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CAS No. : | 955368-90-8 | MDL No. : | MFCD19443206 |
Formula : | C9H10N4OS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JKBQCALHIQOSTC-UHFFFAOYSA-N |
M.W : | 222.27 | Pubchem ID : | 67171470 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.27 |
TPSA : | 88.87 Ų |
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) : | -6.63 cm/s |
Log Po/w (iLOGP) : | 2.03 |
Log Po/w (XLOGP3) : | 1.44 |
Log Po/w (WLOGP) : | 1.03 |
Log Po/w (MLOGP) : | 0.8 |
Log Po/w (SILICOS-IT) : | 1.73 |
Consensus Log Po/w : | 1.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.37 |
Solubility : | 0.945 mg/ml ; 0.00425 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.91 |
Solubility : | 0.272 mg/ml ; 0.00123 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.6 |
Solubility : | 0.553 mg/ml ; 0.00249 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.42 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H320-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 72h;Reflux; | DIPEA (20.8 ml, 120 mmol) and allyl hydrazine 5 (8.23 g, 47.8 mmol) were added to a solution of ethyl 4-chloro-2-methylthio- 5-pyrimidinecarboxylate (6; 1 1.1 g, 47.8 mmol) in THF (150 ml). The reaction mixture was heated at reflux for 72 h, before being concentrated in vacuo. Et20 (50 ml) was added to the residue, and the resultant precipitate was collected by filtration. The filtrate was evaporated to dryness, and the residue was cooled in an ice bath, after which TFA (40 ml) was added. The resultant solution was stirred at RT for 1 h, followed by 70 C for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (50 ml) and cooled in an ice bath, after which 6M NaOH (75 ml) was added. The resultant solution was stirred at RT for 15 min, before 32 being acidified via the addition of cone. HCI (40 ml). The orange solution was evaporated to dryness and the resultant residue was partitioned between chloroform (100 ml) and water (100 ml), and the organic phase was washed with brine (50 ml), dried (Mg2S04), concentrated in vacuo, and triturated with hexanes. The solid precipitate was washed with EtOH and Et20, before being dried under vacuum to give the target compound as a yellow solid (5.44 g, 24.5 mmol, 51 %). Rf 0.45 (9:1 DCM:MeOH); M.p. 125- 128 C; IR (cm-1 ) 3032, 2979, 2926, 2659, 1656, 161 5, 1 566, 1 514; 1 H NMR (400 M Hz, DMSO-d6)2.53 (3H, s, -SCH3), 4.38 (2H, dapp, J = 5.2 Hz, N2-CH2), 5.06-5.20 (2H, m, allyl C-Hcis/trans), 5.87 (1 H, ddt, J = 17.2, 10.5, 5.3 Hz, alkene C-H), 8.67 (1 H, s, H-4), 12.65 (1 H, -1 ); MS [M + H] + m/z 223.1. |
260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2-(methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70 C. for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid.1H-NMR (400 MHz, DMSO-d6) ?: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13 (1.0H, d, J=9.8 Hz), 5.06 (1.0H, d, J=17.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s).ESI-MS Found: m/z[M+H]+ 223.3. | ||
2) Production of 2-allyl-6-(methylthio)-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one:260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, DMSO-d6) delta: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13(l.OH, d, J=9.8 Hz), 5.06 (1.0H, d, J=I 7.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s). ESI-MS Found: m/z[M+H]+ 223.3. |
260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. (0207) The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;copper diacetate; In chloroform; at 20℃; for 72h; | 1) Production of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate 20 mL of pyridine was added to a chloroform solution of 7.5 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 6.1 g of copper(II) acetate and 10 g of [3-(methoxycarbonyl)]phenylboronic acid, and stirred at room temperature for 3 days. Aqueous 30% ammonia solution and saturated saline water were added to the reaction liquid in that order, and extracted with chloroform. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 6.7 g of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oily substance. 1H-NMR (400 MHz, CDCl3) delta: 8.92 (1H, s), 8.11-8.06 (2H, m), 7.65-7.59 (2H, m), 5.68 (1H, ddd, J=17.1, 10.2, 5.9 Hz), 5.13 (1H, dd, J=10.2, 1.0 Hz), 4.97 (1H, dd, J=17.1, 1.0 Hz), 4.45 (2H, d, J=5.9 Hz), 3.96 (3H, s), 2.51 (3H, s). | |
With pyridine;copper diacetate; In chloroform; at 20℃; for 72h; | Production Example 11 Production of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate Pyridine (20 mL) was added to a chloroform solution of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong> (7.5 g), copper(II) acetate (6.1 g) and [3-(methoxycarbonyl)]phenylboronic acid (10 g), and stirred at room temperature for 3 days. Aqueous 30 % ammonia solution and saturated saline water were added to the reaction liquid in order, and extracted with chloroform. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oil (6.7 g). 1H-NMR (400 MHz, CDCl3) delta: 8.92 (1H, s), 8.11-8.06 (2H, m), 7.65-7.59 (2H, m), 5.68 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.13 (1H, dd, J = 10.2, 1.0 Hz), 4.97 (1H, dd, J = 17.1, 1.0 Hz), 4.45 (2H, d, J = 5.9 Hz), 3.96 (3H, s), 2.51 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; at 95℃; | 1) Production of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one 2.4 mL of N,N'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J=10.2 Hz), 4.91 (1H, d, J=17.0 Hz), 4.85 (1H, d, J=6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300. | |
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; | Reference Example 1 :Production of 2-allyl-6-fmethylthio)-l-pyridin-2-yl-3H-pyrazolo[3,4-d1pyrimidin-3-one2.4 mL of N,N'-dimethyl ethyl enediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3,80 <n="30"/>g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.8O g of potassium carbonate, and stirred overnight at 95C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. 1 H-NMR (400 MHz, CDCI3) delta: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz),7.29-7.25 (IH, m), 5.68 (IH, ddt, J=I 7.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=I 7.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300. | |
With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; | 1) Production of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one: N,N'-dimethylethylenediamine (2.4 mL) was added to a 1,4-dioxane (50 mL) solution of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong> (4.44 g), copper(I) iodide (3.80 g), 2-iodopyridine (5.33 g) and potassium carbonate (3.80 g), and stirred overnight at 95C. The reaction liquid was cooled, then aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was crystallized with ethyl acetate to give the entitled compound as a white solid (5.15 g). 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J = 5.1 Hz), 7.90 (2H, d, J = 3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J = 17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J = 10.2 Hz), 4.91 (1H, d, J = 17.0 Hz), 4.85 (2H, d, J = 6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300. |
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; | Production of 2-allyl-6-(methylthio)- 1 -pyridin-2-yl-3 H-pyrazolo [3 ,4-d]pyrimidin-3 -one : 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(memyltWo)-l,2-dmydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3,80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. iH-NMR (400 MHz, CDCI3) 5: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s). | |
5.15 g | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; | Preparative Example 1-1 Production of 2-allyl-6-(methylthio)-l-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one: 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. lH-NMR (400 MHz, CDCI3) delta: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s). |
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; | 2.4 mL of N,N'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain the entitled compound as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J=10.2 Hz), 4.91 (1H, d, J=17.0 Hz), 4.85 (1H, d, J=6.3 Hz), 2.58 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 12h; | Step-2: Synthesis of 2-allyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of ethyl 4-(2-allyl-2-tert-butoxycarbonyl-hydrazino)-2-methylsulfanyl-pyrimidine-5-carboxylate (3.0 g, 8.19 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added TFA (10 mL) dropwise at 0 C. and allowed to stir at RT for 12 h. After completion of reaction, solvent was removed under reduced pressure. Residue was diluted with EtOH (20 mL) and 6N NaOH solution (10 mL) was added at 0 C. and allowed to stir at RT for 1 h. After completion of reaction, the mixture was acidified by using 6N HCl solution. EtOH was removed under reduced pressure; residue obtained was cooled to RT and extracted with chloroform (50 mL*3). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-allyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-one (1.40 g, 76%) as a yellow solid. |
N,N-diisopropylethylamine (260 mL) and the hydrazine (106 g) obtained in the above 1 were added to a tetrahydrofuran (1.5 L) solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (142 g), and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, then diethyl ether (500 mL) was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, then trifluoroacetic acid (400 mL) was gradually added thereto, stirred at room temperature for 1 hour, and further stirred at 70C for 1 hour. The reaction solution was evaporated under reduced pressure, then ethanol (500 mL) was added thereto, and cooled in an ice bath, and then 6 N potassium hydroxide solution (1.0 L) was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was acidified with concentrated hydrochloric acid (400 mL), and then evaporated under reduced pressure. The residue was partitioned between chloroform and water, then the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the formed yellow solid was collected through filtration, washed with ethanol and diethyl ether, and dried to give the entitled compound as a yellow solid (99.1 g). 1H-NMR (400 MHz, DMSO-d6) delta: 8.66 (1H, brs), 5.83 (1H, ddt, J = 17.1, 9.8, 5.4 Hz), 5.13 (1H, d, J = 9.8 Hz), 5.06 (1H, d, J = 17.1 Hz), 4.34 (2H, d, J = 5.4 Hz), 2.51 (3H, s). ESI-MS Found: m/z[M+H]+ 223. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 1h;Inert atmosphere; | N,N'-dimethylethylenediamine (87.25 mg, 989.79 mumol) was added into the mixture of I1 (200.00 mg, 899.81 mumol), cuprous iodide (171.37 mg, 899.81 mumol), 2-trifluoromethyl-6-bromopyridine (209.45 mg, 926.80mumol) and potassium carbonate (174.11 mg, 1.26 mumol) in 3 mL dioxane, the mixture was heated to 95C and stirred for 1 hour under nitrogen atmosphere. The reaction was monitored to be complete by LCMS. The reaction mixture was cooled down, 30 mL ammonia was added, then extracted by EtOAc (10 mL×2), then washed by saturated brine, dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to give the pale brown colloidal product, which was purified by column chromatography (PE/EtOAc =4/1-3/1) to give the compound 46-A. 1H NMR (400MHz, CDCl3) delta = 8.89 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 5.64 -5.54 (m 1H), 4.94 (d, J=10.4 Hz, 1H), 4.90 - 4.83 (m, 3H), 2.54 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 12h;Inert atmosphere; | I1 (1.0 g, 4.5 mmol) was added into 1,4- dioxane (10 mL), and 2-bromo-6-methoxylpyridine (1.02 g, 5.4 mmol, 664 muL), potassium carbonate (622 mg, 4.5 mmol), cuprous iodide (857 mg, 4.5 mmol) and N,N'-dimethylethylenediamine (397 mg, 4.5 mmol, 490 muL) were added while stirring, heated to 95C under nitrogen atmosphere, then reacted for 12 h. 100 mL ammonia was added into the reacted mixture, then extracted by 100 mL EA, the organic phase was washed by 100 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was crystalized by EtOAc, then purified by silica gel chromatography (PE/EA = 10/1 to 2/1), to give the compound 47-1. 1H NMR (400MHz, CDCl3) delta = 8.92 (s, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.83 - 5.69 (m, 1H), 5.07 (d, J=10.4 Hz, 1H), 4.96 (br d, J=17.2 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 3.93 (s, 3H), 2.56 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.44% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃;Inert atmosphere; | Into a 25 mL microwave vial was added 2-allyl-6-(methylthio)-1H-pyrazolo[3,4- d]pyrimidin-3(2H)-one (275 mg, 1.235 mmol) (obtained according to EP2213673B1, Production Example 1, p37), [(5-bromopyridin-3-yl)imino]dimethyl-A6-sulfanon (400 mg, 1.61 mmol), potassium carbonate (239 mg, 1.73 mmol) and dioxane (5 mL). The resultant suspension was degassed (bubbling of N2) and copper (I) iodide (235 mg, 1.235 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.133 mL,1.24 mmol). The vial was capped and the reaction mixture was stirred at 95 00 overnight. After cooling to RT the reaction mixture was transferred to a separation funnel, NH4OH (aq, 20 mL) was added and the resulting mixture was extracted with EtOAc (3 x 30 mL). The organic phases were combined, dried and evaporated under vacuum. The residue was purified using flash chromatography (0-15% MeOH in EtOAc). The product containing fractions were concentrated to give the title compound (60 mg, 12.44 % yield) as an yellowish oil that solidified upon storage. LCMS (Method C): RT = 0.99 mi mlz = 391 [M+H].1H NMR (300 MHz, ODd3) O 9.21 (5, 1H), 8.64 (5, 1H), 8.57 (5, 1H), 8.12 (5, 1H),5.70-5.41 (m, 1H), 5.17 (t, J = 5.1 Hz, 1H), 4.96 (d, J = 17.0 Hz, 2H), 4.53 (d, J = 6.0 Hz, 2H), 3.31 (5, 6H), 2.53 (5, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃;Inert atmosphere; | Into a 25 mL microwave vial was added 2-allyl-6-(methylthio)-1H-pyrazolo[3,4- d]pyrimidin-3(2H)-one (355 mg, 1.60 mmol)) [Prepared according to EP2213673B1 (Production Example 1, p37)], [(2-bromopyrimidin-4-yI)imino]dimethyl-A 6-sulfanone (520 mg, 2.08 mmol), K2003 (309 mg, 2.24 mmol) and dioxane (7 mL). The resultant suspension was degassed (bubbling of N2) and copper (I) iodide (305 mg, 1.60 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.172 mL, 1.60 mmol). The vial was flushed with nitrogen and capped and the reaction mixture was stirred vigorously at 95 00 overnight. The reaction mixture was transferred to a separation funnel, NH4OH (aq) was added (20 mL) and the mixture was extracted with EtOAc (3 x 30 mL). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. The residue was purified by flash chromatography (0- 15% MeOH in EtOAc) and the product containing fractions were concentrated to give the title compound as a white solid (353 mg, 56%).LCMS (Method C): RT = 0.96 mi mlz = 392 [M+H].1H NMR (300 MHz, ODd3) O 8.96 (5, 1H), 8.32 (d, J= 5.7 Hz, 1H), 6.61 (d, J= 5.7 Hz, 1H), 5.75-5.62 (m, 1H), 5.13-4.83 (m, 4H), 3.60 (5, 6H), 2.63 (5, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 18h;Inert atmosphere; | To a 25 mL reactor were added 2-allyl-6-(methylthio)-1 H-pyrazolo[3,4-d]pyrimidin- 3(2H)-one (202 mg, 0.909 mmol) (obtained according to EP2213673B1, Production Example 1, p37), (S)-[(6-bromopyridin-2-yl)imi no](methyl)phenyl-26-sulfanone (283 mg, 0.909 mmol), K2003 (277 mg, 2.001 mmol) and dioxane (4 mL). The resultant suspension was flushed with nitrogen and copper (I) iodide (173 mg, 0.909 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.098 mL, 0.909 mmol). The reactor was capped and the temperature was increased to 95 00. After 18 h of intensive stirring, LCMS confirmed accomplished conversion. The reaction mixture was cooled to RT, NH4OH (aq) was added (5 mL) followed by water (5 mL) and the reaction mixture was extracted using EtOAc (3 x 50 mL), the organic phases were combined, dried (anh. MgSO4) and evapoarted under reduced pressure. The residue was purified using flash chromatography (0-20% MeOH in EtOAc). The product containing fractions were concentrated to give thetitle compound (269 mg, 65 % yield) as a white solid.LCMS (Method C): RT = 1.32 mi mlz = 453 [M+H].1H NMR (300 MHz, ODd3) O 8.84 (5, 1H), 7.95 (dd, J= 7.7, 1.6 Hz, 2H), 7.65 (t, J=7.9 Hz, 1H), 7.60-7.42 (m, 3H), 7.31-7.26 (m, 1H), 6.79 (d, J= 8.0 Hz, 1H), 5.63-5.42 (m, 1H), 4.95 (d, J= 9.5 Hz, 1H), 4.85 (d, J= 18.0 Hz, 1H), 4.74 (dd, J= 15.9, 6.3 Hz, 1H), 4.53 (dd, J= 15.9, 6.2 Hz, 1H), 3.33 (5, 3H), 2.54 (5, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 18h;Inert atmosphere; | In a 25 mL reaction vial were added 2-allyl-6-(methylthio)-1 H-pyrazolo[3,4- d]pyrimidin-3(2H)-one) [Prepared according to EP2213673B1 (Production Example 1, p37)] (80 mg, 0.361 mmol), [(6-bromopyridin-2-yl)methyl]imino}dimethyl-26- sulfanone (95 mg, 0.361 mmol), K2003 (110 mg, 0.794 mmol) and dioxane (2 mL). The resultant suspension was flushed with nitrogen and copper (I) iodide (68.8 mg,0.361 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.039 mL,0.361 mmol). The vial was capped and the temperature was increased to 95 00. After 18 h of intensive stirring, LCMS confirmed accomplished conversion. The reaction mixture was cooled to RT. NH4OH (aq) was added (10 mL) followed by water (10 mL) and the reaction mixture was extracted using EtOAc (3 x 50 mL). The organic phases were combined, dried (anh. MgSO4) and evaporated under reduced pressure. The residue was purified using flash chromatography (0-20% MeOH in DCM). The product containing fractions were evaporated under reduced pressure yielding the title compound as yellowish oil (74 mg, 51%).LCMS (Method C): RT = 0.90 mi mlz = 405 [M+H].1H NMR (300 MHz, ODd3) O 8.92 (5, 1H), 7.87 (t, J= 7.8 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 7.5 Hz, 1H), 5.76-5.59 (m, 1H), 5.02 (d, J= 9.6 Hz, 1H), 4.92 (d, J = 17.1 Hz, 1H), 4.84 (d, J= 6.3 Hz, 2H), 4.41 (5, 2H), 3.11 (5, 6H), 2.56 (5, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyridine; copper diacetate; In chloroform; at 20℃; for 120h; | Pyridine (1.46 mL, 18.0 mmol) was added to a stirred solution of 2-allyl-6- (methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (500 mg, 2.25 mmol) [Prepared according to EP2213673B1 (Production Example 1, p37)], copper(ll) acetate (409 mg, 2.25 mmol) and (3-bromophenyl)boronic acid (745 mg, 3.71 mmol) in chloroform (5.0 mL) at RT in an open flask. After 5 days, ammonium hydroxide solution (aq) (30 mL) and brine (30 mL) were added and the resulting mixture was extracted using EtOAc (3 x 20 mL). The combined organic phase was dried (Phase Separator), the solvents were removed in vacuo and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (587 mg, 69%) as an orange solid.LCMS (Method A): RT = 1.38 mi mlz = 377, 379 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃;Microwave irradiation; Inert atmosphere; | Into a 25 mL microwave vial was added 2-allyl-6-(methylthio)-1H-pyrazolo[3,4- d]pyrimidin-3(2H)-one (355 mg, 1.60 mmol) (obtained according to EP2213673B1, Production Example 1, p37), [(6-bromopyrazin-2-yl)im ino]dimethyl-lambda6-sulfanone (520 mg, 2.08 mmol), K2003 (309 mg, 2.24 mmol) and dioxane (7 mL). The resultant suspension was degassed and copper (I) iodide (305 mg, 1.60 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.172 mL, 1.60 mmol). The vial was flushed with nitrogen, capped and the temperature was increased to 95 00. The reaction mixture was stirred vigorously overnight. After cooling to RT the reaction mixture was transferred to a separation funnel and NH4OH (20 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL).The organic extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (0-15% MeOH in EtOAc). The product containing fractions were concentrated to give the title compound (224 mg, 36%) as a white solid.LCMS (Method C): RT = 1.03 mi mlz = 392 [M+H].1H NMR (300 MHz, ODd3) O 8.93 (5, 1H), 8.72 (bs, 1H), 8.07 (bs, 1H), 5.78-5.47 (m, 1H), 5.14-4.80 (m, 4H), 3.37 (5, 6H), 2.62 (5, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 20℃; for 1h; | Copper(l) iodide (42.2 mg, 0.222 mmol) was added to a stirred suspension of 2-allyl- 6-(methylthio)-1 H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (49.3 mg, 0.222 mmol) [Prepared according to EP221 3673B1 (Production Example 1, p37)], [(6- bromopyridin-2-yl)(methyl)oxo-lambda6-sulfanylidene](cyano)am ine* (75 mg, 0.288 mmol), N,N-dimethylethane-1,2-diamine (0.024 mL, 0.222 mmol), potassium carbonate (42.9 mg, 0.311 mmol) in 1 ,4-dioxane (1.0 mL) at RT. After 1 h, the temperature was increased to 95 00. After 20 h, the reaction mixture was cooled to RT and partitioned between NH4OH (aq) solution and extracted using EtOAc (x 3), the combined organic phase was dried, the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (10.1 mg, 11%) as a pale yellow oil.LCMS (Method A): RT = 0.99 mi mlz = 402 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 18h; | N, N?Dimethylethane-1,2-diamine(0.232 mL, 2.15 mmol) was added to a stirred solution of 2-allyl-6-(methylthio)-1 H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (478 mg, 2.153 mmol) [Prepared according to EP2213673B1 (Production Example 1, p37)], ethyl N-[(6- bromopyridin2yl)(methyl)oxolambda6sulfanylidene]carbamate* (661 mg, 2.15 mmol), copper (I) iodide (410 mg, 2.15 mmol), and potassium carbonate (417 mg, 3.01 mmol) in 1 ,4-dioxane (5.0 mL) at RT. The reaction mixture was heated to 95 00. After 18 h, the reaction mixture was partitioned between saturated ammonium hydroxide (aq) solution and EtOAc, separated, extracted (EtOAc x 3), organics combined, washed with brine, dried (Phase Separator), the solvents were removed in vacuo, and the remaining residue was purified by flash chromatography (0-100%, EtOAc in cyclohexane) to give the title compound (607 mg, 63%) as a colourless oil. LCMS (Method A): RT = 1.04 mm, m/z = 403 [M-OEt]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 20h; | N, N-dimethyiethane- 1 ,2-diamine (0.023 m L,0.213 mmoi) was added to a stirred soiution of 2-aiiyi-6-(methyithio)- 1 H-pyrazoio[3,4- d]pyrimidin-3(2H)-one (47.3 mg, 0.213 mmoi) [Prepared according to EP2213673B1 (Production Exampie 1, p37)], [(6-bromopyridin-2-yi)(methyi)oxo-lambda6- suifanyiidene](methyi)amine (53.1 mg, 0.213 mmoi), copper(i) iodide (40.6 mg, 0.213 mmoi), and potassium carbonate (41.2 mg, 0.298 mmoi) in 1,4-dioxane (1.0 mL) at RT. The reaction mixture was heated to 95 00 After 20 h, the reaction mixture was partitioned between saturated ammonium hydroxide (aq) soiution and EtOAc, separated, extracted (EtOAc x 3), organics combined, dried (Phase Separator), the soivents were removed in vacuo, and the remaining residue was purified by fiash chromatography (0-100%, EtOAc in cyciohexane) to give the titie compound (7.1 mg, 9%) as a paie yeiiow oii.LCMS (Method A): RT = 0.91 mm, mlz = 391 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; | Compound 3.2 (1.9 g, 8.29 mmol),<strong>[955368-90-8]2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one</strong> (1.84 g, 8.29 mmol),Cuprous iodide (1.5 g, 8.29 mmol),Anhydrous potassium carbonate (2.35 g, 17 mmol)And N,N-dimethylethylenediamine (0.73g, 8.29mmol)Add to 1,4-dioxane (30 mL),The reaction system was stirred at 100 C overnight.Cool to room temperature,Filter the reaction solution,The filtrate is concentrated,The residue was purified by silica gel column chromatography (EtOAc /EtOAcCompound 3-1 (1.56 g, yield: 51%) was obtained as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Compound 3.3 (53 g, 0.18 mol)And <strong>[955368-90-8]2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one</strong> (35.7 g, 0.61 mol)Soluble in 1,4-dioxane (530mL)And N,N-dimethylformamide (53 mL),To this was added cuprous iodide (34 g, 178 mmol)And cesium carbonate (116 g, 356 mmol).After 5 minutes, N,N'-dimethylethylenediamine (15.7 g, 178 mmol) was added.Under nitrogen protection,The mixture was stirred at 100 C overnight.The mixture was diluted with ethyl acetate and washed with water.The organic phase was separated and dried over anhydrous sodium sulfate.filter,concentrate.The residue was purified by silica gel column chromatography (EtOAc /EtOAcCompound 4-1 (42 g, yield: 54%) was an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 100℃; | Compound 7-1 (1.7 g, 4.37 mmol),<strong>[955368-90-8]2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one</strong> (971.3 mg, 4.37 mmol),Cuprous iodide (835mg, 4.37mmol),N,N-dimethylethylenediamine (385 mg, 4.37 mmol)And potassium carbonate (1.21 g, 8.74 mmol)Dissolved into 1,4-dioxane (40mL)In a mixed solution with N,N-dimethylformamide (4 mL),The reaction system was stirred at 100 C overnight.The reaction solution was cooled to room temperature.filter,The filtrate is concentrated,The residue was purified by silica gel column chromatography (EtOAc /EtOAcCompound 7-2 (270 mg, yield: 12%) was an oily liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | With pyridine; copper diacetate; In chloroform; at 60℃; for 16h; | 2-Allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (324 mg, 1.46 mmol),Compound 4.2 (400 mg, crude),Copper acetate (358mg, 2.92mmol)And pyridine (3mL)Add to chloroform (30 mL).The reaction system was stirred at 60 C for 16 hours.The reaction solution was directly concentrated under reduced pressure and then purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 4/1)Purification afforded Compound 5-1 (150 mg, yield: 23%) as a colourless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; | Compound 1.1 (255 mg, 1 mmol),<strong>[955368-90-8]2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one</strong> (222 mg, 1 mmol),Cuprous iodide (191 mg, 1 mmol),Anhydrous potassium carbonate (276 mg, 2 mmol)And N,N-dimethylethylenediamine (88 mg, 1 mmol)Add to 1,4-dioxane (20 mL),The reaction system was stirred at 100 C overnight.The reaction solution was then cooled to room temperature.filter,The filtrate is concentrated,The residue was purified by silica gel column chromatography (EtOAc /EtOAcCompound 1-1 (205 mg, yield: 52%) was a red liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; for 16h; | Compound 2.2 (200 mg, 0.67 mmol), <strong>[955368-90-8]2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one</strong> (179 mg, 0.81 mmol), Anhydrous potassium carbonate (186 mg, 1.35 mmol)), Cuprous iodide (128 mg, 0.67 mmol), N,N-dimethylethylenediamine (59 mg, 0.67 mmol) Add to 1,4-dioxane (20 mL), The reaction system was stirred at 100 C for 16 hours. Cool to room temperature, Concentrate the reaction solution, Purified with prep-TLC (petroleum ether/ethyl acetate = 1/1) Compound 2-1 (160 mg, yield: 54%) was obtained as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium on activated carbon; hydrogen; In methanol; under 3102.97 Torr; for 12h; | Step-1: Synthesis of 6-(methylthio)-2-propyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-on (2.0 g, 8.9 mmol, 1.0 eq) in dry MeOH (50 mL), Pd/C (10 wt %) (200 mg) was added under stirring under inert atmosphere in Parr vessel. The reaction was stirred in Parr reactor at 60 psi hydrogen pressure 12 h. The reaction was monitored by LCMS. After completion the mixture was filtered through celite and concentrated to afford, 6-(methylthio)-2-propyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one as yellow solid (1.318 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With [2,2]bipyridinyl; copper diacetate; sodium carbonate; In dichloromethane; at 20℃; for 24h; | Step-1: 2-allyl-1-(2-(tert-butyl)pyridin-4-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong> (540 mg, 2.43 mmol, 1 eq) and 2-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.26 g, 4.84 mmol, 2 eq) in DCM (50 mL) was added 2,2-bipyridine (756 mg, 4.84 mmol, 2 eq), copper acetate (880 mg, 4.84 mmol, 2 eq) and Na2CO3 (773 mg, 7.29 mmol, 3 eq). The reaction mixture was stirred at rt for 24 h in open air. The progress of reaction was monitored by TLC. After completion, the reaction mixture was filtered over celite to remove inorganic impurities. The filtrate was washed with water, dried over Na2SO4, concentrated and purified by column chromatography (Combiflash, Elution: 0-30% EtOAc in Hexane) to afford the desired product, 2-allyl-1-(2-(tert-butyl)pyridin-4-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (380 mg, 44%) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | General procedure: (0211) General procedure for the synthesis of pyrazolopyrimidinones. DIPEA (2.5 equiv.) and the relevant hydrazine (1.05 equiv.) were added to a solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (1.0 equiv.) in THF (3 mL/mmol). The reaction mixture was heated at reflux for 72 h, before being concentrated in vacuo. Et20 (1 mL/mmol) 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 (1 mL/mmol) was added. The resultant solution was stirred at RT for 1H, followed by 70 C for 1H. The solvent was removed in vacuo and the residue was dissolved in EtOH (1 mL/mmol) and cooled in an ice bath, after which 6M NaOH (2 mL/mmol) was added. The resultant solution was stirred at RT for 15 min, before being acidified (pH 3) via the addition of cone. HCI. The solution was evaporated to dryness and the resultant residue was partitioned between chloroform (2 mL/mmol) and water (2 mL/mmol), and the organic phase was washed with brine (1 mL/mmol), dried (Mg2S04), and concentrated in vacuo to afford the target compound. Synthesis of 1 -(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. Ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (0.480 g, 2.06 mmol), tert-butyl 1-methylhydrazine-1-carboxylate (0.316 g, 2.16 mmol) and DIPEA (1.87 mL, 10.7 mmol) were reacted in THF (6 mL) according to the described general procedure. Purification on KP-NH silica (4:1 (0214) DCM:MeOH) yielded the desired compound as a yellow solid (0.302 g, 1.54 mmol, 75%). Rf 0.23 (4:1 DCM:MeOH); M.p. 256-265 C (decomposed); IR (cm 1) 3336, 3024, 2940, 1683, 1638, 1587; 1 H NMR (400 MHz, DMSO-d6) 2.53 (3H, s, SCH3), 3.36 (3H, s, N2-CH3), 8.68 (1 H, s, H-4), 12.60 (1 H, br s, N1-H); 13C NMR (100 MHz, DMSO-d6) 13.9 (SCH3), 31.0 (N2-CH3), 103.8, 158.1; MS [M + H]+ m/z 196.8. |
Tags: 955368-90-8 synthesis path| 955368-90-8 SDS| 955368-90-8 COA| 955368-90-8 purity| 955368-90-8 application| 955368-90-8 NMR| 955368-90-8 COA| 955368-90-8 structure
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Precautionary Statements-General | |
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P103 | Read label before use |
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Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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