TW202029962A - 胺肽酶a抑制劑及包含其的醫藥組合物 - Google Patents
胺肽酶a抑制劑及包含其的醫藥組合物 Download PDFInfo
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- TW202029962A TW202029962A TW108138218A TW108138218A TW202029962A TW 202029962 A TW202029962 A TW 202029962A TW 108138218 A TW108138218 A TW 108138218A TW 108138218 A TW108138218 A TW 108138218A TW 202029962 A TW202029962 A TW 202029962A
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- Prior art keywords
- amino
- hydroxy
- phosphoryl
- methyl
- ethyl
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 12
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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Abstract
本發明提供一種新穎化合物、包含該化合物之組合物、製備該化合物之方法以及該化合物用於治療之用途。特別的,本發明內容具體關於可用於治療及預防原發性及繼發性動脈高血壓(primary and secondary arterial hypertension)、發作(ictus)、心肌缺血(myocardial ischemia)、心臟及腎臟功能不全(cardiac and renal insufficiency)、心肌梗塞(myocardial infarction)、周邊血管疾病(peripheral vascular disease)、糖尿病性蛋白尿(diabetic proteinuria)、X症候群(Syndrome X)及青光眼(glaucoma)的化合物。
Description
本發明提供一種新穎化合物、包含該化合物之組合物、其製備方法以及其在臨床上之應用。具體來說,本發明關於一種可用於治療與預防原發性及繼發性動脈高血壓(primary and secondary arterial hypertension)、發作(ictus)、心肌缺血(myocardial ischemia)、心臟與腎臟功能不全(cardiac and renal insufficiency)、心肌梗塞(myocardial infarction)、周邊血管疾病(peripheral vascular disease)、糖尿病性蛋白尿(diabetic proteinuria)、X症候群(Syndrome X)以及青光眼(glaucoma)的化合物。
原發性高血壓(Essential Hypertension,HTN)與心臟衰竭(Heart Failure,HF)為心血管疾病之兩大主要病理徵狀。原發性高血壓在全世界影響了將近十億名病患,並為冠狀動脈心臟疾病、心臟衰竭、中風與腎功能不全的主要危險因子。即使現已有有效並安全的藥物可供使用,原發性高血壓及其伴隨的危險因子在許多病患的案例中仍無法有效控制原發性。在西方國家,心臟衰竭至今仍是導致超過65歲病患住院治療的主要成因。心臟衰竭在工業化國家影響了每千人當中的一到五人;如果考量了所有年齡層,其患病率為千分之三到二十。在美國,2012年照料心臟衰竭病患花費為兩百一十億元,其中大部分是用於住院照護。即使目前已有大量的心臟衰竭用藥,病患仍有不良的預後,不論患病階段,一年的生存率僅約65%。心臟衰竭仍是心血管死亡的首要原因,因此,該領域仍需求更有效、安全的治療用藥。
全身性的腎素-血管收縮素系統(renin-angiotensin system,RAS)已知在血壓(blood pressure,BP)調節與鈉離子代謝中扮演重要角色。針對腎素-血管收縮素系統之全身性藥物,例如血管收縮素Ⅰ轉化酶抑制劑(angiotensin I converting enzyme (ACE) inhibitors)和血管收縮素II受體第一型拮抗劑 (angiotensin-II receptor type 1 (AT1
) antagonists)在臨床上可有效降低病患的血壓並避免心血管及腎臟病的發病和死亡。此外,腎素-血管收縮素醛固酮系統 (renin-angiotensin aldosterone system,RAAS)的活性在心臟衰竭病患會增加,此不良適應機制可能導致心臟重塑和交感神經活化等副作用。目前實證醫學支持的準則1A建議,針對低收縮分率(ejection fraction)之心臟衰竭用藥主要是腎素-血管收縮素醛固酮(RAAS)活性分子如血管收縮素Ⅰ轉化酶(ACE)抑制劑或血管收縮素II受體第一型(AT1
)阻斷劑和β-腎上腺素受體阻斷劑。
功能性腎素-血管收縮素系統所控制的心血管功能和體液恆定同樣也出現在大腦中。幾個研究顯示,當大腦中腎素-血管收縮素系統的活性增加時,會增加交感神經的活性以及血管升壓素的釋放,同時還顯示大腦腎素-血管收縮素系統的高活性(hyperactivity)在不同的原發性高血壓動物模型中皆扮演了調節高血壓的關鍵角色,且也在心臟衰竭的動物模型中影響了心臟重塑和不良功能(Marc Y, Llorens-Cortes, C Progress in Neurobiology 2011, 95, pp 89-103 ; Westcott KVet al
, Can. J. Physiol. Pharmacol. 2009, 87, pp 979-988)。由於近期的證據支持了血管收縮素III(angiotensin III (Ang III))透過血管收縮素II第一型(AT1
)受體才是大腦腎素-血管收縮素系統控制血壓真正的胜肽作用器,因此可自血管收縮素II(Ang II)產生血管收縮素III(Ang III)的大腦胺肽酶A(aminopeptidase A,APA)便成為了在治療原發性高血壓和心臟衰竭上備受矚目的治療標靶。
胺肽酶A (APA,EC 3.4.11.7)是一個在細胞膜上的鋅金屬蛋白酶,其特徵在於,該酵素負責在大腦中將血管收縮素II (Ang II)轉換為血管收縮素III (Ang III) (Zini Set al
, Proc. Natl. Acad. Sci. USA 1996, 93, pp 11968-11973)。目前已經開發數個胺肽酶A的抑制劑(Chauvel EN et al, J. Med. Chem. 1994, 37, pp 1339-1346; Chauvel ENet al
, J. Med. Chem. 1994, 37, pp 2950-2957; David C et al, J. Med. Chem. 1999, 42, pp 5197-5211; Georgiadis Det al
, Biochemistry 2000, 39, pp1152-1155; Inguimbert Net al
, J. Peptide Res. 2005, 65, pp 175–188)。其中EC33 ((S)-3胺基-4-巰基-磺酸丁酯(3S)-3-amino-4-thiol-butyl sulfonate))被認為是具有專一性及選擇性的胺肽酶A抑制劑。中央注射EC33可以抑制大腦胺肽酶A的活性,阻斷腦室內(intracerebro-ventricular (icv))注射血管收縮素II(Ang II)所引起的腦內升壓反應,並在許多高血壓的實驗模型中降低血壓(Fournié-Zaluski MCet al
Proc. Natl. Acad. Sci. USA 2004, 101, pp 7775-7780)。
進一步顯示,在清醒之DOCA-鹽高血壓大鼠(hypertensive DOCA-salt rats)及SHR大鼠以急性口服投予RB150(亦稱Firibastat,一種可穿透大腦的EC33前驅藥)(劑量:15至150 mg/kg),造成劑量依存性之血壓降低(Bodineau Let al
, Hypertension 2008, 51, pp 1318-1325; Marc Yet al,
Hypertension 2012, 60, pp 411-418)。有趣的是,RB150在DOCA-鹽大鼠和SHR大鼠中降低血壓,首先是透過降低釋放血管升壓素(vasopressin)、增加水性利尿(aqueous diuresis)及尿鈉排泄(natriuresis)來減少血液體積及降低血壓來控制數值,其次才是透過降低交感神經張力來降低血管阻力,最後得以降低血壓。也有報導顯示,慢性中央注射RB150以及AT1
R阻斷劑:Losartan,對於心肌梗塞(myocardial infarction,MI)後導致心臟衰竭的大鼠也可有效地抑制交感神經過亢及心臟功能不良之相似功效(Huang BSet al
, Cardiovascular Res. 2013, 97, pp 424–431)。因此,RB150經口腔投予後可進入大腦,阻斷大腦APA的活性,使高血壓的大鼠血壓正常化,並防止心肌梗塞後的心臟功能不良。大腦APA抑制劑可作為用於治療原發性高血壓(HTN)與心臟衰竭(HF)的新一類中樞作用藥劑(centrally-acting agent)。
本發明人因而界定一種新穎化合物,其作為高強度之APA抑制劑,同時其可有效降低動脈高血壓並可用來治療動脈高血壓以及與動脈高血壓直接或間接相關的疾病,例如心臟衰竭。所述之化合物同時也具有良好的生體可用率及藥物動力學參數,據此成為口服或非口服給藥的良好候選藥物。
據此,本發明提供具有下列式(I)之化合物:
(I)
以及更具體地具有下列式(II)之化合物:
(II)
其中:
AH表示-CO2
H、-SO3
H或-PO3
H2
;
l 為1、2或 3;
m和n個別獨立地為0、1或2;
R3
和R4
個別獨立地表示H、-OH、鹵素原子、烷基或鹵烷基;
環(在式中以一圓圈繪示)表示芳基或雜環基;
R1
和R2
個別獨立地表示氫原子、鹵素原子、氰基(cyano group)、烷基(alkyl group)、烷氧基(alkoxy group)、烷硫基(alkylthio group)、烷亞碸基(alkylsulfoxide group)、烷磺醯基(alkylsulfonyl group)、鹵烷基(haloalkyl group)、鹵烷氧基(haloalkoxy group)、鹵烷硫基(haloalkylthio group)、醯基(acyl group)、O‑環烷基(O‑cycloalkyl group)、雜烷基(heteroalkyl group)、O‑芳基(O-aryl group)、O‑芳烷基(O-arylalkyl group)、芳基(aryl group)、雜環基(heterocycle group)或芳烷基(arylalkyl group);以及
一其醫藥上可接受之鹽、溶劑合物、兩性離子形式或是前藥。
本發明另一態樣揭露一種包含式(I)化合物以及更具體地是式(II)之化合物的組合物。所述組合物具體是一種醫藥組合物。因此,本發明提供一種醫藥組合物,其包含至少一本發明化合物,較佳是與一醫藥上可接受的稀釋劑或載體結合。
根據本發明另一態樣,其關於一種用於預防或治療動脈高血壓(arterial hypertension)或與該動脈高血壓直接及間接相關的疾病之方法,該方法包含投予一治療有效量之本發明化合物。本發明另一態樣提供一種作為活性醫藥成分以用於治療或藥物的本發明化合物,特別是,用於人類藥物,更具體來說是用在治療動脈高血壓或與動脈高血壓直接及間接相關的疾病或障礙。
本發明另一態樣提供本發明化合物用於製備一種用以治療動脈高血壓或與動脈高血壓直接及間接相關的疾病或障礙之醫藥組合物之用途。
本發明另一態樣提供一種用於治療罹患動脈高血壓或與動脈高血壓直接及間接相關的疾病之病患的方法,該方法包含對一亟需之病患投予一治療有效量之本發明化合物。
本發明是關於一種具有下列式(I)之化合物:
(I)
以及更具體地具有下列式(II)之化合物:
(II)
其中:
AH表示 -CO2
H、-SO3
H或-PO3
H2
;
l 為1、2 或3;
m及 n 個別獨立地表示 0、1 或 2;
R3
及 R4
個別獨立地表示氫原子、氫氧基(OH)、鹵素原子、烷基或鹵烷基;
環 (在式中以一圓圈繪示)表示芳基或雜環;
R1
及R2
個別獨立地表示氫原子、鹵素原子、氰基、烷基、烷氧基、烷硫基、烷亞碸基、烷磺醯基、鹵烷基、鹵烷氧基、鹵烷硫基、醯基、O‑環烷基、雜烷基、O-芳基、O-芳烷基、芳基、雜環基或芳烷基。
本發明提供本發明化合物用於預防或治療動脈高血壓或與動脈高血壓直接及間接相關之疾病的用途或方法。所述疾病包含心臟、周邊及腦血管系統、大腦、眼睛和腎臟疾病。具體是包含原發性及繼發性動脈高血壓、發作、心肌缺血、心臟及腎臟功能不全、心肌梗塞、周邊血管疾病、糖尿病性蛋白尿、X症候群及青光眼。
本文使用之「本發明化合物」(a compound of the invention)一詞係指前述之一化合物或一其前藥或一其醫藥上可接受的鹽、溶劑合物或任何兩性離子形式。
在本發明內容內文中:
術語「烷基」(alkyl或Alk)係指一單價或二價、直鏈或支鏈、飽和烴鏈,其具有1至8個碳原子(又名(C1
-C8
)烷基),例如甲基、乙基、丙基、異丙基、正丁基、異丁基、二級丁基(sec-butyl)、三級丁基、三級丁基甲基、正戊基、正己基、正庚基或正辛基。
術語「醯基」(acyl)係指一 –C(O)R基,其中,R為一前述之烷基或一苯基。醯基包含例如乙醯基、乙羰基(ethylcarbonyl)、苯甲醯基。
術語「烷氧基」(alkoxy or alkyloxy)係指 –OAlk基,其中Alk是如前述之烷基。烷氧基的實例包含甲氧基、乙氧基、正丙氧基、或三級丁氧基。
術語「芳基」(aryl)係指一具有4至10個碳原子的芳香單環或雙環系統(又名(C4
-C10
)芳基),當在雙環系統時,也可理解成其中一環為芳香的而另一個環則為芳香的或非飽和的。芳基包含的例子有苯基、萘基(naphthyl)、茚基(indenyl)或苯并環丁烯基(benzocyclobutenyl)。
術語「雜環基」(heterocycle)係指一飽和、非飽和或芳香的、稠合的(fused)、螺-稠合的或架橋的(bridged)單環或雙環系統,並含有3至12員,其具有可相同或不同之1至4個雜原子,其選自由氧原子、硫原子及氮原子,並可能含有1或2個側氧基(oxo,=O)或硫酮基(thioxo,=S)。若是雙環系統之情況,其中一環可以是芳香環,而另一環可以是芳香、飽和或非飽和之環。雜環基包含,舉例來說,哌啶基(piperidyl)、哌嗪基(piperazyl)、呋喃基(furyl)、噻吩基(thienyl)、吡咯基(pyrrolyl)、吡唑基(pyrazolyl)、咪唑基(imidazolyl)、吡啶基(pyridyl)、嘧啶基(pyrimidyl)、吡𠯤基(pyrazinyl)、嗒𠯤基(pyradizinyl)、苯并呋喃基(benzofuryl)、苯并噻吩基(benzothienyl)、吲哚基(indolyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)、苯并二㗁戊基(benzodioxolyl)、苯并二㗁𠯤基(benzodioxinyl)、苯[1,2,5]噻二唑基(benzo[1,2,5]thiadiazolyl)、苯[1,2,5]㗁二唑基(benzo[1,2,5]oxadiazolyl)、[1,2,3]三唑基([1,2,3]triazolyl)或[1,2,4]三唑基([1,2,4]triazolyl)。
術語「烷硫基」(alkylthio)係指一–SAlk基,其中Alk如前述之烷基。烷硫基包含的例子有甲硫基(methylthio)、乙硫基(ethylthio)、異丙硫基(isopropylthio)或庚硫基(heptylthio)。
術語「烷亞碸基」(alkylsulfoxide)係指 –S(O)Alk基,其中Alk如前述之烷基。烷亞碸基包含的例子有甲基亞碸(methylsulfoxide)、乙基亞碸(ethylsulfoxide)或異丙基亞碸(isopropylsulfoxide)。
術語「烷磺醯基」(alkylsulfonyl)係指 –S(O)2
Alk基,其中Alk如前述之烷基。烷磺醯基包含的例子有甲磺醯基(methylsulfonyl)、乙磺醯基(ethylsulfony)或異丙磺醯基(isopropylsulfonyl)。
術語「芳烷基」(arylalkyl)係指 –Alk-Ar基,其中Alk如前述之烷基,Ar則如前述之芳基。
術語「雜烷基」(heteroalkyl)係指一直鏈或支鏈的飽和烴鏈,具有1至5個碳原子和至少1或2個雜原子,例如硫、氮或氧原子。雜烷基包含的例子有‑O(CH2
)2
OCH3
或 -(CH2
)2
OCH3
基。
術語「鹵素原子」(halogen atom)係指氟、溴、氯、碘原子。
術語「環烷基」(cycloalkyl)係指一飽和的單環或多環系統,例如稠合的或架橋的的雙環系統,其具有3至12個碳原子(又名為(C3
-C12
)環烷基),例如環丙基(cyclopropyl)、環丁基(cyclobutyl)、環戊基(cyclopentyl)、環己基(cyclohexyl)、環庚基(cycloheptyl)、環辛基(cyclooctyl)、金剛烷基(adamantly)、十氫萘基(decalinyl)、降冰片(norbornyl)基。
術語「O-環烷基」(O-cycloalkyl)係指一如前述之環烷基和其他的分子以一氧原子相連。O-環烷基包含的例子有O-環戊基(O-cyclopentyl)或O-環己基(O-cyclohexy)。
術語「O-芳基」(O-aryl)係指一如前述之芳基和其他的分子以一氧原子相連。O-芳基包含的例子有O-苯基(O-phenyl)。
術語「O-芳烷基」(O-arylalkyl)係指一如前述之芳烷基和其他的分子以一氧原子相連。O-芳烷基包含的例子有O-苄基(O-benzyl)。
「酯」(ester)係指 –C(O)OR基,R代表為一如前述之烷基、芳基或芳烷基。
術語「鹵烷基」(haloalkyl)係指一直鏈或支鏈的飽和烴鏈,具有1至6個碳原子以及經一或多個,特別是1至6個鹵素原子取代的烴鏈,例如三氟甲基(trifluoromethyl)或2,2,2-三氟乙基(2,2,2-trifluoroethyl)。
術語「鹵烷氧基」(haloalkoxy)係指一直鏈或支鏈的飽和烴鏈,具有1至6個碳原子以及經一或多個,特別是1至6個鹵素原子取代的烴鏈,所述烴鏈也透過氧原子與化合物相連,例如三氟甲氧基(trifluoromethoxy)或2,2,2-三氟乙氧基(2,2,2-trifluoroethoxy)。
術語「鹵烷硫基」(haloalkylthio)係指一直鏈或支鏈的飽和烴鏈,具有1至6個碳原子以及經一或多個,特別是1至6個鹵素原子取代的烴鏈,所述烴鏈也透過硫原子與化合物相連,例如三氟甲硫基(trifluoromethylthio)。
術語「保護基」(protective group或protection group)係指在多官能基的化合物上選擇性的阻斷活性位置,藉以可選擇性的在其他非保護的活性位置進行化學反應,特別是在合成化學上其含義通常與後者相關。
在本發明中,術語「醫藥上可接受」(pharmaceutically acceptable)係指,用於製備安全、無毒及在生物學或其他方面非不良的,並且通常可被獸醫或人類醫藥用途上可接受的醫藥組合物。
本發明化合物之「醫藥上可接受的鹽類」(pharmaceutically acceptable salts)一詞在包含由醫藥上可接受的無機或有機酸或鹼以及季銨鹽所形成之常規鹽類。更具體的合適酸鹽類例子包含氫氯酸鹽(hydrochloric)、氫溴酸鹽(hydrobromic)、硫酸鹽(sulfuric)、磷酸鹽(phosphoric)、硝酸鹽(nitric)、過氯酸鹽(perchloric)、丁烯二酸鹽(fumaric)、乙酸鹽(acetic)、丙酸鹽(propionic)、琥珀酸鹽(succinic)、乙醇酸鹽(glycolic)、甲酸鹽(formic)、乳酸鹽(lactic)、馬來酸鹽(maleic)、酒石酸鹽(tartaric)、檸檬酸鹽(citric)、棕櫚酸鹽(palmoic)、丙二酸鹽(malonic)、羥基馬來酸鹽(hydroxymaleic)、苯乙酸鹽(phenylacetic)、麩胺酸鹽(glutamic)、苯甲酸鹽(benzoic)、水楊酸鹽(salicylic)、富馬酸鹽(fumaric)、甲苯磺酸鹽(toluenesulfonic)、甲磺酸鹽(methanesulfonic)、萘-2-磺酸鹽(naphthalene-2-sulfonic)、苯磺酸鹽(benzenesulfonic)、羥萘甲酸鹽(hydroxynaphthoic)、氫碘酸鹽(hydroiodic)、蘋果酸鹽(malic)、硬脂酸鹽(steroic)、鞣酸鹽(tannic)等。合適鹼鹽的具體例子包含鈉、鋰、鉀、鎂、鋁、鈣、鋅、N,N'-二芐基乙二胺 (N,N'-dibenzylethylenediamine,)、氯普魯卡因(chloroprocaine)、膽鹼(choline)、二乙醇胺(diethanolamine)、乙二胺(ethylenediamine)、N-甲基葡糖胺(N-methylglucamine)和普魯卡因鹽。
舉例來說,理想的鹽形式包含氯水合物。
術語「前藥」(pro-drug)係指本發明化合物的化學衍生物,其在活體內透過生理性介質,特別是酵素、光解作用及/或代謝反應所觸發的單或多個自發性化學反應所產生。在本發明中,本發明化合物的前藥在活體內產生可識別為胺肽酶A抑制劑的化合物。
前藥可自特定不穩定基團部分(moieties)的衍生官能基團所獲得。
具有酸性官能基的前藥(如次磷酸、羧酸、磺酸或膦酸)包含酯類,具有胺類官能基的前藥則包含源自胺甲酸基(carbamate group)的[(2-甲基丙醯基)氧]乙氧羰基([(2-methylpropanoyl)oxy]ethoxycarbonyl)或源自醯胺基(amide group)的2-側氧-[1,3-四氫噻唑-4-基]甲醯胺(2-oxo-[1,3-thiazolidine-4-yl]formamide)。
其他例子可參閱T. Higuchi及V. Stella所著《前藥為新穎的傳遞系統》(“Pro-drugs as Novel Delivery system”),Vol.14, A.C.S Symposium Series, American Chemical Society (1975) 以及E.B. Roche 編著《藥物設計中的生物可逆載體:理論與應用》(Bioreversible Carriers in Grug Design: Theroy and Application) Pergamon Press: New York, 14-21 (1987))。
本發明中,術語「異構物」(isomer)係指有相同化學式但在特性和其原子鍵結序列或其原子在空間中分布有所不同的本發明化合物。其原子在空間中分布不同的異構物稱為「立體異構物」(stereoisomers)。 非彼此鏡像體的立體異構物被稱為「非鏡像異構物」(diastereoisomers),而互成鏡像但無法重疊被稱為「鏡像異構物」(enantiomers)或「光學異構物」(optical isomers)。 「立體異構物」(Stereoisomers)可為消旋物、鏡像異構物和非鏡像異構物。
所屬技術領域中具有知識者將會理解本發明化合物中存在有立體異構物。化合物的任意對掌中心可為(R)、(S)或消旋物。相應的,本發明物包含了式(I)之化合物所有可能的立體異構物或幾何異構物,同時除了消旋化合物,也含括光學活性異構物。根據較佳實施例,本發明化合物具有式(II)。當式(I)的化合物欲為單一鏡像異構物時,其可由最終產物分割,或是利用起始的純異構物材料或任何適合的中間產物進行立體特異性合成來獲得。最終產物、中間產物或起始材料的分割可能會被任何合適的已知方法所影響。可閱E. L. Eliel所著的《碳化合物的立體化學》(Stereochemistry of Carbon Compounds)(Mcgraw Hill, 1962)及S. H. Wilen所著的光學分割劑表格中的例子。
所屬技術領域中具有知識者將會理解本發明化合物可能含有至少一正電或負電荷,因此本發明化合物包含其兩性離子的型態。化學上,兩性離子(又被稱為內鹽)為擁有兩個或多個官能基的分子,其中至少一個官能基會帶正電,另一個則帶負電,其在不同官能基上的電荷可互相抵銷達到平衡,並使整個分子達成電中性。此電中性的酸鹼值被稱為等電點。因此本發明化合物包含了前藥涵蓋了其任何兩性離子形式。
有機化學領域的專家會了解許多有機化合物可以在溶劑中和其反應組成複合物、或從中沉澱或結晶出來。這些複合物被稱為「溶劑合物」(solvates) 。舉例來說,和水組成的複合物被稱為「水合物」(hydrate)。式(I)及(II)之化合物的溶劑合物皆涵蓋在本發明的範疇內。
有機化學領域的專家也會了解許多有機化合物可能以多於一種的結晶型態而存在。舉例來說,結晶型態會依不同的溶劑合物而不同。因此,所有本發明化合物或其醫藥上可接受溶劑合物的結晶型態皆涵蓋在本發明的範圍內。
本文揭示本發明化合物包含式(I)或(II)之化合物及其醫藥上可接受的鹽類、溶劑合物、兩性離子形式或前藥。
根據較佳實例,本發明化合物相當於通式(I)之化合物以及更具體地為式(II)之化合物,其中:
-l表示2 或 3;及/或
-m表示 0或1;及/或
-n表示0或1;及/或
-AH表示CO2
H、SO3
H或PO3
H2
;及/或
-R3
及 R4
均表示 H,或是R3
及R4
均表示甲基;及/或
-環表示芳基或雜環基,以及更具體的苯基(phenyl)、萘基(naphthyl)、吲哚基(indol)、氮吲哚基(aza indol)或異㗁唑基(isoxazol)。
根據特定實施例,R1
及R2
個別獨立地選自由氫原子、鹵素原子、氰基、烷基、烷氧基、烷磺醯基、鹵烷基、鹵烷氧基、O-環烷基、雜烷基、O-芳基、O-芳烷基以及芳基所組成之群組。
根據更佳實例,本發明化合物相當於通式(I)化合物以及更具體之式(II)化合物,其中:
l為2 ;及/或
m + n = 1;及/或
AH為CO2
H或SO3
H;及/或
R3
及 R4
是 H;及/或
環具體地為苯基、萘基或吲哚基。
根據更具體實例,R1
及R2
各別獨立地選自由氫原子、鹵素原子(較佳為氯或氟原子)、 氰基、烷基(較佳為甲基))、烷氧基(較佳為甲氧基)、烷磺醯基(較佳為甲磺醯基)、鹵烷基(較佳為三氟甲基)、鹵烷氧基(較佳為三氟甲氧基)、O-環烷基(較佳為O-環戊基或O-環己基))、雜烷基(較佳為甲氧基乙氧基)、O-芳基(較佳為O-苯基)、O-芳烷基(較佳為O-芐基)以及一芳基(較佳為苯基)。
本文揭示本發明化合物包含式(I)或(II)之化合物及其醫藥上可接受的鹽類、溶劑合物、兩性離子形式或前藥。
根據特定實施例,本發明化合物的前藥可為具有如下式(III)之化合物的產物:
(III)
或是更具體地之如下式(IV)之化合物:
(IV)
其中:
l、m、 n、R1
、R2
、R3
、R4
如上之定義;
A表示-SO3
Z、-CO2
Z或–P(O)(OZ)2
,而Z則選自由氫原子、烷基及芳烷基所組成之群組;
X表示氫原子、-(CO)-烷基、-(CO)-烷氧基、-(CO)-
苄氧基、、、、、、、或,
其中R 表示如上述定義的烷基,而R’及R” 則各別獨立地表示前述定義的氫原子或烷基 ;
Y表示如前述定義的氫原子、烷基、芳基、芳烷基或,
其中R、R’、R”,為相同或相異,如前述定義,
其中Z,X及Y至少其中之一與氫原子不同。
根據具體實例,本發明化合物係選自由:
4-胺基-4-[苄基(羥基)磷醯基]丁酸(4-amino-4-[benzyl(hydroxy)phosphoryl]butanoic acid);
4-胺基-4-{羥基[(2-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-methylphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(3-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-methylphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(4-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methylphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-({[3,5-二(三氟甲基)苯基]甲基}(羥基)磷醯基)丁酸(4-amino-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(hydroxy)phosphoryl) butanoic acid);
4-胺基-4-[({[1,1'-聯苯]-2-基}甲基)(羥基)磷醯基] 丁酸(4-amino-4-[({[1,1'-biphenyl]-2-yl}methyl)(hydroxy)phosphoryl] butanoic acid);
4-胺基-4-[羥基({[3-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[3-(trifluoromethoxy)phenyl]methyl})phosphoryl]butanoic acid);
4-胺基-4-[羥基({[4-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[4-(trifluoromethoxy)phenyl]methyl})phosphoryl]butanoic acid);
4-胺基-4-{羥基[(4-甲磺醯苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methanesulfonylphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(2-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl} butanoic acid);
4-胺基-4-{羥基[(3-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-methoxyphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(4-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methoxyphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{[(3-氰苯基)甲基](羥基)磷醯基}丁酸(4-amino-4-{[(3-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{[(4-氰苯基)甲基](羥基)磷醯基}丁酸(4-amino-4-{[(4-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{羥基[(萘-1-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(naphthalen-1-yl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(2-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-phenoxyphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(3-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-phenoxyphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(4-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-phenoxyphenyl)methyl]phosphoryl}butanoic acid);
4-胺基-4-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丁酸(4-amino-4-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]butanoic acid);
4-胺基-4-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[(5-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl}butanoic acid);
4-胺基-4-[羥基(2-苯乙基)磷醯基]丁酸(4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butanoic acid);
4-胺基-4-{羥基[2-(2-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methylphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(3-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-methylphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(4-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(4-methylphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-[羥基({2-[3-(三氟甲基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[3-(trifluoromethyl)phenyl]ethyl})phosphoryl]butanoic acid);
4-胺基-4-[羥基(2-甲基-2-苯丙基)磷醯基]丁酸(4-amino-4-[hydroxy(2-methyl-2-phenylpropyl)phosphoryl]butanoic acid);
4-胺基-4-{[2-(2-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(2-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{[2-(3-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(3-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(萘-2-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(naphthalen-2-yl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(萘-1-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(naphthalen-1-yl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(3-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-methoxyphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(4-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(4-methoxyphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(2-苯氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-phenoxyphenyl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-({2-[2-(環戊氧基)苯基]乙基}(羥基)磷醯基)丁酸(4-amino-4-({2-[2-(cyclopentyloxy)phenyl]ethyl}(hydroxy)phosphoryl) butanoic acid);
4-胺基-4-[羥基(3-苯丙基)磷醯基]丁酸(4-amino-4-[hydroxy(3-phenylpropyl)phosphoryl]butanoic acid);
4-胺基-4-[羥基({2-[2-(三氟甲氧基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[2-(trifluoromethoxy)phenyl]ethyl})phosphoryl] butanoic acid);
4-胺基-4-[(2-{[1,1'-聯苯]-2-基}乙基)(羥基)磷醯基]丁酸(4-amino-4-[(2-{[1,1'-biphenyl]-2-yl}ethyl)(hydroxy)phosphoryl]butanoic acid);
4-胺基-4-{[2-(2,3-二氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(2,3-dichlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{[2-(3-氯-2-甲氧苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(3-chloro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl} butanoic acid);
3-羧基-1-{羥基[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基} 丙烷-1-氯化銨(3-carboxy-1-{hydroxy[2-(1-methyl-1H-indol-3-yl)ethyl]phosphoryl} propan-1-aminium chloride);
3-羧基-1-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基) 丙烷-1-氯化銨(3-carboxy-1-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl) propan-1-aminium chloride);
3-羧基-1-[羥基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基] 丙烷-1-氯化銨(3-carboxy-1-[hydroxy({2-[2-(2-methoxyethoxy)phenyl]ethyl})phosphoryl] propan-1-aminium chloride);
4-胺基-4-{羥基[2-(3-苯基-1,2-㗁唑-5-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-phenyl-1,2-oxazol-5-yl)ethyl]phosphoryl}butanoic acid);
4-胺基-4-{[2-(4-氟-2-甲氧苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(4-fluoro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl}butanoic acid);
4-胺基-4-{羥基[2-(1H-吲唑-1-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(1H-indazol-1-yl)ethyl]phosphoryl}butanoic acid);
1-({2-[2-(苄氧基)苯基]乙基}(羥基)磷醯基)-3-羧基丙烷-1-氯化銨(1-({2-[2-(benzyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-3-carboxy propan-1-aminium chloride);
5-胺基-5-[羥基(2-苯乙基)磷醯基]戊酸(5-amino-5-[hydroxy(2-phenylethyl)phosphoryl]pentanoic acid);
(1R
)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨((1R
)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride);
(1S
)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨((1S
)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride);
(1R
)-3-羧基-1-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-氯化銨((1R
)-3-carboxy-1-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}propan-1-aminium chloride);
(4R
)-4-胺基-4-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基)丁酸((4R
)-4-amino-4-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl) butanoic acid);
(1-胺基-4-甲氧基-4-酮丁基)(2-苯乙基)次磷酸((1-amino-4-methoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid);
(1-胺基-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸((1-amino-4-ethoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid);
{4-乙氧基-1-[({1-[(2-甲基丙醯基)氧基]乙氧基}羰基)胺基]-4-酮丁基}(2-苯乙基)次磷酸({4-ethoxy-1-[({1-[(2-methylpropanoyl)oxy]ethoxy}carbonyl)amino]-4-oxobutyl}(2-phenyl ethyl)phosphinic acid);
1-[(苄氧基)(2-苯乙基)磷醯基]-4-乙氧基-4-羰基丁烷-1-氯化銨(1-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-ethoxy-4-oxobutan-1-aminium chloride);
[1-胺基-4-(苄氧基)-4-酮丁基](2-苯乙基)次磷酸([1-amino-4-(benzyloxy)-4-oxobutyl](2-phenylethyl)phosphinic acid);
(4-乙氧基-4-側氧-1-{[(4R
)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基}丁基)(2-苯乙基)次磷酸((4-ethoxy-4-oxo-1-{[(4R
)-2-oxo-1,3-thiazolidin-4-yl]formamido}butyl)(2-phenylethyl) phosphinic acid);
3-胺基-3-{羥基[(2-甲氧苯基)甲基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl}propane-1-sulfonic acid);
3-胺基-3-[羥基(2-苯乙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propane-1-sulfonic acid);
3-胺基-3-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}propane-1-sulfonic acid);
3-胺基-3-[羥基(3-苯丙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(3-phenylpropyl)phosphoryl]propane-1-sulfonic acid);
3-胺基-3-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丙烷-1-磺酸(3-amino-3-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]propane-1-sulfonic acid);
3-胺基-3-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}]丙烷-1-磺酸(3-amino-3-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl} propane-1-sulfonic acid);
3-胺基-3-{羥基[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基}]丙烷-1-磺酸(3-amino-3-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl}propane-1-sulfonic acid);
4-胺基-4-[羥基(2-苯乙基)磷醯基]丁烷-1-磺酸(4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butane-1-sulfonic acid);
{3-胺基-3-[羥基(2-苯乙基)磷醯基]丙基}膦酸({3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propyl}phosphonic acid);
[4-乙氧基-1-({[(5-甲基-2-側氧-2H-1,3-二氧呃-4-基)甲氧基]羰基}胺基)-4-酮丁基] (2-苯乙基)次磷酸([4-ethoxy-1-({[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}amino)-4-oxobutyl] (2-phenylethyl)phosphinic acid);
4-({[(5-甲基-2-側氧-2H-1,3-二氧呃-4-基)甲氧基]羰基}胺基)-4-({1-[(2-甲基丙醯基) 氧] 乙氧基}(2-苯乙基)磷醯基)丁酸乙酯(ethyl 4-({[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}amino)-4-({1-[(2-methyl propanoyl)oxy]ethoxy}(2-phenylethyl)phosphoryl)butanoate);
(1-{[(苄氧基)羰基]胺基}-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸((1-{[(benzyloxy)carbonyl]amino}-4-ethoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid);
3-({4-乙氧基-4-側氧-1-[(2-苯乙基)次磷酸]丁基}胺甲醯基)-1-甲吡啶 (3-({4-ethoxy-4-oxo-1-[(2-phenylethyl)phosphinato]butyl}carbamoyl)-1-methylpyridin-1-ium);
{4-乙氧基-4-側氧-1-[({[(4R
)-2-側氧-1,3-四氫噻唑-4-基]甲氧基}羰基)胺基]丁基}(2-苯乙基)次磷酸({4-ethoxy-4-oxo-1-[({[(4R
)-2-oxo-1,3-thiazolidin-4-yl]methoxy}carbonyl)amino]butyl}(2-phenylethyl)phosphinic acid);
(4-乙氧基-4-側氧-1-{[(2-{[(4R
)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基}乙氧基)羰基]胺基}丁基)(2-苯乙基)次磷酸((4-ethoxy-4-oxo-1-{[(2-{[(4R
)-2-oxo-1,3-thiazolidin-4-yl]formamido}ethoxy)carbonyl] amino}butyl)(2-phenylethyl)phosphinic acid);以及
[1-(2-胺乙醯胺)-4-乙氧基-4-酮丁基](2-苯乙基)次磷酸([1-(2-aminoacetamido)-4-ethoxy-4-oxobutyl](2-phenylethyl)phosphinic acid)所組成之群組。
本發明化合物以醫藥組合物的形式便於投藥。此組合物可以常規方式與與一或多種生理學上可接受之載體或賦形劑混合。載體必須與配方中其他成分可相容,且不對接收的個體有害。
雖然本發明化合物在治療上可直接以純化學的形式投予,但也可作為醫藥配方中的活性成分。
因此本發明更提供一種醫藥組合物,其包含與一或多種醫藥上可接受的載體以及選擇性其餘活性成分結合的本發明化合物。
醫藥組合物包含那些適於口服、腸胃外(包含皮下、例如通過注射或貯存錠、皮內、鞘內、眼內、肌肉內、例如貯存和靜脈內)、眼、直腸和局部外用(包含皮膚(即在皮膚上)、頰以及舌下)的組合物或是適合透過吸入或吹入的方式投予之形式,但最適合的方式仍取決於接受者的狀況和病症。所述組合物可以單位劑量形式使用並以藥劑上已熟知的方式來製備。這些方式包含製備本發明化合物的步驟,選擇性地包含至少一其他活性成分,且及由一或多種次要成分組成的載體。配方製劑一般是透過將活性成分和液狀載體或固體狀載體均勻且緊密地結合來製備,如有需要亦可將成品塑形成適宜的配方。
適於口服投予的醫藥組合物可以透過像是膠囊、片劑或錠劑(更具體的如用於兒童投藥的咀嚼錠)的方式,其每單位中均含有固定已知量的活性成分;或以粉末或顆粒的方式;或以水性或非水性的溶液或懸浮液的方式;以水包油液乳劑或油包水液乳劑的方式呈現。活性成分可以推注(bolus)、糖劑(electuary)或糊劑(paste)的方式呈現。
錠劑以壓縮或造模的方式製造,可含有單或多種副成分。透過合適機器將粉狀或顆粒狀的活性成分壓縮製成壓縮錠劑,其活性成分可選擇性地混雜著其他常用的賦形劑例如黏合劑(如糖漿、阿拉伯樹膠、明膠、山梨糖醇、黃芪膠、澱粉膠、聚乙烯吡咯烷酮或羥甲基纖維素)、填料(如乳糖、蔗糖、微晶纖維素、玉米澱粉、磷酸鈣或山梨糖醇)、潤滑劑(如硬脂酸鎂、硬脂酸、滑石粉、聚乙二醇或二氧化矽)、崩散劑(如馬鈴薯澱粉或澱粉羥乙酸鈉)或是潤濕劑,如月桂基硫酸鈉。造模製成的錠劑則可透過合適的機器將從混和的粉狀化合物經由惰性液體稀釋劑增濕後,加以造模製成。錠劑可利用包衣或劃痕來緩釋或控釋其中活性成分。可透過產業中已知的方式來進行錠劑包衣。
抑或是,本發明化合物可混入口服液體製劑中,如水性或油性懸浮液、溶液、乳劑、以及糖漿或酏劑。含有本發明化合物的醫藥組合物(或配方)亦可製為乾燥形式,使用前再與水或其他合適的載體混合使用。此類液體製劑可能含有常用的添加劑如懸浮劑,例如山梨糖醇糖漿、甲基纖維素、葡萄糖或糖漿、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁凝膠或氫化食用脂肪;乳化劑,例如卵磷脂、山梨醇酐單油酸酯或阿拉伯膠;非水載體(可能包含食用油),例如杏仁油、分餾椰子油、油性酯、丙二醇或乙醇;以及防腐劑,例如對羥苯甲酸甲酯或對羥苯甲酸丙酯或山梨酸。這些製劑也可以配製成栓劑,例如含有常用的栓劑賦形劑如可可脂或其他甘油酯。
腸胃外投藥的配方包含了水性和非水性無菌注射溶液,其包含抗氧化劑、緩衝液、抑菌劑和溶質,使配方與預期接收個體的血液形成等張;而水性及非水性無菌懸浮液可包含懸浮劑和增稠劑。配方可以單或多劑量的容器來使用,例如密封的安瓿及小瓶,並可以冷凍乾燥(lyophilize)的條件保存,只需添加無菌液體載體,例如在使用前才添加注射用水。臨場才調製的注射液或懸浮液可以透過前述之無菌散劑、顆粒、錠劑所製備而成。
用於直腸投藥的組合物可以與常見載體如可可脂、硬脂或聚乙二醇一起製成栓劑使用。
用於如頰或舌下等口腔局部投予的製劑,其包含活性成分的調味賦形劑為蔗糖、阿拉伯膠或黃蓍膠的口含錠,以及活性成分之賦形劑存為明膠和甘油或蔗糖與及亞拉伯膠中的丸粒。用於皮膚局部投藥的配方,其化合物可配製成乳膏劑、凝膠劑、軟膏劑或洗劑或透皮貼劑。用於眼睛投藥的組合物,其可為液體溶液(如滴眼液)、凝膠劑、乳膏劑或任何類型的眼科組合物。
這些化合物也可以配製成儲存製劑。這些長效的配方可藉由植入(如皮下或肌內)或以肌內注射的方式投予。因此化合物可與合適聚合或疏水材料(例如存在可接受之油裡面的乳劑)或離子交換樹脂一起配製,或為其微溶衍生物,例如微溶的鹽類。
用於鼻內投藥,本發明化合物可以如液體噴霧劑、散劑或滴劑的形式使用。
用於吸入投藥的本發明化合物可以氣化噴霧劑的形式便於使用,氣化噴霧劑利用合適的推進劑如1,1,1,2-三氟乙烷(1,1,1,2-trifluoroethane HFA 134A)及1,1,1,2,3,3,3-七氟丙烷(1,1,1,2,3,3,3, -heptafluoropropane HFA 227)、二氧化碳或其他合適的氣體從加壓容器或噴霧器中遞輸。在加壓氣化噴霧劑的例子中,可藉由閥門來調節遞輸一定的量來達成確切劑量。如使用於吸入器或吹入器的明膠可製備成膠囊和匣,可用於裝載本發明化合物的混和散劑及合適的粉末賦形劑,如乳糖或澱粉。除上面特別提到的成分外,製備過程可能也含有該製劑類型領域中其他常用的其他試劑,例如適於口服投予的可能就含有調味劑。
本發明所屬技術領域中具有知識者會理解到,此處關於治療到預防以及針對既有疾病和症狀的治療之參考資料。此外,他們也可理解本發明化合物用於治療所需的量,將隨著所治療病症的性質以及患者的年齡及狀況而變化,並最終將由從業之醫師或獸醫所決定。患者可能是任何哺乳動物,包含人類或非人類哺乳動物。本發明更具體的是針對人類,以及更具體的是針對成人。用於成人治療的劑量通常為每天0.02-5000毫克,每天1-1500毫克為最適劑量。所需劑量可以單次、或以適當間隔之每日兩次、三次、四次或多次小劑量的方式進行投予。本發明的配方可包含0.1-99%的活性成分,在錠劑與膠囊中可含有30-95%的活性成分,在液體製劑中則可能含3-50%。
本發明化合物可和單或多種其他臨床活性劑共同使用,例如β-腎上腺素受體拮抗劑、鈣離子通道阻斷劑、噻嗪類利尿劑(thiazide diuretics)、血管收縮素受體拮抗劑及血管收縮素轉化酶抑制劑。本發明因此可進一步提供和其他治療劑的組合來治療動脈高血壓。
當本發明化合物和其他治療劑共同使用時,可依任何適合途徑進行依序或同時的投予。
如前文所提及,與其他臨床藥劑共同使用時,亦可適以醫藥製劑的方式供使用,因此本發明的另一態樣亦包含前述定義最適與醫藥上可接受的載體或賦形劑結合的醫藥製劑。此種藥物製劑中任一獨立成分均可依序或同時的投予,或組合為醫藥製劑使用。
當兩種化合物組成同種製劑進行投予時,他們必須是穩定且可和彼此以及其他成分相容。當分別製備時,也須符合該化合物類型領域中已熟知的製備方式。
當本發明化合物和另一種治療劑共同使用以治療同種疾病時,其投予所需劑量可能和單獨使用時不同。合適的劑量應由該技術領域中具有知識者決定。
另一態樣,本發明化合物之目的其一為預防或治療動脈高血壓及與其直接或間接相關的疾病,其包含投予一治療有效量之本發明化合物。
另一態樣,本發明提供本發明化合物於獸醫或人類臨床用藥上的用途。
本發明同時也與作用為胺肽酶 A選擇性抑制劑之式(I)之化合物與式(II)之化合物的用途有關。
另一態樣,本發明提供本發明化合物之用途,其用於製備治療動脈高血壓及與其直接或間接相關之疾病的藥物。
另一態樣,本發明提供一種治療患有動脈高血壓及與其直接或間接相關疾病之病患的方法,其包含對該病患投予一治療有效量之本發明化合物。
本發明提供了預防或治療動脈高血壓及與其直接或間接相關疾病的方法。這些疾病包含了心臟疾病、心衰竭、中風、周邊及/或腦血管系統疾病、腦、眼以及腎疾病。這些疾病包含原發性及繼發性動脈高血壓、發作、心肌缺血、心臟功能不全與腎臟功能不全、心肌梗塞、周邊血管疾病、糖尿病性蛋白尿、X症候群、青光眼、神經退化性疾病以及記憶障礙。
可以多種方式製備式(I)之化合物,或是較佳為式(II)之化合物。起始材料為市售產品或是從市售或本領域熟知的化合物,根據已知合成反應所製備而成之產品。具體而言,製備本發明化合物的方法包含以下連續步驟:
本發明式(I)之化合物,可使用式(V)、(VI)、(VII)之前驅物經由以下闡述的合成步驟製備而成,
(V)
(VI)
H2
N-X
(VII)
其中: l、 m、 n、 R1
、 R2
、 R3
, R4
、 A及X 如前述定義。
接下來,透過氫解反應可將官能基A的保護基以及胺官能基的保護基X同時去保護,以形成本發明式(I)之化合物。
接著,式(IX)化合物可經過氫解反應,或在符合酸性條件(例如含有三氟乙酸(trifluoroacetic acid)之加熱有機溶劑(如苯甲醚(anisole))中,以提供形成本發明式(I)之化合物。
本發明之發明對象,式(I)的化合物,是藉由使用下列式(Vbis)和(X)之前驅物,根據以下將闡述的合成途徑來製備,
(Vbis)
(X)
其中,l、m、n、Y、R1
、R2
、R3
、R4
以及A如前述定義。
根據本合成途徑中,化合物(Vibs)與磺酸基-亞胺(X)溶於含有像是碳酸銫(cesium carbonate)之有機溶劑(例如二氯甲烷)中,透過文獻已熟知的方法進行反應,以形成式(XI)的化合物:
(XI)
其中l、m、n, Y、R1
、R2
、R3
、R4
以及A如前述定義。
要指出的是,中間物(X)磺酸基-亞胺可經文獻中已熟知的方式以手性合成。當手性誘導保護基被磺酸基-亞胺(X)支持時,該合成組元(syhthon)可產生不對稱合成的式(II)化合物的前驅物。
對外消旋或手性的中間物(XI)進行適當的去保護反應可分別產生本發明式(I)及(II)之化合物。
當m = n = 0時,式(XII)之化合物可藉由和雙(三甲基矽)亞膦酸酯(bis(trimethylsilyl)phosphonite)之有機溶劑(二氯甲烷中),在低溫環境(如0°C)下進行反應以產生式(V)之化合物。
在其他情況中,可將式(XII)之化合物的相應格任亞(Grignard)試劑與在有機溶劑(如乙醚或四氫呋喃)中的氯亞磷酸二乙酯,於低溫環境(0‑10°C)下反應,以產生式(V)之化合物。
(Vbis)之前驅物可藉由前述式(XII)之化合物的碘化類似物和二烷基膦-硼烷(dialkylphosphine-borane)錯合物,透過文獻中熟知的方法反應,以產生下列式(XIII)之化合物,
(XIII)
其中,m、n、Y、R1
、R2
、R3
以及R4
如前述定義。
接著將式(XIII)之化合物置於酸性條件像是含有四氟硼酸二乙醚 (tetrafluoroboric acid diethyl ether)的有機溶劑(如二氯甲烷)內,藉以產生式(Vbis)之化合物。
以下實例係用來說明本發明,但不以任何方式限制本發明之範圍。
實例
起始材料是市售產品,或是從市售化合物或本領域具有通常知識者已知之化合物,根據已知合成反應製備的產物。不同的A、B、C、D、E、F通用步驟均可合成製備本發明化合物時有用的中間產物。步驟G和H則可用來合成本發明的最終化合物。
本揭示內容實例中描述的化合物之結構係由常用的光譜儀技術(核磁共振(NMR)、包含電噴灑游離(ESI)之質譜法)來進行測量,純度則以高效液相層析法(HPLC)來測定。
本發明的合成中間產物及化合物由IUPAC(國際純化學和應用化學聯合會)(The International Union of Pure and Applied Chemistry)的規則命名並以中性形式描述。
下列為各化合物使用之縮寫:
AIBN:偶氮雙異丁腈(azobisisobutyronitrile) |
(Boc)2 O:二碳酸二叔丁酯(di-tert-butyl dicarbonate) |
(n-Bu)4 NBr:溴化四正丁基銨(tetra-n-butylammonium bromide) |
(n-Bu)4 NI:碘化四正丁基銨(tetra-n-butylammonium iodide) |
AcCl:乙醯氯(acetyl chloride) |
AcOH:醋酸(acetic acid) |
BTSP:雙(三甲矽) 膦酸酯(bis(trimethylsilyl)phosphonate) |
Cbz:苄氧羰基(carboxybenzyl) |
CH2 Cl2 或 DCM:二氯甲烷(dichloromethane) |
CHCl3 :氯仿(chloroform) |
cHex:環己烷(cyclohexane) |
CuSO4 :硫酸銅(copper sulfate) |
DCC:N,N' -二環己碳二亞胺(N,N' -dicyclohexylcarbodiimide) |
DTAD :偶氮二羧酸二叔丁酯(di-tert-butyl azodicarboxylate) |
EDCI:1-乙基-(3-二甲基氨基丙基)碳醯二亞胺(1-ethyl-3-(3-dimethylaminopropyl)ethylcarbodiimide) |
Et2 O:乙醚(diethyl ether) |
EtOAc:乙酸乙酯(ethyl acetate) |
HBF4 .Et2 O:四氟硼酸-二乙醚錯合物(tetrafluoroboric acid diethyl ether complex) |
HCl:鹽酸(hydrochloric acid) |
HMDS:1,1,1,3,3,3-六甲基二矽氮烷(1,1,1,3,3,3-Hexamethyldisilazane) |
I2 :碘(iodine) |
i- PrOH:異丙醇(isopropanol) |
K2 CO3 :碳酸鉀(potassium carbonate) |
KOtBu:叔丁醇鉀(potassium tert-botuxide) |
LiAlH4 :鋁氫化鋰(lithium aluminium hydride) |
LiHMDS:雙(三甲矽)醯胺化鋰(lithium bis(trimethylsilyl)amide) |
LiOH.H2 O:氫氧化鋰單一水合物(lithium hydroxide monohydrate (lithine)) |
MeOH:甲醇(methanol) |
Mg:鎂(magnesium) |
Na2 S2 O3 :硫代硫酸鈉(sodium thiosulfate) |
Na2 SO4 :硫酸鈉(sodium sulfate) |
NaBH4 :硼氫化鈉(sodium borohydride) |
NaHCO3 :重碳酸鈉(sodium bicarbonate) |
NEt3 :三乙胺(tritethylamine) |
NH2 Cbz:胺甲醯苄酯(benzyl carbamate) |
NH4 Cl:氯化銨(ammonium chloride) |
Pd(PPh3 )4 :四(三苯基膦)鈀(Tetrakis(triphenylphosphine)palladium(0)) |
TFA:三氟乙酸(trifluoroacetic acid) |
Eq.:當量(equivalent) |
ESI:電噴灑游離(Electrospray Ionisation) |
HPLC:高效液相層析法(High Performance Liquid Chromatography) |
NMR:核磁共振(Nuclear Magnetic Resonance) |
PTFE filter:聚四氟乙烯濾紙(polytetrafluoroethylene filter) |
製備中間產物 (V)的通用製程,其 m = n = 0 (製程A)
在氬氣下將裝有次磷酸銨(ammonium hypophosphite)(5.0或10 當量)的小瓶中加入HMDS(5.0或10當量)。將白色懸浮液在105°C下加熱2小時以合成BTSP。將系統冷卻至0°C,接著加入中間產物(XII)(1.0當量)的DCM溶液(1.4-3.2mL/mmol的中間產物(XII))。將白色懸浮液在室溫下攪拌過夜。加入MeOH以淬火過量的BTSP。將反應混合物通過PTFE過濾器進行過濾,然後真空濃縮。將粗產物在1M之HCl (pH =1)中攪拌20分鐘,並用EtOAc萃取(三次)。合併的有機層經Na2
SO4
乾燥、過濾並真空濃縮,最終得到所需的中間產物(V)。
製備中間產物 (V) 的通用製程,其 m 或 n ≠ 0 (製程B)
將中間產物(XII)轉化為相應的格任亞溶液(0.5至1.0 M在無水THF或Et2
O中,1.05當量),在氬氣中滴加到無水Et2
O (1.0當量)的冷卻溶液(5°C)中,加入1.3 mL/mmol的氯亞磷酸二乙酯(1.0當量),並在添加過程中將內部溫度保持在0-10°C之間。在室溫下攪拌16小時後,將混合物通過矽藻土過濾。減壓濃縮濾液。將殘餘物溶解在水中,並用HCl水溶液(pH = 1)處理。將所得混合物在室溫下攪拌直至獲得無色透明溶液(15分鐘)。將該溶液用EtOAc萃取(三次),並將合併的有機層用鹽水洗滌,用Na2
SO4
乾燥、過濾並真空濃縮。將澄清液體以2M NaOH水溶液中稀釋,並將溶液攪拌1小時。用Et2
O洗滌水層,然後用濃HCl酸化(直到pH = 1)。將所得的酸性水層用DCM萃取(三次)。合併的有機層經Na2
SO4
乾燥、過濾、並真空濃縮,最終得到所需的中間產物(V)。
以膦-硼烷錯合物中間產物(XIII)來製備次磷酸 (Vbis)的通用製程 (製程 C)
二烷氧基膦-硼烷錯合物,(BH3
)P(OY)2
H,可參照 Tetrahedron 2008, 64, 9181-9190,來製備。
在Y= Et, (BH3
)P(OEt)2
H (1.2 當量) ,在-78°C下溶解於THF(3mL/mmol的膦-硼烷錯合物)中,並將得到的溶液脫氣。逐滴添加LiHMDS(1.0M的THF溶液,1.2當量),並將所得的淺黃色溶液在-78°C攪拌1小時。加入由其溴化類似物(XII)的轉化產生的碘化衍生物(1.0當量)於THF溶液中(1.5mL/mmol碘化衍生物),並將該混合物加熱至室溫,並在室內溫度攪拌2小時。加入NH4
Cl/鹽水的飽和溶液的1/1混合物來進行淬火,並加入EtOAc。分離各層,水相層以EtOAc萃取。合併的有機萃取物用鹽水洗滌、經Na2
SO4
乾燥、過濾並在減壓下濃縮。殘餘物以管柱層析法得到中間產物(XIII)。
接著,在0°C下在中間產物(XIII)(1.0當量)的DCM溶液(5mL/mmol中間產物(XIII))中滴加HBF4
.Et2
O (5.0當量)。將所得溶液在室溫攪拌4小時。以減壓濃縮反應混合物,並加入NaOH水溶液(2M,15mL)。攪拌30分鐘後,將水性混合物以MTBE洗滌兩次。逐滴加入濃HCl使水相酸化至pH值約1,並以NaCl對溶液進行飽和。加入EtOAc,並分離各層。用EtOAc萃取水相(兩次)。合併的有機萃取物經Na2
SO4
乾燥、過濾並在減壓下濃縮以獲得所需之中間產物(Vbis)。
多成分反應的通用製程 (製程 D)
在中間產物(V)(1.0當量)和胺甲醯苄酯(VII)(H2
N-X,X=CBz)(1.1當量)的溶液中加入約6:1的AcOH(0.9-1.8 mL/mmol中間產物(V)),並在AcCl(0.09-0.52 mL/ mmol中間產物(V)) 滴加中間物(VI)(1.2當量)。在室溫攪拌18小時後,將反應混合物與甲苯共蒸發(三次)。將殘餘物吸收在DCM,然後添加水以淬火剩餘的AcCl,然後將水層以DCM萃取(三次)。合併的有機層經Na2
SO4
乾燥、過濾並真空濃縮。將粗物質在Et2
O中研磨、過濾、並將收集之固體乾燥,獲得所需的中間產物(VIII)。
多成分反應之替代性通用製程 (製程E)
在含有碳酸銫(2.5當量)的DCM(0.95mL/mmol碳酸銫)溶液中加入次膦酸酯(Vbis)(1.5當量)。15分鐘後,再加入含有外消旋或手性之式(X)之磺酸基-亞胺的DCM (2.4 mL/mmol 的亞胺(X))溶液,並將反應混合物攪拌18小時。將反應混合物用水淬火。以EtOAc萃取水層(3次)。有機萃取物用鹽水洗滌,並經Na2
SO4
乾燥、過濾、真空濃縮。殘餘物以管柱層析法(正相或逆相)純化,以獲取所需之中間產物(XI)。
選擇性去保護的通用製程 (製程 F)
在含有中間產物(VIII)或(XI)(1.0當量)的THF/水(4:1)混合物中,以一批次加入LiOH·H2
O (3.0當量)。混合物立即變成橙色,並在室溫下攪拌直至反應完成。以蒸發THF的方式將混合物濃縮,然後將水層以EtOAc萃取(三次)。接著以HCl水溶液將水層酸化至pH 1,並出現沉澱。大多數情況下,水層用DCM萃取(五次),合併的有機層經Na2
SO4
乾燥、過濾並真空濃縮,以得到相應的選擇性去保護的中間產物(IX)和(XIV)。在某些情況下,酸處理後獲得的沉澱物可直接過濾並乾燥來獲取這些預期的中間產物。
酸性條件下最終去保護之通用製程 (製程 G)
在根據製程F選擇性去保護所得之中間物(IX)或(XIV)中加入TFA/苯甲醚或HCl/二㗁烷。若加入TFA/苯甲醚,於75°C攪拌2至6小時,然後根據需要在室溫下攪拌。若加入HCl /二㗁烷,則在室溫下攪拌。濃縮並與甲苯共蒸發(三次)後,或在出現沉澱的情況下直接過濾後,將粗產物研磨、通過製備型的LC/MS或逆向層析管柱純化,得到所需的本發明式(I)或(II)的化合物。
氫解作用的通用製程 (製程 H)
將中間產物(VIII)(1.0當量)溶解在EtOH /AcOH或MeOH /AcOH的混合物中(總體積:17至34mL/ mmol之受保護的化合物,取決於其溶解度)。粉末以音波振動處理以提高溶解度,然後將澄清溶液送入H-Cube(催化劑=10%Pd/C,T = 40°C,流速= 0.6-0.8 mL/min,全H2
模式或10 bar)中。濃縮後將粗產物以研磨或通過逆向層析管柱純化,得到本發明式(I)之化合物。
製備4-氧丁酸苄酯(benzyl 4-oxobutanoate)
步驟 1: 合成 4-羥基丁酸苄酯(benzyl 4-hydroxybutanoate)
將γ-丁內酯 (20mL、255 mmol、1.0當量)和NaOH(10.2 g,255 mmol,1.0當量)溶於水(170 mL)中,並加熱至70°C。12小時後,將水蒸發去除,並將剩餘之白色糊狀物與甲苯一起蒸發(三次)。白色固體置於真空下並加熱至70°C,2小時。將該固體再次以甲苯除去任何殘餘水份。將獲得的白色固體懸浮在丙酮(280mL)中。加入碘化四丁銨(4.72 g,12.8 mmol,0.05當量)和氯化苄基(29.4 mL,255 mmol,1.0當量)於該懸浮液中。將該溶液回流6小時,並在室溫下過夜,之後將該反應混合物再次回流6小時。在室溫下將混合物過濾並將濾液蒸發,得到粗產物,將其通過矽膠層析法純化。合併含有預期產物的餾分,並將其真空濃縮以得到此標題上的產物(36.5g,74%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.39-7.31 (m, 5H); 5.13 (s, 2H); 3.69 (t, 2H, J = 6.0 Hz); 2.50 (t, 2H, J = 7.0 Hz); 1.93-1.88 (m, 2H)
步驟 2: 合成4-氧丁酸苄酯
將4-羥基丁酸苄酯(10 g,51.49 mmol,1.0當量)溶於二氯甲烷(1.7 L)中,並冷卻至0°C。加入戴斯-馬丁高碘劑(Dess-Martin periodinane)(33g,77.23mmol,1.5當量)後,將混合物在室溫攪拌兩個半小時。將混合物濃縮並將粗產物以矽膠快速層析法純化。合併含有預期產物的餾分並將其真空濃縮,得到標題淺黃色油狀的化合物(8.0g,81%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.82 (s, 1H); 7.39-7.31 (m, 5H); 5.14 (s, 2H); 2.82 (t, 2H, J = 7.0 Hz); 2.71-2.67 (m, 2H)
製備4-氧丁酸甲酯(methyl 4-oxobutanoate)
步驟 1: 4-羥基丁酸甲酯(methyl 4-hydroxybutanoate)
將含有γ-丁內酯(10mL,127.7mmol,1.0當量)的MeOH(638mL)溶液中加入Et3
N (104mL,766.6mmol,6.0當量)後,將其加熱至60°C並攪拌持續19小時。將其冷卻至室溫,以甲苯(200mL)稀釋並真空濃縮。以甲苯共沸去除殘留的甲醇(2 x 40 mL)。將粗物質 (15g)以管柱層析法純化。合併含有預期產物的餾分並將其真空濃縮,得到標題上黃色油狀的化合物(12.1g,80%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 3.67 (m, 5H); 2.44 (m, 2H); 1.89 (m, 3H)
步驟 2: 4-氧丁酸甲酯
將4-羥基丁酸甲酯(6 g,50.79 mmol,1.0當量)溶於CH2
Cl2
(1.7 L)中,冷卻至0°C。加入戴斯-馬丁高碘劑(32.3g,76.19mmol,1.5當量)後,將黃色混合物在室溫下攪拌3小時。混合物濃縮後將粗產物(30g)以管柱層析法純化。合併含有預期產物的餾分並將其真空濃縮,得到標題上淺黃色油狀的化合物(2.25g,38%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.81 (s, 1H), 3.69 (s, 3H); 2.80 (m, 2H); 2.63 (m, 2H)
製備 (4E
)-4-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丁酸苄酯(benzyl (4E)-4-[(2-methylpropane-2-sulfinyl)imino]butanoate)
在室溫下在含有4-氧丁酸苄酯 (3.27 g,17.0 mmol,1.03當量)以及外消旋三級丁亞磺醯胺(tert-butylsulfinamide)(2.0 g,16.5 mmol,1.0當量)的DCM(32 mL)溶液中添加CuSO4
(5.27g,33.0mmol,2.0當量)。將懸浮液在室溫攪拌7小時,接著通過矽藻土過濾(以EtOAc漂洗),並將濾液減壓濃縮。殘餘物以管柱層析法純化,來獲得標題上淺黃色油狀的化合物(4.0g,82%)。MS (ESI+
): [M+H]+
= 296.21
H NMR (500 MHz, CDCl3
) δ (ppm): 8.16 (t, J = 3.1 Hz, 1H); 7.48-7.31 (m, 4H); 5.28-5.04 (m, 2H); 2.99-2.76 (m, 3H); 2.76-2.63 (m, 1H); 1.18 (s, 9H)
製備 (4E
)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸苄酯(benzyl (4E)-4-{[(S)-2-methylpropane-2-sulfinyl]imino}butanoate)
在室溫下在含有(S)-2-甲基丙烷-2-亞磺醯胺(0.75 g,6.19 mmol,1.0當量)的DCM(12.0 mL)溶液中依次添加CuSO4
(1.98 g,12.38 mmol,2.0當量 )和4-氧丁酸苄酯 (1.23 g,6.37 mmol,1.3 當量)。將混合物在室溫攪拌4小時。以矽藻土過濾溶液,並將濾餅以EtOAc洗滌。將濾液真空濃縮後以矽膠管柱層析法純化來獲得殘餘物,並得到預期的無色油狀化合物(1.3g,71%)。MS (ESI+
): [M+H]+
= 296.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.14 (t, 1H, J = 3.0 Hz); 7.38-7.31 (m, 5H); 5.15-5.10 (m, 2H); 2.94-2.66 (m, 4H); 1.15 (s, 9H)
製備 (4E
)-4-{[(R
)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸苄酯(benzyl (4E)-4-{[(R)-2-methylpropane-2-sulfinyl]imino}butanoate)
在室溫下在含有(R
)-2-甲基丙烷-2-亞磺醯胺(0.2 g,1.65 mmol,1.0當量)的DCM(3.3 mL)溶液中依次添加CuSO4
(527 mg,3.3 mmol,2.0當量)和4-氧丁酸苄酯(412 mg,2.15 mmol,1.3當量)。將混合物在室溫攪拌3小時。以矽藻土過濾溶液,並將濾餅以EtOAc洗滌。將濾液真空濃縮後用矽膠管柱層析法來獲得殘餘物,並得到預期的淺黃色油狀化合物(257mg,53%)。MS (ESI+
): [M+H]+
= 296.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.13 (t, 1H, J = 3.0 Hz); 7.38-7.31 (m, 5H); 5.15-5.09 (m, 2H); 2.94-2.66 (m, 4H); 1.15 (s, 9H)
製備 2,2-二甲基丙基 3-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丙烷-1-磺酸鹽(2,2-dimethylpropyl 3-[(2-methylpropane-2-sulfinyl)imino]propane-1-sulfonate)
步驟 1: 2,2-二甲基丙基 甲磺酸鹽(2,2-dimethylpropyl methanesulfonate)
在0°C冷卻、含有2,2-二甲基丙-1-醇(10 g,113.4 mmol,1.0當量)和甲磺醯氯(8.2 mL,323.3 mmol,0.94當量)的DCM(200 mL)溶液中滴加三甲胺(45mL,106.6mmol,2.85當量)。使內部反應溫度保持在10°C以下(內部溫度計)。在 1小時30分鐘內完成添加。將反應混合物在0°C下繼續攪拌2.5小時。然後將混合物用飽和NaHCO3
水溶液洗滌並以Na2
SO4
乾燥、過濾並真空濃縮。以柱層析法純化粗產物,來獲得標題上淺黃色油狀的化合物(16.8g,89%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 3.90 (s, 2H); 3.03 (s, 3H); 1.02 (s, 9H)
步驟 2: 2,2-二甲基丙基 3-羥丙烷-1-磺酸鹽(2,2-dimethylpropyl 3-hydroxypropane-1-sulfonate)
氬氣的環境下,在無水THF(100mL)中,將正丁基鋰溶液(2.5 M的己烷溶液,23 ,57.7 mmol,1.2當量)滴加到先前冷卻(-78°C乾冰,丙酮)的成品 (8.0 g,48.1 mmol,1.0當量)以及四甲基乙二胺(7.9 ,96.2 mmol,2.0當量) 溶液中, 15分鐘內完成滴加。將所得溶液在-78°C繼續攪拌30分鐘,接著在15分鐘內逐滴加入環氧乙烷溶液(3.0M的THF溶液,19.3 mL,57.7 mmol,1.2當量)。將混合物在室溫下攪拌16小時,接著以Et2
O稀釋並以鹽水洗滌。以Et2
O (3次)萃取水層,並將合併的有機層以Na2
SO4
乾燥、過濾並真空濃縮。濃縮後的淺黃色油狀物以管柱層析法純化,並獲得標題上的無色油狀化合物(7.73g,76%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 3.88 (s, 2H); 3.79 (t, J = 5.5 Hz, 2H); 3.26 (t, J = 8.0 Hz, 2H); 2.11 (tt, J = 5.5 and 8.0 Hz, 2H); 0.99 (s, 9H)
步驟 3: 2,2-二甲基丙基 3-氧丙烷-1-磺酸鹽(2,2-dimethylpropyl 3-oxopropane-1-sulfonate)
在室溫下在先前產物(7.7 g,17.6 mmol,1.0當量)的DCM(810 mL)溶液中加入適量之戴斯-馬丁氧化劑(23.3 g,54.9 mmol,1.5當量)。攪拌1.5小時後,溶液將變成乳狀並完全消耗起始原料。將反應混合物真空濃縮、並將殘餘物(25 g)以層析法純化。合併含有預期產物的餾分並將其真空濃縮,並獲得到預期之無色油狀化合物(3.9g,59 %),其靜置時會結晶。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.81 (s, 1H); 3.89 (s, 2H); 3.43 (t, J = 7.5 Hz 2H); 3.07 (t, J = 7.5 Hz 2H); 0.99 (s, 9H)
步驟 4: 2,2-二甲基丙基 (3E)-3-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丙烷-1-磺酸鹽(2,2-dimethylpropyl (3E)-3-[(2-methylpropane-2-sulfinyl)imino]propane-1-sulfonate)
在室溫下在含有先前產物(4.10 g,19.7 mmol,1.0當量)以及外消旋三級丁基亞磺醯胺(3.1 g,25.6 mmol,1.3當量)的DCM(33 mL)溶液中添加CuSO4
(6.28 g, 39.4mmol,2.0當量)。將得到的懸浮液在室溫下攪拌16小時,接著以矽藻土過濾(EtOAc漂洗),並將濾液減壓濃縮。殘餘物以管柱層析法純化,並獲得標題上的白色固體化合物(5.2g,85%)。1
H NMR (500 MHz, CDCl3
) δ (ppm): 8.18 (t, J = 3.1 Hz, 1H); 3.99-3.87 (m, 2H); 3.64-3.40 (m, 2H); 3.19-3.05 (m, 2H); 1.23 (s, 9H); 1.02 (s, 9H)
實例 1: 4-胺基-4-[芐基(羥基)磷醯基]丁酸 (4-amino-4-[benzyl(hydroxy)phosphoryl]butanoic acid)
步驟1: 苄基次磷酸(Benzylphosphinic acid)
透過依照製程A,由在DCM(1.5mL)中之芐基溴(317 µL,2.92 mmol,1.0當量)以及新鮮配置的BTSP(14.62 mmol,5.0當量)製備標題上的無色油狀化合物(252 mg,55%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.34-7.31 (m, 2H); 7.29-7.21 (m, 3H); 6.98 (dt, 1H, J = 560 and 1.8 Hz); 5.93 (bs, 1H); 3.12 (dd, 2H, J = 18.3 and 1.8 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.84
步驟 2: 苄基(1-{[(苄氧基)羰基]胺基}-4-甲氧基-4-酮丁基)次磷酸(Benzyl(1-{[(benzyloxy)carbonyl]amino}-4-methoxy-4-oxobutyl)phosphinic acid)
依照製程D在含有前一步產物(252mg,1.61mmol,1.0當量)以及NH2
Cbz (268mg,1.78mmol,1.1 當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸甲酯(純度90%,208 µL,1.78 mmol),經多成分反應後獲得標題白色粉末狀化合物(522mg,80%)。1
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11.16 (bs, 1H); 7.49-7.17 (m, 11H); 5.07 (s, 2H); 3.72 (m, 1H,); 3.56 (s, 3H); 2.98 (d, 2H, J = 15.0 Hz); 2.43-2.30 (m, 2H); 2.05-1.91 (m, 1H); 1.78-1.69 (m, 1H)
步驟 3: 4-[苄基(羧基)磷醯基]-4-{[(苄氧基)羰基]胺基}丁酸(4-[benzyl(hydroxy)phosphoryl]-4-{[(benzyloxy)carbonyl]amino}butanoic acid)
依照製程F前一步產物(522 mg, 1.29 mmol)在THF/H2
O (4 mL/1 mL)的混合物中加入LiOH·H2
O(92 mg,3.86 mmol, 3.0當量),以製備標題上的白色粉末狀化合物(304 mg,60%)。MS (ESI+
): [M+H]+
= 392.21
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11.60 (bs, 2H); 7.47 (d, 1H, J = 9.6 Hz); 7.42-7.10 (m, 9H); 5.07 (s, 2H); 3.76-3.69 (m, 1H); 2.98 (d, 2H, J = 15.0 Hz); 2.36-2.20 (m, 2H); 2.03-1.97 (m, 1H); 1.73-1.66 (m, 1H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 43.62
步驟 4: 4-胺基-4-[苄基(羥基)磷醯基]丁酸(4-amino-4-[benzyl(hydroxy)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(304 mg,0.78 mmol)在EtOH/AcOH 9/1 (14 mL/1.5 mL)的混合物,氫解製備標題上的白色粉末狀化合物(125 mg,62%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 240.1; [M+H]+
= 258.1; [(Mx2)+H]+
= 512.2; [(Mx3)+H]+
= 772.41
H NMR (D2
O, 500 MHz) δ (ppm): 7.44-7.34 (m, 5H); 3.22 (td, 1H, J = 8.5 and 5.0 Hz); 3.08 (dd, 2H, J = 16.5 and 3.0 Hz); 2.57-2.42 (m, 2H); 2.11-2.04 (m, 1H); 1.94-1.85 (m, 1H)31
P NMR (D2
O, 202 MHz) δ (ppm): 30.41
實例 2: 4-胺基-4-{羥基[(2-甲苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(2-methylphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(2-甲苯基)甲基]次磷酸
可依照製程A由1(溴甲基)-2-甲苯(1.0g,5.40mmol,1.0當量)的DCM (7.9 mL)溶液以及新鮮配置的BTSP (27.02 mmol,5.0當量),以製備標題上的固體化合物(354 mg,38%)。MS (ESI+
): [M+H]+
= 171.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.91 (br s, 1H); 7.18-7.12 (m, 4H); 6.90 (dt, 1H, J = 558.5 and 2.0 Hz); 3.11 (dd, 2H, J = 18.5 and 2.0 Hz); 2.32 (s, 3H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.60
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(2-甲苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(2-methylphenyl) methyl]phosphinic acid)
可依照製程D在含有前一步產物(354mg,2.08mmol,1.0當量)以及NH2
Cbz (320 mg,2.29 mmol,1.1當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(443 mg,2.50 mmol,1.2 當量),經多成分反應後獲得標題上的白色粉末狀化合物(534mg,52%)。MS (ESI+
): [M+H]+
= 496.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.06 (m, 14H); 5.16-5.05 (m, 4H); 4.04-3.99 (m, 1H); 3.19-3.08 (m, 2H); 2.57-2.45 (m, 2H); 2.32 (s, 3H); 2.27-2.19 (m, 1H), 1.93-1.84 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 45.10
步驟 3: 4-胺基-4-{羥基[(2-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-methylphenyl)methyl]phosphoryl}butanoic acid)
標題上的白色固體化合物(92mg,56%)可依照製程H將含有前一步產物(300mg,0.60mmol,1.0當量)的EtOH/AcOH (1:1,18 mL)混合溶液進行氫解製備而成。預估純度: > 95% (由液相層析質譜儀及磁核共振譜儀估計) MS (ESI+
): [(M-H2
O)+H]+
= 254.1; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.2; [(Mx3)+H]+
= 814.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.31-7.28 (m, 1H); 7.15-7.05 (m, 3H); 3.17-3.13 (m, 1H); 3.07 (dd, 2H, J = 16.0 and 1.5 Hz); 2.55 (t, 2H, J = 7.5 Hz); 2.42 (s, 3H); 2.26-2.17 (m, 1H), 2.00-1.90 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.25
實例3:4-胺基-4-{羥基[(3-甲苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(3-methylphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(3-甲苯基)甲基]次磷酸([(3-methylphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-3-甲苯(1.0 g,5.40 mmol,1.0當量)的DCM (1.03 g/ml)溶液以及新鮮配置的BTSP(27.02 mmol,5.0當量),以製備標題上的固體化合物(518 mg,56%,純度80-85%)。MS (ESI+
): [M+H]+
= 171.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.24 (br s, 1H); 7.22-7.17 (m, 1H); 7.08-7.01 (m, 3H); 6.94 (dt, 1H, J = 560 and 2.0 Hz); 3.07 (dd, 2H, J = 18.5 and 2.0 Hz); 2.32 (s, 3H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 32.68
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(3-甲苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(3-methylphenyl) methyl]phosphinic acid)
標題上的白色粉末狀化合物(899 mg,60%)可依照製程D在含有前一步產物(518 mg,3.04 mmol,1.0當量)以及NH2
Cbz (506 mg,3.35 mmol,1.1當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯((702 mg,3.65 mmol,1.2 當量)並經多成分反應後獲得。MS (ESI+
): [M+H]+
= 496.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.40-7.27 (m, 10H); 7.16 (t, 1H, J = 7.5 Hz); 7.10 (br s, 1H); 7.05 (t, 2H, J = 7.5 Hz); 5.12 (s, 2H); 5.11 (s, 2H); 4.00-3.95 (m, 1H); 3.10 (dd, 2H, J = 16.0 and 6.0 Hz); 2.55-2.43 (m, 2H); 2.31 (s, 3H); 2.25-2.17 (m, 1H), 1.93-1.83 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 45.01
步驟 3: 4-胺基-4-{羥基[(3-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-methylphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(400 mg,0.81 mmol,1.0當量)的EtOH/AcOH (1:1,22 mL)混合溶液進行氫解,以製備標題上的白色固體化合物(165 mg,75%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 254.1; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.2; [(Mx3)+H]+
= 814.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.18-7.11 (m, 3H); 7.00 (d, 1H, J = 7.0 Hz); 3.08-3.04 (m, 1H); 3.00 (d, 2H, J = 16.5 Hz); 2.49 (t, 2H, J = 7.5 Hz); 2.31 (s, 3H); 2.19-2.10 (m, 1H), 1.95-1.85 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.33
實例4:4-胺基-4-{羥基[(4-甲苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(4-methylphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(4-甲苯基)甲基]次磷酸
依照製程A由1-(溴甲基)-4-甲苯(1.0 g,5.40 mmol,1.0當量)的DCM (7.9 mL)溶液以及新鮮配置的BTSP (27.02 mmol,5.0當量),以
製備標題上的淺粉紅色固體化合物(574 mg,62%)。MS (ESI+
): [M+H]+
= 171.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.51 (br s, 1H); 7.14-7.09 (m, 4H); 6.93 (dt, 1H, J = 559.0 and 2.0 Hz); 3.07 (dd, 2H, J = 18.5 and 2.0 Hz); 2.31 (s, 3H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.50
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(4-甲苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(4-methylphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(574 mg,3.37 mmol,1.0當量)以及NH2
Cbz(561 mg,3.71 mmol,1.1當量)的AcOH溶液(3.0 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(778 mg,4.05 mmol, 1.2 當量),經多成分反應後獲得標題上的白色粉末狀化合物(940 mg,56%)。MS (ESI+
): [M+H]+
= 496.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.26 (m, 10H); 7.14-7.06 (m, 4H); 5.10-5.09 (m, 4H); 3.97-3.92 (m, 1H); 3.06 (dd, 2H, J = 15.5 and 5.0 Hz); 2.52-2.40 (m, 2H); 2.28 (s, 3H); 2.23-2.15 (m, 1H), 1.90-1.81 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.83
步驟 3: 4-胺基-4-{羥基[(4-甲苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methylphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(400 mg,0.81 mmol,1.0當量)的EtOH/AcOH (1:1,21mL)混合溶液進行氫解,以製備標題上的白色固體化合物(191 mg,87%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 254.1; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.2; [(Mx3)+H]+
= 814.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.22 (dd, 2H, J = 8.0 and 2.0 Hz); 7.09 (d, 2H, J = 7.5 Hz); 3.07-3.02 (m, 1H); 2.99 (d, 2H, J = 16.0 Hz); 2.48 (t, 2H, J = 7.5 Hz); 2.29 (s, 3H); 2.17-2.09 (m, 1H); 1.92-1.85 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.44
實例5:4-胺基-4-({[3,5-雙(三氟甲基)苯基]甲基}(羥基)磷醯基)丁酸(4-amino-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(hydroxy)phosphoryl) butanoic acid)
步驟 1: {[3,5-雙(三氟甲基)苯基]甲基}次磷酸({[3,5-bis(trifluoromethyl)phenyl]methyl}phosphinic acid)
依照製程A由1-(溴甲基)-3,5-雙(三氟甲基)苯(1 g,3.26 mmol,1.0當量)的DCM(5 mL)溶液以及新鮮配置的BTSP(16.28 mmol,5.0當量)製備標題上的白色固體化合物(160mg,17%)。MS (ESI+
): [M+H]+
= 293.01
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.81 (s, 1H); 7.72-7.69 (m, 2H); 7.04 (d, 1H, J = 569.0 Hz); 6.51 (br s, 1H); 3.25 (d, 2H, J = 18.0 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 31.49
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({[3,5-雙(三氟甲基)苯基]甲基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({[3,5-bis(trifluoro methyl)phenyl]methyl})phosphinic acid)
依照製程D在含有前一步產物(160mg,0.55mmol,1.0當量)以及NH2
Cbz(91mg,0.60mmol,1.1當量)的AcOH溶液(0.8 mL)及AcCl的溶液(0.1 mL)中加入4-氧丁酸芐酯(131 mg,0.68 mmol, 1.2 當量)並經多成分反應後獲得標題上的白色固體化合物(149 mg,44%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.89-7.82 (m, 3H); 7.37-7.26 (m, 10H); 5.13-5.06 (m, 4H); 4.00-3.98 (m, 1H); 3.49 (dd, 2H, J = 14.0 and 7.0 Hz); 2.53-2.44 (m, 2H); 2.27-2.19 (m, 1H); 1.93-1.83 (m, 1H)
步驟 3: 4-胺基-4-({[3,5-雙(三氟甲基)苯基]甲基}(羥基)磷醯基)丁酸(4-amino-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(hydroxy)phosphoryl)butanoic acid)
依照製程H將含有前一步產物(149 mg,0.24 mmol,1.0當量)的EtOH/AcOH (9:1,4.3 mL)混合溶液進行氫解,製備標題上的白色粉末狀化合物(53 mg,56%)。預估純度: > 95% (根據液相層析質譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 376.0; [M+H]+
= 394.0; [(Mx2)+H]+
= 787.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.96 (s, 2H); 7.78 (s, 1H); 3.23-3.12 (m, 3H); 2.58 (t, 2H, J = 7.5 Hz); 2.27-2.16 (m, 1H); 1.98-1.90 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 24.89
實例6: 4-胺基-4-[({[1,1'-聯苯]-2-基}甲基)(羥基)磷醯基]丁酸 (4-amino-4-[({[1,1'-biphenyl]-2-yl}methyl)(hydroxy)phosphoryl]butanoic acid)
步驟 1: ({[1,1'-聯苯]-2-基}甲基)次磷酸(({[1,1'-biphenyl]-2-yl}methyl)phosphinic acid)
依照製程A由2(溴甲基)-1,1'-聯苯(1.0 g,4.05 mmol,1.0當量)的DCM (8.2mL)溶液以及新鮮配置的BTSP(20.23 mmol,5.0當量)製備標題上的白色固體化合物(498 mg,53%)。MS (ESI+
): [M+H]+
= 233.01
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.41-7.25 (m, 9.5H); 6.28 (t, 0.5H, J = 2.0 Hz); 4.16 (br s, 1H); 3.13 (dd, 2H, J = 19.0 and 2.0 Hz)
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({[1,1'-聯苯]-2-基}甲基)次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({[1,1'-biphenyl]-2-yl}methyl)phosphinic acid)
依照製程D在含有前一步產物(490mg,2.11 mmol,1.0當量)以及NH2
Cbz (351 mg,2.32 mmol,1.0當量)的AcOH溶液(2.2 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸芐酯(487 mg,2.53 mmol,1.2 當量)並經多成分反應後獲得標題上的白色膠狀化合物(1.0g,85%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.57-7.20 (m, 19H); 5.17-4.94 (m, 4H); 3.89-3.84 (m, 1H); 3.14 (dt, 2H, J = 63.5 and 15.0 Hz); 2.47-2.35 (m, 2H); 2.15-2.05 (m, 1H); 1.83‑1.70 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.42
步驟 3: 4-胺基-4-[({[1,1'-聯苯]-2-基}甲基)(羥基)磷醯基]丁酸(4-amino-4-[({[1,1'-biphenyl]-2-yl}methyl)(hydroxy)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(250 mg,0.45 mmol,1.0當量)的EtOH/AcOH (9:1,8.0 mL)混合溶液進行氫解製備標題上的白色固體化合物(28mg,19%)。預估純度: > 95% (根據液相層析質譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 316.0; [M+H]+
= 334.0; [(Mx2)+H]+
= 667.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.66 (d, 1H, J = 8.0 Hz); 7.48-7.41 (m, 4H); 7.36-7.20 (m, 4H); 3.63-3.00 (m, 2H); 2.84-2.80 (m, 1H); 2.35 (td, 2H, J = 7.5 and 2.5 Hz); 1.89‑1.73 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 29.11
實例7:4-胺基-4-[羥基({[3-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[3-(trifluoromethoxy)phenyl]methyl})phosphoryl] butanoic acid)
步驟 1: {[3-(三氟甲氧基)苯基]甲基}次磷酸({[3-(trifluoromethoxy)phenyl]methyl}phosphinic acid)
可依照製程A由1-(溴甲基)-3-(三氟甲氧基)苯(1.0 g,3.92mmol,1.0當量)的DCM (7.9mL)溶液以及新鮮配置的BTSP(19.6 mmol,5.0當量)製備標題上的淺黃色油狀化合物(460mg,49%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.05 (br s, 1H); 7.35 (t, 1H, J = 8.0 Hz); 7.18-7.11 (m, 3H); 7.00 (d, 1H, J = 569.0 Hz); 3.14 (d, 2H, J = 18.5 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 34.25
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({[3-(三氟 甲氧基)苯基]甲基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({[3-(trifluoro methoxy)phenyl]methyl})phosphinic acid)
依照製程D在含有前一步產物(460 mg,1.92 mmol,1.0當量)以及NH2
Cbz(318 mg,2.11 mmol,1.1當量)的AcOH溶液(2.6 mL)及AcCl的溶液(0.9 mL)中加入4-氧丁酸芐酯(441 mg,2.30 mmol,1.2 當量)並經多成分反應後獲得標題上的白色固體化合物(741mg,68%)。MS (ESI+
): [M+H]+
= 566.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.12 (m, 14H); 5.10 (s, 2H); 5.09 (s, 2H) 3.99-3.94 (m, 1H); 3.17-3.13 (m, 2H); 2.53-2.42 (m, 2H); 2.26-2.17 (m, 1H); 1.91-1.82 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 43.62
步驟 3: 4-胺基-4-[羥基({[3-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[3-(trifluoromethoxy)phenyl]methyl})phosphoryl]butanoic acid)
依照製程H將含有前一步產物(200 mg,0.35 mmol,1.0當量)的EtOH/AcOH (1:1,12 mL)混合溶液進行氫解製備標題上的白色粉末狀化合物(23mg,19%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 324.0; [M+H]+
= 342.0; [(Mx2)+H]+
= 683.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.30 (m, 3H); 7.11-7.09 (m, 1H); 3.12-3.02 (m, 3H); 2.54 (t, 2H, J = 7.5 Hz); 2.23-2.14 (m, 1H); 1.99-1.87 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 25.90
實例8:4-胺基-4-[羥基({[4-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[4-(trifluoromethoxy)phenyl]methyl})phosphoryl] butanoic acid)
步驟 1: {[4-(三氟甲氧基)苯基]甲基}次磷酸({[4-(trifluoromethoxy)phenyl]methyl}phosphinic acid)
依照製程A由1-(溴甲基)-4-(三氟甲氧基)苯(1.0 g,3.92 mmol,1.0當量)的DCM(7.9 mL)溶液以及新鮮配置的BTSP(19.6 mmol,5.0當量)製備標題上的油狀化合物(750 mg,80%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.97 (br s, 1H); 7.27-7.24 (m, 2H); 7.18 (d, 2H, J = 8.5 Hz); 6.98 (dt, 1H, J = 562 and 1.5 Hz); 3.12 (dd, 2H, J = 18.0 and 1.5 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 35.03
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({[4-(三氟 甲氧基)苯基]甲基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({[4-(trifluoro methoxy)phenyl]methyl})phosphinic acid)
依照製程D在含有前一步產物(300 mg,1.25 mmol,1.0當量)以及NH2
Cbz(207 mg,1.37 mmol,1.1當量)的AcOH溶液(1.4 mL)及AcCl的溶液(0.245 mL)中加入4-氧丁酸芐酯(288 mg,1.50 mmol,1.2 當量)並經多成分反應後獲得標題上的白色固體化合物(498 mg,70%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.27 (m, 12H); 7.16 (d, 2H, J = 8.5 Hz); 5.10 (s, 2H); 5.09 (s, 2H); 4.00-3.95 (m, 1H); 3.16 (dd, 2H, J = 15.0 and 3.0 Hz); 2.54-2.42 (m, 2H); 2.24-2.19 (m, 1H); 1.90-1.85 (m, 1H)
步驟 3: 4-胺基-4-[羥基({[4-(三氟甲氧基)苯基]甲基})磷醯基]丁酸(4-amino-4-[hydroxy({[4-(trifluoromethoxy)phenyl]methyl})phosphoryl]butanoic acid)
依照製程H將含有前一步產物(250 mg,0.44 mmol,1.0當量)的EtOH/AcOH (9:1,8.0 mL)混合溶液進行氫解製備標題上的白色粉末狀化合物(96 mg,64%)。預估純度: > 95% (根據液相層析質譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 324.0; [M+H]+
= 342.0; [(Mx2)+H]+
= 683.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.44-7.41 (dd, 2H, J = 9.0 and 2.0 Hz); 7.19-7.17 (m, 2H); 3.12-3.03 (m, 3H); 2.55 (t, 2H, J = 7.5 Hz); 2.22-2.16 (m, 1H); 1.99-1.90 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 26.32
實例9: 4-胺基-4-{羥基[(4-甲磺醯苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methanesulfonylphenyl)methyl]phosphoryl} butanoic acid)
步驟 1: [(4-甲磺醯苯基)甲基]次磷酸([(4-methanesulfonylphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-4-(甲磺醯基)苯(1 (bromomethyl)-4-(methylsulfonyl)benzene)(1.0 g,4.01 mmol,1.0當量)的DCM (5.1mL)溶液以及新鮮配置的BTSP(20.07 mmol,5.0當量)製備標題上的淡黃色固體化合物(218 mg,23%,純度80%)。MS (ESI+
): [M+H]+
= 234.91
H NMR (MeOD, 500 MHz) δ (ppm): 7.94-7.92 (dd, 2H, J = 8.5 and 1.0 Hz); 7.57-7.55 (dd, 2H, J = 8.5 and 2.5 Hz); 7.06 (dt, 1H, J = 555.0 and 1.5 Hz); 3.36-3.32 (m, 2H); 3.11 (s, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 29.75
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(4-甲磺醯苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(4-methanesulfonyl phenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(218 mg,0.93 mmol,1.0當量)以及NH2
Cbz(155 mg,1.02 mmol,1.1當量)的AcOH溶液(1.0 mL)及AcCl的溶液(0.2 mL)中加入4-氧丁酸芐酯(214 mg,1.12 mmol,1.2 當量),在室溫攪拌混合物4小時(而非18小時),再經多成分反應後獲得標題上的黃色油狀化合物(450 mg,87%)。MS (ESI+
): [M+H]+
= 560.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.84 (d, 2H, J = 3.0 Hz); 7.51 (dd, 2H, J = 8.5 and 2.5 Hz); 7.39-7.28 (m, 10H); 5.11 (s, 2H); 5.09 (s, 2H); 3.99-3.94 (m, 1H); 3.24 (dd, 2H, J = 16.0 and 4.0 Hz); 3.07 (s, 3H), 2.54-2.39 (m, 2H); 2.25-2.17 (m, 1H); 1.91-1.82 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 43.19
步驟 3: 4-胺基-4-{羥基[(4-甲磺醯苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methanesulfonylphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(150 mg,0.27 mmol,1.0當量)的EtOH/AcOH (9:1,4.8 mL)混合溶液進行氫解製備標題上的白色固體化合物(19 mg,21%)。預估純度: > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 336.11
H NMR (DMSO-d6, 500 MHz) δ (ppm): 7.77 (d, 2H, J = 8.0 Hz); 7.49 (dd, 2H, J = 8.5 and 1.5 Hz); 3.16 (s, 3H); 3.01-2.98 (m, 2H); 2.78-2.74 (m, 1H); 2.39-2.33 (m, 1H from CH2
, the other H was under the DMSO signal); 1.97-1.88 (m, 1H), 1.85-1.75 (m, 1H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 21.08
實例10:4-胺基-4-{羥基[(2-甲氧苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: 1-(溴甲基)-2-甲氧苯(1-(bromomethyl)-2-methoxybenzene)
以CH2
Cl2
(70 mL)稀釋市售之(2-甲氧苯基)甲醇(2.0 g,14.5 mmol,1.0當量)以及四溴化碳(7.68 g,23.16 mmol,1.6當量)。將溶液冷卻(冰/鹽浴)至-5°C,並分批加入三苯膦(6.07g,23.16mmol,1.6當量)。在室溫下攪拌黃色反應介質過夜。最後將混合物濃縮並以管柱層析法純化可得標題上的淺黃色油狀化合物(2.13g,73%)1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.34-7.26 (m, 2H); 6.94-6.88 (m, 2H); 4.58 (s, 2H); 3.90 (s, 3H)
步驟 2: [(2-甲氧苯基)甲基]次磷酸([(2-methoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-2-甲氧苯 (2.1 g,10.44 mmol,1.0當量)的DCM (16.0mL)溶液以及新鮮配置的BTSP(104.4 mmol,10當量)製備標題上的無色油狀化合物(1.54 g,59%)。 MS (ESI+
): [M+H]+
= 187.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.18 (br s, 1H); 7.29-7.22 (m, 2H); 7.05 (dt, 1H, J = 570.5 and 2.0 Hz); 6.96-6.93 (m, 1H); 6.89 (d, 1H, J = 8.5 Hz); 3.85 (s, 3H); 3.24 (dd, 2H, J = 19.5 and 2.0 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 35.52
步驟 3: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(2-甲氧苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(2-methoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(800 mg,4.30 mmol,1.0當量)以及NH2
Cbz(715mg,4.73mmol,1.1當量)的AcOH溶液(7.8 mL)及AcCl的溶液(1.0 mL)中加入4-氧丁酸芐酯(benzyl 4-oxobutanoate )(991 mg,5.16 mmol,1.2 當量),經多成分反應後獲得標題上的黃色固體化合物(2.2 g,定量產量)。MS (ESI+
): [M+H]+
= 512.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.18 (m, 12H); 6.94-6.84 (m, 2H); 5.17 (s, 4H); 4.01-3.96 (m, 1H); 3.79 (s, 3H); 3.27-3.15 (m, 2H); 2.51-2.36 (m, 2H); 2.23-2.14 (m, 1H); 1.87-1.77 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 45.42
步驟 4: 4-胺基-4-{羥基[(2-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(1.29 g,2.52 mmol,1.0當量)的EtOH/AcOH (9:1,50 mL)混合溶液進行氫解製備標題上的白色固體化合物(39 mg,5%)。預估純度: 93% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 270.2; [M+H]+
= 288.2; [(Mx2)+H]+
= 575.3, [(Mx3)+H]+
= 862.61
H NMR (MeOD, 500 MHz) δ (ppm): 7.34 (dt, 1H, J = 7.5 and 2.5 Hz); 7.19 (tt, 1H, J = 8.0 and 2.0 Hz); 6.95 (d, 1H, J = 8.0 Hz); 6.90 (tt, 1H , J = 7.0 and 1.0 Hz); 3.86 (s, 3H); 3.19-3.12 (m, 1H); 3.04-2.98 (m, 2H); 2.46 (t, 2H, J = 7.5 Hz); 2.20-2.11 (m, 1H); 1.96-1.85 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 28.56
實例11:4-胺基-4-{羥基[(3-甲氧苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(3-methoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(3-甲氧苯基)甲基]次磷酸([(3-methoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-3-甲氧苯 (1.0 g,4.97 mmol,1.0當量)的DCM (10.6mL)溶液以及新鮮配置的BTSP(49.74 mmol,10當量)製備標題上的棕色油狀化合物(393 mg,42%,純度70-80%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.23 (t, 1H, J = 7.5 Hz); 6.96 (dt, 1H, J = 562.0 and 2.0 Hz); 6.82-6.77 (m, 3H); 4.11 (br s, 1H); 3.78 (s, 3H); 3.08 (dd, 2H, J = 18.5 and 2.0 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.26
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(3-甲氧苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(3-methoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(638 mg,2.74 mmol,1.0當量)以及NH2
Cbz (455 mg,3.02 mmol,1.1當量)的AcOH溶液(3.8 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(991 mg,5.16 mmol,1.2 當量)並經多成分反應後獲得標題上的白色粉狀化合物(930 mg,66%)。MS (ESI+
): [M+H]+
= 512.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.25 (m, 10H); 7.16 (t, 1H, J = 7.5 Hz); 6.86-6.76 (m, 3H); 5.094 (s, 2H); 5.088 (s, 2H); 4.00-3.95 (m, 1H); 3.76 (s, 3H); 3.15-3.04 (m, 2H); 2.53-2.41 (m, 2H); 2.24-2.15 (m, 1H); 1.91-1.81 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.60
步驟 3: 4-胺基-4-{羥基[(3-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-methoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(414 mg,0.81mmol,1.0當量)的EtOH/AcOH (1:1,16 mL)混合溶液進行氫解製備標題上的白色固體化合物(135 mg,58%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 270.2; [M+H]+
= 288.2; [(Mx2)+H]+
= 575.3, [(Mx3)+H]+
= 862.61
H NMR (MeOD, 500 MHz) δ (ppm): 7.17 (t, 1H, J = 7.5 Hz); 6.95 (s, 1H); 6.91 (d, 1H, J = 7.5 Hz); 6.75 (m, 1H); 3.78 (s, 3H); 3.09-3.05 (m, 1H); 3.01 (d, 2H, J = 16.5 Hz); 2.50 (t, 2H, J = 7.5 Hz); 2.20-2.11 (m, 1H), 1.95-1.86 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.11
實例12: 4-胺基-4-{羥基[(4-甲氧苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(4-methoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(4-甲氧苯基)甲基]次磷酸([(4-methoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-4-甲氧苯 (1.0 g,4.97 mmol,1.0當量)的DCM (10.6mL)溶液以及新鮮配置的BTSP (49.74 mmol,10當量)製備標題上的棕色油狀化合物(399 mg,43%)。MS (ESI+
): [M+H]+
= 187.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.14 (dd, 2H, J = 8.5 and 2.5 Hz); 6.94 (d, 1H, J = 557.5 Hz); 6.85 (d, 2H, J = 8.5 Hz); 5.93 (br s, 1H); 3.77 (s, 3H); 3.05 (d, 2H, J = 18.0 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.20
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(4-甲氧苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(4-methoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(399 mg,2.14 mmol,1.0當量)以及NH2
Cbz (356 mg,2.36 mmol,1.1當量)的AcOH溶液(3.5 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(494 mg,2.57 mmol,1.2 當量)並經多成分反應後獲得標題上的白色粉狀化合物(625 mg,57%)。MS (ESI+
): [M+H]+
= 512.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.26 (m, 10H); 7.16 (dd, 2H, J = 8.5 and 2.0 Hz); 6.81 (d, 2H, J = 8.5 Hz); 5.09 (br s, 4H); 3.97-3.92 (m, 1H); 3.74 (s, 3H); 3.09-2.99 (m, 2H); 2.52-2.40 (m, 2H), 2.23-2.15 (m, 1H); 1.90-1.81 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 45.05
步驟 3: 4-胺基-4-{羥基[(4-甲氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-methoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(403 mg,0.79 mmol,1.0當量)的EtOH/AcOH (1:1,16 mL)混合溶液進行氫解製備標題上的白色固體化合物(140 mg,62%)。預估純度: 92% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 270.2; [M+H]+
= 288.1; [(Mx2)+H]+
= 575.2, [(Mx3)+H]+
=862.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.25 (dd, 2H, J = 8.5 and 2.5 Hz); 6.84 (d, 2H, J = 10.0 Hz); 3.76 (s, 3H); 3.07-3.02 (m, 1H); 2.96 (dd, 2H, J = 16.5 and 2.0 Hz); 2.49 (t, 2H, J = 7.5 Hz); 2.18-2.10 (m, 1H), 1.94-1.85 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.61
實例13: 4-胺基-4-{[(3-氰苯基)甲基](羥基)磷醯基}丁酸(4-amino-4-{[(3-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid)
步驟 1: [(3-氰苯基)甲基]次磷酸([(3-cyanophenyl)methyl]phosphinic acid)
依照製程A由3-(溴甲基)苄腈(2.0 g,10.2 mmol,1.0當量)的DCM (16.2 mL)溶液以及新鮮配置的BTSP (51.01 mmol,5當量)製備標題上的白色固體化合物(487 mg,26%,純度70% )。MS (ESI+
): [M+H]+
= 182.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.59-7.43 (m, 4.5H); 6.40 (s, 0.5H); 3.53 (br s, 1H); 3.12 (dd, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.70
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(3-氰苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(3-cyanophenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物(478mg,2.64 mmol,1.0當量)以及NH2
Cbz (438 mg,2.90 mmol,1.1當量)的AcOH溶液(3.0 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(608 mg,3.17 mmol,1.2 當量)並經多成分反應後獲得標題上的黃色油狀化合物(937 mg,70%)。粗產物直接於下一步使用。
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{[(3-氰苯基)甲基](羥基)磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[(3-cyanophenyl)methyl](hydroxy)phosphoryl} butanoic acid)
依照製程F在前一步產物(937 mg,1.85 mmol,1當量)以及THF/H2
O (15.8mL/4.6 mL)的混合溶液中加入LiOH.H2
O(233 mg, 5.55 mmol, 3.0當量)製備標題上的化合物(316 mg,41%)。產物直接於下一步使用。
步驟 4: 4-胺基-4-{[(3-氰苯基)甲基](羥基)磷醯基}丁酸(4-amino-4-{[(3-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(316 mg,759 µmmol,1.0當量)的TFA/苯甲醚 (2.6 mL/527 µL)溶液製備標題上的白色固體化合物(30 mg,14%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 265.1; [M+H]+
= 283.1; [(Mx2)+H]+
= 565.1; [(Mx3)+H]+
= 847.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.72 (q, 1H, J = 2.0 Hz); 7.65 (dq, 1H, J = 8.0 and 2.0 Hz); 7.56 (dq, 1H, J = 8.0 and 2.0 Hz); 7.46 (t, 1H, J = 8.0 Hz); 3.13-3.03 (m, 3H); 2.56 (t, 2H, J = 7.5 Hz); 2.24-2.15 (m, 1H), 1.99-1.88 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 25.56
實例14:4-胺基-4-{[(4-氰苯基)甲基](羥基)磷醯基}丁酸 (4-amino-4-{[(4-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid)
步驟 1: [(4-氰苯基)甲基]次磷酸([(4-cyanophenyl)methyl]phosphinic acid)
依照製程A由4-(溴甲基)苄腈(4 (bromomethyl)benzonitrile)(2.0 g,10.2 mmol,1.0當量)的DCM (16.2 mL)溶液以及新鮮配置的BTSP(51.01 mmol,5當量)製備標題上的固體化合物(700 mg,38% )。MS (ESI+
): [M+H]+
= 182.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.64-7.62 (dd, 2H, J = 8.5 and 1.0 Hz); 7.36-7.34 (m, 2H); 6.99 (dt, 1H, J = 549.0 and 1.5 Hz); 4.18 (br s, 1H); 3.18 (dd, 2H, J = 18.5 and 1.5 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.82
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(4-氰苯基) 甲基]次磷酸 ([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(4-cyanophenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,2.76 mmol,1.0當量)以及NH2
Cbz (459 mg,3.04 mmol,1.1當量)的AcOH溶液(3.8 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(benzyl 4-oxobutanoate)(459 mg,3.31 mmol,1.2 當量)並經多成分反應後獲得標題上的淡黃色粉狀化合物 (930 mg,66%)。 MS (ESI+
): [M+H]+
= 507.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.67-7.26 (m, 14H); 5.09 (s, 4H); 3.99-3.94 (m, 1H); 3.26‑3.15 (m, 2H); 2.54-2.39 (m, 2H); 2.25-2.16 (m, 1H), 1.91-1.82 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 43.35
步驟3: 4-{[(苄氧基)羰基]胺基}-4-{[(4-氰苯基)甲基](羥基)磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[(4-cyanophenyl)methyl](hydroxy)phosphoryl} butanoic acid)
依照製程F在前一步產物(500 mg,0.95 mmol,1當量)以及THF/H2
O (9.5 mL/2.4 mL)的混合溶液中加入LiOH.H2
O(120 mg, 2.85 mmol, 3.0當量)製備標題上的化合物 (343 mg,83%)。MS (ESI+
): [M+H]+
= 417.01
H NMR (MeOD, 500 MHz) δ (ppm): 7.67-7.28 (m, 9H); 5.15-5.05 (m, 2H); 3.97-3.91 (m, 1H); 3.26-3.16 (m, 2H); 2.47-2.33 (m, 2H); 2.22-2.14 (m, 1H), 1.89-1.79 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 43.04
步驟 4: 4-胺基-4-{[(4-氰苯基)甲基](羥基)磷醯基}丁酸(4-amino-4-{[(4-cyanophenyl)methyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(343 mg,824 µmmol,1.0當量)的TFA/苯甲醚 (3.8 mL/834 µL)溶液製備標題上的白色固體化合物(84 mg,36%)。 預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 265.1; [M+H]+
= 283.1; [(Mx2)+H]+
= 565.1; [(Mx3)+H]+
= 847.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.63 (d, 2H, J = 7.5 Hz); 7.51 (d, 2H, J = 7.5 Hz); 3.14‑3.10 (m, 3H); 2.55 (t, 2H, J = 6.5 Hz); 2.22-2.16 (m, 1H), 1.96-1.89 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 25.36
實例15: 4-胺基-4-{羥基[(萘-1-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(naphthalen-1-yl)methyl]phosphoryl}butanoic acid)
步驟 1: [(萘-1-基)甲基]次磷酸([(naphthalen-1-yl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)萘(2.0 g,9.05 mmol,1.0當量)的DCM (29.5 mL)溶液以及新鮮配置的BTSP(45.23 mmol,5當量)製備標題上的白色固體化合物(1.4 g,75%)。MS (ESI+
): [M+H]+
= 207.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.93 (d, 1H, J = 10.0 Hz); 7.84 (dd, 1H, J = 5.0 Hz and 1.6 Hz); 7.77-7.75 (m, 1H); 7.54-7.44 (m, 2.5H); 7.40 (pseudo t
, 1H, J = 7.5 Hz); 7.35-7.33 (m, 1H); 6.77 (br s, 1H); 6.41 (s, 0.5H); 3.51 (d, 2H, J = 20.0 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 35.44
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(萘-1-基)甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(naphthalen-1-yl) methyl]phosphinic acid)
依照製程D在含有前一步產物 (700 mg,3.40 mmol,1.0當量)以及NH2
Cbz (564 mg,3.73 mmol,1.1當量)的AcOH溶液(5.6 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(783 mg,4.07 mmol,1.2 當量)並經多成分反應後獲得標題上的白色粉狀化合物 (1.07 g,59%)。 MS (ESI+
): [M+H]+
= 532.21
H NMR (MeOD, 500 MHz) δ (ppm): 8.11 (d, 1H, J = 8.0 Hz); 7.87-7.85 (m, 1H); 7.78 (d, 1H, J = 8.0 Hz); 7.52-7.26 (m, 14H); 5.16-5.07 (m, 4H); 4.12-4.08 (m, 1H); 3.65-3.61 (m, 2H); 2.58-2.46 (m, 2H); 2.31-2.22 (m, 1H); 1.98-1.87 (m, 1H)
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{羥基[(萘-1-基)甲基]磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxy[(naphthalen-1-yl)methyl]phosphoryl} butanoic acid)
依照製程F在前一步產物(523 mg,0.984 mmol,1.0當量)以及THF/H2
O (8.4 mL/2.5 mL)的混合溶液中加入LiOH.H2
O(123 mg,2.95 mmol,3.0當量)製備標題上白色固體的化合物 (384 mg,88%)。MS (ESI+
): [M+H]+
= 442.21
H NMR (MeOD, 500 MHz) δ (ppm): 8.11-8.09 (m, 1H); 7.85-7.83 (m, 1H); 7.76 (d, 1H, J = 8.0 Hz); 7.50-7.26 (m, 9H); 5.13 (pseudo
q, 2H, J = 12.0 Hz); 4.12-4.05 (m, 1H); 3.67-3.57 (m, 2H); 2.50-2.36 (m, 2H); 2.28-2.19 (m, 1H); 1.94-1.84 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.47
步驟 4:4-胺基-4-{羥基[(萘-1-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(naphthalen-1-yl)methyl]phosphoryl}butanoic acid)
依照製程G從含有前一步產物(384 mg,870 µmmol,1.0當量)的TFA/苯甲醚 (2.5 mL/605 µL)溶液製備標題上的白色固體化合物(56 mg,21%)。預估純度: > 95% (根據液相層析質譜儀及磁核共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 290.2; [M+H]+
= 308.2; [(Mx2)+H]+
= 615.3; [(Mx3)+H]+
= 922.61
H NMR (MeOD, 500 MHz) δ (ppm): 8.25 (d, 1H, J = 8.5 Hz); 7.84-7.83 (m, 1H); 7.73 (d, 1H, J = 8.0 Hz); 7.54-7.51 (m, 2H); 7.48-7.45 (m, 1H); 7.41 (t, 1H , J = 7.5 Hz); 3.53 (d, 2H, J = 16.5 Hz); 3.15-3.11 (m, 1H); 2.45 (t, 2H, J = 7.5 Hz); 2.248-2.14 (m, 1H); 1.97-1.89 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 26.94
實例16:4-胺基-4-{羥基[(2-苯氧苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(2-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: (2-苯氧苯基)甲醇
0°C,含氬氣環境下,將2-苯氧苯甲酸(5.0 g,23.34 mmol,1.0當量)的無水THF(12 mL)溶液滴加到氫化鋁鋰 (2M 的THF溶液,23.3 mL,46.68 mmol,2.0 當量)的無水THF(13 mL)溶液中。此反應為放熱反應且混合物會變為黃色。將混合物在室溫攪拌2小時,接著冷卻至0°C,然後用2mL H2
O緩慢淬火。依次加入NaOH水溶液(4mL,15%)以及H2
O (6mL),將其攪拌15分鐘。加入無水Na2
SO4
並將混合物攪拌15分鐘。最後將黃色混合物以矽藻土墊過濾,並將濾液真空濃縮以得到標題上之化合物(4.7g,定量產率)。
MS (ESI+
): [M+H]+
= 183.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.46 (dd, 1H, J = 7.5 and 1.5 Hz); 7.36-7.32 (m, 2H); 7.25 (dt, 1H, J = 7.5 and 1.5 Hz); 7.15-7.09 (m, 2H); 6.99-6.97 (m, 2H); 6.88 (dd, 1H , J = 8.0 及 1.5 Hz); 4.76 (d, 2H, J = 5.5 Hz); 2.04 (t, 1H , J = 6.0 Hz)
步驟 2: 1-(溴甲基)-2-苯氧苯(1-(bromomethyl)-2-phenoxybenzene)
以CH2
Cl2
(50 mL)稀釋先前獲得的(2-苄氧基苯基)甲醇(2.1 g,10.5 mmol,1.0當量)及四溴化碳(5.56 g,16.78 mmol,1.6當量)。將溶液在-5°C(冰/鹽浴)中冷卻,並分批加入三苯膦(4.40g,16.78mmol,1.6當量)。接著將黃色的反應介質在室溫攪拌3小時。最後將混合物濃縮並以管柱層析法純化,得到標題上的黃色油狀化合物(2.8g,定量產率)。
1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.45 (dd, 1H, J = 7.5 and 2.0 Hz); 7.37-7.33 (m, 2H); 7.27-7.23 (m, 1H); 7.14-7.02 (m, 4H); 6.84 (dd, 1H, J = 7.5 and 1.0 Hz); 4.61 (s, 2H)
步驟 3: [(2-苯氧苯基)甲基]次磷酸([(2-phenoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-2-苯氧苯 (1.0 g,4.97 mmol,1.0當量)的DCM (7.6 mL)溶液以及新鮮配置的BTSP(19.0 mmol,5當量),以製備標題上的黃色油狀化合物(572 mg,61%)。MS (ESI+
): [M+H]+
= 249.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.30-7.27 (m, 2H); 7.21-7.10 (m, 2H); 7.06-7.01 (m, 2H); 7.01 (dt, 1H, J = 554.0 and 2.0 Hz); 6.92-6.89 (m, 2H); 6.77-6.75 (m, 1H); 3.18-3.13 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 30.80
步驟 4: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(2-苯氧苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(2-phenoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物 (527 mg,2.30 mmol,1.0當量)以及NH2
Cbz (383 mg,2.53 mmol,1.1當量)的AcOH溶液(4.0 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(531 mg,2.77 mmol,1.2 當量)並經多成分反應後獲得標題上的淡黃色固體化合物 (1.0 g,76%)。MS (ESI+
): [M+H]+
= 574.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.45-7.43 (m, 1H); 7.37-7.24 (m, 13H); 7.20-7.16 (m, 1H); 7.10-7.04 (m, 2H); 6.99 (dd, 1H, J = 8.5 and 1.0 Hz); 6.79 (d, 1H , J = 8.5 Hz); 5.08-5.04 (m, 4H); 4.04-3.99 (m, 1H); 3.25-3.16 (m, 2H); 2.52-2.39 (m, 2H); 2.24-2.17 (m, 1H); 1.89‑1.80 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.73
步驟 5: 4-胺基-4-{羥基[(2-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(2-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(300 mg,0.52 mmol,1.0當量)的EtOH/AcOH (1:1,9.0 mL)混合溶液進行氫解製備標題上的白色固體化合物(75 mg,41%)。預估濃度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 332.2; [M+H]+
= 350.2; [(Mx2)+H]+
= 699.41
H NMR (MeOD, 500 MHz) δ (ppm): 7.53 (dt, 1H, J = 7.5 and 2.0 Hz); 7.36-7.33 (m, 2H); 7.18 (dt, 1H, J = 7.5 and 2.0 Hz); 7.11-7.08 (m, 2H); 7.01-6.99 (m, 2H); 6.82 (d, 1H, J = 8.0 Hz); 3.17-3.05 (m, 3H); 2.48 (dt, 2H, J = 8.0 and 2.5 Hz); 2.22-2.13 (m, 1H); 1.99-1.88 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.49
實例17: 4-胺基-4-{羥基[(3-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(3-苯氧苯基)甲基]次磷酸([(3-phenoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-3-苯氧苯 (1.0 g,3.26 mmol,1.0當量)的DCM (1.5 mL)溶液以及新鮮配置的BTSP (16.28 mmol,5當量)製備標題上的無色油狀化合物(208 mg,44%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.34-7.30 (m, 2H); 7.28-7.25 (m, 1H); 7.10 (m, 1H); 7.01-6.95 (m, 3H); 6.99 (dt, 1H, J = 560 and 1.8 Hz); 6.91-6.88 (m, 2H); 5.18 (bs, 1H); 3.09 (dd, 2H, J = 18.3 and 1.8 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.25
步驟 2: (1-{[(苄氧基)羰基]胺基}-4-甲氧基-4-酮丁基)[(3-苯氧苯基) 甲基]次磷酸((1-{[(benzyloxy)carbonyl]amino}-4-methoxy-4-oxobutyl)[(3-phenoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物 (208 mg,0.84 mmol,1.0當量)以及NH2
Cbz (140 mg,0.92 mmol,1.1當量)的AcOH溶液(1.0 mL)及AcCl的溶液(0.2 mL)中加入4-氧丁酸甲酯(純度90%,98 µL,0.93 mmol),經多成分反應後獲得標題上的白色粉狀化合物 (351 mg,84%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.36-7.27 (m, 7H); 7.18 (t, 1H, J = 7.9 Hz); 7.08-7.05 (m, 1H); 6.98-6.91 (m, 4H); 6.83 (d, 1H, J = 8.4 Hz); 5.15-5.07 (m, 3H); 4.40 (bs, 1H); 3.95 (m, 1H); 3.59 (s, 3H); 3.00 (dd, 2H, J = 15.9 and 3.3 Hz); 2.36 (t, 2H, J = 7.2 Hz); 2.09‑2.03 (m, 1H); 1.81-1.72 (m, 1H)
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{羥基[(3-苯氧苯基)甲基] 磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxy[(3-phenoxyphenyl)methyl] phosphoryl}butanoic acid)
依照製程F在前一步產物(315 mg,0.71 mmol,1.0當量)以及THF/H2
O (3 mL/1 mL)的混合溶液中加入LiOH.H2
O(51 mg,2.12 mmol,3.0當量)製備標題上白色固體的化合物 (310 mg,91%)。MS (ESI+
): [M+H]+
= 484.21
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11.62 (bs, 2H); 7.46 (dd, 1H, J = 9.6 Hz); 7.39-7.20 (m, 8H); 7.12 (td, 1H, J = 7.4 and 1.2 Hz); 7.07-6.96 (m, 3H); 6.95-6.93 (m, 1H); 6.82 (d, 1H, J = 8.3 Hz); 5.05 (s, 2H); 3.71 (qd, 1H, J = 10.0 及 3.7 Hz); 2.99 (d, 2H, J = 15.0 Hz); 2.35-2.18 (m, 2H); 2.03-1.94 (m, 1H); 1.73-1.63 (m, 1H)
步驟 4: 4-胺基-4-{羥基[(3-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(310 mg,0.64 mmol,1.0當量)的EtOH/AcOH (9/1,15.5 mL)混合溶液進行氫解製備標題上的白色粉狀化合物(173 mg,77%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 332.1; [M+H]+
= 350.1; [(Mx2)+H]+
= 699.41
H NMR (DMSO-d6/D2
O, 500 MHz) δ (ppm): 7.33 (t, 2H, J = 7.8 Hz); 7.22 (t, 1H, J = 7.9 Hz); 7.08 (t, 1H, J = 7.4 Hz); 7.02 (d, 1H, J = 7.7 Hz); 6.95-6.91 (m, 3H); 6.72 (d, 1H, J = 8.2 Hz); 2.88-2.84 (m, 3H); 2.37-2.24 (m, 2H); 1.92-1.85 (m, 1H); 1.74-1.65 (m, 1H)
實例18: 4-胺基-4-{羥基[(4-苯氧苯基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(4-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
步驟 1: [(4-苯氧苯基)甲基]次磷酸([(4-phenoxyphenyl)methyl]phosphinic acid)
依照製程A由1-(溴甲基)-4-苯氧苯 (917 mg,3.48 mmol,1.0當量)的DCM (7.0 mL)溶液以及新鮮配置的BTSP(17.42 mmol,5當量)製備標題上的油狀化合物(559 mg,65%,應為純度80%但被重複添加的產品汙染)。MS (ESI+
): [M+H]+
= 249.01
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.32 (m, 2H); 7.28-7.26 (m, 2H); 7.12-7.09 (m, 1H); 6.99 (dt, 1H, J = 553.5 and 2.0 Hz); 6.98 (m, 4H); 3.17 (dd, 2H, J = 18.5 and 2.0 Hz)31
P NMR (MeOD, 202 MHz) δ (ppm): 32.43
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(4-苯氧苯基) 甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(4-phenoxyphenyl) methyl]phosphinic acid)
依照製程D在含有前一步產物 (559 mg,2.25 mmol,1.0當量)以及NH2
Cbz (374 mg,2.48 mmol,1.1當量)的AcOH溶液(2.4 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(519 mg,2.70 mmol,1.2 當量)並經多成分反應後獲得標題上的白色固體化合物 (670 mg,52%)。MS (ESI+
): [M+H]+
= 574.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.17 (m, 14H); 7.09 (t, 1H, J = 7.5 Hz); 6.96 (m, 2H); 6.87 (d, 2H , J = 8.5 Hz); 5.09 (s, 4H); 3.98-3.92 (m, 1H); 3.12-3.08 (m, 2H); 2.54-2.42 (m, 2H); 2.24-2.16 (m, 1H); 1.92-1.82 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.66
步驟 3: 4-胺基-4-{羥基[(4-苯氧苯基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(4-phenoxyphenyl)methyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(250 mg,0.44 mmol,1.0當量)的EtOH/AcOH (1:1,12 mL)混合溶液進行氫解製備標題上的白色固體化合物(21 mg,14%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 332.1; [M+H]+
= 350.1; [(Mx2)+H]+
= 399.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.34-7.30 (m, 4H); 7.08 (tt, 1H, J = 7.5 and 1.0 Hz); 6.96 (m, 2H); 6.91 (d, 2H , J = 8.5 Hz); 3.11-3.06 (m, 1H); 3.02 (dd, 2H, J = 16.0 and 3.5 Hz); 2.52 (t, 2H, J = 7.5 Hz); 2.21-2.12 (m, 1H); 1.96-1.86 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 27.03
實例19: 4-胺基-4-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丁酸) (4-amino-4-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]butanoic acid
步驟 1: {[1,1'-聯苯]-3-基}甲醇({[1,1'-biphenyl]-3-yl}methanol)
在0°C,氬氣的環境中,將[1,1'-聯苯]-3-羧酸乙酯(2.50 g,11.0 mmol,1.0當量)的無水THF(5.5 mL)溶液滴加到市售之氫化鋁鋰(2.0 M 於THF中,11.0 mL,22 mmol,2.0當量)溶液中。將混合物在室溫攪拌1小時。冷卻至0°C後,加入水(0.9 mL)、15% NaOH水溶液(0.9 mL),接著再次加入水(2.7 mL)。攪拌15分鐘後,加入Na2
SO4
,並將懸浮液以矽藻土過濾(以MTBE沖洗)。將濾液減壓濃縮,得到標題上白色固體的化合物(2.0g,98%)。
MS (ESI+
): [(M-H2
O)+H]+
= 167.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.68-7.60 (m, 3H); 7.56 (dt, J = 7.8, 1.6 Hz, 1H); 7.47 (t, J = 7.6 Hz, 3H); 7.44-7.34 (m, 2H); 4.80 (d, J = 5.9 Hz, 2H); 1.71 (t, J = 6.0 Hz, 1H)
步驟 2: 3-(碘甲基)-1,1'-聯苯(3-(iodomethyl)-1,1'-biphenyl)
0°C下,在三苯膦(triphenylphosphine)(3.7g,14mmol,1.3當量)的DCM(60 mL)溶液中加入I2
(3.58 g,14.1 mmol,1.3當量)。在0°C下攪拌15分鐘,將咪唑(961 mg,14.1 mmol,1.3當量)以及前一步的化合物產物(2.0 g,10.9 mmol,1.0當量)加至該溶液中。將混合物在室溫攪拌1小時。讓反應混合物在EtOAc及Na2
S2
O3
飽和溶液中選擇性分離,並引發脫色。分離各層,並將有機層以(鹽水)洗滌,再以Na2
SO4
乾燥、過濾並減壓濃縮。以管柱層析法純化殘餘物,最後得到標題上的淺黃色固體化合物(2.9g,91%)。
1
H NMR (CDCl3
, 500 MHz) δ (ppm): δ 7.67-7.56 (m, 3H); 7.55-7.44 (m, 3H); 7.44-7.34 (m, 3H); 4.55 (s, 2H)
步驟 3: 膦-硼烷錯合中間產物(phosphine-borane complex intermediate)
依照製程C的第一步,在前一步產物(2.70 g,9.20 mmol,1.0當量)的THF(4 mL)溶液中加入(BH3
)P(OEt)2
H (1.50 g,11.0 mmol,1.2 當量)的THF (25 mL)溶液以及LiHMDS (1.0 M 的THF溶液,11.0 mL,11.0 mmol,1.2 當量),以製備標題上的無色油狀化合物 (2.90 g, 100%)。
MS (ESI-
): [(M-H2
)-H]-
= 2991
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.46-7.39 (m, 2H) ; 7.33 (q, J = 2.1 Hz, 1H) ; 7.31 (br d, J = 7.7 Hz, 1H); 7.28-7.21 (m, 2H); 7.21-7.11 (m, 2H); 7.09-7.01 (m, 1H); 3.90-3.79 (m, 4H), 3.08 (d, J = 11.7 Hz, 2H), 1.04 (t, J = 7.1 Hz, 6H), 0.67-0.14 (m, 3H)
步驟 4: ({[1,1'-聯苯]-3-基}甲基)次磷酸(({[1,1'-biphenyl]-3-yl}methyl)phosphinic acid)
依照製程C變化的第二步驟,在前一步產物(1.5g,5.0mmol,1.0當量)的DCM(25 mL)溶液中加入HBF4
.Et2
O (3.38 mL,24.8 mmol,5.0當量),以製備標題上的淺粉紅色固體化合物(862mg,74%)。MS (ESI+
): [M+H]+
= 233.1; [(Mx2)+H]+
= 465.01
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.66-7.62 (m, 2H); 7.59-7.50 (m, 2H); 7.49-7.41 (m, 3H); 7.39-7.32 (m, 1H); 7.32-7.24 (m, 1H); 7.06 (dm, J1 P-H
= 500 Hz, 1H); 3.29 (dd, J = 18.4, 2.0 Hz, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 32.5
步驟 5: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({[1,1'-聯苯]-3-基}甲基)次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({[1,1'-biphenyl]-3-yl}methyl)phosphinic acid)
依照製程D在含有前一步產物 (0.43 g,1.8 mmol,1.0當量)以及NH2
Cbz (308 mg,2.04 mmol,1.1當量)的AcOH溶液(2.6 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(427 mg,2.22 mmol,1.2 當量),經多成分反應後獲得標題上的化合物 (1.2 g,以定量產率看待)。 MS (ESI+
): [M+H]+
= 558.2
步驟 6: 4-{[(苄氧基)羰基]胺基}-4-[({[1,1'-聯苯]-3-基}甲基)( 羥基) 磷醯基]丁酸(4-{[(benzyloxy)carbonyl]amino}-4-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy) phosphoryl]butanoic acid)
依照製程F在前一步產物(1.2 g,2.15 mmol,1.0當量)以及THF/水 (4/1, 11 mL)的混合溶液中加入LiOH·H2
O(270 mg,6.46 mmol,3.0當量),以製備標題上的化合物 (390 mg,分兩步45%)。MS (ESI+
): [M+H]+
= 468.0; [(Mx2)+H]+
= 935.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.70-7.59 (m, 3H); 7.59-7.47 (m, 1H); 7.47-7.41 (m, 2H); 7.41-7.21 (m, 8H); 5.16-5.04 (m, 2H); 4.02 (td, J = 10.0, 3.5 Hz, 1H); 3.30-3.14 (m, 2H); 2.57-2.34 (m, 2H); 2.29-2.13 (m, 1H); 1.95-1.80 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 45.0
步驟 7: 4-胺基-4-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丁酸(4-amino-4-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]butanoic acid)
依照製程G從含有前一步產物(390 mg,834 µmol,1.0當量)的TFA/苯甲醚 (1.7 mL/2.7 mL)溶液,製備標題上的白色固體化合物(81 mg,29%)。預估純度: 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI-
): [M-H]-
= 332.1; [(Mx2)-H]-
= 665.31
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.70-7.59 (m, 3H); 7.51-7.40 (m, 3H); 7.40-7.30 (m, 3H); 3.18-3.08 (m, 3H); 2.54 (t, J = 7.3 Hz, 2H); 2.28-2.18 (m, 1H); 2.03-1.87 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 27.0
實例 20: 4-胺基-4-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸 (4-amino-4-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl}butanoic acid)
步驟 1: 5-甲基-3-苯基-1,2-㗁唑(5-methyl-3-phenyl-1,2-oxazole )
在(Z)-N-羥基苯甲醛肟氯化物(2.0 g,12.9 mmol,1.0 當量)的DCM(26 mL)溶液中加入丙炔(1 M於 THF溶液中,25.7 mL,25.7 mmol,2.0當量)以及Et3
N (2.33mL,16.7mmol,1.3當量)。將混合物在室溫攪拌16小時。接著在EtOAc以及NH4
Cl飽和溶液中進行選擇性分離。分離各層,水相用EtOAc萃取。合併的有機萃取物以鹽水洗滌,並經Na2
SO4
乾燥、過濾、減壓濃縮。殘留物再以管柱層析法純化並得到標題上的白色固體化合物(1.57g,77%)。MS (ESI+
): [M+H]+
= 160.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.88-7.71 (m, 2H); 7.53-7.42 (m, 3H); 6.32 (q, J = 0.9 Hz, 1H); 2.50 (d, J = 0.9 Hz, 3H)
步驟 2: [(3-苯基-1,2-㗁唑-5-基)甲基]次磷酸([(3-phenyl-1,2-oxazol-5-yl)methyl]phosphinic acid)
在-78°C下,在前一步產物(2.94 g,18.5 mmol,1.0當量)的THF(30 mL)溶液中加入新鮮製備的LDA溶液(於THF溶液中,44.3 mL,22.2 mmol,1.2當量)。在-78°C下攪拌1小時,滴加亞磷酸氯二乙酯(3.18 mL,22.2 mmol,1.2當量)。接著在-78°C下攪拌1小時,然後在室溫下再攪拌3小時。加入水(20 mL),然後加入濃HCl水溶液(2 mL)。將該懸浮液以EtOAc進行(3次)萃取,並將合併的有機萃取液以鹽水洗滌,經Na2
SO4
乾燥、過濾並減壓濃縮。將黃色液體以2N NaOH溶液(10mL)處理,並讓混合物在室溫攪拌30分鐘。以Et2
O洗滌水相,並以濃HCl酸化再以DCM進行(3次)萃取。最後將合併的有機萃取物以Na2
SO4
乾燥、過濾並減壓濃縮來獲得標題上的淺黃色油狀化合物(2.6g,63%)。
MS (ESI+
): [M+H]+
= 224.1; [(Mx2)+H]+
= 447.01
H NMR (500 MHz, CDCl3
) δ (ppm): 7.83-7.74 (m, 2H); 7.56-7.36 (m, 3H); 7.28 (dm, J1 P‑H
= 583Hz, 1H); 6.60 (d, J = 2.8 Hz, 1H); 3.45 (d, J = 18.3 Hz, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 27.6
步驟 3: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][(3-苯基-1,2-㗁唑-5-基)甲基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][(3-phenyl-1,2-oxazol-5-yl)methyl]phosphinic acid)
依照製程D在含有前一步產物 (450 mg,2.0 mmol,1.0當量)以及NH2
Cbz (355 mg,2.22 mmol,1.1當量)的AcOH溶液(3.5 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸芐酯(465 mg,2.42 mmol,1.2 當量)並經多成分反應後獲得標題上的化合物 (1.1 g,預期定量產量)。MS (ESI+
): [M+H]+
= 549.1
步驟 4: 4-{[(苄氧基)羰基]胺基}-4-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基] 磷醯基} 丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl] phosphoryl} butanoic acid)
依照製程F在前一步產物(1.1 g,2.0 mmol)以及THF/H2
O (4/1, 10 mL)的混合溶液中加入LiOH·H2
O(252 mg,6.02 mmol,3.0當量)製備標題上白色固體的化合物 (717 mg,78%,分兩步)。MS (ESI+
): [M+H]+
= 459.0; [(Mx2)+H]+
= 917.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.96-7.67 (m, 2H); 7.57-7.42 (m, 3H); 7.41-7.17 (m, 5H); 6.77 (d, J = 2.5 Hz, 1H); 5.24-5.03 (m, 2H); 4.23-4.00 (m, 1H); 3.53-3.38 (m, 2H); 2.55-2.37 (m, 2H); 2.32-2.15 (m, 1H); 1.99-1.80 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 40.4
步驟 5: 4-胺基-4-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl}butanoic acid)
依照製程G從含有前一步產物(717 mg,1.56 mmol,1.0當量)的TFA/苯甲醚 (6 mL/8.5 mL)溶液,製備標題上的白色固體化合物(37 mg,7%)。預估純度: > 100% (根據液相層析質譜儀分析結果) and > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 325.1; [(Mx2)+H]+
= 649.2 MS (ESI-
): [M-H]-
= 323.1; [(Mx2)-H]-
= 647.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.96-7.64 (m, 2H); 7.56-7.31 (m, 3H); 6.78 (d, J = 2.5 Hz, 1H); 3.36 (s, 2H); 3.28 (td, J = 8.1, 5.4 Hz, 1H); 2.63 (t, J = 7.3 Hz, 2H); 2.39-2.18 (m, 1H); 2.10-1.86 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 22.6
實例 21: 4-胺基-4-{羥基[(5-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl}butanoic acid)
步驟 1: 3-甲基-5-苯基-1,2-㗁唑(3-methyl-5-phenyl-1,2-oxazole )
在1-苯丁烷-1,3-二酮(4.87 g,30.0 mmol,1.0當量)的THF / EtOH(1/1,150 mL)溶液中加入羥胺鹽酸鹽(2.08 g,30.0 mmol,1.0 當量 )。將反應混合物回流攪拌24小時。冷卻至室溫,再減壓去除揮發物,並將殘餘物以EtOAc及水進行選擇性分離。分離各層,水相以EtOAc萃取。合併的有機萃取物以鹽水洗滌,並以Na2
SO4
乾燥、過濾、減壓濃縮。殘餘物以管柱層析法純化,最後得到標題上的白色固體化合物(3.78g,79%)。MS (ESI+
): [M+H]+
= 160.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.86-7.70 (m, 2H), 7.55-7.39 (m, 3H), 6.39 (s, 1H), 2.38 (s, 3H)
步驟 2: [(5-苯基-1,2-㗁唑-3-基)甲基]次磷酸苄酯(benzyl [(5-phenyl-1,2-oxazol-3-yl)methyl]phosphinate)
-78°C下,在前一步產物(5.26 g,33.0 mmol,1當量)的THF(5 3mL)溶液中加入新鮮配置的LDA溶液(0.5 M THF溶液,79.3 mL,39.6 mmol,1.2 當量)。於-78°C下攪拌1h後,滴加亞磷酸氯二乙酯(5.69mL,39.6mmol,1.2當量)。繼續在-78°C下攪拌1小時,然後在室溫下攪拌16小時。加入水(20mL),然後加入濃HCl水溶液(2mL)。將該懸浮液以EtOAc進行(三次)萃取,並將合併的有機萃取液以鹽水洗滌,經Na2
SO4
乾燥、過濾、減壓濃縮。接著把黃色液體以2N NaOH溶液(20mL)處理,並將其混合物在室溫攪拌30分鐘。以Et2
O洗滌水相,再以濃HCl水溶液酸化,並用DCM進行(三次)萃取。合併的有機萃取物以Na2
SO4
乾燥、過濾、減壓濃縮,得到4.1g黃色油狀物。將其溶解在DCM(100mL)中,加入苯甲醇(2.48mL; 23.9mmol)和EDCI(5.28g,27.6mmol)。將混合物在室溫攪拌16小時。接著將其以EtOAc及1N HCl水溶液進行選擇性分離。分離各層後,有機相以1N HCl水溶液及鹽水洗滌,以Na2
SO4
乾燥、過濾、減壓濃縮。純化得來的即是標題上的黃色油狀化合物(1.16克,兩步20%)。MS (ESI+
): [M+H]+
= 314.11
H NMR (500 MHz, CD3
OD) δ (ppm): 7.89-7.81 (m, 2H); 7.57-7.48 (m, 3H); 7.40-7.31 (m, 4H); 7.31-7.20 (m, 1H); 6.82 (d,J
= 1.0 Hz, 1H); 4.62 (s, 2H); 3.56-3.41 (m, 2H)
步驟 3: 4-[(苄氧基)[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基]-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸苄酯(benzyl 4-[(benzyloxy)[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl]-4-[(2-methylpropane-2-sulfinyl)amino]butanoate)
依照製程E,在前一步產物(580mg,1.9mmol,1.0當量)及碳酸銫(905mg,2.78 mmol,1.5 當量)的CH2
Cl2
(5 mL)溶液中加入外消旋的(4E
)-4-[(2-甲基丙烷-2-亞磺醯基) 亞胺基]丁酸芐酯(711 mg,2.41 mmol,1.3 當量)的CH2
Cl2
(2.3 mL) 溶液,以製備標題上由4種非鏡像異構物混和而成的黃色油狀化合物 (213mg,19%)。MS (ESI+
): [M+H]+
= 609.31
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.87-7.73 (m, 2H); 7.60-7.47 (m, 3H); 7.45-7.25 (m, 10H); 6.75-6.61 (m, 1H); 5.24-5.02 (m, 4H); 4.00-3.82 (m, 1H); 3.76-3.58 (m, 1H); 3.58-3.43 (m, 1H); 2.87-2.53 (m, 2H); 2.47-2.20 (m, 1H); 2.12-1.93 (m, 1H); 1.30-1.22 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 49.64; 49.32; 48.78; 48.31
步驟 4: 4-{羥基[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基}-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸(4-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl}-4-[(2-methylpropane-2-sulfinyl)amino]butanoic acid)
依照製程F在前一步產物(213 mg,0.35 mmol,1當量)以及THF/H2
O (4/1,2 mL)的混合溶液中加入LiOH·H2
O(44 mg,1.1 mmol,3.0當量)製備而成標題上無色油狀的化合物 (178 mg,定量產量)。MS (ESI+
): [M+H]+
= 429.1; [(Mx2)+H]+
= 857.3
步驟 5: 4-胺基-4-{羥基[(5-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸(4-amino-4-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl}butanoic acid)
依照製程G從含有前一步產物(178 mg,0.416 mmol,1.0當量)的二氧六環(2.31 mL,9.24 mmol,22 當量)溶液製備而成標題上的白色固體化合物(40 mg,27%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 325.0; [(Mx2)+H]+
= 649.1 MS (ESI-
): [M-H]-
= 323.0; [(Mx2)-H]-
= 647.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.93-7.76 (m, 2H); 7.61-7.42 (m, 3H); 6.85 (d, J = 0.9 Hz, 1H); 3.32 – 3.25 (m, 1H); 3.25 – 3.08 (m, 2H); 2.62 (t, J = 7.3 Hz, 2H); 2.38-2.21 (m, 1H); 2.09 – 1.89 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 24.4
實例 22: 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁酸 (4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butanoic acid)
步驟 1: (2-苯乙基)次磷酸
依照製程B在氯亞磷酸二乙酯(1 mL,6.26 mmol,1.0當量)的無水Et2
O (10 mL)溶液中加入苯丙基氯化鎂溶液(1.0M 的THF溶液,6.6 mL,6.56 mmol,1.05當量),製備標題上的淡黃色油狀化合物(700 mg,65%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.94 (bs); 7.12 (dt, 1H, J = 547.0 and 1.9 Hz); 7.32‑7.21 (m, 5H); 2.97-2.91 (m, 2H); 2.14-2.07 (m, 2H)
步驟 2: (1-{[(苄氧基)羰基]胺基}-4-甲氧基-4-酮丁基)(2-苯乙基)次磷酸((1-{[(benzyloxy)carbonyl]amino}-4-methoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid)
依照製程D在含有前一步產物 (200 mg,1.18 mmol,1.0當量)以及NH2
Cbz (195 mg,1.29 mmol,1.1當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸甲酯(純度90%,165 µL,1.41 mmol,1.2 當量)並經多成分反應後獲得標題上的淡黃色粉狀化合物 (356 mg,72%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.53 (bs, 1H); 7.31-7.14 (m, 10H); 5.35 (d, 1H, J = 10.3 Hz); 5.10 (d, 2H, J = 15.0 Hz); 4.05 (tdd, 1H, J = 11.1, 8.1 and 3.5 Hz); 3.60 (s, 3H); 3.00-2.82 (m, 2H); 2.48-2.39 (m, 2H); 2.25 (ddt, 1H, J = 10.8, 7.3 and 3.5 Hz); 2.11-1.99 (m, 2H); 1.97-1.88 (m, 1H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 53.56
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-[羥基(2-苯乙基)磷醯基]丁酸(4-{[(benzyloxy)carbonyl]amino}-4-[hydroxy(2-phenylethyl)phosphoryl]butanoic acid)
依照製程F在前一步產物(200 mg,0.47 mmol,1.0當量)以及THF/H2
O (4 mL/1 mL)的混合溶液中加入LiOH·H2
O(60 mg,1.43 mmol,3.0當量)製備而成標題上白色固體的化合物 (184 mg,95%)。1
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11.94 (bs, 2H); 7.50 (d, 1H, J = 9.7 Hz); 7.37-7.20 (m, 7H); 7.21-7.12 (m, 3H); 5.09 (d, 1H, J = 12.8 Hz); 5.01 (d, 1H, J = 12.7 Hz); 3.73 (ddt, 1H, J = 13.5, 9.6 and 4.7 Hz); 2.83-2.68 (m, 2H); 2.39-2.33 (m, 1H); 2.29‑2.23 (m, 1H); 2.08-2.00 (m, 1H); 1.83-1.69 (m, 2H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 43.44
步驟 4 : 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁酸(4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(184 mg,0.45 mmol,1.0當量)的EtOH/AcOH (9 mL/1 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(62 mg,47%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 254.2; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.3; [(Mx3)+H]+
= 814.61
H NMR (D2
O, 500 MHz) δ (ppm): 7.44-7.37 (m, 4H); 7.34-7.31 (m, 1H); 3.14 (td, 1H, J = 8.8 and 4.8 Hz); 2.95-2.89 (m, 2H); 2.67-2.55 (m, 2H); 2.26-2.17 (m, 1H); 2.05‑1.93 (m, 3H)31
P NMR (D2
O, 202 MHz) δ (ppm): 34.54
實例23: 4-胺基-4-{羥基[2-(2-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methylphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1: [2-(2-甲苯基)乙基]次磷酸([2-(2-methylphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-2-甲苯的無水Et2
O溶液所新鮮配置的格任亞試劑製備標題上的淡黃色油狀化合物(856 mg,62%)。MS (ESI+
): [M+H]+
= 185.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.32 (br s, 1H); 7.17-7.13 (m, 4H); 7.16 (dt, 1H, J = 546.0 and 2.0 Hz); 2.95-2.89 (m, 2H); 2.33 (s, 3H); 2.09-2.02 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.48
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(2-甲苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(2-methylphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,2.71 mmol,1.0當量)以及NH2
Cbz (420 mg,2.78 mmol,1.02當量)的AcOH溶液(4.7 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(582 mg,3.03 mmol,1.12 當量),經多成分反應後獲得標題上的白色固體化合物 (866 mg,63%)。MS (ESI+
): [M+H]+
= 510.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.23 (m, 10H); 7.13-7.07 (m, 4H); 5.15-5.03 (m, 4H); 4.06-4.01 (m, 1H); 2.93-2.79 (m, 2H); 2.58-2.45 (m, 2H); 2.33-2.22 (m, 1H); 2.26 (s, 3H); 1.98-1.82 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.97
步驟 3: 4-胺基-4-{羥基[2-(2-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methylphenyl)ethyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(450 mg,0.88mmol,1.0當量)的EtOH/AcOH (1:2,20 mL)混合溶液進行氫解,製備標題上的白色粉狀化合物(220 mg,87%)。預期純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.2; [M+H]+
= 286.2; [(Mx2)+H]+
= 571.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.19 (dd, 1H, J = 7.5 and 2.0 Hz); 7.12-7.04 (m, 3H); 3.13-3.08 (m, 1H); 2.90 (q, 2H, J = 8.0 Hz); 2.60 (dt, 2H, J = 7.5 and 1.5 Hz); 2.34 (s, 3H); 2.28-2.19 (m, 1H); 1.99-1.79 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.36
實例24: 4-胺基-4-{羥基[2-(3-甲苯基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(3-methylphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1: [2-(3-甲苯基)乙基]次磷酸
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-2-甲苯的無水Et2
O溶液所新鮮配置的格任亞試劑,製備標題上的淺白色油狀化合物(908 mg,71%)。 MS (ESI+
): [M+H]+
= 185.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.18 (t, 1H, J = 8.0 Hz); 7.11 (dt, 1H, J = 543.0 and 2.0 Hz); 7.03-6.99 (m, 3H); 6.57 (br s, 1H); 2.91-2.85 (m, 2H); 2.32 (s, 3H); 2.10‑2.03 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.61
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(3-甲苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(3-methylphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,2.71 mmol,1.0當量)以及NH2
Cbz (451 mg,2.99 mmol,1.1當量)的AcOH溶液(5.0 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(626 mg,3.26 mmol,1.2 當量),並經多成分反應後獲得標題上的白色固體化合物 (961 mg,69%)。MS (ESI+): [M+H]+
= 510.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.28 (m, 7H); 7.27-7.23 (m, 3H); 7.14 (t, 1H, J = 7.5 Hz); 7.01-6.99 (m, 2H); 6.94 (d, 1H, J = 7.5 Hz); 5.17-5.04 (m, 4H); 4.05-4.00 (m, 1H); 2.89-2.73 (m, 2H); 2.66-2.44 (m, 2H); 2.31-2.20 (m, 1H); 2.29 (s, 3H); 2.02‑1.84 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.31
步驟 3: 4-胺基-4-{羥基[2-(3-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-methylphenyl)ethyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(500 mg,0.98 mmol,1.0當量)的EtOH/AcOH (1:1,20 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(123 mg,44%)。預期純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.2; [M+H]+
= 286.2; [(Mx2)+H]+
=571.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.14 (t, 1H, J = 7.5 Hz); 7.08 (s, 1H); 7.04 (d, 1H, J = 8.0 Hz); 6.99 (d, 1H, J = 7.5 Hz); 3.07-3.02 (m, 1H); 2.88-2.83 (m, 2H); 2.59-2.56 (m, 2H); 2.30 (s, 3H); 2.26-2.17 (m, 1H); 1.97-1.85 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.34
實例25: 4-胺基-4-{羥基[2-(4-甲苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(4-methylphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1:[2-(4-甲苯基)乙基]次磷酸([2-(4-methylphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯 (1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-2-甲苯的無水Et2
O溶液所新鮮配置的格任亞試劑,製備標題上的油狀化合物(858 mg,68%)。 MS (ESI+
): [M+H]+
= 185.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.34-7.29 (m, 5H); 7.19 (dt, 1H, J = 540.5 and 2.0 Hz); 3.07-3.01 (m, 2H); 2.49 (s, 3H); 2.26-2.19 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 33.97
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(4-甲苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(4-methylphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,2.71 mmol,1.0當量)以及NH2
Cbz (420 mg,2.78 mmol,1.02當量)的AcOH溶液(4.5 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(528 mg,3.03 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (1.16 g,90%)。MS (ESI+
): [M+H]+
= 510.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.40-7.25 (m, 10H); 7.12-6.97 (m, 4H); 5.17-5.03 (m, 4H); 4.04-4.00 (m, 1H); 2.88-2.72 (m, 2H); 2.66-2.41 (m, 2H); 2.29 (s, 3H); 2.29-2.21 (m, 1H); 2.04-1.83 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.32
步驟 3: 4-胺基-4-{羥基[2-(4-甲苯基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(4-methylphenyl)ethyl]phosphoryl}butanoic acid)
氬氣環境中,在前一步產物(500 mg,0.981 mmol,1.0當量)的H2
O/AcOH (1:1,16 mL)混合溶液中加入5% 以上之Pd(OH)2
/C (137 mg,0.05 當量)。在氫氣 (1 atm)中攪拌過夜。反應完成後,在氬氣中將反應混合物以PTFE膜過濾並濃縮。將粗產物與甲苯共蒸發(三次),在熱的EtOH中研磨、乾燥,最後得到標題上之白色固體化合物(40mg,14%)。預期純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.2; [M+H]+
= 286.2; [(Mx2)+H]+
=571.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.13 (d, 2H, J = 8.0 Hz); 7.08 (d, 2H, J = 8.0 Hz); 3.06-3.02 (m, 1H); 2.88-2.83 (m, 2H); 2.59-2.56 (m, 2H); 2.28 (s, 3H); 2.26-2.15 (m, 1H); 1.97-1.85 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.51
實例26: 4-胺基-4-[羥基({2-[3-(三氟甲基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[3-(trifluoromethyl)phenyl]ethyl})phosphoryl] butanoic acid)
步驟 1: {2-[3-(三氟甲基)苯基]乙基}次磷酸({2-[3-(trifluoromethyl)phenyl]ethyl}phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-3-三氟甲苯的無水Et2
O溶液所新鮮配置的格任亞試劑,製備標題上的淺黃色油狀化合物(953 mg,58%)。MS (ESI+
): [M+H]+
= 239.01
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.51-7.39 (m, 4H); 7.15 (dt, 1H, J = 550.0 and 1.5 Hz); 6.13 (br s, 1H); 3.03-2.97 (m, 2H); 2.15-2.09 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.39
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({2-[3-(三氟甲基)苯基]乙基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({2-[3-(trifluoro methyl)phenyl]ethyl})phosphinic acid)
依照方製程D在含有前一步產物 (400 mg,1.68 mmol,1.0當量)以及NH2
Cbz (387 mg,2.02 mmol,1.1當量)的AcOH溶液(2.4 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(387 mg,2.02 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (350 mg,37%)。MS (ESI+
): [M+H]+
= 564.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.57-7.22 (m, 14H); 5.16-5.05 (m, 4H); 4.06-4.01 (m, 1H); 3.02-2.84 (m, 2H); 2.58-2.45 (m, 2H); 2.30-2.21 (m, 1H); 2.02-1.83 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.36
步驟 3: 4-胺基-4-[羥基({2-[3-(三氟甲基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[3-(trifluoromethyl)phenyl]ethyl})phosphoryl]butanoic acid)
依照製程H將含有前一步產物(200 mg,0.35 mmol,1.0當量)的EtOH/AcOH (1:1,12 mL)混合溶液,進行氫解,以製備標題上的白色粉狀化合物(30 mg,25%)。 預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 322.0; [M+H]+
= 340.1; [(Mx2)+H]+
= 697.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.59 (s, 1H); 7.54-7.53 (m, 1H); 7.49-7.47 (m, 2H); 3.15-3.11 (m, 1H); 3.01-2.96 (m, 2H); 2.62 (t, 2H, J = 7.5 Hz); 2.29-2.20 (m, 1H); 1.99-1.86 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 30.53
實例27: 4-胺基-4-[羥基(2-甲基-2-苯丙基)磷醯基]丁酸 (4-amino-4-[hydroxy(2-methyl-2-phenylpropyl)phosphoryl]butanoic acid)
步驟 1: (2-甲基-2-苯丙基)次磷酸((2-methyl-2-phenylpropyl)phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2O (9 mL)溶液中加入(2-甲基2-苯丙基) 氯化鎂(0.5 M於 THF中,14.5 mL,7.24 mmol,1.05當量),製備標題上的淺黃色油狀化合物(349 mg,26%)。MS (ESI+
): [M+H]+
= 199.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.46-7.44 (m, 2H); 7.35-7.31 (m, 2H); 7.22-7.19 (m, 1H); 6.59 (dt, 1H); 2.19 (dd, 2H); 1.53 (s, 3H); 1.52 (s, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.97
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基](2-甲基-2-苯丙基)次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl](2-methyl-2-phenyl propyl)phosphinic acid)
依照製程D在含有前一步產物 (349 mg,1.76 mmol,1.1當量)以及NH2
Cbz (293 mg,1.94 mmol,1.1當量)的AcOH溶液(1.8 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(406 mg,2.11 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (393 mg,43%)。MS (ESI+
): [M+H]+
= 524.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.38-7.13 (m, 15H); 5.16-5.02 (m, 4H); 3.74-3.69 (m, 1H); 2.47-2.41 (m, 1H); 2.38-2.32 (m, 1H); 2.16-2.07 (m, 3H); 1.81-1.69 (m, 1H); 1.524 (s, 3H), 1.518 (s, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 47.23
步驟 3: 4-胺基-4-[羥基(2-甲基-2-苯丙基)磷醯基]丁酸(4-amino-4-[hydroxy(2-methyl-2-phenylpropyl)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(193 mg,0.37 mmol,1.0當量)的EtOH/AcOH (1:1,12 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(30 mg,27%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 282.1; [M+H]+
= 300.1; [(Mx2)+H]+
= 599.2; [(Mx3)+H]+
= 898.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.49-7.46 (m, 2H); 7.32-7.29 (m, 2H); 7.19-7.16 (m, 1H); 2.38-2.30 (m, 2H); 2.20-2.16 (m, 1H); 2.08-1.98 (m, 3H); 1.76-1.68 (m, 1H); 1.58 (s, 3H); 1.57 (s, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 29.13
實驗例28: 4-胺基-4-{[2-(2-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(2-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
步驟 1: [2-(2-氯苯基)乙基]次磷酸([2-(2-chlorophenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2O (9 mL)溶液中加入溴化(2-氯苯乙基)鎂(0.5 M於 THF中,14.5 mL,7.24 mmol,1.05當量)製備標題上的化合物(734 mg,52%)。MS (ESI+
): [M+H]+
= 205.0及207.01
H NMR (CDCl3, 500 MHz) δ (ppm): 10.18 (br s, 1H); 7.35 (dd, 1H, J = 7.0 and 2.0 Hz); 7.28-7.26 (m, 2H); 7.22-7.16 (m, 1H); 7.16 (dt, 1H, J = 549 and 2.0 Hz); 3.07-3.01 (m, 2H); 2.16-2.09 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.58
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(2-氯苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(2-chlorophenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (350 mg,1.71 mmol,1當量)以及NH2
Cbz (305 mg,2.02 mmol,1.1當量)的AcOH溶液(2.5 mL)及AcCl的溶液(0.9 mL)中加入4-氧丁酸芐酯(424 mg,2.20 mmol,1.2 當量),經多成分反應後獲得標題上的固體化合物 (740 mg,82%)。MS (ESI+
): [M+H]+
= 530.2 and 532.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.20 (m, 14H); 5.17-5.07 (m, 4H); 4.08-4.04 (m, 1H); 3.03-2.98 (m, 2H); 2.60-2.48 (m, 2H); 2.31-2.22 (m, 1H); 2.03-1.88 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.54
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{[2-(2-氯苯基)乙基](羥基) 磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[2-(2-chlorophenyl)ethyl](hydroxy) phosphoryl} butanoic acid)
依照製程F在前一步產物(316 mg,0.596 mmol,1.0當量)以及THF/H2
O (6 mL/1.5 mL)的混合溶液中加入LiOH.H2
O (75 mg,1.79 mmol,3.0當量),以製備標題上白色固體的化合物 (191 mg,73%)。MS (ESI+
): [M+H]+
= 440.0 及 442.01
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.19 (m, 9H); 5.11 (dd, 2H, J = 47.0 and 12.5 Hz); 4.05-4.01 (m, 1H); 3.03-2.93 (m, 2H); 2.52-2.35 (m, 2H); 2.27-2.19 (m, 1H); 2.02-1.95 (m, 2H); 1.92-1.82 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.76
步驟 4: 4-胺基-4-{[2-(2-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(2-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(191 mg,434 µmol,1.0當量)的TFA/苯甲醚(3.0 mL/454 µL) 溶液,以製備標題上的白色固體化合物(73 mg,55%)。 預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 288.1 and 290.1; [M+H]+
= 306.1 and 308.1; [(Mx2)+H]+
= 611.1, 613.1 and 615.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.34 (m, 2H); 7.23 (td, 1H, J = 7.5 and 1.5 Hz); 7.18 (td, 1H, J = 7.5 and 2.0 Hz); 3.16-3.12 (m, 1H); 3.05-3.00 (m, 2H); 2.61 (t, 2H, J = 7.5 Hz); 2.29-2.00 (m, 1H); 2.01-1.83 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 30.65
實例 29: 4-胺基-4-{[2-(3-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(3-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
步驟 1: [2-(3-氯苯基)乙基]次磷酸([2-(3-chlorophenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2O (9 mL)溶液中加入由1‑(2‑溴乙基)‑3‑氯苯的無水Et2O溶液所新鮮配置的格任亞試劑製備標題上的化合物(1.0 g,71%)。MS (ESI+
): [M+H]+
= 205.0 及 207.01
H NMR (CDCl3
, 500 MHz) δ (ppm): 10.26 (br s, 1H); 7.28-7.21 (m, 3H); 7.16 (dt, 1H, J = 549.0 and 2.0 Hz); 7.13 (dt, 1H, J = 7.5 and 1.5 Hz); 2.97-2.91 (m, 2H); 2.15-2.08 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 36.0
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(3-氯苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(3-chlorophenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,2.44 mmol,1當量)以及NH2
Cbz (406 mg,2.93 mmol,1.1當量)的AcOH溶液(3.0 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(564 mg,2.93 mmol,1.2 當量),經多成分反應後,以獲得標題上的白色固體化合物 (748 mg,58%)。MS (ESI+
): [M+H]+
= 530.1及 532.01
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.19 (m, 13H); 7.08 (d, 1H, J = 7.5 Hz); 5.18-5.05 (m, 4H); 4.05-4.00 (m, 1H); 2.92-2.76 (m, 2H); 2.58-2.46 (m, 2H); 2.29-2.21 (m, 1H); 1.99-1.84 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.70
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{[2-(3-氯苯基)乙基](羥基) 磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[2-(3-chlorophenyl)ethyl](hydroxy) phosphoryl} butanoic acid)
依照製程F在前一步產物(200 mg,0.38 mmol,1.0當量)以及THF/H2
O (4 mL/1 mL)的混合溶液中加入LiOH‧H2
O (47 mg,1.13 mmol,3.0當量),製備標題上白色固體的化合物 (157 mg,95%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.35-7.21 (m, 8H); 7.09 (d, 1H, J = 7.5 Hz); 5.13 (dd, 2H, J = 64.5 and 12.5 Hz); 4.04-3.99 (m, 1H); 2.95-2.76 (m, 2H); 2.52-2.36 (m, 2H); 2.27-2.17 (m, 1H); 1.99-1.81 (m, 3H)
步驟 4: 4-胺基-4-{[2-(3-氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(3-chlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(265 mg,602 µmol,1.0當量)的TFA/苯甲醚 (9.0 mL/1.8 mL)溶液,以製備標題上的白色固體化合物(60 mg,33%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 288.1 and 290.1; [M+H]+
= 306.1 and 308.1; [(Mx2)+H]+
= 611.2, 613.1 及 615.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.30 (t, 1H, J = 2.0 Hz); 7.25 (t, 1H, J = 8.0 Hz); 7.20-7.17 (m, 2H); 3.13-3.08 (m, 1H); 2.91-2.86 (m, 2H); 2.61 (t, 2H, J = 7.5 Hz); 2.28-2.19 (m, 1H); 1.99-1.82 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 30.72
實例 30: 4-胺基-4-{羥基[2-(萘-2-基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(naphthalen-2-yl)ethyl]phosphoryl}butanoic acid)
步驟 1: 2-(萘-2-基)乙-1-醇(2-(naphthalen-2-yl)ethan-1-ol)
0°C,氬氣環境下,將2-萘乙酸(5.0 g,26.85 mmol,1.0當量)的無水THF(13 mL)溶液滴加到氫化鋁鋰(2 M 的THF溶液,27 mL,53.70 mmol, 2.0當量)的無水THF(13 mL)溶液中。此反應會放熱,其混合物將變為黃色。將反應混合物在室溫攪拌2小時,冷卻至0°C,然後用2mL H2
O緩慢淬火。依序加入NaOH(4mL,15%)以及H2
O (6mL)的水溶液,並將混合物攪拌15分鐘。加入無水Na2
SO4
並將混合物攪拌15分鐘。將黃色混合物以矽藻土墊過濾,並在真空下將濾液濃縮,得到預期之黃色粉末化合物(4.5 g,97%)。
1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.83-7.79 (m, 3H); 7.69 (t, 1H, J = 1.0 Hz); 7.49-7.43 (m, 2H); 7.37 (dd, 1H, J = 8.0 and 1.5 Hz); 3.96 (t, 2H, J = 6.5 Hz); 3.04 (t, 2H, J = 6.5 Hz)
步驟 2: 2-(2-溴乙基)萘(2-(2-bromoethyl)naphthalene)
將三苯膦(4.72g,18mmol,1.3當量)及N
-溴琥珀醯亞胺(N
‑bromosuccinimide)(3.2g,18mmol,1.3當量)的無水DCM(45mL)溶液攪拌10分鐘。加入前一步產物(2.33g,13.5mmol,1.0當量),然後立即加入咪唑 (919mg,13.5mmol,1.0當量),並將混合物在室溫下攪拌24小時。將反應混合物以H2
O以及DCM進行選擇性分離,並將水層以DCM萃取(三次)。合併的有機萃取物以Na2
SO4
乾燥、過濾並蒸發至乾。以管住層析法純化粗殘餘物,最後得到預期之白色固體化合物(2.3g,72%)。
1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.83-7.80 (m, 3H); 7.67 (br s, 1H); 7.50-7.44 (m, 2H); 7.34 (dd, 1H, J = 8.0 and 1.5 Hz); 3.66 (t, 2H, J = 7.5 Hz); 3.34 (t, 2H, J = 7.5 Hz)
步驟 3: [2-(萘-2-基)乙基]次磷酸([2-(naphthalen-2-yl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2O (9 mL)溶液中加入由2-(2-溴乙基)萘的無水THF溶液所新鮮配置的格任亞試劑製備標題上的白色固體化合物(1.0 g,71%)。MS (ESI+
): [M+H]+
= 221.11
H NMR (CDCl3, 500 MHz) δ (ppm): 7.81-7.76 (m, 3H); 7.66 (br s, 1H); 7.48-7.42 (m, 2H); 7.34 (dd, 1H, J = 8.5 and 1.5 Hz); 7.16 (dt, 1H, J = 550.0 and 2.0 Hz); 3.13-3.08 (m, 2H); 2.23-2.16 (m, 2H)31
P NMR (CDCl3, 202 MHz) δ (ppm): 37.46
步驟 4: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(萘-2-基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(naphthalen-2-yl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (400 mg,1.82 mmol,1.0當量)以及NH2
Cbz (302 mg,2.00 mmol,1.1當量)的AcOH溶液(2.9 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸芐酯(418 mg,2.18 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (880 mg,89%)。 MS (ESI+
): [M+H]+
= 546.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.81 (dd, 1H, J = 7.5 and 2.0 Hz); 7.77 (dd, 2H, J = 7.5 and 2.5 Hz); 7.63 (br s, 1H); 7.46-7.41 (m, 2H); 7.37-7.28 (m, 8H); 7.20-7.13 (m, 3H); 5.18-5.03 (m, 4H); 4.09-4.04 (m, 1H); 3.10-2.95 (m, 2H); 2.58-2.46 (m, 2H); 2.31-2.24 (m, 1H); 2.12-1.99 (m, 2H); 1.95-1.86 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.01
步驟 5: 4-{[(苄氧基)羰基]胺基}-4-{羥基l[2-(萘-2-基)乙基]磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxyl[2-(naphthalen-2-yl)ethyl]phosphoryl} butanoic acid)
依照製程F在前一步產物(440 mg,0.81 mmol,1.0當量)以及THF/H2
O (7 mL/2 mL)的混合溶液中加入LiOH‧H2
O (102 mg,2.42 mmol,3.0當量),以製備標題上白色固體的化合物 (250 mg,68%)。 MS (ESI+
): [M+H]+
= 456.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.82-7.80 (m, 1H); 7.78-7.76 (m, 2H); 7.64 (br s, 1H); 7.46-7.41 (m, 2H); 7.33-7.30 (m, 3H); 7.21-7.14 (m, 3H); 5.13 (dd, 2H, J = 71.5 and 12.5 Hz); 4.08-4.04 (m, 1H); 3.12-2.96 (m, 2H); 2.52-2.38 (m, 2H); 2.29-2.21 (m, 1H); 2.13-2.01 (m, 2H); 1.93-1.84 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.01
步驟 6: 4-胺基-4-{羥基[2-(萘-2-基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(naphthalen-2-yl)ethyl]phosphoryl}butanoic acid)
依照製程G從含有前一步產物(250 mg,549 µmol,1.0當量)的TFA/苯甲醚 (1.6mL/380 µL) 溶液,以製備標題上的白色固體化合物(84 mg,48%)。 預估純度: > 95% (根據高效能液相層析及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 304.1; [M+H]+
= 322.2; [(Mx2)+H]+
= 643.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.81-7.78 (m, 3H); 7.71 (s, 1H); 7.45-7.39 (m, 3H); 3.10-3.05 (m, 3H); 2.57 (t, 2H, J = 7.0 Hz); 2.28-2.19 (m, 1H); 2.04-1.89 (m, 3H)31
P NMR (D2
O, 202 MHz) δ (ppm): 34.98
實例 31: 4-胺基-4-{羥基[2-(萘-1-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(naphthalen-1-yl)ethyl]phosphoryl}butanoic acid)
步驟 1: (2-(萘-1-基)乙基)次磷酸((2-(naphthalen-1-yl)ethyl)phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中,加入由1-(2-溴乙基)萘的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的白色固體化合物(777 mg,51%)。MS (ESI+
): [M+H]+
= 221.11
H NMR (MeOD, 500 MHz) δ (ppm): 8.07 (dq, 1H, J = 8.5 and 1.0 Hz); 7.89-7.87 (m, 1H); 7.77-7.74 (m, 1H); 7.57-7.53 (m, 1H); 7.51-7.47 (m, 1H); 7.43-7.39 (m, 1H); 7.10 (dt, 1H, J = 541.5 and 2.0 Hz); 3.40-3.34 (m, 2H); 2.20-2.13 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 37.79
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(萘-1-基)乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(naphthalen-1-yl)ethyl]phosphinic acid)
依照製程D在含有前一步產物 (777 mg,3.53 mmol,1.0當量)以及NH2
Cbz (587 mg,3.88 mmol,1.1當量)的AcOH溶液(5.0 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(813 mg,4.23 mmol,1.2 當量),經多成分反應後已獲得標題上的白色固體化合物 (520 mg,27%)。MS (ESI+
): [M+H]+
= 546.31
H NMR (MeOD, 500 MHz) δ (ppm): 8.05 (d, 1H, J = 8.0 Hz); 7.88-7.87 (m, 1H); 7.75 (d, 1H, J = 8.0 Hz); 7.51-7.46 (m, 2H); 7.40-7.27 (m, 10H); 7.18-7.17 (m, 2H); 5.15-5.04 (m, 4H); 4.12-4.07 (m, 1H); 2.61-2.47 (m, 2H); 2.33-2.25 (m, 1H); 2.16-1.99 (m, 2H); 1.96-1.86 (m, 1H) – 兩個質子在MeOD峰下。31
P NMR (MeOD, 202 MHz) δ (ppm): 49.08
步驟 3: 4-{[(苄氧基)羰基]胺基}-4-{羥基l[2-(萘-1-基)乙基]磷醯基} 丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxyl[2-(naphthalen-1-yl)ethyl]phosphoryl} butanoic acid)
依照製程F在前一步產物(520 mg,0.90 mmol,1.0當量)以及THF/H2
O (7 mL/2 mL)的混合溶液中加入LiOH‧H2
O (120 mg,2.86 mmol,3.0當量)製備而成標題上白色固體的化合物 (340 mg,78%)。 MS (ESI+
): [M+H]+
= 456.21
H NMR (MeOD, 500 MHz) δ (ppm): 8.06 (d, 1H, J = 7.5 Hz); 7.88‑7.87 (m, 1H); 7.75 (d, 1H, J = 8.0 Hz); 7.52-7.46 (m, 2H); 7.40-7.29 (m, 5H); 7.20-7.19 (m, 2H); 5.11 (dd, 2H, J = 51.0 and 12.5 Hz); 4.12-4.07 (m, 1H); 2.53-2.34 (m, 2H); 2.31-2.22 (m, 1H); 2.15‑2.02 (m, 2H); 1.94-1.84 (m, 1H) – 兩個質子在MeOD峰下。31
P NMR (MeOD, 202 MHz) δ (ppm): 49.31
步驟 4: 4-胺基-4-{羥基[2-(萘-1-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(naphthalen-1-yl)ethyl]phosphoryl}butanoic acid)
依照製程G從含有前一步產物(340 mg,623 µmol,1.0當量)的TFA/苯甲醚 (1.8 mL/435 µL) 溶液,以製備標題上的白色固體化合物(37 mg,15%)。預估純度: > 95% (根據高效能液相層析及核磁共振譜儀分析結果)。MS (ESI+
): [(M-H2
O)+H]+
= 304.2; [M+H]+
= 322.2; [(Mx2)+H]+
= 643.51
H NMR (MeOD, 500 MHz) δ (ppm): 8.18 (d, 1H, J = 8.5 Hz); 7.85 (d, 1H, J = 8.0 Hz); 7.72 (d, 1H, J = 8.0 Hz); 7.55-7.51 (m, 1H); 7.48-7.45 (m, 1H); 7.43-7.37 (m, 2H); 3.38 (q, 2H, J = 8.0 Hz); 3.14-3.10 (m, 1H); 2.59 (t, 2H, J = 7.5 Hz); 2.28-2.19 (m, 1H); 2.07-1.89 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.27
實例 32: 4-胺基-4-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1: [2-(2-甲氧苯基)乙基]次磷酸([2-(2-methoxyphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.75 mL,5.17 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入溴化(2-甲氧苯乙基)鎂(0.5 M溶於THF,10.9 mL,5.43 mmol,1.05當量)溶液,以製備標題上的淺黃色油狀化合物(620 mg,60%)。MS (ESI+
): [M+H]+
= 201.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.22-7.15 (m, 2H); 6.99 (dt, 1H, J = 538.5 and 2.0 Hz); 6.93 (dd, 1H, J = 8.5 and 1.5 Hz); 6.87 (dt, 1H, J = 7.5 and 1.0 Hz); 3.84 (s, 3H); 2.90-2.84 (m, 2H); 2.05-1.98 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 34.83
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(2-甲氧苯基)乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(2-methoxyphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (334 mg,1.67 mmol,1.0當量)以及NH2
Cbz (277 mg,1.84 mmol,1.1當量)的AcOH溶液(1.8 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(384 mg,2.00 mmol,1.2 當量),經多成分反應後,以獲得標題上的白色固體化合物 (605 mg,69%)。 MS (ESI+
): [M+H]+
= 526.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.21 (m, 10H); 7.18 (dt, 1H, J = 7.5 and 1.5 Hz); 7.08 (dd, 1H, 7.5 and 1.5 Hz); 6.90 (d, 1H, J = 8.0 Hz); 6.86-6.83 (m, 1H); 5.15-5.05 (m, 4H); 4.02-3.98 (m, 1H); 3.78 (s, 3H); 2.88-2.83 (m, 2H); 2.56-2.43 (m, 2H); 2.28‑2.19 (m, 1H); 1.99-1.83 (m, 3H).
步驟 3: 4-胺基-4-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(200 mg,0.38 mmol,1.0當量)的EtOH/AcOH (1:2,12 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(23 mg,20%)。預期純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 284.1; [M+H]+
= 302.1; [(Mx2)+H]+
=603.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.19-7.15 (m, 2H); 6.91 (d, 1H, J = 8.0 Hz); 6.85 dt, 1H, J = 7.5 and 1.0 Hz); 3.83 (s, 3H); 3.09-3.05 (m, 1H); 2.90-2.85 (m, 2H); 2.57 (dt, 2H, J = 7.5 and 1.0 Hz); 2.27-2.18 (m, 1H); 2.00-1.79 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.92
實例 33: 4-胺基-4-{羥基[2-(3-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-methoxyphenyl)ethyl]phosphoryl} butanoic acid)
步驟 1: [2-(3-甲氧苯基)乙基]次磷酸([2-(3-methoxyphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2O (9 mL)溶液中加入由1-(2-溴乙基)-3-甲氧苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的淡黃色油狀化合物(657 mg,48%)。MS (ESI+
): [M+H]+
= 201.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.23-7.20 (m, 1H); 7.13 (dt, 1H, J = 547.5 and 2.0 Hz); 6.81-6.76 (m, 3H); 6.30 (br s, 1H); 3.79 (s, 3H); 2.94-2.88 (m, 2H); 2.13-2.07 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.45
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(3-甲氧苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(3-methoxy phenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (657 mg,3.28 mmol,1.0當量)以及NH2
Cbz (546 mg,3.61 mmol,1.1當量)的AcOH溶液(6.0 mL)及AcCl的溶液(0.8 mL)中加入4-氧丁酸芐酯(757 mg,3.94 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (1.3 g,75%)。MS (ESI+
): [M+H]+
= 526.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.23 (m, 10H); 7.17 (t, 1H,J
= 8.0 Hz); 6.76-6.73 (m, 3H); 5.20-5.04 (m, 4H); 4.05-4.00 (m, 1H); 3.76 (s, 3H); 2.91-2.75 (m, 2H); 2.58-2.45 (m, 2H); 2.29-2.20 (m, 1H); 2.03-1.84 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.23
步驟 3: 4-胺基-4-{羥基[2-(3-甲氧苯基)乙基]磷醯基} 丁酸(4-amino-4-{hydroxy[2-(3-methoxyphenyl)ethyl]phosphoryl} butanoic acid)
依照製程H將含有前一步產物(500 mg,0.98 mmol,1.0當量)的EtOH/AcOH (1:1,20 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(151 mg,53%)。 預期純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 284.2; [M+H]+
= 302.2; [(Mx2)+H]+
= 603.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.17 (t, 1H, J = 8.0 Hz); 6.84-6.82 (m, 2H); 6.74-6.72 (m, 1H); 3.77 (s, 3H); 3.08-3.03 (m, 1H); 2.87 (q, 2H, J = 8.5 Hz); 2.62-2.55 (m, 2H); 2.26-2.18 (m, 1H); 1.99-1.86 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.22
實例 34: 4-胺基-4-{羥基[2-(4-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(4-methoxyphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1: [2-(4-甲氧苯基)乙基]次磷酸([2-(4-methoxyphenyl)ethyl]phosphinic acid)
依製程B在氯亞磷酸二乙酯(1 mL,6.90 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-4-甲氧苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的無色油狀化合物(553 mg,40%)。MS (ESI+
): [M+H]+
= 201.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.17-7.15 (m, 2H); 6.99 (dt, 1H, J = 538.5 and 2.0 Hz); 6.86-6.83 (m, 2H); 3.76 (s, 3H); 2.86-2.80 (m, 2H); 2.05-1.98 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 33.82
步驟 2: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(4-甲氧苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(4-methoxyphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (553 mg,2.76 mmol,1.0當量)以及NH2
Cbz (460 mg,3.04 mmol,1.1當量)的AcOH溶液(4.0 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸芐酯(637 mg,3.32 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (1.2 g,83%)。MS (ESI+
): [M+H]+
= 526.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.24 (m, 10H); 7.06 (d, 2H, J = 8.5 Hz); 6.81 (d, 2H, J = 8.5 Hz); 5.17-5.03 (m, 4H); 4.04-3.99 (m, 1H); 3.76 (s, 3H); 2.87-2.71 (m, 2H); 2.57-2.44 (m, 2H); 2.28-2.20 (m, 1H); 2.00-1.83 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.36
步驟 3: 4-胺基-4-{羥基[2-(4-甲氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(4-methoxyphenyl)ethyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(500 mg,0.95 mmol,1.0當量)的EtOH/AcOH (1:1,20 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(220 mg,77%)。預估純度: > 94% (根據液相層析質譜法及核磁共振譜儀分析結果)1
H NMR (MeOD, 500 MHz) δ (ppm): 7.16 (d, 2H, J = 8.5 Hz); 6.83 (d, 2H, J = 9.0 Hz); 3.76 (s, 3H); 3.06-3.01 (m, 1H); 2.86-2.81 (m, 2H); 2.58 (dt, 2H, J = 7.5 and 2.0 Hz); 2.26-2.16 (m, 1H); 1.99-1.84 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.37
實例 35: 4-胺基-4-{羥基[2-(2-苯氧苯基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(2-phenoxyphenyl)ethyl]phosphoryl}butanoic acid)
步驟 1: 2-(2-苯氧苯基)乙-1-醇(2-(2-phenoxyphenyl)ethan-1-ol)
0°C,氬氣環境中,將2-(2-苯氧苯基)乙酸(2.5 g,10.95 mmol,1.0 當量)的無水THF(5.5 mL)溶液滴加到氫化鋁鋰 (2M於 THF中,10.95 mL,21.91 mmol,2.0當量)的無水THF(5.5 mL) 溶液中。此反應會放熱,其混合物將變為黃色。將反應混合物在室溫攪拌2小時,冷卻至0°C,然後以1 mL H2
O緩慢淬火。依序加入NaOH水溶液(2 mL,15%)及H2
O (3 mL),並將混合物攪拌15分鐘。加入無水Na2
SO4
並攪拌15分鐘。將其黃色混合物以矽藻土墊過濾,並真空濃縮濾液,最後得到標題上之黃色油狀化合物(1.9 g,81%)。MS (ESI+
): [M+H]+
= 197.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.34-7.30 (m, 3H); 7.20 (dt, 1H, J = 7.5 and 2.0 Hz); 7.11-7.06 (m, 2H); 6.96-6.93 (m, 2H); 6.89 (dd, 1H, J = 8.5 and 1.5 Hz); 3.87 (t, 2H, J = 6.5 Hz); 2.93 (t, 2H, J = 6.5 Hz)
步驟 2: 1-(2-溴乙基)-2-苯氧苯(1-(2-bromoethyl)-2-phenoxybenzene)
將上一步獲得的2-(2-苯氧苯基)乙烷-1-醇(1.9 g,8.87 mmol,1.0當量)及四溴化碳(4.71 g,14.19 mmol,1.6當量)以CH2
Cl2
(45 mL)稀釋。將溶液在-5°C(冰/鹽浴)中冷卻,並分批加入三苯膦(3.72 g,14.19 mmol,1.6當量)。添加完成後,將其黃色反應物在室溫下攪拌2小時。濃縮混合物並以管柱層析法純化,得到標題上之無色油狀化合物(1.9g,77%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.35-7.31 (m, 2H); 7.29 (dd, 1H, J = 7.5 and 1.5 Hz); 7.22 (dt, 1H, J = 7.5 and 1.5 Hz); 7.11-7.07 (m, 2H); 6.97-6.95 (m, 2H); 6.87 (dd, 1H, J = 8.0 and 1.0 Hz); 3.62 (t, 2H, J = 7.5 Hz); 3.23 (t, 2H, J = 7.5 Hz)
步驟 3: [2-(2-苯氧苯基)乙基]次磷酸([2-(2-phenoxyphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.95 mL,6.55 mmol,1.0當量)的無水Et2
O (9 mL)溶液中加入由1-(2-溴乙基)-2-甲氧苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(950 mg,55%)。MS (ESI+
): [M+H]+
= 263.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.31 (m, 3H); 7.22 (dt, 1H, J = 8.0 and 1.5 Hz); 7.12-7.07 (m, 2H); 6.98 (dt, 1H, J = 540.0 and 2.0 Hz); 6.95-6.92 (m, 2H); 6.85 (dd, 1H, J = 8.0 and 1.5 Hz); 2.94-2.88 (m, 2H); 2.09-2.02 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 34.02
步驟 4: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(2-苯氧苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(2-phenoxyphenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (500 mg,1.91 mmol,1.0當量)以及NH2
Cbz (317 mg,2.10 mmol,1.1當量)的AcOH溶液(4.0 mL)及AcCl的溶液(0.5 mL)中加入4-氧丁酸芐酯(400 mg,2.29 mmol,1.2 當量),經多成分反應,以獲得標題上的白色固體化合物 (622 mg,56%)。MS (ESI+): [M+H]+
= 588.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.18 (m, 14H); 7.08-7.04 (m, 2H); 6.91 (dd, 2H, J = 8.5 and 1.5 Hz); 6.80 (dd, 1H, J = 8.0 and 1.5 Hz); 5.17-4.97 (m, 4H); 4.02-3.98 (m, 1H); 2.94-2.89 (m, 2H); 2.54-2.41 (m, 2H); 2.24-2.15 (m, 1H); 2.04-1.98 (m, 2H); 1.89-1.81 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.20
步驟 5: 4-胺基-4-{羥基[2-(2-苯氧苯基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(2-phenoxyphenyl)ethyl]phosphoryl}butanoic acid)
依照製程H將含有前一步產物(300 mg,0.51 mmol,1.0當量)的EtOH/AcOH (1:1,9.0 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(85 mg,46%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 346.2; [M+H]+
= 364.2; [(Mx2)+H]+
= 727.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.37 (dd, 1H, J = 8.0 and 2.0 Hz); 7.33-7.30 (m, 2H); 7.18 (dt, 1H , J = 8.0 and 2.0 Hz); 7.11-7.04 (m, 2H); 6.93 (dd, 2H, J = 8.5 and 1.5 Hz); 6.82 (dd, 1H, J = 8.0 and 1.5 Hz); 3.07-3.03 (m, 1H); 2.93 (pseudo
q, 2H, J = 8.0 Hz); 2.52 (t, 2H, J = 7.5 Hz); 2.19-2.10 (m, 1H); 1.97-1.85 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.14
實例 36: 4-胺基-4-({2-[2-(環戊氧基)苯基]乙基}(羥基)磷醯基)丁酸 (4-amino-4-({2-[2-(cyclopentyloxy)phenyl]ethyl}(hydroxy)phosphoryl) butanoic acid)
步驟 1: 甲基 2-[2-(環戊氧基)苯基]醋酸鹽(methyl 2-[2-(cyclopentyloxy)phenyl]acetate)
0°C下,在2-(2-羥苯)乙酸甲酯 (1.5 g,9.03 mmol,1.0當量)的DMF(9mL)溶液中加入Cs2
CO3
(4.41 g,13.54 mmol,1.5當量)。 10分鐘後,加入碘代環戊烷(1.57 mL,13.54 mmol,1.5當量)。將反應混合物在室溫下攪拌19小時,然後加入水,水層以Et2
O萃取(兩次)。合併的有機層以鹽水洗滌,並以Na2
SO4
乾燥、過濾、濃縮。以管柱層析法純化粗產物,最後獲得標題上之黃色油狀化合物(1.4 g,66%)。MS (ESI+
): [M+H]+
= 235.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.21 (dt, 1H, J = 8.0 and 2.0 Hz); 7.16 (dd, 1H, J = 7.5 and 2.0 Hz); 6.89-6.84 (m, 2H); 4.80-4.77 (m, 1H); 3.67 (s, 3H); 3.58 (s, 2H); 1.89-1.72 (m, 6H); 1.65-1.59 (m, 2H)
步驟 2: 2-[2-(環戊氧基)苯基]乙烷-1-醇(2-[2-(cyclopentyloxy)phenyl]ethan-1-ol)
在0°C,氬氣環境中,將上一步所得之化合物(1.6 g,6.83 mmol,1.0當量)的無水THF(3.4 mL)溶液滴加到氫化鋰鋁 (2M 的THF溶液,6.8 mL,13.66 mmol,2.0當量) 溶液中。將反應混合物在室溫攪拌1小時,並冷卻至0°C,然後以0.6mL H2
O緩慢淬火。依序加入NaOH(0.6 mL,15%)和H2
O (1.5 mL)的水溶液,並將混合物攪拌15分鐘。加入無水Na2
SO4
並將其再攪拌15分鐘。將黃色混合物以矽藻土墊過濾,將濾液濃縮、以管柱層析法純化粗產物,最後獲得標題之油狀化合物(1.3 g,92%)。MS (ESI+
): [M+H]+
= 207.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.20-7.14 (m, 2H); 6.89-6.85 (m, 2H); 4.82-4.74 (m, 1H); 3.82 (t, 2H, J = 6.5 Hz); 2.88 (t, 2H, J = 6.5 Hz); 1.95-1.76 (m, 6H); 1.68-1.54 (m, 3H)
步驟 3: 1-(2-溴乙基)-2-(環戊氧基)苯(1-(2-bromoethyl)-2-(cyclopentyloxy)benzene)
將上一步驟所得之化合物(1.3 g,6.30 mmol,1.0 當量)及四溴化碳(3.34 g,10.08 mmol,1.6 當量) 以CH2
Cl2
(30 mL)稀釋。將其冷卻於-5°C (冰/鹽浴),並分次加入三苯膦(2.64 g,10.08 mmol,1.6當量)。添加完成後,將黃色反應介質在室溫下攪拌2小時。最後將混合物濃縮並以管柱層析法純化,獲得標題上之化合物(1.3g,77%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.20-7.14 (dt, 1H, J = 7.5 and 1.5 Hz); 7.13 (dd, 1H, J = 7.5 and 1.5 Hz); 6.88-6.84 (m, 2H); 4.81-4.78 (m, 1H); 3.56 (t, 2H, J = 7.5 Hz); 3.14 (t, 2H, J = 7.5 Hz); 1.94-1.76 (m, 6H); 1.69-1.61 (m, 2H)
步驟 4: {2-[2-(環戊氧基)苯基]乙基}次磷酸({2-[2-(cyclopentyloxy)phenyl]ethyl}phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.67 mL,4.62 mmol,1.0當量)的無水Et2
O (4 mL)溶液中加入由1-(2-溴乙基)-2-(環戊氧基)苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(622 mg,53%)。MS (ESI+
): [M+H]+
= 255.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.19-7.13 (m, 2H); 7.10 (dt, 1H, J = 544.0 and 2.0 Hz); 6.85-6.81 (m, 2H); 6.04 (br s, 1H); 4.80-4.77 (m, 1H); 2.90-2.84 (m, 2H); 2.11-2.01 (m, 2H), 1.93-1.75 (m, 6H); 1.68-1.57 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 39.24
步驟 5: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({2-[2-(環戊氧基) 苯基]乙基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({2-[2-(cyclopentyloxy) phenyl]ethyl})phosphinic acid)
依照製程D在含有前一步產物 (622 mg,2.45 mmol,1.0當量)以及NH2
Cbz (407 mg,2.69 mmol,1.1當量)的AcOH溶液(5.3 mL)及AcCl的溶液(0.8 mL)中加入4-氧丁酸芐酯(564 mg,2.94 mmol,1.2 當量),經多成分反應後,獲得標題上的白色固體化合物 (620 mg,44%)。MS (ESI+
): [M+H]+
= 580.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.39-7.29 (m, 10H); 7.26-7.21 (m, 1H); 7.17-7.13 (m, 1H); 7.08-7.06 (m, 1H); 6.88 (d, 1H, J = 8.0 Hz); 6.81 (t, 1H, J = 7.5 Hz); 5.13-5.04 (m, 4H); 4.01-3.96 (m, 1H); 2.87-2.79 (m, 2H); 2.56-2.43 (m, 2H), 2.27-2.19 (m, 1H); 2.04-1.76 (m, 9H); 1.67-1.60 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.82
步驟 6: 4-胺基-4-({2-[2-(環戊氧基)苯基]乙基}(羥基)磷醯基)丁酸(4-amino-4-({2-[2-(cyclopentyloxy)phenyl]ethyl}(hydroxy)phosphoryl) butanoic acid)
依照製程H將含有前一步產物(310 mg,0.53 mmol,1.0當量)的EtOH/AcOH (1:1,9.0 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(50 mg,26%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 338.2; [M+H]+
= 356.2; [(Mx2)+H]+
= 711.51
H NMR (D2
O, 500 MHz) δ (ppm): 6.66-6.62 (m, 2H); 6.40 (d, 1H, J = 8.0 Hz); 6.32 (t, 1H, J = 7.5 Hz); 4.28-4.23 (m, 1H); 2.76-2.72 (m, 1H); 2.32-2.22 (m, 2H); 2.04-1.88 (m, 2H); 1.68-1.51 (m, 3H); 1.46-1.37 (m, 1H); 1.34-1.25 (m, 2H); 1.20-0.97 (m, 6H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.97
實例 37: 4-胺基-4-[羥基(3-苯丙基)磷醯基]丁酸(4-amino-4-[hydroxy(3-phenylpropyl)phosphoryl]butanoic acid)
步驟 1: (3-苯丙基)次磷酸((3-phenylpropyl)phosphinic acid)
最初是由Smid等人(PCT Int. Appl., 2008071738, 2008)描述(3-苯丙基)次膦酸的製備。在氬氣下,在預先脫氣的次磷酸(50 wt%的水溶液,2.47 mL,22.6 mmol)的EtOH(15 mL)溶液中添加烯丙苯(1 mL,7.6 mmol)以及AIBN(100 mg,1.2 mmol) 。將混合物回流6小時,LCMS顯示轉化不完全。然後加入另一部分的AIBN(100 mg,1.2 mmol),並將混合物回流18小時。其混合物在反應期間始終是無色透明的。接著將混合物真空濃縮並將生成的油冷卻至0°C,並添加15 mL 2N NaOH溶液以達到pH 14。將其轉移至分液漏斗中,並將水層以Et2
O洗滌(3× 20 mL)。將水層以2N HCl酸化至pH 1,然後用AcOEt(4× 30 mL)萃取。合併之有機層以鹽水(100mL)洗滌,再以Na2
SO4
乾燥並真空濃縮,最後獲得標題上之無色油狀化合物(1.2g,86%),帶有8%的加成副產物污染。
MS (ESI+
): [M+H]+
= 1851
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.08 (dt, 1H, J = 545.0 and 5.0 Hz); 7.30-7.27 (m, 2H); 7.22-7.18 (m, 1H); 7.18-7.13 (m, 2H); 2.72 (t, 2H, J = 10.0 Hz); 1.97-1.88 (m, 2H); 1.78-1.72 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 39.53
步驟 2: (1-{[(苄氧基)羰基]胺基}-4-甲氧基-4-酮丁基)(3-苯丙基) 次磷酸 ((1-{[(benzyloxy)carbonyl]amino}-4-methoxy-4-oxobutyl)(3-phenylpropyl) phosphinic acid)
依照製程D在含有前一步產物 (200 mg,1.09 mmol,1.0當量)以及NH2
Cbz (181 mg,1.19 mmol,1.1當量)的AcOH溶液(2 mL)及AcCl的溶液(0.4 mL)中加入4-氧丁酸甲酯(純度90%,150 µL,1.3 mmol),經多成分反應後,獲得標題上的白色粉狀化合物 (389 mg,83%)。 MS (ESI+
): [M+H]+
= 4341
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.48-7.30 (m, 5H); 7.28-7.23 (m, 2H); 7.83-7.17 (m,1H); 7.16-7.13 (m, 1H); 6.30-6.20 (brs, 1H); 5.28-5.18 (m, 1H); 5.14-5.08 (m, 2H); 3.67 (ddt, J = 2.0, 9.5 and 10.0 Hz, 1H); 3.63 (s, 3H); 2.65 (t, J = 8.0 Hz, 2H), 2.42 (t, J = 8.0 Hz, 2H); 2.25-2.16 (m, 1H); 1.99-1.81 (m, 3H); 1.76-1.64 (m, 2H)3
C NMR (CDCl3
, 125 MHz) δ (ppm): 173.5; 156.5 (d, J = 5.0 Hz); 141.1; 136.4; 128.8 (2C); 128.7 (2C); 128.6 (2C); 128.5; 128.3; 126.4; 67.5; 51.9; 49.2 (d, J = 102.0 Hz); 36.7 (d, J = 15.0 Hz); 30.5 (d, J = 11.9 Hz); 26.5; 25.8; 23.6; 22.9 (d, J = 3.1 Hz)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 55.29
步驟 3: 4-(((苄氧基)羰基)胺基)-4-(羥基(3苯丙基)磷醯基)丁酸(4-(((benzyloxy)carbonyl)amino)-4-(hydroxy(3phenylpropyl)phosphoryl)butanoic acid)
依照製程F在前一步產物(510 mg,1.18 mmol,1.0當量)以及THF/H2
O (4 mL/1 mL)的混合溶液中加入LiOH‧H2
O (85 mg,3.53 mmol,3.0當量),製備標題上的油狀殘留化合物 (473 mg,96%)。MS (ESI-
): [M-H]-
= 4181
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11.5 (brs, 1H); 7.43 (d, J = 9.5 Hz, 1H); 7.39-7.30 (m, 5H); 7.28 (t, J = 7.5 Hz, 2H); 7.22-7.12 (m, 3H); 5.07 (d, J = 12.0 Hz, 1H); 5.03 (d, J = 12.0 Hz, 1H); 3.69 (m, 1H); 2.58 (d, J = 7.5 Hz, 2H); 2.38-2.30 (m, 1H); 2.26-2.20 (m, 1H); 2.04-1.96 (m, 1H); 1.85-1.62 (m, 3H); 1.52 (ddd, J =7.5, 9.0 and 13.5 Hz, 2H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 46.42
步驟 4: 4-胺基-4-[羥基(3-苯丙基)磷醯基]丁酸(4-amino-4-[hydroxy(3-phenylpropyl)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(473 mg,1.13 mmol,1.0當量)的EtOH/AcOH (9:1,c = 50 mM)混合溶液進行氫解,以製備標題上的白色粉狀化合物(71 mg,60%)。預估純度: 90% (根據高效能液相層析分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.2; [M+H]+
= 286.2; [(Mx2)+H]+ = 571.51
H NMR (D2
O, 500 MHz) δ (ppm): 7.41 (t, J = 7.0 Hz, 2H); 7.34 (d, J = 7.0 Hz, 2H); 7.30 (t, J = 7.0 Hz, 1H); 3.22 (td, J = 7.5及5.0 Hz, 1H); 2.76 (t, J = 7.5 Hz, 2H); 2.59 (td, J = 7.5 and 3.5 Hz, 2H); 2.20-2.09 (m, 1H); 1.99-1.82 (m, 3H); 1.71-1.60 (m, 2H)31
P NMR (D2
O, 202 MHz) δ (ppm): 35.79
實例38: 4-胺基-4-[羥基({2-[2-(三氟甲氧基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[2-(trifluoromethoxy)phenyl]ethyl})phosphoryl] butanoic acid)
步驟 1: 2-[2-(三氟甲氧基)苯基]乙烷-1-醇(2-[2-(trifluoromethoxy)phenyl]ethan-1-ol)
在氬氣環境中,將2-[2-(三氟甲氧基)苯基]乙酸(2.5 g,11 mmol,1.0當量)的0°C無水THF(6 mL)溶液滴加到氫化鋁鋰 (2M於 THF溶液中,23 mmol,11 mL) 溶液中。此反應會放熱,其混合物將變為黃色。將反應混合物在室溫攪拌40分鐘,並冷卻至0°C,然後以0.86 mL H2
O緩慢淬火。依序添加15%的NaOH水溶液(0.86 mL)以及H2
O (2.6 mL),並將混合物攪拌15分鐘。加入無水Na2
SO4
並將混合物攪拌15分鐘。將黃色混合物以矽藻土墊過濾,並將濾液真空濃縮。將混合物濃縮並以管柱層析法純化,最終獲得期望之透明油狀中間產物(2g,85%)。MS (ESI+
): [M+H]+
= 207.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.35 – 7.31 (m, 1H); 7.29 – 7.21 (m, 3H); 3.87 (t, J = 6.8 Hz, 2H); 2.96 (t, J = 6.7 Hz, 2H); 1.46 (s, 1H)
步驟 2: 1-(2-溴乙基)-2-(三氟甲氧基)苯(1-(2-bromoethyl)-2-(trifluoromethoxy)benzene)
將前步驟所得之產物(2.0 g,9.7 mmol,1.0當量)及四溴化碳(5.2 g,15 mmol,1.6 當量)以CH2
Cl2
(50 mL) 稀釋。將溶液於-5°C冷卻,並批次加入三苯膦(4.1 g,15 mmol,1.6當量)。添加完成後,將其於室溫攪拌1小時。將混合物濃縮並以管柱層析法純化,得到期望之淺黃色油狀中間產物(2.27 g,87%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.33-7.29 (m, 2H); 7.27-7.23 (m, 2H); 3.57 (t, J = 7.5 Hz, 2H); 3.24 (t, J = 7.5 Hz, 2H)
步驟 3: {2-[2-(三氟甲氧基)苯基]乙基}次磷酸 ({2-[2-(trifluoromethoxy)phenyl]ethyl}phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.87 mL,6.0 mmol,1.0當量)的無水Et2
O (5 mL)溶液中加入由1-(2-溴乙基)-2-(三氟甲氧基)苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(740 mg,48%)。 MS (ESI+
): [M+H]+
= 255.1; [(Mx2)+H]+
= 509.01
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.69 (t, J = 2.0 Hz, 0.5H); 7.35-7.17 (m, 4H); 6.59 (t, J = 1.9 Hz, 0.5H); 3.04-2.88 (m, 2H); 2.08 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 36.48
步驟 4: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基]({2-[2-(三氟 甲氧基)苯基] 乙基})次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl]({2-[2-(trifluoro methoxy)phenyl] ethyl})phosphinic acid)
依照製程D在含有前一步產物 (740 mg,3.1 mmol,1.0當量)以及NH2
Cbz (481 mg,3.19 mmol,1.1當量)的AcOH溶液(5.2 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(707 mg,3.48 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (800 mg,47%)。 MS (ESI+
): [M+H]+
= 580.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.43-7.19 (m, 14H); 5.18-5.00 (m, 4H); 4.08-3.96 (m, 1H); 3.00-2.89 (m, 2H); 2.59-2.44 (m, 2H); 2.30-2.20 (m, 1H); 1.99-1.81 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.45
步驟 5: 4-胺基-4-[羥基({2-[2-(三氟甲氧基)苯基]乙基})磷醯基]丁酸(4-amino-4-[hydroxy({2-[2-(trifluoromethoxy)phenyl]ethyl})phosphoryl]butanoic acid)
依照製程H將含有前一步產物(350 mg,0.6 mmol,1.0當量)的EtOH/AcOH (1:1,10 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(100 mg,46%)。預估純度: > 95% (根據高效能液相層析及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 338.1; [M+H]+
= 356.1; [(Mx2)+H]+
= 711.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.48-7.39 (m, 1H); 7.31-7.21 (m, 3H); 3.12 (td, J = 8.4, 5.2 Hz, 1H); 2.98 (q, J = 8.4 Hz, 2H); 2.60 (t, J = 7.5 Hz, 2H); 2.30-2.16 (m, 1H); 2.01-1.75 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 30.36
實例 39:4-胺基-4-[(2-{[1,1'-聯苯]-2-基}乙基)(羥基)磷醯基]丁酸 (4-amino-4-[(2-{[1,1'-biphenyl]-2-yl}ethyl)(hydroxy)phosphoryl]butanoic acid)
步驟 1:2-{[1,1'-聯苯]-2-基}乙酸乙鹽(ethyl 2-{[1,1'-biphenyl]-2-yl}acetate)
將2-(2-溴苯基)乙酸乙酯(2.5 g,10 mmol,1.0當量)、苯硼酸(1.5 g,12 mmol,1.2當量)、碳酸鉀(7.1 g,51 mmol,5.0當量)以及四(三苯基膦)鈀(1.2 g,1.03 mmol,0.1當量)置於燒瓶中,並以氬氣吹驅10分鐘。接著加入氬氣脫氣過之二氧六環/水的4/1混合物(0.2 M,50 mL)。添加完成後,將其於80°C攪拌24小時,然後將反應混合物冷卻至室溫。加入水及CH2
Cl2
。並以CH2
Cl2
萃取水層(三次)。合併之有機層經Na2
SO4
乾燥、過濾、真空濃縮。將混合物濃縮並以管柱層析法純化,最後獲得標題上之澄清油狀化合物(2.39 g,97%)。MS (ESI+
): [M+H]+
= 2411
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.45-7.20 (m, 9H); 4.08 (q, J = 7.1 Hz, 2H); 3.59 (s, 2H); 1.19 (t, J = 7.1 Hz, 3H)
步驟 2: 2-{[1,1'-聯苯]-2-基}乙烷-1-醇(2-{[1,1'-biphenyl]-2-yl}ethan-1-ol)
氬氣環境中,將上一步獲得之化合物(2.4 g,9.3 mmol,1.0 當量)的0°C無水THF(5 mL)溶液滴加到氫化鋁鋰 (2 M 的THF溶液,9.9 mL,20 mmol) 溶液中。此反應會放熱,其混合物將變為黃色。將反應混合物在室溫攪拌45分鐘,並冷卻至0°C,然後以0.7 mL H2
O緩慢淬火。依序加入15%的NaOH水溶液(0.7 mL)及H2
O (2.1 mL),並將其攪拌15分鐘。加入無水Na2
SO4
並攪拌15分鐘。將黃色混合物以矽藻土墊過濾,並將其真空濃縮,獲得到標題上之黃色粉末狀化合物(1.17g,59%)。MS (ESI+
): [(M-H2
O)+H]+
= 181.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.49-7.19 (m, 9H); 3.71 (td, J = 6.8, 5.7 Hz, 2H); 2.91 (t, J = 6.9 Hz, 2H)
步驟 3: 2-(2-溴乙基)-1,1'-聯苯 (2-(2-bromoethyl)-1,1'-biphenyl)
將前步驟獲得之化合物(1.17 g,5.90 mmol,1.0當量)以及四溴化碳(3.13 g,9.44 mmol,1.6當量)以CH2
Cl2
(30 mL) 稀釋。將其冷卻至-5°C,並批次加入三苯膦(2.48 g,9.44 mmol,1.6當量)。添加完成後,將其黃色反應物在室溫下攪拌1小時。濃縮混合物並以管柱層析法純化,最後獲得標題上之化合物(1.4 g,90%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.48-7.17 (m, 9H); 3.40-3.29 (m, 2H); 3.17 (dd, J = 8.4, 7.2 Hz, 2H)
步驟 4: (2-{[1,1'-聯苯]-2-基}乙基)次磷酸((2-{[1,1'-biphenyl]-2-yl}ethyl)phosphinic acid)
依照製程B在氯亞磷酸二乙酯(074 mL,5.1 mmol,1.0當量)的無水Et2
O (4 mL)溶液中加入由2-(2-溴乙基)- 1,1'-聯苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(460 mg,37%)。MS (ESI+
): [M+H]+
= 247
步驟 5: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基](2-{[1,1'-聯苯]-2-基}乙基)次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl](2-{[1,1'-biphenyl]-2-yl}ethyl)phosphinic acid)
依照製程D在含有前一步產物 (460 mg,1.9 mmol,1.0當量)以及NH2
Cbz (313 mg,2.07 mmol,1.1當量)的AcOH溶液(2.3 mL)及AcCl的溶液(0.3 mL)中加入4-氧丁酸芐酯(434 mg,2.26 mmol,1.2 當量),經多成分反應後,獲得標題上的白色固體化合物 (245 mg,23%)。MS (ESI+
): [M+H]+
= 572.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.43-7.09 (m, 19H); 5.28-4.94 (m, 4H); 3.88 (m, 1H); 2.86 (m, 2H); 2.62-2.29 (m, 2H); 2.15-1.99 (m, 1H); 1.87-1.66 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.47
步驟 6: 4-胺基-4-[(2-{[1,1'-聯苯]-2-基}乙基)(羥基)磷醯基]丁酸(4-amino-4-[(2-{[1,1'-biphenyl]-2-yl}ethyl)(hydroxy)phosphoryl]butanoic acid)
依照製程H將含有前一步產物(245 mg,0.428 mmol)的EtOH/AcOH (1:1,8.0 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(76 mg,51%)。預估純度: > 97% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 330.2; [M+H]+
= 348; [(Mx2)+H]+
= 695.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.46-7.39 (m, 2H); 7.39-7.27 (m, 5H); 7.23 (td, J = 7.5, 1.4 Hz, 1H); 7.15 (dd, J = 7.5, 1.5 Hz, 1H); 2.93-2.84 (m, 3H); 2.45 (t, J = 7.4 Hz, 2H); 2.05‑1.91 (m, 1H); 1.85-1.63 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 31.05
實例 40: 4-胺基-4-{[2-(2,3-二氯苯基)乙基](羥基)磷醯基}丁酸 (4-amino-4-{[2-(2,3-dichlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
步驟 1: 1-(2-溴乙基)-2,3-二氯苯(1-(2-bromoethyl)-2,3-dichlorobenzene)
將2-(2,3-二氯苯)乙烷-1-醇(1.5 g,7.8 mmol,1.0 當量)以及四溴化碳(4.2 g,12 mmol,1.6 當量)以CH2
Cl2
(40 mL)稀釋。將其在-5°C冷卻,並批次加入三苯膦(3.3 g,12.0 mmol,1.6當量)。添加完成後,將其黃色反應物在室溫攪拌1小時。濃縮混合物並以管柱層析法純化,最後獲得標題上之無色淺黃色油狀化合物(1.8 g,90%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.39 (dd, J = 7.1, 2.4 Hz, 1H); 7.22-7.13 (m, 2H); 3.60 (t, J = 7.4 Hz, 2H); 3.33 (t, J = 7.4 Hz, 2H).
步驟 2: [2-(2,3-二氯苯基)乙基]次磷酸([2-(2,3-dichlorophenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(1.4 mL,6.8 mmol,1.0當量)的無水Et2
O (6 mL)溶液中加入由1-(2-溴乙基)-2,3-二氯苯的無水Et2
O溶液新鮮配置的格任亞試劑,以製備標題上的化合物(690 mg,43%)。 MS (ESI+
): [M+H]+
= 2401
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.65 (t, J = 1.9 Hz, 0.5H); 7.50-7.12 (m, 3H); 6.56 (t, J = 1.9 Hz, 0.5H); 3.16-2.98 (m, 2H); 2.20-2.03 (m, 2H)31
P NMR (CD3
OD, 202 MHz): 32.83
步驟 3: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(2,3-二氯苯基) 乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(2,3-dichlorophenyl) ethyl]phosphinic acid)
依照製程D在含有前一步產物 (690 mg,2.9 mmol,1.0當量)以及NH2
Cbz (479 mg,3.17 mmol,1.1當量)的AcOH溶液(5 mL)及AcCl的溶液(0.6 mL)中加入4-氧丁酸芐酯(665 mg,3.46 mmol,1.2 當量)並經多成分耦合反應後獲得標題上的黃色固體化合物 (1.1 g,67%)。 MS (ESI+
): [M+H]+
= 5651
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.48-7.08 (m, 13H); 5.22-4.98 (m, 4H); 4.15-3.90 (m, 1H); 3.21-2.92 (m, 2H); 2.70-2.37 (m, 2H); 2.33-2.22 (m, 1H); 2.13-1.81 (m, 2H); 1.42‑1.25 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.44
步驟 4: 4-{[(苄氧基)羰基]胺基}-4-{[2-(2,3-二氯苯基)乙基]( 羥基) 磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[2-(2,3-dichlorophenyl)ethyl](hydroxy) phosphoryl}butanoic acid)
依照製程F在前一步產物(1.1 g,1.9 mmol,1.0當量)以及THF/H2
O (3/1,20 mL)的混合溶液中加入LiOH‧H2
O (245 mg,5.85 mmol,3.0當量),以製備標題上淡黃色固體的化合物 (266 mg,29%)。MS (ESI+
): [M+H]+
= 474.01
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.50-7.12 (m, 8H); 5.26-5.01 (m, 2H); 4.05 (ddd, J = 11.9, 8.7, 3.5 Hz, 1H); 3.16-2.97 (m, 2H); 2.55-2.36 (m, 2H); 2.34-2.17 (m, 1H); 2.02‑1.68 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.45
步驟 5: 4-胺基-4-{[2-(2,3-二氯苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(2,3-dichlorophenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(266 mg,561 µmol,1.0當量)的TFA/苯甲醚 (1.7 mL/1.2 mL)溶液,以製備標題上的白色固體化合物(39 mg,20%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 323; [M+H]+
= 341; [(Mx2)+H]+
= 681.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.40 (dd, J = 8.0, 1.5 Hz, 1H); 7.35 (dd, J = 7.7, 1.6 Hz, 1H); 7.24 (t, J = 7.8 Hz, 1H); 3.21-3.14 (m, 1H); 3.13-3.05 (m, 2H); 2.64 (t, J = 7.3 Hz, 2H); 2.33-2.21 (m, 1H); 2.08-1.83 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 30.29
實例 41: 4-胺基-4-{[2-(3-氯-2-甲氧苯基)乙基](羥基)磷醯基}丁酸 (4-amino-4-{[2-(3-chloro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl} butanoic acid)
步驟 1: 3-氯-2-甲氧基苯甲醛(3-chloro-2-methoxybenzaldehyde)
在3-氯-2-羥基-苯甲醛(3.0 g,19 mmol,1.0當量)的DMF(28 mL)溶液中添加K2
CO3
(4.0 g,29 mmol,1.5當量)以及碘甲烷(1.92 mL, 30.6 mmol,1.6當量)。混合物會立即變為黃色,將其在室溫攪拌3小時。以水(140 mL)稀釋並將其轉移至分液漏斗中,然後以EtOAc萃取水層兩次。有機萃取物以Na2
SO4
乾燥、過濾並真空濃縮。再以管柱層析法純化粗產物以獲得到標題上之透明固體產物(3g,92%)。MS (ESI+
): [M+H]+
= 171.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 10.38 (d, J = 0.8 Hz, 1H); 7.76 (dd, J = 7.8, 1.7 Hz, 1H); 7.64 (dd, J = 7.9, 1.7 Hz, 1H); 7.19 (dd, J = 7.9, 0.8 Hz, 1H); 4.01 (s, 3H)
步驟2: 1-氯-2-甲氧基-3-[2-甲氧基乙烯基]苯(1-chloro-2-methoxy-3-[2-methoxyethenyl]benzene)
在0°C,氬氣環境中,在(甲氧基甲基)三苯基氯化鏻(10.5 g,30.6 mmol,1.0當量)的無水THF(88mL)懸浮液中添加適量之KOt
Bu (4.4 g,39 mmol,1.3當量)。將其於0°C下再攪拌10分鐘。少量添加前一步之產物(3.0 g,18 mmol,0.58當量)。30分鐘後,將其以水(50mL)淬火,並以乙醚(50mL)稀釋。分離有機相。再以乙醚(2×50 mL)萃取水相。合併之有機層以鹽水洗滌,並經Na2
SO4
乾燥、過濾、真空濃縮後,得到標題上之化合物(4g,71%)。 MS (ESI+
): [M+H]+
= 199.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.94 (dd, J = 7.9, 1.6 Hz, 0.5H); 7.22-7.09 (m, 2H); 6.97 (dt, J = 22.3, 7.9 Hz, 1H); 6.23 (d, J = 7.2 Hz, 0.5H); 5.99 (d, J = 13.0 Hz, 0.5H); 5.57 (d, J = 7.2 Hz, 0.5H); 3.83-3.70 (m, 6H)
步驟 3: 2-(3-氯-2-甲氧苯基)乙醛(2-(3-chloro-2-methoxyphenyl)acetaldehyde)
在前步驟獲得之產物(4.0 g,20 mmol,1當量)的THF(110mL)溶液中加入10mL 10%之HCl水溶液。混合物加熱並回流1小時。再加入2 mL 10% HCl水溶液,並加熱回流6小時。冷卻至室溫後,將反應混合物以飽和NaHCO3
水溶液中和。將混合物在減壓下濃縮,然後用水及MTBE稀釋。分離有機相。再以MTBE萃取水相。收集之有機層以鹽水洗滌,經Na2
SO4
乾燥、過濾並真空濃縮後,獲得標題上之化合物 (2.74 g,74%)。MS (ESI+
): [M+H]+
= 185.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.74 (t, J = 2.0 Hz, 1H); 7.34 (dd, J = 7.8, 1.9 Hz, 1H); 7.16-6.97 (m, 3H); 3.83 (s, 3H); 3.73 (d, J = 2.0 Hz, 2H)
步驟 4: 2-(3-氯-2-甲氧苯基)乙烷-1-醇(2-(3-chloro-2-methoxyphenyl)ethan-1-ol)
0°C下,在前步所獲得之產物(2.7 g,15 mmol,1.0當量)的MeOH(75mL)溶液中批次添加NaBH4
(674 mg,17.8µmol,1.2 當量)。將混合物在室溫攪拌45分鐘。接著在減壓下濃縮,然後用水及EtOAc稀釋。分離有機相。再以EtOAc萃取水相。收集之有機層以鹽水洗滌,經Na2
SO4
乾燥、過濾並真空濃縮後以管柱層析法純化,最終獲得標題上之黃色油狀化合物(1.4 g,50%)。MS (ESI+
): [(M-H2
O)+H]+
= 169.1; [M+H]+
= 187.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.28-7.25 (m, 1H); 7.18-7.09 (m, 1H); 7.01 (t, J = 7.8 Hz, 1H); 3.87 (s, 5H); 2.93 (t, J = 6.5 Hz, 2H)
步驟 5: 1-(2-溴乙基)-3-氯-2-甲氧苯(1-(2-bromoethyl)-3-chloro-2-methoxybenzene)
將2-(3-氯-2-甲氧苯基)乙烷-1-醇(1.4 g,7.5 mmol,1.0當量)及四溴化碳(4 g,12 mmol,1.6當量)以CH2
Cl2
(40 mL)稀釋。將其冷卻至-5°C,並批次加入三苯膦(3.2 g,12 mmol,1.6當量)。添加完成後,將其黃色反應物在室溫攪拌45分鐘。最後將混合物濃縮並以管柱層析法純化,獲得到標題上之淺黃色油狀化合物(1.6g,85%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.29 (dd, J = 8.0, 1.6 Hz, 1H); 7.13-7.10 (m, 1H); 7.01 (t, J = 7.8 Hz, 1H); 3.88 (s, 3H); 3.58 (dd, J = 7.9, 7.3 Hz, 2H); 3.20 (t, J = 7.6 Hz, 2H)
步驟 6: [2-(3-氯-2-甲氧苯基)乙基]次磷酸([2-(3-chloro-2-methoxyphenyl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.67 mL,6.1 mmol,1.0當量)的無水Et2
O (2.2 mL)溶液中加入由1-(2-溴乙基)-3-氯-2-甲氧苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(245 mg,17%)。MS (ESI+
): [M+H]+
= 235.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.59 (t, J = 1.9 Hz, 0.5H); 7.28 (dd, J = 8.0, 1.6 Hz, 1H); 7.21 (dd, J = 7.7, 1.6 Hz, 1H); 7.05 (t, J = 7.8 Hz, 1H); 6.51 (t, J = 1.9 Hz, 0.5H); 3.86 (s, 3H); 2.98-2.88 (m, 2H); 2.10-2.00 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 33.58
步驟 7: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(3-氯-2-甲氧苯基)乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(3-chloro-2-methoxy phenyl)ethyl]phosphinic acid)
依照製程D在含有前一步產物 (245 mg,1.04 mmol,1.0當量)以及NH2
Cbz (174 mg,1.25 mmol,1.1當量)的AcOH溶液(2 mL)及AcCl的溶液(0.9 mL)中,加入4-氧丁酸芐酯(240 mg,1.25 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (400 mg,68%)。MS (ESI+
): [M+H]+
= 560.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.44 – 7.16 (m, 11H); 7.09 (d, J = 7.5 Hz, 1H); 7.01 (t, J = 7.8 Hz, 1H); 5.25-5.20 (m, 4H); 3.80 (s, 3H); 2.91 (q, J = 7.9 Hz, 2H); 2.68-2.41 (m, 3H); 2.27 (m, 1H); 1.93 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.66
步驟 8: 4-{[(苄氧基)羰基]胺基}-4-{[2-(3-氯-2-甲氧苯基)乙基]( 羥基) 磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{[2-(3-chloro-2-methoxyphenyl)ethyl](hydroxy) phosphoryl}butanoic acid)
依照製程F在前一步產物(400 mg,0.7 mmol,1.0當量)以及THF/H2
O (3 mL/0.5 mL)的混合溶液中加入LiOH‧H2
O (60 mg,1.4 mmol,2.0當量),以製備標題上的化合物 (327 mg,97%)。MS (ESI+
): [M+H]+
= 470.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.44-7.21 (m, 6H); 7.12 (dd, J = 7.7, 1.6 Hz, 1H); 7.03 (t, J = 7.8 Hz, 1H); 5.14 (m, 2H); 4.05 (td, J = 9.2, 8.6, 5.0 Hz, 1H); 3.83 (s, 3H); 2.95 (dt, J = 10.7, 7.0 Hz, 2H); 2.57-2.36 (m, 2H); 2.33-2.17 (m, 1H); 2.07-1.82 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 51.27
步驟 9: 4-胺基-4-{[2-(3-氯-2-甲氧苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(3-chloro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
依照製程G從含有前一步產物(327 mg,695 µmol,1.0當量)的TFA/苯甲醚 (2.14 mL/1.5 mL)溶液,製備標題上的白色固體化合物(69 mg,29%)。 預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 318.1; [M+H]+
= 336.1; [(Mx2)+H]+
= 671.2 MS (ESI-
): [M-H]-
=334.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.23 (m, 2H); 7.03 (t, J = 7.8 Hz, 1H); 3.86 (s, 3H); 3.13 (td, J = 8.5, 5.1 Hz, 1H); 2.95 (q, J = 8.1 Hz, 2H); 2.61 (t, J = 7.2 Hz, 2H); 2.30-2.20 (m, 1H); 2.03-1.79 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 30.85
實例 42: 3-羧基-1-{羥基[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基}丙烷-1-氯化銨(3-carboxy-1-{hydroxy[2-(1-methyl-1H-indol-3-yl)ethyl]phosphoryl}propan-1-aminium chloride)
步驟 1:2-(1-甲基-1H-吲哚-3-基)乙酸甲酯(methyl 2-(1-methyl-1H-indol-3-yl)acetate)
0°C下,在2-(1-甲基-1H-吲哚-3-基)乙酸(3.0 g,16 mmol,1.0當量)的MeOH(30 mL)溶液中的中加入濃H2
SO4
(6滴)。混合物於室溫攪拌過夜。將其減壓濃縮。殘餘物用EtOAc以及飽和NaHCO3
水溶液稀釋,並轉移至分液漏斗中。有機層以EtOAc萃取兩次,並用飽和NaHCO3
水溶液洗滌。有機萃取物以Na2
SO4
乾燥、過濾並真空濃縮,獲得標題上之棕色油狀產物(3.17 g,98%)。MS (ESI+
): [M+H]+
= 204.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.60 (dt, J = 7.9, 1.0 Hz, 1H); 7.30 (dt, J = 8.2, 0.9 Hz, 1H); 7.24 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H); 7.13 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H); 7.05 (d, J = 1.0 Hz, 1H); 3.77 (m, 5H); 3.70 (s, 3H)
步驟 2: 2-(1-甲基-1H-吲哚-3-基)乙烷-1-醇(2-(1-methyl-1H-indol-3-yl)ethan-1-ol)
0°C,氬氣環境中,將前步獲得之化合物(3.2 g,15 mmol,1.0當量)的無水THF(8 mL)溶液滴加到氫化鋁鋰 (2M 的THF溶液,16 mL ,32 mmol) 溶液中。此反應會放熱,其混合物將變為黃色。反應混合物在室溫攪拌40分鐘,冷卻至0°C,然後以1.2 mL H2
O,1.2 mL 15% NaOH水溶液以及第二次3.5 mL H2
O緩慢淬火。將混合物攪拌15分鐘。加入無水Na2
SO4
並再攪拌15分鐘。將黃色混合物以矽藻土墊過濾並將濾液真空濃縮,最後獲得標題上之澄清油狀產物(2.7g,99%)。 MS (ESI+
): [M+H]+
= 176.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.61 (dt, J = 7.9, 1.0 Hz, 1H); 7.31 (dt, J = 8.2, 0.9 Hz, 1H); 7.25-7.22 (m, 1H); 7.12 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H); 6.95 (s, 1H); 3.90 (t, J = 6.3 Hz, 2H); 3.77 (s, 3H); 3.03 (td, J = 6.4, 0.8 Hz, 2H)
步驟 3: 3-(2-溴乙基)-1-甲基-1H-吲哚(3-(2-bromoethyl)-1-methyl-1H-indole )
在前步驟獲得之化合物(1.5 g,8.6 mmol,1.0當量)的CH2
Cl2
(43 mL)溶液中加入四溴化碳(4.5 g,14 mmol,1.6當量)。將溶液在冰/鹽浴中冷卻,並批次加入三苯膦(3.6 g,14 mmol,1.6當量)。加完後,將其黃色反應加熱至室溫45分鐘。混合物減壓濃縮。其殘餘物以管柱層析法純化,得到標題上之淺黃色油狀化合物(1.6g,79%)。 MS (ESI+
): [(M-Br]+
= 158.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.58 (dt, J = 7.9, 1.0 Hz, 1H); 7.31 (dt, J = 8.2, 0.9 Hz, 1H); 7.26-7.22 (m, 1H); 7.13 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H); 6.95 (d, J = 0.9 Hz, 1H); 3.77 (s, 3H); 3.62 (dd, J = 8.1, 7.3 Hz, 2H); 3.33 (td, J = 7.7, 0.8 Hz, 2H)
步驟 4: [2-(1-甲基-1H-吲哚-3-基)乙基]次磷酸([2-(1-methyl-1H-indol-3-yl)ethyl]phosphinic acid)
依照製程B在氯亞磷酸二乙酯(0.71 mL,6.5 mmol,1.0當量)的無水Et2O (3 mL)溶液中加入由3-(2-溴乙基)-1-甲基-1H-吲哚的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(950 mg,65%)。MS (ESI+
): [M+H]+
= 224.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.70 (t, J = 2.1 Hz, 0.5H); 7.60 (dt, J = 8.0, 1.0 Hz, 1H); 7.31 (dt, J = 8.2, 0.9 Hz, 1H); 7.25 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H); 7.13 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H); 6.90 (s, 1H); 6.60 (t, J = 2.1 Hz, 0.5H); 3.75 (s, 3H); 3.18-3.06 (m, 2H); 2.21 (dddd, J = 15.6, 10.0, 6.1, 2.1 Hz, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 38.65
步驟 5: [2-(1-甲基-1H-吲哚-3-基)乙基]次磷酸苄酯(benzyl [2-(1-methyl-1H-indol-3-yl)ethyl]phosphinate)
在前步驟獲得之產物(450 mg,2.02 mmol,1.0當量)及苯甲醇(241µL,2.32 mmol,1.15當量)的CH2
Cl2
(33 mL)溶液中添加適量之固體EDCI(773 mg,4.03 mmol,2 當量)。將反應混合物於室溫攪拌過夜。轉移至分液漏斗中,並以飽和NaHCO3
水溶液洗滌(2次),然後再以鹽水洗滌。有機萃取物以Na2
SO4
乾燥、過濾並真空濃縮。殘餘物以管柱層析法純化,獲得標題上之淺黃色油狀化合物(434mg,78%)。MS (ESI+
): [M+H]+
= 314.1; [(Mx2)+H]+
= 627.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.59 (t, J = 2.1 Hz, 0.5H); 7.51 (dt, J = 7.9, 1.0 Hz, 1H); 7.40-7.29 (m, 6H); 7.16 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H); 7.04 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H); 6.97 (d, J = 1.0 Hz, 1H); 6.49 (t, J = 2.1 Hz, 0.5H); 5.15-4.97 (m, 2H); 3.71 (s, 3H); 3.05 (m, 2H); 2.30-2.17 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 41.58
步驟 6: 4-[(苄氧基)[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基]-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸苄酯(benzyl 4-[(benzyloxy)[2-(1-methyl-1H-indol-3-yl)ethyl]phosphoryl]-4-[(2-methylpropane-2-sulfinyl)amino]butanoate)
依照製程E,在前一步產物(434 mg,1.39 mmol,1.5當量)及碳酸銫(753 mg,2.31 mmol,2.5 當量)的CH2
Cl2
(2.2 mL)溶液中加入外消旋的(4E)-4-[(2-甲基丙烷-2-亞磺醯基) 亞胺基]丁酸芐酯(273 mg,0.924 mmol,1.0 當量)的CH2
Cl2
(2.2 mL) 溶液,以製備標題上的化合物 (579 mg,69%)。MS (ESI+
): [M+H]+
= 609.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.60-7.44 (m, 1H); 7.42-7.27 (m, 11H); 7.20-7.11 (m, 1H); 7.08-6.98 (m, 1H); 6.99-6.93 (m, 1H); 5.16-4.91 (m, 4H); 4.59 (s, 1H); 4.10 (q, J = 7.1 Hz, 1H); 3.75-3.36 (m, 2H); 3.11-2.93 (m, 2H); 2.68-2.12 (m, 5H); 1.98-1.78 (m, 1H); 1.27-1.09 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 57.02; 56.61; 56.31 及 56.05
步驟 7: 4-{羥基[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基}-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸(4-{hydroxy[2-(1-methyl-1H-indol-3-yl)ethyl]phosphoryl}-4-[(2-methylpropane-2-sulfinyl)amino]butanoic acid)
依照製程F在前一步產物(580 mg,0.95 µmol,1.0當量)以及THF/H2
O (5/1,4.7 mL)的混合溶液中加入LiOH.H2
O (120 mg,2.85 mmol,3.0當量),以製備標題上的化合物 (350 mg,86%)。MS (ESI+
): [M+H]+
= 429.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.61-7.53 (m, 1H); 7.37-7.29 (m, 1H); 7.19-7.13 (m, 1H); 7.06-6.99 (m, 2H); 3.75 (s, 3H); 3.47-3.38 (m, 1H); 3.05 (m, 2H); 2.69-2.06 (m, 5H); 1.90 (m, 1H); 1.22 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 49.53
步驟 8: 3-羧基-1-{羥基[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基}丙烷-1-氯化銨(3-carboxy-1-{hydroxy[2-(1-methyl-1H-indol-3-yl)ethyl]phosphoryl}propan-1-aminium chloride)
依照製程G從含有前一步產物(350 mg,0.815 mmol,1.0當量)及4.0 M HCl的二氧六環(4.5 mL,22 當量) 溶液,以製備標題上的米色粉末化合物(122 mg,41%)。預估純度: > 97% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 307.1; [M+H]+
= 325.1; [(Mx2)+H]+
= 649.3 MS (ESI-
): [M-H]-
= 323.1; [(Mx2)-H]-
= 647.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.59 (dt, J = 7.9, 1.0 Hz, 1H); 7.37-7.30 (m, 1H); 7.19-7.15 (m, 1H); 7.09-6.96 (m, 2H); 3.75 (s, 3H); 3.24-3.14 (m, 1H); 3.09 (dt, J = 10.6, 8.1 Hz, 2H); 2.58-2.39 (m, 2H); 2.27-2.14 (m, 3H); 2.00-1.87 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 40.27
實例 43: 3-羧基-1-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基) 丙烷-1-氯化銨(3-carboxy-1-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl) propan-1-aminium chloride)
步驟 1:2-[2-(環己氧基)苯基]乙酸甲酯 (methyl 2-[2-(cyclohexyloxy)phenyl]acetate)
0°C下,在2-(2-羥苯基)乙酸甲酯(2.0 g,12 mmol,1.0 當量)、環己醇(1.81 g,18.1 mmol,1.5 當量)及三苯膦(3.79 g,14.4 mmol,1.2當量)的THF (24 mL)溶液中,加入偶氮二羧酸二(三級丁酯) (3.33 g,14.4 mmol,1.2當量)。將反應混合物在室溫攪拌18小時。減壓濃縮,並將所得之濃漿狀物在戊烷/Et2
O (1/1,100 mL)中研磨。所得之懸浮液以燒結玻璃過濾(戊烷/Et2
O: 1/1洗滌),並將濾液減壓濃縮。殘餘物以管柱層析法純化,最後得到標題上之無色油狀化合物(1.35 g,45%)。MS (ESI+
): [M+H]+
= 249.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26-7.18 (m, 2H); 6.95-6.85 (m, 2H); 4.33 (m, 1H); 3.71 (s, 3H); 3.65 (s, 2H); 1.98-1.89 (m, 2H); 1.83-1.74 (m, 2H); 1.65-1.50 (m, 3H); 1.45‑1.35 (m, 3H)
步驟 2: 2-[2-(環己氧基)苯基]乙烷-1-醇(2-[2-(cyclohexyloxy)phenyl]ethan-1-ol)
在0°C下,在前步獲得之產物 (1.35 g,5.42 mmol,1當量)的THF(10 mL)溶液中滴加市售之LiAlH4
(2.0M的THF溶液,5.4 mL,10.8 mmol,2當量)。將混合物在室溫攪拌1小時。冷卻至0°C,加入水(650 µL)、15% NaOH水溶液(650 µL)及再一次的水(2 mL)。攪拌15分鐘,加入Na2
SO4
並將其以矽藻土過濾(MTBE沖洗)。減壓濃縮濾液。並以管柱層析法純化殘餘物,獲得標題上之嗆鼻無色油狀化合物(1.19 g,100%)。MS (ESI+
): [M+H]+
= 221.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26-7.15 (m, 2H); 6.92-6.88 (m, 2H); 4.34 (m, 1H); 3.88 (m, 2H); 2.95 (t, J = 6.3 Hz, 2H); 2.05-1.95 (m, 2H); 1.92 (br s, 1H); 1.86-1.75 (m, 2H); 1.65-1.55 (m, 3H); 1.46-1.35 (m, 3H)
步驟 3: 1-(環己氧基)-2-(2-碘乙基)苯(1-(cyclohexyloxy)-2-(2-iodoethyl)benzene)
在0°C下,在三苯膦(774 mg,2.95 mmol,1.3當量)的CH2
Cl2
(15 mL)溶液中加入碘(749 mg,2.95 mmol,1.3當量)。其混合物在0°C下攪拌15分鐘,並加入咪唑(201 mg,2.95 mmol,1.3當量)以及前步化合物的溶液(500 mg,2.27 mmol,1.0當量)。混合物於室溫攪拌1小時。再將其以EtOAc及Na2
S2
O3
飽和水溶液進行選擇性分離並脫色。各層分離後,有機相以鹽水洗滌,再以Na2
SO4
乾燥、過濾、減壓濃縮。殘留物以管柱層析法純化,獲得標題上之無色油狀化合物(657 mg,88%)。 MS (ESI+
): [(M-I]+
= 203.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.23 (td, J = 7.8, 1.8 Hz, 1H), 7.15 (dd, J = 7.6, 1.8 Hz, 1H); 6.90-6.86 (m, 2H); 4.34 (m, 1H); 3.42 (t, J = 7.6 Hz, 2H); 3.22 (t, J = 7.6 Hz, 2H); 2.01-1.92 (m, 2H); 1.86-1.76 (m, 2H); 1.67-1.54 (m, 3H); 1.49-1.38 (m, 3H)
步驟 4: 膦-硼烷錯合中間產物
依照製程C的第一步,在前一步產物(650 mg,1.97 mmol,1.0當量)的THF (3 mL)溶液中加入(BH3
)P(OEt)2
H (321 mg,2.36 mmol,1.2 當量)的THF (7 mL)溶液以及LiHMDS(1.0 M 的THF溶液,2.36 mL,2.36 mmol,1.2 當量),以製備標題上的無色油狀化合物 (542 mg,81%)。MS (ESI+
): [(M-H2
)+H]+
= 337.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 6.95-6.88 (m, 2H); 6.69 (d, J = 7.9 Hz, 1H); 6.60 (td, J = 7.5, 1.2Hz, 1H); 4.18 (m, 1H); 4.90-3.75 (m, 4H); 2.60 (m, 2H); 1.82 (m, 2H); 1.77-1.68 (m, 2H); 1.65-1.55 (m, 2H); 1.45-1.30 (m, 3H); 1.28-1.16 (m, 3H); 1.07 (t, J = 7.0 Hz, 6H); 0.65-0.00 (m, 3H)
步驟 5: {2-[2-(環己氧基)苯基]乙基}次磷酸苄酯(benzyl {2-[2-(cyclohexyloxy)phenyl]ethyl}phosphinate)
依照變化的製程C第二步驟,在前一步產物(540 mg,1.6 mmol,1.0當量)的DCM (8 mL)溶液中依序加入HBF4
.Et2
O (1.09 mL,7.98 mmol,5.0當量)、BnOH (224 mg,2.08 mmol,1.3當量)及EDCI.HCl (460 mg, 2.40 mmol,1.5 當量)來進行製備標題上的無色油狀化合物(108 mg,21%)。MS (ESI+
): [M+H]+
= 359.2; [(Mx2)+H]+
= 717.41
H NMR (CDCl3
500 MHz) δ (ppm): 7.45-7.35 (m, 5H); 7.21-7.16 (m, 1H); 7.16 (dm, J = 533 Hz, 1H); 7.13 (dd, J = 7.4, 1.7 Hz, 1H); 6.88-6.83 (m, 2H); 5.17 (dd, J = 11.9, 9.8 Hz, 1H); 5.07 (dd, J = 11.9, 8.3 Hz, 1H); 4.32 (m, 1H); 2.96-2.87 (m, 2H); 2.26-2.13 (m, 2H); 1.99-1.91 (m, 2H); 1.85-1.73 (m, 2H); 1.62-1.53 (m, 3H); 1.47-1.33 (m, 3H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 39.02
步驟 6: 4-[(苄氧基)({2-[2-(環己氧基)苯基]乙基})磷醯基]-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸苄酯(benzyl 4-[(benzyloxy)({2-[2-(cyclohexyloxy)phenyl]ethyl})phosphoryl]-4-[(2-methylpropane-2-sulfinyl)amino]butanoate)
依照製程E,在前一步產物(105 mg,0.293 mmol,1.0當量)及碳酸銫(143 mg,0.439 mmol,1.5 當量)的CH2
Cl2
(1 mL)溶液中加入外消旋的(4E)-4-[(2-甲基丙烷-2-亞磺醯基) 亞胺基]丁酸芐酯(113 mg,0.38 mmol,1.3 當量)的CH2
Cl2
(0.5 mL) 溶液,以製備標題上由4種非鏡像異構物混和而成的橘色油狀化合物 (134 mg,70%)。MS (ESI+
): [M+H]+
= 654.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.50-7.30 (m, 10H); 7.20-7.05 (m, 2H); 6.95-6.80 (m, 2H); 5.20-5.00 (m, 4H); 4.40-4.30 (m, 1H); 3.75-3.60 (m, 1H); 2.98-2.78 (m, 2H); 2.75-2.50 (m, 2H); 2.50-2.15 (m, 3H); 2.05-1.90 (m, 3H); 1.85-1.71 (m, 2H); 1.63-1.47 (m, 3H); 1.45-1.30 (m, 3H); 1.27-1.17 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 56.69; 56.58; 55.73; 55.49
步驟 7: 4-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基)-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸(4-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-4-[(2-methylpropane-2-sulfinyl)amino]butanoic acid)
依照製程F在前一步產物(132 mg,0.202 mmol,1.0當量)以及THF/H2
O (4/1,2.0 mL)的混合溶液中加入LiOH‧H2
O (14.5 mg,0.606 mmol,3.0當量),以製備標題上的白色固體化合物 (82 mg,86%)。MS (ESI+
): [M+H]+
= 474.2 MS (ESI-
): [M-H]-
= 472.2
步驟 8: 3-羧基-1-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基) 丙烷-1-氯化銨(3-carboxy-1-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl)propan-1-aminium chloride)
依照製程G從含有前一步產物(90 mg,0.240 mmol,1.0當量)及4.0 M HCl的二氧六環 (1.73 mL,6.93 mmol,40當量)溶液,以製備標題上的白色固體化合物(40 mg,57%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(Mx2)+H]+
= 739.4 MS (ESI-
): [M-H]-
= 368.1; [(Mx2)-H]-
= 737.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.24-7.16 (m, 2H); 6.97 (d, J = 7.8 Hz, 1H); 6.92 (t, J = 7.4 Hz, 1H); 4.40 (m, 1H); 3.38 (m, 1H); 3.03-2.90 (m, 2H); 2.68-2.53 (m, 2H); 2.30-2.10 (m, 3H); 2.08-1.96 (m, 3H); 1.89-1.79 (m, 2H); 1.67-1.55 (m, 3H); 1.53-1.35 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 42.40
實驗例 44: 3-羧基-1-[羥基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基] 丙烷-1-氯化銨(3-carboxy-1-[hydroxy({2-[2-(2-methoxyethoxy)phenyl]ethyl})phosphoryl] propan-1-aminium chloride)
步驟 1: 2-[2-(2-甲氧乙氧基)苯基]乙烷-1-醇(2-[2-(2-methoxyethoxy)phenyl]ethan-1-ol)
室溫下,在市售的2-(2-羥乙基)酚(1.0 g,7.2 mmol,1.0當量)及1-溴-2-甲氧乙烷(1.09 mL,11.6 mmol,1.6當量)的DMF (7.2 mL)溶液中,加入K2
CO3
(2.0 g,14.5 mmol,2.0當量)。將懸浮液在80°C攪拌4小時。冷卻至室溫後,將反應混合物以在水及EtOAc進行選擇性分離。用EtOAc萃取水相。再以水和鹽水洗滌合併之有機萃取物,然後以Na2
SO4
乾燥、過濾、減壓濃縮。以管柱層析法純化殘餘物,獲得到標題上之無色油狀化合物(1.25克,88%)。MS (ESI+
): [M+H]+
= 197.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26-7.16 (m, 2H); 6.95 (td, J = 7.4, 1.1 Hz, 1H); 6.89 (d, J = 6.2 Hz, 1H); 4.17 (m, 2H); 3.87 (t, J = 6.2 Hz, 2H); 3.79 (m, 2H); 3.47 (s, 3H); 2.96 (t, J = 6.2 Hz, 2H); 2.11 (br s, 1H)
步驟 2: 1-(2-碘乙基)-2-(2-甲氧乙氧基)苯(1-(2-iodoethyl)-2-(2-methoxyethoxy)benzene)
0°C下,在三苯膦(768 mg,2.93 mmol,1.3當量)的DCM (15 mL)溶液中加入碘(743 mg,2.93 mmol,1.3當量)。混合物在0°C攪拌15分鐘,並加入咪唑(199 mg,2.93 mmol,1.3當量)及前步所得之產物(442 mg,2.25 mmol,1當量)。混合物在室溫攪拌1小時。接著將反應混合物以EtOAc及飽和Na2
S2
O3
水溶液進行選擇性分離及脫色。各層分離後,有機相以鹽水洗滌,再以Na2
SO4
,乾燥、過濾並減壓濃縮。殘餘物以管柱層析法純化,最終獲得標題上之無色油狀化合物(625 mg,90%)。MS (ESI+
): [M-I]+
= 179.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26 (td, J = 7.8, 1.8 Hz, 1H); 7.16 (d, J = 7.4 Hz, 1H); 6.93 (t, J = 7.5Hz, 1H); 6.88 (d, J = 8.2 Hz, 1H); 4.16 (m, 2H); 3.79 (m, 2H); 3.49 (s, 3H); 3.43 (t, J = 7.8 Hz, 2H); 3.24 (t, J = 7.8 Hz)
步驟 3: 膦-硼烷錯合中間產物
依照製程C的第一步,在前一步產物(620 mg,2.03 mmol,1.0當量)的THF (3 mL)溶液中加入(BH3
)P(OEt)2
H (330 mg ,2.43 mmol,1.2 當量)的THF (7 mL)溶液以及LiHMDS(1.0 M 的THF溶液,2.43 mL,2.43 mmol,1.2 當量),以製備標題上的無色油狀化合物 (440 mg,69%)。MS (ESI+
): [(M-H2
)+H]+
= 313.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.06 (td, J = 8.0, 1.7 Hz, 1H); 7.02 (dd, J = 7.4, 2.6 Hz, 1H); 6.80 (t J = 8.2 Hz, 1H); 6.88 (td, J = 8.5, 1.1 Hz, 1H); 4.05-4.01 (m, 2H); 4.00-3.87 (m, 4H); 3.66 (m, 2H); 3.33 (s, 3H); 2.72 (m, 2H); 1.96 (m, 2H); 1.18 (t, J = 7.0 Hz, 6H); 0.38 (br m, 3H)
步驟 4:{2-[2-(2-甲氧乙氧基)苯基]乙基}次磷酸乙酯(ethyl {2-[2-(2-methoxyethoxy)phenyl]ethyl}phosphinate)
依照製程C的第二步驟,在前一步產物(435 mg,1.38 mmol,1.0當量)的DCM (7 mL)溶液中加入HBF4
.Et2
O (942µL,6.92 mmol,5.0當量),以製備標題上的無色油狀化合物(382 mg,100%)。 MS (ESI+
): [M+H]+
= 273.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.22 (td, J = 7.7, 1.7 Hz, 1H); 7.18 (dd, J = 7.4, 1.7 Hz, 1H); 7.10 (dt, J = 528, 2.1 Hz, 1H); 6.92 (t, J = 7.4 Hz, 1H); 6.88 (d, J = 8.2 Hz, 1H); 4.20 (m, 1H); 4.16 (m, 2H); 4.11 (m, 1H); 3.79 (m, 2H); 3.47 (s, 3H); 2.93 (m, 2H); 2.21-2.12 (m, 2H); 1.39 (t, J = 7.0 Hz, 3H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 38.60
步驟 5: 4-[乙氧基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基]-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸苄酯(benzyl 4-[ethoxy({2-[2-(2-methoxyethoxy)phenyl]ethyl})phosphoryl]-4-[(2-methylpropane-2-sulfinyl)amino]butanoate)
依照製程E,在前一步產物(375 mg,1.38 mmol,1.0當量)及碳酸銫(673 mg,2.07 mmol,1.5 當量)的CH2
Cl2
(5 mL)溶液中加入外消旋的(4E)-4-[(2-甲基丙烷-2-亞磺醯基) 亞胺基]丁酸芐酯(529 mg,1.79 mmol,1.3 當量)的CH2
Cl2
(2 mL) 溶液,以製備標題上由4種非鏡像異構物混和而成的黃色油狀化合物 (464 mg,60%)。MS (ESI+
): [M+H]+
= 568.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.44-7.30 (m, 5H); 7.25-7.14 (m, 2H); 6.99-6.87 (m, 2H); 5.20-5.11 (m, 2H); 4.24-4.04 (m, 4H); 3.84-3.74 (m, 2H); 3.70-3.54 (m, 1H); 3.46-3.41 (m, 3H); 3.00-2.80 (m, 2H); 2.80-2.53 (m, 2H); 2.54-2.10 (m, 3H); 2.06-1.86 (m, 1H); 1.38-1.30 (m, 3H); 1.28-1.22 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 55.74; 55.38; 54.76; 54.54
步驟 6: 4-[羥基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基]-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸(4-[hydroxy({2-[2-(2-methoxyethoxy)phenyl]ethyl})phosphoryl]-4-[(2-methyl propane-2-sulfinyl)amino]butanoic acid)
依照製程F在前一步所得之非鏡像異構混和物(460 mg,0.81 mmol,1.0當量)以及THF/H2
O (4/1,4 mL)的混合溶液中加入LiOH.H2
O (58 mg,2.4 mmol,3.0當量),以製備標題上的黏滯油狀化合物 (364 mg,100%)。MS (ESI+
): [M+H]+
= 450.1; [(Mx2)+H]+
= 899.5
步驟 7: 3-羧基-1-[羥基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基] 丙烷-1-氯化銨(3-carboxy-1-[hydroxy({2-[2-(2-methoxyethoxy)phenyl]ethyl})phosphoryl]propan-1-aminium chloride)
依照製程G從含有前一步產物(364 mg,0.810 mmol,1.0當量)的4.0 M HCl的二氧六環(4.05 mL,16.2 mmol,20當量) 溶液,以製備標題上的白色固體化合物(230 mg,74%)。預估純度: > 97% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 346.1; [(Mx2)+H]+
= 691.4 MS (ESI-
): [M-H]-
= 344.1; [(Mx2)-H]-
= 689.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.28-7.20 (m, 2H); 6.98 (d, J = 8.6 Hz, 1H); 6.92 (t, J = 7.4Hz, 1H); 4.20 (m, 2H); 3.82 (m, 2H); 3.46 (s, 3H); 3.41 (m, 1H); 3.02-2.93 (m, 2H); 2.68-2.53 (m, 2H); 2.34-2.15 (m, 3H); 2.08-1.96 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 43.76
實例 45: 4-胺基-4-{羥基[2-(3-苯基-1,2-㗁唑-5-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-phenyl-1,2-oxazol-5-yl)ethyl]phosphoryl}butanoic acid)
步驟 1: 2-(3-苯基-1,2-㗁唑-5-基)乙烷-1-醇(2-(3-phenyl-1,2-oxazol-5-yl)ethan-1-ol)
室溫下,在α-氯苯甲醛肟(α-chlorobenzaldoxime)(2.0 g,13 mmol,1.0當量)的DCM溶液中加入3-丁炔-1-醇(1.35 g,19.3 mmol,1.5當量)及Et3
N (2.26 mL, 16.7 mmol,1.3當量)。在室溫攪拌16小時,然後減壓濃縮。殘餘物以管柱層析法純化,最後得到標題上之黃色固體化合物(1.8 g,65%,含有4:1的異構體混合物)。MS (ESI+
): [M+H]+
= 190.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.85-7. 7.70 (m, 2H); 7.50-7.35 (m, 3H); 6.46 (s, 3H); 4.05 (m, 2H); 3.10 (m, 2H)
步驟 2: 5-(2-溴乙基)-3-苯基-1,2-㗁唑(5-(2-bromoethyl)-3-phenyl-1,2-oxazole)
-5°C下,在前步驟所得之化合物(1.7 g,9.0 mmol,1.0當量)及四溴化碳(4.77 g,14.4 mmol,1.6當量)的DCM溶液中批次加入三苯膦 (3.77 g,14.4 mmol,1.6當量)。在室溫攪拌1小時,然後減壓濃縮。殘餘物以管柱層析法純化,最後獲得標題上之黃色固體化合物(2.2 g,97%,含有4:1的異構體混合物)。LCMS (ESI+
): [M+H]+
= 252/2541
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.86-7. 7.80 (m, 2H); 7.53-7.45 (m, 3H); 6.50 (s, 3H); 3.71 (t, J = 7.0 Hz , 2H); 3.42 (t, J = 7.0 Hz, 2H)
步驟3: 5-(2-碘乙基)-3-苯基-1,2-㗁唑(5-(2-iodoethyl)-3-phenyl-1,2-oxazole)
在前步驟所得化合物(2.1 g,8.8 mmol,1.0當量)的丙酮(220 mL)溶液中加入碘化鈉(1.87 g,12.5 mmol,1.5當量)。將反應混合物加熱回流過夜。接著減壓濃縮,然後以水稀釋並轉移至分液漏斗中。將水層用DCM萃取兩次。有機萃取物以Na2
SO4
乾燥,過濾並真空濃縮,以獲得標題上之淺黃色固體化合物(2.4 g,96%)。MS (ESI+
): [M+H]+
= 300.01
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.81-7.79 (m, 2H); 7.48-7.44 (m, 3H); 6.44 (s, 1H); 3.47-3.39 (m, 4H)
步驟 4: 膦-硼烷錯合中間產物
依照製程C的第一步,在前一步驟產物(1.01 g,3.37 mmol,1.0當量)的THF (0.5 mL)溶液中加入(BH3
)P(OEt)2
H (550 mg,4.05 mmol,1.2 當量)的THF (9 mL)溶液以及LiHMDS (1.0 M 的THF溶液,4.05 mL,4.05 mmol,1.2 當量),以製備標題上的無色油狀化合物 (697 mg,66%)。MS (ESI+
): [(M-H2
)+H]+
= 306.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.82-7.80 (m, 2H); 7.49-7.45 (m, 3H); 6.67 (s, 1H); 4.15-4.02 (m, 4H); 3.11-3.05 (m, 2H); 2.26-2.21 (m, 2H); 1.29 (t, 6H, J = 7.0 Hz); 0.86-0.13 (m, 3H)
步驟 5: [2-(3-苯基-1,2-㗁唑-5-基)乙基]次磷酸([2-(3-phenyl-1,2-oxazol-5-yl)ethyl]phosphinic acid)
依照變化之製程C第二步驟,在前一步驟產物(697 mg,2.27 mmol,1.0當量)的DCM (11 mL)溶液中加入HBF4
.Et2
O (1.54 mL,11.4 mmol,5.0當量),以製備標題上的化合物(500 mg,93%)。MS (ESI+
): [M+H]+
= 238.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.89-7.73 (m, 2H); 7.68 (t, J = 1.9 Hz, 0.5H); 7.51-7.42 (m, 3H); 6.70 (s, 1H); 6.58 (t, J = 1.9 Hz, 0.5H); 3.16-3.05 (m, 2H); 2.27-2.17 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 31.74
步驟 6: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(3-苯基-1,2-㗁唑-5-基)乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(3-phenyl-1,2-oxazol-5-yl)ethyl]phosphinic acid)
依照製程D在含有前一步驟產物 (250 mg,1.05 mmol,1.0當量)以及NH2
Cbz (175 mg,1.16 mmol,1.1當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.9 mL)中加入4-氧丁酸芐酯(243 mg,1.26 mmol,1.2 當量),經多成分反應後獲得標題上的白色固體化合物 (447 mg,75%)。MS (ESI+
): [M+H]+ = 563.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.84-7.77 (m, 2H); 7.48 (dd, J = 5.2, 1.9 Hz, 3H); 7.39-7.07 (m, 10H); 6.57 (s, 1H); 5.22-4.93 (m, 4H); 4.04 (ddd, J = 12.0, 8.7, 3.5 Hz, 1H); 3.22-2.91 (m, 2H); 2.64-2.40 (m, 2H); 2.31-2.21 (m, 1H); 2.16-2.08 (m, 2H); 1.91 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 47.65
步驟 7: 4-{[(苄氧基)羰基]胺基}-4-{羥基[2-(3-苯基-1,2-㗁唑-5-基)乙基]磷醯基}丁酸(4-{[(benzyloxy)carbonyl]amino}-4-{hydroxy[2-(3-phenyl-1,2-oxazol-5-yl)ethyl] phosphoryl} butanoic acid)
依照製程F在前一步產物(250 mg,0.44 mmol,1.0當量)以及THF/H2
O (5/1,2.4 mL)的混合溶液中加入LiOH.H2
O (37 mg,0.89 mmol,2.0當量),以製備標題上的化合物 (134 mg,64%)。MS (ESI+
): [M+H]+
= 473.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.84-7.77 (m, 2H); 7.52-7.44 (m, 3H); 7.37-7.32 (m, 2H); 7.31-7.24 (m, 2H); 7.20 (t, J = 7.4 Hz, 1H); 6.57 (s, 1H); 5.19 (d, J = 12.5 Hz, 1H); 5.06 (d, J = 12.5 Hz, 1H); 4.03 (ddd, J = 11.8, 8.6, 3.4 Hz, 1H); 3.21-2.94 (m, 2H); 2.55-2.35 (m, 2H); 2.31-2.18 (m, 1H); 2.18-2.07 (m, 2H); 1.88 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 47.32
步驟 8: 4-胺基-4-{羥基[2-(3-苯基-1,2-㗁唑-5-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(3-phenyl-1,2-oxazol-5-yl)ethyl]phosphoryl}butanoic acid)
根據製程G從含有前一步驟之產物(134 mg,284 µmol,1.0當量)的TFA/苯甲醚 (1.1 mL/0.9 mL)溶液,以製備標題上的白色固體化合物(19.5 mg,20%)。 預估純度: 70% (根據液相層析質譜儀分析結果) 及75% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 339.1; [(Mx2)+H]+
= 677.3 MS (ESI-
): [M-H]-
= 337.1; [(Mx2)+H]+
= 675.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.84-7.78 (m, 2H); 7.51-7.44 (m, 3H); 6.67 (m, 1H); 3.20-3.04 (m, 3H); 2.63 (t, J = 7.2 Hz, 2H); 2.39-2.20 (m, 1H); 2.10-1.91 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 29.86
實例 46: 4-胺基-4-{[2-(4-氟-2-甲氧苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(4-fluoro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl} butanoic acid)
步驟 1: 2-(4-氟-2-甲氧苯基)乙烷-1-醇(2-(4-fluoro-2-methoxyphenyl)ethan-1-ol)
0°C下,在市售之LiAlH4
(2.0 M的THF溶液,5.43 mL,10.9 mmol,2.0當量)中加入2-(4-氟-2-甲氧苯基)乙酸(1.0 g,5.4 mmol,1.0當量)的THF (2.7 mL)溶液。在室溫攪拌1小時。冷卻至0°C後,加入水(0.5 mL)、15% NaOH的飽和水溶液(0.5 mL)以及再一次的水(1.5 mL)。攪拌15分鐘後,加入Na2
SO4
並將懸浮液以矽藻土過濾(MTBE沖洗)。減壓濃縮濾液,並獲得標題上之無色油狀化合物(0.93 g,100%)。MS (ESI+
): [M+H]+
= 153.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.15-7.11 (m, 1H); 6.97-6.60 (m, 2H); 3.83 (t, J = 6.7 Hz, 2H); 2.90 (s, 3H); 2.88 (t, J = 6.7 Hz, 2H)
步驟 2: 1-(2-溴乙基)-4-氟-2-甲氧苯(1-(2-bromoethyl)-4-fluoro-2-methoxybenzene)
將前步驟所得之化合物(0.93 g,5.5 mmol,1.0當量)及四溴化碳(2.9 g,8.7 mmol,1.6當量)以CH2
Cl2
(27 mL) 稀釋。將其在-5°C(冰/鹽浴)中冷卻,並批次加入三苯膦(2.3 g,8.7 mmol,1.6當量)。添加完成後,將黃色反應在室溫攪拌1小時。混合物濃縮並以管柱層析法純化,最終獲得標題上之無色油狀化合物(1.12 g,88%)。1
H NMR (500 MHz, CDCl3
) δ (ppm): 7.17-6.97 (m, 1H); 6.73-6.52 (m, 2H); 3.84 (s, 3H); 3.56 (t, J = 7.6 Hz, 2H); 3.15 (t, J = 7.5 Hz, 2H)
步驟 3: [2-(4-氟-2-甲氧苯基)乙基]次磷酸([2-(4-fluoro-2-methoxyphenyl)ethyl]phosphinic acid)
根據製程B在氯亞磷酸二乙酯(0.50 mL,4.57 mmol,1.0當量)的無水Et2
O (3 mL)溶液中加入由1-(2-溴乙基)-4-氟-2-甲氧苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(720 mg,72%)。MS (ESI+
): [M+H]+
= 219.1; [(Mx2)+H]+
= 437.11
H NMR (500 MHz, MeOD) δ (ppm): 7.17 (dd, J = 8.3, 6.7 Hz, 1H); 7.01 (dm, J1 P-H
= 538 Hz, 1H); 6.76 (dd, J = 11.1, 2.5 Hz, 1H); 6.62 (td, J = 8.4, 2.5 Hz, 1H); 3.87 (s, 3H); 2.98-2.75 (m, 2H); 2.21-1.92 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 34.52
步驟 4: [4-(苄氧基)-1-{[(苄氧基)羰基]胺基}-4-酮丁基][2-(4-氟-2-甲氧苯基)乙基]次磷酸([4-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl][2-(4-fluoro-2-methoxyphenyl)ethyl]phosphinic acid)
根據製程D在含有前一步產物 (350 mg,1.6 mmol,1.0當量)以及NH2
Cbz (267 mg,1.765 mmol,1.1當量)的AcOH溶液(5.0 mL)及AcCl的溶液(1.3 mL)中加入4-氧丁酸芐酯(370 mg,1.93 mmol,1.2 當量),經多成分反應後,以獲得標題上的白色固體化合物 (540 mg,75%)。MS (ESI+
): [M+H]+
= 544.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.45-7.17 (m, 10H); 7.07 (dd, J = 8.3, 6.7 Hz, 1H); 6.72 (dd, J = 11.2, 2.5 Hz, 1H); 6.58 (td, J = 8.4, 2.5 Hz, 1H); 5.25 – 5.04 (m, 4H); 4.03 (ddd, J = 12.1, 9.0, 3.4 Hz, 1H); 3.81 (s, 3H); 2.93-2.79 (m, 2H); 2.65-2.39 (m, 2H); 2.33-2.18 (m, 1H); 2.03-1.72 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 49.7
步驟 5: 4-胺基-4-{[2-(4-氟-2-甲氧苯基)乙基](羥基)磷醯基}丁酸(4-amino-4-{[2-(4-fluoro-2-methoxyphenyl)ethyl](hydroxy)phosphoryl}butanoic acid)
根據製程H將含有前一步驟之產物(300 mg,0.55 mmol)的EtOH/AcOH (1:1,10 mL)混合溶液進行氫解,以製備標題上的白色粉狀化合物(73 mg,42%)。預估純度: > 97% (根據液相層析質譜儀分析結果) and > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 302.1; [M+H]+
= 320.1; [(Mx2)+H]+
= 639.2 MS (ESI-
): [M-H]-
= 318.1; [(Mx2)-H]-
= 637.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.18 (dd, J = 8.4, 6.7 Hz, 1H); 6.73 (dd, J = 11.1, 2.5 Hz, 1H); 6.60 (td, J = 8.4, 2.5 Hz, 1H); 3.85 (s, 3H), 3.16-3.05 (m, 1H); 3.01-2.74 (m, 2H); 2.70-2.48 (m, 2H); 2.37-2.19 (m, 1H); 2.07-1.92 (m, 1H); 1.92-1.76 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 31.6
實例 47: 4-胺基-4-{羥基[2-(1H-吲唑-1-基)乙基]磷醯基}丁酸 (4-amino-4-{hydroxy[2-(1H-indazol-1-yl)ethyl]phosphoryl}butanoic acid)
步驟 1: 2-(1H-吲唑-1-基)乙烷-1-醇(2-(1H-indazol-1-yl)ethan-1-ol)
將2-氟苯甲醛(1.02 mL,9.67 mmol,1.0當量)、2-羥乙基肼(0.79 mL,11.6 mmol,1.2當量)及DIPEA(2.47 mL,14.5 mmol,1.5當量)的NMP (9.4 mL)溶液在200°C的微波輻射下攪拌24小時。以飽和NH4
Cl溶液及EtOAc將混和物選擇性分離。各層分離後,以水及鹽水洗滌有機層,再以Na2
SO4
乾燥、過濾並減壓濃縮。殘餘物以管柱層析法純化後得到標題上之橙色油狀化合物(0.31 g,20%)。MS (ESI+
): [M+H]+
= 163.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.06 (s, 1H); 7.78 (d, J = 8.2 Hz, 1H); 7.52-7.40 (m, 2H); 7.24-7.12 (m, 1H); 4.59-4.47 (m, 2H); 4.25-4.09 (m, 2H); 2.97 (s, 1H)
步驟 2: 1-(2-碘乙基)-1H-吲唑(1-(2-iodoethyl)-1H-indazole)
0°C下,將三苯膦(0.64 g,2.44 mmol,1.3當量)的DCM (12 mL)溶液中加入碘(0.62 g,2.44 mmol,1.3當量),並將混合物在0°C下攪拌15分鐘。再加入咪唑(166 mg,2.44 mmol,1.3當量)以及前步所得之化合物溶液(305 mg,1.88 mmol,1.0當量)。在室溫攪拌1小時。以EtOAc及Na2
S2
O3
飽和溶液進行對反應混和物選擇性分離、脫色。各層分離後,以鹽水洗滌有機層,再以Na2
SO4
乾燥、過濾並減壓濃縮。殘餘物以管柱層析純化後得到標題上之無色油狀化合物(625 mg,100%)。MS (ESI+
): [M+H]+
= 2731
H NMR (CDCl3
, 500 MHz) δ (ppm): 8.07 (d, J = 0.9 Hz, 1H); 7.77 (dt, J = 8.2, 1.0 Hz, 1H); 7.50-7.42 (m, 2H); 7.20 (ddd, J = 7.9, 6.4, 1.4 Hz, 1H); 4.78 (t, J = 7.4 Hz, 2H); 3.63-3.57 (m, 2H)
步驟 3: 膦-硼烷錯合中間產物
依照製程C的第一步驟,在前一步驟之產物(605 mg,2.22 mmol,1.0當量)的THF (10 mL)溶液中加入(BH3
)P(OEt)2
H (363 mg,2.67 mmol,1.2 當量)的THF (8 mL)溶液以及LiHMDS (1.0 M 的THF溶液,2.67 mL,2.67 mmol,1.2 當量),以製備標題上的無色油狀化合物 (574 mg,92%)。 MS (ESI+
): [(M-H2
)+H]+
= 279.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.81 (d, J = 0.9 Hz, 1H); 7.53 (dt, J = 8.1, 1.0 Hz, 1H); 7.32 (br d, J = 8.5 Hz, 1H); 7.21 (ddd, J = 8.6, 6.9, 1.1 Hz, 1H); 6.94 (ddd, J = 7.9, 6.9, 0.9 Hz, 1H); 4.51-4.37 (m, 2H); 3.88-3.62 (m, 4H); 2.24-2.01 (m, 2H); 0.97 (t, J = 7.0 Hz, 6H); 0.71‑0.24 (m, 3H)
步驟 4:[2-(1H-吲唑-1-基)乙基]次磷酸乙酯 (ethyl [2-(1H-indazol-1-yl)ethyl]phosphinate)
根據製程C的第二步驟,在前一步驟產物(570 mg,2.03 mmol,1.0當量)的DCM (10 mL)溶液中加入HBF4
.Et2
O (1.38 mL,10.2 mmol,5.0當量)來進行製備標題上的化合物(355 mg,73%)。 MS (ESI+
): [M+H]+
= 239.11
H NMR (500 MHz, CD3
OD) δ (ppm): 8.12-7.99 (m, 1H); 7.78 (dt, J = 8.1, 1.0 Hz, 1H); 7.67-7.60 (m, 1H); 7.51-7.37 (m, 1H); 7.34-7.02 (m, 1H); 7.05 (dm, J1 P-H
= 560Hz, 1H); 4.74 (dt, J = 16.4, 7.0 Hz, 2H); 4.22-3.89 (m, 2H); 2.69-2.42 (m, 2H); 1.25 (t, J = 7.0 Hz, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 37.1
步驟 5: 4-{乙氧基[2-(1H-吲唑-1-基)乙基]磷醯基}-4-[(2-甲基丙烷-2-亞磺醯基)胺基]丁酸苄酯(benzyl 4-{ethoxy[2-(1H-indazol-1-yl)ethyl]phosphoryl}-4-[(2-methylpropane-2-sulfinyl)amino]butanoate)
依照製程E,在前一步驟之產物(350 mg,1.47 mmol,1.0當量)及碳酸銫(718 mg,2.20 mmol,1.5 當量)的CH2
Cl2
(5 mL)溶液中,加入外消旋的(4E)-4-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丁酸芐酯(564 mg,1.91 mmol,1.3 當量)的CH2
Cl2
(2.3 mL)溶液,以製備標題上由4種非鏡像異構物混和而成的黃色油狀化合物 (725 mg,92%)。MS (ESI+
): [M+H]+
= 534.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 8.10-7.99 (m, 1H); 7.82-7.72 (m, 1H); 7.71-7.60 (m, 1H); 7.49-7.41 (m, 1H); 7.41-7.26 (m, 5H); 7.26-7.11 (m, 1H); 5.22-5.08 (m, 2H); 4.81-4.65 (m, 2H); 4.17-3.88 (m, 2H); 3.72-3.44 (m, 1H); 2.81-2.39 (m, 4H); 2.33-2.11 (m, 1H); 1.98-1.79 (m, 1H); 1.28-1.21 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 52.88; 52.74; 51.83; 51.73
步驟 6: 4-{羥基[2-(1H-吲唑-1-基)乙基]磷醯基}-4-[(2-甲基丙烷-2-亞磺醯基) 胺基]丁酸(4-{hydroxy[2-(1H-indazol-1-yl)ethyl]phosphoryl}-4-[(2-methylpropane-2-sulfinyl) amino]butanoic acid)
根據製程F在前步驟所得之非鏡像異構混和物(712 mg,1.33 mmol,1.0當量)以及THF/H2
O (3/1,13 mL)的混合溶液中加入LiOH‧H2
O (128 mg,5.34 mmol,3.0當量),以製備標題上的化合物 (520 mg,94%)。 MS (ESI-
): [M-H]-
= 414.1
步驟 7: 4-胺基-4-{羥基[2-(1H-吲唑-1-基)乙基]磷醯基}丁酸(4-amino-4-{hydroxy[2-(1H-indazol-1-yl)ethyl]phosphoryl}butanoic acid)
根據製程G從含有前一步產物(520 mg,1.25 mmol,1.0當量)及4.0 M HCl的二氧六環(6.3 mL,20當量) 溶液,以製備標題上的白色固體化合物(20 mg,5%)。預估純度: > 97% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 294.1; [M+H]+
= 312.1; [(Mx2)+H]+
= 623.2 MS (ESI-
): [M-H]-
= 310.1; [(Mx2)-H]-
= 621.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 8.05 (d, J = 0.9 Hz, 1H); 7.77 (dt, J = 8.2, 1.0 Hz, 1H); 7.70 (dd, J = 8.5, 1.0 Hz, 1H); 7.45 (ddd, J = 8.3, 6.8, 1.1 Hz, 1H); 7.18 (ddd, J = 7.9, 6.9, 0.8 Hz, 1H); 4.72 (q, J = 7.9 Hz, 2H); 2.99 (td, J = 8.3, 5.2 Hz, 1H); 2.56 (t, J = 7.3 Hz, 2H); 2.35-2.11 (m, 3H); 2.03-1.79 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 27.9
實例 48: 1-({2-[2-(苄氧基)苯基]乙基}(羥基)磷醯基)-3-羧基 丙烷-1-氯化銨(1-({2-[2-(benzyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-3-carboxy propan-1-aminium chloride)
步驟 1: 2-[2-(苄氧基)苯基]乙烷-1-醇(2-[2-(benzyloxy)phenyl]ethan-1-ol)
在以丙酮(145 mL)稀釋的2-(2-羥乙基)酚 (5.0 g,36 mmol,1.0當量)中加入K2
CO3
(5.5 g,40 mmol,1.1當量)及溴化苄(6.8 g,40 mmol,1.1當量)。在室溫攪拌過夜。接著將混合物減壓濃縮,用水及DCM稀釋,然後轉移到分液漏斗中。水層以DCM萃取兩次。有機萃取物以Na2
SO4
乾燥、過濾並真空濃縮。殘留物以管柱層析法純化後得到標題上之澄清油狀化合物(1.67 g,20%)。 MS (ESI+
): [(M-H2
O)+H+
] = 211.2; [M+H]+
= 229.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.45-7.37 (m, 4H); 7.36-7.30 (m, 1H); 7.21 (dd, J = 7.9, 6.3 Hz, 2H); 6.93 (dd, J = 7.8, 6.8 Hz, 2H); 5.09 (s, 2H); 3.87 (t, J = 6.4 Hz, 2H); 2.97 (t, J = 6.4 Hz, 2H)
步驟 2: 1-(苄氧基)-2-(2-溴乙基)苯(1-(benzyloxy)-2-(2-bromoethyl)benzene)
在前一步驟之化合物(1.6 g,7.0 mmol,1.0當量)CH2
Cl2
(35 mL)溶液中加入四溴化碳(3.7 g,11 mmol,1.6當量)。冷卻至-5°C(冰/鹽浴),並批次加入三苯膦(2.9 g,11 mmol,1.6當量)。將黃色反應物在室溫攪拌1小時。接著減壓濃縮,以管柱層析法純化殘餘物,最後獲得標題上之無色油狀化合物(2.0 g,98%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.49-7.43 (m, 4H); 7.40-7.36 (m, 1H); 7.31-7.22 (m, 2H); 6.97 (m, 2H); 5.15 (s, 2H); 3.66 (t, J = 7.6 Hz, 2H); 3.29 (t, J = 7.6 Hz, 2H)
步驟 3: {2-[2-(苄氧基)苯基]乙基}次磷酸({2-[2-(benzyloxy)phenyl]ethyl}phosphinic acid)
根據製程B在氯亞磷酸二乙酯(0.715 mL,6.53 mmol,1.0當量)的無水Et2O (3 mL)溶液中加入由1-(苄氧基)-2-(2-溴乙基)苯的無水Et2
O溶液所新鮮配置的格任亞試劑,以製備標題上的化合物(1.0 g,55%)。MS (ESI+
): [M+H]+
= 277.1; [(Mx2)+H]+
= 553.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.50 (t, J = 2.2 Hz, 0.5H); 7.46 (d, J = 7.1 Hz, 2H); 7.38 (t, J = 7.5 Hz, 2H); 7.31 (t, J = 7.2 Hz, 1H); 7.18 (dd, J = 8.0, 6.6 Hz, 2H); 7.01 (d, J = 8.2 Hz, 1H); 6.89 (td, J = 7.4, 1.0 Hz, 1H); 6.42 (t, J = 2.1 Hz, 0.5H); 5.12 (s, 2H); 2.99-2.82 (m, 2H); 2.04 (m, 2H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 34.69
步驟 4: {2-[2-(苄氧基)苯基]乙基}次磷酸乙酯 (ethyl {2-[2-(benzyloxy)phenyl]ethyl}phosphinate)
在前一步化合物(1.0 g,3.6 mmol,1.0當量)及乙醇(423 µL,7.24 mmol,2.0當量)的DCM (36 mL)溶液中加入適量之EDCI (1.3 g,4.7 mmol,1.3 當量)。在室溫攪拌過夜。隨著反應停止,添加更多的乙醇(1.5當量)、EDCI (1.5當量)以及Et3
N (2.5mL,5.0當量)。在室溫攪拌5小時30分。接著將反應混合物轉移至分液漏斗中,並以飽和NaHCO3
水溶液洗滌(2次),然後再以鹽水洗滌。有機萃取物以Na2
SO4
乾燥、過濾並真空濃縮。以管柱層析法純化殘餘物後得到標題上之淺黃色油狀化合物(548mg,20%)。MS (ESI+
): [M+H]+
= 305.2; [(Mx2)+H]+
= 609.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.51 (t, J = 2.1 Hz, 0.5H); 7.48-7.45 (m, 2H); 7.42-7.36 (m, 2H); 7.35-7.29 (m, 1H); 7.20 (t, J = 7.5 Hz, 2H); 7.05-7.01 (m, 1H); 6.89 (td, J = 7.4, 1.1 Hz, 1H); 6.42 (t, J = 2.1 Hz, 0.5H); 5.12 (s, 2H); 4.14 – 3.93 (m, 2H); 2.91 (dt, J = 13.3, 8.0 Hz, 2H); 2.20-2.04 (m, 2H); 1.29 (t, J = 7.1 Hz, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 41.26
步驟 5: 4-({2-[2-(苄氧基)苯基]乙基}(乙氧基)磷醯基)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸甲酯(methyl 4-({2-[2-(benzyloxy)phenyl]ethyl}(ethoxy)phosphoryl)-4-{[(S)-2-methylpropane-2-sulfinyl]amino}butanoate)
根據製程E,在前一步驟產物(534 mg,1.79 mmol,1.5當量)及碳酸銫(973 mg,2.99 mmol,2.5 當量)的CH2
Cl2
(3.8 mL)溶液中加入外消旋的(4E)-4-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丁酸甲酯(262 mg,1.19 mmol,1.0 當量)的CH2
Cl2
(2.5 mL)溶液,以製備標題上的化合物 (525 mg,84%)。MS (ESI+
): [M+H]+
= 524.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.54-7.47 (m, 2H); 7.44-7.39 (m, 2H); 7.37-7.32 (m, 1H); 7.28-7.19 (m, 2H); 7.08-7.02 (m, 1H); 6.96-6.89 (m, 1H); 5.18-5.05 (m, 2H); 4.21-3.92 (m, 2H); 3.74-3.62 (m, 3H); 2.95 (m, 2H); 2.69-2.53 (m, 1H); 2.49 (m, 1H); 2.31 (m, 2H); 2.18 (m, 2H); 2.01-1.80 (m, 1H); 1.31-1.16 (m, 12H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 55.49; 55.21; 54.54; 54.37
步驟 6: 4-({2-[2-(苄氧基)苯基]乙基}(羥基)磷醯基)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸(4-({2-[2-(benzyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-4-{[(S)-2-methyl propane-2-sulfinyl]amino}butanoic acid)
依據製程F在前一步產物(425 mg,0.811 mmol,1.0當量)以及THF/H2
O (5/1,4.7 mL)的混合溶液中加入LiOH.H2
O (68 mg,1.6 mmol,2.0當量)並額外添加LiOH.H2
O(2當量,然後4當量),完成反應,以製備標題上的化合物 (470 mg,100%)。MS (ESI+
): [M+H]+
= 482.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.53-7.46 (m, 2H); 7.44-7.36 (m, 2H); 7.35-7.29 (m, 1H); 7.28-7.13 (m, 2H); 7.06-6.98 (m, 1H); 6.95-6.87 (m, 1H); 5.15 (d, J = 5.2 Hz, 2H); 3.55-3.42 (m, 1H); 3.13-2.88 (m, 2H); 2.60-2.39 (m, 1H); 2.31-1.84 (m, 5H); 1.39 (m, 1H); 1.26 (s, 3H); 1.22-1.14 (m, 5H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 49.68; 48.99
步驟 7: 1-({2-[2-(苄氧基)苯基]乙基}(羥基)磷醯基)-3-羧基 丙烷-1-氯化銨(1-({2-[2-(benzyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-3-carboxypropan-1-aminium chloride)
依據製程G從含有前一步驟之產物(470 mg,0.98 mmol,1.0當量)及4.0 M HCl的二氧六環(5.42 mL,21.7 mmol ,22當量) 溶液,以製備標題上的白色粉末化合物(83 mg,20%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 3781
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.48 (dd, J = 7.3, 1.7 Hz, 2H); 7.41-7.36 (m, 2H); 7.33-7.29 (m, 1H); 7.24-7.17 (m, 2H); 7.03 (dd, J = 8.2, 1.1 Hz, 1H); 6.90 (td, J = 7.4, 1.1 Hz, 1H); 5.14 (s, 2H); 3.40-3.31 (m, 1H); 3.07-2.90 (m, 2H); 2.55-2.42 (m, 2H); 2.26-2.04 (m, 3H); 1.96-1.84 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 42.08
實例 49: 5-胺基-5-[羥基(2-苯乙基)磷醯基]戊酸 (5-amino-5-[hydroxy(2-phenylethyl)phosphoryl]pentanoic acid)
步驟 1: 5-羧基戊酸苄酯(benzyl 5-hydroxypentanoate)
在戊內酯(5.0 g,50 mmol,1當量)的水(45 mL)懸浮液中,加入32% NaOH(4.6 mL,50 mmol,1.0當量)的水溶液,並在70°C攪拌16小時。然後將反應混合物真空濃縮。殘餘物碾碎後於室溫懸浮在丙酮(50 mL)中,加入(n-Bu)4
NBr (805 mg,2.50 mmol,0.05當量)及BnBr (7.1 mL,60 mmol,1.2當量)。在回流下攪拌20小時。冷卻至室溫後,加水及EtOAc以分離各層。用EtOAc萃取水相。以水及鹽水洗滌收集的有機萃取物,再以Na2
SO4
乾燥,過濾並減壓濃縮,得到粗產物(12 g)。以管柱層析法純化殘餘物後得到標題上之無色油狀化合物(4.12 g,40%)。 MS (ESI+
): [M+H]+
= 209.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.40-7.30 (m, 5H); 5.13 (s, 2H); 3.65 (br s, 2H); 2.42 (t, J = 7.5 Hz, 2H); 1.75 (m, 2H); 1.61 (m, 2H); 1.48 (br s, 1H, OH)
步驟 2: 5-氧戊酸苄酯(benzyl 5-oxopentanoate)
室溫下,在前一步化合物(1.0 g,4.8 mmol,1.0當量)的DCM (19 mL)溶液中添加戴斯-馬丁高碘劑(3.05 g,7.20 mmol,1.5當量)及一滴水。在室溫攪拌1.5小時。減壓下除去部分溶劑,並將殘餘物以MTBE (100 mL)及NaHCO3
飽和溶液(100 mL)進行選擇性分離,形成在水中的懸浮液。各層分離後,以飽和NaHCO3
溶液及鹽水洗滌有機相。再以Na2
SO4
乾燥、過濾並減壓濃縮後,得到1.15 g的渾濁油狀物。殘餘物以管柱層析法純化,最後獲得標題上之無色油狀化合物(710 mg,72%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.77 (t, J = 1.4 Hz, 1H); 7.41-7.31 (m, 5H); 5.13 (s, 2H); 2.53 (td, J = 7.2 Hz and J = 1.4 Hz, 2H); 2.43 (t, J = 7.3 Hz, 2H); 1.98 (m, 2H)
步驟 3: [5-(苄氧基)-1-{[(苄氧基)羰基]胺基}-5-氧戊基](2-苯乙基) 次磷酸([5-(benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-5-oxopentyl](2-phenylethyl) phosphinic acid)
依照製程D在苯乙基次磷酸(250 mg,1.47 mmol,1.0 當量)及NH2
Cbz (266 mg,1.76 mmol,1.2當量)的AcOH溶液(2 mL)及AcCl的溶液(315 µL)中加入前一步所獲得的醛(363 mg,1.76 mmol,1.2當量),經多成分反應後獲得標題上的黃色油狀化合物 (528 mg)。為下一步驟所用之材料,無須進一步純化。MS (ESI+
): [M+H]+
= 510
步驟 4: 5-胺基-5-[羥基(2-苯乙基)磷醯基]戊酸(5-amino-5-[hydroxy(2-phenylethyl)phosphoryl]pentanoic acid)
依照製程H將含有前一步產物(520 mg,1.02 mmol)的EtOH/AcOH (1/1,10 mL)混合溶液進行氫解,以製備標題上的白色固體化合物(20 mg)。預估純度: > 95% (根據液相層析質譜儀分析結果) and > 85% (根據磁核共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.2; [M+H]+
= 286.1; [(Mx2)+H]+
= 571.2 MS (ESI-
): [M-H]-
= 284.1; [(Mx2)-H]-
= 569.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.31-7.21 (m, 4H); 7.20-7.12 (m, 1H); 2.98-2.83 (m, 3H); 2.40-2.34 (m, 2H); 1.99-1.76 (m, 4H), 1.75-1.64 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 31.64
實例 50: (1R)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨 ((1R)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride)
步驟 1: (2-苯乙基)次磷酸苄酯(benzyl (2-phenylethyl)phosphinate)
在苯乙基次膦酸(2.84 g,16.69 mmol,1.0當量)及苯甲醇(1.91 mL,18.36 mmol,1.1當量)的DCM (284 mL)溶液中加入EDCI (6.40 g,33.38 mmol,2當量)。在室溫攪拌6小時,然後轉移至分液漏斗中,以NaHCO3
的飽和水溶液洗滌 (2次),再以鹽水洗滌。有機層以Na2
SO4
乾燥、過濾並真空濃縮。粗產物以管柱層析法純化後得到期望之淺黃色油狀化合物(2.34 g,54%)。MS (ESI+
): [M+H]+
= 261.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.40-7.34 (m, 5H); 7.30-7.28 (m, 2H); 7.23-7.17 (m, 3H); 7.14 (dt, 1H, J = 535.5 and 2.0 Hz); 5.17-5.03 (m, 2H); 2.95-2.89 (m, 2H); 2.17-2.09 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 37.11
步驟 2: (4R)-4-[(苄氧基)(2-苯乙基)磷醯基]-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸苄酯(benzyl (4R)-4-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-{[(S)-2-methylpropane-2-sulfinyl]amino}butanoate)
依照製程E,在前一步產物(991 mg,3.81 mmol,1.5當量)及碳酸銫(2.07 g,6.35 mmol,2.5 當量)的CH2
Cl2
(16.5 mL)溶液中加入鏡像的(4E)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸芐酯(750 mg,2.54 mmol,1.0 當量)的CH2
Cl2
(9 mL) 溶液,以製備標題上由2種非鏡像異構物混和而成的無色油狀化合物 (471 mg,33%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.39-7.15 (m, 15H); 5.14-5.00 (m, 4H); 4.16 (t, 0.4H, J = 8.5 Hz); 3.87 (br s, 0.6H); 3.54-3.47 (m, 0.4H); 3.45-3.39 (m, 0.6H); 2.97-2.78 (m, 2H); 2.61-2.36 (m, 3H); 2.32-2.21 (m, 1H); 2.21-2.11 (m, 1H); 1.86-1.76 (m, 1H); 1.23 (s, 3.4H); 1.18 (s, 5.6H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 54.86 (0.4P); 53.24 (0.6P)
步驟 3: (4R)-4-[羥基(2-苯乙基)磷醯基]-4-{[(S)-2-甲基丙烷-2-亞磺醯基] 胺基}丁酸((4R)-4-[hydroxy(2-phenylethyl)phosphoryl]-4-{[(S)-2-methylpropane-2-sulfinyl] amino}butanoic acid)
根據製程F在前一步所得之非鏡像混和物(173 mg,0.311 mmol,1.0當量)以及THF/H2
O (3.8 mL/1.0 mL)的混合溶液中加入LiOH‧H2
O (39 mg,0.934 mmol,3.0當量),製備標題上的無色油狀化合物 (90 mg,77%)。 MS (ESI+
): [M+H]+
= 376.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.28-7.27 (m, 4H); 7.21-7.16 (m, 1H); 3.55-3.50 (m, 1H); 2.95-2.89 (m, 2H); 2.61-2.45 (m, 2H); 2.36-2.13 (m, 3H); 1.98-1.88 (m, 1H); 1.28 (s, 9H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.99
步驟 4: (1R)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨((1R)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride)
依照製程G從含有前一步產物(90 mg,0.240 mmol,1.0當量)以及4.0 M HCl的二氧六環(1.3 mL,22當量) 溶液,製備標題上的白色固體化合物(33 mg,45%)。預期純度: 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 254.1; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.2; [(Mx3)+H]+
= 814.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.33-7.28 (m, 4H); 7.24-7.20 (m, 1H); 3.32-3.29 (m, 1H); 2.94 (q, 2H, J = 8.5 Hz); 2.59 (dt, 2H, J = 7.0 and 3.5 Hz); 2.31-2.22 (m, 1H); 2.18-2.06 (m, 2H); 2.03-1.94 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 38.88
實例 51: (1S)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨 ((1S)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride)
步驟 1: (4S)-4-[(苄氧基)(2-苯乙基)磷醯基]-4-{[(R)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸芐酯 (benzyl (4S)-4-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-{[(R)-2-methylpropane-2-sulfinyl]amino}butanoate)
依照製程E,在(2-苯乙基) 次膦酸芐酯(340 mg,1.31 mmol,1.5當量)及碳酸銫(709 mg,2.18 mmol,2.5 當量)的CH2
Cl2
(5.7 mL)溶液中加入鏡像的(4E)-4-{[(R)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸芐酯(257 mg,0.87 mmol,1.0 當量)的CH2
Cl2
(3 mL) 溶液,以製備標題上由2種非鏡像異構物混和而成的化合物 (200 mg,41%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.39-7.15 (m, 15H); 5.14-5.00 (m, 4H); 4.16 (t, 0.4H, J = 8.5 Hz); 3.87 (br s, 0.6H); 3.54-3.47 (m, 0.4H); 3.45-3.39 (m, 0.6H); 2.97-2.78 (m, 2H); 2.61-2.36 (m, 3H); 2.32-2.21 (m, 1H); 2.21-2.11 (m, 1H); 1.86-1.76 (m, 1H); 1.23 (s, 3.4H); 1.18 (s, 5.6H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 54.86 (0.4P); 53.24 (0.6P)
步驟 2: (4S)-4-[羥基(2-苯乙基)磷醯基]-4-{[(R)-2-甲基丙烷-2-亞磺醯基] 胺基}丁酸((4S)-4-[hydroxy(2-phenylethyl)phosphoryl]-4-{[(R)-2-methylpropane-2-sulfinyl] amino}butanoic acid)
依照製程F在前一步所得之非鏡像混和物(284 mg,0.511 mmol,1.0當量)以及THF/H2
O (6.3 mL/1.7 mL)的混合溶液中加入LiOH.H2
O (64 mg,1.53 mmol,3.0當量),來製備標題上的無色油狀化合物 (164 mg,85%)。 MS (ESI+
): [M+H]+
= 376.11
H NMR (MeOD, 500 MHz) δ (ppm): 7.36-7.16 (m, 5H); 3.55-3.50 (m, 1H); 2.97-2.87 (m, 2H); 2.61-2.55 (m, 1H); 2.51-2.45 (m, 1H); 2.36-2.13 (m, 3H); 1.98-1.83 (m, 1H); 1.28 (s, 9H)31
P NMR (MeOD, 202 MHz) δ (ppm): 48.98
步驟 3: (1S)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨((1S)-3-carboxy-1-[hydroxy(2-phenylethyl)phosphoryl]propan-1-aminium chloride)
依照製程G從含有前一步產物(164 mg,0.437 mmol,1.0當量) 以及4.0 M HCl的二氧六環(2.4 mL,22當量)溶液,以製備標題上的白色粉末化合物(71 mg,53%)。預期純度: 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 254.1; [M+H]+
= 272.2; [(Mx2)+H]+
= 543.2; [(Mx3)+H]+
= 814.51
H NMR (MeOD, 500 MHz) δ (ppm): 7.31-7.26 (m, 4H); 7.22-7.18 (m, 1H); 3.35-3.33 (m, 1H); 2.94 (q, 2H, J = 9.0 Hz); 2.61-2.58 (m, 2H); 2.29-2.20 (m, 1H); 2.17-2.08 (m, 2H); 2.02-1.92 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 39.80
實例 52: (1R)-3-羧基-1-{羥基[2-(2-甲氧苯基)乙基]磷醯基} 丙烷-1-氯化銨((1R)-3-carboxy-1-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl} propan-1-aminium chloride)
步驟 1: [2-(2-甲氧苯基)乙基]次磷酸苄酯(benzyl [2-(2-methoxyphenyl)ethyl]phosphinate)
在(2-甲氧苯乙基)次膦酸(825 mg,4.12 mmol,1.0當量)及苯甲醇(0.471 mL,4.53 mmol,1.1當量)的DCM (70 mL)溶液中添加適量之EDCI (1.58 g,8.24 mmol,2.0當量)。將在室溫攪拌過夜,然後轉移至分液漏斗中,先後以NaHCO3
飽和水溶液(2次)以及鹽水洗滌。有機層以Na2
SO4
乾燥、過濾並真空濃縮。粗產物以管柱層析法純化,獲得標題上之無色油狀化合物(840 mg,70%)。 MS (ESI+
): [M+H]+
= 291.21
H NMR (MeOD, 500 MHz) δ (ppm): 7.42-7.34 (m, 5H); 7.21-7.18 (m, 1H); 7.12 (dd, 1H, J = 7.5 and 1.5 Hz); 7.04 (dt, 1H, J = 547.5 and 2.0 Hz); 6.92 (dd, 1H, J = 8.5 and 1.0 Hz); 6.85 (td, 1H, J = 7.5 and 1.0 Hz); 5.13-5.03 (m, 2H); 3.81 (s, 3H); 2.90-2.84 (m, 2H); 2.17-2.10 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 41.41
步驟 2: (4R)-4-[(苄氧基)[2-(2-甲氧苯基)乙基]磷醯基]-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸苄酯(benzyl (4R)-4-[(benzyloxy)[2-(2-methoxyphenyl)ethyl]phosphoryl]-4-{[(S)-2-methylpropane-2-sulfinyl]amino}butanoate)
依照製程E,在前一步產物(2.28 g,7.85 mmol,1.5當量)及碳酸銫(5.24 g,16.08 mmol,2.5 當量)的CH2
Cl2
(18.5 mL)溶液中加入鏡像的(4E)-4-{[(R)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸芐酯(1.90 g,6.43 mmol,103 當量)的CH2
Cl2
(10 mL)溶液,以製備標題上由2種非鏡像異構物混和而成的化合物 (1.5 g,40%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.45-7.28 (m, 10H); 7.18 (td, 1H, J = 8.0 and 1.5 Hz); 7.10 (dd, 1H, J = 17.5, 8.0 Hz); 6.89 (dd, 1H, J = 8.0 and 5.0 Hz); 6.84 (m, 1H); 5.16-4.99 (m, 4H); 3.79 (s, 1.5H); 3.78 (s, 1.5H); 3.68-3.63 (m, 0.5H); 3.60-3.55 (m, 0.5H); 2.89-2.75 (m, 2H); 2.69-2.63 (m, 1H); 2.58-2.49 (m, 1H); 2.40-2.16 (m, 3H); 2.03-1.98 (m, 1H); 1.22 (s, 4H); 1.19 (s, 5H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 56.71 (0.47P); 55.80 (0.53P)
步驟 3: (4R)-4-{羥基[2-(2-甲氧苯基)乙基]磷醯基}-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸((4R)-4-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}-4-{[(S)-2-methylpropane-2-sulfinyl]amino}butanoic acid)
依照製程F在前一步所得之非鏡像混和物(1.5 g,2.56 mmol,1.0當量)以及THF/H2
O (18 mL/6 mL)的混合溶液中加入LiOH.H2
O (322 mg,7.68 mmol,3.0當量),製備標題上的白色固體化合物 (848 mg,82%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.20-7.17 (m, 2H); 6.92 (dd, 1H, J = 8.5 and 1.0 Hz); 6.86 (td, 1H , J = 7.5 and 1.0 Hz); 3.84 (s, 3H); 3.53-3.48 (m, 1H); 2.97-2.84 (m, 2H); 2.62-2.56 (m, 1H); 2.50-2.44 (m, 1H); 2.36-2.14 (m, 3H); 2.00-1.90 (m, 1H); 1.27 (s, 9H)
步驟 4: (1R)-3-羧基-1-{羥基[2-(2-甲氧苯基)乙基]磷醯基} 丙烷-1-氯化銨((1R)-3-carboxy-1-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl} propan-1-aminium chloride)
依照製程G從含有前一步產物(848 mg,2.09 mmol,1.0當量)以及含有4.0 M之HCl的二氧六環(11.6 mL,22當量)溶液,以製備標題上的白色粉末化合物(519 mg,73%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 284.2; [M+H]+
= 302.2; [(Mx2)+H]+
= 603.3; [(Mx3)+H]+
= 904.71
H NMR (MeOD, 500 MHz) δ (ppm): 7.21-7.18 (m, 2H); 6.93 (d, 1H, J = 8.0 Hz); 6.87 (td, 1H, J = 8.0 and 1.0 Hz); 3.84 (s, 3H); 3.26 (td, 1H, J = 8.0 and 5.0 Hz); 2.97-2.85 (m, 2H); 2.64-2.53 (m, 2H); 2.28-2.19 (m, 1H); 2.10-1.93 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 38.10
實例 53: (4R)-4-胺基-4-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基) 丁酸 ((4R)-4-amino-4-({2-[2-(cyclohexyloxy)phenyl]ethyl} (hydroxy) phosphoryl) butanoic acid)
步驟 1:2-[2-(環己氧基)苯基]乙酸甲酯(methyl 2-[2-(cyclohexyloxy)phenyl]acetate)
0°C下,在2-(2-羥苯基)乙酸甲酯(5.95 g,35.82 mmol,1.0當量)、環己醇(5.38 g,53.7 mmol,1.5當量)及三苯膦(11.27 g,43.0 mmol,1.2當量)的THF (70 mL)溶液中,加入DTAD (9.89g,43.0mmol,1.2當量)。在室溫攪拌18小時。接著減壓濃縮,並將得到的濃漿狀物在戊烷/ Et2
O (75/25,200 mL)中磨碎。所得之懸浮液以燒結玻璃過濾(戊烷/ Et2
O: 75/25),並將濾液減壓濃縮。殘留物以管柱層析法純化後得到標題上之無色油狀化合物(4.28 g,48%)。MS (ESI+
): [M+H]+
= 249.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26-7.18 (m, 2H); 6.95-6.85 (m, 2H); 4.33 (m, 1H); 3.71 (s, 3H); 3.65 (s, 2H); 1.98-1.89 (m, 2H); 1.83-1.74 (m, 2H); 1.65-1.50 (m, 3H); 1.45-1.35 (m, 3H)
步驟 2: 2-[2-(環己氧基)苯基]乙烷-1-醇(2-[2-(cyclohexyloxy)phenyl]ethan-1-ol)
0°C下,前步驟所得之酯(4.28 g,17.2 mmol,1.0當量)的THF (69 mL)溶液中滴加市售之LiAlH4
(2.0 M之 THF溶液,17.2 mL,34.5 mmol,2.0當量)溶液。在室溫攪拌1小時。冷卻至0°C後,加入水、15% NaOH的飽和水溶液以及再一次的水。攪拌15分鐘後,加入Na2
SO4
並將懸浮液以矽藻土過濾(MTBE沖洗)。減壓濃縮濾液。殘留物以管柱層析法純化後得到標題上之刺鼻無色油狀化合物(3.73 g,98%)。 MS (ESI+
): [M+H]+
= 221.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.26-7.15 (m, 2H); 6.92-6.88 (m, 2H); 4.34 (m, 1H); 3.88 (m, 2H); 2.95 (t, J = 6.3Hz, 2H); 2.05-1.95 (m, 2H); 1.92 (br s, 1H); 1.86-1.75 (m, 2H); 1.65-1.55 (m, 3H); 1.46-1.35 (m, 3H)
步驟 3: 1-(環己氧基)-2-(2-碘乙基)苯(1-(cyclohexyloxy)-2-(2-iodoethyl)benzene)
0°C下,在PPh3
(3.1 g,11.8 mmol,1.3當量)的DCM (35 mL)溶液中加入碘 (3.0 g,11.8 mmol,1.3當量)。0°C下攪拌15分鐘,再加入咪唑(803 mg,11.8 mmol,1.3當量)及前步所得之醇溶液(2.0 g,9.08 mmol,1.0當量)。混合物於室溫攪拌1小時。將其以EtOAc及Na2
S2
O3
飽和溶液進行選擇性分離、引發脫色。各層分離後,有機相以鹽水洗滌,以Na2
SO4
乾燥、過濾並減壓濃縮。以管柱層析法純化殘餘物後得到標題上之無色油狀化合物(2.74 g,91%)。 MS (ESI+
): [M-I]+
= 203.21
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.23 (td, J = 7.8 Hz and J = 1.8 Hz, 1H); 7.15 (dd, J = 7.6Hz and J = 1.8Hz, 1H); 6.90-6.86 (m, 2H); 4.34 (m, 1H); 3.42 (t, J = 7.6Hz, 2H); 3.22 (t, J = 7.6Hz, 2H); 2.01-1.92 (m, 2H); 1.86-1.76 (m, 2H); 1.67-1.54 (m, 3H); 1.49-1.38 (m, 3H)
步驟 4: 膦-硼烷錯合中間產物
依照製程C的第一步驟,在前一步驟之產物(2.73 g,8.27 mmol,1.0當量)的THF (10 mL)溶液中加入(BH3
)P(OEt)2
H (1.35 g,9.92 mmol,1.2 當量)的THF (30 mL)溶液以及LiHMDS (1.0 M 的THF溶液,9.92 mL,9.92 mmol,1.2 當量),以製備標題上的無色油狀化合物 (1.97 g,70%)。MS (ESI+
): [(M-H2
)+H]+
= 337.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 6.95-6.88 (m, 2H); 6.69 (d, J = 7.9 Hz, 1H); 6.60 (td, J = 7.5 Hz and J = 1.2 Hz, 1H); 4.18 (m, 1H); 4.90-3.75 (m, 4H); 2.60 (m, 2H); 1.82 (m, 2H); 1.77-1.68 (m, 2H); 1.65-1.55 (m, 2H); 1.45-1.30 (m, 3H); 1.28-1.16 (m, 3H); 1.07 (t, J = 7.0 Hz, 6H); 0.65-0.00 (m, 3H)
步驟 5:{2-[2-(環己氧基)苯基]乙基}次磷酸乙酯(ethyl {2-[2-(cyclohexyloxy)phenyl]ethyl}phosphinate)
根據製程C的第二步驟,在前一步驟產物(1.96 g,5.79 mmol,1.0當量)的DCM (23 mL)溶液中加入HBF4
.Et2
O (3.94 mL,29.0 mmol,5.0當量),以製備標題上的淡黃色油狀化合物(1.56 g)。MS (ESI+
): [M+H]+
= 297.1; [(Mx2)+H]+
= 593.31
H NMR (CDCl3
500 MHz) δ (ppm): 7.23-7.15 (m, 2H); 7.11 (dm, J1 P-H
= 545 Hz, 1H); 7.90-6.82 (m, 2H); 4.35 (m, 1H); 4.25-4.16 (m, 1H); 4.15-4.05 (m, 1H); 2.95-2.86 (m, 2H); 2.23-2.10 (m, 2H); 2.02-1.93 (m, 2H); 1.85-1.73 (m, 2H); 1.66-1.55 (m, 3H); 1.47-1.33 (m, 6H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 38.6
步驟 6: (4R)-4-({2-[2-(環己氧基)苯基]乙基}(乙氧基)磷醯基)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸苄酯(benzyl (4R)-4-({2-[2-(cyclohexyloxy)phenyl]ethyl}(ethoxy)phosphoryl)-4-{[(S)-2-methylpropane-2-sulfinyl]amino}butanoate)
依照製程E,在前一步驟產物(2.28 g,7.85 mmol,1.5當量)及碳酸銫(1.28 g,3.92 mmol,1.5 當量)的CH2
Cl2
(10 mL)溶液中加入鏡像的(4E)-4-{[(R)-2-甲基丙烷-2-亞磺醯基]亞胺基}丁酸芐酯(1. 0 g,3.4 mmol,1.3 當量)的CH2
Cl2
(3 mL) 溶液,以製備標題上由2種非鏡像異構物混和而成的無色油狀化合物 (454 mg,29%)。MS (ESI+
): [M+H]+
= 592.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.47-7.30 (m, 5H); 7.23-7.14 (m, 2H); 6.97-6.92 (m, 1H); 6.87-6.82 (m, 1H); 5.21-5.12 (m, 2H); 4.43-4.35 (m, 1H); 4.20-4.05 (m, 2H); 3.70-3.55 (m, 1H); 3.00-2.80 (m, 2H); 2.75-2.53 (m, 2H); 2.40-2.20 (m, 3H); 2.05-1.90 (m, 3H); 1.87-1.77 (m, 2H); 1.65-1.55 (m, 3H); 1.50-1.30 (m, 6H); 1.27-1.20 (m, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 55.74; 54.70
步驟 7: (4R)-4-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基)-4-{[(S)-2-甲基丙烷-2-亞磺醯基]胺基}丁酸((4R)-4-({2-[2-(cyclohexyloxy)phenyl]ethyl}(hydroxy)phosphoryl)-4-{[(S)-2-methyl propane-2-sulfinyl]amino}butanoic acid)
依照製程將前一步產物(445 mg,0.752 mmol)溶於THF/H2
O (6 mL/1.5 mL) 及LiOH.H2
O (54 mg,2.3 mmol) 的混合溶液,以製備標題上的白色泡沫狀化合物 (500 mg,定量產量)。MS (ESI-
): [M-H]-
= 472.1
步驟 8: (4R)-4-胺基-4-({2-[2-(環己氧基)苯基]乙基 (羥基)磷醯基)丁酸((4R)-4-amino-4-({2-[2-(cyclohexyloxy)phenyl]ethyl} (hydroxy) phosphoryl) butanoic acid)
根據製程G從含有前一步產物(354 mg,0.75 mmol,1.0當量) 以及4.0 M HCl的二氧六環(5.6 mL,22.6 mmol,30當量) 溶液,以製備標題上的灰白色固體化合物(125 mg,45%)。預估純度: 99% (根據液相層析質譜儀分析結果) and > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 352.2; [M+H]+
= 370.2; [(Mx2)+H]+
= 739.4 MS (ESI-
): [M-H]-
= 368.2; [(Mx2)-H]-
= 737.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.21 (d, J = 4.5 Hz, 1H); 6.14 (t, J = 7.8 Hz, 1H); 6.92 (d, J = 8.0 Hz, 1H); 6.84 (t, J = 7.4 Hz, 1H); 4.35 (m, 1H); 3.06 (m, 1H); 2.91 (m, 2H); 2.58 (m, 2H); 2.23 (m, 1H); 2.08-1.94 (m, 4H); 1.92-1.79 (m, 3H); 1.66-1.54 (m, 3H); 1.50-1.34 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 32.0
實例 54: (1-胺基-4-甲氧基-4-酮丁基)(2-苯乙基)次磷酸 ((1-amino-4-methoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid)
依照製程H將含有實例22第二步驟的產物(250 mg,0.60 mmol,1.0當量)的MeOH/AcOH (9:1,c = 50 mM)混合溶液進行氫解,以製備標題上的白色粉末化合物(44 mg,26%)。 預估純度: 96% (根據高效能液相層析分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 268.1; [M+H]+
= 286.2; [(Mx2)+H]+ = 571.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.29-7.23 (m, 4H); 7.18-7.14 (m, 1H); 3.69 (s, 3H); 3.05 (td, J = 8.5 and 5.5 Hz, 1H); 2.94-2.84 (m, 2H); 2.76 (t, J = 7.5 Hz, 2H); 2.67-2.56 (m, 2H); 2.28-2.19 (m, 1H); 2.01-1.83 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 31.00
實例 55: (1-胺基-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸 ((1-amino-4-ethoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid)
步驟 1: (1-胺基-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸((1-amino-4-ethoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid)
根據製程H將含有實驗例22第二步產物的4-乙氧基類似物(200 mg,0.46 mmol,1.0當量)的EtOH/AcOH (9 mL/1 mL)混合溶液進行氫解,以製備標題上的白色粉末化合物(111 mg,88%)。 預估濃度: > 95% (根據高效能液相層析分析結果) MS (ESI+
): [(M-H2
O)+H]+
= 282.2; [M+H]+
= 300.2; [(Mx2)+H]+
= 599.41
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.31-7.21 (m, 4H); 7.20-7.16 (m, 1H); 4.17 (q, J = 7.0 Hz, 2H); 3.08 (td, J = 8.5 and 5.5 Hz, 1H); 2.95-2.89 (m, 2H); 2.70-2.55 (m, 2H); 2.30-2.20 (m, 1H); 2.03-1.85 (m, 3H); 1.26 (t, J = 7.0 Hz, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 31.16
實例 56: {4-乙氧基-1-[({1-[(2-甲基丙醯基)氧基]乙氧基}羰基)胺基]-4-酮丁基}(2-苯乙基)次磷酸({4-ethoxy-1-[({1-[(2-methylpropanoyl)oxy]ethoxy}carbonyl)amino]-4-oxobutyl}(2-phenylethyl)phosphinic acid)
在實例22步驟2中獲得產物的4-乙氧基類似物(380 mg,1.27 mmol)的DMF (4 mL)懸浮液中,加入專利文獻W2010/063002中所描述之1-{[[(4-硝苯氧基)羰基]氧基}乙基2-丙酸甲酯(1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2‑methylpropanoate) (566 mg,1.9 mmol)的DMF (4 mL)溶液。0°C下,在此灰白色懸浮液中加入NaHCO3
(533 mg,6.37 mmol)的水(3 mL)溶液。該混合物將立即變為黃色,室溫下攪拌1小時(LCMS分析顯示轉化不完全)。再次加入NaHCO3
(533 mg,1.9 mmol)和1-{[[(4-硝苯氧基)羰基]氧基}乙基2-丙酸甲酯 (188 mg,0.63 mmol),將其攪拌過夜。混合物真空濃縮並將殘餘物溶於水中,以2M HCl水溶液小心酸化至pH 4。真空濃縮,並溶於DCM/MeOH 90/10混合溶液中,再以PTFE過濾去除殘留的NaCl。真空濃縮,殘餘物以管柱層析法純化。將含有產物之餾分真空濃縮,溶於在DCM/MeOH 95/5混合溶液中,再次在PTFE過濾、濃縮,最終獲得標題上之白色泡沫狀化合物(231 mg,40%)。預期純度: 95% (根據高效能液相層析及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 458.2; [(Mx2)+H]+
= 915.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.29-7.19 (m, 4H); 7.33-7.26 (m, 1H); 6.80-6.75 (m, 1H); 4.14 (q, J = 7.0 Hz, 2H); 3.82-3.75 (m, 1H); 2.94-2.80 (m, 2H); 2.60-2.53 (m, 0.5H); 2.52-2.36 (m, 2H); 2.34-2.24 (m, 1.5H); 1.94-1.72 (m, 3H); 1.46 (d, J = 5.5 Hz, 1.5H); 1.44 (d, J = 5.5 Hz, 1.5H); 1.29-1.25 (m, 3H); 1.18 (d, J = 6.0 Hz, 1.5H); 1.17 (d, J = 6.0 Hz, 1.5 Hz); 1.01 (d, J = 5.5 Hz, 1.5H); 0.95 (d, J = 6.0 Hz, 1.5 H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 38.42 及 38.18
實例 57: 1-[(苄氧基)(2-苯乙基)磷醯基]-4-乙氧基-4-羰基丁烷-1-氯化銨(1-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-ethoxy-4-oxobutan-1-aminium chloride)
步驟 1: (1-{[(三級丁氧基)羰基]胺基}-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸((1-{[(tert-butoxy)carbonyl]amino}-4-ethoxy-4-oxobutyl)(2-phenylethyl)phosphinic acid)
在實例22步驟2中獲得產物的4-乙氧基類似物(375 mg,1.25 mmol)的 DMF (2.5 mL)懸浮液中依序滴加(Boc)2
O (273 mg,1.25 mmol)及Et3
N (0.7mL,5.01mmol)。懸浮液將變澄清。在室溫攪拌4小時。將混合物真空濃縮並以水及DCM選擇性分離殘餘物。水層以DCM萃取,有機層則以鹽水洗滌,再以Na2
SO4
乾燥、過濾並真空濃縮,最終獲得標題上之淺黃色油狀化合物(193 mg,39%)。MS (ESI+
): [M+H]+
= 4001
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.28 (t, J = 7.5 Hz, 2H); 7.24 (d, J = 7.5 Hz, 2H); 7.20 (t, J = 7.5 Hz, 1H); 4.16 (q, J = 7.0 Hz, 2H); 3.98 (td, J = 8.5 and 5.5 Hz, 1H); 2.99-2.84 (m, 2H); 2.55-2.39 (m, 2H); 2.31-2.19 (m, 2H); 2.11-1.96 (m, 2H); 1.90-1.80 (m, 1H); 1.45 (s, 9H); 1.28 (t, J = 7.0 Hz, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 48.5
步驟 2:4-[(苄氧基)(2-苯乙基)磷醯基]-4-{[(三級丁氧基)羰基] 胺基}丁酸乙酯(ethyl 4-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-{[(tert-butoxy)carbonyl] amino}butanoate)
在前步驟所得之產物(196 mg,0.49 mmol)的DMF (2.0 mL)溶液中加入碳酸銫(79 mg,0.24 mmol)。再於所得之漿液中滴加溴化苄(64 µL,0.54 mmol)。在室溫攪拌18小時,出現白色沉澱。粗產物濃縮至乾燥,以Et2
O/水(1/1)的混合物稀釋,並將水層用Et2
O萃取兩次。合併之有機層用NaHCO3
(10%)洗滌,再以鹽水洗滌。有機層以Na2
SO4
乾燥、過濾、真空濃縮。殘餘物以管柱層析純化,最後得到標題上之透明油狀產物(172 mg,72%),其靜置時會結晶,並為帶有非鏡像異構體的混合物 (31
P NMR 測量之dr = 50/50)。 MS (ESI+
): [M+H]+
= 4901
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.44-7.30 (m, 5H); 7.27-7.21 (m, 2H); 7.20-7.11 (m, 3H); 5.11-5.04 (m, 2H); 4.17-4.07 (m, 2H); 3.98 (td, J = 8.5 and 5.5 Hz, 1H); 2.99-2.75 (m, 2H); 2.52-2.35 (m, 2H); 2.28-2.03 (m, 3H); 1.89-1.73 (m, 1H); 1.45-1.44 (m, 9H); 1.27-1.23 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 55.95 and 55.89
步驟 3: 1-[(苄氧基)(2-苯乙基)磷醯基]-4-乙氧基-4-羰基丁烷-1-氯化銨(1-[(benzyloxy)(2-phenylethyl)phosphoryl]-4-ethoxy-4-oxobutan-1-aminium chloride)
將前步驟所得之產物(72 mg,0.15 mmol,1當量)的溶液在純甲酸(1 mL)中攪拌4小時,轉化後以LCMS測量。將粗產物倒入冰水中,並批次加入NaHCO3
(注意! 將產生劇烈的氣體逸出)。將水層(pH = 7-8)倒入分液漏斗中,並以Et2
O萃取。水層的LCMS顯示無殘留產物。然後用5當量的2M HCl乙醚溶液酸化醚化物層,酸化將導致絲狀乳化物形成。將醚化物層用冷水萃取3次(3×5 mL),並直接以乾冰凍乾水層,最後得到期望之白色細棉狀產物(31 mg,50%),並為帶有非鏡像異構體的混合物 (31
P NMR 測量之dr = 50/50)。預估純度: > 95% (根據液相層析質譜儀分析結果) MS (ESI+
): [M+H]+
= 3901
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.52-7.37 (m, 5H); 7.33-7.26 (m, 2H); 7.25-7.18 (m, 3H); 5.21-5.15 (m, 2H); 4.17 (q, J = 7.0 Hz, 2H); 3.68-3.61 (m, 1H); 3.00-2.74 (m, 2H); 2.68-2.53 (m, 2H); 2.38-2.22 (m, 3H); 2.09-1.98 (m, 1H); 1.29-1.25 (m, 3H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 51.16 and 51.09
實例58: [1-胺基-4-(苄氧基)-4-酮丁基](2-苯乙基)次磷酸 ([1-amino-4-(benzyloxy)-4-oxobutyl](2-phenylethyl)phosphinic acid)
根據製程G從(4-(芐氧基)-1-((((芐氧基)羰基)胺基)-4-酮丁基)(苯乙基)次膦酸(100 mg,202 µmol,1.0當量)的TFA/苯甲醚 (1.0 mL/200 µL) 溶液,以製備標題上的化合物(7 mg,10%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 362.1; [(Mx2)+H]+
= 723.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.37-7.14 (m, 10H); 5.14 (s, 2H); 3.07-3.02 (m, 1H); 2.90-2.85 (m, 2H); 2.71-2.60 (m, 2H); 2.29-2.00 (m, 1H); 2.01-1.92 (m, 1H), 1.90-1.84 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 30.93
實例 59: (4-乙氧基-4-側氧-1-{[(4R)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基} 丁基)(2-苯乙基)次磷酸 ((4-ethoxy-4-oxo-1-{[(4R)-2-oxo-1,3-thiazolidin-4-yl]formamido} butyl)(2-phenylethyl)phosphinic acid)
步驟 1: (4R)-2-側氧-1,3-四氫噻唑-4-羧酸((4R)-2-oxo-1,3-thiazolidine-4-carboxylic acid)
0°C(冰浴)上,將一水合L-半胱氨酸鹽酸鹽(17.6 g,100 mmol,1.02當量)批次滴加到裝在包含攪拌器、內部溫度調節器及滴液漏斗的三頸圓底燒瓶中的NaOH(43 mL,32% w/w 10.6 M,459 mmol)和水(47 mL)溶液中。反應會微微放熱 (溫度從1°C增至9°C)。晶體完全溶解後,溫度將升高至20°C,此時逐滴加入氯甲酸苯酯(31.3 g,200 mmol,2當量)的甲苯(35 mL)溶液。在25°C下攪拌2小時。分離水層,並以甲苯(35 mL)洗滌,再以濃HCl酸化至pH = 1。將水層真空乾燥並將殘餘物於AcOEt中研磨、過濾並濃縮。收集固體產物,並重複於水中再結晶兩次,最後獲得標題上之白色結晶狀化合物(10.42 g,71%)。 MS (ESI+
): [M+H]+
= 1471
H NMR (DMSO-d6, 500 MHz) δ (ppm): 13.18 (brs, 1H); 8.43 (brs, 1H); 4.39 (ddd, 1H, J = 8.5, 3.5, 1.5 Hz); 3.72 (dd, 1H, J = 11.5, 8.5 Hz); 3.45 (dd, 1H, J = 11.5, 3.5 Hz)
步驟 2: (4-乙氧基-4-側氧-1-{[(4R)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基} 丁基)(2-苯乙基)次磷酸
室溫下,在第一步所得之產物(245 mg,1.67 mmol,1當量)的THF/DMF (1/1,10 mL)溶液中加入DCC和N‑羥基琥珀醯亞胺(326 mg,2.84 mmol,1.7 當量)。 10分鐘後,形成固體。在25°C攪拌1小時(以芐胺淬火部分反應混和物來監測反應;以LCMS測量對應之醯胺(m/z=236)。依序滴加實例22步驟2所得之產物的4-乙氧基類似物 (500 mg,1.67 mmol,1.0當量)的THF/DMF/EtOH (1/1/1,5 mL)混和溶液及DIPEA(2 mL,11.69 mmol,7.0當量)。溶液將變為淺橙色,將其在室溫下攪拌16小時。形成的固體過濾並以AcOEt沖洗。濃縮濾液,並將殘餘物加入EtOAc中,再加入NH4
Cl飽和溶液。分離水層,再以EtOAc萃取。合併之有機層用鹽水洗滌,以Na2
SO4
乾燥並真空濃縮。粗產物以快速管柱層析法純化,可獲得期望之白色泡沫狀化合物(319 m克,39%)。部分產物將重新純化以用於特性分析。預估純度: 87% (根據液相層析質譜儀分析結果) MS (ESI+
): [M+H]+
= 429.1; [(Mx2)+H]+
= 857.31
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.27-7.19 (m, 4H); 7.17-7.11 (m, 1H); 4.49-4.43 (m, 1H); 4.20-4.09 (m, 3H); 3.79 (dd, 1H, J = 11.5, 8.5 Hz); 3.53 (dd, 1H, J = 11.5, 5.0 Hz); 2.93-2.80 (m, 2H); 2.50-2.40 (m, 3H); 1.97-1.87 (m, 1H); 1.83-1.69 (m, 2H); 1.26 (t, 3H, J = 7.0 Hz)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 36.21, 36.01
實例 60: 3-胺基-3-{羥基[(2-甲氧苯基)甲基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl}propane-1-sulfonic acid)
步驟 1: (1-{[(苄氧基)羰基]胺基}-3-[(2,2-二甲基丙氧基)磺醯基]丙基)[(2-甲氧苯基)甲基]次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-[(2,2-dimethylpropoxy)sulfonyl]propyl)[(2-methoxyphenyl)methyl]phosphinic acid)
依照製程D在[(2-甲氧苯基)甲基]次膦酸(740 mg,3.98 mmol,1 當量)及NH2
Cbz (661 mg,4.37 mmol,1.1當量)的AcOH溶液(5.4 mL)及AcCl的溶液(0.7 mL)中加入2,2-二甲基丙基3-氧丙烷-1-磺酸鹽 (993 mg,4.77 mmol,1.2當量),經多成分反應後獲得標題上的黃色固體化合物 (1.2 g,57%)。1
H NMR (MeOD, 500 MHz) δ (ppm): 7.39-7.19 (m, 7H); 6.94 (d, 1H, J = 8.0 Hz); 6.87 (t, 1H, J = 7.5 Hz); 5.13 (s, 2H); 4.01 (dt, 1H, J = 4.0 and 10.5 Hz); 3.85 (s, 2H); 3.81 (s, 3H); 3.28-3.18 (m, 4H); 2.36-2.28 (m, 1H); 2.09-1.99 (m, 1H); 0.97 (s, 9H)31
P NMR (MeOD, 202 MHz) δ (ppm): 44.20
步驟 2: 3-胺基-3-{羥基[(2-甲氧苯基)甲基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[(2-methoxyphenyl)methyl]phosphoryl}propane-1-sulfonic acid)
根據製程G從含有前一步產物(595 mg,1.13 mmol,1.0當量)的TFA/苯甲醚 (3.5 mL/2.5 mL) 溶液,以製備標題上的白色固體化合物(105 mg,29%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 324.1; [(Mx2)+H]+
= 647.21
H NMR (D2
O, 500 MHz) δ (ppm): 7.38-7.32 (m, 2H); 7.10 (d, 1H, J = 8.0 Hz); 7.05 (t, 1H, J = 7.5 Hz); 3.91 (s, 3H); 3.35-3.28 (m, 2H); 3.14-3.03 (m, 3H); 2.38-2.29 (m, 1H); 2.16‑2.06 (m, 1H)31
P NMR (MeOD, 202 MHz) δ (ppm): 34.57
實例 61: 3-胺基-3-[羥基(2-苯乙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propane-1-sulfonic acid)
步驟 1: 3-(乙醯氫硫基)丙醛(3-(acetylsulfanyl)propanal)
室溫下、氬氣環境中,將丙烯醛(900 µL,12.8 mmol)滴加到硫乙酸(1.04 mL,14.7 mmol)中(極度放熱)。在室溫攪拌2小時。真空濃縮以去除過量之硫乙酸,並獲得標題上之化合物(1.50 g,88%)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.75 (t, 1H, J = 0.9 Hz); 3.11 (t, 2H, J = 6.7 Hz); 2.80 (dt, 2H, J = 0.9 Hz and 6.7 Hz); 2.32 (s, 3H)
步驟 2: [3-(乙醯氫硫基)-1-{[(苄氧基)羰基]胺基}丙基](2-苯乙基) 次磷酸([3-(acetylsulfanyl)-1-{[(benzyloxy)carbonyl]amino}propyl](2-phenylethyl) phosphinic acid)
依照製程D,在(2-苯乙基)次磷酸(350 mg,2.23 mmol)及NH2
Cbz (337 mg,2.23 mmol)的AcOH溶液(6 mL)及AcCl的溶液(1 mL)中加入3‑(乙醯氫硫基) 丙醛 (354 mg,2.68 mmol)以進行多成分反應。室溫下攪拌24小時後,再加入NH2
Cbz (168 mg, 1.11 mmol)及3‑(乙醯氫硫基) 丙醛 (147 mg, 1.11 mmol)使反應依製程D繼續進行。最終可得標題上之淡黃色固體化合物 (721 mg,74%)。1
H NMR (DMSO-d6, 500 MHz) δ (ppm): 11 (bs, 1H); 7.58 (d, 1H, J = 9.4 Hz); 7.36-7.25 (m, 7H); 7.20-7.15 (m, 3H); 5.10 (d, 1H, J = 12.6 Hz); 5.02 (d, 1H, J = 12.6 Hz); 3.84-3.78 (m, 1H); 3.00‑2.96 (m, 1H); 2.84-2.71 (m, 3H); 2.33 (s, 3H); 2.00-1.93 (m, 1H); 1.87‑1.78 (m, 3H)
步驟 3: 3-{[(苄氧基)羰基]胺基}-3-[羥基(2-苯乙基)磷醯基] 丙烷-1-磺酸(3-{[(benzyloxy)carbonyl]amino}-3-[hydroxy(2-phenylethyl)phosphoryl] propane-1-sulfonic acid)
在前步驟所得之產物(200 mg,0.46 mmol)的AcOH(1 mL)溶液中滴加過氧化氫水溶液(30%,283 µL,2.78 mmol)。將混合物在60°C下攪拌1小時,並於真空下以配有防爆罩的旋轉濃縮機濃縮。粗產物與庚烷共蒸發後可得標題之白色固體化合物(200 mg,100%)。MS (ESI+
): [M+H]+
= 442.31
H NMR (DMSO-d6, 500 MHz) δ (ppm): 7.56 (d, 1H, J = 9.7 Hz); 7.35-7.26 (m, 7H); 7.20‑7.17 (m, 3H); 5.10 (d, 1H, J = 12.6 Hz); 5.02 (d, 1H, J = 12.6 Hz); 3.78-3.72 (m, 1H); 2.83‑2.68 (m, 2H); 2.60-2.53 (m, 1H); 2.45-2.37 (m, 1H); 2.15-2.07 (m, 1H); 1.87-1.75 (m, 3H)
步驟 4: 3-胺基-3-[羥基(2-苯乙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propane-1-sulfonic acid)
依照製程G從含有前一步產物(200 mg,0.45 mmol,1.0當量)的TFA/苯甲醚 (44 mg/400 µL)溶液,以製備標題上的白色固體化合物(74 mg,53%)。預估純度: 95% (根據磁核共振譜儀分析結果) MS (ESI-
): [M-H]-
= 306.41
H NMR (D2
O, 500 MHz) δ (ppm): 7.43-7.31 (m, 5H); 3.38-3.28 (m, 1H); 3.12-3.03 (m, 2H); 2.96-2.90 (m, 2H); 2.42-2.33 (m, 1H); 2.20-2.10 (m, 1H); 2.10-2.02 (m, 2H).
實例 62: 3-胺基-3-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}propane-1-sulfonic acid)
步驟 1: (1-{[(苄氧基)羰基]胺基}-3-[(2,2-二甲基丙氧基) 磺醯基]丙基)[2-(2-甲氧苯基)乙基]次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-[(2,2-dimethylpropoxy)sulfonyl]propyl)[2-(2-methoxyphenyl)ethyl]phosphinic acid)
依照製程D,在[2-(2-甲氧苯基)乙基]次磷酸(300 mg,1.50 mmol,1當量)及NH2
Cbz (250 mg,1.65 mmol,1當量)的AcOH溶液(2.0 mL)及AcCl的溶液(0.3 mL)中加入3-氧丙烷-1-磺酸2,2-二甲基丙酯(374 mg,1.80 mmol,1.2當量)以進行多成分反應。最終可得標題上之白色固體化合物 (298 mg,37%)。MS (ESI+
): [M+H]+
= 542.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.39-7.24 (m, 5H); 7.21-7.18 (m, 1H); 7.08 (d, 1H, J = 7.5 Hz); 6.91 (d, 1H, J = 8.5 Hz); 6.85 (t, 1H , J = 7.5 Hz); 5.20-5.05 (m, 2H); 4.10-4.02 (m, 1H); 3.89 (s, 2H); 3.79 (s, 3H); 3.30-3.28 (m, 1H); 2.89-2.84 (m, 2H); 2.42-2.34 (m, 1H); 2.15-2.06 (m, 1H); 2.02- 1.96 (m, 2H); 0.99 (s, 9H) {有一H低於MeOD峰下}31
P NMR (MeOD, 202 MHz) δ (ppm): 48.97
步驟 2: 3-胺基-3-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-磺酸(3-amino-3-{hydroxy[2-(2-methoxyphenyl)ethyl]phosphoryl}propane-1-sulfonic acid)
依照製程G從含有前一步產物(298 mg,550 µmol,1.0當量)的TFA/苯甲醚 (1.6 mL/0.385 mL) 溶液,以製備標題上的白色固體化合物(28 mg,15%)。預估純度: > 95% (根據液相層析質譜法及核磁共振譜儀分析結果) MS (ESI+
): [M+H]+
= 338.1; [(Mx2)+H]+
= 675.31
H NMR (MeOD, 500 MHz) δ (ppm): 7.22-7.19 (m, 2H); 6.94 (d, 1H, J = 8.0 Hz); 6.88 (t, 1H, J = 7.5 Hz); 3.85 (s, 3H); 3.56-3.51 (m, 1H); 3.01 (dt, 2H, J = 7.0 and 2.5 Hz); 2.96-2.90 (m, 2H); 2.47-2.37 (m, 1H); 2.21-2.06 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 40.18
實例 63: 3-胺基-3-[羥基(3-苯丙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(3-phenylpropyl)phosphoryl]propane-1-sulfonic acid)
步驟 1: (3-苯丙基)次磷酸((3-phenylpropyl)phosphinic acid)
(3-苯丙基)次膦酸的製備最初由Smid, P. et al, PCT Int. Appl., 2008071738, 2008所描述。
氬氣下,在預先脫氣的次磷酸(50 wt %的水溶液,2.47 mL,22.6 mmol) EtOH(15 mL)溶液中添加烯丙基苯(1 mL,7.6 mmol)及AIBN (100 mg,1.2 mmol) 。回流6小時,LCMS顯示轉化不完全。然後再加入額外的AIBN (100 mg,1.2 mmol),將混合物回流18小時。該混合物在反應期間均為無色透明的。真空濃縮混和物並將所得之油狀物冷卻至0°C,添加2 N NaOH (15 mL)以達到pH 14。將溶液轉移至分液漏斗中,並以Et2
O (3× 20 mL)洗滌水層。將水層以2N HCl酸化至pH 1,然後以AcOEt (4× 30mL)進行萃取。合併之有機層以鹽水(100 mL)洗滌,再以Na2
SO4
乾燥並真空濃縮,最後獲得標題上之無色油狀化合物(1.2 g,86%),含有8%的加成副產物污染。MS (ESI+
): [M+H]+
= 1851
H NMR (CDCl3
, 500 MHz) δ (ppm): 7.08 (dt, 1H, J = 545.0 and 5.0 Hz); 7.30-7.27 (m, 2H); 7.22-7.18 (m, 1H); 7.18-7.13 (m, 2H); 2.72 (t, 2H, J = 10.0 Hz); 1.97-1.88 (m, 2H); 1.78-1.72 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 39.53
步驟 2: (1-{[(苄氧基)羰基]胺基}-3-甲烷亞磺醯基丙基)(3-苯丙基) 次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-methanesulfinylpropyl)(3-phenylpropyl) phosphinic acid)
依照製程D在前一步產物(150 mg,0.814 mmol,1.0 當量)及NH2
Cbz (135 mg,0.895 mmol,1.1當量)的AcOH溶液(1.5 mL)及AcCl的溶液(0.4 mL)中加入實例61步驟1所得之3-(乙醯氫硫基) 丙醛 (130 mg,0.977 mmol,1.2當量)的AcOH (0.5 mL)溶液,經多成分反應後獲得標題上的白色細粉狀化合物 (254 mg,69%)。MS (ESI+
): [M+H]+
= 450 ; [(Mx2)+H]+
= 8991
H NMR (DMSO-d6, 500 MHz) δ (ppm): 7.51 (d, 1H, J = 10.0 Hz); 7.40-7.30 (m, 5H); 7.28 (t, 2H, J = 5.0 Hz); 7.21-7.13 (m, 2H); 5.09 (d, 1H, J = 15.0 Hz); 5.04 (d, 1H, J = 15.0 Hz); 3.74 (dtd, 1H, J = 13.0, 10.0 and 3.5 Hz); 2.97 (ddd, 1H, J = 13.0, 8.0 and 5.0 Hz); 2.97 (dt, 1H, J = 13.0 and 8.0 Hz); 2.58 (t, 2H, 5.0 Hz); 2.32 (s, 3H); 1.95-1.85 (m, 1H); 1.84-1.65 (m, 3H), 1.57-1.47 (m, 2H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 46.36
步驟 3: 3-{[(苄氧基)羰基]胺基}-3-[羥基(3-苯丙基) 磷醯基] 丙烷-1-磺酸(3-{[(benzyloxy)carbonyl]amino}-3-[hydroxy(3-phenylpropyl) phosphoryl] propane-1-sulfonic acid)
在前步驟所得之產物(254mg,0.57mmol)的AcOH(1 mL)溶液中滴加過氧化氫水溶液(30%,384µL,3.39 mmol)。在60°C下攪拌1小時,並將粗產物用配備有防爆罩的旋轉濃縮機真空濃縮。粗產物與庚烷(3次)共蒸發,然後於空氣中放置過夜,產生的沉澱即為標題上之淺黃色固體化合物 (254mg,定量產率)。MS (ESI+
): [M+H]+
= 456; [M+NH3
]+
= 4731
H NMR (DMSO-d6, 500 MHz) δ (ppm): 7.50 (d, J = 9.5 Hz, 1H); 7.30-7.13 (m, 10H); 5.06 (d, J = 12.5 Hz, 1H); 5.02 (d, J = 12.5 Hz, 1H); 3.67 (ddd, J = 20.0, 9.5 and 3.5 Hz, 1H); 2.95-2.62 (m, 2H) 2.40 (td, J = 12.5 and 4.5 Hz, 1H); 2.11-2.00 (m, 1H); 1.86-1.69 (m, 3H); 1.59-1.47 (m, 2H)31
P NMR (DMSO-d6, 202 MHz) δ (ppm): 36.07
步驟 4: 3-胺基-3-[羥基(3-苯丙基)磷醯基]丙烷-1-磺酸(3-amino-3-[hydroxy(3-phenylpropyl)phosphoryl]propane-1-sulfonic acid)
依照製程G從含有前一步產物(252 mg,0.55 mmol)的TFA/苯甲醚 (4 mL/1 mL) 溶液,製備標題上的淺黃色細粉狀化合物(135 mg,75%)。預估純度: 95% (根據高效能液相層析分析結果) MS (ESI-
): [M-H]-
= 320.2; [(Mx2)-H]-
= 641.41
H NMR (D2
O, 500 MHz) δ (ppm): 7.36-7.11 (m, 5H); 3.35-3.26 (m, 1H); 3.09-2.99 (m, 2H); 2.69 (t, J = 7.0 Hz, 2H); 2.33-2.22 (m, 1H); 2.10-1.99 (m, 1H); 1.86-1.75 (m, 2H); 1.67-1.58 (m, 2H)31
P NMR (D2
O, 202 MHz) δ (ppm): 36.27
實例 64: 3-胺基-3-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丙烷-1-磺酸 (3-amino-3-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]propane-1-sulfonic acid)
步驟 1: (1-{[(苄氧基)羰基]胺基}-3-[(2,2-二甲基丙氧基)磺醯基]丙基) ({[1,1'-聯苯]-3-基}甲基)次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-[(2,2-dimethylpropoxy)sulfonyl]propyl) ({[1,1'-biphenyl]-3-yl}methyl)phosphinic acid)
依照製程D在實例6步驟1中所得之次磷酸(430 mg,1.8 mmol,1.0 當量)及NH2
Cbz (308 mg,2.04 mmol,1.1當量)的AcOH溶液(2.6 mL)及AcCl的溶液(0.3 mL)中加入3-氧丙烷-1-磺酸2,2-二甲基丙酯 (463 mg,2.22 mmol,1.2當量),經多成分反應後獲得標題上的化合物 (1.15 g,預期為定量產率)。MS (ESI+
): [M+H]+
= 574.2
步驟 2: 3-胺基-3-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丙烷-1-磺酸(3-amino-3-[({[1,1'-biphenyl]-3-yl}methyl)(hydroxy)phosphoryl]propane-1-sulfonic acid)
依照製程G從含有前一步產物(1.1 g,1.9 mmol,1.0當量)的TFA/苯甲醚 (7.4 mL/6.3 mL) 溶液,製備標題上的淡黃色固體化合物(41 mg,分兩步5%)。預估純度: > 95% (根據液相層析質譜儀分析結果) and 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 370.0; [(Mx2)+H]+
= 739.21
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.71-7.60 (m, 3H), 7.54-7.47 (m, 1H), 7.47-7.29 (m, 5H), 3.50-3.40 (m, 1H), 3.29-3.17 (m, 2H), 3.12-2.94 (m, 2H), 2.55-2.35 (m, 1H), 2.27-2.10 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 30.9
實例 65: 3-胺基-3-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}]丙烷-1-磺酸(3-amino-3-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl} propane-1-sulfonic acid)
步驟 1: (1-{[(苄氧基)羰基]胺基}-3-[(2,2-二甲基丙氧基)磺醯基]丙基)[(3-苯基-1,2-㗁唑-5-基)甲基]次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-[(2,2-dimethylpropoxy)sulfonyl]propyl)[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphinic acid)
依照製程D在[(3-苯基-1,2-㗁唑-5-基)甲基]次磷酸(450 mg,2.0 mmol,1.0 當量)及NH2
Cbz (335 mg,2.22 mmol,1.1當量)的AcOH溶液(3.5 mL)及AcCl的溶液(0.4 mL)中加入3-氧丙烷-1-磺酸2,2-二甲基丙酯(504 mg,2.42 mmol,1.2當量),經多成分反應後獲得標題上的黃色固體化合物 (950 mg,83%)。MS (ESI+
): [M+H]+
= 565.11
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.92-7.78 (m, 2H); 7.57-7.45 (m, 3H); 7.41-7.24 (m, 5H); 6.76 (s, 1H); 5.26-5.02 (m, 2H); 4.24-4.13 (m, 1H); 3.90 (s, 2H); 2.54-2.29 (m, 1H); 2.27-2.06 (m, 1H); 1.44-1.23 (m, 4H); 0.98 (s, 9H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 39.1
步驟 2: 3-胺基-3-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}]丙烷-1-磺酸(3-amino-3-{hydroxy[(3-phenyl-1,2-oxazol-5-yl)methyl]phosphoryl} propane-1-sulfonic acid)
依照製程G從含有前一步產物(915 mg,1.68 mmol ,1.0當量)的TFA/苯甲醚 (6.5 mL/7.35 mL) 溶液,製備標題上的白色固體化合物(302 mg,50%)。預估純度: 96% (根據液相層析質譜儀分析結果) and > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 361.0; [(Mx2)+H]+
= 721.1 MS (ESI-
): [M-H]-
= 359.01
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.95-7.81 (m, 2H); 7.55-7.46 (m, 3H); 6.88 (d, J = 2.8 Hz, 1H); 3.91-3.81 (m, 1H); 3.77-3.62 (m, 2H); 3.11 (t, J = 6.8 Hz, 2H); 2.67-2.41 (m, 1H); 2.37-2.11 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 32.7
實例 66: 3-胺基-3-{羥基[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基}]丙烷-1-磺酸 (3-amino-3-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl} propane-1-sulfonic acid)
步驟 1:3-[(苄氧基)[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基]-3-[(2-甲基丙烷-2-亞磺醯基)胺基]丙烷-1-磺酸2,2-二甲基丙酯(2,2-dimethylpropyl 3-[(benzyloxy)[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl]-3-[(2-methylpropane-2-sulfinyl)amino]propane-1-sulfonate)
依照製程E,在實例21步驟2所得之 [(5- 苯基-1,2-㗁唑-3-基)甲基] 膦酸苄酯 (580 mg,1.9 mmol,1.0當量)及碳酸銫(905 mg,2.78 mmol,1.5 當量)的CH2
Cl2
(19 mL)溶液中加入外消旋的3-[(2-甲基丙烷-2-亞磺醯基)亞胺基]丙烷-1-磺酸2,2-二甲基丙酯(750 mg,2.41 mmol,1.3當量)的CH2
Cl2
(0.5 mL) 溶液來進行製備標題上由4種非鏡像異構物混和而成的黃色油狀化合物 (370 mg,32%)。MS (ESI+
): [M+H]+
= 625.2
步驟 2: {3-[(2,2-二甲基丙氧基)磺醯基]-1-[(2-甲基丙烷-2-亞磺醯基)胺基]丙基}[(5-苯基-1,2-㗁唑-3-基)甲基]次磷酸({3-[(2,2-dimethylpropoxy)sulfonyl]-1-[(2-methylpropane-2-sulfinyl)amino] propyl}[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphinic acid)
根據製程F在前一步所得之非鏡像異構混合物(370 mg,0.59 mmol,1.0當量)以及THF/水 (4/1,3 mL)的混合溶液中加入LiOH.H2
O (75 mg,1.8 mmol,3.0當量),以製備標題上的黃色油狀化合物 (164 mg,50%)。MS (ESI+
): [M+H]+
= 535.1
步驟 3: 3-胺基-3-{羥基[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基}]丙烷-1-磺酸(3-amino-3-{hydroxy[(5-phenyl-1,2-oxazol-3-yl)methyl]phosphoryl} propane-1-sulfonic acid)
根據製程G從含有前一步驟產物(164 mg,0.307 mmol,1.0當量) 以及6.0 M HCl的二氧六環 (9 mL,54 mmol,175當量) 溶液,以製備標題上的淺黃色固體化合物(59 mg,50%)。 預估純度: > 95% (根據液相層析質譜儀及磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 361.0 MS (ESI-
): [M-H]-
= 359.01
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.96-7.79 (m, 2H); 7.58-7.42 (m, 3H); 6.88 (s, 1H); 3.99-3.76 (m, 1H); 3.50 (d, J = 16.1 Hz, 2H); 3.10 (t, J = 6.9 Hz, 2H); 2.67-2.44 (m, 1H); 2.37-2.11 (m, 1H)31
P NMR (CD3
OD, 202 MHz) δ (ppm): 34.5
實例 67: 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁烷-1-磺酸 (4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butane-1-sulfonic acid)
步驟 1: 1-[(4-羥基丁基) 氫硫基]乙烷-1-酮(1-[(4-hydroxybutyl)sulfanyl]ethan-1-one)
將4-氯丁醇(5.0 g,46 mmol,1.0當量,單、聚合體的混合物)及硫代乙酸鉀(7.9 g,69 mmol,1.5 當量)的DMF (23 mL)混合溶液在50°C下攪拌6小時。冷卻至室溫後,加入水及MTBE使各層分離。水相以MTBE萃取,並將合併之有機萃取物用水以及鹽水洗滌,以Na2
SO4
乾燥、過濾並減壓濃縮,可得6 g紅色油狀物。再以管柱層析法純化殘餘物,最終可得標題上之淺橙色油狀化合物(1.14 g,17%)。MS (ESI+
): [M+H]+
= 149.11
H NMR (CDCl3
, 500 MHz) δ (ppm): 3.67 (t, J = 6.2 Hz, 2H); 2.91 (t, J = 7.0 Hz, 2H); 2.33 (s, 3H); 1.73-1.50 (m, 4H)
步驟 2: 4-(乙醯氫硫基)丁醛(4-(acetylsulfanyl)butanal)
-78°C下,在DMSO(1.26 mL,17.7 mmol,2.3當量)的DCM (25 mL)溶液中依序加入草醯氯(1.06 mL,12.3 mmol,1.6當量),以及15分鐘後加入前步所得之醇(1.14 g,7.69 mmol,1.0當量)的DCM (5 mL)溶液。在-78°C下攪拌1小時,加入Et3
N (5.4 mL,38 mmol,5.0當量),並在-78°C下再攪拌0.5小時,然後在室溫下繼續攪拌1小時。以水及MTBE進行選擇性分離。各層分離後,以MTBE萃取水相。合併之有機萃取物用1M HCl溶液洗滌,然後再以鹽水洗滌,並以Na2
SO4
乾燥、過濾並減壓濃縮,最終獲得標題上之橙色油狀化合物(1.19 g,定量產率)。1
H NMR (CDCl3
, 500 MHz) δ (ppm): 9.78 (t, J = 1.3 Hz, 1H); 2.91 (t, J = 7.2 Hz, 2H); 2.54 (td, J = 7.2 Hz and J = 1.4 Hz, 2H); 2.34 (s, 3H); 1.92 (tt, app q, J = 7.2 Hz, 2H)
步驟 3: [4-(乙醯氫硫基)-1-{[(苄氧基)羰基]胺基}丁基](2-苯乙基)次磷酸([4-(acetylsulfanyl)-1-{[(benzyloxy)carbonyl]amino}butyl](2-phenylethyl)phosphinic acid)
根據製程D在苯乙基次磷酸(500 mg,2.94 mmol,1.0 當量)及NH2
Cbz (533 mg,3.53 mmol,1.2當量)的AcOH溶液(5 mL)及AcCl的溶液(0.63 mL)中加入前一步所得之醛(516 mg,3.52 mmol,1.2當量),經多成分反應後獲得標題上的白色固體化合物 (539 mg,41%)。MS (ESI+
): [M+H]+
= 450.1; [(Mx2)+H]+
= 899.51
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.40-7.33 (m, 2H); 7.33-7.24 (m, 5H); 7.23-7.12 (m, 3H); 5.20 (d, AB syst, J = 12.5 Hz, 1H); 5.10 (d, AB syst, J = 12.5 Hz, 1H); 3.97 (m, 1H); 3.00-2.79 (m, 4H); 2.33 (s, 3H); 2.08-1.88 (m, 3H); 1.82-1.58 (m, 3H)31
P NMR (MeOD, 202 MHz) δ (ppm): 49.66
步驟 4: 4-{[(苄氧基)羰基]胺基}-4-[羥基(2-苯乙基)磷醯基]丁烷-1-磺酸(4-{[(benzyloxy)carbonyl]amino}-4-[hydroxy(2-phenylethyl)phosphoryl]butane-1-sulfonic acid)
室溫下,在前步驟之產物(539 mg,1.20 mmol,1.0當量)的AcOH(4.8 mL)溶液中滴加H2
O2
(30%的水溶液,735 µL,7.19 mmol,6.0當量)。在50°C下攪拌1.5小時。冷卻至室溫後,在防爆罩下,將反應混合物減壓濃縮,並將殘餘物與庚烷共沸乾燥,最後可得標題上之淺黃色泡沫狀產物(580mg,定量產率)。MS (ESI-
): [M-H]-
= 454.2; [(Mx2)-H]-
= 909.61
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.40-7.33 (m, 2H); 7.33-7.24 (m, 5H); 7.23-7.12 (m, 3H); 5.21 (d, AB syst, J = 12.5 Hz, 1H); 5.06 (d, AB syst, J = 12.5 Hz, 1H); 3.99 (m, 1H); 3.01-2.79 (m, 4H); 2.13-1.93 (m, 4H), 1.92-1.73 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 50.33
步驟 5: 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁烷-1-磺酸(4-amino-4-[hydroxy(2-phenylethyl)phosphoryl]butane-1-sulfonic acid)
根據修改過之製程G從含有前一步驟之產物 (290 mg,0.64 mmol,1.0當量)的TFA (3.2 mL)溶液,以製備標題上的白色固體化合物(25 mg,12%)。 MS (ESI+
): [M+H]+
= 322.1; [(Mx2)+H]+
= 643.2 MS (ESI-
): [M-H]-
= 320.0; [(Mx2)-H]-
= 641.21
H NMR (CD3
OD, 500 MHz) δ (ppm): 7.38-7.28 (m, 4H); 7.28-7.22 (m, 1H); 3.00 (td, J = 8.6 Hz and J = 3.4 Hz, 1H); 2.93-2.79 (m, 4H); 2.02-1.83 (m, 4H), 1.82-1.65 (m, 2H)31
P NMR (MeOD, 202 MHz) δ (ppm): 35.21
實例 68: {3-胺基-3-[羥基(2-苯乙基)磷醯基]丙基}膦酸({3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propyl}phosphonic acid)
步驟 1: 二苄基 [2-(1,3-二氧環戊烷-2-基)乙基]膦酸酯(dibenzyl [2-(1,3-dioxolan-2-yl)ethyl]phosphonate)
室溫下,在二苄膦酸酯(2.50 g,9.53 mmol,1.0當量)的DMF (19 mL)溶液中加入(n-Bu)4
NI (704 mg,1.91 mmol,0.2當量)、Cs2
CO3
(4.66 g ,14.30mmol,1.5當量)及2-(2-溴乙基)-1,3-二氧環戊烷(1.34 mL,11.4 mmol,1.2當量)。在室溫攪拌80小時。加入水及MTBE使各層分離。以MTBE萃取水相,再以水及鹽水洗滌合併之有機萃取物,以Na2
SO4
乾燥、過濾並減壓濃縮後,得到無色油狀物。殘餘物以管柱層析純化,獲得標題上之無色油狀化合物(2.86 g,83%)。MS (ESI+
): [M+H]+
= 363.11
H NMR (500 MHz, CDCl3
) δ (ppm): 7.43-7.30 (m, 10H), 5.07 (dd, J = 11.9, 8.8 Hz, 2H), 4.99 (dd, J = 11.9, 7.9 Hz, 2H), 4.95-4.87 (m, 1H), 3.98-3.90 (m, 2H), 3.90-3.81 (m, 2H), 2.07-1.84 (m, 4H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 33.1
步驟 2: 二苄基 (3-氧丙基) 膦酸酯(dibenzyl (3-oxopropyl)phosphonate)
室溫下,在前步所得之縮醛(1.0 g,2.79 mmol,1.0當量)的丙酮(2.8 mL)溶液中加入2 N HCl溶液(8.28 mL,16.7 mmol,6.0 當量)。在50°C下攪拌3小時。冷卻至室溫後,加入水及MTBE以分離各層。用MTBE萃取水相。合併之有機萃取物用飽和NaHCO3
溶液以及接續的鹽水洗滌,以Na2
SO4
乾燥、過濾並減壓濃縮,最終獲得標題上之淺黃色油狀化合物(0.82 g,純度85%,79%)。MS (ESI+
): [M+H]+
= 3191
H NMR (500 MHz, CDCl3
) δ (ppm): 9.76-9.62 (m, 1H), 7.45-7.31 (m, 10H), 5.08 (dd, J = 11.8, 9.0 Hz, 2H), 4.98 (dd, J = 11.8, 8.4 Hz, 2H), 2.81-2.64 (m, 2H), 2.14-2.00 (m, 2H)31
P NMR (CDCl3
, 202 MHz) δ (ppm): 31.8
步驟 3: (1-{[(苄氧基)羰基]胺基}-3-[雙(苄氧基)磷醯基] 丙基)(2-苯乙基)次磷酸((1-{[(benzyloxy)carbonyl]amino}-3-[bis(benzyloxy)phosphoryl]propyl)(2-phenylethyl)phosphinic acid)
依照製程D在苯乙基次磷酸(310 mg,1.82 mmol,1.0 當量)及NH2
Cbz (331 mg,2.19 mmol,1.2當量)的AcOH溶液(7.3 mL)及AcCl的溶液(0.39 mL)中加入(3-氧丙基)膦酸二苄酯 (純度85%,819 mg,2.19 mmol,1.2當量),經多成分反應後,獲得標題上的油狀化合物 (528 mg)。可直接為下一步驟所用,無須分離。MS (ESI-
): [M-H]-
= 620
步驟 4: {3-胺基-3-[羥基(2-苯乙基)磷醯基]丙基}膦酸({3-amino-3-[hydroxy(2-phenylethyl)phosphoryl]propyl}phosphonic acid)
依照製程G從含有前一步產物的TFA/苯甲醚 (6.96 mL/4.95 mL) 溶液,以製備標題上的米色固體化合物(80 mg,分兩步14%)。預估純度: > 97% (根據液相層析質譜儀分析結果) and > 95% (根據磁核共振譜儀分析結果) MS (ESI+
): [M+H]+
= 308.1; [(Mx2)+H]+
= 615.1 MS (ESI-
): [M-H]-
= 306.1; [(Mx2)-H]-
= 613.11
H NMR (CD3
OD, 500 MHz) δ (ppm): δ 7.34-7.25 (m, 4H), 7.21-7.16 (m, 1H), 3.16-3.06 (m, 1H), 2.99-2.82 (m, 2H), 2.38-2.16 (m, 1H), 2.06-1.75 (m, 5H).31
P NMR (CD3
OD, 202 MHz) δ (ppm): 32.6; 24.7
實例69: 活體外量測APA之活性
活體外量測APA活性的方式是根據Goldbarg的規範(Chauvel et al., 1994),並依微量盤(microplates) (Pro BindTM 3915)的檢測尺度而做適度修正。在活體外測試,當含有鈣離子時,APA可將α-L-麩胺醯基-β-萘醯胺(α-L-glutamyl-β-naphthylamide,GluβNa)水解為麩胺酸鹽(glutamate)及β-萘胺(β-naphthylamine,βNa)。若β-萘胺存在,重氮化反應將會於酸性介質上顯示為紫紅色複合體;利用分光光度測定即可知有多少複合體形成,參照標準曲線來計算β-萘胺的濃度,並推得樣品的酵素活性。
試劑
將Glu-βNa受質(供應商:Bachem)以及β-萘胺(供應商:Sigma)分別溶於50% DMSO及0.1N之HCl中,並以10-2
M的濃度保存於-20°C。於亞硝酸鈉(87 mM)、氨基磺酸銨(130 mM)及N-(1-萘基)-乙二胺二鹽酸鹽(濃度為23 mM,溶於95%乙醇)進行重氮化反應。
酵素反應
反應可於含鈣離子(4 mM CaCl2
)之pH 7.4 的50 mM tris-HCl緩衝液中進行;重組小鼠之APA以及其受質(200 µM Glu-βNa) 於37° C培養,依實驗需求添加或不添加不同濃度之抑制劑,總體積為100 µL。加入3N HCl以終止反應。利用2-萘胺於0.1 N之HCl中重氮化濃度的增加(直至0.2 mM)可用來製備β-萘胺的標準曲線。
產物之結果揭示
每個孔盤中加入以下試劑:25 µL的亞硝酸鈉 (NaNO2
) (混合後,於室溫放置5分鐘),50 µL的氨基磺酸銨 (混合後,於室溫放置5分鐘),接著加入25 µL的N-(1-萘基)乙二胺二鹽酸鹽(混合後,置於37° C約30分鐘直到紫紅色穩定呈現)。量測540 nm的吸光值。
申請號WO99/36066所描述之化合物 EC33 ((S)-3胺基-4-巰基-丁磺酸)當作對照組的化合物。
實驗結果示於表1。最佳的化合物(分組a)展現最高的APA抑制活性,比對照組化合物高出至少20倍。
表1. 舉例之抑制劑於體外抑制胺肽酶A的結果
活性 (µM) | 分組 |
IC50 > 0.030 | a |
0.030 ≤ IC50 > 0.300 | b |
0.300 ≤ IC50 > 10 | c |
實例 | 結果 | 實例 | 結果 | 實例 | 結果 | ||
10 | a | 1 | b | 5 | c | ||
11 | a | 2 | b | 6 | c | ||
15 | a | 3 | b | 9 | c | ||
22 | a | 4 | b | 20 | c | ||
23 | a | 7 | b | 27 | c | ||
24 | a | 8 | b | 47 | c | ||
25 | a | 12 | b | 49 | c | ||
28 | a | 13 | b | 51 | c | ||
30 | a | 14 | b | 61 | c | ||
31 | a | 16 | b | 63 | c | ||
32 | a | 17 | b | 64 | c | ||
33 | a | 18 | b | 65 | c | ||
34 | a | 19 | b | 66 | c | ||
35 | a | 21 | b | 68 | c | ||
36 | a | 26 | b | EC33 | c | ||
38 | a | 29 | b | ||||
40 | a | 37 | b | ||||
43 | a | 39 | b | ||||
44 | a | 41 | b | ||||
46 | a | 42 | b | ||||
48 | a | 45 | b | ||||
50 | a | 60 | b | ||||
52 | a | 62 | b | ||||
53 | a | 67 | b |
實例 70:量測大腦APA活性 (生物離體實驗)
測定大腦胺肽酶A的活性如上述所示。
活體內,對小鼠(雄性,18-20 g,Charles River)靜脈內投予實例22以及實例52(分別投予5 mg/kg及4 mg/kg,總體積為200 µL)。每一測試條件包含五隻小鼠。小鼠在投予後10、30、60、120及180分鐘後犧牲。立即將大腦移除,並在10倍體積的冰冷 50mM Tris-HCl 緩衝液 (pH7.4)中以超音波震盪的方式均質化。使用大腦均漿來測定APA的酵素活性:將部分組織均漿(16 µL)與200 µM的GluβNA、4 mM CaCl2
及1 µM bestatin抑制劑(含/不含 5 µM EC33),置於總體積為100 µL 的 50 mM Tris-HCl buffer (pH 7.4)中,於37° C培養30分鐘。然後如上所述進行測定。
第1圖顯示實例22以靜脈路徑給予以量測有意識小鼠大腦APA活性抑制的方式來展示其跨越血腦屏障(BBB)進入大腦的能力。實例22(5 mg/kg,靜脈內注射,每隻投予295 nmol)可逐步抑制大腦APA的活性,在10分鐘時(每小時、每mg蛋白質之GluNA水解37.5 ± 3.3 nmol vs 70.0 ± 4.6, P >0.001),顯著且最大程度地降低其47%的活性,直至60分鐘時。並在120分鐘後回到基礎值。
第2圖顯示實例52以靜脈投予以量測有意識小鼠大腦APA活性抑制的方式來展示其跨越血腦屏障(BBB)進入大腦的能力。實例52(4 mg/kg,靜脈內注射,每隻投予237 nmol)可逐步抑制大腦APA的活性,在10分鐘後(每小時、每mg蛋白質之GluNA水解12.0 ± 4.0 nmol vs 62.1 ± 1.8, P >0.001),最大程度地降低其81%的活性,直至30分鐘時。大腦APA活性在注射120分鐘後仍顯著地被抑制達35%。
無
第1圖顯示實例22靜脈內投予(5 mg/kg)後,其抑制老鼠大腦APA活體外活性之時程。
第2圖顯示實例52靜脈內投予(4 mg/kg)後,其抑制老鼠大腦APA活體外活性之時程。
Claims (12)
- 如申請專利範圍第1項所述之化合物,其中該化合物為對應於式(I),且更具體地為式(II),其中: - l為2或3;及/或 - m為0 或1;及/或 - n為 0或1;及/或 - AH為CO2 H、SO3 H或PO3 H2 ;及/或 - R3 及R4 皆為H,或R3 及R4 皆為甲基;及/或 -該環係為芳基或雜環基,且更具體地為苯基、萘基、吲哚基、氮吲哚基或異㗁唑基。
- 如申請專利範圍第1或2項所述之化合物,其中R1 及R2 係各自獨立地選自由氫原子、鹵素原子、氰基、烷基、烷氧基、烷磺醯基、鹵烷基、鹵烷氧基、O-環烷基、雜烷基、O-芳基、O-芳烷基及芳基所組成之群組。
- 如申請專利範圍第1至3項中任一項所述之化合物,其中該化合物為對應於式(I),且更具體地為式(II),其中: - l為2;及/或 - m + n = 1;及/或 - AH 為CO2 H或SO3 H;及/或 - R3及R4 為H;及/或 - 該環係更具體地為苯基、萘基或吲哚基。
- 如申請專利範圍第1至4項中任一項所述之化合物,其中R1 及R2 係各自獨立地選自由氫原子、鹵素原子(較佳為氯或氟原子)、氰基、烷基(較佳為甲基)、烷氧基(較佳為甲氧基)、烷磺醯基 (較佳為甲磺醯基)、鹵烷基(較佳為三氟甲基)、鹵烷氧基(較佳為三氟甲氧基)、O-環烷基(較佳為O-環戊基或O-環己基)、雜烷基(較佳為甲氧基乙氧基)、O-芳基(較佳為O-苯基)、O-芳烷基(較佳為O-芐基)以及一芳基(較佳為苯基)所組成之群組。
- 如前述申請專利範圍中任一項所述之化合物,其選自由: 4-胺基-4-[苄基(羥基)磷醯基]丁酸; 4-胺基-4-{羥基[(2-甲苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(3-甲苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(4-甲苯基)甲基]磷醯基}丁酸; 4-胺基-4-({[3,5-二(三氟甲基)苯基]甲基}(羥基)磷醯基)丁酸; 4-胺基-4-[({[1,1'-聯苯]-2-基}甲基)(羥基)磷醯基]丁酸; 4-胺基-4-[羥基({[3-(三氟甲氧基)苯基]甲基})磷醯基]丁酸; 4-胺基-4-[羥基({[4-(三氟甲氧基)苯基]甲基})磷醯基]丁酸; 4-胺基-4-{羥基[(4-甲磺醯苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(2-甲氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(3-甲氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(4-甲氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-{[(3-氰苯基)甲基](羥基)磷醯基}丁酸; 4-胺基-4-{[(4-氰苯基)甲基](羥基)磷醯基}丁酸; 4-胺基-4-{羥基[(萘-1-基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(2-苯氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(3-苯氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(4-苯氧苯基)甲基]磷醯基}丁酸; 4-胺基-4-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丁酸; 4-胺基-4-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸; 4-胺基-4-{羥基[(5-苯基-1,2-㗁唑-5-基)甲基]磷醯基}丁酸; 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁酸; 4-胺基-4-{羥基[2-(2-甲苯基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(3-甲苯基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(4-甲苯基)乙基]磷醯基}丁酸; 4-胺基-4-[羥基({2-[3-(三氟甲基)苯基]乙基})磷醯基]丁酸; 4-胺基-4-[羥基(2-甲基-2-苯丙基)磷醯基]丁酸; 4-胺基-4-{[2-(2-氯苯基)乙基](羥基)磷醯基}丁酸; 4-胺基-4-{[2-(3-氯苯基)乙基](羥基)磷醯基}丁酸; 4-胺基-4-{羥基[2-(萘-2-基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(萘-1-基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(3-甲氧苯基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(4-甲氧苯基)乙基]磷醯基}丁酸; 4-胺基-4-{羥基[2-(2-苯氧苯基)乙基]磷醯基}丁酸; 4-胺基-4-({2-[2-(環戊氧基)苯基]乙基}(羥基)磷醯基)丁酸; 4-胺基-4-[羥基(3-苯丙基)磷醯基]丁酸; 4-胺基-4-[羥基({2-[2-(三氟甲氧基)苯基]乙基})磷醯基]丁酸; 4-胺基-4-[(2-{[1,1'-聯苯]-2-基}乙基)(羥基)磷醯基]丁酸; 4-胺基-4-{[2-(2,3-二氯苯基)乙基](羥基)磷醯基}丁酸; 4-胺基-4-{[2-(3-氯-2-甲氧苯基)乙基](羥基)磷醯基}丁酸; 3-羧基-1-{羥基[2-(1-甲基-1H-吲哚-3-基)乙基]磷醯基}丙烷-1-氯化銨; 3-羧基-1-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基)丙烷-1-氯化銨; 3-羧基-1-[羥基({2-[2-(2-甲氧乙氧基)苯基]乙基})磷醯基]丙烷-1-氯化銨; 4-胺基-4-{羥基[2-(3-苯基-1,2-㗁唑-5-基)乙基]磷醯基}丁酸; 4-胺基-4-{[2-(4-氟-2-甲氧苯基)乙基](羥基)磷醯基}丁酸; 4-胺基-4-{羥基[2-(1H-吲唑-1-基)乙基]磷醯基}丁酸; 1-({2-[2-(苄氧基)苯基]乙基}(羥基)磷醯基)-3-羧基丙烷-1-氯化銨; 5-胺基-5-[羥基(2-苯乙基)磷醯基]戊酸; (1R)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨; (1S)-3-羧基-1-[羥基(2-苯乙基)磷醯基]丙烷-1-氯化銨; (1R)-3-羧基-1-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-氯化銨; (4R)-4-胺基-4-({2-[2-(環己氧基)苯基]乙基}(羥基)磷醯基)丁酸; (1-胺基-4-甲氧基-4-酮丁基)(2-苯乙基)次磷酸; (1-胺基-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸; {4-乙氧基-1-[({1-[(2-甲基丙醯基)氧基]乙氧基}羰基)胺基]-4-酮丁基}(2-苯乙基)次磷酸; 1-[(苄氧基)(2-苯乙基)磷醯基]-4-乙氧基-4-羰基丁烷-1-氯化銨; [1-胺基-4-(苄氧基)-4-酮丁基](2-苯乙基)次磷酸; (4-乙氧基-4-側氧-1-{[(4R)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基}丁基)(2-苯乙基)次磷酸; 3-胺基-3-{羥基[(2-甲氧苯基)甲基]磷醯基}丙烷-1-磺酸; 3-胺基-3-[羥基(2-苯乙基)磷醯基]丙烷-1-磺酸; 3-胺基-3-{羥基[2-(2-甲氧苯基)乙基]磷醯基}丙烷-1-磺酸; 3-胺基-3-[羥基(3-苯丙基)磷醯基]丙烷-1-磺酸; 3-胺基-3-[({[1,1'-聯苯]-3-基}甲基)(羥基)磷醯基]丙烷-1-磺酸; 3-胺基-3-{羥基[(3-苯基-1,2-㗁唑-5-基)甲基]磷醯基}]丙烷-1-磺酸; 3-胺基-3-{羥基[(5-苯基-1,2-㗁唑-3-基)甲基]磷醯基}]丙烷-1-磺酸; 4-胺基-4-[羥基(2-苯乙基)磷醯基]丁烷-1-磺酸; {3-胺基-3-[羥基(2-苯乙基)磷醯基]丙基}膦酸; [4-乙氧基-1-({[(5-甲基-2-側氧-2H-1,3-二氧呃-4-基)甲氧基]羰基}胺基)-4-酮丁基] (2-苯乙基)次膦酸; 4-({[(5-甲基-2-側氧-2H-1,3-二氧呃-4-基)甲氧基]羰基}胺基)-4-({1-[(2-甲丙醯基) 氧] 乙氧基}(2-苯乙基)磷醯基)丁酸乙酯; (1-{[(苄氧基)羰基]胺基}-4-乙氧基-4-酮丁基)(2-苯乙基)次磷酸; 3-({4-乙氧基-4-側氧-1-[(2-苯乙基)次磷酸]丁基}胺甲醯基)-1-甲吡啶; {4-乙氧基-4-側氧-1-[({[(4R)-2-側氧-1,3-四氫噻唑-4-基]甲氧基}羰基)胺基]丁基}(2-苯乙基)次磷酸; (4-乙氧基-4-側氧-1-{[(2-{[(4R)-2-側氧-1,3-四氫噻唑-4-基]甲醯胺基}乙氧基)羰基]胺基}丁基)(2-苯乙基)次磷酸;以及 [1-(2-胺乙醯胺)-4-乙氧基-4-酮丁基](2-苯乙基)次磷酸所組成之群組。
- 如前述申請專利範圍中任一項所述之化合物,其係用作藥物。
- 一種醫藥組合物,其包含如申請專利範圍第1至7項中任一項所述之至少一化合物,且較佳地與一醫藥上可接受之稀釋劑或載體結合。
- 如申請專利範圍第1至7項中任一項所述之化合物或如申請專利範圍第9項所述之醫藥組合物,其係用於治療動脈高血壓及與其直接或間接相關之疾病。
- 一種如申請專利範圍第10項所述之化合物或組合物之用途,其係用於製備供治療與動脈高血壓直接或間接相關疾病之藥物,其中該疾病係選自由心臟病、心衰竭、中風、周邊及/或腦血管系統疾病、腦、眼及/或腎疾病所組成之群組。
- 一種如申請專利範圍第10項所述之化合物或組合物之用途,其係用於製備供治療疾病之藥物,其中該疾病係選自由原發性及/或繼發性動脈高血壓、發作、心肌缺血、心臟功能不全、腎臟功能不全、心肌梗塞、周邊血管疾病、糖尿病性蛋白尿、X症候群、青光眼、神經退化性疾病以及記憶障礙組成之群組。
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EA202191151A1 (ru) * | 2018-10-26 | 2021-07-15 | Квантум Дженомикс | Новые аминофосфиновые производные в качестве ингибиторов аминопептидазы а |
TW202207917A (zh) * | 2020-05-06 | 2022-03-01 | 法商量子基因科技有限公司 | 包含腦胺肽酶抑制劑、利尿劑及全身性腎素-血管收縮素系統阻斷劑之醫藥組合物 |
CN115385789B (zh) * | 2022-09-19 | 2024-06-04 | 安徽大学 | 一种4-氧代丁酸甲酯的合成方法 |
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FR2773712B1 (fr) * | 1998-01-16 | 2000-06-02 | Inst Nat Sante Rech Med | Composition pharmaceutique comprenant au moins un inhibiteur de l'aminopeptidase a |
ES2369256T3 (es) * | 2000-06-26 | 2011-11-28 | Helen Of Troy Limited | Sistema de lámpara recargable. |
AR058296A1 (es) * | 2005-12-09 | 2008-01-30 | Kalypsys Inc | Inhibidores de histona desacetilasa y composicion farmaceutica |
AR064275A1 (es) | 2006-12-14 | 2009-03-25 | Solvay Pharm Bv | Inhibidores selectivos de enzimas que degradan la neurotensina |
FR2934267B1 (fr) | 2008-07-23 | 2010-08-13 | Pharmaleads | Derives aminophosphiniques utiles dans le traitement de la douleur |
EA202191151A1 (ru) | 2018-10-26 | 2021-07-15 | Квантум Дженомикс | Новые аминофосфиновые производные в качестве ингибиторов аминопептидазы а |
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US11192907B2 (en) | 2021-12-07 |
IL282591B (en) | 2022-08-01 |
EA202191150A1 (ru) | 2021-07-15 |
CA3112851A1 (en) | 2020-04-30 |
IL282591A (en) | 2021-06-30 |
ZA202103580B (en) | 2022-08-31 |
CN113166182A (zh) | 2021-07-23 |
BR112021007116A2 (pt) | 2021-07-20 |
KR102380042B1 (ko) | 2022-03-28 |
MX2021004741A (es) | 2022-03-16 |
US20210309678A1 (en) | 2021-10-07 |
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