TW201625645A - 抑制mcl-1蛋白之化合物 - Google Patents
抑制mcl-1蛋白之化合物 Download PDFInfo
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- TW201625645A TW201625645A TW104128490A TW104128490A TW201625645A TW 201625645 A TW201625645 A TW 201625645A TW 104128490 A TW104128490 A TW 104128490A TW 104128490 A TW104128490 A TW 104128490A TW 201625645 A TW201625645 A TW 201625645A
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- naphthalene
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/11—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/18—Benzotriazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
Abstract
本發明提供骨髓細胞白血病1蛋白(Mcl-1)抑制劑、其製備方法、相關醫藥組合物及其使用方法。舉例而言,本發明提供式I化合物
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及其醫藥學上可接受之鹽及含有該等化合物之醫藥組合物。本發明所提供之該等化合物及組合物可用於例如治療疾病或病狀,諸如癌症。
Description
本申請案主張2014年8月29日申請的美國臨時申請案第62/043,929號之權益,該申請案以引用的方式併入本文中。
本發明係關於抑制骨髓細胞白血病1蛋白(Mcl-1,亦簡稱為MCL-1或MCL1)之化合物;使用該等化合物治療疾病或病狀(諸如癌症)之方法;及含有該等化合物之醫藥組合物。
人類癌症之一個常見特徵為Mcl-1過度表現。Mcl-1過度表現會使癌細胞免於進行經程序控制的細胞死亡(細胞凋亡),儘管有普遍性的基因損傷,仍能讓該等細胞存活。
Mcl-1為Bcl-2蛋白家族之一成員。Bcl-2家族包括促細胞凋亡成員(諸如BAX及BAK),其經活化後在粒線體外膜中形成均寡聚物,導致孔隙形成及粒線體內容物流失,該步驟觸發細胞凋亡。Bcl-2家族之抗細胞凋亡成員(諸如,Bcl-2、Bcl-XL及Mcl-1)阻斷BAX及BAK之活性。其他蛋白(諸如,BID、BIM、BIK及BAD)展現額外調節功能。
研究已展示Mcl-1抑制劑可適用於治療癌症。MC1-1在許多癌症中過度表現。參見Beroukhim等人(2010)Nature 463,899-90在Mcl-1及Bcl-2-1-1抗細胞凋亡基因周圍含有擴增之癌細胞之存活率視此等基因之表現而定。Beroukhim等人Mcl-1為用於在許多癌細胞中再引發細
胞凋亡之相關標靶。參見G.Lessene,P.Czabotar及P.Colman,Nat.Rev.Drug.Discov.,2008,7,989-1000;C.Akgul Cell.Mol.Life Sci.第66卷,2009;及Arthur M.Mandelin II,Richard M.Pope,Expert Opin.Ther.Targets(2007)11(3):363-373。
用於製備及調配Mcl-1抑制劑之新組合物及方法將為有用的。
在一個實施例中,本發明提供式I化合物,
其中,由符號表示之b為可為順式或反式之單化學鍵或雙化學鍵;R為鹵基;R1為H、C1-6烷基及(CH2CH2O)nCH3,其中n為1至4之整數;R2為H或C1-6烷基;R2A為H或C1-6烷基;R3為H或C1-6烷基;且R3A為H、C1-6烷基、C3-6環烷基或(CH2)m-C3-6環烷基,其中m為1至4之整數。在一個實施例中,R為Cl。在一個實施例中,R1為C1-6烷基。在另一實施例中,R1為CH3。在一個實施例中,R2為H且R2A為C1-6烷基。在一個實施例中,R3為H且R3A為C1-6烷基。在另一實施例中,b指示雙鍵。
在本發明之一些實施例中,式I化合物為式II化合物,
其中R1、R2、R2A、R3及R3A如上文所定義。
在本發明之一些實施例中,本發明提供具有以下結構之化合物:
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之一個實施例係關於一種化合物,其中該化合物具有選自以下之結構:
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之一個實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受
之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之另一實施例係關於一種具有以下結構之化合物
或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。
本發明之一個實施例係關於一種包含式I化合物之醫藥組合物,或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑。
本發明之另一實施例係關於一種抑制細胞之骨髓細胞白血病1蛋白(Mcl-1)之方法,其包含使該細胞與有效量之式I化合物接觸以抑制Mcl-1,結合上文或下文實施例中之任一者。在一個實施例中,該接觸為活體外。在另一實施例中,該接觸為活體內。在一個實施例中,該接觸包含向個體投與該化合物。在一個實施例中,投與為口服、非經腸、經由注射、經由吸入、經皮或經黏膜的。在一個實施例中,個體罹患癌症。
本發明之一個實施例係關於一種治療癌症之方法,其包含向有需要之患者投與治療有效量之式I化合物或包含式I化合物之醫藥組合物,或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑,結合上文或下文實施例中之任一者。在一個實施例中,癌症為血液科惡性疾病。在一個實施例中,癌症選自由以下組成之群:乳癌、結腸直腸癌、皮膚癌、黑色素瘤、卵巢癌、腎癌、肺癌、非小細胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、骨髓瘤、多發性骨髓瘤、白血病及急性骨髓性白血病。在一個實施例中,癌症為多發性骨髓瘤。在另一實施例中,該方法進一步包含向有需要之患者投與治療有效量之至少一種額外醫藥活性化合物之步驟。在一個實施例
中,額外醫藥活性化合物為卡非佐米(carfilzomib),結合上文實施例中之任一者。
除非另外定義,否則本文所用之所有技術及科學術語均具有與一般熟習本發明所屬技術者通常所理解相同的含義。本文描述之方法及物質適用於本發明;亦可使用此項技術中已知之其他適合方法及物質。該等物質、方法及實例僅為說明性的且不意欲為限制性的。本文所提及之所有公開案、專利申請案、專利、序列、資料庫項目及其他參考文獻均以全文引用的方式併入。在有矛盾的情況下,將以本說明書(包括定義)為準。
本發明之其他特徵及優點將自以下實施方式及圖式及申請專利範圍顯而易知。
圖1說明實例4之化合物之Mcl-1抑制劑活體內功效。
圖2說明實例17之化合物之Mcl-1抑制劑活體內功效。
圖3說明實例20之化合物之Mcl-1抑制劑活體內功效。
符號「-」表示共價鍵,且亦可用於自由基中用以指示附接至另一基團之點。在化學結構中,該符號-常用於表示分子中之甲基。
如本文所用,含有一或多個用虛線及粗體鍵(亦即,及)描繪之立體中心的化學結構意欲指示存在於化學結構中之立體中心之絕對立體化學。如本文所用,由簡單線表示之鍵不指示立體偏好。除非另外相反指示,否則包括本文說明之不指示絕對或相對立體化學的一或多個立體中心之化學結構涵蓋化合物之所有可能立體異構形式(例如,非對映異構體、對映異構體)及其混合物。具有單一粗線或虛線及至少一個額外簡單線之結構涵蓋所有可能非對映異構體之單一對映異構系列。
如本文所用,術語「約」意欲考慮因實驗錯誤所致之變化。除非另外明確陳述,否則本文所報導之所有量測均應理解為由術語「約」修飾,無論是否明確使用該術語。除非本文另外明確規定,否則如本文所用,單數形式「一(a/an)」及「該」包括複數個指示物。
術語「烷基」意謂直鏈或分支鏈烴。烷基之代表性實例包括甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、第二丁基、戊基及己基。典型烷基為具有1至8個碳原子之烷基,該等基團通常表示為C1-8烷基。
如本文所用之術語「化合物」意謂包括所描繪結構之所有立體異構體、幾何異構體、互變異構體及同位素。除非另外規定,否則在本文中藉由名稱或結構鑑別為一種特定互變異構形式之化合物意欲包括其他互變異構形式。
發現所有化合物及其醫藥學上可接受之鹽可與其他物質(諸如水及溶劑)一起存在(例如,水合物及溶劑合物)。
術語「環烷基」意謂環狀非芳族烴。環烷基之代表性實例包括環丙基、環丁基、環戊基、環己基及環庚基。環烷基可含有一或多個雙鍵。含有雙鍵之環烷基之代表性實例包括環戊烯基、環己烯基、環己二烯基及環丁二烯基。常見環烷基為C3-8環烷基。
如本文所用之術語「賦形劑」意謂任何醫藥學上可接受之添加劑、載劑、稀釋劑、佐劑或其他成分(除活性醫藥成分(API)以外),其通常包括於調配物內及/或投與患者。醫藥賦形劑手冊(Handbook of Pharmaceutical Excipients),第5版,編者為R.C.Rowe,P.J.Sheskey及S.C.Owen,Pharmaceutical Press,2005,Hardback,928,0853696187。
對於術語「例如」及「諸如」及其語法等效物,除非另外明確陳述,否則片語「但不限於」應理解為遵循。
術語「鹵素」或「鹵基」意謂F、Cl、Br或I。
術語「患者」意謂個體,包括諸如狗、貓、牛、馬、羊之動物及人類。特定患者為哺乳動物。術語患者包括雄性及雌性。
術語「有需要之患者」意謂患有或處於患有一或多種涉及Mcl-1蛋白之疾病或病狀(諸如癌症)之風險的患者。鑑別有需要之患者可為個體或健康護理專業人員之判斷,且可為主觀(例如,意見)或客觀(例如,可藉由測試或診斷方法量測)的。
如本文所用之片語「非經腸投與(parenteral administration/administered parenterally)」意謂除經腸及局部投與以外的投與模式,通常藉由注射,且包括(但不限於)靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊柱內及腦幹內注射及輸注。
適合於非經腸注射之組合物可包含生理學上可接受之無菌水性或非水性溶液、分散液、懸浮液或乳液,及用於復原成無菌可注射溶液或分散液之無菌散劑。適合水性及非水性載劑、稀釋劑、溶劑或媒劑之實例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油及其類似物)、其適合混合物、植物油(諸如橄欖油)及可注射之有機酯(諸如油酸乙酯)。舉例而言,可藉由使用包衣(諸如卵磷脂)、維持所需粒度(在分散液之情況下)及使用界面活性劑來維持適當流動性。
術語「醫藥學上可接受」在本文中用於指在合理醫學判斷之範疇內、適合於向患者投與、與合理的權益/風險比相稱之彼等配位體、物質、組合物及/或劑型。
如本文所用之片語「醫藥學上可接受之載劑」意謂醫藥學上可接受之物質、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封物質。如本文所用,語言「醫藥學上可接受之載劑」包括緩衝劑、注射用無菌水、溶劑、分散介質、包衣、抗菌劑及抗真菌劑、等張延遲劑及吸收延遲劑及其類似物,與醫藥投與相容。各載
體在與調配物之其他成分相容且對患者無害的意義上必須為「可接受的」。可充當醫藥學上可接受之載劑之物質之一些實例包括:(1)糖,諸如乳糖、葡萄糖及蔗糖;(2)澱粉,諸如玉米澱粉、馬鈴薯澱粉及經取代或未經取代之β-環糊精;(3)纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)粉末狀黃蓍;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,諸如可可脂及栓劑蠟;(9)油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,諸如丙二醇;(11)多元醇,諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,諸如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,諸如氫氧化鎂及氫氧化鋁;(15)褐藻酸;(16)無熱原質水;(17)等張鹽水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸鹽緩衝溶液;及(21)醫藥調配物中採用之其他無毒相容性物質。在某些實施例中,本文所提供之醫藥組合物為非熱解的,亦即,在投與患者時不誘導顯著溫度升高。
術語「醫藥學上可接受之鹽」係指本文所提供之化合物之相對無毒的無機酸及有機酸加成鹽。此等鹽可在本文所提供之化合物之最終分離及純化期間當場製備,或藉由分別使游離鹼形式之化合物與適合有機酸或無機酸反應且分離由此形成之鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、丁二酸鹽、酒石酸鹽、萘二甲酸鹽、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽、月桂基磺酸鹽及胺基酸鹽及其類似鹽。(參見例如Berge等人(1977)「Pharmaceutical Salts」,J.Pharm.Sci.66:1-19。)
如本文所用之片語「全身性投與(systemic administration/administered systemically)」、「周邊投與(peripheral
administration/administered peripherally)」意謂經由除直接進入中樞神經系統以外的途徑(例如,皮下投與)投與配位體、藥物或其他物質以使得其進入患者之系統,且因此經受代謝及其他類似過程。
術語「治療有效量」意謂改善、減輕或消除特定疾病或病狀之一或多種症狀,或防止或延遲特定疾病或病狀之一或多種症狀發作的化合物量。
術語「治療(treating/treat/treatment)」及其類似者包括預防性(例如,預防疾病性)及緩解性治療。
本文所提供之方法包括製造及使用醫藥組合物,該醫藥組合物包括一或多種本文所提供之化合物。亦包括醫藥組合物自身。
在一些實施例中,本文所提供之化合物可含有一或多個酸性官能基,且因此能夠與醫藥學上可接受之鹼形成醫藥學上可接受之鹽。術語「醫藥學上可接受之鹽」在此等情況下係指本文所提供之化合物之相對無毒的無機鹼及有機鹼加成鹽。此等鹽同樣可在化合物之最終分離及純化期間當場製備,或藉由分別使自由酸形式之純化化合物與適合鹼(諸如醫藥學上可接受之金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽)、氨或醫藥學上可接受之有機一級、二級或三級胺反應來製備。代表性鹼金屬鹽或鹼土金屬鹽包括鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽及鋁鹽及其類似鹽。適用於形成鹼加成鹽之代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪及其類似物(參見例如Berge等人,見上文)。
濕潤劑、乳化劑及潤滑劑(諸如月桂基硫酸鈉及硬脂酸鎂)以及著色劑、脫模劑、塗佈劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑。
醫藥學上可接受之抗氧化劑之實例包括:(1)水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸
鈉及其類似物;(2)油溶性抗氧化劑,諸如棕櫚酸抗壞血酸酯、丁基化羥基大茴香醚(BHA)、丁基化羥基甲苯(BHT)、卵磷脂、沒食子酸丙酯、α-生育酚及其類似物;及(3)金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其類似物。
醫藥組合物亦可含有佐劑,諸如防腐劑、濕潤劑、乳化劑及分散劑。可藉由包括各種抗菌劑及抗真菌劑,例如對羥基苯甲酸酯、氯丁醇、苯酚山梨酸及其類似物來確保對微生物作用之預防。將張力調節劑(諸如糖)及其類似物包括在組合物內亦可為合乎需要的。另外,可注射醫藥形式之延長吸收可藉由包括延遲吸收劑(諸如單硬脂酸鋁及明膠)來達成。
在一些情況下,為延長本文所提供之一或多種化合物之效果,需要減緩自皮下或肌肉內注射吸收化合物。舉例而言,非經腸投與之化合物之延遲吸收可藉由將化合物溶解或懸浮於油性媒劑中來實現。
本發明化合物以治療有效量投與患者。該等化合物可單獨投與或作為醫藥學上可接受之組合物或調配物之一部分投與。另外,化合物或組合物可同時一起投與,例如藉由多次快速注射,諸如藉由一系列錠劑,或在一定時間段內實質上均勻地遞送,例如使用經皮遞送。化合物或組合物之劑量可隨時間推移而變化。涵蓋所有組合、遞送方法及投與順序。
本發明及一些實施例中之化合物、其他額外醫藥活性化合物可經口、經直腸、非經腸(例如,經靜脈內、肌肉內或皮下)、腦池內、陰道內、腹膜內、膀胱內、局部(例如,散劑、軟膏或滴劑)或以口腔或鼻腔噴霧形式投與患者。涵蓋熟習此項技術者使用之投與醫藥活性劑之所有方法。
如本文所描述製備之組合物可視患者之待治療病症、年齡、條件及體重而定以各種形式投與,如同此項技術中熟知一樣。舉例而
言,當組合物經口投與時,其可調配為錠劑、膠囊、顆粒、散劑或糖漿;或對於非經腸投與,其可調配為注射劑(靜脈內、肌肉內或皮下)、滴注製劑或栓劑。對於藉由眼黏膜途徑施用,其可調配為滴眼劑或眼軟膏。此等調配物可藉由習知手段結合本文所描述之方法製備,且若需要,活性成分可與任何習知添加劑或賦形劑混合,添加劑或賦形劑諸如結合劑、崩解劑、潤滑劑、矯味劑、助溶劑、懸浮助劑、乳化劑或塗佈劑。
適合於口服投與之調配物可呈以下形式:膠囊(例如,明膠膠囊)、扁囊劑、丸劑、錠劑、口含錠(使用調味基質,通常蔗糖及阿拉伯膠或黃蓍)、散劑、糖衣錠、顆粒;或呈於水性或非水性液體中之溶液或懸浮液形式;或呈水包油或油包水液體乳液形式;或呈酏劑或糖漿形式;或呈片劑(使用惰性基質,諸如明膠及甘油,或蔗糖及阿拉伯膠)及/或漱口劑形式;及其類似形式,各含有預定量之本文所提供之化合物作為活性成分。組合物亦可以大丸劑、舐劑或糊劑形式投與。口服組合物一般包括惰性稀釋劑或可食用載劑。
可包括醫藥學上相容性結合劑及/或佐劑物質作為口服組合物之一部分。在口服投與之固體劑型(膠囊、錠劑、丸劑、糖衣藥丸、散劑、顆粒及其類似物)中,活性成分可與一或多種醫藥學上可接受之載劑混合,載劑諸如檸檬酸鈉或磷酸二鈣及/或以下中任一者:(1)填充劑或增量劑,諸如澱粉、環糊精、乳糖、蔗糖、糖精、葡萄糖、甘露糖醇及/或矽酸;(2)結合劑,諸如羧甲基纖維素、微晶纖維素、黃蓍膠、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及/或阿拉伯膠;(3)保濕劑,諸如甘油;(4)崩解劑,諸如瓊脂、碳酸鈣、馬鈴薯、玉米或木薯澱粉、褐藻酸、澱粉羥基乙酸鈉、某些矽酸鹽及碳酸鈉;(5)溶液阻滯劑,諸如石蠟;(6)吸收促進劑,諸如四級銨化合物;(7)濕潤劑,諸如乙醯基醇及單硬脂酸甘油酯;(8)吸附劑,諸如高嶺土及
膨潤土;(9)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、斯特羅特斯(Sterotes)、固體聚乙二醇、月桂基硫酸鈉及其混合物;(10)滑動劑,諸如膠態二氧化矽;(11)著色劑;及(12)調味劑,諸如胡椒薄荷、水楊酸甲酯或橙味劑。在膠囊、錠劑及丸劑之情況下,醫藥組合物亦可包含緩衝劑。亦可使用諸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑將類似類型之固體組合物用作軟填充及硬填充明膠膠囊中之填充劑。
可藉由視情況與一或多種附屬成分一起壓縮或模製來製成錠劑。可使用結合劑(例如,明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如,羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉)、表面活性劑或分散劑來製備壓縮錠劑。可藉由在適合機器中模製經惰性液體稀釋劑濕潤之粉末狀化合物之混合物來製成模製錠劑。
錠劑及其他固體劑型,諸如糖衣藥丸、膠囊、丸劑及顆粒可視情況刻痕或製備有包衣及外殼,諸如醫藥調配技術中熟知之腸包衣及其他包衣。其亦可使用例如不同比例之羥丙基甲基纖維素以提供所要釋放曲線、其他聚合物基質、脂質體、微球體及/或奈米粒子來調配以便提供其中活性成分之緩慢或控制釋放。其可藉由例如經由細菌截留過濾器過濾或藉由以臨用前可溶解於無菌水或一些其他無菌可注射介質中之無菌固體組合物形式併入滅菌劑來滅菌。此等組合物亦可視情況含有遮光劑且可為視情況以延遲方式僅僅或優先在胃腸道之某一部分中釋放活性成分之組合物。可使用之包埋組合物之實例包括聚合物質及蠟。活性成分亦可適當時與一或多種上文所描述之賦形劑一起呈微囊封形式。
用於口服投與之液體劑型包括醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性成分之外,液體劑型還可含
有此項技術中常用之惰性稀釋劑(諸如,水或其他溶劑)、增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其為棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫呋喃醇、聚乙二醇及脫水山梨糖醇之脂肪酸酯及其混合物。
除惰性稀釋劑外,口服組合物亦可包括佐劑,諸如濕潤劑、乳化劑及懸浮劑、甜味劑、調味劑、著色劑、芳香劑及防腐劑。
除活性化合物之外,懸浮液還可含有懸浮劑,例如乙氧基化異硬脂醇、聚氧化乙烯山梨糖醇及脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃蓍膠及其混合物。
適合於非經腸投與之醫藥組合物可包括一或多種本文所提供之化合物,以及一或多種醫藥學上可接受之無菌水性或非水性溶液、分散液、懸浮液或乳液,或可僅在使用之前復原成無菌可注射溶液或分散液之無菌散劑,其可含有抗氧化劑、緩衝劑、抑菌劑、溶質(其用預定接受者之血液使調配物等張)或懸浮劑或增稠劑。
在一個實施例中,靜脈內(IV)調配物由含有在8與10之間pH範圍內的羥丙基β環糊精作為緩衝或無緩衝溶液之組合物組成。IV調配物可調配為即用於注射之無菌溶液、即用於稀釋成IV摻合物或復原用無菌固體之無菌溶液。IV調配物中之API可以游離酸/鹼或原位鹽形式存在。
可用於本文所提供之醫藥組合物中的適合水性及非水性載劑之實例包括注射用水(例如,注射用無菌水)、抑菌水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇(諸如液體聚乙二醇)及其類似物)、無菌緩衝劑(諸如檸檬酸鹽緩衝劑)及其適合混合物、植物油(諸如橄欖油)、可注射有機酯(諸如油酸乙酯)及十六醇聚氧乙烯醚ELTM(BASF,Parsippany,NJ)。在所有情況下,該組合物必須為無菌的且流動性應
達到存在易於注射性之程度。可例如藉由使用包衣物質(諸如卵磷脂)、維持所需粒度(在分散液之情況下)及使用界面活性劑來維持適當流動性。
組合物在製造及儲存條件下應為穩定的,且必須針對微生物(諸如細菌及真菌)之污染作用加以保存。微生物作用之預防可藉由各種抗菌劑及抗真菌劑達成,例如對羥基苯甲酸酯、氯丁醇、酚、抗壞血酸、硫柳汞及其類似物。在許多情況下,組合物中將較佳包括等張劑(例如糖)、多元醇(諸如甘露醇、山梨醇)及氯化鈉。可注射組合物之延長吸收可藉由在組合物中包括延遲吸收劑(例如,單硬脂酸鋁及明膠)來達成。
無菌可注射溶液可藉由如下方法製備:將所需量之活性化合物與上文所列舉之成分中之一者或組合一起併入適當溶劑中,視需要隨後進行過濾滅菌。一般而言,藉由將活性化合物併入含有鹼性分散介質及來自上文所列舉之彼等成分之所需其他成分的無菌媒劑中來製備分散液。在用於製備無菌可注射溶液的無菌散劑之情況下,製備方法為冷凍乾燥(凍乾),其產生活性成分加上來自其先前無菌過濾溶液之任何額外所需成分的散劑。
可藉由在生物可降解聚合物(諸如聚乳酸交酯-聚乙交酯)中形成本文所提供之化合物之微膠囊或奈米膠囊基質來製得可注射積存形式。視藥物與聚合物之比率及所用特定聚合物之性質而定,可控制藥物釋放之速率。其他生物可降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。亦藉由將藥物包覆在與身體組織相容之脂質體、微乳液或奈米乳液中來製備積存可注射調配物。
對於藉由吸入投與,化合物可以氣霧劑噴霧形式自含有適合推進劑(例如氣體,諸如二氧化碳)的加壓容器或分配器或噴霧器遞送。此類方法包括美國專利第6,468,798號中所描述之方法。另外,可實現
鼻內遞送,如尤其描述於Hamajima等人,Clin.Immunol.Immunopathol.,88(2),205-10(1998)中。亦可使用脂質體(例如,如描述於美國專利第6,472,375號中,其以全文引用的方式併入本文中)、微膠囊及奈米膠囊。亦可使用生物可降解可靶向微粒遞送系統或生物可降解可靶向奈米粒子遞送系統(例如,如描述於美國專利第6,471,996號中,其以全文引用的方式併入本文中)。
如本文所描述之治療性化合物亦可藉由經黏膜或經皮手段來全身性投與。用於局部或經皮投與本文所提供之化合物之劑型包括散劑、噴霧、軟膏、糊劑、乳膏、洗劑、凝膠、溶液、貼片及吸入劑。活性組分可在無菌條件下與醫藥學上可接受之載劑及可能需要之任何防腐劑、緩衝劑或推進劑混合。對於經黏膜或經皮投與,在調配物中使用適於待滲透之障壁的滲透劑。此類滲透劑一般為此項技術中已知,且對於經黏膜投與,包括例如清潔劑、膽汁鹽及梭鏈孢酸衍生物。經黏膜投與可經由使用經鼻噴霧或栓劑實現。對於經皮投與,如此項技術中一般已知將活性化合物調配至軟膏、油膏、凝膠或乳膏中。
軟膏、糊劑、乳膏及凝膠除一或多種本文所提供之化合物之外還可含有賦形劑,諸如動物及植物脂肪、油、蠟、石蠟、澱粉、黃蓍、纖維素衍生物、聚乙二醇、聚矽氧、膨潤土、矽酸、滑石及氧化鋅或其混合物。
除本文所提供之化合物之外,散劑及噴霧還可含有賦形劑,諸如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺散劑或此等物質之混合物。噴霧可另外含有習用推進劑,諸如氯氟烴及揮發性未經取代之烴,諸如丁烷及丙烷。
本文所提供之化合物可藉由氣霧劑投與。此藉由製備含有本文所提供之化合物或組合物之水性氣霧劑、脂質體製劑或固體粒子來實
現。可使用非水性(例如,碳氟化合物推進劑)懸浮液。在一些實施例中,使用音波噴霧器,因為其使試劑暴露於剪應力(可導致化合物降解)降至最低。
通常,水性氣霧劑可藉由將試劑之水性溶液或懸浮液與習知醫藥學上可接受之載劑及穩定劑調配在一起來製成。載劑及穩定劑隨特定組合物之要求而變化,但通常包括非離子界面活性劑(TWEEN®(聚山梨醇酯)、PLURONIC®(泊洛沙姆(poloxamer))、脫水山梨糖醇酯、卵磷脂、CREMOPHOR®(聚乙氧基化物))、醫藥學上可接受之共溶劑(諸如聚乙二醇)、無害蛋白(如血清白蛋白)、脫水山梨糖醇酯、油酸、卵磷脂、胺基酸(諸如甘胺酸)、緩衝劑、鹽、糖或糖醇。氣溶膠一般由等張溶液製備。
經皮貼片具有提供本文所提供之化合物可控遞送至身體之附加優點。可藉由將試劑溶解或分散於適當介質中來製成此類劑型。亦可使用吸收增進劑來增加化合物通過皮膚之流量。該流量之速率可藉由提供速率控制膜或使化合物分散於聚合物基質或凝膠中來控制。
醫藥組合物亦可以栓劑或保留灌腸劑形式製備用於直腸及/或陰道遞送。以栓劑形式呈現之調配物可藉由混合一或多種本文所提供之化合物與一或多種適合之無刺激性賦形劑或載劑來製備,賦形劑或載劑包含例如可可脂、甘油酯、聚乙二醇、栓劑蠟或水楊酸酯,其在室溫下為固體,但在體溫下為液體,且因此將熔融在直腸或陰道腔中且釋放活性劑。適合於陰道投與之調配物亦包括含有諸如此項技術中已知為適合之載劑之子宮托、棉塞、乳膏、凝膠、糊劑、泡沫或噴霧調配物。
在一個實施例中,治療性化合物用將保護治療性化合物免於自身體快速消除之載劑來製備,載劑諸如控制釋放配製物,包括植入物及微囊封遞送系統。可使用生物可降解、生物相容性聚合物,諸如乙
烯乙酸乙烯酯、聚酸酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。此類調配物可使用標準技術製備,或商業獲得(例如,獲自Alza Corporation及Nova Pharmaceuticals,Inc)。脂質體懸浮液(包括靶向具有針對細胞抗原之單株抗體之所選細胞的脂質體)亦可用作醫藥學上可接受之載劑。此等可根據熟習此項技術者已知之方法製備,例如如描述於美國專利第4,522,811號中,出於所有目的其以全文引用的方式併入本文中。
本發明化合物用於治療藉由Mcl-1抑制介導之疾病、病症或症狀。藉由Mcl-1抑制介導之疾病、病症或症狀之實例包括(但不限於)癌症。癌症之非限制性實例包括乳癌、結腸直腸癌、皮膚癌、黑色素瘤、卵巢癌、腎癌、肺癌、非小細胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤、骨髓瘤、多發性骨髓瘤、白血病及急性骨髓性白血病。
癌症可包括癌瘤(起源於皮膚及內部膜之細胞外層,例如乳房、腎、肺、皮膚);肉瘤(源自結締組織,諸如骨、肌肉、軟骨及血管)及血液科惡性疾病(例如,淋巴瘤及白血病,其產生於血液或諸如脾、淋巴結及骨髓之血液形成器官中)。癌細胞可包括例如腫瘤細胞、贅生性細胞、惡性細胞、轉移性細胞及增生性細胞。
在一實施例中,疾病、病症或症狀為過度增殖性病症,例如淋巴瘤、白血病、癌瘤(例如,腎、乳房、肺、皮膚)、多發性骨髓瘤或肉瘤。在一個實施例中,白血病為急性骨髓白血病。在一個實施例中,過度增殖性病症為復發性或難治性癌症。
本文所提供之醫藥組合物中活性成分之實際劑量水準可變化以便獲得有效達成特定患者、組合物及投與模式之所要治療反應而對患者無毒性的活性成分之量。
特定劑量及劑量範圍視多個因素而定,包括患者要求、所治療病狀或疾病之嚴重程度、所用化合物之藥物動力學特徵及投與途徑。
在一些實施例中,本文所提供之組合物可以除其他物質外含有約0.1-10% w/v本文所揭示之化合物的水溶液形式提供用以非經腸投與。典型劑量範圍可包括每日體重之約0.01mg/kg至約50mg/kg,以1-4個分次劑量給與。各分次劑量可含有相同或不同化合物。該劑量將視包括患者之整體健康狀況及所選化合物之調配物及投與途徑之幾個因素而定為治療有效量。
可製備含有在0.005%至100%範圍內的如本文所描述之化合物而其餘部分由無毒載劑製造之劑型或組合物。熟習此項技術者已知製備此等組合物之方法。所涵蓋之組合物可含有約0.001%-100%活性成分,在一個實施例中約0.1至約95%,在另一實施例中約75至約85%。儘管劑量將視患者之症狀、年齡及體重、待治療或預防之病症的性質及嚴重程度、投與途徑及藥物形式而變化,一般而言,建議成人人類患者之日劑量為約0.01mg至約3,000mg之化合物,且此可以單次劑量或分次劑量投與。可與載劑物質組合以產生單一劑型之活性成分之量一般將為產生治療效果之化合物的量。
醫藥組合物可一次投與,或可分成多個較小劑量以時間間隔投與。應理解,治療之精確劑量及持續時間隨所治療疾病而變,且可使用已知測試方案或藉由自活體內或活體外測試資料推斷而憑經驗確定。應指出,濃度及劑量值亦可隨待緩解之病狀的嚴重程度變化。應進一步理解,對於任何特定患者,特定給藥方案應根據個人需要及管理或監督組合物投與之人員的專業判斷而隨時間調整,且本文所闡述之濃度範圍僅為例示性且不意欲限制所主張之組合物的範疇或實踐。
在給定患者中將在治療功效方面產生最有效結果之組合物的精確投與時間及/或量將視特定化合物之活性、藥物動力學及生物可用性、患者生理條件(包括年齡、性別、疾病類型及階段、一般物理條件、對給與劑量之反應及藥物類型)、投與途徑等而定。然而,以上
準則可用作微調治療之基礎,例如確定投與之最佳時間及/或量,其將僅需要由監測患者及調節劑量及/或時序組成之常規實驗。
本發明化合物可單獨、與本發明之其他化合物或與其他醫藥活性化合物或試劑組合投與。其他醫藥活性化合物/試劑可意欲與本發明化合物一樣治療相同疾病或病狀,或治療不同疾病或病狀。若患者將接收或正接收多種醫藥活性化合物或試劑,則該等化合物可同時或依序投與。
本發明化合物或其醫藥學上可接受之鹽可與一或多種額外醫藥活性化合物/試劑組合使用。
一或多種額外醫藥活性化合物或試劑可分開投與,作為多種給藥方案之一部分,自式I化合物(例如依序,例如基於在投與一或多種式I化合物之情況下的不同重疊進度(包括其任何亞屬或特定化合物)。在其他實施例中,一或多種額外化合物/試劑可為單一劑型之一部分,與式I化合物一起混合於單一組合物中。在再一實施例中,一或多種額外化合物/試劑可以獨立劑量給與,在約與投與一或多種式I化合物相同的時間投與(例如,與投與一或多種式I化合物同時(包括其任何亞屬或特定化合物)。式I化合物及一或多種額外化合物/試劑均可以單一療法方案中通常投與之劑量的約1至100%之間且更佳約5至95%之間的劑量水準存在。
在一特定實施例中,額外醫藥活性化合物/試劑為可用於治療癌症之化合物或試劑。舉例而言,額外醫藥活性化合物/試劑可選自抗腫瘤劑、抗血管生成劑、化學治療劑及肽性癌症治療劑。在另一實施例中,抗腫瘤劑選自抗生素類藥劑、烷基化劑、抗代謝物劑、激素劑、免疫劑、干擾素類試劑、激酶抑制劑、蛋白酶體抑制劑及其組合。應指出,額外醫藥活性化合物/試劑可為傳統小有機化學分子,或可為大分子,諸如蛋白、抗體、肽體、DNA、RNA或此類大分子之
片段。
可用於治療癌症且可與一或多種本發明化合物組合使用之額外醫藥活性化合物/試劑之實例包括:醋孟南(acemannan);阿克拉黴素(aclarubicin);阿地介白素(aldesleukin);亞利崔托寧(alitretinoin);胺磷汀(amifostine);胺柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿格拉濱(arglabin);三氧化二砷;BAM 002(Novelos);比卡魯胺(bicalutamide);溴尿苷(broxuridine);西莫介白素(celmoleukin);西曲瑞克(cetrorelix);克拉屈濱(cladribine);克黴唑(克黴唑);DA 3030(Dong-A);達利珠單抗(daclizumab);地尼介白素迪夫托斯(denileukin diftitox);德舍瑞林(deslorelin);地拉齊普(dilazep);多可沙諾(docosanol);度骨化醇(doxercalciferol);脫氧氟尿苷(doxifluridine);溴麥角環肽(bromocriptine);阿糖胞苷(cytarabine);HIT雙氯芬酸(HIT diclofenac);干擾素α;維甲酸;依地福新(edelfosine);依決洛單抗(edrecolomab);依氟鳥胺酸(eflornithine);乙嘧替氟(emitefur);表柔比星(epirubicin);倍他依泊汀(epoetin beta);磷酸依託泊苷(etoposide phosphate);依昔舒林(exisulind);法屈唑(fadrozole);非那雄安(finasteride);磷酸氟達拉濱(fludarabine phosphate);福美司坦(formestane);福莫司汀(fotemustine);硝酸鎵;吉妥珠單抗奧唑米星(gemtuzumab zogamicin);吉美拉西(gimeracil)/奧特拉西(oteracil)/喃氟啶(tegafur)組合;甘胺酸;戈舍瑞林(goserelin);庚鉑(heptaplatin);人類絨膜促性腺激素;人類胎兒α胎蛋白;伊班膦酸(ibandronic acid);干擾素α;天然干擾素α;干擾素α-2;干擾素α-2a;干擾素α-2b;干擾素α-N1;干擾素α-n3;干擾素α-1;天然干擾素α;干擾素β;干擾素β-1a;干擾素β-1b;天然干擾素γ;干擾素γ-1a;干擾素γ-1b;介白素-1β;碘苄胍(iobenguane);伊索拉啶(irsogladine);蘭瑞肽(lanreotide);LC 9018
(Yakult);來氟米特(leflunomide);來格司亭(lenograstim);香菇多醣硫酸鹽(lentinan sulfate);來曲唑(letrozole);白血球α干擾素;亮丙瑞林(leuprorelin);左旋咪唑(levamisole)+氟尿嘧啶(fluorouracil);利阿唑(liarozole);洛鉑(lobaplatin);氯尼達明(lonidamine);洛伐他汀(lovastatin);馬索羅酚(masoprocol);美拉胂醇(melarsoprol);甲氧氯普胺(metoclopramide);米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);錯配雙鏈RNA;丙脒腙(mitoguazone);二溴衛矛醇(mitolactol);米托蒽醌(mitoxantrone);莫拉司亭(molgramostim);那法瑞林(nafarelin);納洛酮(naloxone)+戊唑星(pentazocine);那托司亭(nartograstim);奈達鉑(nedaplatin);尼魯米特(nilutamide);諾斯卡品(noscapine);新穎紅血球生成刺激蛋白;NSC 631570奧曲肽(octreotide);奧普瑞介白素(oprelvekin);奧沙特隆(osaterone);紫杉醇(paclitaxel);帕米膦酸(pamidronic acid);聚乙二醇化干擾素α-2b;戊聚醣聚硫酸鈉(pentosan polysulfate sodium);噴司他汀(pentostatin);畢西巴尼(picibanil);吡柔比星(pirarubicin);兔抗胸腺細胞多株抗體;聚乙二醇干擾素α-2a;卟吩姆鈉(porfimer sodium);雷替曲塞(raltitrexed);拉布立酶(rasburicase);Re 186依替膦酸錸;RII維甲醯胺;羅莫肽(romurtide);來昔決南釤(153Sm);沙格司亭(sargramostim);西佐喃(sizofuran);索布佐生(sobuzoxane);索納明(sonermin);氯化鍶-89;蘇拉明(suramin);他索那明(tasonermin);他紮羅汀(tazarotene);喃氟啶;替莫泊芬(temoporfin);替尼泊苷(teniposide);四氯十氧化物;胸腺法新(thymalfasin);促甲狀腺激素α;托瑞米芬(toremifene);托西莫單抗(tositumomab)-碘131;曲奧舒凡(treosulfan);維甲酸;曲洛司坦(trilostane);曲美沙特(trimetrexate);曲普瑞林(triptorelin);天然腫瘤壞死因子α;烏苯美司(ubenimex);膀胱癌疫苗;丸山(Maruyama)
疫苗;黑色素瘤溶解物疫苗;戊柔比星(valrubicin);維替泊芬(verteporfin);維力金(virulizin);淨司他丁(zinostatin);司他美(stimalamer);阿巴瑞克(abarelix);AE 941(Aeterna);胺莫司汀(ambamustine);反義寡核苷酸;bcl-2(Genta);APC 8015(Dendreon);右旋胺魯米特;地吖醌(diaziquone);EL 532(Elan);EM 800(Endorecherche);恩尿嘧啶(eniluracil);依他噠唑(etanidazole);非瑞替尼(fenretinide);加洛他濱(galocitabine);胃泌素17免疫原;HLA-B7基因療法(Vical);顆粒球巨噬細胞群落刺激因子;組胺二鹽酸鹽;替伊莫單抗(ibritumomab tiuxetan);伊洛馬司他(ilomastat);IM 862(Cytran);介白素-2;普洛昔芬(iproxifene);LDI 200(Milkhaus);來立司亭(leridistim);林妥珠單抗(lintuzumab);CA 125單株抗體(MAb)(Biomira);癌症MAb(Japan Pharmaceutical Development);HER-2及Fc MAb(Medarex);個體基因型105AD7 MAb(CRC Technology);個體基因型CEA MAb(Trilex);LYM-1-碘131 MAb(Techniclone);多晶型上皮黏蛋白-釔90 MAb(Antisoma);馬立馬司他(marimastat);美諾立爾(menogaril);米妥莫單抗(mitumomab);莫特沙芬釓(motexafin gadolinium);MX 6(Galderma);諾拉曲特(nolatrexed);P 30蛋白;派格索曼(pegvisomant);泊非羅黴素(porfiromycin);普啉司他(prinomastat);RL 0903(Shire);魯比替康(rubitecan);沙鉑(satraplatin);苯基乙酸鈉;斯帕磷酸(sparfosic acid);SRL 172(SR Pharma);SU 5416(SUGEN);TA 077(Tanabe);四硫鉬酸鹽;噻立拉斯汀(thaliblastine);血小板生成素;錫乙基艾迪普林(tin ethyl etiopurpurin);替拉紮明(tirapazamine);癌症疫苗(Biomira);黑色素瘤疫苗;黑色素瘤腫瘤溶解物疫苗;病毒黑色素瘤細胞溶解物疫苗;伐司朴達(valspodarl);氟尿嘧啶;5-氟尿嘧啶;紫杉醇;伊馬替尼
(imatinib);六甲蜜胺(altretamine);克拉屈濱;環磷醯胺;達卡巴嗪(decarazine);伊立替康(irinotecan);絲裂黴素(mitosmycin);米托坦(mitoxane);拓朴替康(topotecan);長春瑞濱(vinorelbine);阿德力黴素(adriamycin);密特拉(mithram);咪喹莫特(imiquimod);雷妥珠單抗(alemtuzmab);依西美坦(exemestane);貝伐單抗(bevacizumab);西妥昔單抗(cetuximab);阿紮胞苷(azacitidine);氯法拉濱(clofarabine);地西他濱(decitabine);德莎替尼(desatinib);右雷佐生(dexrazoxane);多烯紫杉醇(docetaxel);表柔比星(epirubicin);奧沙利鉑(oxaliplatin);埃羅替尼(erlotinib);雷洛昔芬(raloxifene);氟維司群(fulvestrant);來曲唑;吉非替尼(gefitinib);吉妥珠單抗;曲妥珠單抗(trastuzumab);吉非替尼(gefitinib);伊沙匹隆(ixabepilone);拉帕替尼(lapatinib);來那度胺(lenalidomide);胺基乙醯丙酸;替莫唑胺(temozolomide);奈拉濱(nelarabine);索拉非尼(sorafenib);尼羅替尼(nilotinib);培門冬酶(pegaspargase);培美曲塞(pemetrexed);利妥昔單抗;達沙替尼(dasatinib);撒利多胺(撒利多胺);貝瑟羅汀(bexarotene);替西羅莫司(temsirolimus);硼替佐米(bortezomib);卡非佐米(carfilozmib);奧普洛佐米(oprozomib);伏立諾他(vorinostat);卡培他濱(capecitabine);唑來膦酸(zoledronic acid);阿那曲唑(anastrozole);舒尼替尼(sunitinib);阿瑞匹坦(aprepitant)及奈拉濱(nelarabine);或其醫藥學上可接受之鹽。
可用於治療癌症且可與一或多種本發明化合物組合使用之額外醫藥活性化合物/試劑包括:阿法依泊汀(epoetin alfa);阿法達貝泊汀(darbepoetin alfa);帕尼單抗(panitumumab);派非格司亭(pegfilgrastim);帕利夫明(palifermin);非格司亭(filgrastim);德諾單抗(denosumab);安西司亭(ancestim);AMG 102;AMG 386;AMG 479;AMG 655;AMG 745;AMG 951;及AMG 706,或其醫藥學上
可接受之鹽。
在某些實施例中,本文所提供之組合物與化學治療劑結合投與。適合化學治療劑可包括:天然產品,諸如長春花生物鹼(vinca alkaloid)(例如,長春鹼(vinblastine)、長春新鹼(vincristine)及長春瑞濱);紫杉醇;表鬼臼毒素(epidipodophyllotoxin)(例如,依託泊苷及替尼泊苷);抗生素(例如,更生黴素(dactinomycin)(放線菌素D(actinomycin D))、道諾黴素(daunorubicin)、小紅莓(doxorubicin)及艾達黴素(idarubicin));蒽環黴素(anthracyclines);米托蒽醌;博來黴素(bleomycin);普卡黴素(plicamycin)(光神黴素(mithramycin));絲裂黴素(mitomycin);酶(例如,L-天冬醯胺酶,其全身性地代謝L-天冬醯胺且剝奪不能夠合成其自身天冬醯胺之細胞);抗血小板劑;抗增殖/抗有絲分裂烷基化劑,諸如氮芥(nitrogen mustard)(例如,氮芥(mechlorethamine)、環磷醯胺及類似物、美法侖(melphalan)及苯丁酸氮芥);乙烯亞胺及甲基三聚氰胺(例如,六甲基三聚氰胺及噻替派(thiotepa));CDK抑制劑(例如,塞利希布(seliciclib)、UCN-01、P1446A-05、PD-0332991、戴那西里(dinaciclib)、P27-00、AT-7519、RGB286638及SCH727965);磺酸烷基酯(例如,白消安(busulfan));亞硝基脲(例如,卡莫司汀(carmustine,BCNU)及類似物,及鏈脲菌素);達卡巴嗪(trazenes-dacarbazinine,DTIC);抗增殖/抗有絲分裂抗代謝物,諸如葉酸類似物(例如,甲胺喋呤(methotrexate));嘧啶類似物(例如,氟尿嘧啶、氟尿苷及阿糖胞苷);嘌呤類似物及相關抑制劑(例如,巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴司他汀及2-氯脫氧腺苷);芳香酶抑制劑(例如,阿那曲唑、依西美坦及來曲唑);及鉑配位複合物(例如,順鉑及卡鉑);丙卡巴肼(procarbazine);羥基脲;米托坦(mitotane);胺魯米特(aminoglutethimide);組蛋白脫乙醯基酶(HDAC)抑制劑(例如,曲古黴素(trichostatin)、丁酸鈉、阿
匹西坦(apicidan)、辛二醯基醯苯胺氫胺酸、伏立諾他(vorinostat)、LBH 589、羅米地辛(romidepsin)、ACY-1215及帕比司他(panobinostat));mTor抑制劑(例如,替西羅莫司、依維莫司(everolimus)、地磷莫司(ridaforolimus)及西羅莫司(sirolimus));KSP(Eg5)抑制劑(例如,Array 520);DNA結合劑(例如,Zalypsis);PI3K δ抑制劑(例如,GS-1101及TGR-1202);PI3K δ及γ抑制劑(例如,CAL-130);多激酶抑制劑(例如,TG02及索拉非尼);激素(例如,雌激素)及激素促效劑,諸如黃體生成激素釋放激素(LHRH)促效劑(例如,戈舍瑞林、亮丙立德(leuprolide)及曲普瑞林);BAFF中和抗體(例如,LY2127399);IKK抑制劑;p38MAPK抑制劑;抗IL-6(例如,CNTO328);端粒酶抑制劑(例如,GRN 163L);極光激酶抑制劑(例如,MLN8237);細胞表面單株抗體(例如,抗CD38(HUMAX-CD38)、抗CS1(例如,埃羅妥珠單抗(elotuzumab)));HSP90抑制劑(例如,17 AAG及KOS 953);P13K/Akt抑制劑(例如,哌立福新(perifosine));Akt抑制劑(例如,GSK-2141795);PKC抑制劑(例如,恩紮妥林(enzastaurin));FTI(例如,ZarnestraTM);抗CD138(例如,BTO62);Torc1/2特異性激酶抑制劑(例如,INK128);激酶抑制劑(例如,GS-1101);ER/UPR靶向劑(例如,MKC-3946);cFMS抑制劑(例如,ARRY-382);JAK1/2抑制劑(例如,CYT387);PARP抑制劑(例如,奧拉帕尼(olaparib)及維利帕尼(veliparib)(ABT-888));BCL-2拮抗劑。其他化學治療劑可包括氮芥、喜樹鹼(camptothecin)、異環磷醯胺、他莫昔芬(tamoxifen)、雷洛昔芬、吉西他濱(gemcitabine)、溫諾平(navelbine)、索拉非尼或前述各者之任何類似物或衍生物變體。
本發明化合物亦可與輻射療法、激素療法、手術及免疫療法組合使用,該等療法為熟習此項技術者所熟知。
在某些實施例中,本文所提供之醫藥組合物與類固醇結合投
與。適合類固醇可包括(但不限於)21-乙醯氧基妊烯醇酮、阿氯米松(alclometasone)、阿爾孕酮、安西縮松(amcinonide)、倍氯米松(beclomethasone)、倍他米松(betamethasone)、布地奈德(budesonide)、氯潑尼松(chloroprednisone)、氯倍他索(clobetasol)、氯可托龍(clocortolone)、氯潑尼醇(cloprednol)、皮質酮、可的松(cortisone)、可的伐唑(cortivazol)、地夫可特(deflazacort)、地奈德(desonide)、去羥米松(desoximetasone)、地塞米松(dexamethasone)、二氟拉松(diflorasone)、二氟可龍(diflucortolone)、二氟孕甾丁酯(difuprednate)、甘草次酸(enoxolone)、氟紮可特(fluazacort)、氟氯奈德(flucloronide)、氟米松(flumethasone)、氟尼縮松(flunisolide)、丙酮化氟新龍(fluocinolone acetonide)、醋酸氟輕鬆(fluocinonide)、氟考丁酯(fluocortin butyl)、氟可龍(fluocortolone)、氟米龍(fluorometholone)、乙酸氟培龍(fluperolone acetate)、乙酸氟潑尼定(fluprednidene acetate)、氟潑尼龍(fluprednisolone)、氟氫縮松(flurandrenolide)、丙酸氟替卡松(fluticasone propionate)、氟甲醯龍(formocortal)、哈西奈德(halcinonide)、丙酸鹵貝他索(halobetasol propionate)、鹵米松(halometasone)、氫化可的松(hydrocortisone)、氯替潑諾(loteprednol etabonate)、馬潑尼酮(mazipredone)、甲羥松(medrysone)、甲潑尼松(meprednisone)、甲潑尼龍(methylprednisolone)、糠酸莫米松(mometasone furoate)、帕拉米松(paramethasone)、潑尼卡酯(prednicarbate)、潑尼松龍(prednisolone)、潑尼松龍25-二乙胺基乙酸鹽、潑尼松龍磷酸鈉、潑尼松(prednisone)、潑尼松龍戊酸酯(prednival)、潑尼立定(prednylidene)、利美索龍(rimexolone)、替可的松(tixocortol)、曲安西龍(triamcinolone)、曲安奈德(triamcinolone acetonide)、苯曲安奈德(triamcinolone benetonide)、己曲安奈德(triamcinolone
hexacetonide),及其鹽及/或衍生物。在一特定實施例中,本發明化合物亦可與治療噁心之額外醫藥活性劑組合使用。可用於治療噁心之試劑之實例包括:屈大麻酚(dronabinol);格拉司瓊(granisetron);甲氧氯普胺;昂丹司瓊(ondansetron);及丙氯拉嗪(prochlorperazine);或其醫藥學上可接受之鹽。
由於本發明之一個態樣涵蓋用可分開投與之醫藥活性化合物之組合治療疾病/病狀,本發明進一步關於以套組形式組合獨立醫藥組合物。套組包含兩種獨立醫藥組合物:本發明化合物及第二醫藥化合物。套組包含用於容納獨立組合物之容器,諸如分開之瓶或分開之箔片包裝。容器之額外實例包括注射器、盒子及袋子。在一些實施例中,套組包含使用獨立組分之說明。當獨立組分較佳以不同劑型(例如,口服及非經腸)投與時,以不同給藥時間間隔投與時或當處方健康護理專業人員需要滴定組合之個別組分時,該套組形式尤其有利。
本發明化合物可以醫藥學上可接受之鹽、酯、醯胺或前藥形式投與。術語「鹽」係指本發明化合物之無機鹽及有機鹽。鹽可在化合物之最終分離及純化期間當場製備,或藉由分別使游離鹼或游離酸形式之純化化合物與適合之有機或無機鹼或酸反應且分離由此形成之鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、乙酸鹽、草酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、丁二酸鹽、酒石酸鹽、萘二甲酸鹽、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽及月桂基磺酸鹽及其類似鹽。該等鹽可包括基於鹼金屬及鹼土金屬(諸如鈉、鋰、鉀、鈣、鎂及其類似物)之陽離子,以及無毒銨、四級銨及胺陽離子,包括(但不限於)銨、四甲銨、四乙銨、甲胺、二甲胺、三甲胺、三乙胺、乙胺及其類似物。參見例如S.M.Berge等人,「Pharmaceutical Salts」,J Pharm Sci,66:1-19(1977)。
術語「前藥」意謂經活體內轉型以產生本發明化合物之化合物。轉型可藉由各種機制發生,諸如經由在血液中水解。A.C.S.Symposium Series之T.Higuchi及W.Stella,「Pro-drugs as Novel Delivery Systems」,第14卷及在Bioreversible Carriers in Drug Design,Edward B.Roche編,American Pharmaceutical Association and Pergamon Press,1987中提供前藥用途之論述。
舉例而言,若本發明化合物含有羧酸官能基,則前藥可包含藉由用諸如以下之基團置換酸基中之氫原子而形成之酯:(C1-C8烷基、(C2-C12)烷醯氧基甲基、具有4至9個碳原子之1-(烷醯氧基)乙基、具有5至10個碳原子之1-甲基-1-(烷醯氧基)乙基、具有3至6個碳原子之烷氧基羰氧基甲基、具有4至7個碳原子之1-(烷氧基羰氧基)乙基、具有5至8個碳原子之1-甲基-1-(烷氧基羰氧基)乙基、具有3至9個碳原子之N-(烷氧羰基)胺甲基、具有4至10個碳原子之1-(N-(烷氧羰基)胺甲基、3-酞基、4-巴豆酸內酯基、γ-丁內酯-4-基、二-N,N-(C1-C2)烷胺基(C2-C3)烷基(諸如β-二甲胺基乙基)、胺甲醯基-(C1C2)烷基、N,N-二(C1-C2)烷基胺甲醯基-(C1-C2)烷基及哌啶基(C2-3)烷基、吡咯啶基(C2-3)烷基或N-嗎啉基(C2-3)烷基。
類似地,若本發明化合物包含醇官能基,則前藥可藉由用諸如以下之基團置換醇基中之氫原子而形成:(C1-C6)烷醯基氧基甲基、1-((C1-C6)烷醯氧基)乙基、1-甲基-1-((C1-C6)烷醯氧基)乙基、(C1-C6)烷氧基羰氧基甲基、N-(C1-C6)烷氧羰基胺甲基、丁二醯基、(C1-C6)烷醯基、α-胺基(C1-C4)烷醯基、芳醯基及α-胺醯基或α-胺醯基-α-胺醯基(其中各α-胺醯基獨立地選自天然存在之L-胺基酸)、-P(O)(OH)2、-P(O)(O(C1-C6)烷基)2或醣基(該基團藉由移除半縮醛形式碳水化合物中之羥基而產生)。
本發明化合物可含有不對稱或對掌性中心,且因此以不同立體
異構形式存在。預計該等化合物之所有立體異構形式以及其混合物(包括外消旋混合物)形成本發明之一部分。另外,本發明涵蓋所有幾何及位置異構體。舉例而言,若化合物含有雙鍵,則涵蓋順式及反式形式(分別稱為Z及E)以及混合物。
立體異構體之混合物,諸如非對映異構體混合物可基於其物理化學差異藉由諸如層析及/或分步結晶之已知方法分成其個別立體化學組分。對映異構體亦可藉由與適當光學活性化合物(例如,醇)反應將對映異構混合物轉化為非對映異構混合物,分離非對映異構體且將個別非對映異構體轉化(例如,水解)為相應純對映異構體而分離。
本發明化合物可以非溶合形式以及與醫藥學上可接受之溶劑(諸如水(水合物)、乙醇及其類似物)的溶合形式存在。本發明考慮及涵蓋溶合形式及非溶合形式。
亦有可能本發明化合物可以不同互變異構形式存在。涵蓋本發明化合物之所有互變異構體。熟習此項技術者將認識到,本文中所含有之化合物名稱及結構可基於化合物之特定互變異構體。雖然可使用僅特定互變異構體之名稱或結構,除非另外說明,否則本發明意欲涵蓋所有互變異構體。
亦意欲本發明涵蓋使用諸如合成化學家熟知之實驗室技術的實驗室技術活體外合成或使用諸如經由代謝、醱酵、消化及其類似者之活體內技術合成之化合物。亦涵蓋本發明化合物可使用活體外技術與活體內技術之組合合成。
本發明化合物可以各種固體狀態存在,包括結晶狀態及非晶形狀態。涵蓋本發明化合物之不同結晶狀態(亦稱為多晶型物)及非晶形狀態作為本發明之一部分。
以下呈現之實例說明本發明之特定實施例。此等實例意欲為代
表性的且不意欲以任何方式限制申請專利範圍之範疇。可在本文中使用以下縮寫:
應指出,當關於液體使用百分比(%)時,其為相對於溶液之體積百分比。當關於固體使用時,其為相對於固體組合物之百分比。
使用時差式螢光共振能量轉移(TR-FRET)分析來量測Mcl-1/Bim相互作用之抑制。在Amgen Inc(Thousand Oaks,CA)產生重組人類Mcl-1(C-末端6xHis標記之含有殘基171-327之Mcl-1)。來源於人類Bim(殘基51-76)之生物素標記肽購自CPC Scientific(San Jose,CA)。TR-FRET分析以40μL總體積在384孔白色OptiPlateTM(PerkinElmer,Waltham,MA)中進行。反應混合物含有0.1nM Mcl-1(171-327)、0.05nM生物素-Bim(51-76)、0.05nM LANCE® Eu-W1024抗6xHis(PerkinElmer)、0.072nM抗生蛋白鏈菌素-XLent(Cisbio,Bedford,MA),且在20mM Hepes(pH 7.5)、150mM NaCl、0.016mM Brij®35及1mM二硫蘇糖醇之結合緩衝劑中連續稀釋測試化合物。測試化合物與Mcl-1(171-327)及生物素-Bim(51-76)一起預培育60min,隨後添加偵測混合物(LANCE® Eu-W1024抗6xHis及抗生蛋白鏈菌素-XLent)。反應培養盤進一步培育隔夜,且隨後在Envision®多模式讀取器(PerkinElmer)上讀取。在320nm(75nm頻寬)下激發之後在60μs延遲之情況下量測620nm(40nm頻寬)及665nm(7.5nm頻寬)下之螢光信號。665/620nm下的信號比率對應於Mcl-1/Bim相互作用且用於所有資料分析中。藉由使用GraphPad Prism(GraphPad Software,San Diego,CA)或Genedata Screener®(Genedata,Basel,Switzerland)中之四參數S形模型分析競爭曲線以根據重複資料測定測試化合物之IC50值。
開展分裂螢光素酶補充分析來確定細胞中Mcl-1/Bak蛋白間相互
作用之抑制。編碼與人類Bak融合之螢火蟲螢光素酶之胺基酸(1-298)的pcDNA-Luc(1-298)-BAK表現載體連同編碼與人類Mcl-1基因融合之螢火蟲螢光素酶之胺基酸(395-550)的pcDNA-Luc(395-550)-Mcl-1表現載體一起產生。人胚腎(HEK)293M細胞經3:1 DNA混合比率之pcDNA-Luc(1-298)-BAK及pcDNA-Luc(395-550)-Mcl-1短暫轉染。使用Lipofectamine® LTX/PlusTM試劑(Life Technologies,Grand Island,NY)進行短暫轉染。轉染後24h,使用非酶基細胞解離緩衝劑StemPro® Accutase®(Life Technologies)收集細胞,且再懸浮於無血清Opti-MEM®(Life Technologies)中。隨後將細胞以5000個細胞/孔之密度接種至分析培養盤中具有連續稀釋之測試化合物的0.3% DMSO中。細胞隨後在37℃下在補充有5% CO2之細胞培養培育箱中培育4h。將測試培養盤平衡至室溫後持續30min,隨後向各測試孔中添加30μL穩定Glo®螢光素酶分析試劑(Promega,Madison,WI)。在添加偵測試劑之後25min使用EnVision®多標記盤式讀取器測定螢光。隨後使用GraphPad Prism(GraphPad Software,San Diego,CA)或Genedata Screener®(Genedata,Basel,Switzerland)中之邏輯4參數擬合模型藉由Xlfit計算IC50值。
將人類多發性骨髓瘤細胞株OPM-2在含有RPMI 1640及10%胎牛血清(FBS)之完全生長培養基中培養。細胞以3000個細胞/孔之密度接種至384孔培養盤中之含有10% FBS之完全生長培養基中,且在具有5% CO2之37℃培育箱中與連續稀釋之測試化合物培育16h。使用CellTiter-Glo®分析(Promega,Madison,WI)根據製造商建議測試細胞活力。在添加偵測試劑之後25min使用EnVision®多標記盤式讀取器測定螢光。隨後使用GraphPad Prism(GraphPad Software,San Diego,CA)或Genedata Screener®(Genedata,Basel,Switzerland)中之邏輯4參
數擬合模型藉由Xlfit計算IC50值。
生物學分析中所測試之化合物之結果闡述於下文中。
雌性無胸腺裸體小鼠(Harlan,Inc.,Indianapolis,IN)皮下接種有5百萬個OPM-2細胞。圖1、圖2及圖3說明用各種濃度之測試化合物治療相比於定義為不含活性化合物之賦形劑的媒劑之結果,且在圖2中另外與bortezomibTM進行比較,其為可購自Millennium Pharmaceuticals,Inc.(Cambride,MA)之化合物。在腫瘤已達到100-200mm3之平均體積時14天後開始治療且持續額外10天。每週兩次分
別使用電子測徑規及分析度盤記錄腫瘤體積及體重。使用重複量測方差分析(Repeated Measures ANOVA,RMANOVA)進行統計分析,隨後進行鄧尼特事後分析(Dunnett's post-hoc analysis)。
以下合成流程一般展示如何製得中間物及本發明化合物。
可使用標準化學技術製備中間物III。舉例而言,環丁烷甲醛II與噁氮呯I在適當溶劑中在低於RT之溫度(較佳約0℃)下組合。添加氰基硼氫化鈉,且將混合物添加至NaOH溶液中,提供化合物III。
可使用標準肽樣化學製備中間物IV。舉例而言,在適當溶劑中在低於RT之溫度(較佳約0℃)下將DMAP添加至羧酸中間物AA及中間物EE中,隨後添加EDC鹽酸鹽。將混合物升溫至環境溫度,提供甲醯胺IV。
可使用標準化學技術製備實例A中間物。舉例而言,甲醯胺IV與
DCM組合,隨後添加赫維達-格拉布斯II(Hoveyda-Grubbs II)。將混合物冷卻至環境溫度,提供實例A。
可使用標準化學技術製備中間物V。舉例而言,中間物AA與中間物EE在適當溶劑中組合,隨後添加赫維達-格拉布斯II,提供化合物V。
可使用標準化學技術製備實例A中間物。舉例而言,N,N-二甲基吡啶-4-胺與化合物VI在適當溶劑中在低於RT之溫度(較佳約0℃)下組合,隨後添加N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽。將所得混合物升溫至環境溫度,提供實例A。
可使用標準化學技術製備實例B中間物。舉例而言,在低於RT之溫度(較佳約0℃)下將氫化鈉添加至實例A之溶液中,隨後添加MeI。將所得混合物升溫至環境溫度,提供實例B。
可使用標準化學技術製備諸如實例C之中間物。舉例而言,實例A及/或B及/或VII及氧化鉑(IV)在適當溶劑中在環境溫度下組合,提供實例C。
本發明化合物一般可將由市售之起始物質產生之合成中間物組合且進一步加工來製備。此等中間物之合成概述於下文,且在所提供之特定實例中發現進一步例證說明。
步驟1:(R)-6-氯-3,4-二氫-2H-螺[萘-1,2'-環氧乙烷]及(R)-6-氯-3,4-二氫-2H-螺[萘-1,2'-環氧乙烷]
向2L 4頸RBF中饋入6-氯-3,4-二氫-1(2H)-萘酮(123g,681mmol)、碘化三甲鋶(143g,701mmol)及DMSO(1100mL)。添加KOH(76g,1362mmol)(集結粒)。將懸浮液在環境溫度下攪拌2天,在該時間之後粗1H NMR未展示剩餘起始物質。將溶液傾入800g碎冰
中,用MTBE(200mL)沖洗,且添加額外部分之MTBE(700mL)。所得混合物攪拌5min,且在分開之後用MTBE萃取底部水層兩次(500mL、300mL),且與主要MTBE萃取物合併。合併之有機流用鹽水(2×600mL)洗滌,且添加330g Al2O3(中性)。所得懸浮液在22℃下攪拌5min,過濾且用MTBE(400mL)洗滌。濃縮濾液得到呈紅色黏性油狀之產物(125g,94%)。
步驟2:(S)-6-氯-1,2,3,4-四氫萘-1-甲醛及(R)-6-氯-1,2,3,4-四氫萘-1-甲醛
向3L 3頸RBF中饋入外消旋6-氯-3,4-二氫-2H-螺[萘-1,2'-環氧乙烷](160g,822mmol)及THF(1760mL)。在用乾冰/IPA浴將批料冷卻至-8℃之後,添加三氟化硼合二乙醚(5.07mL,41.1mmol)歷經3min。放熱使批料溫度即刻升高至10℃。批料在-5℃至0℃下攪拌5min,且樣品(在冷NaHCO3溶液中淬滅)之LC/MS分析展示完全轉化。藉由在-5℃下添加飽和NaHCO3(300mL)隨後MTBE(400mL)來淬滅反應,且將混合物轉移至分液漏斗且用MTBE(240mL)沖洗。在分開之後,水層連同一些白色固體(可能為硼酸或硼砂)一起丟棄。有機層用鹽水(350mL)洗滌且在減壓下濃縮,得到紅色油狀物。粗物質直接用於步驟4。
步驟3:(6-氯-1,2,3,4-四氫萘-1,1-二基)二甲醇
將外消旋6-氯-1,2,3,4-四氫-1-萘甲醛饋入3L 3頸RBF中,且用二乙二醇(1000mL)沖洗。添加甲醛(37% H2O溶液;652mL,8757mmol),且用乾冰/IPA浴將所得兩相乳液冷卻至5℃。添加KOH(45%
水溶液,652mL,11.9mol)歷時約30min,維持溫度低於20℃。完全添加後,將批料(20℃)緩慢加熱至45℃(注意:放熱反應)且老化1h。HPLC展示完全轉化。形成一些黏性不溶焦油,在水溶液處理之前移除其。向批料中添加鹽水(500mL),且用DCM萃取混合物直至水相中之產物含量小於5%。將合併之DCM萃取物濃縮為750mL紅色油狀物,用H2O(500mL)洗滌,且產物開始結晶出來。分離之後,丟棄澄清頂部水層,且底層在冰/H2O浴中攪拌30min,過濾且用DCM(約100mL)及H2O(100mL)洗滌。產物在乾燥空氣/真空下乾燥,得到第一批產物(113g,498mmol,57%產率)。將來自所得母液之DCM層分離且濃縮至200-300g(KF=0.5%),接種且在冰/H2O浴中攪拌30min。過濾產物,用DCM(50mL)洗滌,且在乾燥空氣/真空中乾燥,得到第二批產物(14.3g,63.1mmol,7%產率),合併之總產量為127g(64%)之6-氯-1,2,3,4-四氫萘-1,1-二基)二甲醇。
步驟4:4-溴苯甲酸(S)-(6-氯-1-(羥甲基)-1,2,3,4-四氫萘-1-基)甲酯
向2,6-雙((R)-5,5-二丁基-4-苯基-4,5-二氫噁唑-2-基)吡啶(R,R-康催化劑)(1.57g,2.64mmol)於無水DCM(450mL)中之溶液中添加氯化銅(II)(0.355g,2.64mmol),且所得綠色溶液在rt下攪拌1h。此溶液經由套管添加至(6-氯-1,2,3,4-四氫萘-1,1-二基)二甲醇(30g,132.73mmol)於無水DCM(800mL)中之溶液中。將所得混合物冷卻至-78℃,且觀測到淡綠色沈澱物。隨後緩慢添加4-溴苯甲醯氯(34.77g,158.79mmol)於DCM(500mL)中之溶液,隨後逐滴添加N-乙基-N-異丙基丙-2-胺(20g,154mmol)。所得反應混合物在-78℃下攪拌3h,隨後用pH 3磷酸鹽緩衝劑(1L)淬滅其且在劇烈攪拌下升溫至環境溫
度。混合物隨後用DCM(2L)稀釋,且分離各層。有機相用pH 3緩衝劑(1L)、飽和NaHCO3(1L)及鹽水(2L)洗滌,隨後其經Na2SO4乾燥,過濾且濃縮。藉由管柱層析經由SiO2凝膠(100-200目,80% DCM/Hex)純化粗物質,得到純4-溴苯甲酸(S)-(6-氯-1-(羥甲基)-1,2,3,4-四氫萘-1-基)甲酯(45g,84%;e.r=91.4:8.6)。ChiralCel® OD-H(250mm×4.6mm);移動相:正己烷:IPA:90:10;運行時間:20min;流動速率:1mL/min;樣品製備:IPA。滯留時間(主峰)-9.32min;滯留時間(副峰)-11.46min)。
步驟5:4-溴苯甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯
在10℃下向4-溴苯甲酸(S)-(6-氯-1-(羥甲基)-1,2,3,4-四氫萘-1-基)甲酯(100g,244.5mmol)於DCM(2.5L)中之攪拌溶液中添加戴斯-馬丁高碘烷(121.4g,293.3mmol)。在添加之後移除冷卻浴,且反應混合物在環境溫度下攪拌30min。隨後添加H2O(9mL),且所得兩相混合物在環境溫度下攪拌30min。反應混合物冷卻至0℃且用10% Na2S2O3/NaHCO3飽和溶液之1:1混合物2L淬滅。反應混合物在環境溫度下進一步攪拌10min,隨後分離各層且用EtOAc(2×1.5L)萃取水層。合併之有機層用1L 10% Na2S2O3/NaHCO3飽和溶液及1L鹽水洗滌,隨後其經Na2SO4乾燥,過濾且濃縮。藉由管柱層析經由SiO2凝膠(100-200目,5% EtOAc/Hex)純化殘餘物,提供4-溴苯甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯(80g,81%)。
標題化合物之對映異構純度可藉由以下程序改進:將4-溴苯甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯(190g)添加至甲苯(950mL)中,且加熱至50℃以完全溶解。將均質溶液冷卻至環境溫度且接
種外消旋化合物。溶液冷卻至-25℃且老化隔夜。隨後將母液傾析且濃縮,得到160g對映異構性增濃之4-溴苯甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯(94% ee,如藉由對掌性HPLC所測定)。對掌性HPLC條件:管柱:ChiralCel® OD-H(250mm×4.6mm);移動相:正己烷:IPA:90:10。運行時間:20min。流動速率:1mL/min。樣品製備:乙醇。滯留時間(主峰):8.488min(96.97%);滯留時間(副峰):9.592min(3.03%)。
步驟6:(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲醇
向4-溴苯甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯(75g,183.8mmol)於無水MeOH(1L)中之溶液中添加對甲苯磺酸(p-TsOH)(1g,9.2mmol)及原甲酸三甲酯(58.4mL,551mmol),且將反應混合物回流直至完全消耗起始物質(約4h)。將反應物質濃縮至50%體積且用THF(1L)及1N NaOH(1L,1mol)稀釋。所得反應混合物在40℃下攪拌隔夜,且隨後在減壓下濃縮。將殘餘物用EtOAc(1.5L)稀釋。分離水層且用EtOAc(2×500mL)萃取,且合併之有機層用1N NaOH(1L)及鹽水(1L)洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析經由100-200目尺寸之SiO2凝膠(10% EtOAc/Hex)純化粗物質,得到呈淡棕色稠油狀之純(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲醇(44g,89%)。
步驟7:第三丁基-4-氟-3-硝基苯甲酸酯
向4-氟-3-硝基苯甲酸(100g,540.2mmol)於第三丁醇(2.5L)中之溶液中添加DMAP(13.18g,108.04mmol)及二碳酸二-第三丁酯(248
mL,1080.4mmol),且將反應混合物在40℃下加熱隔夜。完成後,反應混合物用H2O稀釋,且水相用EtOAc(3×1.5L)萃取。合併之有機層進一步用H2O(1×1L)、鹽水(1×1L)洗滌,且經Na2SO4乾燥。在減壓下移除溶劑,且由此獲得之粗物質藉由管柱層析(100-200目尺寸之SiO2凝膠,用100% Hex:5% EtOAc/Hex梯度溶離)純化,得到呈淡黃色固體狀之純第三丁基-4-氟-3-硝基苯甲酸酯(70g,54%)。
步驟8:4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯
將(R)-(6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲醇(70g,259.2mmol)於無水THF(3.5L)中之溶液冷卻至0℃,且逐滴添加LiHMDS(1M THF;363mL,363mmol)。5min之後,經由滴液漏斗逐滴添加4-氟-3-硝基苯甲酸第三丁酯(74.9g,311mmol)於THF(500mL)中之溶液,且將所得混合物升溫至環境溫度。完成後(約1h),將混合物冷卻至0℃,用NH4Cl飽和溶液(1L)淬滅且用EtOAc(3×1L)萃取。合併之有機層用NH4Cl(1L)及鹽水(1L)洗滌,經Na2SO4乾燥且在減壓下濃縮。由此獲得之粗物質藉由管柱層析使用100-200目尺寸之SiO2凝膠(5% EtOAc/己烷)純化,得到呈黃色稠油狀之4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯(110g,87%產率)。
步驟9A:(R)-4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸
向4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯(35g,71.25mmol)於MeCN(1L)中之溶液中添加三氟甲磺酸鉺(4.3g,7.1mmol)及H2O(13mL)。將所得混合物加熱至80℃隔夜。隨後在減壓下移除溶劑,且將殘餘物溶解於Et2O(1.5L)中且用1N HCl(500mL)及鹽水(500mL)洗滌。有機層經Na2SO4乾燥,過濾且濃縮,得到(R)-4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(30g),其不經進一步純化即可使用。
或者,(R)-4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸可如下由(6-氯-1,2,3,4-四氫萘-1,1-二基)二甲醇(步驟4)製備:向250mL 3頸RBF中饋入氯化銅(II)(0.095g,0.02eq)、2,6-雙((R)-5,5-二丁基-4-苯基-4,5-二氫噁唑-2-基)吡啶(0.42g,0.02eq)及THF(28.5g,4V)。在用N2惰化之後,批料在20℃下攪拌0.5h。向同源綠色溶液中添加(6-氯-1,2,3,4-四氫萘-1,1-二基)二甲醇(8.0g,1.00eq)隨後THF(14.2g,2V)及4-甲基嗎啉(3.75g,1.05eq)。將反應混合物冷卻至-20℃,且將1-萘甲醯氯(7.06g,1.05eq)於THF(21.3g,3V)中之溶液添加至批料中歷經0.5h,維持溫度低於-15℃。在-20℃下老化20h之後,取樣反應漿液之等分試樣且藉由HPLC分析。在將溫度維持在-20℃時經由玻璃燒結漏斗直接過濾漿液。用經由反應容器沖洗之兩份冷(<-10℃)THF(2×14.2g,2V)洗滌濾餅。將濾餅(4-甲基嗎啉‧HCl)轉移至標記容器中。將母液及洗液濃縮至最小體積,且藉由饋入甲苯使蒸餾溶劑交換直至批料體積為6V且如藉由QNMR所量測甲苯/THF比率為>98:2(v/v)。在20℃下向批料中添加庚烷(11g,
2V),且將漿液加熱至85℃(觀測到溶解)。溶液冷卻至75℃且饋入種子(0.27g,0.02eq)。漿液冷卻至20℃歷經3h,且老化>1h。經由玻璃燒結過濾器過濾批料,且濾餅用甲苯/庚烷(3:1 v/v)(11g,2V)隨後甲苯/庚烷(1:1 v/v)(11g,2V)洗滌。濾餅在N2下在環境溫度下乾燥12h,且藉由QNMR(<1wt%甲苯及庚烷)分析濾餅乾燥。獲得呈灰白色固體狀之產物(8.75g,重量調整後為63%)。
向裝有漂白洗滌器之60L夾套反應器中饋入1-萘甲酸(S)-(6-氯-1-(羥甲基)-1,2,3,4-四氫萘-1-基)甲酯(2.693Kg,88.6wt%,6.3mol)隨後DCM(17.9Kg,5vol)及EtNiPr2(2.84Kg,3.5eq)。在N2惰化之後,攪拌批料且冷卻至0℃。在維持批料溫度低於15℃時向反應器中醇漿液混合物中添加新製備之三氧化硫吡啶溶液(2.10Kg,2.5eq三氧化硫吡啶/7.43Kg(3vol.)DMSO)歷經30min。添加之後,HPLC分析展示>99%轉化。藉由添加H2O(14L,5vol)淬滅批料歷經約20min.,維持批料溫度低於15℃且隨後添加甲苯(16.8L,6vol)。在分開之後,有機層用H2O(14L,5vol)及甲苯(16.8L,6vol)處理。頂部有機層用2N HCl洗滌兩次(每次14L,5vol)且用鹽水(14L,5vol)洗滌。有機層排出至清潔容器,藉由HPLC分析,且隨後經由內嵌過濾器轉移回至清潔60L反應器。將批料濃縮至最小體積且溶劑轉換為MeOH直至批料體積為28L(10vol)且MeOH/甲苯比率如藉由QNMR所量測為3:1(v/v)。隨後經由內嵌過濾器將批料轉移至30L夾套反應器中。在將批料溫度調整至30℃之後,批料用醛(51g,0.02eq)接種於MeOH(400mL)中作為漿液。在漿液在30℃下老化30min之後,藉由蒸餾使批料與MeOH進行溶劑轉換直至批料體積為11L(4vol)且MeOH/甲苯比率為99:1(v/v)。隨後將批料冷卻至5℃,且添加MeOH/H2O混合物(3.70Kg MeOH+1.34Kg H2O)歷經1.5h,使總溶劑體積為大約5.5vol且最終MeOH/H2O為90/10(v/v)。將批料加熱至65
℃歷經30min,且冷卻至20℃歷經2h且老化約2h。批料經由裝備有25μm過濾布之Aurora®過濾器過濾。濾餅用MeOH/H2O(10:1)(1×2vol)隨後MeOH/H2O(2:1)(1×2vol)洗滌。濾餅在N2下在環境溫度下乾燥4h直至乾燥,得到呈灰白色固體狀之產物(1.99Kg,wt%調整後為72%)。
向3頸250mL RBF中饋入1-萘甲酸(R)-(6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲酯(10g,94.4wt%,95.3% LCAP,>99% ee)、甲醇(100mL)、原甲酸三甲酯(7mL)及TsOH.H2O(0.24g)。RBF經N2惰化,且開始攪拌。將批料加熱至60℃且老化2h。HPLC分析展示98%轉化。
使用旋轉蒸發器將批料在真空(約150-190托,外部溫度為約40℃)下濃縮至最小體積。藉由三次饋入THF(每次50mL)且在真空(約165托,外部溫度為約40℃)下蒸餾將批料移至THF中。在前兩次THF饋入之每一次之後,將批料濃縮至最小體積,且在最後THF饋入及蒸餾之後,樣品之QNMR分析展示THF/MeOH(v/v)之目標比率>20/1。將LiOH.H2O(10.46g,10eq)及H2O(50mL)饋入3頸250mL RBF中。反應混合物加熱至65℃且老化18h。HPLC分析展示>99%轉化。將批料冷卻至20℃且轉移至500mL分液漏斗中。將MTBE(106mL)饋入分液漏斗且使漏斗充分震盪。沈降5min之後,排出底部水層。頂部有機層用20% K2CO3洗滌兩次(32mL及11mL)。將批料轉移至250mL RBF中。藉由HPLC之分析展示<2%之萘甲酸副產物。在減壓下在旋轉蒸發器(300毫巴,外部溫度為約40℃)上將批料濃縮至最小體積。藉由添加及蒸餾THF(約50mL,約50mL)使用旋轉蒸發器(約250毫巴,外部溫度為約40℃)將批料轉至THF中。在每次THF饋入之後,將批料蒸餾至最小體積。將THF(50mL)饋入250mL RBF中。樣品之KF展示0% H2O(0.1%可接受)。批料經過濾處理(60mL中等玻璃料漏斗)至清潔且乾燥之250mL 3頸RBF中,使用THF(50mL)進行沖洗及
體積調整。向批料中添加4-氟-3-硝基苯甲酸(4.61g,1.0eq),將混合物冷卻至-20℃,且添加20%第三丁醇鉀THF溶液(40mL)歷經1.5h,維持批料溫度在-20±10℃(放熱)。完成添加之後,批料在-20℃下老化,且在1.5h之後藉由HPLC分析之等分試樣展示98%轉化。向燒瓶中之批料中添加NH4Cl飽和溶液(10mL),維持溫度在-20±10℃下,隨後在-20±20℃下添加H2O(20mL)及MeTHF(34mL)。將混合物升溫至20℃且攪拌13h。將批料轉移至分液漏斗中,使其沈澱約5min,且移除底部水層,保留殘餘有機流。在20℃下用NH4Cl飽和溶液(10mL)及H2O(20mL)洗滌頂部有機流。在沈降約5min之後,分離水層。在250mL 3頸RBF中向總粗有機流(KF=14%)中添加MSA(4mL)。將批料加熱至回流(65℃)後持續25h,且LC分析展示完全轉化(97%)。
將批料冷卻至<20℃,且添加K3PO4.H2O(4.5g)及H2O(7mL)。將批料轉移至分液漏斗中且排出底部水層,得到醛產物粗溶液。使用旋轉式蒸發器將經合併之有機粗流濃縮至最小體積。向500mL RBF中之批料中饋入AcOH(約50mL,約50mL)且在減壓(30毫巴,外部溫度為約40℃)下使用旋轉式蒸發器蒸餾。藉由QNMR量測THF水準,且未觀測到任何。將混合物轉移至250mL 3頸RBF中,且在發生結晶時添加AcOH以將總體積調整至約40mL。向批料中添加H2O(12mL)歷經約1h。在老化>1h之後,LC分析之上清液濃度為9mg/mL。若濃度>10mg/mL,則可添加一小部分H2O(0.2vol);在藉由LC檢查之後,在必要時重複。將批料過濾,用20% H2O/AcOH(23mL)洗滌,且在N2/真空下乾燥3.25h,得到呈灰白色固體狀之標題化合物(8.22g)(純度校正之產率為82%)。
步驟9B:4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯
向4-((6-氯-1-(二甲氧基甲基)-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯(1g,2.033mmol)於無水丙酮(41mL)中之溶液中添加amberlyst®-15(1g,2.033mmol;用2×10mL無水丙酮預洗滌)。將混合物加熱至50℃後持續3.5h,隨後過濾且用DCM沖洗。濃縮濾液且在高真空下乾燥隔夜(其變為深紅色)。LC/MS及NMR分析表明約10%相應羧酸以及0.5eq異亞丙基丙酮(mesityl oxide)存在。混合物不經進一步純化即推進至步驟11。
步驟10:(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
將粗(R)-4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(30g,77.10mmol)於AcOH(1L)中之溶液加熱至70℃,且添加鐵粉(28g,500mmol)。所得混合物在70℃下加熱約4h。隨後在減壓下移除AcOH,且將殘餘物溶解於DCE(1L)中。逐份添加三乙醯氧基硼氫化鈉(46.5g,740mmol),且反應混合物在環境溫度下攪拌1h。隨後用H2O隨後10%檸檬酸水溶液(500mL)淬滅反應物。用DCM(2×1L)萃取水相,且合併之有機層用鹽水(500mL)洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析使用100-200目尺寸之SiO2凝膠(40% EtOAc/Hex)純化殘餘物,得到呈白色固體狀之純(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(24g,兩個步驟後為99%)。
或者,(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-
3,1'-萘]-7-甲酸與((1S,4R)-7,7-二甲基-2-側氧基雙環[2.2.1]庚-1-基)甲磺酸(1:1)可如下製備:
向壓力反應器中饋入(R)-4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(20g,94wt%)、5% Pt/S/C濕(2.2g)、THF(400mL)及異丙醇鈦(0.5mL)。將反應器密封,用惰性氣體吹掃(3次循環,至少一次在攪拌下),且隨後用H2吹掃(1次循環)。反應器用H2加壓至70磅/平方吋(psig),開始攪拌(950rpm),且溫度升高至90℃,維持反應器中之H2壓力(在22-30℃下為70磅/平方吋,在50-60℃下為80磅/平方吋且在88-91℃下為90磅/平方吋)。16h後,將反應器冷卻至環境溫度且用惰性氣體吹掃(3次循環)。反應之HPLC分析證實>98%轉化。
反應混合物經由Celite®墊(2吋)過濾,使用額外THF沖洗,且在減壓下在40℃下濃縮濾液。向殘餘物中添加IPA(60mL)及2-4% MeOH水溶液(10mL)。混合物攪拌10min且隨後其經由Celite®墊(2吋)過濾。MeOH在減壓下在40℃下蒸發,且向冷卻至環境溫度之濃縮IPA溶液中逐滴添加+CSA(56.0g)於IPA(200mL)中之溶液歷經2h。在已添加10% CSA溶液之後,將混合物接種標題化合物之晶體(10-15mg),隨後添加剩餘CSA溶液。在環境溫度下攪拌隔夜後,過濾混合物,且用100mL IPA洗滌濾餅且在真空/N2下在環境溫度下乾燥。產物經分離為白色固體:(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸與((1S,4R)-7,7-二甲基-2-側氧基雙環[2.2.1]庚-1-基)甲磺酸(1:1)(85-88%產率,>99.5% ee)。
步驟11A:6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
向(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(130g,379mmol)於甲醇(6L)中之溶液中添加amberlyst®-15(130g,用無水甲醇預洗滌),且加熱至回流後持續10h。隨後藉由過濾移除Amberlyst®且用甲醇(3×300mL)沖洗。濃縮合併之濾液且藉由管柱層析純化殘餘物,得到呈白色固體狀之純6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(105g,77%)。對掌性HPLC條件:管柱:ChiralCel® OD-H(250mm×4.6mm,5μm);移動相:正己烷:EtOH:95:05。運行時間:25min。流動速率:1mL/min。滯留時間(副峰):10.162min(1.98%);滯留時間(主峰):12.292min(98.02%)。
步驟11B:6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯
在70℃下向4-((6-氯-1-甲醯基-1,2,3,4-四氫萘-1-基)甲氧基)-3-硝基苯甲酸(R)-第三丁酯(0.9g,2.018mmol)於AcOH(20.22mL,353mmol)中之溶液中添加鐵(0.676g,12.11mmol)。將混合物劇烈攪拌4h,隨後濃縮,且用20mL 1,2-DCE稀釋殘餘物。添加三乙醯氧基氫硼化鈉(1.711g,8.07mmol),且混合物在環境溫度下攪拌20min。在藉由添加20mL H2O淬滅後,形成黏稠漿液。添加20mL 10%檸檬酸溶液,且混合物之顏色變得較淡。分離各層,且用2×20mL DCM萃取水層。合併之有機物用10mL 10%檸檬酸及10mL鹽水洗滌,經
MgSO4乾燥,過濾且濃縮。殘餘物沈積於3g SiO2凝膠上且使用5-10% EtOAc/Hex純化,得到6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(557mg,1.393mmol,69.0%產率)。進一步用30% EtOAc/Hex溶離,提供(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(132mg,0.384mmol,19.02%產率)。
步驟12:(1R,2S)-1,2-環丁烷二基二甲醇
在3000mL 3頸RBF中在氬氣流下向在環境溫度下快速攪拌之LAH(1.0M THF溶液,1000mL,1000mmol)溶液中逐漸添加固體(1R,5S)-3-氧雜雙環[3.2.0]庚烷-2,4-二酮(40g,317mmol)歷經2h,維持反應混合物之內部溫度低於50℃。在環境溫度下在氬氣下攪拌反應物隔夜。16h後,反應混合物藉由冰浴冷卻至10℃,且在快速氬氣流下,在劇烈攪拌(500rpm)下藉由加料漏斗以溫度維持在12℃與15℃之間之大約1mL/min速率逐滴添加36mL H2O溶液。混合物隨後在冰浴中劇烈攪拌(500rpm)1h,隨後自該浴移除且攪拌至rt後持續1h,隨後再次用冰浴冷卻至5-10℃。向混合物中添加36mL 15% NaOH水溶液歷經45min時段,維持溫度在10℃與20℃之間。藉由加料漏斗向混合物中逐滴添加108mL H2O,維持溫度在10℃與20℃之間歷經約1h。在完成添加H2O之後,自冰浴移除燒瓶,平衡至rt且保持在氬氣下劇烈攪拌隔夜。攪拌16h後,過濾混合物且在減壓下濃縮濾液,得到無色稍微不透明油狀物。將油狀物溶解於Et2O中,且經無水MgSO4攪拌且經由Celite®墊過濾。在減壓下濃縮濾液,得到32.8g無色油狀物(89%產率),其不經進一步純化即用於下一步驟。
步驟13:順-環丁烷-1,2-二基雙(亞甲基)二乙酸酯
將Ac2O(2.59mL;3.0eq)添加至順-1,2-環丁烷二基二甲醇(1.06g,9.15mmol)中,且將所得溶液加熱至50℃。在攪拌隔夜之後,藉由GC分析混合物且展示完全轉化。混合物隨後用15mL庚烷稀釋且在真空下濃縮,得到澄清油狀物。將油狀物溶解於15mL庚烷中且濃縮回至油狀物(共沸移除Ac2O),得到呈油狀之標題化合物(1.827g,88%產率,使用苯甲酸苄酯作為內標藉由QNMR之純度為88.3%)。
步驟14:乙酸((1R,2S)-2-(羥甲基)環丁基)甲酯
向裝備有機械攪拌器之12L 3頸RBF中饋入1M檸檬酸鈉溶液(藉由混合檸檬酸鈉三價二水合物;682g,2320mmol)與H2O來製備以達到約2.3L總體積)及3.48L H2O(約25℃)。使用冰/H2O浴將混合物冷卻至約20.2℃。pH為約8.46(用pH探針量測)。隨後以一次饋入添加來自螢光假單胞菌(Pseudomonas fluorescens)之天野脂肪酶(Amano Lipase)(41.8g,1547mmol)(pH為約8.12),且混合物在環境溫度下劇烈攪拌約5min。以一次饋入添加(1R,2S)-環丁烷-1,2-二基雙(亞甲基)二乙酸酯(348g,1547mmol),且在監測內部溫度及pH之環境溫度下劇烈攪拌所得混合物。在攪拌混合物隔夜(約20.9℃且pH為約5.45)之後,收集等分試樣,用IPAc萃取,用MeCN稀釋且藉由GC分析,且認為反應完成(1.21% SM殘餘,0.17%對映異構體,1.8%二醇)。將Celite®(70g)添加至反應混合物中,且漿液在中等孔隙率玻璃過濾器上經由Celite®墊過濾(快速過濾,15-20min),用2.5L IPA沖洗。將兩相混合物轉移至12L萃取器中且攪拌1min。分離水層且用IPAc(1×4L)萃取,且在真空中濃縮經合併之有機萃取物,獲得337.28g(99.6%
ee;藉由1HNMR為約50-60mol%殘餘IPA;QNMR:37.63mg+苯甲酸苄酯(Aldrich目錄號B6630,批次號MKBG9990V,61.27mg;結果:約65wt%;校正產率89%)。粗產物按原樣用於下一步驟。
步驟15:乙酸((1R,2R)-2-甲醯基環丁基)甲酯
向2L阿特拉斯(Atlas)反應器中饋入乙酸((1R,2S)-2-(羥甲基)環丁基)甲酯(126.39g,藉由QNMR為79.6wt%;636mmol)及1L DCM,且夾套溫度設定為20℃。添加呈固體狀之二乙酸碘苯(225g,700mmol)(吸熱增加:溫度降至15℃)。一次性添加呈固體狀之TEMPO(3.97g,25.4mmol),產生混濁橙色溶液,其歷經20min時程變得澄清。在20℃下攪拌隔夜之後,收集等分試樣,用MeOH稀釋且藉由GC分析。在必要時額外噴射饋入二乙酸碘苯及TEMPO可用於推進反應完成。隨後將反應混合物冷卻至1.8℃(內部溫度,冰/乾冰/H2O浴),且經由加料漏斗逐滴添加DIPEA(194mL,1113mol)歷經65min,保持內部溫度<5℃。移除冷卻浴,且在攪拌下使混合物升溫至環境溫度。48h後,收集等分試樣,用甲醇稀釋,且藉由GC分析,展示12:1之反式異構體:順式異構體比率。反應混合物隨後冷卻至<5℃(冰/H2O浴),且添加H2O(230mL)歷經約10min(內部溫度達到14℃)。分離有機層,用H2O(125mL)及1M NaH2PO4水溶液(90mL)洗滌且在真空中濃縮,得到273.4g乙酸((1R,2R)-2-甲醯基環丁基)甲酯(QNMR:68.85mg+苯甲酸苄酯(Aldrich目錄號B6630,批次號MKBG9990V,72.36mg)。粗產物按原樣用於下一步驟。
步驟16:乙酸((1R,2R)-2-((R)-(1H-苯并[D][1,2,3]三唑-1-基)(羥基)甲基)環丁基)甲酯
向粗乙酸((1R,2R)-2-甲醯基環丁基)甲酯(5g,10.27mmol)於8mL MTBE中之溶液中添加呈固體狀之苯并三唑(1.296g,10.00mmol)(稍微放熱)。澄清溶液變得愈來愈混濁且形成沈澱物。使混合物在環境溫度下平衡隔夜,隨後添加庚烷(6mL)。在老化6h之後,在環境溫度下過濾混合物且用10mL之1:1 MTBE/庚烷洗滌。將白色固體在玻璃料上在真空下空氣乾燥,獲得2.48g乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羥基)甲基)環丁基)甲酯。
步驟17:5-(((1S,2R)-2-乙醯氧基環丁基)甲基)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
將乙酸((1R,2R)-2-甲醯基環丁基)甲酯(來自步驟16;4.36g,27.9mmol)添加至6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(5.0g,13.97mmol)(步驟12)於DCM(78mL)及AcOH(38.8mL)中之溶液中。溶液在環境溫度下攪拌10min,隨後冷卻至0℃,且緩慢添加氰基硼氫化鈉(1.463mL,27.9mmol)歷經1h。混合物在0℃下攪拌10min,隨後緩慢傾入冷NaOH溶液中,且用EtOAc(120mL)萃取。有機相用鹽水洗滌、經無水Na2SO4乾燥且濃縮。將殘餘物裝載至220g ISCO金色管柱中,且用0%至10% EtOAc/Hex溶離,提供呈白色固體狀之標題化合物之6.0g標題化合物。m/z(ESI陽離子)498.1(M+H)+。
步驟18A:6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
將KOH(0.278mL,10.14mmol)添加至5-(((1R,2S)-2-(乙醯氧基甲基)環丁基)甲基)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自步驟18;1.530g,3.07mmol)於MeOH(99mL)中之溶液中。混合物在環境溫度下攪拌4h,隨後用1N HCl中和至pH=7,且在減壓下濃縮。水性殘餘物用EtOAc(400mL)萃取,且有機萃取物用鹽水洗滌,經無水Na2SO4乾燥,且經由SiO2凝膠短塞過濾,得到呈白色固體狀之標題化合物。獲得1.354g。m/z(ESI,陽離子)456.2(M+H)+。
或者,6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯可如下製備:向(S)-6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸與((1S,4R)-7,7-二甲基-2-側氧基雙環[2.2.1]庚-1-基)甲磺酸(1:1)(步驟11)(32.22g,52.5mmol)及乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羥基)甲基)環丁基)甲酯(步驟17)(15.89g,57.7mmol)於DCM(226mL,7mL/g)中之漿液中添加4份三乙醯氧基硼氫化鈉(13.90g,65.6mmol)歷經30min。添加額外乙酸((1R,2R)-2-((R)-(1H-苯并[d][1,2,3]三唑-1-基)(羥基)甲基)環丁基)甲酯(2.89g,10.50mmol)及三乙醯氧基硼氫化鈉(2.78g,13.12mmol)以驅動反應完成(藉由HPLC分析測定)。隨後添加80mL H2O,且所得混合物攪拌5min。分離各層,有機相用60mL H2O及20mL鹽水洗滌,且隨後在減壓下濃縮為油狀物。將殘餘物溶解於50mL MeOH中,且隨後在環境溫度下添加40mL之5N NaOH(放熱)。在反應完成(藉由HPLC分析測定)後,將反應混合物分配於133mL MTBE與35mL之1.5M檸檬酸之
間。將有機相轉移至RBF,且溶劑經由常壓蒸餾交換為MeCN。此溶液在62℃下接種(漿液發展),使其達到環境溫度,且隨後老化隔夜。漿液在20.5℃下經由粗糙玻璃料燒結漏斗過濾,且濾餅使用60mL MeCN洗滌,隨後在真空烘箱中在40℃下乾燥至恆重。最終質量:21.87g(藉由HPLC為96.4wt%)。
向100mL 3頸RBF中饋入(S)-6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(4.53g,1.0eq)、MeOH(45mL,10vol)及隨後所製備之SOCl2溶液(11.28mL,1.0M MeCN,1.1eq)。在N2氛圍下,將批料加熱至55℃且攪拌18h(或直至如藉由HPLC所測定>99%轉化)。隨後使反應混合物冷卻至20℃歷經2h。向所得白色漿液中添加惠寧氏鹼(Hunig's base)(3.94mL,2.2eq),且在老化0.5h之後添加H2O(9.0mL,2V)作為反溶劑歷經1h。白色漿液老化>2h,且批料經由玻璃燒結過濾器過濾,且濾餅用MeOH/H2O(5:1 v/v)(9.0mL,2V)隨後MeOH/H2O(2:1 v/v)(9.0mL,2V)洗滌。在環境溫度下濾餅在N2下在真空下乾燥12h。獲得呈白色固體狀之產物(4.36g,92%產率)。
步驟18B:6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯
按照針對中間物AA11A之步驟18-19A)所描述的程序由6'-氯-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(中間物AA11A,步驟12B)合成標題化合物。
步驟19A:6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
在用N2惰化之1L 3頸RBF中以維持溫度低於-70℃之速率向DMSO(7.12mL,2.5eq)及DCM(183mL,10vol)之冷卻(-70℃)溶液中添加乙二醯氯(26.1mL,1.0M DCM,1.3eq)。批料在低於-70℃下老化30min,且隨後以維持反應溫度<-70℃之速率添加6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自步驟19A;18.3g,1.0eq)於DCM(183mL,10vol)中之製備溶液。批料老化1.5h,且隨後以維持批料溫度<-70℃之速率添加Et3N(22.4mL,4.0eq)。老化1h後,使批料升溫至-20℃且添加H2O(366mL,20vol)。批料在20℃下攪拌且分離各相。有機層用2×1N HCl(183mL,10vol)及鹽水(183mL,10vol)洗滌。有機層經過濾處理且在真空中濃縮,得到呈褐色泡沫狀之6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(19.91g,wt%校正之產率為94%)。
步驟19B:6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯
按照針對中間物AA11A之步驟20A所描述的程序由6'-氯-5-(((1R,2R)-2-(羥甲基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(中間物AA11A,步驟19B)合成標題化合物。
步驟20:6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
在氬氣吹掃下將裝備有均壓加料漏斗、熱電偶及磁力攪拌棒之烘箱乾燥之3頸RBF冷卻至環境溫度。針對氬氣正壓向燒瓶中饋入(1R,2S)-2-(N-嗎啉基)-1-苯基丙-1-醇(40.2g,182mmol;根據Brubaker,J.D.;Myers,A.G.Org.Lett. 2007,9,3523-3525之文獻程序製備)。向加料漏斗中饋入甲苯(450mL),將其滴入反應器中。溶液在乙二醇-CO2浴(約-12℃)中冷卻且用丁基鋰溶液(2.5M Hex,72.6mL,182mmol)處理,引起白色固體沈澱,在攪拌其時逐漸進入溶液歷經30min。添加二乙烯基鋅溶液(605mL,182mmol;根據Brubaker,J.D.;Myers,A.G.Org.Lett. 2007,9,3523-3525製備。二乙烯基鋅溶液之濃度藉由對碘滴定來測定(Krasovskiy,A.;Knochel,P.Synthesis 2006,890-891;濃度一般為約0.25M),且溶液在攪拌下在冷浴中老化1h;內部溫度為-15℃。經由套管(16 G)以甲苯溶液(200mL,150mL+2×25mL套管/小瓶沖洗)形式添加6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自步驟20A;48.5g,107mmol)(用甲苯共沸三次),歷經約20min。內部溫度上升至-10℃。在維持內部反應溫度低於-5℃時攪拌混合物90min。向加料漏斗中饋入30% w/w檸檬酸水溶液(450mL),隨後藉由添加溶液至反應混合物中來淬滅反應。自浴移除反應器且准許在環境溫度下攪拌。將溶液轉移至分液漏斗,且用甲苯及30%檸檬酸水溶液(每次50mL)沖洗燒瓶。混合各層且隨後分離。有機層用H2O(250mL)隨後鹽水(250mL)洗滌,且最後經MgSO4
乾燥。過濾且濃縮溶液,在20:1 dr下真空隔夜之後產生約90g黃色油狀物。將此分成3批且藉由管柱層析(10至20% EtOAc/Hex 1.5kg SiO2)純化,提供(S)-甲基-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸酯(43.3g,84%)。將水層及洗滌液置放於冰/H2O浴中,且藉由添加8N NaOH水溶液鹼化為pH>13。隨後用甲苯(3×250mL)萃取此溶液。合併之有機萃取物用H2O(250mL)及鹽水(250mL)洗滌,隨後經MgSO4乾燥。過濾且濃縮溶液以恢復>95%產率之配位體。
步驟21:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
向6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自步驟21;4.59g,9.52mmol)於THF(18mL)、MeOH(6.00mL)及H2O(6.00mL)之混合物中之溶液中添加LiOH.H2O(0.799g,19.05mmol),且反應在50℃下攪拌4h。將反應混合物濃縮至約15mL,冷卻至0℃且用2N HCl酸化至pH=3。所得黏性油狀物用20mL H2O及50mL EtOAc稀釋,且獲得澄清雙層混合物。添加更多EtOAc(約200mL),且將有機層分離,用鹽水洗滌,經MgSO4乾燥,過濾且在減壓下濃縮。將粗物質裝載至管柱(220g)上,且用EtOAc/Hex使用以下梯度純化:0-2.5min 0% EtOAc、2.5m-6m 0-20% EtOAc、6m-35m 20-60% EtOAc、35m-40m 70% EtOAc,得到呈白色固體狀之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(4.22g,9.02mmol,95%產率)。
步驟1A:6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
在氬氣氛圍下,將饋入無水Hex(27mL)之乾燥3頸RBF冷卻至0℃。向此溶液中添加硼烷-甲硫醚複合物(3.29mL,34.6mmol)及環己烯(7.01mL,69.3mmol),且混合物在0℃下攪拌2h。向所得白色懸浮液中添加1-戊炔(3.41mL,34.6mmol),且混合物在環境溫度下攪拌0.5h。隨後將混合物冷卻至-78℃,且添加二乙基鋅/1.0M Hex溶液(32.3mL,32.3mmol)。在添加之後,將混合物升溫至0℃,攪拌3min隨後再冷卻至-78℃。此溶液命名為溶液A。向獨立燒瓶中饋入6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸((S)-甲酯(中間物AA11A,步驟20A,5.24g,11.54mmol)及(2s)-3-外-(N-嗎啉基)異冰片(0.486g,2.032mmol)於Hex(50.9mL)及甲苯(16.97mL)中之混合物。混合物在環境溫度下攪拌直至所有固體溶解,隨後冷卻至0℃。在氬氣氛圍下,在1.6h期間經由注射器緩慢添加54mL溶液A。在0℃下攪拌5min後,混合物用NH4Cl飽和溶液(70mL)淬滅,用H2O(30mL)稀釋且用EtOAc(3×270mL)萃取,用鹽水洗滌,經無水Na2SO4乾燥且濃縮。將殘餘物裝載至330g ISCO金色管柱,且用0%至5% EtOAc/Hex溶離,提供呈白色固體狀之3.8g標題化合物。m/z(ESI,陽離子)524.1
(M+H)+。
步驟1B:6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯及6'-氯-5-(((1R,2R)-2-((R,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯
按照針對中間物AA12A之步驟1A所描述的程序由6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(3.19g,中間物AA11A,步驟20B)合成標題化合物。將粗物質吸附至SiO2塞上且在330g ISCO金色管柱上用0至15% EtOAc/庚烷溶離歷經45min來純化,提供6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(2.36g)。進一步溶離提供6'-氯-5-(((1R,2R)-2-((R,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(0.45g)。
步驟2:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
將6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自中間物AA12A,步驟A;4.6g,8.78mmol)及LiOH.H2O(3.68g,88mmol)於MeOH(98mL)及THF(98mL)中之混合物(具有幾滴H2O)在50℃下攪拌隔夜。移除溶劑,且用1N HCl將殘餘物酸化至pH
2-3。用EtOAc(80mL×3)萃取混合物,且合併之有機層用鹽水(10mL)洗滌,經無水MgSO4乾燥且在減壓下濃縮,得到(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(4.25g,8.34mmol,95%產率)。
或者,標題化合物可如下合成:向6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(中間物AA12A,步驟1B,第一溶離異構體,4.50g,7.95mmol)與LiOH.H2O(1.66g,39.7mmol)之固體混合物中添加溶劑二噁烷/MeOH(1:1)(159mL)。將混合物加熱至65℃,且攪拌隔夜。混合物隨後用H2O稀釋且用1.0N HCl酸化至pH約為4。在減壓下蒸發有機溶劑,且向殘餘物中添加H2O。水溶液混合物隨後用EtOAc萃取三次,且將合併之有機萃取物濃縮。在120g SiO2凝膠管柱上用0-70% EtOAc/Hex梯度溶離來純化殘餘物,提供(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(3.80g,7.45mmol,94%產率)。
步驟1A:6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯
將在氬氣下饋入(1R,2R)-N-甲基-1-苯基-1-(((1S,5S,10R)-10-(三甲基矽烷基)-9-硼雙環[3.3.2]癸-9-基)氧基)丙-2-胺(5.40g,14.54mmol)於Et2O(73mL)中之懸浮液之烘箱乾燥之200mL燒瓶冷卻至-78℃,且用烯丙基溴化鎂(13.22mL,13.22mmol)溶液逐滴處理。使混合物升溫至環境溫度且攪拌1h。隨後將溶液(約0.17M;溶液A)再冷卻至-78℃。
將在氬氣下饋入含6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸((S)-甲酯(中間物AA11A,步驟20A,2.0g,4.41mmol)的Et2O(22.03mL)之獨立200mL燒瓶冷卻至-78℃。向此溶液中添加40mL上文提及之溶液A,且所得混合物在-78℃下攪拌40min。隨後添加4-甲基嗎啉4-氧化物(3.10g,26.4mmol),且使混合物升溫至環境溫度後持續10min。添加甲醇(10mL),且揮發性有機物在環境溫度下在減壓下蒸發。添加額外甲醇(100mL),且在環境溫度下攪拌1h之後濃縮混合物。殘餘物用EtOAc(450mL)稀釋,用1N HCl(15mL)、Na2CO3溶液(10mL)及鹽水(6mL)洗滌,經無水Na2SO4乾燥且濃縮。將殘餘物裝載至220g ISCO金色管柱,且用0%至5% EtOAc/Hex溶離,提供呈白色固體狀之1.88g標題化合物。m/z(ESI,陽離子)496.0(M+H)+。
步驟1B:6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯
按照針對中間物AA13A之步驟1A所描述的程序由6'-氯-5-(((1R,2R)-2-甲醯基環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(中間物AA11A,步驟20B;3.0g)合成標題化合物。在220g SiO2凝膠管柱上用5% EtOAc/Hex溶離歷經60min來純化粗物質,提供6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b[1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(2.19g)。
步驟2:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
將6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-甲酯(來自中間物AA13A,步驟1A;1.88g,3.79mmol)及LiOH溶液(1M)(34.1mL,34.1mmol)於MeOH(34mL)及THF(50mL)中之混合物在65℃下攪拌50min。在冷卻至環境溫度之後,將混合物用1N HCl酸化至pH 2至3,用EtOAc(350mL)萃取,經無水Na2SO4乾燥且濃縮,提供呈白色固體狀之1.82g標題化合物。m/z(ESI,陽離子)482.0(M+H)+。
或者,標題化合物可如下合成:在環境溫度下向6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(S)-第三丁酯(中間物AA13A,步驟1B,250mg,0.465mmol)於DCM(3.717mL)中之溶液中添加TFA(0.929mL),且將反應混合物攪拌4h。隨後濃縮粗反應混合物,將殘餘物溶解於EtOAc中,用飽和
NaHCO3洗滌一次,經MgSO4乾燥,過濾且濃縮,得到白色泡沫。粗物質不經進一步純化即按原樣使用。
使用迪恩-斯塔克(Dean-Stark)設備將4-甲氧基苯甲醛(Spectrochem;100g,734.5mmol)及4-甲氧基苄基胺(G.L.R.;100g,734.5mmol)於甲苯(0.8L)中之溶液在130℃下回流6h。藉由TLC監測反應,且在完成後,在減壓下移除過量溶劑且將殘餘物溶解於甲醇(0.8L)中。將所得溶液冷卻至0℃,且逐份添加硼氫化鈉(36.12g,954.8mmol)。完成添加後,反應混合物在環境溫度下攪拌3h。移除甲醇,且用H2O(1.0L)及EtOAc(2.0L)稀釋殘餘物。分離各層,且用EtOAc(2×1.0L)萃取水層。合併之有機層用H2O、鹽水洗滌,且經Na2SO4乾燥。在減壓下移除溶劑,且所獲得之粗物質藉由管柱層析經由SiO2凝膠(100-200目尺寸)用100% Hex:25% EtOAc/Hex梯度溶離來純化,得到呈無色但不透明液體狀之標題化合物(160g,84.6%)。
將甲磺醯胺(Sigma-Aldrich,5g,52.6mmol)、對甲氧基苄氯(14.98mL,110mmol)、無水K2CO3(36.3g,263mmol)及碘化鉀(0.873g,5.26mmol)於無水2-丁酮(175mL)中之混合物回流(75℃)隔夜。藉由TLC及LC/MS監測反應,且在完成後,將混合物冷卻至環境溫度,過濾,用Et2O洗滌且濃縮。粗物質(17.54g,52.3mmol,99%
產率)不經進一步純化即可使用。MS(ESI,陽離子)m/z:358.1(M+Na)。
向N,N-雙(4-甲氧基苄基)胺(中間物EE11;200g,775.19mmol)於DCM(2.5L)中之溶液中添加Et3N(336.17mL,2325.5mmol),且將反應混合物冷卻至0℃。以逐滴方式添加乙磺醯氯(95mL,1007.75mmol)隨後DMAP(19.0g,155.03mmol)。所得反應混合物在環境溫度下攪拌30min。藉由TLC監測反應,且在完成後,用H2O稀釋混合物,且分離各層且用DCM(3×1.5L)萃取水相。合併之有機層用H2O、鹽水洗滌,且經Na2SO4乾燥。在減壓下移除溶劑,得到粗物質,其藉由管柱層析經由SiO2凝膠(100-200目)用0-12% EtOAc/Hex梯度溶離來純化,得到呈白色蓬鬆固體狀之標題化合物(145g,53.4%)。
向N,N-雙(4-甲氧基苄基)胺(中間物EE11;405g,1569.7mmol)於DCM(4.0L)中之溶液中添加Et3N(681.0mL,4709.3mmol),且將反應混合物冷卻至0℃。以逐滴方式添加丙磺醯氯(231mL,2040.6mmol)隨後DMAP(38.3g,313.9mmol)。所得混合物在環境溫度下攪拌30min。藉由TLC監測反應,且在完成後,用2.0L H2O稀釋混合物,分離各層且用DCM(3×2.0L)萃取水相。合併之有機層用H2O、鹽水洗滌,且經Na2SO4乾燥。在減壓下移除溶劑,得到粗物質,其藉由
管柱層析經由SiO2凝膠(100-200目)用0-12% EtOAc/Hex梯度溶離來純化,得到呈白色蓬鬆固體狀之標題化合物(300g,52.44%)。
步驟1:丁-3-烯-1-磺酸鈉
將4-溴-1-丁烯(LLBChem,3.01mL,29.6mmol)及亞硫酸鈉(4.11g,32.6mmol)於H2O(20mL)中之混合物在110℃下攪拌隔夜。藉由TLC監測反應,且在完成後,在減壓下移除H2O且用丙酮濕磨殘餘物。過濾所獲得之固體,得到呈白色固體狀之標題化合物(4.53g),其按原樣用於下一步驟。
步驟2:丁-3-烯-1-磺醯胺
將丁-3-烯-1-磺酸鈉(4.50g,28.5mmol)與氧氯化磷(70mL)之混合物在135℃下攪拌7h。隨後在減壓下移除氧氯化磷,獲得含有深色殘餘物之白色固體。用MeCN(20mL)稀釋殘餘物,且隨後過濾以移除沈澱物。將濾液冷卻至0℃且用氨溶液(30%水溶液)(30mL)逐滴處理。在完成添加之後,將反應在0℃下攪拌30min。混合物用EtOAc(300mL)稀釋,用鹽水洗滌,且經無水Na2SO4乾燥。在減壓下移除溶劑,且藉由管柱層析經由SiO2凝膠(100-200目;用1:1 EtOAc/Hex溶離)來純化殘餘物,得到呈白色固體狀之標題化合物(1.55g,產率:40%)。MS(ESI,陽離子)m/z:117.1(M+1)。
將丁-3-烯-1-磺醯胺(中間物EE15;1.5g,11.10mmol)、對甲氧基苄氯(3.76mL,27.7mmol)、無水K2CO3(7.67g,55.5mmol)及碘化鈉(0.166g,1.110mmol)於無水2-丁酮(55.5mL)中之混合物回流(75℃)隔夜。藉由TLC及LC/MS監測反應,且在完成後,將混合物冷卻至環境溫度,過濾且濃縮。將粗物質吸附至SiO2凝膠塞上且藉由層析經由SiO2凝膠(100-200目)用0至30% EtOAc/Hex溶離來純化,提供呈無色油狀之標題化合物(4.10g,10.92mmol,98%產率)。MS(ESI,陽離子)m/z:376.2(M+1)。
步驟1:(S)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺
將N,N-雙(4-甲氧基苄基)丁-3-烯-1-磺醯胺(中間物EE16;50.0g,133.2mmol)用甲苯共沸且在真空下乾燥1h。添加THF(890mL)且將混合物冷卻至-78℃。隨後添加丁基鋰(2.5M Hex,63.9mL,159.9mmol),且反應混合物在-78℃下攪拌1h。將此陰離子溶液緩慢添加至MeI(16.8mL,266.5mmol)於THF(300mL)中之溶液(冷卻至-78℃)中。所得反應混合物在-78℃下再攪拌15min。在反應完成(藉由TLC監測)時,混合物用NH4Cl飽和溶液淬滅且用EtOAc萃取。有機層經Na2SO4乾燥且在減壓下濃縮,獲得粗物質,其藉由管柱層析經由SiO2
凝膠用5-10% EtOAc/Hex溶離來純化,提供呈外消旋混合物狀之具有半固體性質的標題化合物(22.0g)。藉由SFC(管柱:Chiralpak® AD-H,50×250mm,5μm;移動相A:CO2;移動相B:乙醇;等度:40% B與CO2回收;流動速率:200g/min;裝載:2.0mL如上所述製備之樣品(約100mg);偵測:在230nm下之UV;循環時間:5min;總溶離時間:10min;儀器:Thar 350(Lakers))分離對映異構體,提供呈第一溶離異構體狀之(S)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺(滯留時間:2.22min)及呈第二溶離異構體狀之(R)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺(滯留時間:2.57min)。
步驟2:(R)-戊-4-烯-2-磺醯胺
向(R)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺(中間物EE17,步驟1,第二溶離異構體;221mg,0.567mmol)於DCM(2.8mL)中之溶液中逐滴添加三氟乙酸(1.7mL,22.70mmol)(澄清溶液極快速變深色)。攪拌7h之後(TLC 30% EtOAc/Hex展示起始物質完全損耗),混合物用EtOAc稀釋,用飽和NaHCO3洗滌,用EtOAc反萃取,經MgSO4乾燥且濃縮。粗物質經由層析(12g ISCO金色管柱;0-40% EtOAc Hex)純化,提供(R)-戊-4-烯-2-磺醯胺(70mg,0.469mmol,83%產率)
使用針對中間物EE17之步驟2所描述的程序由(S)-N,N-雙(4-甲氧基苄基)戊-4-烯-2-磺醯胺(中間物EE17,步驟1,第一溶離異構體)合成此中間物。
步驟1:(S)-N,N-雙(4-甲氧基苄基)己-5-烯-3-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)己-5-烯-3-磺醯胺
N,N-雙(4-甲氧基苄基)丁-3-烯-1-磺醯胺(中間物EE16;40.0g,106.6mmol)在甲苯中在真空下共沸2h。在氬氣氛圍下添加THF(700mL),且將反應混合物冷卻至-78℃。添加丁基鋰(2.5M Hex;71.6mL,127.9mmol),且反應混合物在-78℃下攪拌1h。將此陰離子溶液緩慢添加至乙基碘(36.44mL,340.1mmol)於THF(40mL)中之溶液(冷卻至-78℃)中。所得反應混合物隨後用NH4Cl飽和溶液淬滅,使其達到環境溫度且用EtOAc萃取。有機層經Na2SO4乾燥且在減壓下濃縮,獲得粗物質,其藉由管柱層析經由SiO2凝膠用5-10% EtOAc/Hex溶離來純化,提供呈外消旋混合物狀之具有半固體性質的標題化合物(24g)。MS(ESI,陽離子)m/z;404.03(M+1)藉由SFC(樣品製備:MeOH:DCM(3:1)之14.4g/200mL(72mg/mL)樣品溶液;管柱:Chiralpak® AD-H,30×250mm,5μm;移動相A:CO2;移動相B:MeOH(20mM NH3);等度:50% B,流動速率:100mL/min;出口壓力:100巴;裝載:1.0mL如上所述製備之樣品溶液(72mg);偵測:在227nm下之UV;循環時間:8min;總溶離時間:17min;儀器:Thar 350 SFC)分離對映異構體,提供呈第一溶離異構體狀之(S)-N,N-雙(4-甲氧基苄基)己-5-烯-3-磺醯胺及呈第二溶離異構體狀之(R)-N,N-雙(4-甲氧基苄基)己-5-烯-3-磺醯胺。
步驟2:(R)-己-5-烯-3-磺醯胺
使用針對中間物EE17之步驟2所描述的程序由(R)-N,N-雙(4-甲氧
基苄基)己-5-烯-3-磺醯胺(中間物EE18,步驟1,第二溶離異構體)合成此中間物。
使用針對中間物EE17之步驟2所描述的程序由(S)-N,N-雙(4-甲氧基苄基)己-5-烯-3-磺醯胺(中間物EE18,步驟1,第一溶離異構體)合成此中間物。
步驟1:戊-4-烯-1-磺酸鈉
向裝備有機械攪拌器、N2進氣口、冷凝器及溫度探針之3L 3頸RBF中饋入5-溴-1-戊烯(Sigma Aldrich,200g,1342mmol)、亞硫酸鈉(Strem Chemicals;186g,1476mmol)及H2O(400mL)。將混合物加熱至回流(設定在100℃下且在93-94℃下回流)持續4h;等分試樣NMR展示>95%轉化。將混合物濃縮且用丙酮共沸以移除H2O。粗固體用丙酮洗滌且過濾,得到戊-4-烯-1-磺酸鈉(350g,2033mmol)。
步驟2:戊-4-烯-1-磺醯胺
向裝備有機械攪拌器、N2進氣口、冷凝器及溫度探針之3L 3頸RBF中饋入戊-4-烯-1-磺酸鈉(100g,581mmol)(約150g來自步驟1之粗物質)及氧氯化磷(Sigma Aldrich;532mL,5808mmol)。將混合物
加熱至90℃後持續18h,之後過濾反應物且用MeCN洗滌固體。將有機溶液濃縮且用MeCN共沸以移除POCl3,得到85g戊-4-烯-1-磺醯氯中間物。將此物質(300mL MeCN溶液)饋入裝備有機械攪拌器、N2進氣口、冷凝器及溫度探針之1L 3頸RBF中。將反應物冷卻至0-5℃,且緩慢添加NH4OH(Sigma Aldrich;28% NH3;404mL,2904mmol)歷經30min。反應物在0-5℃下攪拌1h,之後添加EtOAc(300mL),且混合物用EtOAc萃取且濃縮,得到呈棕色油狀之戊-4-烯-1-磺醯胺(50g,335mmol,57.7%產率)。
步驟3:N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺
按照針對中間物EE16所描述的程序由戊-4-烯-1-磺醯胺(4.5g,30.2mmol)合成標題化合物。粗物質之純化提供呈無色油狀之N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺(11.4g,29.3mmol,97%產率)。
步驟1:(S)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺
將N,N-雙(4-甲氧基苄基)乙磺醯胺(中間物EE13;140.0g,400.64mmol)於THF(1.4L,THF在使用前用氬氣吹掃15min)中之溶液冷卻至-78℃,且逐滴添加丁基鋰溶液(2.6M Hex,200.0mL,520.83mmol)。所得溶液在-78℃下攪拌10min,且添加4-溴-1-丁烯(73.2mL,721.15mmol)歷經2min。5min後,使反應物達到環境溫度且攪拌1h。藉由TLC監測反應,且在完成後,混合物用飽和NH4Cl溶液
(400mL)淬滅,且所得水層用EtOAc(2×1.0L)萃取。合併之有機層用鹽水洗滌且經Na2SO4乾燥。在減壓下移除溶劑,得到粗物質,其藉由管柱層析(SiO2凝膠100-200目)用0-4%丙酮/Hex梯度溶離來純化,得到呈無色稠油狀之標題化合物(外消旋混合物,80.0g,49.5%)。MS(ESI,陽離子)m/z:404.25(M+1)。藉由SFC(樣品製備:75g/1.5L(50mg/mL)樣品MeOH溶液;管柱:Chiralpak® IF,21×250mm,5μm;移動相A:CO2;移動相B:MeOH(0.2% DEA);等度:40% B,流動速率:80mL/min;出口壓力:100巴;裝載:3.0mL如上所述製備之樣品溶液(150mg);偵測:在225nm下之UV;循環時間:3.9min;總溶離時間:6min;儀器:Thar 80 SFC)分離對映異構體,提供呈第一溶離異構體狀之(S)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺及呈第二溶離異構體狀之(R)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺。
步驟2:(R)-己-5-烯-2-磺醯胺
使用針對中間物EE17之步驟2所描述的程序由(R)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺(中間物EE20,步驟1,第二溶離異構體)合成標題化合物。
使用針對中間物EE17之步驟2所描述的程序由(S)-N,N-雙(4-甲氧基苄基)己-5-烯-2-磺醯胺(中間物EE20,步驟1,第一溶離異構體)合成標題化合物。
步驟1:(S)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺
使用針對中間物AA20之步驟1所描述的程序由N,N-雙(4-甲氧基苄基)丙磺醯胺(中間物EE14)合成標題化合物。藉由SFC(樣品製備:40.55g/170mL(238.5mg/mL)樣品MeOH溶液;管柱:Chiralpak® AD-H,50×150mm,5μm;移動相A:CO2;移動相B:MeOH(20mM NH3);等度:50% B,流動速率:190mL/min;出口壓力:100巴;裝載:1.5mL如上所述製備之樣品溶液(357.8mg);偵測:在227nm下之UV;循環時間:17.5min;總溶離時間:21min;儀器:Thar 350 SFC)分離對映異構體,提供呈第一溶離異構體狀之(S)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺及呈第二溶離異構體狀之(R)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺。
步驟2:(R)-庚-6-烯-3-磺醯胺
使用針對中間物EE17之步驟2所描述的程序由(R)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺(中間物EE21,步驟1,第二溶離異構體)合成標題化合物。
使用針對中間物EE17之步驟2所描述的程序由(S)-N,N-雙(4-甲氧基苄基)庚-6-烯-3-磺醯胺(中間物EE21,步驟1,第一溶離異構體)合成標題化合物。
步驟1:(4S,5S)-4,5-二甲基-1,3,2-二氧硫雜環戊烷2,2-二氧化物
向500mL 3頸RBF(裝備有H2O冷卻回流冷凝器及HCl收集器)中添加(2s,3s)-(+)-2,3-丁二醇(Aldrich;15.00mL,166mmol)及CCl4(120mL)。隨後經由注射器逐滴添加附加試劑SOCl2(14.57mL,200mmol)歷經20min時段,且將所得混合物加熱至98℃後持續45min,隨後使其冷卻至rt。隨後在冰/H2O浴中冷卻反應混合物,添加MeCN(120mL)及H2O(150mL)隨後氯化釕(III)(0.035g,0.166mmol)。隨後緩慢逐份添加高碘酸鈉(53.4g,250mmol)歷經30min。劇烈攪拌所得兩相棕色混合物,同時使其達到rt後持續1.5h時段(內部溫度從未升高至rt以上)。TLC(50% EtOAc/庚烷)展示完全轉化。隨後將粗混合物傾入冰H2O中且用300mL Et2O萃取兩次。合併之有機層用200mL飽和碳酸氫鈉洗滌一次,用200mL鹽水洗滌一次,經Na2SO4乾燥且藉由旋轉蒸發濃縮,得到呈紅色油狀之(4S,5S)-4,5-二甲基-1,3,2-二氧硫雜環戊烷2,2-二氧化物(21.2g,139mmol)。
步驟2:(2S,3S)-3-甲基己-5-烯-2-醇
向500mL燒瓶中添加(4S,5S)-4,5-二甲基-1,3,2-二氧硫雜環戊烷2,2-二氧化物(來自中間物EE22,步驟1;21.2g,139mmol)及THF(220mL),此時將溶液冷卻至-78℃且用氬氣進行3次抽真空/回填循環。向溶液中添加四氯銅酸二鋰(ii)(0.1M THF溶液,69.7mL,6.97
mmol)。所得混合物在-78℃下攪拌30min,且隨後經由套管緩慢添加烯丙基溴化鎂(1.0M Et2O溶液,397mL,397mmol)歷經80min。所得混合物在0℃下攪拌4h。用200mL H2O淬滅混合物且使其達到rt,此時藉由旋轉蒸發移除揮發物。隨後向水性殘餘物中添加50% H2SO4(150mL),混合物攪拌5min,隨後添加Et2O(400mL)且混合物在rt下劇烈攪拌隔夜。分離各層;水層用300mL Et2O萃取,且合併之有機層用300mL飽和NaHCO3洗滌,經Na2SO4乾燥,過濾且藉由旋轉蒸發濃縮,得到呈澄清油狀之(2S,3S)-3-甲基己-5-烯-2-醇(6.7g,58.7mmol)。
步驟3:2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶
在氬氣氛圍下向在0℃下含有三丁基膦(57.7mL,231mmol)於1000mL脫氣THF(用氬氣鼓泡30min加5次抽吸/添加氬氣循環)中之攪拌溶液之2000mL乾燥RBF中逐滴添加偶氮二甲酸二乙酯(40wt.%甲苯溶液;103mL,262mmol)。經由注射器-過濾器(0.45um)將(2S,3S)-3-甲基己-5-烯-2-醇(來自中間物EE22,步驟2;17.6g,154mmol;經Na2SO4乾燥)溶液以50mL THF溶液形式逐滴添加至膦/偶氮二甲酸二乙酯複合物之溶液中。所得ROH/偶氮二甲酸二乙酯/三-正丁基膦混合物在零度下老化15min(溶液變為淡橙色),此時在正氬氣壓力下將嘧啶-2-硫醇(49.3g,439mmol)逐漸添加至反應容器頂部(呈固體狀)。反應物在0℃下攪拌1h,隨後在rt下攪拌15h(藉由LC/MS,在12h反應未完成)。隨後過濾粗反應物以移除過量嘧啶-2-硫醇,用1000mL EtOAc稀釋,用500mL之1N K2CO3萃取兩次且用500mL鹽水萃取一次。水層用300mL EtOAc反萃取,且合併之有機層經Na2SO4乾燥。隨後過濾有機溶液,藉由旋轉蒸發移除溶劑,且過濾粗
物質以移除反應中產生之二氮烯-1,2-二甲酸(E)-二乙酯。使濾液(125g)通過SiO2塞(500g SiO2,用2L DCM溶離),在移除溶劑之後得到75g粗產物。同樣在Combiflash®(125g金色SiO2管柱)上用10% EtOAc/庚烷溶離來純化粗產物,得到呈淡黃色油狀之2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶(20.37g,98mmol)。
步驟4:2-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)嘧啶
向具有回流冷凝器之500mL 3頸RBF中添加苯膦酸(3.95g,24.96mmol)、鎢酸鈉氧化二水合物(8.23g,24.96mmol)、四丁基硫酸銨(50wt.% H2O溶液,28.7mL,24.96mmol)、催化量之過氧化氫(30% H2O,12.75mL,125mmol)、甲苯(200mL)及2-(((2R,3S)-3-甲基己-5-烯-2-基)硫基)嘧啶(來自中間物EE22,步驟3;52g,250mmol)。反應物在45℃下攪拌5min,此時逐份(一次10mL)添加過氧化氫(30% H2O,58.6mL,574mmol)。在添加第一份過氧化氫之後5min,觀測到放熱(65℃),自油浴取出反應物,停止添加且將燒瓶置放於H2O浴中直至溫度穩定。自H2O浴取出燒瓶,且以內部溫度保持在45℃與55℃之間之速率持續逐份添加過氧化氫(約40min)。若溫度上升超過60℃,則利用冰浴,且若溫度下降低於45℃,則使用油浴。反應物隨後在45℃下攪拌1h。反應物用1400mL EtOAc稀釋,且用500mL H2O萃取兩次並用500mL鹽水萃取一次。有機層經Na2SO4乾燥,過濾,濃縮,且在Combiflash®(每30公克粗物質330g金色SiO2管柱)上用0%-50% EtOAc/庚烷溶離來純化粗物質,得到呈淡黃色油狀之2-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)嘧啶(55.7g,232mmol)。
步驟5:(2R,3S)-3-甲基己-5-烯-2-亞磺酸鈉
在rt下向2-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)嘧啶(來自中間物EE22,步驟4;52g,216mmol)於MeOH(400mL)中之溶液中添加甲醇鈉溶液(51.0mL,223mmol)歷經70min。逐份添加甲醇鈉,監測內部溫度,且使添加減緩或在H2O浴中冷卻反應物,從未使內部溫度超出30℃。藉由旋轉蒸發濃縮混合物,且將蠟質固體用MTBE(添加200mL MTBE,使用刮刀打碎凝集塊來攪拌1h)濕磨,過濾(在濾餅上使用N2流)且用100mL冷MTBE洗滌,獲得呈灰白色固體狀之(2R,3S)-3-甲基己-5-烯-2-亞磺酸鈉(46g,250mmol)。
步驟6:(2R,3S)-3-甲基己-5-烯-2-磺醯胺
在rt下向1000mL 3頸RBF中添加(2R,3S)-3-甲基己-5-烯-2-亞磺酸鈉(來自中間物EE22,步驟5;46g,225mmol)、500mL H2O及KOAc(44.1g,449mmol)。將燒瓶置放於45℃油浴中,且逐份添加羥胺-O-磺酸(21.09g,187mmol)歷經90min。監測反應之內部溫度,且自油浴移除反應物(若需要)以控制放熱(Tmax=55℃)。藉由LC/MS每10min監測反應,且在添加0.83eq.羥胺-O-磺酸之後完成反應。隨後使混合物冷卻至rt且用1000mL EtOAc萃取。有機相用500mL之1N HCl萃取三次,用300mL飽和碳酸氫鈉萃取兩次,用200mL鹽水萃取一次,經Na2SO4乾燥,過濾且藉由旋轉蒸發濃縮,提供呈白色固體狀之(2R,3S)-3-甲基己-5-烯-2-磺醯胺(32g,181mmol)。
實例1. (1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-11',11'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:2,2-二甲基戊-4-烯-1-醇
向100mL燒瓶中添加2,2-二甲基戊-4-烯酸甲酯(Sigma-Aldrich;8.40g,59.1mmol)、四氫硼酸鋰(4.06mL,124mmol)及隨後緩慢添加(每5min 1mL)MeOH(5.26mL,130mmol)。反應物在22℃下攪拌2h。反應物隨後用300mL H2O淬滅且用300mL Et2O萃取2次。有機層經Na2SO4乾燥,過濾且藉由旋轉蒸發(用H2O浴在0℃下緩慢進行歷經4h且緩慢降低壓力,收集器中無微量產物)移除溶劑,得到呈澄清油狀之2,2-二甲基戊-4-烯-1-醇(6.75g,59.1mmol,100%產率)。
步驟2:甲磺酸2,2-二甲基戊-4-烯-1-基酯
向2,2-二甲基戊-4-烯-1-醇(來自步驟1,6.5g,56.9mmol)於DCM(40mL)中之溶液(冷卻至-78℃)中添加MsCl(6.75mL,85mmol)。在添加之後,將混合物置放於冰浴中且攪拌16h(16h後浴在rt下)。將反應物過濾且用400mL DCM稀釋。有機層用200mL H2O萃取一次且再次用200mL之1N HCl萃取。有機層經Na2SO4乾燥,過濾且濃縮,得到橙色油狀物。在Combiflash®(80g金色SiO2管柱)上用10%至50% EtOAc/庚烷溶離來純化粗產物,得到呈澄清油狀之甲磺酸2,2-二甲基戊-4-烯-1-基酯(6.66g,34.6mmol,60.8%產率)。
步驟3:2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶
將嘧啶-2-硫醇(962mg,8.58mmol)及甲醇鈉(30wt%甲醇溶液,1.825mL,9.83mmol)於MeOH(8mL)中之溶液用甲磺酸2,2-二甲基戊-4-烯-1-基酯(1500mg,7.80mmol)於2mL MeOH中之溶液處理。向溶液中添加20mL DMF,且隨後藉由將氬氣鼓泡通過反應混合物10min使溶液脫氣。將反應物加熱至130℃,同時經由兩個18規格針排出
MeOH持續11h。反應物用300mL EtOAc稀釋且用200mL鹽水萃取兩次。有機層經Na2SO4乾燥,過濾,濃縮,且在Combiflash®(24g金色SiO2管柱)上用10%至50% EtOAc/庚烷溶離來純化粗物質,得到呈澄清油狀之2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶(1250mg,6.00mmol,77%產率)。
步驟4:2-((2,2-二甲基戊-4-烯-1-基)磺醯基)嘧啶
向25mL燒瓶中添加苯膦酸(0.056mL,0.504mmol)、鎢酸鈉氧化二水合物(0.051mL,0.504mmol)、四丁基硫酸銨(50wt.% H2O溶液,0.580mL,0.504mmol)及過氧化氫(30% H2O,1.287mL,12.60mmol)。反應物在22℃下攪拌5min,此時以5mL甲苯溶液之形式添加2-((2,2-二甲基戊-4-烯-1-基)硫基)嘧啶(來自步驟3,1050mg,5.04mmol)。相較於在50℃下攪拌1h,反應物在22℃下攪拌30min。反應物用300mL EtOAc稀釋,且用100mL H2O萃取一次且隨後用100mL鹽水萃取一次。有機層經Na2SO4乾燥,過濾,濃縮,且在Combiflash®(12g金色SiO2管柱)上用10%至50% EtOAc/庚烷溶離來純化粗物質,得到呈澄清油狀之2-((2,2-二甲基戊-4-烯-1-基)磺醯基)嘧啶(910mg,3.79mmol,75%產率)。
步驟5:2,2-二甲基戊-4-烯-1-亞磺酸鈉
向100mL燒瓶中添加2-((2,2-二甲基戊-4-烯-1-基)磺醯基)嘧啶(來自步驟4,910mg,3.79mmol)及MeOH(20mL),此時在22℃下添加甲醇鈉溶液(30wt%甲醇溶液,0.710mL,3.79mmol),且將混合物攪拌45min。隨後藉由旋轉蒸發濃縮反應混合物,且用Et2O濕磨殘餘物。收集固體且乾燥,得到呈亮橙色固體狀之2,2-二甲基戊-4-烯-1-亞
磺酸鈉(465mg,2.52mmol,66.7%產率)。
步驟6:2,2-二甲基戊-4-烯-1-磺醯胺
在rt下向2,2-二甲基戊-4-烯-1-亞磺酸鈉(來自步驟5,465mg,2.52mmol)及乙酸鈉(414mg,5.05mmol)於H2O(20mL)中之溶液中添加羥胺-o-磺酸(571mg,5.05mmol)。將混合物加熱至50℃且攪拌1h,隨後在rt下攪拌4h。混合物用EtOAc萃取,有機相經Na2SO4乾燥,過濾且濃縮。在Combiflash®(12g金色SiO2管柱)上用10%至50% EtOAc/庚烷溶離來純化粗物質,提供呈白色固體狀之2,2-二甲基戊-4-烯-1-磺醯胺(246mg,1.388mmol,55.0%產率)。
步驟7:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-5,5-二甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
向100mL燒瓶中添加(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;100mg,0.196mmol)、2,2-二甲基戊-4-烯-1-磺醯胺(來自步驟6,104mg,0.588mmol)及DCE(2mL)。溶液用氬氣鼓泡15min,此時在rt下以0.2mL DCE溶液之形式添加(1,3-二基咪唑啶-2-亞基)(2-異丙基亞苄基)氯化釕(VI)(12.29mg,0.020mmol)。混合物在rt下攪拌16h。反應混合物隨後用空氣軋泡5min且過濾。自濾液移除溶劑,且在Combiflash®(12g金色SiO2管柱)上用50%-90% EtOAc/庚烷+0.2% AcOH溶離來直接純化粗產物,得到呈白色固體狀之(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-5,5-二甲基-6-胺磺
醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(98mg,0.159mmol,81%產率)。
步驟8:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-11',11'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.0~3,6~.0~19,24~]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向含有(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-5,5-二甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(來自步驟7,98mg,0.159mmol)之先前藉由用5mL甲苯共沸兩次乾燥之250mL燒瓶中添加N,N-二甲基吡啶-4-胺(33.0mg,0.270mmol)及100mL DCM。將反應混合物冷卻至0℃,在0℃下添加N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(60.9mg,0.318mmol)。反應物在rt下攪拌12h。混合物隨後用100mL之1N鹽酸淬滅且用300mL DCM萃取。有機層經無水Na2SO4乾燥,過濾且藉由旋轉蒸發濃縮。首先在Combiflash®(12g金色SiO2管柱)上用30%-70% EtOAc/庚烷+0.2% AcOH溶離,隨後製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;Phenomenex,Torrance,CA;在兩種溶劑均含有0.1% TFA時,10%至90% MeCN/H2O梯度溶離,45min方法)來純化粗物質,得到呈白色固體狀之(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-11',11'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(2.5mg,4.17μmol,2.63%產率)。1H NMR(400MHz,CDCl3)δ 8.35(br.s.,1H),7.70(d,J=8.4Hz,1H),7.18(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.93(s,2H),6.85-6.79(m,1H),5.98-5.82(m,1H),5.69(dd,J=8.1,15.4Hz,1H),4.27-4.17(m,1H),4.14-4.01(m,2H),4.15-3.94(m,1H),3.79-3.60(m,2H),3.25(d,J=13.3Hz,2H),3.14-
2.95(m,1H),2.86-2.62(m,2H),2.49-2.21(m,3H),2.14-1.89(m,4H),1.86-1.80(m,3H),1.69-1.61(m,1H),1.48-1.36(m,1H),1.26(s,6H)。m/z(ESI,陽離子)599.0(M+H)+。
實例2. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
將DMAP(3.42g,28.0mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA11A;7.7g,16.45mmol)及(2R,3S)-3-甲基己-5-烯-2-磺醯胺(中間物EE22;5.83g,32.9mmol)於DCM(411mL)中之溶液(冷卻至0℃)中。隨後緩慢逐份添加EDC鹽酸鹽(6.31g,32.9mmol)。攪拌混合物同時使其達到環境溫度隔夜。混合物用1N HCl及鹽水洗滌,且水層用EtOAc反萃取。合併之有機物經MgSO4乾燥,過濾且濃縮。將黃色油性殘餘物裝載至220ISCO金色管柱上,且用0%至20% EtOAc(含有0.3%AcOH)/庚烷溶離來純化,提供(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-
萘]-7-甲醯胺(7.89g,12.58mmol,76%產率)。
步驟2:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向氬氣覆蓋之20L反應器中饋入14L 1,2-DCE。以400mL 1,2-DCE溶液之形式添加(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(18.75g,29.9mmol),隨後400mL沖洗劑。將反應器密封且用氬氣吹掃。以150mL 1,2-DCE溶液之形式添加赫維達-格拉布斯II(1.873g,2.99mmol),隨後50mL沖洗劑。將反應器加熱至60℃歷經1h,用氬氣吹掃頂部空間且保持在溫度下9h。反應物藉由添加2-(2-(乙烯基氧基)乙氧基)乙醇(1.501g,11.36mmol)淬滅,冷卻至環境溫度,且藉由旋轉蒸發濃縮至約200mL體積。將反應物轉移至1L RBF,且用1,2-DCE稀釋至500mL體積。將反應物在40℃下在攪拌下用52g Silicycle矽硫醇(SiliCycle Inc.,Quebec City,Quebec CANADA目錄號R51030B)處理9h,過濾且用2×65mL DCM沖洗。使溶液通過沃特曼(Whatman)GF/F濾杯(GE Healthcare Bio-Sciences Pittsburgh,PA,USA),得到透明黃色溶液。濃縮反應物,得到質量為27.4g之粗產物。將殘餘物在250mL IPAc中製成漿液且蒸發至乾三次。將反應物懸浮於270mL IPAc中,加熱至溶解,使其冷卻至環境溫度,且攪拌18。過濾固體且用65mL IPAc洗滌。將固體空氣乾燥30min,隨後置放在高真空下3h,得到12.56g(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,其按重量計為91.7%。1H NMR(500MHz,CD2Cl2)δ 8.06(s,1 H),7.71
(d,J=8.56Hz,1 H),7.17(dd,J=8.44,2.32Hz,1 H),7.09(d,J=2.20Hz,1 H),6.91(s,3 H),5.81(ddd,J=14.92,7.82,4.16Hz,1 H),5.71(dd,J=15.41,8.31Hz,1 H),4.16-4.26(m,2 H),3.83(d,J=14.43Hz,1 H),3.69(d,J=14.43Hz,1 H),3.25(d,J=14.43Hz,1 H),3.04(dd,J=15.28,9.66Hz,1 H),2.68-2.84(m,2 H),2.41(app qd,J=9.80,3.70Hz,1 H),2.25-2.34(m,1 H),1.93-2.00(m,5 H),1.74-2.11(m,9 H),1.62-1.73(m,1 H),1.43(d,J=7.09Hz,3 H)1.35-1.42(m,1 H)1.03(d,J=6.60Hz,3 H)。MS(ESI,陽離子)m/z 599.2(M+H)+。
實例3. (1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向1000mL RBF中饋入(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-N-(((2R,3S)-3-甲基己-5-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(實例2,步驟1,710mg,1.132mmol)及DCM(569.00mL)。溶液用氬氣鼓泡15min,隨後添加赫維達-格拉布斯II(70.9mg,0.113mmol)。混合物在45℃下攪拌15h。反應混合物用空氣鼓泡20min同時冷卻至環境溫度,隨後在減壓下濃縮。將粗物質油吸附至SiO2凝膠塞上,且經由220g ISCO金色管柱用10-20(15min)-50% EtOAc(含有0.3% AcOH)/庚烷溶離歷經36min來純化,提供呈第一溶離次要異構體狀之(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實
例3),隨後呈第二溶離主要異構體狀之(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2)。將由此獲得之半純物質裝載至SiO2凝膠管柱上且用5%丙酮/DCM溶離來純化,提供標題化合物。1H NMR(500MHz,CD2Cl2)δ 8.83(br.s.,1H),7.71(d,J=8.3Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.11(dd,J=1.6,8.2Hz,1H),7.09(d,J=2.2Hz,1H),7.02(s,1H),6.93(d,J=8.1Hz,1H),5.82-5.75(m,1H),5.67(dd,J=6.5,11.4Hz,1H),4.43(s,1H),4.12-4.05(m,2H),3.85-3.76(m,2H),3.67(d,J=14.4Hz,1H),3.25(d,J=14.4Hz,1H),3.28-3.19(m,1H),2.83-2.65(m,3H),2.38-2.23(m,2H),2.19-2.11(m,2H),2.10-1.99(m,3H),1.97-1.87(m,2H),1.87-1.80(m,1H),1.79-1.70(m,2H),1.47(d,J=7.3Hz,3H),1.47-1.40(m,1H),1.06(d,J=6.6Hz,3H)。MS(ESI,陽離子)m/z 599.1(M+H)+。
實例4. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
在N2下向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2;32.6g,49.1mmol)(含有9.8%甲苯,起始物質並非完全可溶於Me-THF)及MeI(15.2mL,245mmol)於Me-THF(820mL)中之漿液中逐滴添加KHMDS(1.0M THF,167mL,167mmol)持續30min,同時
維持反應溫度在-44℃與-38℃之間。在-44℃下攪拌混合物30min之後,使反應物升溫至rt且攪拌1.5h(LC/MS證實反應完成)。將反應混合物冷卻至5℃,淬滅(170mL NH4Cl飽和水溶液及170mL H2O),同時維持溫度在5℃與14℃之間,且酸化(340mL之10%檸檬酸水溶液)。分離有機層,且水層用EtOAc(500mL)反萃取。合併之有機層用鹽水(3×500mL)洗滌,乾燥(MgSO4)且在減壓下濃縮,提供呈亮黃色固體狀之粗目標化合物(30.1g,49.1mmol,定量)(根據HPLC,純度>98%,不具有超過1%主要雜質)。在相同規模之反應重複四次之後,將所有粗產物(4×49.1mmol=196mmol)溶解於EtOAc中,合併且在減壓下濃縮。隨後將合併之粗產物如下再結晶:將乙醇(800mL)添加至粗產物中,且震盪所得漿液溶液同時將溶液加熱20min。在rt下逐滴添加H2O(250mL)持續30min,且將漿液冷卻至0℃。在漿液在冰浴中保持4h之後,經由濾紙過濾固體產物。濾餅用冰冷30% H2O/EtOH(300mL)沖洗且空氣乾燥2天。產物在高真空下在40℃下進一步乾燥4天,提供呈白色固體狀之純目標化合物(115g,188mmol,96%產率)。1H NMR(600MHz,DMSo-d 6 )δ 11.91(s,1 H),7.65(d,J=8.6Hz,1 H),7.27(dd,J=8.5,2.3Hz,1 H),7.17(d,J=2.4Hz,1 H),7.04(dd,J=8.2,2.0Hz,1 H),6.90(d,J=8.2Hz,1 H),6.76(d,J=1.8Hz,1 H),5.71(ddd,J=15.1,9.7,3.5Hz,1 H),5.50(ddd,J=15.2,9.2,1.1Hz,1 H),4.08(qd,J=7.2,7.2,7.2,1.5Hz,1 H),4.04(d,J=12.3Hz,1 H),3.99(d,J=12.3Hz,1 H),3.73(d,J=14.9Hz,1 H),3.56(d,J=14.1Hz,1 H),3.53(dd,J=9.1,3.3Hz,1 H),3.19(d,J=14.1Hz,1 H),3.09(s,3 H),3.03(dd,J=15.4,10.4Hz,1 H),2.79(dt,J=17.0,3.5,3.5Hz,1 H),2.69(ddd,J=17.0,10.7,6.3Hz,1 H),2.44-2.36(m,1 H),2.24-2.12(m,2 H),2.09(ddd,J=15.5,9.6,2.3Hz,1 H),1.97(dt,J=13.6,3.6,3.6Hz,1 H),1.91-1.80(m,4 H),1.80-1.66
(m,3 H),1.38(td,J=12.3,12.3,3.5Hz,1 H),1.33(d,J=7.2Hz,3 H),0.95(d,J=6.8Hz,3 H);[α]D(24℃,c=0.0103g/mL,DCM)=-86.07°;熔點222.6-226.0℃;FT-IR(KBr):3230(b),2931(b),1688(s),1598(s),1570(s),1505(s),1435(s),1384(s),1335(s),1307(s),1259(s),1155(s),1113(s),877(s),736(s)cm-1;C33H41ClN2O5S之計算分析:C,64.64;H,6.74;N,4.57;Cl,5.78;S,5.23。實驗值:C,64.71;H,6.81;N,4.65;Cl,5.81;S,5.11;HRMS(ESI)m/z 613.2493[M+H]+(C33H41ClN2O5S需要613.2503)。
在減壓下濃縮母液,且藉由急驟管柱層析(200g SiO2,10%及10%至45%及45% EtOA/Hex w/0.3% AcOH,梯度溶離)進一步純化殘餘物,提供呈灰白色固體狀之額外純產物(3.1g,5.1mmol,2.6%)。
實例5. (1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例3;34mg;0.057mmol)於THF中之溶液(冷卻至0℃)中添加氫化鈉(60%礦物油分散液;22.70mg,0.567mmol)。反應混合物在0℃下攪拌20min,且隨後添加MeI(0.018mL,0.284mmol)。反應混合物在環境溫度下攪拌1h,隨後用NH4Cl水溶液淬滅且用EtOAc稀釋。有機層經MgSO4乾燥且濃縮。經由管柱層析用10-40% EtOAc(含有0.3% AcOH)/庚烷溶離來純化粗物質,提供(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-
氯-7'-甲氧基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(34mg,0.054mmol,95%產率)。1H NMR(400MHz,CD2Cl2)δ 8.29(s,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.3Hz,1H),7.01(dd,J=1.6,7.8Hz,1H),6.92(d,J=8.2Hz,1H),6.88(s,1H),5.90-5.80(m,1H),5.54(t,J=10.2Hz,1H),4.14-4.04(m,3H),3.87-3.79(m,2H),3.73(d,J=14.7Hz,1H),3.32(d,J=14.5Hz,1H),3.23(s,3H),3.28-3.19(m,1H),2.82-2.73(m,2H),2.62(t,J=10.6Hz,1H),2.55-2.44(m,1H),2.29-2.21(m,1H),2.10-1.97(m,4H),1.97-1.80(m,4H),1.75(dd,J=8.9,18.7Hz,1H),1.48(d,J=7.4Hz,3H),1.43(br.s.,1H),1.08(d,J=6.5Hz,3H)。MS(ESI,陽離子)m/z 613.3(M+H)+。
實例6. (1S,3'R,6'R,7'S,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
將(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2,7.5mg,0.013mmol)及氧化鉑(IV)(2.84mg,0.013mmol)於EtOAc(1.536mL)中之混合物在H2(氣球)氛圍下在環境溫度下攪拌45min。隨後經由針筒過濾器過濾反應混合物。藉由層析經由Redi-Sep®預裝填SiO2凝膠管柱(4g)用15%至50% EtOAc(含有0.3% AcOH)/庚烷溶離來純化粗物質,提供標題產物。1H NMR(400MHz,CD2Cl2)δ
8.24(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.2Hz,1H),7.06(d,J=1.8Hz,1H),6.99(dd,J=2.0,8.0Hz,1H),6.93(d,J=8.2Hz,1H),4.10(s,2H),4.05(ddd,J=1.2,7.2,14.3Hz,1H),3.82(d,J=15.3Hz,1H),3.74-3.69(br.S.,1H),3.68(d,J=14.3Hz,1H),3.23(d,J=14.3Hz,1H),3.06(dd,J=7.3,15.4Hz,1H),2.84-2.68(m,2H),2.38(d,J=3.5Hz,2H),2.08-1.96(m,3H),1.96-1.88(m,1H),1.88-1.75(m,2H),1.74-1.56(m,4H),1.47(d,J=12.1Hz,2H),1.40(d,J=7.2Hz,3H),1.32-1.26(m,2H),1.23-1.15(m,2H),1.00(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 601.2(M+H)+。
實例7. (1S,3'R,6'R,7'S,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照實例6中所描述之程序由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物(實例4)之混合物合成標題化合物。1H NMR(500MHz,CD2Cl2)δ 8.14(s,1H),7.72(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.2Hz,1H),7.00(d,J=1.7Hz,1H),6.95(dd,J=2.0,8.1Hz,1H),6.92(d,J=8.1Hz,1H),4.10(s,2H),4.07(ddd,J=1.2,7.1,14.2Hz,1H),3.81(dd,J=2.0,15.2Hz,1H),3.68(d,J=14.2Hz,1H),3.25(s,3H),3.22(dd,J=9.0,14.4Hz,1H),3.03(dd,J=8.6,15.4Hz,1H),2.83-2.69(m,2H),2.60-2.51(m,1H),2.41-2.32(m,1H),2.07-2.01(m,1H),1.99-1.88(m,2H),1.88-1.77(m,1H),1.76-
1.68(m,1H),1.68-1.58(m,2H),1.53-1.46(m,2H),1.45-1.42(m,1H),1.40(d,J=7.1Hz,3H),1.29(br.s.,1H),1.25-1.21(m,2H),1.20-1.10(m,2H),0.99(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 615.1(M+H)+。
實例8. (1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
向100mL燒瓶中添加(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;500mg,0.980mmol)、戊-4-烯-1-磺醯胺(中間物EE19;878mg,5.88mmol)及DCE(14mL)。溶液用氬氣鼓泡15min,此時在rt下以0.2mL DCE溶液之形式添加赫維達-格拉布斯II(61.4mg,0.098mmol)。混合物在rt下攪拌且用氬氣鼓泡(將小瓶排氣)2h。反應混合物隨後用空氣軋泡5min且過濾以分離不溶性磺醯胺均二聚體。在Combiflash®(24g金色SiO2管柱)上用50%-90% EtOAc/庚烷+0.2% AcOH)溶離來純化粗產物,得到呈白色固體狀之(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-6-胺磺醯基己-2-烯-1-基)環丁基)
甲基)-3',4,4',5-四氫-2h,2'h-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(439mg,0.745mmol,76%產率)。
步驟2:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向含有(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(來自步驟1,439mg,0.745mmol)之先前藉由用10mL甲苯共沸兩次乾燥之1L燒瓶中添加N,N-二甲基吡啶-4-胺(155mg,1.267mmol)及400mL DCM。將反應混合物冷卻至0℃,此時緩慢添加N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(286mg,1.490mmol)。反應物隨後在rt下攪拌18h。混合物用200mL之1N HCl淬滅且用600mL EtOAc萃取。有機層經無水Na2SO4乾燥,過濾且藉由旋轉蒸發濃縮。在Combiflash®(24g金色SiO2管柱)上用30%-70% EtOAc/庚烷溶離來純化粗產物,得到呈白色固體狀之標題化合物。1H NMR(500MHz,CD3OD)δ 7.75(d,J=8.3Hz,1H),7.20(dd,J=2.9,7.6Hz,1H),7.12(d,J=3.7Hz,1H),7.00(dd,J=1.7,8.8Hz,1H),6.94(d,J=8.3Hz,1H),6.88(d,J=2.2Hz,1H),5.95-5.86(m,1H),5.70(dd,J=8.8,15.9Hz,1H),4.25-4.19(m,1H),4.22(dd,J=4.4,8.6Hz,1H),4.14-4.06(m,3H),4.14-4.05(m,3H),3.84(d,J=15.2Hz,1H),3.68(d,J=15.2Hz,1H),3.09(dd,J=8.3,15.9Hz,1H),2.87-2.74(m,2H),2.45-2.30(m,3H),2.14-1.88(m,5H),1.86-1.69(m,4H)。m/z(ESI,陽離子)571.2(M+H)+。
實例9. (1S,3'R,6'R,7'S,8'E)-6-氯-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向100mL燒瓶中添加(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例8,138mg,0.242mmol)、THF(10mL)及氫化鈉(29.0mg,1.208mmol)。反應物在rt下攪拌15min,此時添加MeI(0.092mL,1.480mmol)。反應物在rt下攪拌2h,此時添加額外氫化鈉(58.0mg,2.42mmol)及MeI(0.092mL,1.480mmol),且反應物在rt下攪拌額外16h。反應物用100mL飽和NH4Cl淬滅且用400mL EtOAc萃取。有機層經Na2SO4乾燥,過濾且藉由旋轉蒸發移除溶劑。在Combiflash®(12g金色SiO2管柱)上用10%至50% EtOAc/庚烷溶離來純化粗產物,得到呈灰白色固體狀之(1S,3'R,6'R,7'S,8'E)-6-氯-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(120mg,0.205mmol,85%產率)。1H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.70(d,J=8.6Hz,1H),7.19(dd,J=2.2,8.5Hz,1H),7.10(d,J=2.2Hz,1H),6.97-6.87(m,2H),6.84(d,J=1.6Hz,1H),5.88(ddd,J=5.2,8.1,15.1Hz,1H),5.53(dd,J=8.7,15.4Hz,1H),4.30(ddd,J=4.8,9.8,15.0Hz,1H),4.15-3.98(m,2H),3.84-3.69(m,2H),3.67(dd,J=3.8,8.7Hz,1H),3.36-3.21(m,2H),3.25(s,3H),3.01(dd,J=10.3,15.2Hz,1H),2.87-2.64(m,2H),2.52-2.29(m,3H),2.25-1.91(m,5H),1.88-1.75(m,3H),1.71-1.60(m,2H),1.41(t,J=12.4Hz,1H)。m/z(ESI,陽離子)585.0(M+H)+。
實例10. (1S,3'R,6'R,7'S)-6-氯-7'-羥基-3,4-二氫-2H,15'H螺[萘-1,22'[20]
氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1:(1'S)-N-(丁-3-烯-1-基磺醯基)-6'-氯-5-(((1R,2R)-2-(1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
將DMAP(0.830g,6.80mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;1.82g,3.78mmol)及丁-3-烯-1-磺醯胺(EE15;1.873g,13.86mmol)於DCM(140mL)中之溶液(冷卻至0℃)中。逐份添加EDC(1.303g,6.80mmol),且其在環境溫度下攪拌16h。反應混合物用EtOAc(400mL)稀釋,用1N HCl溶液(2×5mL)、鹽水(3mL)洗滌,經無水Na2SO4乾燥且濃縮。將殘餘物裝載至80g ISCO金色管柱,且用0%至15% EtOAc(含有0.3% AcOH)/Hex(含有0.3% AcOH)溶離,提供呈白色固體狀之標題化合物(2.09g)。m/z(ESI,陽離子)599.0(M+H)+。
步驟2:(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
向1L RBF中饋入含(1'S)-N-(丁-3-烯-1-基磺醯基)-6'-氯-5-(((1R,2R)-2-(1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(來自步驟1,1.02g,1.70mmol)之甲苯(587mL)。混合物在環境溫度下攪拌10min以溶解固體起始物質,且隨後用N2進行三次抽真空/回填循環。向均質溶液中添加赫維達-格拉布斯II(0.213g,0.340mmol)於甲苯(20mL)中之溶液。在106℃下在N2下攪拌混合物75min之後,將空氣吹10min以使催化劑去活化,且隨後濃縮。將殘餘物裝載至330g ISCO金色管柱,且用0%至25% EtOAc(含有0.3% AcOH)/Hex(含有0.3% AcOH)溶離。第二峰為呈白色固體狀之標題化合物(0.27g)。1H NMR(400MHz,CD2Cl2)δ 9.96(br.s.,1H),7.78-7.65(m,1H),7.37(dd,J=1.96,8.22Hz,1H),7.16(dd,J=2.35,8.61Hz,1H),7.10(d,J=2.15Hz,1H),7.04(br.s.,1H),6.98(m,1H),5.66-5.47(m,2H),4.23-4.09(m,2H),3.98(ddd,J=5.18,10.56,15.55Hz,1H),3.86(dd,J=3.81,9.49Hz,1H),3.64-3.49(m,2H),3.38(td,J=4.74,15.36Hz,2H),2.92(br.s.,1H),2.81(br.s.,1H),2.79-2.73(m,2H),2.73-2.63(m,1H),2.52(d,J=12.72Hz,1H),2.40-2.25(m,2H),2.18(d,J=8.22Hz,1H),2.01-1.52(m,8H)。m/z(ESI,陽離子)571.0(M+H)+。
步驟3:(1S,3'R,6'R,7'S)-6-氯-7'-羥基-3,4-二氫-2H,15'H螺[萘-1,22'[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
在H2下在環境溫度下將(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自步驟2,0.112g,0.196mmol)及氧化鉑(IV)(0.045g,0.196mmol)於EtOAc(33mL)中之混合物攪拌3h。經由針筒過濾器過濾混合物以移除固體催化劑,且濃縮溶液,提供呈白色固體狀之標題化合物(112mg)。1H NMR(400MHz,CD2Cl2)δ 8.93(m,1H),7.71(m,1H),7.15(m,3H),7.09(d,J=2.35Hz,1H),6.95(m,1H),4.10(m,2H),3.78-3.62(m,4H),3.46-3.34(m,1H),3.26(d,J=14.28Hz,1H),3.16(dd,J=9.00,15.26Hz,1H),2.82-2.71(m,2H),2.45-2.33(m,1H),2.26-2.16(m,1H),2.08-1.16(m,17H)。m/z(ESI,陽離子)573.2(M+H)+。
實例11. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物及實例12. (1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例2中所描述之方式的方式使用(R)-己-5-烯-磺醯胺(中間物EE20)與(S)-己-5-烯-磺醯胺(中間物EE202)之混合物製備標題化合物,且使所要產物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自製備型逆相HPLC之第一差向異構體,實例11)與(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺
[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自製備型逆相HPLC之第二差向異構體,實例12)分離。實例11之共晶體結構證實12位置處之甲基具有R立體化學。(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物:1H NMR(400MHz,CD3OD)δ 7.74(d,J=8.0Hz,1H),7.19(dd,J=3.5,11.5Hz,1H),7.12(d,J=1.8Hz,1H),7.01(d,J=9.2Hz,1H),7.01(d,J=7.6Hz,1H),6.94(d,J=8.0Hz,1H),6.88(s,1H),5.89-5.81(m,1H),5.73(dd,J=7.4,14.5Hz,1H),4.22(dd,J=3.5,7.6Hz,1H),4.18-4.12(m,1H),4.09(d,J=2.0Hz,2H),3.85(d,J=15.1Hz,1H),3.85(d,J=15.3Hz,1H),3.68(d,J=14.1Hz,1H),3.08(dd,J=10.2,15.1Hz,1H),2.87-2.73(m,2H),2.48-2.18(m,4H),2.11(d,J=13.7Hz,1H),2.05-1.65(m,8H),1.52(d,J=6.8Hz,3H),1.47-1.41(m,1H)。m/z(ESI,陽離子)585.2(M+H)+;(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物:1H NMR(400MHz,CD3OD)δ 7.73(d,J=9.2Hz,1H),7.19(dd,J=2.5,8.6Hz,1H),7.13(d,J=2.3Hz,1H),7.12-7.10(m,1H),7.05(dd,J=1.8,8.0Hz,1H),6.94(d,J=8.6Hz,1H),5.93-5.83(m,1H),5.65(dd,J=5.5,15.5Hz,1H),4.12(d,J=6.8Hz,2H),4.06(dd,J=4.1,10.2Hz,1H),3.91(dd,J=6.3,12.5Hz,1H),3.67-3.55(m,2H),3.53-3.46(m,1H),3.29-3.08(m,1H),2.88-2.70(m,2H),2.64-2.52(m,1H),2.49-2.31(m,2H),1.98-1.91(m,3H),1.99-1.89(m,4H),1.86-1.73(m,4H),1.49(d,J=7.4Hz,3H)。m/z(ESI,陽離子)585.2(M+H)+。
實例13. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例4中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例11)製備標題化合物,且所要產物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物經分離為白色固體。1H NMR(400MHz,CD3OD)δ 7.75(d,J=8.4Hz,1H),7.19(dd,J=1.8,8.8Hz,1H),7.12(d,J=2.0Hz,1H),7.00(dd,J=2.2,7.8Hz,1H),6.95(d,J=8.4Hz,1H),6.86(d,J=1.6Hz,1H),5.92-5.84(m,1H),5.58(dd,J=9.0,15.1Hz,1H),4.85-4.85(m,1H),4.20(ddd,J=3.0,6.7,9.8Hz,1H),4.08(d,J=2.2Hz,2H),3.86(d,J=15.3Hz,1H),3.73(dd,J=2.9,8.6Hz,1H),3.67(d,J=14.1Hz,1H),3.26-3.23(m,3H),3.08(dd,J=10.3,15.2Hz,1H),2.88-2.72(m,2H),2.54-2.25(m,4H),2.12(d,J=13.1Hz,1H),1.99-1.71(m,7H),1.53(d,J=6.8Hz,3H),1.50-1.40(m,1H)。m/z(ESI,陽離子)599.2(M+H)+。
實例14. (1S,3'R,6'R,7'S,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十
五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((R)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
按照針對實例2之步驟1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;166mg,0.344mmol)及(R)-戊-4-烯-2-磺醯胺(中間物EE17;87mg,0.585mmol)合成標題化合物。粗物質之純化提供(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((R)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(134mg,0.219mmol,63.5%產率)。
步驟2. (1S,3'R,6'R,7'S,9'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
向500mL RBF中饋入含(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((R)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(134mg,0.219mmol)之甲苯(146.00mL)。混合物在環境溫度下攪拌10min以溶解固體起始物質,且隨後用N2進行三次抽真空/回填循環。在環境溫度下向均質溶液中添加赫維達-格拉布斯II(27.4mg,0.044mmol)於甲苯(8mL)中之溶液。混合物在106℃下在N2下攪拌80min。吹動空氣通過溶液10min以使催化劑去活化,且隨後濃縮混合物。將粗深色油狀物吸附至SiO2凝膠塞上,且藉由層析經由24g ISCO管柱用10%至20%至40% EtOAc(含有0.3% AcOH)/Hex溶離歷經90min.來純化,提供標題化合物之混合物。
步驟3:(1S,3'R,6'R,7'S,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例6所描述的程序由(1S,3'R,6'R,7'S,9'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物與(1S,3'R,6'R,7'S,9'Z,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物之
混合物(來自步驟2,119mg,0.203mmol)合成標題化合物(94mg,0.160mmol,79%產率)。1H NMR(400MHz,CD2Cl2)δ 9.03(br.s.,1H),7.71(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.4Hz,1H),7.13(dd,J=2.2,8.2Hz,1H),7.10(br.s.,1H),7.09(d,J=2.3Hz,1H),6.93(d,J=8.2Hz,1H),4.09(s,2H),3.86(td,J=5.3,6.8Hz,1H),3.74(d,J=14.1Hz,1H),3.70(br.s.,1H),3.65(d,J=14.9Hz,1H),3.25(d,J=14.1Hz,1H),3.13(dd,J=8.2,15.5Hz,1H),2.85-2.68(m,2H),2.44(quin,J=8.8Hz,1H),2.25(ddd,J=5.5,9.6,17.8Hz,1H),2.04-1.94(m,2H),1.89(dt,J=5.0,9.5Hz,2H),1.85-1.77(m,2H),1.76-1.68(m,2H),1.68-1.60(m,4H),1.60-1.50(m,3H),1.48(d,J=7.0Hz,3H),1.46-1.35(m,2H)。MS(ESI,陽離子)m/z 587.1(M+H)+。
實例15. (1S,3'R,6'R,7'S,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((S)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
按照針對實例2之步驟1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;15mg;0.031mmol)
及(S)-戊-4-烯-2-磺醯胺(中間物EE172;5.6mg,0.037mmol)合成標題化合物。粗物質之純化提供(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((S)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(19mg,0.031mmol)。
步驟2:(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例14之步驟2所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((S)-戊-4-烯-2-基磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(來自步驟1,42.5mg,0.067mmol)合成標題化合物。藉由層析經由24g ISCO管柱用10%至20%至40% EtOAc(含有0.3% AcOH)/Hex溶離歷經90min.來純化,隨後經由12g ISCO管柱用0%至30% EtOAc(含有0.3% AcOH)/Hex溶離來第二次純化,提供呈第一溶離異構體狀之(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(13.4mg,0.023mmol,34.3%產率),且獲得呈第二溶離異構體狀之(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮
13',13'-二氧化物(13.2mg,0.023mmol,34.3%產率)。
步驟3:(1S,3'R,6'R,7'S,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例6所描述的程序由(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自步驟2,10.8mg,0.018mmol)合成標題化合物(7.5mg,0.013mmol,71%產率)。1H NMR(400MHz,CD2Cl2)δ 9.72(br.s.,1H),7.71(d,J=8.6Hz,1H),7.30(dd,J=2.0,8.4Hz,1H),7.28(s,1H),7.16(dd,J=2.4,8.5Hz,1H),7.09(d,J=2.3Hz,1H),6.94(d,J=8.4Hz,1H),4.10-4.05(m,2H),3.85-3.76(m,1H),3.70(d,J=15.1Hz,1H),3.60(br.s.,1H),3.60(d,J=13.9Hz,1H),3.26(d,J=14.3Hz,1H),3.23-3.14(m,1H),2.83-2.69(m,2H),2.33(quin,J=8.6Hz,1H),2.12(quin,J=8.2Hz,1H),2.04-1.94(m,2H),1.94-1.85(m,1H),1.84-1.71(m,5H),1.71-1.64(m,2H),1.64-1.52(m,3H),1.49(d,J=7.2Hz,3H),1.52-1.43(m,2H),1.38-1.28(m,2H)。MS(ESI,陽離子)m/z 587.2(M+H)+。
實例16. (1S,3'R,6'R,7'S,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
將(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例13;5mg,8.34μmol)及氧化鉑(iv)(0.379mg,1.67μmol,Omega)於EtOAc(2.8mL)中之混合物在H2(氣球)下在rt下攪拌3hr,隨後經由Celite®過濾以移除固體催化劑,濃縮,且藉由製備型逆相HPLC (GeminiTM Prep C18 5μm管柱;40%至95% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化,得到(1S,3'R,6'R,7'S,12'R)-6-氯-7'-甲氧基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(4.4mg,7.32μmol)。1H NMR(400MHz,CD3OD)δ 7.73(d,J=8.4Hz,1H),7.16(d,J=8.7Hz,1H),7.11-7.03(m,2H),6.93(d,J=9.1Hz,2H),4.14-4.03(m,3H),3.83(d,J=14.7Hz,1H),3.69(d,J=14.3Hz,1H),3.33-3.29(m,3H與溶劑重疊),3.23(d,J=14.5Hz,1H),3.06(dd,J=9.1,15.4Hz,1H),2.85-2.71(m,2H),2.62(d,J=8.2Hz,1H),2.36(t,J=8.5Hz,1H),2.10-1.84(m,5H),1.84-1.56(m,6H),1.55-1.40(m,6H),1.38-1.24(m,3H)。m/z(ESI,陽離子)601.2(M+H)+。
實例17. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物、
實例18. (1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物及實例19. (1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例2中所描述之方式的方式使用(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA11A)及(R)-庚-6-烯-3-磺醯胺(中間物EE21)與(S)-庚-6-烯-3-磺醯胺(中間物EE212)之外消旋混合物來製備標題化合物,且使如下所要產物分離:(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例17),呈來自製備型逆相HPLC之第一溶離主要異構體狀;(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例18),呈來自製備型逆相HPLC之第二溶離次要異構體狀;及(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例19),呈來自製備型逆相HPLC之第三溶離主要異構體狀。
(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例17):1H NMR(400MHz,CD3OD)δ 7.75(d,J=8.4Hz,1H),7.19(dd,J=2.0,8.8Hz,1H),7.12(d,J=2.2Hz,1H),7.00(dd,J=1.8,8.0Hz,1H),6.93(d,J=8.2Hz,1H),6.87(d,J=1.6Hz,1H),5.90-5.82(m,1H),5.73(dd,J=7.8,15.1Hz,1H),4.21(dd,J=3.7,7.8Hz,1H),4.09(dd,J=12.1,14.7Hz,2H),4.02(dd,J=6.5,13.5Hz,1H),3.85(d,J=15.1Hz,1H),3.68(d,J=14.1Hz,1H),3.29(d,J=14.3Hz,1H),3.08(dd,J=10.0,15.3Hz,1H),2.88-2.73(m,2H),2.46-2.22(m,4H),2.16-2.05(m,2H),2.02-1.79(m,8H),1.73(dd,J=9.0,17.6Hz,1H),1.46(t,J=12.6Hz,1H),1.20(t,J=7.5Hz,3H)。m/z(ESI,陽離子)599.2(M+H)+;(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例18)。1H NMR(500MHz,CD3OD)δ 7.75(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,1H),7.12(d,J=2.2Hz,1H),7.03(dd,J=2.0,8.1Hz,1H),6.97-6.92(m,2H),5.62-5.55(m,2H),4.49(dd,J=3.5,7.9Hz,1H),4.09(dd,J=12.5,21.8Hz,2H),3.88(d,J=15.7Hz,1H),3.71(d,J=14.4Hz,1H),3.62(br.s.,1H),2.87-2.74(m,2H),2.49-2.38(m,3H),2.26-2.10(m,3H),2.06-1.89(m,8H),1.84-1.73(m,3H),1.55-1.40(m,1H),1.16(t,J=7.5Hz,3H)。m/z(ESI,陽離子)599.2(M+H)+;及(1S,3'R,6'R,7'S,8'E,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例19):1H NMR(400MHz,CD3OD)δ 7.74(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,
1H),7.13(d,J=2.2Hz,1H),7.08-7.02(m,2H),6.95(d,J=9.0Hz,1H),5.92(ddd,J=5.9,14.7,21.5Hz,1H),5.66(dd,J=6.1,15.3Hz,1H),4.15-4.05(m,3H),3.74-3.62(m,3H),3.47(d,J=14.3Hz,1H),3.51-3.43(m,1H),2.88-2.74(m,2H),2.58-2.33(m,3H),2.24-2.03(m,4H),1.97-1.73(m,8H),1.63-1.45(m,1H),1.17(t,J=7.5Hz,3H)。m/z (ESI,陽離子)599.2(M+H)+。
實例20. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例4中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例17)製備標題化合物,且所要產物(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物經分離為白色固體。1H NMR(400MHz,CD3OD)δ 7.75(d,J=8.6Hz,1H),7.18(dd,J=2.2,8.6Hz,1H),7.12(d,J=2.0Hz,1H),7.00(dd,J=1.8,8.2Hz,1H),6.94(d,J=8.0Hz,1H),6.86(d,J=1.6Hz,1H),5.94-5.85(m,1H),5.58(dd,J=8.9,15.2Hz,1H),4.13-4.02(m,3H),3.85(d,J=14.9Hz,1H),3.74(dd,J=3.9,9.0Hz,1H),3.68(d,J=14.3Hz,1H),3.26(s,3H),3.22-3.04(m,1H),2.88-2.73(m,2H),2.54-2.39
(m,2H),2.33(t,J=7.4Hz,2H),2.12(qd,J=7.3,14.4Hz,2H),2.02-1.69(m,10H),1.45(t,J=12.0Hz,1H),1.21(t,J=7.5Hz,3H)。m/z(ESI,陽離子)613.2(M+H)+。
實例21. (1S,3'R,6'R,7'S,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
以類似於實例6中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例20)製備標題化合物,且使所要產物(1S,3'R,6'R,7'S,12'R)-6-氯-12'-乙基-7'-甲氧基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物分離。1H NMR(500MHz,CD3OD)δ 7.76(d,J=8.6Hz,1H),7.19(dd,J=2.3,8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.06(dd,J=2.0,8.3Hz,1H),7.00(d,J=1.7Hz,1H),6.95(d,J=8.3Hz,1H),4.11(ddd,J=2.9,12.0,14.2Hz,2H),3.88-3.81(m,2H),3.69(d,J=14.2Hz,1H),3.30(s,3H),3.12(dd,J=8.1,14.9Hz,1H),2.86-2.74(m,2H),2.69-2.62(m,1H),2.35(t,J=7.7Hz,1H),2.15-2.05(m,2H),2.01-1.85(m,5H),1.82-1.63(m,4H),1.47(br.s.,5H),1.42-1.24(m,4H),1.18(t,J=7.6Hz,3H)。m/z(ESI,陽離子)615.2(M+H)+。
實例22. (1S,3'R,6'R,7'S,12'R)-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘
-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
將(1S,3'R,6'R,7'S,8'Z,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例18;5.2mg,8.68μmol)及活性碳濕上之鈀10wt.%(乾基)(4.6mg,4.34μmol)於1:1比率之EtOAc:EtOH(3.0mL)中之混合物在H2下在rt下攪拌隔夜,隨後經由Celite®過濾以移除固體催化劑。將有機層濃縮,且藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;40%至95% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化,得到(1S,3'R,6'R,7'S,12'R)-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(1.9mg,3.35μmol)。1H NMR(400MHz,CD3OD)δ 7.77(d,J=7.0Hz,1H),7.21-7.02(m,4H),6.97(d,J=8.2Hz,1H),6.93(d,J=2.2Hz,1H),4.13(dd,J=12.1,22.7Hz,2H),3.92-3.80(m,2H),3.76-3.70(m,2H),3.13(dd,J=8.8,19.2Hz,1H),2.87-2.75(m,2H),2.44-2.29(m,2H),2.15-2.04(m,2H),1.99-1.37(m,17H),1.18(t,J=7.6Hz,3H)。m/z(ESI,陽離子)567.2(M+H)+。
實例23. (1S,3'R,6'R,7'S,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1:(S)-6'-氯-N-((R)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺及(S)-6'-氯-N-((S)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
按照針對實例2之步驟1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;224mg,0.465mmol)及(R)-己-5-烯-3-磺醯胺(中間物EE18)與(S)-己-5-烯-3-磺醯胺(中間物EE182;167mg,1.023mmol)之外消旋混合物合成標題化合物。粗物質之純化提供(S)-6'-氯-N-((R)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺與(S)-6'-氯-N-((S)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺之混合物(235mg,0.375mmol,81%產率)。
步驟2. (1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺
[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例14之步驟2所描述的程序由(S)-6'-氯-N-((R)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺與(S)-6'-氯-N-((R)-己-5-烯-3-基磺醯基)-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺之混合物(來自步驟1,235mg,0.375mmol)合成標題化合物。藉由層析經由24g ISCO管柱用10%至20%至40% EtOAc(含有0.3% AcOH)/Hex溶離歷經60min對粗物質進行第一次純化,提供標題化合物之混合物。
步驟3:(1S,3'R,6'R,7'S,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例6所描述的程序由(1S,3'R,6'R,7'S,9'Z,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物與(1S,3'R,6'R,7'S,9'E,12'S)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物之
混合物(來自步驟2,12mg,0.020mmol)合成標題化合物(6.3mg,0.010mmol,52.3%產率)。1H NMR(400MHz,CD2Cl2)δ 10.11(br.s.,1H),7.70(d,J=8.6Hz,1H),7.36(dd,J=2.1,8.3Hz,1H),7.28(d,J=1.8Hz,1H),7.15(dd,J=2.3,8.4Hz,1H),7.08(d,J=2.3Hz,1H),6.93(d,J=8.2Hz,1H),4.06(d,J=11.5Hz,1H),3.99(d,J=12.1Hz,1H),3.76(d,J=15.5Hz,1H),3.65-3.61(m,1H),3.59(d,J=14.1Hz,1H),3.57-3.50(m,1H),3.16(d,J=14.3Hz,1H),3.09(dd,J=8.5,15.2Hz,1H),2.83-2.67(m,2H),2.25(quin,J=9.0Hz,1H),2.20-2.08(m,3H),2.03-1.88(m,3H),1.89-1.74(m,7H),1.72-1.57(m,3H),1.55-1.39(m,2H),1.36-1.19(m,2H),1.10(t,J=7.4Hz,3H)。MS(ESI,陽離子)m/z 601.2(M+H)+。
實例24. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(3R,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺及(3S,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺
按照針對實例26之步驟1所描述的程序由N,N-雙(4-甲氧基苄基)丙烷-1-磺醯胺(中間物EE14;1512mg,4.16mmol)及4-甲基苯磺酸(R)-戊-4-烯-2-基酯(根據Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411之程序製備;1999mg,8.32mmol)合成標題化
合物。獲得呈不可分離的混合物狀之(3R,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺及(3S,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺(335mg,0.776mmol,18.7%產率)。
步驟2:(3R,4S)-4-甲基庚-6-烯-3-磺醯胺及(3S,4S)-4-甲基庚-6-烯-3-磺醯胺
按照針對實例26之步驟2所描述的程序由(3R,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺及(3S,4S)-N,N-雙(4-甲氧基苄基)-4-甲基庚-6-烯-3-磺醯胺(335mg,0.776mmol,步驟1)合成標題化合物。獲得呈不可分離的混合物狀之(3R,4S)-4-甲基庚-6-烯-3-磺醯胺及(3S,4S)-4-甲基庚-6-烯-3-磺醯胺(67.6mg,0.35mmol,45.5%產率)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
按照針對實例26之步驟3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;40mg,0.078mmol)及(3R,4S)-4-甲基庚-6-烯-3-磺醯胺與(3S,4S)-4-甲基庚-6-烯-3-磺醯胺之混合物(67.6mg,0.35mmol)合成標題化合物。(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環
丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸與(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸之混合物(46mg,0.073mmol,92%產率)用於下一步驟。
步驟4. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例26之步驟4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基辛-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(63mg,0.100mmol)合成標題化合物。藉由層析經由12g ISCO金色管柱用10-40-50% EtOAc(含有0.3% AcOH)/Hex溶離歷經24min來純化粗物質,提供呈第二溶離主要異構體狀之(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物。此物質藉由層析經由12g ISCO金色管柱用0-10%丙酮/DCM溶離來再純化,提供標題化合物(20mg,0.033mmol,32.7%產率)。1H NMR(400MHz,CD2Cl2)δ 8.33(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.96-6.88(m,3H),5.86(ddd,J=3.9,9.0,15.1Hz,1H),5.71(dd,J=8.2,15.1Hz,1H),4.22(dd,J=3.9,8.2Hz,1H),4.09-4.08(m,2H),3.98(ddd,J=1.2,3.7,8.8Hz,1H),3.82(d,J=14.7Hz,1H),3.69(d,J=14.3Hz,1H),3.25(d,J=14.3
Hz,1H),3.04(dd,J=9.5,15.4Hz,1H),2.85-2.69(m,2H),2.41(ddd,J=3.7,9.8,18.4Hz,1H),2.35-2.24(m,1H),2.21-2.11(m,1H),2.10-2.03(m,2H),1.99-1.90(m,3H),1.90-1.74(m,5H),1.67(quin,J=9.5Hz,2H),1.45-1.34(m,1H),1.27(t,J=7.4Hz,3H),1.02(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 613.0(M+H)+。
實例25. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例24;10mg,0.016mmol)合成標題化合物。粗物質經由管柱層析用10-40% EtOAc(含有0.3% AcOH)/庚烷溶離來純化,提供(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(7.3mg,0.012mmol,71.4%產率)。1H NMR(500MHz,CD2Cl2)δ 8.13(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.0Hz,1H),6.91(s,2H),6.87(s,1H),5.84(ddd,J=3.4,9.6,15.1Hz,1H),5.51(dd,J=9.0,15.2Hz,1H),4.11-4.06(m,2H),4.04-4.00(m,1H),3.82(d,J=15.4Hz,1H),3.69(d,J=14.2Hz,1H),3.64(dd,J=3.3,9.2Hz,1H),3.25(d,J=14.2Hz,1H),3.18(s,3H),3.03(dd,J=10.1,15.3Hz,1H),2.84-2.69(m,2H),2.44(ddd,J=3.2,9.8,18.6
Hz,1H),2.33(quin,J=8.8Hz,1H),2.28-2.21(m,1H),2.15-2.09(m,1H),2.09-2.02(m,2H),2.01-1.90(m,3H),1.90-1.73(m,4H),1.72-1.61(m,1H),1.39(t,J=12.6Hz,1H),1.28(t,J=7.3Hz,3H),1.02(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 627.1(M+H)+。
實例26. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(2R,3R)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺及(2S,3R)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺
將N,N-雙(4-甲氧基苄基)乙磺醯胺(中間物EE13;1030mg,2.95mmol)在甲苯中在真空下共沸2h。在氬氣下,添加THF,且將溶液冷卻至-78℃。隨後添加正丁基鋰溶液(2.5M Hex,1.533mL,3.83mmol),且混合物在-78℃下攪拌60min。以3mL溶液之形式添加4-甲基苯磺酸(S)-戊-4-烯-2-基酯(根據Sigman,M.S.等人,J.Am.Chem.Soc.,2012,134(28),11408-11411之程序製備;1417mg,5.90mmol)。隨後添加THF。5min後,使混合物升溫至環境溫度且在氬氣下攪拌隔夜。混合物用飽和NH4Cl淬滅且用EtOAc萃取,經MgSO4乾燥且濃
縮。將粗物質注入SiO2凝膠濾筒中,且藉由層析經由40g ISCO管柱用5%至10%至20%至40% EtOAc/Hex溶離來純化,提供2.3:1之標題化合物之混合物(420mg,1.00mmol,34.1%產率)。
步驟2:(2R,3R)-3-甲基己-5-烯-2-磺醯胺及(2S,3R)-3-甲基己-5-烯-2-磺醯胺
在環境溫度下向(2R,3R)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺及(2S,3R)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺(2.3:1非對映異構體混合物;420mg,1.00mmol)及苯甲醚(1.093mL,10.06mmol)於DCM(5.029mL)中之溶液中緩慢添加三氟乙酸(2.99mL,40.2mmol)。攪拌隔夜後,濃縮混合物。殘餘物用EtOAc稀釋,用飽和NaHCO3洗滌,用EtOAc反萃取,經MgSO4乾燥且濃縮。經由層析在24g ISCO金色管柱上用0-50% EtOAc/Hex)梯度溶離來純化粗物質,提供2.3:1標題化合物之混合物(153mg,0.863mmol,86%產率)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6R,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6S,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
向小瓶中饋入含(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-
基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;75mg,0.147mmol)及(2R,3R)-3-甲基己-5-烯-2-磺醯胺與(2S,3R)-3-甲基己-5-烯-2-磺醯胺之2.3:1混合物(153mg,0.863mmol)之1,2-DCE(2.101mL)。溶液用氬氣鼓泡,隨後在環境溫度下以1mL 1,2-DCE溶液之形式添加赫維達-格拉布斯II(9.21mg,0.015mmol)。在環境溫度下攪拌所得混合物(用氬氣鼓泡且使小瓶排氣)。2h後,反應混合物用空氣鼓泡5min且過濾以分離不溶性磺醯胺均二聚體。將濾液直接注入12g ISCO金色管柱中,且用0-20-50-100% EtOAc/Hex溶離歷經16min來純化,得到標題化合物之混合物(74mg,0.120mmol,82%產率)。
步驟4. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下將N,N-二甲基吡啶-4-胺(24.90mg,0.204mmol)添加至(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6R,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,6S,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(74mg,0.120mmol)(先前用2.0mL PhMe共沸3h)於DCM(59.900mL)中之溶液中。隨後緩慢逐份添加N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(46.0mg,0.240mmol),且攪拌所得混合物同時使其升溫至環境溫度後持續15h。混合物用1N HCl及鹽水洗滌,水溶液用EtOAc反萃取,且合併之有機物
經無水硫酸鎂乾燥,隨後濃縮。藉由層析經由12g ISCO金色管柱用10-40-50% EtOAc(含有0.3% AcOH)/Hex溶離歷經24min來純化粗物質,提供呈第一溶離主要異構體狀之(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(19.5mg,0.033mmol,27.1%產率,90%純度)。1H NMR(400MHz,CD2Cl2)δ 8.31(br.s.,1H),7.65(d,J=8.4Hz,1H),7.62(br.s.,1H),7.14(dd,J=2.4,8.5Hz,1H),7.10(d,J=2.3Hz,1H),6.93(dd,J=2.0,8.2Hz,1H),6.90(d,J=8.0Hz,1H),5.66(dd,J=3.7,15.8Hz,1H),5.58-5.45(m,1H),4.22(s,2H),4.15-4.08(m,2H),3.87(br.s.,1H),3.74(d,J=13.9Hz,1H),3.33(d,J=14.1Hz,1H),3.11(d,J=13.9Hz,1H),2.79-2.69(m,2H),2.57-2.39(m,2H),2.06-1.92(m,2H),1.91-1.81(m,4H),1.80-1.73(m,4H),1.71-1.55(m,2H),1.41(d,J=7.4Hz,3H),1.04(d,J=6.7Hz,3H)。MS(ESI,陽離子)m/z 599.1(M+H)+。
實例27. (1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如針對實例26之步驟4所描述合成標題化合物。(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(11.5mg,0.019mmol,16.0%產率,95%純度)經分離為第二溶離次要異構體。1H NMR(400MHz,CD2Cl2)δ 9.08-8.57(m,1H),7.72(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),7.06(d,J=8.6Hz,1H),6.93(d,J=8.0Hz,1H),6.83(s,1H),6.03(ddd,J=5.3,8.2,15.7Hz,1H),5.76(dd,J=7.8,15.7Hz,1H),4.20(dd,J=3.2,7.9Hz,1H),4.14-4.03(m,3H),3.78-3.63(m,2H),3.29(d,J=14.3Hz,1H),3.12(dd,J=9.9,15.4Hz,1H),2.85-2.68(m,2H),2.62(br.s.,1H),2.55-2.42(m,1H),2.36(dq,J=3.2,9.2Hz,1H),2.26-2.16(m,1H),2.14-2.07(m,1H),2.04-1.93(m,3H),1.90(dd,J=4.1,9.2Hz,1H),1.87-1.74(m,3H),1.73-1.63(m,1H),1.46(d,J=7.2Hz,3H),1.46-1.39(m,1H),1.07(d,J=7.0Hz,3H)。MS(ESI,陽離子)m/z 599.0(M+H)+。
實例28. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(2R,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺
按照針對實例26之步驟1所描述的程序由N,N-雙(4-甲氧基苄基)乙磺醯胺(中間物EE13;1148mg,3.29mmol)及4-甲基苯磺酸(R)-戊-4-烯-2-基酯(根據Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411之程序製備;1579mg,6.57mmol)合成標題化合物。獲得呈2.4:1混合物狀之(2R,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺(539mg,1.29mmol,39.3%產率)。
步驟2:(2R,3S)-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-3-甲基己-5-烯-2-磺醯胺
按照針對實例26之步驟2所描述的程序由(2R,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-N,N-雙(4-甲氧基苄基)-3-甲基己-5-烯-2-磺醯胺(539mg;1.29mmol)合成標題化合物。獲得呈2.3:1混合物狀之(2R,3S)-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-3-甲基己-5-烯-2-磺醯胺(203mg,1.15mmol,89%產率)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁
氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
按照針對實例26之步驟3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;75mg,0.147mmol)及(2R,3S)-3-甲基己-5-烯-2-磺醯胺與(2S,3S)-3-甲基己-5-烯-2-磺醯胺之2.3:1混合物(153mg,0.863mmol)合成標題化合物。(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸與(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸之混合物(73mg,0.118mmol,80%產率)用於下一步驟。
步驟4. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例26之步驟4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6R,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,6S,E)-1-羥基-5-甲基-6-胺磺醯基庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(73mg,0.118mmol)合成標題化合物。藉由層析經由12g
ISCO金色管柱用10-40-50% EtOAc(含有0.3% AcOH)/Hex溶離歷經24min來純化粗物質,提供呈第一溶離次要異構體狀之(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物。此物質經由製備型逆相HPLC用50-70% MeCN(含有0.1% TFA)/H2O(含有0.1% TFA)溶離來再純化,提供標題化合物(5.8mg,0.0097mmol,8.2%產率,90%純度)。1H NMR(400MHz,CD2Cl2)δ 8.21(s,1H),7.71(d,J=8.4Hz,1H),7.18(dd,J=2.3,8.4Hz,1H),7.14(dd,J=2.1,8.1Hz,1H),7.09(d,J=2.3Hz,1H),6.95(d,J=8.2Hz,1H),6.69(br.s.,1H),6.10-5.99(m,1H),5.67(dd,J=6.4,15.4Hz,1H),4.20-4.14(m,1H),4.11(d,J=12.1Hz,1H),4.06(d,J=11.9Hz,1H),3.84-3.74(m,1H),3.76(d,J=15.5Hz,1H),3.65(d,J=14.7Hz,1H),3.44(d,J=14.7Hz,1H),3.33-3.20(m,1H),2.86-2.70(m,2H),2.60-2.48(m,2H),2.31-2.20(m,2H),2.08-1.98(m,2H),1.97-1.80(m,4H),1.79-1.68(m,1H),1.67-1.49(m,2H),1.46(d,J=7.2Hz,3H),1.42(br.s.,1H),1.08(d,J=7.0Hz,3H)。MS(ESI,陽離子)m/z 599.1(M+H)+。
實例29. (1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺
將N,N-雙(4-甲氧基苄基)甲磺醯胺(中間物EE12;1.05g,3.13mmol)在PhMe中在真空下共沸12h。在氬氣下,添加THF(21mL)且將溶液冷卻至-78℃。隨後添加丁基鋰溶液(2.5M Hex;1.63mL,4.07mmol),且混合物在-78℃下攪拌30min。以1.5mL THF溶液之形式添加4-甲基苯磺酸戊-4-烯-2-基酯(根據Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411之程序製備;1.3g,5.41mmol)。完成添加後,使混合物升溫至環境溫度且攪拌隔夜。LC/MS分析展示50%轉化為所要產物;延長攪拌另一24h並未提高轉化率。混合物隨後用飽和NH4Cl淬滅,且用EtOAc萃取,經MgSO4乾燥且濃縮。藉由層析經由24g ISCO管柱用10%至20%至60% EtOAc/Hex溶離來純化粗物質,提供(S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺與(R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺之外消旋混合物(408mg,1.01mmol,32%產率)。
步驟2:(S)-2-甲基戊-4-烯-1-磺醯胺及(R)-2-甲基戊-4-烯-1-磺醯胺
按照針對實例26之步驟2所描述的程序由(S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺(506mg,1.25mmol)合成標題化合物。獲得呈外消旋混合物狀之(S)-2-甲基戊-4-烯-1-磺醯胺及(R)-2-甲基戊-4-烯-1-磺醯胺
(152mg,0.93mmol,74%產率)。
步驟3:6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯及6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯
將小瓶饋入6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸((S)-第三丁酯(中間物AA12A,步驟1B,第一溶離異構體;120mg,0.212mmol)及(S)-2-甲基戊-4-烯-1-磺醯胺與(R)-2-甲基戊-4-烯-1-磺醯胺於1,2-DCE(3.028mL)中之外消旋混合物(156mg,0.954mmol)。溶液用氬氣鼓泡,且在環境溫度下以1.5mL 1,2-DCE溶液之形式添加赫維達-格拉布斯II(13.28mg,0.021mmol)。混合物在環境溫度下攪拌(用氬氣鼓泡且使小瓶排氣)1.5h(藉由LC/MS分析為70%轉化)。反應混合物隨後用空氣鼓泡5min,濃縮,且直接注入24g ISCO金色管柱中,且用0-20-50-100% EtOAc/Hex溶離歷經16min來純化,得到6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯與6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯之混合物(63mg,0.096mmol,45.1%產率)。
步驟4:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-甲基-6-胺磺醯基
己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
向6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯與6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(1'S)-第三丁酯(63mg,0.096mmol)及LiOH單水合物(0.013mL,0.478mmol)之固體混合物中添加二噁烷/MeOH之1:1混合物(1.911mL)。將反應加熱至70℃。1.5h後幾乎未觀測到反應;添加H2O(約0.4mL),且混合物攪拌40h。混合物隨後用1N HCl(1.0mL)淬滅,用鹽水稀釋,用EtOAc萃取,經MgSO4乾燥且濃縮。所獲得之粗物質不經進一步純化即用於下一步驟。
步驟5. (1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例26之步驟4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-
氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-甲基-6-胺磺醯基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(57mg,0.095mmol)合成標題化合物。藉由層析經由12g ISCO金色管柱用10-40-50% EtOAc(含有0.3% AcOH)/Hex溶離歷經24min來純化粗物質,提供呈第一溶離次要異構體狀之(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(11mg,0.019mmol,19.9%產率,90%純度)。1H NMR(400MHz,CD2Cl2)δ 8.41(s,1H),7.66(d,J=8.4Hz,1H),7.50(br.s.,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.3Hz,1H),6.95(dd,J=2.0,8.2Hz,1H),6.90(d,J=8.0Hz,1H),5.69(dd,J=4.3,15.8Hz,1H),5.63-5.54(m,1H),4.20(s,2H),4.04(d,J=15.3Hz,1H),3.94(dd,J=2.2,5.2Hz,1H),3.89-3.81(m,1H),3.74-3.63(m,1H),3.39(d,J=15.3Hz,1H),3.26-3.17(m,1H),3.09-2.96(m,1H),2.81-2.71(m,2H),2.57-2.41(m,2H),2.16(dd,J=6.5,11.7Hz,1H),1.92-1.76(m,6H),1.75-1.63(m,3H),1.62-1.41(m,2H),1.19(d,J=6.1Hz,3H)。MS(ESI,陽離子)m/z 585.1(M+H)+。
實例30. (1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如針對實例29之步驟5所描述合成標題化合物。(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(11.6mg,0.020mmol,21.0%產率)經分離為第二溶離主要異構體。1H NMR(400MHz,CD2Cl2)δ 8.44(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.95-6.90(m,2H),6.89(s,1H),5.82(ddd,J=5.1,7.6,15.1Hz,1H),5.70(dd,J=8.2,15.3Hz,1H),4.24(dd,J=3.9,12.3Hz,1H),4.20(dd,J=4.7,8.8Hz,1H),4.10-4.05(m,2H),3.82(d,J=14.9Hz,1H),3.69(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.05(dd,J=9.6,15.1Hz,1H),2.98(dd,J=8.0,15.3Hz,1H),2.84-2.67(m,2H),2.41(ddd,J=4.3,9.8,18.0Hz,1H),2.36-2.28(m,1H),2.24(ddd,J=2.2,7.9,15.2Hz,1H),2.08-1.99(m,2H),1.98-1.87(m,3H),1.87-1.74(m,4H),1.68(dd,J=9.4,18.8Hz,1H),1.46-1.35(m,1H),1.15(d,J=6.5Hz,3H)。MS(ESI,陽離子)m/z 585.1(M+H)+。
實例31. (1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五
烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例29;8.0mg,0.014mmol)合成標題化合物。粗物質之純化提供(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(8.1mg,0.014mmol,99%產率,94%純度)。1H NMR(400MHz,CD2Cl2)δ 8.22(s,1H),7.69(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.97-6.88(m,3H),5.84(td,J=6.3,15.6Hz,1H),5.48(dd,J=7.3,15.4Hz,1H),4.15-4.03(m,2H),3.64(dd,J=6.5,15.3Hz,1H),3.61-3.56(m,2H),3.55-3.46(m,2H),3.38(d,J=14.1Hz,1H),3.29(s,3H),3.23(d,J=14.1Hz,1H),2.84-2.68(m,2H),2.48-2.31(m,2H),2.27-2.15(m,3H),2.02-1.93(m,1H),1.93-1.82(m,3H),1.77-1.63(m,3H),1.56-1.44(m,1H),1.16(d,J=6.5Hz,3H)。MS(ESI,陽離子)m/z 599.0(M+H)+。
實例32. (1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-
2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例4所描述的程序由(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例30;8.0mg,0.014mmol)合成標題化合物。粗物質之純化提供(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(8.1mg,0.014mmol,99%產率)。1H NMR(400MHz,CD2Cl2)δ 8.18(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.93-6.87(m,2H),6.82(s,1H),5.82(ddd,J=5.7,7.6,14.9Hz,1H),5.52(dd,J=9.2,15.3Hz,1H),4.32(dd,J=4.9,15.3Hz,1H),4.07(s,2H),3.81(d,J=14.9Hz,1H),3.70(d,J=14.3Hz,1H),3.64(dd,J=3.5,9.2Hz,1H),3.23(d,J=14.3
Hz,1H),3.19(s,3H),3.02(dd,J=6.1,15.3Hz,1H),2.99(dd,J=3.2,15.2Hz,1H),2.85-2.67(m,2H),2.44(ddd,J=3.3,9.6,18.6Hz,1H),2.36-2.23(m,2H),2.15-2.02(m,1H),2.00-1.89(m,2H),1.88-1.82(m,1H),1.82-1.74(m,2H),1.71-1.62(m,1H),1.59-1.48(m,2H),1.44-1.34(m,1H),1.14(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 599.0(M+H)+。
實例33. (1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(S)-2-乙基-N,N-雙(4-甲氧基苄基戊-4-烯-1-磺醯胺及(R)-2-乙基-N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺
根據針對中間物26之步驟1所描述的程序由N,N-雙(4-甲氧基苄基)甲磺醯胺(中間物EE12;1.10g,3.28mmol)及4-甲基苯磺酸己-5-烯-3-基酯(根據Sigman,M.S.等人;J.Am.Chem.Soc.,2012,134(28),11408-11411之程序製備;1.50g,5.90mmol)合成標題化合物。獲得呈外消旋混合物狀之(S)-2-乙基-N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺及(R)-2-乙基-N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺(435mg,1.04mmol,31.8%產率)。
步驟2:(S)-2-乙基戊-4-烯-1-磺醯胺及(R)-2-乙基戊-4-烯-1-磺醯胺
根據針對實例26之步驟2所描述的程序由(S)-2-乙基-N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺與(R)-2-乙基-N,N-雙(4-甲氧基苄基)戊-4-烯-1-磺醯胺之外消旋混合物(435mg,1.04mmol)合成標題化合物。獲得呈外消旋混合物狀之(S)-2-乙基戊-4-烯-1-磺醯胺及(R)-2-乙基戊-4-烯-1-磺醯胺(149mg,0.84mmol,81%產率)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲酸
按照針對實例26之步驟3所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;80mg,0.157mmol)及(S)-2-乙基戊-4-烯-1-磺醯胺與(R)-2-乙基戊-4-烯-1-磺醯胺之混合物(149mg,0.84mmol)合成標題化合物。粗物質用0-20-50-100% EtOAc/庚烷之梯度,隨後20-50% EtOAc(含有0.3% AcOH)/庚烷之梯度溶離來純化,提供(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸與(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸之不可分離混合物(75
mg,0.122mmol,77%產率)。
步驟4. (1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例26之步驟4所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((1S,5S,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸及(S)-6'-氯-5-(((1R,2R)-2-((1S,5R,E)-1-羥基-5-(胺磺醯基甲基)庚-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(75mg,0.122mmol)合成標題化合物。藉由層析經由12g ISCO金色管柱用10-30-50% EtOAc(含有0.3% AcOH)/Hex溶離歷經24min來純化粗物質,提供呈第一溶離異構體狀之(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-11'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(20.4mg,0.034mmol,28.0%產率)。1H NMR(400MHz,CD2Cl2)δ 8.45(br.s.,1H),7.67(d,J=8.6Hz,1H),7.44(br.s.,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.3Hz,1H),6.96(dd,J=1.8,8.0Hz,1H),6.91(d,J=8.0Hz,1H),5.71(dd,J=4.7,15.7Hz,1H),5.66-5.55(m,1H),4.24-4.13(m,2H),3.96(br.s.,1H),3.92(d,J=15.7Hz,1H),3.79(br.s.,1H),3.64(d,J=13.3Hz,1H),3.42(d,J=14.5Hz,1H),3.30-3.11(m,2H),2.79-2.71(m,2H),2.56-2.41(m,2H),2.29(dd,J=5.5,13.9Hz,1H),1.91-1.75(m,7H),1.75-1.63(m,4H),1.45(dt,J=7.6,14.3Hz,2H),0.92(t,J=7.3Hz,3H)。MS(ESI,陽離子)m/z 599.0(M+H)+。
實例34. (1S,3'R,6'R,7'S,8'E,11'S)-6-氯-11'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
如針對實例33之步驟4所描述合成標題化合物。(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-11'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物呈第二溶離異構體狀。此物質用60% EtOAc/庚烷溶離來再純化,提供純標題化合物(15.7mg,0.026mmol,21.6%產率)。1H NMR(500MHz,CD2Cl2)δ 8.59(br.s.,1H),7.69(d,J=8.6Hz,1H),7.15(dd,J=2.3,8.4Hz,1H),7.08(d,J=2.2Hz,1H),6.93(dd,J=2.0,8.1Hz,1H),6.90(d,J=8.1Hz,1H),6.85(d,J=1.5Hz,1H),5.81(td,J=6.6,15.2Hz,1H),5.68(dd,J=8.3,15.2Hz,1H),4.19(dd,J=3.9,8.1Hz,1H),4.12(dd,J=5.9,15.4Hz,1H),4.06(s,2H),3.78(d,J=14.9Hz,1H),3.68(d,J=14.4Hz,1H),3.23(d,J=14.2Hz,1H),3.13(dd,J=6.7,15.5Hz,1H),3.02(dd,J=9.7,15.3Hz,1H),2.82-2.68(m,2H),2.39(ddd,J=4.2,9.8,18.1Hz,1H),2.36-2.25(m,2H),2.06-1.96(m,3H),1.96-1.88(m,2H),1.87-1.70(m,4H),1.69-1.56(m,3H),1.42-1.35(m,1H),0.90(t,J=7.5Hz,3H)。MS(ESI,陽離子)m/z 599.2(M+H)+。
實例35. (1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
將(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例26;17mg,0.028mmol)及氧化鉑(IV)(6.44mg,0.028mmol)於EtOAc(3.5mL)中之混合物在H2(氣球)下在環境溫度下攪拌50min。隨後經由針筒過濾器過濾反應混合物。藉由層析經由Redi-Sep®預裝填SiO2凝膠管柱(4g)用20%至50% EtOAc(含有0.3% AcOH)/庚烷溶離來純化粗物質,提供(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(12.1mg,0.020mmol,70.9%產率)。1H NMR(500MHz,CD2Cl2)δ 8.55(br.s.,1H),7.67(d,J=8.6Hz,1H),7.48(br.s.,1H),7.14(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.2Hz,1H),7.03(dd,J=1.7,8.1Hz,1H),6.92(d,J=8.3Hz,1H),4.22-4.13(m,2H),4.05-3.96(m,1H),3.66(br.s.,1H),3.61(d,J=13.7Hz,1H),3.51-3.45(m,1H),3.43(d,J=14.4Hz,1H),3.28(d,J=12.2Hz,1H),2.81-2.69(m,2H),2.62-2.53(m,1H),
2.48-2.41(m,1H),2.16-2.08(m,2H),1.91(q,J=9.0Hz,1H),1.87-1.78(m,3H),1.78-1.72(m,1H),1.68(q,J=8.6Hz,2H),1.59(dd,J=6.1,10.3Hz,2H),1.50-1.43(m,1H),1.41(d,J=7.1Hz,3H),1.37-1.25(m,4H),1.00(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 601.0(M+H)+。
實例36. (1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例35所描述的程序由(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例27;9.4mg,0.016mmol)合成標題化合物。粗物質之純化提供(1S,3'R,6'R,7'S,11'R,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(5.2mg,0.0087mmol,55.1%產率)。1H NMR(500MHz,CD2Cl2)δ 9.70(br.s.,1H),7.70(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.3Hz,1H),7.16(d,J=8.3Hz,1H),7.10(d,J=2.2Hz,1H),6.97(d,J=8.1Hz,1H),4.18(d,J=11.7Hz,1H),4.12(d,J=12.0Hz,1H),3.69-3.57(m,3H),3.49(d,J=14.7Hz,1H),3.38(d,J=14.2Hz,1H),3.33(br.s.,1H),2.90(d,J=4.6Hz,2H),2.82-2.70(m,2H),2.46-2.36(m,1H),2.31-2.20(m,1H),2.11-2.01(m,1H),1.99-1.91(m,3H),1.90-1.78(m,3H),1.77-1.70(m,2H),1.70-1.62(m,4H),1.61-1.55(m,1H),1.45(m,1H),1.42(d,J=7.3Hz,3H),0.97(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 601.1(M+H)+。
實例37. (1S,3'R,6'R,7'S,11'S,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例35所描述的程序由(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例28;3.9mg,0.0065mmol)合成標題化合物。粗物質之純化提供(1S,3'R,6'R,7'S,11'S,12'S)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物(2.8mg,0.0047mmol,71.6%產率,90%純度)。1H NMR(500MHz,CD2Cl2)δ 10.44(s,1H),7.73(d,J=8.3Hz,1H),7.43(dd,J=2.2,8.3Hz,
1H),7.32(d,J=2.2Hz,1H),7.17(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.4Hz,1H),6.96(d,J=8.3Hz,1H),4.10-4.05(m,2H),3.87(d,J=15.4Hz,1H),3.66(d,J=13.9Hz,1H),3.61(q,J=8.8Hz,1H),3.55(ddd,J=1.2,7.1,14.4Hz,1H),3.16(d,J=14.2Hz,1H),3.09(dd,J=8.7,15.3Hz,1H),2.84-2.69(m,2H),2.46-2.37(m,1H),2.34(d,J=8.6Hz,1H),2.24(quin,J=8.8Hz,1H),2.17-2.08(m,2H),2.06(d,J=8.8Hz,1H),2.04-1.96(m,1H),1.96-1.87(m,1H),1.86-1.71(m,5H),1.71-1.61(m,2H),1.51-1.46(m,1H),1.45-1.41(m,1H),1.40(d,J=7.3Hz,3H),1.35-1.28(m,1H),1.03(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 601.1(M+H)+。
實例38. (1S,3'R,6'R,7'S,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'二氧化物或(1S,3'R,6'R,7'S,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1:(S)-苄基(2-甲基丁-3-烯-1-基)硫烷及(R)-苄基(2-甲基丁-3-烯-1-基)硫烷
將2-甲基丁-3-烯-1-醇(1.198mL,11.61mmol)、苯基甲硫醇(2.044mL,17.42mmol)及2-(三丁基正膦亞基)MeCN(4.67mL,17.42mmol)在100℃下加熱2h。將反應混合物冷卻至rt,用EtOAc稀釋,用
NH4Cl飽和水溶液及鹽水洗滌,經Na2SO4乾燥且濃縮。將粗產物吸附至30g SiO2凝膠中且乾燥,且隨後藉由在SiO2凝膠上層析用Hex溶離來純化,提供呈無色油狀之標題產物(1.62g,72.4%)。1H NMR(400MHz,CDCl3)δ 7.44-7.27(m,5H),5.84(ddd,J=17.17,10.32,6.75Hz,1H),5.16-5.03(m,2H),3.79(s,2H),2.58-2.39(m,3H),1.19-1.14(m,3H)。
步驟2:(S)-2-甲基丁-3-烯-1-磺醯胺及(R)-2-甲基丁-3-烯-1-磺醯胺
在劇烈攪拌下向(S)-苄基(2-甲基丁-3-烯-1-基)硫烷、(R)-苄基(2-甲基丁-3-烯-1-基)硫烷(0.650g,3.38mmol)及氧碘苯(2.454g,11.15mmol)於133mL醚中之溶液中緩慢添加濃HCl(18.31mL,220mmol)。所得混合物攪拌30min。使反應混合物沈降且分離各層。在減壓下濃縮有機層。殘餘物在高真空下乾燥1h。將殘餘物於8mL DCM中之溶液添加至氨7.0M甲醇溶液(2.414mL,16.90mmol)、N,N-DIPEA(2.94mL,16.90mmol)及4-(二甲胺基)吡啶(8.26mg,0.068mmol)於10mL DCM中之混合物中。將反應混合物在rt下攪拌16h之後濃縮。藉由在SiO2凝膠上層析用0%至60% EtOAc/己烷溶離來純化粗產物,提供標題化合物(0.076g,15.1%)。1H NMR(400MHz,CDCl3)δ 5.82(ddd,J=17.36,10.03,7.63Hz,1 H),5.21-5.05(m,4 H),3.25-3.07(m,2 H),2.92-2.78(m,1 H),1.20(d,J=6.85Hz,3 H)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-(((S)-2-甲基丁-3-烯-1-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺及(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-(((R)-2-甲基丁-3-烯-1-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
將(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;0.010g,0.021mmol)、(S)-2-甲基丁-3-烯-1-磺醯胺與(R)-2-甲基丁-3-烯-1-磺醯胺(0.019g,0.124mmol)、1-(3-二甲胺基丙基)-3-乙基碳化二亞胺鹽酸鹽(0.012g,0.062mmol)及4-(二甲胺基)吡啶(7.60mg,0.062mmol)於DCM(0.5mL)中之混合物在rt下攪拌16h。將混合物直接裝載至管柱(5g SiO2凝膠)上用於藉由層析用0%至50% EtOAc(含有0.2% AcOH)/己烷溶離來純化,提供標題化合物(0.011g,86%)。m/z(ESI,陽離子)613.2(M+H)+。
步驟4:(1S,3'R,6'R,7'S,9'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(116762-34-3)及(1S,3'R,6'R,7'S,9'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
將(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-(((S)-2-甲基丁-3-烯-1-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺及(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-(((R)-2-甲基丁-3-烯-1-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(21mg,0.034mmol)於甲苯(80mL)中之溶液用N2進行三次抽真空/回填循環。在rt下向均質溶液中添加赫維達-格拉布斯II(4.29mg,6.85μmol)於1mL甲苯中之溶液。將反應混合物在106℃下在N2下攪拌2h。將空氣吹至混合物中。將反應物冷卻至rt且濃縮。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;40%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化殘餘物,提供標題化合物之混合物。
步驟5:(1S,3'R,6'R,7'S,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
將(1S,3'R,6'R,7'S,9'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(116762-34-3)及(1S,3'R,6'R,7'S,9'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'Z,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自步驟4,1.6mg,2.73μmol)及氧化鉑(iv)(0.621mg,2.73μmol)於EtOAc(2.0mL)中之混合物在H2(氣球)下在rt下攪拌2h。使用針筒過濾器過濾出固體催化劑,且濃縮濾液得到粗產物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;40%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化殘餘物,提供呈白色固體狀之第二溶離異構體形式之標題化合物。1H NMR(500MHz,CDCl3)δ 9.02(br.s.,1H),7.73-7.69(m,1 H),7.22-7.16(m,3 H),7.09(d,J=2.20Hz,1 H),6.96(d,J=8.07Hz,1 H),4.16-4.09(m,2 H),3.88-3.63(m,6 H),3.28-3.22(m,1 H),3.17(dd,J=15.16,5.87Hz,1 H),3.13-3.07(m,1 H),2.80-2.74(m,2 H),2.36-2.29(m,2 H),2.21-2.18(m,1 H),2.03-1.98(m,2 H),1.94-1.77(m,2 H),1.75-1.27(m,9 H),1.13(d,J=6.85Hz,3 H)。m/z(ESI,陽離子)587.2(M+H)+。
實例39. (1S,3'R,6'R,7'S,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜
[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
標題化合物經分離為實例38中來自製備型逆相HPLC之第二溶離異構體。1H NMR(400MHz,CDCl3)δ 9.38(br.s.,1H),7.69(d,J=8.61Hz,1H),7.29(m,1H),7.25-7.15(m,2H),7.10(d,J=2.35Hz,1H),6.98(d,J=8.22Hz,1H),4.16(s,2H),3.89-3.83(m,1H),3.67(d,J=7.83Hz,1H),3.61-3.44(m,4H),3.41(d,J=12.52Hz,2H),2.81-2.68(m,3H),2.23-2.06(m,3H),2.02-1.72(m,5H),1.64-1.51(m,5H),1.49-1.38(m,2H),1.25-1.13(m,1H),1.06(d,J=6.85Hz,3H)。m/z(ESI,陽離子)587.1(M+H)+。
實例40. (1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物及實例41. (1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:2-甲基己-5-烯-2-磺醯胺
以類似於中間物EE20中所描述之方式的方式使用5eq.丁基鋰溶液、2.5M己烷(Aldrich)及5eq.MeI(Aldrich)製備標題化合物,且所要產物1-(三氟甲氧基)庚-6-烯-3-磺醯胺經分離為淺棕色油狀物。
步驟2:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例2之步驟1及2中所描述之方式的方式使用中間物AA11A及來自步驟1之2-甲基己-5-烯-2-磺醯胺製備標題化合物,且使如下所要產物分離:(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例40),呈來自製備型逆相HPLC之第一溶離主要異構體狀;及(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例41),呈來自製備型逆相HPLC之第二溶離主要異構體狀。(1S,3'R,6'R,7'S,8'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例40):1H NMR(500MHz,CD3OD)δ 7.75(d,J=8.6Hz,1H),7.20(dd,J=2.2,8.6Hz,1H),7.13(d,J=2.2Hz,1H),7.07(br.s.,1H),6.94(d,J=7.8Hz,2H),5.82(br.s.,1H),5.65(dd,J=7.5,15.5Hz,1H),4.17(br.s.,1H),4.10(dd,J=12.0,46.0Hz,2H),3.78(d,J=14.4Hz,1H),3.67(d,J=13.4Hz,1H),3.11-3.00(m,1H),2.87-2.75(m,
2H),2.54(br.s.,1H),2.41-2.07(m,5H),2.01-1.88(m,3H),1.80(dd,J=8.1,14.2Hz,3H),1.70(dd,J=9.0,18.3Hz,1H),1.54-1.42(m,2H),1.45(d,J=8.1Hz,6H)。m/z(ESI,陽離子)599.2(M+H)+;(1S,3'R,6'R,7'S,8'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例41):1H NMR(400MHz,CD3OD)δ 7.76(d,J=8.6Hz,1H),7.29(d,J=7.8Hz,1H),7.20(dd,J=2.2,8.4Hz,1H),7.17(br.s.,1H),7.13(d,J=2.2Hz,1H),6.96(d,J=7.5Hz,1H),5.68-5.60(m,1H),5.53(dd,J=8.4,11.2Hz,1H),4.59(dd,J=1.8,8.6Hz,1H),4.11(s,2H),4.07(d,J=13.7Hz,1H),3.74(d,J=15.3Hz,1H),3.45(d,J=14.5Hz,1H),2.90-2.75(m,2H),2.72-2.53(m,1H),2.50-2.40(m,1H),2.40-2.23(m,2H),2.14(d,J=13.1Hz,1H),2.08-1.96(m,4H),1.96-1.78(m,5H),1.53(d,J=12.7Hz,6H)1.52-1.46(m,1H)。m/z(ESI,陽離子)599.2(M+H)+。
實例42. (1S,3'R,6'R,7'S)-6-氯-7'-羥基-12',12'-乙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
步驟1. N,N-雙(4-甲氧基苄基)2-甲基戊-4-烯-2-磺醯胺
將N,N-雙(4-甲氧基苄基)丁-3-烯-1-磺醯胺(中間物EE16;500
mg,1.332mmol)在PhMe中在真空下共沸1h。在氬氣下,添加THF且將溶液冷卻至-78℃。隨後添加丁基鋰溶液(Sigma Aldrich,2.5M己烷;1.065mL,2.66mmol),且混合物在-78℃下攪拌60min。添加MeI(Sigma Aldrich;0.166mL,2.66mmol),且混合物在-78℃下攪拌額外30min(LC/MS分析展示完成轉化為單甲基化產物與二甲基化產物之1:1混合物)。混合物用飽和NH4Cl淬滅,使其達到環境溫度,用EtOAc萃取,經MgSO4乾燥且濃縮。經由24g ISCO金色管柱用5-10% EtOAc/己烷之梯度溶離來純化粗物質,提供N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-2-磺醯胺(173mg,0.429mmol,32.2%產率)。
步驟2. 2-甲基戊-4-烯-2-磺醯胺
向N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-2-磺醯胺(173mg,0.429mmol)於DCM中之溶液中添加硫代苯甲醚(0.503mL,4.29mmol),隨後逐滴添加三氟乙酸(1.2mL,16.15mmol)。攪拌6h之後(30% EtOAc/己烷之TLC展示起始物質完全損耗),混合物用EtOAc稀釋,用飽和NaHCO3洗滌,用EtOAc反萃取,經MgSO4乾燥且濃縮。經由層析經由12g ISCO金色管柱用10-50% EtOAc/己烷之梯度溶離來純化粗物質,提供2-甲基戊-4-烯-2-磺醯胺(45mg,0.276mmol,64.3%產率)。
步驟3:(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[B][1,4]噁氮呯-3,1'-萘]-7-甲醯胺
按照針對實例2之步驟1所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA13A;41mg,0.085mmol)及2-甲基戊-4-烯-2-磺醯胺(45mg,0.276mmol)合成標題化合物。粗物質之純化提供(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(45.8mg,0.073mmol,86%產率)。
步驟4:(1S,3'R,6'R,7'S,9'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照針對實例14之步驟2所描述的程序由(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基丁-3-烯-1-基)環丁基)甲基)-N-((2-甲基戊-4-烯-2-基)磺醯基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(45.8mg,0.073mmol)合成標題化合物。藉由層析經由12g ISCO管柱用10%至20% EtOAc(含有0.3% AcOH)/己烷溶離歷經90min來純化粗物質,提供標題化合物之混合物。
步驟5:(1S,3'R,6'R,7'S)-6-氯-7'-羥基-12',12'-乙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[16,18,24]三烯]-15'-酮13',13'-二氧化物
按照針對實例14之步驟3所描述的程序由(1S,3'R,6'R,7'S,9'Z)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物及(1S,3'R,6'R,7'S,9'E)-6-氯-7'-羥基-12',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[9,16,18,24]四烯]-15'-酮13',13'-二氧化物(來自步驟4,9mg,0.015mmol)合成標題化合物(6.4mg,0.011mmol,71%產率)。1H NMR(400MHz,CD2Cl2)δ 10.50(br.s.,1H),7.70(d,J=8.6Hz,1H),7.47(dd,J=1.2,8.4Hz,1H),7.35(s,1H),7.14(dd,J=2.0,8.2Hz,1H),7.08(d,J=2.2Hz,1H),6.91(d,J=8.4Hz,1H),4.02(d,J=12.1Hz,1H),3.96(d,J=11.9Hz,1H),3.73(d,J=15.5Hz,1H),3.64-3.54(m,1H),3.13(d,J=14.3Hz,1H),3.05(dd,J=9.1,15.6Hz,1H),2.94(d,J=8.6Hz,1H),2.82-2.71(m,2H),2.33(quin,J=8.6Hz,1H),2.20-2.06(m,2H),2.05-1.96(m,2H),1.95-1.87(m,3H),1.86-1.74(m,4H),1.73-1.59(m,4H),1.49(s,3H),1.47(s,3H),1.44-1.34(m,3H)。MS(ESI,陽離子)m/z 601.2(M+H)+。
實例43. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-11',12'-二甲基-7'-(1-甲基乙氧基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2;20.4mg,0.034mmol)於THF(0.681mL)中之溶液(冷卻至0℃)中添加氫化鈉(60%礦物油分散液;13.62mg,0.340mmol)。反應混合物在0℃下攪拌15min,且隨後添加2-碘丙烷(3.40μl,0.034mmol)。反應混合物在環境溫度下攪拌4天,添加更多試劑以驅動反應。混合物隨後用NH4Cl水溶液淬滅且用EtOAc稀釋.有機層經MgSO4乾燥且濃縮。藉由層析經由Redi-Sep®預裝填SiO2凝膠管柱(4g)用10-40% EtOAc(含有0.3% AcOH)/庚烷溶離來純化粗物質,提供標題化合物(0.6mg)。1H NMR(500MHz,CD2Cl2)δ 8.03(br.s.,1H),7.71(d,J=8.3Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.4Hz,1H),6.91-6.89(m,2H),6.88(s,1H),5.72(ddd,J=3.4,9.3,15.2Hz,1H),5.53(dd,J=8.8,15.4Hz,1H),4.29-4.22(m,1H),4.08(s,2H),3.85-3.80(m,2H),3.69(d,J=14.2Hz,1H),3.59(td,J=6.1,12.2Hz,1H),3.28-3.22(m,2H),3.02(dd,J=9.7,15.3Hz,1H),2.83-2.70(m,2H),2.39-2.24(m,2H),2.20-2.02(m,3H),2.01-1.89(m,3H),1.83(dd,J=5.6,12.7Hz,1H),1.81-1.75(m,1H),1.70-1.59(m,1H),1.44(d,J=7.3Hz,3H),1.43-1.35(m,1H),1.09(d,J=5.9Hz,3H),1.04(d,J=6.1Hz,3H),1.02(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 641.0(M+H)+。
實例44. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(2S)-甲基戊-4-烯醛及(2R)-甲基戊-4-烯醛
在N2下在-60℃下向乙二醯氯(6.65mL,74.9mmol)於DCM(30mL)中之溶液中添加無水DMSO(10.62mL,150mmol)於DCM(20mL)中之溶液,且攪拌2min。添加2-甲基戊-4-烯-1-醇(5.00g,49.9mmol)於DCM(20mL)中之溶液,且所得混合物在-60℃下攪拌15min。隨後添加Et3N(34.7mL,250mmol),且反應混合物在環境溫度下攪拌20min。混合物用DCM及H2O淬滅。有機層用鹽水洗滌,乾燥(MgSO4)且過濾。濃縮濾液,得到標題化合物(4.90g,100%),其不經進一步純化。
步驟2:(1S,2R)-1-環丙基-2-甲基-4-戊烯-1-醇,及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-醇,及(1S,2S)-1-環丙基-2-甲基-4-戊烯-1-醇,及(1R,2S)-1-環丙基-2-甲基-4-戊烯-1-醇
及及及
在-78℃下向(2S)-甲基戊-4-烯醛及(2R)-甲基戊-4-烯醛(9.80g,100mmol)於THF(30mL)中之溶液中添加環丙基溴化鎂(1.0M 2-MeTHF)(300mL,150mmol)。反應混合物在環境溫度下攪拌3h。混合物用NH4Cl飽和水溶液淬滅,且用醚萃取。有機層用鹽水洗滌,乾燥(Na2SO4)且濃縮。將所得殘餘物層析(SiO2凝膠,0至40% EtOAc/己烷),得到標題化合物(4.20g,30.0%)。
步驟3:(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺
及及及
按照E22中步驟3至6所描述之類似程序由(1S,2R)-1-環丙基-2-甲基-4-戊烯-1-醇、(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-醇、(1S,2S)-1-環丙基-2-甲基-4-戊烯-1-醇及(1R,2S)-1-環丙基-2-甲基-4-戊烯-1-醇(來自步驟2)之混合物作為起始醇來製備標題化合物。
步驟4:(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照實例2之步驟1及2中所描述之類似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A)及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺、(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺、(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺及(1R,2R)-1-環丙基-2-甲基-4-戊烯-1-磺醯胺之混合物(來自步驟3)製備標題化合物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化粗物質油,得到呈第一溶離異構體狀之標題化合物(12mg,6.7%)。1H NMR(400MHz,CD2Cl2)δ 8.15(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.93-6.88(m,3H),5.91-5.63(m,2H),4.22(dd,J=3.9,7.6Hz,1H),3.81(d,J=15.1Hz,1H),3.68(d,J=14.3Hz,1H),3.40(d,J=11.0Hz,1H),3.25(d,J=14.3Hz,1H),3.04(dd,J=9.8,15.3Hz,1H),2.82-2.67(m,2H),2.49-2.23(m,3H),2.14-1.84(m,11H),1.73-1.62(m,1H),1.45-1.34(m,1H),1.20(d,J=6.8Hz,3H),1.17-1.07(m,1H),0.93-0.76(m,3H),0.50-0.37(m,1H)。m/z(ESI,陽離子)625.2(M+H)+。
實例45. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例49中製備型逆相HPLC分離獲得呈第二溶離異構體狀之標題化合物(5mg,2.8%)。1H NMR(400MHz,CD2Cl2)δ 9.04(br.s.,1H),7.83-7.61(m,1H),7.17(d,J=8.4Hz,1H),7.09(m,1H),6.97-6.88(m,1H),6.84(m,1H),6.15(br.s.,1H),5.92-5.69(m,1H),4.26-4.04(m,2H),3.68(d,J=14.1Hz,1H),3.36-2.94(m,3H),2.77(m,2H),2.38(d,J=7.6Hz,2H),2.24-1.87(m,6H),1.69(dd,J=9.8,19.4Hz,2H),1.53-1.41(m,1H),1.30-1.06(m,10H),0.83(d,J=3.1Hz,2H),0.44(br.s.,1H)m/z(ESI,陽離子)625.2(M+H)+。
實例46. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二
氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例49中製備型逆相HPLC分離獲得呈第三溶離異構體狀之標題化合物(9mg,5.0%)。1H NMR(400MHz,CD2Cl2)δ 8.21(br.s.,1H),7.66(d,J=8.6Hz,1H),7.44(br.s.,1H),7.14(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.94-6.86(m,2H),5.62(br.s.,2H),4.20(s,2H),3.92(d,J=7.4Hz,1H),3.85(d,J=13.9Hz,1H),3.66(d,J=14.1Hz,1H),3.39(d,J=14.3Hz,1H),3.33(d,J=11.0Hz,1H),3.17(d,J=13.7Hz,1H),2.74(t,J=5.3Hz,2H),2.57(d,J=7.6Hz,1H),2.40(td,J=8.7,17.1Hz,1H),2.29-2.16(m,1H),2.03-1.62(m,10H),1.60-1.45(m,1H),1.22(d,J=6.7Hz,3H),1.17-1.04(m,1H),0.91-0.78(m,3H),0.52-0.41(m,1H)。m/z(ESI,陽離子)625.2(M+H)+。
實例47. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例49中製備型逆相HPLC分離獲得呈最慢溶離異構體狀之標題化合物(3mg,1.9%)。1H NMR(400MHz,CD2Cl2)δ 8.14(br.s.,1H),7.71(d,J=8.6Hz,1H),7.22-7.06(m,3H),6.98-6.91(m,1H),6.62(br.s.,1H),6.05(d,J=7.2Hz,1H),5.69(dd,J=5.8,15.2Hz,1H),4.19(br.s.,1H),4.15-3.99(m,2H),3.79(d,J=14.5Hz,1H),3.65(d,J=14.5Hz,1H),3.43(d,J=14.5Hz,1H),3.33-3.22(m,1H),2.99(d,J=11.0Hz,1H),2.86-2.66(m,3H),2.51(br.s.,2H),2.32-
2.18(m,2H),2.09-1.87(m,5H),1.75(d,J=10.4Hz,2H),1.52-1.38(m,2H),1.19(d,J=7.0Hz,3H),1.11(br.s.,1H),0.93-0.73(m,3H),0.54-0.40(m,1H)。m/z(ESI,陽離子)625.2(M+H)+。
實例48. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用實例46中所描述之類似程序由(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環
丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例49)製備標題化合物(9.5mg,62%)。1H NMR(400MHz,CD2Cl2)δ 8.15-7.94(m,1H),7.71(d,J=8.41Hz,1H),7.17(dd,J=2.35,8.41Hz,1H),7.09(d,J=2.15Hz,1H),6.91(d,J=0.98Hz,2H),6.86(s,1H),5.81-5.70(m,J=3.13,9.39Hz,1H),5.51(ddd,J=1.17,8.41,14.67Hz,1H),4.08(s,2H),3.80(d,J=15.06Hz,1H),3.69(d,J=14.28Hz,1H),3.62(dd,J=3.33,9.00Hz,1H),3.45(d,J=10.17Hz,1H),3.25(d,J=14.28Hz,1H),3.17(s,3H),3.03(dd,J=10.17,15.26Hz,1H),2.80-2.72(m,2H),2.59-2.39(m,2H),2.38-2.25(m,1H),2.17-1.73(m,8H),1.72-1.59(m,1H),1.21(d,J=6.85Hz,3H),1.17-1.08(m,1H),0.92-0.78(m,4H),0.47-0.37(m,1H)。m/z(ESI,陽離子)639.2(M+H)+。
實例49. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-
3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(3R,4R)-2,4-二甲基庚-6-烯-3-醇及(3R,4S)-2,4-二甲基庚-6-烯-3-醇及(3S,4R)-2,4-二甲基庚-6-烯-3-醇及(3S,4S)-2,4-二甲基庚-6-烯-3-醇
及及及
在0℃下向2-甲基戊-4-烯醛(2.40g,24.4mmol)於THF(10mL)中之溶液中添加異丙基氯化鎂(2.0M THF)(24.4mL,48.9mmol)。使反應混合物升溫至環境溫度。在環境溫度下攪拌12h後,將反應混合物淬滅(飽和NH4Cl),萃取(2×Et2O)且洗滌(鹽水)。將合併之有機層乾燥(Na2SO4)且在減壓下濃縮。將殘餘物注入40g ISCO金色管柱中,且藉由Combi-Flash®用0%至20% EtOAc/己烷溶離來純化,得到標題化合物(550mg,3.85mmol)。
步驟2:(3S,4R)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺及
(3S,4S)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4R)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4S)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺
按照中間物EE22之步驟3至6中所描述之類似程序由(3R,4R)-2,4-二甲基庚-6-烯-3-醇、(3R,4S)-2,4-二甲基庚-6-烯-3-醇、(3S,4R)-2,4-二甲基庚-6-烯-3-醇及(3S,4S)-2,4-二甲基庚-6-烯-3-醇之混合物(來自步驟1)製備標題化合物。
步驟3:(3S,4R)-2,4-二甲基庚-6-烯-3-磺醯胺及(3S,4S)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4R)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4S)-2,4-二甲基庚-6-烯-3-磺醯胺
按照針對實例26之步驟2所描述的類似程序由(3S,4R)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺、(3S,4S)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺、(3R,4R)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4S)-N,N-雙(4-甲氧基苄基)-2,4-二甲基庚-6-烯-3-磺醯胺之混合物(來自步驟2)合成標題化合物。
步驟4:(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲
基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(異構體1)
按照實例2之步驟1及2中所描述之類似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A)及(3S,4R)-2,4-二甲基庚-6-烯-3-磺醯胺、(3S,4S)-2,4-二甲基庚-6-烯-3-磺醯胺、(3R,4R)-2,4-二甲基庚-6-烯-3-磺醯胺及(3R,4S)-2,4-二甲基庚-6-烯-3-磺醯胺之混合物製備標題化合物。將殘餘物注入40g ISCO金色管柱中,且藉由Combi-Flash®用10%至100% EtOAc(含有0.5% AcOH)/己烷溶離來純化,得到呈較快溶離異構體狀之粗產物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化此粗產物,提供呈白色泡沫狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.30(s,1H),7.79-7.70(m,1H),7.66(d,J=8.4Hz,1H),7.14(m,1H),7.10(m,1H),6.95-6.87(m,2H),5.67(dd,J=4.1,15.8Hz,1H),5.44-5.34(m,1H),4.29-4.13(m,3H),4.04(m,1H),3.89-3.77(m,
2H),3.29(d,J=14.3Hz,1H),3.05(dd,J=3.5,16.0Hz,1H),2.78-2.69(m,2H),2.62-2.53(m,1H),2.48(m,1H),2.31-2.19(m,1H),2.05-1.70(m,9H),1.61(m,1H),1.37(d,J=7.0Hz,3H),1.35-1.26(m,4H),1.17(d,J=6.7Hz,3H);m/z(ESI,陽離子)627(M+H)+。
實例50. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例54中所描述之Combi-Flash®分離獲得呈第二(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ
ppm 8.13(s,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.91(m,3H),5.79-5.67(m,2H),4.22-4.13(m,2H),4.09(s,2H),3.90-3.78(m,1H),3.69(d,J=14.3Hz,1H),3.24(d,J=14.3Hz,1H),3.03(dd,J=9.3,15.4Hz,1H),2.83-2.70(m,2H),2.46-2.37(m,1H),2.35-2.23(m,2H),2.19-1.91(m,6H),1.88-1.75(m,3H),1.70-1.61(m,1H),1.44-1.30(m,7H),1.14(d,J=6.7Hz,3H);m/z(ESI,陽離子)627(M+H)+。
實例51. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例54中所描述之Combi-Flash®分離獲得呈第三(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.11(s,1H),7.77-7.69(m,1H),7.16(d,J=8.4Hz,1H),7.13-7.06(m,1H),7.00-6.88(m,3H),5.85-5.60(m,2H),4.24-4.06(m,4H),3.95-3.80(m,1H),3.69(d,J=14.1Hz,1H),3.51-3.34(m,2H),2.83-2.70(m,2H),2.46-2.24(m,3H),2.18-1.90(m,6H),1.87-1.70(m,4H),1.35(dd,J=7.0,14.3Hz,7H),1.22-1.07(m,3H);m/z(ESI,陽離子)627(M+H)+。
實例52. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例54中所描述之Combi-Flash®分離獲得呈第四(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.11(br.s.,1H),7.71(t,J=6.9Hz,1H),7.25-6.87(m,5H),5.88-5.43(m,2H),4.20-4.02(m,3H),3.84(m,1H),3.74-3.55(m,2H),3.55-3.40(m,1H),3.40-3.12(m,1H),2.82-2.62(m,3H),2.53(d,J=5.3Hz,2H),2.32(m,3H),2.08-1.62(m,8H),1.37-1.12(m,10H);m/z(ESI,陽離子)627(M+H)+。
實例53. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-甲氧基-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向產物(來自實例54;9mg,0.014mmol)於THF(1mL)中之溶液中添加氫化鈉(60%礦物油分散液)(1.43mg,0.036mmol)隨後MeI(3.1mg,0.022mmol)。在室溫下攪拌溶液隔夜。隨後將反應物用飽和NH4Cl及鹽水淬滅,萃取(2×Et2O)且洗滌(1×鹽水)。將合併之有機層乾燥(Na2SO4)且在減壓下濃縮。將殘餘物注入4g ISCO金色管柱中,且藉由Combi-Flash®用0%至100% EtOAc(含有0.5% AcOH)/己烷溶離來純化,得到呈無色油狀之標題化合物中之一者(7mg,10.9μmol)。1H NMR(400MHz,CD2Cl2)δ ppm 8.15(br.s.,1H),7.71(d,J=8.4Hz,1H),7.17(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.2Hz,1H),6.90(m,2H),6.84(m,1H),5.73(ddd,J=3.9,8.7,15.2Hz,1H),5.52(dd,J=8.8,15.5Hz,1H),4.23(m,1H),4.12-4.04(m,2H),3.82(d,J=15.1Hz,1H),3.72-3.62(m,2H),3.25-3.17(m,4H),3.02(dd,J=10.0,15.5Hz,1H),2.83-2.69(m,2H),2.47-2.38(m,1H),2.35-2.23(m,3H),2.21-2.02(m,3H),1.97-1.72(m,5H),1.68-1.60(m,1H),1.40-1.30(m,7H),1.13(d,J=6.7Hz,3H);m/z(ESI,陽離子)641(M+H)+。
實例54. (1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-12'-(1-甲基乙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向來自實例54之產物(10mg,0.016mmol)於THF(1mL)中之溶液中添加氫化鈉(60%礦物油分散液)(1.6mg,0.040mmol)隨後2-溴乙
基甲醚(2.2mg,0.016mmol)。在室溫下攪拌溶液約48h。隨後將反應物用飽和NH4Cl及鹽水淬滅,萃取(2×Et2O)且洗滌(1×鹽水)。將合併之有機層乾燥(Na2SO4)且在減壓下濃縮。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化此粗產物,提供呈白色非晶形固體狀之標題化合物中之一者(4mg,5.8μmol)。1H NMR(400MHz,CD2Cl2)δ ppm 8.09(s,1H),7.70(d,J=8.6Hz,1H),7.16(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.94-6.87(m,2H),6.84(s,1H),5.71(ddd,J=4.0,8.5,15.3Hz,1H),5.60-5.48(m,1H),4.21(m,1H),4.08(s,2H),3.86-3.74(m,2H),3.68(d,J=13.9Hz,1H),3.53-3.36(m,4H),3.32(s,3H),3.23(d,J=14.3Hz,1H),3.01(dd,J=10.1,15.2Hz,1H),2.83-2.69(m,2H),2.48-2.39(m,1H),2.34-2.12(m,4H),2.12-2.01(m,2H),1.99-1.75(m,5H),1.72-1.63(m,1H),1.45-1.30(m,7H),1.13(d,J=6.8Hz,3H);m/z(ESI,陽離子)685(M+H)+。
實例55. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(R)-2-甲基戊-4-烯醛及(S)-2-甲基戊-4-烯醛
在N2下在-60℃下向乙二醯氯(6.65mL,74.9mmol)於DCM(30mL)中之溶液中添加無水DMSO(10.6mL,150mmol)於DCM(20mL)中之溶液。攪拌2min後,添加2-甲基戊-4-烯-1-醇(5.00g,49.9mmol)於DCM(20mL)中之溶液,且所得混合物在-60℃下攪拌15min。隨後添加Et3N(34.7mL,250mmol)。在環境溫度下攪拌20min後,將混合物用DCM及H2O淬滅,萃取(2×Et2O)且洗滌(1×鹽水)。將合併之有機層乾燥(Na2SO4)且在減壓下濃縮,得到標題化合物。標題化合物不經進一步純化即用於下一步驟。
步驟2:(1R,2R)-1-環丁基-2-甲基戊-4-烯-1-醇及(1R,2S)-1-環丁基-2-甲基戊-4-烯-1-醇及(1S,2R)-1-環丁基-2-甲基戊-4-烯-1-醇及(1S,2S)-1-環丁基-2-甲基戊-4-烯-1-醇
在-78℃下向(R)-2-甲基戊-4-烯醛及(S)-2-甲基戊-4-烯醛(5g,
50.9mmol)(實例183,步驟1)於THF(30mL)中之溶液中添加環丁基溴化鎂(17.8g,112mmol)。使反應物升溫至室溫。在室溫下攪拌3h後,將反應物淬滅(飽和NH4Cl),萃取(2×Et2O)且洗滌(1×鹽水)。將合併之有機層乾燥(Na2SO4)且在減壓下濃縮。將殘餘物注入40g ISCO金色管柱中,且藉由Combi-Flash®用0%至30% EtOAc/己烷溶離來純化,得到標題化合物(4.2g,27.2mmol)。
步驟3:(1S,2R)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(1R,2R)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(1S,2S)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(1R,2S)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺
按照中間物EE22之步驟3至6中所描述之類似程序由(1R,2R)-1-環丁基-2-甲基戊-4-烯-1-醇、(1R,2S)-1-環丁基-2-甲基戊-4-烯-1-醇、(1S,2R)-1-環丁基-2-甲基戊-4-烯-1-醇及(1S,2S)-1-環丁基-2-甲基戊-4-烯-1-醇之混合物(來自步驟2)製備標題化合物。
步驟3:(1S,2R)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺及(1R,2R)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺及(1S,2S)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺及(1R,2S)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺
按照實例26之步驟2中所描述之類似程序由(1S,2R)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺、(1R,2R)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺、(1S,2S)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(1R,2S)-1-環丁基-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺之混合物(來自步驟2)合成標題化合物。
步驟4:(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
按照實例2之步驟1及2中所描述之類似程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12)及(1S,2R)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺、(1R,2R)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺、(1S,2S)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺及
(1R,2S)-1-環丁基-2-甲基戊-4-烯-1-磺醯胺之混合物(來自步驟3)製備標題化合物。將殘餘物注入40g ISCO金色管柱中,且藉由Combi-Flash®用10%至100% EtOAc(含有0.5% AcOH)/己烷溶離來純化,得到呈較快溶離異構體狀之粗產物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至90% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化此粗產物,提供呈白色泡沫狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.26(br.s.,1H),7.71(d,J=8.4Hz,1H),7.16(dd,J=2.3,8.4Hz,1H),7.09(d,J=2.3Hz,1H),6.95-6.89(m,3H),5.91(ddd,J=3.8,8.9,15.0Hz,1H),5.70(dd,J=8.1,15.2Hz,1H),4.25(dd,J=3.8,8.1Hz,1H),4.12-4.05(m,3H),3.84(m,1H),3.68(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.09-3.02(m,1H),3.00-2.89(m,1H),2.82-2.70(m,2H),2.47-2.38(m,1H),2.36-2.12(m,5H),2.06-1.94(m,6H),1.88-1.77(m,4H),1.73-1.62(m,1H),1.49-1.32(m,2H),1.08(d,J=6.8Hz,3H);m/z(ESI,陽離子)639(M+H)+。
實例56. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例55中所描述之Combi-Flash®分離獲得呈第二(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.10(br.s.,1H),7.73-7.67(m,1H),7.17(m,1H),7.11-7.05(m,2H),6.97-6.89(m,2H),6.01(m,1H),5.65(dd,J=6.1,15.5Hz,1H),4.18(m,1H),4.13-4.01(m,2H),3.75(m,2H),3.60(m,1H),3.40(m,1H),3.25(m,1H),2.92(m,1H),2.83-2.72(m,2H),2.53(m,2H),2.35-1.56(m,16H),1.44(m,1H),1.15-1.03(m,3H);m/z(ESI,陽離子)639(M+H)+。
實例57. (1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-環丁基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例55中所描述之Combi-Flash®分離獲得呈第三(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.22(br.s.,1H),7.67(d,J=8.4Hz,1H),7.58(m,1H),7.15(dd,J=2.3,8.4Hz,1H),7.10(d,J=2.2Hz,1H),6.94-6.88(m,2H),5.78-5.61(m,2H),4.26-4.18(m,2H),4.07(d,J=11.0Hz,1H),4.02-3.87(m,2H),3.72(m,1H),3.36(m,1H),3.14(m,1H),3.00-1.60(m,21H),1.55-1.40(m,1H),1.10(d,J=6.7Hz,3H);m/z(ESI,陽離子)639(M+H)+。
實例58. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-
3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(2S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(2R)-N,N-雙(4-甲氧基苄基)-2-甲基-4-戊烯-1-磺醯胺
按照實例26之步驟1中所描述之類似程序由中間物EE12及4-甲基苯磺酸戊-4-烯-2-基酯製備標題化合物。
步驟2:(2S,3R)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺及(2R,3S)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺及(2R,3R)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺及(2S,3S)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺
在-78℃下在N2下向(2S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(2R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺(600mg,1.49mmol)於THF中之溶液中添加丁基鋰溶液(2.5N己烷)(0.624mL,1.561mmol)。在-78℃下攪拌反應物15min後,添加(溴甲基)-環丙烷(0.288mL,2.97mmol)於THF(1mL)中之溶液。反應混合物在-78℃下攪拌1h,且隨後使其升溫至環境溫度。將混合物用H2O淬滅且用EtOAc萃取。有機層用H2O洗滌且乾燥(Na2SO4)。蒸發溶劑,且藉由層析(SiO2凝膠,10至50% EtOAc/己烷)純化所得殘餘物,得到呈無色液體狀之標題化合物。
步驟3:(120637-9):(2S,3S)-1-環丙基-3-甲基己5-烯-2-磺醯胺及(2S,3R)-1-環丙基-3-甲基己-5-烯-2-磺醯胺及(2R,3S)-1-環丙基-3-甲基己-5-烯-2-磺醯胺及(2R,3R)-1-環丙基-3-甲基己-5-烯-2-磺醯胺
及及及
將(2S,3R)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺、(2R,3S)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺、(2R,3R)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺及(2S,3S)-1-環丙基-N,N-雙(4-甲氧基苄基)-3-甲基-5-己烯-2-磺醯胺之混合物(510mg,1.11mmol)用苯甲醚(1.81g,16.7mmol)在TFA(3.81g,33.4mmol)中處理。將混合物在40℃下攪拌、加熱18h,且隨後濃縮。藉由層析(SiO2凝膠,己烷/EtOAc,9:1至1:1)純化所得殘餘物,得到呈淡棕色油狀之標題化合物。
步驟4:(3S)-6'-氯-N-(((2R,3S)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-
5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-N-(((2R,3R)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-N-(((2S,3S)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-N-(((2S,3R)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺
將(2S,3S)-1-環丙基-3-甲基己-5-烯-2-磺醯胺、(2S,3R)-1-環丙基-3-甲基己-5-烯-2-磺醯胺、(2R,3S)-1-環丙基-3-甲基己-5-烯-2-磺醯胺及(2R,3R)-1-環丙基-3-甲基己-5-烯-2-磺醯胺之混合物(160mg,0.74mmol)添加至含(S)-6'-氯-5-(((1R,2S)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A;250mg,0.49mmol)、1-(3-二甲胺基丙基)-3-乙基碳化二亞胺鹽酸鹽(141mg,0,74mmol)、DMAP(90mg,0.74mmol)及Et3N(0.20mL,1.47mmol)之DCM(1mL)中。在環境溫度下攪拌反應混合物3天。隨後用DCM稀釋混合物且添加H2O。將有機層乾燥(MgSO4)且濃縮。將所得殘餘物層析(SiO2凝膠,1:0至1:1,己烷
/EtOAc+0.5% HOAc),得到標題化合物。
步驟5:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
向RBF中饋入以上(3S)-6'-氯-n-(((2R,3S)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺、(3S)-6'-氯-n-(((2R,3R)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺、(3S)-6'-氯-n-(((2S,3S)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-n-(((2S,3R)-1-環丙基-3-甲基-5-己烯-2-基)磺醯基)-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺於DCE(100mL)中之混合物(210mg,0.30mmol)。在用氬氣鼓泡至燒瓶中15min之後,向均質溶液中添加赫維達-格拉布斯II(65mg,0.35mmol),且將燒瓶之內含物
在50℃下攪拌18h。冷卻反應混合物,且藉由鼓泡將空氣引入燒瓶中持續2min。蒸發溶劑,且藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;25%至75% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化粗殘餘物,得到呈第一溶離異構體狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.08(s,1 H),7.70(d,J=8.3Hz,1 H),7.19(dd,J=2.2,8.6Hz,1 H),7.10(d,J=2.0Hz,1 H),6.99(br s,1 H),6.97-6.89(m,2 H),5.97-5.88(m,1 H),5.72(dd,J=8.1,15.2Hz,1 H),4.30-4.22(m,2 H),4.10(s,2 H),3.82(d,J=14.9Hz,1 H),3.69(d,J=14.2Hz,1 H),3.26(d,J=14.2Hz,1 H),3.06(br s,1 H),2.85-2.71(m,2 H),2.53-2.39(m,1 H),2.33(quin,J=8.7Hz,1 H),2.27-2.12(m,2 H),2.09-1.86(m,5 H),1.86-1.77(m,3 H),1.75-1.61(m,1 H),1.50-1.31(m,2 H),1.23-1.12(m,1 H),1.05(d,J=6.8Hz,3 H),0.63(d,J=7.8Hz,2 H),0.35-0.25(m,1 H),0.13-0.06(m,1 H)。m/z(ESI,陽離子)639.2(M+H)+。
實例59. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例58中之製備型逆相HPLC分離獲得呈單一異構體(第二溶離峰)狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.17(br s,1 H),7.79(d,J=8.6Hz,1 H),7.24-7.15(m,2 H),7.10(s,1 H),6.98(d,J=8.3Hz,1 H),6.67(br s,1 H),6.03(m,1 H),5.66(dd,J=6.4,15.2Hz,1 H),4.32-4.02(m,3 H),3.91-3.82(m,1 H),3.80-3.72(m,1 H),3.63(m,1 H),3.42-3.38(m,1 H),3.30-3.20(m,1 H),2.85-2.73(m,2 H),2.55-2.50(m,2 H),2.29(br s,1 H),2.20-2.15(m,1 H),2.10-1.60(m,9 H),1.55-1.43(m,2 H),1.42-1.35(m,1 H),1.13(d,J=7.1Hz,3 H),0.61(d,J=8.6Hz,2 H),0.30-0.25(m,1 H),0.15-0.11(m,1 H)。m/z(ESI,陽離子)639.2(M+H)+。
實例60. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-
3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例58中之製備型逆相HPLC分離獲得呈單一異構體(第三溶離峰)狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.19(br s,1 H),7.72(br s,1 H),7.65(d,J=8.6Hz,1 H),7.17(dd,J=2.2,8.6Hz,1 H),7.11(s,1 H),6.92(s,2 H),5.72(dd,J=3.7,15.7Hz,1 H),5.55(br s,1 H),4.27-4.20(m,2 H),4.20-4.14(m,1 H),4.14-4.10(m,1 H),4.00-3.88(m,1 H),3.79(d,J=12.7Hz,1 H),3.30(d,J=13.9Hz,1 H),3.10(d,J=15.7Hz,1 H),2.80-2.70(m,2 H),2.58-2.39(m,2 H),2.35-2.06(m,3 H),2.05-1.93(m,3 H),1.90-1.62(m,4 H),1.70-1.64(m,1 H),1.51-1.30(m,2 H),1.24-1.15(m,1 H),1.11(d,J=5.1Hz,3 H),0.71-0.50(m,2 H),0.31(qd,J=4.8,9.4Hz,1 H),0.15(qd,J=4.6,9.3Hz,1 H)。m/z(ESI,陽離子)639.2(M+H)+。
實例61. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'Z,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例58中之製備型逆相HPLC分離獲得呈單一異構體(第四溶離峰)狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 7.72(d,J=11Hz,1 H),7.50-7.44(m,1 H),7.21-7.16(m,1 H),7.15-7.05(m,2 H),7.00(d,J=8.3Hz,1 H),5.75(m,1 H),5.54(m,1 H),4.42(br s,1 H),4.16-4.01(m,2 H),3.90(d,J=15.2Hz,1 H),3.80-3.60(m,2 H),3.25-3.04(m,2 H),2.87-2.70(m,2 H),2.27-2.10(m,3 H),2.09-1.52(m,9 H),1.53-1.39(m,3 H),1.21-1.14(m,1 H),1.08(d,J=6.8Hz,3 H),0.71-0.50(m,2 H),0.31-0.20(m,1 H),0.16-0.10(m,1 H)。m/z(ESI,陽離子)639.2(M+H)+。
實例62. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下向15mL RBF中添加含氫化鈉(60%礦物油分散液)(8.3mg,0.203mmol)及(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2h,15'h-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(13mg,0.020mmol)之THF(1mL)。在0℃下攪拌反應混合物30min,且添加MeI(6.32μl,0.102mmol)。攪拌混合物且使其自0℃升溫至環境溫度後持續18h,用1.0N HCl水溶液淬滅,且用EtOAc萃取。將有機層乾燥(MgSO4)且濃縮。將殘餘物層析(SiO2凝膠,10-40%,EtOAc+10%甲醇/己烷),得到呈白色固體狀之標題化合物。1H NMR(400MHz,CDCl3)δ ppm 8.08(s,1 H),7.70(d,J=8.4Hz,
1 H),7.19(dd,J=2.2,8.5Hz,1 H),7.10(d,J=2.2Hz,1 H),6.96-6.90(m,3 H),5.90-5.70(m,1 H),5.53(dd,J=9.8,14.5Hz,1 H),4.32(dd,J=4.7,7.0Hz,1 H),4.10(s,2 H),3.83(d,J=15.1Hz,1 H),3.74-3.66(m,2 H),3.28-3.20(m,4 H),3.02(dd,J=10.2,15.3Hz,1 H),2.84-2.71(m,2 H),2.51-2.43(m,1 H),2.39-2.18(m,3 H),2.14-1.92(m,4 H),1.90-1.75(m,3 H),1.65-1.50(m,2 H),1.47-1.35(m,2 H),1.25-1.18(m,1 H),1.05(d,J=6.8Hz,3 H),0.67-0.58(m,2 H),0.34-0.26(m,1 H),0.12-0.04(m,1 H)。m/z(ESI,陽離子)653.2(M+H)+。
實例63. (1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(2R,3R)-1-環丁基-3-甲基己-5-烯-2-磺醯胺及(2S,3S)-1-環丁基-3-甲基己-5-烯-2-磺醯胺及(2R,3S)-1-環丁基-3-甲基己-5-烯-2-磺醯胺及(2S,3R)-1-環丁基-3-甲基己-5-烯-2-磺醯胺
及及及
藉由類似於實例58之步驟2至3中所描述之程序的程序由(R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(溴甲基)環丁烷製備標題化合物。
步驟2:(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
藉由類似於實例58之步驟4至5中所描述之程序的程序由(S)-6'-氯
-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12)及(2R,3R)-1-環丁基-3-甲基己-5-烯-2-磺醯胺、(2S,3S)-1-環丁基-3-甲基己-5-烯-2-磺醯胺、(2R,3S)-1-環丁基-3-甲基己-5-烯-2-磺醯胺及(2S,3R)-1-環丁基-3-甲基己-5-烯-2-磺醯胺之混合物(來自步驟1)製備標題化合物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至95% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化殘餘物,提供呈白色泡沫狀之較快溶離異構體形式之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.09(s,1H),7.70(d,J=8.4Hz,1H),7.16(dd,J=2.2,8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.95-6.88(m,3H),5.82-5.68(m,2H),4.19(dd,J=4.1,7.6Hz,1H),4.08(s,2H),3.93(dd,J=2.5,8.8Hz,1H),3.82(m,1H),3.68(d,J=14.3Hz,1H),3.25(d,J=14.3Hz,1H),3.05(dd,J=9.4,15.3Hz,1H),2.83-2.68(m,3H),2.41(m,1H),2.31(m,1H),2.23-2.10(m,4H),2.08-2.00(m,2H),1.98-1.52(m,12H),1.48-1.33(m,1H),1.01(d,J=6.8Hz,3H);m/z(ESI,陽離子)653(M+H)+。
實例64. (1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丁基甲基)-7'-羥基-11'-甲基-
3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例63中所描述之製備型逆相HPLC獲得呈第二(較慢)溶離異構體狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.05(s,J=7.4,7.4Hz,1H),7.70(d,J=8.4Hz,1H),7.17(dd,J=2.2,8.5Hz,1H),7.14-7.08(m,2H),6.97-6.90(m,1H),6.65(m,1H),6.00(m,1H),5.65(dd,J=6.1,15.1Hz,1H),4.19-4.02(m,3H),3.76(m,1H),3.61(m,1H),3.52(m,1H),3.43(d,J=14.5Hz,1H),3.24(m,1H),2.83-2.73(m,2H),2.73-2.62(m,1H),2.55-2.46(m,1H),2.35-2.10(m,5H),2.08-1.96(m,3H),1.95-1.81(m,6H),1.79-1.65(m,5H),1.47(d,J=15.3Hz,1H),1.16-1.07(m,3H);m/z(ESI,陽離子)653(M+H)+。
實例65. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(4R,5R)-2,5-二甲基辛-7-烯-4-磺醯胺及(4S,5S)-2,5-二甲基辛-7-烯-4-磺醯胺及(4R,5S)-2,5-二甲基辛-7-烯-4-磺醯胺及(4S,5R)-2,5-二甲基辛-7-烯-4-磺醯胺
及及及
藉由類似於實例58之步驟2至3中所描述之程序的程序由(R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺(實例58,步驟1)及異丁基溴製備標題化合物。
步驟2:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲
基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-2'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
藉由類似於實例58之步驟4至5中所描述之程序的程序由(S)-6'-氯-5-(((1R,2R)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12)及(4R,5R)-2,5-二甲基辛-7-烯-4-磺醯胺、(4S,5S)-2,5-二甲基辛-7-烯-4-磺醯胺、(4R,5S)-2,5-二甲基辛-7-烯-4-磺醯胺及(4S,5R)-2,5-二甲基辛-7-烯-4-磺醯胺之混合物(來自步驟1)製備標題化合物。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;50%至95% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)純化殘餘物,提供呈白色泡沫狀之較快溶離異構體形式之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.09(s,1H),7.71(d,J=8.5Hz,1H),7.17(dd,J=2.3,8.6Hz,1H),7.09(d,J=2.3Hz,1H),6.96-6.90(m,3H),5.86-5.78(m,1H),5.76-5.68(m,1H),4.22-4.12(m,2H),4.09(s,2H),3.84(m,1H),3.69(d,J=14.3Hz,1H),3.26(d,J=14.3Hz,1H),3.05(dd,J=9.4,15.3Hz,1H),2.83-2.70(m,2H),2.46-2.28(m,2H),2.18-1.91(m,8H),1.88-1.76(m,3H),1.76-1.66(m,1H),1.46-1.31
(m,2H),1.04-0.98(m,9H);m/z(ESI,陽離子)641(M+H)+。
實例66. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例65中所描述之製備型逆相HPLC獲得呈單一異構體(第二較慢溶離峰)狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.11-8.04(m,1H),7.71(d,J=8.4Hz,1H),7.18(dd,J=2.2,8.4Hz,1H),7.15-7.09(m,2H),6.97-6.90(m,1H),6.65(m,1H),6.04
(m,1H),5.65(dd,J=6.4,15.4Hz,1H),4.17(m,1H),4.07(q,J=12.2Hz,2H),3.81-3.69(m,2H),3.63(m,1H),3.43(d,J=14.3Hz,1H),3.24(m,1H),2.82-2.71(m,2H),2.56-2.48(m,1H),2.29-2.18(m,1H),2.07-1.82(m,9H),1.81-1.65(m,2H),1.51-1.38(m,3H),1.09(d,J=7.0Hz,3H),1.05-0.93(m,6H);m/z(ESI,陽離子)641(M+H)+。
實例67. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-(2-甲基丙基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用如實例65中所描述之製備型逆相HPLC獲得呈單一異構體(第三溶離峰)狀之標題化合物中之一者。1H NMR(400MHz,CD2Cl2)δ ppm 8.17(br.s.,1H),7.74(d,J=8.6Hz,1H),7.66(d,J=8.8Hz,1H),7.16(s,1H),7.10(d,J=3.1Hz,1H),6.98(d,J=8.2Hz,1H),6.91(s,1H),5.73-5.66(m,2H),4.43(br.s.,1H),4.23(s,2H),4.15-4.04(m,4H),3.90(d,J=15.1Hz,1H),3.70(d,J=14.3Hz,1H),3.33(d,J=12.9Hz,1H),3.22(d,J=14.5Hz,1H),3.11(d,J=15.1Hz,2H),2.75(d,J=5.7Hz,3H),2.51(d,J=6.5Hz,1H),2.07-1.88(m,10H),1.06-1.00(m,9H)m/z(ESI,陽離子)641(M+H)+。
實例68. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(4R,5S)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺,及(4S,5S)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺,及(4S,5R)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺,及(4R,5R)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺,及
按照實例58之步驟2中所描述之類似程序由(2S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(2R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺(來自實例58,步驟1)與1-溴丙烷製備標題化合物。
步驟2:(4R,5S)-5-甲基-7-辛烯-4-磺醯胺,及(4R,5R)-5-甲基-7-辛烯-4-磺醯胺,及(4S,5S)-5-甲基-7-辛烯-4-磺醯胺,及(4S,5R)-5-甲基-7-辛烯-4-磺醯胺
及及及
藉由實例58之步驟3中所描述之類似程序由(4R,5S)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺、(4S,5S)-N,N-雙(4-甲氧基苄基)-
5-甲基-7-辛烯-4-磺醯胺、(4S,5R)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺及(4R,5R)-N,N-雙(4-甲氧基苄基)-5-甲基-7-辛烯-4-磺醯胺之混合物製備標題化合物。
步驟3:(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6S)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6R)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6S)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6R)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸
藉由將氬氣鼓泡至反應燒瓶中將(S)-6'-氯-5-(((1R,2S)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A,120mg,0.24mmol)、(4R,5S)-5-甲基-7-辛烯-4-磺醯胺、(4R,5R)-5-甲基-7-辛烯-4-磺醯胺、(4S,5S)-5-甲基-7-辛烯-4-磺醯胺及(4S,5R)-5-甲基-7-辛烯-4-磺醯胺之
混合物(來自步驟2,121mg;0.59mmol)於1,2二氯乙烷(2mL)中之混合物引入氬氣持續20min。隨後添加赫維達-格拉布斯II。將混合物在環境溫度下攪拌2h,濃縮,且將殘餘物層析(SiO2凝膠,9:1至0:1,己烷/0.3% AcOH+EtOAc),得到呈灰色油狀之標題化合物。
步驟4:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下將(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6S)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸、(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5R,6R)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸、(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6S)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E,5S,6R)-1-羥基-5-甲基-6-胺磺醯基-2-壬烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲酸之混合物(110mg,0.170mmol)添加至含1-(3-二甲胺基丙基)-3-乙基碳化
二亞胺、HCl(98mg,0.51mmol)及DMAP(41.7mg,0.341mmol)之DCM(80mL)中。隨後使反應混合物升溫至環境溫度且攪拌18h。蒸發溶劑,且將粗殘餘物層析(SiO2凝膠,9:1至0:1,己烷/EtOAc+0.3% AcOH),得到灰色油狀物(65mg)。藉由製備型逆相HPLC(GeminiTM Prep C18 5μm管柱;25%至75% MeCN/H2O梯度溶離,其中兩種溶劑均含有0.1% TFA,30min方法)進一步純化油狀物,得到呈白色固體狀之第一溶離異構體作為標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.07(s,1 H),7.70(d,J=8.3Hz,1 H),7.19(dd,J=2.0,8.6Hz,1 H),7.10(s,1 H),6.98-6.88(m,3 H),5.93-5.85(m,1 H),5.72(dd,J=7.9,15.3Hz,1 H),4.26(dd,J=4.0,8.2Hz,1 H),4.16-4.06(m,3 H),3.83(d,J=14.9Hz,1 H),3.70(d,J=14.4Hz,1 H),3.24(d,J=14.2Hz,1 H),3.03(dd,J=9.8,15.2Hz,1 H),2.83-2.72(m,2 H),2.45(dd,J=3.7,8.6Hz,1 H),2.32(t,J=9.0Hz,1 H),2.16-1.94(m,7 H),1.91-1.74(m,5 H),1.74-1.62(m,2 H),1.40(t,J=12.8Hz,1 H),1.10-0.98(m,6 H)。m/z(ESI,陽離子)627.2(M+H)+。
實例69. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,
或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例68中之製備型逆相HPLC分離獲得呈第二溶離異構體狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 7.71(d,J=8.3Hz,1 H),7.11-7.08(m,1 H),7.00-6.87(m,2 H),6.84(br s,1 H),6.14(br s,1 H),5.81(br s,1 H),4.23(br s,1 H),4.19-4.04(m,3 H),3.69(d,J=14.4Hz,2 H),3.58(br s,1 H),3.40-3.18(br,2 H),3.15-3.00(br s,1 H),2.85-2.70(m,2 H),2.44(br s,1 H),2.35(br s,2 H),2.18(br s,1 H),2.10-1.90(m,3 H),1.80-1.63(m,6 H),1.63-1.54(m,1 H),1.48(br s,1 H),1.11(br s,3 H),1.05-0.99(m,3 H)。m/z(ESI,陽離子)627.2(M+H)+。
實例70. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或
(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-7'-羥基-11'-甲基-12'-丙基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例68中之製備型逆相HPLC分離獲得呈第三溶離異構體狀之標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.32(br s,1 H),7.70(d,J=8.6Hz,1 H),7.23-7.16(m,2 H),7.10(s,1 H),6.97(d,J=8.3Hz,1 H),6.66(br s,1 H),6.08(br s,1 H),5.66(dd,J=6.2,15.3Hz,1 H),4.21(br s,1 H),4.15-4.00(m,2 H),3.83-3.60(m,3 H),3.42(d,J=14.7Hz,1 H),3.25(br s,1 H),2.85-2.74(m,2 H),2.60-2.47(m,2 H),2.38-2.18(m,2 H),2.15-2.00(m,3 H),2.00-1.58(m,9 H),1.46(br s,1 H),1.17-1.08(m,3 H),1.07-0.96(m,3 H)。m/z(ESI,陽離子)627.2(M+H)+。
實例71. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或
(1S,3'R,6'R,7'S,8'E,11'R,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
步驟1:(4S,5R)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺,及(4R,5R)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺,及(4S,5S)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺,及(4R,5S)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺
按照實例58之步驟2中所描述之類似程序由(2S)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺及(2R)-N,N-雙(4-甲氧基苄基)-2-甲基戊-4-烯-1-磺醯胺(來自實例58,步驟1)與1-溴丁烷製備標題化合物。
步驟2:(4S,5R)-4-甲基-1-壬烯-5-磺醯胺,及(4S,5R)-4-甲基-1-壬烯-5-磺醯胺,及(4S,5R)-4-甲基-1-壬烯-5-磺醯胺,及(4S,5R)-4-甲基-1-壬烯-5-磺醯胺
藉由實例58之步驟3中所描述之類似程序由(4S,5R)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺、(4R,5R)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺、(4S,5S)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺、(4R,5S)-N,N-雙(4-甲氧基苄基)-4-甲基-1-壬烯-5-磺醯胺之混合物製備標題化合物。
步驟3:(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺,及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺
使用實例58之步驟4中所描述之類似程序由(4S,5R)-4-甲基-1-壬烯-5-磺醯胺、(4R,5R)-4-甲基-1-壬烯-5-磺醯胺、(4S,5S)-4-甲基-1-壬烯-5-磺醯胺及(4R,5R)-4-甲基-1-壬烯-5-磺醯胺之混合物(步驟2)及(S)-
6'-氯-5-(((1R,2S)-2-((S,E)-1-羥基己-2-烯-1-基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(中間物AA12A)製備標題化合物。
步驟4:(1S,3'R,6'R,7'S,8'E,11'S,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用實例58之步驟5中所描述之類似程序由以上(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺及(3S)-6'-氯-5-(((1R,2R)-2-((1s,2e)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-
3,1'-萘]-7-甲醯胺及(3S)-6'-氯-5-(((1R,2R)-2-((1S,2E)-1-羥基-2-己烯-1-基)環丁基)甲基)-N-(((2R,3S)-3-(2-丙烯-1-基)-2-庚基)磺醯基)-3',4,4',5-四氫-2'H-螺[1,5-苯并噁氮呯-3,1'-萘]-7-甲醯胺之混合物製備標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.07(br s,1 H),7.70(d,J=8.6Hz,1 H),7.19(d,J=8.3Hz,1 H),7.11-7.09(m,1 H),6.99-6.87(m,3 H),5.93-5.86(m,1 H),5.72(dd,J=8.2,15.3Hz,1 H),4.26(dd,J=3.9,8.3Hz,1 H),4.13-4.07(m,3 H),3.83(d,J=15.4Hz,1 H),3.70(d,J=14.4Hz,1 H),3.24(d,J=14.2Hz,1 H),3.03(dd,J=9.5,15.2Hz,1 H),2.83-2.72(m,2 H),2.51-2.39(m,1 H),2.32(t,J=9.4Hz,1 H),2.20-1.64(m,6 H),1.63-1.63(m,7 H),1.63-1.53(m,1 H),1.50-1.33(m,3 H),1.06(d,J=6.8Hz,3 H),0.97(t,J=7.3Hz,3 H)。m/z(ESI,陽離子)641.2(M+H)+。
實例72. (1S,3'R,6'R,7'S,8'Z,11'R,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'R,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'S,12'R)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'Z,11'S,12'S)-12'-丁基-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環
[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
根據實例71中之製備型逆相HPLC分離獲得呈單一異構體(第二溶離峰)狀之標題化合物。1H NMR(500MHz,CDCl3)δ=9.92(br s,1 H),7.71(d,J=8.6Hz,1 H),7.47(d,J=8.1Hz,1 H),7.20-7.12(m,1 H),7.12-7.06(m,2 H),6.98(d,J=8.3Hz,1 H),5.75(br s,1 H),5.53(td,J=2.4,2.4,11.8Hz,1 H),4.41(br s,1 H),4.13-4.01(m,2 H),3.88(d,J=15.4Hz,1 H),3.64(d,J=14.4Hz,1 H),3.57(br s,1 H),3.19-2.99(m,2 H),2.83-2.71(m,2 H),2.29-2.15(m,2 H),2.13-2.02(m,2 H),2.02-1.87(m,4 H),1.77-1.63(m,7 H),1.62-1.50(m,1 H),1.49-1.31(m,3 H),1.12-1.03(m,3 H),1.02-0.88(m,3 H)。m/z(ESI,陽離子)641.2(M+H)+。
實例73. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-7'-丁氧基-6-氯-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
在0℃下向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例2;60mg,0.1mmol)於THF(2mL)中之溶液中添加60%氫化鈉/礦物油(20mg,0.5mmol)。在0℃下攪拌混合物30min。添加1-碘丁烷(92mg,54uL,0.5mmol),且由此獲得之混合物在0℃下攪拌4h,且HPLC-MS分析指示反應完成。反應物用飽和NH4Cl淬滅且用EtOAc萃取。合併之有機層用鹽水洗滌且經MgSO4乾燥。在減壓下蒸發溶劑,且藉由急驟層析在SiO2凝膠(24g,HP SiO2,Teledyne ISCO)上用15%至65% EtOAc/己烷溶離來純化殘餘物,提供呈白色固體狀之(1S,3'R,6'R,7'S,8'E,11'S,12'R)-7'-丁氧基-6-氯-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(15mg,23%產率)。1H NMR(500MHz,CDCl3)δ ppm 8.13(s,1 H),7.70(d,J=8.4,2.3Hz,1 H),7.09(d,J=2.2Hz,1 H),6.92-6.95(m,2 H),6.89(s,1 H),5.80(ddd,J=15.1,9.6,3.2Hz,1 H),5.54(dd,J=15.1,9.6Hz,1 H),4.31-4.36(m,1 H),4.07-4.11(m,2 H),3.84(d,J=15.4Hz,1 H),3.68-3.74(m,2 H),3.39(dt,J=9.3,6.7Hz,1 H),3.22-3.27(m,2 H),3.00(dd,J=15.2,10.3Hz,1 H),2.75-2.83(m,2 H),2.41-2.47(m,1 H),2.30-2.36(m,1 H),2.14-2.21(m,1 H),1.94-2.12(m,2 H),1.73-1.88(m,4 H),1.58-1.62(m,1 H),1.48-1.55(m,4 H),1.20-1.42(m,4 H),1.05(d,J=10.0Hz,3 H),0.92(t,J=10.0Hz,3H);MS m/z
(ESI,陽離子)656.0(M+H)+。
實例74. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-甲氧基乙氧基)-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-二氧化物
向(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2,100mg,0.167mmol)於DMF(3.34mL)中之溶液(冷卻至0℃)中添加氫化鈉(60%礦物油分散液)(66.8mg,1.67mmol)。在0℃下攪拌反應混合物15min,且隨後添加2-溴乙基甲醚(Alfa Aesar,0.078mL,0.834mmol)。在環境溫度下攪拌反應混合物。48h後,混合物用NH4Cl水溶液淬滅且用水稀釋,隨後用EtOAc萃取。有機層經MgSO4乾燥且濃縮。藉由層析經由Redi-Sep預裝填矽膠管柱(12g)用10-40% EtOAc(含有0.3% AcOH)/庚烷溶離來純化粗物質,提供標題化合物(61mg,0.093mmol,55.6%產率)。1H NMR(500MHz,CD2Cl2)δ 8.02(s,1H),7.70(d,J=8.6Hz,1H),7.17(dd,J=2.2,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.91(s,2H),6.86(s,1H),5.79(ddd,J=3.3,9.6,15.2Hz,1H),5.54(dd,J=9.8,14.4Hz,1H),4.26(ddd,J=1.0,7.3,14.4Hz,1H),4.12-4.04(m,2H),3.82(d,J=15.2Hz,1H),3.75(dd,J=3.3,9.2Hz,1H),3.69(d,J=14.7Hz,1H),3.53-3.49(m,1H),3.48-3.41(m,2H),3.39-3.34(m,1H),3.32(s,3H),3.25(d,J=14.2Hz,1H),3.02(dd,
J=10.3,15.4Hz,1H),2.83-2.70(m,2H),2.49-2.41(m,1H),2.36-2.28(m,1H),2.21-2.13(m,1H),2.13-2.07(m,1H),2.05(d,J=13.7Hz,1H),1.99-1.91(m,3H),1.89-1.77(m,3H),1.71-1.59(m,1H),1.44(d,J=7.3Hz,3H),1.39(t,J=13.1Hz,1H),1.02(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 657.1(M+H)+。
實例75. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-(2-甲氧基乙氧基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例74中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-12'-乙基-7'-羥基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例17)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(400MHz,CD3OD)δ 7.75(d,J=8.6Hz,1H),7.19(dd,J=2.2,8.8Hz,1H),7.12(d,J=2.2Hz,1H),7.01(dd,J=1.6,8.2Hz,1H),6.94(d,J=8.2Hz,1H),6.88(d,J=1.6Hz,1H),5.89(ddd,J=6.1,13.1,21.5Hz,1H),5.60(dd,J=9.0,15.1Hz,1H),4.09(dd,J=12.7,15.3Hz,2H),4.05-3.99(m,1H),3.91-3.82(m,2H),3.69(d,J=14.5Hz,1H),3.62-3.57(m,1H),3.53(dd,J=4.1,8.0Hz,2H),3.50-3.45(m,1H),3.38(s,3H),3.08(dd,J=10.3,15.2Hz,1H),2.87-2.73(m,2H),2.55-2.40(m,2H),2.40-2.26(m,2H),2.11(dd,
J=7.4,15.1Hz,2H),1.98-1.65(m,10H),1.46(t,J=10.9Hz,1H),1.20(t,J=7.4Hz,3H)。m/z(ESI,陽離子)657.2(M+H)+。
實例76. (1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-(2-甲氧基乙氧基)-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例74中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,12'R)-6-氯-7'-羥基-12'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'二氧化物(實例11)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(400MHz,CD3OD)δ 7.72(d,J=8.6Hz,1 H),7.16(dd,J=8.5,2.2Hz,1 H),7.10(d,J=2.2Hz,1 H),6.98(d,J=8.3Hz,1 H),6.91(d,J=8.2Hz,1 H),6.85(d,J=1.8Hz,1 H),5.80-5.87(m,1 H),5.58(dd,J=15.5,8.8Hz,1 H),4.03-4.18(m,3 H),3.80-3.86(m,2 H),3.41-3.68(m,5 H),3.35(s,3 H),3.06(dd,J=15.3,10.4Hz,1 H),2.70-2.81(m,2 H),2.24-2.53(m,4 H),2.09(d,J=13.7Hz,1 H),1.68-1.96(m,7 H),1.50(d,J=7.0Hz,3 H),1.39-1.47(m,2 H)。m/z(ESI,陽離子)643.2(M+H)+。
實例77. (1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,
或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例74中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例30)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.32(s,1 H),7.68(d,J=8.6Hz,1 H),7.17(dd,J=2.2,8.6Hz,1 H),7.09(d,J=2.0Hz,1 H),7.05-6.97(m,1 H),6.92(d,J=8.1Hz,1 H),5.94-5.85(m,1 H),5.51(dd,J=7.0,15.3Hz,1 H),4.17-4.04(m,2 H),3.75-3.68(m,2 H),3.66-3.46(m,7 H),3.44-3.34(m,4 H),2.80-2.72(m 2 H),2.45-2.40(m,2 H),2.22-2.10(m,3 H),2.00-1.75(m,6 H),1.75-1.55(m,2 H),1.53-1.48(m,1 H),1.18(d,J=6.4Hz,3 H)。m/z(ESI,陽離子)643.2(M+H)+。
實例78. (1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或
(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例74中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,11'S)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R)-6-氯-7'-甲氧基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例31)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(500MHz,CDCl3)δ ppm 8.22(s,1 H),7.70(d,J=8.6Hz,1 H),7.18(dd,J=2.1,8.4Hz,1 H),7.09(d,J=2.0Hz,1 H),6.95-6.88(m,2 H),6.83(s,1 H),5.88-5.80(m,1 H),5.56(dd,J=9.0,15.2Hz,1 H),4.36(dd,J=4.8,15.3Hz,1 H),4.14-4.04(m,2 H),3.85-3.78(m,2 H),3.71(d,J=14.2Hz,1 H),3.60-3.48(m,3 H),3.45-3.34(m,4 H),3.23(d,J=14.4Hz,1 H),3.09-2.91(m,2 H),2.84-2.71(m,2 H),2.53-2.44(m,1 H),2.36-2.23(m,2 H),2.13-1.92(m,5 H),1.89-1.74(m,3 H),1.69-1.54(m,1 H),1.39(t,J=12.6Hz,1 H),1.16(d,J=6.6Hz,3 H)。m/z(ESI,陽離子)643.2(M+H)+。
實例79. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-(2-甲氧基乙氧基)乙氧基)-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮
13',13'-二氧化物
將無水(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(15mg,0.025mmol)(實例2)及氫化鈉(60%礦物油分散液)(9.9mg,0.43mmol)於DMF中之混合物在氬氣下攪拌10min。在環境溫度下添加1-(2-溴乙氧基)-2-甲氧基乙烷(22.6mg,0.124mmol)。反應混合物攪拌18h,用NH4Cl飽和水溶液淬滅,且用EtOAc(×3)萃取。將合併之有機層乾燥(MgSO4)且濃縮。將殘餘物層析(矽膠,0-50%,EtOAc+0.3% HOAc/己烷),得到呈白色固體狀之標題化合物。1H NMR(400MHz,CDCl3)δ ppm 8.09(s,1 H),7.70(d,J=8.6Hz,1 H),7.18(dd,J=2.2,8.5Hz,1 H),7.09(d,J=2.2Hz,1 H),6.95-6.87(m,3 H),5.82(ddd,J=3.2,9.4,15.1Hz,1 H),5.54(dd,J=9.1,15.2Hz,1 H),4.35-4.24(m,1 H),4.16-4.05(m,2 H),3.87-3.74(m,2 H),3.70-3.54(m,8 H),3.45-3.44(m,1 H),3.40(s,3 H),3.23(d,J=14.3Hz,1 H),2.99(dd,J=10.2,15.3Hz,1 H),2.84-2.71(m,2 H),2.53-2.42(m,1 H),2.38-2.24(m,1 H),2.15-1.93(m,4 H),1.90-1.72(m,3 H),1.72-1.57(m,3 H),1.49(d,J=7.2Hz,3 H),1.42-1.35(m,1 H),1.05(d,J=6.8Hz,3 H)。m/z(ESI,陽離子)701.2(M+H)+。
實例80. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用實例79中所描述之類似程序用1-溴-2-[2-(2-甲氧基乙氧基)乙氧基]乙烷置換1-(2-溴乙氧基)-2-甲氧基乙烷由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2)製備標題化合物。1H NMR(400MHz,CDCl3)δ ppm 7.97(s,1 H),7.70(d,J=8.4Hz,1 H),7.19(dd,J=2.2,8.4Hz,1 H),7.10(d,J=2.0Hz,1 H),6.95-6.87(m,3 H),5.86-5.75(m,1 H),5.54(dd,J=9.0,15.1Hz,1 H),4.35-4.22(m,1 H),4.13-4.05(m,2 H),3.86-3.76(m,2 H),3.72-3.63(m,7 H),3.63-3.54(m,5 H),3.44-3.42(m,1 H),3.40(s,3 H),3.23(d,J=14.3Hz,1 H),2.99(dd,J=10.1,15.4Hz,1 H),2.84-2.71(m,2 H),2.48(d,J=10.6Hz,1 H),2.38-2.26(m,1 H),2.21-1.90(m,4 H),1.89-1.72(m,3 H),1.70-1.58(m,3 H),1.50(d,J=7.2Hz,3 H),1.45-1.32(m,1 H),1.06(d,J=6.8Hz,3 H)。m/z(ESI,陽離
子)745.2(M+H)+。
實例81. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-11',12'-二甲基-7'-(3,6,9,12-四氧雜十三-1-基氧基)-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
使用實例79中所描述之類似程序用三乙二醇2-溴乙基甲醚置換1-(2-溴乙氧基)-2-甲氧基乙烷由(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-7'-羥基-11',12'-二甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例2)製備標題化合物。1H NMR(400MHz,CDCl3)δ ppm 8.02(s,1 H),7.70(d,J=8.6Hz,1 H),7.19(dd,J=2.2,8.4Hz,1 H),7.09(d,J=2.2Hz,1 H),6.94-6.88(m,3 H),5.85-5.77(m,1 H),5.54(dd,J=8.5,15.4Hz,1 H),4.31(q,J=7.4Hz,1 H),4.09(s,2 H),3.85-3.75(m,2 H),3.74-3.62(m,11 H),3.62-3.50(m,5 H),3.45-3.42(m,1 H),3.39(s,3 H),3.23(d,J=14.3Hz,1 H),3.03-2.95(m,1 H),2.83-2.72(m,2 H),2.52-2.43(m,1 H),2.32(t,J=9.5Hz,1 H),
2.21-1.92(m,4 H),1.90-1.74(m,3 H),1.68-1.56(m,3 H),1.50(d,J=7.2Hz,3 H),1.40(t,J=13.2Hz,1 H),1.06(d,J=6.8Hz,3 H)。m/z(ESI,陽離子)789.2(M+H)+。
實例82. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物,或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物
以類似於實例74中所描述之方式的方式使用
(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'S,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'R)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物或(1S,3'R,6'R,7'S,8'E,11'R,12'S)-6-氯-12'-(環丙基甲基)-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例59)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(400MHz,CDCl3)δ ppm 8.05(s,1 H),7.70(d,J=8.6Hz,1 H),7.18(dd,J=2.2,8.5Hz,1 H),7.09(d,J=2.2Hz,1 H),6.96-6.90(m,3 H),5.91-5.83(m,1 H),5.56(dd,J=9.0,15.1Hz,1 H),4.30(dd,J=4.5,7.2Hz,1 H),4.09(s,2 H),3.87-3.79(m,2 H),3.74-3.67(m,1 H),3.59-3.50(m,3 H),3.48-3.41(m,1 H),3.41-3.35(s,3 H),3.23(d,J=14.5Hz,1 H),3.00(dd,J=10.2,15.3Hz,1 H),2.84-2.71(m,2 H),2.50(d,J=10.6Hz,1 H),2.37-2.16(m,3 H),2.13-1.92(m,4 H),1.91-1.73(m,3 H),1.71-1.52(m,2 H),1.51-1.34(m,2 H),1.23-1.14(m,1 H),1.05(d,J=6.8Hz,3 H),0.67-0.58(m,2 H),0.29(dd,J=4.4,9.1Hz,1 H),0.08(dd,J=4.1,9.0Hz,1 H)。m/z(ESI,陽離子)697.3(M+H)+。
實例83. (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-(2-甲氧基乙氧基)-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮-13',13'-
二氧化物
以類似於實例74中所描述之方式的方式使用(1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-氯-12'-乙基-7'-羥基-11'-甲基-3,4-二氫-2H,15'H-螺[萘-1,22'-[20]氧雜[13]硫雜[1,14]二氮雜四環[14.7.2.03,6.019,24]二十五烷[8,16,18,24]四烯]-15'-酮13',13'-二氧化物(實例24)及1-溴-2-甲氧基乙烷(Aldrich)製備標題化合物。1H NMR(500MHz,CD2Cl2)δ 8.08(s,1H),7.71(d,J=8.6Hz,1H),7.17(dd,J=2.4,8.6Hz,1H),7.09(d,J=2.2Hz,1H),6.91(d,J=0.7Hz,2H),6.87(s,1H),5.82(ddd,J=3.4,9.4,15.3Hz,1H),5.54(dd,J=9.4,15.8Hz,1H),4.11-4.05(m,2H),4.00(dd,J=2.8,9.4Hz,1H),3.82(d,J=14.9Hz,1H),3.78(dd,J=3.2,9.0Hz,1H),3.69(d,J=14.4Hz,1H),3.53(ddd,J=3.4,5.4,9.3Hz,1H),3.45(dt,J=3.7,5.0Hz,2H),3.38(ddd,J=3.4,5.9,9.5Hz,1H),3.32(s,3H),3.25(d,J=14.4Hz,1H),3.02(dd,J=10.3,15.4Hz,1H),2.84-2.70(m,2H),2.45(ddd,J=3.7,10.0,19.1Hz,1H),2.37-2.29(m,1H),2.29-2.19(m,1H),2.13-2.08(m,1H),2.08-2.01(m,2H),2.00-1.89(m,3H),1.89-1.77(m,4H),1.66(quin,J=8.6Hz,1H),1.44-1.35(m,1H),1.28(t,J=7.3Hz,3H),1.02(d,J=6.8Hz,3H)。MS(ESI,陽離子)m/z 671.1(M+H)+;693.1(M+Na)+。
前述描述僅說明本發明且不意欲將本發明限於所揭示之化合物、組合物及方法。熟習此項技術者顯而易見之變化及改變意欲在本發明之範疇及性質內,如所附申請專利範圍中所定義。根據前述描述,熟
習此項技術者可易於確定本發明之基本特徵,且在不脫離本發明之精神及範疇的情況下可對本發明作出各種改變及修改以使其適應各種用途及條件。本文所述之所有專利及其他公開案均以全文引用的方式併入本文中。
Claims (13)
- 一種式I化合物
- 如請求項1之化合物,其中b 意指雙鍵。
- 如請求項1之化合物,其中R為Cl。
- 如請求項1中任一項之化合物,其中R1為C1-6烷基。
- 如請求項4之化合物,其中R1為CH3。
- 如請求項1之化合物,其中R2為H且R2A為C1-6烷基。
- 如請求項1之化合物,其中R3為H且R3A為C1-6烷基。
- 如請求項1之化合物,其中該式I化合物具有式II:
- 一種化合物,其中該化合物具有選自以下之結構:
- 一種醫藥組合物,其包含如請求項1中任一項之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之賦形劑。
- 一種化合物,其中該化合物具有選自以下之結構:
- 一種醫藥組合物,其包含如請求項11之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之賦形劑。
- 一種治療癌症之方法,其包含向有需要之患者投與治療有效量之如請求項1或11中任一項之化合物或其醫藥學上可接受之鹽,其中該癌症為血液科惡性疾病、乳癌、結腸直腸癌、皮膚癌、黑色素瘤、卵巢癌、腎癌、肺癌、非小細胞肺癌、淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、骨髓瘤、多發性骨髓瘤、白血病及急性骨髓性白血病。
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