* 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.
Ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate (30 g, 140 mmol) was added to a three-vial flask.Add 20g of thionyl chloride (168mmol)The reaction was heated to 60°C for 3 hours. After the reaction was complete, it was cooled to 0-5°C. 100 ml of water was added and crystallized at 0-5°C for 1-2 hours. The mixture was filtered and vacuum dried at 50°C to give 30.1 g of white solid product. Yield 92 percent, pure 99.8percent,
77%
for 5 h; Heating / reflux
A mixture of 4-hydroxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (50 g, 0.234 mmol), POC13 (110 mL, 1.17 mmol) and diethylamide (70 mL, 0.28 mmol) was refluxed for 5h. The solvent was removed under vacuum and the residue was dissolved in ice H2O and cautiously neutralized with aqueous NaHCO3. After extraction with EtOAc (3x400 mL), the organic extracts were combined, dried and concentrated to give 4-chloro-2- (methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (42 g, 77percent yield).
77%
With trichlorophosphate In acetonitrile for 6 h; Reflux
the ethyl 4-hydroxy-2-methylsulfanyl-5-carboxylate obtained in the step S1 (55.6 g, 0.26 mol) was added to 150 mL of acetonitrile.Stir for 25min,Slowly add 135 mL of POCl3 to the reaction solution.After the addition is completed,The reaction solution was heated to reflux for 6 h.Then the reaction solution is slightly cold,The reaction solution was concentrated and the residue was poured into an ice water mixture and stirred.Adjust the pH of the reaction solution to neutral with saturated sodium bicarbonate solution.When a large amount of white solid precipitates, suction filtration is performed.The filter cake is used in turn (135mL × 3),Anhydrous ethanol (30 mL × 3) was rinsed.Then dried in vacuo to give a white solid (47.8 g, 77percent);
40%
at 10 - 65℃; for 7 h;
Step 2. Preparation of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (B19-2): Neat POCl3 (120 mL) was cooled to 10° C. and treated portion-wise over 4 hours with B19-1 (50 g, 232 mmol) without exceeding a temperature of 25° C. The mixture was then heated at 65° C. After 3 hours the mixture was cooled to 10° C., poured into crushed ice (350 g), treated drop-wise with water (676 mL) under vigorous stirring. The resultant solids were collected and dried under reduced pressure to provide B19-2 as a pale yellow solid. Yield: 22 g, 40percent. 1H NMR (CDCl3): δ 8.95 (s, 1H), 4.44 (q, 2H), 2.62 (s, 3H) and 1.42 (t, 3H).
Reference：
[1] Patent: CN108101853, 2018, A, . Location in patent: Paragraph 0015-0018
[2] Patent: WO2006/71940, 2006, A2, . Location in patent: Page/Page column 354
[3] Patent: CN108707141, 2018, A, . Location in patent: Paragraph 0027; 0030; 0039; 0048
[4] Patent: US2009/54395, 2009, A1, . Location in patent: Page/Page column 45-46
[5] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1645 - 1648
[6] Patent: WO2015/1567, 2015, A1, . Location in patent: Page/Page column 24; 25
[7] Journal of the Chinese Chemical Society, 2018, vol. 65, # 4, p. 445 - 451
8
[ 53554-29-3 ]
[ 5909-24-0 ]
Reference：
[1] Cancer Research, 1959, vol. 19, p. 729,730,731
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
[3] Cancer Research, 1959, vol. 19, p. 729,730,731
[4] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
[5] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 673 - 690
9
[ 87-13-8 ]
[ 5909-24-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1645 - 1648
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 14, p. 6210 - 6225
[4] Patent: WO2015/1567, 2015, A1,
[5] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 673 - 690
[6] Journal of the Chinese Chemical Society, 2018, vol. 65, # 4, p. 445 - 451
[7] Patent: CN108707141, 2018, A,
10
[ 5909-24-0 ]
[ 776-53-4 ]
Yield
Reaction Conditions
Operation in experiment
99%
With ammonium hydroxide; triethylamine In tetrahydrofuran; water at 30℃; for 2 h;
step 1. To a 2 L three-necked flask was added ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (100 g, 0.43 mol), THF (500 mL), and TEA (186 mL, 1.29 mol). Ammonium hydroxide (28percent in water, 400 mL) was added by portions keeping the internal temperature below 30° C. After 2 h, water (1000 mL) was added and THF was distilled off under vacuum. The resulting solid was filtrated and dried in vacuo at 50° C. to afford ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (90 g, 99percent). LC/MS: m/z=213.9 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) δ 8.57 (s, 1H), 8.03 (br, 1H), 7.65 (br, 1H), 4.27 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
97%
With ammonium hydroxide; triethylamine In tetrahydrofuran at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried overanhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8(97percent) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
97%
With ammonium hydroxide; triethylamine In tetrahydrofuran at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried overanhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8 g (97percent) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
97%
With ammonium hydroxide; triethylamine In tetrahydrofuran at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHC03 solution and brine, dried over anhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8 g (97percent) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
92%
With ammonium hydroxide; triethylamine In tetrahydrofuran at 10 - 55℃;
Method B: Charge reaction vessel with 1190g of THF and 660g of ethyl 4-chloro-2- (methylsulfanyl)pyrimidine-5-carboxylate (l .Oeq. 2.84 mol). Stir at 10-20 °C for 20-30mins, and then add 907 g of NH3-H20 and 989 g of Et3N to the mixture. Heat to 45-55°C, and stir for 2-6hrs at 45-55°C. After reaction is complete, cool to 8-12°C and add 4000g water. Stir for 4-8hrs at 8-12°C, filter and risen with 200g water. Dry the cake in vacuum at 80°C for 8- 24hrs to obtain title compound (560g; 98.8percent purity in 92percent yield; [M+l]=213.8, 1H NMR (d6-DMSO, 400 MHz): δ = 8.564 (s, 1H), 8.278 (s, 1H), 8.01 l(s, 1H),7.649 (s, 1H), 4.293- 4.240 (dd, Ji=6.8, J2=14, 2H), 2.462 (s, 3H), δ 1.308-1.272 (m, 3H)).
90%
With ammonium hydroxide; triethylamine In tetrahydrofuran at 20℃;
General procedure: 4-Chloro-2-(methylsulfanyl)pyrimidine-5 -carboxylic acid ethyl ester (1) (1 equiv.), wasdissolved in THF to which triethylamine (3 equiv.) alkyl amine (1.1 equiv.) was added and stirred overnight at room temperature. The precipitated salts were filtered and the solvent evaporated under reduced pressure. The resulting oil was dissolved in EtOAc, washed with sodium bicarbonate, then dried over Na2SO4. The salts were filtered, and the solvent was evaporated in vacuum to give the product.Starting from 4-chloro-2-(methylsulfanyl)pyrimidine-5 -carboxylic acid ethyl ester (1) and ammonium hydroxide, (2a) was obtained in 90percent yield using the method described inGeneral Procedure A. ‘H NMR (300 MHz, CDC13), ö 1.25 (t, OCH2CH3, 3H), 2.45 (s, S-CH3,3H), 4.30 (q, OCH2CH3, 2H), 8.10 (br s, NH2, 2H), 8.58 (s, Ar-H, 1H).
79%
With ammonia; triethylamine In tetrahydrofuran at 20℃;
In a 15 mL vial, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.00 g, 4.30 mmol) was dissolved in THF (10 mL) and triethylamine (2.00 ml, 14.35 mmol) was added, followed by ammonia (2 ml, 4.30 mmol). The resulting mixture was stirred overnight at room temperature. After completion of the reaction, the solvents were evaporated and the crude mixture was purified by silica gel chromatography using hexane/ethyl acetate (0-40percent) as the eluent to give the title compound INT-8 (0.72 g, 3.38 mmol, 79percent yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.02 (br s, 1H), 7.64 (br s, 1H), 4.24 (q, 2H), 2.44 (s, 3H), 1.27 (t, 3H)
66%
Stage #1: With ammonia In methanol at 0 - 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In methanol; water; ethyl acetate
To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-5- pyrimidinecarboxylate (4.50 g, 19.4 mmol) in MeOH is added 7 Ν NH3 (13.9 mL) in MeOH at 0 °C and the mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer is dried over MgSψ4, filtered and concentrated. The crude product is crystallized from the mixed solvent of EtOAc and hexanes to give 2.90 g (66percent) of ethyl 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate as a white solid.
94%
With ammonium hydroxide In tetrahydrofuran; triethylamine
Example 65 An Alternative Preparation of 3-(2-Chlorophenyl)-7-methylthio-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1450 g, 6.23 mole) (Aldrich Chemical Co., Milwaukee, Wis., USA) in 2987 mL of tetrahydrofuran was cooled to 5-10° C. and treated slowly with a mixture of 2407 mL of a 37percent solution of ammonium hydroxide in 2978 mL triethylamine. After stirring for 16 hours, the reaction mixture was concentrated in vacuo to approximately 5L and filtered. The filter cake was washed with hexanes and dried in a vacuum oven at 60-65° C. The filtrate was evaporated under reduced pressure to give 1314 g (94percent) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid. m.p. 130.1-130.7° C.
3.5 kg
With ammonium hydroxide In tetrahydrofuran at 20℃; for 5 h; Large scale
Scheme 1, Step A: Ammonium hydroxide (8.4 L, 17 wtpercent, 6.86 mol) is added over 1 hour to a solution of ethyl 4-chioro-2-(nethyithio)pyrimidine-5-carboxyiate (4 Kg, 10.74 mol) in THF (34.4 L) at room temperature. After stirring for 4 hours, water is added and the mixture is extracted with MTBE. The organic phase is washed with brine, dried overNa2SO4, filtered, and concentrated. The crude product is slurried with petroleum ether (3L), filtered, and dried under vacuum to provide the title compound as a white solid (3.5Kg, 89percent purity, 95percent yield) which is carried on without further purification. MS (mlz):214 (M+H).
With triethylamine In tetrahydrofuran; hexane; ethyl acetate
EXAMPLE 1 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic Acid Ethyl Ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran is added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide is added, and stirring is continued for 1 hour. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane are added, and the resultant solid is collected by filtration to provide 10.84 g (79percent) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
95%
With triethylamine In tetrahydrofuran; dichloromethane; water
Step 2.1 Preparation of Ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (25.4 g, 106 mmol, Aldrich Chemical Co., Milwaukee, Wis., USA) in 300 mL of tetrahydrofuran was treated with 50 mL of triethylamine and 40 mL of aqueous ammonium hydroxide. After stirring for 4 hours, 300 mL of water was added and the phases were separated. The organic layer was washed with 300 mL of brine, concentrated in vacuo, dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 16.5 g (95percent) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
79%
With triethylamine In tetrahydrofuran; hexane; ethyl acetate
Example 11 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran was added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide was added, and stirred was continued for 1 hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane were added, and the resultant solid was collected by filtration to provide 10.84 g (79percent) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
79%
With triethylamine In tetrahydrofuran; hexane; ethyl acetate
Example 11 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran was added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide was added, and stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane were added, and the resultant solid was collected by filtration to provide 10.84 g (79percent) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
[00719j Methylamine in EtOH (33percent, 17.5 mL, 140 mmol) was slowly added to a solution of Intermediate 3 (10.0 g, 43.1 mmol) in 120 mL of dichloromethane at 0 °C. The solution was stirred for 30 mm. Water (150 ml) was added, and the resultant mixture was separated, the organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (9.77 g, 100percent) as white solid.
100%
With triethylamine In tetrahydrofuran at 50℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43 mmol) inanhydrous THF (100 mL) was added triethylamine (6.0 mL,43 mmol) and monomethylamine (2M in THF, 22 mL, 43 mmol) The reaction mixture was heated to 50 °C overnight, then diluted with water (100 mL) and extracted into ethyl acetate (3 x 100 mL) . The combined organic phases were dried over Na2SQ4, filtered and concentrated to drynessunder reduced pressure to give the title compound (10 g, quantitative yield) as an off—white solid. ‘H NMR (500 MHz, CDC13) : 6 8.60 (s, 1H) , 8.16 (br s, 1H) , 4.31 (q, 2H), 3.07 (d, 3H), 2.54 (s, 3H), 1.36 (t, 3H). LCMS (Method A): RT = 1.14 mi m/z = 228 [M+H].
97%
at 0℃; for 0.5 h;
To a 0° C. solution of 20 g (86 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich Chemical Co., Milwaukee, Wis., USA) in 250 mL of dichloromethane was slowly added 35 mL (281 mmol) of a 33percent solution of methylamine in ethanol. After stirring for 30 minutes, 150 mL of water was added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 19 g (97percent) of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
96%
at 20℃; for 2 h;
Step 1: Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylateNpercentrCO2Et MeNH2 in MeOH Nt.CO2EtMeSNCI THF, RT MeSNNA mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol)and 29percent methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran(THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated toafford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96percent) as a yellowish solid. MS (ES+) C9H13N302S requires: 227, found: 228 [M + H].
96%
at 20℃; for 2 h;
Step 1: Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29percent methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran (THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3*50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96percent) as a yellowish solid. MS (ES+) C9H13N3O2S requires: 227, found: 228 [M+H]+.
96%
at 20℃; for 2 h;
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29percent methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran (THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96percent) as a yellowish solid. MS (ES+) C9H13N3O2S requires: 227, found: 228 [M+H]+.
94%
at 0℃; for 0.75 h;
Ethyl 4- (methylamino) -2- (methylthio) pyrimidine-5-carboxylate. To a stirred solution of compound 1 (40 g, 172 mmol) in 500 mL of DCM 70 mL of a 23solution of methylamine in ethanol at 0was slowly added. The resulting mixture was stirred at 0for 45 min. After compound 1 was completely consumed as monitored by TLC, 300mL of water was added to the mixture. The organic layer was separated and washed with brine (2 × 200 mL) , dried over anhydrous MgSO4, filtered and evaporated to give 36.86 g of the desired product as a white solid. Yield: 94 percent.
92%
at 0 - 20℃; for 1 h;
Example 31 Synthesis of N-(3-((6-(2-chlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)-amino)phenyl)-2-cyano-3-cyclopropylacrylamide Step 1. To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 42.98 mmol, 1.0 eq) in THF (100 mL) at 0° C. was added methylamine (43 mL, 86.0 mmol, 2 eq, 2M in THF). The resulted mixture was stirred at room temperature for 1 h. The solvent was removed and the residue dissolved in EtOAc and then washed with brine, dried and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as a brown solid (9.0 g, 92percent in yield).
89%
With triethylamine In tetrahydrofuran; water at 20℃; for 1 h;
To a solution of 50.261 g (0.216 mol) of commercially available 4-chloro-2- methylsulfanyl-5-pyrimidinecarboxylate ethyl ester in 600 mL OF THF was added 91 mL (0.244 mol) of triethylamine followed by 93 mL of 40percent aqueous methylamine. The solution warmed up slightly and was stirred for 1 hour. The THF was evaporated and the remaining aqueous slurry of white solid was partitioned between 300 mL OF CHCI3 and 200 mL of saturated aqueous NAHCO3. The organic layer was washed with 200 mL of brine and dried over MGS04. The drying agent was removed by filtration and the CHCl3 was concentrated to find a white solid. The solid was triturated in hexane, collected and dried under high vacuum to provide 43.71 g (89 percent) of 4-methylamino-2-methylsulfanyl-5- pyrimidinecarboxylate ethyl ester. The spectral data matched literature values.
89%
at 0 - 20℃; for 1 h;
S To a solution of ethyl 4chioro—2--( ethylthio)pyrirnidine-5--carboxylate (2.0 g, 8.6 mrnol) in THF (20 rnL) was added 2.0 M methylamine solution in THF (11.34 mE, 21.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for hi and concentrated to half of the original volume of solvent under reduced pressure. To the reaction mixture was added water (2000 mE) and the resulting precipitate was collected by filtration. The sohd was10 blown thy using nitrogen gas to give ethyl 4.-(rnethylamino)-2-inethyIthio)pyrimidine-5-carboxylate (1.75 g, 89percent yield) as a white solid, 1H NMR 600 MHz (CDCI3) ö 8.60 (s, 1H),8.16 (bs, 1ff), 4.32 (q,J= 7.2 Hz,J= 13.8 Hz, 2H), 3.07 (dJ 5.4 Hz, 3H), 2.54 (s, 3H),1.36 0, J= 7,2 Hz, 3Ff); ‘Fl NMR 400 MHz (DMSO-d6) 8.49 (s, 1Ff), 8.23 (bs, 1Ff), 4.26 (qJ= 7.1 Hz,J= 14.1 Hz, 2H), 2,96 d,]= 4.8 Hz. 3H), 2.48 (s, 3H\ 1.2.8 (t,J 7.1 Hz, 3H).
88%
at 0℃; for 3 h;
To a solution of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (42 g, 0.181 mol) in EtOH (400 mL) was added MeNH2 (12.3 g, 0.398 mmol) in EtOH (100 mL) at 0 °C and the mixture stirred for 3h. The mixture was concentrated to remove most of the solvent and then partitioned between H2O (200 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine, dried and concentrated to give 4-(methylamino)-2- (methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a white solid (36.0 g, 88percent yield).
88%
at 0℃; for 3 h;
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (42 g, 181 mmol) in EtOH (400 mL) was treated with a solution of methylamine (12.3 g, 397 mmol) in EtOH (100 mL) at 0 0C and the mixture was stirred for 3 h. The mixture was concentrated and <n="89"/>then partitioned between H2O (200 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give ethyl 4-(methylamino)-2- (methylthio)pyrimidine-5-carboxylate as a white solid (36.0 g, 88percent yield). 1H NMR (300 MHz, CDCl3): 8.59 (s, 1 H)5 8.18 (br s, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.05 (d, J = 4.8 Hz, 3 H), 2.52 (s, 3 H), 1.34 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 228.1 (M+H*).
With methylamine In ethanol; dichloromethane; water
Step 1.1 Preparation of Ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate A solution of 20 g (86 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich Chemical Co., Milwaukee, Wis., USA) in 250 mL of dichloromethane was cooled to 0° C. and treated slowly with 35 mL (281 mmol) of a 33percent solution of methylamine in ethanol. After stirring for 30 minutes, 150 mL of water was added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 19 g (97percent) of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
97%
With methylamine In ethanol; dichloromethane; water
Example 1 This example illustrates the preparation of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one beginning with ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate. A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (20 g, 86 mmol) (Aldrich Chemical Co., Milwaukee, Wis., USA) in 250 mL of dichloromethane was cooled to 0° C. and treated slowly with a 33percent solution of methylamine in ethanol (35 mL, 281 mmol). After stirring for 30 minutes, 150 mL of water were added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 19 g (97percent) of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
81%
With triethylamine; methylamine In tetrahydrofuran; hexane
Example 8 4-Methylamino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol) followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes, then was concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester, mp 91-93° C. Literature mp 93-94° C.: J Org. Chem., 1960:2137. Analysis calculated for C9H13N3O2S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
97%
With methylamine In ethanol; dichloromethane; water
a) A solution of 20 g (86 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 250 ml of dichloromethane was cooled to 0° C. and treated slowly with 35 ml (281 mmol) of a 33percent solution of methylamine in ethanol. After stirring for 30 minutes 150 ml of water were added and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 19 g (97percent) of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
81%
With triethylamine; methylamine In tetrahydrofuran; hexane
Example 8 4-Methylamino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol) followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes, then was concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester, mp 91-93° C. Literature mp 93-94° C.: J. Org. Chem., 1960:2137. Analysis calculated for C9H13N3O2S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1793 - 1816
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 1984 - 2004
[3] Patent: WO2011/75616, 2011, A1, . Location in patent: Page/Page column 62
15
[ 5909-24-0 ]
[ 76360-82-2 ]
[ 185040-32-8 ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 16A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93° C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester, mp 91°-93° C. Analysis calcd. for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91°-93° C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
Reference：
[1] Patent: US5945422, 1999, A,
[2] Patent: US5620981, 1997, A,
[3] Patent: US5733914, 1998, A,
16
[ 5909-24-0 ]
[ 73781-88-1 ]
Yield
Reaction Conditions
Operation in experiment
98.2%
With 10% palladium on activated carbon; Degussa type; hydrogen; sodium carbonate In ethanol for 48 h;
Ethyl 2-(methylsulfanyl)pyrimidine-5-carboxylate To the stirred solution of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (4.0 g, 17.2 mmol) in ethanol in hydrogenation vessel, Na2CO3 (1.4 g, 16.7 mmol) and 10percent Pd-C (2.0 g) was added and degassed for about 10 min. The reaction mixture was kept in hydrogenation parr shaker (60 psi) for 48 h. The reaction mixture was filtered through the celite, washed with ethanol, concentrated under reduced pressure to get the title product as a pale yellow liquid (3.3 g. yield: 98.2 g, percent). m/z=199.1 (M+H)+.
70%
With hydrogen; sodium hydrogencarbonate In ethanol for 48 h;
Step 1: Ethyl 2-(methylthio)pyrimidine-5-carboxylate (148)A solution of 147 (3.00 g, 12.9 mmol) and NaHCO3 (1.08 g, 12.9 mmol) in EtOH (60 ml) was hydrogenated over Pd/C 10percent (2.3 g, 11.6 mmol) for 2 days. The suspension was filtered through a Celite.(R). pad (rinsed with MeOH after the filtration). The filtrate and washings were collected, evaporated and the crude product was purified by flash chromatography (eluent 5-85 (AcOEt/Hexane) to afford the title compound 148 as transparent oil (1.79 g, 70percent yield). LRMS (ESI): (calc.) 198.1; (obt.) 199.1 (M+H)+.
63%
With acetic acid; zinc In tetrahydrofuran for 6 h; Heating / reflux
The ethyl 2-(methylthio)-5-pyrimidinecarboxylate used as starting material was prepared as follows : - To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (5 g, 21.49 mmol) in THF (25 mL) was carefully added zinc powder (4. 213 g, 64.46 mmol) and the resulting mixture heated to reflux. Glacial acetic acid (1.23mL, 21.49 mmol) was added and the reaction mixture stirred and heated for 6 h. The mixture was cooled and filtered through diatomaceous earth (CeliteNo.) and the filtrate evaporated to dryness to give a solid residue which was triturated with DCM and isohexane. The filtrate was evaporated to dryness to give the title compound as a solid (2.68 g, 63percent); NMR Spectrum: (DMSOd6) 1.33 (t, 3H), 2.59 (s, 3H), 4.35 (q, 2H), 9.03 (s, 2H).
61%
With ammonium chloride; zinc In water; benzene at 80℃; for 30 h;
Preparation of ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (intermediate F); Intermediate F; Scheme 3; Stage 1 - Chloro reduction; Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (12.5g, 53.88mmol) and Zn powder (14.1g, 215.52mmol) were combined and benzene (6OmL) and 3M NH4CI (14OmL) were added. The suspension was stirred vigorously and heated to 8O0C for 3Oh. The reaction mixture was filtered through celite and washed with EtOAc (20OmL). The filtrate was concentrated in vacuo to about 5OmL and then partitioned between H2O (40OmL) and EtOAc (40OmL). The aqueous layer was further extracted with EtOAc (25OmL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to a dark oil. This was purified by column chromatography (neat heptane followed by 1 :1:1 heptane/CH2CI2/Et20 and finally 2:2:0.5 heptane/CH2CI2/Et20). The desired product was EPO <DP n="37"/>35 obtained as a colourless oil (13g, 61percent). m/z = 199 [M+H]+, 1H NMR (300MHz, c/6-DMSO) δ: 1.30 (3H, t), 2.60 (3H, s), 4.35 (2H, q), 9.0 (2H, s).
61%
With ammonium chloride; zinc In water; benzene at 80℃; for 30 h;
Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (12.5g, 53.88mmol) and Zn powder (14.1 g, 215.52mmol) were combined and benzene (60ml) and 3M NH4Cl (140ml) were added. The suspension was stirred vigorously and heated to 8O0C for 30 h. The reaction mixture was filtered through celite and washed with EtOAc (200ml). The filtrate was concentrated in vacuo to about 50ml and then partitioned between H2O (400ml) and EtOAc (400ml). The aqueous layer was further extracted with EtOAc (250ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to a dark oil. This was purified by column chromatography eluting with neat heptane followed by 1 :1 :1 heptane/CH2CI2/Et20 and finally 2:2:0.5 heptane/CH2CI2/Et20. The title compound was obtained as a colourless oil (13g, 61percent). m/z 199 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.30 (3H, t), 2.60 (3H, s), 4.35 (2H, q), 9.0 (2H, s).
56%
With ammonium chloride; zinc In water; toluene at 80℃; for 36 h;
Zn powder (1.17 g, 18 mmol)And 3M NH4Cl (5.2 mL)Was added to compound 1 (466 mg, 2 mmol)In toluene (2.5 mL)The mixture was stirred at 80 ° C for 36 hours,filter,CH2Cl2,The filtrate was concentrated in vacuo,CH2Cl2 (30 mL) and water (30 mL) were added,The aqueous phase was extracted with CH2Cl2 (30 mL)The organic phase was combined and washed with saturated brine (40 mL), dried over Na2SO4 and evaporated to dryness under reduced pressure to give the crude product.Silica gel column separation (petroleum ether / ethyl acetate = 10/1) to give the target product 12. Yield56percent
52%
With hydrogen; magnesium oxide In methanol for 6 h; Inert atmosphere
Step A: Ethyl 2-(methylthio)pyrimidine-5-carboxylateEthyl 4-chloro-2- methylthiopyrimidine-5- carboxylate (5.0 g, 21.4 mmol) and magnesium oxide (0.9 g, 21.4 mmol) was added to methanol (200 mL) in par-shaker vessel. Dry 10percent Pd/C (5 g) was added and the flask was evacuated, purged with nitrogen and the contents allowed to react under 50 psi pressure hydrogen for 6 hours. The system was evacuated and purged with nitrogen. After dilution with methanol the solution was filtered through a pad of celite. The filter cake was washed with methanol and the filtrate was evaporated to get the crude material. Further on column purification using hexane/ethyl acetate solvent mixture yielded the title compound (2.2 g, Yield 52 percent).
36%
With acetic acid; zinc In ethanol; chloroform; water at 20℃; for 2 h;
Commercially available ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.00 g, 21.5 mmol) was dissolved in ethanol (72 mL) and water (14 mL), and zinc powder (14.0 g, 214 mmol) was added to the solution. Then, the mixture was added with acetic acid (2.95 mL, 51.5 mmol) in three portions, followed by stirring at room temperature for 2 hours. After removing the insoluble material by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the organic layer was separated from the aqueous layer. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain ethyl 2-(methylthio)pyrimidine-5-carboxylate (1.54 g, 36percent). ESI-MS: m/z 199 [M + H]+1H NMR (CDCl3)δ(ppm): 1.41 (t, J = 7.1 Hz, 3H), 2.61 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 9.02 (s, 2H).
Reference：
[1] Patent: US2016/333004, 2016, A1, . Location in patent: Paragraph 0385
[2] Patent: US2008/227826, 2008, A1, . Location in patent: Page/Page column 27-28
[3] Patent: WO2005/61465, 2005, A1, . Location in patent: Page/Page column 61
[4] Patent: WO2008/53131, 2008, A1, . Location in patent: Page/Page column 34-35
[5] Patent: WO2006/123121, 2006, A1, . Location in patent: Page/Page column 17; 26
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8663 - 8678
[7] Chemical Biology and Drug Design, 2016, vol. 87, # 3, p. 472 - 477
[8] Patent: CN106279044, 2017, A, . Location in patent: Paragraph 0026; 0030; 0068; 0069
[9] Patent: WO2012/117421, 2012, A1, . Location in patent: Page/Page column 44
[10] Patent: EP1724271, 2006, A1, . Location in patent: Page/Page column 91
[11] Patent: WO2007/118137, 2007, A1, . Location in patent: Page/Page column 104-105
[12] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 155
[13] Patent: WO2017/144637, 2017, A1, . Location in patent: Page/Page column 87
[14] Patent: WO2017/144635, 2017, A1, . Location in patent: Page/Page column 51; 52
Stage #1: With acetic acid; zinc In tetrahydrofuranReflux Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃;
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol) was suspended in dry THF (50 ml), and zinc powder (8.43 g, 129 mmol) was carefully added. The suspension was heated to reflux in a previously heated bath, and then acetic acid (2.460 ml, 43.0 mmol) was added drop wise. The mixture was reacted at the same temperature overnight. The suspension was filtered through a celite pad washing with DCM and MeOH; the filtrate was evaporated and the residue was triturated with DCM:Et2O=1:1. The precipitate was discarded and the solution evaporated and purified by flash chromatography on silica gel column (petroleum ether:ethyl acetate=9:1). After solvent evaporation, the residue was treated with diethyl ether and the precipitate was filtered off. The filtrate was evaporated to dryness affording a mixture of ethyl 2-(methylthio)pyrimidine-5-carboxylate and ethyl 2,4-bis(methylthio)pyrimidine-5-carboxylate (about 1:1 ratio) as a colorless oil (3.47 g, MS/ESI+ 199.1 [MH]+; MS/ESI+ 245.0 [MH]+) A mixture of ethyl 2-(methylthio)pyrimidine-5-carboxylate and ethyl 2,4-bis(methylthio)pyrimidine-5-carboxylate (about 1:1 ratio; 3.47 g) was dissolved in DCM (78 ml), and m-CPBA (77percent w/w; 10.54 g, 47.0 mmol) was added portion wise stirring at room temperature. The reaction was stirred at the same temperature overnight. The obtained suspension was filtered washing with DCM and the filtrate was evaporated. The crude was dissolved in ethyl acetate (250 ml) and washed twice with a sat. NaHCO3 (100 ml×2); the organic phase was dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel column (DCM:iPr2O=3:7) affording ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate as an off-white solid (2.154 g, 9.31 mmol, 21.7percent yield over two steps, MS/ESI+ 231.0 [MH]+). This intermediate proved to be instable on air and it must be kept under vacuum
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8663 - 8678
[2] Patent: WO2012/117421, 2012, A1,
[3] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 1022; 1023
[4] Chemical Biology and Drug Design, 2016, vol. 87, # 3, p. 472 - 477
[5] Patent: WO2016/30443, 2016, A1,
[6] Patent: US2016/333004, 2016, A1,
[7] Patent: CN106279044, 2017, A,
[8] Patent: WO2017/144637, 2017, A1,
[9] Patent: WO2017/144635, 2017, A1,
[10] Patent: WO2013/45280, 2013, A1,
21
[ 5909-24-0 ]
[ 185039-89-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 17, p. 3276 - 3292
22
[ 5909-24-0 ]
[ 76360-82-2 ]
[ 185040-32-8 ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 16A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93° C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester, mp 91°-93° C. Analysis calcd. for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
81%
With triethylamine; methylamine In tetrahydrofuran
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40percent aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81percent) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91°-93° C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
Reference：
[1] Patent: US5945422, 1999, A,
[2] Patent: US5620981, 1997, A,
[3] Patent: US5733914, 1998, A,
3-chloro-4-methoxybenzylamine (45.6 g, 0.27 mol) was dissolved in 180 mL of acetone, then triethylamine (40.4 g, 0.4 mol) was added.4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester obtained in the step S2(53.3 g, 0.24 mol) dissolved in 250 mL of acetone and slowly dropped into the reaction solution.And reacted at room temperature for 3 h, and poured the reaction solution into the ice water mixture.Extracted with ethyl acetate,The combined organic phases were washed with 10percent aqueous citric acid (250 mL x 3).Dry the organic layer with anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.Dry in vacuo to a white solid (86.0 g, 87.0percent).
76%
With triethylamine In dichloromethane at 20℃; for 10 h;
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2 -(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76 percent yield).
145 g
With tetrabutylammomium bromide; sodium carbonate In dichloromethane; water at 25 - 30℃;
To 600ml of methylene dichloride was added lOOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500m1 of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30°C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95percent of HPLC purity.
42.3 g
With triethylamine In ethyl acetate at 0 - 30℃;
After dissolving 50.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 59.9 ml of triethylamine into 430 ml of ethyl acetate, respectively, the mixture was cooled to 0 ° C, 44.7g of 3-chloro-4-methoxybenzylamine was added in portions, the reaction was carried out at 0-5 ° C for 30min and the reaction was continued at 20-30 ° C for 0.5-1h. The reaction was concentrated under reduced pressure, and then added ethyl acetate and citric acid solution 400ml each wash 2 times, the organic phase was washed with water and saturated brine each time, dried, filtered and concentrated under reduced pressure to give the crude 73.0g. Finally, with anhydrous ethanol at 55 ~ 60 ° C dissolved crude, stirring crystallization 12-18h, filtered and dried to give the product 42.3g.
Stage #1: With triethylamine In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; Cooling with ice
In a flask, tetrahydrofuran (4.5 L) was added, 3-chloro-4-methoxybenzylamine hydrochloride (500 g, 2.4 mol) was added under stirring, triethylamine (836 mL, 6.01 mol) was added dropwise, the mixture was stirred at room temperature for 30 min, cooled with ice-water, then ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (466 g, 2.0 mol) was added, the reaction was stirred overnight at room temperature. TLC was used to monitor the reaction. After the end of reaction, solvent was removed by evaporation under reduced pressure. Ethyl acetate (2.5 L) and water (1 L) were added, the mixed liquid phases were separated, the organic phase was sequentially washed with diluted hydrochloric acid, water (1 L), saturated sodium bicarbonate (1 L) and saturated sodium chloride (1 L), dried over anhydrous sodium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to obtain an oily substance, to which was added methanol (3 L), and a large white solid was precipitated. After stirring for 30 min, filtration was carried out, and the filter cake was vacuum dried to obtain the product (650 g, yield of 88.3percent).
78%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h; Cooling with ice
Compound 13 (5 g, 21.86 mmole) and compound 18 (5.34 g, 25.4 mmol) were added to 75 ml of dry DMF 1 and dissolved with stirring. After stirring for 10 minutes, the reaction system was placed in an ice-water mixture. Triethylamine (21.4 g, 0.217 mole) was slowly added dropwise to the reaction flask and slowly warmed to room temperature. After 4 hours, TLC showed the reaction was completed. Dichloromethane was added, washed with water five times, dried and filtered, concentrated by rotary evaporation and passed through a column (PE: EA = 25: 1). Compound 19 (7.3 g, yield 78percent) was obtained as a white powder.
74.2%
Stage #1: With triethylamine In tetrahydrofuran at 20℃; for 0.25 h; Cooling with ice Stage #2: at 20℃;
In THF (150 mL) was suspended 3-chloro-4-methoxybenzylamine hydrochloride salt (16.0 g, 76.9 mmol). The suspension was cooled in an ice bath, and triethylamine (19.4 g, 192.3 mmol) was added dropwisely. The reaction mixture was stirred at ambient temperature for 15 min, then was added ethyl 4-chloro-2-thiomethyl-5-pyrimidine carboxylate (14.9 g, 64.1 mmol). The reaction mixture was stirred at ambient temperature overnight. TLC was used to monitor the reaction. After the completion of the reaction, the solvent was removed by rotary evaporation. Acetic ether (500 mL) and water (200 mL) were added. The organic phase was separated, washed with hydrochloric acid (1N), saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The solvent was removed by rotary evaporation to give oil. Methanol (100 mL) was added to precipitate a large amount of white solid. The mixture was filtrated and the solid was dried in vacuum to give ethyl 4-((3-chloro-4-methoxybenzyl)amine)-2-thiomethyl-5-pyrimidine carboxylate (21 g, 74.2 percent yield).
90 g
With sodium carbonate In water at 25 - 30℃; for 4 h;
(3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35°C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred until complete dissolution. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.Yield: 90 gms; Melting range: 81 -84°C; Purity by HPLC: 95.3percent.
With tetrabutylammomium bromide; sodium carbonate In water at 25 - 30℃; for 8 h;
(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30°C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 40-45°C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30°C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. The reaction mixture was heated to 65-70°C and stirred 15 minutes. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65°C and stirred for 30 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound.Yield: 102 gms; Melting range: 80-84°C; Purity by HPLC: 99.25percent
Example 14 4-(4-Methoxybenzylamino)-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6.05 g, 26.07 mmol) in 60 mL of tetrahydrofuran was added triethylamine (11 mL, 79.5 mmol) followed by 3.6 mL (27.6 mmol) of 4-methoxybenzylamine. The solution was stirred for 1 hour then filtered. The white solid was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 7.60 g (88percent) of 4-(4-methoxybenzylamino)-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester, mp 72-74° C. Analysis calculated for C16H19N3O3S: C, 57.64; H, 5.74; N, 12.60. Found: C, 57.65; H, 5.80; N, 12.57.
5.20 g
With triethylamine In N,N-dimethyl-formamide at 0℃; for 1 h;
Ethyl 4—chloro—2—(methylthio)pyrimidine—5—carboxylate (3g, 12.9 mmol) was dissolved in DMF (10 mL) and cooled to0 °C. A solution of triethylamine (2 mL, 14.4 mmol) and(4-methoxyphenyl)methanamine (1.85 mL, 14.2 mmol) in DMF(10 mL) was added slowly. The mixture was stirred for 1 hthen poured into ice / 10percent citric acid solution. The mixture was extracted with ethyl acetate (x 2) . The combined organic layers were washed with citric acid solution then brine, then dried with Mg504, filtered andconcentrated in vacuo. The residue was azeotroped with cyclohexane / DCM to give a syrup which crystallised to yield 5.20 g of a white solid on standing. This was dissolved in ethanol (25 mL) and 2 M NaOH (25 mL) and the solution was stirred overnight. The mixture wasconcentrated in vacuo, then acidified (2 M HC1) . The precipitated solid was collected by filtration, then dried in vacuo to give the title compound as a white solid (4.1 g, quantitative) . ‘H NMR (500 MHz, DMSO—d6) : 5 13.30 (br s, 1H), 8.85 (t, 1H), 8.53 (s, 1H), 7.29 (t,2H), 6.90 (t, 2H), 4.63 (d, 2H), 3.74 (s, 3H), 2.45 (s,3H) . LCMS (Method A) : = 1.05 mm, m/z = 306 [M+H].
Stage #1: at 20℃; for 37.333 h; Heating / reflux Stage #2: With hydrogenchloride In water
A. 4-Chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride A slurry of potassium trimethylsilyl oxide (90percent tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford 4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid as a white solid (8.8 g, 47 mmol, 73percent yield). MS (-ESI) m/z 185 (M-, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97percent yield). 1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 2.63 (s, 3H).
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 72 h; Reflux
DIPEA (20.8 ml, 120 mmol) and allyl hydrazine 5 (8.23 g, 47.8 mmol) were added to a solution of ethyl 4-chloro-2-methylthio- 5-pyrimidinecarboxylate (6; 1 1.1 g, 47.8 mmol) in THF (150 ml). The reaction mixture was heated at reflux for 72 h, before being concentrated in vacuo. Et20 (50 ml) was added to the residue, and the resultant precipitate was collected by filtration. The filtrate was evaporated to dryness, and the residue was cooled in an ice bath, after which TFA (40 ml) was added. The resultant solution was stirred at RT for 1 h, followed by 70 °C for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (50 ml) and cooled in an ice bath, after which 6M NaOH (75 ml) was added. The resultant solution was stirred at RT for 15 min, before 32 being acidified via the addition of cone. HCI (40 ml). The orange solution was evaporated to dryness and the resultant residue was partitioned between chloroform (100 ml) and water (100 ml), and the organic phase was washed with brine (50 ml), dried (Mg2S04), concentrated in vacuo, and triturated with hexanes. The solid precipitate was washed with EtOH and Et20, before being dried under vacuum to give the target compound as a yellow solid (5.44 g, 24.5 mmol, 51 percent). Rf 0.45 (9:1 DCM:MeOH); M.p. 125- 128 °C; IR (cm-1 ) 3032, 2979, 2926, 2659, 1656, 161 5, 1 566, 1 514; 1 H NMR (400 M Hz, DMSO-d6)2.53 (3H, s, -SCH3), 4.38 (2H, dapp, J = 5.2 Hz, N2-CH2), 5.06-5.20 (2H, m, allyl C-Hcis/trans), 5.87 (1 H, ddt, J = 17.2, 10.5, 5.3 Hz, alkene C-H), 8.67 (1 H, s, H-4), 12.65 (1 H, -1 ); MS [M + H] + m/z 223.1.
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 20℃; for 3h;
7) Ethyl 2-(trifluoromethyl)-4-moropholinopyrimidine-5-carboxylate (v)
General procedure: To a mixture of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (1 g, 3.93mmol) and N,N-diisopropylethylamine (1.37mL, 7.87mmol) in 2-propanol (8 mL) was added morpholine (0.42 mL, 4.92 mmol). The mixture was stirred at room temperature for 3 h and was then concentrated in vacuo. The resulting residue was purified by column chromatography (40% EA/Hex) to give ethyl 2-(trifluoromethyl)-4-moropholinopyrimidine-5-carboxylate as a white solid (1.2g, 98%).
Ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate (30 g, 140 mmol) was added to a three-vial flask.Add 20g of thionyl chloride (168mmol)The reaction was heated to 60C for 3 hours. After the reaction was complete, it was cooled to 0-5C. 100 ml of water was added and crystallized at 0-5C for 1-2 hours. The mixture was filtered and vacuum dried at 50C to give 30.1 g of white solid product. Yield 92 %, pure 99.8%,
77%
With N,N-diethylaniline; trichlorophosphate; for 5h;Heating / reflux;
A mixture of 4-hydroxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (50 g, 0.234 mmol), POC13 (110 mL, 1.17 mmol) and diethylamide (70 mL, 0.28 mmol) was refluxed for 5h. The solvent was removed under vacuum and the residue was dissolved in ice H2O and cautiously neutralized with aqueous NaHCO3. After extraction with EtOAc (3x400 mL), the organic extracts were combined, dried and concentrated to give 4-chloro-2- (methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (42 g, 77% yield).
77%
With trichlorophosphate; In acetonitrile; for 6h;Reflux;
the ethyl 4-hydroxy-2-methylsulfanyl-5-carboxylate obtained in the step S1 (55.6 g, 0.26 mol) was added to 150 mL of acetonitrile.Stir for 25min,Slowly add 135 mL of POCl3 to the reaction solution.After the addition is completed,The reaction solution was heated to reflux for 6 h.Then the reaction solution is slightly cold,The reaction solution was concentrated and the residue was poured into an ice water mixture and stirred.Adjust the pH of the reaction solution to neutral with saturated sodium bicarbonate solution.When a large amount of white solid precipitates, suction filtration is performed.The filter cake is used in turn (135mL × 3),Anhydrous ethanol (30 mL × 3) was rinsed.Then dried in vacuo to give a white solid (47.8 g, 77%);
40%
With trichlorophosphate; at 10 - 65℃; for 7h;
Step 2. Preparation of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (B19-2): Neat POCl3 (120 mL) was cooled to 10 C. and treated portion-wise over 4 hours with B19-1 (50 g, 232 mmol) without exceeding a temperature of 25 C. The mixture was then heated at 65 C. After 3 hours the mixture was cooled to 10 C., poured into crushed ice (350 g), treated drop-wise with water (676 mL) under vigorous stirring. The resultant solids were collected and dried under reduced pressure to provide B19-2 as a pale yellow solid. Yield: 22 g, 40%. 1H NMR (CDCl3): delta 8.95 (s, 1H), 4.44 (q, 2H), 2.62 (s, 3H) and 1.42 (t, 3H).
With trichlorophosphate; In toluene; at 55 - 105℃; for 4h;
The wet solid obtained in step-a) was dissolved in toluene (800 ml) by heating the reaction mixture to 85-90C. The reaction mixture was kept aside for 15 minutes and both the organic and aqueous layers were separated. The organic layer was heated to 110-115C to remove water from it. Cooled the reaction mixture to 55-60C. Phosphoryl chloride (106.36 g) was added to the organic layer at 55-60C, heated the reaction mixture to 100-105C and then stirred for 4 hours. The reaction mixture was cooled to 0-5C and then quenched with water at a temperature below 40C. The reaction mixture was heated to 40-45 C and separated both the organic and aqueous layers. The organic layer was washed with 5% sodium carbonate solution followed by water. The organic layer containing the title compound is taken to the next step.
With ammonium hydroxide; triethylamine; In tetrahydrofuran; water; at 30℃; for 2h;
step 1. To a 2 L three-necked flask was added ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (100 g, 0.43 mol), THF (500 mL), and TEA (186 mL, 1.29 mol). Ammonium hydroxide (28% in water, 400 mL) was added by portions keeping the internal temperature below 30 C. After 2 h, water (1000 mL) was added and THF was distilled off under vacuum. The resulting solid was filtrated and dried in vacuo at 50 C. to afford ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (90 g, 99%). LC/MS: m/z=213.9 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) delta 8.57 (s, 1H), 8.03 (br, 1H), 7.65 (br, 1H), 4.27 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
98%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; water; at 20℃; for 2h;Inert atmosphere;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1) (100 mg, 0.43 mmol) in dry THF (2 mL) was added triethylamine (0.2 mL, 1.29 mmol) and ammonium hydroxide (0.5 mL). The resulting mixture was stirred at rt for 2 h till completion. After evaporation in vacuo to remove THF, the crude mixture then partitioned between H2O and EtOAc. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (15 % EtOAc/hexane) to afford 2 (90 mg, 98%) as white solid. lH NMR (400 MHz, CDCb) delta (ppm) 8.65 (s, 1H), 7.81 (s, 1H), 6.05 (s, 1H), 4.29 (q, / = 7.2 Hz, 2H), 2.46 (s, 3H), 1.32 (t, / = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCb) delta 176.06, 166.42, 161.87, 158.93, 101.15, 61.02, 14.32, 14.14.
97%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried overanhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8(97%) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
97%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried overanhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8 g (97%) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
97%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 20℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30 g, 129.3 mmol, 1.00 equiv) and Et3N (51 mL) in THF (225 mL) was added NH3.H20 (300 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated and diluted with EtOAc. The organic phase was washed with sat. NaHC03 solution and brine, dried over anhydrous sodium sulfate. The solids were filtered and concentrated under vacuum to give 26.8 g (97%) of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate as a white solid.
92%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 10 - 55℃;
Method B: Charge reaction vessel with 1190g of THF and 660g of ethyl 4-chloro-2- (methylsulfanyl)pyrimidine-5-carboxylate (l .Oeq. 2.84 mol). Stir at 10-20 C for 20-30mins, and then add 907 g of NH3-H20 and 989 g of Et3N to the mixture. Heat to 45-55C, and stir for 2-6hrs at 45-55C. After reaction is complete, cool to 8-12C and add 4000g water. Stir for 4-8hrs at 8-12C, filter and risen with 200g water. Dry the cake in vacuum at 80C for 8- 24hrs to obtain title compound (560g; 98.8% purity in 92% yield; [M+l]=213.8, 1H NMR (d6-DMSO, 400 MHz): delta = 8.564 (s, 1H), 8.278 (s, 1H), 8.01 l(s, 1H),7.649 (s, 1H), 4.293- 4.240 (dd, Ji=6.8, J2=14, 2H), 2.462 (s, 3H), delta 1.308-1.272 (m, 3H)).
90%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 20℃;
General procedure: 4-Chloro-2-(methylsulfanyl)pyrimidine-5 -carboxylic acid ethyl ester (1) (1 equiv.), wasdissolved in THF to which triethylamine (3 equiv.) alkyl amine (1.1 equiv.) was added and stirred overnight at room temperature. The precipitated salts were filtered and the solvent evaporated under reduced pressure. The resulting oil was dissolved in EtOAc, washed with sodium bicarbonate, then dried over Na2SO4. The salts were filtered, and the solvent was evaporated in vacuum to give the product.Starting from 4-chloro-2-(methylsulfanyl)pyrimidine-5 -carboxylic acid ethyl ester (1) and ammonium hydroxide, (2a) was obtained in 90% yield using the method described inGeneral Procedure A. ?H NMR (300 MHz, CDC13), oe 1.25 (t, OCH2CH3, 3H), 2.45 (s, S-CH3,3H), 4.30 (q, OCH2CH3, 2H), 8.10 (br s, NH2, 2H), 8.58 (s, Ar-H, 1H).
89.3%
With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 2h;
1.2.1 Synthesis of Compound 1 5.00 g (21.5 mmol) of ethyl 2-methylsulfide-4-chloropyrimidine-5-carboxylate was dissolved in 20 mL of tetrahydrofuran.5mL of 25% ammonia solution was added to the reaction solution, and the reaction was performed at room temperature for 2h. The reaction was monitored by TLC. After the reaction is completed, 30 mL of a saturated ammonium chloride solution is added to the reaction solution to quench the reaction, and the mixture is extracted with ethyl acetate (20 mL × 3).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column separation (PE / EA, 1: 1) to obtain 4.12 g of a white solid with a yield of 89.3 %
79%
With ammonia; triethylamine; In tetrahydrofuran; at 20℃;
In a 15 mL vial, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.00 g, 4.30 mmol) was dissolved in THF (10 mL) and triethylamine (2.00 ml, 14.35 mmol) was added, followed by ammonia (2 ml, 4.30 mmol). The resulting mixture was stirred overnight at room temperature. After completion of the reaction, the solvents were evaporated and the crude mixture was purified by silica gel chromatography using hexane/ethyl acetate (0-40%) as the eluent to give the title compound INT-8 (0.72 g, 3.38 mmol, 79% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): delta 8.55 (s, 1H), 8.02 (br s, 1H), 7.64 (br s, 1H), 4.24 (q, 2H), 2.44 (s, 3H), 1.27 (t, 3H)
66%
To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-5- pyrimidinecarboxylate (4.50 g, 19.4 mmol) in MeOH is added 7 Nu NH3 (13.9 mL) in MeOH at 0 C and the mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer is dried over MgStheta4, filtered and concentrated. The crude product is crystallized from the mixed solvent of EtOAc and hexanes to give 2.90 g (66%) of ethyl 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate as a white solid.
57.6%
With ammonium hydroxide; triethylamine; In tetrahydrofuran; for 4h;
To a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol) in tetrahydrofuran (125 mL) was added triethylamine (20 mL, 143 mmol), followed by aqueous ammonium hydroxide (16 mL, 237 mmol). The mixture was stirred for 3 hours. Additional ammonium hydroxide (4 mL, 59.2 mmol) was added to the mixture and stirring was continued for 1 hour. The mixture was poured into water (125 mL) and the two layers were separated. The organic layer was washed with brine and evaporated under reduced pressure. The remaining solid was triturated with ethyl acetate:hexanes, collected via vacuum filtration, washed with hexane and dried in vacuo to give ethyl 4-amino-2-(methylthio)pyrimidine-5- carboxylate (4.74 g, 22.23 mmol, 51 .7 %yield) as a white solid. The filtrate was evaporated under reduced pressure and the remaining solid was triturated with 1 :4 EtOAc-hexane, collected via vacuum filtration, washed with hexane and dried in vacuo to give ethyl 4-amino-2- (methylthio)pyrimidine-5-carboxylate (539 mg, 2.53 mmol, 5.9 % yield) as a white solid. 1H NMR (400 MHz, CD3SOCD3) delta 1 .28 (t, J = 7 Hz, 3 H), 2.45 (s, 3 H), 4.26 (q, J = 7 Hz, 2 H), 7.65 (br s, 1 H), 8.03 (br s, 1 H), 8.56 (s, 1 H); LC-MS (LC-ES) M+H = 214.
1314 g (94%)
With ammonium hydroxide; In tetrahydrofuran; triethylamine;
Example 65 An Alternative Preparation of 3-(2-Chlorophenyl)-7-methylthio-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1450 g, 6.23 mole) (Aldrich Chemical Co., Milwaukee, Wis., USA) in 2987 mL of tetrahydrofuran was cooled to 5-10 C. and treated slowly with a mixture of 2407 mL of a 37% solution of ammonium hydroxide in 2978 mL triethylamine. After stirring for 16 hours, the reaction mixture was concentrated in vacuo to approximately 5L and filtered. The filter cake was washed with hexanes and dried in a vacuum oven at 60-65 C. The filtrate was evaporated under reduced pressure to give 1314 g (94%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid. m.p. 130.1-130.7 C.
With ammonium hydroxide; In ethanol; water;
EXAMPLE 74 4-Amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a suspension of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (25 g) in ethanol (200 mL) was added 30% ammonium hydroxide (38 mL). After stirring 5 hours at room temperature, the reaction was concentrated in vacuo. The residue was suspended in water and filtered. The filter pad, washed with water then diethyl ether, gave 17.68 g of the title compound, CIMS (1% NH3 in CH4): 242=M+ +C2 H5, 214=M+ +H (Base), 213=M+, 168=M+ -OEt.
With ammonia; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;
Example 3: Synthesis of t°t-butyl 4-f {6-f2-methylrhohenyl)-8-lY3S>l- (methylsulfonyl)pyrrolidm-3-yl1-7-oxo-7,8-dihvdropyridor2,3-J1pyrimidin-2- yl}amino)piperidine-l-carboxylate ("Compound No. 77)Step a: Ethyl 4-amino-2-(methyIthio)pyrimidme-5-carboxyIate; To a suspension of ethyl-4-chloro-2-methylthio-5-pyrimidine-carboxylate (commercially available) (20.0 g, 85.9 mmol) in dry tetrahydrofuran (150 mL) was added triethylamine (13.01g, 128.9 mmol) and aqueous ammonia (25 %, 17.5 g, 258.2 mmol) at 0 0C and the mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated under reduced pressure followed by addition of water. The residue thus separated was filtered and dried under reduced pressure to yield the title compound. Yield = 17.0 g.
With ammonia; In ethanol; water; at 20℃; for 20.3h;
Preparation 1 N-(t-Butyl)-N'-[6-(2,6-dichlorophenyl)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidin-7-yl]urea.; 1.1 Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate. 140 ml of a 20% NH4OH solution was added to a suspension of 50.7 g of ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml of EtOH over 20 minutes, keeping the temperature at about 20 C. After stirring for 20 hours at ambient temperature, the reaction medium was concentrated under vacuum almost to dryness, then the residue was taken up in 350 ml of water, stirred for 20 minutes, filtered, and washed with 3×60 ml of water then vacuum dried in the presence of P2O5. A white solid was obtained: MP=134-135 C., m=39.9 g.
With ammonia; In ethanol; water; at 20℃; for 20h;
140 ml of a 20% NH4OH solution are added, in 20 minutes, and while maintaining the temperature at around 20 C., to a suspension of 50.7 g of ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml of EtOH. After stirring at ambient temperature for 20 hours, the reaction medium is concentrated under vacuum almost to dryness, and the residue is then taken up in 350 ml of water, stirred for 20 minutes, filtered, washed with 3×60 ml of water, and then dried under vacuum in the presence of P2O5. A white solid is obtained, Mp=134-135 C., m=39.9 g.
With ammonia; In tetrahydrofuran; methanol; water;
(1) To a solution of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine (10.0 g) in tetrahydrofuran (150 ml) is added 28% aqueous ammonia (30 ml) to obtain emulsion. The emulsion is changed to a clear solution by adding methanol (about 20 ml), and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and extracted with ethyl acetate. The organic layer is washed successively with water (x2) and brine, dried over sodium sulfate, concentrated in vacuo to give a colorless solid. The solid is recrystallized from ethyl acetate (high temperature, about 100 ml) to give 2-methylthio-5-ethoxycarbonyl-4-aminopyrimidine (7.00 g) as colorless prism crystals. M.p. 131-132 C, MS (m/z): 214 (MH+). IR(nujol): 3412, 3269, 3133, 1693, 1630, 1567, 1367, 1311, 1206, 1096 cm-1.
With ammonium hydroxide; triethylamine; In tetrahydrofuran; at 20℃; for 4h;
The mixture of ethyl 4-chloro-2-methylthio-5 -pyrimidine carboxylate (20.0 mmol), Et3N (10 ml), and 50% aq NH3. H20 (8 ml) in THF (100 mL) was stirred at room temperature for 4 h. After evaporation of the resulting residue,the mixture was diluted with H20 and extracted with EtOAc. After evaporation, get the crude amino substituted pyrimidine. To this crude amino substituted pyrimidine in THF (100 mL) was added dropwise LiA1H4 (11.0 mmol) in 30 ml Et20 at 0C. After stirring at room temperature for 8 h, H20 (3.0 mL), 2N NaOH (10 mL), and H20 (3.0 mL) were added sequentially. The crude product waspurified by column chromatography to afford intermediate alcohol 1 (73 % yield for steps).
3.5 kg
With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 5h;Large scale;
Scheme 1, Step A: Ammonium hydroxide (8.4 L, 17 wt%, 6.86 mol) is added over 1 hour to a solution of ethyl 4-chioro-2-(nethyithio)pyrimidine-5-carboxyiate (4 Kg, 10.74 mol) in THF (34.4 L) at room temperature. After stirring for 4 hours, water is added and the mixture is extracted with MTBE. The organic phase is washed with brine, dried overNa2SO4, filtered, and concentrated. The crude product is slurried with petroleum ether (3L), filtered, and dried under vacuum to provide the title compound as a white solid (3.5Kg, 89% purity, 95% yield) which is carried on without further purification. MS (mlz):214 (M+H).
Stage #1: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester; ethylamine In acetonitrile
Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃;
Stage #3: With manganese(IV) oxide In dichloromethane
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 72h;Reflux;
DIPEA (20.8 ml, 120 mmol) and allyl hydrazine 5 (8.23 g, 47.8 mmol) were added to a solution of ethyl 4-chloro-2-methylthio- 5-pyrimidinecarboxylate (6; 1 1.1 g, 47.8 mmol) in THF (150 ml). The reaction mixture was heated at reflux for 72 h, before being concentrated in vacuo. Et20 (50 ml) was added to the residue, and the resultant precipitate was collected by filtration. The filtrate was evaporated to dryness, and the residue was cooled in an ice bath, after which TFA (40 ml) was added. The resultant solution was stirred at RT for 1 h, followed by 70 C for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (50 ml) and cooled in an ice bath, after which 6M NaOH (75 ml) was added. The resultant solution was stirred at RT for 15 min, before 32 being acidified via the addition of cone. HCI (40 ml). The orange solution was evaporated to dryness and the resultant residue was partitioned between chloroform (100 ml) and water (100 ml), and the organic phase was washed with brine (50 ml), dried (Mg2S04), concentrated in vacuo, and triturated with hexanes. The solid precipitate was washed with EtOH and Et20, before being dried under vacuum to give the target compound as a yellow solid (5.44 g, 24.5 mmol, 51 %). Rf 0.45 (9:1 DCM:MeOH); M.p. 125- 128 C; IR (cm-1 ) 3032, 2979, 2926, 2659, 1656, 161 5, 1 566, 1 514; 1 H NMR (400 M Hz, DMSO-d6)2.53 (3H, s, -SCH3), 4.38 (2H, dapp, J = 5.2 Hz, N2-CH2), 5.06-5.20 (2H, m, allyl C-Hcis/trans), 5.87 (1 H, ddt, J = 17.2, 10.5, 5.3 Hz, alkene C-H), 8.67 (1 H, s, H-4), 12.65 (1 H, -1 ); MS [M + H] + m/z 223.1.
260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2-(methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70 C. for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid.1H-NMR (400 MHz, DMSO-d6) ?: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13 (1.0H, d, J=9.8 Hz), 5.06 (1.0H, d, J=17.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s).ESI-MS Found: m/z[M+H]+ 223.3.
2) Production of 2-allyl-6-(methylthio)-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one:260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, DMSO-d6) delta: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13(l.OH, d, J=9.8 Hz), 5.06 (1.0H, d, J=I 7.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s). ESI-MS Found: m/z[M+H]+ 223.3.
260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. (0207) The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Heating / reflux;
1) Production of ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate At room temperature, 16.2 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (300 mL) solution of 9.4 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of 2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18 hours. The solvent was concentrated under reduced pressure, water was added to this, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain crude ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate as a yellow oily substance.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 80℃; for 16h;
Diisopropylethylamine (3.58 g, 27.67 mmol) was added into 4-chloro-2-methylthiopyrimidin-5-ethyl carboxylate (2.80 g, 12.03 mmol) and 2-chloro phenyl hydrazine (2.48 g, 13.83 mmol) in 90 mL THF solution, then heated to 80C and stirred for 16 hours. The reaction was monitored to be complete by LCMS. After concentrated under reduced pressure to remove the solvent, water 50 mL was added, and extracted by 20 mL EtOAc for 3 times, the combined EtOAc phase were washed by brine 20 mL, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the compound 39-A. 1H NMR (400MHz, CDCl3) delta = 9.65 (br d, J=3.8 Hz, 1H), 8.71 - 8.65 (m, 1H), 7.30 (dd, J=1.2, 8.0 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.92 (dd, J=1.6, 8.0 Hz, 1H), 6.84 (dt, J=1.6, 8.0 Hz, 1H), 6.78 (d, J=4.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 2.25 (s, 3H), 1.42 (t, J=7.0 Hz, 3H)
3-chloro-4-methoxybenzylamine (45.6 g, 0.27 mol) was dissolved in 180 mL of acetone, then triethylamine (40.4 g, 0.4 mol) was added.4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester obtained in the step S2(53.3 g, 0.24 mol) dissolved in 250 mL of acetone and slowly dropped into the reaction solution.And reacted at room temperature for 3 h, and poured the reaction solution into the ice water mixture.Extracted with ethyl acetate,The combined organic phases were washed with 10% aqueous citric acid (250 mL x 3).Dry the organic layer with anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.Dry in vacuo to a white solid (86.0 g, 87.0%).
76%
With triethylamine; In dichloromethane; at 20℃; for 10.0h;
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2 -(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76 % yield).
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.833333h;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10 % aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g).
With triethylamine; citric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g).
With triethylamine; citric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and the mixture is extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g), m.p. 86 C.
With triethylamine; In tetrahydrofuran;
(1)-a) A mixture of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine 1.0 g, (3-chloro-4-methoxyphenyl)methylamine 0.81 g, triethylamine 0.66 ml and tetrahydrofuran 12 ml is stirred for 4 hours at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; hexane:ethyl acetate=5:1) and concentrated in vacuo to give a colorless oil. The oil is left overnight at room temperature to give 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as crystals, 1.58 g. mp 82-83 C.
With triethylamine; In N,N-dimethyl-formamide;
(1) To a solution of 2-methylthio-4-chloro-5-ethoxy-carbonylpyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for another 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10 % aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is washed with n-hexane to give 2-methylthio-4-(3-chloro-5-methoxybenzylamino)-5-ehoxy-carbonylpyrimidine (38.34 g). M.p. 86 C.
145 g
With tetrabutylammomium bromide; sodium carbonate; In dichloromethane; water; at 25 - 30℃;
To 600ml of methylene dichloride was added lOOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500m1 of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95% of HPLC purity.
42.3 g
With triethylamine; In ethyl acetate; at 0 - 30℃;
After dissolving 50.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 59.9 ml of triethylamine into 430 ml of ethyl acetate, respectively, the mixture was cooled to 0 C, 44.7g of 3-chloro-4-methoxybenzylamine was added in portions, the reaction was carried out at 0-5 C for 30min and the reaction was continued at 20-30 C for 0.5-1h. The reaction was concentrated under reduced pressure, and then added ethyl acetate and citric acid solution 400ml each wash 2 times, the organic phase was washed with water and saturated brine each time, dried, filtered and concentrated under reduced pressure to give the crude 73.0g. Finally, with anhydrous ethanol at 55 ~ 60 C dissolved crude, stirring crystallization 12-18h, filtered and dried to give the product 42.3g.
With triethylamine In acetonitrile at 0 - 20℃; for 4h;
90%
With triethylamine In tetrahydrofuran at 20℃;
2.A
Into an Argonaut Technologies' Quest 205 100 mL reactor was added 8.0 g (34.4 mmol) of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in 70 mL of dry THF. To the reaction mixture was added 1.1 equivalents of triethylamine followed by a solution of 1.1 equivalents of amine (R^NH2) iϖ 10 mL of dry THF. The reaction mixture was agitated overnight under a nitrogen atmosphere at room temperature. The THF solution was drained from the reaction vessel, and the residue was washed with THF. The THF solutions were combined, evaporated, and redissolved in 35 mL of ethyl acetate. The ethyl acetate solution was added back into the reaction vessel containing the residue, followed by 40 mL of 0.5 M NaOH. The reaction was agitated and the aqueous layer removed. The ethyl acetate solution was washed twice with 0.5 M NaOH EPO and once with a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. The residue was stirred with pentane and evaporated to give the desired product.4-Cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester Using procedure A, 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester and 2.16 g (37.8 mmol) of cyclopropylamine were reacted to give 7.80 g (90%) of the title compound as a solid: mp 41°C-42°C. MS (APCI) (m+1)/z 254.0. Analysis calculated for C1 1H15N3SO2: C, 52.16; H, 5.97; N, 16.59. Found: C, 52.26; H,5.82; N, 16.53.
90%
With triethylamine In tetrahydrofuran at 20℃;
2.A 2) Preparation of Esters ; Procedure A; General Procedure for the Parallel Synthesis of 4-Substituted-2-methylsulfanyl-pyrimidine-5-carboxylic Acid Ethyl Esters (2)
Into an Argonaut Technologies' Quest 205 100 mL reactor was added 8.0 g (34.4 mmol) of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in 70 mL of dry THF. To the reaction mixture was added 1.1 equivalents of triethylamine followed by a solution of 1.1 equivalents of amine (R1NH2) in 10 mL of dry THF. The reaction mixture was agitated overnight under a nitrogen atmosphere at room temperature. The THF solution was drained from the reaction vessel, and the residue was washed with THF. The THF solutions were combined, evaporated, and redissolved in 35 mL of ethyl acetate. The ethyl acetate solution was added back into the reaction vessel containing the residue, followed by 40 mL of 0.5 M NaOH. The reaction was agitated and the aqueous layer removed. The ethyl acetate solution was washed twice with 0.5 M NaOH and once with a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. The residue was stirred with pentane and evaporated to give the desired product.; 4-Cyclopropylamino-2-methylsulfanyl-pyrimidine-5-Carboxylic Acid Ethyl Ester; Using procedure A, 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester and 2.16 g (37.8 mmol) of cyclopropylamine were reacted to give 7.80 g (90%) of the title compound as a solid: mp 41° C.-42° C. MS (APCI) (m+1)/z 254.0. Analysis calculated for C11 H15N3SO2: C, 52.16; H, 5.97; N, 16.59. Found: C, 52.26; H, 5.82; N, 16.53.
With triethylamine In dichloromethane at 15 - 42℃; for 2h; Inert atmosphere;
4.4.1 Step 4.1: Conversion of Compound K to Compound D-1
Reactor A was charged with Compound K (37.4 kg), dichloromethane (96.8 kg) and triethylamine (17.1 kg). The mixture was agitated under nitrogen until all solid dissolved (internal temperature 15-30 °C). A solution of cyclopropylamine (9.7 kg) in dichloromethane (13.2 kg) was prepared at room temperature under nitrogen in Reactor B. The solution of cyclopropylamine (9.7 kg) in dichloromethane (13.2 kg) was transferred from Reactor B to Reactor A, resulting in an exothermic reaction. The addition rate was controlled to keep the temperature at 42 °C (addition time 2 h). A rinse solution of dichloromethane (19.8 kg) was added to Reactor B and then from Reactor B to Reactor A. Internal temperature of Reactor A was maintained at 15-25 °C for 2h. Water (64.9 kg) was added to Reactor A, with addition rate controlled by temperature (20-30 °C). The mixture in Reactor A was agitated at 20-30 °C, then the phases were allowed to separate. The layers were separated and the lower (organic) layer was transferred into Reactor C. The reaction mixture in Reactor C was washed with water (64.9 kg x2). Dichloromethane (19.8 kg) was added to Reactor C, The mixture was distilled to remove dichloromethane. The resulting melted (50 °C) Compound D-1 was filtered.
4-(1H-6-Indazolylamino)-2-methylthio-5-pyrimidinecarboxylic Acid Ethyl Ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; In methanol; at 20 - 35℃; for 5h;
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 6-aminoindazole (3.15 g) in methanol (70 ml) was added N,N-diisopropylethylamine (4.2 ml), and then the solution was reacted at 30-35 C. for 4 hr. The reaction mixture was cooled, and then stirred at 20 C. for 1 hr. The reaction mixture was filtered, washed with methanol (20 ml) and dried at 40-50 C. in vacuo to obtain the desired compound (5.8 g, 82%). m.p.: 212-214 C. 1H-NMR (DMSO-d6), ppm: delta 1.33(t, 3H), 2.53(s, 3H), 4.33(m, 2H), 7.10(d, 1H), 7.70(d, 1H), 8.00(s, 1H), 8.22(s, 1H), 8.72(s, 1H), 10.40(s, 1H), 13.09(br s, 1H)
With triethylamine; In 1,4-dioxane; for 1h;Heating / reflux;
A solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (897 mg, 3.86 mmol) (Aldrich) and triethylamine (1.2 ML, 870 mg, 8.49 mmol) (Aldrich) in dioxane (20 ML) was treated with (R)-3-aminotetrahydrofuran p-toluene-sulfonic acid salt (1.0 g, 3.86 mmol) (Fluka).The mixture was stirred at reflux for 1 hour, then cooled and partitioned between brine and ethyl acetate.The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography with a silica gel column using a 0-100% ethyl acetate in hexanes gradient to give (R)-2-methylsulfanyl-4-(tetrahydrofuran-3-ylamino)-pyrimidine-5-carboxylic acid ethyl ester as a colorless viscous oil. (Yield 1.0 g, 92%). HRMS m/z calcd for C12H17N3O3S [M+]: 283.0991. Found: 283.0989.
A1.a
Example Al; a) Preparation of (intermediate 1); TEA (0.159 mol) was added at room temperature to a mixture of 4-chloro-2- (methylthio)-5-pyrimidinecarboxylic acid ethyl ester (0.0534 mol) and 2- cyclohexylhydrazinecarboxylic acid 1,1-dimethylethyl ester (0.1068 mol) in THF (125 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in DCM. The organic layer was washed with saturated NaHCO3, dried (MgSO4), filtered and the solvent was evaporated, yielding 37.2 g (>100%) of intermediate 1.
100%
With triethylamine In tetrahydrofuran at 20℃;
A.1.a
Example Al a) Prepar^on.ofjnteϖnedjate.1;TEA (0.159 mol) was added at room temperature to a mixture of 4-chloro-2- (methylthio)-5-pyrimidinecarboxylic acid ethyl ester (0.0534 mol) and 2- cyclohexylhydrazinecarboxylic acid 1,1-dimethylethyl ester (0.1068 mol) in THF (125 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in DCM. The organic layer was washed with satured NaHCO3, dried (MgSO4), filtered and the solvent was evaporated, yielding 37.2 g (>100%) of intermediate 1.
With triethylamine; In tetrahydrofuran; hexane; ethyl acetate;
EXAMPLE 1 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic Acid Ethyl Ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran is added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide is added, and stirring is continued for 1 hour. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane are added, and the resultant solid is collected by filtration to provide 10.84 g (79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
16.5 g (95%)
With triethylamine; In tetrahydrofuran; dichloromethane; water;
Step 2.1 Preparation of Ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (25.4 g, 106 mmol, Aldrich Chemical Co., Milwaukee, Wis., USA) in 300 mL of tetrahydrofuran was treated with 50 mL of triethylamine and 40 mL of aqueous ammonium hydroxide. After stirring for 4 hours, 300 mL of water was added and the phases were separated. The organic layer was washed with 300 mL of brine, concentrated in vacuo, dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 16.5 g (95%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
10.84 g (79%)
With triethylamine; In tetrahydrofuran; hexane; ethyl acetate;
Example 11 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran was added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide was added, and stirred was continued for 1 hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane were added, and the resultant solid was collected by filtration to provide 10.84 g (79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
10.84 g (79%)
With triethylamine; In tetrahydrofuran; hexane; ethyl acetate;
Example 11 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (15.0 g, 65 mmol) in 200 mL of tetrahydrofuran was added 25 mL of triethylamine followed by 35 mL of aqueous ammonium hydroxide. After stirring at room temperature for 1.5 hours, an additional 30 mL of aqueous ammonium hydroxide was added, and stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Ethyl acetate and hexane were added, and the resultant solid was collected by filtration to provide 10.84 g (79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester.
With triethylamine; methylamine; In tetrahydrofuran;
EXAMPLE 16A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40% aqueous solution of methylamine. The solution was stirred for 30 minutes at 25 C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93 C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
14.70 g (81%)
With triethylamine; methylamine; In tetrahydrofuran;
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40% aqueous solution of methylamine. The solution was stirred for 30 minutes at 25 C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester, mp 91-93 C. Analysis calcd. for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
14.70 g (81%)
With triethylamine; methylamine; In tetrahydrofuran;
EXAMPLE 18A Alternative synthesis of 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40% aqueous solution of methylamine. The solution was stirred for 30 minutes at 25 C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93 C. Analysis calculated for C9 H13 N3 O2 S: C, 47.56; H, 5.76; N, 18.49. Found: C, 47.93; H, 5.67; N, 18.58.
ethyl 4-[3-(ethoxycarbonylmethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.4 g (92%)
With hydrogenchloride; triethylamine; In 1,4-dioxane; ethyl acetate;
c) A mixture of 5 g (21.5 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate and 4 g (22.3 mmol) of <strong>[52273-79-7]ethyl 3-aminophenylacetate</strong> in 80 ml of 1,4-dioxan was treated with 6 ml (43 mmol) of triethylamine and then heated at 60 C. for 4 hours. The mixture was cooled and evaporated. The residue was partitioned between 120 ml of ethyl acetate and 100 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 7.4 g (92%) of ethyl 4-[3-(ethoxycarbonylmethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate as a pale orange colored oil which solidifies slowly to a white solid. [Mass spectrum (ESI) MH+ =376].
A. 4-Chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride A slurry of potassium trimethylsilyl oxide (90% tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford 4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid as a white solid (8.8 g, 47 mmol, 73% yield). MS (-ESI) m/z 185 (M-, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97% yield). 1H NMR (300 MHz, CDCl3) delta 9.15 (s, 1H), 2.63 (s, 3H).
Example 1: Synthesis of tert-butyl 4-['6-r2-methylphenyl)-7-oxo-8-(tetrahydro-2H'- pyran-4-yl)-7,8-dihvdropyridof2,3-cpipyrimidin-2-yl]ammo}piperidine-l-carboxylate (Compound No. 1) Step a: 2-MethylsuIfanyl-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-5- carboxylic acid ethyl ester; To a suspension of ethyl-4-chloro-2-methylthio-5-pyrimidine carboxylate (commercially available) (3.0 g, 12 mmol) in dry tetrahydrofuran (50 mL) was added triethylamine (2.6 g, 25 mmol) and <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (1.94 g, EPO <DP n="44"/>14 mmol) at room temperature and the mixture was stirred for 4 hours. The organic solvent was evaporated under reduced pressure followed by addition of cold water. The residue thus obtained was filtered, washed with water and dried under vacuum to yield the title compound. Yield = 2.7 g.
A mixture of 5 g of ethyl 4-chloro-2-(methyIthio)pyrimidne-5-carboxylate, 250 mL of methanol and 5 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 5 hrs, quenched with 10 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 100 mL of saturated sodium bicarbonate and 200 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1) = 215.1; 1H NMR (400 MHz, CDCB) 8.85 (s, IH), 4.1 (s, 3H), 4.05 (s, 3H), 3.85 (s, 3H).
A. 4-methoxy-2-methylsulfanyl-pyrimidine-5-carbonyl chloride A suspension of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (3 g, 12.9 mmol) in 40 mL methanol and 20 mL 1N NaOH solution was heated at 50° C. for 12 hrs. The reaction mixture was poured onto ice water and acidified with conc. HCl. The white creamy mixture was extracted with EtOAc. The organic fractions were dried (Na2SO4) filtered and the filtrate was concentrated to give a white solid (2 g). The solid was dissolved in 50 mL of CH2Cl2, and cooled under N2 in an ice-water bath. To the reaction was slowly added oxalyl chloride (2 mL, 19 mmol) and a drop of DMF. The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to give the title compound as a brown solid. This material was used in the next step without further purification.
Stage #1: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester; N-methyl-N-(4-methoxyphenyl)amine With hydrogenchloride In water; isopropyl alcohol at 23℃; for 16h;
Stage #2: With water; sodium carbonate In dichloromethane; isopropyl alcohol
3
EXAMPLE 3; Ethyl 4-[(4-methoxyphenyl)(methyl)amino]-2-(methylthio)pyrimidine-5- carboxylate; [00100] A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate 0.466 g (2.0 mmol) and 4-methoxy-N-methylaniline 0.274 g (2.0 mmol) with cone. HCl aq 1 mL in zsø-propanol 10 mL was stirred for 16 h at 23 0C. Dichloromethane 3OmL was added to the reaction mixture, and the organic layer was neutralized with sat. νa2Cθ3 aqueous solution, water and dried over anhydrous MgSO4. After removal of solvent, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 50%) to give the titled compound in 75% yield. 1H NMR (CDCl3, 400 MHz): δ 8.26 (s, IH), 7.07 (d, 2H, J = 9.0 Hz), 6.87 (d, 2H, J = 9.0 Hz), 3.80 (s, 3H), 3.68 (q, 2H, J = 7.1 Hz), 3.53 (s, 3H), 2.57 (s, 3H), 1.07 (t, 3H, J = 7.1 Hz). m/e: 334.1966 (M+l).
Step 1 4-Chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester A mixture of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10.0 g), formic acid (1.65 mL), and hydrogen peroxide (30% aqueous, 19.5 mL) in methylene chloride (80 mL) was stirred at room temperature for 12 hours. The reaction was quenched with cold saturated aqueous Na2SO3 solution, and the mixture was extracted with methylene chloride. The combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (6.6 g).
With diisobutylaluminium hydride; In tetrahydrofuran; at -78℃; for 0.75h;Inert atmosphere;
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 1.0 eq) was dissolved in THF (100 mL) to give a yellow solution. The mixture was cooled in a -78C bath under nitrogen atmosphere. DIBAL-H (1.5 M in THF. 86 mL, 3.0 eq) was added over 45 min. via syringe. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (50 mL). The mixture was then warmed to room temperature. Ethyl acetate (100 mL) and saturated aqueous sodium potassium tartrate (200 mL) were added. The mixture was stirred vigorously for 30 min. After separation of the layers, the aqueous layer was extracted with ether and the combined organics washed with brine, dried with sodium sulfate, filtered and concentrated under vacuum to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a yellow solid (7.2 g, 87.9%). 1H NMR (400 MHz, DMSO-d 6 ) delta 8.63 (s, 1H), 5.56 (t, J = 5.6 Hz, 1H), 4.52 (dd, J = 5.5, 0.6 Hz, 2H), 2.54 (s, 3H). LRMS (ESI) for C 6 H 8 ClN 2 OS [M + H]+, calcd: 191.9. Found: 191.8.
84%
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (67 mmol) was dissolved in THF (900 mL) to give a yellow solution. The mixture was cooled in a -78C bath under nitrogen atmosphere (internal temp. about -70C). DIBAL-H (1 M in THF; 200 mmol) was added over 45 min. via syringe. The reaction was warmed to -60C after the addition, and then allowed to warm slowly to 0C over night. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (200 mL). The mixture was then warmed to room temperature. Ether (400 mL) and saturated aqueous sodium potassium tartrate (200 mL) were added. The mixture was stirred vigorously for 30 min. After separation of the layers, the aqueous layer was extracted with ether and the combined organics washed with brine, dried with sodium sulfate, filtered and concentrated under vacuum to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a solid (84%). LCMS (method B) 6.07 min; mass M+H+ 191; UV 230, 265, 315 nm. (4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol (105 mmol) was dissolved in CHCl3 (500 mL) to give a yellow suspension. Manganese(IV) oxide (546 mmol) was added in 0.5 g portions over 15 min. The mixture was stirred at room temperature for 6 h. Further Manganese(IV) oxide (210 mmol) was added. The mixture was stirred at room temperature for 18 h. Again, manganese(IV) oxide (210 mmol) was added. The mixture was stirred at room temperature for 20 h, then at 40C for 4 h, and then overnight at room temperature. The mixture was then stirred at 40C for 6 h, allowed to cool to room temperature, filtered though Celite, washed with 400 mL CHCl3 and concentrated under reduced pressure to give 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde as a solid (72%). LCMS (method B) 3.72 min; mass M+H+ 193; UV 310 nm.
84%
With diisobutylaluminium hydride; In tetrahydrofuran; at -78 - 0℃;Inert atmosphere;
Example 1 4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (67 mmol) was dissolved in THF (900 mL) to give a yellow solution. The mixture was cooled in a -78 C. bath under nitrogen atmosphere (internal temp. about -70 C.). DIBAL-H (1 M in THF; 200 mmol) was added over 45 min. via syringe. The reaction was warmed to -60 C. after the addition, and then allowed to warm slowly to 0 C. over night. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (200 mL). The mixture was then warmed to room temperature. Ether (400 mL) and saturated aqueous sodium potassium tartrate (200 mL) were added. The mixture was stirred vigorously for 30 min. After separation of the layers, the aqueous layer was extracted with ether and the combined organics washed with brine, dried with sodium sulfate, filtered and concentrated under vacuum to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a solid (84%). LCMS (method B) 6.07 min; mass M+H+ 191; UV 230, 265, 315 nm.
60%
With diisobutylaluminium hydride; In tetrahydrofuran; hexane; at 0℃; for 0.5h;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.32 g, 10 mmol) in THF (60 mL) was added DIBAL-H (1N in hexane, 30 mL) dropwise at 0C, the reaction was stirred at 0C for 30 min, then H20 was added followed by 2N HCl solution (45 mL). The mixture was extracted with EtOAc, the organic layers were washed with brine, dried over Na2S04, concentrated to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a yellow solid, which was used for the next step without further purification. Yield: 60%, MS (m/z): 190.9 (M+1) +.
59%
To ethyl 4-chloro-2- (methylthio)pyrimidine-5-carboxylate (20.0 g, 86 mmol) in dichloromethane (400 mL) at -78 <n="130"/>0C was added diisobutylaluminum hydride, 1.0 M in toluene (172 mL, 172 mmol). The reaction was allowed to warm to 0 0C over 2 h. To the reaction was added a 20% Rochelle's (1600 mL) and diethyl ether (750 mL). The emulsion was stirred for 30 min. The organics were sequestered and the aqueous was extracted further with diethyl ether (2 x 500 mL). The combined organics were washed with water (500 mL), brine (500 mL), dried over MgSO4, and concentrated in vacuo and filtered through a plug of silica eluting with 1:1; ethyl acetate:CH2Cl2 to obtain compound 223 (9.6 g, 59% yield). 1H NMR (500 MHz, CDCl3) delta 8.55 (s, 1 H) 4.75 (d, J=5.87 Hz, 2 H) 2.58 (s, 3 H) 2.06 - 2.25 (m, J=5.14 Hz, 1 H) ppm.
44%
step 1: To ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (370.0 g, 1.59 mol) in DCM (7.4 L) at -78 C. was added diisobutylaluminum hydride (1.5 M in toluene, 2.1 L, 3.18 mol). The reaction mixture was allowed to warm to 0 C. over 2 h. To the reaction was added a 20% Rochelle's salt solution (5.0 L). The emulsion was stirred for 30 min. The mixture was filtered through a bed of CELITE. The organic layer was separated and the aqueous layer extracted with EtOAc (1.0 L×3). The combined organic layers were dried ((Na2SO4)), filtered, and concentrated in vacuo to give the crude product (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a solid. The crude product was purified by SiO2 chromatography eluting with DCM/EtOAc (1:1) to afford the pure product (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (133.0 g, 44.0%) as a solid. 1H NMR (400 MHz, CDCl3) delta 8.55 (s, 1H), 4.74 (s, 2H), 2.58 (s, 3H); MS: 191 [M+H]+.
General Procedure 5-1 : (4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol[00194] To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.7 g, 46 mmol), in dry THF (50 mL), on an ice-bath, DIBAL (185 mL, 1 M in THF, Aldrich Cat. No. 214981, 185 mmol) was added dropwise over 30 minutes (via pressure equalizing dropping funnel) under the nitrogen atomosphere. The resulting yellow transparent solution was stirred for additional 30 minutes before being transferred to a dry 1 L Erlenmeyer flask. On an ice bath, the reaction mixture was then quenched carefully, added dropwise with saturated solution of Na2SO4 to give a yellow warm gel-like solid mixture. To this solid mixture, EtOAc (200 mL) was added, followed by dropwise addition of 6.0 N aqueous HCl to dissolve the solid into an aqueous solution of pH 3-4. The EtOAc layer was collected. The aqueous layer was again <n="57"/>extracted twice with EtOAc (twice, 200 mL each). The combined EtOAc layers were washed with water (twice, 200 mL each time), dried with MgSO4, and concentrated to give an off-white solid which was suspended in 75 mL petroleum ether and refluxed for 10 minutes. The mixture was cooled to the ambient temperature and then filtered to give the title compound (4.67 g, 53%, HPLC: 97% pure). HPLC Rt: 4.72 min.1H-NMR (CDCl3): delta 8.54 (s, IH), 4.74 (d, 2H), 2.57 (s, 3H), 2.10 (t, IH).
With diisobutylaluminium hydride; In tetrahydrofuran; hexane; at 0℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.32 g, 10 mmol) in THF (60 mL) was added DIBAL-H (IN in hexane, 30 mL) dropwise at 0C, the reaction was stirred at 0C for 30 min, then H20 was added followed by 2N HCl solution (45 mL). The mixture was extracted with EtOAc, the organic layers were washed with brine, dried over Na2S04, concentrated to give (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as a yellow solid, which was used for the next step without further purification. Yield: 60%, MS (m/z): 190.9 (M+l) +.
To a solution of the commercially available ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate, i3, (15 g, 64 mmol) in CH2CI2 (250 mL) at 780Cwas added Dibal-H (diisobutylaluminium hydride) (i .0 M in toluene, i 28 mL,i28 mmol) slowly. The reaction mixture was stirred at 000 for 2 h. Thereaction mixture was added Na2SO4.iOH2O (i44 g, 640 mmol) and stirred for30 mm. The organ ics were sequestered and the aqueous was extractedfurther with 0H2012, the organic layer was washed with water, brine, dried withanhydrous Na2SO4, concentrated to give the crude KR-i8 (9.8 g, 80.9%) as ayellow solid which was used directly in the next step. ESI-MS (M+i): i 9i .0calc. for 06H701N20S: i90.0.
With diisobutylaluminium hydride; In 2-methyltetrahydrofuran; at -78 - 0℃; for 4h;
Step 1: Intermediate 2 [00359j Intermediate 2 was prepared according to literature procedures from Intermediate 1(EP21 12150 Al, 2009).
With diisobutylaluminium hydride; In tetrahydrofuran; at 0℃; for 2.5h;
[4-C hlor o-2-(methylthio)pyrimidin-5-yl] methanol. 4-Chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (62 g, 260 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) in a 3-necked 5L round bottomed flask fitted with a mechanical stirrer, addition funnel, temperature probe and nitrogen inlet. The solution was cooled to 0C. Diisobutylaluminum hydride in tetrahydrofuran (1M solution, 800 mL) was added dropwise over a period of 2 hours. After the addition was complete, the reaction mixture was kept at 0C for 0.5 hours. The reaction was quenched at 0C by the slow addition of saturated aqueous sodium sulfate (265.3 mL, 530.7 mmol) keeping the internal reaction temperature below 10C. Ethyl acetate (900 mL) was added and the reaction slowly warmed to room temperature overnight. 6M HC1 was added till the reaction mixture was slightly acidic (pH 6). The reaction mixture was filtered thru a pad of Celite and the aluminum salts were washed with ethyl acetate (1L). The filtrate was poured into a separatory funnel and washed twice with water (600 mL) and finally with brine (600 mL). The organic layer was dried over sodium sulfate, filtered thru Celite and the solvent concentrated in vacuo to afford 39.2g (77% crude yield) of a dark yellow oil. The material was used as is for the next step. NMR (CDCI3) delta 8.56 (s, 1H), 4.76 (s, 2H), 2.59 (s, 3H); MS (ESI+) for C6H7C1N20S m/z 191.0 (M+H)+ .
With diisobutylaluminium hydride; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere;
(3) 50 g of the compound of formula (5) was dissolved in 300 ml of tetrahydrofuran,Nitrogen protection,Add 400ml (1.5mol / L)Diisobutylaluminum hydride,Room temperature stirring,Reaction for 4 hours,Add 300ml saturated ammonium chloride dissolved in quenching,Further, 600 ml of ethyl acetate and 300 ml of potassium tartrate solution were added and stirring was continued for 1.5 hours,Dispensing,Concentrate the organic phase of the compound of formula (6)
4.5 g
With diisobutylaluminium hydride; In toluene; at -78 - 0℃; for 2h;
To a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (20.0 g, 86.20 mmol) in CH2C12 (400 mL) was added 1 M diisobutylaluminium hydride in toluene (172.0 mL, 172.41 mmol) at -78C slowly and the resulting reaction mixture was allowed to stir at 0C for 2 h. The reaction mixture was quenched with 20% aqueous sodium potassiumtartrate solution (800 mL) and then EtOAc (800 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over Na2504, filtered and concentrated under reduced pressure. Crude product was purified with silica gel chromatography using 20% EtOAc / petroleum ether as eluent afforded 4.5 g of (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol as gummyliquid.LC-MS (ES+) [M+1]: 191.0.
To a stirred solution of 5 ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.0 g, 12.893 mmol, 1.0 eq), in 30 MeOH (15 mL) was added 1M solution of 8 NaOH (20 mL) at rt. The resulting mixture was stirred at the same temperature for 3 h. The reaction mixture was concentrated and acidified with 1N HCl solution (10 mL) to adjusted the pH 4-5, the formation of white precipitate was observed which was filtered and dried under vacuum to afford the desired compound 426 4-methoxy-2-(methylthio)pyrimidine-5-carboxylic acid (1.71 g, 66.25%) as white solid. (0498) LCMS: 201.1[M+1]+
With sodium hydroxide; at 20℃; for 3h;
Weigh ethyl 4-chloro-2-methylthio 5-pyrimidinecarboxylate (2 g, 8.6 mmol) into a 100 mL eggplant-shaped flask, and add 30 mL MeOH and 10 mL 2N NaOH solution sequentially.After stirring at room temperature for 3 hours, most of the methanol was evaporated to dryness, the resulting solution was acidified with 2N dilute hydrochloric acid solution to a pH of 4-5, filtered to obtain a pure white solid, and vacuum dried overnight.Without further purification directly to the next step.
With water; sodium hydroxide;
(1) Using ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate as the starting material, the intermediate (I-1) was obtained in methanol and aqueous sodium hydroxide (J.Med.Chem.2009 , 52, 1081-1099).
To a stirred solution of (3-hydroxyphenyl)carbamic acid tert-butyl ester 2 (1.79 g,8.59 mmol) at O 0C was added a suspension of sodium hydride (60% dispersion in mineral oil) (0.34 g, 8.9 mmol) in anhdyrous THF (30 mL). The mixture was stirred at 0 0C for 20 minutes. <n="230"/>The phenoxide solution was then added dropwise at 0 0C to a solution of 4-chloro-(2- methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester 1 (2 g, 8.59 mmol) in THF (20 mL). The reaction mixture was stirred at 0 0C for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (50 mL) and then brine (50 mL). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was washed with CH2Cl2:hexane (1 :9) to afford the title compound 3 as a white solid (2.43 g, 70%).
23
The reduction was carried out on a 2 g scale using LiAlH4 and the desired alcohol was obtained in 98% yield. Oxidation to obtain the aldehyde in 68% yield was performed using freshly prepared IBX. The homologation reaction using carbethoxymethylene-triphenylphosphorane was carried out on a 2 g scale and the reaction complete after reflux for 1 h to obtain the a,b-unsaturated ester in 46% yield. The cyclization reaction was performed with DBU and Hunig's base as a solvent at 120° C. in 18 h, with acid work up and purification by chromatography to yield the cyclized derivative in 30% yield.
With potassium carbonate; In N,N-dimethyl-formamide;Inert atmosphere; Heating;
ethyl 4-chloro-2-methylmercaptopyrimidine-5-carboxylate (5g, 21.5mmol), 4-amino-1-tert-butoxycarbonylpiperidine (4.53g, 22.3mmol), K2CO3 (5.9g, 43mmol) was dissolved in 50 mL anhydrous DMF, under argon, was heated to 80C , stirring overnight. Cooling to room temperature, 200mL of ice water added with stirring, large amount of solid precipitated. Filtered under reduced pressure, and dried in vacuo to give a white oil 7.78g (91%).
86.9%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
General procedure for the synthesis of 5a-5f. To a solution of 3(21 g, 90.3 mmol) and 4e (21.7 g, 108.3 mmol) in DMF (300 mL) wasadded K2CO3 (25 g, 180.9 mmol). The reaction was heated to 60 Covernight. After the mixture was cooled to room temperature, itwas added to ice-water. The precipitate was filtered, and thefiltered cake was washed with cool water and dried in a vacuumoven to afford 5e (31.1 g, 86.9%). 1H NMR (400 MHz, CDCl3), delta 8.63 (s,1H), 8.50 (d, J 7.2 Hz, 1H), 4.31 (q, J 7.2 Hz, 2H), 4.27-4.21 (m,1H), 4.00-3.97 (m, 2H), 3.02 (t, J 11.4 Hz, 2H), 2.51 (s, 3H),2.03-1.99 (m, 2H), 1.54-1.49 (m, 2H), 1.46 (s, 9H), 1.36 (t, J 7.2 Hz,3H). MS (ESI) m/z 397.1 [M+H]+.
86.9%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (300) (21 g,90.3 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (21.7 g, 108.3 mmol) in DMF(300 mL) was added K2C03(25 g, 180.9 mmol). The reaction was heated to 60C overnight.After the mixture was cooled to room temperature, it was added to ice-water. The precipitatewas filtered, and the filtered cake was washed with cool water and dried in a vacuum oven toafford 301 (31.1 g, 86.9 h). 1H NMR (400 MHz, CDCI3) O 8.63 (5, 1H), 8.50 (d, J = 7.2 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.27-4.21 (m, 1H), 4.00-3.97 (m, 2H), 3.02 (t, J = 11.4 Hz, 2H), 2.51 (5, 3H), 2.03-1.99 (m, 2H), 1.54-1.49 (m, 2H), 1.46 (5, 9H), 1.36 (t, J = 7.2 Hz, 3H).
With triethylamine; In tetrahydrofuran; for 2.5h;
The pyrimidine (5.7 g, 24.4 mmol) was dissolved in THF, and the amine (5.9 g, 29.4 mmol) was then added and then treated with Et3N, allowed to stir for 2.5 h, the solids filtered off, and the filtrate concentrated to yield the product with residual THF (11.22 g).
With triethylamine; In tetrahydrofuran; at 0 - 20℃;
To a stirred solution of ethyl 4-chloro-2-methyIthiopyrimidine-5-carboxylate (2.24 g, 9.62 mmol) in 35 mL of anhydrous tetrahydrofuran was added triethylamine (4.00 mL, 2.90 g, 28.72 mmol). The solution was cooled to 0-5 0C and 7-methoxy-l -aminoindane hydrochloride (2.00 g, 10.01 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred 48 h. The precipitate was filtered off, washed with ethyl acetate (1 x 25 mL), and the combined filtrates were evaporated to dryness. The residue was dissolved in dichloromethane (35 mL) washed with saturated sodium bicarbonate solution (1 x 17 mL), dried over magnesium sulfate, filtered and concentrated to give 4-(7-methoxy- 2,3-dihydro-l H-inden-l -ylamino)-2-(methylthio)pyrimidine-5-carboxylate as an oil (3.31 g, 9.21 mmol, 95%). ESMS m/z 360 (M+H)+; 1H NMR (400 MHz, CDCl3) delta ppm 8.63 (s, I H), 8.43 (d, J = 6.5 Hz, I H), 7.21 - 7.26 (m, I H), 6.88 (d, J= 7.5 Hz, I H), 6.72 (d, J= 8.3 Hz, I H), 5.69 - 5.78 (m, IH), 4.26 (q, J= 7.2 Hz, 2H), 3.78 (s, 3H), 3.01 - 3.13 (m, I H), 2.82 - 2.94 (m, I H), 2.59 - 2.67 (m, I H), 2.56 (s, 3H), 2.04 - 2.14 (m, IH), 1.33 (t, J= 7.2 Hz, 3H).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 6h;
268.2
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (550 mg, 2.36 mmol) and 1-phenylcyclopropanamine (420 mg, 3.16 mmol) in CH3CN (6 mL) at room temperature was added DIEA (0.5 mL, 2.60 mmol). The mixture was stirred at room temperature for 3 h and 50 0C for 3 h. The mixture was diluted with EtOAc, washed with IN HCl, Sat. NaHCO3, brine, dried and concentrated to give ethyl 2-(methylthio)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxylate (810 mg).
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol) was suspended in dry THF (50 ml), and zinc powder (8.43 g, 129 mmol) was carefully added. The suspension was heated to reflux in a previously heated bath, and then acetic acid (2.460 ml, 43.0 mmol) was added drop wise. The mixture was reacted at the same temperature overnight. The suspension was filtered through a celite pad washing with DCM and MeOH; the filtrate was evaporated and the residue was triturated with DCM:Et2O=1:1. The precipitate was discarded and the solution evaporated and purified by flash chromatography on silica gel column (petroleum ether:ethyl acetate=9:1). After solvent evaporation, the residue was treated with diethyl ether and the precipitate was filtered off. The filtrate was evaporated to dryness affording a mixture of ethyl 2-(methylthio)pyrimidine-5-carboxylate and ethyl 2,4-bis(methylthio)pyrimidine-5-carboxylate (about 1:1 ratio) as a colorless oil (3.47 g, MS/ESI+ 199.1 [MH]+; MS/ESI+ 245.0 [MH]+) A mixture of ethyl 2-(methylthio)pyrimidine-5-carboxylate and ethyl 2,4-bis(methylthio)pyrimidine-5-carboxylate (about 1:1 ratio; 3.47 g) was dissolved in DCM (78 ml), and m-CPBA (77percent w/w; 10.54 g, 47.0 mmol) was added portion wise stirring at room temperature. The reaction was stirred at the same temperature overnight. The obtained suspension was filtered washing with DCM and the filtrate was evaporated. The crude was dissolved in ethyl acetate (250 ml) and washed twice with a sat. NaHCO3 (100 ml×2); the organic phase was dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel column (DCM:iPr2O=3:7) affording ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate as an off-white solid (2.154 g, 9.31 mmol, 21.7percent yield over two steps, MS/ESI+ 231.0 [MH]+). This intermediate proved to be instable on air and it must be kept under vacuum
With triethylamine In acetonitrile for 16h; Reflux;
5
Preparation 5Ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5- carboxylate [00134]A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.00 g, 43.0 mmol), ethyl 3-(methylamino)propanoate (7.00 g, 53.4 mmol) and TEA (8.00 mL, 57.3 mmol) in ACN (120 mL) is refluxed for 16 h, cooled down to room temperature and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 4: 1 ) to give the title compound (14.55 g, 99%) as a yellow thick oil.
43%
In tetrahydrofuran at 50℃; for 1h; Inert atmosphere;
1.1 Step 1: Ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5-carboxylate:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (426 mg, 1.833 mmol)[commercially available] was added to a stirred solution of ethyl 3-(methylamino)propanoate (240 mg, 1.83 mmol) [prepared according to the literature procedure: J. Org. Chem., 1985, 50, p3979-3982; J. Med. Chem., 2005, 48,p4100-4110] in THF (5.0 mL) at RT under nitrogen. The temperature was increased to 50 °C. After 1 h, the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (256 mg, 43%) as a colourless oil. LCMS (Method A) : RT = 1.37 mi m/z =328 [M+H].
With N-ethyl-N,N-diisopropylamine; In ethanol; at 60℃; for 15h;
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate (1.4 g, 6.0 mmol), (lS,2S)-2-aminocyclopentanol hydrochloride (0.7 g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 mL) was heated at 60 C for 15 h. After being cooled to room temperature, the reaction solution was concentrated and the residue was purified on silica gel column (eluting with 0-10% ethyl acetate in petroleum ether) to give ethyl 4-((lS,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 4.37 mmol, yield 73%) as a white solid. MS (ESI): m/z 298.5 [M+l]+.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 60℃; for 2h;
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (lS,3R)-<strong>[1110772-04-7]3-aminocyclohexanol</strong> (2.276 g, 19.76 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) were dissolved in ethanol (75 mL) before adding DIEA (4.93 ml, 28.2 mmol) and heating to 60 C. After 2 hrs, LCMS showed the desired product mass was the dominant peak formed. The reaction was removed from heat and concentrated. The crude material was purified on a 340G SNAP Biotage column (20-100% ethyl acetate in hexane) to give ethyl 4-((lR,3S)-3-hydroxy- cyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (5 g, 16.06 mmol, 85 % yield) as a white foam; MS (ESI) m/z 312.1 [M+l]+
With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃;
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5 -carboxylate(200 g, 0.86 mol), bicyclo[l . l .l]pentan-l -amine hydrochloride (171 g, 1.11 mol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (278 g, 2.15 mol) in ethanol (2.4 L) was stirred overnight at room temperature. After completion of the reaction, the solvents were concentrated under reduced pressure to give the crude product, which was diluted with water (1 L). The aqueous layer was extracted with chloroform (2 x 1 L) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents afforded the desired compound (231 g, 0.83 mol, 96% yield) as a pale brown oil which was contaminated with trace amounts of DIEA. This product was used in the next reaction without further purification; 1H NMR (400 MHz, CDCls) delta ppm 8.61 (s, 2H), 4.30 (q, J= 7.2 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 1H), 2.20 (s, 6H), 1.35 (t, J= 7.2 Hz, 3H).
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.5 g, 10.74 mmol) and sodium methoxide (2.50 mL, 13.11 mmol) in methanol (107 mL) was stirred at room temperature under nitrogen for 4 h, quenched with acetic acid (5 mL), and concentrated. The oily residue was purified by flash chromatography on silica gel using 0-40% ethyl acetate in hexanes to give methyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate as a white solid (0.52 g, 23%) and ethyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate as a colorless oil (0.61 g, 25%). Methyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate: 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.83 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 2.60 (s, 3H). LCMS: R.T.=0.92; [M+H]+=229.1. Ethyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate: 1H NMR (400 MHz, CHLOROFORM-d) delta 8.82 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 2.60 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LCMS: R.T.=0.92; [M+H]+=229.1.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃;
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.00 g, 21.5 mmol) was dissolved in 50 mL DMF. To it were added 3-(2H-l,2,3-triazol-2-yl)aniline (4.13 g, 25.8 mmol) and DIEA (7.50 mL, 43.0 mmol). The mixture was stirred at 40C for overnight. To it was poured 300 mL water. Solid ethyl 4-(3-(2H-l,2,3-triazol-2-yl)phenylamino)-2- (methylthio)pyrimidine-5-carboxylate crashed out. It was collected by filtration, washed with water. The solid was then dissolved in 100 mL dioxane. To it was added LiOH hydrate (2.80 g, 64.5 mmol) and 50 mL water. The mixture was stirred for overnight. To the mixture was added HCl to adjust the pH to 2. Solid carboxylic acid crashed out. It was isolated by filtration, washed with water and dried in vacuum oven. This solid was dissolved in 100 mL DMF. To it were added EDC.HC1 (5.76 g, 30 mmol) and HOBt.H20 (4.60 g, 30 mmol). The mixture was stirred for 2.5 h. To it was added ammonium hydroxide solution (28%, 9.1 mL, 100 mmol). The mixture was stirred for 2 h. To it was poured 300 mL water. Solid 4-(3-(2H- 1,2,3 -triazol-2- yl)phenylamino)-2-(methylthio)pyrimidine-5-carboxamide crashed out. It was collected by filtration, washed with water and dried in vacuum oven (5.77 g). 4-(3-(2H-l ,2,3-Triazol-2-yl)phenylamino)-2-(methylthio)pyrimidine-5-carboxamide (50 mg, 0.15 mmol) was dissolved in 3 mL NMP. To it was added MCPBA (65%, 48 mg, 0.18 mmol). The mixture was stirred for 1.5 h. To it were added DIEA (78 , 0.45 mmol) and tert-butyl (lR,2S)-2-aminocyclohexylcarbamate (64 mg, 0.30 mmol). The mixture was stirred at 90C for 2 h. It was diluted with 100 mL EtOAc, washed with IN NaOH and brine, dried, concentrated in vacuo. The residue was treated with neat TFA at RT for 2 h. It was concentrated and subjected to reverse phase preaparative HPLC to isolate the title compound. MS found for C19H23N90 as (M+H)+ 394.4. UV: lambda=249 nm.
With triethylamine; In ethanol; at 20 - 40℃; for 7h;Inert atmosphere; Large scale;
Reactor A was charged with solid ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.00kg). Reactor A was then charged with absolute ethanol (5.OOL, 4.0kg). Reactor A was then charged with triethylamine (0.62L, 0.45kg). The content of Reactor A was then cooled to about 20 C. Reactor A was then charged 3-amino-N-phenyl-triazole (0.70kg). The reaction mixture was slowly heated to 30-40 C over about 1 hour to give an off white suspension. The contents of Reactor A was stirred between 30-40 C for about 6 hours. 8) Sample solution for ion pair chromatography for less than 1% (area) by HPLC of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate. If the sample result complies with criterion proceed to the next step, otherwise agitate for an additional 2 hours between 30-40C and sample again. The reaction mixture generally turns into almost unmixable slurry toward the end of the reaction. The contents of Reactor A was cooled to about 20 C. Tap water (8.OOL, 8.00kg) was charged into Reactor B and the temperature of the contents of Reactor B was adjusted to about 15 C. The contents of Reactor B was charged into Reactor A, while maintaining the temperature at about 15C in Reactor A. The contents of Reactor A was stirred for about 30 minutes at about 15C. The contents of Reactor A was filtered using a filter cloth of about 8im or smaller to accommodate the particle size, or an oyster-style filter with a 3 - 5 im polypropylene filter cloth. Reactor B was charged with tap water (10.OOL, 10.00kg) and half the contents of Reactor B was charged to the filter to wash the solids. The remaining contents of Reactor B was charged to the filter to wash the solids. Reactor B was charged with methyl tert-butyl ether (3.OOL, 2.22kg). The contents of Reactor B was then charged to the filter to wash the solids. The contents of the filter was dried under vacuum such as in a vacuum tray dryer at about 55 C for about 12 hours, until the water (by Karl Fischer) is < 1 % w/w.The title compound was prepared according to Process Example 1 starting with 25.0 kg of ethyl 4-chloro-2-methylthio-5-pyrimidine, 11.25 kg triethylamine, 100 kg absolute ethanol and 17.5 kg 3-amino-N-phenyl-triazole. A 90.4% yield of the title compound was obtained.
Stage #1: 3-chloro-4-methoxybenzyl alcohol With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice;
Stage #2: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester In N,N-dimethyl-formamide for 3h;
1.1 (1) Preparation of ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine -5-carboxylate
(1) Preparation of ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine -5-carboxylate 3-Chloro-4-methoxybenzyl alcohol (20g, 116mmol) was dissolved in 200mL of DMF, NaH (7.0 g, 174 mmol) was added under ice-water-bath. After 1 h of reaction, ethyl 4-chloro-2-(methylmercapto)pyrimidine-5-carboxylate (27g, 116mmol) was added in portions for continuing the reaction for 3h. 300mL of water was added, extraction was performed with ethyl acetate, the organic layer was dried, concentrated and separated with silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain ethyl 4-(3-chloro-4-methoxybenzyloxy) -2-(methylmercapto)pyrimidine-5-carboxylate as white solid (5.0g, 12%).
12%
Stage #1: 3-chloro-4-methoxybenzyl alcohol With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1h; Cooling with ice;
Stage #2: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester In N,N-dimethyl-formamide; mineral oil for 3h;
1.1 (1) Preparation of ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate
(1) Preparation of ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate 3-Chloro-4-methoxybenzyl alcohol (20 g, 116 mmol) was dissolved in 200 mL of DMF, NaH (7.0 g, 174 mmol) was added under ice-water-bath. After 1 h of reaction, ethyl 4-chloro-2-(methylmercapto)pyrimidine-5-carboxylate (27 g, 116 mmol) was added in portions for continuing the reaction for 3 h. 300 mL of water was added, extraction was performed with ethyl acetate, the organic layer was dried, concentrated and separated with silica gel column (petroleum ether: ethyl acetate=10:1) to obtain ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate as white solid (5.0 g, 12%).
Multi-step reaction with 2 steps
1: triethylamine / tetrahydrofuran / 20 °C
2: sodium hydroxide / water; ethanol / 20 °C
Multi-step reaction with 2 steps
1: triethylamine / tetrahydrofuran / 20 °C
2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C
Multi-step reaction with 2 steps
1.1: triethylamine / tetrahydrofuran / 0.25 h / 20 °C / Cooling with ice
1.2: 20 °C
2.1: sodium hydroxide; water / tetrahydrofuran; methanol / 10 h / 60 °C
Multi-step reaction with 2 steps
1: triethylamine / dichloromethane / 10 h / 20 °C
2: sodium hydroxide; water / tetrahydrofuran; methanol / 10 h / 60 °C
Multi-step reaction with 2 steps
1: tetrabutylammomium bromide; sodium carbonate / dichloromethane; water / 25 - 30 °C
2: water; sodium hydroxide / methanol / Reflux
Multi-step reaction with 2 steps
1: triethylamine / ethyl acetate / 0 - 30 °C
2: sodium hydroxide / ethanol / 20 - 55 °C
Multi-step reaction with 2 steps
1.1: triethylamine / N,N-dimethyl-formamide / 4 h / 20 °C / Cooling with ice
2.1: tetrahydrofuran / 0.25 h / 20 °C
2.2: 20 °C
Multi-step reaction with 2 steps
1: triethylamine / acetone / 3 h / 20 °C
2: methanol; sodium hydroxide / 4.5 h / 20 - 30 °C
In a flask, tetrahydrofuran (4.5 L) was added, <strong>[41965-95-1]3-chloro-4-methoxybenzylamine hydrochloride</strong> (500 g, 2.4 mol) was added under stirring, triethylamine (836 mL, 6.01 mol) was added dropwise, the mixture was stirred at room temperature for 30 min, cooled with ice-water, then ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (466 g, 2.0 mol) was added, the reaction was stirred overnight at room temperature. TLC was used to monitor the reaction. After the end of reaction, solvent was removed by evaporation under reduced pressure. Ethyl acetate (2.5 L) and water (1 L) were added, the mixed liquid phases were separated, the organic phase was sequentially washed with diluted hydrochloric acid, water (1 L), saturated sodium bicarbonate (1 L) and saturated sodium chloride (1 L), dried over anhydrous sodium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to obtain an oily substance, to which was added methanol (3 L), and a large white solid was precipitated. After stirring for 30 min, filtration was carried out, and the filter cake was vacuum dried to obtain the product (650 g, yield of 88.3%).
78%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Cooling with ice;
Compound 13 (5 g, 21.86 mmole) and compound 18 (5.34 g, 25.4 mmol) were added to 75 ml of dry DMF 1 and dissolved with stirring. After stirring for 10 minutes, the reaction system was placed in an ice-water mixture. Triethylamine (21.4 g, 0.217 mole) was slowly added dropwise to the reaction flask and slowly warmed to room temperature. After 4 hours, TLC showed the reaction was completed. Dichloromethane was added, washed with water five times, dried and filtered, concentrated by rotary evaporation and passed through a column (PE: EA = 25: 1). Compound 19 (7.3 g, yield 78%) was obtained as a white powder.
74.2%
In THF (150 mL) was suspended <strong>[41965-95-1]<strong>[41965-95-1]3-chloro-4-methoxybenzylamine hydrochloride</strong> salt</strong> (16.0 g, 76.9 mmol). The suspension was cooled in an ice bath, and triethylamine (19.4 g, 192.3 mmol) was added dropwisely. The reaction mixture was stirred at ambient temperature for 15 min, then was added ethyl 4-chloro-2-thiomethyl-5-pyrimidine carboxylate (14.9 g, 64.1 mmol). The reaction mixture was stirred at ambient temperature overnight. TLC was used to monitor the reaction. After the completion of the reaction, the solvent was removed by rotary evaporation. Acetic ether (500 mL) and water (200 mL) were added. The organic phase was separated, washed with hydrochloric acid (1N), saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The solvent was removed by rotary evaporation to give oil. Methanol (100 mL) was added to precipitate a large amount of white solid. The mixture was filtrated and the solid was dried in vacuum to give ethyl 4-((3-chloro-4-methoxybenzyl)amine)-2-thiomethyl-5-pyrimidine carboxylate (21 g, 74.2 % yield).
90 g
With sodium carbonate; In water; at 25 - 30℃; for 4h;
(3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75C and stirred until complete dissolution. The reaction mixture was cooled to 10-15C and stirred for 3 hours. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.Yield: 90 gms; Melting range: 81 -84C; Purity by HPLC: 95.3%.
(3-chloro-4-methoxyphenyl)methanamine malate[ No CAS ]
[ 330785-81-4 ]
Yield
Reaction Conditions
Operation in experiment
102 g
With tetrabutylammomium bromide; sodium carbonate; In water; at 25 - 30℃; for 8.0h;
(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30C. The reaction mixture was heated to 40-45C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. The reaction mixture was heated to 65-70C and stirred 15 minutes. The reaction mixture was cooled to 10-15C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65C and stirred for 30 minutes. Cooled the reaction mixture to 25-30C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound.Yield: 102 gms; Melting range: 80-84C; Purity by HPLC: 99.25%
Stage #1: 2'-chloro-benzeneacetic acid With tert-butylmagnesium chloride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 0.5h; Inert atmosphere;
Stage #2: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester In tetrahydrofuran; diethyl ether at 20℃; for 16h; Inert atmosphere;
29.1; 33.1 Step 1: 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-(2- chlorophenyl)ethanone:
To a solution of 2-(2-chlorophenyl)acetic acid (10 g, 58.6 mmol) in THF (120 mL) under nitrogen, was added tert-butylmagnesium chloride 2M in ether (73.3 mL, 147 mmol) at 0°C. Theresulting solution was warmed to room temperature and a white precipitate crashed out of solution. Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (12.3 g, 52.8 mmol) in THF (50 mL) was added giving a clear yellow solution and then after 10 minutes a yellow precipitatecrashed out. The reaction mixture was left stirring at room temperature for 16 hours. 2M HC1 (200 mL) was added and the product extracted with EtOAc. The combined organic layers were dried over Na2504, and then concentrated in vacuo. The residue was purified by flashchromatography on silica (0-100% DCM in cyclohexane) to afford the title compound as a yellow solid (13.2 g, 72%) . ‘H NMR (500 MHz, DMSO-d6) : ö 9.15 (s, 1H), 7.49-7.45 (m, 1H), 7.44-7.38 (m, 1H), 7.39-7.33 (m, 2H), 4.55 (s, 2H), 2.61 (s, 3H) . LCMS (Method A): = 1.45 mi m/z =313-315 [M+H].
ethyl-4-(((1r,4r)-4-(tert-butoxycarbonylamino)cyclohexyl)methylamino)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With triethylamine; In tetrahydrofuran; water; at 20℃;Inert atmosphere;
step 1: To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.00 g, 13.0 mmol) in dry THF (60 ml) under N2 was added TEA (1.32 g, 13.04 mmol) and tert-butyl (1r,4r)-4-(aminomethyl)cyclohexylcarbamate (3.56 g, 15.65 mmol) at RT. The solution was stirred at RT overnight. Water (40 mL) was added and the solution was extracted with DCM (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to afford ethyl 4-(((1r,4r)-4-(tert-butoxycarbonylamino)cyclohexyl)methylamino)-2-(methylthio)pyrimidine-5-carboxylate (2.1 g, 38%) as a white solid. LCMS (ESI): m/z=424.1 [M+1]+.
ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With triethylamine; In dichloromethane; at 20℃; for 0.5h;
In DCM (50 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5 -carboxylate (1.5 g, 6.46 mmol), <strong>[123652-95-9]3-fluoro-4-methoxybenzylamine</strong> (1.0 g, 6.45 mmol) and triethylamine (1.3 g, 12.9 mmol). The reaction mixture was stirred at ambient temperature for 30 min, and washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine -5-carboxylate as a yellow oil (2.2 g, yield: 97 %).
ethyl 4-(4-methoxy-3-methylbenzylamino)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine; In dichloromethane; at 20℃; for 0.5h;
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.46 mmol), 3-methyl-4-methoxy benzylamine (0.72 g, 4.7 mmol) and triethylamine (1.3 g, 12.9 mmol) were dissolved in dichloromethane (50 mL), the reaction was stirred at room temperature for 30 min. The reaction liquid was washed with water, the organic layer was dried over anhydrous sodium sulfate, concentrated to obtain the title compound (2.1 g, yield of 92%) in yellow oil.
9-methyl-2-(methylthio)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium <i>tert</i>-butylate In tetrahydrofuran; water at 20℃; for 24.1667h;
INT 10. 9-Methyl-2-(methylthio)-67,8,9-tetrahydro-5H^yrimido[4,5-e][1 ,4]diazepin- 5-one
A solution of potassium tert-butoxyde (1 .0 g, 8.42 mmol) in THF (with 0.2% content in water, 25 mL) was stirred under air at rt for 10 min. Then, a solution of ethyl 4-chloro-2- (methylthio)pyrimidine-5-carboxylate (1 .0 g, 4.21 mmol) and N 1-methylethane-1 ,2- diamine (329 mg, 4.21 mmol) in THF (with 0.2% water content, 18 mL) was added dropwise and the mixture was stirred at rt for 24 h. Additional amounts of potassium tert- butoxyde were added after 4 h (4.21 mmol) and 16 h (6.31 mmol) to complete the reaction. The reaction mixture was concentrated under vacuum, DCM was added and the solution was washed successively with water, NH4CI sat solution and brine. The organic phase was concentrated under vacuum to afford the titled product as white solid (388 mg, 41 % yield). ESI+-HRMS m/z, 225.0813 (M+H).
41%
With potassium <i>tert</i>-butylate In tetrahydrofuran; water at 20℃;
ethyl 4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h;
Intermediate 5: 4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde
A suspension of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (CASNo.5909-24-0, 16 g, 68.7 mmol), cycloheptylamine (9.34 g, 82.5 mmol) and DIPEA (17.8 g, 138 mmol) in THF (150 mL) was stirred at room temperature for 18 h. Solvents were evaporated, the residue dissolved in water (150 mL), and the solution extracted with EtOAc (150 mL*2). The combined organics were washed with sat. aq NaCl (150 mL*2), dried over sodium sulfate, and concentrated to give ethyl 4-(cycloheptylamino)-2-(methylsulfanyl)pyrimidine-5-carboxylate (5a, 21 g, 99%) as yellow oil. MS: 310 [M+H]+.
99%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h;
90%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
2.1 Step 1: Preparation of ethyl 4-(cycloheptylamino)-2-(methylthio)pyrimidine-5-carboxylate
Add cycloheptyl amine (1.1 eq) and triethylamine (1.5 eq) to ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1 eq) dissolved in DMF and stirred at room temperature for 4 hours . When the reaction was completed, water was added, and the resulting pale white solid was filtered and dried to obtain the desired ethyl 4-(cycloheptylamino)-2-(methylthio)pyrimidine-5-carboxylate (90%).
(3-Nitrophenyl)methanamine (6.1 g, 40.lmmol) was dissolved in THF. Ethyl 4-chloro- 2-(methylthio)pyrimidine-5-carboxylate (314) (7.8 g, 33.5 mmol) and Et3N (14 mL) were added to the solution. The reaction mixture was stirred at room temperature overnight. After removal of the THF, the residue was dissolved in ethyl acetate. The mixture was washed withsaturated aqueous NaHCO3 to remove <strong>[7409-18-9](3-nitrophenyl)methanamine</strong>. The organic layer was separated, washed with brine and concentrated in vacuo to give compound 315 (10.8 g, 93h). MS (ESI) m/z 349 [M + H].
ethyl 4-(2-(tert-butoxycarbonyl)-2-ethylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.03%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 16h;
Step-3: Synthesis of ethyl 4-(2-(tert-butoxycarbonyl)-2-ethylhydrazinyl)-2-(methylthio) pyrimidine-5-carboxylate To a stirred solution of ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (2.0 g, 8.595 mmol, 1.0 eq) and <strong>[955370-01-1]tert-butyl 1-ethylhydrazine-1-carboxylate</strong> (2.06 g, 12.893 mmol, 1.5 eq) in (50 mL) of THF was added DIPEA (3.73 mL, 21.487 mmol, 2.5 eq) and stirred at 60 C. for 16 h. Solvent was removed under reduced pressure. Residue was diluted with water (50 mL) and extracted with EtOAc (50 mL*2). Organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the desired compound, ethyl 4-(2-(tert-butoxycarbonyl)-2-ethylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate (2.91 g, 95.03%) as light yellow liquid.
With water; sodium hydroxide; In ethanol; at 110.0℃; for 2h;
To a stirred solution of 5 ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (10 g, 43.1 mmol, 1.0 eq) in 150 mL of 6 ethanol: 7 water (2:1) was added 8 NaOH (17.2 g, 431 mmol, 10 eq). Reaction was heated at 110 C. for 2 h. Progress of reaction was monitored by LCMS. Upon the consumption of starting material, solvent was removed under reduced pressure. Residue was diluted with 100 mL of water and pH of mixture was adjusted up to 5 with 3N HCl solution. Precipitated compound was filtered off, washed with water (50 mL) and dried under vacuum to obtain the desired 9 product, 10 4-hydroxy-2-methyl sulfanyl-pyrimidine-5-carboxylic acid (6.0 g, 75%). (0219) LCMS: 187 [M+1]+
ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.38%
Step-1: Synthesis of ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate To a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.66 g, 10.3 mmol, 1.2 eq) in EtOH (50 mL) was added DIPEA (4.48 g, 34.3 mmol, 4 eq) at RT. The resulting reaction mixture was stirred at RT for 30 min, followed by addition of 1 (2 g, 8.621 mmol, 1 eq) at RT. The resulting reaction mixture was stirred at RT for 3 h. The progress of reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (100 mL), extracted with EtOAc (2*200 mL). The combined organic layers were washed with water (100 mL), with brine (100 mL), dried over Na2SO4, concentrated under reduced pressure to afford ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate (2.19 g, 89.38percent) as off white solid.
ethyl 4-[2-(ethylsulfamoyl)anilino]-2-(methylsulfanyl)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester; 2-amino-N-ethylbenzene-1-sulfonamide With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 20h;
Stage #2: In 1-methyl-pyrrolidin-2-one at 130℃; for 6h;
5.1.27. Ethyl 4-[2-(ethylsulfamoyl)anilino]-2-(methylsulfanyl)pyrimidine-5-carboxylate (27)
To a solution of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (25, 4.65 g, 20 mmol) in toluene (58 mL) were addedDIPEA (3.77 mL, 22 mmol) and 2-amino-N-ethylbenzene-1-sulfonamide(26, 4.01 g, 20 mmol). After stirring at 110 °C for 20 h, the solvent wasreplaced with NMP. After stirring at 130 °C for 6 h, the mixture waspoured into H2O. The resulting precipitate was filtered, washed withEt2O and dried to give the product (5.61 g, 71%) as a colorless solid. 1HNMR (CDCl3): δ 1.02 (3H, t, J = 7.2 Hz), 1.41 (3H, t, J = 7.1 Hz), 2.46(3H, s), 2.94-3.08 (2H, m), 4.44 (2H, q, J = 7.0 Hz), 4.89 (1H, br s),7.23-7.32 (1H, m), 7.54-7.60 (1H, m), 8.03 (1H, d, J = 7.8 Hz), 8.24(1H, d, J = 8.4 Hz), 8.84 (1H, s), 10.67 (1H, s); MS (ESI) m/z [M+H]+397.
ethyl 4-((4-(benzyloxy)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With N-ethyl-N,N-diisopropylamine In dimethylsulfoxide-d6 at 20 - 80℃; for 2h;
A Step A: ethyl 4-((4-(benzyloxy)phenyl)amino)-2-(methylthio)pyrimidine-5- carboxylate
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.0 g, 4.3 mmol, 1.0 eq.) in DMSO (10 mL) was added 4-(benzyloxy)aniline (950 mg, 4.7 mmol, 1.1 eq.) and DIPEA (1.6 g, 12.9 mmol, 3.0 eq.) at room temperature. The reaction mixture was stirred at 80 °C for 2 hrs. Then the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give ethyl 4-((4- (benzyloxy)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (1.6 g, 95% yield) as a white solid. LC-MS (ESI): m/z 396 [M+H]+.
ethyl 4-((3-ethoxypropyl)amino)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In 1,4-dioxane at 20℃; for 16h;
S110.1 Step-1: Synthesis of ethyl 4-((3-ethoxypropyl)amino)-2-(methylthio)pyrimidine- 5-carboxylate
To a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3000 mg, 12.9 mmol, 1 equiv) in 1,4-Dioxane (30 mL), was added Et3N (3.6 mL, 25.79 mmol, 2.0 equiv) and 3-ethoxypropan-1-amine (1600 mg, 15.47 mmol, 1.2 equiv) at RT. The resultant reaction mixture was allowed to stir for overnight at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted wit ethyl acetate (150 mL × 2). Organic layer was washed with water (100 mL), brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain title compound.
ethyl 4-[2-(1H-indol-2-carbonyl)hydrazinyl]-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
General procedure for the synthesis of ethyl 4-(2-hydrazido)-2- (methylthio)pyrimidine-5-carbocarboxylate derivatives (77-91).
General procedure: To 10.0 g (42 mmol) of dried 60 were added 30 mL of phosphoryl oxychloride dropwise at 0 °C. After the addition was completed, the mixture was refluxed for 5 h. The excess of phosphoryl oxychloride was then removed under reduced pressure and ice and cold water were added to the solid residue (150 mL). The mixture was extracted with diethylether (3x50 mL), dried over sodium sulfate anhydrous and the solvent was removed by evaporation under reduced pressure to give the 4-chloro-2-methylthio-5- carbethoxypyrimidine (61), which was readily used in the next step without purification. The chloropyrimidine obtained (61) and 74 mmol of the required hydrazide (62-76) were dissolved in 60 mL THF, while 74 mmol of DBU were added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was then removed, the residue was dissolved in dichloromethane (300 mL) and the resulting solution was washed with water (3x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography.
ethyl 4-(2-(4-(benzyloxy)benzoyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
General procedure for the synthesis of ethyl 4-(2-hydrazido)-2- (methylthio)pyrimidine-5-carbocarboxylate derivatives (77-91).
General procedure: To 10.0 g (42 mmol) of dried 60 were added 30 mL of phosphoryl oxychloride dropwise at 0 °C. After the addition was completed, the mixture was refluxed for 5 h. The excess of phosphoryl oxychloride was then removed under reduced pressure and ice and cold water were added to the solid residue (150 mL). The mixture was extracted with diethylether (3x50 mL), dried over sodium sulfate anhydrous and the solvent was removed by evaporation under reduced pressure to give the 4-chloro-2-methylthio-5- carbethoxypyrimidine (61), which was readily used in the next step without purification. The chloropyrimidine obtained (61) and 74 mmol of the required hydrazide (62-76) were dissolved in 60 mL THF, while 74 mmol of DBU were added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was then removed, the residue was dissolved in dichloromethane (300 mL) and the resulting solution was washed with water (3x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography.
ethyl 4-(2-(3-methoxybenzoyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
General procedure for the synthesis of ethyl 4-(2-hydrazido)-2- (methylthio)pyrimidine-5-carbocarboxylate derivatives (77-91).
General procedure: To 10.0 g (42 mmol) of dried 60 were added 30 mL of phosphoryl oxychloride dropwise at 0 °C. After the addition was completed, the mixture was refluxed for 5 h. The excess of phosphoryl oxychloride was then removed under reduced pressure and ice and cold water were added to the solid residue (150 mL). The mixture was extracted with diethylether (3x50 mL), dried over sodium sulfate anhydrous and the solvent was removed by evaporation under reduced pressure to give the 4-chloro-2-methylthio-5- carbethoxypyrimidine (61), which was readily used in the next step without purification. The chloropyrimidine obtained (61) and 74 mmol of the required hydrazide (62-76) were dissolved in 60 mL THF, while 74 mmol of DBU were added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was then removed, the residue was dissolved in dichloromethane (300 mL) and the resulting solution was washed with water (3x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography.
ethyl 4-(2-(3-fluorobenzoyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
General procedure for the synthesis of ethyl 4-(2-hydrazido)-2- (methylthio)pyrimidine-5-carbocarboxylate derivatives (77-91).
General procedure: To 10.0 g (42 mmol) of dried 60 were added 30 mL of phosphoryl oxychloride dropwise at 0 °C. After the addition was completed, the mixture was refluxed for 5 h. The excess of phosphoryl oxychloride was then removed under reduced pressure and ice and cold water were added to the solid residue (150 mL). The mixture was extracted with diethylether (3x50 mL), dried over sodium sulfate anhydrous and the solvent was removed by evaporation under reduced pressure to give the 4-chloro-2-methylthio-5- carbethoxypyrimidine (61), which was readily used in the next step without purification. The chloropyrimidine obtained (61) and 74 mmol of the required hydrazide (62-76) were dissolved in 60 mL THF, while 74 mmol of DBU were added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was then removed, the residue was dissolved in dichloromethane (300 mL) and the resulting solution was washed with water (3x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography.
ethyl 4-(2-(3-(benzyloxy)benzoyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
General procedure for the synthesis of ethyl 4-(2-hydrazido)-2- (methylthio)pyrimidine-5-carbocarboxylate derivatives (77-91).
General procedure: To 10.0 g (42 mmol) of dried 60 were added 30 mL of phosphoryl oxychloride dropwise at 0 °C. After the addition was completed, the mixture was refluxed for 5 h. The excess of phosphoryl oxychloride was then removed under reduced pressure and ice and cold water were added to the solid residue (150 mL). The mixture was extracted with diethylether (3x50 mL), dried over sodium sulfate anhydrous and the solvent was removed by evaporation under reduced pressure to give the 4-chloro-2-methylthio-5- carbethoxypyrimidine (61), which was readily used in the next step without purification. The chloropyrimidine obtained (61) and 74 mmol of the required hydrazide (62-76) were dissolved in 60 mL THF, while 74 mmol of DBU were added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was then removed, the residue was dissolved in dichloromethane (300 mL) and the resulting solution was washed with water (3x100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography.
With potassium carbonate In acetonitrile at 70℃; for 16h;
5.1 Step 1:
A mixture of 3- (methylsulfonyl) -1H-indole (6.9 g, 35 mmol), potassium carbonate (12.4 g, 90 mmol) and ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.8 g, 25 mmol) in acetonitrile (200 mL) was stirred at 70°C for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with methyl tert-butyl ether to afford 46-1 .
With potassium carbonate In acetonitrile at 70℃; for 16h;
5.1 Step 1:
A mixture of 3- (methylsulfonyl) -1H-indole (6.9 g, 35 mmol), potassium carbonate (12.4 g, 90 mmol) and ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.8 g, 25 mmol) in acetonitrile (200 mL) was stirred at 70°C for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with methyl tert-butyl ether to afford 46-1 .
With potassium carbonate In acetonitrile at 70℃; for 16h;
5.1 Step 1:
A mixture of 3- (methylsulfonyl) -1H-indole (6.9 g, 35 mmol), potassium carbonate (12.4 g, 90 mmol) and ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.8 g, 25 mmol) in acetonitrile (200 mL) was stirred at 70°C for 16 h. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with methyl tert-butyl ether to afford 46-1 .
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;
ethyl4-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-(methylthio) pyrimidine-5-carboxylate (24)
General procedure: To the solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.14 g, 13.5 mmol) in THF (60 ml) was added DIPEA (5.58 ml, 33.7 mmol) followed by tert-butyl (3-(aminomethyl)phenyl)carbamate (3.3 g, 14.8 mmol) at 0 . The reaction was stirred at room temperature overnight and diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with water (50 ml × 2) and brine, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;
ethyl4-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-(methylthio) pyrimidine-5-carboxylate (24)
General procedure: To the solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.14 g, 13.5 mmol) in THF (60 ml) was added DIPEA (5.58 ml, 33.7 mmol) followed by tert-butyl (3-(aminomethyl)phenyl)carbamate (3.3 g, 14.8 mmol) at 0 . The reaction was stirred at room temperature overnight and diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with water (50 ml × 2) and brine, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
