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【结 构 式】 
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【分子编号】62106 【品名】4-amino-5-ethyl-1-methyl-1H-pyrazole-3-carboxamide 【CA登记号】 |
【 分 子 式 】C7H12N4O 【 分 子 量 】168.19864 【元素组成】C 49.99% H 7.19% N 33.31% O 9.51% |
合成路线1
该中间体在本合成路线中的序号：(XIX)Claisen condensation between diethyl oxalate (X) and 2-butanone (XI) leads to the diketo ester (XII), which is subsequently cyclized with hydrazine hydrate to furnish the pyrazolecarboxylate (XIII). After alkaline hydrolysis of ester (XIII), the resultant pyrazolecarboxylic acid (XIV) is nitrated by fuming HNO3 in hot H2SO4 to provide (XV). Chlorination of acid (XV) with SOCl2, followed by treatment with ammonia in THF yields the pyrazolecarboxamide (XVI). The alkylation of pyrazole (XVI) with iodomethane and Cs2CO3 leads to a mixture of N-methylated regioisomers (XVII) and (XVIII), which are separated by crystallization, followed by column chromatography. The desired isomer (XVII) is further reduced by catalytic hydrogenation to the aminopyrazole (XIX)
| 【1】 Street, S.D.A.; Wood, A.; Bunnage, M.E.; Mathias, J.P. (Pfizer Inc.; Pfizer Ltd.); Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. WO 9954333 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (XI) | 33891 | Methyl ethyl ketone; 2-Butanone | 78-93-3 | C4H8O | 详情 | 详情 |
| (XII) | 62099 | ethyl 2,4-dioxohexanoate | C8H12O4 | 详情 | 详情 | |
| (XIII) | 62100 | ethyl 3-ethyl-1H-pyrazole-5-carboxylate | C8H12N2O2 | 详情 | 详情 | |
| (XIV) | 62101 | 3-ethyl-1H-pyrazole-5-carboxylic acid | C6H8N2O2 | 详情 | 详情 | |
| (XV) | 62102 | 3-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid | C6H7N3O4 | 详情 | 详情 | |
| (XVI) | 62103 | 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide | C6H8N4O3 | 详情 | 详情 | |
| (XVII) | 62105 | 5-ethyl-1-methyl-4-nitro-1H-pyrazole-3-carboxamide | C7H10N4O3 | 详情 | 详情 | |
| (XVIII) | 62104 | 3-ethyl-1-methyl-4-nitro-1H-pyrazole-5-carboxamide | C7H10N4O3 | 详情 | 详情 | |
| (XIX) | 62106 | 4-amino-5-ethyl-1-methyl-1H-pyrazole-3-carboxamide | C7H12N4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Coupling between pyridinecarboxylic acid (IX) and aminopyrazole (XIX) by means of EDC/HOBt leads to the diamide adduct (XX). Subsequent intramolecular cyclization of (XX) in an ethanolic solution of potassium bis(trimethylsilyl)amide at 120 C in a sealed vessel furnishes the pyrazolopyrimidinone derivative (XXI). Reaction of (R)-propylene oxide (XXII) with sodium methoxide yields (R)-1-methoxy-2-propanol (XXIII). Finally, displacement of the ethoxy group of (XXI) with the potassium alkoxide of (XXIII) gives rise to the title compound
| 【1】 Street, S.D.A.; Wood, A.; Bunnage, M.E.; Mathias, J.P. (Pfizer Inc.; Pfizer Ltd.); Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. WO 9954333 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 62098 | 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinic acid | C14H21N3O5S | 详情 | 详情 | |
| (XIX) | 62106 | 4-amino-5-ethyl-1-methyl-1H-pyrazole-3-carboxamide | C7H12N4O | 详情 | 详情 | |
| (XX) | 62107 | N-[3-(aminocarbonyl)-5-ethyl-1-methyl-1H-pyrazol-4-yl]-2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinamide | C21H31N7O5S | 详情 | 详情 | |
| (XXI) | 62108 | 5-{2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-3-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one | C21H29N7O4S | 详情 | 详情 | |
| (XXII) | 62110 | (R)-(+)-PROPYLENE OXIDE; 1,2-Epoxypropane; R(+)-Propylene oxide; R(+)-Methyloxirane; (R)-propylene oxide; [(R-(+)-1,2-EPOXYPROPANE]; (R)-(+)-1,2-Propylene oxide; (R)-(+)-1,2-Epoxypropane | 15448-47-2 | C3H6O | 详情 | 详情 |
| (XXIII) | 62109 | (2R)-1-methoxy-2-propanol; (R)-(-)-1-Methoxy-2-propanol; (R)-(-)-1,2-Propandiol-1-monomethylether | 4984-22-9 | C4H10O2 | 详情 | 详情 |