* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2724 - 2727
2
[ 180869-36-7 ]
[ 1074-68-6 ]
Yield
Reaction Conditions
Operation in experiment
34%
Stage #1: With hydrogenchloride In water at 60℃; for 3 h; Stage #2: With sodium hydrogencarbonate In water
Example 4 2-(methylthio)pyrimidine-4-carbaldehyde (4): 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3.x.150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34percent). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1, pg 67.
34%
Stage #1: at 60℃; for 3 h; Stage #2: at 20℃;
4-(dimethoxymethyl)-2- (methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1 .2 N aqueous HCl (300 mL, 268 mmol, 1 .0 equiv.) and stirred at 60°C for 3hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3 x 1 50 mL) and the combined organic layer was concentrated under reduced pressure to afford 2- (methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid ( 14.2 g, 41.5 g theoretical, 34percent). LC-MS m/z 1 55 (M+ 1 ). Reference: W2006009734A 1 , pg 67.
34%
With hydrogenchloride In water at 60℃; for 3 h;
2-(methylthio)pyrimidine-4-carbaldehyde(6): 4-(dimethoxymethyl)-2-(methylthio)pyrimidine(5) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL,268 mmol, 1.0 equiv.) and stirred at 60°C for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodiumbicarbonate. The crude mixture wasextracted with diethyl ether (3 x 150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (6) as a yellow solid (14.2g, 41.5 g theoretical, 34percent). LC-MSm/z 155 (M+1).
96%
With conc H2SO4 In glacial AcOH; dichloromethane
c) 2-Methylthiopyrimidine-4-carboxaldehyde 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal (30.0 g, 150 mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc H2SO4 and heated at 80° C. After 10 h, the solution was cooled to 25° C. and the AcOH was removed in vacuo. The residue was diluted in 200 mL of CH2Cl2 and washed with saturated NaHCO3 (3*50 mL), H2O (50 mL) and brine (50 mL). The organics were dried (MgSO4) and concentrated to give the title compound as a brown oil; yield 22.1 g (96percent); or
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[2] Patent: WO2016/7966, 2016, A2, . Location in patent: Paragraph 0024
[3] Journal of Medicinal Chemistry, 2018,
[4] Patent: US2011/152235, 2011, A1, . Location in patent: Page/Page column 67
[5] Patent: WO2011/103289, 2011, A2, . Location in patent: Page/Page column 73; 74
[6] Patent: US2012/270892, 2012, A1, . Location in patent: Page/Page column 57
[7] Tetrahedron Letters, 2015, vol. 56, # 23, p. 3186 - 3190
[8] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 22, p. 3111 - 3116
[9] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 9, p. 1123 - 1126
[10] Patent: US2005/113392, 2005, A1, . Location in patent: Page/Page column 20
[11] Patent: US5658903, 1997, A,
[12] Patent: US5739143, 1998, A,
[13] Patent: US6218537, 2001, B1,
[14] Patent: US6218537, 2001, B1,
[15] Patent: US2003/225082, 2003, A1, . Location in patent: Page 9; 8
[16] Patent: WO2015/97123, 2015, A1, . Location in patent: Page/Page column 135
3
[ 497-19-8 ]
[ 180869-36-7 ]
[ 1074-68-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride In ethyl acetate
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3 N HCl (42 mL, 126 mmol) were combined and stirred at 48° C. for 16 h, cooled to 23° C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 SO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97percent) of the title compound 1 H NMR (CDCl3): δ9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
97%
With hydrogenchloride In ethyl acetate
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3 N HCl (42 mL, 126 mmol) were combined and stirred at 48° C. for 16 h, cooled to 23° C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 DO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97percent) of the title compound 1 H NMR (CDCl3): δ 9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
97%
With hydrogenchloride In ethyl acetate
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3N HCl (42 mL, 126 mmol) were combined and stirred at 48° C. for 16 h, cooled to 23° C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 SO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97percent) of the title compound 1 H NMR (CDCl3): δ9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
Reference：
[1] Patent: US5977103, 1999, A,
[2] Patent: US6046208, 2000, A,
[3] Patent: US5756499, 1998, A,
Example 4 2-(methylthio)pyrimidine-4-carbaldehyde (4): <strong>[180869-36-7]4-(dimethoxymethyl)-2-(methylthio)pyrimidine</strong> (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60 C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1, pg 67.
34%
4-(dimethoxymethyl)-2- (methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1 .2 N aqueous HCl (300 mL, 268 mmol, 1 .0 equiv.) and stirred at 60C for 3hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3 x 1 50 mL) and the combined organic layer was concentrated under reduced pressure to afford 2- (methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid ( 14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 1 55 (M+ 1 ). Reference: W2006009734A 1 , pg 67.
34%
<strong>[180869-36-7]4-(dimethoxymethyl)-2-(methylthio)pyrimidine</strong> (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60 C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1 (incorporated by reference), pg 67.
34%
With hydrogenchloride; In water; at 60℃; for 3h;
2-(methylthio)pyrimidine-4-carbaldehyde(6): <strong>[180869-36-7]4-(dimethoxymethyl)-2-(methylthio)pyrimidine</strong>(5) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL,268 mmol, 1.0 equiv.) and stirred at 60C for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodiumbicarbonate. The crude mixture wasextracted with diethyl ether (3 x 150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (6) as a yellow solid (14.2g, 41.5 g theoretical, 34%). LC-MSm/z 155 (M+1).
With water;hydrogenchloride; at 60℃; for 3h;
The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyl-pyrimidine-4-carbaldehyde.
12 g (62%)
With hydrogenchloride; sodium hydrogencarbonate;
b 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (25 g, 125 mmol) and 3N HCl were heated to 40 C. for 18 h. The reaction mixture was cooled to ambient temperature and neutralized by addition of solid NaHCO3 and extracted with EtOAc (5*500 mL). The combined extracts were dried (Na2 SO4) and concentrated. The residue was purified by flash chromatography eluding with dichloromethane to afford the title compound as an off-white solid; yield 12 g (62 %). 1 H NMR (CDCl3 l) delta 9.95 (s, 1H), 8.77 (d, 1H), 7.43 (d, 1H), 2.63 (s, 3H); or
12 g (62%)
With hydrogenchloride; sodium hydrogencarbonate;
b 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (25 g, 125 mmol) and 3N HCl were heated to 40 C. for 18 h. The reaction mixture was cooled to ambient temperature and neutralized by addition of solid NaHCO3 and extracted with EtOAc (5*500 mL). The combined extracts were dried (Na2 SO4) and concentrated. The residue was purified by flash chromatography eluding with dichloromethane to afford the title compound as an off-white solid; yield 12 g (62%). 1 H NMR (CDCl3) delta 9.95 (s, 1H), 8.77 (d, 1H), 7.43 (d, 1H), 2.63 (s, 3H); or
12 g (62%)
With hydrogenchloride; sodium hydrogencarbonate;
b) 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (25 g, 125 mmol) and 3 N HCl were heated to 40 C. for 18 h. The reaction mixture was cooled to ambient temperature and neutralized by addition of solid NaHCO3 and extracted with EtOAc (5*500 mL). The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluding with dichloromethane to afford the title compound as an off-white solid; yield 12 g (62%). 1H NMR (CDCl3) delta9.95 (s, 1H), 8.77 (d, 1H), 7.43 (d, 1H), 2.63 (s, 3H); or
22.1 g (96%)
With conc H2SO4; In glacial AcOH; dichloromethane;
c) 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (30.0 g, 150 mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc H2SO4 and heated at 80 C. After 10 h, the solution was cooled to 25 C. and the AcOH was removed in vacuo. The residue was diluted in 200 mL of CH2Cl2 and washed with saturated NaHCO3 (3*50 mL), H2O (50 mL) and brine (50 mL). The organics were dried (MgSO4) and concentrated to give the title compound as a brown oil; yield 22.1 g (96%); or
With hydrogenchloride; water; at 60℃; for 3h;
The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1 M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1
With hydrogenchloride; In water; at 60℃;
General procedure: The appropriate acetal (1.0 eq.) was stirred with 2N HC1 solution (3 mL/mmol) at 60C until no further conversion was observed. Reaction mixture was cooled to 0C, then NaOH (5.7 eq.) was added portionwise. The p1-I was adjusted to 8 using 10% K2C03 solution,then sodium borohydride (2,0 eq.) was added portionwise keeping the temperature under5C and the mixture was stirred for 30 mm at 0C. Reaction mixture was extracted with EtOAc, the combined organic phases were dried over Na2804, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAe as eluents.Starting from 4-(dimethoxymethyl)-2-methylsulfanyl-pyrimidine (Preparation 9a2) using General Procedure 9A the title product was obtained as white crystals.?H NMR (400 MHz, DMSO-d6): 8.61 (d, lH), 7.25 (d, in), 5.63 (t, 111), 4.49 (d, 2H), 2.49(s, 3n).
With hydrogenchloride; In water; at 50℃;
Aqueous 4 M HCI (13 ml) was added to a solution of 4-dimethoxymethyl-2- methylsulfanyl-pyrimidine (4.10 g, 20.5 mmol). The resulting mixture was heated to 50 C overnight. 1H NMR analysis indicated conversion to the carbaldehyde so the mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and neutralized with K2CO3 solution. The aqueous phase was extracted with EtOAc, dried with MgSO4 and concentrated. The crude material was used in the next step without purification (2.74 g, 87%). 1H NMR (CDCI3, 400 MHz) delta 2.64 (3 H, s), 7.44 (1 H, d, J = 4.8 Hz), 8.77 (1 H, d, J = 4.8 Hz), 9.96 (1 H, s).
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3 N HCl (42 mL, 126 mmol) were combined and stirred at 48 C. for 16 h, cooled to 23 C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 SO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97%) of the title compound 1 H NMR (CDCl3): delta9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
7.49 g (97%)
With hydrogenchloride; In ethyl acetate;
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3 N HCl (42 mL, 126 mmol) were combined and stirred at 48 C. for 16 h, cooled to 23 C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 DO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97%) of the title compound 1 H NMR (CDCl3): delta 9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
7.49 g (97%)
With hydrogenchloride; In ethyl acetate;
b 2-Methylthiopyrimidine-4-carboxaldehyde The product of example 1(a) (9.96 g, 50 mmol), and 3N HCl (42 mL, 126 mmol) were combined and stirred at 48 C. for 16 h, cooled to 23 C., combined with EtOAc (200 mL) and made basic by the addition of solid Na2 CO3 (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4*150 mL, dried (Na2 SO4), concentrated and the residue was filtered through a pad of silica (ca 150 mL) with CH2 Cl2 to afford 7.49 g (97%) of the title compound 1 H NMR (CDCl3): delta9.96 (s,1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s,3).
b 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (30.0 g, 150 mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc. H2 SO4 and heated at 80 C. After 10 h, the solution was cooled to 25 C. and the AcOH was removed in vacuo, leaving a brown oil residue. This residue was diluted in 200 mL of CH2 Cl2 and washed with saturated NaHCO3 (3*50 mL), H2 O (5.0 mL) and brine (50 mL). The organics were dried over MgSO4 and concentrated to yield 22.1 g (96%) of the title compound as a brown oil.
22.1 g (96%)
In glacial AcOH; dichloromethane;
b) 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (30.0 g, 150 mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc. H2 SO4 and heated at 80 C. After 10 h, the solution was cooled to 25 C. and the AcOH was removed in vacuo, leaving a brown oil residue. This residue was diluted in 200 mL of CH2 Cl2 and washed with saturated NaHCO3 (3*50 mL), H2 O (50 mL) and brine (50 mL). The organics were dried over MgSO4 and concentrated to yield 22.1 g (96%) of the title compound as a brown oil.
c 2-Methylthiopyrimidine-4-carboxaldehyde <strong>[180869-36-7]2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal</strong> (30.0 g, 150 mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc H2 SO4 and heated at 80 C. After 10 h, the solution was cooled to 25 C. and the AcOH was removed in vacuo. The residue as diluted in 200 mL of CH2 Cl2 and washed with saturated NaHCO3 (3*50 mL), H2 O (50 mL) and brine (50 mL). The organics were dried (MgSO4) and concentrated to give the title compound as a brown oil; yield 22.1 g (96%); or
With sodium methylate; thiourea; In hydrogenchloride; methanol; water; ethyl acetate;
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C. a 40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidin. The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1 M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyl-pyrimidin-4-carbaldehyde, 1.
With sodium methylate; thiourea; In hydrogenchloride; methanol; water; ethyl acetate;
To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 C. to about 80 C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 C. and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 C. The mixture is stirred for 5 hours at room temperature, cooled to 20 C., then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 C.a40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of <strong>[180869-36-7]4-dimethoxymethyl-2-methylsulfanyl-pyrimidine</strong>. The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 C. for 3 hours in 1 M HCl. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1.
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