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Structure of 294-90-6 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium hydroxide In water at 80℃; for 24 h;
To the three-necked flask was added 1,4,7,10-tetraazacyclododecane (100 g, 0.58 mol)10 ml of deionized water, stirred, 30percent KOH solution was added dropwise,The pH was adjusted to 8.5 and then chloroacetic acid (263 g, 2.78 mol) was added,And then 30percent KOH solution to adjust the pH to 8.5,Heated to 80 ° C for 24 h, during which the pH was maintained between 8.5 and 9.After the reaction, cooling, adding concentrated hydrochloric acid to adjust the pH to 2, a white precipitate produced, filtered. The filter cake was recrystallized from a water-ethanol solution and the resulting crystals were washed with ethanol, ether, dried,183 g of DOTA crystals was obtained in a yield of 78percent.
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, # 3, p. 197 - 209
[2] Dalton Transactions, 2016, vol. 45, # 23, p. 9553 - 9564
[3] Patent: WO2014/114664, 2014, A1, . Location in patent: Page/Page column 28-29
[4] Patent: WO2015/117911, 2015, A1, . Location in patent: Paragraph 0081; 0082; 0083; 0084
[5] Patent: CN104447598, 2017, B, . Location in patent: Paragraph 0096; 0098; 0099
Reference：
[1] Chemical Communications, 2013, vol. 49, # 6, p. 564 - 566
[2] Patent: KR101851981, 2018, B1,
5
[ 50-00-0 ]
[ 294-90-6 ]
[ 91987-74-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, p. 777 - 782[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 4, p. 844 - 849
6
[ 683-57-8 ]
[ 294-90-6 ]
[ 157599-02-5 ]
Yield
Reaction Conditions
Operation in experiment
66%
With triethylamine In ethanol at 80℃; for 4 h;
To a 100 mL round bottom flask fitted with a reflux condenser and stir bar was added 1.4696 g Cyclen (8.5 mmol). 5.44 11 g of 2-bromoacetamide (39.4 mmol, 4.6 eq) was added with 4.5748 g triethylamine (44.9 mmol, 5.3 eq) in 30 mL absolute ethanol. The contents were refluxed for 4 hours at 80 °C, after which time a white precipitate formed in the flask. After cooling to room temperature, the precipitate was decanted and placed in a 250 mL round bottom flask, then dissolved in 200 mL of hot 80 percent ethanol/20 percent water. The volume was reduced by approximately 30 percent on a roto-evaporator, then placed in the refrigerator overnight to produce white crystals. The remaining solvent was removed by filtration and the crystals were transferred to a 50 mL round bottom flask to dry on a Schlenk line under vacuum for several hours (66 percent yield). ESI-MS: m/z = 401.3 (100 percent), 402.3 (15 percent) [M + H]+; 423.4 (25 percent), 424.4 (< 10 percent) [M + Na]+. 1H NMR (500 MHz, D20), ppm: 3.02 (s, amide pendent CH28H), 2.57 (s, Cyclen ring 16 H). 13C NMR (125 MHz, D20), ppm: 174.07 (carbonyl C),55.86 (amide CH2), 50.42 (ring CH2).
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 25, p. 6698 - 6707
[2] Journal of the Chemical Society, Chemical Communications, 1994, # 8, p. 1007 - 1008
8
[ 24424-99-5 ]
[ 294-90-6 ]
[ 175854-39-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine In chloroform at 20℃;
A solution of di-tert-butyl dicarbonate (1.77 g, 8.12 mmol) in chloroform (10 mL) was added slowly via addition funnel to a solution of cyclen (7, 0.51 g, 2.90 mmol) and triethylamine (1.25 mL, 8.99 mmol) in chloroform (40 mL) at rt. The reaction mixture was stirred at rt overnight and then concentrated through rotary evaporation. The resulting residue was purified by column chromatography over silica gel with gradient elution from ethyl acetate to 5percent methanol/dichloromethane to yield the product as a white solid (1.02 g, 80percent). Characterizations matched previous reports.61
72%
With triethylamine In chloroform at 20℃; for 24 h;
Molecule A can be prepared by slowly, i.e. within 3 hours, adding a solution of di-tert-butyl dicarbonate (7.9 g, 36 mmol) in CHCl3 (100 mL, passed through Al2O3) to a solution of cyclen (2.2 g, 13 mmol) and triethylamine (5.5 mL, 39 mmol) in CHCl3 (120 mL) at room temperature. The reaction mixture is stirred for 24 hours at room temperature, and the organic solvent is removed under reduced pressure. The remaining residue is purified by silica gel column chromatography (hexanes/AcOEt) to provide molecule A as a colourless, amorphous solid (4.4 g, 72percent)[ E. Kimura, J. Am. Chem. Soc., 1997, 199, 3068-3076].The tri-BOC protected molecule A (15.2 g) is then dissolved in 20 mL of acetonitrile, after which 19 mL of diisopropylethylamine and 7.9 g of benzylbromoacetate in 10 mL acetonitrile are added. The solution is heated up to 60-65° C. and stirred overnight under an argon atmosphere. The mixture is then concentrated by evaporation of the solvent and dissolved in dichloromethane. The solution is washed with 1 M NaOH. The organic layer is dried with Na2SO4 and thereafter reduced by evaporation and co-evaporation with toluene. The pure product, molecule B, is isolated by silica column chromatography using hexane/ethyl acetate(1/1) as eluent. The yield is about 90percent.Molecule B (6.22 g) is dissolved in 60 mL dichloromethane and 60 mL trifluoracetic acid (TFA). The solution is stirred under a nitrogen atmosphere. After 3 hours the solvents are evaporated and another portion of TFA (40 mL) is added. After 2 hours of further stirring the TFA is evaporated and the remaining mixture is co-evaporated twice with toluene, leaving the crude TFA-salt of molecule C as an oil, of which then 10 g is used in a following step without further purification. The oil is dissolved and stirred in 45 mL DMF and 31 mL diisopropylethylamine. Then, 4.7 g bromo acetamide is added and the mixture is stirred for two days at 50° C., during which time a precipitate is developed. The mixture is brought in 600 mL ether, is stirred and the brown precipitate is isolated by filtration and washing with ether. The solid is then washed four times with portions of 25 mL of 25percent NH3 solutions in water and finally with 30 mL of water. Drying under vacuum at 40° C. results in a white solid product of molecule D (yield=85percent).Molecule D (1.7 g) is then hydrogenated at 70 psi overpressure in 100 mL water using Pd/C (10percent) as catalyst. The mixture is filtered over celite, the celite is washed with some water and the filtrate is freeze dried and then dried over P2O5 in vacuum to afford 1.1 gram of a fine white hygroscopic powder of molecule E.For the coupling of molecule E to the carrier, in the example given to a PPI dendrimer, the amide coupling agent HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) is used. The coupling of the paramagnetic complex to the dendrimer is illustrated in FIG. 5. For convenience, the dendrimers are denoted as circles. The dendrimers used are commercially available poly(propylene imine) (PPI) dendrimers (from Aldrich under the name DAB-Am-X or from SyMO-Chem) with a diaminobutane (DAB) derived core. The most used name for those dendrimers is DAB-Am-X, wherein X refers to the number of surface amino groups. In this synthesis, DAB-Am-4 and DAB-Am-16 have been used in order to respectively obtain a DOTAM-G1 complex and a DOTAM-G3 complex. The formation of DOTAM-G1 and DOTAM-G3 is similar, only the value for the number n of end groups is different, i.e. for DOTAM-G1 n=4 and for DOTAM-G3 n=16.For the coupling of molecule E to the G1 PPI dendrimer, 0.39 mL diisopropylethylamine is added to a mixture of 312 mg HBTU in 3 mL dry DMF. Molecule E (300 mg) is added, the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. Subsequently, 60 mg DAB-Am-4 in 3 mL DMF is added. The mixture is stirred overnight under an inert atmosphere, after which it is dropped into 150 mL of ether. The sticky precipitate is taken up in a small amount of methanol and precipitated into ether giving a white solid, that is again precipitated from methanol into ether. Finally, the solid is dissolved in methanol and eluted over an anion exchange column (Dowex OH-). Evaporation of the solvent gave about 200 mg of product, which in the further synthesis will be called molecule II.For the coupling of molecule E to the G3 PPI dendrimer, 0.25 mL diisopropylethylamine is added to a mixture of 164 mg HBTU in 1 mL dry DMF. Molecule E (172 mg) is added and the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. The third generation PPI-dendrimer DAB-Am-16 (41 mg) in 1 mL dry DMF is then added and the solution is stirred overnight under an inert atmosphere of nitrogen. The mixture is poured into 40 mL of stirred ether giving a precipitate; the ether is replaced by another portion of ether (washing step), and the precipitate is dried. Finally, the precipitate is dissolved in water and triethylamine and this solution is dialysed using a membrane with a molecular weight cut-off of 1000 and using 1.2 L of water and 20 mL of triethyl amine as washing solvent. After overnight dialysis, the washing solution is replaced by 1.2 L of water and dialysis is continued for another 24 hours. Freeze drying of the solution in the dialysis tube gave ca. 200 mg of a fluffy white product, which in the further synthesis will be called molecule III.FIG. 6 illustrates the coupling of molecule E to an aliphatic/aromatic tail. A similar synthetic and purification procedure as used for molecule II may be applied, using N-carbobenzoxy-1,5-diaminopentane (mono Cbz-protected 1,5-pentyldiamine) as amine starting product. The resulting product will in the further synthesis be referred to as molecule IV.A last step in the synthesis is the complexation with Yb3+ ions. For the formation of the Yb-DOTAM-G1 complex, a solution of 0.1 mmol YbCl3 in 5 mL water is added dropwise to a stirring solution of 49 mg (0.1 mmol) of molecule II in 8 mL water. Subsequently, the solution is heated up to 60° C. for 2 hours while stirring, meanwhile maintaining a pH of 7 to 8 by adding small drops of NH4OH. The solution is dialysed for 24 hours using a membrane with a molecular weight cut-off of 500 and running water as washing solvent. Freeze drying of the solution yields a white powder in a yield of 80percent.For the formation of the Yb-DOTAM-G3 complex the complexation procedure is similar as for the Yb-DOTAM-G1 complex, but now molecule III is used instead of molecule II.For the formation of the Yb-DOTAM-tail complex, the complexation procedures is also similar as for the Yb-DOTAM-G1 complex but now molecule IV is used instead of molecule II and a dialysis membrane with a molecular weight cut-off of 100 is used.It has to be understood that the above-described synthesis may also be used to form other CEST contrast agents comprising, for example, other lanthanides than Yb or derivatives of the DOTAM chelating ligand.
72%
With triethylamine In chloroform at 0 - 20℃; Inert atmosphere
To a solution of cyclen (S4, 1.73 g, 10.0 mmol) and triethylamine (4.20 mL, 30.1 mmol)in CHCI3 (120 mL, freshly passed through A1203 (activated, neutral, Brockmann I)) at 0°C was added dropwise a solution of di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) inCHCl (100 mL, freshly passed through A1203 (activated, neutral, Brockmann I)) under N2. After the addition was complete, the resulting solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, EtOAc:hexane = 3:2 ramping to EtOAc) to give S6 as a white foam (3.41 g, 72percent).RF (EtOAc:hexane = 4:1) 0.63. IR vmax/cm1 3313, 2974, 2931, 2818, 1679, 1463, 1412,365, 1313, 1247, 1156, 1 046, 771, 736. 1H NMR (400 MHz, CDCI3) 5 1.45 (5, 1 8H, 2 x C(CH3)3), 1.47 (5, 9H, C(CH3)3), 2.78-2.92 (m, 4H, CH2NHCH2), 3.16-3.34 (m, 6H),3.34-3.50 (m, 2H), 3.55-3.75 (m, 4H) (total 12H, 3 x CH2N(Boc)CH2) (one secondary amine proton signal (NH) not observed). ‘3C NMR (100 MHz, CDCI3) 5 28.1, 28.2, 28.3,28.4, 28.5, 44.7, 45.7, 48.8, 49.2, 50.3, 50.8, 78.9, 79.1, 155.1, 155.4 (eight carbon signals overlapping or obscured). MS (ESI) m/z 472.9 ([M+H], 27percent), 495.0 ([M+Na], 99percent), 967.1 ([2M+Na], 100percent). The spectroscopic data were in agreement with those in the literature.3739
68%
With triethylamine In chloroform at 20℃; for 6 h;
In a 200 mL round bottom flask, 1,4,7,10-tetraazacyclododecane (2 g), chloroform (50 mL), three Ethylamine (11.2 mL, 7.2 eq) was stirred at room temperature. Dissolve 30 mL of di-tert-butyl dicarbonate (6.87 g, 2.7 eq) The chloroform solution was added dropwise to the system at room temperature, and after 6 hours of reaction, TLC dot plate detection reaction is over, Condensed by vacuum distillation, and purified by column chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) 1,4,7,10-tetraazacyclododecyl-1,4,7-tricarboxylic acid tri-tert-butyl ester (3.73 g) was obtained. The product was obtained as a colorless oil, yield 68percent.
57%
With diisopropylamine In chloroform for 12 h; Inert atmosphere
Di-tert-butyl dicarbonate (16.5 g, 0.076 mol) in chloroform (100 mL) was added dropwise to a chilled mixture of 1 ,4,7,10-tetraazacyclododecane (5.0 g, 0.029 mol) and diisopropylamine (15 mL, 0.087 mol) in chloroform (200 mL) over a period of three hours. The reaction was then stirred overnight under an atmosphere of nitrogen. The reaction was concentrated, brought up in ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (200 mL), followed by one wash of monobasic potassium phosphate (200 mL of 1 M) and brine (200 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated. The crude reaction was purified using flash chromatography (4:1 ethyl acetate :hexanes) to yield a white solid (7.84 g, 57percent). 1H NMR (400 MHz, CDCI3) δ 3.67-3.52 (br, 4H), 3.46-3.14 (m, 8H), 2.88-2.72 (br, 4H), 1 .44 (s, 9H), 1 .42 (s, 18H); 13C NMR (100 MHz, CDCI3) δ 155.4, 79.2, 79.1 , 50.8, 49.3, 49.3, 48.7, 45.8, 44.8, 28.5, 28.3; LRMS (ESI): m/z [M+H]+ calc'd for C23H45N406+ 473.33, found 473.33.
57%
With diisopropylamine In chloroform at 0 - 20℃; Inert atmosphere
Di-tert-butyl dicarbonate (16.5 g, 0.076 mol) in chloroform (100 mL) was added dropwise to a chilled mixture (0 °C) of 1,4,7,10-tetraazacyclododecane (5.0 g, 0.029 mol) and diisopropylamine (15 mL, 0.087 mol) in chloroform (200 mL), over a period of three hours. The reaction was then stirred overnight under an atmosphere of nitrogen at room temperature. The reaction was concentrated, brought up in ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (200 mL), followed by one wash of monobasic potassium phosphate (200 mL of 1M) and brine (200 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated. The crude reaction was purified using flash chromatography (80 percent ethyl acetate, 20percent hexanes) to yield a white solid (7.84 g, 57percent).1H NMR (400 MHz, CDCl3) δ 1.37-1.50 (m, 27H, 3 x Boc (CH3)3), 2.79-2.89 (br, 4H, 2 x cyclen CH2), 3.17-3.47 (m, 8H, 4 x cyclen CH2), 3.54-3.70 (br, 4H, 2 x cyclen CH2);13C NMR (100 MHz, CDCl3) δ 28.61, 28.80, 45.10, 46.11, 48.97, 49.59, 50.00, 51.12, 79.34, 79.46, 70.60, 155.53, 155.74, 155.92; LRMS (ESI): m/z [M+H]+calc’d for C23H45N4O6+473.33, found 473.33.
56%
at 20℃; for 18 h;
A solution of di-tert-butyl dicarbonate (6.08 g, 27.86 mmol) in CH2Cl2 (100 ml) was added dropwise to a stirred solution of cyclen (2.00 g, 11.61 mmol) in CH2Cl2 (300 ml).The mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to yield a transparent oil, which was purified by <n="32"/>column chromatography on silica (gradient elution: 100percent CH2Cl2 - 5 percent MeOH/CH2Cl2, Rf = 0.29 10percent MeOH/CH2Cl2) to afford the title compound as a white crystalline solid (3.08 g, 6.51 mmol, 56 percent). δH (CDCI3, 300 MHz) 1.42 (18H, s, 3 x tBu), 1.44 (9H, s, tBu), 2.81 (4H, br s, cyclen 2 x CH2), 3.28 (8H, br s, cyclen 4 x CH2), 3.60 (4H, br s, cyclen 2 x CH2). δc (CDCI3, 75 MHz) 28.9 (tBu), 29.0 ^Bu), 46.1 (cyclen CH2), 49.9 (cyclen CH2), 51.2 (cyclen CH2), 79.4 (C), 79.6 (C), 155.8 (C=O), 156.0 (C=O). MS (ES+) m/z 473.4 (100 percent, [M + H]+).
56%
at 20℃;
A solution of di-te/t-butyl dicarbonate (6.08 g, 27.8 mmol) in anhydrous CH2CI2 (100 ml) was added dropwise to a stirred solution of cyclen (2.00 g, 11.61 mmol) in anhydrous CH2CI2 (300 ml). The reaction mixture was stirred at room temperature, for 18 h. The solvent was removed under reduced pressure to afford a transparent oil. The crude material was purified by column chromatography on silica (gradient elution: CH2CI2 to 5 percent CH3OH : CH2CI2, utilising 0.1 percent CH3OH increments) to yield the title compound 17 as a colourless crystalline solid (3.08 g, 6.51 mmol, 56 percent); RF = 0.29 (Silica, CH2CI2 - CH3OH, 9 : 1, v/v); 1H NMR (CDCI3, 500 MHz) δ 1.42 (18H, s, feoc CH3), 1.44 (9H, s, *Boc CH3), 2.81 (4H, br s, cyclen CH2), 3.28 (8H, br s, cyclen CH2), 3.60 (4H, br s, cyclen CH2); 13C NMR (CDCI3, 125 MHz, 1H decoupled 500 MHz) δ 28.9 (6C, 'Boc CH3), 29.0 (3C, 'Boc CH3), 46.1 (2C, cyclen CH2), 49.9 (2C, cyclen CH2), 51.2 (4C, cyclen CH2), 79.4 (2C, fex*,)), 79.6 (1C, ^oqq)), 155.8 (2C, feoc C = O), 156.0 (1C, 'Boc C = O); MS (ES+) m/z 473.3 (100 percent, [M + H]+); HRMS (ES+) m/z found 473.3330 [M + H]+ C23H45O6N4 requires 473.3333.
48%
With triethylamine In chloroform at 0 - 20℃; for 20 h;
Place the rotor in a 50 mL eggplant flask, dissolve 0.4649 g (2.703 mmol) of cyclen in 131.2 mL of CHCl 3, add 1.16 mmol of Et 3 N,Immersed in an ice bath and brought to 0 ° C.A solution of 1.780 g (8.213 mmol) of (Boc) 2 O in 10.1 mL of CHCl 3 was added dropwise at 0 ° C. over 2 hours. After the dropwise addition, the ice bath was removed and the mixture was stirred at room temperature for 18 hours.After this, the solution was washed three times with H 2 0 in a separating funnel,The organic phase was dried over Na 2 SO 4 and concentrated to give an oily substance which was vacuum dried to give a white solid. This solid was dissolved in a minimum amount of CHCl 3,Purification by open column chromatography (packing agent: silica gel, developing solvent: CHCl 3: MeOH = 20: 1) gave the fractions containing the desired product collected and concentrated to give the desired white solid(Yield 0.6133 g, 48percent).
Reference：
[1] Journal of Materials Chemistry, 2012, vol. 22, # 36, p. 18784 - 18787
[2] Journal of the American Chemical Society, 2004, vol. 126, # 30, p. 9248 - 9256
[3] RSC Advances, 2016, vol. 6, # 28, p. 23645 - 23652
[4] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 115 - 123
[5] Chemical Communications, 2011, vol. 47, # 21, p. 6036 - 6038
[6] Tetrahedron, 2011, vol. 67, # 21, p. 3803 - 3808
[7] Angewandte Chemie - International Edition, 2006, vol. 45, # 32, p. 5340 - 5344
[8] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[9] Journal of the American Chemical Society, 2011, vol. 133, # 51, p. 20704 - 20707
[10] Research on Chemical Intermediates, 2012, vol. 38, # 8, p. 2085 - 2096
[11] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2745 - 2748
[12] Tetrahedron, 2006, vol. 62, # 24, p. 5748 - 5755
[13] Inorganic Chemistry, 2017, vol. 56, # 7, p. 3773 - 3780
[14] Journal of the American Chemical Society, 1997, vol. 119, # 13, p. 3068 - 3076
[15] Patent: US2008/193384, 2008, A1, . Location in patent: Page/Page column 4-5
[16] Patent: WO2014/153624, 2014, A1, . Location in patent: Page/Page column 42; 43
[17] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 1, p. 65 - 73
[18] Chemistry - A European Journal, 2010, vol. 16, # 17, p. 5018 - 5025
[19] Advanced Synthesis and Catalysis, 2014, vol. 356, # 6, p. 1243 - 1254
[20] Patent: CN108047209, 2018, A, . Location in patent: Paragraph 0041; 0051; 0052
[21] Patent: WO2015/179955, 2015, A1, . Location in patent: Paragraph 00107; 00108; 00109
[22] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4542 - 4547
[23] Patent: WO2009/10580, 2009, A1, . Location in patent: Page/Page column 23; 30-31
[24] Patent: WO2010/84090, 2010, A1, . Location in patent: Page/Page column 43; 44
[25] Angewandte Chemie - International Edition, 2018, vol. 57, # 6, p. 1611 - 1615[26] Angew. Chem., 2018, vol. 130, # 6, p. 1627 - 1631,5
[27] Patent: JP2018/135304, 2018, A, . Location in patent: Paragraph 0041; 0042
[28] Synlett, 2004, # 3, p. 453 - 456
[29] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 376 - 385
[30] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 696 - 701
[31] Bioorganic Chemistry, 2005, vol. 33, # 5, p. 374 - 385
[32] Chemistry and Biodiversity, 2009, vol. 6, # 8, p. 1273 - 1282
[33] Chemistry - A European Journal, 2010, vol. 16, # 43, p. 12935 - 12940
[34] Inorganica Chimica Acta, 2010, vol. 363, # 12, p. 2896 - 2904
[35] Frontiers of Chemistry in China, 2010, vol. 5, # 2, p. 184 - 192
[36] Journal of Coordination Chemistry, 2015, vol. 68, # 2, p. 335 - 349
[37] Patent: CN104478984, 2016, B, . Location in patent: Paragraph 0061-0063
With sodium hydrogencarbonate In acetonitrile at 0 - 20℃; for 49 h; Inert atmosphere
1,4,7,10-Tetraazacyclododecane (1 g, 5.81 mmol) was dissolved in dry acetonitrile (20 ml) under nitrogen at 0oC. NaHCO3 (1.464 g, 17.44 mmol) was added with stirring. tert-Butyl bromoacetate(3.4 g, 17.44 mmol) in 10 ml acetonitrile was added slowly from a dropping funnel in 1 h. The reaction was stirred at 0oC for another 3 h and at room temperature for 45 h. The progress of the reaction was monitored by TLC using dichloromethane (DCM):methanol (9:1) (Rf 0.67). On completion of reaction, reaction mixture was filtered and filtrate was evaporated to dryness. Crude compound was purified by column chromatography over silica gel using 2percent methanol in DCM as eluant to give compound 2 as white powder.Yield: 83.5percent
83%
With potassium carbonate In acetonitrile at 70℃; for 6 h;
With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 120 h;
In a 500 ml round bottom flask, the compound (1) (2 g, 11.62 mmol) and sodium acetate (2.85 g, 34.8 mmol) were dissolved in N, N-dimethylacetamide (DMA, 25 mL). Tert-butyl bromoacetate (6.79 g, 34.82 mmol) was dissolved in N, N-dimethylacetamide (10 mL) at 0 ° C under ice-cooling, and reacted at room temperature for 5 days, After the completion of the reaction and then pour 125ml of water, then the reaction will be slightly yellow solution, And then slowly add sodium bicarbonate, will find the reaction of white precipitate produced, The precipitate was filtered and the precipitate was dissolved in 150 mL of chloroform, and washed with water (3 x 100 mL), discard the aqueous phase. The organic phase was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The organic phase was recrystallized from diethyl ether to give the compound (2) (4.1 g, 78percent) as a white solid. Having a structure of the following formula 3:
77%
Stage #1: With triethylamine In chloroform for 2.5 h; Stage #2: With potassium carbonate In chloroform for 14 h;
3.3 equivalents of tert-butyl bromoacetate (773.0 mg, 7.6 mmol) dissolved in 10.0 mL anhydrous chloroform was added dropwise to a mixture of 1,4, 7,10-tetraazacyclododecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equivalents of triethylamine (2.3 g, 23.2 mmol) in 40 mL anhydrous chloroform under an argon atmosphere for about half an hour. The reaction mixture was stirred for another 2 hours, and 0.5 equivalents of anhydrous K2CO3 was added. After a further 14 hours of reaction, the resulting solution was washed by water (3 x 40 mL). Then anhydrous Na2SO4 was used to dry the organic phase and the solvent was removed under vacuum to give a transparent oil. This crude product was purified by flash chromatography on aluminium oxide (dichloromethane/methane = 200: 5 (volume/volume), Rf = 0.35) to give tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (1) as a white powder (0.92 g, 1.78 mmol), yield: 77percent. mp 178-180°C, 1H NMR (400 MHz, CDCl3) : δ 3.34 (4H, s), 3.26 (214, s), 3.05 (4H, s), 2.89-2. 85 (12H, m), 1.47 (27H, s) ; 13C NMR (100 MHz, CDCl3) : δ 170.5 (2 x C), 169.6 (C), 81.6 (3 x C), 58.2 (3 x CH2), 51. 3 (2 x CH2), 51. 1 (2 x CH2) 49.2 (2 x CH2), 47.5 (2 x CH2) 28.2 (3 x CH3) ; ESIMS m/z 515.3 (M+H)+; HRFABMS m/z 515. 3811 (M+H)+ [Calcd. For C26H51N4O6(M+H)+, 515.3809].
73%
With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 120 h; Inert atmosphere
Example 1-Synthesis of Tri-tert-butyl 2,2',2'-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate The protocol from O. Axelsson et al in was used. Cyclen (1,4,7, 10-tetraazacyclododecane) (5.0 g, 29 mmol) and AcONa (7.22 g. 88 mmol) were introduced in dry DMA (80 mL) under argon. α-bromo-tert-butylacetate (13 mL, 87 mmol) dissolved in dry DMA (13 mL) was added drop by drop at 0 °C and the reaction was performed at room temperature during 5 days. At the end of the reaction, water (140 mL) was poured into the mixture and pH was adjusted at 9 with Na2CO3 before the introduction of KBr (5.05 g, 42.4 mmol). The mixture was filtrated and the beige precipitate was solubilized in CH2Cl2 and water was extracted. The organic layer was dried over Na2SO4, was concentrated, and the residue was washed with cooled EtOAc to isolate a white powder. This purification process led to the isolation of tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate as an amorphous white powder (10.9 g, 73 percent). Mp : 179 °C (recrystallised from toluene to give yellow crystals). Rf : 0.7 (CH2Cl2/MeOH/NH4OH 80:15:5, Draggendorf visualization) 1H NMR (CDCl3, 300 MHz) δ 3.36 (s, 4H, H8), 3.28 (s, 2H, H13), 3.07 (m, 4H, H6), 2.88 (m, 12H, H2, H3, H5), 1.46 (s, 18H, H12), 1.45 (s, 9H, H17). 13C NMR (CDCl3, 75 MHz) δ 170.7 (C9), 169.9 (C14), 81,9 (C16), 81.7 (C11), 58.3 (C8 - C13), 51.5 (C5), 49.6 (C2 - C3), 47.7 (C6), 28.4 (C17), 28.3 (C12). MS (ESI+) : m/z 515 [M+H]+.
73%
With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 120 h; Inert atmosphere
The protocol from O. Axelsson et al in WO200612723 2006 was used. Cyclen (1,4,7,10-tetraazacyclododecane) (5.0 g, 29 mmol) and AcONa (7.22 g. 88 mmol) were introduced in dry DMA (80 mL) under argon, α-bromo-tert-butylacetate (13 mL, 87 mmol) dissolved in dry DMA (13 ml) was added drop by drop at 0 °C and the reaction was performed at room temperature during 5 days. At the end of the reaction, water (140 ml) was poured into the mixture and pH was adjusted at 9 with Na2CO3 before the introduction of KBr (5.05 g, 42.4 mmol). The mixture was filtrated and the beige precipitate was solubilized in CH2Cl2 and water was extracted. The organic layer was dried over Na2SO4, was concentrated, and the residue was washed with cooled EtOAc to isolate a white powder. This purification process led to the isolation of tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate as an amorphous white powder (10.9 g, 73 percent). Mp : 179 °C (recrystallised from toluene to give yellow crystals). Rf : 0.7 (CH2Cl2/MeOH/NH4OH 80:15:5, Draggendorf visualization) 1H NMR (CDCl3, 300 MHz) δ 3.36 (s, 4H, H8), 3.28 (s, 2H, H13), 3.07 (m, 4H, H6), 2.88 (m, 12H, H2, H3, H5), 1 .46 (s, 18H, H12), 1 .45 (s, 9H, H17). 13C NMR (CDCl3, 75 MHz) δ 170.7 (C9), 169.9 (C14), 81 ,9 (C16), 81.7 (C11), 58.3 (C8 - C13), 51.5 (C5), 49.6 (C2 - C3), 47.7 (C6), 28.4 (C17), 28.3 (C12). MS (ESI+) : m/z 515 [M+H]+.
73%
With sodium acetate In N,N-dimethyl acetamide at -20℃; for 24 h;
To a suspension of cyclen (5.00 g, 29 mmol) and sodium acetate (7.86 g, 96 mmol) in DMA (60 mL) at -20 °C was added a solution of f-butyl bromoacetate (18.7 g, 14.1 mL, 96 mmol) in DMA (20 mL) dropwise over a period of 0.5 hour. The temperature was maintained at -20 °C during the addition, after which the reaction mixture was allowed to come to room temperature. After 24 hours of vigorous stirring, the reaction mixture was poured into water (300 mL) to give a clear solution. Solid KHCO3 (15 g, 1 50 mmol) was added portion wise, and compound 2 precipitated as a white solid. The precipitate was collected by filtration and dissolved in CHCI3 (250 mL). The solution was washed with water (100 mL), dried (MgSO4), filtered and concentrated to about 20-30 mL. Ether (250 mL) was added, after which compound 3 crystallized as a white fluffy solid. Yield: 1 2.5 g (73 percent). ESI-MS found: [M+H]+ = 515.5. 3
72%
at 20℃; for 72 h;
A solution of 2.20 equivalents of tert-butylbromoacetate in CHCl3 (40 ml) was added dropwise to a solution of one equivalent of tetraazacyclododecane in in CHCl3 and the solution was stirred at room temperature for 72 hours. The free protonated tetraazacyclododecane was then removed by filtration, and the resulting filtrate was washed with water and dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure yielding 72percent of tri-N-substituted tetraazacyclododecane 1, which was used for the next step without further purification. ESI-MS(+): found: 515 [M+H]+; calculated for C26H50N4O6: m/z 514, Rf = 0.64 (CHCl3/MeOH: 5:1), 1H NMR (250 MHz, CDCl3): 1.45 (s, 27H), 2.17 to 2.81 (m, 16H), 3.33 (s, 6H), 10.01 (br, 1 H); 13C NMR (CDCl3): 28.61 (C-16); 48.08 (C-9, C-11); 50.69 (C-2, C-6); 52.32(C-8, C-12); 53.02 (C-3, C-5); 57.21 (C-13); 80.74 (C15); 171.25, 171.41 (C-14a, C-14c). Elemental analysis: calculated (found) for: C26H50N4O6; C, 60.67(60.69); H, 9.79 (9.81); N, 10.89 (10.87); O, 18.65 (18.71). MS-MS of 515 in ESI mode: (El/intensity in percent) (Scheme 2): m/z= 459 (100percent); 409 (88percent), 347 (20percent).
64%
With sodium acetate In N,N-dimethyl acetamide at 20℃; for 120 h; Cooling with ice
Dissolve 2.0 g (11.6 mmol) starting material-1,4,7,10-tetraazacyclododecane in 25 ml dimethylacetamide and add 2.85 g (34.7 mmol) sodium acetate into the solution. Place the mixture in a 0 t ice bath, add 6.9 g (35.6 mmol) tert-butyl bromoacetate drop by drop, and stir the mixture at room temperature for 5 days. Then the mixture is poured into 125 ml water and add sodium bicarbonate into the mixed solution in batches. A solid is obtained after filtration and then is dissolved in 150 ml chloroform and washed with 75 ml water. Next get the organic layer, and add anhydrous sodium sulfate for dehydration. After vacuum evaporation for concentration and dissolution in 20 ml chloroform, add 150 ml alcohol for recrystallization to get 3.83 g (64.0percent) white solid product. The product is 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane. Analytic data of 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane: IR(KBr) ν 3980 (NH), 1730 and 1720 (C═O), 1162 and 1140 (CO) cm−1. 1H NMR (CDCl3) δ 10.05 (br, 1H, NH), 3.38 (s, 4H, CH2CO2), 3.29 (s, 2H, CH2CO2), 3.09 (s, 2H, NHCH2CH2), 2.91-2.88 (m, 8H, CH2CH2NHCH2CO2), 1.46 (s, 27H, (CH3)3). 13C NMR (CDCl3) δ 171.13 and 170.24 (CO). 82.28 (C(CH3)3), 58.80 (NCH2CO2), 51.92 and 51.80 (NCH2CH2N), 49.77 (NCH2CH2NH), 48.13 (NCH2CH2NH), 28.83 and 28.80 (C(CH3)3). MS m/z 515 ((M+H)+).
64%
With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 120 h;
Take 2.0 grams (g),11.6 millimol (mmol) of starting material 1,4,7,10-tetraazacyclododecane (1,4,7,10-tetraazacyclododecane) dissolved in 25 ml (ml) of dimethyl acetamidine In the case of dimethylacetamide,Then add 2.85 grams,34.7 milliliters of sodium acetate,Placed in a 0 degree ice bath,Add 6.9 grams dropwise,35.6 mmol of tert-butyl bromoacetate Moore (tert-butyl bromoacetate),Stir at room temperature for five days.Then, the aforementioned starting solution is poured into 125 ml of water.And add sodium bicarbonate in batches,After filtration, a solid is obtained.The above solid was dissolved in 150 ml of chloroform (Chloroform).And add 75 ml of water for cleaning.Next, take out the organic layer,Add anhydrous sodium sulfate to remove water,After concentration under reduced pressure, it was placed in 20 ml of chloroform.Recrystallization from 150 ml of ethanol,3.83 g of a 64.0percent white solid product are obtained as 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane.
48%
With sodium hydrogencarbonate In acetonitrile at -5 - 20℃; for 24 h;
A solution of cyclen S1 (2.90 g, 16.83 mmol), NaHCO3 (4.25 g, 50.59 mmol) and CH3CN (40 mL) was stirred at −5 °C before tert-butyl bromoacetate (7.6 mL, 51.47 mmol) was added dropwise. The reaction was slowly warmed to ambient temperature and stirring was maintained for 24 h. The thick white suspension was filtered under vacuum and the pale yellow filtrate was collected and concentrated under reduced pressure. The crude material was dissolved in hot PhMe (ca. 80 mL) and the desired product was isolated as the HBr salt using vacuum filtration. The white solid was dissolved in CH2Cl2 (50 mL) and washed with sat. NaHCO3 (3 × 40 mL), brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (4.178 g, 48percent) as a white solid. m.p 187–188 °C. (lit. 190–191 °C). ADDIN EN.CITE Jagadish2011484484817Jagadish, BhumasamudramBrickert-Albrecht, Gayle L.Nichol, Gary S.Mash, Eugene A.Raghunand, NatarajanOn the synthesis of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecaneTetrahedron LettersTetrahedron Letters2058-20615217SynthesisDOTADO3AContrast agentMRIX-ray crystallography20114/27/0040-4039http://www.sciencedirect.com.autorpa.lib.fju.edu.tw:2048/science/article/pii/S0040403910018630http://dx.doi.org.autorpa.lib.fju.edu.tw:2048/10.1016/j.tetlet.2010.10.07441H NMR (500 MHz, DMSO-d6) δ 8.78 (2H, br s, NH2), 3.41 (4H, s, 2 × CH2CO2), 3.35 (2H, s, CH2CO2), 3.02–2.96 (4H, m, 2 × CH2), 2.85–2.83 (4H, m, 2 × CH2), 2.71–2.66 (8H, m, 4 × CH2), 1.43–1.42 (27H, m, 9 × CH3). 13C NMR (125 MHz, DMSO-d6) δ 170.6 (2 × C), 170.0, 80.6, 80.5 (2 × C), 56.0 (2 × C), 52.1 (2 × C), 51.1, 49.6 (2 × C), 48.4 (2 × C), 45.5 (2 × C), 27.9 (6 × C), 27.8 (3 × C). HRMS (ESI, m/z) for C26H50N4O6 [M + H]+ calc. 515.3803; found 515.3810.
47%
at 0 - 20℃; for 18.5 h;
Reaction of cyclen with 3.0 eq of tert-butyl bromoacetate: (0169) To a solution of cyclen 1 (500 mg, 2.9 mmol) in anhydrous CHCl3 (5 mL) at 0° C. was added a solution of tert-butyl bromoacetate (1.70 g, 8.7 mmol) in anhydrous CHCl3 (10 mL) over 30 min. The resulting mixture was gradually warmed to rt, and continuously stirred for 18 h after which the reaction mixture was filtered while washing with CH2Cl2 to afford cyclen and mono-substituted cyclen (451 mg) as solid. The filtrate was concentrated in vacuo, and H2O (7 mL) was added into the residue, and the resulting solution was treated with 0.1 M HCl and 0.5 M NaOH to adjust the pH to 7. The resulting aqueous solution was evaporated, and the residue was dissolved in CH2Cl2 and filtered to remove NaCl salt. The filtrate was evaporated to dryness and the residue was washed with H2O to provide pure Compound 2 (696 mg, 47percent). The aqueous and ether layers were evaporated and dried to afford bi-substituted cyclen (115 mg, 9.9percent) and tetra-substituted cyclen (47 mg, 0.3percent), respectively. The 1H and 13C NMR spectra of Compound 2 were essentially identical to data reported previously. Reaction of cyclen with 2.4 eq of tert-butyl bromoacetate: (0170) To a solution of cyclen 1 (1.00 g, 5.8 mmol) in anhydrous CHCl3 (5 mL) at 0° C. was added a solution of tert-butyl bromoacetate (2.72 g, 13.95 mmol) in anhydrous CHCl3 (10 mL) over 30 min. The resulting mixture was stirred at 0° C. for 1 h, gradually warmed to rt, and continuously stirred for 17 h after which the reaction mixture was concentrated in vacuo. H2O (15 mL) was added into the residue, and pH of the resulting solution was adjusted to 7. Diethyl ether (15 mL) was added into the aqueous solution, and the white solid that formed was filtered off, washed with water, and dissolved in CH2Cl2. The organic solution was dried over MgSO4, filtered, and evaporated to the dryness to afford pure Compound 2 (1.34 g, 45percent). The 1H and 13C NMR spectra of Compound 2 were essentially identical to data reported previously.
36.5%
With triethylamine In chloroformInert atmosphere
3.5 equiv. of appropriate tert-Butyl bromoacetate (1.2 mL, 7.6 mmol) dissolved in 10.0 mL of anhydrous chloroform was added dropwise to a mixture of 1,4,7,10-tetraazacyclododecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equiv. triethylamine (2.3 g, 23.2 mmol) in 40 mL of anhydrous chloroform under N2. The reaction mixture was stirred for a further 16-20 h. The resulting solution was washed by water (40 mL×3), and the organic phase was dried by Na2SO4. The solvent was removed, and the crude products were purified by column chromatography on Al2O3 to afford the products 3 (437 mg, 36.5percent).
32%
With sodium hydrogencarbonate In acetonitrile at 20℃; for 24 h;
To a solution of tert-butyl bromoacetate (8.67 g, 44.23 mmol) in dry MeCN (75 cm3) was added cyclen (2.54 g, 14.70 mmol) and sodium hydrogen carbonate (3.72 g, <n="30"/>44.23 mmol). The reaction mixture was then stirred at room temperature under argon for 24 h. The solution was filtered and the filtrate solvent removed under reduced pressure to afford an orange residual oil, which crystallised upon standing. The crude material was purified by chromatography on silica gel (gradient elution: CH2Cl2: to 30percent CH2Cl2 / 60percent THF / 5percent MeOH / 5percent NH3) to yield the title compound as a white crystalline solid (2.41 g, 4.68 mmol, 32percent). δH (CDCI3, 500 MHz) 1.47 (27H, s, tBu), 2.88 (12H, br d, cyclen CH2), 3.11 (4H, br s, cyclen CH2), 3.30 (2H, s, acetate CH2),3.39 (4H, s, acetate CH2), 10.04 (1H, br s, NH). δc (CDCI3, 125 MHz) 28.4 (tBu), 30.6, 31.2, 47.8 (cyclen CH2), 49.4 (acetate CH2), 51.4 (cyclen CH2), 58.5 (acetate CH2), 81.9 (CtBu), 82.1(CtBu), 125.8, 169.9 (C=Oester), 170.8 (C=Oester). m/z (ES+) 515.6 (100percent, M + H).
32%
With sodium hydrogencarbonate In acetonitrile at 20℃; for 24 h; Inert atmosphere
This cyclen derivative was prepared according to the procedure described by O. Reany et al., J. Chem. Soc. Perkin. Trans 2., 2000, 1819. A mixture of cyclen (2.54 g, 14.7 mmol), te/t-butγl bromoacetate (8.67 g, 44.2 mmol) and NaHCO3 (3.72 g, 44.2 mmol) in anhydrous XH3CN (75 ml) was stirred at it, under argon, for 24 h. The solution was filtered and the filtrate concentrated under reduced pressure to afford a residual orange oil, which crystallised upon standing. The crude material was purified by column chromatography on silica (gradient elution: CH2CI2 to 5 percent CH3OH : CH2CI2, utilising 0.1 percent CH3OH increments) to yield the title compound 16 as a colourless crystalline solid (2.41 g, 4.68 mmol, 32 percent); m.p. 179-181 °C; 1H NMR (CDCI3, 500 MHz) δ 1.47 (27H, s, *Boc CH3), 2.88 (12H, br s, cyclen CH2), 3.11 (4H, br s, cyclen CH2), 3.30 (2H, s, CH2CO2^Bu), 3.39 (4H, s, CH2CO2^Bu), 10.04 (1H, br s, NH); 13C NMR (CDCI3, 125 MHz, 1H decoupled 500 MHz) δ 28.4 (9C, feoc CH3), 30.6- 31.2 (6C, cyclen CH2), 47.8 (1C, cyclen CH2), 49.4 (2C, CH2CO), 51.4 (1C, cyclen CH2), 58.5 (1C, CH2CO), 81.9 (2C, feoqq)), 82.1(1C, teoc(q)), 169.9 (2C, C = O), 170.8 (1C, C = O); MS (ES+) m/z 515.6 (100 percent, [M + H]+).
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 8, p. 918 - 920
[2] Tetrahedron Letters, 2009, vol. 50, # 31, p. 4459 - 4462
[3] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 12 - 20
[4] Patent: WO2014/200872, 2014, A1, . Location in patent: Page/Page column 73; 77
[5] Organic and Biomolecular Chemistry, 2011, vol. 9, # 5, p. 1591 - 1599
[6] Journal of Drug Targeting, 2011, vol. 19, # 9, p. 761 - 769
[7] Dalton Transactions, 2013, vol. 42, # 14, p. 4994 - 5003
[8] Molecular Pharmaceutics, 2014, vol. 11, # 2, p. 445 - 456
[9] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6747 - 6757
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 3, p. 1007 - 1010[11] Angew. Chem., 2015, vol. 127, # 3, p. 1021 - 1024,4
[12] Patent: TW2017/13632, 2017, A, . Location in patent: Paragraph 0012; 0015
[13] Patent: WO2005/3105, 2005, A1, . Location in patent: Page 8
[14] Chemistry - A European Journal, 2016, vol. 22, # 13, p. 4521 - 4527
[15] Journal of Materials Chemistry B, 2017, vol. 5, # 39, p. 8004 - 8012
[16] Journal of Labelled Compounds and Radiopharmaceuticals, 2012, vol. 55, # 4, p. 140 - 148
[17] Dalton Transactions, 2011, vol. 40, # 13, p. 3346 - 3351
[18] RSC Advances, 2016, vol. 6, # 9, p. 7288 - 7301
[19] Journal of the Chemical Society, Dalton Transactions, 2002, vol. 2, # 1, p. 48 - 54
[20] Patent: EP2740491, 2014, A1, . Location in patent: Paragraph 0123; 0124; 0125
[21] Patent: WO2014/86942, 2014, A1, . Location in patent: Page/Page column 31; 32
[22] Patent: WO2016/26841, 2016, A1, . Location in patent: Page/Page column 21
[23] Patent: EP1637524, 2006, A1, . Location in patent: Page/Page column 6
[24] Dalton Transactions, 2015, vol. 44, # 40, p. 17800 - 17809
[25] New Journal of Chemistry, 2016, vol. 40, # 5, p. 4606 - 4616
[26] New Journal of Chemistry, 2016, vol. 40, # 7, p. 5846 - 5854
[27] Dalton Transactions, 2007, # 45, p. 5260 - 5267
[28] Patent: US9981953, 2018, B1, . Location in patent: Page/Page column 8
[29] Patent: TW2018/13964, 2018, A, . Location in patent: Paragraph 0034; 0045; 0046; 0047
[30] Chemical Communications, 2007, # 12, p. 1269 - 1271
[31] Dalton Transactions, 2013, vol. 42, # 19, p. 6724 - 6727
[32] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 1987 - 1991
[33] Inorganica Chimica Acta, 2017, vol. 462, p. 236 - 240
[34] Patent: US9115094, 2015, B2, . Location in patent: Page/Page column 51; 52
[35] Dalton Transactions, 2011, vol. 40, # 24, p. 6451 - 6457
[36] Journal of Pharmacy and Pharmacology, 2002, vol. 54, # 8, p. 1073 - 1081
[37] Chemical Communications, 2011, vol. 47, # 31, p. 8835 - 8837
[38] Inorganic Chemistry, 2017, vol. 56, # 14, p. 7960 - 7974
[39] Synthetic Communications, 2015, vol. 45, # 5, p. 661 - 672
[40] Patent: WO2009/10580, 2009, A1, . Location in patent: Page/Page column 28-29
[41] Patent: WO2010/84090, 2010, A1, . Location in patent: Page/Page column 40; 41
[42] Chemical Communications, 2003, # 13, p. 1550 - 1551
[43] Chemical Communications, 2005, # 2, p. 259 - 261
[44] Chemical Communications, 2006, # 8, p. 909 - 911
[45] Patent: US5679810, 1997, A,
[46] Patent: WO2006/112723, 2006, A1, . Location in patent: Page/Page column 14
[47] Patent: WO2006/60797, 2006, A2, . Location in patent: Page/Page column 14-15
[48] Inorganic Chemistry, 2012, vol. 51, # 4, p. 2325 - 2331
[49] Journal of the American Chemical Society, 2012, vol. 134, # 8, p. 3647 - 3650
[50] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5294 - 5297
[51] Pharmaceutical Research, 2015, vol. 32, # 3, p. 955 - 967
[52] Patent: WO2015/89639, 2015, A1, . Location in patent: Paragraph 00221-00223
11
[ 107-59-5 ]
[ 294-90-6 ]
[ 122555-91-3 ]
Yield
Reaction Conditions
Operation in experiment
36%
With sodium hydrogencarbonate In acetonitrile at 20℃; for 40 h;
To a mixture of 1,4,7,10-tetraazacyclododecane (cyclen) (2.00 g, 11 mmol) and NaHCO3 (3.22 g, 38.4 mmol) in CH3CN (80 mL) was added t-butyl chloroacetate (5.42 g, 36 mmol) and the resulting mixture was stirred at room temperature for 40 h. After filtration, the filtrate was concentrated in vacuo and CHCl3 was added to the residue. The insoluble materials were removed through a pad of celite and the solvent was evaporated. The crude product was recrystallized from toluene to yield DO3A(tBu)3. Yield: 2.0 g (36percent). 1H NMR (CDCl3, 270 MHz): d 1.46 (s, 9H), 1.47 (s, 18H), 2.89-2.92 (br, 12H), 3.09-3.11 (br, 4H), 3.30 (s, 2H), 6.26 (s, 1H), 3.38 (s, 4H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7410 - 7413
1-10 1,4,7-tetraazacyclododecane
Dowex TM 1 × 8 200-400 mesh strong basic type I anion exchange resin (Cl type) was placed in a 300 mL beaker and dissolved in 1 M HCl.After filtering this with Nutche, the obtained filtrate was dissolved in distilled water and poured into a chromatographic tube filled with cotton and sea sand.After adding 1 M HCl until the pH of the droplet became 1, the pH was adjusted to 5 with distilled water. Then add 1 M NaOH until the pH reaches 12 and thenThe pH was adjusted to 7 using distilled water. A solution prepared by dissolving 1,4,7,10-tetraazacyclododecane tetrahydrochloride (1.50 g, 4.72 mmol) in the smallest amount of distilled water was put therein, and droplets having a basic pH were collected.This solution is concentrated on a rotary evaporator andVacuum drying gave a yellow solid. Dissolve this in CHCl3, add Na2SO4 to dehydrate it, filter it with Nutche, wash it with a small amount of CHCl3, collect the filtrate, and concentrate it with a rotary evaporator.Vacuum dried and left in the refrigerator to give a yellow solid(0.772 g, Yield 95%).
91.3%
With potassium hydroxide In water at 0 - 10℃;
5 Step 5: Preparation of cyclen
174g of cyclen · 4 hydrochloride was added to the reaction vessel, 100-200 ml of pure water was added, the temperature was raised to 80-100 ° C, and a solution of KOH (150-200 g) in water (150-200 ml) was added dropwise. After cooling to room temperature, crystals are precipitated. The ice-water bath is further cooled to 0-10 ° C, stirred for 1 hour, filtered, and the mother liquor is used to wash the filter cake. The filter cake is refluxed to remove water with toluene (500-800ml). Toluene (200-300 ml) was recrystallized to obtain 86 g of a white crystalline solid with a purity of 99.98% and a yield of 91.3%.
With potassium hydroxide
13.77 g
With sodium hydroxide In toluene at 40℃; for 1h; Reflux;
1.4
In a 500 ml reaction flask equipped with a stirrer, a condenser, and a water separator, 38 g of IV (0.20 mol) was placed,25% sodium hydroxide 47. 5 mL (0.6 mol) (controlled internal temperature below 40 degrees), stirred for 1 hour,Add 142. 5mL toluene, heated to reflux, until the anhydrous separation, slightly cold (60 degrees), suction toluene overnight,Residue plus 25% sodium hydroxide 47. 5 mL (temperature, same as above),Add 142. 5mL toluene reflux to the water, static, take out the toluene solution,The combined toluene solution was concentrated at room temperature for about 57 mL and cooled to room temperature. The crystals were precipitated, filtered,The crude product was then recrystallized with 4 times (wet weight) of toluene,To give 13. 77 g of product (vacuum at room temperature). Content> 99% (GC).
12 g
With sodium hydroxide In water; toluene
d Step d,
In a 500 mL reaction flask equipped with a stirrer, a condenser tube, and a water separator, 50 L of water and 50 g of water were successively added.Compound 4: 80g of sodium hydroxide with a concentration of 50%, stirred and crystallized, discharged, centrifuged, and the solid product was collected to obtain crude 15 g of cyclophanate, purified by toluene-water extraction, and the organic phase was collected and added to 142.5 mL. Toluene, heated to reflux, until no moisture is removed, cooled to 60°C, and the toluene was aspirated overnight. The residue was further added with 50% sodium hydroxide (temperature, ibid), and 142.5 mL of toluene was added to reflux to separate the water. Stir, suck out the toluene solution, combine the normal pressure of the toluene solution to concentrate about 57mL remaining at room temperature, cool to room temperature, crystallize out, and filter to obtain a crude product which is then recrystallized with 4 times (wet weight) toluene and concentrated to collect a white solid, which is dried under reduced pressure at 50°C. The product was obtained as 12 g of cyclosporine, yielding about 87.6%. . The reaction formula is as follows:
Stage #1: 1,4,7,10-tetraazacyclododecan With tris(dimethylamino)borane; sodium hydride In toluene for 4h; Heating;
Stage #2: benzyl bromide In toluene at 110℃; for 1h;
89%
In acetonitrile for 1h; Heating;
89%
With sodium carbonate In acetonitrile
1 1-Benzyl-1,4,7,10-tetraazacyclododecane
EXAMPLE 1 1-Benzyl-1,4,7,10-tetraazacyclododecane A solution of benzyl bromide (4.96 g; 0.029 mol) in acetonitrile (50 ml) is added in 1 h to a solution of 1,4,7,10-tetraazacyclododecane (50 g, 0.29 mol) in acetonitrile (450 ml) at refluxing temperature of the solvent and under inert atmosphere. After 30 minutes from the end of the addition, the reaction mixture is cooled at 5 C. and part of the 1,4,7,10-tetraazacyclododecane in excess precipitate. After filtration, the reaction mixture is evaporated under reduced pressure. The residue, dissolved in 5% aqueous solution of sodium carbonate (200 ml), is extracted with toluene (3*200 ml). The organic phase is washed with water (100 ml), anhydrified (Na2 SO4) and evaporated to dryness. After crystallization by petrol ether (m.p. 40-60 C.), the desired product is obtained (6.8 g) as a white solid. Yield 89%. m.p.: 85 C. Titre: 98% (G.C.) 1 H-NMR (CDCl3): δ2.4 (m, 8H); 2.5 (m, 4H); 2.6 (bt, 4H); 3.4 (bs, 2H); 7.2 (bm, 5H). 13 C-NMR (CDCl3): δ44.90; 46.13; 46.98; 51.03; 59.04; 126.84; 128.11; 128.80; 138.74.
89%
With sodium carbonate In acetonitrile
1 1-Benzyl-1,4,7,10-tetraazacyclododecane
EXAMPLE 1 1-Benzyl-1,4,7,10-tetraazacyclododecane A solution of benzyl bromide (4.96 g; 0.029 mol) in acetonitrile (50 ml) is added in 1 h to a solution of 1,4,7,10-tetraazacyclododecane (50 g, 0.29 mol) in acetonitrile (450 ml) at refluxing temperature of the solvent and under inert atmosphere. After 30 minutes from the end of the addition, the reaction mixture is cooled at 5 C and part of the 1,4,7,10-tetraazacyclcdodecane in excess precipitate. After filtration, the reaction mixture is evaporated under reduced pressure. The residue, dissolved in 5% aqueous solution of sodium carbonate (200 ml), is extracted with toluene (3*200 ml). The organic phase is washed with water (100 ml), anhydrified (Na2 SO4) and evaporated to dryness. After crystallization by petrol ether (m.p. 40-60 C), the desired product is obtained (6.8 g) as a white solid. Yield 89%. m.p.: 85 C. Titre: 98% (G.C.) 1 H-NMR (CDCl3):δ2.4 (m, 8H); 2.5 (m, 4H); 2.6 (bt, 4H); 3.4 (bs, 2H); 7.2 (bm, 5H). 1 H-NMR (CDCl3):δ44.90; 46.13; 46.98; 51.03; 59.04; 126.84; 128.11; 128.80; 138.74.
84%
In chloroform
63%
With triethylamine In chloroform for 15h; Heating;
Yield given. Multistep reaction;
2.49 g
Stage #1: 1,4,7,10-tetraazacyclododecan With hexacarbonyl molybdenum In dibutyl ether at 140℃; for 2h;
Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 0.5h;
Stage #3: benzyl bromide In N,N-dimethyl-formamide for 2h; Heating; Further stages.;
Stage #1: cyclen tetratosylate With sulfuric acid at 100℃; for 0.05h; Microwave irradiation;
Stage #2: With hydrogenchloride In water
Stage #3: With sodium hydroxide In water
85%
With sulfuric acid at 100 - 105℃; Heating; 30-48 h;
70%
With hydrogen bromide; acetic acid; phenol at 50℃; for 14h;
70%
With sulfuric acid at 100℃; for 39h;
70%
With sulfuric acid at 100℃; for 48h;
60%
With sulfuric acid at 130℃; for 72h;
60%
Stage #1: cyclen tetratosylate With sulfuric acid at 170℃; for 6h;
Stage #2: With hydrogen bromide In water
Stage #3: With sodium hydroxide for 24h;
59%
With sulfuric acid at 100℃; for 48h;
57%
With sulfuric acid at 160℃; for 0.5h; Inert atmosphere;
1.1.4 1,4,7,10-tetraazacyclododecane (cyclen)
Put a rotor in a 200 mL recovery flask,9.24 g (0.01171 mol) of cyclen · 4Ts and 46 mL of H 2 SO 4 were added, a reflux pipe equipped with a three way cock and a balloon was attached, vacuum drying and nitrogen substitution were carried out.The reaction vessel was immersed in an oil bath,Slowly raise the temperature to 160 ° C,The mixture was stirred at this temperature for 30 minutes. after that,Remove the oil bath, cool down to room temperature, remove the reflux tube, attach a 200 mL pressure equalizing dropping funnel,50 mL of EtOH was slowly added dropwise.Next, when 80 mL of Et 2 O was dropped slightly earlier, a dark brown solid precipitated, which was filtered and washed with EtOH and Et 2 O. This solid was dissolved in distilled water, filtered through celite, and the filtrate was concentrated with an evaporator to obtain a dark brown oily substance.When HCl and EtOH were added to the solution, a solid precipitated, which was washed and filtered with EtOH to obtain a pale brown solid of the desired hydrochloride(Yield 1.564 g, 42%).1.500 g (4.777 mmol) of this cyclen · 4 HCl was applied to an ion exchange column,The basic fractions were collected and concentrated to give a white solid.When CHCl 3 was added to this, impurities precipitated, so they were removed and again concentrated to obtain a white solid(Yield 0.4649 g, 57%).
54%
With sulfuric acid at 110℃; for 72h;
33%
With sulfuric acid at 115℃; for 28h;
With sulfuric acid
With sulfuric acid
a) Richman and Atkins Procedure
This is one of the most commonly used methods for the synthesis of cyclen, consisting of multistep protection-deprotection strategy.5-7 The key step of this method involves reaction of a preformed salt of a tritosylamide with sulfonate esters as leaving group in N,N-Dimethylformamide (DMF). Final separation of cyclen needs severe conditions to remove the tosyl protecting groups. For this purpose, 97% H2SO4 is used. This is a useful method provided that care is taken in the useof pure and dry starting materials. It has been reported to produce cyclen with a high yield (more than 60 %).
To a 100 mL round bottom flask fitted with a reflux condenser and stir bar was added 1.4696 g Cyclen (8.5 mmol). 5.44 11 g of <strong>[683-57-8]2-bromoacetamide</strong> (39.4 mmol, 4.6 eq) was added with 4.5748 g triethylamine (44.9 mmol, 5.3 eq) in 30 mL absolute ethanol. The contents were refluxed for 4 hours at 80 C, after which time a white precipitate formed in the flask. After cooling to room temperature, the precipitate was decanted and placed in a 250 mL round bottom flask, then dissolved in 200 mL of hot 80 % ethanol/20 % water. The volume was reduced by approximately 30 % on a roto-evaporator, then placed in the refrigerator overnight to produce white crystals. The remaining solvent was removed by filtration and the crystals were transferred to a 50 mL round bottom flask to dry on a Schlenk line under vacuum for several hours (66 % yield). ESI-MS: m/z = 401.3 (100 %), 402.3 (15 %) [M + H]+; 423.4 (25 %), 424.4 (< 10 %) [M + Na]+. 1H NMR (500 MHz, D20), ppm: 3.02 (s, amide pendent CH28H), 2.57 (s, Cyclen ring 16 H). 13C NMR (125 MHz, D20), ppm: 174.07 (carbonyl C),55.86 (amide CH2), 50.42 (ring CH2).
Stage #1: benzyl chloroformate; 1,4,7,10-tetraazacyclododecan In chloroform; water at 0 - 20℃; for 10h;
Stage #2: With sodium hydroxide In chloroform
7
Preparation of 1,7-bis-(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane (18) In a vessel containing ice water, benzyl chloroformate (34.32 ml, 41.59 g, 243.8 mmol) was added dropwise to a solution of cyclen compound (17) (20 g, 116.1 mmol) dissolved in CHCl3 (200 ml). The temperature was maintained below 0°C. When the addition was completed, the mixture was stirred at an ambient temperature for 10 hours so that sufficient solid was formed. The solvent was then evaporated under reduced pressure to obtain a white solid, to which ether (200 ml) was added. The solid was filtered and washed with ether (2 x 50 ml). Drying in vacuo while maintaining the temperature at 45°C gave dihydrochloride salt (59.01 g, 99% yield) as a white solid. To the solid was added 3 M NaOH (250 ml) to obtain the free base. The aqueous layer was extracted with CHCl3 (3 x 200 ml), and the combined extract was washed with brine and dried over MgSO4. The solvent was removed by using a rotary evaporator, and the residue was dried in vacuo for several hours to obtain a solidified clear oily compound (18) (50.12 g, 98% yield). 1H NMR (400 MHz, CDCl3): δ 7.52-7.32 (m, 10H), 5.18 (s, 4H), 3.83-3.65 (m, 8H), 3.10-2.83 (m, 8H); 13C NMR (100.6 MHz, CDCl3): δ 156.5, 136.3, 136.2, 129.0, 128.8, 128.7, 128.4, 128.3, 128.2, 68.1, 68.0, 50.9, 50.8, 50.6, 50.5, 50.3, 50.0, 49.6, 49.3.
98%
In chloroform
97%
In chloroform
95%
In chloroform at 0 - 20℃; Inert atmosphere;
2.1.1 Synthesis and characterisation of Zn(II)-Cyclen-(Trp)2
2.1.1 Dibenzyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (1) 12 Under an inert atmosphere, to a stirring solution of 1,4,7,10-tetraazacyclododecane (500 mg, 2.90 mmol) in dry chloroform (40 mL), benzyl chloroformate (828.65 μL, 5.80 mmol) dissolved in dry chloroform (20 mL) was added dropwise at 0 °C. The reaction was further allowed to stir for an additional 24 h at room temperature. After completion of the reaction, organic layer was separated and washed with water (3 * 50 mL), dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to give compound 1 in 95.0% yield. δH (400 MHz; CDCl3): 2.75-3.01 (10H, m, -NCH2-), 3.40-3.45 (8H, m, -NCH2-), 5.16 (4H, s, 2 * -COOCH2-), 7.28 (10H, m, ArH); δc (100 MHz, CDCl3): 49.0, 49.3, 49.6, 50.0, 50.2, 50.2, 50.5, 50.6 (-CH2- cyclen ring), 67.8, 67.9 (-COOCH2-), 128.0, 128.0, 128.4, 128.4, 128.7, 128.7 (-ArC-), 135.8, 135.9 (-COOCH2C-), 156.1, 156.1 (-NCOO-); (ESI-MS, m/z accuracy: +-0.2 u): Mass calculated for C24H32N4O4 440.2; found [M+H]+ 441.7.
88%
With pH 2-3
74%
Stage #1: benzyl chloroformate; 1,4,7,10-tetraazacyclododecan With hydrogenchloride; disodium hydrogenphosphate In 1,4-dioxane; water at 20℃; for 20h;
Stage #2: With potassium hydroxide In water
3
Disodium hydrogen phosphate (14.0 g, 98.6 mmol) was added to a solution of cyclen (5.00 g, 29.0 mmol) in H2O - 1,4-dioxane (50 : 20 v/v, 70 ml) and the pH adjusted to pH 2.5 by the addition of cone. HCl(aq) (12 M). Benzyl chloroformate (10.0 ml, 70.1 mmol) in dioxane (20 ml) was added dropwise to the stirred solution at room temperature, over 2 h, followed by stirring for a further 18 h to afford a colourless solution containing a white precipitate. The solvent was removed under reduced pressure and the residue dissolved in H2O (100 ml). The pH of the aqueous phase was then raised to pH 7 by the addition of 1 M KOH(aq). The aqueous phase was then extracted with diethyl ether (2 x 100 ml), followed by CH2CI2 (2 x 100 ml). The CH2CI2 extracts were combined, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to afford a colourless oil. The material was repeatedly washed with diethyl ether and concentrated under reduced pressure (3 x 50 ml) to yield the title compound 31 as a colourless crystalline solid (9.47 g, 21.5 mmol, 74 %); m.p. 113- 116 °C; 1H NMR (CDCI3, 500 MHz) δ 2.05 (2H, br s, NH), 2.86-3.12 (8H, br m, cyclen CH2), 3.47-3.79 (8H, br m, cyclen CH2), 5.18 (4H, s, Cbz CH2), 7.33-7.40 (1OH, m, Ph); 13C NMR (CDCI3, 125 MHz, 1H decoupled 500 MHz) δ 49.2 (1C, cyclen CH2), 49.4 (1C, cyclen CH2), 49.9 (1C, cyclen CH2), 50.1 (1C, cyclen CH2), 50.5 (1C, cyclen CH2), 50.7 (1C, cyclen CH2), 50.9 (1C, cyclen CH2), 68.1 (2C, Cbz CH2), 68.2 (1C, cyclen CH2), 128.3 (2C, Ph), 128.4 (2C, Ph), 128.7 (2C, Ph), 128.8 (2C, Ph), 129.0 (2C, Ph), 129.1 (2C, Ph), 136.1 (2C, Ph(q)), 136.2, 156.4 (1C, C = O), 156.5 (1C, C = O); MS (ES+) m/z 441.4 (100 %, [M + H]+).
72%
In dichloromethane at 0℃; for 3h;
72%
In dichloromethane at 0 - 20℃;
Synthesis of dibenzyl 1,4,7,1 0-tetra azacyclododecane-1 , 7-dicarboxylate (1):
1,4,7,10-tetraazacyclododecane (cyclen, 18.06 g, 105 mmol) was dissolved in 500 mL dichloromethane in a 1 L round bottom flask and cooled to 0 °C using an ice bath. Benzyl chloroformate (34 g, 200 mmol) was dissolved in 250 mL dichloromethane and addeddropwise over the course of three hours while keeping the temperature at 0 °C. The light yellow solution was allowed to slowly warm to room temperature and was stirred overnight. The solvent was evaporated to roughly 25% of its initial volume. 500 mL of diethyl ether were added to induce precipitation of the entire product. The white solid was filtered off using a Buchner funnel and washed with portions of diethyl ether (3 x lOOmL). Aftersuspending the solid in 500 mL of water in a 2 L beaker, a sodium hydroxide solution (20%) was slowly added upon vigorous stirring until a pH of 14 was reached. The milky solution was transferred to a 100 mL separatory funnel and extracted with diethyl ether (3 x 200 mL). The organic layer was washed with water (3 x 200 mL) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. A viscous, colorless oil was obtained. Yield: 33.30g (75.6 mmol, 72%) ‘H NMR (300 MHz, CDC13): ö 2.75-2.91 (m, 8H), 3.11-3.20 (m, 8H),5.11 (s, 4H), 7.22-7.3 1 (m, 1OH). LCMS-ESI: 441.54 (M+H).
69%
With hydrogenchloride; disodium hydrogenphosphate; triethylamine In 1,4-dioxane; water at 20℃; for 18h; Inert atmosphere;
57%
In chloroform at 60℃; for 1.66667h; Inert atmosphere;
3.2.6. Synthesis of Dibenzyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (6)
Under an inert atmosphere, cyclen (1 g, 5.80 mmol) was dissolved in CHCl3 (52 mL) andCbzCl (1.69 mL, 11.90 mmol) was added dropwise, resulting in the formation of a white precipitate.The mixture was heated to 60 C and stirred for 1 h and 40 min. The pH at the end of the reaction wasconfirmed to be acidic. The solvent was evaporated under reduced pressure to yield a white solidmixed with a yellow solid. The solid was washed over a filter with Et2O and the residue was taken upwith 4M aq. NaOH and extracted 4 times with Et2O. The organic layers were washed with 1M aq.NaOH (2) and then dried over Na2SO4. The solvent was evaporated under reduced pressure to yieldcompound 6 (1.47 g, 3.33 mmol, 57%) as a colourless oil. 1H-NMR (500 MHz, CDCl3): 7.36-7.28 (m,Har, 10H), 5.15 (s, O-CH2-bz), 3.51-3.35 (m, Hring, 8H), 2.99-2.70 (m, Hring, 8H) 13C-NMR (300 MHz,CDCl3): 128.77 (Car), 128.37 (Car), 128.12 (Car), 67.63 (O-C-bz), 51.07 (Cring), 50.66 (Cring), 50.09 (Cring), 49.52 (Cring), 48.89 (Cring), 48.60 (Cring) ESI+-MS: C38H58N8O16 [M + H]+ m/zcalc 441.24963 m/zfound441.25100.
In water
In chloroform
In water
Stage #1: benzyl chloroformate; 1,4,7,10-tetraazacyclododecan
Stage #2: With sodium hydroxide In water
In chloroform at 20℃;
With hydrogenchloride; sodium hydroxide In 1,4-dioxane; water for 20h;
3 Synthesis of 1 ,7-bis(benzyloxycarbonyl)- 1,4,7,1 0-tetraazacyclododecane (bis-CBZCyclen)
Cyclen was dissolved in water (2.5 g in 18 mL) and the pH was adjusted to 3 by adding HC1 (5 mL of 6M) followed by the addition of 15 mL of dioxane. Benzylchloroformate (6.4 g) was dissolved in dioxane. This solution was added to the reaction mixture over approximately 20 hours while the solution pH was maintained at 2-3 by addition of NaOH. Upon completion of the reaction, the solvents were removed by evaporation and the resulting solid was extracted with diethylether to give an oil. The remaining residue was dissolved in basic solution and extracted with diethylether. The combined extracts gaveadditional product to give a total yield of 80%.
40 mL of CH2Cl2, 12.0 g of cyclen and 30 mL of triethylamine were added to the reaction vessel with stirring.A solution of 4.6 g of Boc anhydride in 20 mL of CH 2 Cl 2 was added dropwise at 0 C.After completion of the reaction, the organic phase was separated to give 29.6 g of Compound 2.The yield was 90%.
80%
With triethylamine; In chloroform; at 20℃;
A solution of di-tert-butyl dicarbonate (1.77 g, 8.12 mmol) in chloroform (10 mL) was added slowly via addition funnel to a solution of cyclen (7, 0.51 g, 2.90 mmol) and triethylamine (1.25 mL, 8.99 mmol) in chloroform (40 mL) at rt. The reaction mixture was stirred at rt overnight and then concentrated through rotary evaporation. The resulting residue was purified by column chromatography over silica gel with gradient elution from ethyl acetate to 5% methanol/dichloromethane to yield the product as a white solid (1.02 g, 80%). Characterizations matched previous reports.61
72%
With triethylamine; In chloroform; at 20℃; for 24h;
Molecule A can be prepared by slowly, i.e. within 3 hours, adding a solution of di-tert-butyl dicarbonate (7.9 g, 36 mmol) in CHCl3 (100 mL, passed through Al2O3) to a solution of cyclen (2.2 g, 13 mmol) and triethylamine (5.5 mL, 39 mmol) in CHCl3 (120 mL) at room temperature. The reaction mixture is stirred for 24 hours at room temperature, and the organic solvent is removed under reduced pressure. The remaining residue is purified by silica gel column chromatography (hexanes/AcOEt) to provide molecule A as a colourless, amorphous solid (4.4 g, 72%)[ E. Kimura, J. Am. Chem. Soc., 1997, 199, 3068-3076].The tri-BOC protected molecule A (15.2 g) is then dissolved in 20 mL of acetonitrile, after which 19 mL of diisopropylethylamine and 7.9 g of benzylbromoacetate in 10 mL acetonitrile are added. The solution is heated up to 60-65 C. and stirred overnight under an argon atmosphere. The mixture is then concentrated by evaporation of the solvent and dissolved in dichloromethane. The solution is washed with 1 M NaOH. The organic layer is dried with Na2SO4 and thereafter reduced by evaporation and co-evaporation with toluene. The pure product, molecule B, is isolated by silica column chromatography using hexane/ethyl acetate(1/1) as eluent. The yield is about 90%.Molecule B (6.22 g) is dissolved in 60 mL dichloromethane and 60 mL trifluoracetic acid (TFA). The solution is stirred under a nitrogen atmosphere. After 3 hours the solvents are evaporated and another portion of TFA (40 mL) is added. After 2 hours of further stirring the TFA is evaporated and the remaining mixture is co-evaporated twice with toluene, leaving the crude TFA-salt of molecule C as an oil, of which then 10 g is used in a following step without further purification. The oil is dissolved and stirred in 45 mL DMF and 31 mL diisopropylethylamine. Then, 4.7 g bromo acetamide is added and the mixture is stirred for two days at 50 C., during which time a precipitate is developed. The mixture is brought in 600 mL ether, is stirred and the brown precipitate is isolated by filtration and washing with ether. The solid is then washed four times with portions of 25 mL of 25% NH3 solutions in water and finally with 30 mL of water. Drying under vacuum at 40 C. results in a white solid product of molecule D (yield=85%).Molecule D (1.7 g) is then hydrogenated at 70 psi overpressure in 100 mL water using Pd/C (10%) as catalyst. The mixture is filtered over celite, the celite is washed with some water and the filtrate is freeze dried and then dried over P2O5 in vacuum to afford 1.1 gram of a fine white hygroscopic powder of molecule E.For the coupling of molecule E to the carrier, in the example given to a PPI dendrimer, the amide coupling agent HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) is used. The coupling of the paramagnetic complex to the dendrimer is illustrated in FIG. 5. For convenience, the dendrimers are denoted as circles. The dendrimers used are commercially available poly(propylene imine) (PPI) dendrimers (from Aldrich under the name DAB-Am-X or from SyMO-Chem) with a diaminobutane (DAB) derived core. The most used name for those dendrimers is DAB-Am-X, wherein X refers to the number of surface amino groups. In this synthesis, DAB-Am-4 and DAB-Am-16 have been used in order to respectively obtain a DOTAM-G1 complex and a DOTAM-G3 complex. The formation of DOTAM-G1 and DOTAM-G3 is similar, only the value for the number n of end groups is different, i.e. for DOTAM-G1 n=4 and for DOTAM-G3 n=16.For the coupling of molecule E to the G1 PPI dendrimer, 0.39 mL diisopropylethylamine is added to a mixture of 312 mg HBTU in 3 mL dry DMF. Molecule E (300 mg) is added, the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. Subsequently, 60 mg DAB-Am-4 in 3 mL DMF is added. The mixture is stirred overnight under an inert atmosphere, after which it is dropped into 150 mL of ether. The sticky precipitate is taken up in a small amount of methanol and precipitated into ether giving a white solid, that is again precipitated from methanol into ether. Finally, the solid is dissolved in methanol and eluted over an anion exchange column (Dowex OH-). Evaporation of the solvent gave about 200 mg of product, which in the further synthesis will be called molecule II.For the coupling of molecule E to the G3 PPI dendrimer, 0.25 mL diisopropylethylamine is added to a mixture of 164 mg HBTU in 1 mL dry DMF. Molecule E (172 mg) is added and the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. The third generation PPI-dendrimer DAB-Am-16 (41 mg) in 1 mL dry DMF is then added and the solution is stirred overnight under an inert atmosphere of nitrogen. The mixture is poured into 40 mL of stirred ether giving a precipitate; the ether is replaced by another portion of ether (washing step), and the precipitate is dried. Finally, the precipitate is dissolved in water an...
72%
With triethylamine; In chloroform; at 0 - 20℃;Inert atmosphere;
To a solution of cyclen (S4, 1.73 g, 10.0 mmol) and triethylamine (4.20 mL, 30.1 mmol)in CHCI3 (120 mL, freshly passed through A1203 (activated, neutral, Brockmann I)) at 0C was added dropwise a solution of di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) inCHCl (100 mL, freshly passed through A1203 (activated, neutral, Brockmann I)) under N2. After the addition was complete, the resulting solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, EtOAc:hexane = 3:2 ramping to EtOAc) to give S6 as a white foam (3.41 g, 72%).RF (EtOAc:hexane = 4:1) 0.63. IR vmax/cm1 3313, 2974, 2931, 2818, 1679, 1463, 1412,365, 1313, 1247, 1156, 1 046, 771, 736. 1H NMR (400 MHz, CDCI3) 5 1.45 (5, 1 8H, 2 x C(CH3)3), 1.47 (5, 9H, C(CH3)3), 2.78-2.92 (m, 4H, CH2NHCH2), 3.16-3.34 (m, 6H),3.34-3.50 (m, 2H), 3.55-3.75 (m, 4H) (total 12H, 3 x CH2N(Boc)CH2) (one secondary amine proton signal (NH) not observed). ?3C NMR (100 MHz, CDCI3) 5 28.1, 28.2, 28.3,28.4, 28.5, 44.7, 45.7, 48.8, 49.2, 50.3, 50.8, 78.9, 79.1, 155.1, 155.4 (eight carbon signals overlapping or obscured). MS (ESI) m/z 472.9 ([M+H], 27%), 495.0 ([M+Na], 99%), 967.1 ([2M+Na], 100%). The spectroscopic data were in agreement with those in the literature.3739
68%
With triethylamine; In chloroform; at 20℃; for 6h;
In a 200 mL round bottom flask, 1,4,7,10-tetraazacyclododecane (2 g), chloroform (50 mL), three Ethylamine (11.2 mL, 7.2 eq) was stirred at room temperature. Dissolve 30 mL of di-tert-butyl dicarbonate (6.87 g, 2.7 eq) The chloroform solution was added dropwise to the system at room temperature, and after 6 hours of reaction, TLC dot plate detection reaction is over, Condensed by vacuum distillation, and purified by column chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) 1,4,7,10-tetraazacyclododecyl-1,4,7-tricarboxylic acid tri-tert-butyl ester (3.73 g) was obtained. The product was obtained as a colorless oil, yield 68%.
57%
With diisopropylamine; In chloroform; for 12h;Inert atmosphere;
Di-tert-butyl dicarbonate (16.5 g, 0.076 mol) in chloroform (100 mL) was added dropwise to a chilled mixture of 1 ,4,7,10-tetraazacyclododecane (5.0 g, 0.029 mol) and diisopropylamine (15 mL, 0.087 mol) in chloroform (200 mL) over a period of three hours. The reaction was then stirred overnight under an atmosphere of nitrogen. The reaction was concentrated, brought up in ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (200 mL), followed by one wash of monobasic potassium phosphate (200 mL of 1 M) and brine (200 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated. The crude reaction was purified using flash chromatography (4:1 ethyl acetate :hexanes) to yield a white solid (7.84 g, 57%). 1H NMR (400 MHz, CDCI3) delta 3.67-3.52 (br, 4H), 3.46-3.14 (m, 8H), 2.88-2.72 (br, 4H), 1 .44 (s, 9H), 1 .42 (s, 18H); 13C NMR (100 MHz, CDCI3) delta 155.4, 79.2, 79.1 , 50.8, 49.3, 49.3, 48.7, 45.8, 44.8, 28.5, 28.3; LRMS (ESI): m/z [M+H]+ calc'd for C23H45N406+ 473.33, found 473.33.
57%
With diisopropylamine; In chloroform; at 0 - 20℃;Inert atmosphere;
Di-tert-butyl dicarbonate (16.5 g, 0.076 mol) in chloroform (100 mL) was added dropwise to a chilled mixture (0 C) of 1,4,7,10-tetraazacyclododecane (5.0 g, 0.029 mol) and diisopropylamine (15 mL, 0.087 mol) in chloroform (200 mL), over a period of three hours. The reaction was then stirred overnight under an atmosphere of nitrogen at room temperature. The reaction was concentrated, brought up in ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (200 mL), followed by one wash of monobasic potassium phosphate (200 mL of 1M) and brine (200 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated. The crude reaction was purified using flash chromatography (80 % ethyl acetate, 20% hexanes) to yield a white solid (7.84 g, 57%).1H NMR (400 MHz, CDCl3) delta 1.37-1.50 (m, 27H, 3 x Boc (CH3)3), 2.79-2.89 (br, 4H, 2 x cyclen CH2), 3.17-3.47 (m, 8H, 4 x cyclen CH2), 3.54-3.70 (br, 4H, 2 x cyclen CH2);13C NMR (100 MHz, CDCl3) delta 28.61, 28.80, 45.10, 46.11, 48.97, 49.59, 50.00, 51.12, 79.34, 79.46, 70.60, 155.53, 155.74, 155.92; LRMS (ESI): m/z [M+H]+calc?d for C23H45N4O6+473.33, found 473.33.
56 - 60%
In dichloromethane; at 20℃; for 18h;
A solution of di-tert-butyl dicarbonate (6.08 g, 27.86 mmol) in CH2Cl2 (100 ml) was added dropwise to a stirred solution of cyclen (2.00 g, 11.61 mmol) in CH2Cl2 (300 ml).The mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to yield a transparent oil, which was purified by <n="32"/>column chromatography on silica (gradient elution: 100% CH2Cl2 - 5 % MeOH/CH2Cl2, Rf = 0.29 10% MeOH/CH2Cl2) to afford the title compound as a white crystalline solid (3.08 g, 6.51 mmol, 56 %). deltaH (CDCI3, 300 MHz) 1.42 (18H, s, 3 x tBu), 1.44 (9H, s, tBu), 2.81 (4H, br s, cyclen 2 x CH2), 3.28 (8H, br s, cyclen 4 x CH2), 3.60 (4H, br s, cyclen 2 x CH2). deltac (CDCI3, 75 MHz) 28.9 (tBu), 29.0 ^Bu), 46.1 (cyclen CH2), 49.9 (cyclen CH2), 51.2 (cyclen CH2), 79.4 (C), 79.6 (C), 155.8 (C=O), 156.0 (C=O). MS (ES+) m/z 473.4 (100 %, [M + H]+).
56%
In dichloromethane; at 20℃;
A solution of di-te/t-butyl dicarbonate (6.08 g, 27.8 mmol) in anhydrous CH2CI2 (100 ml) was added dropwise to a stirred solution of cyclen (2.00 g, 11.61 mmol) in anhydrous CH2CI2 (300 ml). The reaction mixture was stirred at room temperature, for 18 h. The solvent was removed under reduced pressure to afford a transparent oil. The crude material was purified by column chromatography on silica (gradient elution: CH2CI2 to 5 % CH3OH : CH2CI2, utilising 0.1 % CH3OH increments) to yield the title compound 17 as a colourless crystalline solid (3.08 g, 6.51 mmol, 56 %); RF = 0.29 (Silica, CH2CI2 - CH3OH, 9 : 1, v/v); 1H NMR (CDCI3, 500 MHz) delta 1.42 (18H, s, feoc CH3), 1.44 (9H, s, *Boc CH3), 2.81 (4H, br s, cyclen CH2), 3.28 (8H, br s, cyclen CH2), 3.60 (4H, br s, cyclen CH2); 13C NMR (CDCI3, 125 MHz, 1H decoupled 500 MHz) delta 28.9 (6C, 'Boc CH3), 29.0 (3C, 'Boc CH3), 46.1 (2C, cyclen CH2), 49.9 (2C, cyclen CH2), 51.2 (4C, cyclen CH2), 79.4 (2C, fex*,)), 79.6 (1C, ^oqq)), 155.8 (2C, feoc C = O), 156.0 (1C, 'Boc C = O); MS (ES+) m/z 473.3 (100 %, [M + H]+); HRMS (ES+) m/z found 473.3330 [M + H]+ C23H45O6N4 requires 473.3333.
48%
With triethylamine; In chloroform; at 0 - 20℃; for 20h;
Place the rotor in a 50 mL eggplant flask, dissolve 0.4649 g (2.703 mmol) of cyclen in 131.2 mL of CHCl 3, add 1.16 mmol of Et 3 N,Immersed in an ice bath and brought to 0 C.A solution of 1.780 g (8.213 mmol) of (Boc) 2 O in 10.1 mL of CHCl 3 was added dropwise at 0 C. over 2 hours. After the dropwise addition, the ice bath was removed and the mixture was stirred at room temperature for 18 hours.After this, the solution was washed three times with H 2 0 in a separating funnel,The organic phase was dried over Na 2 SO 4 and concentrated to give an oily substance which was vacuum dried to give a white solid. This solid was dissolved in a minimum amount of CHCl 3,Purification by open column chromatography (packing agent: silica gel, developing solvent: CHCl 3: MeOH = 20: 1) gave the fractions containing the desired product collected and concentrated to give the desired white solid(Yield 0.6133 g, 48%).
With triethylamine; In chloroform; at 20℃; for 24h;
At room temperature, the 20mmol1,4,7,10- tetraazacyclo dodecane, 60mmoltriethylamine were dissolved in 30mL of chloroform, and then at a rate of 1 to 2 drops /sec dropwise 55.5mmol di tert-butyl ester was dissolved in 100 mL of chloroform solutionof 1,4,7,10-tetraazacyclododecane-cyclododecane and triethylamine, the molar ratio ofdi-tert-butyl ester of 1: 3.0: 2.8 , the 1,4,7,10-tetraazacyclododecane-cyclododecane,triethylamine were dissolved in chloroform, the quality 1,4,7,10-tetraazacyclododecaneof cyclododecane and chloroform ratio of 1:13, the mass ratio of the two was dissolvedin chloroform tert-butyl dicarbonate, di-tert-butyl ester and chloroform 1:12, after theaddition was stirred at room temperature for 24 hours under reduced pressure distilledchloroform, ethyl acetate and petroleum ether volume ratio of 3: 2 mixed solution as themobile phase, silica gel as stationary phase column chromatographic separation of theresulting residue, compound of formula II
2,3,5,6,8,9-hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine[ No CAS ]
[ 294-90-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With lithium aluminium hydride In tetrahydrofuran; toluene at 0 - 130℃; for 1h;
2 <Example 2. Synthesis of 1,4,7,10-tetraazacyclododecane>
Compound 1 synthesized in Example 1 (100 mg, 0.61 mmol) was dissolved in anhydrous toluene (5.2 mL), and cooled to 0 ° C. LiAlH 4 (1.83 mL, 3.65 mmol, at the same temperature) 2.0 M THF [(Tetrahydrofuran)] solution) Was added and heated to reflux at 130 ° C. for one hour. After the reflux reaction, the reaction was cooled to 0 ° C., and then quenched LiAlH4, slowly adding water (0.14 mL) based on LiAlH4 (1.83 mL, 0.14 g, 3.65 mmol) used in the reaction, followed by anhydrous sodium An aqueous 15% (w / v) hydroxide solution (0.14 mL) was added again in the same volume. Next, three volumes of water (0.42 mL) were added and reacted at room temperature for 30 minutes. The formed gel was removed after filtration using celite 545, but washed with chloroform (200 mL). The filtrate was concentrated and dried under reduced pressure to obtain 1,4,7,10-tetraazacyclododecane (general name: cyclen, white solid, 74 mg) in a yield of 70%.
58%
With diisobutylaluminium hydride In toluene for 16h; Cooling with ice; Reflux; Inert atmosphere;
With triethylamine In tetrahydrofuran for 7h; Heating;
53%
With triethylamine In tetrahydrofuran at 65℃; for 48h; Inert atmosphere;
2.2. Synthesis
General procedure: N-n-butyl bromoacetamide and N-benzyl bromoacetamide were prepared by previously published methods [32,33]. DOTAM n-butyl and DOTAM-benzyl were synthesized according to Scheme1. Under a nitrogen atmosphere at room temperature, triethylamine (5.06 g, 50 mmol) was added to a solution of 1,4,7,10-tetraazacyclododecane (1.03 g, 6 mmol) and bromoacetamide (24 mmol) in 100 mL CH3CN (for DOTAM-n-butyl) or THF (for DOTAM-benzyl). The reaction mixture was stirred at 65 °C for 2 days. After cooling, the white solid was filtered and washed with cold CH3CN and ice-cold water, then dried under vacuum and recrystallized from CH3CN to afford the title compound as a colorless solid.
Stage #1: 1,4,7,10-tetraazacyclododecan; Benzyl bromoacetate In chloroform at 4℃; for 26h;
Stage #2: With sodium hydrogencarbonate In water
3; 9.9A
This example shows the synthetic route used to make 1,4,7,10-tetraazacyclododecane-1-acetic acid phenylmethyl ester, (6) in Scheme 3 above.To a solution of TACD (21.5 g, 0.125 mol) in CHCl3 (200 mL) was added benzyl-2-bromoacetate (11.45 g, 7.92 mL, 0.05 mol) in CHCl3 (50 mL) dropwise over a period of 2 h and the reaction mixture was allowed to stand at 4° C. for 24 h. Chloroform was removed on a rotary evaporator and the residue was treated with a saturated solution of sodium bicarbonate (200 mL). The mixture was extracted with methylene chloride and the methylene chloride solution was washed with water and the organic layer was removed and dried with sodium sulfate. Methylene chloride was removed to give 6 as a viscous oil, which was dried, under vacuum for 24 h. Yield 12.0 g. (75%). The crude 1,4,7,10-tetraazacyclododecane-1-acetic acid phenylmethyl ester 6 was used in the next step without further purification.MS: (M+H)+=3211H-NMR (CDCl3): δ 2.55 and 2.75 (m, 16H), 3.48 (s, 2H), 5.12 (s, 2H), 7.32 (m, 5H).
With sodium hydrogencarbonate; In acetonitrile; at 0 - 20℃; for 49h;Inert atmosphere;
1,4,7,10-Tetraazacyclododecane (1 g, 5.81 mmol) was dissolved in dry acetonitrile (20 ml) under nitrogen at 0oC. NaHCO3 (1.464 g, 17.44 mmol) was added with stirring. tert-Butyl bromoacetate(3.4 g, 17.44 mmol) in 10 ml acetonitrile was added slowly from a dropping funnel in 1 h. The reaction was stirred at 0oC for another 3 h and at room temperature for 45 h. The progress of the reaction was monitored by TLC using dichloromethane (DCM):methanol (9:1) (Rf 0.67). On completion of reaction, reaction mixture was filtered and filtrate was evaporated to dryness. Crude compound was purified by column chromatography over silica gel using 2% methanol in DCM as eluant to give compound 2 as white powder.Yield: 83.5%
83%
With potassium carbonate; In acetonitrile; at 70℃; for 6h;
With sodium acetate; In N,N-dimethyl acetamide; at 0 - 20℃; for 120h;
In a 500 ml round bottom flask, the compound (1) (2 g, 11.62 mmol) and sodium acetate (2.85 g, 34.8 mmol) were dissolved in N, N-dimethylacetamide (DMA, 25 mL). Tert-butyl bromoacetate (6.79 g, 34.82 mmol) was dissolved in N, N-dimethylacetamide (10 mL) at 0 C under ice-cooling, and reacted at room temperature for 5 days, After the completion of the reaction and then pour 125ml of water, then the reaction will be slightly yellow solution, And then slowly add sodium bicarbonate, will find the reaction of white precipitate produced, The precipitate was filtered and the precipitate was dissolved in 150 mL of chloroform, and washed with water (3 x 100 mL), discard the aqueous phase. The organic phase was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The organic phase was recrystallized from diethyl ether to give the compound (2) (4.1 g, 78%) as a white solid. Having a structure of the following formula 3:
77%
3.3 equivalents of tert-butyl bromoacetate (773.0 mg, 7.6 mmol) dissolved in 10.0 mL anhydrous chloroform was added dropwise to a mixture of 1,4, 7,10-tetraazacyclododecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equivalents of triethylamine (2.3 g, 23.2 mmol) in 40 mL anhydrous chloroform under an argon atmosphere for about half an hour. The reaction mixture was stirred for another 2 hours, and 0.5 equivalents of anhydrous K2CO3 was added. After a further 14 hours of reaction, the resulting solution was washed by water (3 x 40 mL). Then anhydrous Na2SO4 was used to dry the organic phase and the solvent was removed under vacuum to give a transparent oil. This crude product was purified by flash chromatography on aluminium oxide (dichloromethane/methane = 200: 5 (volume/volume), Rf = 0.35) to give tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (1) as a white powder (0.92 g, 1.78 mmol), yield: 77%. mp 178-180C, 1H NMR (400 MHz, CDCl3) : delta 3.34 (4H, s), 3.26 (214, s), 3.05 (4H, s), 2.89-2. 85 (12H, m), 1.47 (27H, s) ; 13C NMR (100 MHz, CDCl3) : delta 170.5 (2 x C), 169.6 (C), 81.6 (3 x C), 58.2 (3 x CH2), 51. 3 (2 x CH2), 51. 1 (2 x CH2) 49.2 (2 x CH2), 47.5 (2 x CH2) 28.2 (3 x CH3) ; ESIMS m/z 515.3 (M+H)+; HRFABMS m/z 515. 3811 (M+H)+ [Calcd. For C26H51N4O6(M+H)+, 515.3809].
73%
With sodium acetate; In N,N-dimethyl acetamide; at 0 - 20℃; for 120h;Inert atmosphere;
Example 1-Synthesis of Tri-tert-butyl 2,2',2'-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate The protocol from O. Axelsson et al in was used. Cyclen (1,4,7, 10-tetraazacyclododecane) (5.0 g, 29 mmol) and AcONa (7.22 g. 88 mmol) were introduced in dry DMA (80 mL) under argon. alpha-bromo-tert-butylacetate (13 mL, 87 mmol) dissolved in dry DMA (13 mL) was added drop by drop at 0 C and the reaction was performed at room temperature during 5 days. At the end of the reaction, water (140 mL) was poured into the mixture and pH was adjusted at 9 with Na2CO3 before the introduction of KBr (5.05 g, 42.4 mmol). The mixture was filtrated and the beige precipitate was solubilized in CH2Cl2 and water was extracted. The organic layer was dried over Na2SO4, was concentrated, and the residue was washed with cooled EtOAc to isolate a white powder. This purification process led to the isolation of tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate as an amorphous white powder (10.9 g, 73 %). Mp : 179 C (recrystallised from toluene to give yellow crystals). Rf : 0.7 (CH2Cl2/MeOH/NH4OH 80:15:5, Draggendorf visualization) 1H NMR (CDCl3, 300 MHz) delta 3.36 (s, 4H, H8), 3.28 (s, 2H, H13), 3.07 (m, 4H, H6), 2.88 (m, 12H, H2, H3, H5), 1.46 (s, 18H, H12), 1.45 (s, 9H, H17). 13C NMR (CDCl3, 75 MHz) delta 170.7 (C9), 169.9 (C14), 81,9 (C16), 81.7 (C11), 58.3 (C8 - C13), 51.5 (C5), 49.6 (C2 - C3), 47.7 (C6), 28.4 (C17), 28.3 (C12). MS (ESI+) : m/z 515 [M+H]+.
With (-)-cycleanine; sodium hydroxide; In water; at 80 - 85℃;pH 10 - 11;Large scale;
11.8 kg of chloroacetic acid along with 121 purified water were added to a 100 L reactor, stirred and dissolved, and 151 water in which 5 kg of sodium hydroxide was dissolved was added in an ice bath, 3.2kg of the cycleanine suspended in 6 l water and added to the reaction, the temperature was raised to 80~85 C, 6L of water with 5.2kg of sodium hydroxide was added drop wise to control the pH of the reaction system at 10~11, reacted overnight, after cooling to room temperature, 10.41 concentrated hydrochloric acid was added drop wise, the pH was adjusted to 2 to 2.5, stirred and crystallized, and the filter cake was collected by filtration and dried to obtain 7.5 kg of crude D0TA. The content of the compound of formula II was about 3.1%. 7.5kg of crude DOTA, 18 kg of purified water was added to the 50L reactor, after heating and stirred to dissolve, crystallization was cooled, filtered, washed, dried to obtain D0TA 6.21kg, the yield was 82.7 %, and the salt content was 2%, formula II compound content was 0.05%.
With sodium hydroxide; In water; at 25℃; for 20h;
Example 1 - Kinetic study for DOTA production during the step a) of the process This example illustrates the kinetics of step a) of the process for production of DOTA according to the present invention. The reaction was conducted for 72h at a temperature of 25C, using chloroacetic acid as the halo-acetic acid (4.3 eq.) and sodium hydroxide as a base (11.0 eq.) in water (12x - 12 parts of water for 1 part of initial amount of cyclen in weight) and samples were taken at different times for in-process control analysis via HPLC- chromatography (see above) . The results are shown in Table 1 as surface area % in the HPLC chromatograms and the conversion value (%) is found according to the following formula: Conversion (%) = 100% - X wherein X is the amount of cyclen. Measured impurities comprise unreacted alkylating acid, intermediate cyclen derivatives and counterions introduced by the halo-acetic acid and by the treatment with a base . Table 1 : Kinetic study data *RRT = Relative Retention Time These results show that in the settled conditions the reaction is completed after 20h, i.e at that time the conversion rate is 100%, which means that the starting material was completely consumed and therefore, that the process of the present invention can be carried out at temperatures as low as 20 C.
With sodium hydroxide; In water; at 5 - 25℃; for 20h;Large scale;
3. Preparation of DOTA to be purifiedSeven batches of DOTA were prepared. Batch B-01 was prepared by adding chioroacetic acid (54.86 Kg, 580.48 mol) to a solution of 1,4,7,10- tetraaza cyclododecane (20 Kg, 116.1 mol) in water (120 L) and the reaction mixture was cooled to 5±5C. A solution of sodium hydroxide (48.77 Kg in 120 L water, 1219 mol) was added slowly to the reaction mass by maintaining the internal temperature at 10±5C. The reaction mass was slowly warmed to 25±5C and stirred for 20 h. The obtained DOTA batch B-01, according to IPC has a DOTA content of 75.53 (area)%, contains also an intermediate compound (at retention time of 0.84 from the retention time of DOTA) of 1.2 (area)% and a cyclene content of 0.0%.
183 g
With potassium hydroxide; In water; at 80℃; for 24h;pH 8.5;
To the three-necked flask was added 1,4,7,10-tetraazacyclododecane (100 g, 0.58 mol)10 ml of deionized water, stirred, 30% KOH solution was added dropwise,The pH was adjusted to 8.5 and then chloroacetic acid (263 g, 2.78 mol) was added,And then 30% KOH solution to adjust the pH to 8.5,Heated to 80 C for 24 h, during which the pH was maintained between 8.5 and 9.After the reaction, cooling, adding concentrated hydrochloric acid to adjust the pH to 2, a white precipitate produced, filtered. The filter cake was recrystallized from a water-ethanol solution and the resulting crystals were washed with ethanol, ether, dried,183 g of DOTA crystals was obtained in a yield of 78%.
1,4,7-tris-(trifluoroacetyl)-1,4,7,10-tetraazacyclododecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine In methanol at 20℃;
89%
With triethylamine In methanol at 20℃;
12.b
1,4,7,10-Tetraazacyclododecane (10 mmol) was dissolved in methanol (15 ml). To the system was added triethylamine (2 ml), and then slowly dropwise added at room temperature ethyl trifluoroacetate (50 mmol). Upon the completion of dropwise addition, the mixture was allowed to react at room temperature over night, concentrated and then column separated (eluant: ethyl acetate) to obtain 4.1 g of a white solid, yield 89%, MS[M]+=460.3 m/e.
With triethylamine In methanol; dichloromethane
1 Preparation of 1,4,7-tris-(trifluoroacetyl)-1,4,7,10-tetraazacyclododecane
Example 1 Preparation of 1,4,7-tris-(trifluoroacetyl)-1,4,7,10-tetraazacyclododecane Cyclen (2.13 g, 12.35 mmol) was dissolved in MeOH (20 mL). To the clear solution was added NEt3 (1.70 mL, 12.35 mmol) in one portion, followed by slow addition of ethyl trifluoroacetate (7.35 mL, 61.76 mmol) during a period of 5 minutes. The reaction may be chilled to keep temperature under 25° C. Stirring was continued under N2 for 15 hours. Volatiles were then removed under vacuum. The residue was dissolved in the minimum amount of CH2Cl2 (~2.0mL) and passed through a short silica gel pad, eluted with 100% EtOAc. The eluent was concentrated to give the product as a white semi solid (5.25 g, 92.5%). 1H NMR (300 MHz, CDCl3): δ3.90-3.76 (broad multiplet, 4 H, 3.68-3.20 (multiplet, 8 H), 3.10-2.65 (multiplet, 4 H), 1.40-1.25 (multiplet, 1 H). Mass C14H17F9N4O3 requires C 36.53, H 3.72, N 12.17, O 10.43, found C 36.49, H 3.71, N 12.11, O 10.59.
With potassium carbonate In acetonitrile at 45 - 50℃; for 12h;
86%
With potassium carbonate In acetonitrile at 45 - 50℃; for 12h;
86%
With potassium carbonate In acetonitrile at 65 - 70℃; for 12.5h;
1; 2.b
1-(N-acetyl-aza-15-crown-5)-1,4,7,10-tetraazacyclododecane (1b). 260.0 mg (0.88 mmol) 1a dissolved in 10 mL anhyrous acetonitrile was added dropwise to a mixture of cyclen (378.5 mg, 2.20 mmol, 2.5 equiv.), potassium carbonate (5.0 equivs) in 40 mL warm anhydrous acetonitrile under N2 atmosphere for approximately half an hour. The mixture was then stirred at 65-70° C. for about 12 h. The solution was filtered under reduced pressure and the filtrate was evaporated to leave a crude oil that was purified by column chromatography on aluminium oxide with DCM:MeOH=100:5 as an eluent. The product 2 was isolated as a colorless oil (326.6 mg, 0.76 mmol, 86%). 1H NMR (400 MHz, CDCl3): δ 3.74-3.66 (2H, t, J=6.2 Hz), 3.59-3.47 (14H, m), 3.46-3.36 (6H, m), 2.95-2.93 (1H, br), 2.84-2.81 (1H, br), 2.79-2.70 (7H, m), 2.62-2.54 (7H, m); 13C NMR (100 MHz, CDCl3): δ 171.3 (C), 71.4 (CH2), 70.5 (CH2), 70.2 (CH2), 69.9 (3×CH2), 69.7 (CH2), 69.3 (CH2), 56.9 (CH2), 56.0 (CH2), 52.3 (CH2), 52.1 (CH2), 49.6 (CH2), 49.4 (CH2), 48.5 (CH2), 48.0 (CH2), 46.7 (CH2), 45.6 (CH2), 45.3 (CH2); ESI-MS m/z 432.4 (M+H)+; HRFAB-MS m/z 432.3193 (M+H)+[Calcd. for C20H42N5O5 (M+H)+, 432.3186].
2,3,4,5,6,7,8,8c-octahydro-1H-4a,6a,8a-triaza-2a-azoniacyclopent[fg]acenaphthylene bromide salt[ No CAS ]
[ 294-90-6 ]
Yield
Reaction Conditions
Operation in experiment
93.2%
With potassium hydroxide In water at 100℃;
3-5 Example 5 Production and purification of the ring
90 kg of potassium hydroxide and 100 kg of water were added to the reaction vessel to obtain an aqueous potassium hydroxide solution. 40 kg of the bromine salt intermediate compound was added to 140 kg of water to obtain an aqueous solution of the bromine salt intermediate compound, and the potassium hydroxide aqueous solution was heated to 100 ° C to add a bromine salt. The intermediate compound is kept in an aqueous solution for 4 to 5 hours.The reaction solution was cooled to 15 ° C for the first time and filtered.The filtrate was cooled to 8 ° C for a second time and allowed to stand for 20 hours. It was separated by centrifugation, and solid dried at 30 ° C in vacuo to obtain a ring-round product (23.3 kg, yield 93.2%).
88%
With caustic In water for 0.5h; Heating;
71%
With potassium hydroxide In water for 0.5h; Heating;
In dichloromethane at 20℃; for 24h; regioselective reaction;
79%
In dichloromethane at 20℃; for 24h;
79%
In dichloromethane at 0 - 20℃; for 24h;
Synthesis of the compound ethyl 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (3)
A solution of ethyl bromoacetate ( 1.0 g; 6.0 mmol ) in DCM ( 10 ml) is added dropwise over 10 minutes to a solution of commercial cyclen 2 ( 1.36 g, 7.9 mmol) in DCM ( 16 ml) cooled in an ice bath After 2 hours, the reaction mixture is brought to room temperature and left to react for additional 22 hours The resulting suspension is filtered and the filtrate is evaporated under reduced pressure The crude, oily yellow, reaction product is finally purified by flash chromatography (from 100% DCM to DCM/methanol/ammonia/water 70:30: 5 : 5) thus obtaining the compound 3 ( 1.61 g, 79%) in form of white viscous oil 1H-NMR (CDCl3) d ppm: 1.27 (t, J=7.2 Hz, 3H; CH2CH3), 2.84 (m, 8 H, CH2 2.95 (m, 8H, CH2), 3.49 (m, 2H, NCH2COOCH2CH3), 4.16 (q, J=7.2 Hz, 3H, C(O)OCH2CH3) MS (ESI): 259 [M + H]+
77%
In chloroform at 20℃;
44%
With potassium carbonate In acetonitrile at 0 - 20℃; for 26.5h;
0.40 g
Stage #1: 1,4,7,10-tetraazacyclododecan With hexacarbonyl molybdenum In dibutyl ether at 140℃; for 2h;
Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 2h;
Stage #3: ethyl bromoacetate In N,N-dimethyl-formamide Heating; Further stages.;
With caesium carbonate; potassium iodide In acetonitrile for 72h; Heating;
87%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere;
1.b Preparation of DOTA-4EDA-BOC
The cyclen is 0.25g (1.45mmol), CA-EDA-BOC 1.60g (6.76mmol),Potassium carbonate 1.2g(8.7 mmol), 1.2 g (7.23 mmol) of potassium iodide dissolved in 8 mL DMF,The reaction solution was heated under magnetic protection at 70 ° C for 24 h under nitrogen.The reaction solution was then transferred to a separatory funnel and dissolved in 100 mL of chloroform.Wash with 3 x 50 mL of water,The organic layer is rotary evaporated to obtain a DOTA-4EDA-BOC solid product.The yield was 87%.
86.9%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere;
N-(tert-Butoxycarbonyloxy)succinimide (2.50 g, 11.62 mmol) inchloroform (30 mL) was added dropwise into the solution of1,4,7,10-tetraazacyclododecane (1.00 g, 5.80 mmol) in CHCl3(50 mL) during 7 h. The reaction mixture was stirred 24 h at roomtemperature and the solvent was removed under reduced pressure. The residue was suspended in aqueous NaOH (3 M, 50 mL) and theaqueous phase was extracted with CHCl3 (3 50 mL). The combinedextracts were dried with K2CO3 and evaporated to drynessto give 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane(10) in quantitative yield.1,3,5-Tris(bromomethyl)benzene (7.65 g, 21.62 mmol) was dissolvedin CHCl3 (150 mL) and Na2CO3 (1.71 g, 16.15 mmol) wasadded. Compound 10 (1.08 g, 2.90 mmol) in CHCl3 (50 mL) wasadded dropwise into the reaction mixture during 11 hours at52 C. The reaction mixture was refluxed for 3 days at 62 C,filtrated, and evaporated to dryness. The residue was purified bysilica gel chromatography (40-70% EtOAc in hexane), giving 11 in27% yield (0.722 g). 1H NMR (500 MHz, CDCl3) d 7.33 (s, 6H), 4.45(s, 8H), 3.71 (s, 4H), 3.21-3.57 (m, 8H), 2.55-2.68 (m, 8H), 1.27(s, 18H). 13C NMR (100 MHz, CDCl3) dppm 155.8, 140.8, 138.5,129.9, 128.3, 79.3, 59.5, 55.2, 46.1, 32.9, 28.4. HRMS(ESI): obsd.921.0840 [M+H]+, Calcd. 921.0795 [M+H]+.
With sodium hydroxide; In chloroform;
Synthesis of 1,7-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane Cyclen (1.05 g) was dissolved in chloroform (50 mL), to which <strong>[13139-12-3]N-(tert-butoxycarbonyloxy)succinimide</strong> (2.62 g) was added, followed by stirring at room temperature. After 48 hours of stirring, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in chloroform (50 mL), washed with an aqueous solution of sodium hydroxide, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the resulting product was dried in a vacuum to give the title compound (2.27 g).
With potassium carbonate In acetonitrile at 80℃; for 12h;
64%
With potassium carbonate In acetonitrile at 20℃; for 16h; Inert atmosphere;
64%
With potassium carbonate In acetonitrile at 20℃; for 16h; Inert atmosphere;
Synthesis of ethyl 3-(1,4,7,10-tetraazacyclododecan-1-yl)propanoate
Synthesis of ethyl 3-(1,4,7,10-tetraazacyclododecan-1-yl)propanoate K2CO3 (300 mg, 2.2 mmol) and ethyl 3-bromopropanoate (100 mg, 0.61 mmol) were added to a stirred solution of cyclen (380 mg, 2.2 mmol) in anhydrous CH3CN (10 mL), and the resulting solution was stirred at room temperature for 16 hours under N2 atmosphere. Complete consumption of the starting materials was confirmed by TLC [stationary phase = Basic alumina TLC, mobile phase = CH2Cl2 : MeOH (10:1)]. The resulting product was separated from K2CO3 by filtration, and evaporated to dryness under reduced pressure. Column chromatography was used to obtain a pure compound (100 mg, 64%). 1H NMR (CDCl3, 400 MHz): δ1.27 (t, J = 7.2 Hz, 3H), 2.38-2.57 (m, 10H), 2.64-2.67 (m, 4H), 2.76-2.84 (m, 6H), 4.07-4.18 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ14.10, 32.55, 44.38, 45.64, 46.39, 49.61, 50.92, 60.31, 172.67.
63%
With triethylamine In chloroform for 15h; Inert atmosphere; Reflux;
A compound having the structure shown as the final product in the scheme detailed in FIG. 4 was synthesized and characterized. Reaction step (1) (shown in isolation in FIG. 6) proceeds well and the product was characterized by 1H NMR spectroscopy (peak obtained at MW=214). This product was readily purified by recrystallization from hot n-hexane. The yield of this reaction in our hands was not established. The literature value is 89% isolated yield. L. D. Taylor and R. B. Davis, J. Org. Chem. 1963, 28, 1713. [0074] Reaction step (2) (shown in isolation in FIG. 7) also proceeded and the crude product was purified by recrystallization from ethanol/tetrahydrofuran. Small, square-shaped orange crystals were obtained over a period of two days in ca. 12% yield. Analysis of these crystals via 1H NMR spectroscopy suggests that their crystal structure may contain tetrahydrofuran (see FIG. 8). Mass spectroscopy yielded an m/z peak at 352. Further addition of tetrahydrofuran to the ethanol mixture yielded a second crop of similar crystals. However, this second crop was coated in orange-colored viscous oil, characteristic of material that had come out of solution too quickly. This material is to be further recrystallized to improve product yield. [0075] Reaction step (3) (shown in isolation in FIG. 9) was carried out under reflux (approximately 80 C.) proceeded well and yielded a solid product as expected. Previous attempts to synthesize this compound have yielded viscous oil. Purification of the product from reaction (2) appears to lead to a purer product from reaction (3) as we obtained a solid instead of an oil. This product was analyzed by 1H NMR and by ES mass spectral analysis: FW ca. 506, [M]+504 (100%). [0076] Reaction step (4) (shown in isolation in FIG. 10) was conducted overnight at pH=10-11. However, the pH dropped to a value of 9 after 24 h. Thus, the pH was again raised to a value of ca. 10 and allowed to react for a further 24 h, during which time the reaction mixture maintained its pH value of ca. 10. It appears that at least 48 hours are necessary for the reaction to go to completion as indicated by the lack of further pH change. ES mass spectral analysis indicated a prominent peak at 701 (expected mass of the ligand+Na+). [0077] Reaction step 5 (i.e., the final reaction step shown in FIG. 4) involves the insertion of the metal to the macrocycle. The sample was run through a Chelex 100 column after first neutralizing the reaction mixture to pH=7. However, upon eluting with water, only pale yellow oil was obtained. This did not display the characteristic absorbances of ca. 510 and 550 nm upon exposure to UV-light irradiation. In addition, it was observed that a band of purple-colored material was trapped at the top of the Chelex column. Various solvents were used to try to pass this band through the column, and ethanol and chloroform each were found to be effective to elute the product. This purple-colored material displayed characteristic color changes expected for the final product. UV irradiation (described in the following example) produced a product with absorbances at ca. 510 and 550 nm. Irradiation with white light eliminates these absorbance peaks. Mass spec for the product from step 5 yielded a peak at 835 and also peak at 678 (representing either free ligand or artifactual dissociation of product during electrospray).
With hydrogenchloride; sodium hydroxide; bromine In water; toluene
9 EXAMPLE 9
EXAMPLE 9 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with bromine. 1.66 kg (8.55 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene (prepared according to Examples 1 and 2) are dissolved in 15 kg of deionized water. 18.5 kg of 1N HCl are added up to pH 4.5, then the solution is cooled to 20° C. and 3.42 kg of bromine (21.48 mol) and 46.7 kg of 1N NaOH are dropwise added to keep pH 4.5. After one night at room temperature 8.4 kg of NaOH are added, up to pH 14. The solution is transferred to the autoclave and hydrolyzed at 180°-185° C. for 5.5 h then cooled to room temperature. The solution is concentrated under reduced pressure. The resulting suspension is kept under stirring at room temperature for 24 h, then the precipitate is filtered. The wet solid is dried in an oven under vacuum to give 1,4,7,10-tetraazacyclododecane contaminated by inorganic salts. The solid is suspended in 16 kg of toluene and heated under reflux, the water is removed through azeotropic distillation and then the suspension volume is reintegrated with fresh toluene. The inorganic salts are removed by filtering the hot solution, and washed with toluene preheated at 60° C. The filtrate is concentrated up to a residual weight of 3 kg, then cooled to 17° C. for 2 h and up to 0° C. for 1 h. The crystallized solid is filtered and washed with few cold toluene and the product is dried at 50° C. under vacuum to give 0.9 kg (5.22 mol) of 1,4,7,10-tetraazacyclododecane (GC: 99.23%). From toluene mother liquors, concentrated to 250 mL, 108 g (0.63 mol) are obtained as second crop. Total yield: 68%.
99.23%
With hydrogenchloride; sodium hydroxide; bromine In water; toluene
9 EXAMPLE 9
EXAMPLE 9 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with bromine. 1.66 kg (8.55 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene (prepared according to Examples 1 and 2) are dissolved in 15 kg of deionized water. 18.5 kg of 1N HCl are added up to pH 4.5, then the solution is cooled to 20°C and 3.42 kg of bromine (21.48 mol) and 46.7 kg of 1N NaOH are dropwise added to keep pH 4.5. After one night at room temperature 8.4 kg of NaOH are added, up to pH 14. The solution is transferred to the autoclave and hydrolyzed at 180-185°C for 5.5 h then cooled to room temperature. The solution is concentrated under reduced pressure. The resulting suspension is kept under stirring at room temperature for 24 h, then the precipitate is filtered. The wet solid is dried in an oven under vacuum to give 1,4,7,10-tetraazacyclododecane contaminated by inorganic salts. The solid is suspended in 16 kg of toluene and heated under reflux, the water is removed through azeotropic distillation and then the suspension volume is reintegrated with fresh toluene. The inorganic salts are removed by filtering the hot solution, and washed with toluene preheated at 60°C. The filtrate is concentrated up to a residual weight of 3 kg, then cooled to 17°C for 2 h and up to 0°C for 1 h. The crystallized solid is filtered and washed with few cold toluene and the product is dried at 50°C under vacuum to give 0.9 kg (5.22 mol) of 1,4,7,10-tetraazacyclododecane (GC: 99.23%). From toluene mother liquors, concentrated to 250 mL, 108 g (0.63 mol) are obtained as second crop. Total yield: 68%.
55%
With hydrogenchloride; bromine In water
The synthesis of cyclen 3
Tetracyclic derivative I (2 mmol) was solved in water (4 mL). The pH of this solution was adjusted to about 6 by diluted HCl. Bromine (0.4 mL)was added dropwise. The mixture was allowed to be stirred at room temperature overnight. NaOH (0.6 mmol) was added portionwise, and the mixture was allowed to reflux for 36 hours. After the completion of the reaction, the mixture was cooled to room temperature, and the insoluble material was filtered off. Then the filtrate was extracted by toluene. The organic layer was dried with Na2SO4. After the removement of organic solvent under reduced pressure, the final product 3 was afforded as white solid (0.19 g, 55%). 1,4,7,l0-Tetraazacyclododecan (3) [16]1H NMR (400 MHz, CDCl3, TMS) 2.06 (s, 4 H), 2.62(s, 16 H); 13C NMR (100 MHz, CDCl3) 46.1; MS (ESI)[M+H]+ 173.3; M.p. 109-110 °C.
45%
With sodium hydroxide; sodium hydrogensulfite In water
12 EXAMPLE 12
EXAMPLE 12 Oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with sodium bisulfite. 40 g (0.206 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene are dissolved in 500 g of water. 86 g of sodium bisulfite (0.824 mol) are added and the solution is heated to 95° C. for 17 h then cooled to room temperature. NaOH is added up to 14 and then the procedure is carried out according to Example 9 to give 15.9 g (0.093 mol) of 1,4,7,10-tetraazacyclododecane (GC: 98.5%). Yield: 45%.
45%
With sodium hydroxide; sodium hydrogensulfite In water
12 Oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with sodium bisulfite.
EXAMPLE 12 Oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with sodium bisulfite. 40 g (0.206 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene are dissolved in 500 g of water. 86 g of sodium bisulfite (0.824 mol) are added and the solution is heated to 95°C for 17 h then cooled to room temperature. NaOH is added up to 14 and then the procedure is carried out according to Example 9 to give 15.9 g (0.093 mol) of 1,4,7,10-tetraazacyclododecane (GC: 98.5%). Yield: 45%.
38%
With sodium hypochlorite In water
5 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with hypochlorite STR32
EXAMPLE 5 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with hypochlorite STR32 30 g (0.15 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene, dissolved in 300 of water, are treated with 550 g (0.89 mol) of sodium hypochlorite (approx. 12% aqueous solution) for 24 h at 80° C. The final solution is cooled and hydrolyzed under conditions analogous to those described in Example 4. 9.8 g (1st and 2nd crop) of 1,4,7,10-tetraazacyclododecane are obtained. Yield: 38%.
38%
With bromine; acetic acid In sodium hydroxide
7 EXAMPLE 7
EXAMPLE 7 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with bromine in acetic buffer. 26 g (0.13 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene are dissolved in 1.3 L of sodium hydroxide 2N. The solution is buffered to pH 5 through addition of 300 g of acetic acid, then 43.8 g (0.27 mol) of bromine are dropwise added and kept for 2 h at 25° C. 200 g of sodium hydroxide are added and the solution is heated in autoclave at 150° C. for 24 h, then the solution is cooled and concentrated up to 400 mL. The product crystallizes at room temperature (25° C.) for one night to give 8.7 g of 1,4,7,10-tetraazacyclododecane. Yield: 38%
38%
With bromine; acetic acid In sodium hydroxide
7 EXAMPLE 7
EXAMPLE 7 Preparation of 1,4,7,10-tetraazacyclododecane through oxidation of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene with bromine in acetic buffer. 26 g (0.13 mol) of 2a,4a,6a,8a-decahydro-tetraazacyclopent[fg]acenaphthylene are dissolved in 1.3 L of sodium hydroxide 2N. The solution is buffered to pH 5 through addition of 300 g of acetic acid, then 43.8 g (0.27 mol) of bromine are dropwise added and kept for 2 h at 25°C. 200 g of sodium hydroxide are added and the solution is heated in autoclave at 150°C for 24 h, then the solution is cooled and concentrated up to 400 mL. The product crystallizes at room temperature (25°C) for one night to give 8.7 g of 1,4,7,10-tetraazacyclododecane. Yield: 38%
Multi-step reaction with 2 steps
1: sulfuric acid / ethanol / 5 h / 0 °C
2: hydrazine hydrate / 12 h / 90 °C
1 2,5-Bis-(1,4,7,10-tetraazacyclododecan-1-yl)hexan-1,6-dioic acid
EXAMPLE 1 STR16 2,5-Bis-(1,4,7,10-tetraazacyclododecan-1-yl)hexan-1,6-dioic acid A mixture of cyclen (60.75 g, 350 mmol), meso-2,5-dibromoadipic acid (10.57 g, 35 mmol), and 1M lithium hydroxide (70 mL, 70 mmol) in water (104 mL) was heated to 60° C. under nitrogen for 170 hours. After cooling to ambient temperature, the reaction mixture was applied to an AG1X8 anion exchange column ›400 mL[(OH-form)]. The column was washed thoroughly with water (4 L), and the product was eluted with 0.5M acetic acid (2 L). Fractions containing product were combined, chased with water (3*200 mL) and ethanol (3*100 mL) to yield the title product (8.75 g, 51.8%) as a white, hygroscopic foam. Unreacted cyclen was reclaimed by concentration of the first 2 L of eluent and recrystallization from water. 1 H NMR: (D2 O) δ 2.75-2.90 (br mult, 34H), 1.52 (br, 4H). 13 C NMR: (D2 O) 24.3, 40.5, 41.1, 41.3, 41.6, 43.1, 44.9, 63.0, 177.1. MS (FAB): m/e 487.4 (MH+).
N-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
In chloroform;
EXAMPLE E Preparation of N-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane. To a stirred chloroform solution (20 ml) containing 2.9 g of 1,4,7,10-tetraazacyclododecane (16.8 mmole) was added a chloroform solution (20 ml) containing 2.1 g of <strong>[3913-23-3]2-methoxy-5-nitrobenzyl bromide</strong> (8.5 mmole) in one portion. After stirring at room temperature for three hours the reaction mixture was filtered and the filtrate concentrated (in vacuo) to give a residue which was chromatographed (silica, Solvent System 3). The monoalkylated product was isolated in 79 percent yield (MP=154-156 C.), and characterized by: 13 C NMR (CDCl3) 162.47, 140.63, 127.92, 125.49, 124.53, 109.91, 55.88, 53.25, 50.90, 47.18, 45.45, 45.29.
1
The Gd(III) chelator was synthesized using a hydrogenation labile protection scheme with benzyl 2-bromoacetate and benzyl 5-bromopentanoate as the chelating arms of the macrocycle (Figure 1). Addition of three benzyl 2-bromoacetate arms to cyclen was followed by addition of benzyl 5-bromopentanoate. Global deprotection by hydrogenation of the chelator and subsequent metallation with GdCl3 afforded molecule Gd (III) ion 6 to be conjugated to the protein polymer.
68%
With sodium hydrogencarbonate In acetonitrile at 25℃; for 48h; Inert atmosphere;
4.3.2. General Procedure A for the Synthesis of DOTA Precursors (6-8)
General procedure: To a suspension of cyclen (5.81 mmol) and sodium bicarbonate (17.43 mmol) in dry acetonitrile (100 mL), a solution of the respective bromoacetate (3-5, 17.43 mmol) in dry acetonitrile (10 mL) was added dropwise under argon atmosphere. The mixture was stirred for 48 h at 25 °C. After usual aqueous work-up, the solvent was removed under reduced pressure, and the crude products were subjected to column chromatography (silica gel, chloroform/methanol mixtures) affording DOTA precursors 6-8 (50-68%).
54.6%
With triethylamine In chloroform at 20℃; for 20h;
As shown in step S1, take a 1,4,7,10-tetraazacyclododecane (1.0 g, 5.8 mmol)Dissolve in monochloroform (50 ml) and add triethylamine (8.2 ml, 59.1 mmol). Subsequently, benzyl bromoacetate (3.04 ml, 19.1 mmol) was added dropwise to perform a substitution reaction, and stirred at room temperature for 20 hours.In this substitution reaction step,One benzyl acetate on the 2-bromoacetic acid benzyl ester replaces at least one hydrogen group on the 1,4,7,10-tetraazacyclododecane.After that, add one more water (8 ml) to wash three times, take the organic layer formed to remove water with anhydrous sodium sulfate, and concentrate under reduced pressure.In the step of S1, a liquid chromatography method (SiO2, DCM: MeOH = 5: 1, Rf = 0.75) is further used for separation and purification to obtain a first product(1.95 g, 54.6%).
2 g
With sodium acetate In N,N-dimethyl acetamide at 20℃; for 20.33h;
9.1 Example 9
(1) To a suspension of 1,4,7,10-tetraazacyclododecane (5.0 g), sodium acetate trihydrate (13.0 g), and DMAc (40 mL), a solution of benzyl bromoacetate (22 g) in DMAc (20 mL) was added dropwise at 20° C. or lower over 20 minutes, and then, the mixture was stirred at room temperature for 20 hours. Ethyl acetate (500 mL) was added to the reaction mixture, and the mixture was washed three times with water (300 mL), then dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate/methanol=5/1 to 1/1) to obtain compound (I11) (2.0 g). TLC Rf: 0.07 (ethyl acetate/methanol=5/1)
2 g
With sodium acetate In N,N-dimethyl acetamide at 20℃; for 20.3h;
11.1 Reference Example 11
(1)1,4,7,10-tetraazacyclododecane (5.0 g),To a suspension of sodium acetate trihydrate (13.0 g) and DMAc (40 mL)A solution of benzyl bromoacetate (22 g) in DMAc (20 mL) was heated at 20 ° C.In 20 minutes, and the mixture was stirred at room temperature for 20 hours.Ethyl acetate (500 mL) was added to the reaction mixture, which was washed three times with water (300 mL)It was dried over anhydrous sodium sulfate,Purification by silica gel column chromatography (ethyl acetate / methanol = 5/1 to 1/1) gave (I1) (2.0 g).
[1-(3-dibenzylamino-2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane] pentahydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Zu 100 g (580. 48 MMOL) 1,4, 7, 10-TETRAAZACYCLODODECAN, geloest in 700 ml Toluol, gibt man 100 ml (752.77 MMOL) N, N-DIMETHYLFORMAMIDDIMETHYLACETAL und erhitzt 2 h auf 120 C unter Stickstoff. Dabei wird kontinuierlich ein METHANOL/TOLUOL-ACEOTROPH ABDESTILLIERT. ANCHLIE END engt man die Reaktionsmischung bei 70 C im Vakuum ein, gibt 157 g (620 mmol) DIBENZYLOXIRANYLMETHYLAMIN hinzu und erhitzt unter Sticktoff 24 h auf 110 C. Nach Abkuehlen auf Raumtemp. wird mit 500 ML Wasser versetzt und zweimal mit je 200 ML ETHYLACETAT extrahiert. Die waessrige Phase wird mit 250 ml konz. HCI versetzt und anschliessend 12 h auf 80 C erhitzt. Es wird zur Trockene eingedampft, mit 200 ML Ethanol und 200 ml Methanol versetzt und erneut zur Trockene eingedampft. Der Rueckstand wird in 600 ml Ethanol in der Hitze geloest, und anschliessend langsam auf 0 C ABGEK HLT, wobei ein weisser Feststoff auskristallisiert. Der Feststoff wird abfiltriert, mit Ethanol gewaschen und anschliessend bei 50 C im Vakuum getrocknet. Ausbeute : 280 g (79 % d. Th. ) eines farblosen Feststoffes Elementaranalyse : ber. : C 49. 39 H 7.29 N 11. 52 Cl 29.16 gef. : C 49. 67 H 7.44 N 11.56 CL28. 22
79%
100 ml (752.77 mmol) of N,N-dimethylformamide dimethyl acetal is added to 100 g (580.48 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 700 ml of toluene, and it is heated for 2 hours to 120 C. under nitrogen. In this case, a methanol/toluene azeotrope is distilled off continuously. Then, the reaction mixture is concentrated by evaporation at 70 C. in a vacuum, 157 g (620 mmol) of dibenzyloxiranylmethylamine is added, and it is heated under nitrogen for 24 hours to 110 C. After cooling to room temperature, it is mixed with 500 ml of water and extracted twice with 200 ml each of ethyl acetate. The aqueous phase is mixed with 250 ml of concentrated HCl and then heated for 12 hours to 80 C. It is evaporated to the dry state, mixed with 200 ml of ethanol and 200 ml of methanol and evaporated again to the dry state. The residue is dissolved in 600 ml of ethanol while being heated, and then it is slowly cooled to 0 C., whereby a white solid is crystallized out. The solid is filtered off, washed with ethanol and then dried at 50 C. in a vacuum. [0227] Yield: 280 g (79% of theory) of a colorless solid [0228] Elementary analysis: Cld.: C, 49.39; H, 7.29; N, 11.52; Cl, 29.16. Fnd.: C, 49.67; H, 7.44; N, 11.56; Cl, 28.22.
[1-(3-benzylmethylamino-2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane] pentahydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: 1,4,7,10-tetraazacyclododecan With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In toluene at 120℃; for 2h;
Stage #2: N-benzyl-N-methyl-1-(oxiran-2-yl)methanamine In toluene at 110℃; for 24h;
Stage #3: With hydrogenchloride In water at 80℃; for 12h;
6.b b) [1- (3-BENZYLMETHYLAMINO-2-HYDROXYPROPYL)-1, 4, 7, 10-TETRAAZACYCLODODECAN] PENTAHYDROCHLORID
Zu 100 g (580.48 mmol) 1,4, 7, 10-Tetraazacyclododecan, gelöst in 700 ML Toluol, gibt man 100 ML (752.77 mmol) N, N-DIMETHYLFORMAMIDDIMETHYLACETAL und erhitzt 2 h auf 120 C unter Stickstoff. Dabei wird kontinuierlich ein METHANOF/TOLUOL-ACEOTROPH ABDESTILLIERT. ANCHLIE END engt man die Reaktionsmischung bei 70 °C im Vakuum ein, gibt 110 g (620 mmol) 1-Benzyl- 1-methyl (OXIRANYLMETHYL) amin hinzu und erhitzt unter Sticktoff 24 h auf 110 C. Nach Abkühlen auf Raumtemp. wird mit 500 ml Wasser versetzt und zweimal mit je 200 ml Ethylacetat extrahiert. Die wässrige Phase wird mit 250 ml konz. HCl versetzt und anschließend 12 h auf 80 C ERHITZT. Es wird zur Trockene eingedampft, mit 200 ml Ethanol und 200 mi Methanol versetzt und erneut zur Trockene eingedampft. Der Rückstand wird in 600 ml Ethanol in der Hitze gelöst, und anschließend langsam auf 0 C ABGEK HLT, wobei ein weißer Feststoff auskristallisiert. Der Feststoff wird abfiltriert, mit ETHANOT gewaschen und anschließend bei 50 C im Vakuum getrocknet. Ausbeute : 235 9 (76 % d. Th. ) eines farblosen Feststoffes Elementaranalyse : ber. : C 42.91 H 7.58 N 13.17 CI 33.33 gef. : C 43. 34 H 7. 60 N 13. 29 Cl 32. 78
76%
Stage #1: 1,4,7,10-tetraazacyclododecan With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In toluene at 120℃; for 2h;
Stage #2: N-benzyl-N-methyl-1-(oxiran-2-yl)methanamine at 110℃; for 24h;
Stage #3: With hydrogenchloride In water at 20 - 80℃; for 12h;
6.b
100 ml (752.77 mmol) of N,N-dimethylformamide dimethyl acetal is added to 100 g (580.48 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 700 ml of toluene, and it is heated for 2 hours to 120° C. under nitrogen. In this case, a methanol/toluene azeotrope is continuously distilled off. Then, the reaction mixture is concentrated by evaporation at 70° C. in a vacuum, 110 g (620 mmol) of 1-benzyl-1-methyl(oxiranylmethyl)amine is added, and it is heated under nitrogen for 24 hours to 110° C. After cooling to room temperature, it is mixed with 500 ml of water and extracted twice with 200 ml each of ethyl acetate. The aqueous phase is mixed with 250 ml of concentrated HCl and then heated for 12 hours to 80° C. It is evaporated to the dry state, mixed with 200 ml of ethanol and 200 ml of methanol and again evaporated to the dry state. The residue is dissolved in 600 ml of ethanol while being heated, and they) it is slowly cooled to 0° C., whereby a white solid crystallizes out. The solid is filtered off, washed with ethanol and then dried at 50° C. in a vacuum. [0249] Yield: 235 g (76% of theory) of a colorless solid [0250] Elementary analysis: Cld.: C, 42.91; H, 7.58; H, 13.17; Cl, 33.33. Fnd.: C, 43.34; H, 7.60; N, 13.29; Cl, 32.78.
1,3,5-triiodo-2,4,6-tris-(oxiranylmethoxymethyl)benzene[ No CAS ]
[ 294-90-6 ]
[ 752252-95-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: 1,4,7,10-tetraazacyclododecan With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In toluene at 120℃; for 2h;
Stage #2: 1,3,5-triiodo-2,4,6-tris-(oxiranylmethoxymethyl)benzene In toluene at 110℃; for 24h;
Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;
7.b b) 1,3, 5-TRIIOD- {2, 4,6-tris [2-HYDROXY-3- (1, 4,7, 10-TETRAAZACYCLODODECAN-1- YL) PROPYLOXY-METHYL] benzen
Zu 10 g (58.05 MMOL) 1,4, 7, 10-TETRAAZACYCLODODECAN, gelöst in 100 ML Toluol, gibt man 10 mi (75.28 MMOL) N, N-Dimethylformamiddimethylacetal und erhitzt 2 h auf 120 C unter Stickstoff. Dabei wird kontinuierlich ein METHANOL/TOLUOL- Aceotroph abdestilliert. Anchließend engt man die Reaktionsmischung bei 70 C im Vakuum ein, gibt 13. 6 G (19.1 MMOL) 1,3, 5-TOD-2, 4,6-tris- (OXIRANYLMETHOXYMETHYL) benzen hinzu und erhitzt unter Sticktoff 24 h auf 110 C. Nach Abkühlen auf Raumtemp. wird mit 100 ml 2 N HCI versetzt und anschließend 12 h auf 80 C erhitzt. Es wird zur Trockene eingedampft, mit 50 mi Ethanol und 50 mi Methanol versetzt und erneut zur Trockene eingedampft. Der Rückstand wird in 100 ml Ethanol in der Hitze gelöst, und anschließend langsam auf 0"C ABGEK HLT, wobei ein weißer Feststoff auskristallisiert. Der Feststoff wird abfiltriert, mit Ethanol gewaschen und anschließend bei 50 C im Vakuum getrocknet. Der Feststoff wird in in 100 ML Wasser und 100 ml Dichlormethan gelöst und unter starkem Rühren wird so lange 32proz. NaOH-Lösung hinzugegeben, bis ein pH-Wert von 10 erreicht ist. Die organische Phase wird abgetrennt, die wässrige Phase dreimal mit je 100 ML DICHLORMETHAN extrahiert, die vereinigten organischen Phasen über Magnesiumsulfat getrocknet und zur Trockene eingeengt. Ausbeute : 19.0 g (81 % d. Th. ) eines farblosen Feststoffes Elementaranalyse : ber. : C 40.98 H 6.63 N 13. 66 1 30. 93 gef. : C 41. 32 H 6.71 N 13.54 No. 30. 77
81%
Stage #1: 1,4,7,10-tetraazacyclododecan With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In toluene at 120℃; for 2h;
Stage #2: 1,3,5-triiodo-2,4,6-tris-(oxiranylmethoxymethyl)benzene at 110℃; for 24h;
Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;
7.b
10 ml (75.28 mmol) of N,N-dimethylformamide dimethyl acetal is added to 10 g (58.05 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 100 ml of toluene, and it is heated for 2 hours to 120° C. under nitrogen. In this case, a methanol/toluene azeotrope is distilled off continuously. Then, the reaction mixture is concentrated by evaporation at 70° C. in a vacuum, 13.6 g (19.1 mmol) of 1,3,5-triiodo-2,4,6-tris-(oxiranylmethoxymethyl)benzene is added, and it is heated under nitrogen for 24 hours to 110° C. After cooling to room temperature, it is mixed with 100 ml of 2N HCl and then heated for 12 hours to 80° C. It is evaporated to the dry state, mixed with 50 ml of ethanol and 50 ml of methanol and evaporated to the dry state again. The residue is dissolved in 100 ml of ethanol while being heated, and then slowly cooled to 0° C., whereby a white solid crystallizes out. The solid is filtered off, washed with ethanol and then dried at 50° C. in a vacuum. The solid is dissolved in 100 ml of water and 100 ml of dichloromethane, and 32% NaOH solution is added while being stirred vigorously until a pH of 10 is reached. The organic phase is separated, the aqueous phase is extracted three times with 100 ml each of dichloromethane, the combined organic phases are dried on magnesium sulfate and evaporated to the dry state. [0271] Yield: 19.0 g (81% of theory) of a colorless solid [0272] Elementary analysis: Cld.: C, 40.98; H, 6.63; N, 13.66; I, 30.93. Fnd.: C, 41.32; H, 6.71; N, 13.54; I, 30.77.
With potassium carbonate In acetonitrile at 80℃; for 18h;
4.2.1. Compound 2
Cyclen (59 mg, 0.34 mmol) was dissolved in CH3CN (10 ml), K2CO3 (458 mg, 3.31 mmol) was added and the suspension was stirred for 15 min. Bromide 1 (465 mg, 1.65 mmol) in CH3CN (10 ml) was added dropwise and the mixture was heated at 80 °C for 18 h. After cooling the solid material was removed by filtration, the solvent was evaporated and the residue purified by column chromatography (CH2Cl2/CH3OH 92:8) to yield 290 mg (88%) of 2. Analytical data match to those previously reported for this molecule.
61%
With potassium carbonate In acetonitrile at 65℃; for 24h; Inert atmosphere;
10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate gadolinium[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
160 kg of cyclen (1 ,4,7, 10-tetraazacyclododecane), 154 kg of 4,4-dimethyl-3,5,8- trioxabicyclo[5,1 ,0]octane and 34.7 kg of lithium chloride are initially charged in 325 kg of isopropanol and heated under reflux for 1320 minutes.1250 I of water are added, and the mixture is distilled until an internal temperature of 78C is reached. The mixture is then made up with 805 I of water, and 375 kg of sodium monochloroacetate are added at 35C, followed by 120 kg of 50% strength aqueous sodium hydroxide solution. The mixture is heated to an internal temperature of 65C, and a further 85 kg of 50% strength aqueous sodium hydroxide solution are added. If the pH drops below 12, it is re-adjusted with 10 kg of 50% strength aqueous sodium hydroxide solution (step-wise). The mixture is stirred at an internaltemperature of 65C for 90 minutes. After cooling to 50C, 240 kg of 36% aqueous hydrochloric acid are added such that the pH is now 3.1 - 4.9 (if appropriate, additional hydrochloric acid has to be added; it is important that the target pH is reached). At a jacket temperature of 95C and under reduced pressure, solvent (isopropanol/water mixture) is then distilled off to a total amount of 1200 kg.At 40C, 2554 kg of methanol are added and the pH is adjusted to 1.4 or less (1 .1 - 1 .3, optimum 1 .2) using 282 kg of 36% aqueous hydrochloric acid. The mixture is stirred at 40C for 35 minutes. The mixture is then cooled to 20C and theprecipitated sodium chloride (NaCI) is separated off using a centrifuge or a pressure nutsche filter (the filter cake is washed with methanol since the product is in solution). 996 (this is still being examined) I of water are added, and the methanol issubstantially distilled off at a jacket temperature of 90C (250 mbar), with water, the mixture is concentrated to a mass of 966 kg, and a further 1200 I of water are then added. 155 kg of gadolinium oxide are added to this solution, and the mixture is heated at 95C for 120 minutes. The mixture is allowed to cool to 50C and adjusted to pH 7.1 - 7.4 using lithium hydroxide monohydrate (this requires about 85 kg of lithium hydroxide monohydrate). At a jacket temperature of 120C and under reduced pressure, 895 kg of water are then distilled off. The mixture is allowed to cool to 73C, 5286 kg of alcohol (MEK = methyl ethyl ketone denaturized) are added and the water content is checked using the Karl-Fischer method. The water content is adjusted to 8.5%. (If the value is less than 7.0, an appropriately calculated amount of water is added. If the value is greater than 9.5%, an appropriate amount of ethanol is added. For the process, it is important that the value is in the range from 7.0 to 9.5). The mixture is then heated under reflux (78C) for 60 minutes. Eventually,spontaneous crystallization occurs. The mixture is stirred at a jacket temperature of 100C for 480 minutes and then allowed to cool to 20C.The product is isolated using a centrifuge or pressure nutsche, the filter cake twice being washed with ethanol. In a paddle drier, the crude product is dried at a jacket temperature of 58C for 90 minutes under reduced pressure (until a pressure of < 62 mbar and a temperature of > 46C are reached) or washed with ethanol three times and dried at < 34C. The product is then dried at an internal temperature of 48C for 60 minutes. The crude product is cooled to 20C and filled into containers. This gives 540 kg of a colourless crystalline powder (yield > 96%).
4,7-bis-tertbutoxycarbonylmethyl-1,4,7,10-tetraazacyclododec-1-yl acetic acid tertbutyl ester hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With sodium acetate In N,N-dimethyl acetamide at -20 - 20℃; for 24.5h;
i,4,7Tris(tert-butoxycarbonyimethvI)-i,4,7,iO-tetraazacvciododecane hydrobromicte (HHY-330)
To a suspension of cyclen (500 g, 29 rnrnol) and sodium acetate (7.86 g, 96 mrnol) in N,N-dirnethylacetarnide (DMA, 60 rnL) at 2O °C was added a solution of t-butyl bromoacetate (18.7 g, 14.1 mL, 96 mmol) in DMA (20 rnL) dropwise over a period of 0.5 h. The temperature was maintained at -20 °C during the addition, after which the reaction mixture was allowed to come to room temperature. After 24 h of vigorous stirring, thereaction mixture was poured into water (300 rnL) to give a clear solution. Solid KHCO3 (15 g, 150 rnrnol) was added portion wise, and 4 precipitated as a white solid. The precipitate was collected by filtration and dissolved in CHCI3 (250 mL). The solution was washed with water (100 mL), dried (MgSO4), filtered, and concentrated to about 2O3O tnL. Ether (250 mE) was added, after which HHY-330 crystallized as a white fluffy solid.Yield: 12.5 g (73%). ESI-MS found: [M+Ht = 515.5 (Moore, D. A. Org. Synth. 2008, 85,1O-14).
61%
With sodium hydrogencarbonate In acetonitrile at 0 - 20℃; for 48.5h;
1-1.3 (3) Synthesis of DO3A-(tBuO)3.HBr
To a stirred mixture of cyclen (1,4,7,10-tetraazacyclododecane) (Strem, USA) (5.34 g, 30 mmol) and NaHCO3 (8.34 g, 99 mmol) in CH3CN (120 mL) at 0° C. was added tert-butyl bromoacetate (19.35 g, 99 mmol) dropwise over 30 min. The reaction mixture was further stirred for 48 h at room temperature. Any inorganic solids were removed by filtration, and the solvent was removed from the filtrate to leave a solid. The solid was taken up in chloroform, and the solid suspension was removed by filtration. The filtrate was concentrated, and the resulting solid was recrystallized from toluene to obtain DO3A-(tBuO)3.HBr as a white solid. Yield: 11.30 g (61%). 1H NMR (CDCl3): δ=3.37 (s, 4H, 2×CH2 acetates), 3.29 (s, 2H, CH2 unique acetate), 3.10 (br, 4H, -CH2CH2-ring), 2.88-2.93 (br m, 12H, -CH2CH2-ring), 1.55 (s, 27H, C(CH3)3). 13CNMR (CDCl3): δ=28.19 (-C(CH3)), 47.52 (-CH2CH2-, cyclic ring, asymmetric), 49.15 (-CH2 CH2-, cyclic ring, asymmetric), 51.31 (-CH2CH2-, cyclic ring, symmetric), 58.17 (-CH2COO-, acetate), 81.66 (-C(CH3)), 169.62 (-CH2 COO-, unique acetate), 170.51 (-CH2 COO-, acetate). Anal. Calc. for C26H51N4O6.HBr: C, 52.43; H, 8.63; N, 9.41. Found: C, 52.10; H, 8.90; N, 9.00 (purity>95%). MALDI-TOF MS (m/z): Calc. for C26H51N4O6, 515.38 ([MH]+). Found: 515.39.
25%
Stage #1: 1,4,7,10-tetraazacyclododecan With sodium hydrogencarbonate In acetonitrile for 0.5h; Cooling with ice;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In acetonitrile at 20℃; for 72.5833h; Cooling with ice;
Stage #1: 1,4,7,10-tetraazacyclododecan With sodium acetate In N,N-dimethyl acetamide for 0.5h;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In N,N-dimethyl acetamide at 0 - 20℃; for 120h;
Stage #3: With potassium bromide In N,N-dimethyl acetamide; water at 50℃;
1
The synthesis scheme for a protected tri-tertbutyl ester DO3A derivative is shown in Figure 5. All reagents were purchased from Sigma Aldrich and used without further purification unless specified. 30 g of cyclen (1,4,7J0-tetraazacyclododecane) was combined with 42.9 g of powdered, dry sodium acetate in 400 rnL of N,N-dimethylacetamide in a round bottom flask and stirred for 30 minutes with an overhead glass rod stirrer. The round bottom flask containing the slurry was placed in an ice bath until the temperature reached 0°C. 77.1 m[ of tert-butyl bromoacetate was dissolved in 150 mL of N, N,-dimethylacetarnide and added drop-wise to the slurry at 0°C over a period of 25 minutes. The slurry was equilibrated back to room temperature and stirred for 5 days. A separ’ te solution was prepared by dissolving 30 g of potassium bromide (KBr in 2 1 of deionized water (Millipore) followed by stirring and heating to a temperature of 50°C. After the KBr solution reached 50°C, it was added to the slurry forming a yellow colored solution. The pH was adjusted to 9.0 by the addition of powdered sodiumbicarbonate (checked via litmus paper) when the desired product, acetic acid tert-hutyl ester hydrobromide (4,7-bis-tert-butoxycarbonylmethyi- 1,4,7,1 0-tetraaza-cyclododec- i-yl) precipitated. It was allowed to settle for 4 hours without stirring, followed by vacuum filtering and drying, yielding a white powder. 10.0 g of this acetic acid tert-butyl ester hydrobromide was dissolved in 50 mL of MeCN and combined with 5.1077 g (2.2 eq.) of finely powdered, dry potassium carbonate and stirred for 30 minutes. 2.927 mL of Benzyl bromo acetate (1.1 eq.) was added drop-wise to the solution and stirred overnight at 50°C-60°C. The mixture was then cooled to room temperature and vacuum filtered, with the desired product in the filtrate. The solid was washed twice with MeCN. The combined MeCN was removed by evaporation under vacuum, yielding the tri-tert-butyi ester form of DO3A, a viscous yellow gel. NMR and ES1-MS confirmed the presence of the desired product. The crude product was purified using flash- column chromatography using 50.0 g of silica gel for every 1.0 g of tri-tert-butyi ester fonn of DO3A using DCM as the mobile phase. The product was eluted from the colunm using a gradient elution, starting with 2% MeOH in DCM to 6% of MeOH in DCM. The elution of the desired product was followed by Thin Layer Chromatography, using 10% MeOH in DUd as the mobile phase. Pure fractions were combined and the solvents evaporated under vacuum, The residue was then dissolved in approximately 50 mL of MeOH in deionized water (Millipore) at a ratio of 9:1. Palladium on carbon catalyst was added to the solution in 20% by weight with respect to tri-tert-hutyl ester form of DO3A. The sample was hydrogenated under 50-psi hydrogen pressure overnight followed by filtration of the solid catalyst. The filtrate containing DO3A was evaporated under vacuum to remove the methanol then 100 mL of deonzed water was added to the solution. Diethyl ether (50 mL) was added 3 times to the solution in a separatory funnel to extract the non-hydrogenated product. Solvent was removed by evaporation and the solution was freeze-dried to remove remaining deionized water, yielding a yellowish powder. NIVIR spec roscopy and ES1-MS were used to confirm the presence of DO3A and check purty.
[1,4,7-tris(ethoxycarbonylmethyl)]1,4,7,10-tetraazacyclododecane hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium acetate In N,N-dimethyl-formamide at -20 - 20℃; for 6.16667h; Inert atmosphere;
[1,4,7-Tris(ethoxycarbonylmethyl)]1,4,7,10-tetraazacyclododecane hydrobromide (8).
To a suspension of cyclen (1.00 g, 5.81 mmol) and sodium acetate (1.57 g, 19.17 mmol) in DMF (8 mL) at -20 °C was added a solution of methyl bromoacetate (2.66 g, 1.70 mL, 17.43 mmol) in DMF (4 mL) dropwise over 10 min. The temperature was maintained at -20 °C during the addition, after which the reaction mixture was allowed to come to room temperature. After 6 h of vigorous stirring, the reaction mixture was diluted with CH2Cl2 (50 mL) and the salts removed by filtration. The filtrate was evaporated under reduced pressure and the resulting oil was loaded onto a flash silica gel column (100 g). Elution with CH2Cl2 (200 mL), followed by CH2Cl2/MeOH (95:5), gave a tan oil. Scratching of the oil under ether at -20 °C gave 7 (2.12 g, 4.53 mmol, 78%) as a white solid, mp 92-94 °C, Rf 0.57 (CH2Cl2/MeOH 5:1). 1H NMR (500 MHz, CDCl3) 1.24 (9, t, J = 7.5 Hz), 2.84 (m, 4), 2.91 (8, m), 3.09 (4, m), 3.38 (2, s), 3.45 (4, s), 4.13 (6, q, J = 7.5 Hz), 9.97 (1, br s); 13C NMR (125 MHz, CDCl3) 14.2, 14.2, 47.3, 48.3, 49.2, 51.3, 51.4, 57.1, 60.6, 170.1, 171.0. Anal. Calcd for C20H39BrN4O6: C, 46.97; H, 7.69; N, 10.95. Found: C, 46.81; H, 7.92; N, 10.98.
37%
With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 144h;
37%
Stage #1: ethyl bromoacetate; 1,4,7,10-tetraazacyclododecan With sodium acetate In N,N-dimethyl acetamide at 0 - 20℃; for 144.5h;
Stage #2: With sodium carbonate; potassium bromide In diethyl ether; N,N-dimethyl acetamide; water
2 Synthesis of “Ethyl DO3 A”: 1,4,7,10-Tetraazacyclododecane-1,4,7-tris(ethyl acetate) HBr
To a 250 mL RBF were added cyclen (9.5036 g, 55.16 mmol, 1 eq.), sodium acetate (13.575 g, 165.5 mmol, 3 eq.), and dimethyl acetamide (130 mL). Ethyl bromoacetate (18.38 mL, 165.5 mmol, 3 eq.) was added dropwise to the mixture at 0° C. over 30 minutes, and the reaction mixture was allowed to warm to room temperature and stirred for 6 days. The reaction slurry was poured out into 700 mL DI water, producing a clear, yellow solution. The pH was adjusted to 9 with the addition of solid sodium carbonate, and the volume was adjusted to 1300 mL with DI water. KBr (9.5201 g, 79.99 mmol, 1.45 eq.) was added, along with 10 mL diethyl ether. The solution was extracted in batches with chloroform (3 times) and concentrated in vacuo. The remaining yellow liquid was taken up in chloroform and washed 6 times with DI water, then dried over sodium sulfate and concentrated in vacuo. The yellow oil was dissolved in 100 mL ethyl acetate, and an equal portion of diethyl ether was added, forming a cloudy mixture, which was placed in a freezer for three days to allow for precipitation to occur (attempting this procedure too quickly led to an oil instead of the desired solid). The resulting off-white solid was washed with diethyl ether and dried, yielding 10.429 g (37% yield). ESI-MS: m/z (M+H)+: 431.2
1,4-tetrakis(pyrazol-3-methyl)-1,4,7,10-tetraazacyclododecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 65℃; for 6h;
To a solution of Cyclen (1 g) in dry acetonitrile was added four equivalents of <strong>[69658-97-5]3-(chloromethyl)pyrazole hydrochloride</strong> and eight equivalents of diisopropylethylamine. The mixture was stirred at 65 C for 6 hours. The solvent was removed by rotary evaporation. The crude product was purified by column chromatography using basic alumina. Methanol (1% to 12%) in dichloromethane was used as an eluent. Fractions with pure product were combined, solvent removed in vacuo giving 38% yield.
With diisobutylaluminium hydride In toluene for 15h; Reflux;
b) Weisman and Reed Synthesis
This is an easy method to implement in the laboratory for the synthesis of cyclen.8 However, this procedure requires expensive starting materials and reactants. This method utilizes two steps synthesis of cyclen from triethylenetetraamine and dithiooxamide. An important step is the double reductive ring expansion (in refluxing toluene for 15 h producing cyclene of more than 90% purity) of tricyclic bis-amidine with Diisobutylaluminium hydride (DIBALH) to produce cyclen. This reduction step is carried out in refluxing toluene for 15 h producing cyclene of more than 90% purity. The overall yield of cyclen has been reported to be about 57%. However, a drawback of this method is the formation of byproduct “ethanethiol” which needs to be flushed from the reaction mixture.
To a solution of 1,4,7,10-tetraazacyclododecane free base 1(714 mg, 4.067 mmol) in chloroform (35 mL), N-(tert-Butoxycarbonyloxy)succinimide (8.134 mmol) was added. The reaction mixture was stirred at room temperature for 28 h. Solvent was removed by rotary evaporation and 30 mL of NaOH 3 M was added to the remaining residue. The aqueous phase was extracted with chloroform (3.3 mL). The extracts were combined and dried (over K2CO3). The solvent was removed by rotary evaporation and the residue was dried in vacuum for several hours. 513 mg of the unpurified compound from the preceding reaction (1.3761 mmol)was solubilized in acetonitrile. 0.67 mL (2.87 mmol) of benzyl bromoacetate and 0.474 g (3.412 mmol) K2CO3 were added to this solution at room temperature, after which the mixture was heated under reflux for 8 h. The solids were discarded by filtration over Celite and the solvent was removed under vacuum. Chromatographic purification (alumina, 98/2 DCM/MeOH) yielded 2 as aslowly solidifying colourless oil (736 mg, 87% over all for two steps). 1H NMR (500 MHz, CDCl3) d (ppm): 7.31 (m, 10H), 5.11 (s,4H), 3.54 (s, 4H), 3.49 (m, 8H), 2.86 (m, 8H), 1.41 (s, br 18H). 13C(500 MHz, CDCl3) d (ppm): 171.48, 157.11, 136.02, 79.33, 66.04,55.04, 54.51, 46.68, 28.46. ESI-MS (C36H52N4O8); m/z = 668 [M+H]+.
2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tris(N-(tert-butyl)acetamide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydrogencarbonate; In acetonitrile; at 20℃; for 24h;Inert atmosphere;
2-bromo-N- (tert-butyl) acetamide (10.1g, 52.2 mmol) was added into the solution of 1, 4, 7, 10-tetraazacyclododecane (3.0 g, 17.4 mmol) in anhydrous acetonitrile (80 mL) , followed by NaHCO3(21.9 g, 261 mmol) . The resulting solution was stirred at room temperature for 24 hours. After filtration of the resulting mixture, filtrate was concentrated and recrystallized from hot water to obtain a white solid as the product. (4.8 g, 8.7 mmol, yield 50%)1H NMR (400 MHz, CDCl3) : δ 6.78 (s, 1 H) , 6.68 (s, 2 H) , 3.05 (s, 4 H) , 3.05 (s, 2 H) , 2.70 (m, 16 H) , 1.37 (s, 18 H) 1.36 (s, 9 H) (Figure 22)13C NMR (100 MHz, CDCl3) : δ 170.1, 170.0, 60.5, 59.6, 53.4, 52.9, 52.3, 51.1, 50.9, 46.7, 28.9, 28.8 (Figure 23) HRMS (MALDI-TOF) m/z calcd. For C26H54N7O3[M + H]+512.4288 found 512.4285.
50%
With sodium hydrogencarbonate; In acetonitrile; at 20℃; for 24h;
2-promo-N-(tert-butyl)acetamide (10.1 g, 52.2 mmol) was added into the solution of 1,4,7,10-tetraazacyclododecane (3.0 g, 17.4 mmol) in anhydrous acetonitrile (80 mL), followed by NaHCO3 (21.9 g, 261 mmol). The resulting solution was stirred at room temperature for 24 hours. After filtration of the resulting mixture, filtrate was concentrated and recrystallized from hot water to obtain a white solid as the product. (4.8 g, 8.7 mmol, yield=50%) 1H NMR (400 MHz, CDCl3): δ6.78 (s, 1 H), 6.68 (s, 2 H), 3.05 (s, 4 H), 3.05 (s, 2 H), 2.70 (m, 16 H), 1.37 (s, 18 H) 1.36 (s, 9 H); () 13C NMR (100 MHz, CDCl3): δ170.1, 170.0, 60.5, 59.6, 53.4, 52.9, 52.3, 51.1, 50.9, 46.7, 28.9, 28.8; () HRMS (MALDI-TOF) m/z calcd. For C26H54N7O3 [M+H]+ 512.4288 found 512.4285.
42.3%
With sodium hydrogencarbonate; In acetonitrile; at 20℃; for 24h;
To 1, 4, 7, 10 - tetraazacyclododecane (4.0 g, 23 . 22 mmol) of CH3CN (150 ml) is added in the solution NaHCO3(19.50G,232 . 20 mmol). Next adds by drops at room temperature 2 - bromo - N - (tert-butyl) acetamide (compound II - 1) (13.97 g, 72 . 50 mmol) of 150 ml CH3CN solution. The reaction mixture stirring at room temperature 24 hours, the solid for CH3CN washing several times. The combined organic phase, removing the solvent to obtain the yellow solid. The solid is dissolved in 250 ml water, and 1 M NaOH aqueous solution to adjust the pH of the solution to 8. For the aqueous phase DCM (3 × 50 ml) washing, then for 1 M NaOH aqueous solution to adjust the pH of the solution to the 13, and DCM (5 × 50 ml) extraction. Finally combined organic phase, removing the solvent, the resulting solid water recrystallization, vacuum drying. At the end of the white solid product 2, 2 ', 2' - (1, 4, 7, 10 - tetramethyl - 1, 4, 7 - of three-) three (N - (tert-butyl) acetamide) 5.00 g, yield 42.3% (compound II - 2).
With sodium hydroxide; In water; for 5h;pH 11;Large scale;
A 6000 L reactor was charged with water (360 L) followed by cyclen (Kinsy, Spain; 180 kg, 1.O4Skrnol).A solution of sodium chloroacetate (Akzo Nobel, 540 kg, 4.55 kmol) in water (900 L) was added over a period of 1.5 hours, together with sodium hydroxide solution (377 kg50% w/w concentration; 4.71 kmol NaOH;) being added continuously to maintain the reaction pH at around pH 11. After the addition was complete, the reaction mixture was stirred for a further 5 hours.Concentrated hydrochloric acid (35%; ca. 462 kg) was added until the pH of the mixture was about pH 3.2. Then methanol was added (2340 L) at ca. 55 C and cooled to 10 C, cooling rate ca. 5 C per hour.The precipitated crude DOTA was filtered off, and washed with aqueous methanol (1:2 vollvol; 4 x 315 L). The resulting cake was dried in the filter using reduced pressure and heating (55 C jacket temperature).The above crude DOTA was dissolved in water and sampled for measurement of quantity and sodium content (369 kg DOTA; 87 % yield; 5.26 % Na) and subjected tonanofiltration whereby the sodium content was reduced from 5.26 w% to 0.84 w%. The aqueous solution this reduced salt DOTA was concentrated and then methanol added to induce crystallization and remove the remaining sodium chloride. The isolated crystals had a sodium content NMT 10 ig/g DOTA.
(Z) -1- (3,4,5-trimethoxyphenyl) -2- (3-amino-4-methoxyphenyl) ethylene (20 g, 63 mmol)Dissolved in 200 ml of dichloromethane,Adding diisopropylethylamine 13ml,Stir,A solution of 1,1'-carbonyldiimidazole (12.3 g, 76 mmol) was added to the ice bath,After 1.5 h of reaction, a solution of cyclone (13 g, 76 mmol) in DMF (100 ml)Plus room temperature after overnight reaction, TLC tracking. After completion of the reaction, the reaction solution was concentrated to dryness,The column was separated by flash column chromatography and eluted with eluent:Dichloromethane / methanol / triethylamine = 9/1 / 0.5 to give 23 g of the desired product in 71% yield.
tetraethyl 5,5',5'',5'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetranicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.1%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 5,5-dimethyl-1,3-cyclohexadiene; at 50℃; for 0.5h;
Cyclen, 58.7 g of ethyl 5-bromonicotinate, 27.9 g of t-BuONa, and 400 ml of xylene are added and stirred. 2.4 g of 50% (t-Bu) 3P toluene solution was added to the mixture, and the mixture was stirred for 30 minutes. After heating to 50 C, 1.7 g of Pd (dba) 2 was added and the mixture was heated to reflux. After cooling to room temperature, 1000 ml of purified water is added, and the mixture is left to stand for 30 minutes to separate the layers, and the aqueous layer is discarded. The organic layer was treated with MgSO4, concentrated in vacuo and purified by MC-MeOH column to obtain tetraethyl 5,5 ', 5' ', 5' '' - (1,4,7,10-tetraazacyclododecane-1,4,7,10- 17.9 g of tetranicotinate was obtained. (Yield: 40.1%).
tetraethyl 5,5',5'',5'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(furan-2-carboxylate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In toluene; at 50℃; for 0.5h;
Cyclen, 56.0 g of <strong>[6132-37-2]ethyl 5-bromofuran-2-carboxylate</strong>, 27.9 g of t-BuONa and 400 ml of toluene were added and stirred. 2.4 g of 50percent (t-Bu) 3P toluene solution was added to the mixture, and the mixture was stirred for 30 minutes. After heating to 50 ° C, 1.7 g of Pd (dba) 2 was added and the mixture was heated to reflux. After cooling to room temperature, 1000 ml of purified water is added, and the mixture is left to stand for 30 minutes to separate the layers, and the aqueous layer is discarded. The organic layer was treated with MgSO4, concentrated in vacuo and purified by MC-MeOH column to obtain tetraethyl 5,5 ', 5' ', 5' '' - (1,4,7,10-tetraazacyclododecane-1,4,7,10- 12.6 g of tetrakis (furan-2-carboxylate) was obtained. (Yield: 30.0percent)
3 -(1,4,7,10-tetraazacyclododecan-1-yl)butane-1,2,4-triol tetrahydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100 g of cyclones (1,4,7,10-tetraazacyclododecane) Dissolve in 500ml of purified water and warm to 40-45 C84 g of 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octaneAdd slowly React for 24 hours, add 408 ml of hydrochloric acid dropwise and stir at 75 C. for 2 hours. The reaction solution was concentrated in vacuo, 500 ml of ethanol was added thereto, stirred at reflux, and the resulting crystals were filtered.
With tetrabutylammomium bromide; In ethanol; at 80℃; for 8h;
In a 500 mL reactor, 200 mL of ethanol, 62 g (1.03 mol) of ethylenediamine, 282 g (1 mol) of 1,2-diiodoethane, and 9.66 g (0.03 mol) of tetrabutylammonium bromide were added, and stirring was started. The temperature was raised to 80 C, and the reaction was kept for 8 hours. After cooling to 40 C, 20 wt% of liquid alkali was added dropwise to pH=7-8, and the temperature was further lowered to 10-15 C to cool and crystallize to obtain a crude ring of cyclen. The crude product was recrystallized from 2 times by weight of ethanol to obtain 76 g of the finished product of the ring of cyclen, HPLC ? 99%, and the yield was 88.4%.
With lithium chloride; In isopropyl alcohol; at 25 - 85℃;
92. Og of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane (5) was added to a reaction mixture of lOOg of l,4,7,l0-tetraazacyclododecane (6) in 200mL of isopropyl alcohol at 25-30 C. To this solution 25 g of lithium chloride was added and heated to 80-85 C for 23-24hrs. On completion of reaction, the reaction mass was distilled off completely under vacuum. 500mL water was added to the crude and stirred. The pH of the reaction mixture was adjusted to 7-10.0 by adding 57.0 mL of acetic acid. The reaction mixture was diluted with 900 mL of dichloromethane and stirred at 25- 30 C. The phases were separated, the aqueous layer was treated with 50% sodium hydroxide and stirred for l0-l5mins. The reaction mixture was diluted with 600mL of the dichloromethane and phases were separated. The organic layer was dried over sodium sulphate, filtered and the filtrate so obtained was distilled off under vacuum to obtain solid 2,2-dimethyl-6-(l,4,7,l0-tetraazacyclododecan-l-yl)-l,3-dioxepan- 5-ol of formula (4). Yield: 78%; Purity: 86.96%.
1,4,7,10-tetra-n-butyl-1,4,7,10-tetraazacyclododecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.7%
With potassium carbonate In acetonitrile at 30℃; for 6h; Inert atmosphere; Reflux;
9.4 Step (4): Preparation of compound 1,4,7,10-tetrabutyl-1,4,7,10-tetraazacyclododecane of formula 6
Keep a slight positive pressure of nitrogen, add 3L acetonitrile, 691.05g (5.0mol) potassium carbonate and 145.23g (0.843mol) compound of formula 5 to the 5L reaction flask, add 548.08g (4.0mol) 1- Bromobutane, control the temperature not to exceed 30 , stir well. After the addition, the temperature was raised to reflux for reaction. The reaction was maintained under reflux for 6 hours, and the reaction was completed. The reaction solution was cooled to room temperature, filtered, and the filtrate was rotary evaporated to recover the solvent. The residue was recrystallized with an appropriate amount of toluene to obtain 320.15 g (0.807 mol) of a white solid product. The yield is 95.7%, the total yield of the four-step reaction is 80.7%, Product titration purity: 99.2% (by HClO4),
45%
With potassium carbonate In acetonitrile at 60℃; for 24h;
Stage #1: 1,4,7,10-tetraazacyclododecan With potassium carbonate In acetonitrile for 2h; Reflux;
Stage #2: C22H19BrO2 In acetonitrile at 20℃; for 24h;
2.3 Synthesis of star compound (St1)
Cyclen tetrachlorohydrate (0.013g, 0.041mmol) and K2CO3 (0.056g, 0.41mmol) were added into a 50mL round bottom flask with anhydrous MeCN (15mL). The reaction mixture was heated to reflux for 2h. After this time, the mixture was cooled to room temperature and compound 2 added allowing the mixture to react for 24h. Then, the resulting reaction mixture was filtered through celite to remove the salts, and further purified by column chromatography in silica gel, eluting with a mixture DCM/MeOH (1%). The pure product was obtained as a slight yellowish white solid in 87% yield. 1H NMR (400MHz, CDCl3), δ (ppm): 8.11-7.56 (m, 36H, Arpy), 3.82 (wide signal, 8H, CH2-O), 3.03 (s, 8H, CH2 aliphatic), 2.80 (wide signal, 8H, CH2-C=O), 1.83 (wide signal, 16, CH2-N), 1.56 (m, 8H, CH2 aliphatic), 1.39 (m, 8H, CH2 aliphatic). 13C{1H}-NMR (100MHz, CDCl3), δ (ppm): 27.8, 28.3, 30.7, 32.7, 54.9, 64.9, 123.1, 124.8, 124.9, 125.0, 125.1, 125.2, 126.1, 126.8, 127.2, 127.4, 127.5, 128.5, 129.9, 130.8, 131.5, 136.0, 173.7. ATR-FTIR (cm-1): 3037, 2919, 2850, 1725, 1450, 1209, 1105, 1066, 846, 723. MALDI-TOF: [M+Na]+ m/z=1453.33. Elemental analysis, calculated: C, 80.53; N, 3.91; H, 6.62; Found: C, 81.20; N, 3.84; H, 6.65.
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