TWI364296B

TWI364296B -

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Publication number: TWI364296B
Application number: TW98123679A
Authority: TW
Priority date: 2009-07-14
Filing date: 2009-07-14
Publication date: 2012-05-21
Also published as: TW201102093A

Description

1364296 __,_ 101:年.03月ok日修正脊換頁六、發明說明：【發明所屬之技術領域】 [0001] 本發明係有關於一種標幟前驅物製備方法，其尤指一種製備標幟前驅物Ν,Ν’ -二（三甲基曱氧羰）-3-(三正丁基錫）苯曱胍（N，Ν’ -bis(tert-butyloxycarbony1)-3 [0002] -(tri-n-butyIt in)benzyl guanidine) (MSnBG)之方法。 • [0003] 【先前技術】按，自從於1 980年代被發現，3-碘苯甲胍 (3-iodobenzylguanidine ， MIBG)之1-123與1-131標幟產物（[1231]讨^〇與[1311]11^〇就廣泛應用於心臟疾病及神經母細胞瘤（neuroblastoma)等之核醫造影劑，協助疾病之正確診斷。此外，由於1-131之半化期為 80.5日，蛻變時釋出之能量為0.97 MeV，可應用於Μ瘤之放射治療，因此[1311 ]MIBG亦應用於神經母細胞瘤等 • 之標靶放射治療》長久以來，放射性碘標幟之3-碘苯曱胍 ([*1 ]MIBG)之製備，全係使用同位素交換法（isotopic exchange method)標幟碘 1-131 或 1-125，如第一圖所示。此法所得之產物，除含有具活性碘的MIBG外，尚含大量起始反應物天然碘MIBG。兩者無法分離，以致在應用為腫瘤治療劑時，這種混合物在注射進入人體後， [*I]MIBG與MIBG相互競爭可結合之受體。由於mibg之量遠大於[*I]MIBG，因此受體大量被MIBG佔據，致使有第3頁/共16頁 1013079372-0 0981236淨單編號删1 1364296 | ioim〇3^ 02 a 藥效之[* I ] ΜIBG不能完全發揮功能，也會影響放射治療之藥理效應。雖然文獻上G. Vaidyanathan，D. J. Affleck, K. L. Alaton and M. R. Zalutsky, J. Label.1364296 __, _ 101: year. March ok day correction ridges page six, invention description: [Technical field of invention] [0001] The present invention relates to a method for preparing a precursor of a label, which particularly refers to a preparation flag Precursor Ν, Ν'-bis(trimethylhydrazine)-3-(tri-n-butyltin)benzoquinone (N,Ν'-bis(tert-butyloxycarbony1)-3 [0002] -(tri-n- ButyIt in)benzyl guanidine) (MSnBG) method. • [0003] [Prior Art] According to the discovery of 1-iodobenzylguanidine (MIBG) 1-123 and 1-131 label products since the 1980s ([1231] [1311]11^〇 is widely used in nuclear medicine and neuroblastoma and other nuclear medicine contrast agents to assist in the correct diagnosis of the disease. In addition, since the half-ization period of 1-131 is 80.5 days, the metamorphosis is released. The energy is 0.97 MeV, which can be applied to the radiotherapy of tumors. Therefore, [1311] MIBG is also applied to the target radiotherapy of neuroblastoma, etc.] 3-iodobenzoquinone of radioactive iodine label for a long time. ([*1]MIBG) was prepared using the isotopic exchange method for the iodine 1-131 or 1-125, as shown in the first figure. The product obtained by this method contains active iodine. In addition to MIBG, there is a large amount of the initial reactant natural iodine MIBG. The two cannot be separated, so that when applied as a tumor therapeutic agent, this mixture can be combined with MIBG after injection into the human body. [*I]MIBG competes with MIBG. Receptor. Since the amount of mibg is much larger than [*I]MIBG, the receptor is largely MIBG. According to the report, there is a third page / a total of 16 pages 1013079372-0 0981236 net order number deletion 1 1364296 | ioim〇3 ^ 02 a efficacy [* I ] Μ IBG can not fully function, it will also affect the pharmacological effects of radiation therapy. Although in the literature G. Vaidyanathan, DJ Affleck, KL Alaton and MR Zalutsky, J. Label.

Comp. Radiopharm·，50，177-182 (2007)有類似標幟前驅物的研究報告’但其所揭示之製備方法為D. S.Comp. Radiopharm, 50, 177-182 (2007) has a research report similar to the precursor of the label 'but the method of preparation disclosed is D. S.

Dodd and A. P. Kozikowski, Tetrahedron Lett.， 35， 977-979 (1994)與G. Vaidyanathan and M. R. Zalutsky, J. 〇rg. Chem., 62， 4867-4869 (1997) ’如第二圖所示》此外，該標幟前 ® 驅物（C14)之離去基為（CH3)3Sn。【發明内容】本發明之主要目的，係在於提供一種製備標幟前驅物N，N’ -二（三曱基曱氧羰）-3-(三正丁基錫）苯甲胍 (N,N -bis(tert-butyloxycarbony 1) -3-(tri-n-buty1tin)benzylguanidine) (MSnBG) 之方法’其係使用Bu3Sn是一個優良的易離去基，在取代反應中，易於被取代。本發明之次要目的，係在於提供一種製備標幟前驅物N，N’ -二（三甲基甲氧羰）-3一（三正丁基錫）笨甲胍 (N,N -bis(tert-butyloxycarbony 1) ~3-(tri-n-butyIt in)benzyl guanidine) (MSnBG) 之方法，該製備方法其反應步驟簡單，完成後只需過濾洗淨，不必經任何繁複之分離純化。為了達到上述之目的，本發明係提供一種製備標幡 1013079372-0 前驅物N，N，-二（三甲基甲氧羰）-3-(三正丁基錫）苯甲 09812367^MSt A〇101 第 4 頁 / 共 16 頁 1364296Dodd and AP Kozikowski, Tetrahedron Lett., 35, 977-979 (1994) and G. Vaidyanathan and MR Zalutsky, J. 〇rg. Chem., 62, 4867-4869 (1997) 'as shown in the second figure' The leaving of the pre-marker (C14) is (CH3)3Sn. SUMMARY OF THE INVENTION The main object of the present invention is to provide a preparation precursor N, N'-bis(trimethylsulfonium oxycarbonyl)-3-(tri-n-butyltin) benzamidine (N, N-bis). (tert-butyloxycarbony 1) -3-(tri-n-buty1tin)benzylguanidine) (MSnBG) The method of using Bu3Sn is an excellent easy leaving group, which is easily substituted in the substitution reaction. A secondary object of the present invention is to provide a precursor for the preparation of a N,N'-bis(trimethylmethoxycarbonyl)-3-(tri-n-butyltin) adenosine (N,N-bis(tert-) Butyloxycarbony 1) ~3-(tri-n-butyIt in)benzyl guanidine) (MSnBG) method, the preparation method has simple reaction steps, and only needs to be washed and washed after completion, without any complicated separation and purification. In order to achieve the above object, the present invention provides a preparation of the standard 1013079372-0 precursor N, N,-bis(trimethylmethoxycarbonyl)-3-(tri-n-butyltin)benzene 98912367^MSt A〇101 4 pages / total 16 pages 1364296

1^1年.03月Oi日梭正_頁胍（N，Ν’ -bis(tert-butyloxycarbonyi) -3-(tri-n-butyltin)benzylguanidine) (MSnBG) 之方法，其係揭示之製造方法其反應步驟簡單完成後只需過渡洗淨’不必經任何繁複之分離純化。標織前驅物MSnBG中的Bupn是一個優良的易離去基，在取代反應中’易於被取代。而且MSnBG係用以製備無栽體添加 (no-carrier-added)之放射性碘標幟之[*i]Mibg，以應用為核醫造影劑與治療劑；此法所得之[51ci]Mibg在廣用為神經母細胞瘤之治療劑時遠優於傳統添加載體程序所獲得之[*I]MI.BG。【實施方式】 [0005] 茲為使貴審查委員對本發明之結構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：本發明係為解決習知技術之標幟前驅物（C14)之離去基為（CH3)3Sn ’在進行取代反應時’其易離去之程度可能不如本發明所使用之Bu3Sn ’其係因由於當碳數越多時，極性越低就越容易溶於溶劑中；溶媒效應較佳，參加反應時更易離去，故後者優於前者為優良的易離去基。再者，習知技術所製備之MIBG含有具活性峨的mibg外，尚含大量起始反應物天然埃MIBG，本發明製備之產物完全不含天然碘。請參閱第三A圖及第三B圖’係本發明之一較佳實施例之製造流程圖與反應方程式圖。如圖所示，本發明提供一種製備N，N’ -二（三曱基曱氧羰）-3-(三正丁基錫）苯甲胍（N，Ν’ -bis(tert-butyloxycarbonyl) 1013079372-0 09812367#單織A0101 第5頁/共16頁 1364296 101年.03月0乏日梭正替^頁 -3-(tri-n-butyltin)benzylguanidine) (MSnBG) 之方法，其步驟係包含：步驟S10，將起始反應物3-碘笨甲胺鹽酸鹽（Cl)與氰胺 (C2)進行加成反應，生成碳酸氫（3-碘苯甲胍）（C4); 步驟S20 ’以二碳酸二（三甲基丁基）（C6)為NH之保護反應劑，將化合物C4在硫磺化二甲基（C5)之溶液中轉變成 N，N’ -二（三曱基甲氧羰）-N_(3-碘苯甲）胍（C7);及步驟S30，使用鈀化合物為催化劑，將化合物C7與二（三正丁基錫）（C8)在1，4-二氧環己烷（C10)中進行取代反應而生成終產物MSnBG。其中，於步騾S10中碳酸氫（3-碘苯甲胍）（C4)之合成’係將3-碘苯甲胍鹽酸鹽（ci) (5.88 g，21.8 ramo1)與氰胺（C2) (2.06 g，47.96 mraol)之混合物在 105 °C加熱迴流4小時’冷卻後加入水（1〇 mL)，完全溶解後加入含有碳酸氫鈉（C3)(l.83 g，21.8 mmol)之水溶液（10 mL) ’析出固體，過濾，先後用冷水，丙酮及乙鍵清洗’乾燥後得化合物C4 (6. 7g, 91% )。進行驗證合成結果，IR (KBr) η 3352 (NH), 1697 (CO) οιη-1.^ NMR (CD„0D) d 7.71 (s, 1 H, C6H4), 7.68 (d, J = 7.8 Hz, 1 H, CgH^, 7.33 (d, J = 7. 8 Hz, 1 H, C H J, 7. 15 (t, J = 7. 8 D 4Method for manufacturing a method of revealing N-Ν(-bis(tert-butyloxycarbonyi) -3-(tri-n-butyltin)benzylguanidine) (MSnBG) After the reaction step is simply completed, only the transition washing is required 'without any complicated separation and purification. The Bupn in the standard weaving precursor MSnBG is an excellent easy leaving group which is easily substituted in the substitution reaction. Moreover, MSnBG is used to prepare [*i]Mibg of no-carrier-added radioactive iodine label for use as a nuclear medicine contrast agent and therapeutic agent; [51ci]Mibg obtained by this method is widely used. When used as a therapeutic agent for neuroblastoma, it is far superior to [*I]MI.BG obtained by the conventional addition of a vector program. [Embodiment] [0005] For a better understanding and understanding of the structural features and the effects of the present invention, the present invention will be described with reference to the preferred embodiments and the detailed description. The leaving group of the precursor of the conventional technique (C14) is (CH3)3Sn 'when the substitution reaction is carried out, the degree of easy removal may not be as good as the Bu3Sn used in the present invention. The higher the carbon number, the lower the polarity is, the easier it is to dissolve in the solvent; the solvent effect is better, and it is easier to leave when participating in the reaction, so the latter is superior to the former as an excellent easy leaving group. Furthermore, the MIBG prepared by the prior art contains a miRg having an active oxime, and contains a large amount of the starting reactant natural angstrom, and the product prepared by the present invention is completely free of natural iodine. Please refer to FIG. 3A and FIG. 3B for a manufacturing flow chart and a reaction equation diagram of a preferred embodiment of the present invention. As shown, the present invention provides a process for preparing N,N'-bis(trimethylsulfonyloxy)-3-(tri-n-butyltin)benzonitrile (N,Ν'-bis(tert-butyloxycarbonyl) 1013079372-0 09812367#单织A0101 Page 5 of 16 Page 1364296 101.03. 0 method of -3- (tri-n-butyltin) benzylguanidine) (MSnBG), the steps of which include: S10, adding the starting reactant 3-iodomethylamine hydrochloride (Cl) and cyanamide (C2) to form hydrogencarbonate (3-iodobenzidine) (C4); step S20' Di(trimethylbutyl)carbonate (C6) is a protective reactant for NH, and compound C4 is converted into N,N'-bis(trimethylmethoxycarbonyl) in a solution of sulfurized dimethyl (C5). -N_(3-iodophenyl)phosphonium (C7); and step S30, using a palladium compound as a catalyst, and a compound C7 and bis(tri-n-butyltin) (C8) in 1,4-dioxane (C10) The substitution reaction is carried out to form the final product MSnBG. Among them, the synthesis of hydrogencarbonate (3-iodobenzidine) (C4) in step S10 is 3-iodobenzidine hydrochloride (ci) (5.88 g, 21.8 ramo1) and cyanamide (C2) A mixture of (2.06 g, 47.96 mraol) was heated to reflux at 105 °C for 4 hours. After cooling, water (1 mL) was added. After complete dissolution, an aqueous solution containing sodium hydrogencarbonate (C3) (1.83 g, 21.8 mmol) was added. (10 mL) 'Precipitate solid, filter, and then rinse with cold water, acetone and ethyl bond. After drying, compound C4 (6.7 g, 91%) was obtained. The results of the verification synthesis were carried out, IR (KBr) η 3352 (NH), 1697 (CO) οιη-1.^ NMR (CD„0D) d 7.71 (s, 1 H, C6H4), 7.68 (d, J = 7.8 Hz, 1 H, CgH^, 7.33 (d, J = 7. 8 Hz, 1 H, CHJ, 7. 15 (t, J = 7. 8 D 4

Hz, 1 H, C6H4), 4.36 (s, 2 H, CH2). 13C NMR (CD3〇D) d 160.51 (C〇), 1 57.67 (C = N), 139·27，l36·92，136.12，130.52, 126.41 及 94.0 (C6H4)， 43.58 (CH2)。 09812367Pg 1013079372-0 其中，於步騾S2〇中N，N，_二（三曱基甲氧羰第6頁/共16頁 1364296Hz, 1 H, C6H4), 4.36 (s, 2 H, CH2). 13C NMR (CD3〇D) d 160.51 (C〇), 1 57.67 (C = N), 139·27, l36·92, 136.12, 130.52, 126.41 and 94.0 (C6H4), 43.58 (CH2). 09812367Pg 1013079372-0 Wherein, N, N, _ bis (trimethyl methoxycarbonyl) in step S2 第 Page 6 of 16 1364296

：ί〇1%03^ 02 0 Ί$Έ.ψά^ )-N-(3-碘苯曱）胍（C7)之合成，將化合物C4 (6.7 g， 19. 9 raraol)溶於無水硫磺化二甲基（C5)(3〇 mL)中，加入二碳酸二（二曱基丁基）（C6) (11.0 mL，46. 4 mmol)，在室溫攪拌隔夜，析出固體產物。過濾，固體產物經水洗淨後烘乾，得產物C7(7. 3 g，77 %)。進行驗證合成結果，IR (KBr) η 3386 (NH)， 1717 (CO) οιη-1.^ NMR (CDC1) d 9. 2 - 9. 5 0 (br，2 H，NH2)，7.64 (s，1 H，C6H4)，7.57 (d， J = 7.8 Hz, 1 H, C6H4), 7.24 (d, J = 7. 8 Hz, 1 H, C6H4), 7. 〇3 (t, J = 7. 8 Hz, 1 H, C6H4), 5.11 (s, 2 H, CH2), 1.50 (s, 9 H, Bu), 1.37 (s，9 H, Bu).13C NMR (CDCl·,) d 1 63.58 及 1 60.55 (CO), 154.67 (C = N), 141.14, 136.52, 1 35.93，129.91，1 26.40 及 93.84 (C6H4)，84.35 及 78.93 (L(CH3)3), 46.78 (CH2)，28.25 及 27.80 (CH3). MS m/z 475 (M+)。其中’於步驟S30中N, Ν’ -二（三甲基甲氧羰）-3-( 三正丁基錫）笨甲胍（MSnBG)之合成，將化合物C7 (1. 111 g ’ 2. 34 mmol)，二（三正丁基錫）（C8) (1.75 mL，3.51 mmol)及二氣化二（（三笨膦）鈀）（匸9) (0.16 g，0.23 mmol)共溶於無水1，4-二氧環己烧 (C10)(30 mL)中，在80°C加熱5小時。過濾後減壓蒸乾溶劑，用正己烷（30 mL)溶解殘留物，再將正己烷減壓濃縮，使用液相層析法（Si〇2，乙酸乙酯：正己烷=1 : 10)分離純化，得產物C7(0· 892 g，1.9 mmol)與 MSnBG (0.266 g，90. 2 %)。 1013079372-0 09812367#單編號A〇101 第7頁/共16頁 1364296 101 年.03月 02 日 · 進行驗證合成結果，IR (neat) η 3382 (NH)， 1716 (C0) αη'1.^ NMR (CDC1 ) d 9.60-9.30 ο (br，2 H，NH2)，7.20-7.13 (m，4 H，C6H4), 5.17 (s, 2 H, 1.60-1.48 (in, 6 H, CH.2CH ), 1.49 (s, 9 H, C(CHJQ), 1.30 (s, 9 H, C(CH3)3), 1.38-1.27 (m, 6 H, Cfl^CH^Hg), I. 03 (m，6 H，CH2Sn)，0.88 (t, J = 7.2 Hz，9 H，CH2CIL3).13CNMR(CDCl3)dl 63.75A161.0 (CO)，1 55.02 (C = N)，141.59，138.22， 134. 87，134. 76，127. 61 及 126.40 (H)，83. 76 · 及78.72 (C(CH3)3)，47.70 (LH2C6H4)，29.03 (i!H2CH3),28.27A27.71(C(iIH3)3),27.30 (i!H2CH2Sn)，13.62 (CJI3CH2)，9.46 (CH2Sn)· MS id/z 的群集峰值落於639 (M+)，582 (M + - C(CH )) 3 3 本發明係依下述構想研發而得，即是將該被置換的天然碘用易離去基Bu3Sn取代而形成標幟前驅物，在製備核醫藥物時則是採用取代法，即用μι ] +離子去取代標幟前驅物中的Bu3Sn，所得之產物完全不含天然碘，如第四圖所示。本發明之優點如下： 1.本發明方法中’將3-碘苯甲胺鹽酸鹽（C1)與氰胺（C2) 在無溶劑下加熱進行加成反應，生成化合物3-峨笨甲胍鹽酸鹽。待反應完成後將反應物溶於水中，然後加入碳酸氫鈉水溶液，立刻產生不溶於水的碳酸氫（3-碘笨甲胍 )(C4)析出’只要過濾洗淨，即可獲得純質化合物以，不 09812367#單編號A0101 第8頁/共16頁 1013079372-0 1364296:ί〇1%03^ 02 0 Ί$Έ.ψά^ )-N-(3-iodobenzoquinone) oxime (C7) synthesis, compound C4 (6.7 g, 19. 9 raraol) dissolved in anhydrous sulfur To the dimethyl (C5) (3 〇 mL), bis(dimercaptobutyl)dicarbonate (C6) (11.0 mL, 44.6 mmol) was added and stirred at room temperature overnight to precipitate a solid product. After filtration, the solid product was washed with water and dried to give product C7 (7.3 g, 77%). The results of the verification synthesis were carried out, IR (KBr) η 3386 (NH), 1717 (CO) οιη-1.^ NMR (CDC1) d 9. 2 - 9. 5 0 (br, 2 H, NH 2), 7.64 (s, 1 H, C6H4), 7.57 (d, J = 7.8 Hz, 1 H, C6H4), 7.24 (d, J = 7. 8 Hz, 1 H, C6H4), 7. 〇3 (t, J = 7. 8 Hz, 1 H, C6H4), 5.11 (s, 2 H, CH2), 1.50 (s, 9 H, Bu), 1.37 (s, 9 H, Bu).13C NMR (CDCl·,) d 1 63.58 and 1 60.55 (CO), 154.67 (C = N), 141.14, 136.52, 1 35.93, 129.91, 1 26.40 and 93.84 (C6H4), 84.35 and 78.93 (L(CH3)3), 46.78 (CH2), 28.25 and 27.80 (CH3 ) MS m/z 475 (M+). Wherein 'in the synthesis of N, Ν'-bis(trimethylmethoxycarbonyl)-3-(tri-n-butyltin) benzoate (MSnBG) in step S30, compound C7 (1. 111 g ' 2. 34 mmol) ), bis(tri-n-butyltin) (C8) (1.75 mL, 3.51 mmol) and di-gasified di((triphenylphosphine)palladium) (匸9) (0.16 g, 0.23 mmol) are co-dissolved in anhydrous 1,4- The mixture was heated at 80 ° C for 5 hours in dioxane (C10) (30 mL). After filtration, the solvent was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh Purification gave the product C7 (0· 892 g, 1.9 mmol) and MSnBG (0.266 g, 90.2%). 1013079372-0 09812367#单号A〇101 Page 7 of 16 1364296 101 Year. March 02 · Perform verification verification synthesis, IR (neat) η 3382 (NH), 1716 (C0) αη'1.^ NMR (CDC1) d 9.60-9.30 ο (br,2 H,NH2), 7.20-7.13 (m,4 H,C6H4), 5.17 (s, 2 H, 1.60-1.48 (in, 6 H, CH.2CH ) , 1.49 (s, 9 H, C(CHJQ), 1.30 (s, 9 H, C(CH3)3), 1.38-1.27 (m, 6 H, Cfl^CH^Hg), I. 03 (m,6 H, CH2Sn), 0.88 (t, J = 7.2 Hz, 9 H, CH2CIL3). 13CNMR (CDCl3) dl 63.75A161.0 (CO), 1 55.02 (C = N), 141.59, 138.22, 134. 87,134 76,127.61 and 126.40 (H), 83.76 · and 78.72 (C(CH3)3), 47.70 (LH2C6H4), 29.03 (i!H2CH3), 28.27A27.71 (C(iIH3)3), 27.30 (i!H2CH2Sn), 13.62 (CJI3CH2), 9.46 (CH2Sn)· The cluster peak of MS id/z falls at 639 (M+), 582 (M + - C(CH )) 3 3 The present invention is based on the following concept R & D, that is, the replaced natural iodine is replaced by the easy-off radical Bu3Sn to form a label precursor. In the preparation of nuclear medicine, the substitution method is adopted, that is, the label precursor is replaced by μι ] + ion. Bu3Sn in the product, the product obtained is not at all Containing natural iodine, as shown in the fourth figure. The advantages of the present invention are as follows: 1. In the method of the present invention, 'heating 3-iodobenzylamine hydrochloride (C1) and cyanamide (C2) without solvent The reaction is carried out to form the compound 3-indolecarboxamidine hydrochloride. After the reaction is completed, the reactant is dissolved in water, and then an aqueous solution of sodium hydrogencarbonate is added to immediately produce water-insoluble hydrogencarbonate (3-iodocaptocaramidine) ( C4) Precipitation 'As long as the filter is washed, the pure compound can be obtained, not 09812367# single number A0101 page 8 / total 16 pages 1013079372-0 1364296

| ί〇1：年:03月6日梭正^寅I 必經過任何繁複之分離純化。 2. 本發明方法中’化合物C4的NH保護反應係選用硫磺化二甲基（C5)為溶劑，其優點是化合物C4與保護反應劑二碳酸二（二甲基丁基）（C6)皆可溶於溶劑C5中，但產物 N，N _二（三甲基甲氧羰）-N-(3-碘笨甲）胍（C7)卻不溶於溶劑C5中而析出’反應完成後只需過濾洗淨即可獲知純質化合物C7 ’不必經任何繁複之分離純化。 3. 本發明方法中，化合物C7與二（三正丁基錫）（C8)的| 〇1: Year: On March 6th, the shuttle is 寅I will be separated and purified by any complicated. 2. In the method of the present invention, the NH protection reaction of the compound C4 uses sulfurized dimethyl (C5) as a solvent, and the advantage is that the compound C4 and the protective reactant di(dimethylbutyl)carbonate (C6) can be used. Soluble in solvent C5, but the product N,N-bis(trimethylmethoxycarbonyl)-N-(3-iodoacyryl)pyrene (C7) is insoluble in solvent C5 and precipitates. After washing, the pure compound C7' can be obtained without any complicated separation and purification. 3. In the process of the invention, compound C7 and bis(tri-n-butyltin) (C8)

取代反應’選用I 4-二氧環己烧（C10)為溶劑，二氣化一（（二苯膦）鈀）（C9)為催化劑，在8(TC反應，使 MSnBG之產率高達9〇%以上。 4. 本發明方法中，標幡前驅物MSnBG㈣Bu3Sn是-個優良的易離去基，在取代反應中，易於被取代。 5. 本發明方法中’ MSnBG中NH的保護基是 B〇c((CH3)3GCG)，該保護基在驗性溶液中穩定，但在酸The substitution reaction 'selects I 4-dioxocyclohexane (C10) as the solvent, di-gasified mono((diphenylphosphine)palladium) (C9) as the catalyst, and the yield of MSnBG is up to 9〇 at 8 (TC reaction). In the method of the present invention, the standard precursor MSnBG(tetra)Bu3Sn is an excellent easy leaving group, which is easily substituted in the substitution reaction. 5. In the method of the present invention, the protecting group of NH in MSnBG is B〇. c((CH3)3GCG), the protecting group is stable in the test solution, but in acid

性♦液t則易於水解而離去。因此，當驗抓與蛾之取代反應％成後’只要加人適量酸^即可去除保護基而獲得核醫藥物[*i]mibg，製備程序相對簡單。 6. MSnBG係用在無添加載體程序以製備[*ι ]m權之標幟前驅物’此法所得之[*I]MIBG在應縣神經母細胞瘤之療劑時遠優於傳統添加載體程序所獲得之[*i ]m 、’’、a ’本發明係實為-具有新祕、進步性及可供產業利用者’應符合_專利法所規定之專利申請要件無疑，爰依法提出發明專獅請，祈自局早日賜准利，至感為禱。 09_7严編號A〇101 作上所述者，僅為本發明之—較佳實施例而已’ 第9頁/共16頁 1013079372-0 1364296 101年.03月日梭正替换頁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内。【圖式簡單說明】 [0006] 第一圖：係為為習知技術中[*I]MIBG之反應方程式圖；第二圖：係為習知技術中另一種標幟前驅物（C14)之反應方程式圖；第三A圖：係本發明之一較佳實施例之M S η B G之反應方程式圖；第三Β圖：係本發明之一較佳實施例之MSnBG之製造流程圖 ;及第四圖：係本發明之一較佳實施例之標幟前驅物MSnBG製備[*I]MIBG之反應方程式圖。【主要元件符號說明】 [0007] S10 步驟 S10 S20步驟S20 S30 步驟 S30 · 09812367#單編號 A〇101 第10頁/共16頁 1013079372-0Sex ♦ liquid t is easy to hydrolyze and leave. Therefore, when the % of the substitution reaction with the moth is completed, the protective substrate can be removed by adding an appropriate amount of acid to obtain the nuclear medicine [*i] mibg, and the preparation procedure is relatively simple. 6. MSnBG is used in the no-addition carrier program to prepare [*ι]m-weighted flag precursors. [*I]MIBG is far superior to traditionally added carriers in the treatment of Yingxian neuroblastoma. The [*i]m, '', a 'acquired by the program is a new secret, progressive and available to the industrial user's patent application requirements that should be met in accordance with the Patent Law. Invent the lion, please pray for the early benefit of the bureau, and feel the prayer. 09_7 Strictly numbered A〇101 As described above, it is only the preferred embodiment of the present invention. [9th page/total 16 pages 1013079372-0 1364296 101.03 month Japanese shuttle replacement page is not used to limit this </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; [Simple diagram of the drawing] [0006] The first figure is a reaction equation diagram of [*I] MIBG in the prior art; the second figure is another flag precursor (C14) in the prior art. Reaction equation diagram; third A diagram: a reaction equation diagram of MS η BG according to a preferred embodiment of the present invention; third diagram: a manufacturing flow diagram of MSnBG according to a preferred embodiment of the present invention; Four figures: A reaction equation diagram of [*I] MIBG prepared by the flag precursor MSnBG of a preferred embodiment of the present invention. [Main component symbol description] [0007] S10 Step S10 S20 Step S20 S30 Step S30 · 09812367# Single No. A〇101 Page 10 of 16 1013079372-0

Claims

1364296 . 七、申請專利範圍：/乂 i1364296 . VII. Patent application scope: /乂 i

• 一種製備放射性3-碘標幟前驅物之方法，包括：一將起始反應物3-碘苯甲胺鹽酸鹽（3-iodobenzylamine hydrochlori de)與氰胺（cyanami de)之混合物共溶後溶於水中’加入碳酸氫鈉，使產物碳酸氫（3-碘苯甲胍） (3-i〇dobenzylguanidine bicarbonate)析出；以二碳酸二（三甲基丁基）（di-tert-butyl dicarbonate)為保護劑，將碳酸氫（3-碘笨甲胍） (3-iodobenzylguanidine bicarbonate)在硫確化二甲基（dimethyl sulfoxide)溶液中轉變成為N，N’ -二 (三甲基甲氧羰）-N-(3-碘笨甲）胍（N，Ν’ -bis(tert-butyloxycarbonyl) -N-(3-iodobenzyl)guanidine);及使用鈀化合物為催化劑，將N，N’ -二（三曱基甲氧羰 )-N-(3-碘苯甲）胍（Ν，Ν’ -bis(tert-butyloxycarbony 1 ) -N-(3-iodobenzyl)guanidine)與二（三正丁基錫 )(bis(tri-n-butyltin))在 1,4-二氧環己烧 (l，4-dioxane)溶液中進行取代反應而生成MSnBG，其化學結構式為 0• A method of preparing a radioactive 3-iodo label precursor comprising: first co-dissolving a mixture of the starting reactant 3-iodobenzylamine hydrochlori de and cyanami de Dissolved in water 'added sodium bicarbonate to precipitate the product 3-i〇dobenzylguanidine bicarbonate; di-tert-butyl dicarbonate As a protective agent, 3-iodobenzylguanidine bicarbonate is converted into N,N'-bis(trimethylmethoxycarbonyl)- in a dimethyl sulfoxide solution. N-(3-iodobenzyl)guanidine; and using a palladium compound as a catalyst, N,N'-di(trimium) -N-(3-iodobenzyl) hydrazine (Ν, Ν'-bis(tert-butyloxycarbony 1 ) -N-(3-iodobenzyl)guanidine) and bis(tri-n-butyltin) (bis(tri) -n-butyltin)) Substituting a solution in a 1,4-dioxane solution to form MSnBG with a chemical structural formula of 0

Bu3Sn C-OC(CH3)3 表單編號A0101 第11頁/共16頁 .如申凊專利範圍第1項所述之製備放射性3-破笨甲胍之標幡則驅物之方法，其中於反應物3-碘笨曱胺鹽酸鹽與氰胺共炫之步驟中，其共熔溫度之溫度為80 420^。 .如申請專利範圍第1項之製備放射性3-碘苯甲胍之標幟前驅物之方法’其中於以二碳酸二（三甲基丁基 )(di-tert-butyl dicarbonate)為保護劑之步驟中，該保護劑之溶劑係選自硫磺化二甲基（dimethyl sulfoxide)或 N，N’ -甲酸二醯胺 (N，N-dimthylf〇rmamide)中之任一種。 .如申請專利範圍第1項之製備放射性3-碘苯曱胍之標幟前驅物之方法，其中於以二破酸二（三甲基丁基 )(di-tert-butyl dicarbonate)為保護劑之步驟中，其反應溫度為20〜70°C。 •如申請專利範圍第1項之製備放射性3-碘苯甲胍之標幟前驅物之方法，其中使用鈀化合物為催化劑，將N，N，-二（三甲基甲氧羰）-N-(3-碘苯甲）胍與二（三正丁基錫）在 1，4-二氧環己烷溶液中進行取代反應之步驟中，其取代反應所使用之溶劑係選自1，4-二氡環己烷 (l，4-dioxane)，三乙胺（triethylamine)及四氫呋喃 (tetrahydrofaran)中任一種。 .如申凊專利範圍第1項之製備放射性3_峨苯甲脈之標幡前驅物之方法’其中使用鈀化合物為催化劑，將N，N’ -二（三甲基甲氧羰）-N-(3-碘苯甲）胍與二（三正丁基踢）在 1，4-二氧環己烷溶液中進行取代反應之步驟中，其取代反應所使用之催化劑係選自二氣化二（（三苯膦）鈀） (bis(tripheny1 phosphine)pal ladium(11) 1364296 . dichlonide)或四（三笨膦）把 )(0)(tetrakis(triphenylphosphine)palladium(O)) 中之任一種。 7 .如申請專利範圍第1項之製備放射性3-碘苯甲胍之標織前驅物之方法，其中使用鈀化合物為催化劑，將N，N’ -二（三甲基甲氧羰）-N-(3-碘苯曱）胍與二（三正丁基錫）在 1,4-二氡環己烷溶液中進行取代反應之步驟中’其取代反應所使用之溫度為60〜100°C。表單編號A0101 第13頁/共16頁Bu3Sn C-OC(CH3)3 Form No. A0101 Page 11 of 16. A method for preparing a radioactive 3-broken beetle, as described in claim 1, in which the reaction is carried out. In the step of co-condensing the 3-iodoguanamine hydrochloride with cyanamide, the temperature of the eutectic temperature is 80 420^. The method for preparing a radioactive 3-iodobenzidine label precursor according to the first aspect of the patent application, wherein di-tert-butyl dicarbonate is used as a protective agent. In the step, the solvent of the protective agent is selected from the group consisting of dimethyl sulfoxide or N,N-dimthylf〇rmamide. A method for preparing a radioactive 3-iodobenzoquinone label precursor according to the first aspect of the patent application, wherein di-tert-butyl dicarbonate is used as a protective agent In the step, the reaction temperature is 20 to 70 °C. • A method for preparing a radioactive 3-iodobenzidine precursor precursor according to the scope of claim 1, wherein a palladium compound is used as a catalyst to N, N,-bis(trimethylmethoxycarbonyl)-N- In the step of performing a substitution reaction of (3-iodophenyl) hydrazine with bis(tri-n-butyltin) in a 1,4-dioxane solution, the solvent used in the substitution reaction is selected from the group consisting of 1,4-dioxane Any of cyclohexane (1,4-dioxane), triethylamine and tetrahydrofaran. A method for preparing a radioactive 3* benzophenone-labeled precursor precursor according to claim 1 of the patent scope, wherein a palladium compound is used as a catalyst, and N,N'-bis(trimethylmethoxycarbonyl)-N is used. - (3-iodobenzyl) hydrazine and di(tri-n-butyl butyl) in a step of performing a substitution reaction in a 1,4-dioxane solution, the catalyst used in the substitution reaction is selected from the group consisting of two gasification Any of (bis(triphenylphosphine)palladium) (bis(tripheny1 phosphine)pal ladium(11) 1364296 . dichlonide) or tetrakis(triphenylphosphine)palladium(O) . 7. A method of preparing a radioactive 3-iodobenzamide-based woven precursor according to claim 1, wherein a palladium compound is used as a catalyst to N,N'-bis(trimethylmethoxycarbonyl)-N The temperature at which the substitution reaction is carried out in the step of performing a substitution reaction of -(3-iodobenzoquinone) hydrazine with bis(tri-n-butyltin) in a 1,4-dioxane solution is 60 to 100 °C. Form No. A0101 Page 13 of 16