* 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] Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1146 - 1157
[2] Patent: WO2018/92034, 2018, A1, . Location in patent: Paragraph 0075
2
[ 5751-20-2 ]
[ 49844-90-8 ]
Reference：
[1] Yakugaku Zasshi, 1949, vol. 69, p. 491[2] Chem.Abstr., 1950, p. 3456
[3] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1982, vol. 36, # 1 B, p. 15 - 18
3
[ 5751-20-2 ]
[ 49844-90-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1499 - 1506
4
[ 5751-20-2 ]
[ 63810-78-6 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1982, vol. 36, # 1 B, p. 15 - 18
[2] Patent: CN107488175, 2017, A,
5
[ 5751-20-2 ]
[ 81560-03-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-Bromosuccinimide In dichloromethane for 6 h; Reflux
Step 2, Preparation of 5-bromo-2-methylthio-4-pyrimidinone: Take 142 g of 2-methylthio-4-pyrimidinone, dissolve in 500 ml of methylene chloride, add NBS 190 g, reflux for 6 hours, After the reaction is completed, cool to room temperature, filter, wash the filtrate, organicThe phase was dried and recrystallized on an ice bath to give 190 g of a pale yellow solid in a yield of 87percent.
62%
at 0 - 20℃; for 16 h;
(EX-6B) A solution of EX-6A (74.0 g, 520.5 mmol) in glacial acetic acid (2275 mL) was cooled to 0° C. with an ice bath and treated with Br2. The reaction mixture was allowed to warm to room temperature, and to stir for 16 h. A yellow precipitate formed which was filtered and washed with ether three times. 97.2 g of EX-6B was isolated in 62percent yield.
45%
With bromine In acetic acid at 20℃; for 0.5 h;
To a solution containing 2.0 g (14 mmol) of 2- (methylthio) pyrimidin-4(3H)-one in 10 ml of acetic acid under a nitrogen atmosphere was added 1.04 ml (14 mmol) of bromine in 2 ml acetic acid. The reaction was allowed to stir at room temperature for 30 min. The precipitated product was filtered, washed with acetic acid and suspended in hot acetic acid- To this suspention was added 0.2 ml bromine in 1ml acetic acid. The product was collected, washed with acetic acid and recrystallized from ethanol to yield 1.4 g (45 percent) of product. 1H NMR (CD30D) 5: 2. 61 (s, 3H) , 8.29 (s, 1H).
Reference：
[1] Patent: CN107488175, 2017, A, . Location in patent: Paragraph 0008; 0010
[2] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1982, vol. 36, # 1 B, p. 15 - 18
[3] Patent: US6653316, 2003, B1, . Location in patent: Page/Page column 117-118
[4] Patent: WO2005/99688, 2005, A2, . Location in patent: Page/Page column 173
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 1753,1755
[6] Patent: WO2011/130908, 2011, A1, . Location in patent: Page/Page column 54-55
[7] Patent: WO2011/133444, 2011, A1, . Location in patent: Page/Page column 53-54
2B) 2-MORPHOLIN-4-VL-PYRIMIDIN-4-OL To the 2-thiomethyluracil (4.0 g, 0.0281 mol) is added morpholine (3.05 G, 0.035 MOL). The mixture is heated to 145°C for 2 hours then cooled to room temperature. The solid is crystallized from ethanol. White needles are collected (2.0 g). Second crop of crystals form approximately 0.50 g (49percent). M+H = 181. 'H NMR (CDC13) ; 612. 1 (bs, 1H), 7.85 (d, 1H), 5.79 (d, 1H), 3.75 (m, 8H).
With phosphorus(V) oxybromide In acetonitrile at 80℃; for 5 h;
To a stirred solution of 2-(methylthio)pyrimidin-4(3H)-one (5 g, 35.21 mmol, leq) in ACN (lOOmL) was added POBr3 (12.1 g, 42.3 mmol, 1.2 eq) at RT, then the reaction mixture was heated to 80°C for 5h. Monitored by TLC, the reaction mixture was cooled to RT and quenched in ice cold water then extracted with EtOAc (2X100mL). The combined organic layer was dried over Na2SC>4 and concentrated to crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-10percent EtOAc in pet ether as eluent to afford 4- bromo-2-(methylthio)pyrimidine (6g, 83percent) as off-white solid. LCMS: [M+H]+ 204.9.
With lithium hexamethyldisilazane; In N,N-dimethyl-formamide; at 0 - 20℃;
Example B4: A 0°C suspension of 2-(methylthio)pyrimidin-4(3H)-one (2.0 g, 14.1 mmol) in DMF (40 mL) was treated with solid LiHMDS (3.06 g, 18.3 mmol), followed by methyl iodide (1.14 mL, 18.3 mmol), warmed to RT and stirred overnight. The mixture was quenched with water, extracted with EtO Ac (3x) and the combined organics were dried over Na2S04, concentrated to dryness and purified via silica gel chromatography (EtO Ac/Hex) to afford 3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.37 g, 62percent). 1H NMR (400 MHz, DMSO-<): delta 7.83 (d, J = 6.5 Hz, 1 H), 6.17 (d, J = 6.5 Hz, 1 H), 3.39 (s, 3 H), 2.54 (s, 3 H); MS (ESI) m/z: 157.1 (M+H+).
Step 2: Preparation of 3-methyl-2-methylthio-3H-pyrimidin-4-one; 2-Methylthio-3i-pyrimidin-4-one (Step 1, 6.29 g, 44.2 itraiol) was suspended in DMF (100 piiL) , cooled to 0 0C, and additional DMF (50 iriL) was added. Solid LiHMDS (9.58 g, 57.3 mmol) was added in one portion, and the reaction was stirred at 0 0C. MeI (3.6 mL, 57.8 mmol) was added via syringe, and the reaction was warmed to RT and stirred for 20.75 h. At this time, the mixture was poured into 300 mL H2O and extracted exhaustively with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (3:1 ->.bul. 3:2 -> 1:1 hexanes/EtOAc) to give the title compound. MS (ESI pos. ion) m/z: 157. CaIc'd for C6H8N2OS: 156.04.
With N-iodo-succinimide; In chloroform; at 70℃; for 2h;
Step 2: 5-iodo-2-(methylthio')pyrimidin-4(3H)-one (3) To a solution of 2-(methylthio)pyrimidin-4(3H)-one (2) (4.74 g, 33.3 mmol) in chloroform (45 mL), NIS (8.25 g, 36.7 mmol) was added. The solution was heated to 70 °C for 2 hours. The mixture was concentrated under reduced pressure. EtOAc was added and the organics were washed with water, filtered and dried to give the title compound (8.8 g, 97percent) as a white solid. NMR (CD3OD) delta 8.30 (s, 1H), 2.45 (s, 3H); LCMS (Condition B): 1.43 min, 269 (M+H).
87%
With iodine; sodium hydroxide; In water; at 80℃; for 7h;
2-Thiouracile (10 g, 0.078 mol) was mixed with aq. solution of sodium hydroxide (6.24 g in 55 mL of water), then methyl iodide (5.5 mL, 0.088 mol) was added. The resulting mixture was stirred at ambient temperature for 16 h. The resulting solution was acidified with glacial acetic acid (4.5 mL), formed crystals were filtered, washed with cold water and air-dried to give 2-(methylsulfanyl)pyrimidin-4(3H)-one. Yield 10.5 g (95percent); colorless solid; mp 196?197 °C; 1 H NMR (400 MHz, DMSO-d 6 ): delta 7.85 (d, J = 7.5 Hz, 1), 6.08 (d, J = 7.5 Hz, 1), 2.45 (s, 3). Mixture of 2-(methylsulfanyl)pyrimidin-4(3H)-one (4.3 g, 0.03 mol), iodine (9.15 g, 0.036 mol), sodium hydroxide (1.5 g, 0.037 mol) and water (23 ml) was stirred at 80 ° for 7 h. After neutralization with acetic acid the resulting precipitate was filtered and recrystallized from ethanol to give 5-iodo-2-(methylsulfanyl)pyrimidin-4(3H)-one. Yield 6.98 g (87percent); colorless solid; mp 210?211 °C (decomp.); 1 H NMR (400 MHz, DMSO-d 6 ): delta 8.31 (s, 1), 2.46 (s, 3). Mixture of 5-iodo-2-(methylsulfanyl)pyrimidin-4(3H)-one (6.98 g, 0.026 mol) and phosphorus oxychloride (12 ml, 0.13 mol) was refluxed during 3 h. Reaction mixture was poured into crushed ice, the resulting precipitate was filtered, washed with cold water and air-dried to give compound 3a. Yield 6.94 g (93percent); colorless solid; mp 60?62 °C (lit. [9] mp 63?64 °); 1 H NMR (400 MHz, CDCl 3 ): delta 8.69 (s, 1), 2.55 (s, 3).
50%
With N-iodo-succinimide; In chloroform; at 70℃;Inert atmosphere;
Purchased 2-methylthio-4-pyrimidinone (42.6 g, 300 mmol)And N-iodosuccinimide dissolved in 200 ml of chloroform,The system was stirred under nitrogen for seventy degrees until the reaction was complete.After cooling, the solvent was removed under reduced pressure, three hundred mL water was added, filtered, and washed with water.After drying, Compound B (40.3 g, 150 mmol, 50percent yield) was obtained.
In diethylene glycol dimethyl ether; for 18h;Heating / reflux;
EXAMPLE 2; N4-[3-(dimethylamino)-2,2-dimethylpropyl]-N2-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine hydrochloride (7); Preparation of 2-(3-trifluoromethylphenylamino)pyrimidin-4(3H)-one (5); To 2-(methyl-thio)pyrimidine-4(3H)-one, 1, (5 g, 35.21 mmol) in diglyme (25 mL) is added 3-trifluoromethylaniline (5.26 mL, 42.25 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 1.9 g (21percent yield) of the desired compound. MS (ESI, pos. ion) m/z: 256 (M+1).
In diethylene glycol dimethyl ether; for 18h;Heating / reflux;
EXAMPLE 4; N4-(3-(dimethylamino)propyl)-N2-m-biphenylpyrimidine-2,4-diamine hydrochloride (11); Preparation of 2-(3-biphenylamino)pyrimidin-4(3H)-one (9): To 2-(methylthio)-pyrimidine-4(3H)-one, 1, (790 mg, 5.5 mmol) in diglyme (5 mL) is added 3-amino-biphenyl (1.91 g, 11.2 mmol). The resulting mixture is stirred at reflux for 18 hours. The mixture is cooled to room temperature and hexane is added and a precipitate forms which is collected by filtration to afford 1.34 g (92percent yield) of the desired compound which is used without further purification. MS (ESI, pos. ion) m/z: 264 (M+1).
92%
In diethylene glycol dimethyl ether; for 18h;Heating / reflux;
EXAMPLE 3; N2-Biphenyl-3-yl-N4-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (10); Preparation of 2-(3-biphenylamino)pyrimidin-4(3H)-one (8); To 2-(methylthio)-pyrimidine-4(3H)-one (790 mg, 5.5 mmol) in 5 mL of diglyme is added 3-amino-biphenyl (1.91 g, 11.2 mmol). The resulting mixture is stirred at reflux for 18 hours. The mixture is cooled to room temperature and hexanes are added to form a precipitate which is collected by filtration to afford 1.34 g (92percent yield) of the desired compound which is used without purification. MS (ESI, pos. ion) m/z: 264 (M+1).
In diethylene glycol dimethyl ether; for 18h;Heating / reflux;
EXAMPLE 5; N4-(3-(dimethylamino)propyl)-N2-(3-(2-methylthiazol-4-yl)phenyl)pyrimidine-2,4-diamine hydrochloride (13); Preparation of 2-(3-(2-methylthiazol-4-yl)phenylamino)pyrimidin-4(3H)-one (11); To 2-(methyl-thio)pyrimidine-4(3H)-one, 1, (1 g, 14.08 mmol) in diglyme (9 mL) is added 3-(2-methylthiazol-4-yl)benzenamine (3.20 g, 16.90 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 1.0 g (25percent yield) of the desired compound. MS (ESI, pos. ion) m/z: 285 (M+1).
E-1) 2-methylsulphanyl-1H-pyrimidin-4-one 20 g (153 mmol) 2-thiouracil is suspended in 250 mL methanol and then 8.7 g (152.9 mmol, 1 eq) of sodium methoxide is added. The solution is stirred for 5 min at RT and then 12.4 mL (198.8 mmol, 1.3 eq) of methyl iodide is added dropwise. The reaction mixture is stirred overnight, then poured onto water and extracted 3* with about 150 ml chloroform. The combined organic phases are dried on magnesium sulphate, the solvent is eliminated in vacuo and 16 g (121.5 mmol, 74percent) E-1 is obtained in the form of a colourless solid.
> 60 - 67%
Step 1: Preparation of intermediate 2-(methylthio)pyrimidine-4(3H)-one; This compound can be used in the preparation of each analog encompassed by the present invention. The general procedure follows. To a solution of sodium hydroxide (8 g, 200 mmol) in H2O (75 mL) at room temperature is added thiouridine (14.2 g, 100 mmol). The resulting mixture is stirred at room temperature for 20 minutes. Methyl iodide (6.86 mL, 110 mmol) is slowly added dropwise in THF (10 mL) and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. At this point the mixture is cooled in an ice bath and allowed to stand for approximately 2 hours after which the final product separates as a white solid and can be collected by filtration. First crop of crystals typically yields the desired product in an excess of 60percent yield. 1H NMR (DMSO-d6, 300 MHz): delta 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).; EXAMPLE 1; N2-(3-chlorophenyl)-N4-(3-(dimethylamino)propyl)pyrimidine-2,4-diamine (4); Preparation of 2-(methylthio)pyrimidine-4(3H)-one (1); To a solution of sodium hydroxide (6.24 g, 156.07 mmol) in H2O (55 mL) at room temperature is added thiouridine (10 g, 78.03 mmol). The resulting mixture is stirred at room temperature for 20 min. Methyl iodide (5.45 mL, 87.40 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. The mixture is allowed to stand at 0° C. (ice bath) for 2 hours and filtered to afford 7.4 g (67percent yield) of the desired compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): delta 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).
> 60 - 67%
Step 1: Preparation of intermediate 2-(methylthio)pyrimidine-4(3H)-one; This compound can be used in the preparation of each analog encompassed by the present invention. The general procedure follows. To a solution of sodium hydroxide (8 g, 200 mmol) in H2O (75 mL) at room temperature is added thiouridine (14.2 g, 100 mmol). The resulting mixture is stirred at room temperature for 20 minutes. Methyl iodide (6.86 mL, 110 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. At this point the mixture is cooled in an ice bath and allowed to stand for approximately 2 hours after which the final product separates as a white solid and can be collected by filtration. First crop of crystals typically yields the desired product in an excess of 60percent yield. 1H NMR (DMSO-d6, 300 MHz): delta 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).; EXAMPLE 1; N2-(3-chlorophenyl)-N4-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (4); Preparation of 2-(methylthio)pyrimidine-4(3H-one (1): To a solution of sodium hydroxide (6.24 g, 156.07 mmol) in H2O (55 mL) at room temperature is added thiouridine (10 g, 78.03 mmol). The resulting mixture is stirred at room temperature for 20 min. Methyl iodide (5.45 mL, 87.40 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. The mixture is allowed to stand at 0° C. (ice bath) for 2 hours and filtered to afford 7.4 g (67percent yield) of the desired compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): delta 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).
2-[3-(N-benzyl-N-(pyridin-2-yl)amino)propylamino]pyrimid-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(iii) 2-[N-(3-Aminopropyl)-N-benzylamino]pyridine (1.07 g) and S-methyl-2-thiouracil (2 g) were fused together on an oil bath at 130°-60° C. for 4.5 hr. On cooling the residue was chromatographed (silica gel, ammoniacal methanol/chloroform 1:25). The solvent was evaporated from the fractions containing the required product and the residue recrystallized from ethanol to give 2-[3-(N-benzyl-N-(2-pyridyl)amino)propylamino]pyrimid-4-one, (1.0 g; 68percent) m.p. 162°-3° C. C19 H21 N5 O: Found: C, 68.08; H, 6.51; N, 20.87. Requires: C, 68.04; H, 6.31; N, 20.88percent.
2-[3-[N-(3-chlorobenzyl)-N-(pyridin-2-yl)amino]propylamino]pyrimid-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol;
(ii) 2-[N-(3-Aminopropyl)-N-(3-chlorobenzyl)amino]pyridine (2.11 g) and S-methyl-2-thiouracil (0.91 g) were fused together on an oil bath at 160 C. for 3 hr. On cooling the residue was crystallized from ethanol/water and then chromatographed (silical gel, 1% methanol/chloroform). The solvent was evaporated from the fractions containing the required product and the residue crystallized from ethanol/water to give 2-[3-[N-(3-chlorobenzyl)-N-(2-pyridyl)amino]propylamino]pyrimid-4-one 0.7 H2 O, (0.89 g; 36%) m.p. 74-8 C. C19 H20 ClN5 O 0.7 H2 O: Found: C, 59.54; H, 5.57; N, 18.58; Cl, 9.32. Requires: C, 59.66; H, 5.64; N, 18.31; Cl, 9.27%.
2-[3-[N-(4-chlorobenzyl)-N-(pyridin-2-yl)amino]propylamino]pyrimid-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine;
(ii) 2-[N-(3-Aminopropyl)-N-(4-chlorobenzyl)amino]pyridine (2.11 g) and S-methyl-2-thiouracil (0.91 g) were heated together under reflux in pyridine (5 ml) for 24 hr. On cooling, the solvent was evaporated. The residue was triturated with ether and recrystallized from ethanol to give 2-[3-[N-(4-chlorobenzyl)-N-(2-pyridyl)amino]propylamino]pyrimid-4-one 0.2 H2 O, 1.55 g (65percent) m.p. 168°-70° C. C19 H20 ClN5 O 0.2 H2 O: Found: C, 61.45; H, 5.62; N, 18.47; Cl, 9.30. Requires: C, 61.11; H, 5.51; N, 18.75; Cl, 9.49percent.
2-[3-[N-(2-chlorobenzyl)-N-(pyridin-2-yl)amino]propylamino]pyrimid-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine;
(ii) 2-[N-(3-Aminopropyl)-N-(2-chlorobenzyl)amino]pyridine (1 g) and S-methyl-2-thiouracil (0.43 g) were heated together under reflux in pyridine (5 ml) for 20 hr. After evaporating the solvent, the residue was triturated with ether and recrystallized twice from ethanol/water to give 2-[3-[N-(2-chlorobenzyl)-N-(2-pyridyl)amino]propylamino]pyrimid-4-one 0.5 H2 O, (0.72 g; 54percent), m.p. 153°-54° C. C19 H20 ClN5 O 0.5 H2 O: Found: C, 60.45; H, 5.34; N, 18.22; Cl, 9.55. Requires: C, 60.23; H, 5.59; N, 18.49, Cl, 9.36percent.
2-[2-(N-benzyl-N-(pyridin-2-yl)amino)ethylamino]pyrimid-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(iii) 2-[N-(2-Aminoethyl)-N-benzylamino]pyridine (1 g) and S-methyl-2-thiouracil (0.52 g) were fused together on an oil bath at 160° C. for 3 hr. On cooling the residue was triturated with ethanol and after chromatography (silica gel, 1percent methanol/chloroform) and crystallisation from ethanol, gave 2-[2-(N-benzyl-N-(2-pyridyl)amino)ethylamino]pyrimid-4-one, (0.46 g; 37percent), m.p. 187°-90° C. C18 H19 N5 O 0.25 C2 H5 OH: Found: C, 66.58; H, 6.10; N, 21.16. Requires: C, 66.74; H, 6.21; N, 21.04percent.
In diglyme (diethyleneglycol dimethylether); for 16h;Heating / reflux;
E-2) 4-(6-oxo-1,6-dihydro-pyrimidin-2-ylamino)-benzoic acid 4.1 g (28.8 mmol) E-1 is dissolved in 10 mL diglyme (diethyleneglycol dimethylether) and this solution is combined with 4.79 g (34.6 mmol, 1.2 eq) 4-aminobenzoic acid. The reaction mixture is refluxed for 16 h. After cooling to RT the precipitate is suction filtered, washed with a little diglyme, then with diethyl ether and dried in vacuo. 5.27 g (22.8 mmol, 79percent) E-2 are obtained as a colourless solid. MS-ESI+: 232 (M+H)+
In diethylene glycol dimethyl ether; for 16h;Heating / reflux;
4.1 g (28.8 mmol) E-1 are dissolved in 10 mL diglyme (diethyleneglycol dimethylether) and this solution is combined with 4.79 g (34.6 mmol, 1.2 eq) 4-aminobenzoic acid. The reaction mixture is refluxed for 16 h. After cooling to RT the precipitate is suction filtered, washed with a little diglyme, then with diethyl ether and dried in vacuo. 5.27 g E-2 are obtained.MS-ESI+: 232 (M+H)+.
In diethylene glycol dimethyl ether; at 165℃; for 18h;Inert atmosphere;
3,4,5-Trimethoxyaniline (6.82 g) and 2-(methylthio)pyrimidin-4(3H)-one (5.26 g) were suspended in diglyme (50 ml) and heated at 165° C. for 18 hours under nitrogen to give a red solution. The reaction was cooled to room temperature then poured into 500 ml diethyl ether with stirring to give an oily precipitate that was filtered and re-dissolved in water (250 ml). A solid precipitate formed which was stirred for 30 minutes then filtered to give the title compound as a cream solid (3.80 g, 37percent); NMR Spectrum (300 MHz, DMSO) 3.63 (s, 3H), 3.76 (s, 6H), 5.80 (d, 1H), 6.95 (s, 2H), 7.76 (d, 1H); Mass Spectrum MH+ 278.5.
In 1-methyl-pyrrolidin-2-one; at 210℃; for 0.666667h;Microwave irradiation;
2.2.2 Synthesis of intermediate E-1 (method I).D-1 (910 mg, 3.19 mmol) in anhydrous acetic acid (5 mL) is combined at 0 °C with bromine (180 muIota_, 3.51 mmol) in anhydrous acetic acid (5 mL) and stirred for 60 min at rt. The precipitated solid is isolated by filtration.
With hydrogenchloride; In water; at 130 - 160℃; for 1.5h;Inert atmosphere;
2-Methylthiopyrimidin-4-one (5.0 g, 0.035 mol) and methyl 3-amino-4- methylbenzoate (7.1 g. 0.043 mol) were heated to 130 °C. Hydrochloric acid (0.20 ml, 35percent, 0.002 mol) was added to homogenous melt and the heating was continued at 160 °C for 1.5 h while the melt solidified. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Hot acetone (60 ml) was added to the mixture cooled down to 50 °C, the mixture was stirred for 0.5h and cooled to room temperature. Solid was filtered off and washed with water (15 ml) afforded 7.64 g (84percent) of methyl 4-methyl-3-(4-oxopyrimidin-2-ylamino)benzoate. M.p. 231 -233°C. The mixture of 2-methylthiopyrimidin-4-one (39.0 g, 0.274 mol), methyl 3- amino-4-methylbenzoate (51.9 g. 0.314 mol) and pivalic acid (270 ml) was heated under stirring at 130 °C for 15 h. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Reaction mixture was cooled to 50- 60 °C, petrol ether (700 ml) was added and the mixture was stirred for 0.5 h. The precipitate filtered off was washed with petrol ether and crystallized from methanol (1.4 L) to afford title compound in 50.0 g (74percent) amount. 1H NMR (CDCIs): 2.39 (s, 3H), 3.86 (s, 3H), 5.82 (d J=6.7 Hz, 1 H), 7.31 (d J=7.9Hz, 1 H), 7.61 (broad, 1 H), 7.80 (dd J=7.9; 2.1 Hz, 1 H), 8.17 (d J=2.1 Hz, 1 H).
With hydrogenchloride; In water; at 130 - 160℃; for 1.5h;
2-Methythiopyrimidin-4-one (18.6 g, 0.13 mol) and 2-methyl-5- nitrophenylamine (29.7 g, 0.195 mol) were heated to melt at approximately 130 °C. The reaction is conducted in a sealed system with a vent line to exhaust the methanethiol liberated in the reaction. The methanethiol is absorbed in two caustic scrubbers in series connected to vent line, with an empty trap between the reaction vessel and scrubbers to avoid reverse flow of caustic solution into the reaction vessel. Hydrochloric acid (1 ml, 35percent, 0.01 1 mol) was added and the melt heated at 160 °C for 1.5 h forming a solid. Hot acetone (200 ml) was added at 45-50 °C and the mixture was stirred for 0.5 h. Solid was filtered off and washed with acetone (130 ml) and water (60 ml) yielding 24.5 g (76percent) of 2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one. M.p. 271 -273 °C. 1H NMR (DMSO-Ok): 2.12 (s, 3H), 2.36 (s, 3H), 5.74 (s, 1 H), 7.49 (d J=8.4 Hz, 1 H), 7.86 (dd J=8.4;2.5 Hz, 1 H), 8.34 (br.s, 1 H), 9.04 (d J=2.5 Hz, 1 H), 1 1.13 (br.s, 1 H).
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