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The solution of I-03a (11 g, 56.12 mmol) in HCI (121 mL, 6 M) was heated to100 00 overnight. The reaction mixture was concentrated under vacuo and extracted with EA, washed with water and the organic layer was concentrated under vacuo to give I-04a (9.4 g, 98percent yield). ESI-MS (Mi-i): 169 calc. for 08H12N202: 168.1.
98%
at 100℃;
Preparation of intermediate l-04a: 1 -Methyl-3-propyl-1 /-/-pyrazole-5- carboxylic acid The solution of l-03a (1 1 g, 56.12 mmol) in HCI (121 mL, 6 M) was heated to 100 °C overnight. The reaction mixture was concentrated under vacuo and extracted with EA, washed with water and the organic layer was concentrated under vacuo to give l-04a (9.4 g, 98percent yield). ESI-MS (M+1 ): 169 calc. for C8H12N2O2: 168.1 .
96%
Stage #1: at 80℃; for 2 h;
Step 4 2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid: 2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (29.4 g, 150 mmol) was suspended in 6N sodium hydroxide (120 mL, 720 mmol) and heated to 80° C. for 2 hours, cooled, diluted with water (100 mL) and acidified with 5N hydrochloric acid (200 mL) to give a precipitate which was filtered off and dried to give the title compound as a white solid (24.2 g, 96percent). 1H NMR (300 MHz, CDCl3) δ 6.76 (s, 1H), 4.17 (s, 3H), 2.63 (t, 2H, J=7.2 Hz), 1.70-1.68 (m, 2H), 0.98 (t, 3H, J=7.2 Hz); LC-MS: m/z=169 (M+H)+;
90%
at 75℃; for 3 h;
Step 3: Synthesis of l-methyl-3-propyl-1H-pyrazole-5-carboxylic acid:-Ethyl 1-methyl-3-propyl-1H-pyrazole-5-carboxylate (19 gm 9.6 mini) was suspended in 6N NaOHsolution (48 ml 20.0 m.ml). The mixture was heated to 75 °C for 3 hours then cooled to 20 °C, diluted with 50 ml water and acidified with cone. HCI. Filtration gave the carboxylic acid as pale brown compound; Yield 90percent. 1H NMR (400 MHz, CDCI3) ö 9.15(br s 1H) 6.8 (s, 1H), 4.15(s, 3H) 2.50 (t, J7.6Hz 3H) 1.75 (m 2H) 0.98(tJ=7.6Hz3H). ppm. MASS: ESI [M + Na] : 191.09
Reference：
[1] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 80
[2] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 50
[3] Patent: US2008/194529, 2008, A1, . Location in patent: Page/Page column 56-57
[4] Patent: WO2015/114647, 2015, A1, . Location in patent: Page/Page column 46; 47
[5] Patent: US5250534, 1993, A,
[6] Patent: US5272147, 1993, A,
[7] Patent: US6200980, 2001, B1,
[8] Patent: US6200980, 2001, B1,
[9] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1819 - 1824
[10] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[11] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
The reaction mixture was cooled to ~90 C. and 5N sodium hydroxide solution (64 mL) was added and the reaction mixture was stirred at 80-90 C. for 30 min. The reaction mixture was cooled in an ice bath and was acidified to pH 4 with 2N hydrochloric acid resulting precipitation of the product. The precipitate was filtered, washed with cold water and dried under vacuum to yield the title compound (12.0 g, 81%). 1H NMR (CDCl3): delta 6.70 (s, 1H), 4.14 (s, 3H), 2.64 (t, J=7.60 Hz, 2H), 1.72-1.61 (m, 2H), 0.95 (t, J=7.30 Hz, 3H).
Yield
Reaction Conditions
Operation in experiment
34%
PREPARATION 4 1-Methyl-4-nitro-3-propyl-1H-5-pyrazole Carboxylic Acid Nitrating agent was prepared by adding 90% nitric acid (7.18 mL) to concentrated sulphuric acid (13.8 mL) at 75-78 C. 1-Methyl-3-propyl-1H-5-pyrazole carboxylic acid (11.5 g, 68.4 mmol) obtained in preparation 3, was added to the nitrating agent portion wise with stirring so that the temperature is maintained at ~85 C. After the complete addition, the mixture was heated at 100 C. for 2 h. The reaction mixture was cooled and poured into crushed ice. The suspension was filtered cold (10 C.) and the solids were washed with ice cold brine and dried to yield the title compound (5.0 g, 34%). 1H NMR (CDCl3): delta 6.90 (broad s, D2O exchangeable, 1H), 4.20 (s, 3H), 2.90 (t, J=7.60 Hz, 2H), 1.79-1.64 (m, 2H), 1.02 (t, J=7.40 Hz, 3H).
ethyl 2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)pyrimidine-5-carboxylate[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)pyrimidine-5-carboxylic acid[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)pyrimidine-5-carboxamide[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide trifluoroacetic acid salt[ No CAS ]
ethyl 2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenoxymethyl]-piperidin-1-yl)pyrimidine-5-carboxylate[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenoxymethyl]-piperidin-1-yl)pyrimidine-5-carboxylic acid[ No CAS ]
N-(tetrahydro-2H-pyran-2-yloxy)-2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenoxymethyl]-piperidin-1-yl)pyrimidine-5-carboxamide[ No CAS ]
N-hydroxy-2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenoxymethyl]-piperidin-1-yl)pyrimidine-5-carboxamide trifluoroacetic acid salt[ No CAS ]
2-[4-[[3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)phenoxy]methyl]-1-piperidyl]-N-tetrahydropyran2-yloxy-pyrimidine-5-carboxamide[ No CAS ]
tert-butyl N-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-N-[4-(tetrahydropyran-2-yloxycarbamoyl)phenyl]carbamate[ No CAS ]
2-[4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]-pyrimidin-5-yl)anilino]-1-piperidyl]-N-tetrahydropyran-2-yloxy-pyrimidine-5-carboxamide[ No CAS ]
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