* 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
2
[ 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
3
[ 87-13-8 ]
[ 53554-29-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: at 0℃; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
To a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol (15 mL) was added S-methylisothiourea sulfate (5.57 g, 40.0 mmol) at 0 °C. After a few minutes, diethyl ethoxymethylenemalonate (4.00 mL, 19.8 mmol) was added. After stirring at 0 °C for 3 h, a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol (15 mL) was added. The resulted solution was stirred at room temperature overnight. Ethanol was removed under reduced pressure and the pale yellow residue was dissolved in water. After filtration, the aqueous filtrate was washed with ether and acidified with acetic acid (10 mL). The organic materials were extracted with CHCl3. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Recrystallization of the residue with CHCl3 gave compound 10 (3.44 g, 81percent) as colorless needles. Mp 129-130 °C (CHCl3), lit.16 132-133 °C (benzene/petroleum ether). IR (KBr) 3435, 2902, 2805, 1739, 1701, 1529, 1170 cm-1. δH (400 MHz, CDCl3) 1.42 (3H, t, J 6.8 Hz, CH2CH3), 2.60 (3H, s, SCH3), 4.43 (2H, q, J 6.8 Hz, CH2CH3), 8.75 (1H, s, C4-H). δC (150 MHz, DMSO;d6) 13.0, 14.1, 60.2, 111.7, 157.8, 158.9, 163.6, 168.0. LRMS (EI) m/z 214 (M+). HRMS (EI): M+, found 214.0458. C8H10N2O3S requires 214.0412.
Reference：
[1] Tetrahedron, 2011, vol. 67, # 14, p. 2661 - 2669
[2] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 673 - 690
4
[ 36239-09-5 ]
[ 53554-29-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 1, p. 93 - 98
5
[ 2986-19-8 ]
[ 87-13-8 ]
[ 53554-29-3 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
6
[ 53114-57-1 ]
[ 87-13-8 ]
[ 53554-29-3 ]
Reference：
[1] American Chemical Journal, 1907, vol. 37, p. 396
7
[ 38026-46-9 ]
[ 77-78-1 ]
[ 53554-29-3 ]
Reference：
[1] Journal of the Chemical Society, 1953, p. 4175
In N,N-dimethyl-formamide; at 160℃; for 2h;Neat (no solvent);
Example 3: 2-(2-Fluoro-5-methoxv-phenvlamiotano-4-(2-methanesulfonvl-phenylamiotano)- py?miotadiotane-5-carboxyliotac acid amide (3); Step a: 2-(2-Fluoro-5-methoxy-phenylamiotano)-6-oxo-1 ,6-diotahydro-rhoy?miotadiotane-5-carboxyliotac acid ethyl ester (3a); A mixture of 2-methylsulfonyl-6-oxo-1 ,6-diotahydro-py?miotadiotane-5-carboxyliotac acid ethyl ester (CA Reg No 53554-29-3, 108 mg) and 2-fluoro-5-methoxy-aniotaliotane (CA Reg No 62257-15-2, 90 mg) is heated without solvent in an oil bath of 160 0C After 2h the reaction is cooled, and the residue is crystallized from methanol affording 3a (UPLC method C, tret 1 93 mm, MS 308/ES+)
ethyl 1,6-dihydro-2-(4-butoxycarbonylanilino)-6-oxo-5-pyrimidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 38 Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and butyl -4-aminobenzoate (10.8 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(4-butoxycarbonylanilino)-6-oxo-5-pyrimidinecarboxylate (7.0 g). M.p. 281-283 C. Elemental analysis for C18 H21 N3 O5: Calcd. (%): C, 60.16; H, 5.89; N, 11.69. Found (%): C, 59.81; H, 5.87; N, 11.46. IR numaxnujol cm-1: 2500-3300 (NH), 1725 (C=O), 1715 (C=O), 1650 (C=O). NMR (DMSO-d6) delta: 0.98 (3H, t, J=7 Hz, OCH2 CH2 CH2 CH3), 1.31 (3H, t, J=7 Hz, OCH2 CH3), 1.50 (2H, m, OCH2 CH2 CH2 CH3), 1.70 (2H, m, OCH2 CH2 CH2 CH3), 4.31 (2H, q, J=7 Hz, OCH2 CH2 CH2 CH3), 4.33 (2H, q, J=7 Hz, OCH2 CH3), 7.80-8.20 (4H, m, Ar--H), 8.64 (1H, s, C4 --H), 8.40-11.60 (2H, b, 2*NH). Mass m/e: 359 (M+).
Reference Example 2-1 ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate To a solution of indoline (3.58 g, 30 mmol) in ethanol (50 mL) was added <strong>[53554-29-3]ethyl 2-methylthio-4-hydroxypyrimidine-5-carboxylate</strong> (5.35 g, 25 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and the precipitated crystals were collected by filtration. The crystals were washed several times with cold ethanol and dried to give the title compound (5.5 g, 77%) as crystals.
With hydrogenchloride; sodium hydroxide; In ethanol;
Reference Example 1 ethyl 2-methylthio-4-hydroxypyrimidine-5-carboxylate To a 4N sodium hydroxide solution (200 mL) was added S-methylisothioureasulfate (55.6 g, 0.2 mol), and after stirring for 30 min, at room temperature a solution of diethyl ethoxymethylenemalonate (80.8 mL, 0.35 mol) in ethanol (100 mL) was dropwise added slowly over 1 h. After stirring for 18 h, the precipitated crystals were collected by filtration, washed several times with cold ethanol and the obtained crystals were added to 1N hydrochloric acid (300 mL). The mixture was stirred for 30 min and the precipitated crystals were collected by filtration, washed several times with cold water and dried with heating under vacuum to give the title compound (26 g, 61%) as crystals. 1H-NMR (delta ppm, CDCl3): 1.42 (3H, t, J=7.0 Hz), 2.60 (3H, s), 4.44 (2H, q, J=7.0 Hz), 8.76 (1H, s), 13.25 (1H, br)
Step-I: Preparation of ethyl 4-hydroxy-2-((4-((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxyIate.A mixture of commercially available <strong>[53554-29-3]ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate</strong> (35 g, 0.16 mol), 4-aminophenyl methanesulfonate (36.7 g, 0.196 mol) in Mrbutanol (175 mL) was refluxed for 4-5 h. After completion of reaction the mixture was cooled to 25-30 C and EtOAc (200 mL) was added and stirred mixture for 1 h. The pptd compound was filtered and washed with cold EtOAc to get desired title product (18 g, 31%).
ethyl 2-((1-benzylpyrrolidin-3-yl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 80 - 90℃;
Ethyl 2-(methylthio)-6-oxo- 1 ,6-dihyropyrimidine-5 -carboxylate (313 mg, 1.460 mmol) and 1-benzylpynolidin-3-amine (257 rng, 1.460 mmol) were dissolved in 10 mEethanol and heated at 80C overnight. The precipitate was not evident so the solution was heated to 90C overnight. The final product was then recovered.
With sodium carbonate; In water; at 25 - 30℃; for 12h;
Diethyl 2-(ethoxymethylene)malonate compound of formula-2 (100 g) was added to a mixture of 2-methyl-2-pseudothiourea sulfate compound of formula-3 (77.24 g) and water (300 ml) at 25-30C. Sodium carbonate solution (98.04 g of sodium carbonate in 300 ml of water) was slowly added to the reaction mixture at 25-30C and stirred for 12 hours at the same temperature. After completion of the reaction, quenching the reaction mixture with dilute hydrochloric acid and stirred for 1 hour at 15-20C. Filtered the precipitated solid and washed with water to obtain title compound. This wet solid taken into next step.
With sodium hydroxide; In ethanol; for 2.0h;Reflux;
Take 50g (231.4mmol) diethyl ethoxymalonate to the three-neck flask, add 100ml of absolute ethanol, 32g (115.7mmol) S-methylisothiourea sulfate, 13.8g sodium hydroxide at room temperature,Heat to reflux for 2 hours, cool to room temperature, concentrate and evaporate the ethanol, add 200ml of water, 2N hydrochloric acid adjusted PH=3-4, precipitate a white solid, and filter to obtain ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylate 40.6 g, yield 82%, purity: 99.7%.
In a 500 mL autoclave, Compound 1 (214 g, 1 mol) and 200 mL of 30% by mass of hydrogen peroxide were added.Gradually heat up to 120 C to carry out the reaction, after the reaction is over,The autoclave was cooled to room temperature, and the reaction solution was spun dry.Recrystallization from ethanol gave a white solid in a yield of 95%.
95%
With dihydrogen peroxide; at 120℃;Autoclave; Green chemistry;
In a 500 mL autoclave, compound 1 (214 g, 1 mol) and 200 mL of 30% by mass of hydrogen peroxide were added,and the reaction was gradually heated to 120 C to carry out the reaction. After the reaction was completed, the autoclave was cooled to room temperature, and the reaction solution was spin-dried with ethanol. Recrystallization gave a white solid in a yield of 95%, and the HPLC purity was 98.5%
With dihydrogen peroxide; potassium carbonate; at 120℃;Autoclave;
In a 500 mL autoclave,Compound 1 (214 g, 1 mol) was added,200mL of 30% hydrogen peroxide and 138g of potassium carbonate,Gradually heat up to 120 C to carry out the reaction,After the reaction, the autoclave was cooled to room temperature, and the pH of the mixed system was adjusted to neutral with dilute hydrochloric acid.Filtration gave a white solid in a yield of 93%.The HPLC purity was 97.5%.
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