TWI364296B - - Google Patents

Description

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) has a research report similar to the precursor of the label 'but the method of preparation disclosed is D. S.

Dodd 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

Method 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 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-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

| 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)

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

Sex ♦ 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 (1)

1364296 . VII. Patent application scope: /乂 i • 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 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