* 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.
With tetrachloromethane; triphenylphosphine In 1,2-dichloro-ethane at 70℃; for 2.5 h; Inert atmosphere
tert-Butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of the product of Intermediate 1, step a (1.26 g, 5.02 mmol) in DCE (36 mL) was added PPh3 (2.69 g, 10.05 mmol) followed by CCl4 (1.46 mL, 15.07 mmol) and the mixture was heated to 70° C. for 2.5 h. The mixture was concentrated in vacuo and chromatographed on SiO2 eluting with EtOAc/Hex to afford the desired compound as a pale yellow solid (1.20 g, 88percent). MS (ESI) mass calcd. C12H16ClN3O2, 269.09. m/z found 270.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79 (s, 1H), 4.65 (br s, 2H), 3.80-3.68 (m, 2H), 2.93-2.82 (m, 2H), 1.49 (s, 9H).
87%
Stage #1: With triphenylphosphine In 1,2-dichloro-ethane Stage #2: With tetrachloromethane In 1,2-dichloro-ethane at 70℃; for 2.5 h;
STEP C: A mixture of 4-hydroxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7- carboxylic acid ter/-butyl ester ( 1 .4 g, 5.6 mmol) and triphenylphosphine (2.9 g, 1 1.1 mmol) was stirred in DCE (41 mL) until the solution became clear, and then carbon tetrachloride ( 1.6 mL, 16.7 mmol) was added. The reaction mixture was heated to 70°C and stirred for 2.5 hours. The volatiles were removed in vacuo and the crude material was directly purified by flash chromatography on silica gel (0-50percent EtOAc/ heptanes) to afford the title compound as an off-white solid (1.31 g, 87percent yield). MS (ESI) m/e (M+H+): 269.73
81%
With tetrachloromethane; triphenylphosphine In 1,2-dichloro-ethane at 70℃; for 1 h;
The Preparation of Compound 12: Compound 12F (1.6 g, 6.3 mmol), triphenylphosphine (3.33 g, 12.6 mmol) and tetrachloromethane (2.93 g, 18.9 mmol) were mixed in 1,2-dichloroethane (1,2-DCE, 64 mL), heated to 70° C. for 1 hour. The reaction was monitored via TLC (DCM/Methanol=10:1). The reaction mixture was concentrated and purified by silica gel chromatography to obtain a purified compound 12 (1.38 g, yield: 81percent) as a light yellow solid.
81%
With tetrachloromethane; triphenylphosphine In 1,2-dichloro-ethane at 70℃; for 1 h;
Compound 12F (1.6 g, 6.3 mmol), triphenylphosphine (3.33 g, 12.6 mmol) and tetrachloromethane (2.93 g, 18.9 mmol) were mixed in 1,2-dichloroethane (1,2-DCE, 64 mL), heated to 70° C. for 1 hour. The reaction was monitored via TLC (DCM/Methanol=10:1). The reaction mixture was concentrated and purified by silica gel chromatography to obtain a purified compound 12 (1.38 g, yield: 81percent) as a light yellow solid.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃; for 4h;
31-C. 4-(lH-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-</]pyrimidine-7-carboxylic acid tert-buty ester.; To a solution of 4-Chloro-5,8-dihydro-6H-pyrido[3,4-</]pyrimidine-7-carboxylic acid tert-butyl ester (5.46 g, 20.2 mmol), 5-hydroxyindole (3.50 g, 26.3 mmol) and CH3CN (100 mL) is added DBU (4.0 mL, 26.3 mmol). The mixture is then heated at 50 0C for 4 h. At that time the solvent is removed in vacuo and the residue separated via FCC (10-50% EtO Ac/heptane) to give the title compound. MS (ESI) m/z 367.1 (M+l).
With tetrachloromethane; triphenylphosphine; In 1,2-dichloro-ethane; at 70℃; for 2.5h;
31-B. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-</]pyrimidine-7-carboxylic acid tert-buty ester.; Triphenylphosphine (17.3 g, 66.1 mmol) is added to a solution of 4-0x0-4,5, 6,8-tetrahydro-3H- pyrido[3,4-(/|pyrimidine-7-carboxylic acid tert-butyl ester (8.30 g, 33.0 mmol), CCl4 (9.6 mL, 99 mmol), and 1,2-dichloroethane (250 mL). The solution is heated at 70 0C for 2.5 h. The solution is concentrated in vacuo to about 50 mL. The contents of the flask are then filtered over a silica gel plug eluting with 60% EtO Ac/heptane. The residue following concentration is then further separated via flash chromatography (10-30% EtO Ac/heptane) to give the title compound.MS (ESI) m/z 270.0 & 272.0 (M+l); 1H NMR (400 MHz, CDCl3) delta ppm 8.79 (s, 1 H), 4.65 (s, 2 H), 3.74 (t, J=5.8 Hz, 2 H), 2.87 (t, J=5.8 Hz, 2 H), 1.49 (s, 9 H).
With caesium carbonate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 180℃; for 0.583333h;Microwave irradiation;
A 20 mL oven-dried vial equipped with a teflon cap was charged with Pd2(dba)3 (0.01 eq), cesium carbonate (1.4 eq), and 2'-(dicyclohexylphosphino)-N,N- di methyl biphenyl-2-amine (DavePhos) (0.03 eq). The vial was then capped and purged with nitrogen. Dioxane (1.5 mL) was added, and the resulting suspension was stirred for 15 minutes under an atmosphere of nitrogen. A solution of sulfonamide (1 eq) and heteroaryl chloride (1 eq) in dioxane (1.0 mL/ mmol II) was added. After 5 minutes, the mixture was placed in a microwave and heated at 180C for 30 minutes. The solvent was then filtered through a pad of magnesium sulfate, rinsing with CH2C12. The filtrate was concentrated to provide an orange solid. The solid was redissolved in CH2C12 and the resulting solution was washed with saturated aqueous NaHC03 followed by brine. The combined aqueous layers were extracted twice with CH2C12 and once with EtOAc. The combined organic layers were dried over MgS04, concentrated, and the crude residue was purified by flash chromatography on silica gel (gradient: 0 to 40% methanol/C¾CI2). Following the general procedure, 4-(( ^)-3-mophiholin-4-yl- l-phenylsulfanylmethyl- propylamino)-3-trifluoromethanesulfonyl-benzenesuIfonamide (616 mg, 1.1 mmol) and <strong>[1053656-57-7]4-chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester</strong> (300 mg, 1.1 mmol) afforded the title compound (600 mg, 68% yield). MS (ESI) m/e (M+H+): 787.4
With tetrachloromethane; triphenylphosphine; In 1,2-dichloro-ethane; at 70℃; for 2.5h;Inert atmosphere;
tert-Butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of the product of Intermediate 1, step a (1.26 g, 5.02 mmol) in DCE (36 mL) was added PPh3 (2.69 g, 10.05 mmol) followed by CCl4 (1.46 mL, 15.07 mmol) and the mixture was heated to 70 C. for 2.5 h. The mixture was concentrated in vacuo and chromatographed on SiO2 eluting with EtOAc/Hex to afford the desired compound as a pale yellow solid (1.20 g, 88%). MS (ESI) mass calcd. C12H16ClN3O2, 269.09. m/z found 270.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79 (s, 1H), 4.65 (br s, 2H), 3.80-3.68 (m, 2H), 2.93-2.82 (m, 2H), 1.49 (s, 9H).
87%
STEP C: A mixture of 4-hydroxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7- carboxylic acid ter/-butyl ester ( 1 .4 g, 5.6 mmol) and triphenylphosphine (2.9 g, 1 1.1 mmol) was stirred in DCE (41 mL) until the solution became clear, and then carbon tetrachloride ( 1.6 mL, 16.7 mmol) was added. The reaction mixture was heated to 70C and stirred for 2.5 hours. The volatiles were removed in vacuo and the crude material was directly purified by flash chromatography on silica gel (0-50% EtOAc/ heptanes) to afford the title compound as an off-white solid (1.31 g, 87% yield). MS (ESI) m/e (M+H+): 269.73
81%
With tetrachloromethane; triphenylphosphine; In 1,2-dichloro-ethane; at 70℃; for 1h;
The Preparation of Compound 12: Compound 12F (1.6 g, 6.3 mmol), triphenylphosphine (3.33 g, 12.6 mmol) and tetrachloromethane (2.93 g, 18.9 mmol) were mixed in 1,2-dichloroethane (1,2-DCE, 64 mL), heated to 70 C. for 1 hour. The reaction was monitored via TLC (DCM/Methanol=10:1). The reaction mixture was concentrated and purified by silica gel chromatography to obtain a purified compound 12 (1.38 g, yield: 81%) as a light yellow solid.
81%
With tetrachloromethane; triphenylphosphine; In 1,2-dichloro-ethane; at 70℃; for 1h;
Compound 12F (1.6 g, 6.3 mmol), triphenylphosphine (3.33 g, 12.6 mmol) and tetrachloromethane (2.93 g, 18.9 mmol) were mixed in 1,2-dichloroethane (1,2-DCE, 64 mL), heated to 70 C. for 1 hour. The reaction was monitored via TLC (DCM/Methanol=10:1). The reaction mixture was concentrated and purified by silica gel chromatography to obtain a purified compound 12 (1.38 g, yield: 81%) as a light yellow solid.
Example 59: 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-5,6- dihydropyrido[3,4-d]pyrimidine-7(8H)-sulfonamide Step 1 : 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride A solution of PdCl2(dppf)-CH2Cl2 adduct (0.091 g, 0.1 11 mmol), (2-methoxy-4- (trifluoromethyl)phenyl)boronic acid (0.815 g, 3.71 mmol), tert-butyl 4-chloro-5,6- dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.000 g, 3.71 mmol), and potassium carbonate (2.050 g, 14.83 mmol) in 12 mL of dioxane and 4mL water was heated to 1 10C for one hour. The reaction mixture was then diluted with DCM, the organics were dried over MgS04 and concentrated. The crude residue was treated with HC1 (4N in dioxane) (9.27 ml, 37.1 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was diluted with ether, and the resulting solids were filtered off and dried yielding 4-(2-methoxy- 4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (1.333 g, 3.86 mmol, 104 % yield) as a gray solid with minor impurities. (M+H)+= 310.2.
tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 140℃; for 1.5h;Microwave irradiation; Sealed tube; Inert atmosphere;
Example 11, Step a: tert-Butyl 4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a microwave vial was added Intermediate 2 (136 mg, 0.50 mmol) and Pd(Ph3)4 (29 mg, 0.03 mmol). To these solid reagents were quickly added degassed dioxane (3 mL) and 2-tri-n-butylstannylpyridine (327 mg, 0.75 mmol). The microwave tube was sealed and the reaction heated at 140 C. for 90 min. The mixture was diluted with saturated aqueous KF and stirred for 30 min. EtOAc was added and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product (157 mg, 99%). MS (ESI) mass calcd. C17H20N4O2, 312.16. m/z found 313.2 [M+H]+.
4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With trifluoroacetic acid; In dichloromethane; for 3h;Inert atmosphere;
Intermediate 3, step a: 4-Chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine To Intermediate 2 (521 mg, 1.93 mmol) in DCM (10 mL) was added TFA (4 mL). After stirring 3 h, the mixture was concentrated in vacuo and the residue was redissolved in DCM, cooled to 0 C. in an ice bath and treated with saturated aqueous NaHCO3 solution. After stirring for 30 min, the layers were separated and the aqueous layer extracted with 5% IPA in DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to a very pale yellow solid (304, 93%). This material was used as is without further purification. MS (ESI) mass calcd. C7H8ClN3, 169.04. m/z found 170.1 [M+H]+.
tert-butyl 4-(1H-pyrazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation; Inert atmosphere;
Example 4, Step a: tert-butyl 4-(1H-pyrazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a microwave vial was added Intermediate 2 (113 mg, 0.42 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (138 mg, 0.71 mmol) followed by dioxane (4 mL) and 2M Na2CO3 (0.52 mL). To this mixture was added Pd(PPh3)4 (24 mg, 0.02 mmol) and the reaction heated in the microwave for 1 h at 150 C. The reaction was diluted with water and extracted with DCM and EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product as a slowly crystallizing white solid (97 mg, 77%). MS (ESI) mass calcd. C15H19N5O2, 301.15. m/z found 302.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.96 (s, 1H), 8.21 (s, 2H), 4.68 (s, 2H), 3.82-3.70 (m, 2H), 3.07-2.93 (m, 2H), 1.51 (s, 9H).
tert-butyl 4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃;Inert atmosphere;
Example 109, Step a: tert-butyl 4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) was added 1,2,4 triazole (0.657 mL, 11.1 mmol) in one portion followed by Hunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110 C. overnight. The solvents were removed in vacuo and chromatography on SiO2 eluting with EtOAc/Hex afforded the desired compound (579 mg, 34%). MS (ESI) mass calcd. C14H18N6O2, 302.1. m/z found 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.04 (s, 1H), 7.98 (s, 2H), 4.81-4.75 (m, 2H), 3.75-3.69 (m, 2H), 3.29-3.22 (m, 2H), 1.51 (s, 9H).
tert-butyl 4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃;Inert atmosphere;
Example 110, Step a: tert-butyl 4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) was added 1,2,4 triazole (0.657 mL, 11.1 mmol) in one portion followed by Hunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110 C. overnight. The solvents were removed in vacuo and chromatography on SiO2 eluting with EtOAc/Hex afforded the desired compound (855 mg, 50%). MS (ESI) mass calcd. C14H18N6O2, 302.1. m/z found 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.96 (s, 1H), 8.66-8.61 (m, 1H), 7.87-7.84 (m, 1H), 4.78 (s, 2H), 3.76-3.71 (m, 2H), 3.43-3.36 (m, 2H), 1.51 (s, 9H).
The Preparation of Compound 13: Compound 7 (50 mg, 0.15 mmol) and K2CO3 (62.2 mg, 0.45 mmol) were dissolved in DMSO (2 mL), stirred at room temperature under nitrogen atmosphere for 1.5 hours, and then compound 12 (121.4 mg, 0.45 mmol) was added. The resulted reaction mixture was stirred for 1.5 hours, and monitored via TLC (DCM/methanol=20:1). After the reaction was completed, the reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried with Na2SO4 and concentrated, to obtain a crude product. The crude product was purified by TLC to obtain a purified compound 13 (10 mg, yield: 12.2%) as a white solid.
12.2%
Compound 7 (50 mg, 0.15 mmol) and K2CO3 (62.2 mg, 0.45 mmol) were dissolved in DMSO (2 mL), stirred at room temperature under nitrogen atmosphere for 1.5 hours, and then compound 12 (121.4 mg, 0.45 mmol) was added. The resulted reaction mixture was stirred for 1.5 hours, and monitored via TLC (DCM/methanol=20:1). After the reaction was completed, the reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried with Na2SO4 and concentrated, to obtain a crude product. The crude product was purified by TLC to obtain a purified compound 13 (10 mg, yield: 12.2%) as a white solid.
tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine; In N,N-dimethyl acetamide; at 90℃; for 5h;Sealed tube;
In 2 mL of dimethyl acetamide were combined tert-butyl 4- chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90 C with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSC"4, and concentrated under reduced pressure to a thick oil. The oil was chromatographed (RediSep, 24 g) eluting withl : l ethyl acetate/Hexanes to give tert-butyl 4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.3 g, 2.9 mmol, 77 % yield). ES+APCI MS m/z 454.2 [M+H]+.
77%
With triethylamine; In N,N-dimethyl acetamide; at 90℃; for 5h;Sealed tube;
In 2 mL of dimethyl acetamide were combined <strong>[1053656-57-7]tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate</strong> (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90° C. with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSO 4, and concentrated under reduced pressure to a thick oil. The oil was chromatographed (RediSep , 24 g) eluting with 1:1 ethyl acetate/Hexanes to give tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido [3,4-d]pyrimidine-7(6H)-carboxylate (1.3 g, 2.9 mmol, 77% yield). ES+APCI MS m/z 454.2 [M+H] +.
benzyl 4-(7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate[ No CAS ]
tert-butyl 4-fluoro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With cesium fluoride; In dimethyl sulfoxide; at 70℃; for 3h;
A mixture of <strong>[1053656-57-7]tert-butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate</strong> (200 mg, 0.74 mmol) and cesium fluoride (169 mg, 1.11 mmol) in DMSO (3.7 mL) was heated at 70oC for 3 h. The reaction mixture was diluted with methanol and was purified by preparative HPLC (elution with 10-60% ACN in water containing 0.05% TFA). Fractions containing product were combined, diluted with an aqueous solution of NaHCO3 and extracted with ethyl acetate. Combined organics were dried over MgSO4 and concentrated to afford the title compound (67 mg, 37%) as a yellow semi-solid. [M+H] = 254.1.
tert-butyl 4-cyano-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere;
A mixture of <strong>[1053656-57-7]tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate</strong> (500 mg, 1.85 mmol), DMF (10 mL), dicyanozinc (272 mg, 2.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (214 mg, 0.19 mmol) was degassed by bubbling nitrogen through the mixture for 1 min then the mixture was heated at 90oC for 2 h. The mixture was diluted with ethyl acetate, filtered through Celite, washed with water and brine, dried (MgSO4) and concentrated. The residue was adsorbed to silica and purified by flash chromatography (elution with 0-25% ethyl acetate in heptane) to provide the title compound (374 mg, 78%). 1H NMR (400 MHz, CDCl3) delta 9.14 (s, 1H), 4.74 (s, 2H), 3.81 (t, J = 5.87 Hz, 2H), 3.08 (t, J = 5.75 Hz, 2H), 1.52 (s, 9H).
(R)-tert-butyl 4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃; for 16h;
tert-Butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (226 mg, 0.84 mmol) in DMA (2.5 mL) was treated with (3R)-3-fluoropyrrolidine (1.58 g, 1.26 mmol) and DIEA (0.44 mL, 2.51 mmol) and the mixture was heated at 80oC for 16 h. The mixture was cooled, concentrated under vacuum and the residue was purified by flash LC (elution with 0-75% A in B, where A is 10% methanol in ethyl acetate and B is heptane) to afford the title compound (212 mg, 78%) as a colorless semi-solid. [M+H] = 323.1.
tert-butyl 4-vinyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In water; acetonitrile; at 90℃; for 2h;Inert atmosphere;
A mixture of <strong>[1053656-57-7]tert-butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate</strong> (500 mg, 1.85 mmol), potassium vinyltrifluoroborate (372 mg, 2.78 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (76 mg, 0.09 mmol), ACN (7.4 mL), and aqueous sodium bicarbonate (1 M, 3.3 mL, 3.3 mmol) was degassed for 1 min with nitrogen and then heated to 90oC for 2 h. The mixture was filtered through Celite, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated to a red oil. This material was adsorbed onto silica using DCM and flash chromatography (elution with 0-25% ethyl acetate in heptane) afforded the title compound (300 mg, 62%) as an oil.1H NMR (400 MHz, CDCl3) delta 8.97 (s, 1H), 6.91 (dd, J = 10.64, 16.87 Hz, 1H), 6.68 (dd, J = 1.83, 16.99 Hz, 1H), 5.77 (dd, J = 1.83, 10.64 Hz, 1H), 4.65 (s, 2H), 3.75 (t, J = 5.87 Hz, 2H), 2.89 (t, J = 5.75 Hz, 2H), 1.51 (s, 9H). [M+H] = 262.2.
tert-butyl 4-ethoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In tetrahydrofuran; for 0.25h;
tert- Butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (700 mg, 2.60 mmol) was dissolved in tetrahydrofuran (7 mL). Sodium ethoxide (25% w/w, 1.12 mL, 3.9 mmol) was added and stirring was continued for 15 min. The reaction was quenched with aqueous ammonium chloride (3.5 mL) and water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organics were dried (MgSO4), concentrated and the residue was purified by flash chromatography (elution with 0-60% ethyl acetate in heptane) to afford the title compound (729 mg, 100%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.58 (s, 1H), 5.32 (s, 1H), 4.56 (s, 2H), 4.47 (q, J = 7.05 Hz, 2H), 3.69 (t, J = 5.81 Hz, 2H), 2.70 (t, J = 5.38 Hz, 2H), 1.51 (s, 9H), 1.42 (s, 3H). [M+H] = 280.0.
tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.26%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;
Example 17. Synthesis of Compound 136 Tert-Butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate A mixture of <strong>[393-39-5]4-fluoro-2-(trifluoromethyl)aniline</strong> (6.64 g, 37.074 mmol, 2 equiv), tert-butyl 4-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5 g, 18.537 mmol, 1 equiv), Pd(AcO)2 (0.83 g, 3.707 mmol, 0.2 equiv), XantPhos (4.29 g, 7.415 mmol, 0.4 equiv.) and Cs2CO3 (12.08 g, 37.074 mmol, 2 equiv.) in 1,4-dioxane (80 mL) was stirred at 110 C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography, eluted with PE:EA (20:1 to 1:2) to afford tert-butyl 4-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5.6 g, 73.26%) as a white solid.
tert-butyl 4-[[4-(trifluoromethyl)pyridin-3-yl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.86%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;
Example 22. Synthesis of Compound 131 Tert-butyl 4-[[4-(trifluoromethyl)pyridin-3-yl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate To a stirred mixture of tert-butyl 4-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (500 mg, 1.854 mmol, 1 equiv.) and <strong>[175204-80-5]4-(trifluoromethyl)pyridin-3-amine</strong> (601.03 mg, 3.707 mmol, 2.0 equiv.) in 1,4-dioxane (5 mL) were added Pd(AcO)2 (83.24 mg, 0.371 mmol, 0.2 equiv.) and Cs2CO3 (1207.95 mg, 3.707 mmol, 2.0 equiv.) and XantPhos (429.04 mg, 0.741 mmol, 0.4 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 110 degrees C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3*2 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column:C18,120 g; Mobile Phase A:Water/0.05% NH4HCO3, Mobile Phase B:ACN; Flow rate:45 mL/min; Gradient: 45% B to 65% B in 15 min; Detector, 254 nm and 220 nm, the desired product were collected at 64% B) to afford tert-butyl 4-[[4-(trifluoromethyl)pyridin-3-yl]amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (600 mg, 81.86%) as a white solid.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 2h;
1 Example 1.
Example 1. Synthesis of Compound 100 tert-butyl 4-[4-fluoro-2-(trifluoromethyl)phenoxy]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate To a stirred solution of tert-butyl 4-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (400 mg, 1.48 mmol, 1 equiv.) and 4-fluoro-2-(trifluoromethyl)phenol (400.6 mg, 2.22 mmol, 1.5 equiv.) in acetonitrile (10 mL) was added DBU (451.5 mg, 2.97 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred for 2 h at 80° C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with DCM (3*100 mL). The combined organic layers were washed with brine (3*100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2:1) to afford tert-butyl 4-[4-fluoro-2-(trifluoromethyl)phenoxy]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (110 mg, 17.94%) as a brown solid.
17.94%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 2h;
1 tert-butyl 4- [4-fluoro-2-(trifluoromethyl)phenoxy]-5H,6H,7H,8H-pyrido [3, 4-d] pyrimidine- 7-carboxylate
To a stirred solution of tert-butyl 4-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate(400 mg, 1.48 mmol, 1 equiv.) and 4-fluoro-2-(trifluoromethyl)phenol (400.6 mg, 2.22 mmol, 1.5 equiv.) in acetonitrile(10 mL) was added DBU (451.5 mg, 2.97 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred for 2 h at 80°C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2: 1) to afford tert-butyl 4-[4-fluoro-2- (trifluoromethyl)phenoxy]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate(110 mg, 17.94%) as a brown solid.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;
1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate.
General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;
1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate.
General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;
1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate.
General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;
1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate.
General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).
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