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Product Details of [ 5909-24-0 ]

CAS No. :5909-24-0 MDL No. :MFCD00006085
Formula : C8H9ClN2O2S Boiling Point : -
Linear Structure Formula :- InChI Key :SNNHLSHDDGJVDM-UHFFFAOYSA-N
M.W : 232.69 Pubchem ID :80008
Synonyms :

Calculated chemistry of [ 5909-24-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.38
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 54.85
TPSA : 77.38 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 2.23
Log Po/w (WLOGP) : 2.03
Log Po/w (MLOGP) : 1.07
Log Po/w (SILICOS-IT) : 2.26
Consensus Log Po/w : 1.95

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.74
Solubility : 0.423 mg/ml ; 0.00182 mol/l
Class : Soluble
Log S (Ali) : -3.49
Solubility : 0.0753 mg/ml ; 0.000323 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.25
Solubility : 0.129 mg/ml ; 0.000556 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.96

Safety of [ 5909-24-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5909-24-0 ]

* 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.

  • Upstream synthesis route of [ 5909-24-0 ]
  • Downstream synthetic route of [ 5909-24-0 ]

[ 5909-24-0 ] Synthesis Path-Upstream   1~39

  • 1
  • [ 5909-24-0 ]
  • [ 770-31-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4606 - 4616
[3] Patent: WO2013/134243, 2013, A1,
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[5] Patent: WO2014/151682, 2014, A1,
[6] Patent: WO2014/144737, 2014, A1,
[7] Patent: WO2014/182829, 2014, A1,
[8] Patent: WO2016/191172, 2016, A1,
[9] Patent: US2015/31674, 2015, A1,
[10] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[11] Patent: WO2015/84936, 2015, A1,
[12] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[13] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[14] Patent: WO2015/120049, 2015, A1,
[15] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1241 - 1246
[16] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5520 - 5541
  • 2
  • [ 5909-24-0 ]
  • [ 57401-76-0 ]
Reference: [1] Patent: US2013/79313, 2013, A1,
[2] Patent: WO2013/45280, 2013, A1,
  • 3
  • [ 5909-24-0 ]
  • [ 588-36-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4606 - 4616
[3] Patent: WO2013/134243, 2013, A1,
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[5] Patent: WO2014/151682, 2014, A1,
[6] Patent: WO2014/144737, 2014, A1,
[7] Patent: WO2014/182829, 2014, A1,
[8] Patent: WO2016/191172, 2016, A1,
[9] Patent: US2015/31674, 2015, A1,
[10] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[11] Patent: WO2015/84936, 2015, A1,
[12] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[13] Patent: WO2015/120049, 2015, A1,
[14] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1241 - 1246
[15] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5520 - 5541
[16] Patent: WO2017/19429, 2017, A1,
  • 4
  • [ 5909-24-0 ]
  • [ 771-81-3 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[2] Patent: WO2015/84936, 2015, A1,
  • 5
  • [ 5909-24-0 ]
  • [ 51940-64-8 ]
Reference: [1] Patent: WO2015/19037, 2015, A1, . Location in patent: Page/Page column 66
  • 6
  • [ 5909-24-0 ]
  • [ 144-55-8 ]
  • [ 51940-64-8 ]
Reference: [1] Patent: US2003/32647, 2003, A1,
  • 7
  • [ 53554-29-3 ]
  • [ 5909-24-0 ]
YieldReaction ConditionsOperation in experiment
92% at 60℃; for 3 h; 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 ]
YieldReaction ConditionsOperation 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).

Reference: [1] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 0319
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1241 - 1246
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5520 - 5541
[4] Patent: WO2014/182829, 2014, A1, . Location in patent: Page/Page column 42
[5] Patent: WO2015/120049, 2015, A1, . Location in patent: Page/Page column 126; 127
[6] Patent: WO2016/191172, 2016, A1, . Location in patent: Page/Page column 56-57
[7] Patent: WO2013/134243, 2013, A1, . Location in patent: Page/Page column 15-16
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[10] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[11] Patent: WO2014/151682, 2014, A1, . Location in patent: Page/Page column 52; 53
[12] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4606 - 4616
[13] Patent: US2016/75720, 2016, A1, . Location in patent: Paragraph 0259
[14] Organic and Biomolecular Chemistry, 2010, vol. 8, # 9, p. 2164 - 2173
[15] Patent: WO2006/135824, 2006, A1, . Location in patent: Page/Page column 15
[16] Patent: US6451804, 2002, B1,
[17] Patent: US5733913, 1998, A,
[18] Patent: WO2007/36791, 2007, A1, . Location in patent: Page/Page column 55
[19] Patent: US2007/167469, 2007, A1, . Location in patent: Page/Page column 4
[20] Patent: US2008/176874, 2008, A1, . Location in patent: Page/Page column 4
[21] Patent: EP1364950, 2003, A1, . Location in patent: Page/Page column 222
[22] Patent: WO2014/144737, 2014, A1, . Location in patent: Paragraph 00619
[23] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[24] Patent: WO2015/84936, 2015, A1, . Location in patent: Page/Page column 91
[25] Patent: WO2017/19429, 2017, A1, . Location in patent: Page/Page column 9; 15; 16
  • 11
  • [ 1336-21-6 ]
  • [ 5909-24-0 ]
  • [ 776-53-4 ]
YieldReaction ConditionsOperation in experiment
79% 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.

Reference: [1] Patent: US2003/73668, 2003, A1,
[2] Patent: US2002/55513, 2002, A1,
[3] Patent: US6498163, 2002, B1,
[4] Patent: US2004/224958, 2004, A1,
  • 12
  • [ 5909-24-0 ]
  • [ 74-89-5 ]
  • [ 76360-82-2 ]
YieldReaction ConditionsOperation in experiment
100% at 0℃; for 0.5 h; [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*).

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[2] Patent: WO2015/19037, 2015, A1, . Location in patent: Page/Page column 87; 88
[3] Patent: US2003/207900, 2003, A1, . Location in patent: Page/Page column 15
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5439 - 5448
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[6] Patent: WO2014/11900, 2014, A2, . Location in patent: Page/Page column 30; 31
[7] Patent: US2015/197519, 2015, A1, . Location in patent: Paragraph 0166; 0167
[8] Patent: US9695165, 2017, B2, . Location in patent: Page/Page column 48
[9] Patent: WO2016/168992, 2016, A1, . Location in patent: Paragraph 151
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[20] Patent: US2009/36472, 2009, A1, . Location in patent: Page/Page column 22
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  • 13
  • [ 5909-24-0 ]
  • [ 76360-82-2 ]
YieldReaction ConditionsOperation in experiment
97% 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.

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  • [ 593-51-1 ]
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  • 15
  • [ 5909-24-0 ]
  • [ 76360-82-2 ]
  • [ 185040-32-8 ]
YieldReaction ConditionsOperation 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.
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  • 16
  • [ 5909-24-0 ]
  • [ 73781-88-1 ]
YieldReaction ConditionsOperation 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).

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[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
  • 17
  • [ 5909-24-0 ]
  • [ 5909-25-1 ]
  • [ 73781-88-1 ]
Reference: [1] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 1022
[2] Patent: WO2013/45280, 2013, A1, . Location in patent: Page/Page column 275
  • 18
  • [ 5909-24-0 ]
  • [ 17759-30-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 17, p. 3276 - 3292
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2255 - 2265
[3] Patent: WO2011/75616, 2011, A1,
[4] Patent: WO2014/11900, 2014, A2,
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[6] Patent: WO2014/144737, 2014, A1,
[7] Patent: US2014/323464, 2014, A1,
[8] Patent: WO2015/6492, 2015, A1,
[9] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[10] Patent: US2015/197519, 2015, A1,
[11] Patent: US9695165, 2017, B2,
[12] Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 1984 - 2004
[13] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2138 - 2141
[14] Patent: WO2016/168992, 2016, A1,
[15] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1793 - 1816
[16] Patent: WO2008/78249, 2008, A1,
  • 19
  • [ 5909-24-0 ]
  • [ 148256-82-0 ]
Reference: [1] Patent: US2011/257207, 2011, A1,
[2] Patent: WO2014/15675, 2014, A1,
[3] Patent: WO2014/15830, 2014, A1,
[4] Patent: US2015/31674, 2015, A1,
[5] Patent: WO2015/161287, 2015, A1,
[6] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1241 - 1246
[7] Patent: CN106749259, 2017, A,
  • 20
  • [ 5909-24-0 ]
  • [ 148550-51-0 ]
YieldReaction ConditionsOperation in experiment
2.154 g
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 ]
YieldReaction ConditionsOperation 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,
  • 23
  • [ 5909-24-0 ]
  • [ 185040-32-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 17, p. 3276 - 3292
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2255 - 2265
[3] Patent: WO2011/75616, 2011, A1,
[4] Patent: WO2014/11900, 2014, A2,
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[6] Patent: WO2014/144737, 2014, A1,
[7] Patent: US2014/323464, 2014, A1,
[8] Patent: WO2015/6492, 2015, A1,
[9] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
[10] Patent: US2015/197519, 2015, A1,
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 1984 - 2004
[12] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2138 - 2141
[13] Patent: WO2016/168992, 2016, A1,
[14] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1793 - 1816
[15] Patent: US9695165, 2017, B2,
[16] Patent: WO2008/78249, 2008, A1,
  • 24
  • [ 5909-24-0 ]
  • [ 74-89-5 ]
  • [ 185040-32-8 ]
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 18, p. 3177 - 3180
  • 25
  • [ 5909-24-0 ]
  • [ 211244-81-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4606 - 4616
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 413 - 418
  • 26
  • [ 5909-24-0 ]
  • [ 571188-82-4 ]
Reference: [1] Patent: EP2429566, 2016, B1,
[2] Patent: CN105622638, 2016, A,
[3] Patent: US9808461, 2017, B2,
  • 27
  • [ 5909-24-0 ]
  • [ 330784-47-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5460 - 5465
[2] Patent: WO2015/1567, 2015, A1,
[3] Patent: WO2015/1567, 2015, A1,
[4] Patent: WO2015/177807, 2015, A1,
[5] Patent: WO2015/177807, 2015, A1,
[6] Patent: WO2015/177807, 2015, A1,
[7] Patent: CN104059025, 2017, B,
[8] Patent: CN104059025, 2017, B,
[9] Patent: CN104710411, 2017, B,
  • 28
  • [ 5909-24-0 ]
  • [ 115514-77-7 ]
  • [ 330785-81-4 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine In acetone at 20℃; for 3 h; 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.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5460 - 5465
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 7, p. 1431 - 1435
[3] Patent: CN108707141, 2018, A, . Location in patent: Paragraph 0027; 0031; 0036; 0040; 0045; 0049
[4] Patent: EP2886540, 2015, A1, . Location in patent: Paragraph 0168; 0169
[5] Patent: EP1366760, 2003, A1, . Location in patent: Page 19
[6] Patent: US2003/195220, 2003, A1,
[7] Patent: US2003/32647, 2003, A1,
[8] Patent: US2004/142930, 2004, A1,
[9] Patent: EP1364950, 2003, A1, . Location in patent: Page/Page column 19
[10] Patent: WO2015/177807, 2015, A1, . Location in patent: Page/Page column 14; 15
[11] Patent: CN104059025, 2017, B, . Location in patent: Paragraph 0035; 0036-0038; 0053-0055; 0069-0071; 0085-0087
  • 29
  • [ 5909-24-0 ]
  • [ 41965-95-1 ]
  • [ 330785-81-4 ]
YieldReaction ConditionsOperation in experiment
88.3%
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.

Reference: [1] Patent: US2016/46654, 2016, A1, . Location in patent: Paragraph 0204; 0205
[2] Patent: CN104710411, 2017, B, . Location in patent: Paragraph 0025; 0050; 0051; 0052; 0053; 0054; 0055; 0056
[3] Patent: EP2886540, 2015, A1, . Location in patent: Paragraph 0467; 0468
[4] Patent: WO2015/1567, 2015, A1, . Location in patent: Page/Page column 23; 24
  • 30
  • [ 5909-24-0 ]
  • [ 330785-81-4 ]
YieldReaction ConditionsOperation in experiment
102 g 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
Reference: [1] Patent: WO2015/1567, 2015, A1, . Location in patent: Page/Page column 25
  • 31
  • [ 5909-24-0 ]
  • [ 330785-84-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5460 - 5465
[2] Patent: WO2015/1567, 2015, A1,
[3] Patent: WO2015/1567, 2015, A1,
[4] Patent: EP2886540, 2015, A1,
[5] Patent: EP2886540, 2015, A1,
  • 32
  • [ 5909-24-0 ]
  • [ 2393-23-9 ]
  • [ 211230-35-2 ]
YieldReaction ConditionsOperation in experiment
88% With triethylamine In tetrahydrofuran 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].
Reference: [1] Patent: US2004/224958, 2004, A1,
[2] Patent: US6498163, 2002, B1,
[3] Patent: WO2015/92431, 2015, A1, . Location in patent: Page/Page column 94; 95
  • 33
  • [ 5909-24-0 ]
  • [ 74840-34-9 ]
Reference: [1] MedChemComm, 2015, vol. 6, # 9, p. 1693 - 1697
[2] Patent: US2008/114007, 2008, A1, . Location in patent: Page/Page column 82
  • 34
  • [ 5909-24-0 ]
  • [ 10519-96-7 ]
  • [ 397308-78-0 ]
YieldReaction ConditionsOperation in experiment
73%
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).
Reference: [1] Patent: US7176310, 2007, B1, . Location in patent: Page/Page column 48
  • 35
  • [ 5909-24-0 ]
  • [ 21075-86-5 ]
  • [ 955368-90-8 ]
YieldReaction ConditionsOperation in experiment
51% 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.
Reference: [1] Patent: WO2017/75629, 2017, A2, . Location in patent: Page/Page column 33; 34
[2] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[3] Patent: US2007/254892, 2007, A1, . Location in patent: Page/Page column 30-31
[4] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 28
[5] ACS Chemical Biology, 2016, vol. 11, # 4, p. 921 - 930
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Reference: [1] ACS Chemical Biology, 2016, vol. 11, # 4, p. 921 - 930
[2] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[3] Patent: WO2017/75629, 2017, A2,
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Reference: [1] Patent: WO2012/18540, 2012, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
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Reference: [1] MedChemComm, 2015, vol. 6, # 9, p. 1693 - 1697
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Reference: [1] Patent: WO2013/134243, 2013, A1,
[2] Patent: WO2013/134243, 2013, A1,
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
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