TW201516051A - Preparation method of nonradioactive standard substance ReO-MN 16-ET - Google Patents
Preparation method of nonradioactive standard substance ReO-MN 16-ET Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
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本發明係關於一種無放射性標準品N-(2-乙硫基)-3-氮雜-19-乙氧羰基-3-(2-硫乙基)十八醯胺]錸錯合物(簡稱ReO-MN 16-ET)之製備方法，尤指一種製程快速且具有高產率之無放射性標準品ReO-MN 16-ET之製備方法。The present invention relates to a non-radioactive standard N-(2-ethylthio)-3-aza-19-ethoxycarbonyl-3-(2-thioethyl)octadecylamine] ruthenium complex (abbreviation) The preparation method of ReO-MN 16-ET), especially the preparation method of the non-radioactive standard ReO-MN 16-ET with rapid process and high yield.
一般最常見的肝癌形成原因是原發性肝癌(primary hepatocellular carcinoma, HCC)，特別是在亞洲與次撒哈拉非洲地區；而在美國與歐洲，肝癌發生率更是急遽的增加中，其中尤其以C型肝炎病例居多。因此，肝癌的防治已是現代醫學上的重要課題之一。The most common cause of liver cancer formation is primary hepatocellular carcinoma (HCC), especially in Asia and sub-Saharan Africa. In the United States and Europe, the incidence of liver cancer is even more rapid, especially in C. Hepatitis cases are mostly. Therefore, the prevention and treatment of liver cancer has become one of the important topics in modern medicine.
目前治療肝癌的方式包括外科手術切除、化學治療、放射治療以及肝動脈栓塞等，其中外科手術切除仍是治療肝癌之首選，但卻有85%患者因延誤就醫等因素，導致無法選擇執行手術切除方式。因此尋求另類有效的肝癌治療法，就顯得格外迫切。近年來已發展一種具有治療肝癌潛力之新藥188 ReO-MN 16-ET，此藥物是以H3 -MN 16-ET為配位子，與放射性188 Re反應形成188 ReO-MN 16-ET之後，再將其溶於利比多(Lipiodol)當中，即可獲得兼具有診斷與治療雙重功能特性之188 ReO-MN 16-ET/Lipiodol核醫藥物。Current treatments for liver cancer include surgical resection, chemotherapy, radiation therapy, and hepatic artery embolization. Among them, surgical resection is still the first choice for treating liver cancer, but 85% of patients are unable to choose surgical resection due to delays in medical treatment and other factors. the way. Therefore, it is particularly urgent to seek alternative and effective treatment methods for liver cancer. In recent years, a new drug 188 ReO-MN 16-ET has been developed, which has the potential of H 3 -MN 16-ET as a ligand and reacts with radioactive 188 Re to form 188 ReO-MN 16-ET. Further, by dissolving it in Lipiodol, 188 ReO-MN 16-ET/Lipiodol nuclear medicine having both diagnostic and therapeutic dual-function properties can be obtained.
利比多是一種碘化的罌粟子油，許多國內外研究均顯示肝癌組織對利比多有顯著的攝取量，因此近來若干研究者試圖在利比多上標幟131 I，90 Y及188 Re等放射性同位素，以應用為腫瘤治療劑。其中利比多之131 I標幟物已在歐洲上市，應用於肝腫瘤之治療。然而，由於131 I係放射高能量之γ射線會引起較高之體內總劑量，同時131 I之價格又較為昂貴，限制了它的廣泛使用性。相較之下，放射性同位素188 Re可由發生器(generator)汲取，容易獲得，而且其放射能量與半衰期均適用於疾病之診斷與治療，是一種具發展潛力之醫用同位素，尤其是在腫瘤的體內放射治療上，預期有極為重要的表現。因此，載有188 Re之利比多，被視為是體內放射治療肝癌的有效治療劑。Libido is an iodinated poppy seed oil. Many domestic and foreign studies have shown that liver cancer tissue has a significant intake of libido. Therefore, several researchers have recently tried to target 131 I, 90 Y and 188 on Libido. Reactive isotopes such as Re are used as therapeutic agents for tumors. Among them, Libiduo's 131 I label has been listed in Europe and is used in the treatment of liver tumors. However, since the 131 I system emits high-energy gamma rays, it causes a higher total dose in the body, and the price of 131 I is more expensive, which limits its widespread use. In contrast, the radioactive isotope 188 Re can be easily obtained by a generator, and its radiation energy and half-life are suitable for the diagnosis and treatment of diseases. It is a medical isotope with potential for development, especially in tumors. In vivo radiation therapy is expected to have extremely important performance. Therefore, it contains more than 188 Re, which is considered to be an effective therapeutic agent for radiation therapy of liver cancer in vivo.
188 ReO-MN 16-ET不具放射性的標準品(standards)係為ReO-MN 16-ET，關於其現有的製造方法上，請參考第一圖所示之流程，其係將H3 -MN 16-ET(化合物5)直接和ReO(PPh3 )2 Cl3 (化合物A)反應生成ReO-MN 16-ET(化合物7)。然而，這種方法需要歷經繁瑣的合成化合物A之預備程序，以及需要花費大量時間等待ReO-MN 16-ET偶合完成；再者，其產率偏低，僅能得到20%之ReO-MN 16-ET，這也意味著有大量的化學合成廢料需要處理。 188 ReO-MN 16-ET Non-radioactive standards are ReO-MN 16-ET. For the existing manufacturing methods, please refer to the process shown in the first figure, which will be H 3 -MN 16 - ET (Compound 5) is directly reacted with ReO(PPh 3 ) 2 Cl 3 (Compound A) to form ReO-MN 16-ET (Compound 7). However, this method requires a cumbersome preparatory procedure for the synthesis of Compound A, and it takes a lot of time to wait for the completion of ReO-MN 16-ET coupling; in addition, the yield is low, and only 20% of ReO-MN 16 can be obtained. -ET, which also means that a large amount of chemical synthetic waste needs to be disposed of.
另外，此方法未將H3 -MN 16-ET的硫端保護基CPh3 進行去保護之處理，因此會限制H3 -MN 16-ET與Re(PPh3 )2 Cl3 之反應速率，甚至有可能不反應。且即使是使用已作硫端去保護的MN 16-ET與Re(PPh3 )2 Cl3 在熱乙醇溶液下反應，也會驅使乙基與硫醇基反應，產生大量的副產物8A、8B以及8C，如第二A~二C圖所示，而造成「去硫端保護基也不能使ReO-MN 16-ET產率有顯著提升」的誤解。Further, this method is not the end of the sulfur H 3 -MN 16-ET CPh 3 protecting group Deprotection of the processing, thus limiting the H 3 -MN 16-ET and Re (PPh 3) 2 Cl 3 of the reaction rate, even It may not respond. Moreover, even the reaction of MN 16-ET and Re(PPh 3 ) 2 Cl 3 which have been desulfated to the sulfur end in a hot ethanol solution will drive the ethyl group to react with the thiol group to produce a large amount of by-products 8A, 8B. And 8C, as shown in the second A to C diagram, and the misunderstanding that the "desulfurization end protecting group can not significantly improve the ReO-MN 16-ET yield".
因此，如何提出一種新穎的合成方法，以在具有高效率及高產率下，更為快速地取得大量的無放射性標準品ReO-MN 16-ET，即是本發明所要克服的技術問題。Therefore, how to propose a novel synthesis method to obtain a large amount of the non-radioactive standard ReO-MN 16-ET more quickly with high efficiency and high yield is a technical problem to be overcome by the present invention.
本發明之主要目的，係提供一種無放射性標準品ReO-MN 16-ET之製備方法，其係使用NH4 ReO4 為反應物而避免在合成過程中產生多種無用副產物，以提升ReO-MN 16-ET的產率，並且減少化學化學廢棄物處理的問題。The main object of the present invention is to provide a method for preparing a non-radioactive standard product ReO-MN 16-ET, which uses NH 4 ReO 4 as a reactant to avoid generation of various useless by-products in the synthesis process to enhance ReO-MN. The yield of 16-ET and the problem of chemical chemical waste disposal.
本發明之次要目的，係提供一種無放射性標準品ReO-MN 16-ET之製備方法，其可有效模擬具有放射性之188 ReO-MN 16-ET的標幟流程，為具有實際效益之無放射性標準品。A secondary object of the present invention is to provide a method for preparing a non-radioactive standard product ReO-MN 16-ET, which can effectively simulate the labeling process of radioactive 188 ReO-MN 16-ET, which is practically non-radioactive. Standard.
本發明之再一目的，係提供一種無放射性標準品ReO-MN 16-ET之製備方法，其可減少ReO-MN 16-ET在合成上所需花費的時間，另外也透過降低反應所需之溫度，而縮短升溫、降溫等時間花費，進一步提高生產效率。A further object of the present invention is to provide a method for preparing a non-radioactive standard ReO-MN 16-ET, which can reduce the time required for the synthesis of ReO-MN 16-ET, and also reduces the reaction required The temperature is reduced, and the time spent on heating, cooling, and the like is shortened, and the production efficiency is further improved.
為了達到上述之目的，本發明揭示了一種無放射性標準品ReO-MN 16-ET之製備方法，其係包含步驟：製備N-[2-((三苯甲基)硫基)乙基]-3-氮雜-18-乙氧羰基-3-[2-((三苯甲基)硫基)乙基]十八醯胺(簡稱H3 -MN 16-ET)；混合該H3 -MN-16-ET、三氟乙酸(TFA)以及三乙基矽烷，經反應生成17-(2-硫乙基)-19-[(2-硫乙基)胺基]-17-氮雜-19-氧基十九烷酸乙酯(簡稱MN 16-ET)；以及加入過錸酸銨於該MN 16-ET之中，經反應生成稱ReO-MN 16-ET。依此流程之操作，即可讓不具放射性的標準品ReO-MN 16-ET能被快速且大量地製造。In order to achieve the above object, the present invention discloses a preparation method of a non-radioactive standard ReO-MN 16-ET, which comprises the steps of: preparing N-[2-((trityl)thio)ethyl]- 3-aza-18-ethoxycarbonyl-3-[2-((trityl)thio)ethyl]octadecylamine (H 3 -MN 16-ET for short); mixing the H 3 -MN -16-ET, trifluoroacetic acid (TFA) and triethyldecane are reacted to form 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-aza-19 Ethyl octadecanoic acid ethyl ester (abbreviated as MN 16-ET); and ammonium perruthenate added to the MN 16-ET, which is reacted to form ReO-MN 16-ET. According to the operation of this process, the non-radioactive standard ReO-MN 16-ET can be manufactured quickly and in large quantities.
S1~S3‧‧‧步驟S1~S3‧‧‧ steps
(1)~(7)‧‧‧化合物(1)~(7)‧‧‧ compounds
(8A)~(8C)‧‧‧化合物(8A)~(8C)‧‧‧ compounds
第一圖：其係為先前技術合成ReO-MN 16-ET之化學反應式圖；
第二A~C圖：其係為先前技術使用Re(PPh3
)2
Cl3
為反應物而產生之無用副產物之化學結構圖；
第三圖：其係為本發明所揭示方法之步驟流程圖；
第四圖：其係為本發明合成ReO-MN 16-ET之化學反應式圖；以及
第五圖：其係為本發明中，製備所使用之反應起始物H3
-MN 16-ET之化學反應式圖。
First: it is a chemical reaction diagram of the prior art synthesis of ReO-MN 16-ET;
Second A~C diagram: it is a chemical structure diagram of the useless by-product produced by the prior art using Re(PPh 3 ) 2 Cl 3 as a reactant;
Third: it is a flow chart of the steps of the method disclosed in the present invention;
Figure 4 is a chemical reaction diagram of the synthetic ReO-MN 16-ET of the present invention; and a fifth diagram: it is the reaction starting material H 3 -MN 16-ET used in the preparation of the present invention. Chemical reaction diagram.
為使本發明之特徵及所達成之功效有更進一步之瞭解與認識，謹佐以較佳之實施例及配合詳細之說明，說明如後：For a better understanding and understanding of the features and advantages of the present invention, the preferred embodiments and the detailed description are described as follows:
首先，請參考第三圖，其係揭示了本發明在製備方法上的核心技術特徵，其步驟係包含：First, please refer to the third figure, which reveals the core technical features of the present invention on the preparation method, and the steps thereof include:
步驟S1：製備H3 -MN 16-ET；Step S1: preparing H 3 -MN 16-ET;
步驟S2：混合該H3 -MN-16-ET、三氟乙酸(TFA)以及三乙基矽烷(triethylsilane)，經反應生成17-(2-硫乙基)-19-[(2-硫乙基)胺基]-17-氮雜-19-氧基十九烷酸乙酯 (Ethyl 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-aza-Step S2: mixing the H 3 -MN-16-ET, trifluoroacetic acid (TFA) and triethylsilane to form 17-(2-thioethyl)-19-[(2-thioethyl) Ethyl 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-aza-
19-oxononadecanoate) (簡稱MN 16-ET)；19-oxononadecanoate) (referred to as MN 16-ET);
步驟S3：加入過錸酸銨 (ammonium perrhenate)於該MN 16-ET之中，經反應生成ReO-MN 16-ET。Step S3: Ammonium perrhenate is added to the MN 16-ET to form ReO-MN 16-ET by reaction.
請一併參考第四圖之反應流程，本發明所揭示的製備方法為求增進金屬錸的標幟轉化率，使用NH4 ReO4 為反應物來模擬188 Re產生器所生成之產物188 ReO4 - ；而同時，本發明將H3 -MN 16-ET的硫端去保護設定為必須，並使經去保護處理後所生成之MN 16-ET在還原劑氯化亞錫(SnCl2 )的存在下，應有較佳的反應活性，可將原本ReO-MN 16-ET的製程時間自16小時縮短至3小時。Referring to the reaction scheme of the fourth figure together, the preparation method disclosed in the present invention is to improve the conversion rate of the metal ruthenium, and use NH 4 ReO 4 as a reactant to simulate the product 188 ReO 4 generated by the 188 Re generator. -; and at the same time, the present invention is a sulfur terminal H 3 -MN 16-ET is set to be deprotected, and the deprotected MN 16-ET generated after treatment in the reducing agent stannous chloride (SnCl 2) is In the presence of, there should be better reactivity, and the process time of the original ReO-MN 16-ET can be shortened from 16 hours to 3 hours.
本發明係以H3 -MN 16-ET(化合物5)為反應起始物，其製備方法係有多種，本發明並不限定其來源，而是著重於其進一步合成。在步驟S2當中，所揭示之方法係將H3 -MN 16-ET在具有三氟乙酸以及三乙基矽烷的環境下，使用超音波震至反應物全溶後，在室溫攪拌2小時。接著以己烷(hexane)清洗以及使用二氯甲烷萃取，於30℃之下將反應物反覆進行三次濃縮後，上真空並抽隔夜而可得到MN 16-ET(化合物6)，係為淡黃色油狀物。The present invention uses H 3 -MN 16-ET (Compound 5) as a reaction starting material, and its preparation method is various, and the present invention does not limit its source, but focuses on its further synthesis. In the step S2, the disclosed method is to stir the H 3 -MN 16-ET in the environment with trifluoroacetic acid and triethyl decane using ultrasonic waves until the reactants are completely dissolved, and then stir at room temperature for 2 hours. Then, it was washed with hexane (hexane) and extracted with dichloromethane, and the reaction was concentrated three times at 30 ° C, and then vacuumed and pumped overnight to obtain MN 16-ET (compound 6), which was pale yellow. Oily.
經過步驟S2之處理，原本作為H3 -MN 16-ET的硫端保護基的三苯甲基即被移除，以讓其硫基接下來能有效接合於金屬錸，如此可以提高MN 16-ET之使用率，以簡化ReO-MN 16-ET之純化流程，達到製程簡化及製程時間縮短的目的。After the treatment of step S2, the trityl group originally serving as the sulfur end protecting group of H 3 -MN 16-ET is removed, so that the sulfur group can be effectively bonded to the metal ruthenium, thereby improving MN 16- The use rate of ET to simplify the purification process of ReO-MN 16-ET, to achieve process simplification and shortened process time.
待進入步驟S3，其係加入過錸酸銨(NH4 ReO4 )於步驟S2所製成之MN 16-ET，並且使用一反應液。該反應液係包含酒石酸以及氯化亞錫，其中的氯化亞錫為還原劑，得以減少MN 16-ET被形成為無用副產物而浪費掉的可能。在此步驟中，由於係直接使用NH4 ReO4 為合成起始物，可省去三苯基膦(PPh3 )之使用，並免除在合成過程中金屬錸之耗損。此外，其也更接近由188 Re產生器所產生之188 ReO4 - 的標幟狀態，係為合適的無放射性標準品ReO-MN 16-ET之製備方法。To proceed to step S3, MN 16-ET made by ammonium perruthenate (NH 4 ReO 4 ) in step S2 is added, and a reaction liquid is used. The reaction solution contains tartaric acid and stannous chloride, and the stannous chloride is a reducing agent, which reduces the possibility that MN 16-ET is formed as an unwanted by-product. In this step, since NH 4 ReO 4 is directly used as a synthesis starting material, the use of triphenylphosphine (PPh 3 ) can be omitted and the loss of metal ruthenium during the synthesis can be eliminated. In addition, it is also closer to the state of the flag of 188 ReO 4 - produced by the 188 Re generator, and is a suitable method for preparing the non-radioactive standard ReO-MN 16-ET.
如本發明步驟S3之操作，其另一優點係在於可將ReO-MN 16-ET之製程溫度下降至40℃，接近於室溫，而可因此減少升溫、降溫過程之等待時間，提高製備的效率。Another advantage of the operation of the step S3 of the present invention is that the process temperature of the ReO-MN 16-ET can be lowered to 40 ° C, which is close to room temperature, thereby reducing the waiting time of the heating and cooling processes and improving the preparation. effectiveness.
而在本發明所使用之反應起始物H3 -MN 16-ET的製備方法上，請配合參考第五圖所示之化學反應式流程，其操作步驟則係包含：For the preparation method of the reaction starting material H 3 -MN 16-ET used in the present invention, please refer to the chemical reaction type flow shown in the fifth figure, and the operation steps include:
步驟S11：合成16-溴十六酸乙酯(化合物1)；Step S11: synthesizing ethyl 16-bromohexadecanate (compound 1);
步驟S12：合成2-[(三苯甲基)硫基]乙胺(化合物2)；Step S12: synthesizing 2-[(trityl)thio]ethylamine (Compound 2);
步驟S13：混合2-[(三苯甲基)硫基]乙胺、二氯甲烷以及三氟乙酸，室溫下攪拌後加入氯化氫溶液，經萃取後獲得N-[2-((三苯甲基)硫基)乙基]氯乙醯胺(化合物3)；Step S13: mixing 2-[(trityl)thio]ethylamine, dichloromethane and trifluoroacetic acid, stirring at room temperature, adding a hydrogen chloride solution, and extracting to obtain N-[2-((triphenyl) Thio)ethyl] chloroacetamide (compound 3);
步驟S14：取2-[(三苯甲基)硫基]乙胺與N-[2-((三苯甲基)硫基)乙基]氯乙醯胺溶於二氯甲烷後，再加入三氟乙酸，經50℃油浴迴流72小時後，依序透過萃取、濃縮以及液相層析分離純化，獲得N-[2-((三苯甲基)硫基)乙基][2-((三苯甲基)硫基)乙基胺基]乙醯胺(化合物4)；以及Step S14: taking 2-[(trityl)thio]ethylamine and N-[2-((trityl)thio)ethyl]chloroacetamide dissolved in dichloromethane, and then adding Trifluoroacetic acid was refluxed in an oil bath at 50 ° C for 72 hours, and then purified by extraction, concentration and liquid chromatography to obtain N-[2-((trityl)thio)ethyl][2- ((tritylmethyl)thio)ethylamino]acetamide (compound 4);
步驟S15：將N-[2-((三苯甲基)硫基)乙基][2-((三苯甲基)硫基)乙基胺基]乙醯胺、16-溴十六酸乙酯以及氫氧化鉀溶於乙腈，經95℃油浴迴流48小時後，依序透過萃取、濃縮以及液相層析分離純化，獲得H3 -MN 16-ET(化合物5)。Step S15: N-[2-((trityl)thio)ethyl][2-((trityl)thio)ethylamino]acetamide, 16-bromohexadecanoic acid The ethyl ester and potassium hydroxide were dissolved in acetonitrile, and refluxed in an oil bath at 95 ° C for 48 hours, and then purified by extraction, concentration and liquid chromatography to obtain H 3 -MN 16-ET (Compound 5).
以下則是本發明於實際操作之數據及細部流程：The following is the actual operation data and detailed process of the present invention:
［Ethyl 16-bromohexadecanate (化合物1)之合成］[Synthesis of Ethyl 16-bromohexadecanate (Compound 1)]
於250ml圓底燒瓶中，取16-溴十六酸乙酯(5.0g，14.9 mmol)，氯化亞碸(SOCl2 ，30ml)及正己烷(30ml)之混液加熱80℃迴流2小時，以40℃減壓蒸出過量之氯化亞碸及溶劑。加入經分子篩除水之乙醇(30 ml)，在室溫攪拌隔夜後，40℃減壓蒸出過量之乙醇。添加三氯甲烷(CHCl3 ，50 ml)溶解殘餘物後，以30℃減壓濃縮。再次添加三氯甲烷(50 ml)溶解殘餘物後，以30℃減壓濃縮。於室溫下靜置隔夜，得白色固體產物為化合物1 (5.4 g, 99%)。In a 250 ml round bottom flask, a mixture of 16-bromohexadecanoic acid ethyl ester (5.0 g, 14.9 mmol), hydrazine chloride (SOCl 2 , 30 ml) and n-hexane (30 ml) was heated at 80 ° C for 2 hours. Excess myridine chloride and solvent were distilled off under reduced pressure at 40 °C. Ethanol (30 ml), which was dehydrated with molecular sieves, was added, and stirred at room temperature overnight, and excess ethanol was evaporated under reduced pressure at 40 °C. After adding a residue of chloroform (CHCl 3 , 50 ml), it was concentrated under reduced pressure at 30 °C. After adding chloroform (50 ml) again, the residue was dissolved and concentrated under reduced pressure at 30 °C. After standing overnight at room temperature, the product was obtained as a white solid (1 g, 5.4 g, 99%).
化合物1之分析數據：Analytical data for Compound 1:
1 H-NMR(CDCl3 )：δ4.13 (q, 2H, C17 -H 2 ), 3.41 (t, 2H, C1 -H 2 ), 2.28 (t, 2H, C15 -H 2 ), 1.83 (m, 2H, C2 -H 2 ), 1.61 (m, 2H, C14 -H 2 ), 1.41 (m, 2H, C3 -H 2 ), and 1.26 (m, 23H, C4 -H 2 , C5 -H 2 , C6 -H 2 , C7 -H 2 , C8 -H 2 , C9 -H 2 , C10 -H 2 , C11 -H 2 , C12 -H 2 , C13 -H 2 and C18 -H 3 ) 1 H-NMR (CDCl 3 ): δ 4.13 (q, 2H, C 17 - H 2 ), 3.41 (t, 2H, C 1 - H 2 ), 2.28 (t, 2H, C 15 - H 2 ), 1.83 (m, 2H, C 2 - H 2 ), 1.61 (m, 2H, C 14 - H 2 ), 1.41 (m, 2H, C 3 - H 2 ), and 1.26 (m, 23H, C 4 - H 2 , C 5 - H 2 , C 6 - H 2 , C 7 - H 2 , C 8 - H 2 , C 9 - H 2 , C 10 - H 2 , C 11 - H 2 , C 12 - H 2 , C 13 - H 2 and C 18 - H 3 )
［2-[(Triphenylmethyl)thio]ethylamine (化合物2)之合成］Synthesis of [2-[(Triphenylmethyl)thio]ethylamine (Compound 2)]
於250ml雙頸圓底燒瓶中，取2-mercaptoethyl hydrochloride (6.0 g，52.9 mmol)、三苯甲醇(triphenylmethanol，13.0g，50.0mmol)及100ml三氯甲烷後，再加入三乙胺(TEA，10ml，72.1mmol)並將燒瓶置於75℃油浴鍋內，使溶液迴流(須加乾燥管)。待反應物完全溶解後，分批慢慢滴入三氟化硼***(boron trifluoride diethyl etherate，20ml，159mmol)。滴完後，繼續以75℃迴流四小時。回到室溫後，冰浴並加入碳酸氫鈉(約5.0 g)及20ml去離子水攪拌5分鐘，再以100ml飽合碳酸氫鈉水溶液萃取兩次，取下層有機溶液。再於40℃減壓濃縮後，真空抽隔夜，可得白色固體產物為化合物2 (15.8g, 98%)。In a 250 ml two-necked round bottom flask, 2-mercaptoethyl hydrochloride (6.0 g, 52.9 mmol), triphenylmethanol (13.0 g, 50.0 mmol) and 100 ml of chloroform were added followed by triethylamine (TEA, 10 ml). , 72.1 mmol) and the flask was placed in a 75 ° C oil bath to reflux the solution (dry tube required). After the reaction mixture was completely dissolved, boron trifluoride diethyl etherate (20 ml, 159 mmol) was slowly added dropwise in portions. After the completion of the dropwise addition, the mixture was further refluxed at 75 ° C for four hours. After returning to room temperature, it was stirred in an ice bath with sodium hydrogencarbonate (about 5.0 g) and 20 ml of deionized water for 5 minutes, and extracted twice with 100 ml of a saturated aqueous sodium hydrogencarbonate solution, and the organic layer was taken. After concentration under reduced pressure at 40 ° C, the title compound was obtained as a white solid (15.8 g, 98%).
化合物2之分析數據：Analytical data for Compound 2:
1 H-NMR(CDCl3 )：δ7.41 (m, 6H, 3*2*meta-Ph-H ), 7.23 (m, 9H, 3*2*ortho-Ph-H and 3*para-Ph-H ), 2.57 (t, 2H, C1 -H 2 ), 2.31 (t, 2H, C2 -H 2 ), and 1.34 (br, 2H, N-H 2 ) 1 H-NMR (CDCl 3 ): δ 7.41 (m, 6H, 3*2*meta-Ph- H ), 7.23 (m, 9H, 3*2*ortho-Ph- H and 3*para-Ph- H ), 2.57 (t, 2H, C 1 - H 2 ), 2.31 (t, 2H, C 2 - H 2 ), and 1.34 (br, 2H, N- H 2 )
HPLC(30%MeCN/0.1%TFA(aq) with gradient, 210nm, Merck Chromo- lith RP-18 100*4.6mm, 1.0ml/min)：6.53min, 95%HPLC (30% MeCN/0.1% TFA (aq) with gradient, 210 nm, Merck Chromo- lith RP-18 100*4.6 mm, 1.0 ml/min): 6.53 min, 95%
［N-[2-((Triphenylmethyl)thio)ethyl] chloroacetamide (化合物3)之合成］Synthesis of [N-[2-((Triphenylmethyl)thio)ethyl] chloroacetamide (Compound 3)]
於250ml圓底燒瓶中，依序取化合物2 (15.8g, 49.5mmol)、100ml二氯甲烷及TEA(13ml，93.7mmol)後，置於冰浴中。慢慢滴入已溶於10ml二氯甲烷當中之氯乙醯氯(chloroacetyl chloride，7.5ml，94.2mmol)溶液後，並在室溫下攪拌2小時。將50ml水緩緩倒入50ml 氯化氫水溶液，並以此溶液萃取反應液，取下層有機層。冰浴並加入碳酸氫鈉(約5.0 g)及20ml去離子水攪拌5分鐘，再以100ml飽合碳酸氫鈉水溶液萃取兩次，取下層有機溶液。再於30℃減壓濃縮後，真空抽隔夜，可得淡棕色固體產物為化合物3 (18.9g, 96%)17。Compound 2 (15.8 g, 49.5 mmol), 100 ml of dichloromethane and TEA (13 ml, 93.7 mmol) were sequentially taken in a 250 ml round bottom flask and placed in an ice bath. The solution of chloroacetyl chloride (7.5 ml, 94.2 mmol) dissolved in 10 ml of dichloromethane was slowly added dropwise, and stirred at room temperature for 2 hours. 50 ml of water was slowly poured into 50 ml of an aqueous hydrogen chloride solution, and the reaction solution was extracted with this solution, and the lower organic layer was taken. The mixture was stirred with ice water and sodium hydrogencarbonate (ca. 5.0 g) and 20 ml of deionized water for 5 minutes, and extracted twice with 100 ml of a saturated aqueous sodium hydrogencarbonate solution to remove the organic layer. After concentrating under reduced pressure at 30 ° C, the mixture was evaporated in vacuo to give a pale brown solid product as compound 3 (18.9 g, 96%).
化合物3之分析數據：Analytical data for Compound 3:
1 H-NMR(CDCl3 )：δ7.41 (m, 6H, 3*2*meta-Ph-H ), 7.23 (m, 9H, 3*2*ortho-Ph-H and 3*para-Ph-H ), 6.64 (br, 1H, N-H ), 3.98 (s, 2H, C5 -H 2 ), 3.15 (q, 2H, C1 -H 2 ), and 2.42 (t, 2H, C2 -H 2 ) 1 H-NMR (CDCl 3 ): δ 7.41 (m, 6H, 3*2*meta-Ph- H ), 7.23 (m, 9H, 3*2*ortho-Ph- H and 3*para-Ph- H ), 6.64 (br, 1H, N- H ), 3.98 (s, 2H, C 5 - H 2 ), 3.15 (q, 2H, C 1 - H 2 ), and 2.42 (t, 2H, C 2 - H 2 )
HPLC(40%MeCN/0.1%TFA(aq) with gradient, 210nm, Merck Chromo- lith RP-18 100*4.6mm, 1.0ml/min)：18.77min, 98%HPLC (40% MeCN/0.1% TFA (aq) with gradient, 210 nm, Merck Chromo- lith RP-18 100*4.6 mm, 1.0 ml/min): 18.77 min, 98%
［N-[2-((Triphenylmethyl)thio)ethyl] [2-((triphenyl-[N-[2-((Triphenylmethyl)thio)ethyl] [2-((triphenyl-)
methyl)thio) ethyl amino]acetamide (化合物4)之合成］Synthesis of methyl)thio) ethyl amino]acetamide (compound 4)
於250ml圓底燒瓶中，將化合物2(15.8g，49.5mmol)及化合物3(18.9g，47.8mmol)溶於100ml二氯甲烷，再加入TEA(9.5ml，68.5mmol)後，置於50℃之油浴鍋迴流72小時(須加乾燥管)。回至室溫後，冰浴並加入碳酸氫鈉(約5.0 g)及20ml去離子水攪拌5分鐘，再以100ml飽合碳酸氫鈉水溶液萃取兩次，取下層有機溶液。再於30℃減壓濃縮。分8次以液相層析分離純化(SiO2 ，ethylacetate：hexane = 1：1)，可得淡黃色油狀產物為化合物4 (14.7 g, 45%)。In a 250 ml round bottom flask, compound 2 (15.8 g, 49.5 mmol) and compound 3 (18.9 g, 47.8 mmol) were dissolved in 100 ml of dichloromethane, then TEA (9.5 ml, 68.5 mmol) was added and placed at 50 ° C The oil bath is refluxed for 72 hours (drying tube is required). After returning to room temperature, it was ice-cooled and added with sodium hydrogencarbonate (about 5.0 g) and 20 ml of deionized water for 5 minutes, and extracted twice with 100 ml of a saturated aqueous sodium hydrogencarbonate solution to remove the organic layer. It was concentrated under reduced pressure at 30 °C. It was isolated and purified by liquid chromatography (SiO 2 , ethylacetate: hexane = 1:1) to give compound 4 (14.7 g, 45%) as pale yellow oil.
化合物4之分析數據：Analytical data for Compound 4:
1 H-NMR(CDCl3 )：δ7.41 (m, 12H, 2*3*2*meta-Ph-H ), 7.23 (m, 18H, 2*3*2*ortho-Ph-H and 2*3*para-Ph-H ), 6.75 (br, 1H, C4 ON-H ), 3.07 (m, 2H, C1 -H 2 ), 3.02 (s, 2H, C5 -H 2 ), 2.42 (m, 2H, C6 -H 2 ), 2.31 (m, 4H, C2 -H 2 and C7 -H 2 ), and 1.57 (br, H, N-H ) 1 H-NMR (CDCl 3 ): δ 7.41 (m, 12H, 2*3*2*meta-Ph- H ), 7.23 (m, 18H, 2*3*2*ortho-Ph- H and 2* 3*para-Ph- H ), 6.75 (br, 1H, C 4 ON- H ), 3.07 (m, 2H, C 1 - H 2 ), 3.02 (s, 2H, C 5 - H 2 ), 2.42 ( m, 2H, C 6 - H 2 ), 2.31 (m, 4H, C 2 - H 2 and C 7 - H 2 ), and 1.57 (br, H, N- H )
HPLC(50%MeCN/0.1%TFA(aq) with gradient, 210nm, Merck Chromo- lith RP-18 100*4.6mm, 1.0ml/min)：12.39min, 96%HPLC (50% MeCN/0.1% TFA (aq) with gradient, 210 nm, Merck Chromo- lith RP-18 100*4.6 mm, 1.0 ml/min): 12.39 min, 96%
［N-[2-((Triphenylmethyl)thio)ethyl] 3-aza-18-[N-[2-((Triphenylmethyl)thio)ethyl] 3-aza-18-
ethyloxycarbonyl-3-[2-((triphenylmethyl)thio) ethyl]octadecanamide (H3 -MN 16-ET，化合物5)之合成］Synthesis of ethyloxycarbonyl-3-[2-((triphenylmethyl)thio) ethyl]octadecanamide (H 3 -MN 16-ET, compound 5)]
於250ml圓底燒瓶中，將化合物1(5.4g，14.9mmol)、化合物4(10.0g，14.7mmol)、氫氧化鉀(KOH，1.2g，21.4mmol)溶於100ml乙腈(MeCN)，再加入4g 4A分子篩後，置於95℃之油浴鍋迴流48小時(不加乾燥管並塞住)。回至室溫後，冰浴攪拌15分鐘，過濾取濾液。再於50℃減壓濃縮，再以真空抽隔夜。分2次以液相層析分離純化(SiO2 ，ethylacetate：hexane = 1：4)流至column無色後，再將沖堤液改成ethylacetate：hexane = 1：2，可得橘黃色油狀產物5 (H3 -MN 16-ET，2.7 g，26%)。In a 250 ml round bottom flask, Compound 1 (5.4 g, 14.9 mmol), Compound 4 (10.0 g, 14.7 mmol), potassium hydroxide (KOH, 1.2 g, 21.4 mmol) were dissolved in 100 ml of acetonitrile (MeCN) and then added. After 4 g of 4A molecular sieve, it was placed in an oil bath at 95 ° C for 48 hours (without drying tube and plugged). After returning to room temperature, it was stirred for 15 minutes in an ice bath, and the filtrate was filtered. It was concentrated under reduced pressure at 50 ° C, and then vacuumed overnight. After separation and purification by liquid chromatography (SiO 2 ,ethylacetate:hexane = 1:4) to the column colorless, the dyke solution was changed to ethylacetate:hexane = 1:2 to obtain an orange oily product. 5 (H 3 -MN 16-ET, 2.7 g, 26%).
化合物5之分析數據：Analytical data for Compound 5:
IR(neat)：νN-H = 3349 cm-1 ,νC=O = 1734 cm-1 ,νC=O = 1681 cm-1 IR(neat): ν NH = 3349 cm -1 , ν C=O = 1734 cm -1 , ν C=O = 1681 cm -1
1 H-NMR(CDCl3 )：δ7.44 (br, 1H, C4 CON-H ), 7.41 (m, 12H, 3*2*2* meta-Ph-H ), 7.23 (m, 18H, 3*2*2*ortho-Ph-H and 3*2*para-Ph-H ), 4.10 (q, 2H, C25 -H 2 ), 3.00 (q, 2H, C1 -H 2 ), 2.83 (s, 2H, C5 -H 2 ), 2.38 (m, 4H, C2 -H 2 and C23 -H 2 ), 2.23 (m, 4H, C7 -H 2 and C9 -H 2 ), 1.61 (m, 2H, C6 -H 2 ), and 1.29 (m, 29H, C10 -H 2 , C11 -H 2 , C12 -H 2 , C13 -H 2 , C14 -H 2 , C15 -H 2 , C16 -H 2 , C17 -H 2 , C18 -H 2 , C19 -H 2 , C20 -H 2 , C21 -H 2 , C22 -H 2 , and C26 -H 3 ) 1 H-NMR (CDCl 3 ): δ 7.44 (br, 1H, C 4 CON- H ), 7.41 (m, 12H, 3*2*2* meta-Ph- H ), 7.23 (m, 18H, 3 *2*2*ortho-Ph- H and 3*2*para-Ph- H ), 4.10 (q, 2H, C 25 - H 2 ), 3.00 (q, 2H, C 1 - H 2 ), 2.83 ( s, 2H, C 5 - H 2 ), 2.38 (m, 4H, C 2 - H 2 and C 23 - H 2 ), 2.23 (m, 4H, C 7 - H 2 and C 9 - H 2 ), 1.61 (m, 2H, C 6 - H 2 ), and 1.29 (m, 29H, C 10 - H 2 , C 11 - H 2 , C 12 - H 2 , C 13 - H 2 , C 14 - H 2 , C 15 - H 2 , C 16 - H 2 , C 17 - H 2 , C 18 - H 2 , C 19 - H 2 , C 20 - H 2 , C 21 - H 2 , C 22 - H 2 , and C 26 - H 3 )
13 C-NMR(CDCl3 )：δ174 (C 24 O), 171 (C 4 O), 140 (2*3*sub’d-Ph-C ), 129 (2*3*2*ortho-Ph-C ), 128 (2*3*2*meta-Ph-C ), 127 (m, 18H, 3*2*para- Ph-C ), 67 (C 3 andC 8 ), 60 (C 25 ), 58 (C 5 ), 55 (C 6 ), 54 (C 9 ), 38 (C 1 ), 34 (C 23 ), 31 (C 2 ), 29 (C 12 ,C 13 ,C 14 ,C 15 ,C 16 ,C 17 ,C 18 ,C 19 ,C 20 , andC 21 ), 27 (C 10 andC 11 ), 25 (C 7 andC 22 ), and 14 (C 26 ) 13 C-NMR (CDCl 3 ): δ 174 ( C 24 O), 171 ( C 4 O), 140 (2*3*sub'd-Ph- C ), 129 (2*3*2*ortho-Ph- C ), 128 (2*3*2*meta-Ph- C ), 127 (m, 18H, 3*2*para- Ph- C ), 67 ( C 3 and C 8 ), 60 ( C 25 ), 58 ( C 5 ), 55 ( C 6 ), 54 ( C 9 ), 38 ( C 1 ), 34 ( C 23 ), 31 ( C 2 ), 29 ( C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , and C 21 ), 27 ( C 10 and C 11 ), 25 ( C 7 and C 22 ), and 14 ( C 26 )
HPLC(80%MeCN/0.1%TFA(aq) with gradient, 210nm, Merck Chromolith RP-18e 100*4.6mm, 1.0ml/min)：6.73min, 93%HPLC (80% MeCN/0.1% TFA (aq) with gradient, 210 nm, Merck Chromolith RP-18e 100*4.6 mm, 1.0 ml/min): 6.73 min, 93%
［Ethyl 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-[Ethyl 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-
aza-19-oxononadecanoate (MN 16-ET，化合物6)之合成］Synthesis of aza-19-oxononadecanoate (MN 16-ET, compound 6)
將化合物5(2.7g，2.8mmol)、TFA(8ml)及三乙基矽烷(9ml，56mmol) 置於100ml圓底燒瓶中，以超音波震至反應物全溶後，在室溫攪拌2小時。上真空抽隔夜。以己烷(30ml)清洗及二氯甲烷(30ml)溶解，再於30℃濃縮反覆進行三次。上真空抽隔夜可得淡黃色油狀物為化合物6 (1.4g, 95%)。Compound 5 (2.7 g, 2.8 mmol), TFA (8 ml) and triethyl decane (9 ml, 56 mmol) were placed in a 100 ml round bottom flask, which was sonicated to the reaction mixture and then stirred at room temperature for 2 hours. . Vacuum on the night. It was washed with hexane (30 ml) and dissolved in dichloromethane (30 ml), and then concentrated three times at 30 ° C. A light yellow oil was obtained as a compound 6 (1.4 g, 95%).
化合物6之分析數據：Analytical data of compound 6:
IR(KBr)：νN-H = 3214 cm-1 ,νC=O = 1735 cm-1 ,νC=O =1681 cm-1 IR(KBr): ν NH = 3214 cm -1 , ν C=O = 1735 cm -1 , ν C=O =1681 cm -1
1 H-NMR(CDCl3 )：δ8.95 (br, 1H, C3 O-NH ), 4.13 (m, 4H, C23 -H 2 and C4 -H 2 ), 3.44 (m, 2H, C1 -H 2 ), 3.40 (br, 2H, 2*N-H -Cl), 3.06 (m, 2H, C2 -H 2 ), 2.85 (m , 2H, C6 -H 2 ), 2.29 (m, 6H, C5 -H 2 , C7 -H 2 and C21 -H 2 ), 1.82 (br, 2H, 2*S-H ), 1.64 (m, 2 H, C20 -H 2 ),1.36 (m, 2H, C8 -H 2 ), and 1.29 (m, 25H, C9 -H 2 , C10 -H 2 , C11 -H 2 , C12 -H 2 , C13 -H 2 , C14 -H 2 , C15 -H 2 , C16 -H 2 , C17 -H 2 , C18 -H 2 , C19 -H 2 , and C24 H 3 ) 1 H-NMR (CDCl 3 ): δ 8.95 (br, 1H, C 3 ON H ), 4.13 (m, 4H, C 23 - H 2 and C 4 - H 2 ), 3.44 (m, 2H, C 1 - H 2 ), 3.40 (br, 2H, 2*N- H -Cl), 3.06 (m, 2H, C 2 - H 2 ), 2.85 (m , 2H, C 6 - H 2 ), 2.29 (m, 6H, C 5 - H 2 , C 7 - H 2 and C 21 - H 2 ), 1.82 (br, 2H, 2*S- H ), 1.64 (m, 2 H, C 20 - H 2 ), 1.36 ( m, 2H, C 8 - H 2 ), and 1.29 (m, 25H, C 9 - H 2 , C 10 - H 2 , C 11 - H 2 , C 12 - H 2 , C 13 - H 2 , C 14 - H 2 , C 15 - H 2 , C 16 - H 2 , C 17 - H 2 , C 18 - H 2 , C 19 - H 2 , and C 24 H 3 )
13 C-NMR(CDCl3 )：δ173 (C 22 ), 164 (C 3 ), 60 (C 4 andC 23 ), 57 (C 5 ), 55 (C 7 ), 43 (C 1 ), 34 (C 21 ), 29 (C 10 ,C 11 ,C 12 ,C 13 ,C 14 ,C 15 ,C 16 ,C 17 ,C 18 , andC 19 ), 27 (C 8 ), 25 (C 2 andC 9 ), 24 (C 20 ) , 19 (C 6 ) and 14 (C 24 ) 13 C-NMR (CDCl 3 ): δ 173 ( C 22 ), 164 ( C 3 ), 60 ( C 4 and C 23 ), 57 ( C 5 ), 55 ( C 7 ), 43 ( C 1 ), 34 ( C 21 ), 29 ( C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , and C 19 ), 27 ( C 8 ), 25 ( C 2 and C 9 ), 24 ( C 20 ) , 19 ( C 6 ) and 14 ( C 24 )
［[N-(2-Thioethyl)-3-aza-19-ethyloxycarbonyl-3-(2-[[N-(2-Thioethyl)-3-aza-19-ethyloxycarbonyl-3-(2-
thioethyl)octadecanamido] oxorhenium (ReO-MN 16-ET，化合物7)之合成］Thioethyl)octadecanamido] oxorhenium (ReO-MN 16-ET, compound 7) synthesis]
於1000ml量瓶中，依序加入500ml去離子水及9.86ml 37%濃鹽酸後，加入去離子水使液面下緣貼近量瓶標示線。將此1000ml 0.1M 氯化氫水溶液保存於1000ml血清瓶中。將NH4 ReO4 (0.456g，1.7mmol)及酒石酸 (1.875g, 12.5mmol)溶於25ml去離子水中，並以氮氣泡驅趕溶液氧氣至少10分鐘。於25ml圓底燒瓶中，將氯化亞錫(0.323g，1.7mmol)溶於2ml 0.1M 氯化氫中，再將此溶液倒入前述之100ml圓底燒瓶中。於另一個100ml圓底燒瓶中，將化合物6(1g，1.7mmol)及TEA(11ml)溶於10ml無水乙醇後，將NH4 ReO4 －酒石酸－氯化亞錫溶液加入此乙醇溶液中。溶液在40℃下攪拌1小時。以陶瓷漏斗搭配矽藻土(Celite)過濾後，濾液以25ml氯仿萃取三次，合併下層萃取液於40℃減壓濃縮抽乾。殘餘物以液相層析分離純化(SiO2 ，ethylacetate：hexane = 1：2)，可得深紫色固體產物為化合物7 (920mg, 80%)。In a 1000 ml volumetric flask, 500 ml of deionized water and 9.86 ml of 37% concentrated hydrochloric acid were added in sequence, and deionized water was added to bring the lower edge of the liquid surface close to the measuring bottle line. This 1000 ml of 0.1 M aqueous hydrogen chloride solution was stored in a 1000 ml serum bottle. NH 4 ReO 4 (0.456 g, 1.7 mmol) and tartaric acid (1.875 g, 12.5 mmol) were dissolved in 25 ml of deionized water and the solution was purged with nitrogen gas for at least 10 minutes. In a 25 ml round bottom flask, stannous chloride (0.323 g, 1.7 mmol) was dissolved in 2 ml of 0.1 M hydrogen chloride, and the solution was poured into the above-mentioned 100 ml round bottom flask. In a separate 100 ml round bottom flask, after dissolving compound 6 (1 g, 1.7 mmol) and TEA (11 ml) in 10 ml of absolute ethanol, a solution of NH 4 ReO 4 -tartaric acid-stann chloride was added to the ethanol solution. The solution was stirred at 40 ° C for 1 hour. After filtration through a ceramic funnel and celite (celite), the filtrate was extracted three times with 25 ml of chloroform, and the mixture was combined and concentrated under reduced pressure at 40 ° C. The residue was purified by chromatography (SiO 2 , ethylacetate:hexane = 1:2) to give the product as dark purple solid as compound 7 (920mg, 80%).
化合物7之分析數據：Analytical data for Compound 7:
IR(KBr)：νC=O = 1733 cm-1 ,νC=O = 1662 cm-1 ,νRe=O =968 cm-1 IR(KBr): ν C=O = 1733 cm -1 , ν C=O = 1662 cm -1 , ν Re=O =968 cm -1
1 H-NMR(CDCl3 )：δ4.65 (d, 1H, C4 -H ), 4.58 (m, 1H, C5 -H ), 4.13 (m, 3H, C4 -H and C23 -H 2 ), 3.98 (m, 1H, C5 -H ), 3.55 (m, 2H, C1 -H 2 ), 3.35 (m, 2H, C7 -H 2 ), 3.25 (m, 3H, C2 -H 2 and C6 -H ), 2.85 (dd , 1H, C6 -H ), 2.29 (t, 2H, C21 -H 2 ), 1.79 (m, 2H, C8 -H 2 ), 1.64 (m, 4H, C9 -H 2 and C20 -H 2 ), and 1.29 (m, 23H, C10 -H 2 , C11 -H 2 , C12 -H 2 , C13 -H 2 , C14 -H 2 , C15 -H 2 , C16 -H 2 , C17 -H 2 , C18 -H 2 , C19 -H 2 , and C24 -H 3 ) 1 H-NMR (CDCl 3 ): δ 4.65 (d, 1H, C 4 - H ), 4.58 (m, 1H, C 5 - H ), 4.13 (m, 3H, C 4 - H and C 23 - H 2 ), 3.98 (m, 1H, C 5 - H ), 3.55 (m, 2H, C 1 - H 2 ), 3.35 (m, 2H, C 7 - H 2 ), 3.25 (m, 3H, C 2 - H 2 and C 6 - H ), 2.85 (dd , 1H, C 6 - H ), 2.29 (t, 2H, C 21 - H 2 ), 1.79 (m, 2H, C 8 - H 2 ), 1.64 (m , 4H, C 9 - H 2 and C 20 - H 2 ), and 1.29 (m, 23H, C 10 - H 2 , C 11 - H 2 , C 12 - H 2 , C 13 - H 2 , C 14 - H 2 , C 15 - H 2 , C 16 - H 2 , C 17 - H 2 , C 18 - H 2 , C 19 - H 2 , and C 24 - H 3 )
13 C-NMR(CDCl3 )：δ187 (C 3 ) 173 (C 22 ), 67 (C 4 ), 64 (C 5 andC 7 ), 60 (C 1 andC 23 ), 48 (C 2 ), 39 (C 6 ), 34 (C 21 ), 29 (C 10 ,C 11 ,C 12 ,C 13 ,C 14 ,C 15 ,C 16 ,C 17 ,C 18 , andC 19 ), 24 (C 20 ), and 14 (C 24 ). 13 C-NMR (CDCl 3 ): δ 187 ( C 3 ) 173 ( C 22 ), 67 ( C 4 ), 64 ( C 5 and C 7 ), 60 ( C 1 and C 23 ), 48 ( C 2 ), 39 ( C 6 ), 34 ( C 21 ), 29 ( C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , and C 19 ), 24 ( C 20 ), and 14 ( C 24 ).
MS m/z：677 [(M+1)+ ] and 675 [(M-1)+ ]MS m/z: 677 [(M+1) + ] and 675 [(M-1) + ]
HPLC(70%MeCN/0.1%TFA(aq) with gradient, 210nm, Merck Chromolith RP-18 100*4.6mm, 1.0ml/min)：10.17min, 96%HPLC (70% MeCN/0.1% TFA (aq) with gradient, 210 nm, Merck Chromolith RP-18 100*4.6 mm, 1.0 ml/min): 10.17 min, 96%
綜上所述，本發明詳細揭示了一種無放射性標準品ReO-MN 16-ET之製備方法，其產率可達75%以上，其透過移除H3 -MN 16-ET的硫端保護基而獲得MN 16-ET後，使用NH4 ReO4 進行反應以合成錯合物ReO-MN 16-ET，排除了過去使用Re(PPh3 )2 Cl3 為反應物時會產生的大量無用副產物，並且反應時間也大幅縮短。在產率以及所需時間都有長足的改善之下，總結而言，本發明無疑提供了一種充分展現經濟價值之一種無放射性標準品ReO-MN 16-ET之製備方法。In summary, the present invention discloses in detail a preparation method of a radioactive standard ReO-MN 16-ET, which has a yield of more than 75%, which removes the sulfur end protecting group of H 3 -MN 16-ET. After obtaining MN 16-ET, the reaction was carried out using NH 4 ReO 4 to synthesize the complex ReO-MN 16-ET, excluding a large amount of useless by-products which were produced when Re(PPh 3 ) 2 Cl 3 was used as a reactant in the past. And the reaction time is also greatly shortened. In summary, both the yield and the desired time are greatly improved. In summary, the present invention undoubtedly provides a process for the preparation of a non-radioactive standard ReO-MN 16-ET which fully demonstrates economic value.
惟以上所述者，僅為本發明之較佳實施例而已，並非用來限定本發明實施之範圍，舉凡依本發明申請專利範圍所述之形狀、構造、特徵及精神所為之均等變化與修飾，均應包括於本發明之申請專利範圍內。The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the variations, modifications, and modifications of the shapes, structures, features, and spirits described in the claims of the present invention. All should be included in the scope of the patent application of the present invention.
(5)~(7)‧‧‧化合物 (5)~(7)‧‧‧ compounds
Claims (6)
製備N-[2-((三苯甲基)硫基)乙基]-3-氮雜-18-乙氧羰基-3-[2-((三苯甲基)硫基)乙基]十八醯胺；
混合該N-[2-((三苯甲基)硫基)乙基]-3-氮雜-18-乙氧羰基-3-[2-((三苯甲基)硫基)乙基]十八醯胺、三氟乙酸(TFA)以及三乙基矽烷(triethylsilane)，經反應生成17-(2-硫乙基)-19-[(2-硫乙基)胺基]-17-氮雜-19-氧基十九烷酸乙酯；以及加入過錸酸銨於該17-(2-硫乙基)-19-[(2-硫乙基)胺基]-17-氮雜-19-氧基十九烷酸乙酯之中，經反應生成N-(2-乙硫基)-3-氮雜-19-乙氧羰基-3-(2-硫乙基)十八醯胺]錸錯合物，為無放射性標準品ReO-MN 16-ET。A method for preparing a non-radioactive standard product ReO-MN 16-ET, comprising the steps of:
Preparation of N-[2-((trityl)thio)ethyl]-3-aza-18-ethoxycarbonyl-3-[2-((trityl)thio)ethyl] Octaamine;
Mixing the N-[2-((trityl)thio)ethyl]-3-aza-18-ethoxycarbonyl-3-[2-((trityl)thio)ethyl] Octadecylamine, trifluoroacetic acid (TFA) and triethylsilane are reacted to form 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-nitrogen a hetero-19-oxopentanoic acid ethyl ester; and the addition of ammonium perrhenate to the 17-(2-thioethyl)-19-[(2-thioethyl)amino]-17-aza- Among the ethyl 19-oxydodecanoate, reacted to form N-(2-ethylthio)-3-aza-19-ethoxycarbonyl-3-(2-thioethyl)octadecylamine The 铼 complex is a radioactive standard ReO-MN 16-ET.
合成16-溴十六酸乙酯；
合成2-[(三苯甲基)硫基]乙胺；
混合該2-[(三苯甲基)硫基]乙胺、二氯甲烷以及三氟乙酸，室溫下攪拌後加入氯化氫溶液，經萃取後獲得N-[2-((三苯甲基)硫基)乙基]氯乙醯胺；
取該2-[(三苯甲基)硫基]乙胺以及該N-[2-((三苯甲基)硫基)乙基]氯乙醯胺溶於二氯甲烷後，再加入三氟乙酸，經50℃油浴迴流72小時後，依序透過萃取、濃縮以及液相層析分離純化，獲得N-[2-((三苯甲基)硫基)乙基][2-((三苯甲基)硫基)乙基胺基]乙醯胺；以及將該N-[2-((三苯甲基)硫基)乙基][2-((三苯甲基)硫基)乙基胺基]乙醯胺、該16-溴十六酸乙酯以及氫氧化鉀溶於乙腈，經95℃油浴迴流48小時後，依序透過萃取、濃縮以及液相層析分離純化，獲得該N-[2-((三苯甲基)硫基)乙基]-3-氮雜-18-乙氧羰基-3-[2-((三苯甲基)硫基)乙基]十八醯胺。The preparation method of claim 5, wherein the N-[2-((trityl)thio)ethyl]-3-aza-18-ethoxycarbonyl-3-[ In the step of 2-((trityl)thio)ethyl]octadecylamine, the steps are included:
Synthesis of ethyl 16-bromohexadecanate;
Synthesis of 2-[(trityl)thio]ethylamine;
Mixing the 2-[(trityl)thio]ethylamine, dichloromethane and trifluoroacetic acid, stirring at room temperature, adding a hydrogen chloride solution, and extracting to obtain N-[2-((trityl)) Thio)ethyl] chloroacetamide;
Taking the 2-[(trityl)thio]ethylamine and the N-[2-((trityl)thio)ethyl]chloroacetamide dissolved in dichloromethane, then adding three The fluoroacetic acid was refluxed in an oil bath at 50 ° C for 72 hours, and then purified by extraction, concentration and liquid chromatography to obtain N-[2-((trityl)thio)ethyl][2-( (tritylmethyl)thio)ethylamino]acetamide; and the N-[2-((trityl)thio)ethyl][2-((trityl))sulfide Ethylamino]acetamide, the ethyl 16-bromohexadecanate and potassium hydroxide are dissolved in acetonitrile, and refluxed in an oil bath at 95 ° C for 48 hours, followed by extraction, concentration and separation by liquid chromatography. Purification to obtain the N-[2-((trityl)thio)ethyl]-3-aza-18-ethoxycarbonyl-3-[2-((tritylmethyl)thio) Base] octadecylamine.
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| TWI609871B (en) * | 2016-07-18 | 2018-01-01 | 行政院原子能委員會核能研究所 | High performane liquid chromatography method for analysis of mn diagnostic and therapeutic ligand and precursor |
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