* 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.
General procedure: A 10 mL Schlenk tube was charged with III (0.0128 g, 0.0075 mmol), N,N'-diisopropylcarbodiimide (0.189 g, 1.5 mmol), and aniline (0.140 g, 1.5 mmol) under dried argon. The resulting mixture was stirred at 25 °C for 30 min. The reaction mixture was extracted with ether and filtered to give a clean solution. After removing the solvent under vacuum, the residue was recrystallized in ether to provide a white solid 1 in >99percent yield.
96%
With zinc(II) oxide In toluene at 110℃; for 10 h;
General procedure: A mixture of amine (1 mmol), carbodiimide (1.1 mmol) and nanocrystalline ZnO (20 mol percent, 0.016 g) was stirred in toluene (1 mL) at 80 °C for 8 h (for aromatic and aliphatic primary amines) or at 110 °C for 10 h (for secondary amines). The progress of the reaction was monitored by TLC analysis. At the end of the reaction, the reaction mixture was allowed to cool to room temperature, centrifuged and filtered the supernatant through a sintered funnel. The catalyst was then washed with ethyl acetate, centrifuged and filtered. The combined filtrate was concentrated under reduced pressure, and further purified by column chromatography on neutral alumina using ethyl acetate/hexane as the eluent to afford the desired product in good yields.
96%
With iron(II) acetate In toluene at 140℃; for 5 h; Inert atmosphere
General procedure: A Schlenk tube under nitrogen was charged with Fe(OAc)2 (8.70 mg, 0.05 mmol), the corresponding amine (1 mmol) and carbodiimide (1.2 mmol) and toluene (2 mL). The resulting suspension was heated at 140 oC and the progress of the reaction was monitored by TLC. At the end of the reaction, the reaction mixture was allowed to cool to room temperature and then hydrolyzed with water (5 mL), extracted with dichloromethane (3 10 mL), dried over anhydrous Na2SO4 and filtered. Then, the solvent was evaporated under reduced pressure to give the crude product which was purified by recrystallization method in hexane or diethyl ether and also by column chromatography to afford the desired products in good yields.
96%
With 1,3-di-tert-butylimidazol-2-ylidene:Mg[N(SiMe3)2]2 In toluene at 110℃; for 24 h; Schlenk technique; Inert atmosphere; Glovebox
General procedure: A 30 mL Schlenk tube under inert atmosphere (N2-glovebox) was charged with the catalyst ItBu:Mg[N(SiMe3)2]2 (0.03 equiv), secondary amine (1.0 equiv), and toluene (5 mL). To this mixture carbodiimides (1.0 equiv) was added. The flask was then closed to prevent evaporation of amines with low boiling points, and the resulting mixture was heated to 110 °C for the desired time. The solvent was removed under reduced pressure; the residue was extracted with hexane (3 x 15 mL) and filtered to give a clean solution. After removing the hexane under reduced pressure, the final products were obtained.
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 8966 - 8972
[2] Tetrahedron, 2011, vol. 67, # 45, p. 8790 - 8799
[3] Tetrahedron, 2012, vol. 68, # 29, p. 5730 - 5737
[4] Tetrahedron Letters, 2012, vol. 53, # 38, p. 5156 - 5158
[5] Journal of Organometallic Chemistry, 2014, vol. 769, p. 112 - 118
[6] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6347 - 6349
[7] Journal of Organometallic Chemistry, 2012, vol. 713, p. 27 - 34
[8] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 8, p. 1211 - 1220
2
[ 108-91-8 ]
[ 4975-73-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 22, p. 3693 - 3700
3
[ 36903-85-2 ]
[ 4975-73-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 22, p. 3693 - 3700
N,N'-Dicyclohexyl-morpholine-4-carboxamidine; compound with phosphoric acid mono-((2R,3S,4S,5R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl) ester[ No CAS ]
N,N'-Dicyclohexyl-morpholine-4-carboxamidine; compound with (4aR,7R,8R,8aS)-2-oxo-hexahydro-2λ5-pyrano[3,2-d][1,3,2]dioxaphosphinine-2,6,7,8-tetraol[ No CAS ]
With pyridine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 100℃; for 16.0h;
To a stirred suspension of cidofovir (1.0 g, 3.17 mmol) in N,N-DMF (25 mL) was added N,N-dicyclohexyl-4-morpholine carboxamidine (DCMC, 1.0 g, 3.5 mmol). The mixture was stirred overnight to dissolve the cidofovir. This clear solution was then charged to an addition funnel and slowly added (30 min.) to a stirred, hot pyridine solution (25 mL, 6O0C.) of 1,3-dicyclohexyl carbodiimide (1.64 g, 7.9 mmol). This reaction mixture was stirred at 1000C for 16 h then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was adsorbed on silica gel and purified by flash column chromatography using gradient elution (CH2Cl2 +MeOH). The UV active product was finally eluted with 5:5:1 CH2Cl2 /MeOH/H2O Evaporation of the solvent gave 860 mg of a white solid. The 1H and 31P NMR spectrum showed this to be the DCMC salt of cyclic cidofovir (yield=44%).
44%
As described in U.S. Pat. No. 6,716,825, in Step 1 of the scheme above, cidofovir was suspended in N,N-DMF and N,N'-dicyclohexyl-4-morpholine-carboxamide was added. The mixture was stirred overnight to dissolve the cidofovir. The clear solution was then charged to an addition funnel and slowly added (30 min) to a stirred, hot pyridine (60 C.) solution containing 1,3-dicyclohexyl carbodiimide. The resulting reaction mixture was stirred at 100 C. for 16 h, cooled to room temperature and the solvents were removed under reduced pressure. The reaction mixture was adsorbed on silica gel and the product was purified by flash column chromatography using gradient elution (CH2Cl2 and MeOH) followed by 5:5:1 CH2Cl2/MeOH/H2O. The fractions containing the product were combined and concentrated in vacuo. The product, the DCMC salt of cyclic cidofovir was isolated in a 44% yield. In step 2, a solution of cyclic cidofovir DCMC salt in dry N,N-DMF was charged with 1-bromo-3-hexadecyloxypropane and the mixture was stirred and heated at 80 C. for 6 h. The solution was concentrated in vacuo, the residue adsorbed on silica gel and purified by flash column chromatography using gradient elution (CH2Cl2 and ethanol). The product was eluted with 90:10 CH2Cl2/EtOH. The fractions containing pure product were concentrated in vacuo. Hexadecyloxypropyl-cyclic cidofovir was obtained in a 55% yield. In Step 3, hexadecyloxypropyl-cyclic cidofovir was dissolved in 0.5M NaOH and stirred at room temperature for 1.5 h. 50% aqueous acetic acid was then added dropwise to adjust the pH to 9. The precipitated hexadecyloxypropyl-cidofovir was isolated by filtration, rinsed with water, and dried. The product was crystallized from 3:1p-dioxane/water to give hexadecyloxypropyl-cidofovir (HDP-CDV, i.e., CMX001).
With [Li(THF)(DME)]3La[mu-eta2eta1(iPrN)2C(NC6H4p-Cl)]3; at 50℃; for 2.0h;Inert atmosphere;
General procedure: A 10 mL Schlenk tube was charged with III (0.0128 g, 0.0075 mmol), N,N'-diisopropylcarbodiimide (0.189 g, 1.5 mmol), and aniline (0.140 g, 1.5 mmol) under dried argon. The resulting mixture was stirred at 25 C for 30 min. The reaction mixture was extracted with ether and filtered to give a clean solution. After removing the solvent under vacuum, the residue was recrystallized in ether to provide a white solid 1 in >99% yield.
96%
With zinc(II) oxide; In toluene; at 110℃; for 10.0h;
General procedure: A mixture of amine (1 mmol), carbodiimide (1.1 mmol) and nanocrystalline ZnO (20 mol %, 0.016 g) was stirred in toluene (1 mL) at 80 C for 8 h (for aromatic and aliphatic primary amines) or at 110 C for 10 h (for secondary amines). The progress of the reaction was monitored by TLC analysis. At the end of the reaction, the reaction mixture was allowed to cool to room temperature, centrifuged and filtered the supernatant through a sintered funnel. The catalyst was then washed with ethyl acetate, centrifuged and filtered. The combined filtrate was concentrated under reduced pressure, and further purified by column chromatography on neutral alumina using ethyl acetate/hexane as the eluent to afford the desired product in good yields.
96%
With iron(II) acetate; In toluene; at 140℃; for 5.0h;Inert atmosphere;
General procedure: A Schlenk tube under nitrogen was charged with Fe(OAc)2 (8.70 mg, 0.05 mmol), the corresponding amine (1 mmol) and carbodiimide (1.2 mmol) and toluene (2 mL). The resulting suspension was heated at 140 oC and the progress of the reaction was monitored by TLC. At the end of the reaction, the reaction mixture was allowed to cool to room temperature and then hydrolyzed with water (5 mL), extracted with dichloromethane (3 10 mL), dried over anhydrous Na2SO4 and filtered. Then, the solvent was evaporated under reduced pressure to give the crude product which was purified by recrystallization method in hexane or diethyl ether and also by column chromatography to afford the desired products in good yields.
96%
With 1,3-di-tert-butylimidazol-2-ylidene:Mg[N(SiMe3)2]2; In toluene; at 110℃; for 24.0h;Schlenk technique; Inert atmosphere; Glovebox;
General procedure: A 30 mL Schlenk tube under inert atmosphere (N2-glovebox) was charged with the catalyst ItBu:Mg[N(SiMe3)2]2 (0.03 equiv), secondary amine (1.0 equiv), and toluene (5 mL). To this mixture carbodiimides (1.0 equiv) was added. The flask was then closed to prevent evaporation of amines with low boiling points, and the resulting mixture was heated to 110 C for the desired time. The solvent was removed under reduced pressure; the residue was extracted with hexane (3 x 15 mL) and filtered to give a clean solution. After removing the hexane under reduced pressure, the final products were obtained.
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