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【结 构 式】

【药物名称】UK-371800

【化学名称】3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-[2-methoxy-1(R)-methylethoxy]pyridin-3-yl]-2-methyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-7-one

【CA登记号】

【 分 子 式 】C23H33N7O5S

【 分 子 量 】519.62736

【开发单位】Pfizer (Originator)

【药理作用】RENAL-UROLOGIC DRUGS, Treatment of Erectile Dysfunction, Treatment of Male Sexual Dysfunction, Phosphodiesterase V (PDE5A) Inhibitors

合成路线1

Reaction of 2-chloronicotinic acid (I) with an ethanolic solution of potassium tert-butoxide affords 2-ethoxynicotinic acid (II), which is further converted to the corresponding ethyl ester (III) by alkylation with iodoethane in the presence of Cs2CO3. Nitration of (III) employing ammonium nitrate and trifluoroacetic anhydride leads to ethyl 2-ethoxy-5-nitropyridine-3-carboxylate (IV). This is then reduced to the aminopyridine (V) by catalytic hydrogenation over Raney Ni. Diazotization of amine (V), followed by treatment with SO2 and CuCl2 gives rise to the sulfonyl chloride (VI). Acid chloride (VI) is subsequently coupled to N-ethylpiperazine (VII), producing sulfonamide (VIII). Alkaline hydrolysis of ethyl ester (VIII) yields the intermediate pyridinecarboxylic acid (IX)

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
(I) 28827 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione C11H13ClN2OS 详情 详情
(II) 62092 2-ethoxynicotinic acid C8H9NO3 详情 详情
(III) 62093 ethyl 2-ethoxynicotinate C10H13NO3 详情 详情
(IV) 62094 ethyl 2-ethoxy-5-nitronicotinate C10H12N2O5 详情 详情
(V) 62095 ethyl 5-amino-2-ethoxynicotinate C10H14N2O3 详情 详情
(VI) 62096 ethyl 5-(chlorosulfonyl)-2-ethoxynicotinate C10H12ClNO5S 详情 详情
(VII) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情
(VIII) 62097 ethyl 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinate C16H25N3O5S 详情 详情
(IX) 62098 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinic acid C14H21N3O5S 详情 详情

合成路线2

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3

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
Extended Information