TWI553000B - 反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物及其製備方法 - Google Patents
反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物及其製備方法 Download PDFInfo
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- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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Description
本發明係有關於化合物及其製備方法,特別係指一種反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物及其製備方法。
按,肝臟疾病係儼然成為目前現代人健康之重大隱憂。更進一步來說,酒精、藥物、毒品或病毒等因子係會導致持續或反覆發生慢性肝實質炎症,造成肝臟細胞持續損傷,甚而壞死,使個體面臨脂肪肝、肝硬化等肝臟疾病之高風險,更有極高可能發展成為肝癌。而肝纖維化係為慢性肝損害所導致之病理現象,主要成因在於當肝細胞遭受持續且長期之損害時,肝纖維結締組織之增生與分解處於一個不平衡狀態,使肝內細胞外基質過度沈積,而肝纖維化亦為慢性肝疾病轉變為肝硬化或肝癌中之一個必經過程。
肝纖維化係非一個不可逆轉之過程,目前臨床上係有少數有效藥物可提供用於治療肝纖維化,例如秋水仙素、副腎皮質素、干擾素等,惟,該等藥物仍不免存在副作用,並且該等藥物繩僅能阻斷部份肝纖維化之情形,而無法達到全面抑制纖維化之效果。除西藥之外,中醫係有許多能夠用以治療肝纖維化之中草藥,如丹蔘、三七、鱉甲、柴胡等,雖然使
用中草藥可減少對於個體之副作用,惟,中草藥需要較長時間之服用才能發揮效用,則須耗費較多成本,並且於中草藥來源不明之狀況下,仍有可能混雜不良成份而影響其效用。
此外,部份食材係具有強化免疫力之功能,而具有治療肝臟疾病之療效,一般常用者如蜆,然而,須每日大量服用始得於個體上發揮效用,是以,對於治療疾病來說亦有其實施上之困難所在。而為避免上述缺失,如台灣專利第I370747號中係將蜆肉先以酒精萃取後,再以管柱純化之方式,從中獲得一對於抗肝臟纖維化之活性物質,惟,先前技術中所揭萃取及純化方法須透過繁複之步驟始能獲得活性物質,換言之,先前技術所揭方法係包含如下缺失:其一、需要大量蜆作為原料,導致量產成本過於昂貴;其二、須經過至少二次純化步驟始能獲得活性物質,產率過低。
據此,先前技術中仍缺乏一種對於肝纖維化有具體療效並且低副作用之有效成份,因此,目前重要之課題即在於開發出一種低製造成本、低副作用並且能夠有效抑制肝纖維化之物質,能夠提供作為臨床治療肝臟相關疾病之用。
本發明之主要目的係在於提供一種反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物(trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane)或其醫藥上可接受之鹽類,其中,該反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物係如式(I)所示:
本發明之另一目的係在於提供一種反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物或其醫藥上可接受之鹽之製備方法,其係將式(Ⅱ)化合物:及式(Ⅲ)化合物:,進行縮醛反應,而得到含有式(I)化合物之混合物。
其中:於本發明之實施例中,式(Ⅱ)化合物係由式(Ⅳ)化合物:,與氯鉻酸吡啶鹽(pyridinium chlorochromate)於有機溶劑中進行氧化反應所形成。
於本發明之實施例中,縮醛反應中係存在一酸催化劑。
於本發明之實施例中,該含有式(I)化合物之混合物係得以分離技術進行純化,而該分離技術包含有,但不限於,管柱層析、沖堤分離或是所屬該項技術領域而具通常知識者所熟知之方法。
第一圖係為本發明實例二所得活性成份之1H-NMR光譜圖。
第二圖係為本發明實例二所得活性成份之13C-NMR光譜
圖。
第三圖係為本發明實例二所得活性成份之質譜圖。
以下,將茲舉若干實例,更進一步說明本發明如后。
首先,將等量之與氯鉻酸吡啶鹽(pyridinium chlorochromate,PCC)一起溶於二氯甲烷(CH2Cl2)中,並且於30℃下進行攪拌混合,其中,於本實例中,式(Ⅳ)化合物與氯鉻酸吡啶鹽分別為1公克,二氯甲烷為20毫升。將含有式(Ⅳ)化合物與氯鉻酸吡啶鹽之二氯甲烷溶液以矽鈣石(celite)進行抽氣過濾而獲得一濾液,而後將該濾液減壓濃縮而得式(Ⅱ)化合物:,其係為一白色固體。而上述化學反應之反應式如下所示。
將式(Ⅱ)化合物溶於50毫升之甲苯(toluene),加入700毫克之式(Ⅲ)化合物:以及300毫克之對甲苯磺酸
(p-toluenesulfonic acid,TsOH),加熱迴流約3小時。將反應完成之溶液以減壓濃縮方式移除甲苯,再加入濃度為1%之20毫升碳酸鈉水溶液(Na2CO3),以乙酸乙酯(ethyl acetate)萃取三次。收集萃取液,經減壓濃縮方式移除乙酸乙酯,得到一混合物,其係含有式(I)化合物:。而上述化學反應之反應式如下所示。
而為能獲得純化之式(I)化合物,將該混合物溶於5毫升之己烷,以矽膠管柱層析法分離出呈白色之式(I)化合物,共約260毫克,其中,矽膠管柱層析法中所使用之沖提液為己烷/乙酸乙酯(9:1)。
參考先前技術之內容,取65公斤之蜆,經剝殼後得到約27.7公斤之蜆肉。將蜆肉以熱風乾燥,乾燥後之蜆肉重量約2.5公斤,再浸泡於約乾燥蜆肉3倍量之酒精內,進行萃取,得到約1公斤之一酒蜆萃取物。
取900公克之該酒蜆萃取物與水及乙酸乙酯以體積比1:2:3之比例混合,再利用分液漏斗分離萃取得到一乙酸乙酯層,而將該乙酸乙酯層濃縮凍乾,得到一乙酸乙酯酒蜆萃取物,並且取900公克乙酸乙酯層以管柱層析進行分離,藉由矽膠(40~63孔)吸附,依序以己醇:乙酸乙酯
比例為10:1、5:1、3:1、1:1、1:3、1:5及1:10及甲醇沖提,得到18個片段。將該18個片段以薄層層析法(thin layer chromatography,TLC)分析,分離出一具護肝功能之活性成份,約1公克,其中,該活性成份之護肝功效係已於台灣專利第I370747號揭露,故於此不加以贅言。
該活性成份係為白色固體狀,熔點約為51℃,比旋光度[α]D25+1.15(c 0.75甲醇),以薄層層析法於己醇/乙酸乙酯為4:1之條件下時,該活性成份之Rf直為0.3。更進一步,將該活性成份以氫核磁共振光譜儀(1H-NMR)以及碳13核磁共振光譜儀(13C-NMR)進行分析,得到之光譜圖如第一圖及第二圖所示,其中,使用溶劑為氘代氯仿(CDCl3),而氫核磁共振光譜儀為400MHz。而由第一圖顯示該活性成份之δH值為4.96(1H,t,J=4.8Hz,H-2),4.17(1H,m,H-4),4.08(1H,dd,J=8.4,6.4Hz,H-5a),3.67(1H,dd,J=11.6,3.6Hz,H-6b),3.62(1H,dd,J=8.4,7.2Hz,H-5b),3.58(1H,dd,J=11.6,5.6Hz,H-6b),2.15(1H,br.s,6-OH),1.59-1.63(2H,m,H-1’),1.27-1.43(2H,m,H-2’),1.01-1.25(32H,br s,H-3’-18’),0.87(t,3H,J=6.6Hz,H-19’);由第二圖顯示式(I)化合物之δC值為104.7(C-2),76.1(C-5),66.5(C-4),62.6(C-6),34.1(C-1’),31.9(C-17’),29.3-29.9(C-3’-16’),24.0(C-2’),22.7(C-18’),14.1(C-19’)。
並且,將該活性成份以電子撞擊式質譜儀(Electron Impact-Mass Spectrophotometer,EI-MS)進行分析,結果如第三圖所示。由第三圖可知式(I)化合物分子離子峰[M]+質荷比(m/z)及相對強度(%)為370(20),355(65),341(22),327(11),267(5),185(3),157(9),103(100),57(51)。
將實例一所得式(I)化合物與實例二所得活性成份比對可知,藉由本發明所揭方法製備而得之式(I)化合物係與實例二所得活性成份結構一致,換言之,本發明所揭式(I)化合物係具有預防或治療肝臟疾病之功效,尤其是與肝纖維化相關之肝臟疾病,因而將有效量之式(I)化合物做為醫藥組合物之有效成份或是製備成為日常營養補充品。再者,透過實例二所揭方法,以27.7公斤蜆肉,僅能獲得1公克活性成份,產率僅有0.004%,相較於此,本發明所揭方法係僅使用2公克原料而獲得260毫克之式(I)化合物,其產率為13%,明顯高於習用技術所揭方法。據此,本發明所揭製備方法係可以有效達到提昇式(I)化合物之產率,並且同時減少製作成本之功效。
以上僅是藉由各該實施例詳細說明本發明,熟知該技術領域者於不脫離本發明精神下,而對於說明書中之實施例所做的任何簡單修改或是變化,均應為本案申請專利範圍所得涵攝者。
Claims (4)
- 一種將製備式(I)化合物:(I)之方法,其係將式(Ⅱ)化合物:(Ⅱ)及式(Ⅲ)化合物:(Ⅲ),進行縮醛反應,得到含有式(I)化合物之混合物。
- 依據申請專利範圍第1項所述方法,其中,式(Ⅱ)化合物係由式(Ⅳ)化合物:(Ⅳ),與氯鉻酸吡啶鹽(pyridinium chlorochromate)於有機溶劑中進行氧化反應所形成。
- 依據申請專利範圍第1項所述方法,其中,縮醛反應中係存在一酸催化劑。
- 依據申請專利範圍第1項所述方法,其中,該含有式(I)化合物之混合物係得以分離技術進行純化。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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TW103102539A TWI553000B (zh) | 2014-01-23 | 2014-01-23 | 反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物及其製備方法 |
CN201410099171.4A CN104803966A (zh) | 2014-01-23 | 2014-03-17 | 反式-2-19烷基-4-羟甲基-1,3-二氧戊环化合物及其制备方法 |
KR1020140036865A KR101644450B1 (ko) | 2014-01-23 | 2014-03-28 | 트랜스-2-노나데실-4-히드록시메틸-1,3-다이옥살란 화합물 및 그 제조방법 |
JP2014085186A JP2015137277A (ja) | 2014-01-23 | 2014-04-17 | トランス−2−ノナデシル−4−ヒドロキシメチル−1、3−ジオキソラン化合物とその調製方法 |
US14/456,066 US20150203466A1 (en) | 2014-01-23 | 2014-08-11 | Trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane and method for producing thereof |
MYPI2014702242A MY182857A (en) | 2014-01-23 | 2014-08-12 | Trans-2-Nonadecyl-4-Hydroxymethyl-1,3-Dioxolane Compound and Preparation Method Thereof |
JP2016095437A JP6326086B2 (ja) | 2014-01-23 | 2016-05-11 | トランス−2−ノナデシル−4−ヒドロキシメチル−1、3−ジオキソラン化合物とその調製方法 |
US15/228,202 US10285972B2 (en) | 2014-01-23 | 2016-08-04 | Trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane and producing methodthereof |
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TW103102539A TWI553000B (zh) | 2014-01-23 | 2014-01-23 | 反式-2-19烷基-4-羥甲基-1,3-二氧戊環化合物及其製備方法 |
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TW201529564A TW201529564A (zh) | 2015-08-01 |
TWI553000B true TWI553000B (zh) | 2016-10-11 |
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JP (2) | JP2015137277A (zh) |
KR (1) | KR101644450B1 (zh) |
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FR2906807A1 (fr) * | 2006-10-09 | 2008-04-11 | Arkema France | Procede de synthese d'acetals cycliques par extraction reactive d'un polyol en solution concentree |
FR2950894B1 (fr) * | 2009-10-06 | 2011-12-23 | Arkema France | Utilisation d'acetals de glycerol comme agents de coalescence pour laques, peintures ou vernis et compositions les comprenant |
TW201114465A (en) * | 2009-10-19 | 2011-05-01 | Univ Nat Kaohsiung Marine | Purification process and substance for clam |
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2014
- 2014-01-23 TW TW103102539A patent/TWI553000B/zh active
- 2014-03-17 CN CN201410099171.4A patent/CN104803966A/zh active Pending
- 2014-03-28 KR KR1020140036865A patent/KR101644450B1/ko active IP Right Grant
- 2014-04-17 JP JP2014085186A patent/JP2015137277A/ja active Pending
- 2014-08-11 US US14/456,066 patent/US20150203466A1/en not_active Abandoned
- 2014-08-12 MY MYPI2014702242A patent/MY182857A/en unknown
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2016
- 2016-05-11 JP JP2016095437A patent/JP6326086B2/ja active Active
Non-Patent Citations (1)
Title |
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蔡晨瑜,台灣養殖蜆有效成分抑制二甲基亞胺誘發轉型生長因子-beta1表現之保健功效,國立高雄海洋科技大學,2009 * |
Also Published As
Publication number | Publication date |
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US20150203466A1 (en) | 2015-07-23 |
KR20150088162A (ko) | 2015-07-31 |
JP6326086B2 (ja) | 2018-05-16 |
MY182857A (en) | 2021-02-05 |
CN104803966A (zh) | 2015-07-29 |
TW201529564A (zh) | 2015-08-01 |
JP2015137277A (ja) | 2015-07-30 |
KR101644450B1 (ko) | 2016-08-10 |
JP2016138150A (ja) | 2016-08-04 |
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