* 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.
Reference：
[1] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[2] Chem.Abstr., 1951, p. 5150
[3] Chemische Berichte, 1901, vol. 34, p. 1242
[4] Patent: WO2013/78254, 2013, A1, . Location in patent: Paragraph 00491
2
[ 13162-26-0 ]
[ 20090-69-1 ]
Yield
Reaction Conditions
Operation in experiment
29%
With ammonium chloride; zinc In methanol at 70℃; for 50 h; Inert atmosphere
To a solution of 2 4-dichloro-6-methyl-5-nitropyrimidine (10 g 48.1 mmol) and NH4Cl (25.7 g 481 mmol) in MeOH (100 mL) stirred under N2at 20 was added zinc (31.4 g 481 mmol) in one charge. The reaction mixture was stirred at 70 for 50 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (DCM/MeOH 301) . All fractions found to contain product by TLC (EA/EA1 11 Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-chloro-4-methylpyrimidin-5-amine (2 g 13.93 mmol 29.0 yield) 1HNMR(400 MHz CDCl3) δ 7.95 (s 1H) 3.66 (s 2H) 2.88 (s 3H) ES-LCMS m/z 144.2 (M+H) .
Reference：
[1] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 138
[2] Chemische Berichte, 1901, vol. 34, p. 1242
[3] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[4] Chem.Abstr., 1951, p. 5150
[5] Patent: EP2100894, 2009, A1, . Location in patent: Page/Page column 20
[6] Patent: CN105906621, 2016, A,
3
[ 13162-26-0 ]
[ 63211-98-3 ]
Reference：
[1] Chemische Berichte, 1901, vol. 34, p. 1242
4
[ 13162-26-0 ]
[ 13162-27-1 ]
Yield
Reaction Conditions
Operation in experiment
65.1%
With palladium on activated charcoal; hydrogen In ethyl acetate at 20℃;
The raw material 13 (860mg) and Pd / C (180mg) were dissolved in ethyl acetate (30ml), hydrogen was ventilated three times, reacted at room temperature under hydrogen pressure 40psi. After the reaction was complete, Pd / C was filtered, To give a yellow solid 14 (500 mg) in 65.1percent yield.
Reference：
[1] Heterocyclic Communications, 2014, vol. 20, # 5, p. 275 - 279
[2] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0032
[3] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 3, p. 832 - 839
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 1953
[5] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[6] Chem.Abstr., 1951, p. 5150
[7] Journal of Chemical Research, 2016, vol. 40, # 10, p. 633 - 636
[8] Research on Chemical Intermediates, 2018, vol. 44, # 11, p. 6877 - 6893
5
[ 16632-21-6 ]
[ 13162-26-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In N,N-dimethyl-formamide at 120℃; for 8 h;
The raw material 12 (1 eq) was dissolved in 17.54 ml of phosphorus oxychloride, and 2.92 ml of N, N-dimethylaniline (1 eq) was slowly added dropwise at room temperature, and 8.04 ul of DMF (0.00445 eq) 120 under reflux reaction 8h, after the completion of the reaction of raw materials, vacuum distillation of phosphorus oxychloride, adding ice water, adding ethyl acetate extraction, combined organic layer, washed with saturated brine, dried over anhydrous sodium sulfate, spin dry Solvent to give a yellowish brown oil which was dryly chromatographed and finally purified to give a yellow solid 13 (1 g) in 65percent yield.
Reference：
[1] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0031
[2] Bulletin de la Societe Chimique de France, 1951, p. 428
[3] Helvetica Chimica Acta, 1951, vol. 34, p. 835,837
[4] Journal of the Chemical Society, 1951, p. 1004,1015[5] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, vol. 24, p. 84
[6] Journal of the Chemical Society, 1955, p. 1113,1115
[7] Journal of the Chemical Society, 1954, p. 3832,3833
[8] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5723 - 5730
[9] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5723 - 5730
6
[ 16632-21-6 ]
[ 13162-26-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4879 - 4883
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 8, p. 2188 - 2192
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2497 - 2500
[4] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 6, p. 1395 - 1399
7
[ 626-48-2 ]
[ 13162-26-0 ]
Reference：
[1] Patent: CN105906621, 2016, A,
8
[ 626-48-2 ]
[ 13162-26-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2497 - 2500
[2] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 6, p. 1395 - 1399
9
[ 16632-21-6 ]
[ 121-69-7 ]
[ 13162-26-0 ]
[ 7460-27-7 ]
Reference：
[1] Journal of the Chemical Society, 1951, p. 1004,1015[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, vol. 24, p. 84
10
[ 16632-21-6 ]
[ 10025-87-3 ]
[ 13162-26-0 ]
Reference：
[1] Chemische Berichte, 1901, vol. 34, p. 1242
11
[ 13162-26-0 ]
[ 84538-40-9 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1060 - 1064
[2] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1060 - 1064
With N,N-dimethyl-aniline; trichlorophosphate; In N,N-dimethyl-formamide; at 120℃; for 8.0h;
The raw material 12 (1 eq) was dissolved in 17.54 ml of phosphorus oxychloride, and 2.92 ml of N, N-dimethylaniline (1 eq) was slowly added dropwise at room temperature, and 8.04 ul of DMF (0.00445 eq) 120 under reflux reaction 8h, after the completion of the reaction of raw materials, vacuum distillation of phosphorus oxychloride, adding ice water, adding ethyl acetate extraction, combined organic layer, washed with saturated brine, dried over anhydrous sodium sulfate, spin dry Solvent to give a yellowish brown oil which was dryly chromatographed and finally purified to give a yellow solid 13 (1 g) in 65percent yield.
methyl 2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)amino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With sodium hydrogencarbonate; In diethyl ether; water;
General procedure: The appropriate methyl ester of amino acid (2a-d) (5 mmol) wereadded portion wise to a vigorously stirring mixture of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (1) (5 mmol, 1.04 g) and NaHCO3 (19mmol,1.6 g) in diethyl ether (5 mL) and water (10 mL) and the mixture wasvigorously stirred overnight. After the completion of the reaction(monitored by TLC using, ethyl acetate: hexane 1:4), the organic phasewas separated and washed with water (2×30 mL), dried over Na2SO4and removed under reduced pressure. The residue was recrystallisedfrom ethanol
With ammonium chloride; zinc; In methanol; at 70℃; for 50h;Inert atmosphere;
To a solution of 2 4-dichloro-6-methyl-5-nitropyrimidine (10 g 48.1 mmol) and NH4Cl (25.7 g 481 mmol) in MeOH (100 mL) stirred under N2at 20 was added zinc (31.4 g 481 mmol) in one charge. The reaction mixture was stirred at 70 for 50 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (DCM/MeOH 301) . All fractions found to contain product by TLC (EA/EA1 11 Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-chloro-4-methylpyrimidin-5-amine (2 g 13.93 mmol 29.0 yield) 1HNMR(400 MHz CDCl3) delta 7.95 (s 1H) 3.66 (s 2H) 2.88 (s 3H) ES-LCMS m/z 144.2 (M+H) .
1: 2-chloro-4-methylpyrimidin-5-amine A mixture of 2,4-dichloro-6-methyl-5-nitropyrimidine (1.100 g) and 10% Pd/C (0.110 g) in ethyl acetate (40 ml) was hydrogenated at room temperature, at a pressure of 40 psi of hydrogen, for 24 hours. The catalyst was filtered off and the solvent was evaporated to give of a white solid. A mixture of 0.200 g of the obtained solid, triethylamine (0.236 ml) and 10% Pd/C (0.02 g) in 96% ethanol (7 ml) was hydrogenated at a pressure of 20 psi of hydrogen for 20 minutes. The catalyst was filtered off and the solvent was evaporated. The residue was purified on silica gel (eluent: ethyl acetate/petroleum ether 1/2 (v/v) to give the title compound as white solid. 1H NMR (DMSO-d6) delta (ppm): 7.92 (s, 1 H); 5.49 (br. s., 2 H); 2.26 (s, 3 H). MS (ESI Pos, 3.2 kV, 20 V, 400C): m/z 144,13 (MH+).
With triethanolamine; titanium(IV) dioxide; water; In isopropyl alcohol; for 7h;Irradiation; Green chemistry;
Dissolve <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (1 g, 4.8 mmol) in isopropanol (100 mL) and stir to clarify, add 10 mL purified water and 10 mL triethanolamine, then Add 1 g of rutile nano-titanium dioxide as a catalyst. The system is a white suspension. After stirring for 0.5 h, it is placed in a photochemical reactor and irradiated with a 365nm LED light for 6.5 h. TLC or HPLC monitors the disappearance of the raw materials and stops the light to obtain the product system. The product system was placed in a centrifuge for centrifugal separation, and the upper organic phase was concentrated under reduced pressure to obtain 735 mg of 2,4-dichloro-6-methylpyrimidin-5-amine with a separation yield of 86%.
65.1%
With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; under 2068.65 Torr;
The raw material 13 (860mg) and Pd / C (180mg) were dissolved in ethyl acetate (30ml), hydrogen was ventilated three times, reacted at room temperature under hydrogen pressure 40psi. After the reaction was complete, Pd / C was filtered, To give a yellow solid 14 (500 mg) in 65.1% yield.
With sodium tetrahydroborate; In water; at 20℃;Green chemistry;
Reduction of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> was carried out in aconventional round-bottomed flask according to the following procedure: 15 mg(0.072 mmol) <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> was dissolved in 5 mldeionized water. Then, 2.1 mmol NaBH4 and different amounts (1, 3, 5, and7 mg) of GO-Fe3O4 catalyst were added to the solution and stirred at ambienttemperature. Sampling from the mixture was performed after 1, 5, and 10 min tomonitor reaction progress via ultraviolet-visible (UV-Vis) spectrophotometry(Photonix Ar). For this purpose, each sample was diluted in deionized water.Adsorption spectra were collected in the range of 200-400 nm. The concentrationchange of 2,4-dichloro-6-methyl-5-aminopyrimidine was represented by the changeof the adsorption peak at wavelength of 235 nm. In addition, reaction completionwas confirmed by thin-layer chromatography (TLC) using chloroform/methanol(10:1) as eluent after 10 min. After reaction completion, the nanomagnetic catalystwas separated from the reaction mixture by applying an external magnetic field. Toextract product from deionized water, 5 ml ethyl acetate (EtOAc) was added to theresultant solution. The organic phase was separated from water in decanter, driedover Na2SO4, and allowed to evaporate to give crude solid 2,4-dichloro-6-methylpyrimidin-5-amine in yield of 98% as red powder; m.p. 102-103 C; H NMR(CDCl3): d 2.32 (s, 3H, CH3), 6.08 (s, 2H, NH2, D2O exchangeable); IR: m 3472,3371, 1621, 1555, 1527 cm-1; MS (m/z) 178 (M?), 180 (M? ?2). Anal. Calcd. forC5H5Cl2N3: C, 33.73; H, 2.83; N, 23.60. Found: C, 33.71; H, 2.83; N, 23.59
With ammonia; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; at -10℃; for 2.5h;
Reference example 59 2-Chloro-6-methyl-5-nitropyrimidine-4-amine To a solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (20 g) in tetrahydrofuran (321 mL) were added dropwise N,N-diisopropylethylamine (24.5 mL) and ammonia (7.0 mol/L methanol solution, 20.6 mL) at -10C, and the mixture was stirred at -10C for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo to give the title compound (17.5 g). LC-MS [M+H]+/Rt (min): 188.8/0.503 (Method C)
With triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred solution of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (5.0 g, 24.15 mmol) in CH2Cl2 (50 mL) was added a solution of morpholine (2.1 mL, 24.15 mmol) in CH2Cl2 (20 mL), followed by the addition of triethylamine (6.7 mL, 48.3 mmol) at 0 C. The resulting mixture was stirred at room temperature overnight and diluted with CH2Cl2. The organic solution was washed with water and brine, and dried over MgSO4. The solvent was removed by evaporation under reduced pressure, and the residue was purified by flash chromatography to give the titled compound as yellow solid (6.17 g, 99% yield). MS (ESI) m/z 259.0
92%
In chloroform; at 20℃; for 2h;
General procedure: 2-Chloro-4-methyl-5-nitro pyrimidines 3a-3g(general procedure). A solution of 4 mmol of amine2a-2g in 5 mL of chloroform was added to a solutionof 0.416 g (2 mmol) of 2,4-dichloro-6-methyl-5-nitro- pyrimidine in chloroform. The reaction mixturewas stirred for 2 h at room temperature and, after thereaction had been complete (by TLC), it was fi ltered andconcentrated under reduced pressure. The product waswashed with water and recrystallized from ethanol. 2-Chloro-4-methyl-6-morpholino-5-nitropyrimidine(3d). Yield 0.47g (92 %), yellow crystals, mp115-116C. IR spectrum, ν, cm-1: 1424 (N-O symm),1496 (N-O asym), 2925 (CH), 1583 (C=N). 1H NMR(CDCl3), δ, ppm: 2.63 s (3H, CH3), 3.53 t (4H, 2CH2, J6.0 Hz), 3.72 t (4H, 2CH2, J 6.0 Hz). 13C NMR spectrum(CDCl3), δ, ppm: 21.4, 47.1, 63.4, 130.8, 152.2, 158.4,161.6. Mass spectrum, m/z (Irel, %): 258.1 (88.7) [M]+,241.2 (20.3), 225.2 (9.0), 213.2 (15.3), 195.2 (15.7),185.2 (60.5), 169.2 (58.1), 157.2 (15.1), 133.2 (19.7),93.1 (18.5), 73.1 (46.0), 66.2 (60.9), 42.2 (100). Found,%: C 41.72; H 4.11; N 21.53. C9H11ClN4O3. Calculated,%: C 41.79; H 4.29; N 21.66.
41%
With triethylamine; In dichloromethane; at 0 - 20℃;
4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4-yl)-morpholine (Compound 1.1 ) To a solution of 2,4-dichloro-6-methyl-5-nitropyrinnidine (2.5g; 12 mmol) in DCM (200 ml_) was added triethylamine (3.35 ml 24 mmol) and then morpholine (1.15 ml 13.2 mmol) while keeping the temp at 0-50C. The reaction mixture was stirred at this temperature for 40 min. and then RT overnight. The reaction mixture was washed with 1 N HCI (aq) and with NaHCO3. The organic phase was dried over MgSO4, evaporated to dryness and purified by column chromatography (elu- ent: 0-10 % EtOAc in P-ether (80-1000C fraction)) to give 1.3g (41 %) of a yellow solid identical to the title compound.
With palladium on activated charcoal; hydrogen; potassium acetate; In methanol;Inert atmosphere;
To a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (7 g, 34 mmol) and CH3COOK (9.8 g, 100 mmol) in MeOH (150 mL) was added Pd C (3 g). The mixture was stirred at H2 atmosphere for overnight. The reaction mixture was filtered, and the solvent was concentrated under reduced pressure to give the product 4-methylpyrimidin-5 -amine (1.5 g, 43%), which was used to next step without furthermore purification. 'HNMR: MeOD 400MHz ? 8.28(s, 1H), 8.04(s, 1H), 2.3 l(s, 3H).
2-chloro-4-(3-cyclopentyloxy-4-methoxybenzylamino)-5-nitro-6-methylpyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran;
Example 1 Synthesis of 2-chloro-4-(3-cyclopentyloxy-4-methoxybenzylamino)-5-nitro-6-methylpyrimidine 2,4-Dichloro-5-nitro-6-methylpyrimidine (2.0 g) was dissolved in tetrahydrofuran (14 ml) and added with a solution of 3-cyclopentyloxy-4-methoxybenzylamine (2.25 g) dissolved in tetrahydrofuran (7 ml) with stirring and cooling on a salt-ice bath (-10C). Then, the mixture was added dropwise with triethylamine (1.4 ml), and stirred for 30 minutes on a salt-ice bath (-10C). The reaction mixture was further added with saturated brine, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was suspended and washed in a mixed solvent of ether and hexane (50:50) to obtain 3.11 g of the title compound. 1H-NMR (CDCl3) δ ppm: 1.59-1.64 (m, 2H), 1.80- 1.96 (m, 6H), 2.73 (s, 3H), 3.84 (s, 3H), 4.70 (d, 2H, J=5.4Hz), 4.74-4.79 (m, 1H), 6.83-6.91 (m, 3H), 8.36 (bs, 1H)
With triethylamine; In tetrahydrofuran; at -10℃; for 0.5h;
EXAMPLE 1 Synthesis of 2-Chloro-4-(3-cyclopentyloxy-4-methoxybenzylamino)-5-nitro-6-methylpyrimidine (Compound (X)) 2,4-Dichloro-5-nitro-6-methylpyrimidine (2.0 g) was dissolved in tetrahydrofuran (14 ml), and added with a solution of 3-cyclopentyloxy-4-methoxybenzylamine (2.25 g) dissolved in tetrahydrofuran (7ml) with stirring and cooling on a salt-ice bath (-10 C.).. Then, the mixture was added dropwise with triethylamine (1.4 ml), and stirred for 30 minutes on a salt-ice bath (-10 C.).. The reaction mixture was further added with saturated brine, and then extracted with ethyl acetate.. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was suspended and washed in a mixed solvent of ether and hexane (50:50) to obtain 3.11 g of the title compound. 1H-NMR (CDCl3) δ ppm: 1.59-1.64 (m, 2H), 1.80-1.96 (m, 6H), 2.73 (s, 3H), 3.84 (s, 3H), 4.70 (d, 2H, J=5.4 Hz), 4.74-4.79 (m, 1H), 6.83-6.91 (m, 3H), 8.36 (bs, 1H)
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 0.0833333h;
A solution of 5-cyclopropyl-lH-pyrazol-3-amine (1.8 g, 14.0 mmol) in ϖ-BuOH (25 ml) was slowly added to the n-BuOH (60 ml) solution of 2,4-dichloro-6-methyl-5- nitropyrimidine (3.0 g, 14.0 mmol) and DIEA (2.4 g, 19.0 mmol). After 5 minutes, the reaction was diluted with hexane (100 ml). The resulting precipitate was collected by filtration to yield the title compound (4.1 g, 96%). MS: Calcd.: 294; Found: [M+H]+ 295.
2-(N,N-diethylamino)-4-(2-methylimidazolyl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethanol;
Example 7 2-(N,N-diethylamino)-4-(2-methylimidazolyl)-6-methyl-5-nitropyrimidine (k). To a cooled (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (208 mg, 1.0 mmol, 1.0 equiv. in 2 mL each of EtOH and THF) was added 2.0 equiv. of 2-methylimidazole in 2 mL of EtOH. The resulting mixture was stirred for 1 hr at -78 C., then for 2 hr at 0 C. Diethylamine (0.413 mL, 4.0 equiv.) was added dropwise and the reaction was stirred overnight. The resulting mixture was diluted with dichloromethane, washed with 0.1 N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent was removed by evaporation and the residue was purified by silica gel chromatography to provide 35 mg of the target compound k.
2-(N-methylanilino)-4-pyrrolidino-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethanol;
Example 8 2-(N-methylanilino)-4-pyrrolidino-6-methyl-5-nitropyrimidine (r). To a cooled (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (208 mg, 1.0 mmol, 1.0 equiv. in 2 mL each of EtOH and THF) is added 1.1 equiv. of pyrollidine in 1.0 mL of EtOH. The resulting solution is stirred for 1 hr at -78 C., then for 2 hr at 0 C. N-methylaniline (0.432 mL, 4.0 equiv.) is added dropwise and the reaction is stirred overnight. The resulting mixture is diluted with dichloromethane, washed with 0.1 N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent is removed by evaporation and the residue is purified by chromatography to provide the target compound r.
2-(N-methyl-4-chloroanilino)-4-(2-methylimidazolyl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In tetrahydrofuran; ethanol; hexane;
Example 4 2-(N-methyl-4-chloroanilino)-4-(2-methylimidazolyl)-6-methyl-5-nitropyrimidine (g). To a stirred, cold (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (207.5 mg, 1.0 mmol, 1.0 equiv.) in THF (2.25 mL) and EtOH (2.25 mL) was added 2-methylimidazole (164 mg, 2.00 mmol, 2.0 equiv.) in a solution of EtOH (2.25 mL) dropwise. After 45 min., the dry ice bath was replaced with a water ice bath and stirring was continued for an additional 2 h and 15 min. 4-Chloro-N-methylaniline (0.485 mL, 4.0 mmol, 4.0 equiv.) was then added and the reaction solution was stirred for 2 h and 40 min. Solvent was removed by evaporation and the residue was diluted with dichloromethane, washed three times with 0.1 M HCl, three times with saturated aqueous NaCl solution and dried over MgSO4. Solvent was removed from the organic phase and the residue was purified by silica gel chromatography (1:1 hexane/diethyl ether, 1% AcOH as eluant) to provide g (55.9 mg, 15.6%).
2-(4-benzylpiperazin-1-yl)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane;
Example 11 2-(4-Benzylpiperazine)-4-(2-methylimidazolyl)-6-methyl-5-nitro pyrimidine (u). To a solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (175 mg, 0.84 mmol) in dioxane (5 mL) at 80 C. was added 2-methylimidazole (85 mg, 0.84 mmol) and 1-benzylpipirazine (148 μL, 0.84 mmol). The solution was stirred overnight at 80 C., cooled, and directly chromatographed (1/1 hexane diethyl ether) to yield product.
With hydrogenchloride; ammonia; In 1,4-dioxane; water; acetone;
EXAMPLE 1 6-Methyl-4-morpholino-5-nitro-2-piperazino-pyrimidine A solution of 2.6 gm (0.01 mol) of 2-chloro-6-methyl-4-morpholino-5-nitro-pyrimidine (m.p. 127-129C, prepared from 2,4-dichloro-6-methyl-5-nitro-pyrimidine and morpholine) in 100 ml of acetone/dioxane (1:1) was added dropwise, while stirring and cooling, to a solution of 19.4 gm (0.1 mol) of piperazine hexahydrate in 300 ml of acetone/dioxane (1:1) at about 5C. After about 1 hour the solvents were distilled off in vacuo, and the residue was taken up in about 100 ml of water. The insoluble reaction product was suction-filtered off, washed with water and dried. Yield: 3.0 gm (97% of theory). After one reprecipitation from about 0.2 N hydrochloric acid with 2 N ammonia, the reaction product of the formula SPC5 had a melting point of 143-145C. Analysis: C13 H20 N6 O3; molecular weight 308.3. Calculated: C - 50.65%; H - 6.55%; N - 27.21%. Found: C - 50.70%; H - 6.74%; N - 27.55%.
(a) 15 ml of triethylamine are added to a solution of 15.6 g of 2,4-dichloro-5-nitro-6-methylpyrimidine (0.075 mole) in 300 ml of absolute ethanol. With ice cooling, 6.6 g of sec. butylamine (0.09 mole) are added dropwise at 0-5 C over the course of c. 40 minutes to the dark red solution. After the mixture has been stirred for c. 3/4 hour at this temperature, it is poured into c. 700 ml of ice water and the water is extracted 3 times with ether. The ethereal extracts are dried over magnesium sulphate and evaporated. The resultant red oily substance is crystallized from petroleum ether to yield 10.5 g of 2-chloro-4-sec. butylamino-5-nitro-6-methyl-pyrimidine of m.p. 40-43 C.
With acetic acid; In tetrahydrofuran; ethanol; hexane;
To a stirred, cold (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (187.7 mg, 0.9 mmol, 1.0 eq) in THF (2.25 mL) and EtOH (2.25 mL) was added 2-methylimidazole (148 mg, 1.8 mmol, 2.0 eq) in a solution of EtOH (2.25 mL) dropwise. After 45 minutes, the dry ice bath was replaced with a water ice bath and the mixture was stirred for an additional 2.2 hours. At this time N-methylbenzylamine (0.465 mL, 3.6 mmol, 4.0 eq) was added. After stirring for 2.7 hours, the solvents were removed by evaporation. The residue was diluted with dichloromethane and washed three times with 0.1M HCl and three times with saturated aqueous NaCl solution. Solvent was removed from the organic phase and the residue was purified by chromatography on silica gel (1:1 hexane/diethyl ether, 1% AcOH, as eluant) to provide d (32 mg), e (116.3 mg) and f (104.8 mg).
2-(N-methylanilino)-4-pyrrolidino-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethanol;
EXAMPLE 8 This example illustrates the synthesis of 2-(N-methylanilino)4-pyrrolidino-6-methyl-5-nitropyrimidine (r). To a cooled (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (208 mg, 1.0 mmol, 1.0 eq. in 2 mL each of EtOH and THF) is added of pyrrolidine (78 mg, 1.1 eq) in 1.0 mL of EtOH. The resulting solution is stirred for 1 hour at -78 C., then for 2 hours at 0 C. N-methylaniline (0.432 mL, 4.0 eq.) is added dropwise and the reaction is stirred overnight. The resulting mixture is diluted with dichloromethane, washed with 0.1N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent is removed by evaporation and the residue is purified by chromatography to provide the target compound (r).
2-(N,N-diethylamino)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethanol;
EXAMPLE 7 This example illustrates the synthesis of 2-(N,N-diethylamino)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine (k). To a cooled (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (208 mg, 1.0 mmol, 1.0 eq. in 2 mL each of EtOH and THF) was added 2-methylimidazole (164 mg, 2.0 mmol, 2.0 eq.) in 2 mL of EtOH. The resulting mixture was stirred for 1 hour at -78 C., then for 2 hours at 0 C. Diethylamine (0.413 mL, 4.0 eq.) was added dropwise and the reaction was stirred overnight. The resulting mixture was diluted with dichloromethane, washed with 0.1N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent was removed by evaporation and the residue was purified by silica gel chromatography to provide 35 mg of the target compound k as an oil.
2-(N-methylanilino)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In tetrahydrofuran; hexane;
EXAMPLE 1 This example illustrates the synthesis of 2-(N-methylanilino)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine (a) and an isomer 4-(N-methylanilino)-2-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine (b). To a stirred cold (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (2.25 g, 10.8 mmol, 1.0 eq) in THF (15 mL) was added 2-methylimidazole (977 mg, 11.9 mmol, 1.1 eq) in a solution of THF (15 mL) dropwise. After 1 hour, the dry ice bath was replaced with a water ice bath and stirring was continued for an additional 2 hours and 15 minutes. At this time N-methylaniline (4.6 mL, 43.2 mmol, 4.0 eq) was added. The reaction solution was stirred 1 hour and 15 minutes at -78 C. and at room temperature overnight. At this time the solvent was removed and the residue was diluted with dichloromethane and washed three times with 0.1M HCl and three times with saturated aqueous NaCl solution. The organic phase was evaporated and the residue was purified by chromatography on silica gel (1:1 hexane/diethyl ether, 1% AcOH as eluant) to provide 209 mg of the target compound a (6%) along with an isomer (400 mg) and b (104.8 mg).
2-(N-methyl4-chloroanilino)4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.6%
With acetic acid; In tetrahydrofuran; ethanol; hexane;
EXAMPLE 4 This example illustrates the synthesis of of 2-(N-methyl4-chloroanilino)4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine (g). To a stirred, cold (-78 C.) solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (207.5 mg, 1.0 mmol, 1.0 eq) in THF (2.25 mL) and EtOH (2.25 mL) was added 2-methylimidazole (164 mg, 2.0 mmol, 2.0 eq) in a solution of EtOH (2.25 mL) dropwise. After 45 minutes, the dry ice bath was replaced with a water ice bath and stirring was continued for an additional 2.25 hours. 4-Chloro-N-methylaniline (0.485 mL, 4.0 mmol, 4.0 eq) was then added and the reaction solution was stirred for 2.7 hours. Solvent was removed by evaporation and the residue was diluted with dichloromethane, washed three times with 0.1M HCl, three times with saturated aqueous NaCl solution and dried over MgSO4. Solvent was removed from the organic phase and the residue was purified by silica gel chromatography (1:1 hexane/diethyl ether, 1% AcOH as eluant) to provide g (55.9 mg, 15.6%).
2-(4-benzylpiperazin-1-yl)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane;
EXAMPLE 11 This example illustrates the synthesis of 2-(4-benzylpiperazin-1-yl)-4-(2-methylimidazol-1-yl)-6-methyl-5-nitropyrimidine (u). To a solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (175 mg, 0.84 mmol) in dioxane (5 mL) at 80 C. was added 2-methylimidazole (85 mg, 0.84 mmol) and 1-benzylpiperazine (148 μL, 0.84 mmol). The solution was stirred overnight at 80 C., cooled, and directly chromatographed (1/1 hexane diethyl ether) to yield the title compound (u).
With potassium carbonate; In acetone; at 20℃; for 4h;
Methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]glycinate Methyl 2-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylamino]acetate (Intermediate 10) (1.15 g, 4.81 mmol) in acetone (10 mL) was added to a stirred mixture of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (1 g, 4.81 mmol) and potassium carbonate (731 mg, 5.29 mmol) in acetone (20 mL) and the mixture stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and water (200 mL) added and extracted with ethyl acetate (3*100 mL). The organics were combined and concentrated in vacuo and the residue was purified by column chromatography (eluding with 0 to 100% ethyl acetate in isohexane) and appropriate fractions combined to yield Intermediate 28 as an orange oil (958 mg, 49%); 1H NMR spectrum (400 MHz, CDCl3) δ2.19 (3H, s), 2.24 (3H, s), 2.37 (3H, s), 3.76 (6H, s), 4.41 (2H, s), 4.71 (2H, s), 8.14 (1H, s); Mass spectrum: (M+H)+ 410.
Step A: 4-(4-bromo-2,6-dimethylphenoxy)-2-chloro-6-methyl-5-nitropyrimidine; A solution of LiHMDS in THF (1M, 77 ml, 77 mmol) was added at -78 C. to a mixture of 2,6-dimethoxy-4-bromophenol (14.07 g, 70 mmol) in THF (100 ml) over 15 minutes. The mixture was stirred for an additional 2 hours. Phenoxide salt was observed as solid suspension. The mixture was cooled with liquid nitrogen to a temperature around -100 C. and then a solution of 2,6-dichloro-4-methyl-5-nitropyrimidine (17.47 g, 84 mmol) in THF (50 ml) was added rapidly to the mixture, which turned dark red. The reaction was kept at a temperature around -100 C. for 1 hour. After warming to room temperature, the mixture was filtered and the solid was washed with ethanol to yield 16.75 g of the title product. The filtrate was concentrated and crystallized to obtain an additional 5.60 giving a total amount of 22.35 g of desired compound (60 mmol, 85%). 1H NMR (CDCl3, 400 MHz) δ 2.11 (s, 6H), 2.63 (s, 3H), 7.27 (s, 2H).
Step A: 4-(4-bromo-2,6-dimethylphenylthio)-2-chloro-6-methyl-5-nitropyrimidine; A solution of LiHMDS in THF (77 mmol) is added to a mixture of 4-bromo-2,6-dimethylbenzenethiol (70 mmol) in THF (100 ml) at -78 C. over 15 minutes and the mixture stirred for an additional 2 hours. The mixture is cooled with liquid nitrogen to around -100 C. and a solution of 2,6-dichloro-4-methyl-5-nitropyrimidine (84 mmol) in THF (50 ml) is added rapidly. The reaction is maintained at around -100 C. for 1 hour and then allowed to warm to room temperature. The mixture is filtered and the isolated solid washed with ethanol. The filtrate may be concentrated and crystallized to obtain additional compound.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20 - 60℃; for 48h;
Step A: N-(4-bromo-2,6-dimethylphenyl)-2-chloro-6-methyl-5-nitropyrimidin-4-amine; To a solution of 4-bromo-2,6-dimethylaniline (19.8 m g, 99.0 mmol) and 3,4-dichloro-6-methyl-5-nitropyrimimidine (20.6 g, 99.0 mmol) in THF (198 ml) at ambient temperature was added diisopropylethylamine (18.0 ml, 108.9 mmol). The reaction mixture was heated to 60 C. and stirred for 2 days. Upon completion, the volatiles were removed in vacuo. The resulting crude was slurried in cold ethanol and filtered. The resulting solids were washed 2× with cold ethanol and dried under vacuum overnight to give 18.6 g (51%) of N-(4-bromo-2,6-dimethylphenyl)-2-chloro-6-methyl-5-nitropyrimidin-4-amine as an orange powder. 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (s, 6H) 2.80 (s, 3H) 7.31 (s, 2H) 9.23 (br. s., 1H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
To a solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (716 mg, 3.46 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.48 mL, 3.46 mmol) at 0 C., followed by addition of tert-butyl (2-amino-ethoxy)acetate (605 mg, 3.46 mmol). The resulting mixture was stirred at room temperature for 3 h, and diluted with 50 mL of CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was dissolved in 2 mL of DME. To this solution were added 3-benzyloxyphenylboronic acid (1.18 g, 5.19 mmol), Pd(PPh3)4 (200 mg, 5 mol %), and 1.5 mL of 2M Na2CO3 aqueous solution. The resulting mixture was heated at 110 C. for 30 min in microwave oven, and cooled to room temperature. The mixture was filtered, and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound as yellow solid (854 mg, 50% yield). MS (ESI) m/z 495.3
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 0.5h;
Isopropylamine(4.5ml) and N,N-diisopropylethylamine(13.2ml) were dissolved into 150ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine(10.7g) in dichloromethane(30ml) at 0C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid(10.2g) in a yield of 86.8%. 1H NMR(400 MHz, CDCl3): δ 8.01(s, 1H), 4.48(m, J=4.1, 1H), 2.72(s, 3H), 1.32(d, J=6.8Hz, 6H)ppm.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;
Cyclopentylamine(5.2ml) and N,N-diisopropylethylamine(13.2ml) were dissolved into 150ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine(10.7g) in dichloromethane(30ml) at 0C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid(11.2g) in a yield of 84.8%. 1H NMR(400 MHz, CDCl3): δ 8.44(s, 2H), 4.41(m, 1H), 2.64(s,3H), 2.01-2.15(m, 2H), 1.61-1.76(m, 4H), 1.45-1.63(m, 2H)ppm.
In tetrahydrofuran; at -78 - 20℃; for 0.5h;Inert atmosphere;
To the solution of 2,4-Dichloro-6-methyl-5-nitro-pyrimidine (2.08 g, lO.OOmmol) in THF (50 mL) at -78 C was slowly added the solution of [l-(4-Amino-phenyl)- cyclobutyl]-carbamic acid tert-butyl ester (2.62 g, 10.00 mmol) in THF (20 mL). The reaction mixture was stirred at ambient temperature for 30 min.. Then it was concentrated to remove the solvent. The obtained residue was dissolved in ethyl acetate (250 mL) and washed by saturated. NaHC03 solution, followed by brine. The separated organic layer was dried over sodium sulfate, filtered and concentrated to give { l-[4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4-ylamino)-phenyl]- cyclobutyl}-carbamic acid tert-butyl ester. (4.3 g, 98%yield). MS (ESI+) e/z: 370.9 / 372.9 [M+l]+.
methyl 2-[(2-chloro-6-methyl-5-nitro-4-pyrimidinyl)amino]-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydrogencarbonate; In diethyl ether; water;
General procedure: The appropriate methyl ester of amino acid (2a-d) (5 mmol) wereadded portion wise to a vigorously stirring mixture of 2,4-dichloro-6-methyl-5-nitropyrimidine (1) (5 mmol, 1.04 g) and NaHCO3 (19mmol,1.6 g) in diethyl ether (5 mL) and water (10 mL) and the mixture wasvigorously stirred overnight. After the completion of the reaction(monitored by TLC using, ethyl acetate: hexane 1:4), the organic phasewas separated and washed with water (2×30 mL), dried over Na2SO4and removed under reduced pressure. The residue was recrystallisedfrom ethanol
methyl 2-[(2-chloro-6-methyl-5-nitro-4-pyrimidinyl)amino]-4-methylpentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium hydrogencarbonate; In diethyl ether; water;
General procedure: The appropriate methyl ester of amino acid (2a-d) (5 mmol) wereadded portion wise to a vigorously stirring mixture of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (1) (5 mmol, 1.04 g) and NaHCO3 (19mmol,1.6 g) in diethyl ether (5 mL) and water (10 mL) and the mixture wasvigorously stirred overnight. After the completion of the reaction(monitored by TLC using, ethyl acetate: hexane 1:4), the organic phasewas separated and washed with water (2×30 mL), dried over Na2SO4and removed under reduced pressure. The residue was recrystallisedfrom ethanol
methyl 2-[(2-chloro-6-methyl-5-nitro-4-pyrimidinyl)amino]-3-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydrogencarbonate; In diethyl ether; water;
General procedure: The appropriate methyl ester of amino acid (2a-d) (5 mmol) wereadded portion wise to a vigorously stirring mixture of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (1) (5 mmol, 1.04 g) and NaHCO3 (19mmol,1.6 g) in diethyl ether (5 mL) and water (10 mL) and the mixture wasvigorously stirred overnight. After the completion of the reaction(monitored by TLC using, ethyl acetate: hexane 1:4), the organic phasewas separated and washed with water (2×30 mL), dried over Na2SO4and removed under reduced pressure. The residue was recrystallisedfrom ethanol
methyl 3-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)amino)-2-naphthoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃;
A mixture of compound 1 (480 mg, 2.4 mmol, 1.0 eq), N,N-diisopropylethylamine (DIEA) (0.83 mL, 4.8 mmol, 2.0 eq) and 2,4-dichloro-6-methyl-5-nitropyrimidine (0.76 g, 3.6 mmol, 1.5 eq) in 2-propanol (43 mL) was stirred at rt overnight. The product crashed out of 2-propanol, and was collected by filtration and dried in vacuo. The crude compound 2 (0.79 g, 88%) was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) delta 12.04 (s, 1H), 8.94 (s, 1H), 8.68 (s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.63 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.51 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 4.05 (s, 3H), 2.73 (s, 3H). MS (ESI) calcd for [C17H14ClN4O4]+: 373. found 373.
With triethylamine; In dichloromethane; at 5℃; for 5h;
To a stirred suspension of J-1 (10.0 g, 48.0 mmol) and J-2 (8.94 g, 48.0 mmol) in DCM (150 mL) at 5 C is added triethylamine (14.6 g, 144 mmol). The reaction is stirred at that temperature for 5 h. The solution is poured into water ( 200 mL), extracted with DCM (3 X 250 mL). The combined organic phase is dried (Na2S04), decanted and concentrated. The resulting residue is purified by Si02 flash chromatography to yield J-3.
1-(1H-pyrazolo[4,3-d]pyrimidin-1-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.1%
[A] 1- (1H-Pyrazolo [4 3-d] pyrimidin-1-yl) ethanone[0313][0314]To a stirred solution of 2 4-dichloro-6-methyl-5-nitropyrimidine (42 g 202 mmol) and AcOK (40g 404mmol) in MeOH (900mL) was added Pd/C (18g) at room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (DCM/MeOH201) to give a yellow solid intermediate (6 g) which was then re-dissolved in tiluene (110 mL) . To this solution was added AcOK (21.6 g 220 mmol) AcOH (22 mL) and Ac2O (22 mL) and the resulting reaction mixture was heated to reflux temperatue at 120 . After the addtion of isopentyl nitrite (12.9 g 110 mmol) was added the heating continued for another 2 h at 120 . After cooling to room temperature the mixture was diluted with EtOAc (300 mL) washed with satd. aq. NaHCO3solution and brine. The organic layer was dried over anhy. Na2SO4 filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (DCM/MeOH 1001/100) to give the title compound (4.1 g 62.1yield) as a yellow solid.1HNMR (400 MHz DMSO-d6) δ 9.73 (s 1H) 9.29 (s 1H) 8.43 (s 1H) 2.75 (s 3H) .
To a solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> 7a (4.576 g, 22 mmol) in THF (45 mL) was added aqueous MeNH2 solution (25-30%, 3.4 mL) at -40 C and the reaction mixture was stirred at -40 C for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc = 10:1) to afford 7b as a yellow solid (3.4 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (br s, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.51 (s, 3H). MS (ESI+) m/z 202.9 [M + H]+
tert-butyl 3-(4-(aminomethyl)phenyl)pyrrolidine-1-carboxylate[ No CAS ]
tert-butyl 3-(4-[(2-chloro-6-methyl-5-nitropyrimidin-4-yl)amino]methyl}phenyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.06 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 0.5h;Cooling with ice;
Reference example 60 tert-Butyl 3-(4-[(2-chloro-6-methyl-5-nitropyrimidin-4-yl)amino]methyl}phenyl)pyrrolidine-1-carboxylate To an ice-cooled solution of <strong>[13162-26-0]2,4-dichloro-6-methyl-5-nitropyrimidine</strong> (502 mg) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (0.506 ml), and a solution of tert-butyl 3-(4-(aminomethyl)phenyl)pyrrolidine-1-carboxylate (714 mg) in tetrahydrofuran (15 mL). The reaction mixture was warmed to room temperature, and then stirred for 30 minutes. To the mixture in ice bath was water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.06 g). 1H-NMR (400 MHz, CDCl3) δ: 8.40 (1H, t, J = 5.5 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz), 4.76 (2H, d, J = 5.5 Hz), 3.87-3.72 (1H, m), 3.66-3.52 (1H, m), 3.45-3.22 (3H, m), 2.73 (3H, s), 2.32-2.21 (1H, m), 2.02-1.93 (1H, m), 1.47 (9H, s).
ethyl 1-(methylamino)cyclopropane-1-carboxylate[ No CAS ]
ethyl 1-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.5%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 1h;
Step 2: Ethyl 1-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate A solution of ethyl 1-(methylamino)cyclopropane-1-carboxylate (0.87 g, 6.1 mmol) in THF was added to a cooled (0 C.) mixture of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (1.264 g, 6.1 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.291 mmol) in tetrahydrofuran (12 mL) and stirred for 1 hour. The reaction was quenched with aq. NH4Cl (5 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo afford the crude product as a red liquid. The crude was purified by column chromatography (SiO2)eluting with a gradient of 0-30% ethyl acetate in hexane in to give the desired product, wt 468 mg (24.5% yield); ESMS(M+1)=315.43.
methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.5 g
With sodium hydrogencarbonate; In cyclohexane;Dean-Stark; Reflux;
Step A: Methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate A flask with 2,4-Dichloro-6-methyl-5-nitropyrimidine (10 g, 48.1 mmol), methyl methyl-L-valinate hydrochloride (9.61 g, 53 mmol), and sodium bicarbonate (20.2 g, 240.4 mmol) in cyclohexane (100 ml) was equipped with a Dean Stark trap and heated to reflux. The hot reaction mixture was filtered through Celite hot. The filtrate was evaporated in vacuo to afford the title product, wt. 15.5 g that was used without further purification. 1H NMR (300 MHz, CDCl3) delta 4.99 (d, J=10.5 Hz, 1H), 3.77 (s, 3H), 2.95 (s, 3H), 2.49 (s, 3H), 2.45-2.23 (m, 1H), 1.10 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.7 Hz, 3H); ESMS (M+1)=317.04.
methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.5%
With potassium carbonate; In water; acetone; at 20℃; for 16h;
A-40. Methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate A solution of 2,4-Dichloro-6-methyl-5-nitro-pyrimidine (1.86 g, 8.96 mmol) in 20 ml of acetone was added dropwise to a mixture of methyl (2S)-2-(methylamino)propanoate (1 g, 8.54 mmol) and potassium carbonate (1.77 g, 12.8 mmol) in acetone and water. The reaction was stirred at room temperature for 16 hours. The mixture was evaporated in vacuo and the residue was taken into a water and extracted with ethyl acetate (3*75 ml). The combined extracts were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title product as a viscous yellow oil, wt. 1.54 g (62.5% yield). 1H NMR (300 MHz, CDCl3) δ 5.34 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 2.88 (s, 3H), 2.48 (s, 3H), 1.57 (d, J=7.3 Hz, 3H).
methyl (2S,3R)-3-tert-butoxy-2-(methylamino)butanoate[ No CAS ]
methyl O-(tert-butyl)-N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-allothreoninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With sodium hydrogencarbonate; at 20℃; for 16h;
Step 1: Methyl O-(tert-butyl)-N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-allothreoninate Methyl (2S,3R)-3-tert-butoxy-2-(methylamino)butanoate (2.65 g, 13 mmol), 2,4-dichloro-6-methyl-5-nitro-pyrimidine (4.85 g, 23.32 mmol), and NaHCO3 (3.3 g, 39.28 mmol) and stirred at room temperature for 16 hours. After filtration to remove the solid, the solution was concentrated and the crude product was purified by column chromatography (SiO2, 40 g) eluting with a gradient of 0-30% EtOAc in Hexanes to give the title product as a sticky oil (2 g, 23% yield). 1H NMR (400 MHz, CDCl3) δ 5.49 (d, J=4.0 Hz, 1H), 4.53 (qd, J=6.3, 3.9 Hz, 1H), 3.78 (s, 3H), 3.13 (s, 3H), 2.48 (s, 3H), 1.24 (d, J=6.3 Hz, 3H), 1.18 (s, 9H). ESI-MS m/z calc. 374.1357, found 375.52 (M+1)+
methyl 1-(methylamino)cyclobutane carboxylate hydrochloride[ No CAS ]
methyl 1-[(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-methylamino]cyclobutane carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.5%
With potassium carbonate; In water; acetone; at 0℃; for 1h;
Step 4: Methyl 1-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-methyl-amino]cyclobutanecarboxylate At 0 C., a cooled solution of K2CO3 (1.32 g, 9.205 mmol) in ice water (10 mL) was added to 2,4-dichloro-6-methyl-5-nitro-pyrimidine and methyl 1-(methylamino)cyclobutanecarboxylate hydrochloride (661.5 mg, 3.682 mmol) in acetone (20 mL) and stirred for 1 hour at 0 C. The reaction was quenched with saturated NH4Cl (5 mL) and extracted with diethyl ether. extracts were evaporated in vacuo to provide the desired product as a red liquid. Purification by silica gel chromatography (0-30% EtOAc/Hexane for 30 minutes) provided desired product, methyl 1-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-methyl-amino]cyclobutanecarboxylate, as yellow sticky liquid (206 mg, 17.5% yield. major isomer with lower Rf). 1H NMR (300 MHz, CDCl3) δ 3.71 (s, 3H), 2.81 (s, 3H), 2.65 (ddd, J=13.5, 5.8, 3.7 Hz, 2H), 2.41 (s, 3H), 2.39-2.24 (m, 2H), 2.24-2.06 (m, 1H), 1.92-1.71 (m, 1H). ESMS(M+1)=315.12.
(7S)-2-chloro-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
To a 2-L round bottom flas was added 2,4-dichloro-6-methyl-5-nitro-pyrimidine (55.0 g, 256.5 mmol), NaHCO3(108.4 g, 1.290 mol), and cyclohexane (600 mL). Let stir to dissolve pyrimidine (5 min), then added methyl (2S)-3-methyl-2-(methylamino)butanoate (Hydrochloride salt) (49.0 g, 256.2 mmol). The flask was equipped with a Dean-Stark trap and the reaction was heated to 110C. LC-MS (UPLC_CSH_C18_5to95_ACN_TFA_1p4min) showed reaction complete after 2.5 h. The mixture was stirred for another 30 min, filtered reaction hot through Celite and washed solid with 1 L hot cyclohexane. Concentrated mixture to a yellow oil. 1H NMR showed pure. In a 2-L Parr bottle was added platinum (13.34 g of 3% w/w, 2.051 mmol). Dissolved oil in THF (550 mL) and added to Parr bottle under N2. The bottle was placed on a Parr shaker under 50 psi of H2. The Parr shaker was refilled to 50 psi several times. Let go overnight. LC-MS showed small amt of dechlorinated intermediate. Added bis[(E)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (1.36 g, 5.129 mmol) and placed the bottle on the Parr shaker under 50 psi of H2. The Parr shaker was refilled to 50 psi three times. After 5 h, no more consumption of H2. Filtered rxn through Florisil and eluted with EtOAc/DCM (1:1) until no more material was detected by UV (4 L). Concentrated filtrate. Yellow solid. Stirred resulting solid with MTBE (1 L) for 2 h. Filtered and washed white solid with MTBE (2×250 mL). Dried under vacuum in funnel.Optical rotation: CHCl3, 100 mg/10 mL conc, [alpha]D=118.12, temp=22.8C. Chiral HPLC: AD-H column, 4.6 mm×2 50 mm, 40% EtOH/hex isocratic gradient, 20 min run,>99% ee. (7S)-2-chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one (57.75 g, 88%).1H NMR (300 MHz, Chloroform-d)delta9.32 (s, 1H), 3.96 (d, J=4.1 Hz, 1H), 2.35 (s, 3H), 2.32-2.18 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H). ESI-MS m/z calc. 254.09, found 255.12 (M+1)-; Retention time: 0.63 minutes.
Chemistry
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