-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】1-(3-Fluoronaphthalen-2-yl)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)-1H-pyrazole-5-carboxamide

【CA登记号】330801-94-0

【分子式】C₂₇H₂₁FN₄O₃S

【分子量】500.55582

【开发单位】Millennium (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors

合成路线1 合成路线2

合成路线1

3-Amino-2-naphthoic acid (I) is diazotized with NaNO2/HCl, and the obtained diazonium salt is then isolated as the corresponding tetrafluoroborate (II). Subsequent thermal decomposition of the diazonium tetrafluoroborate (II) in refluxing xylene leads to 3-fluoro-2-naphthoic acid (III). After chlorination of (III) with oxalyl chloride, the resultant acid chloride (IV) is treated with NaN3 to produce the acyl azide (V), which undergoes Curtius rearrangement to the amine (VI) in refluxing aqueous DMF. Diazotization of (VI), followed by reduction with SnCl2 gives rise to hydrazine (VII). Treatment of ethyl 2,4-dioxovalerate (VIII) with O-methylhydroxylamine gives oxime (IX), which is then condensed with hydrazine (VII), yielding the intermediate pyrazole (X).

参考文献中间体

【1】 Jia, Z.J.; et al.; Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides. Bioorg Med Chem Lett 2002, 12, 12, 1651.
【2】 Wang, L.; Zhu, B.-Y.; Li, W.; Zhang, P.; Huang, W.; Song, Y.; Goldman, E.; Zuckett, J.; Scarborough, R. (Millennium Pharmaceuticals, Inc.); Benzamides and related inhibitors of factor Xa. EP 1216228; EP 1216231; WO 0119788; WO 0119798 .

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)	47431	3-amino-2-naphthoic acid	5959-52-4	C₁₁H₉NO₂	详情	详情
(II)	57028			C₁₁H₇BF₄N₂O₂	详情	详情
(III)	57029	3-fluoro-2-naphthoic acid		C₁₁H₇FO₂	详情	详情
(IV)	57030	3-fluoro-2-naphthoyl chloride		C₁₁H₆ClFO	详情	详情
(V)	57031	3-fluoro-2-naphthoyl azide		C₁₁H₆FN₃O	详情	详情
(VI)	57032	3-fluoro-2-naphthalenamine; 3-fluoro-2-naphthylamine		C₁₀H₈FN	详情	详情
(VII)	57033	1-(3-fluoro-2-naphthyl)hydrazine		C₁₀H₉FN₂	详情	详情
(VIII)	42500	ethyl 2,4-dioxopentanoate	615-79-2	C₇H₁₀O₄	详情	详情
(IX)	44129	ethyl 2-(methoxyimino)-4-oxopentanoate		C₈H₁₃NO₄	详情	详情
(X)	57034	ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate		C₁₇H₁₅FN₂O₂	详情	详情

合成路线2

Addition of triisopropyl borate to the ortho-lithiated derivative of N-tert-butyl benzenesulfonamide (XI), followed by acid aqueous work-up, gives rise to the boronic acid (XII). Subsequent Suzuki coupling between (XII) and 4-bromoaniline (XIII) affords the biphenyl sulfonamide (XIV). Then, trimethylaluminum-catalyzed condensation of the pyrazole ester (X) with the biphenyl amine (XIV) generates amide (XV). The N-tert-butyl protecting group of (XV) is finally cleaved with trifluoroacetic acid to furnish the title compound.

参考文献中间体

【1】 Jia, Z.J.; et al.; Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides. Bioorg Med Chem Lett 2002, 12, 12, 1651.
【2】 Wang, L.; Zhu, B.-Y.; Li, W.; Zhang, P.; Huang, W.; Song, Y.; Goldman, E.; Zuckett, J.; Scarborough, R. (Millennium Pharmaceuticals, Inc.); Benzamides and related inhibitors of factor Xa. EP 1216228; EP 1216231; WO 0119788; WO 0119798 .

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)	57034	ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate		C₁₇H₁₅FN₂O₂	详情	详情
(XI)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(XII)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(XIII)	22531	4-Bromoaniline; 4-Bromophenylamine	106-40-1	C₆H₆BrN	详情	详情
(XIV)	23363	4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide		C₁₆H₂₀N₂O₂S	详情	详情
(XV)	57035	N-{2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl}-1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxamide		C₃₁H₂₉FN₄O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)