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With acetic acid In water for 0.25 h; Inert atmosphere
Sodium pyrazolo[l,5-α]pyrinidin-5-olate (13.47g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane methanol solution. The combined dichloromethane methanol solution was concentrated to dryness. The solid product was suspended in 1 :1 hexane: dichloromethane and filtered to yield 9.9 g (85percent) pyrazolo[l,5- α]pyrimidin-5(4H)-one. LCMS (ESI) m+H = 136.0; 1H NMR (400 MHz, DMSO-^) δ: 12.1 (s broad exchangeable, 1 H), 8.47 (d, 1 H, J=7.9), 7.75 (d, 1 H, J=I.9), 5.94 (d, IH, J=7.5), 5.81 (d, 1 H, J=1.7).
85%
With acetic acid In water for 0.25 h; Inert atmosphere
Sodium pyrazolo[1,5-a]pyrimidin-5-olate (13.47 g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane:methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane:methanol solution. The combined dichloromethane:methanol solution was concentrated to dryness. The solid product was suspended in 1:1 hexane:dichloromethane and filtered to yield 9.9 g (85percent) pyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) δ: 12.1 (s broad exchangeable, 1H), 8.47 (d, 1H, J=7.9), 7.75 (d, 1H, J=1.9), 5.94 (d, 1H, J=7.5), 5.81 (d, 1H, J=1.7).
Reference:
[1] Patent: WO2010/51549, 2010, A1, . Location in patent: Page/Page column 42; 75
[2] Patent: US2012/22043, 2012, A1, . Location in patent: Page/Page column 33
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10090 - 10107
With sodium ethanolate; In ethanol; for 1h;Reflux; Inert atmosphere;
A mechanically stirred mixture of 3-aminopyrazole (9.38 g, 0.11 mM, 1.0 equiv), <strong>[874-14-6]1,3-dimethyluracil</strong> (14.7 g, 0.11 mM, 1.0 equiv) and 21percent sodium ethoxide in ethanol (170 mL, 5.0 equiv) was heated to reflux. Within minutes, a heavy precipitate formed. After refluxing for 1 hour, <strong>[874-14-6]1,3-dimethyluracil</strong> could no longer be detected by thin layer chromatography (tic) (92:8 dichloromethane (dichloromethane):MeOH). The reaction mixture was cooled, filtered, washed with cold ethanol and vacuum dried to give 13.47 g (95percent) of sodium pyrazolo[l,5-alpha]pyrimidin-5-olate. LCMS (ESI) m+H = 136.0; 1H NMR (400 MHz, OMSO-d6) delta: 8.0 (d, 1 H), 7.43 (d, 1 H), 5.65 (d, IH), 5.37 (d, 1 H).
95%
With sodium ethanolate; In ethanol; for 1h;Reflux; Inert atmosphere;
A mechanically stirred mixture of 3-aminopyrazole (9.38 g, 0.11 mM, 1.0 equiv), <strong>[874-14-6]1,3-dimethyluracil</strong> (14.7 g, 0.11 mM, 1.0 equiv) and 21percent sodium ethoxide in ethanol (170 mL, 5.0 equiv) was heated to reflux. Within minutes, a heavy precipitate formed. After refluxing for 1 hour, <strong>[874-14-6]1,3-dimethyluracil</strong> could no longer be detected by thin layer chromatography (tlc) (92:8 dichloromethane (dichloromethane):MeOH). The reaction mixture was cooled, filtered, washed with cold ethanol and vacuum dried to give 13.47 g (95percent) of sodium pyrazolo[1,5-a]pyrimidin-5-olate. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) delta: 8.0 (d, 1H), 7.43 (d, 1H), 5.65 (d, 1H), 5.37 (d, 1H).
With acetic acid; In water; for 0.25h;Inert atmosphere;
Sodium pyrazolo[l,5-alpha]pyrinidin-5-olate (13.47g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane methanol solution. The combined dichloromethane methanol solution was concentrated to dryness. The solid product was suspended in 1 :1 hexane: dichloromethane and filtered to yield 9.9 g (85%) pyrazolo[l,5- alpha]pyrimidin-5(4H)-one. LCMS (ESI) m+H = 136.0; 1H NMR (400 MHz, DMSO-^) delta: 12.1 (s broad exchangeable, 1 H), 8.47 (d, 1 H, J=7.9), 7.75 (d, 1 H, J=I.9), 5.94 (d, IH, J=7.5), 5.81 (d, 1 H, J=1.7).
85%
With acetic acid; In water; for 0.25h;Inert atmosphere;
Sodium pyrazolo[1,5-a]pyrimidin-5-olate (13.47 g) was dissolved in 500 mL of acetic acid and 100 mL of water, stirred 15 minutes then evaporated to dryness under vacuum. The residue was suspended in 300 mL of 9:1 dichloromethane:methanol and vacuum filtered through silica gel to remove sodium acetate. The silica gel pad was washed with 700 mL of additional dichloromethane:methanol solution. The combined dichloromethane:methanol solution was concentrated to dryness. The solid product was suspended in 1:1 hexane:dichloromethane and filtered to yield 9.9 g (85%) pyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) delta: 12.1 (s broad exchangeable, 1H), 8.47 (d, 1H, J=7.9), 7.75 (d, 1H, J=1.9), 5.94 (d, 1H, J=7.5), 5.81 (d, 1H, J=1.7).
With sodium ethanolate; In ethanol; at 75℃;Inert atmosphere;
10405] A solution of 1H-pyrazol-5-amine and 1,3-dimeth- ylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer,steam pot, a reflux condenser, a J-Kem temperature probe and an N2 adaptor for positive N2 pressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOR under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt percent solution in EtOR), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOR. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1 .5 area percent of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC tofollow the progression of the reaction using 20 tL of slurry diluted in 4 mE deionized water and 5 tE injection at 220 mm10406] After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mE/g) of heptane and then refluxed at 70° Celsius for 1 hout The slurry was then cooled to room temperature overnight. The solid was collected by filtrationa tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mE/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1 ,5-a] -pyrimidin-5-olate was obtained in 93-96percent yield (corrected) and larger than 99.5 area percent observed by HPEC (1 mgmE dilution in deionized water, TRK1PM1 at 220 nm).
With sodium ethanolate; In ethanol; at 75℃;Inert atmosphere;
A solution of lH-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(lH,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an N2 adaptor for positive N2 pressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wtpercent solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area percent of 1H-pyrazol-5-amine was observed by TRK1PM1 E1PLC to follow the progression of the reaction using 20 pL of slurry diluted in 4 mL deionized water and 5 pL injection at 220 nm. After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[l,5-a]-pyrimidin-5-olate was obtained in 93-96percent yield (corrected) and larger than 99.5 area percent observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).
With nitric acid In water at 10 - 40℃; Inert atmosphere;
A.B Step B-Preparation of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one:
A tared round bottom flask was charged with sodium pyrazolo[l,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4xweight of starting material was observed (1.4 vol/1.4 mL/g deionized water content). Gas chromatography (GC) for residual EtOH (30 pL of solution dissolved in -1 mL MeOEl) was performed showing less than 100 ppm with traces of ethyl nitrate fumes being observed below upon later addition of HN03. In some cases, the original solution was charged with an additional 1.5 vol.(1.5 mL/g) of DI water, then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4x weight of starting material was observed (1.4 vol/ 1.4 mL/g DI water content). Gas chromatograph for residual EtOH (30 pL of solution dissolved in about 1 mL MeOH) was performed showing 100 ppm of residual EtOH without observing any ethyl nitrate fumes below upon later addition of HNO3. A round bottom vessel outfitted with a mechanical stirrer, a steam pot,a reflux condenser, a J-Kem temperature probeand an N2 adaptor for positive N2 pressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HN03 and cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HN03 solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[l,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[l, 5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2x0.1 vol. (2x0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[l,5-a]pyrimidin-5- olate to 3-nitropyrazolo[l,5-a]pyrimidin-5(4H)-one.
With nitric acid In water at 35 - 50℃; for 3h; Inert atmosphere;
B Step 13--Preparation of3-nitropyrazolo[ 1 ,5-a]pyrimidin-5(4H)-one
A round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an N2 adaptor for positive N2 pressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HNO3 and cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HNO3 solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2×0.1 vol. (2×0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[1,5-a]pyrimidin-5-olate to 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one.