TW201105352A - H3LMN series of marker precursor of therapeutic agent for liver cancer and method of producing the same - Google Patents

Abstract

The present invention provides a H3LMN series of marker precursor of therapeutically agent for liver cancer and method of producing the same. According to the invention, initiators 2-thioethylamine hydrochloride and triphenylmethanol are used to perform thiol-protection reaction to form 2-[(triphenylmethyl)thio]ethylamine, which is reacted with chloroactyl chloride to undergo amidation reaction in order to form N-[2-((triphenylmethyl)thio)ethyl] chloroacetamide, which is reacted with 2-[(triphenylmethyl)thio]ethylamine to undergo a substitution reaction in order to form N-[2-((triphenylmethyl)thio)ethyl] [2-((triphenylmethyl)thio)ethylamino]acetamide, which is an amine-amide-thiol-containing ligand, which separately react with 1-bromotetradecane, 1-bromohexadecane and ethyl 16-bromohexadecanoate for separately obtaining H3LMN series of products. This type of amine-amidedithiol tetradentate organic ligands are reactive with MO3+ (M=Technetium or Rhenium) to undergo complex-forming reactions for producing electro-neutral complexes, which have high fat solubility and are soluble in Lipoid. These electro-neutral complexes can be used together with Lipoid for research on in vivo radioactive treatment of liver cancer.

Description

201105352 VI. Description of the Invention: [Technology Leading to the Invention] The present invention relates to a label precursor and a preparation method thereof, and more particularly to a liver cancer therapeutic agent precursor precursor *H3LMN series and a manufacturing method thereof. [Prior Art] [0002] 098126480 According to the fact that liver cancer is the most important cause of death in the country, according to the information released by the Department of Health, 7,809 people died of liver cancer in the Republic of China in 1996. Therefore, the prevention and treatment of liver cancer is an important topic in local medicine. Traditional treatments for cancer, such as surgical resection, chemotherapy and extracorporeal radiation therapy, have not yet yielded a satisfactory cure for liver cancer. It is particularly urgent to seek alternative and effective treatments for liver cancer. Lipiodol is an iodinated f millet oil. Studies at home and abroad have shown that liver cancer tissue has a significant intake of libido. Therefore, several researchers have tried to use the radioisotopes such as 131, ^9〇 and ^1 in Libido to apply them as tumor therapeutics. Among them, Libido 1-131, which has been used in Europe, is used in the treatment of liver tumors, and because of the high energy of the Bu 131 system, it will cause more than ',,, The total dose in the body 'at the same time - the price of 1-131 is higher than that of ^, and it is only used to imprison this, which limits its widespread use. The radioisotope 铢 is a kind of radiation, called max=2. 12Mev) and Gama (r = 155 KeV) of the box ", (for 16.9 hours. Because 铢-188 can be generator (ge / Tan, half-stage nerat 〇r) is easy to obtain, and its radiation energy and half-time are suitable for the diagnosis and treatment of diseases. It is a medical isotope with great development potential. It is in the radiotherapy of tumors. There will be a very heavy performance. Therefore, Libido containing 铢-188, J is an effective therapeutic agent for radiation therapy for liver cancer in vivo. Form No. A0101 Page 4 of 26 0982045393- 201105352 188Re-DD has High fat solubility, early hepatocyte uptake is quite good, but the retention in liver cancer cells is low. YS Lee, JM Jeong, YJ Kim, et a 1., Nucl. Med. Com-mu., 23, 237-242 (2002) shows that because the neutral 188Re-DD is in the cell body fluid, it will absorb a proton and become a positive ion. As shown in the first figure, it is hydrophilic and easy to be lost from the cell, so it is in liver cancer. The amount of retention in the cells is much lower than expected. ❹ [0003] , (Zi Lin, FL Liao, SL Wang., "Synth. React. Inorg. Met. Org. Chem., 27, 1 167-1 182 (1997). (1-carboethoxy-2-thioethy1) [ When N-(2-thioethyl) amino] aceta-mide (HL) and ReO(PPh) Cl are subjected to a wrong 40 L· Ο Ο reaction, two compounds are obtained, as shown in the second figure. ReOHL has electricity Sex, while ReOL is an anion with a negative charge, and ReOL is obviously formed by the loss of a proton by ReOHL. From this fact, it is believed that 188Re-DD may also lose a proton in the body fluid, become an anion and have water solubility. ' Mercaptan is easy to oxidize in neutral or alkaline state, especially the molecule of dithiol, its thiol is very easy to generate SS bond. In the molecule, if the SS bond is generated, SM will not be generated. M = Tc or Re) bonding, that is, it cannot be used to prepare liver cancer therapeutics. DADT (diamide dithiol) and BAT (bis-aminoethanethiol) are organic ligands commonly used to form complexes with sputum or sputum. The structure of MDT and BAT and its mismatch with chromium or bismuth as shown in the third A and third B, (M = T c or 098126480 Form No. A0101 Page 5 of 26 0982045393-0 201105352

Re), the present invention forms an electrically neutral complex when a three-proton on the amine, guanamine and thiol is simultaneously released to form a mismatch with M03 + (M = Tc or Re). The complex compound has good fat solubility due to long-burning base; it is easily soluble in libido and can be used as an effective therapeutic agent for radiation treatment of liver cancer in vivo [Abstract] [0004] 098126480 The main purpose of the present invention is The invention provides a liver cancer therapeutic agent standard weaving precursor HgLMN series and a manufacturing method thereof. The manufacturing method thereof is a long alkyl bond of a bond of tetradecyl, hexadecyl or hexadecyl acrylate, which enables recording or chromium The complex compound has high fat solubility and is soluble in libido, thereby increasing the effect of the band remaining in liver cancer cells. The second object of the present invention is to provide a liver cancer therapeutic agent standard weaving precursor hLMN series and a manufacturing method thereof, which use cp and a thiol diprotective group to improve the thiol to be easily oxidized, and thus cannot be combined with chromium or strontium. The problem of a mismatch reaction is chemically stable. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, In vivo radiation therapy. Method: 铢 铢 成 成 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : It is a thiol "base' to increase its solubility. Organic ligand can protect agent. The four of such amine-dithiols are electrically neutral complexes. Re) produces a mismatch reaction and forms Form No. A0101. The thiol in the nitrogen-sulfur ligand has a protective group of 6 pages/total 26 stomach _ 201105352 Protection to avoid oxidation, convenient, and the protective group is in the case of a mismatch reaction Can automatically detach. The chromium or ruthenium complex has high fat solubility due to its amino bond to the long alkyl bond of the ten-female, hexadecane or hexadecyl-ethyl ester, °' in Libie. Therefore, the organic ligand series are applicable to the label of chrome or bismuth, and can be used in combination with libido for radiation therapy in liver cancer. [Embodiment] [0005] In order to make the structural features of the present invention The understanding of the effects achieved is further understood and understood. The best examples and detailed explanations are given as follows:

The present invention utilizes DADT to misalign with M03+ (M = TC or Re) to release two protons and two protons on two thiols, so the complex is an anion; BAT and M03 + (M = or know) When the error is combined, only three protons are released, and the complex is electrically neutral. Moreover, the present invention synthesizes an amine, a chiral amine and a thiol AADT (monoamine-monamide dithiol), and finds that it forms a mismatch reaction with Μ03+(Μο-Tc or Re). The protons and the three protons on the sulphuric acid are released to form an electrically neutral complex, and the four protons on the amine, guanamine and thiol can be simultaneously released to form an anion complex. According to the above experience, the present invention synthesizes an N2S2 ligand consisting of a tertiary amine, a guanamine and a dithiol, and forms an electrically neutral complex with M03 + (M = Tc or Re). In this type of ligand, there are only three free protons which form a stable complex with Re03+. Such a complex compound is a subject of the present invention because it contains a long alkyl group, has good fat solubility, is easily soluble in Lipiodol, and is suitable for in vivo radiation therapy for liver cancer. Furthermore, mercaptan is easily oxidized and needs protection. Commonly used protecting groups are 098126480 0982045393-0 Form No. A0101 Page 7 of 26 201105352 C〇C6H5, CH2C6H4〇CH3 and CPh3, etc. The protecting group of the thiol must be removed prior to the mismatch reaction. For example, with (3) and % as the protecting group, before the mismatching reaction, mag3 must be hydrolyzed in an alkaline solution to remove the protecting group. In the present invention, we use (3)^ as a thiol protecting group, and this protecting group can be automatically detached in the case of a mismatch reaction without removing it in advance to make the use of the difunctional compound more convenient. Referring to Figures 4A and 4B, a manufacturing flow diagram and a reaction equation diagram of a preferred embodiment of the present invention are shown. As shown in the figure, the present invention provides a liver cancer therapeutic agent precursor precursor *h3lmn series and a manufacturing method thereof, the steps of which include: Step S10 '2-aminoethanethiol (C1) as a starting reactant, first sulfur The protective reaction of alcohol produces 2-[(Triphenylmethyl)thio]ethylamine (C6); Step S20, followed by esterification with chloroethane gas (C8) to obtain [2-((Triphenylmethyl)thio) [0006] ethyl Chloroacetamide (C9 j ; Step S30, Compound C6 is substituted with Compound C9 to form the intermediate N-[2-((Triphenylmethyl)thio)ethyl] [2-((triphenylmethyl)thio) ethyl-amino] [0007] acetamide (Cl 0); and in step S40, the compound CIO is substituted with 1-bromotetradecane (Cll), 1-bromohexadecane (C15) and ethyl 16-bromohexadecanoate (C17), respectively, and after separation and purification, the HQLMN series product [N- 〇[2-((triphenylmethyl)thio)ethyl] 098126480 Form No. A0101 Page 8 of 26 0982045393-0 201105352 3-aza-3-[2-((triphenylmethyl)thio)ethyl] [0008] heptadecanamide (H) LMN-14) (C14), N- 0 [2-((triphenylraethyl)thio)ethyl] 3-aza-3-[2-((triphenyl) Methyl) thio)ethy1]nonadecanamide (H LMN-16) (C16) ό and N-[2-((triphenylmethyl)thio)ethyl] 3-aza-18-ethyloxycarbony1-3-[2-((triphenylmethyl) thio) Ethyl] octadecan-〇amide (H3LMN-16ET) (C18)] H 3 L Μ N series (C14, C16 and C18) are tetrachelone organic ligands of amine-guanamine-dithiol 'H, LMN When the series is chelated with M03+, ό 'coexistes three protons to form electric neutralization. The Μ03 + is selected from the following Tc-99, Tc-99ro, Tc-95m, Re-186 and One of the groups consisting of Re-188. The complex M〇-HAMN has no protons that can be re-released, nor is it capable of accepting foreign protons. That is to say, the complex MO-H, LMN cannot be converted into an anion in any environment. Or cationic and hydrophilic. This property can increase the retention of MO-H3LMN in liver cancer cells. In addition, the long alkyl group can promote the fat solubility of MO-H3LMN, increase the affinity with ribidol, and increase the effect of retention in liver cancer cells. The removal of the thiol protecting group CPh3 is carried out by dissolving H3LMN in trifluoroacetic acid and adding an excess of triethoxymethane. Then, CP is separated from the mercaptan to form a solid insoluble in difluoroacetic acid, which can be removed by filtration or used. The method of alkane cleaning is simple. If you want h3lmn to form a complex with ruthenium or chrome, then the thiol protection group can be 098126480. Form No. A0101 Page 9 / Total 26 Page 0982045393-0 201105352 H3LMN can be directly mismatched with bismuth or chromium without prior removal. The reaction forms a complex of hydrazine or hydrazine, and the protecting group cph of the thiol is automatically detached in the erroneous reaction. The complexes of chromium and strontium are electrically neutral, fat-soluble and easily soluble in libido. Therefore, Re-1 88 can be used as a marker and dissolved in libido to study the treatment of liver cancer. Wherein, in step S10, the synthesis of 2_[(Tripheny lmethyl )thio] ethyl amine (C6) is taken as 2-thi〇ethylamine hydrochloride (Cl) (5 8^4.0 mmol) » tripheny lmethanol (C2) (11.5 g' 44.0 mmol) and triethyiajnine (C3) (7.4 mL, 52. 8 mmol), co-dissolved in trichloromethane (C4) (80d. Slowly drip into the catalyst borontrifluor ethyl ether complex (C5) (14) 9 mL, 118.8 mmol), heating and refluxing for 4 hours. After cooling, it was washed with aqueous sodium hydrogen carbonate (2×100 mL), and the organic phase was evaporated. 〇To verify the synthesis result of C6, IR (neat) 3381 (NH2) cm-1.NMR (CDC13) 7. 42 (m, 3 Η,

Ph), 7.30 (m, 12 H, Ph), 2.58 (t, J = 6.6 Hz, 2 H, CH2N), 2. 32 (t, J = 6. 6 Hz, 2 H, CH2S), 1.45 (br , 2 H, NHJ. 13C NMR (CDC1 ) L o 144.80, 192.52, 127.81 and 126.60 (Ph), 66.51 (CPh), 40.94 (CH9N), 36.09 (CHS). MS m/z 319 (M+), 243 ( M+ - C6H5+ 1) wherein, in step S20, [2-((Triphenylmethyl)thio)ethyl] chloroacet- 098126480 Form No. A0101 Page 10 of 26 page 0982045393-0 201105352 amide (C9) synthesis, Compound C6 (9.2 g, 28.9 mmol) was dissolved in trimethylmethane (C7) (l〇〇mL) with triethylamine (C3) (4.8 mL, 34·7 匪ol). In an ice bath, slowly Dilute the solution of chloroacetyl chloride (C8) (2.8 mL, 34.7 mmol) in anhydrous di-methane (C7) (10 mL). After the dropwise addition, stir at room temperature for 2 hours, then use the following to clean organically. Phase: 2N HCl aqueous solution 'saturated aqueous solution of sodium carbonate. The organic phase was concentrated under reduced pressure of Na 2 EtOAc EtOAc (EtOAc) EtOAc (EtOAc) NH), 1662 (CO) cm-1. ]H NMR (CDC1 ) . 3 7.41 (m, 3 H, P h), 7.24 (m, 12 H, Ph), 6.48 (br, 1 Η, NH), 3.97 (s, 2 H, CH0C1), 3.12 L ;'.; (q,J = 6.3 Hz, 2 H, CH2N), 2.43 (t, J = 6.3 Hz, 2 H, CH2S).13C NMR (CDC13) 165.63 (CO), 144.47, 129. 48,1 27. 97 and 126.81 (Ph), 66.52 <CPh), 42.54 (CH0C1), 38.35 (CH2N), 31.67 (CH2S). MS m/z 397 and 395 (M+), 243 ((CPhJ + ). o where, in step S30, [2-((Triphenyl methyl)) Synthesis of thio)ethyl][2-((triphenylmethy1)thio)ethyl-amino]acetam ide (CIO), compound C9 (11.2 g, 28.3 mmol) and compound C6 (9.0 g, 28.3 mmol) are dissolved in anhydrous Digastric (C7) (100 mL), then triethyamine (C3) (6 mL, 42.5 mmol) was added and heated to reflux for three days. After cooling, 098126480 Form No. A0101 Page 11 / Total 26 Page 0982045393-0 201105352 3Aqueous solution is washed and the organic layer is taken. The organic phase was dried over Na EtOAc (EtOAc) (EtOAc) To verify the synthesis results of CIO, IR (neat) 3330 (NH), 1 670 (CO) cm-1. NMR (CDC1) 7.42 3 (in, 4 H, HNCO and Ph), 7.20 (m, 12 H, Ph ), 3.07 (m, 4 H, CH2NC0 and CH2C0), 2.38 (m, 6 H, CH2NHCH2C0 and CH2S), 1.94 (br, 1 H, NHCH2C0).13C NMR (CDC13) 170.84 (CO), 144.61, 129.47, 127. 88 and 126.69 (Ph), 66.72 and 66.65 (CPh„), 51. 62 (CHoC0), 48.19 (CH2NHCH2CO), 37.70 (CH2NHC0), 32.12 and 31.97 (CHS). MS m/z 243 ((CPHJ + B3 [0009] wherein, in step S40, 忖-[2-((Triphenylmethy1) thievethy 1 ] 3-aza-3-[2-((triphenyl methyl) thio)ethyl]nonadecanafflide (HqLliN-14) (C14) Synthesis of compound CIO (3.2 g, 4.2 mmol), 1-bromotetradecane (Cll) (2.3 mL, 8.4 mmol) and KOH (C12) (0.3 g, 5.0 mmol) in acetonitrile (C13) (60 mL), heated under reflux for 24 hours, suction filtered, and the filtrate was taken; concentrated under reduced pressure and purified by liquid chromatography (Si〇9, ethyl acetate: L. hexane = 1 : 1) , produced *HQLMN-14 (C14) (1·6 g, 43.2%). Verification of the synthesis result of C14, IR (neat) 33 50 098126480 Form No. A0101 Page 12 of 26 0982045393-0 (NH), 1681 (CO) οιη-1.^ NMR (CDC1) o 7.22- 7.16 (m, 31 Η, NH and Ph), 3.0 (q , J = 6.3 Hz, 2 H, CH2NH), 2.84 (S, 2 H, CH2C0), 2.4h2.20 (m, 8H, CH2SandCOCH2N(CH2)2), 1.26 (m, 22 H, (CHJ^CHJ, 0.88 (t, J = 6.9 Hz, 3 H, CHJ. 13C NMR (CDC1J 171.23 (CO), 0 o 144.73, 144.69, 129.49, 127.85, 1 26.63 and 126.61 (Ph), 66.69 and 66.63 (CPh), 58.23, 54.82, 53.78, 37.87, 31.95, 31.88, 29.97, 29.66, 29.61, 29.47, 27.27, 22.65 (CHJ,

L 14.09 (CHQ). MS m/z 243 ((CPh,)+). Ο i wherein, in step S40, [2-((Triphenylmethyl)thio)eLhyl] 3-aza-3-[2-((triphenylmethy1) thio)ethy1]nonadecanamide (H LMN-16 ) (C16) Synthesis, taking compound C.1.0 (;3.4. g, 5.:0,.mmol), 1-bromohexadecane (C15)... (6.2 g, 20.3 mmol) and K0HCC12) (0.3 g, 6.1 mmol) Dissolved in acetonitrile (C13) (80 mL), heated under reflux for 72 hours, filtered, concentrated under reduced pressure, and then purified by liquid chromatography (Si〇2, ethyl acetate: hexane = 1 : 4) to yield *H3LMN -16 (C16) (3.2 g, 70°/〇). To verify the synthesis result of C16, IR (neat) 3350 (NH), 1681 (CO) οπι-1.^ NMR (CDC1) ό 7.22- 7.16 (m, 31 H, NH and Ph), 3.0 (q, J = 6.3 Hz, 2 H, CH2NH), 2.84 (S, 2 H, CH2C0), 2.4m 〇 (m, 8H, CH2SandCOCH2N(CH2)2), Form No. A0101 Page 13 of 26 〇98ί 201105352 1.26 (m , 28 H, (CHJ, XHJ, 0.88 (t, J = 6.9 Hz, 3 H, CH3).13C NMR (CDC13) 171.21 (CO), 144.71, 144.68,1 29.50, 1 27.85,1 26.64 and 126.61 (Ph ), 66.72 and 66.63 (CPh), 58.18, 54.79,53.76,37,88,31.91,31.88,29.66, 29.62,29.46,29.31,27.25,22.64 (CH2), 14.09 (CH3). MS m/z 243 (( CPh3)+). wherein, in step S40, Tri- ΐ^ 2-((Tripheny lmethy 1 HhicOethylD-aza-lQ-COOlO) ethyloxycarbonyl-3-[2- [0011] ((triphenylmethyl)thio)ethyl]octadecanamide (H3LMN-16ET) (C18) Synthesis of compound CIO (3.6 g, 4.8 mmol), ethyl 16-bromohexadecanoate (C17) (2.1 g, 5.8 mmol) and K0H (C12) (0.34 g, 6.1 mmol) ), co-dissolved in acetonitrile ((; 13) (80 mL), heated under reflux for 48 hours, concentrated, concentrated under reduced pressure, in liquid phase The analytical method (Si09,ethyl acetate: hexane = 1 : 4) was purified to give the oily product H3LMN-16ET (C18) (2.4 g, 48%). To verify the synthesis result of C18, IR (neat) 3349 ( NH), 1734 and 1681 (CO) cm-1. !H NMR (CDC1) u 7.25-7.18 (m, 31 Η, NH and Ph), 4.10 (q, J = 7.2 Hz, CHCHJ, 3.0 (q, J = 6. 3 Hz, 2 L 〇H, CH2NH), 2.83 (S, 2 H, CH2C0N), 2.30-2.20 (m, 10 H, CH2S, SCH2CH2N, CH2CH2CH2N and CH2COOEt), 1.61 (m, 2 H, CH2CH2CH2N ), 1.24 098126480 Form No. A0101 Page 14 of 26 Page 0992045393-0 201105352

(m, 31 H, CH2CH2(CH2)12CH2COOCH2CH3).13C NMR (CDC13) 173.82 and 171.22 (CO), 144.70, 144.65, 129.47, 127.81, 127.52, 126.59 and 126.57 (Ph), 66.66 and 66.60 (CPh), 60.05 , m.z. (M. CPh3)+). Furthermore, the present invention discloses that the HQLMN series and the M03+ chelation reaction are described in the example of [N-(2-Thioethy!) 3-aza-3-[0012] (2-thioethyl)nonadecanamido For example, the synthesis of oxorhenium (V) (ReOLMN-16) (C21), see the fifth figure, taking the compound H3LO-16 (C16) (0. 68 g, 0. 76 mmol),

ReO(PPh3)2Cl3(C19) (0.76 g, 0.9 mmol) and triethylamine (C3) (0.38 g, 3.8 mmol), dissolved in methanol (C20) (50 mL), heated overnight at 55 ° C, filtered After the reaction mixture was evaporated to dryness, the residue was evaporated to mjjjjjjjjjjjjjjjjjj The product (Si 〇, 2 ethyl acetate : hexane = 1 : 2) was isolated and purified to give red brown oily product ReOLMN-16 (C21) (93.8 mg, 20%). To verify the synthesis result of C21, IR (neat) 1664 (CO), 967 (ReO) cm-1. !H NMR (CDC13) 4. 64 (d, J = 16.5 Hz, 1 H, CH2C0), 4.56 (dd , J = 3.9 and 1.2 Hz, 1 H, CH2NC0), 4. 12 (d, J = 16. 5 Hz, 1 H, CH2C0)' 4.06 (m,1 H, 098126480 Form No. A0101 Page 15 of 26 Page 0982045393-0 201105352 NCO), 3.86 (m,1 H,CH2(CH2)14CH3), 3.48 (m, 1 H, CH2(CH2)14CH2), 3. 35 (m, 1 H, CH2CH2NCH2CO), 3.21 ( m, 3 H, CH2CH2NCOCH2NCH2CH2S), 2.86 (dd, J = 13.8 and 4.8 Hz, 1 H, SCH2CH2NCH2CO), 1.78 (m, 2 H, CH2CH2CH2N), 1.58 (m, 1 H, SCH2CH2NCH2CO), 1.40-1.20 (m , 26 H, (CH2)13CH3), 0.88 (t, J = 6. 6 Hz, 3 H, CHq). 13C Li R (CDC1J 187.07 (CO), 67.05, 63.94, 63.88, 59.77, 47.76, 38.81, 31.89 , 29.62, 29. 54, 29. 42, 29.36, 29.32, 29.21, 26.77, 23.60 and 22.65 (CH)' 2 14. 09 (CH3). MS m/z 618 and 616 (M+). An example showing the H3LMN series and the M03+ chelation reaction is described as [N-(2-Thioethyl)3-aza-19-ethyloxycarbonyl-3- - . . . . . . : .-:-- · * [0013] (2-thioethy 1 ) octadecanamido] oxorhenium (V) (ReOLMN-HET) (C22) winter life into an example, please refer to the sixth figure 'take compound H3LMN-16ET (C18) (0. 77 g, 0. 8 mmol) · ReO(PPh3)2Cl3(C19) (0.76 g, 0.9 mmol) and triethylamine (C3) (0.38 g, 3.8 mmol), co-dissolved in decyl alcohol (C20) (50 mL) 'When heating at 55 °C overnight, filter the reaction solution to reduce pressure? Prepare dry'. Dissolve the residue with squid (C4) (30 mL), wash with water (30 mL), and use anhydrous sodium sulfate. After removal by water, concentration under reduced pressure and separation and purification by liquid chromatography (Si 〇 2, ethyl acetate : hexane = 1 : 2) was obtained as reddish brown oily product Re〇LMN_16ET (C22) (119 098126480 Form No. A0101 No. 16 Page / Total 26 pages 0982045393-0 201105352 mg, 22%). To verify the synthesis result of C22, IR (neat) 1 733 and 1 662 (CO), 968 (ReO) cm'1. !H NMR (CDC13) 4.65 (d, J = 16.5 Hz, 1 H, CH2C0N), 4.12 (m, 4 H, CH2CH3, CH2C0 and CH2CH2NC0), 3.98 (m, 1 H, CH2CH2CH2N), 3.56 (m, 1 H, CH2CH2CH2N), 3.36 (m, 1 H, SCH.CHNCH.CO), 3.21 (m , 3 H, L· u L· Ο CH2CH2NCOCH2NCH2), 2.85 (dd, J = 13.5 and 4.2 Hz, 1 H, SCH2CH2NCH2CO), 2.29 (t, J = 7.2 Hz, 2 H, CH2C00), 1.79 (m , 2 HnCH2(CH2)13COO), 1.60 (m, 1 H, SCH9CHoNGHoC0), 1.20-1.10 (m, 25 H, (CH2)12CH2C00CH2CH3).13C NMR (CDC13) 187.10 and 173.90 (CO), 67. 05, 63.95, 63.87, 60.1 1, 59.77, 47.76, 38.81, 34,35, 29.66, 29.55, 29.53, 29.40, 29.34, 29.21, 29.1 9, Ο 29.10,26.75,24.94,23.59 (CH2),14.22 (CH3). MS m/z 6T6 and 674: (M+). The advantages of the present invention are as follows: 1. The method for synthesizing the liver cancer therapeutic agent precursor precursor H LMN series of the present invention 0 The N S9 ligand composed of a tertiary amine, a guanamine and a dithiol, can be used as L·L· The key is recorded or 铢' applied as a nuclear medicine. 2. The synthesis of the liver cancer therapeutic agent precursor precursor H LMN series of the present invention, which contains only three free protons in such a ligand, and can form an electrical neutrality with M〇3 + (M = TC or Re). The complex is suitable for the preparation of nuclear medicine. 3. The method for synthesizing the liver cancer therapeutic agent η LMN series of the invention has the CPh3 protection, and the thiol is easily oxidized, so that the form number A0101 is a 0 201105352 The problem of mismatching with chromium or bismuth is chemically stable and easy to store. 4. The method for synthesizing the liver cancer therapeutic agent precursor precursor H3LMN series of the present invention, the thiol protecting group 0?\ can be automatically detached when it is subjected to a miscible reaction with chromium or bismuth, without prior removal. 5. The method for synthesizing the liver cancer therapeutic agent precursor precursor H3LMN series of the present invention bonds a long alkyl bond of tetradecyl, cetyl or ethyl hexadecanoate to make the complex of ruthenium with high fat Soluble, soluble in libido. 6. The method for synthesizing the liver cancer therapeutic agent precursor precursor H 3 L Μ N series of the present invention can increase their retention in liver cancer cells. In addition, the long alkyl group can promote the fat solubility of MO-HJMN, increase the affinity with libido, and increase the effect of retention in liver cancer cells. In summary, the present invention is a novelty, progressive and available for industrial use, and should conform to the patent application requirements stipulated in the Patent Law of China, and the invention patent application is filed according to law. Quasi-profit, to the feeling of prayer. However, the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the shapes, structures, features, and spirits described in the claims are equivalently changed. Modifications are intended to be included in the scope of the patent application of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS [0014] The first figure is a reaction equation diagram of 188Re-DD which is a positive ion in the prior art; the second figure is a conventional technique! ^- (l-carboethoxy) -2-thioethyl)[N-(2-thioethyl)a mino] aceta-mide O^L) is mismatched with ReCKPPWClqi anti 4 ό Δ ο 098126480 Form No. 1010101 Page 18 of 26 0982045393-0 201105352 Response Equations; 苐3A to 3C. The system is aa. 糸 is the reaction equation of the n2s2 ligand and its complex (M = Tc or Re) of the known technology; Figure: is the invention

Heart - Manufacturing Flow Chart of the Label Precursor H LMN Series of the Preferred Embodiment; Fourth Diagram: Figure 5 is a reaction equation diagram of the h3lmn series of the flag precursor of the preferred embodiment of the present invention; : is the standard precursor of the preferred embodiment of the present invention [the problem _ u 16 and Re reaction equation diagram; and the sixth diagram: one of the present invention compared to the embodiment of the flag precursor LLMN-3 16ET and Re reaction equation diagram. , [Main component symbol description] [0015] No I» ◎ c:n 098126480 Form No. A0101 Page 19 of 26 0982045393-0

Claims (1)

201105352 VII. Patent application scope: 1. A liver cancer therapeutic agent precursor precursor H3LMN series, which includes: Wherein R is selected from one of (ch2)i3ch3, (ch2)15ch3&(CH2)15C00C2H5. For example, the precursor of the cancer cancer agent described in the first paragraph of the patent application HgLMN series, wherein the j^lMN series of compounds can be dissolved in libido, combined with libido for radiation therapy in liver cancer. A method for producing a liver cancer therapeutic agent precursor precursor h3lmn series, the steps comprising: reacting 2-thioethylamine hydrochloride with CPh, 幵i into 2-[(triphenylmethyl)thio]ethyl'.ami ne; [(tripheny lmethyl )thio]ethy lamine ) and chloroacty 1 ch lor ide are subjected to amidation by tri ethyl amine to form N-[2-((triphenylmethyl)thio)ethyl] chloroacetamide; (tripheny lmethyl )thio]ethy lamine reacts with the N-[2-((triphenylmethyl)thio)ethyl] chloroacetamide to form an amine-melamine-thiol-containing ligand N-[2-((triphenylmethyl)thio)ethyl [2-((triphenylmethyl)thio)ethylamino]acetamide 098126480 Form No. A0101 Page 20 of 26 0982045393-0 201105352 The N-[2-((triphenylmethyl.)thio)ethyl] [2-((triphenyl) Methyl) thio)ethylamino]acetamide reacts with 1-bromotetradecane, 1-bromohexadecane and ethyl 16-bromo-hexadecanoate to obtain H LMN series productsΟ 4. The manufacturing method according to claim 3, further comprising a reaction of synthesizing M03 + with HQLMN series, the steps comprising: 取 taking elbow 03+ and 1131^1^ to react to generate M0- The method of manufacturing the method of claim 4, wherein the M03+ is selected from the following Tc-99, Tc. One of a group of -99m, Tc-95m, Re-186, and Re-188. 6. The production method according to claim 4, wherein the reaction is carried out in a decyl alcohol solution using triethyamine as an acid scavenger. 7. The production method according to claim 3, wherein in the step 0 of reacting 2-thioethylamine hydrochloride with CPh, triammonium alcohol is used as a reactant, and boron trifluoride etherate complex is used as a catalyst. 9. The method of claim 3, wherein in the step of subjecting the 2-[(triphenylmethy1)thio]ethylamine) to chi oroacty 1 chloride under the action of a triethyl amine, The reaction was carried out in an anhydrous dioxane solution using chloroactyl chloride as the reactant. The manufacturing method according to claim 3, wherein the 098126480 form number A0101 page 21/26 pages 0982045393-0 201105352 2-[(1:1^口11611丫111161;1171)1; ^〇]61:1171&1111116 In the step of reacting with N-[2-((triphenylmethyl)thio)ethyl] chloroacetamide, the reaction is carried out in an anhydrous dichloromethane solution using triethyamine as an acid scavenger. 10. The production method according to claim 3, wherein the N-[2-((triphenylmethyl)thio)ethyl] [2-((triphenylmethyl) thicOethylami no]acetamide and 1-bromotetradecane, 1- The brofflohexadecane or ethyl 16-bromo-hexadecanoate reaction step is carried out by using KOH as the acid scavenger and reacting in acetonitrile. 098126480 Form nickname A0101 Page 22 of 26 0982045393-0