400MHz,氯仿-d)δ 7.38-7.31(m,5H),5.31(d,J=3.8Hz,1H),5.23-5.13(m,2H),5.10(d,J=4.5Hz,1H),4.70(d,J=2.0Hz,1H),4.62-4.54(m,2H),4.51-4.40(m,1H),4.28-4.22(m,2H),3.81-3.67(m,1H),3.63(ddd,J=12.5,5.8,3.5Hz,1H),3.37(ddd,J=12.4,9.9,2.9Hz,1H),3.21(ddd,J=12.4,8.5,5.8Hz,1H),3.09(ddd,J=9.9,6.0,3.5Hz,1H),3.03-2.95(m,1H),2.93-2.66(m,5H),2.64-2.32(m,5H),2.17-2.08(m,3H),2.00-1.77(m,8H),1.69(s,3H),1.64-1.48(m,8H),1.18-1.01(m,8H),0.99-0.80(m,16H)。
步驟2. 製備4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉-3-甲酸乙酯1,1-二氧化物
在0℃下,向4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-
1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉基-3-甲酸乙酯(32mg,0.037mmol)於MeOH(2mL)中之混合物溶液中添加OXONE®(34.4mg,0.056mmol)於水(2.00mL)中之懸浮液,隨後添加丙酮(5mL)。在0℃下攪拌所得混合物12小時。反應混合物用水(10mL)稀釋且用乙酸乙酯萃取。有機層用亞硫酸氫鈉洗滌,接著經硫酸鈉乾燥,過濾且減壓濃縮獲得呈固體狀之標題化合物。30mg粗產物未經進一步純化即用於下一步驟中。MS:m/e 889.55.(M+H)+,3.26min(方法9)。
步驟3. 製備4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-(((第三丁基二甲基矽烷基)氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉-3-甲酸乙酯1,1-二氧化物
遵照上文針對製備1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-(((第三丁基二甲基矽烷基)氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯所述的程序,使用4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉-3-甲酸乙酯1,1-二氧化物代替1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸二乙酯作為起始物質,製備標
題化合物,97%產率。MS:m/e 913.65.(M+H)+,3.204min(方法9)
步驟4. 向4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-(((第三丁基二甲基矽烷基)氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉-3-甲酸乙酯1,1-二氧化物(20mg,0.022mmol)於THF(4mL)中之溶液中添加TBAF(THF中1M)(0.032mL,0.032mmol)。在室溫下攪拌混合物30分鐘。藉由製備型HPLC(方法9)純化混合物獲得兩種產物:實例14:呈白色固體狀之(1R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-(乙氧羰基)-1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(異構體1)(2mg,11.43%)。LCMS:m/e 799.50(M+H)+,2.866min(方法9)。1H NMR(400MHz,氯仿-d)δ 5.40-5.29(m,1H),5.19(d,J=4.8Hz,1H),4.83(s,1H),4.71(s,1H),4.64-4.55(m,1H),4.49(q,J=8.6Hz,1H),4.37-4.25(m,2H),3.74-3.62(m,1H),3.46-2.85(m,10H),2.68-2.53(m,2H),2.26-2.06(m,5H),2.02-1.75(m,7H),1.72(s,3H),1.67-1.50(m,7H),1.37-1.27(m,8H),1.13(s,3H),1.09-1.01(m,4H),1.04(s,3H),0.97(s,3H),0.94-0.91(m,3H),0.88(s,3H),及實例15:呈白色固體狀之(1R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-(乙氧羰基)-1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸異構體2(2mg,
11.43%)作為異構體2。LCMS:m/e 799.55(M+H)+,2.778min(方法9)。1H NMR(400MHz,氯仿-d)δ 5.44-5.31(m,1H),5.20(d,J=4.5Hz,1H),4.83(s,1H),4.75-4.69(m,1H),4.67-4.56(m,1H),4.55-4.43(m,1H),4.37-4.29(m,2H),4.28-4.22(m,1H),3.67(br.s.,1H),3.51-3.42(m,2H),3.34-3.09(m,5H),3.05-2.86(m,3H),2.61(d,J=5.8Hz,1H),2.33-2.22(m,2H),2.19-2.15(m,2H),2.14-2.09(m,1H),2.05-1.76(m,14H),1.73(s,3H),1.64-1.01(m,12H),1.12(s,3H),1.06(s,3H),0.98(s,3H),0.93(s,3H),0.88(s,3H)。19F NMR(376MHz,氯仿-d)δ -224.87 - -225.57(m,1F)。
向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4,4-雙(乙氧羰基)哌啶-1-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(5mg,6.09μmol)於1,4-二噁烷(2mL)及MeOH(1mL)中之溶液中添加氫氧化鈉(1mL,1.000mmol)。混合物在66℃下攪拌2小時,接著冷卻至室溫。藉由製備型HPLC(方法9)純化反應混合物獲得呈膜狀之標題化合物(0.8mg,15.46%)。LCMS:m/e 765.60(M+H)+,2.928min(方法9)。
在純化1-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-羧基-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)哌啶-4,4-二甲酸期間分離出標題化合物。(白色固體,1.2mg,22.36%)。LCMS:m/e 793.60(M+H)+,2.992min(方法9)。1H NMR(400MHz,氯仿-d)δ 5.37(br.s.,1H),5.18(d,J=6.0Hz,1H),4.77(s,1H),4.69(s,1H),4.63-4.37(m,2H),4.31-4.18(m,2H),3.80-3.71(m,1H),3.69-3.61(m,1H),3.58-3.53(m,1H),3.52-3.47(m,2H),3.46-3.41(m,1H),3.24-3.09(m,2H),2.65-2.60(m,1H),2.56-1.17(m,40H),1.10(s,3H),1.02(s,3H),0.97(s,3H),0.9(s,3H),0.87(s,3H)。
向4-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((R)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙基)硫代嗎啉-3-甲酸乙酯(0.030g,0.035mmol)於1,4-二噁烷(2mL)及MeOH(1mL)中之溶液中添加氫氧化鈉(1mL,1.000mmol)。在66℃下攪拌混合物2小時,且形成澄清溶液。藉由製備型HPLC(方法10)純化粗反應混合物獲得呈白色固體狀之標題化合物(4.5mg,16.53%)。LCMS:m/e 739.55(M+H)+,2.838min(方法9)。1H NMR(400MHz,甲醇-d4)δ 5.35(br.s.,1H),5.21(d,J=5.8Hz,1H),4.85-4.80(m,1H),4.75-4.68(m,1H),4.63-4.51(m,1H),4.49-4.37(m,1H),3.44-3.36(m,1H),3.22-2.90(m,4H),2.89-2.68(m,4H),2.66-2.48(m,3H),2.44-2.23(m,2H),2.18-1.98(m,8H),1.85(d,J=12.5Hz,2H),1.77(d,J=4.0Hz,3H),1.74-1.28(m,14H),1.25-1.17(m,3H),1.14(d,J=11.3Hz,2H),1.11-1.08(m,3H),1.00(s,3H),0.96(s,3H),0.94-0.89(m,3H)。19F NMR(376MHz,甲醇-d4)δ -226.92(m,1F)。
步驟1. 製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羥基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向含(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(氮丙啶-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(230mg,0.337mmol)之CH3CN(6mL)中添加硫代嗎啉-3,5-二基二甲醇(77mg,0.472mmol)、碘化鈉(55.6mg,0.371mmol)及磷酸鉀(215mg,1.012mmol)。在125℃下加熱所得懸浮液15小時。反應混合物用乙酸乙酯稀釋,用碳酸氫鈉水溶液及鹽水洗滌。有機層經硫酸鈉乾燥且濃縮至乾燥。使用矽膠純化粗物質獲得灰白色固體(6mg,2.5%)。LCMS:m/e 700.55(M+H)+,2.925min(方法9)。
步驟2. 將(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羥基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(6mg,8.57μmol)溶解於MeOH(2mL)與二噁烷(2mL)之混合物中。添加氫氧化鈉(1mL,1.000mmol)。在25℃下攪拌所得混合物15小時且藉由製備型HPLC(方法9)純化獲得呈白色固體
狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羥基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(2.0mg,36.3%)。LCMS:m/e 610.55(M+H)+,2.928min(方法9)。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基吡咯啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向含有(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.1g,0.152mmol)及1-(2-氯乙基)吡咯啶-2-酮(0.056g,0.381mmol)之可密封燒瓶中添加磷酸,鉀鹽(0.129g,0.610mmol)及碘化鉀(0.038g,0.229mmol)。混合物用乙腈(2mL)稀釋,用氮氣吹洗,接著密封小瓶且加熱至100℃持續21小時。使混合物冷卻至室溫,用水(10mL)稀釋且用二氯甲烷(3×10mL)萃取。有機層經硫酸鈉乾燥,過濾且減壓濃縮。藉由急驟層析法使用含0至5%甲醇之二氯甲烷梯度及12g矽膠管柱純化殘餘物獲得呈透明膜狀之標題化合物(0.104g,0.136mmol,89%產率)。LCMS:m/e 767.6(M+H)+,2.20min(方法3)。
步驟2. 向(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基吡咯啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(0.104g,0.136mmol)於1,4-二噁烷(2mL)及MeOH(0.5mL)中之溶液中添加NaOH(1N)(0.542mL,0.542mmol)。將混合物加熱至60℃。加熱4.5小時後,混合物冷卻至室溫且藉由逆相層析法使用25-100% A至B梯度(A=添加有0.1% TFA的9:1水:乙腈,B=添加有0.1% TFA之1:9水:乙腈)及50g C18管柱純化。合併含有產物之溶離份且減壓濃縮獲得呈白色固體狀之標題化合物之TFA鹽(0.076g,0.096mmol,71%產率)。LCMS:m/e 677.4(M+H)+,1.73min(方法3)。1H NMR(500MHz,乙酸d4)δ 5.37(br.s.,1H),5.22(d,
J=4.4Hz,1H),4.87(s,1H),4.73(s,1H),4.63-4.45(m,2H),3.81-3.68(m,2H),3.66-3.54(m,3H),3.51-3.44(m,1H),2.83-2.74(m,1H),2.63-2.48(m,3H),1.74(s,3H),1.15(s,3H),1.07(s,3H),2.34-1.04(m,29H),0.98(s,3H),0.97(s,3H),0.93(s,3H)。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-側氧基吡咯啶-1-基)丙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向含有(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.1g,0.152mmol)及1-(3-氯丙基)吡咯啶-2-酮(0.074g,0.457mmol)的可密封燒瓶中添加磷酸,鉀鹽(0.129g,0.610mmol)及碘化鉀(0.038g,0.229mmol)。混合物用乙腈(2mL)稀釋,用氮氣吹洗,接著密封小瓶且加熱至100℃持續16小時。使混合物冷卻至室溫,用水(10mL)稀釋且用二氯甲烷
(3×10mL)萃取。有機層經硫酸鈉乾燥,過濾且減壓濃縮。藉由急驟層析法使用含0-5% MeOH之DCM梯度及12g矽膠管柱純化殘餘物。合併含有產物之溶離份且減壓濃縮獲得呈透明膜狀之標題化合物(0.074g,0.095mmol,62%產率)。LCMS:m/e 781(M+H)+,2.20min(方法3)。
步驟2. 向(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((3-(2-側氧基吡咯啶-1-基)丙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(0.074g,0.095mmol)於1,4-二噁烷(2mL)及甲醇(0.4mL)中之溶液中添加1N NaOH(0.379mL,0.379mmol)且將混合物升溫至60℃。加熱4小時後,混合物冷卻至室溫且藉由製備型HPLC(方法11)純化。合併含有產物之溶離份且減壓濃縮獲得呈白色固體狀之標題產物之TFA鹽(0.042g,0.052mmol,55%產率)。LCMS:m/e 691.5(M+H)+,1.73min(方法3)。1H NMR(500MHz,乙酸d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.85(s,1H),4.73(s,1H),4.65-4.47(m,2H),3.56-3.41(m,4H),3.28-3.16(m,2H),2.90-2.81(m,1H),2.65-2.58(m,1H),2.52(t,J=8.1Hz,2H),1.75(s,3H),1.18(s,3H),1.10(s,3H),2.36-1.06(m,31H),1.01(s,3H),0.99(s,3H),0.95(s,3H)。
步驟1. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸2-(三甲基矽烷基)乙酯
使(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(180mg,0.248mmol)及N,N'-二異丙基胺基亞胺酸2-(三甲基矽烷基)乙酯(91mg,0.371mmol)於四氫呋喃(10mL)中之混合物在80℃下回流4小時。減壓濃縮反應混合物且用甲醇(3mL)及四氫呋喃(4mL)稀釋殘餘物。所得混合物留在室溫下14小時。形成白色固體且藉由過濾移除。減壓濃縮濾液。此殘餘物用甲醇(2mL)及水(5mL)處理獲得白色沈澱物。固體藉由過濾收集且用乙醚(4mL)洗滌獲得呈白色固體狀之標題化合物(130mg,60%)。LCMS:m/e 827.8(M+H)+,2.39min(方法3)。
步驟2. 製備(R)-4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-1-異丙基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊
并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸2-(三甲基矽烷基)乙酯
在20℃下,在氫氣氛圍下,攪拌(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸2-(三甲基矽烷基)乙酯(50mg,0.060mmol)及Pd-C(6.43mg,6.04μmol)於四氫呋喃(2mL)及甲醇(1mL)中之混合物31小時。反應混合物經矽藻土墊過濾移除鈀催化劑且用四氫呋喃(10mL)洗滌。減壓濃縮濾液獲得呈白色固體狀之標題化合物(40mg,64%,80%純)。LCMS:m/e 829.8(M+H)+,2.43min(方法3)。
步驟3. 在20℃下攪拌(R)-4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-1-異丙基-5a,5b,8,8,11a-五甲基-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸2-(三甲基矽烷基)乙酯(15mg,0.014mmol)及氟化四-N-丁基銨(101mg,0.289mmol)於二噁烷(1mL)中之混合物5小時。過濾反應混合物且藉由製備型HPLC使用0-70乙腈/水/TFA純化獲得呈無色油狀之所要產物(6mg,54%)。LCMS:m/e 729.7(M+H)+,1.90min(方法3)。1H NMR(500MHz,乙酸)δ 5.40(br.s.,1H),5.31-5.17(m,1H),4.73-4.56(m,1H),4.55-4.40(m,1H),3.58-3.02(m,12H),2.62(d,J=16.9Hz,1H),2.35-2.30(m,1H),2.25-1.13(m,28H),1.26(s,3H),1.10(s,3H),1.03(s,3H),0.99(s,3H),0.99(s,3H),0.93(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H)。
在20℃下攪拌(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸2-(三甲基矽烷基)乙酯(18mg,0.022mmol)及Pd-C(4.63mg,4.35μmol)於四氫呋喃(2mL)及甲醇(2mL)中之混合物3天。反應混合物經矽藻土墊過濾,接著用四氫呋喃(2mL)洗滌,減壓濃縮濾液獲得固體。將固體溶解於四氫呋喃(2mL)中且添加氟化四-N-丁基銨(152mg,0.435mmol),且反應。在20℃下攪拌混合物2天。過濾反應混合物且藉由製備型HPLC使用0-70乙腈/水/TFA純化獲得呈白色固體裝之標題化合物(4mg,24%)。LCMS:m/e 731.8(M+H)+,1.87min(方法3)。1H NMR(500MHz,乙腈-d3)δ 5.28(dd,J=6.5,1.6Hz,1H),4.41(s,1H),4.31(s,1H),3.27-2.97(m,11H),2.94-2.83(m,1H),2.20-1.24(m,32H),1.16(s,3H),1.13-1.11(m,1H),1.05(s,3H),1.01(s,3H),0.94(s,3H),0.92(d,J=6.9Hz,3H),0.88(s,3H),0.84(d,J=6.6Hz,3H)。
步驟1. 製備4-(2-氯乙基)-2,6-二甲基硫代嗎啉1,1-二氧化物
在室溫下攪拌2,6-二甲基硫代嗎啉1,1-二氧化物(100mg,0.613mmol)、2-氯乙醛(135mg,0.858mmol)及硼烷-2-甲基吡啶複合物(72.1mg,0.674mmol)於甲醇(2mL)及乙酸(1mL)中之混合物17小時。反應混合物用飽和碳酸鈉(10mL)洗滌且用乙酸乙酯(3×10mL)萃取。經合併之有機相經硫酸鈉乾燥,過濾且減壓濃縮獲得呈無色油狀之標題化合物(90mg,65%)。LCMS:m/e 226.2(M+H)+,0.54min(方法3)。
步驟2. 在120℃下加熱4-(2-氯乙基)-2,6-二甲基硫代嗎啉1,1-二氧化物(20.65mg,0.091mmol)、(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(30mg,0.046mmol)、碘化鉀(8.35mg,0.050mmol)及磷酸鉀(48.5mg,0.229mmol)於乙腈(1mL)中之混合物16小時。反應混合物冷卻至室溫,用蒸餾水(3mL)淬滅且用二氯甲烷(3×3mL)萃取。經合併之有機相用鹽水(3mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮獲得白色固體。此固體溶解於乙腈(1mL)中且添加氫氧化鈉(0.457mL,0.457mmol)。在80℃下加熱混合物3小時,接著將其過濾且藉由製備型HPLC使用乙腈/水/TFA純化獲得呈白色固體狀之(1R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(2,6-二甲基-1,1-二
氧離子基N-硫代嗎啉基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(12mg,33%)。LCMS:m/e 755.8(M+H)+,1.96min(方法3)。1H NMR(500MHz,甲醇-d4)δ 5.36(br.s.,1H),5.22(dd,J=6.1,1.7Hz,1H),4.86(br.s.,1H),4.76(s,1H),4.62-4.51(m,1H),4.50-4.39(m,1H),3.39-3.11(m,7H),3.01-2.73(m,4H),2.57(d,J=17.7Hz,1H),2.38-1.15(m,27H),1.79(s,3H),1.30(dd,J=6.8,3.3Hz,6H),1.17(s,3H),1.13(s,3H),1.02(s,3H),0.98(s,3H),0.95(s,3H)。
在120℃下加熱(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(30mg,0.046mmol)、4-(2-氯乙基)-2,6-二甲基硫代嗎啉1,1-二氧化物(20.65mg,0.091mmol)、碘化鉀(8.35mg,0.050mmol)及磷酸鉀(48.5mg,0.229mmol)於乙腈(1mL)中之混合物16小時。反應混合物冷卻至室溫,用蒸餾水(3mL)淬
滅且用二氯甲烷(3×3mL)萃取。經合併之有機相用鹽水(3mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮獲得白色固體。此白色固體溶解於乙腈(1mL)中且添加氫氧化鈉(0.457mL,0.457mmol)。混合物在80℃下加熱3小時,過濾且藉由製備型HPLC使用乙腈/水/TFA純化獲得呈白色固體狀之標題化合物(12mg,33%)。LCMS:m/e 755.8(M+H)+,1.92min(方法3)。1H NMR(500MHz,甲醇-d4)δ 5.35(br.s.,1H),5.22(dd,J=6.1,1.6Hz,1H),4.86(s,1H),4.76(d,J=1.3Hz,1H),4.61-4.51(m,1H),4.50-4.38(m,1H),3.39-3.07(m,7H),3.01-2.73(m,4H),2.57(d,J=16.6Hz,1H),2.37-1.20(m,27H),1.78(s,3H),1.30(dd,J=6.7,3.1Hz,6H),1.17(s,3H),1.13(s,3H),1.00(s,3H),0.98(s,3H),0.95(s,3H)。
步驟1. 製備4-(2-氯乙基)-6-甲基-1,4-噻氮呯1,1-二氧化物
在室溫下攪拌6-甲基-1,4-噻氮呯1,1-二氧化物(100mg,0.613mmol)、2-氯乙醛(0.107mL,0.858mmol)及硼烷-2-甲基吡啶複合物(72.1mg,0.674mmol)於甲醇(1mL)及乙酸(0.5mL)中之混合物17小時。反應混合物用飽和碳酸鈉(3mL)洗滌且用乙酸乙酯(3×2mL)萃取。經合併之有機相經硫酸鈉乾燥,過濾且減壓濃縮獲得呈無色油狀
之標題化合物(105mg,76%)。LCMS:m/e 226.2(M+H)+,0.33min(方法3)。
步驟2. 在120℃下加熱(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(20mg,0.030mmol)、4-(2-氯乙基)-6-甲基-1,4-噻氮呯1,1-二氧化物(27.5mg,0.122mmol)、碘化鉀(5.57mg,0.034mmol)及磷酸鉀(32.4mg,0.152mmol)於乙腈(1mL)中之混合物16小時。反應混合物冷卻至室溫,用蒸餾水(3mL)淬滅且用二氯甲烷(3×2mL)萃取。經合併之有機相用鹽水(3mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮獲得呈白色固體狀之所要中間物。將此固體溶解於二噁烷(1mL)中且添加氫氧化鈉(0.305mL,0.305mmol)。在80℃下加熱混合物3小時。過濾反應混合物且藉由製備型HPLC使用0-70乙腈/水/TFA純化獲得呈無色油狀之(1R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(6-甲基-1,1-二氧離子基-1,4-噻氮呯-4-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(9.8mg,40%)。LCMS:m/e 755.9(M+H)+,1.93min(方法3)。1H NMR(500MHz,甲醇-d4)δ 5.36(br.s.,1H),5.22(dd,J=6.1,1.7Hz,1H),4.86(br.s.,1H),4.76(s,1H),4.61-4.51(m,1H),4.50-4.40(m,1H),3.69-3.14(m,9H),3.11-2.75(m,4H),2.57(d,J=17.2Hz,1H),2.49-2.24(m,2H),2.22-1.15(m,26H),1.78(s,3H),1.19(d,J=3.0Hz,3H),1.13(s,3H),1.09(dd,J=7.0,4.8Hz,3H),1.01(s,3H),0.97(s,3H),0.95(d,J=2.0Hz,3H)。
在120℃下加熱(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(20mg,0.030mmol)、4-(2-氯乙基)-6-甲基-1,4-噻氮呯1,1-二氧化物(34.4mg,0.152mmol)、碘化鉀(5.57mg,0.034mmol)及磷酸鉀(32.4mg,0.152mmol)於乙腈(1mL)中之混合物16小時。將反應混合物冷卻至室溫,用蒸餾水(3mL)淬滅且用二氯甲烷(3×2mL)萃取。經合併之有機相用鹽水(3mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮獲得白色固體。將此固體溶解於二噁烷(1mL)中且添加氫氧化鈉(0.305mL,0.305mmol)。在80℃下加熱混合物3小時。過濾反應混合物且藉由製備型HPLC使用0-70乙腈/水/TFA純化獲得呈無色油狀之標題化合物(6mg,25%)。LCMS:m/e 755.9(M+H)+,1.90min(方法3)。1H NMR(500MHz,甲醇-d4)δ 5.35(br.s.,1H),5.22(dd,J=6.1,1.7Hz,1H),4.86(br.s.,1H),4.76(s,1H),4.62-4.51(m,1H),4.51-4.40(m,1H),3.67-3.15(m,9H),3.10-2.75(m,4H),2.57(d,J=18.1Hz,1H),2.49-2.23(m,2H),2.21-1.14(m,26H),1.78(s,3H),1.22-1.17(m,3H),1.13(s,3H),1.10-1.06(m,3H),1.00(s,3H),0.98(s,3H),0.96(s,3H)。
步驟1. 製備2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((S)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙酸.
(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.250g,0.381mmol)及2-側氧基乙酸單水合物(0.053g,0.572mmol)於甲醇(1mL)、THF(1mL)及乙酸(0.5mL)中之混合物用硼烷2-甲基吡啶複合物(0.061g,0.572mmol)處理。混合物在添加時立即起泡且在室溫下攪拌。攪拌2.5小時後,用額外硼烷2-甲基吡啶複合物(0.061g,0.572mmol)及2-側氧基乙酸單水合物(0.053g,0.572mmol)處理混合物且在室溫下再攪拌所得溶液96小時。藉由逆相製備型HPLC(製備
型HPLC方法14)純化粗混合物獲得呈無色玻璃態固體TFA鹽形式之所要材料(0.213g,78%產率)。LCMS:m/z 714.4(M+H)+,2.63min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 7.59(s,2H),7.38-7.26(m,3H),5.31(br.s.,1H),5.21-5.12(m,2H),5.10(d,J=4.9Hz,1H),4.81(s,1H),4.73(s,1H),4.61-4.38(dm,J=47.2Hz,2H),3.50(s,2H),2.70-2.54(m,2H),2.12(d,J=7.8Hz,3H),2.08-1.87(m,6H),1.84-1.67(m,8H),1.67-1.57(m,3H),1.56-1.40(m,6H),1.40-1.28(m,3H),1.28-1.21(m,1H),1.17(s,3H),1.11-1.00(m,4H),0.93-0.82(m,9H)。
步驟2. 將2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((S)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙酸TFA鹽(0.050g,0.060mmol)與LiOH,1M水溶液(0.483mL,0.483mmol)及THF(0.5mL)與MeOH(0.5mL)之混合物組合。在80℃下攪拌所得混合物30分鐘。藉由逆相製備型HPLC(製備型HPLC方法15)純化粗混合物獲得呈白色固體狀TFA鹽形式之標題化合物(0.0318g,71%產率)。LCMS:m/z 624.4(M+H)+,2.43min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.18(d,J=4.4Hz,1H),4.81(s,1H),4.73(s,1H),4.60-4.39(dm,J=47.2Hz,2H),3.43(s,2H),2.65(td,J=11.0,5.1Hz,1H),2.55(d,J=17.9Hz,1H),2.29-2.11(m,2H),2.11-1.86(m,7H),1.85-1.66(m,8H),1.66-1.43(m,8H),1.43-1.24(m,4H),1.18(s,4H),1.14-1.01(m,4H),0.96(s,3H),0.93(s,3H),0.89(s,3H)。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
在具有PTFE襯裡之螺帽之1打蘭小瓶中,在THF(1mL)中,組合2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((S)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙酸,TFA(0.025g,0.030mmol)與硫代嗎啉1,1-二氧化物(10.20mg,0.075mmol)及HATU(0.029g,0.075mmol)。向混合物中添加DIPEA(0.026mL,0.151mmol),且在室溫下攪拌所得溶液隔夜。藉由逆相製備型HPLC(製備型HPLC方法16)純化粗混合物獲得呈白色粉末狀TFA鹽形式之產物(0.0269g,94%產率)。LCMS:m/z 831.5(M+H)+,2.50min(方法1)。
步驟2. 在具有PTFE襯裡之螺帽之1打蘭小瓶中,組合(S)-4-
((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,TFA(0.0269g,0.028mmol)與LiOH,1M水溶液(0.063mL,0.063mmol)及THF(0.5mL)與MeOH(0.5mL)之混合物。在70℃下攪拌所得混合物30分鐘,接著至80℃持續1小時。添加額外LiOH,1M水溶液(0.080mL,0.080mmol)且將混合物加熱至70℃持續20分鐘,接著至80℃持續30分鐘。藉由逆相製備型HPLC(製備型HPLC方法4)純化粗混合物獲得呈白色玻璃態固體TFA鹽形式之標題化合物(0.0178g,66%產率)。LCMS:m/z 741.5(M+H)+,2.34min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.4Hz,1H),4.82(s,1H),4.74(s,1H),4.59-4.40(dm,J=47.2Hz,2H),4.33-4.21(m,2H),4.13-3.86(m,4H),3.25(t,J=4.9Hz,2H),3.18(t,J=4.9Hz,2H),2.76-2.65(m,1H),2.55(d,J=16.4Hz,1H),2.29-2.13(m,2H),2.13-2.07(m,2H),2.07-1.91(m,5H),1.91-1.71(m,7H),1.71-1.20(m,14H),1.18(s,3H),1.15-1.02(m,4H),0.96(s,3H),0.93(s,3H),0.90(s,3H)。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯.
在具有PTFE襯裡之螺帽之1打蘭小瓶中,在THF(1mL)中,組合2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((S)-4-((苯甲氧基)羰基)-4-(氟甲基)環己-1-烯-1-基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-3a-基)胺基)乙酸,TFA(0.025g,0.030mmol)與4-甲基哌啶-4-醇(8.69mg,0.075mmol)及HATU(0.029g,0.075mmol)。向混合物中添加DIPEA(0.026mL,0.151mmol),且在室溫下攪拌所得溶液隔夜。藉由逆相製備型HPLC(製備型HPLC方法16)純化粗混合物獲得呈玻璃態固體狀TFA鹽形式之產物(0.0280g,100%產率)。LCMS:m/z 811.6(M+H)+,2.54min(方法1)。
步驟2. 將(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯,TFA(0.028g,
0.030mmol)溶解於1,2-二氯乙烷(1mL)中且向所得溶液中添加三乙胺(10.97μl,0.079mmol)、第三丁基二甲基矽烷(0.015mL,0.091mmol)及乙酸鈀(II)(1.699mg,7.57μmol)。混合物用氮氣吹洗且加熱至60℃持續1小時。混合物接著經氮氣流濃縮成殘餘物,接著再溶解於THF(0.8mL)中。向混合物中添加TBAF,THF中1.0M(0.106mL,0.106mmol),且在室溫下攪拌所得混合物30分鐘。藉由逆相製備型HPLC(製備型HPLC方法16)純化粗混合物獲得呈白色固體狀TFA鹽形式之標題化合物(0.0204g,79%產率)。LCMS:m/z 721.5(M+H)+,2.16min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.9Hz,1H),4.82(s,1H),4.74(s,1H),4.44(d,J=4.4Hz,1H),4.25-4.13(m,1H),4.13-3.96(m,1H),3.96-3.80(m,1H),3.53-3.45(m,2H),2.73-2.60(m,1H),2.60-2.49(m,1H),2.28-2.13(m,2H),2.13-1.92(m,7H),1.90-1.71(m,7H),1.71-1.45(m,13H),1.45-1.30(m,4H),1.28(d,J=4.2Hz,3H),1.20(s,3H),1.10(d,J=6.8Hz,1H),1.07(s,3H),0.96(s,3H),0.94(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用4-(甲基磺醯基)哌啶(0.012g,0.075mmol)代替4-甲基哌啶-4-醇製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0205g,2步驟70%產率)。LCMS:m/z 769.4(M+H)+,2.33min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.22-5.16(m,1H),4.82(s,1H),4.74(s,1H),4.72-4.61(m,2H),4.48-4.40(m,1H),4.22-4.06(m,1H),4.02-3.87(m,2H),3.29-3.13(m,1H),3.00-2.87(m,4H),2.73-2.62(m,1H),2.55(d,J=17.4Hz,1H),2.28-2.19(m,3H),2.19-2.11(m,1H),2.11-1.92(m,7H),1.89-1.75(m,5H),1.74(s,3H),1.71-1.60(m,4H),1.58(br.s.,1H),1.55-1.41(m,5H),1.40-1.25(m,3H),1.19(s,3H),1.13-1.08(m,1H),1.07(s,3H),0.96(s,3H),0.94(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用嗎啉(6.58μl,0.075mmol)代替4-甲基哌啶-4-醇製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0185g,經2步驟74%產率)。LCMS:m/z 693.4(M+H)+,2.35min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)d 5.33(br.s.,1H),5.22-5.16(m,1H),4.81(s,1H),4.73(s,1H),4.48-4.39(m,1H),4.05(d,J=15.2Hz,1H),3.88(d,J=15.9Hz,1H),3.78-3.71(m,4H),3.71-3.64(m,2H),3.53-3.45(m,2H),2.72-2.61(m,1H),2.55(d,J=16.4Hz,1H),2.19(d,J=19.3Hz,2H),2.13-2.07(m,1H),2.07-1.90(m,6H),1.88-1.75(m,3H),1.74(s,3H),1.72-1.56(m,5H),1.56-1.42(m,5H),1.42-1.25(m,4H),1.19(s,4H),1.15-1.08(m,1H),1.07(s,3H),0.96(s,3H),0.93(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用1-(甲基磺醯基)哌嗪(0.012g,0.075mmol)代替4-甲基哌啶-4-醇,製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0210g,經2步驟77%產率)。LCMS:m/z 770.5(M+H)+,2.33min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.22-5.16(m,1H),4.82(s,1H),4.74(s,1H),4.48-4.40(m,1H),4.21(d,J=16.1Hz,1H),3.96(d,J=15.9Hz,1H),3.92-3.83(m,1H),3.73(ddd,J=13.6,7.3,3.3Hz,1H),3.67-3.52(m,2H),3.31-3.20(m,2H),2.88(s,3H),2.71(td,J=11.1,4.9Hz,1H),2.55(d,J=15.9Hz,1H),2.29-2.13(m,2H),2.13-1.91(m,7H),1.89-1.71(m,7H),1.71-1.60(m,4H),1.60-1.41(1,6H),1.41-1.21(m,4H),1.19(s,4H),1.13-1.08(m,1H),1.07(s,3H),0.96(s,3H),0.94(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用1,4-噻氮呯1,1-二氧化物(0.011g,0.075mmol)代替4-甲基哌啶-4-醇來製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0188g,經2步驟70%產率)。LCMS:m/z 755.4(M+H)+,2.32min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=4.9Hz,1H),4.82(s,1H),4.74(s,1H),4.49-4.39(m,1H),4.25-4.10(m,1H),4.04-3.91(m,2H),3.91-3.81(m,1H),3.81-3.66(m,3H),3.66-3.48(m,1H),3.41(t,J=5.9Hz,1H),3.30-3.23(m,1H),2.77-2.64(m,1H),2.55(d,J=17.9Hz,1H),2.32-2.13(m,3H),2.13-1.91(m,8H),1.90-1.75(m,3H),1.74(s,3H),1.71-1.60(m,4H),1.59-1.44(m,5H),1.44-1.29(m,4H),1.19(d,J=2.2Hz,4H),1.10(d,J=7.1Hz,1H),1.07(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用噻唑啶1,1-二氧化物(9.15mg,0.075mmol)代替4-甲基哌啶-4-醇來製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式之標題化合物(0.0117g,經2步驟45%產率)。LCMS:m/z 727.4(M+H)+,2.31min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=6.1Hz,1H),4.81(s,1H),4.72(br.s.,1H),4.64(br.s.,1H),4.47-4.40(m,1H),4.19-4.08(m,2H),4.01-3.84(m,1H),3.49(t,J=6.1Hz,1H),3.41(t,J=7.2Hz,1H),2.74-2.63(m,1H),2.55(d,J=17.1Hz,1H),2.30-2.12(m,2H),2.09(br.s.,1H),2.07-1.92(m,5H),1.92-1.75(m,4H),1.73(s,3H),1.69-1.44(m,9H),1.44-1.36(m,2H),1.36-1.24(m,2H),1.17(d,J=4.6Hz,3H),1.14-1.01(m,
4H),0.96(s,3H),0.93(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用3-(甲基磺醯基)吡咯啶(0.011g,0.075mmol)代替4-甲基哌啶-4-醇來製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0117g,經2步驟57%產率)。LCMS:m/z 755.4(M+H)+,2.31min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.19(d,J=5.4Hz,1H),4.82(s,1H),4.74(br.s.,1H),4.47-4.39(m,1H),4.19-3.97(m,2H),3.97-3.81(m,3H),3.81-3.61(m,2H),3.09-3.01(m,3H),2.75-2.46(m,4H),2.30-2.12(m,2H),2.12-1.91(m,7H),1.88-1.75(m,3H),1.74(s,3H),1.71-1.61(m,4H),1.59-1.42(m,6H),1.41-1.29(m,3H),1.26(br.s.,1H),1.19(s,4H),1.10
(d,J=8.6Hz,1H),1.07(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H)。
藉由與用於製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)-2-側氧基乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸相同之程序,但在步驟1中使用(1S,4S)-2-硫雜-5-氮雜雙環[2.2.1]庚烷2,2-二氧化物,氫溴酸鹽(0.017g,0.075mmol)代替4-甲基哌啶-4-醇來製備標題化合物。藉由逆相製備型HPLC(製備型HPLC方法12)純化步驟2之粗混合物獲得呈白色固體狀之TFA鹽形式的標題化合物(0.0154g,經2步驟57%產率)。LCMS:m/z 753.4(M+H)+,2.31min(方法1)。1H NMR(400MHz,CDCl3與CD3OD之1:1混合物,CD3OD鎖定)δ 5.33(br.s.,1H),5.22-5.16(m,1H),5.11(d,J=3.4Hz,1H),4.82(s,1H),4.76-4.70(m,1H),4.48-4.39(m,1H),4.17-4.07(m,1H),3.99-3.84(m,2H),3.84-3.69(m,1H),3.30-3.13
(m,2H),2.75-2.60(m,2H),2.60-2.42(m,2H),2.29-2.12(m,2H),2.12-1.90(m,7H),1.87-1.75(m,3H),1.74(s,3H),1.72-1.59(m,4H),1.59-1.41(m,6H),1.41-1.21(m,4H),1.21-1.15(m,4H),1.10(d,J=7.6Hz,1H),1.07(s,3H),0.96(s,3H),0.93(s,3H),0.89(s,3H)。
步驟1. 製備(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(((三氟甲基)磺醯基)氧基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]e-3a-甲酸.
在N2(g)氛圍下,向(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(((三氟甲基)磺醯基)氧基)-
2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]e-3a-甲酸苯甲酯(1.500g,2.216mmol)於DCE(20mL)及乙酸(5mL)中之溶液中添加鈀黑(0.047g,0.443mmol)。反應容器用H2(g)吹掃且在H2(g)氛圍下攪拌5小時,過濾,用DCM(50mL)洗滌且濃縮成白色固體。用最少DCM及己烷濕磨粗物質,濃縮成白色漿液,過濾且用己烷洗滌獲得第1批所要產物。液體濾液另外濃縮成白色漿液,過濾且用己烷洗滌獲得第二批。在真空下組合及乾燥兩批獲得呈白色固體狀之(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(((三氟甲基)磺醯基)氧基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]e-3a-甲酸(1.1g,1.875mmol,85%產率)。LCMS:m/e 587.2(M+H)+,3.23min(方法1)。1H NMR(400MHz,氯仿-d)δ 5.57(d,J=3.9Hz,1H),4.76(br.s.,1H),4.63(br.s.,1H),3.03(br.s.,1H),2.46-2.10(m,3H),2.00(d,J=6.8Hz,2H),1.81-1.63(m,6H),1.59-1.32(m,12H),1.25(br.s.,3H),1.13(br.s.,3H),1.02(br.s.,3H),1.00(br.s.,6H),0.93(br.s.,3H)。13C NMR(101MHz,氯仿-d)δ 182.0,155.4,150.3,113.7,109.8,56.4,53.3,49.2,48.9,46.9,42.5,40.6,40.3,38.5,37.9,37.1,36.4,33.3,32.1,30.6,29.7,27.5,25.5,21.4,19.4,19.39-19.33,18.9,16.2,15.7,14.6。19F NMR(376MHz,氯仿-d)δ -74.82(br.s.,3F)。
步驟2. 製備(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯.
向(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-9-(((三氟甲基)磺醯基)氧基)-
2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]e-3a-甲酸(0.500g,0.852mmol)及N,N-二異丙基乙胺(0.520mL,2.98mmol)於DCM(10mL)中之溶液中添加HATU(0.389g,1.023mmol)及4-(2-胺基乙基)硫代嗎啉1,1-二氧化物(0.182g,1.023mmol)。在室溫下攪拌反應物(10:25am)。2小時後,反應物用DCM稀釋且用20mL 5%檸檬酸水溶液洗滌。用DCM(25mL)萃取水層。經合併之有機物用10% Na2CO3、鹽水洗滌,經MgSO4乾燥,過濾且濃縮成澄清黏稠油狀物。粗物質藉由管柱層析法(SiO2,24g Isco濾芯,用97:3 DCM:MeOH溶離)純化且真空乾燥獲得呈白色固體狀之(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(394mg,0.527mmol,61.9%產率)。LCMS:m/e 747.5(M+H)+,2.75min(方法1)。1H NMR(400MHz,氯仿-d)δ 5.87(t,J=5.4Hz,1H),5.56(dd,J=6.6,1.7Hz,1H),4.74(d,J=1.5Hz,1H),4.61(s,1H),3.37(q,J=6.0Hz,2H),3.15-3.07(m,1H),3.05(s,7H),2.66(t,J=6.2Hz,2H),2.56-2.46(m,1H),2.16(dd,J=17.1,6.8Hz,1H),1.97-1.88(m,2H),1.79-1.71(m,3H),1.69(s,3H),1.66-1.54(m,3H),1.52-1.30(m,10H),1.25-1.16(m,2H),1.12(s,3H),1.10-1.06(m,1H),1.01(s,3H),0.98(s,3H),0.97(s,3H),0.91(s,3H)。13C NMR(101MHz,氯仿-d)δ 176.3,155.3,150.6,113.7,109.6,55.7,55.6,53.3,51.3,50.7,50.0,49.0,46.8,42.5,40.6,40.2,38.6,38.4,37.9,37.8,36.3,36.3,33.8,33.5,30.8,29.4,27.4,25.5,21.5,19.5,19.4,19.0,16.2,15.9,14.6。19F NMR(376MHz,氯仿-d)δ -74.83(s,3F)。
步驟3. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基
-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,TFA.
組合(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-三氟甲磺酸3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基酯(250mg,0.335mmol)、(R)-1-(氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)環己-3-烯甲酸苯甲酯(150mg,0.402mmol)與布赫瓦爾德預催化劑(Buchwald precatalyst)13(92371-003-01)(10.53mg,0.013mmol)。將反應容器在真空烘箱中抽真空15分鐘,接著用N2(g)再填充回來。向反應燒瓶中裝入預噴射N2(g)之THF(4mL)及0.5M K3PO4水溶液(1.673mL,0.837mmol)。反應混合物用N2(g)噴射且在72℃下攪拌15小時,且冷卻至室溫隔夜。反應物用EtOAc(50mL)稀釋且用1.5N K3PO4洗滌。用EtOAc(50mL)萃取水層。經合併之有機層用鹽水洗滌,經MgSO4乾燥,過濾且濃縮成褐色黏稠油狀物。粗物質藉由急驟管柱層析法(矽膠,12g,用97:3 DCM:MeOH溶離)純化且乾燥獲得產物,但仍被偶合雜質污染。此材料藉由逆相製備型HPLC(製備型HPLC方法8)進一步純化且真空乾燥獲得呈白色固體狀之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,TFA(161mg,0.166mmol,49.6%產率)。LCMS:m/e 845.7(M+H)+,3.25min(方法1)。1H NMR(400MHz,氯仿-d)δ 7.39-7.30(m,5H),6.78(br.s.,1H),5.32(br.s.,1H),5.24-5.14(m,2H),5.11(d,J=4.6Hz,1H),4.74(s,1H),4.62(s,1H),4.60-4.54(m,1H),4.50-4.40(m,1H),3.82-3.57(m,6H),3.46(br.s.,4H),3.25(t,J=5.6Hz,2H),3.05(td,J=11.0,
3.9Hz,1H),2.60(d,J=17.1Hz,1H),2.41-2.31(m,1H),2.24-2.03(m,4H),2.02-1.90(m,3H),1.88-1.72(m,3H),1.69(s,3H),1.66-1.61(m,1H),1.60-1.46(m,4H),1.46-1.18(m,10H),1.05(d,J=8.8Hz,2H),0.97(s,3H),0.92(s,6H),0.87(s,3H),0.84(s,3H)。
步驟4. 向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,TFA(96mg,0.100mmol)於THF(1.0mL)及MeOH(0.5mL)中之溶液中添加1N氫氧化鋰溶液(0.500mL,0.500mmol)且在60℃下攪拌(11:25AM)。2小時後,LC/MS顯示反應完成且將其冷卻至室溫。反應混合物藉由逆相製備型HPLC(製備型HPLC方法12)純化且真空乾燥獲得呈白色固體狀之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)胺甲醯基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(66.1mg,0.075mmol,75%產率)。LCMS:m/e 755.5(M+H)+,2.69min(方法1)。1H NMR(400MHz,1:1 CDCl 3 :甲醇-d 4 )δ 5.30(br.s.,1H),5.16(d,J=4.6Hz,1H),4.69(d,J=1.7Hz,1H),4.45-4.36(m,1H),3.09(s,6H),3.06-3.01(m,1H),2.67(t,J=6.4Hz,2H),2.57-2.45(m,2H),2.30-2.19(m,1H),2.12(br.s.,1H),2.08-2.04(m,1H),2.02(br.s.,1H),2.00-1.92(m,2H),1.91-1.81(m,1H),1.80-1.69(m,3H),1.67(s,3H),1.63-1.52(m,3H),1.50-1.30(m,10H),1.29-1.14(m,5H),1.09-0.99(m,2H),0.97(s,3H),0.95(s,3H),0.94(br.s.,3H),0.89(s,3H),0.84(s,3H).)。13C NMR(101MHz,1:1 CD3Cl 3 :甲醇-d 4 )δ 178.7,178.0,151.6,148.9,140.0,122.3,122.2,110.0,78.6,56.6,56.2,53.9,
51.7,51.5,50.9,50.4,47.6,46.2,46.1,43.2,42.6,41.4,39.0,38.7,38.3,37.1,36.9,34.57-34.44,33.9,31.6,30.3,30.2,29.9,29.8,27.1,26.6,22.2,22.1,20.45-20.36(m,1C),19.8,16.9,16.5,15.1。19F NMR(376MHz,1:1 CDCl 3 :甲醇-d 4 )δ -76.79(s,3F),-226.23(t,J=47.7Hz,1F)。
步驟1. (1S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((1,1,1-三氟-3-硝基丙-2-基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯.
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-
5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(190mg,0.290mmol)於DCM(2mL)中之溶液中添加(1E)-3,3,3-三氟-1-硝基丙-1-烯(64.5mg,0.434mmol)且在室溫下攪拌。16小時後,將反應物濃縮成褐色黏稠油狀物,且藉由急驟管柱層析法(SiO2,24g Isco濾芯,用9:1 Hex:EtOAc溶離)純化且真空乾燥獲得呈白色固體狀之(1S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((1,1,1-三氟-3-硝基丙-2-基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(171.2mg,0.215mmol,74.2%產率)。LCMS:m/e 797.5(M+H)+,4.55min(方法10)。
步驟2.(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
向(1S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-3a-((1,1,1-三氟-3-硝基丙-2-基)胺基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(26mg,0.033mmol)於THF(1mL)中之溶液中添加1N HCl(0.489mL,0.489mmol)。向所得漿液中添加THF中之1.5N里克鋅溶液(Rieke zinc solution)(0.217mL,0.326mmol)。向所得灰色漿液中添加MeOH(1mL)。反應物變成均質溶液且在室溫下攪拌隔夜。15小時之後,濃縮反應物。所得殘餘物用THF(5mL)溶解,用1.5 K3PO4(5mL)中和且用2×25mL EtOAc萃取混合物。經合併之有機層用鹽水洗滌,經MgSO4乾燥,過濾且濃縮成白色
泡沫體。材料以粗物質形式用於下一步驟中。LCMS:m/e 767.6(M+H)+,4.96min(方法10)。
步驟3. (1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(異構體A)及(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA異構體B).
向來自實驗99699-178之粗物質(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(25mg,0.033mmol)於THF(1mL)及MeOH(0.5mL)中之溶液中添加1N氫氧化鋰溶液(0.114mL,0.114mmol)。在65℃下攪拌反應物。4小時後,使反應物冷卻至室溫且藉由逆相製備型HPLC(製備型方法13)純化且真空乾燥獲得異構體A,(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA及異構體B,(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA;皆呈白色固體。
實例39:異構體A:LCMS:m/e 675.8(M+H)+,4.29min(方法11)。1H NMR(400MHz,1:1氯仿-d:甲醇-d 4 )δ 5.31(br.s.,1H),5.16(d,J=4.9Hz,1H),4.72(br.s.,1H),4.67(br.s.,1H),4.54-4.49(m,2H),4.45-4.38(m,2H),4.25(br.s.,2H),3.73(t,J=6.5Hz,2H),3.59(br.s.,1H),3.15-3.05(m,1H),3.03-2.96(m,1H),2.69(td,J=11.0,5.6Hz,1H),2.53(d,J=18.3Hz,1H),2.17(d,J=18.6Hz,2H),2.05(d,J=18.1Hz,1H),2.01-1.90(m,2H),1.89-1.84(m,2H),1.82-1.71(m,4H),1.68(s,3H),1.66-1.61(m,1H),1.56(d,J=16.4Hz,1H),1.44(d,J=6.4Hz,6H),1.38-1.22(m,5H),1.20(s,1H),1.07(br.s.,2H),1.04(s,3H),0.97(s,3H),0.94(s,3H),0.91(s,2H),0.85(s,3H)。19F NMR-1H去偶376MHz,1:1氯仿-d:甲醇-d 4 )δ -73.36(s,3F),-76.38(s,3F),-226.33(s,1F)。19F NMR(376MHz,1:1氯仿-d:甲醇-d 4 )δ -73.37(d,J=6.9Hz,3F),-76.39(s,3F),-226.14- -226.54(m,1F)。
實例40:異構體B:LCMS:m/e 675.7(M+H)+,4.63min(方法11)。1H NMR(400MHz,1:1氯仿-d:甲醇-d 4 )δ 5.30(br.s.,1H),5.16(d,J=4.6Hz,1H),4.70(s,1H),4.46-4.36(m,2H),3.72(t,J=6.6Hz,1H),3.64(dd,J=7.2,3.5Hz,1H),3.24-3.15(m,1H),3.14-3.04(m,1H),2.62-2.46(m,2H),2.30-2.11(m,2H),2.10-2.00(m,2H),1.99-1.89(m,4H),1.86(dt,J=6.7,3.2Hz,1H),1.80-1.70(m,3H),1.68(s,3H),1.66(br.s.,1H),1.64-1.57(m,1H),1.55-1.48(m,3H),1.47-1.38(m,5H),1.38-1.29(m,2H),1.28-1.18(m,2H),1.12(br.s.,2H),1.07(s,3H),1.04(br.s.,1H),0.97(s,3H),0.94(s,3H),0.91(s,3H),0.86(s,3H)。19F NMR(376MHz,1:1氯仿-d:甲醇-d 4 )δ -73.84(s,3F),-76.35(s,5F),-226.26(s,1F)。
步驟1. 製備(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
向(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-胺基-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(107mg,0.139mmol)於2-丙醇(3mL)中之溶液中添加二乙烯基碸(0.020mL,0.167mmol)且在85℃下攪拌。22小時後,使反應物冷卻至室溫且濃縮獲得呈黏稠褐色油狀之(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五
甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,且其直接用於下一步驟中。
步驟2. 製備(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(異構體A)及(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(異構體B).
將(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯溶解於THF(1mL)及MeOH(1mL)中且用1N氫氧化鋰溶液(0.697mL,0.697mmol)處理,加熱至65℃持續4小時且冷卻至室溫。使用下文之製備型方法對反應內容物進行逆相HPLC純化且真空乾燥獲得異構體A(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(32mg,0.035mmol,24.98%產率)及異構體B(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-1,1,1-三氟丙-2-基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-
烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,TFA(24.3mg,0.026mmol,18.97%產率),皆呈白色固體。
實例41:異構體A:LCMS:m/e 795.6(M+H)+,4.11min(方法11)。1H NMR(400MHz,1:1 CDCl3:甲醇-d 4 )δ 5.30(br.s.,1H),5.16(t,J=4.0Hz,1H),5.12(s,1H),4.70(d,J=9.5Hz,1H),4.46-4.36(m,2H),4.21-4.06(m,1H),3.23-2.94(m,10H),2.88-2.76(m,1H),2.70-2.46(m,3H),2.44-2.27(m,1H),2.26-2.12(m,3H),2.11-2.01(m,2H),2.00-1.85(m,4H),1.81-1.69(m,3H),1.68(s,1H),1.66(s,2H),1.61(d,J=11.7Hz,1H),1.58-1.51(m,1H),1.51-1.34(m,7H),1.34-1.18(m,4H),1.11-1.05(m,1H),1.04(s,2H),0.98(s,1.5H),0.96(s,1.5H),0.94(s,6H),0.91(s,3H),0.86(s,1.5H),0.85(br.s.,1.5H)。
實例42:異構體B:LCMS:m/e 795.6(M+H)+,4.19min(方法11)。1H NMR(400MHz,1:1 CDCl3:甲醇-d 4 )δ 5.30(br.s.,1H),5.20-5.14(m,1H),5.12(s,1H),4.77-4.67(m,1H),4.60-4.48(m,3H),3.86(d,J=3.4Hz,1H),3.21-2.99(m,9H),2.96-2.71(m,2H),2.70-2.57(m,2H),2.52(d,J=17.4Hz,1H),2.34-2.12(m,3H),2.05(d,J=19.1Hz,2H),2.01-1.89(m,3H),1.81-1.67(m,4H),1.66(s,3H),1.62-1.54(m,2H),1.54-1.36(m,7H),1.35-1.12(m,5H),1.07(br.s.,1H),1.05(s,3H),0.97(s,3H),0.95(s,1H),0.93(s,3H),0.90(s,3H),0.84(s,3H)。
步驟1. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)磺醯基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯.
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(0.100g,0.152mmol)於DCE(1mL)中之溶液中添加二乙烯基碸(0.037mL,0.305mmol)且在65℃下攪拌15小時且冷卻至室溫。LCMS:m/e 774.5(M+H)+,4.53min(方法10)。
向上述反應混合物中添加硫代嗎啉1,1-二氧化物(0.041g,0.305mmol),在85℃下攪拌8小時且冷卻回到室溫。濃縮反應物且真空乾燥獲得呈黏稠深褐色油狀之粗(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)磺醯基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯,且以粗物質形式用
於下一步驟中。LCMS:m/e 909.8(M+H)+,4.79min(方法10)。
步驟2. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)磺醯基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,2 TFA.
向粗(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)磺醯基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(139mg,0.153mmol)於THF(1mL)及MeOH(0.5mL)中之溶液中添加1N氫氧化鋰溶液(0.535mL,0.535mmol)。在65℃下攪拌反應物3小時且冷卻至室溫。藉由逆相製備型HPLC(製備型方法12)純化反應內容物且真空乾燥獲得呈白色固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((2-(1,1-二氧離子基N-硫代嗎啉基)乙基)磺醯基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸,2 TFA(66.7mg,0.061mmol,三個反應步驟39.6%產率)。LCMS:m/e 819.7(M+H)+,3.90min(方法12)。1H NMR(400MHz,氯仿-d)δ 5.34(br.s.,1H),5.19(d,J=4.6Hz,1H),4.80(s,1H),4.71(s,1H),4.60(s,1H),4.48(s,1H),4.35-4.24(m,1H),4.07(br.s.,3H),3.78(t,J=6.6Hz,1H),3.67-3.47(m,4H),3.32(dt,J=14.7,5.6Hz,1H),3.20-3.00(m,10H),2.86-2.76(m,1H),2.56(d,J=17.4Hz,1H),2.26-2.16(m,3H),2.15-2.05(m,3H),2.03-1.92(m,3H),1.70(s,3H),1.69(br.s.,1H),1.63-1.49(m,4H),1.44(br.s.,4H),1.37(d,J=11.0Hz,1H),1.30(br.s.,2H),1.10(s,3H),1.06(d,J=7.6Hz,2H),1.03(s,3H),0.95(s,3H),0.92(s,3H),0.88(s,
3H)。19F NMR(376MHz,氯仿-d)δ -75.76(s,6F),-224.87(s,1F)。
部分2
LC/MS方法
LC/MS方法2-1
條件:經2分鐘梯度0% B→100% B;在100% B下保持1分鐘
溶劑A:90%水,10%甲醇,0.1% TFA
溶劑B:10%水,90%甲醇,0.1% TFA
管柱:Phenomenex Luna C18,2.0×50mm,3μm
流動速率:1mL/min
偵測器波長:220nm
LC/MS方法2-2
條件:經4分鐘梯度0% B→100% B;在100% B下保持1分鐘
溶劑A:90%水,10%甲醇,0.1% TFA
溶劑B:10%水,90%甲醇,0.1% TFA
管柱:Phenomenex Luna C18,3mm,2.0×50mm
流動速率:1mL/min
偵測器波長:220nm
LC/MS方法2-3
條件:經4分鐘梯度0% B→100% B;在100% B下保持2分鐘
溶劑A:90%水,10%甲醇,0.1% TFA
溶劑B:10%水,90%甲醇,0.1% TFA
管柱:Phenomenex Luna C18,3mm,2.0×50mm
流動速率:0.8mL/min
偵測器波長:220nm
製備型HPLC方法
製備型HPLC方法2-1
條件:經20分鐘梯度30% B→100% B;在100% B下保持4分鐘
溶劑A:5%乙腈,95%水,0.1% TFA
溶劑B:95%乙腈,5%水0.1% TFA
管柱:Waters Xbridge 30×100mm,5μm
流動速率:40mL/min
偵測器波長:220nm
製備型HPLC方法2-2
條件:參看實驗部分
溶劑A:5:95乙腈:水,具有10-mM乙酸銨
溶劑B:95:5乙腈:水,具有10-mM乙酸銨
管柱:Waters Xbridge C18,19×200mm,5-μm
流動速率:20mL/min
偵測器波長:220nm
製備型HPLC方法2-3
條件:經20分鐘梯度50 B→100% B;在100% B下保持5分鐘
溶劑A:5:95乙腈:水,具有0.1%三氟乙酸
溶劑B:95:5乙腈:水,具有0.1%三氟乙酸
管柱:Xbridge C18,19×200mm,5-μm粒子
流動速率:20mL/min
偵測器波長:220nm
製備型HPLC方法2-4
條件:經20分鐘梯度10% B→100% B;在100% B下保持5分鐘
溶劑A:5%乙腈,95%水,0.1% TFA
溶劑B:95%乙腈,5%水0.1% TFA
管柱:Waters Sunfire 30×150mm,5um
流動速率:40mL/min
偵測器波長:220nm
製備型HPLC方法2-5
條件:經20分鐘梯度30% B→100% B;在100% B下保持5分鐘
溶劑A:5%乙腈,95%水,0.1% TFA
溶劑B:95%乙腈,5%0.1% TFA
管柱:Waters Sunfire 30×150mm,5um
流動速率:40mL/min
偵測器波長:220nm
製備型HPLC方法2-6
條件:經20分鐘梯度10% B→100% B;在100% B下保持2分鐘
溶劑A:10%甲醇,90%水,0.1% TFA
溶劑B:90%甲醇,10%水0.1% TFA
管柱:Waters Sunfire 30×100mm,5μm
流動速率:40mL/min
偵測器波長:220nm
分析型HPLC方法
分析型HPLC方法2-1
條件:經15分鐘梯度10% B→100% B;在100% B下保持10分鐘
溶劑A:10%甲醇,90%水,0.1% TFA
溶劑B:90%甲醇,10%水,0.1% TFA
管柱:Waters Sunfire C18,4.6×150mm,3.5mm
流動速率:1mL/min
偵測器波長:220nm
分析型HPLC方法2-2
條件:經15分鐘梯度10% B→100% B;在100% B下保持10分鐘
溶劑A:10%甲醇,90%水,0.1% TFA
溶劑B:90%甲醇,10%水,0.1% TFA
管柱:Waters Xbridge苯基,4.6×150mm,3.5mm
流動速率:1mL/min
偵測器波長:220nm
分析型HPLC方法2-3
梯度:經3分鐘0→100% B,接著在100% B下保持0.5分鐘
溶劑A:5:95乙腈:水,具有10mM乙酸銨
溶劑B:95:5乙腈:水,具有10mM乙酸銨
管柱:Waters BEH C18,2.0×50mm,1.7-μm粒子
流動速率:1mL/min
偵測器波長:220nm
溫度:50℃
分析型HPLC方法2-4
梯度:經3分鐘0→100% B,接著在100% B下保持0.5分鐘
溶劑A:5:95乙腈:水,具有10mM乙酸銨
溶劑B:95:5乙腈:水,具有10mM乙酸銨
管柱:Waters BEH C18,2.0×50mm,1.7-μm粒子
流動速率:1mL/min
偵測器波長:220nm
溫度:50℃
分析型HPLC方法2-5
條件:經15分鐘梯度10% B→100% B;在100% B下保持10分鐘
溶劑A:5%乙腈,95%水,0.1% TFA
溶劑B:95%乙腈,5%水,0.1% TFA
管柱:Waters Sunfire C18,3.0×150mm,3.5um
流動速率:0.5mL/min
偵測器波長:220nm
分析型HPLC方法2-6
條件:經15分鐘梯度10% B→100% B;在100% B下保持10分鐘
溶劑A:5%乙腈,95%水,0.1% TFA
溶劑B:95%乙腈,5%水,0.1% TFA
管柱:Waters Xbridge苯基,3.0×150mm,3.5um
流動速率:0.5mL/min
偵測器波長:220nm
步驟1. 製備4-甲基苯磺酸3-羥基-3-甲基丁酯
在0℃下,向3-甲基丁-1,3-二醇(1.00g,9.60mmol)於吡啶(10mL)中之溶液中添加對甲苯磺醯氯(2.014g,10.56mmol)。攪拌反應混合物16小時,同時藉由冰-水浴之散熱使反應混合物緩慢升溫至室溫。將混合物轉移至含有乙酸乙酯(100mL)之分液漏斗中。有機層用1N HCl(3×50mL)洗滌。有機層接著用NaHCO3飽和溶液(50mL)、鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中之30%→50%乙酸乙酯;220g管柱)純化產物獲得呈無色油狀之4-甲基苯磺酸3-羥基-3-甲基丁酯(2.03g,7.86mmol,82%產率):1H NMR(400MHz,氯仿-d)δ 7.85-7.78(m,2H),7.37(dd,J=8.5,0.8Hz,2H),4.23(t,J=6.9Hz,2H),2.47(s,3H),1.88(t,J=6.9Hz,2H),1.24(s,6H);LC/MS:產物未離子化,t R=1.78min(方法2-1)。
步驟2. 製備4-溴-2-甲基丁-2-醇
在室溫下,向4-甲基苯磺酸3-羥基-3-甲基丁酯(400mg,1.548mmol)於THF(15mL)中之溶液中添加溴化鋰(403mg,4.65mmol)。在室溫下攪拌反應混合物隔夜。將反應混合物轉移至含有NaHCO3飽和水溶液(10mL)及水(10mL)的分液漏斗中。用乙醚(3×20mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中之20%→40%乙酸乙酯;80g管柱)純化產物獲得呈無色油狀之4-溴-2-甲基丁-2-醇(231mg,1.383mmol,89%產率):1H NMR(500MHz,氯仿-d)δ 3.55-3.49(m,2H),2.15-2.09(m,2H),1.28(s,6H)。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羥基-3-甲基丁基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向烘乾之小瓶中的(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(70mg,0.107mmol)、4-溴-2-甲基丁-2-醇(24.96mg,0.149mmol)、磷酸三鉀(68.0mg,0.320mmol)及碘化鉀(24.80mg,0.149mmol)的混合物中添加乙腈(0.8mL)。密封蓋子且在120℃下加熱反應混合物2小時。在此期間蒸發溶劑。添加額外乙腈(0.8mL)且在120℃下加熱反應混合物1小時。將混合物轉移至含有水(5mL)之分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羥基-3-甲基丁基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(56.6mg,0.076mmol,72%產率):1H NMR(500MHz,氯仿-d)δ 7.42-7.31(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.2,1.8Hz,1H),4.72(s,1H),4.63-4.55(m,2H),4.52-4.45(m,1H),2.86-2.78(m,1H),2.77-2.68(m,1H),2.65-2.53(m,2H),2.18-0.86(m,29H),1.69(s,3H),1.27(s,
6H),1.07(s,3H),0.98(s,3H),0.91(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 742.6[(M+H)+,C49H73FNO3計算值742.6],t R=4.86min(方法2-3)。
步驟4. 用氫氧化鈉(2M水溶液)(0.243mL,0.485mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羥基-3-甲基丁基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(72mg,0.097mmol)於1,4-二噁烷(1.4mL)及EtOH(0.7mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-羥基-3-甲基丁基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(55.4mg,74%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.27-5.21(m,1H),4.82(s,1H),4.72(s,1H),4.61(dt,J=10.8,9.0Hz,1H),4.51(dt,J=10.8,9.2Hz,1H),3.46-3.38(m,1H),3.38-3.30(m,1H),2.91-2.83(m,1H),2.61(d,J=17.1Hz,1H),2.32-1.09(m,29H),1.75(s,3H),1.36(s,3H),1.33(s,3H),1.13(s,3H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.94(s,3H);LC/MS m/e 652.5[(M+H)+,C42H67FNO3計算值652.5],t R=4.40min(方法2-2);HPLC(方法2-1):t R=18.97min;HPLC(方法2-2):t R=20.16min。
步驟1. 製備4-甲基苯磺酸2-羥基-2-甲基丙酯
在0℃下,向2-甲基丙-1,2-二醇(415mg,4.60mmol)於吡啶(5mL)中之溶液中添加對甲苯磺醯氯(966mg,5.07mmol)。攪拌反應混合物16小時,同時藉由冰-水浴之散熱使反應混合物緩慢升溫至室溫。將混合物轉移至含有乙酸乙酯(50mL)之分液漏斗中。有機層用1N HCl(3×25mL)洗滌。有機層接著用NaHCO3飽和溶液(25mL)、鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中之30%→50%乙酸乙酯;120g管柱)純化產物獲得呈無色油狀之4-甲基苯磺酸2-羥基-2-甲基丙酯(1.01g,4.13mmol,90%產率):1H NMR(400MHz,氯仿-d)δ 7.86-7.78(m,2H),7.38(d,J=8.0Hz,2H),3.86(s,2H),2.48(s,3H),1.24(s,6H);LC/MS:產物未經離子化,t R=1.70min(方法2-1)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
3a-((2-羥基-2-甲基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向4-甲基苯磺酸2-羥基-2-甲基丙酯(22.35mg,0.091mmol)於乙腈(0.7mL)中之溶液中添加(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)、磷酸三鉀(32.4mg,0.152mmol,2當量)及碘化鉀(63.27mg,0.381mmol)。在100℃下加熱反應混合物6小時。接著添加額外4-甲基苯磺酸2-羥基-2-甲基丙酯(56mg,0.229mmol,3當量)及磷酸三鉀(16mg,0.076mmol,1當量)且在120℃下加熱反應混合物22小時。接著添加額外4-甲基苯磺酸2-羥基-2-甲基丙酯(37mg,0.153mmol,2當量)、磷酸三鉀(32mg,0.152mmol,2當量)及碘化鉀(28mg,0.168mmol,2.2當量)且在120℃下再加熱反應混合物18小時。將反應混合物冷卻至室溫。將混合物轉移至含有水(10mL)之分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。產物未經進一步純化直接用於下一步驟中:LC/MS m/e 728.6[(M+H)+,C48H71FNO3計算值728.5],t R=4.72min(方法2-2)。
步驟3. 用氫氧化鈉(0.189mL,0.378mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羥基-2-甲基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(55mg,0.076mmol)於1,4-二噁烷(0.5mL)及EtOH(0.25mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-羥基-2-甲基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(2.7mg,5%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.83(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.55-4.46(m,1H),3.51(d,J=12.7Hz,1H),3.06(d,J=12.4Hz,1H),3.03-2.95(m,1H),2.61(d,J=16.9Hz,1H),2.32-1.07(m,27H),1.75(s,3H),1.43(s,3H),1.41(s,3H),1.18(s,3H),1.10(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 738.6[(M+H)+,C41H65FNO3計算值738.5],t R=4.29min(方法2-2)。HPLC(方法2-1):t R=18.88min;HPLC(方法2-2):t R=20.24min。
步驟1. 製備5,5-二甲基四氫呋喃-2-醇
在-78℃下,在氮氣下,將DIBAL(1.314mL,1.314mmol)添加至5,5-二甲基二氫呋喃-2(3H)-酮(100mg,0.876mmol)於THF(10mL)中之溶液中。在-78℃下攪拌反應混合物3小時。向反應混合物添加洛歇爾鹽(Rochelle's salt)溶液,在室溫下攪拌30分鐘。接著將反應混合物分配於EtOAc與水之間。有機層用鹽水洗滌,經硫酸鎂乾燥且真空濃縮獲得粗產物(35mg,0.301mmol,34%產率)。粗產物之1H-NMR顯示其為4-羥基-4-甲基戊醛與5,5-二甲基四氫呋喃-2-醇之間的平衡,5,5-二甲基四氫呋喃-2-醇(35mg,0.301mmol,34%產率)為主要形式。1H NMR(400MHz,氯仿-d)δ 5.51(d,J=4.8Hz,1H),2.90(br.s.,1H),2.03-1.94(m,2H),1.82-1.64(m,2H),1.43(s,3H),1.22(s,3H)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-羥基-4-甲基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(25mg,0.038mmol)及5,5-二甲基四氫呋喃-2-醇(13.28mg,0.114mmol)於DCE(0.6mL)中之溶液中添加異丙醇鈦(IV)(0.018mL,0.061mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(16.15mg,0.076mmol)且在室溫下攪拌混合物16小時。將反應混合物分配於DCM與碳酸氫鈉溶液飽和水溶液之間。有機層用鹽水洗滌,經硫酸鎂乾燥且真空濃縮獲得(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-羥基-4-甲基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(28.8mg,0.038mmol,100%產率)。粗產物未經進一步純化即用於下一步驟中。LC/MS m/e 756.7[(M+H)+,C50H74FNO3計算值756.6]tR=2.66min(方法2-1)。
步驟3. 將氫氧化鈉(0.048mL,0.190mmol,4N水溶液)添加至粗(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-羥基-4-甲基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(28.7mg,.038mmol)於二噁烷(1
mL)及乙醇(0.500mL)中之溶液中。在70℃下攪拌反應混合物2小時。混合物冷卻至室溫且藉由逆相製備型HPLC(方法2-2,梯度:經10分鐘60-100% B,接著在100%下保持15分鐘)純化粗物質獲得(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-羥基-4-甲基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(2.8mg,4.08μmol,11%產率);LC/MS m/e 666.6[(M+H)+,C43H68FNO3計算值666.5]tR=2.40min(方法2-1);HPLC(方法2-3):t R=2.76min;HPLC(方法2-4):t R=2.11min。
步驟1. 製備3-乙基己-5-烯-3-醇
在0℃下,向溴化烯丙基鎂(13.93mL,13.93mmol)於THF(10mL)中之溶液中添加戊-3-酮(400mg,4.64mmol)。移除冷卻浴且在室溫下攪拌反應混合物1小時。在冰-水浴中冷卻反應混合物且藉由添加NH4Cl飽和水溶液(20mL)淬滅。將混合物轉移至分液漏斗中且用乙酸乙酯(4×25mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色油狀之3-乙基己-5-烯-3-醇(595mg,4.64mmol,100%產率)。產物未經進一步純化直接用於下一步驟中。1H NMR(400MHz,氯仿-d)δ 5.86(ddt,J=16.7,10.6,7.5Hz,1H),5.21-5.07(m,2H),2.23(dt,J=7.4,1.2Hz,2H),1.57-1.43(m,4H),0.90(t,J=7.5Hz,6H)
步驟2. 製備3-乙基-3-羥基戊醛
在0℃下,向3-乙基己-5-烯-3-醇(595mg,4.64mmol)於二噁烷(30mL)及水(7.50mL)中之溶液中添加2,6-二甲基吡啶(1.081mL,9.28mmol)、四氧化鋨(t-BuOH中2.5%)(1.165mL,0.093mmol及過碘酸鈉(3970mg,18.56mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌16小時。將混合物轉移至含有水(20mL)及NaHCO3飽和水溶液(30mL)的分液漏斗中。用乙酸乙酯(3×30mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之0%→8%甲醇;40g管柱)純化產物獲得呈無色油狀之3-乙基-3-羥基戊醛(217mg,1.667mmol,36%產率):1H NMR(400MHz,氯仿-d)δ 9.85(t,J=2.4Hz,1H),3.66(s,2H),1.65-1.41(m,4H),0.86(t,J=7.5Hz,6H)。
步驟3. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
3a-((3-乙基-3-羥基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
將異丙醇鈦(IV)(0.036mL,0.122mmol)添加至(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及3-乙基-3-羥基戊醛(15.88mg,0.122mmol)於DCE(0.6mL)中之溶液中。在室溫下攪拌反應混合物1小時。添加三乙醯氧基硼氫化鈉(32.3mg,0.152mmol)且攪拌反應混合物3天。將反應混合物分配於碳酸氫鈉飽和水溶液與CH2Cl2之間。用CH2Cl2(3×10mL)萃取水層。經合併之有機層用鹽水洗滌,經硫酸鎂乾燥且濃縮。藉由矽膠管柱層析法(0% 9:1丙酮/甲醇/100%己烷→40% 9:1丙酮/甲醇/60%己烷;24g管柱,λ=220nm)純化產物獲得呈無色油狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-乙基-3-羥基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(14mg,0.018mmol,24%產率):LC/MS(ESI)m/e 770.6[(M+H)+,C51H76FNO3計算值770.6]tR=2.61min(方法2-1)。
步驟4. 將氫氧化鈉(0.023mL,0.091mmol)添加至(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-乙基-3-羥基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(14mg,0.018mmol)於二噁烷(1mL)及乙醇(0.500mL)中之溶液中。在70℃下攪拌反應混合物2小時。將混合物冷卻至室溫。藉由逆相製備型HPLC(方法2-2,梯度經15分鐘60-100% B,接著在100% B下保持6分鐘)純化粗物質獲得(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-乙基-3-羥基戊基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(5.9mg,8.5μmol,47%產率);1H NMR(500MHz,DMSO-d6)δ 5.25(br.s.,1H),5.12(d,J=5.1Hz,1H),4.67(br.s.,1H),4.55(br.s.,1H),4.48(s,1H),4.38(s,1H),2.61-2.53(m,1H),2.48-2.38(m,3H),2.23-2.08(m,1H),2.07-0.93(m,32H),1.65(s,3H),1.02(s,3H),0.92(s,3H),0.91(s,3H),0.88(s,3H),0.82(s,3H),0.80-0.77(m,6H);LC/MS(ESI)m/e 680.5[(M+H)+,C44H70FNO3計算值680.5]tR=2.38min(方法2-1);HPLC(方法2-3):t R=2.29min;HPLC(方法2-4):t R=2.40min。
步驟1. 製備1,1-二環丙基丁-3-烯-1-醇
在0℃下,向溴化烯丙基鎂(10.89mL,10.89mmol)於THF(10mL)中之溶液中添加二環丙基甲酮(400mg,3.63mmol)。移除冷卻浴且在室溫下攪拌反應混合物1小時。在冰-水浴中冷卻反應物且藉由添加NH4Cl飽和水溶液(20mL)淬滅。將混合物轉移至分液漏斗中且用乙酸乙酯(4×25mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色油狀之1,1-二環丙基丁-3-烯-1-醇(553mg,3.63mmol,100%產率)。產物未經進一步純化直接用於下一步驟中。1H NMR(400MHz,氯仿-d)δ 6.16-5.98(m,1H),5.21-5.08(m,2H),2.37(dt,J=7.5,1.1Hz,2H),0.94-0.79(m,2H),0.49-0.25(m,8H)。
步驟2. 製備3,3-二環丙基-3-羥基丙醛
在0℃下,向1,1-二環丙基丁-3-烯-1-醇(553mg,3.63mmol)於二噁烷(12mL)及水(3mL)中之溶液中添加2,6-二甲基吡啶(0.846mL,7.26mmol)、四氧化鋨(水中4%)(0.444mL,0.073mmol)及過碘酸鈉(3,106mg,14.52mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌16小時。將混合物轉移至含有水(20mL)及NaHCO3飽和水溶液(30mL)的分液漏斗中。用乙酸乙酯(3×30mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之0%→8%甲醇;40g管柱)純化產物獲得呈無色油狀之3,3-二環丙基-3-羥基丙醛(152mg,0.986mmol,27%產率):1H NMR(400MHz,氯仿-d)δ 9.96(t,J=2.8Hz,1H),2.63(d,J=2.8Hz,2H),0.94(tt,J=8.2,5.8Hz,2H),0.51-0.38(m,8H)。
步驟3. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基-3-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(40mg,0.061mmol)及
3,3-二環丙基-3-羥基丙醛(14.10mg,0.091mmol)於MeOH(0.5mL)及乙酸(0.1mL)中之溶液中添加硼烷-2-甲基吡啶複合物(9.78mg,0.091mmol)。在室溫下攪拌反應混合物16小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(0% 9:1丙酮/甲醇/90%己烷→40% 9:1丙酮/甲醇/60%己烷;24g管柱,λ=220nm)純化產物獲得呈無色固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基-3-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(11mg,0.014mmol,23%產率):LC/MS(ESI)m/e 794.6[(M+H)+,C53H76FNO3計算值794.6]tR=2.66min(方法2-1)。
步驟4. 將氫氧化鈉(0.017mL,0.069mmol)添加至(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基-3-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(11mg,0.014mmol)於二噁烷(1mL)及乙醇(0.500mL)中之溶液中。在70℃下攪拌反應混合物2小時。將反應混合物冷卻至室溫。藉由逆相製備型HPLC(方法2-2,經10分鐘70-100% B,接著在100% B下保持15分鐘)純化粗物質獲得(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基-3-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(1.0mg,1.37μmol,10%產率);1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(dd,J=6.1,
1.7Hz,1H),4.82(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.56-4.47(m,1H),3.53-3.41(m,2H),2.97-2.87(m,1H),2.62(d,J=16.7Hz,1H),2.31-2.32(m,28H),1.14-1.10(m,1H),1.75(s,3H),1.11(s,3H),1.09(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H),0.87-0.76(m,2H),0.65-0.35(m,8H);LC/MS(ESI)m/e 704.6[(M+H)+,C46H70FNO3計算值704.5]tR=2.44min(方法2-1);HPLC(方法2-3):t R=2.43min;HPLC(方法2-4):t R=2.46min。
步驟1. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基烯丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
將異丙醇鈦(IV)(0.036mL,0.122mmol)添加至(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及3,3-二環丙基-3-羥基丙醛(18.81mg,0.122mmol)於DCE(0.6mL)中之溶液中。在室溫下攪拌反應混合物1小時。添加三乙醯氧基硼氫化鈉(32.3mg,0.152mmol)且攪拌反應混合物3天。將反應混合物分配於碳酸氫鈉飽和水溶液(10mL)與CH2Cl2(10mL)之間。用CH2Cl2(3×10mL)萃取水層。經合併之有機層用鹽水洗滌,經硫酸鎂乾燥且濃縮。粗產物(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基烯丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(32mg,0.041mmol,54%產率)未經進一步純化用於下一步驟中。LC/MS(ESI)m/e 776.6[(M+H)+,C53H74FNO2計算值776.6],tR=2.67min(方法2-1)。
步驟2. 將氫氧化鈉(0.052mL,0.206mmol)添加至(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基烯丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并
[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(32mg,0.041mmol)於二噁烷(1mL)及乙醇(0.500mL)中之溶液中。在70℃下攪拌反應混合物2小時。將混合物冷卻至室溫。藉由逆相製備型HPLC(方法2-2,經20分鐘90-100% B,接著在100% B下保持25分鐘)純化粗物質獲得(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3,3-二環丙基烯丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸(1.0mg,1.34μmol,3.3%產率);1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,2H),5.27-5.22(m,1H),4.84(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.56-4.48(m,1H),4.01(t,J=6.9Hz,2H),2.89(br.s.,1H),2.62(d,J=16.7Hz,1H),2.30-0.85(m,31H),1.75(s,3H),1.18(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.96(s,3H),0.80(d,J=8.4Hz,2H),0.66-0.60(m,2H),0.47-0.36(m,2H);LC/MS(ESI)m/e 686.6[(M+H)+,C46H68FNO2計算值686.5]tR=2.44min(方法2-1);HPLC(方法2-3):t R=2.62min;HPLC(方法2-4):t R=1.96min。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(異戊基胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(35mg,0.053mmol)及3-甲基丁醛(7.35mg,0.085mmol)於DCE(0.6mL)中之溶液中添加異丙醇鈦(IV)(0.025mL,0.085mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(22.62mg,0.107mmol)且在室溫下攪拌混合物隔夜。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層
析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(異戊基胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(20mg,0.028mmol,52%產率):LC/MS m/e 726.6[(M+H)+,C49H73FNO2計算值726.6],t R=5.10min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.069mL,0.138mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(異戊基胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(20mg,0.028mmol)於1,4-二噁烷(0.5mL)及EtOH(0.25mL)中之溶液。在70℃下加熱反應混合物2小時。混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-3)純化獲得(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(異戊基胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(9.9mg,48%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.28-5.22(m,1H),4.84(s,1H),4.73(s,1H),4.61(dt,J=10.9,8.8Hz,1H),4.52(dt,J=11.0,8.8Hz,1H),3.29-3.15(m,2H),2.92-2.84(m,1H),2.62(d,J=16.6Hz,1H),2.30-1.10(m,30H),1.75(s,3H),1.19(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.97(s,3H),0.95(s,6H);LC/MS m/e 636.3[(M+H)+,C42H67FNO2計算值636.5],t R=4.49min(方法2-2);HPLC
(方法2-3):t R=2.54min;HPLC(方法2-4):t R=2.59min。
步驟1. 製備4-(3-氯-2-羥基丙基)硫代嗎啉1,1-二氧化物
經針筒向硫代嗎啉1,1-二氧化物(2.40g,17.75mmol)於DCE(4.4mL)中之溶液中緩慢添加2-(氯甲基)環氧乙烷(1.392mL,17.75mmol)。在50℃下攪拌反應混合物48小時。藉由過濾移除所形成之白色固體(4,4'-(2-羥基丙-1,3-二基)雙(硫代嗎啉1,1-二氧化物)。濃縮濾液且藉由矽膠管柱層析法(CH2Cl2中之3%→5%甲醇;120g管柱)純化獲得呈無色油狀之4-(3-氯-2-羥基丙基)硫代嗎啉1,1-二氧化物(2.57g,11.29mmol,64%產率),其在靜置時固化:1H NMR(400MHz,氯仿-d)δ 3.95(dq,J=8.9,4.6Hz,1H),3.69-3.55(m,2H),3.26-3.15(m,2H),3.14-3.03(m,6H),2.75(dd,J=13.1,4.3Hz,1H),2.65(dd,
J=13.1,8.5Hz,1H);LC/MS m/e 228.1[(M+H)+,C7H15ClNO3S計算值228.0],tR=0.26min,(離子化峰,無UV)(方法2-1)。
步驟2. 製備(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-2-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在烘乾之小瓶中組合(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(120mg,0.183mmol)、4-(3-氯-2-羥基丙基)硫代嗎啉1,1-二氧化物(146mg,0.640mmol)、磷酸三鉀(175mg,0.823mmol)及碘化鉀(137mg,0.823mmol)。添加乙腈(2mL),密封小瓶,且在120℃下加熱反應混合物20小時。添加額外4-(3-氯-2-羥基丙基)硫代嗎啉1,1-二氧化物(83mg,0.366mmol,2當量)、磷酸三鉀(78mg,0.366mmol,2當量)及碘化鉀(60.7mg,0.366mmol,2當量)且再加熱反應混合物16小時。將混合物冷卻至室溫。將混合物轉移至含有水(10mL)之分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;40g管柱,λ=220nm)純化產物獲得呈淺藍色發泡體狀之(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-2-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(71.4mg,0.084mmol,
46%產率):1H NMR(500MHz,氯仿-d)δ 7.39-7.31(m,5H),5.33(br.s.,1H),5.23-5.15(m,2H),5.15-5.10(m,1H),4.72(s,1H),4.61(d,J=1.4Hz,1H),4.60-4.54(m,1H),4.52-4.45(m,1H),3.80-3.67(m,1H),3.23-3.03(m,8H),2.73-2.53(m,5H),2.37(dd,J=11.7,7.2Hz,1H,非對映異構體A),2.29(dd,J=11.7,8.1Hz,1H,非對映異構體B),2.19-0.83(m,47H)(非對映異構體之混合物);LC/MS m/e 847.6[(M+H)+,C51H76FN2O5S計算值847.5],t R=4.58min(方法2-2)。
步驟3. 用氫氧化鈉(0.089mL,0.177mmol)處理(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-2-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(30mg,0.035mmol)於1,4-二噁烷(0.5mL)及EtOH(0.2mL)中之溶液。在70℃下加熱反應混合物2小時。經針筒過濾器過濾混合物,且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(1S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(1,1-二氧離子基N-硫代嗎啉基)-2-羥基丙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(13.6mg,43%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.9Hz,1H),4.85(d,J=5.3Hz,1H),4.75(br.s.,1H),4.73-4.67(m,1H),4.64-4.56(m,1H),4.54-4.47(m,1H),3.98-3.89(m,3H),3.65-3.51(m,6H),3.49-3.43(m,2H),3.23(dd,J=12.4,8.5Hz,1H,非對映異構體A),3.07(t,J=11.4Hz,1H,非對映異構體B),2.94-2.79(m,1H),2.61(d,J=17.1Hz,1H),2.32-1.09(m,27H),1.76(s,3H,非對映異構體A),
1.76(s,3H,非對映異構體B),1.15(s,3H),1.11(s,3H,非對映異構體A),1.10(s,3H,非對映異構體B),1.00(s,3H),0.99(s,3H),0.95(s,3H)(非對映異構體之混合物;LC/MS m/e 757.6[(M+H)+,C44H70FN2O5S計算值757.5],t R=4.24min(方法2-2);HPLC(方法2-1):t R=18.72min;HPLC(方法2-2):t R=20.02min。
步驟1. 製備1-烯丙基環丁醇
在0℃下,向溴化烯丙基鎂(12.8mL,12.8mmol)於THF(10mL)中之溶液中添加環丁酮(300mg,4.28mmol)於THF(5mL)中之溶液。移除冷卻浴且在室溫下攪拌反應混合物16小時。在冰-水浴中冷卻反應物且藉由添加NH4Cl飽和溶液(20mL)淬滅。將混合物轉移至分液漏
斗中且用乙酸乙酯(4×25mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色油狀之1-烯丙基環丁醇(377mg,3.36mmol,79%產率)。產物未經進一步純化直接用於下一步驟中:1H NMR(400MHz,氯仿-d)δ 5.90(ddt,J=16.4,10.7,7.3Hz,1H),5.27-5.16(m,2H),2.41(d,J=7.3Hz,2H),2.13-2.05(m,4H),1.93(s,1H),1.83-1.71(m,1H),1.65-1.51(m,1H)。
步驟2. 製備2-(1-羥基環丁基)乙醛
在0℃下,向1-烯丙基環丁醇(350mg,3.12mmol)於二噁烷(30mL)及水(7.50mL)中之溶液中添加2,6-二甲基吡啶(0.727mL,6.24mmol)、四氧化鋨(水中4%)(0.490mL,0.062mmol)及過碘酸鈉(2670mg,12.48mmol)。使反應混合物升溫至室溫且攪拌16小時。將反應混合物分配於EtOAc(25mL)與碳酸氫鈉飽和水溶液(25mL)之間。用乙酸乙酯(3×25mL)萃取水層。經合併之有機層用鹽水洗滌,經硫酸鎂乾燥且真空濃縮。藉由矽膠管柱層析法(CH2Cl2中之0%→8%甲醇;40g管柱)純化產物獲得呈油狀之2-(1-羥基環丁基)乙醛(187mg,1.638mmol,53%產率):1H NMR(400MHz,氯仿-d)δ 9.86(t,J=1.8Hz,1H),2.32-1.95(m,4H),1.92-1.73(m,2H),1.69-1.43(m,2H)。
製備3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基環丁基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向小瓶中的(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及2-(1-羥基環丁基)乙醛(13.92mg,0.122mmol)於二氯乙烷(0.6mL)中之溶液中添加異丙醇鈦(IV)(0.036mL,0.122mmol)。在室溫下攪拌反應混合物1小時。添加三乙醯氧基硼氫化鈉(32.3mg,0.152mmol)且攪拌反應混合物4天。將反應混合物分配於碳酸氫鈉飽和水溶液(10mL)與CH2Cl2(10mL)之間。用CH2Cl2(3×10mL)萃取水層。經合併之有機層用鹽水洗滌,經硫酸鎂乾燥且濃縮。藉由矽膠管柱層析法(100%己烷→40%含有10%甲醇之丙酮/60%己烷;24g管柱,λ=220nm)純化產物獲得呈油狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基環丁基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(51mg,0.068mmol,89%產率):LC/MS(ESI)m/e 754.6[(M+H)+,C50H72FNO3計算值754.6],tR=2.74min(方法2-1)。
步驟4. 用氫氧化鈉(0.085mL,0.338mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基環丁基)
乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(51mg,0.068mmol)於二噁烷(1mL)及乙醇(0.500mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基環丁基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(12.9mg,0.016mmol,24%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.29-5.21(m,1H),4.84(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.55-4.47(m,1H),3.44-3.36(m,1H),3.28(t,J=9.9Hz,1H),2.94-2.84(m,1H),2.61(d,J=16.8Hz,1H),2.31-0.83(m,35H),1.75(s,3H),1.14(s,3H),1.08(s,3H),1.00(s,3H),0.99(s,3H),0.94(s,3H);LC/MS(ESI)m/e 664.6[(M+H)+,C43H66FNO3計算值664.5],tR=2.43min(方法2-1)。HPLC(方法2-1):t R=19.00min;HPLC(方法2-2):t R=20.57min。
步驟1. 製備3-烯丙基氧雜環丁烷-3-醇
在-78℃下,向溴化烯丙基鎂(7.29mL,7.29mmol)於THF(40mL)中之溶液中添加氧雜環丁-3-酮(500mg,6.94mmol)於THF(10mL)中之溶液。在-78℃下攪拌反應混合物30分鐘。藉由添加NH4Cl飽和溶液(40mL)來淬滅反應物。將混合物轉移至分液漏斗中,且分離各層。用乙醚(3×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色油狀之3-烯丙基氧雜環丁烷-3-醇(735mg,6.44mmol,93%產率)。產物未經進一步純化即用於下一步驟中:1H NMR(400MHz,氯仿-d)δ 5.97-5.78(m,1H),5.28(t,J=1.0Hz,1H),5.27-5.22(m,1H),4.64(d,J=7.3Hz,2H),4.55-4.50(m,2H),2.65(d,J=7.0Hz,2H);13C NMR(101MHz,氯仿-d)δ 131.8,120.1,83.2,73.3,42.4。
步驟2. 製備2-(3-羥基氧雜環丁烷-3-基)乙醛
在100mL圓底燒瓶中,將3-烯丙基氧雜環丁烷-3-醇(508mg,4.45mmol)溶解於CH2Cl2(35mL)及MeOH(3.5mL)中。添加N-甲基嗎
啉-N-氧化物(NMO)(626mg,5.34mmol)且將混合物冷卻至-78℃[Schwartz,C.,Raible,J.,Mott,K.,Dussault,P.H.Org.Lett.2006,8,3199-3201]。將臭氧鼓泡通過反應混合物直至溶液用臭氧飽和(變為藍色)且此後若干分鐘(總計時間10分鐘)。氮氣接著鼓泡通過反應混合物直至藍色消失。接著添加二甲基硫醚(3.29mL,44.5mmol)且在0℃下攪拌反應混合物14小時。真空濃縮混合物。藉由矽膠管柱層析法(具有1%甲醇之50%乙酸乙酯/50%己烷→具有1%甲醇之100%乙酸乙酯;80g管柱)純化產物獲得呈無色油狀之2-(3-羥基氧雜環丁烷-3-基)乙醛(287mg,2.472mmol,56%產率):1H NMR(400MHz,氯仿-d)δ 9.85(s,1H),4.71(d,J=7.5Hz,2H),4.52-4.47(m,2H),3.14(d,J=0.5Hz,2H);13C NMR(100MHz,氯仿-d)δ 201.1,83.0,71.4,50.7。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在室溫下,在小瓶中,攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(500mg,0.762mmol)、硼烷-2-甲基吡啶複合物(163mg,1.524mmol)及2-
(3-羥基氧雜環丁烷-3-基)乙醛(177mg,1.524mmol)於MeOH(8mL)及乙酸(1.6mL)中之混合物16小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(50mL)的分液漏斗中。用二氯甲烷(3×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→40% 9:1丙酮:甲醇/60%己烷;80g管柱,λ=220nm)純化產物獲得呈無色油狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(320mg,0.423mmol,56%產率):LC/MS(ESI)m/e 756.6[(M+H)+,C49H70FNO4計算值756.5],tR=2.59min(方法2-1)。
步驟4. 用氫氧化鈉(0.529mL,2.116mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(320mg,0.423mmol)於二噁烷(4mL)及乙醇(2mL)中之溶液。在70℃下加熱反應混合物2.5小時。LC/MS顯示形成所要產物。經針筒過濾器過濾混合物,且藉由逆相製備型HPLC(方法2-5)純化。在旋轉蒸發器上移除有機溶劑且將水性混合物冷凍及置於凍乾器上獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(220mg,0.282mmol,67%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),
4.83(s,1H),4.81-4.77(m,2H),4.75-4.68(m,2H),4.67-4.57(m,2H),4.55-4.46(m,1H),3.52-3.42(m,1H),3.33-3.23(m,1H),2.92-2.81(m,1H),2.61(d,J=16.8Hz,1H),2.57-2.42(m,2H),2.31-1.32(m,25H),1.14-1.12(m,2H),1.75(s,3H),1.15(s,3H),1.09(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 666.5[(M+H)+,C42H67FNO4計算值666.5],tR=2.44min(方法2-1);HPLC(方法2-1):t R=18.63min;HPLC(方法2-2):t R=19.94min。
步驟1. 製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
將(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.152mmol)及2-(3-羥基氧雜環丁烷-3-基)乙醛(31.9mg,0.274mmol)懸浮於MeOH(1.2mL)中。添加硼烷-2-甲基吡啶複合物(29.4mg,0.274mmol),隨後添加乙酸(0.24mL),且在室溫下攪拌混合物16小時。混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)及碳酸鈉飽和水溶液(1mL)之分液漏斗中。用二氯甲烷(4×5mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(具有5%甲醇之20%乙酸乙酯/80%己烷→具有5%甲醇之90%乙酸乙酯/10%己烷;24g管柱)純化產物獲得呈無色油狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(110mg,0.145mmol,95%產率):1H NMR(500MHz,氯仿-d)δ 7.42-7.31(m,5H),5.34(br.s.,1H),5.24-5.16(m,2H),5.12(d,J=5.7Hz,1H),4.73(br.s.,1H),4.69(t,J=5.3Hz,2H),4.64-4.55(m,2H),4.53-4.46(m,2H),4.43(d,J=6.0Hz,1H),2.90-2.83(m,1H),2.72-2.48(m,3H),2.26-1.87(m,8H),
1.82-0.91(m,21H),1.69(s,3H),1.06(s,3H),0.98(s,3H),0.94(s,3H),0.89(s,3H),0.86(s,3H);LC/MS m/e 756.6[(M+H)+,C49H71FNO4計算值756.6],tR=4.59min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.347mL,0.694mmol)處理(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(105mg,0.139mmol)於1,4-二噁烷(1.5mL)及MeOH(0.5mL)中之溶液。在70℃下加熱反應混合物4小時。將混合物冷卻至室溫且藉由添加6N HCl(70μL)部分中和。接著經針筒過濾器過濾混合物,且藉由逆相製備型HPLC(方法2-5)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(3-羥基氧雜環丁烷-3-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(38.0mg,0.048mmol,35%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.7Hz,1H),4.83(s,1H),4.80(d,J=7.3Hz,2H),4.74-4.69(m,2H),4.66-4.57(m,2H),4.55-4.46(m,1H),3.47(ddd,J=12.7,6.1,3.2Hz,1H),3.28(ddd,J=12.5,9.2,2.9Hz,1H),2.90-2.83(m,1H),2.61(d,J=17.2Hz,1H),2.56-2.44(m,2H),2.37-2.28(m,1H),2.22-1.32(m,24H),1.75(s,3H),1.15(s,3H),1.14-1.12(m,2H),1.09(s,3H),1.02(s,3H),0.98(s,3H),0.95(s,3H);LC/MS m/e 666.5[(M+H)+,C42H65FNO4計算值666.5],tR=4.31min(方法2-2);HPLC(方法2-5):t R=10.94min;HPLC(方法2-6):t R=10.82min。
步驟1. 製備4-烯丙基四氫-2H-哌喃-4-醇
在0℃下,經導管向溴化烯丙基鎂(20.98mL,20.98mmol)於THF(40mL)中之溶液中添加二氫-2H-哌喃-4(3H)-酮(700mg,6.99mmol)於THF(10mL)中之溶液。移除冷卻浴且在室溫下攪拌反應混合物2小時。在冰-水浴中冷卻反應物且藉由添加NH4Cl飽和溶液(40mL)淬滅。將混合物轉移至分液漏斗中,且分離各層。用乙酸乙酯(3×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中20%→60%乙酸乙酯;80g管柱)純化產物獲得呈無色油狀之4-烯丙基四氫-2H-哌喃-4-醇(818mg,5.75mmol,82%產率):1H NMR(400MHz,氯仿-d)δ 5.90(ddt,
J=17.2,9.9,7.5Hz,1H),5.28-5.14(m,2H),3.85-3.74(m,4H),2.28(d,J=7.5Hz,2H),1.80-1.68(m,2H),1.51(dq,J=14.0,2.5Hz,3H)。
步驟2. 製備2-(4-羥基四氫-2H-哌喃-4-基)乙醛
在0℃下,向4-烯丙基四氫-2H-哌喃-4-醇(150mg,1.055mmol)於二噁烷(12mL)及水(3mL)中之溶液中添加2,6-二甲基吡啶(0.246mL,2.110mmol)、四氧化鋨(0.265mL,0.021mmol)及過碘酸鈉(903mg,4.22mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有水(10mL)及NaHCO3飽和水溶液(10mL)的分液漏斗中。用乙酸乙酯(3×20mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之3%→6%甲醇;40g管柱)純化產物獲得呈無色油狀之2-(4-羥基四氫-2H-哌喃-4-基)乙醛(67mg,0.465mmol,44%產率):1H NMR(400MHz,氯仿-d)δ 9.89(t,J=1.3Hz,1H),3.90-3.80(m,2H),3.78-3.69(m,2H),3.50(s,1H),2.70(d,J=1.3Hz,2H),1.75-1.66(m,4H)。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基四氫-2H-哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(40mg,0.061mmol)及2-(4-羥基四氫-2H-哌喃-4-基)乙醛(13.19mg,0.091mmol)於DCE(0.5mL)中之溶液中添加異丙醇鈦(IV)(0.027mL,0.091mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(25.8mg,0.122mmol)且在室溫下攪拌混合物隔夜。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮/甲醇/90%己烷→40% 9:1丙酮/甲醇/60%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基四氫-2H-哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(33.2mg,0.042mmol,69%產率):1H NMR(400MHz,氯仿-d)δ 7.43-7.32(m,5H),5.36-5.31(m,1H),5.23-5.16(m,2H),5.14(dd,J=6.0,1.8Hz,1H),4.75(d,J=1.8Hz,1H),4.64-4.57(m,2H),4.53-4.45(m,1H),3.94-3.82(m,2H),3.80-3.70(m,2H),2.86-2.69(m,2H),2.67-2.51(m,2H),2.19-0.86(m,33H),1.70(s,3H),1.06(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,3H),0.86(s,3H);LC/MS m/e 784.6[(M+H)+,C51H75FNO4計算值784.6],t R=4.69min(方法2-2)。
步驟4. 用氫氧化鈉(2M水溶液)(0.179mL,0.357mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基四氫-2H-哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-
2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(56mg,0.071mmol)於1,4-二噁烷(0.7mL)及EtOH(0.35mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基四氫-2H-哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(37.1mg,64%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.28-5.21(m,1H),4.83(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.55-4.46(m,1H),3.97-3.79(m,4H),3.46-3.31(m,2H),2.92-2.83(m,1H),2.61(d,J=16.8Hz,1H),2.34-1.09(m,33H),1.75(s,3H),1.18(s,3H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.96(s,3H);LC/MS m/e 694.6[(M+H)+,C44H69FNO4計算值694.5],t R=4.27min(方法2-2);HPLC(方法2-1):t R=18.95min;HPLC(方法2-2):t R=20.14min。
步驟1. 製備4-烯丙基-4-羥基四氫-2H-硫代哌喃1,1-二氧化物
在0℃下,經導管向溴化烯丙基鎂(10.83mL,10.83mmol)於THF(15mL)中之溶液中添加二氫-2H-硫代哌喃-4(3H)-酮1,1-二氧化物(1.07g,7.22mmol)於THF(50mL)中之溶液(藉由在油浴中升溫至70℃溶解)。移除冷卻浴且在室溫下攪拌反應混合物30分鐘。在冰-水浴中冷卻反應物且藉由添加NH4Cl飽和溶液(50mL)淬滅。將混合物轉移至分液漏斗中且用乙酸乙酯(4×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色固體狀之4-烯丙基-4-羥基四氫-2H-硫代哌喃1,1-二氧化物(1.42g,7.46mmol,103%產率)。產物未經進一步純化直接用於下一步驟中:1H NMR(400MHz,氯仿-d)δ 5.85(ddt,J=17.2,9.9,7.6Hz,1H),5.34-5.28(m,1H),5.23(dq,J=17.1,1.4Hz,1H),3.43(td,J=13.6,3.8Hz,2H),2.92-2.84(m,2H),2.32(d,J=7.5Hz,2H),2.23(td,J=13.8,3.3Hz,2H),2.05
-1.97(m,2H)。
步驟2. 製備2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙醛
在0℃下,向4-烯丙基-4-羥基四氫-2H-硫代哌喃1,1-二氧化物(1.52g,7.99mmol)於二噁烷(80mL)及水(20mL)中之溶液中添加2,6-二甲基吡啶(1.861mL,15.98mmol)、四氧化鋨(水中4%)(1.254mL,0.160mmol)及過碘酸鈉(6.84g,32.0mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有1N HCl溶液(50mL)之分液漏斗中。用乙酸乙酯(12×50mL)萃取水層。經合併之有機層用1N HCl溶液(10mL)、NaHCO3飽和水溶液(10mL)、鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之3%→10%甲醇;80g管柱)純化產物獲得呈無色油狀之2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙醛(821mg,4.27mmol,54%產率):1H NMR(400MHz,氯仿-d)δ 9.86(s,1H),3.54-3.43(m,3H),2.91-2.83(m,2H),2.80(s,2H),2.28-2.14(m,4H)。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(632mg,0.963mmol)及2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙醛(296mg,1.542mmol)於DCE(7.5mL)中之溶液中添加異丙醇鈦(IV)(0.452mL,1.542mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(408mg,1.927mmol)且在室溫下攪拌混合物隔夜。將混合物轉移至含有碳酸氫鈉飽和水溶液(25mL)的分液漏斗中。用二氯甲烷(4×50mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→40% 9:1丙酮:甲醇/60%己烷;80g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(591mg,0.710mmol,74%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.32(m,5H),5.34(br.s.,1H),5.23-5.16(m,2H),5.14(dd,J=6.2,1.8Hz,1H),4.75(d,J=1.5Hz,1H),4.63(s,1H),4.61-4.55(m,1H),4.53-4.46(m,1H),3.58-3.46(m,2H),2.91-2.81(m,3H),2.78-2.70(m,1H),2.62(d,J=16.6Hz,1H),2.53(td,J=10.8,5.6Hz,1H),2.17-1.06(m,33H),1.70(s,3H),1.06(s,3H),0.99(s,3H),0.92(s,3H),0.91(s,3H),0.87(s,3H);LC/MS m/e 832.6[(M+H)+,C51H75FNO5S計算值832.5],t R=4.64min(方法2-2)。
步驟4. 用氫氧化鈉(2M水溶液)(1.502mL,3.00mmol)處理(S)-1-
(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(500mg,0.601mmol)於1,4-二噁烷(6mL)及EtOH(3mL)中之溶液。在70℃下加熱反應混合物2.5小時。混合物冷卻至室溫且添加6N HCl(0.20mL,2當量)以部分中和反應混合物。經針筒過濾器過濾混合物,且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(435mg,84%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.6Hz,1H),4.82(s,1H),4.73(s,1H),4.65-4.56(m,1H),4.55-4.47(m,1H),3.59-3.33(m,4H),3.10-2.97(m,2H),2.88-2.78(m,1H),2.61(d,J=16.6Hz,1H),2.42-1.12(m,33H),1.75(s,3H),1.18(s,3H),1.10(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 742.6[(M+H)+,C44H69FNO5S計算值742.5],tR=4.19min(方法2-2);HPLC(方法2-1):t R=18.71min;HPLC(方法2-2):t R=19.66min。
步驟1. 製備4-烯丙基-1-(甲基磺醯基)哌啶-4-醇
在0℃下,經導管向溴化烯丙基鎂(5.08mL,5.08mmol)於THF(15mL)中之溶液中添加1-(甲基磺醯基)哌啶-4-酮(300mg,1.693mmol)於THF(5mL)中之溶液。移除冷卻浴且在室溫下攪拌反應混合物30分鐘。在冰-水浴中冷卻反應物且藉由添加NH4Cl飽和溶液(20mL)淬滅。將混合物轉移至分液漏斗中且用乙酸乙酯(4×25mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色固體狀之4-烯丙基-1-(甲基磺醯基)哌啶-4-醇(423mg,1.929mmol,114%產率(不純)),其未經進一步純化直接用於下一步驟中。1H NMR(500MHz,氯仿-d)δ 5.87(ddt,J=17.2,10.0,7.6Hz,1H),5.28-5.24(m,1H),5.23-5.17(m,1H),3.61(dt,J=11.4,2.4Hz,2H),3.05(td,J=11.9,3.0Hz,2H),2.80(s,3H),2.27(d,J=7.5Hz,2H),1.80-1.71(m,2H),1.70-1.61(m,2H)。
步驟2. 製備2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙醛
在0℃下,向4-烯丙基-1-(甲基磺醯基)哌啶-4-醇(210mg,0.958mmol)於二噁烷(12mL)及水(3mL)中之溶液中添加2,6-二甲基吡啶(0.223mL,1.915mmol)、四氧化鋨(水中4%)(0.150mL,0.019mmol)及過碘酸鈉(819mg,3.83mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有水(10mL)及NaHCO3飽和水溶液(10mL)的分液漏斗中。用乙酸乙酯(5×20mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之3%→8%甲醇;40g管柱)純化產物獲得呈無色油狀之2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙醛(101mg,0.456mmol,48%產率):1H NMR(400MHz,氯仿-d)δ 9.87(s,1H),3.64-3.55(m,2H),3.15-3.05(m,3H),2.81(s,3H),2.73(d,J=0.8Hz,2H),1.93-1.85(m,2H),1.73(dd,J=12.8,4.5Hz,2H)。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-
五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙醛(25.3mg,0.114mmol)於DCE(0.6mL)中之溶液中添加異丙醇鈦(IV)(0.034mL,0.114mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(32.3mg,0.152mmol)且在室溫下攪拌混合物隔夜。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(49mg,0.057mmol,75%產率):1H NMR(500MHz,氯仿-d)δ 7.41-7.31(m,5H),5.33(br.s.,1H),5.22-5.16(m,2H),5.13(dd,J=6.2,1.8Hz,1H),4.75(d,J=1.5Hz,1H),4.62(s,1H),4.61-4.55(m,1H),4.49(td,J=8.9,5.5Hz,1H),3.67-3.58(m,2H),3.16-3.05(m,2H),2.86-2.79(m,1H),2.82(s,3H),2.77-2.69(m,1H),2.62(d,J=16.8Hz,1H),2.55(td,J=10.9,5.6Hz,1H),2.18-0.86(m,33H),1.70(s,3H),1.05(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,3H),0.86(s,3H);LC/MS m/e 861.6[(M+H)+,C52H78FN2O5S計算值861.6],t R=4.63min(方法2-2)。
步驟4. 用氫氧化鈉(2M水溶液)(0.139mL,0.279mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-
1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(48mg,0.056mmol)於1,4-二噁烷(0.7mL)及EtOH(0.35mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-1-(甲基磺醯基)哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(38.6mg,77%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.83(s,1H),4.73(s,1H),4.66-4.57(m,1H),4.55-4.47(m,1H),3.65-3.50(m,2H),3.47-3.34(m,2H),3.25-3.12(m,2H),2.88(s,3H),2.87-2.79(m,1H),2.61(d,J=17.5Hz,1H),2.33-1.09(m,33H),1.75(s,3H),1.17(s,3H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 771.6[(M+H)+,C45H72FN2O5S計算值771.5],t R=4.43min(方法2-2);HPLC(方法2-1):t R=18.97min;HPLC(方法2-2):t R=20.11min。
步驟1. 製備1-(4-烯丙基-4-羥基哌啶-1-基)乙酮
在-10℃(丙酮/冰浴)下,向1-乙醯基哌啶-4-酮(1.00g,7.08mmol)於THF(50mL)中之溶液中添加溴化烯丙基鎂(乙醚中1M)(7.44mL,7.44mmol)。在-10℃下攪拌反應混合物30分鐘。藉由添加NH4Cl飽和溶液(50mL)來淬滅反應物。將混合物轉移至分液漏斗中且用乙酸乙酯(3×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈褐色油狀之1-(4-烯丙基-4-羥基哌啶-1-基)乙酮(836mg,4.56mmol,64%產率)。產物未經進一步純化直接用於下一步驟中。1H NMR(400MHz,氯仿-d)δ 5.88(ddt,J=17.2,10.1,7.6Hz,1H),5.28-5.22(m,1H),5.19(ddt,J=17.1,2.1,1.2Hz,1H),4.41-4.33(m,1H),3.65-3.56(m,1H),3.52-3.43(m,1H),3.04(ddd,J=13.4,9.3,6.1Hz,1H),2.26(d,J=7.8Hz,2H),2.12(s,3H),1.63-1.55(m,4H)。
步驟2. 製備2-(1-乙醯基-4-羥基哌啶-4-基)乙醛
在0℃下,向1-(4-烯丙基-4-羥基哌啶-1-基)乙酮(280mg,1.528mmol)於二噁烷(12mL)及水(3mL)中之溶液添加2,6-二甲基吡啶(0.356mL,3.06mmol)、四氧化鋨(t-BuOH中2.5%)(0.384mL,0.031mmol)及過碘酸鈉(1307mg,6.11mmol)。移除冷卻浴且在室溫下攪拌反應混合物2.5小時。將混合物轉移至含有水(10mL)及NaHCO3飽和水溶液(10mL)的分液漏斗中。用含5%甲醇之氯仿(8×20mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之4%→10%甲醇;24g管柱)純化產物獲得呈無色油狀之2-(1-乙醯基-4-羥基哌啶-4-基)乙醛(48.6mg,0.262mmol,17%產率)。1H NMR顯示產物不完全純。產物直接用於下一步驟。1H NMR(400MHz,氯仿-d)δ 9.88(t,J=1.0Hz,1H),4.41-4.33(m,1H),3.61-3.56(m,1H),3.56-3.45(m,3H),3.12-3.00(m,1H),2.11(s,3H),1.87-1.76(m,2H),1.54(tdd,J=12.8,8.0,4.9Hz,2H)。
步驟3. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-乙醯基-4-羥基哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-
五甲基-1-(丙-1-烯-2-基)2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(50mg,0.076mmol)及2-(1-乙醯基-4-羥基哌啶-4-基)乙醛(42.4mg,0.229mmol)於DCE(0.6mL)中之溶液中添加異丙醇鈦(IV)(0.067mL,0.229mmol)。在室溫下攪拌混合物1小時。添加三乙醯氧基硼氫化鈉(48.5mg,0.229mmol)且在室溫下攪拌混合物隔夜。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮/甲醇/90%己烷→40% 9:1丙酮/甲醇/60%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-乙醯基-4-羥基哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(46mg,0.056mmol,73%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.31(m,5H),5.33(br.s.,1H),5.22-5.16(m,2H),5.15-5.10(m,1H),4.74(s,1H),4.62(d,J=1.2Hz,1H),4.60-4.55(m,1H),4.52-4.46(m,1H),4.38(d,J=13.1Hz,1H),3.64-3.49(m,2H),3.15-3.05(m,1H),2.87-2.70(m,2H),2.64-2.52(m,2H),2.19-0.87(m,33H),2.11(s,3H),1.70(s,3H),1.07(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 825.6[(M+H)+,C53H78FN2O4計算值825.6],tR=4.74min(方法2-3)。
步驟4. 用氫氧化鈉(2M水溶液)(0.136mL,0.273mmol)處理(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-乙醯基-4-羥基哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并
[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(45mg,0.055mmol)於1,4-二噁烷(0.7mL)及EtOH(0.35mL)中之溶液。在50℃下加熱反應混合物2小時,接著在65℃下加熱1小時。將混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-乙醯基-4-羥基哌啶-4-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(34mg,73%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=5.0Hz,1H),4.83(br.s.,1H),4.73(s,1H),4.64-4.57(m,1H),4.55-4.47(m,1H),4.43-4.28(m,1H),3.78-3.67(m,1H),3.66-3.52(m,1H),3.47-3.35(m,2H),3.26-3.10(m,1H),2.92-2.77(m,1H),2.61(d,J=17.2Hz,1H),2.39-1.10(m,33H),2.18(s,3H),1.75(s,3H),1.17(s,3H),1.10(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 735.6[(M+H)+,C46H76FN2O4計算值739.6],tR=4.27min(方法2-2);HPLC(方法2-1):t R=18.86min;HPLC(方法2-2):t R=19.90min。
步驟1. 製備8-甲基-1,4-二氧雜螺[4.5]癸-8-醇
在-78℃下,在N2下,在圓底燒瓶中,經注射器向THF(100mL)中添加溴化甲基鋰(48.0mL,77mmol)及溴化甲基鎂(12.81mL,38.4mmol)。在-78℃下攪拌1小時後,經導管添加含1,4-二氧雜螺[4.5]癸-8-酮(5.00g,32.0mmol)之THF(50mL)。在-78℃下攪拌反應混合物1.5小時。藉由添加NH4Cl飽和水溶液(100mL)淬滅反應物。混合物轉移至含有水(50mL)之分液漏斗中且用乙酸乙酯(3×150mL)萃取水層。經合併之有機層用鹽水(100mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得8-甲基-1,4-二氧雜螺[4.5]癸-8-醇(5.47g,99%產率)。產物未經進一步純化即用於下一步驟中。1H NMR(400MHz,氯仿-d)δ 4.03-3.91(m,4H),1.97-1.84(m,2H),1.79-1.56(m,6H),1.28(s,3H),1.17(s,1H);13C NMR(100MHz,氯仿-d)δ 108.27,68.52,63.87,63.81,36.33,30.47,29.39。
步驟2. 製備4-羥基-4-甲基環己酮
在室溫下,向8-甲基-1,4-二氧雜螺[4.5]癸-8-醇(5.26g,30.5mmol)於丙酮(40mL)及水(60mL)中之溶液中添加4M HCl(22.91mL,92mmol)。在40℃下加熱反應混合物14小時。將混合物冷卻至室溫且藉由添加固體碳酸鈉中和。在旋轉蒸發器上移除丙酮且用乙酸乙酯(7×150mL)萃取水層。經合併之有機層經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中之70%乙酸乙酯)純化產物獲得呈白色固體狀之4-羥基-4-甲基環己酮(3.27g,25.5mmol,84%產率):1H NMR(400MHz,氯仿-d)δ 2.80-2.68(m,2H),2.30-2.20(m,2H),2.04-1.94(m,2H),1.92-1.80(m,2H),1.56(s,1H),1.39(s,3H);13C NMR(100MHz,氯仿-d)δ 211.55,68.14,38.40,36.80,29.51。
步驟3. 製備(反)-1-烯丙基-4-甲基環己烷-1,4-二醇及(順)-1-烯丙基-4-甲基環己烷-1,4-二醇
在0℃下,向4-羥基-4-甲基環己酮(3.20g,24.97mmol)於THF(200mL)中之溶液中添加溴化烯丙基鎂(乙醚中1M)(62.4mL,62.4mmol)。在0℃下攪拌反應混合物30分鐘。藉由添加NH4Cl飽和溶液(70mL)來淬滅反應物。將混合物轉移至分液漏斗中且用乙酸乙酯(3×150mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(己烷中之30%→90%乙酸乙酯;330g管柱,35分鐘梯度)純化產物獲得呈白色固體狀之(反)-1-烯丙基-4-甲基環己烷-1,4-二醇(1.90g,11.16mmol,45%產率)及呈無色油狀之(順)-1-烯丙基-4-甲基環己烷-1,4-二醇(2.35g,13.80mmol,55%產率),其靜置時固化。
(反)-1-烯丙基-4-甲基環己烷-1,4-二醇:
1H NMR(400MHz,氯仿-d)δ 5.92(ddt,J=17.3,10.1,7.5Hz,1H),5.23-5.12(m,2H),2.26(d,J=7.5Hz,2H),1.85-1.71(m,4H),1.55-1.43(m,4H),1.28(s,3H);13C NMR(100MHz,氯仿-d)δ 133.08,118.72,69.66,68.77,47.59,33.87,32.29,30.80。
藉由X射線結晶學確認(反)-1-烯丙基-4-甲基環己烷-1,4-二醇之結構。
(順)-1-烯丙基-4-甲基環己烷-1,4-二醇:1H NMR(400MHz,氯仿-d)δ 5.90(ddt,J=17.2,10.0,7.5Hz,1H),5.21-5.10(m,2H),2.25(dt,J=7.5,1.0Hz,2H),1.81-1.66(m,4H),1.57-1.47(m,4H),1.24(s,3H);13C NMR(100MHz,氯仿-d)δ 133.12,118.59,70.01,69.34,44.54,35.55,33.99,26.76。
步驟4a. 製備2-((反)-1,4-二羥基-4-甲基環己基)乙醛(方法A)
在0℃下,向(反)-1-烯丙基-4-甲基環己烷-1,4-二醇(0.98g,5.76mmol)於二噁烷(40mL)及水(10mL)中之溶液中添加2,6-二甲基吡啶(1.341mL,11.51mmol)、四氧化鋨(水中之4%)(0.704mL,0.115mmol)及過碘酸鈉(4.92g,23.03mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有1N HCl(水溶液)(25mL)之分液漏斗中。用乙酸乙酯(20×50mL)萃取水層。(難以自水層萃取產物。)經合併之有機層用NaHCO3飽和溶液(8mL)洗滌,經MgSO4乾燥,過濾且濃縮。碳酸氫鹽洗滌液之TLC顯示一些產物進入水層中。濃縮此層。將殘餘物懸浮於二氯甲烷中且與來自有機萃取物之殘餘物一起藉由矽膠管柱層析法(具有3%甲醇之70%乙酸乙酯/30%己烷→具有3%甲醇之100%乙酸乙酯;120g管柱)純化獲得呈白色固體狀之2-((反)-1,4-二羥基-4-甲基環己基)乙醛(0.78g,4.53mmol,
79%產率):1H NMR(400MHz,氯仿-d)δ 9.91(t,J=1.6Hz,1H),2.65(d,J=1.8Hz,2H),1.91-1.73(m,4H),1.69-1.62(m,2H),1.53-1.46(m,2H),1.28(s,3H)。
步驟4a. 製備2-((反)-1,4-二羥基-4-甲基環己基)乙醛之替代方法(方法B)
在250mL圓底燒瓶中,將(反)-1-烯丙基-4-甲基環己烷-1,4-二醇(1.00g,5.87mmol)溶解於CH2Cl2(50mL)及MeOH(10mL)中。添加N-甲基嗎啉-N-氧化物(NMO)(0.826g,7.05mmol)且將混合物冷卻至-78℃[Schwartz,C.,Raible,J.,Mott,K.,Dussault,P.H.Org.Lett.2006,8,3199-3201]。將臭氧鼓泡通過反應混合物直至溶液用臭氧飽和(變為藍色)且此後若干分鐘(總計時間10分鐘)。氮氣接著鼓泡通過反應混合物直至藍色消失。接著添加二甲基硫醚(4.34mL,58.7mmol)且在0℃下攪拌反應混合物2.5小時。真空濃縮混合物。藉由矽膠管柱層析法(具有1%甲醇之50%乙酸乙酯/50%己烷→具有1%甲醇之95%乙酸乙酯/5%己烷;80g管柱)純化產物獲得呈白色固體狀之2-((反)-1,4-二羥基-4-甲基環己基)乙醛(937mg,5.44mmol,93%產率):1H NMR(400MHz,氯仿-d)δ 9.90(s,1H),2.65(s,2H),1.89-1.74(m,4H),1.69-1.62(m,2H),1.52-1.46(m,2H),1.28(s,3H);13C NMR(100MHz,氯仿-d)δ 203.02,69.65,68.45,55.15,33.34,32.46,30.90。
步驟4b. 製備2-((順)-1,4-二羥基-4-甲基環己基)乙醛
在0℃下,向(順)-1-烯丙基-4-甲基環己烷-1,4-二醇(185mg,1.087mmol)於二噁烷(8mL)及水(2mL)中之溶液添加2,6-二甲基吡啶(0.253mL,2.173mmol)、四氧化鋨(水中之4%)(0.133mL,0.022mmol)及過碘酸鈉(930mg,4.35mmol)。反應混合物隨著冰-水浴融化
升溫至室溫且同時攪拌14小時。將混合物轉移至含有1N HCl(水溶液)(15mL)之分液漏斗中。用乙酸乙酯(10mL)萃取水層。第一萃取後,用氯化鈉使水層飽和且用乙酸乙酯(17×10mL)萃取水層。經合併之有機層用NaHCO3飽和水溶液(2mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之8%→12%甲醇;40g管柱)純化產物獲得呈無色油狀之2-((順)-1,4-二羥基-4-甲基環己基)乙醛(146mg,0.848mmol,78%產率):1H NMR(400MHz,氯仿-d)δ 9.91(t,J=1.8Hz,1H),2.65(d,J=2.0Hz,2H),1.91-1.76(m,4H),1.63-1.46(m,4H),1.26(s,3H)。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
將(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(1.00g,1.524mmol)及2-((反)-1,4-二羥基-4-甲基環己基)乙醛(0.420g,2.439mmol)溶解於MeOH(12.5mL)及乙酸(2.5mL)中。添加硼烷-2-甲基吡啶複合物(0.261g,2.439mmol)且在室溫下攪拌混合物14小時。向反應混合物中添加額外2-((反)-1,4-二羥基-4-甲基環己基)乙醛(0.131g,0.762mmol,0.5當量)及硼烷-2-甲基吡啶複合物(0.082g,0.762mmol,0.5當量)且繼續攪拌1小時。藉由添加水(5mL)及固體碳酸鈉中和反應混合物。將混合物轉移至含有碳酸氫鈉飽和水溶液(50mL)的分液漏斗中。用乙酸乙酯(7×50mL)萃取水層。經合併之有機層用鹽水(15mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(具有5%甲醇之20%乙酸乙酯/80%己烷→具有5%甲醇之90%乙酸乙酯/10%己烷;120g管柱,25分鐘梯度)純化產物獲得呈無色發泡體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(856mg,1.054mmol,69%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.31(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.2,1.8Hz,1H),4.74(d,J=1.5Hz,1H),4.62-4.56(m,2H),4.53-4.46(m,1H),2.85-2.78(m,1H),
2.77-2.70(m,1H),2.66-2.55(m,2H),2.18-1.02(m,37H),1.69(s,3H),1.30(s,3H),1.06(s,3H),0.98(s,3H),0.91(s,3H),0.91(s,3H),0.86(s,3H);LC/MS m/e 812.6[(M+H)+,C53H79FNO4計算值812.6],tR=4.89min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(1.234mL,2.469mmol)處理(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(401mg,0.494mmol)於1,4-二噁烷(7.5mL)及EtOH(2.5mL)中之水溶液。在70℃下加熱反應混合物2.5小時。混合物冷卻至室溫,用甲醇(4mL)稀釋(溶解沈澱物),經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-4)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(267mg,0.316mmol,64%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.27-5.22(m,1H),4.82(s,1H),4.72(s,1H),4.66-4.57(m,1H),4.55-4.44(m,1H),3.42-3.35(m,2H),2.89-2.81(m,1H),2.61(d,J=16.9Hz,1H),2.31-1.34(m,35H),1.75(s,3H),1.30(s,3H),1.17(s,3H),1.15-1.11(m,2H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 722.6[(M+H)+,C46H73FNO4計算值722.6],tR=4.36min(方法2-2);HPLC(方法2-1):t R=19.03min;HPLC(方法2-2):t R=20.26min。
步驟1. 製備(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
將(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(120mg,0.183mmol)及2-((反)-1,4-二羥基-4-甲基環己基)乙醛(56.7mg,0.329mmol)溶解於
MeOH(1.5mL)及乙酸(0.3mL)中。添加硼烷-2-甲基吡啶複合物(35.2mg,0.329mmol)且在室溫下攪拌混合物16小時。混合物轉移至含有碳酸氫鈉飽和水溶液(20mL)及碳酸鈉飽和水溶液(2mL)之分液漏斗中。用二氯甲烷(4×25mL)萃取水層。經合併之有機層用鹽水(15mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(具有5%甲醇之20%乙酸乙酯/80%己烷→具有5%甲醇之90%乙酸乙酯/10%己烷;80g管柱,20分鐘梯度)純化產物獲得呈無色發泡體狀之(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(96.7mg,0.119mmol,65%產率):1H NMR(500MHz,氯仿-d)δ 7.39-7.31(m,5H),5.33(br.s.,1H),5.22-5.15(m,2H),5.11(dd,J=6.1,1.5Hz,1H),4.73(s,1H),4.62-4.55(m,2H),4.52-4.45(m,1H),2.83-2.69(m,2H),2.65-2.53(m,2H),2.21-0.87(m,37H),1.69(s,3H),1.29(s,3H),1.05(s,3H),0.97(s,3H),0.93(s,3H),0.88(s,3H),0.86(s,3H);LC/MS m/e 812.6[(M+H)+,C53H79FNO4計算值812.6],tR=4.58min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.292mL,0.585mmol)處理(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(95mg,0.117mmol)於1,4-二噁烷(1.5mL)及MeOH(0.5mL)中之溶液。在70℃下加熱反應混合物4小時。反應完成。將混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-4)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(R)-4-
((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(40.8mg,0.049mmol,42%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=5.4Hz,1H),4.83(s,1H),4.72(s,1H),4.66-4.57(m,1H),4.55-4.47(m,1H),3.43-3.36(m,2H),2.90-2.82(m,1H),2.62(d,J=16.9Hz,1H),2.38-2.28(m,1H),2.26-1.35(m,34H),1.75(s,3H),1.31(s,3H),1.17(s,3H),1.14(d,J=9.5Hz,2H),1.10(s,3H),1.02(s,3H),0.98(s,3H),0.95(s,3H);LC/MS m/e 722.6[(M+H)+,C46H73FNO4計算值722.6],tR=4.34min(方法2-2);HPLC(方法2-5):t R=11.74min;HPLC(方法2-6):t R=11.29min。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
3a-((2-((順)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.152mmol)、2-((順)1,4-二羥基-4-甲基環己基)乙醛(52.5mg,0.305mmol)及硼烷-2-甲基吡啶複合物(32.6mg,0.305mmol)於MeOH(1.4mL)及乙酸(0.35mL)中之混合物18小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;40g管柱,λ=220nm)純化產物獲得呈白色發泡體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(72.5mg,0.089mmol,59%產率):1H NMR(500MHz,氯仿-d)δ 7.38-7.34(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.1,1.5Hz,1H),4.73(d,J=1.7
Hz,1H),4.62-4.56(m,2H),4.53-4.46(m,1H),2.83-2.75(m,1H),2.73-2.66(m,1H),2.64-2.52(m,2H),2.18-1.00(m,37H),1.69(s,3H),1.24(s,3H),1.07(s,3H),0.98(s,3H),0.91(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 812.7[(M+H)+,C53H79FNO4計算值812.6],tR=4.78min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.200mL,0.400mmol)處理(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(65mg,0.080mmol)於1,4-二噁烷(1.0mL)及EtOH(0.5mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。產物(37mg)含有大量雜質(約10%)。產物接著藉由逆相製備型HPLC(方法2-5)再純化獲得呈白色非晶形固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1,4-二羥基-4-甲基環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(22.1mg,33%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.83(s,1H),4.72(s,1H),4.64-4.56(m,1H),4.55-4.46(m,1H),3.44-3.37(m,1H),3.36-3.28(m,1H),2.91-2.82(m,1H),2.61(d,J=16.6Hz,1H),2.31-1.11(m,37H),1.75(s,3H),1.27(s,3H),1.17(s,3H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 722.6[(M+H)+,C46H73FNO4計算值722.6],t R=4.34min(方法2-2);HPLC(方法2-1):t R=18.87min;HPLC(方法2-2):t R=20.20min。
步驟1. 製備4-甲基苯磺酸1,4-二氧雜螺[4.5]癸-8-基酯
向1,4-二氧雜螺[4.5]癸-8-醇(10g,63.2mmol)、三乙胺(13.22mL,95.0mmol)及N,N-二甲基吡啶-4-胺(0.772g,6.32mmol)於CH2Cl2(400mL)中之0℃溶液中逐份添加4-甲基苯-1-磺醯氯(13.26g,69.5mmol)。使反應混合物升溫至室溫,同時攪拌16小時。反應混合物用CH2Cl2(400mL)稀釋且用水(2×400mL)洗滌。經合併之有機層經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法純化(己烷中之0%→30%乙酸乙酯;粗產物分成一半且在兩個330g管柱上純化)產物獲得4-甲基苯磺酸1,4-二氧雜螺[4.5]癸-8-基酯(19.6g,62.7mmol,99%產率):1H NMR(400MHz,CDCl3)δ 7.82(d,J=8.3Hz,2H),7.35(d,J=8.0Hz,2H),4.66(tt,J=6.0,3.0Hz,1H),3.98-3.88(m,4H),2.47(s,3H),1.95-1.74(m,5H),1.63-1.51(m,3H);LC/MS(ESI)m/e 335.2[(M+Na)+,C15H20O5SNa計算值335.1],tR=2.06min(方法2-1)。
步驟2. 製備8-(甲基硫基)-1,4-二氧雜螺[4.5]癸烷
向硫代甲醇鈉(13.19g,188mmol)於MeOH(80mL)中之溶液中添加含4-甲基苯磺酸1,4-二氧雜螺[4.5]癸-8-基酯(19.6g,62.7mmol)之乙醇(26.7mL)。在密封壓力容器中,在80℃下加熱反應混合物16小時。LC-MS顯示形成所要產物。將反應混合物分配於乙酸乙酯與水之
間。用乙酸乙酯(3×250mL)萃取水層且真空濃縮經合併之有機層。將殘餘物分配於CH2Cl2與碳酸氫鈉溶液飽和水溶液之間。用額外CH2Cl2萃取水層。經合併之有機層經硫酸鈉乾燥,真空濃縮且藉由矽膠管柱層析法(100%己烷→具有5%甲醇之25%乙酸乙酯/75%己烷;330g管柱)純化呈無色油狀之8-(甲基硫基)-1,4-二氧雜螺[4.5]癸烷(9.6g,51.0mmol,81%產率):1H NMR(400MHz,CDCl3)δ 3.93(s,4H),2.62(tt,J=9.9,3.8Hz,1H),2.08(s,3H),2.02-1.93(m,2H),1.87-1.78(m,2H),1.72-1.52(m,4H);LC/MS(ESI)m/e 189.2[(M+H)+,C9H16O2S計算值189.1],tR=1.91min(方法2-1)。
步驟3. 製備8-(甲基磺醯基)-1,4-二氧雜螺[4.5]癸烷
在0℃下,向8-(甲基硫基)-1,4-二氧雜螺[4.5]癸烷(9.6g,51.0mmol)於CH2Cl2(400mL)中之溶液中添加mCPBA(22.85g,102mmol)。溶液升溫至室溫且攪拌15小時。反應混合物轉移至含有1N氫氧化鈉水溶液(200mL)之分液漏斗中且用乙酸乙酯(3×200mL)萃取。經合併之有機層用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮獲得8-(甲基磺醯基)-1,4-二氧雜螺[4.5]癸烷(9.42g,42.8mmol,84%產率)。產物未經進一步純化即用於下一步驟中。1H NMR(400MHz,CDCl3)δ 3.99-3.95(m,4H),2.90-2.80(m,1H),2.85(s,3H),2.29-2.19(m,2H),1.98-1.83(m,4H),1.67-1.56(m,2H)。
步驟4. 製備4-(甲基磺醯基)環己酮
在圓底燒瓶中,向8-(甲基磺醯基)-1,4-二氧雜螺[4.5]癸烷溶液(9.4g,42.7mmol)中添加HCl(71.1mL,427mmol)。在室溫下攪拌
反應混合物16小時隔夜。真空部分濃縮反應混合物且分配於EtOAc(200mL)與水(200mL)之間。用EtOAc(3×200mL)萃取水層。經合併之有機層用碳酸氫鈉飽和水溶液、鹽水洗滌,經MgSO4乾燥,過濾且真空濃縮。藉由矽膠管柱層析法(具有1%甲醇之70%乙酸乙酯/30%己烷→具有1%甲醇之100%乙酸乙酯;330g管柱)純化粗產物獲得4-(甲基磺醯基)環己酮(4.7g,26.7mmol,63%產率):1H NMR(400MHz,CDCl3)δ 3.35-3.21(m,1H),2.92(s,3H),2.65-2.56(m,2H),2.54-2.35(m,4H),2.16-2.01(m,2H)。
向(甲基磺醯基)乙烯(10.0g,94mmol)於苯(50mL)中之溶液中添加(丁-1,3-二烯-2-基氧基)三甲基矽烷(14.07g,99mmol)及氫醌(20mg,0.182mmol)。在加熱之前,混合物在-78℃下脫氣若干次。密封內容物且在105℃下加熱48小時。在CDCl3中藉由NMR分析反應物,顯示約10%乙烯基碸殘餘物。添加額外(丁-1,3-二烯-2-基氧基)三甲基矽烷(4mL)且再重新開始加熱48小時。在室溫(約19℃)下,在真空下,將反應混合物蒸發成濃稠膠狀物。混合物用丙酮(250mL)再稀釋,導致形成澄清溶液。在冰浴中冷淬混合物直至冷卻。添加4mL 0.25N HCl(在同一冰浴中預冷淬)導致形成混濁混合物,其在0℃下攪拌15分鐘後變得澄清,接著再過10分鐘回到混濁狀態,其餘攪拌時段保持渾濁。在總共約一小時反應時間之後,丙酮溶液經H型短矽膠床過濾,接著用更多丙酮洗滌。在19℃浴槽溫度下,在旋轉蒸發器上濃縮濾液。粗產物再分成兩部分用於純化,各7.75gm。藉由矽膠管柱層析法(30%乙酸乙酯→己烷中100%乙酸乙酯;兩個330g管柱)純化產物獲得呈白色固體狀之4-(甲基磺醯基)環己酮(16.7g,100%產
率):1H NMR(400MHz,氯仿-d)δ 3.29(tt,J=11.0,3.9Hz,1H),2.94(s,3H),2.73-2.62(m,2H),2.58-2.37(m,4H),2.15(qd,J=11.9,4.5Hz,2H)。
步驟1. 製備(順)-1-烯丙基-4-(甲基磺醯基)環己醇及(反)-1-烯丙基-4-(甲基磺醯基)環己醇
在0℃下,經導管向4-(甲基磺醯基)環己酮(1.03g,5.84mmol)於THF(40mL)中之溶液中添加溴化烯丙基鎂(7.60mL,7.60mmol)。在0℃下攪拌反應混合物30分鐘。藉由添加NH4Cl飽和溶液(25mL)來淬滅反應物。將混合物轉移至分液漏斗中且用乙酸乙酯(5×50mL)萃取水層。經合併之有機層用鹽水(20mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(具有1%甲醇之70%乙酸乙酯/30%己烷→具有1%甲醇之100%乙酸乙酯;40g管柱)純化產物獲得呈白色固體狀之(順)-1-烯丙基-4-(甲基磺醯基)環己醇(374mg,1.713mmol,29%產率)及呈無色油狀之(反)-1-烯丙基-4-(甲基磺醯基)環己醇(551mg,
2.52mmol,43%產率)。
(順)-1-烯丙基-4-(甲基磺醯基)環己醇:1H NMR(400MHz,CDCl3)δ 5.96-5.79(m,1H),5.26-5.21(m,1H),5.18(ddt,J=17.1,2.1,1.2Hz,1H),2.85(s,3H),2.80(tt,J=12.5,3.6Hz,1H),2.25(d,J=7.5Hz,2H),2.15-2.07(m,2H),1.97(qd,J=13.0,3.8Hz,2H),1.88-1.81(m,2H),1.52-1.42(m,2H);13C NMR(100MHz,CDCl3)δ 132.50,120.02,69.06,62.26,47.86,36.85,35.67,21.13。
藉由X射線結晶學確認(順)-1-烯丙基-4-(甲基磺醯基)環己醇之結構。
(反)-1-烯丙基-4-(甲基磺醯基)環己醇:1H NMR(400MHz,CDCl3)δ 5.88(ddt,J=17.2,10.1,7.4Hz,1H),5.28-5.16(m,2H),2.98-2.91(m,1H),2.90(s,3H),2.35(d,J=7.5Hz,2H),2.23-2.14(m,2H),2.02-1.93(m,2H),1.90-1.78(m,2H),1.57-1.46(m,2H);13C NMR(100MHz,CDCl3)δ 132.62,120.19,69.20,62.41,48.00,36.98,35.83,21.29。
步驟2a. 製備2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(方法A)
在0℃下,向(順)-1-烯丙基-4-(甲基磺醯基)環己醇(125mg,0.573mmol)於二噁烷(4.4mL)及水(1.1mL)中之溶液中添加2,6-二甲基吡啶(0.133mL,1.145mmol)、四氧化鋨(水中之4%)(0.070mL,0.011mmol)及過碘酸鈉(490mg,2.290mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有1N HCl(水溶液)(10mL)之分液漏斗中。用乙酸乙酯(20×15mL)萃取水層。(難以自
水層萃取產物。)經合併之有機層用NaHCO3飽和溶液(8mL)洗滌,經MgSO4乾燥,過濾且濃縮。碳酸氫鹽洗滌液之TLC顯示一些產物進入水層中。濃縮此層。將殘餘物懸浮於二氯甲烷中且與來自有機萃取物之殘餘物一起藉由矽膠管柱層析法(具有3%甲醇之80%乙酸乙酯/20%己烷→具有3%甲醇之100%乙酸乙酯;40g管柱)純化獲得呈無色油狀之2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(94.4mg,0.429mmol,75%產率),其靜置時固化:1H NMR(400MHz,CDCl3)δ 9.87(t,J=1.3Hz,1H),2.85(s,3H),2.82-2.75(m,1H),2.68(d,J=1.0Hz,2H),2.13-1.98(m,6H),1.50-1.39(m,2H)。
步驟2a. 製備2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(方法B)
在500mL圓底燒瓶中,將(反)-1-烯丙基-4-(甲基磺醯基)環己醇(3.4g,15.57mmol)溶解於CH2Cl2(160mL)及MeOH(32.0mL)中。添加N-甲基嗎啉-N-氧化物(NMO)(2.189g,18.69mmol)且將混合物冷卻至-78℃[Schwartz,C.,Raible,J.,Mott,K.,Dussault,P.H.Org.Lett.2006,8,3199-3201]。將臭氧鼓泡通過反應混合物直至溶液用臭氧飽和(變為藍色)且此後若干分鐘(總計時間25分鐘)。氮氣接著鼓泡通過反應混合物直至藍色消失。接著添加二甲基硫醚(11.52mL,156mmol)且在0℃下攪拌反應混合物16小時。真空濃縮混合物。藉由矽膠管柱層析法(具有1%甲醇之50%乙酸乙酯/50%己烷→具有1%甲醇之95%乙酸乙酯/5%己烷;330g管柱)純化產物獲得呈白色固體狀之2-((1s,4s)-1-羥基-4-(甲基磺醯基)環己基)乙醛(3.31g,15.03mmol,96%產率):1H NMR(400MHz,氯仿-d)δ 9.87(t,J=1.1Hz,1H),2.85(s,3H),2.82-2.76(m,1H),2.67(d,J=1.3Hz,2H),2.13-1.98(m,6H),1.50-1.38(m,2H);13C NMR(101MHz,氯仿-d)δ 202.5,68.9,61.9,54.9,36.8,35.9,20.8。
步驟2b. 製備2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙醛
在0℃下,向(反)-1-烯丙基-4-(甲基磺醯基)環己醇(242mg,1.108mmol)於二噁烷(10mL)及水(2.5mL)中之溶液中添加2,6-二甲基吡啶(0.258mL,2.217mmol)、四氧化鋨(水中之4%)(0.135mL,0.022mmol)及過碘酸鈉(948mg,4.43mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有1N HCl(水溶液)(10mL)之分液漏斗中。用乙酸乙酯(20×20mL)萃取水層。(難以自水層萃取產物。)經合併之有機層用NaHCO3飽和溶液(8mL)洗滌,經MgSO4乾燥,過濾且濃縮。碳酸氫鹽洗滌液之TLC顯示一些產物進入水層中。濃縮此層。將殘餘物懸浮於二氯甲烷中且與來自有機萃取物之殘餘物一起藉由矽膠管柱層析法(具有3%甲醇之80%乙酸乙酯/20%己烷→具有3%甲醇之100%乙酸乙酯;40g管柱)純化獲得呈無色油狀之2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙醛(191mg,0.867mmol,78%產率):1H NMR(400MHz,CDCl3)δ 9.89(t,J=1.3Hz,1H),3.13(br.s.,1H),3.02-2.93(m,1H),2.91(s,3H),2.79(d,J=1.3Hz,2H),2.29-2.17(m,2H),2.13-2.04(m,2H),1.92-1.78(m,2H),1.68-1.57(m,2H)。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(550mg,0.838mmol)、2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(406mg,1.845mmol)及硼烷-2-甲基吡啶複合物(197mg,1.845mmol)於MeOH(8mL)及乙酸(1.6mL)中之混合物14小時。LC/MS顯示具有所要物質以及一些剩餘起始物質的峰。添加額外2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(56mg,0.254mmol,0.3當量)及硼烷-2-甲基吡啶複合物(27mg,
0.252mmol,0.3當量)且繼續攪拌3小時。混合物轉移至含有碳酸氫鈉飽和水溶液(20mL)及碳酸鈉飽和水溶液(2mL)之分液漏斗中。用二氯甲烷(4×50mL)萃取水層。經合併之有機層用鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→70% 9:1丙酮:甲醇/30%己烷,20分鐘梯度;80g管柱,λ=220nm)純化產物獲得呈白色固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(566mg,0.658mmol,78%產率):1H NMR(500MHz,氯仿-d δ 7.41-7.31(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.2,1.8Hz,1H),4.75(d,J=1.8Hz,1H),4.64-4.55(m,2H),4.53-4.46(m,1H),2.85(s,3H),2.83-2.69(m,3H),2.64-2.51(m,2H),2.19-1.02(m,36H),1.70(s,3H),1.06(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,3H),0.86(s,3H);LC/MS m/e 860.6[(M+H)+,C53H79FNO5S計算值860.6],tR=4.63min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(1.561mL,3.12mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(537mg,0.624mmol)於1,4-二噁烷(9mL)及EtOH(3mL)中之溶液。在70℃下加熱反應混合物2.5小時。混合物冷卻至室溫,用甲醇(4mL)稀釋(溶解沈澱物),經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-1)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-
((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(438mg,0.495mmol,79%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.27-5.21(m,1H),4.83(s,1H),4.73(s,1H),4.65-4.56(m,1H),4.55-4.47(m,1H),3.47-3.33(m,2H),3.08-2.99(m,1H),2.96(s,3H),2.89-2.80(m,1H),2.61(d,J=16.8Hz,1H),2.31-1.11(m,37H),1.75(s,3H),1.18(s,3H),1.10(s,3H),1.00(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 770.5[(M+H)+,C46H73FNO5S計算值770.5],tR=4.22min(方法2-2);HPLC(方法2-1):t R=18.75min;HPLC(方法2-2):t R=19.89min。
步驟1. 製備(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五
甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向(R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.152mmol)及2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙醛(60.4mg,0.274mmol)於MeOH(1.2mL)中之懸浮液中添加硼烷-2-甲基吡啶複合物(29.4mg,0.274mmol),隨後乙酸(0.24mL),且在室溫下攪拌混合物16小時。混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)及碳酸鈉飽和水溶液(1mL)之分液漏斗中。用二氯甲烷(4×5mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(具有5%甲醇之20%乙酸乙酯/80%己烷→具有5%甲醇之90%乙酸乙酯/10%己烷;24g管柱)純化產物獲得呈無色發泡體狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(120mg,0.139mmol,92%產率):1H NMR(500MHz,氯仿-d)δ 7.41-7.30(m,5H),5.33(br.s.,1H),5.23-5.15(m,2H),5.11(d,J=5.7Hz,1H),4.74(s,1H),4.64-
4.55(m,2H),4.51-4.45(m,1H),2.85(s,3H),2.83-2.69(m,4H),2.64-2.49(m,2H),2.21-0.90(m,36H),1.70(s,3H),1.05(s,3H),0.98(s,3H),0.93(s,3H),0.88(s,3H),0.85(s,3H);LC/MS m/e 860.6[(M+H)+,C53H79FNO4計算值812.6],tR=4.62min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.334mL,0.668mmol)處理(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(115mg,0.134mmol)於1,4-二噁烷(1.5mL)及MeOH(0.5mL)中之溶液。在70℃下加熱反應混合物4小時。反應完成。將混合物冷卻至室溫。將混合物冷卻至室溫且藉由添加6N HCl(70μL)部分中和。接著經針筒過濾器過濾混合物,且藉由逆相製備型HPLC(方法2-5)純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(R)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((順)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(72.6mg,0.082mmol,61%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.7Hz,1H),4.83(s,1H),4.72(s,1H),4.65-4.57(m,1H),4.54-4.46(m,1H),3.47-3.34(m,2H),3.09-2.99(m,1H),2.96(s,3H),2.90-2.81(m,1H),2.61(d,J=16.8Hz,1H),2.35-1.71(m,21H),1.75(s,3H),1.65-1.32(m,14H),1.17(s,3H),1.13(d,J=6.0Hz,2H),1.09(s,3H),1.02(s,3H),0.97(s,3H),0.95(s,3H);LC/MS m/e 770.5[(M+H)+,C46H73FNO5S計算值770.5],tR=4.33min(方法2-2);HPLC(方法2-5):t R=11.55min;HPLC(方法2-6):t R=11.20min。
步驟1. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(150mg,0.229mmol)、
2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙醛(126mg,0.572mmol)及硼烷-2-甲基吡啶複合物(61.1mg,0.572mmol)於甲醇(2.5mL)及乙酸(0.5mL)中之混合物16小時。混合物轉移至含有碳酸氫鈉飽和水溶液(10mL)及碳酸鈉飽和水溶液(2mL)之分液漏斗中。用二氯甲烷(4×20mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→50% 9:1丙酮:甲醇/50%己烷;24g管柱,λ=220nm)純化產物獲得呈無色膜狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(143mg,0.166mmol,73%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.32(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.1,1.7Hz,1H),4.73(d,J=1.7Hz,1H),4.63-4.56(m,2H),4.52-4.46(m,1H),2.99-2.91(m,1H),2.89(s,3H),2.83-2.76(m,1H),2.71-2.50(m,3H),2.19-1.04(m,36H),1.69(s,3H),1.06(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 860.6[(M+H)+,C53H79FNO5S計算值860.6],tR=4.61min(方法2-3)。
步驟2. 用氫氧化鈉(2M水溶液)(0.232mL,0.465mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(80mg,0.093mmol)於1,4-二噁烷(1mL)及EtOH(0.5mL)中之溶液。在70℃下加熱反應混合物2小時。將混合物冷卻至室溫,經針筒過濾器過濾且藉由逆相製備型HPLC(方法2-1)純化。產物(59mg)含有大量雜質(約5-10%)。產
物接著藉由逆相製備型HPLC(方法2-6)再純化。在旋轉蒸發器上蒸發有機溶劑且凍乾水性混合物獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((反)-1-羥基-4-(甲基磺醯基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(27.2mg,33%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.6Hz,1H),4.83(s,1H),4.72(s,1H),4.66-4.57(m,1H),4.54-4.47(m,1H),3.42(dd,J=8.2,4.7Hz,1H),3.36-3.28(m,1H),3.18-3.10(m,1H),2.98(s,3H),2.91-2.83(m,1H),2.61(d,J=16.6Hz,1H),2.31-1.11(m,37H),1.75(s,3H),1.14(s,3H),1.09(s,3H),1.00(s,3H),0.99(s,3H),0.94(s,3H);LC/MS m/e 770.5[(M+H)+,C46H73FNO5S計算值770.5],tR=4.20min(方法2-2);HPLC(方法2-1):t R=18.74min;HPLC(方法2-2):t R=20.05min。
步驟1. 製備甲烷磺酸4-側氧基環己酯
向4-羥基環己酮(1g,8.76mmol)於二氯甲烷(10mL)中之溶液中添加甲烷磺醯氯(0.746mL,9.64mmol)及三乙胺(1.343mL,9.64mmol)。在室溫下攪拌反應混合物16小時。濃縮混合物且藉由矽膠管柱層析法(0%己烷→60% 9:1丙酮:甲醇/40%己烷,80g管柱,λ=220nm)純化產物獲得呈無色油狀之甲烷磺酸4-側氧基環己酯(1.65g,8.58mmol,98%產率):1H NMR(400MHz,氯仿-d)δ 5.14(tt,J=5.5,2.8Hz,1H),3.11(s,3H),2.75-2.59(m,2H),2.49-2.28(m,4H),2.24-2.06(m,2H)。
步驟2. 製備甲烷磺酸4-烯丙基-4-羥基環己酯
在-78℃下,向溴化烯丙基鎂(9.83mL,9.83mmol)於THF(75mL)中之溶液中添加甲烷磺酸4-側氧基環己酯(1.8g,9.36mmol)。在-78℃下攪拌混合物2小時。藉由添加NH4Cl飽和溶液(60mL)來淬滅反應物。將混合物轉移至分液漏斗中,且分離各層。用乙醚(5×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得呈無色油狀之甲烷磺酸4-烯丙基-4-羥基環己酯(1.15g,4.91mmol,52%產率)。藉由矽膠管柱層析法(10%己烷:乙酸乙酯:MeOH(4:4:1)/90%己烷→50%己烷:乙酸乙酯:MeOH(4:4:1)/50%己烷;120g管柱)純化產物獲得甲烷磺酸4-烯丙基-4-羥基環己酯(1.15g,4.91mmol,52%產率):1H NMR(400MHz,氯仿-d)δ 5.83(ddt,J=17.2,9.9,7.5Hz,1H),5.20-5.04(m,2H),4.68-4.53(m,1H),2.99(s,3H),2.18(d,J=7.3Hz,2H),1.99-1.87(m,4H),1.71(s,2H),1.53-1.37(m,2H)。
步驟3. 製備甲烷磺酸4-羥基-4-(2-側氧基乙基)環己酯
在0℃下,向甲烷磺酸4-烯丙基-4-羥基環己酯(182mg,0.777mmol)於二噁烷(12mL)及水(3.00mL)中之溶液中添加2,6-二甲基吡啶(0.181mL,1.553mmol)、四氧化鋨(t-BuOH中2.5%)(0.195mL,0.016mmol)及過碘酸鈉(665mg,3.11mmol)。反應混合物隨著冰-水浴融化升溫至室溫且同時攪拌14小時。將混合物轉移至含有水(50mL)及NaHCO3飽和水溶液(50mL)的分液漏斗中。用乙酸乙酯(3×50mL)萃取水層。經合併之有機層用鹽水(50mL)洗滌,經MgSO4乾燥,
過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之0%→8%甲醇;40g管柱)純化產物獲得呈無色油狀之甲烷磺酸4-羥基-4-(2-側氧基乙基)環己酯(91mg,0.385mmol,50%產率):1H NMR(400MHz,氯仿-d)δ 9.86(t,J=1.3Hz,1H),4.66(tt,J=10.5,4.2Hz,1H),3.03(s,3H),2.65(d,J=1.3Hz,2H),2.12-2.00(m,2H),2.00-1.89(m,4H),1.54-1.43(m,2H)。
步驟4. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基-4-((甲基磺醯基)氧基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(60mg,0.091mmol)、甲烷磺酸4-羥基-4-(2-側氧基乙基)環己酯(32.4mg,0.137mmol)及硼烷-2-甲基吡啶複合物(14.68mg,0.137mmol)於MeOH(1mL)及乙酸(0.200mL)中之混合物16小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(5mL)的分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮獲得(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥
基-4-((甲基磺醯基)氧基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(15mg,17%產率)。粗產物未經進一步純化即用於下一步驟中。LC/MS m/e 876.6[(M+H)+,C53H78FNO6S計算值876.6],tR=2.66min(方法2-1)。
步驟5. 將氫氧化鈉(0.038mL,0.150mmol)添加至(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基-4-((甲基磺醯基)氧基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(13.14mg,0.015mmol)於二噁烷(0.5mL)及乙醇(0.125mL)中之溶液中。在70℃下攪拌反應混合物16小時。粗物質經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-2,經10分鐘梯度50-100% B,接著在100% B下保持15分鐘)純化獲得經純化之產物,(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-羥基-4-((甲基磺醯基)氧基)環己基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸(3.2mg,3.87μmol,26%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=5.2Hz,1H),4.84(s,1H),4.76-4.67(m,2H),4.65-4.57(m,1H),4.56-4.47(m,1H),3.79(s,1H),3.40(d,J=12.0Hz,1H),3.35-3.25(m,1H),3.15(q,J=7.1Hz,1H),3.10(s,3H),2.90(br.s.,1H),2.62(d,J=17.2Hz,1H),2.35-0.91(m,35H),1.75(s,3H),1.20(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.97(s,3H);LC/MS m/e 786.8[(M+H)+,C46H72FNO6S計算值786.5],tR=2.46min(方法2.1);HPLC(方法2-3):t R=2.54min;HPLC(方法2-4):t R=2.29min。
步驟1. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.152mmol)、
2-氯乙醛(0.028mL,0.229mmol)及硼烷-2-甲基吡啶複合物(24.46mg,0.229mmol)於MeOH(1mL)及乙酸(0.2mL)中之混合物18小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(10mL)的分液漏斗中。用二氯甲烷(4×15mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→50% 9:1丙酮:甲醇/50%己烷;40g管柱,λ=220nm)純化產物獲得呈白色泡沫體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(57mg,0.079mmol,52%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.31(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.14(dd,J=6.1,1.7Hz,1H),4.73(d,J=2.0Hz,1H),4.63-4.56(m,2H),4.53-4.46(m,1H),3.72-3.65(m,2H),2.85-2.72(m,2H),2.67-2.57(m,2H),2.17-1.02(m,27H),1.71(s,3H),1.08(s,3H),0.97(s,3H),0.92(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 718.6[(M+H)+,C46H66ClFNO2計算值718.5],tR=4.82min(方法2-3)。
步驟2. 在80℃下加熱(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(15mg,0.021mmol)、4-甲基哌啶-4-醇(7.21mg,0.063mmol)、惠寧鹼(Hunig's base)(0.018mL,0.104mmol)及碘化鉀(4.16mg,0.025mmol)於DMSO(0.4mL)中之混合物14小時。接著將反應混合物冷卻至室溫且添加NaOH(0.052mL,0.104mmol)。在70℃下加熱反應混合物2小時。過濾反應混合物
且藉由逆相製備型HPLC(方法2-1)純化獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-羥基-4-甲基哌啶-1-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.2 TFA(9.5mg,48%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.6Hz,1H),4.85(s,1H),4.74(s,1H),4.65-4.56(m,1H),4.55-4.47(m,1H),3.85-3.70(m,4H),3.56(br.s.,2H),3.43(br.s.,2H),2.85-2.76(m,1H),2.61(d,J=16.9Hz,1H),2.31-1.11(m,32H),1.75(s,3H),1.35(s,3H),1.15(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H);LC/MS(ESI)m/e 707.6[(M+H)+,C45H72FN2O3計算值707.6],t R=4.31min(方法2-2);HPLC(方法2-1):t R=18.63min;HPLC(方法2-2):t R=19.58min。
步驟1. 製備3-(2-溴乙基)噁唑啶-2-酮
向3-(2-羥基乙基)噁唑啶-2-酮(1.0g,7.63mmol)於CH2Cl2(30mL)中之溶液中添加四溴化碳(3.03g,9.15mmol)。將溶液冷卻至0℃後,分部分添加三苯膦(2.80g,10.68mmol)。在室溫下攪拌所得溶液18小時。濃縮混合物。將殘餘物懸浮於乙醚(75mL)中,且攪拌30分鐘。藉由過濾移除固體且濃縮濾液。藉由矽膠管柱層析法(含1%→4%甲醇之二氯甲烷;220g管柱)純化產物。自層析法分離之第一化合物主要為呈無色油狀之產物(1.01g),其靜置時固化(由於存在三苯膦氧化物)。產物藉由矽膠管柱層析法(含0.5%→3%甲醇之CH2Cl2;120g管柱)再純化獲得呈無色油狀之3-(2-溴乙基)噁唑啶-2-酮(785mg,4.05mmol,53%產率)。1H NMR指示產物被三苯膦氧化物污染。三苯膦氧化物以7:1莫耳比產物比三苯膦氧化物形式存在。產物未經進一步純化即用於下一步驟中。1H NMR(400MHz,氯仿-d)δ 4.46-4.35(m,2H),3.82-3.67(m,4H),3.58-3.52(m,2H)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基噁唑啶-3-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向烘乾之壓力容器中的(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(70mg,0.107mmol)、3-(2-溴乙基)噁唑啶-2-酮(72.5mg,0.373mmol)、磷酸三鉀(91mg,0.427mmol)與碘化鉀(62.0mg,0.373mmol)之混合物中添加乙腈(1.0mL)。密封蓋子且在120℃下加熱反應混合物14小時。將混合物轉移至含有水(10mL)之分液漏斗中。用二氯甲烷(3×15mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→30% 9:1丙酮:甲醇/70%己烷;24g管柱,λ=220nm)純化產物獲得呈無色發泡體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基噁唑啶-3-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(54.5mg,0.071mmol,66%產率):1H NMR(500MHz,氯仿-d)δ 7.41-7.32(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.13(dd,J=6.1,1.7Hz,1H),4.72(d,J=2.0Hz,1H),4.63-4.55(m,2H),4.53-4.44(m,1H),4.38-4.32(m,2H),3.77-3.62(m,2H),3.49-3.41(m,1H),3.33(dt,J=14.1,5.5Hz,1H),2.70(ddd,J=12.0,7.3,5.0Hz,1H),2.65-2.52(m,3H),2.19-1.10(m,27H),1.70(s,3H),1.06(s,3H),0.96(s,3H),0.91(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 769.6[(M+H)+,C49H70FN2O4計算值769.5],t R=4.65min(方法2-2)。
步驟3. 用氫氧化鈉(2M水溶液)(0.172mL,0.345mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基噁唑啶-3-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并
[a]-9-基)環己-3-烯甲酸苯甲酯(53mg,0.069mmol)於1,4-二噁烷(0.7mL)及EtOH(0.35mL)中之溶液。在70℃下加熱反應混合物2小時。混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-1)純化獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基噁唑啶-3-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(31.4mg,62%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.7Hz,1H),4.86(s,1H),4.74(s,1H),4.64-4.57(m,1H),4.55-4.43(m,3H),3.84(q,J=8.2Hz,1H),3.80-3.72(m,3H),3.65-3.58(m,1H),3.57-3.51(m,1H),2.85-2.77(m,1H),2.61(d,J=16.6Hz,1H),2.32-1.11(m,27H),1.76(s,3H),1.17(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 679.5[(M+H)+,C42H64FN2O4計算值679.5],t R=4.18min(方法2-2);HPLC(方法2-1):t R=18.68min;HPLC(方法2-2):t R=19.92min。
步驟1. 製備4-甲基苯磺酸2-(2-側氧基咪唑啶-1-基)乙酯
在0℃下向1-(2-羥基乙基)咪唑啶-2-酮(500mg,3.84mmol)於吡啶(5mL)中之溶液中添加對甲苯磺醯氯(806mg,4.23mmol)。攪拌反應混合物16小時,同時藉由冰-水浴之散熱使反應混合物緩慢升溫至室溫。將混合物轉移至含有乙酸乙酯(50mL)之分液漏斗中。用1N HCl(2×25mL)洗滌水層。經合併之有機層用飽和NaHCO3(25mL)、鹽水(25mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(二氯甲烷中之3%→7%甲醇;120g管柱)純化產物獲得呈黃色固體狀之4-甲基苯磺酸2-(2-側氧基咪唑啶-1-基)乙酯(356mg,1.252mmol,33%產率):1H NMR(400MHz,氯仿-d)δ 7.86-7.77(m,2H),7.38(d,J=8.0Hz,2H),4.51(br.s.,1H),4.17(t,J=5.0Hz,2H),3.59-3.52(m,2H),3.47(t,J=5.0Hz,2H),3.43-3.35(m,2H),2.48(s,3H);LC/MS m/e 285.1[(M+H)+,C12H17N2O4S計算值285.1],t R=1.58min(方法2-1)。
步驟2. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
在小瓶中組合(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(40mg,0.061mmol)、4-甲基苯磺酸2-(2-側氧基咪唑啶-1-基)乙酯(69.4mg,0.244mmol)、磷酸三鉀(64.7mg,0.305mmol)及碘化鉀(50.6mg,0.305mmol)。添加乙腈(1mL),密封小瓶,且在120℃下加熱反應混合物16小時。將混合物轉移至含有水(10mL)之分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮/甲醇/90%己烷→40% 9:1丙酮/甲醇/60%己烷;40g管柱,λ=220nm)純化產物獲得呈無色泡沫體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(31mg,0.040mmol,66%產率):1H NMR(500MHz,氯仿-d)δ 7.38-7.33(m,5H),5.33(br.s.,1H),5.19(d,J=2.4Hz,2H),5.13(dd,J=6.1,1.7Hz,1H),4.72(d,J=1.8
Hz,1H),4.63-4.55(m,2H),4.53-4.45(m,1H),4.32(s,1H),3.61-3.47(m,3H),3.46-3.35(m,4H),3.24(dt,J=13.8,5.3Hz,1H),2.70-2.52(m,4H),2.20-0.85(m,26H),1.70(s,3H),1.05(s,3H),0.96(s,3H),0.91(s,3H),0.90(s,3H),0.85(s,3H);LC/MS m/e 768.6[(M+H)+,C49H71FN3O3計算值768.5],t R=4.61min(方法2-2)。
步驟3. 用氫氧化鈉(0.101mL,0.202mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(31mg,0.040mmol)於1,4-二噁烷(0.5mL)及EtOH(0.25mL)中之溶液。在70℃下加熱反應混合物2小時。混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-1)純化獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(19.0mg,58%產率)。
1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.24(d,J=4.6Hz,1H),4.89(s,1H),4.75(s,1H),4.65-4.56(m,1H),4.55-4.46(m,1H),3.73-3.66(m,1H),3.65-3.51(m,6H),3.47-3.43(m,2H),2.84-2.75(m,1H),2.61(d,J=17.5Hz,1H),2.32-1.08(m,26H),1.76(s,3H),1.15(s,3H),1.10(s,3H),1.00(s,3H),0.99(s,3H),0.94(s,3H);LC/MS m/e 678.5[(M+H)+,C42H65FN3O3計算值678.5],t R=4.30min(方法2-2);HPLC(方法2-1):t R=18.88min;HPLC(方法2-2):t R=20.30min。
步驟1. 製備4-甲基苯磺酸2-(3-甲基-2-側氧基咪唑啶-1-基)乙酯
在0℃下,向4-甲基苯磺酸2-(2-側氧基咪唑啶-1-基)乙酯(135mg,0.475mmol)於THF(4mL)中之溶液中添加雙(三甲基矽烷基)胺基鈉(0.522mL,0.522mmol)。攪拌5分鐘後,經注射器添加碘甲烷(0.119mL,1.899mmol)。移除冷卻浴且使混合物升溫至室溫,且攪拌2小時。將混合物轉移至含有NaHCO3飽和水溶液(10mL)的分液漏斗中。用乙酸乙酯(4×10mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(CH2Cl2中之1%→5%甲醇;40g管柱)純化產物獲得呈淺綠色油狀物之4-甲基苯磺酸2-(3-甲基-2-側氧基咪唑啶-1-基)乙酯(91.3mg,0.306mmol,
65%產率):1H NMR(400MHz,氯仿-d)δ 7.83-7.77(m,2H),7.37(d,J=8.0Hz,2H),4.15(t,J=5.1Hz,2H),3.45(t,J=5.0Hz,2H),3.43-3.37(m,2H),3.29-3.23(m,2H),2.77(s,3H),2.47(s,3H);LC/MS(ESI)m/e 299.2[(M+H)+,C13H19N2O4S計算值299.1],t R=1.61min(方法2-1)。
步驟2. 製備1-(2-溴乙基)-3-甲基咪唑啶-2-酮
在室溫下,向4-甲基苯磺酸2-(3-甲基-2-側氧基咪唑啶-1-基)乙酯(158mg,0.530mmol)於THF(5mL)中之溶液中添加溴化鋰(138mg,1.589mmol)。在室溫下攪拌反應混合物隔夜。接著在60℃下加熱反應混合物3小時。將混合物轉移至含有NaHCO3飽和水溶液(5mL)及水(5mL)的分液漏斗中。用乙酸乙酯(4×10mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(含2%→5%甲醇之CH2Cl2;40g管柱)純化產物獲得呈黃色油狀之1-(2-溴乙基)-3-甲基咪唑啶-2-酮(92.3mg,0.446mmol,84%產率):1H NMR(400MHz,氯仿-d)δ 3.65-3.60(m,2H),3.52-3.44(m,4H),3.38-3.32(m,2H),2.82(s,3H);LC/MS(ESI)m/e 207.2[(M+H)+,C6H12BrN2O計算值207.0],t R=1.70min(方法2-1)。
步驟3. 製備(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯
向烘乾之壓力容器中的(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(60mg,0.091mmol)、1-(2-溴乙基)-3-甲基咪唑啶-2-酮(56.8mg,0.274mmol)、磷酸三鉀(78mg,0.366mmol)與碘化鉀(45.6mg,0.274mmol)之混合物中添加乙腈(1.0mL)。密封蓋子且在120℃下加熱反應混合物14小時。將混合物轉移至含有水(5mL)之分液漏斗中。用二氯甲烷(3×10mL)萃取水層。經合併之有機層用鹽水(5mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→50% 9:1丙酮:甲醇/50%己烷;24g管柱,λ=220nm)純化產物獲得呈白色泡沫狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(47.7mg,0.061mmol,66%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.33(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.14(dd,J=6.2,1.6Hz,1H),4.72(d,J=2.0Hz,1H),4.63-4.56(m,2H),4.53-4.47(m,1H),3.45-3.20(m,6H),2.82(s,3H),2.68-2.51(m,4H),2.19-0.87(m 27H),1.70(s,3H),1.03(s,3H),0.96(s,3H),0.91(s,3H),0.90(s,3H),0.85(s,3H);
LC/MS m/e 782.6[(M+H)+,C50H73FN3O3計算值782.6],t R=4.56min(方法2-3)。
步驟4. 用氫氧化鈉(2M水溶液)(0.147mL,0.294mmol)處理(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸苯甲酯(46mg,0.059mmol)於1,4-二噁烷(0.7mL)及EtOH(0.35mL)中之溶液。在70℃下加熱反應混合物2小時。混合物冷卻至室溫,經針筒過濾器過濾,且藉由逆相製備型HPLC(方法2-1)純化獲得呈白色非晶形固體狀之(S)-1-(氟甲基)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-五甲基-3a-((2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)胺基)-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)環己-3-烯甲酸.TFA(35.6mg,74%產率):1H NMR(500MHz,Acetic Acid-d4)δ 5.39(br.s.,1H),5.25(d,J=4.7Hz,1H),4.88(s,1H),4.75(s,1H),4.64-4.57(m,1H),4.55-4.47(m,1H),3.63-3.40(m,8H),2.84(s,3H),2.85-2.81(m,1H),2.61(d,J=16.5Hz,1H),2.31-1.12(m,27H),1.76(s,3H),1.15(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H);LC/MS m/e 692.6[(M+H)+,C43H67FN3O3計算值692.5],tR=4.19min(方法2-2);HPLC(方法2-1):t R=18.80min;HPLC(方法2-2):t R=20.44min。
步驟1. 製備4-乙醯基-3,3-二甲基哌嗪-2-酮
在0℃下,向3,3-二甲基哌嗪-2-酮(50mg,0.390mmol)於CH2Cl2(1.2mL)中之溶液中添加N,N-二異丙基乙胺(0.204mL,1.170mmol),隨後緩慢添加乙醯氯(0.031mL,0.429mmol)。在0℃下攪拌反應混合物4小時。接著濃縮混合物。藉由矽膠管柱層析法(具有0.2% NH4OH之25% 4:1 CH2Cl2:MeOH/75% CH2Cl2→具有0.2% NH4OH之100% 4:1 CH2Cl2:MeOH;40g管柱,λ=220nm)純化產物獲得呈無色固體狀之4-乙醯基-3,3-二甲基哌嗪-2-酮(59.6mg,0.350mmol,90%產率):1H NMR(400MHz,氯仿-d)δ 3.64-3.57(m,2H),3.46-3.39(m,2H),2.16(s,3H),1.77(s,6H);LC/MS(ESI)m/e 171.3[(M+H)+,C8H15N2O2計算值171.2],t R=0.43min(方法2-1)。
步驟2. 製備(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-
3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯
在室溫下攪拌(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-胺基-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(100mg,0.152mmol)、2-氯乙醛(0.028mL,0.229mmol)及硼烷-2-甲基吡啶複合物(24.46mg,0.229mmol)於MeOH(1mL)及乙酸(0.2mL)中之混合物18小時。將混合物轉移至含有碳酸氫鈉飽和水溶液(10mL)的分液漏斗中。用二氯甲烷(4×15mL)萃取水層。經合併之有機層用鹽水(10mL)洗滌,經MgSO4乾燥,過濾且濃縮。藉由矽膠管柱層析法(10% 9:1丙酮:甲醇/90%己烷→50% 9:1丙酮:甲醇/50%己烷;40g管柱,λ=220nm)純化產物獲得呈無色泡沫體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(57mg,0.079mmol,52%產率):1H NMR(500MHz,氯仿-d)δ 7.40-7.31(m,5H),5.33(br.s.,1H),5.23-5.16(m,2H),5.14(dd,J=6.1,1.7Hz,1H),4.73(d,J=2.0
Hz,1H),4.63-4.56(m,2H),4.53-4.46(m,1H),3.72-3.65(m,2H),2.85-2.72(m,2H),2.67-2.57(m,2H),2.17-1.02(m,27H),1.71(s,3H),1.08(s,3H),0.97(s,3H),0.92(s,3H),0.90(s,3H),0.86(s,3H);LC/MS m/e 718.6[(M+H)+,C46H66ClFNO2計算值718.5],tR=4.82min(方法2-3)。
步驟3. 在0℃下,在氮氣下,向(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-氯乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸苯甲酯(22mg,0.031mmol)、4-乙醯基-3,3-二甲基哌嗪-2-酮(15.64mg,0.092mmol)及溴化四丁基銨(9.87mg,0.031mmol)於THF(0.6mL)中之混合物中添加雙(三甲基矽烷基)胺基鈉(0.092mL,0.092mmol)。在0℃下攪拌混合物5分鐘。移除冷卻浴且接著在75℃下加熱反應混合物14小時。濃縮混合物且將殘餘物溶解於二噁烷/甲醇/水中且藉由添加2N HCl(0.10mL)中和。過濾溶液且藉由逆相製備型HPLC(方法2-1)純化獲得呈白色非晶形固體狀之(S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-乙醯基-3,3-二甲基-2-側氧基哌嗪-1-基)乙基)胺基)-5a,5b,8,8,11a-五甲基-1-(丙-1-烯-2-基)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-十八氫-1H-環戊并[a]-9-基)-1-(氟甲基)環己-3-烯甲酸.TFA(9.6mg,34%產率):1H NMR(500MHz,乙酸-d4)δ 5.39(br.s.,1H),5.25(d,J=4.7Hz,1H),4.88(s,1H),4.76(s,1H),4.65-4.57(m,1H),4.55-4.47(m,1H),3.96-3.76(m,3H),3.73-3.64(m,3H),3.53(t,J=4.1Hz,2H),2.82(t,J=11.1Hz,1H),2.61(d,J=16.6Hz,1H),2.31-1.12(s,27H),2.22(s,3H),1.79(s,3H),1.77(s,6H),1.22(s,3H),1.10(s,3H),1.01(s,3H),0.99(s,3H),0.96(s,3H);LC/MS(ESI)m/e 762.6
[(M+H)+,C47H73FN3O4計算值762.6],t R=4.29min(方法2-2);HPLC(方法2-1):t R=19.04min;HPLC(方法2-2):t R=20.23min。
HIV細胞培養分析-MT-2細胞及293T細胞獲自NIH AIDS Research and Reference Reagent Program。MT-2細胞在補充有10%加熱不活化胎牛血清、100μg/mL青黴素G(penicillin G)及高達100單位/mL鏈黴素(streptomycin)之RPMI 1640培養基中繁殖。293T細胞在補充有10%加熱不活化胎牛血清(FBS)、100單位/mL青黴素G及100μg/mL鏈黴素之DMEM培養基中繁殖。NL4-3之原病毒DNA純系獲自NIH AIDS Research and Reference Reagent Program。使用重組NL4-3病毒作為參考病毒,其中來自NL4-3之nef基因的部分置換為Renilla螢光素酶基因。此外,將殘基Gag P373轉化成P373S。簡言之,藉由轉染改變之NL4-3原病毒純系來製備重組病毒。根據製造商說明使用來自Invitrogen之LipofectAMINE PLUS(Carlsbad,CA)在293T細胞中進行轉染。使用螢光素酶酶活性作為標記在MT-2細胞中滴定病毒。對製造商方案進行修正,使用Dual Luciferase kit from Promega(Madison,WI)定量螢光素酶。經稀釋之被動溶解溶液與再懸浮之螢光素酶分析試劑以及再懸浮之停止及Glo襯底預混合(2:1:1比率)。向分析板上之各經抽吸孔中添加50μL混合物且立即在Wallac TriLux(Perkin-Elmer)上量測螢光素酶活性。藉由量測在抑制劑連續稀釋液存在下感染NLRluc重組物4-5天的細胞中之螢光素酶活性來定量抑制劑對重組病毒之抗病毒活性。化合物之EC50資料顯示於下表1中。
測定WT之EC50、A364V之EC50及92UG029病毒之EC50:WT係指野生型HIV病毒。
表現Renilla螢光素酶基因之HIV-1 NL4-3藉由定點突變誘發轉化成gag A364V病毒。A364V為定點突變體。
HIV-1 92UG029獲自NIH(目錄號:1650)。此為來自Uganda之A
亞型Gag以及A亞型Env,X4(SI)病毒。參考文獻:WHO Network for HIV Isolation and Characterization.AIDS Res Hum Retroviruses 10:1359,1994。使用來自92UG029之Gag/Pr區置換表現Renilla螢光素酶基因之HIV-1 NL4-3病毒中的彼等區。
兩種重組病毒皆如上文所述用於NL4-3病毒的HIV細胞培養分析法中。化合物之EC50 WT、EC50 A364V及EC50 92UG029資料顯示於表1及表2中。
表2資料使用比表1中報導之針對常規篩選資料產生的資料高3倍的病毒輸入產生。
EC50之生物資料關鍵詞
對於此態樣,製備呈1-(R)及1-(S)-非對映異構體形式的比較化合物A及B(其已在US 20130210787-WO 2013/123019中闡述及描述)以及作為本文之本發明之部分的化合物2,且評估相比於WT,A364V抗性病毒及A進化枝病毒92UG029之效能。化合物A對WT展現良好效能,但相較於化合物2對A364V及92UC029分別的效力分別低約7倍及低超過100倍。當與化合物2比較時,化合物B具有相當的對WT之效能。然而,化合物B相較於化合物2對其他兩種病毒(A364V及92UC029)的效力低6倍。亦評估所選化合物在大鼠中之藥物動力學特性(如所示)。結果闡述於下表2中。化合物2相較於化合物A及B具有較佳組合概況(EC50 WT+EC50 A364V+EC5092UC029)。因此,單個非對映異構體化合物2a及2b各別地分離及/或合成用於進一步評估。單個非對映異構體(化合物2a及2b)效能/PK亦與非對映異構體混合物(化合物2)所觀測之結果相當。因此,2a及2b亦為有活性的化合物。因為產生對任何抗逆轉錄病毒藥物之病毒抗性可為HIV-1感染治療中的重大問題,所以對HIV-1病毒之野生型及突變形式皆具有最佳效能概況的彼等化合物通常為藥物開發的優良候選物。
為了進行化合物於大鼠中之PO藥物動力學研究,將化合物各自溶解於PEG-400/乙醇(90/10)中作為溶液。
大鼠.使用頸靜脈中植入插管的雄性史泊格多利大白鼠(300-350g,Hilltop Lab Animals,Inc.,Scottsdale,PA)。大鼠在PO藥物動力學研究中禁食隔夜。自頸靜脈將0.3mL血液樣品收集於含有EDTA之microtainer管(Becton Dickinson,Franklin Lakes,NJ)中,且離心以分離血漿。
在測試化合物之PO研究中,大鼠(n=3)接受5mg/kg經口劑量之指定化合物。在給藥之前以及給藥之後15、30、45、60、120、240、360、480及1440分鐘收集連續血液樣品。
血漿中之化合物定量。藉由用兩體積含有類似化合物之內標的乙腈使血漿蛋白質沈澱來準備用於分析之來自大鼠研究的血漿樣品等
分試樣。藉由離心10分鐘將所得上澄液與沈澱之蛋白質分離且轉移至自動取樣器小瓶中。手動或使用Tomtec自動液體處置器製備樣品。注射5μL等分試樣用於分析。
HPLC系統由兩個Shimadzu LC10AD泵(Columbia,MD)、一個Shimadzu SIL-HTC自動取樣器(Columbia,MD)及一個Hewlett Packard Series 1100管柱隔間(Palo Alto,CA)組成。管柱為YMC Pro C18(2.0×50mm,3mm粒子,Waters Co.,Milford,MA),保持在60℃下且流動速率為0.3mL/min。移動相由10mM甲酸銨及含0.1%甲酸之水(A)以及100% 10mM甲酸銨及含0.1%甲酸之甲醇(B)組成。初始移動相組成為95% A。樣品注射後,移動相經2分鐘變為15% A/85% B且保持彼組成持續額外1分鐘。移動相接著返回到初始條件且將管柱再平衡1分鐘。總分析時間為4分鐘。
HPLC與Micromass Quattro LC接合。使用超高純度氮氣作為噴霧及去溶劑化氣體,噴霧的流動速率為100L/h且去溶劑化之流動速率為1100L/h。去溶劑化溫度為300℃且源溫度為150℃。資料獲取採用所選反應物監測(SRM)。在MS1中選擇表示化合物及內標的(M+H)+物質之離子且與2×10-3托壓力之氬氣碰撞解離形成特定產物離子,其隨後藉由MS2監測。
前述描述僅為說明性的且不應理解為以任何方式限制本發明的範疇或潛在原理。實際上,根據以下實例及前述描述,除了本文中顯示及描述的修改之外,本發明之各種修改對熟習此項技術者而言將變得顯而易知。所述修改亦打算屬於所附申請專利範圍之範疇內。
Claims (22)
- 一種式I化合物,包括其醫藥學上可接受之鹽:
- 如請求項1之化合物,其中R1為異丙烯基。
- 如請求項2之化合物,其中W不存在。
- 如請求項1之化合物,其中X為C4-8環烯基。
- 如請求項4之化合物,其中X為C6環烯基。
- 如請求項5之化合物,其中A為C1-C3烷基-鹵基。
- 如請求項6之化合物,其中A為甲基-氟。
- 如請求項1之化合物,其中A為甲基-鹵基。
- 如請求項8之化合物,其中A為甲基-氟。
- 如請求項1之化合物,其中Y為-COOR2。
- 如請求項10之化合物,其中Y為-COOH。
- 一種化合物,包括其醫藥學上可接受之鹽,其係選自以下之群:
- 一種醫藥組合物,其包含一或多種如請求項1之化合物以及一或多種醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
- 一種醫藥組合物,其包含一或多種如請求項12之化合物以及一或多種醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
- 一種醫藥組合物,其包含化合物 ,以及一或多種醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
- 如請求項14之醫藥組合物,其適用於治療HIV感染,其另外包含選自由以下組成之群的AIDS治療劑:(a)AIDS抗病毒劑;(b)抗感染劑;(c)免疫調節劑;以及(d)HIV進入抑制劑。
- 一種如請求項1之化合物及一或多種醫藥學上可接受之載劑、賦形劑或稀釋劑之用途,其用於製備用以治療感染HIV病毒之哺乳動物的藥劑。
- 一種中間化合物,其係選自以下之群:
- 一種化合物,包括其醫藥學上可接受之鹽,其係選自以下之群:
- 一種醫藥組合物,其包含一或多種如請求項19之化合物以及一或多種醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
- 如請求項9之化合物,其中Y為-COOH。
- 一種式I化合物,包括其醫藥學上可接受之鹽:
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Families Citing this family (9)
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WO2015157483A1 (en) | 2014-04-11 | 2015-10-15 | Bristol-Myers Squibb Company | Triterpenoids with hiv maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent |
EP3377177A2 (en) * | 2015-11-20 | 2018-09-26 | VIIV Healthcare UK(No.4) Limited | Hiv maturation inhibitor formulations |
AR107512A1 (es) * | 2016-02-04 | 2018-05-09 | VIIV HEALTHCARE UK Nº 5 LTD | Triterpenoides modificados en c-3 y c-17 como inhibidores del vih-1 |
US20190183901A1 (en) * | 2016-08-31 | 2019-06-20 | Viiv Healthcare Company | Combinations and uses and treatments thereof |
US20210347813A1 (en) * | 2018-04-24 | 2021-11-11 | Viiv Healthcare Uk (No. 5) Limited | Compounds with hiv maturation inhibitory activity |
PT3894424T (pt) * | 2018-12-10 | 2023-02-28 | Viiv Healthcare Uk No 4 Ltd | Sal mesilato de um composto de amino-lupano com atividade inibidora da maturação do vih |
CN109705189B (zh) * | 2018-12-29 | 2020-06-05 | 中国医学科学院药用植物研究所 | 具有式i所示结构的三萜衍生物及其制备方法和应用 |
CN110981765A (zh) * | 2019-11-07 | 2020-04-10 | 肇庆巨元生化有限公司 | 一种25-羟基维生素d3中间体的制备方法 |
UY38982A (es) * | 2019-12-09 | 2021-06-30 | Viiv Healthcare Co | Composiciones farmacéuticas |
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US4906661A (en) | 1981-11-12 | 1990-03-06 | E. I. Du Pont De Nemours And Company | Esters of aryloxypropanolamine derivatives |
US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
US5679828A (en) | 1995-06-05 | 1997-10-21 | Biotech Research Labs, Inc. | Betulinic acid and dihydrobetulinic acid derivatives and uses therefor |
AR035311A1 (es) | 1999-01-27 | 2004-05-12 | Wyeth Corp | Derivados de acido hidroxamico que contienen alquinilo, como inhibidores de las metalloproteinasas de matriz y de la tace, composicion farmaceutica y el uso de los mismos para la manufactura de un medicamento |
US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
US7365221B2 (en) | 2002-09-26 | 2008-04-29 | Panacos Pharmaceuticals, Inc. | Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
RU2387665C2 (ru) | 2004-03-17 | 2010-04-27 | Панакос Фармасьютикалз, Инк. | Фармацевтические соли 3-о-(3', 3'-диметилсукцинил)бетулиновой кислоты |
TW200628161A (en) | 2004-11-12 | 2006-08-16 | Panacos Pharmaceuticals Inc | Novel betulin derivatives, preparation thereof and use thereof |
WO2008115281A2 (en) | 2006-10-16 | 2008-09-25 | Myriad Genetics, Inc. | Compounds for treating viral infections |
EP2178376A4 (en) * | 2007-08-03 | 2011-12-14 | Advanced Life Sciences Inc | LUPANIC TRITERPENOIDS MODIFIED IN 30-POSITION AND ITS ANALOG |
AU2009214779A1 (en) | 2008-02-14 | 2009-08-20 | Virochem Pharma Inc. | Novel 17beta lupane derivatives |
US9067966B2 (en) | 2009-07-14 | 2015-06-30 | Hetero Research Foundation, Hetero Drugs Ltd. | Lupeol-type triterpene derivatives as antivirals |
ES2548905T3 (es) | 2010-06-04 | 2015-10-21 | Bristol-Myers Squibb Company | Amidas C-28 de derivados del ácido betulínico C-3 modificados como inhibidores de la maduración del VIH |
WO2011153315A1 (en) * | 2010-06-04 | 2011-12-08 | Bristol-Myers Squibb Company | Modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
EP2670764B1 (en) | 2011-01-31 | 2015-09-02 | Bristol-Myers Squibb Company | C-28 amines of c-3 modified betulinic acid derivatives as hiv maturation inhibitors |
JP6001560B2 (ja) | 2011-01-31 | 2016-10-05 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Hiv成熟阻害活性を有するc−17およびc−3修飾トリテルペノイド |
US8906889B2 (en) * | 2012-02-15 | 2014-12-09 | Bristol-Myers Squibb Company | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
US8889854B2 (en) * | 2012-05-07 | 2014-11-18 | Bristol-Myers Squibb Company | C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity |
WO2015157483A1 (en) | 2014-04-11 | 2015-10-15 | Bristol-Myers Squibb Company | Triterpenoids with hiv maturation inhibitory activity, substituted in position 3 by a non-aromatic ring carrying a haloalkyl substituent |
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